Recent Advances in Methylation: A Guide For Selecting Methylation Reagents

DOI: 10.1002/chem.
201803642 Review
& Methylation
Recent Advances in Methylation:

A Guide for Selecting Methylation Reagents
Yantao Chen*[a]
Chem. Eur. J. 2019, 25, 3405 – 3439

3405 T 2019 Wiley-VCH Verlag GmbH & Co. KGaA,
Weinheim
Revie
Abstract: Methylation is a well-known structural modifica- select the appropriate reagents for methylation chemistry.
tion in organic and medicinal chemistry. This review Based on the large diversity of methylation reagents and
summarizes recent advances in methylation by their wide scope, this review also broadens perspectives
categorizing specific methylation reagents. The challenges on which strategies to select for utilizing a particular
of mono N-methylation of aliphatic amines and N- methylation, resulting in an increased flexibility in
methylation of peptides are discussed. This review will be synthetic route planning.
useful for chemists wanting to
1. Introduction The ORCID identification number for the author of this article can be found
under https://doi.org/10.1002/chem.201803642.
Methylation as a popular structural modification has been

widely employed in medicinal chemistry.[1] A recent survey re-
vealed over 526 N-methylated and 437 O-methylated drugs
under different active stages of development. [2] A summary
by NjarMarson and co-workers in the Top 200
Pharmaceutical Products in 2016 showed that over 77 % of
small-molecule drugs have at least one methyl group.[3]
Conformational changes resulting from methylation are well
known in the chemistry community.[1a,4] In medicinal
chemistry, the “magic” methyl concept has seen several
successful examples.[1b,c,e,5] Re- cently, methylation in late-stage
functionalization has been applied as a valuable tool in drug
discovery.[6] In peptide chemistry, N-methylation has been a
common motif used in peptide modification to gain desired
properties.[7]
Figure 1 shows an interesting case, in which the only
difference in these three lipid-lowering drugs is the methyl
substitution pattern. However, Mevastatin has never been
marketed. Lovastatin, a methylated analog of Mevastatin,
was the first marketed statin drug. Simvastatin, a statin with
an additional methyl group has improved profiles and was
launched in 1992.[8]
Figure 1. Representative examples of methylated drugs.
Stegobinone and its diastereomeric form, that is, epi-

stegobinone (Figure 2) have opposite biological effects. The
former natural isomer is a female-produced sex pheromone
of the drugstore beetle, whereas the latter is a repellent to
the male species rather than an attractant.[9]
[a] Dr. Y. Chen

Medicinal Chemistry, Cardiovascular
Renal and Metabolism, IMED Biotech
Unit AstraZeneca Gothenburg
(Sweden)
E-mail: [email protected]
Chem. Eur. J. 2019, 25, 3405 – www.chemeurj.o 34 T 2019 Wiley-VCH Verlag GmbH & Co. KGaA,
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Figure 2. Chemical structure of stegobinone and epi-stegobinone.
Owing to the importance of methylation in medicinal

chemistry, research in this area has been steadily
increasing. Several recent reviews on methylation focused
on different as- pects, for example, using dimethyl
carbonate as the methylation reagent,[10] carbon dioxide for
transition-metal-free catalysis for N-methylation,[11]
peroxides,[12] other radical sources to generate the methyl
radical,[13] metal-catalyzed methylation,[14] decarboxylative
methylation,[13b] the use of methanol in Mitsu- nobu
reactions,[15] hydrogen borrowing strategies,[16] nickel-cat-
alyzed reductive couplings of alkyl electrophiles,[17] cross-
coupling methods for C-methylation,[18] and photoredox
catalysis.[19] In 2009, Lamoureux and Ageero published a
review com- paring several alkylating agents.[20] Among
other reviews, the one by Aurelio and Hughes is
noteworthy. The authors summarized several methylation
approaches, including 1) using methylamine for an SN2
substitution of a-bromo acids, which is out of the scope of
this review; 2) using methyl iodide and different inorganic
bases; 3) using dimethylsulfate and sodium hydride; 4)
using methanol in the Mitsunobu reaction; 5) using formic
acid to reduce a Schiff’s base, which is formed from an
amine and formaldehyde (HCHO); 6) using sodium
cyanoborohydride or sodium triacetoxyborohydride to
reduce the Schiff’s base; 7) quaternization of an imino
species with dimethyl sulfate, methyl iodide or
methyltriflate followed by basic hydroly- sis; and 8) using
triethylsilane-trifluoroacetic acid (TFA) or hydrogen-Pd/C-
TFA, or sodium cyanoborohydride to reduce N- protected-5-
oxazolidinones.[21] However, a review that covers a
comprehensive list of methylation reagents has not been
available as yet.
This review summarizes methylation methods in the
catego- ries of these different reagents: 1) trimethyl
orthoformate (TMOF), N,N-dimethylformamide dimethyl
acetal (DMF-DMA), trimethyl orthoacetate (TMOA) and
N,N-dimethylacetamide dimethyl acetal (DMA-DMA); 2)
N,N-dimethylformamide (DMF);
3) methanol (MeOH); 4) acetic acid (HOAc); 5) dimethyl
sulfoxide (DMSO); 6) formic acid (FA); 7) formaldehyde
(HCHO);
8) carbon dioxide (CO2); 9) peroxides; 10) methyl boronic
acid (MBA); 11) trimethylboroxine (TMB); 12) potassium
methyltrifluoroborate (MeBF3K); 13) other alkylboron
reagents; 14) gem- bis[(pinacolato)boryl]methane
(BpinCH2Bpin); 15) dimethyl car-
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bonate (DMC); 16) methyl iodide (MeI) and its derivatives; Scheme 1. The application of four methyl orthocarboxylates in N-
methylation.
17) methyl sulfonates; 18) dimethyl sulfate (DMS) and
dimethyl sulfite (DMSi); 19) trimethyloxonium
tetrafluoroborate (Me3OBF4) and diazomethane (CH2N2); 20)
dimethyl phosphite, trimethyl phosphite, and trimethyl
phosphate; 21) methyl organometals; and 22) borane
dimethylamine complex/N,N-dimethylformamide (Me2NH-
BH3/DMF), etc.
In this review, only representative structures are selected
from the original literature. Owing to the large and growing
number of methylation reports in the literature, it is
impossible to cover all recent publications. Instead, the
advances of methylation chemistry using the above 22
different methylation reagents and approaches are
presented in Section 2. Owing to the importance of N-
methylation, selective mono N-methylation is highlighted in
Section 3.
To highlight the methylated position, the newly generated
R@Me bond is highlighted in red. Chemical structures are
coded with a unique number or a commonly used name.
2. Methylation by Using Conventional

Reagents
2.1. Trimethyl orthoformate (TMOF), N,N-dimethylformamide
dimethyl acetal (DMF-DMA), trimethyl orthoacetate (TMOA),
and N,N-dimethylacetamide dimethyl acetal (DMA-DMA)
TMOF was used as a selective mono C-methylation reagent
to convert arylacetonitriles into the corresponding 2-aryl
proprio- nitriles. However, the synthetic procedures for the
direct monomethylation of arylacetonitriles failed when
using classical methylation reagents, such as methyl iodide
and dimethyl sulfate.[22] In 2002, Janin et al. studied
different methyl orthocarboxylates for selective N-
methylation (Scheme 1). The reaction of TMOF with 2-
pyridone only gave the acetal product 1. When DMF-DMA or
TMOA was used, the methylated product 2 was the major
product. The reaction of DMA-DMA with hydan- toin
selectively afforded the methylated product 3.[23]
DMF-DMA has been used in the methylation of functional-
ized nucleic acids. Methylation of 8-oxoadenosine with DMF-
DMA occurs at the N7 position through two pathways: 1) for-
mylation with the key intermediate 4 to afford intermediate 5,
followed by an intramolecular pathway to form the
methylated product 6 ; and 2) intermolecular reaction of 8-
oxoadenosine with 4 to afford product 6 (Scheme 2).[24]
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Cardiovascular, Renal, and Metabolic Diseases IMED Biotech Unit (CVRM
iMed) for more than 15 years and has con- tributed to both lead generation
and lead optimization projects. In 2015, he explored a novel one-pot
synthetic approach to access sulfonimidamides from easily obtained
sulfonamides. Since then, he has started his independent research in the
area of sulfonamides and analogs such as sulfonimidamides.
Scheme 2. Two pathways for methylation of 8-oxoadenosine.
Fairley et al. at AstraZeneca used DMF-DMA for the

methylation of NH-containing groups in heterocycles.
They discovered that the optimal reaction temperature
varied according to the calculated pKa values of substrates
(Table 1).[25]
The pKa–temperature correlation provides a useful guide
for applying the appropriate methylation conditions for the
indole derivatives. For instance, at 60 8C, the mono N-
methylated 7
was isolated at 83 % yield. However, the same starting
material
was transformed to the di-methylated 10 when the reaction
was performed at 110 8C.
Besides N-methylation, DMF-DMA has been used for a-
methylation of ketones via enaminones (Scheme 3). Gogoi
et al. have devised a synthetic approach that comprises
the condensation of ketones 12 with DMF-DMA followed
by the
Yantao Chen ( ) received his

B.S. degree in chemistry from ShanDong
Normal University in 1991. Then, he
moved to Peking
University and started his journey as a
synthetic chemist. Under the
supervision of Pro- fessor Wenting Hua,
he explored a novel synthetic approach
to Ramipril and obtained his
M.S. degree in 1994. During 1994–1997,
he focused on the synthesis of chiral
macrocycles in the same group and
received his Ph.D. in 1997. In 1999, he
moved to Linkçping Univer- sity (Sweden)
for postdoctoral research in the area of
antimalaria under the supervision of Dr.
asa Rosenqvist, Professor Ingemar Kvarn-
strçm, and Professor Bertil Samuelsson. In 2001, he was employed as a
senior research chemist at Thin Film Electronics AB (Sweden). In 2003, he
joined Astra- Zeneca Gothenburg as a senior research scientist. He has
been working in the Medicinal Chemistry department at the
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vent the formation
Table 1. Calculated pKa guided methylation by using DMF-DMA at specific temperatures. of 18, Xue, Xiao, and co-workers explored
a Rh-catalyzed direct methylation of ketones with DMF
(Table 2).[28] Both electron-donating (20–21) and electron-
withdrawing (23–25) substituents are tolerated. However,
the formation of regioisomers 26 and 27 showed that the
regioselectivity of a substrate with an a-hydrogen on both
sides of the carbonyl group is not well controlled.
Nevertheless, the C16- methylated estrone 3-methyl ether
(28) was isolated in 43 % yield, showing the potential of the
method in modifying natural products, although the
diastereomeric selectivity is not high.
Table 2. Rh-catalyzed methylation of ketones.
Mechanistically, oxidation of DMF by persulfate affords the

iminium intermediate 29. The reaction of 29 with the enolate
30 forms the intermediate 31, which undergoes a C@N bond
cleavage via the enolate form of 31, affording the
unsaturated ketone intermediate 32. Under the reaction
conditions, a hydride is delivered from the Rh@H complex to
32 to afford the methylated product 22 (Scheme 4).[28]
Scheme 3. a-Methylation of aryl methyl ketones.
hydrogenation–hydrogenolysis of enaminones 14, 15 to

afford products 18, 19 through the Pd/C-catalyzed
hydrogenation– hydrogenolysis of 16 and 17, respectively.[26]
When the aromatic ring is substituted with an electron-rich
group, or there is an ortho substituent, the a-methylated
product 19 is the main product.
In addition, it is well known that enaminone 14 is the key
precursor for the synthesis of many different heterocycles,
such as pyrazole, isoxazole, pyrimidine, and pyridine.[27]
Scheme 4. The mechanism for the formation of 22.
2.2. N,N-Dimethylformamide (DMF)
As shown in Scheme 3, the formation of 19 is favored when In the synthesis of a-amino nitriles 33, Xia et al. developed
the aromatic ring is substituted with an electron-rich group or a copper(I)-catalyzed activation of DMF at room temperature
has an ortho substituent, whereas the formation of 18 is pre- to form the intermediate 29 via the formation of the free
ferred for an electron-deficient substituted substrate. To pre- radical intermediate 34 (Scheme 5).[29]
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Table 3. Multicomponent synthesis of a-branched methylated ketones.
Scheme 5. An additional proposed mechanism of the formation of 29.
2.3. Methanol
Methanol, the simplest alcohol, has often been used as a C 1

source for methylations. Along with the increasing application
of methanol, most commonly used methodologies such as
metal-catalyzed pathways[16a,c,30] and the Mitsunobu proto- Product 40 was also prepared by Das and co-workers by
col[4k,31] have been reviewed. using the ethyl ketone as a substrate. The authors used poly-
mer-stabilized palladium nanoparticles (Pd@PS) as the catalyst
for the a-methylation of acyclic, cyclic, and aliphatic ketones
2.3.1. Methanol in hydrogen-borrowing strategies
with methanol.[35] Mechanistically, in the presence of air, the
A typical metal-catalyzed hydrogen-borrowing mechanism is oxidized catalyst 43 transforms methanol into HCHO through
shown in Scheme 6. The pathway includes four steps: 1) the intermediate 44 (Scheme 7). The condensation of the
in- itial oxidation of methanol, producing formaldehyde substrate and HCHO forms unsaturated intermediate 45. The
(HCHO) and the metal hydride intermediate 35 through a addition of 45 with the hydrogenated catalyst 46 affords the
hydrogen transfer process; 2) the condensation of HCHO intermediate 47, which tautomerized to 48. Methanolysis of
with an amine 48 forms the methylated product 40, and the key
intermediate 44 is re- newed.
Scheme 6. Representative pathway for a general metal-catalyzed hydrogen-

borrowing methylation.
or an amide to give the intermediate 36; 3) formation of 37

by the loss of water from 36; and 4) the hydrogenation of 37 Scheme 7. a-Methylation of ketones with polymer bounded Pd catalyst.
with the metal hydride, which is generated in step 1), forming
the methylated product 38. It is noteworthy that the hydro-
gen-borrowing strategy works well with methyl ketones as In 2018, Shimizu et al. developed a heterogeneous
substrates. As a result, analogs of compound 22 can be syn- catalytic method for the C-methylation of alcohols, ketones,
thesized by using this strategy.[30,32] and indoles with methanol under oxidant-free conditions by
In the presence of other primary alcohols, product 22 can using a Pt- loaded carbon (Pt/C) catalyst in the presence of
be further alkylated. For instance, Obora and Ogawa devised sodium hy- droxide. This catalytic system is compatible with
an Ir-catalyzed cross methyl-alkylation of methyl ketones with various substrates to achieve: 1) b-methylation of primary
methanol and primary alcohols to form a-methyl-a-alkyl ke- alcohols; 2) a- methylation of ketones; and 3) selective C3-
tones.[33] Kundu et al. reported that a-branched a-methylated methylation of indoles (Figure 3).[36]
methyl ketones can be prepared through a Ru-catalyzed
tandem synthesis with multicomponent reactions following
the hydrogen-borrowing process (Table 3).[34]
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as an alkylation approach. For recent advances of

photoredox alkylation, the reader is referred to the reviews
by Fagnoni and MacMillan and their respective co-workers.
[19a,41]
Historically, photoalkylation of heteroarenes was reported

for the first time in the late 1960s. Under these conditions, al-
kylation proceeded only very slowly, and the conversion was
moderate.[42] In 2015, by using silver-loaded titanium dioxide
(Ag/TiO2) as a photocatalyst, Saito et al. reported the N-
methylation of amines in anhydrous or aqueous methanol
at room temperature in good to excellent yields. Functional
groups such as aldehyde, ketone, alcohol, acetal, alkene,
Boc, and carboxylic acid, were tolerated. The mechanistic
Figure 3. Selected examples for the Pt-catalyzed hydrogen-borrowing study reveals that the newly generated -CH3 includes two
methylation. hydrogens from CH3 and one hydrogen from the OH of
methanol. This method leads to a tertiary product when
starting from a primary amine (Table 5).[43]
2.3.2. Methanol in hydrogenolytic deprotection/hydrogenation

Table 5. Photocatalytic N-methylation of amines.
In 1991, Rocchi et al. observed partial N-alkylation of amino organocatalysis.[40] Since then, the photoredox reaction has
acids during hydrogenolytic deprotection in a primary alcohol shown great promise
solution.[37] In 1992, Mazaleyrat and co-workers reported
similar results. They found that by using longer reaction times
for the hydrogenolytic deprotection of N6-Cbz-lysine resulted
in the formation of N-methylated lysine as the side product.[38]
So far, only a few examples of N-methylation under such
hydrogenolytic deprotection or hydrogenation conditions
have been reported and the application of the
hydrogenation conditions in methanol as an effective
methylation method had not been applied until Huang et al.
published their results describing chemoselective alkylation
of amines/amino acids.[39] Mechanis- tically, in the presence
of Pd/C, methanol is oxidized to HCHO through
dehydrogenation. The reductive amination of HCHO with
amines/amino acids affords the methylated products (Table
4).
Table 4. One-pot methylation of amines/amino acids under catalytic hydrogenation conditions.
2.3.3. Methanol in metal-free photoinduced reactions

In 2014, MacMillan and Jin reported a direct alkylation of
heteroaromatic C@H bonds by using photoredox
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In 2017, Li et al. described a simple photoinduced

methylation of heteroarenes with methanol. This metal-
free protocol is driven by photons in the absence of an
external photosensitiz- er. The methylation mechanism
includes two main steps:
1) the generation of hydroxymethyl radical (CCH2OH) in the re-
action mixture; and 2) the nucleophilic attack of this radical
onto the protonated heteroarene substrate to afford the
methylated product through loss of water, deprotonation,
and tautomerization (aromatization). The success of the
protocol lies in the addition of both CH2Cl2 as a co-solvent
to generate the hydroxymethyl radical and trifluoroacetic
acid (TFA) as the additive to protonate the substrates. In
addition, the protocol is compatible with moisture and air.
Therefore, this protocol can be applied as a
complementary strategy to where anhydrous conditions
are needed. With this method, various heteroarenes with
diverse functional groups can be methylated. The authors
also outlined the limitations of the method, for instance,
78 was not formed from the corresponding nicotine under
the conditions (Table 6).[44] Similarly, Barriault and co-
workers described a photochemical alkylation and
reduction of quinolines, pyridines, and phenanthridines.
Instead of TFA, HCl was used as the additive for the
protonation of substrates. As a comparison, 72(b) was
obtained in 80 % yield.[45]
Considering this recent success, I believe that these
metal- free photoinduced alkylations will inspire chemists to
explore
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tion
Table 6. Photoinduced methylation of heteroarenes with MeOH in CH2Cl2/TFA. by using PhI(OAc)2 as the methyl radical source and ap-
plied the transition-metal-enabled decarboxylation strategy
for the synthesis of aryl acid methyl esters. A radical
mechanism for the methylation of aryl acids was proposed
(Scheme 8).[49]
Scheme 8. [Cu]-catalyzed decarboxylative methylation of aryl acids.
First, PhI(OAc)2 (83) decomposes to yield acetoxy radicals

84, which undergo decarboxylation to afford the methyl
radical. The resulting methyl radical is oxidized by CuII or CuIII
appropriate metal-free conditions to generate hydroxymethyl to form the electrophilic CH3+ and generate the CuI species.
radicals (CCH2OH), and design reactions towards additional aro- The CH3+ reacts with acids to form methyl ester 85, and the
matic systems commonly used in the chemistry community. CuI is oxidized to CuII or CuIII to continue the catalytic cycle.
The first example of using HOAc as a methylation reagent
under metal-catalyzed direct decarbonylative conditions was
2.4. Acetic acid (HOAc) reported by Shi et al. In the presence of a RhI catalyst and an
appropriate activator, N-(2-pyrimidyl)indoles could undergo
HOAc has been used as the source of the methyl radical efficient and selective decarbonylative C2-arylation when
since 1971 when Minisci and co-workers produced the using aryl acids in the absence of external oxidants under
methyl radical through a silver-catalyzed oxidative mild conditions. The protocol worked excellently when
decarboxylation of HOAc by peroxydisulfate. The homolytic HOAc was used (91 % yield).[50]
methylation of heteroaromatics afforded the methylated The first example of using acetic acid as the methyl radical
products in good yields (Table 7).[46] resource under photoredox conditions was reported by Sher-
Later, a radical-enabled decarboxylation was further wood and co-workers.[51] From a mechanistic standpoint, as
developed by Sugimori and Yamada, by using iron(III) shown in Scheme 9, the N-(acyloxy)phthalimide 86 formed in
sulfate as the oxidant. Under light irradiation, HOAc is
oxidized into the COAc free radical, which affords the methyl
free radical after decar-
boxylation. Similarly, as shown in Table 7, the nucleophilic
methyl radical reacts with a protonated aromatic base to give
methylated products.[47]
Since 2011, this decarboxylative transformation of
carboxylic acids has been extensively used in organic
synthesis.[48] Howev- er, the use of HOAc as the methyl
radical source in metal-catalyzed decarboxylative
conditions remains challenging.[49] In 2014, Zhang et al.
developed a copper-catalyzed
Table 7. Minisci-type methylation. decarboxyla-
Scheme 9. Photoredox approach to methylation of heteroarenes.
situ oxidatively quenches the excited photocatalyst by a

single-electron transfer (SET) and undergoes reductive frag-
mentation to generate the methyl radical. The radical attacks
a protonated heteroarene 87 to generate adduct 88, which
can undergo deprotonation to generate the a-amino radical
89. The intermediate 89 undergoes SET with the oxidized
form of the photocatalyst to generate the protonated product
90 and to turn over the catalytic cycle.
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2.5. Dimethyl sulfoxide (DMSO)
In 2014, Wang, Xiao, and co-workers observed that N’,N-
dimethyl-p-anisidine 105 (Scheme 11) was formed from p-
Methylation of aromatic hydrocarbons with DMSO was first anisi-
reported in 1966. The reactive species, the carbanion dine in DMSO in the presence of formic acid (FA) and
intermediate (CH3SOCH2@), was formed by treatment of triethyla- mine (TEA). Initially, as formamides can be easily
DMSO in a strong base, such as sodium hydride.[52] In 1970, formed from amines and FA, it was assumed that the methyl
Torssell et al. produced methyl radicals by mixing the Fenton group originat- ed from FA. However, results from isotope
reagent,[53] a solution of hydrogen peroxide with a catalytic labeling experi- ments revealed that the carbon atom and
amount of an iron(II) salt in DMSO, with appropriate two protons in the methyl group originate from DMSO, and
substrates to give the the third proton is from FA. Mechanistically, DMSO
methylated products (Table 8).[54] In the same manner, transforms into two possible intermediates, 101 and 102,
Giorda- no et al. used protonated pyrimidine as the substrate leading to the formation of 103. The electrophilic 103 reacts
and obtained 4-methylpyrimidine.[55] with the amine to form the unsta- ble hemiaminal-like methyl
thiol ether 104, which affords the imine 37 through the
Table 8. Methyl radicals from DMSO with Fenton reagent.
elimination of methanethiol. After the reduction by FA, the
monomethylated product 38 is formed, which reacts further
to afford the dimethylated products. In addition, the protocol
allows a one-pot transformation of aromatic nitro
compounds into dimethylated amines in the presence of an
iron(II) catalyst.[58]
In 2016, Guo et al. disclosed that in the presence of CuII,
methyl radicals are formed via the intermediate 113—the
reaction product of DMSO with a hydroxyl radical generated
from H2O2. Under basic conditions, a carboxylic acid reacts
with the copper salt to form the electrophilic intermediate 114.
The reaction between the methyl radical formed from 113
and intermediate 114 gives the O-methylated product, and
the liberat- ed CuI is oxidized into CuII to continue the
By using the Fenton reagent, Kasai et al. studied DNA catalytic cycle (Scheme 12).[59]
methylation in DMSO. When 2’-deoxycytidine (dC) was
It is known that under Fenton chemistry conditions, the ad-
treated with DMSO, 5-methyl-2’-deoxycytidine (m5dC) (98)
dition of concentrated sulfuric acid can improve the methyla-
was formed (Scheme 10).[56] Similarly, methylation of 2’-
deoxyguanosine tion yields.[54] In 2016, Antonchick et al. used TFA instead,
through a free radical mechanism leads to the formation of 8- and devised a trideuteromethylation procedure under radical
methyl-2’-deoxyguanosine (Me8dG) (99) and N2-methyl-dG reaction conditions by using deuterated [D6]DMSO as a
(100; Figure 4).[57] reagent to obtain the desired trideuteromethylation products
from isoqui- nolines and quinolines.[60]
2.6. Formic acid (FA)
In Scheme 11, FA acts as a reducing reagent to transfer the

intermediate 37 into the methylated product 38.[58] The
chemical structure of FA means it can function both as an
acid and as an aldehyde. In addition to the N-methylation
product, an N- formylated product is often a common
byproduct. Thus, in most cases, reaction condition
Scheme 10. Methylation of dC by Fenton reagent in DMSO. screening is needed to mini- mize N-formylation.[61] Table 9
illustrates three recent reports that used N-methylaniline as
the starting material for optimiz- ing the reaction conditions.
[61]
In general, all three protocols gave moderate to excellent
yields. However, when a primary aniline was used, all
protocols afforded dimethylated products. When Cu(OAc)2
was used as the catalyst, the dominant pathway is the
formation of HCHO from FA, and then HCHO reacts with an
amine in the presence of hydrosilane to furnish the
methylation product. However, the conversion from 124 to
112(b) under the optimal conditions supports that a conven-
Figure 4. Chemical structures of the methylation products of 2’- tional amide reduction[62] of 124 is a viable approach to form
deoxyguanosine. the methylated product 112(b).[61c]
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Owing to the ease of synthesis of amines from the
relevant organic nitro compounds, N,N-dimethylated
amines have been
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Scheme 11. Methylation of amines with DMSO/FA.
Scheme 12. O-Methylation of aryl acids with DMSO.
Table 9. FA as methylation reagent.

2.7. Formaldehyde (HCHO)
HCHO has been used in Eschweiler–Clarke reactions, in

which a primary or secondary amine is transformed into an
N,N-dimethylated or N-methylated tertiary amine by
treatment with an excess amount of aqueous HCHO in the
presence of FA as a hydride donor.[64]
In the late 1970s, Weinreb et al. developed N-methylation
through the reduction of an N-hydroxymethylated intermedi-
ate formed from an amide, lactam, or urea with HCHO.[65]
Sev- eral decades later, Gundala et al. synthesized N-
methylated products through the reduction of an N-protected-
5-oxazolidi- none.[66] In 2013, Koch, Kunz, and co-workers
used the same strategy in the synthesis of N-Fmoc-N-methyl
amino acids in a flow reactor.[67] In 2007, Bieber et al.
devised a reductive methylation of primary and secondary
amines and amino acids by aqueous HCHO and zinc.
Careful control of reaction times and selection of an
synthesized directly from nitro substrates by using FA as a appropriate base led to mono N-methylation of amino acids
re- newable C1 source and silanes as the reducing agents. in good yields.[68] In 2010, Alinezhad et al. furnished a
The domino reaction (reduction/methylation) can be reductive methylation of primary and secondary amines with
accomplished in the presence of a heterobimetallic cubane- 37 % HCHO when using N-methylpyrrolidine zinc
type Mo3PtS4 catalyst.[63] At room temperature, N- borohydride as the reducing agent, forming the
heterocyclic arenes, double bonds, ketones, cyanides, and corresponding tertiary amines in excellent yields (88–94 %).
[69]
ester groups are well tolerated. In addition, benzylic type and
aliphatic nitro compounds can be methylated under the In addition to traditional reductants, such as sodium
conditions. borohydride, sodium cyanoborohydride, and sodium
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triacetoxyborohydride, the development of novel
methodologies for reduc-
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tive amination is still required owing to limitations in the pro-
through 4-electron reduction by using hydrosilane as a
cedure, for example, dimethylation of a primary amine when
reductant, and TBD as an organocatalyst; and 3)
the secondary product is expected.[70]
methylamines through 6-electron reductions by using
In 2015, Wu et al. disclosed a simple transition-metal-free
hydrosilane as reductant, and proazaphosphatrane
N- methylation of primary and secondary anilines by using
superbase or an N-heterocyclic carbene (NHC) as an
HCHO as both the reducing agent and the carbon source.
organocatalyst. The authors concluded that hierarchical
However, an electron-withdrawing aniline afforded poor
reduction of CO2 with amines usually affords at least two
yields (125,
products, for example, formamides and methylamines.
0.5 %), and only the dimethylated product 126(a) is formed
Successful chemoselectivity can be achieved by applying
when starting from a primary aniline (Table 10).[71]
different catalysts, tuning the hydrosilane, altering reaction
temperature, or changing the CO2 pressure.
Table 10. Methylation of different amines with formaldehyde. It is noteworthy that NHCs have been used for N-methyla-
tion in gram-scale reactions and feature a broad substrate
scope, for example, aliphatic or aromatic and sterically hin-
dered primary/secondary amines.[77] In 2015, Cazin et al.
used an NHC–copper(I) complex as the reduction catalyst to
transform aromatic and aliphatic primary and secondary
amines into N-methylated products. However, the
chemoselectivity of the formylation and methylation remains
unsolved.[78] To tackle the issue, Lin, Fu, and co-workers
screened various alkali-metal carbonates and found that
cesium carbonate could efficiently catalyze both formylation
and methylation reactions. The selectivity can be
In 2016, Shi et al. presented a nano-Au/Al 2O3-catalyzed re-
conveniently controlled by varying the reaction temperature
ductive N-methylation of amines with paraformaldehyde by
and silane. In general, the use of PhSiH3 at room
using water as the co-hydrogen donor. Isotope tracing reac-
temperature in MeCN leads to N-formylation, whereas the
tions confirmed the transformation of one hydrogen from
application of Ph2SiH2 at 80 8C preferentially affords the N-
water into the final product. The reaction works nicely on ali-
methy-
phatic primary or secondary amines and alkyl-substituted
lated products (Table 11).[79]
anilines, but has a limitation with non-substituted aniline.
Addi- tionally, an electron-withdrawing substituent is not
favored, the reaction only forming a dimethylated product if Table 11. N-Methylation of amines with CO2.
starting from a primary amine.[72]
Under the above reductive amination protocols, in most
cases, it is difficult to achieve selective mono N-methylation.
In 2016, M8tay et al. for the first time used paraformaldehyde
as the methylation reagent and heterogeneous Pd/C as the
catalyst for the selective mono N-methylation of primary
amines. However, employing CaH2 as a reductant limits the
application of this method.[73] Most recently, Shi et al. have
developed a selective mono-N-methylation reaction of
amines with paraformaldehyde and H2 in the presence of a
CuAlOx catalyst[74] or a Pd/TiO2 catalyst.[75]
2.8. Carbon dioxide (CO )

2
Besides organocatalysts, metals are also efficient catalysts

at activating CO2 for methylation chemistry.[80] It is known
that
CO2 is a trace gas in our atmosphere and a vital molecule in methylation using CO2, which produces three N-
the carbon cycle on Earth. As a result of elevated CO 2 emis- functionalized products:[11] 1) formamides through a 2-electron
sions, an efficient transformation of CO2 into C1 building reduction by using H2, hydrosilane, or hydroboran as a
blocks is an ideal “green” solution from a chemistry reductant, and 1,5,7-triaza- bicyclo[4.4.0]dec-5-ene (TBD) as an
perspective.[76] As there is great interest in N-alkylated organocatalyst; 2) aminals
products in medicinal chemistry, here different methods for
using CO2 in N-methylations are summarized.
He et al. described a transition-metal-free catalyzed N-
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the methylation of amines with CO2 can be achieved
through two different pathways: 1) formylation of the amine
to give 133, followed by reductive deoxygenation to give
the product 134; and 2) urea formation (135) followed by
reduction to give 134 (Scheme 13).[81]
Owing to the high thermodynamic and kinetic stability of
CO2 and the strength of the C=O bond, suitable catalytic
systems are crucial for benign methylation. In 2017, Beller
et al. summarized recent developments using
organocatalysts, ho- mogeneous, or heterogeneous
organometallic catalysts in the methylation of amines with
CO2 in the presence of silanes, hy- droboranes, or H2.[81]
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alysts, methylated pyrimidinones and pyridinones 138 were

synthesized;[86] 3) in the presence of catalytic Pd(OAc)2,
methylation is ortho selectively (139, 140), presumably
owing to chelation-directed C@H activation;[87] 4) a mono N-
methylation of phosphonamides and phosphinamides 141
was furnished by using CuI as the catalyst and 1,10-
phenanthroline (Phen) as the ligand in a sealed tube; [88] 5) a
similar chelation-directed C@H activation was proposed for
the formation of the ortho-methylated amides 142.[89]
Chemistry towards 143 in Scheme 16 represents a useful
complement to the traditional a-methylation of 1,3-dicarbonyl
compounds, in which toxic methyl iodide is often used. [90] An
Scheme 13. Two pathways for methylation of amines with
CO2.
iron-catalyzed methylation of olefins under the desired condi-
In the work by Lin, Fu and colleagues, only two

mono N-methylated aliphatic products were report-
ed (131, 132, Table 11). In terms of selectivity, the
monomethylation of aniline was not successful. In
2017, Tamura, Tomishige, and co-workers applied
CeO2-supported Cu sub-nanoparticles as the effective
heterogeneous catalyst for the N-methylation of
aniline when using CO2 and H2. The CeO2 support
plays an important role to suppress over-
methylation of N- methylaniline to N,N-
dimethylaniline.[82]
In 2017, a catalyst-free N-formylation of amines
with CO2 by using BH3NH3 as the reductant was de-
veloped by Hu, Wu, and co-workers for the first
time.[83] However, the catalyst-free approach for N-
methylation with CO2 is still underexplored. Scheme 15. Recent advances of methylation by using peroxide DCP.
2.9. Peroxides
In 1977, Wong and Zady reported the use of tert-butyl Scheme 14. General methylation from frequently used peroxides.
perace- tate as the methyl radical source in the methylation
of purine bases and nucleosides at the C8 position.[84] It is
known that peroxides possess a relatively weak O@O bond,
which can easily undergo bond fission and is initiated either
by elevated temperatures or light, forming an alkoxyl radical.
Subsequently,
the alkoxyl radical can either act as a radical initiator or
undergo further bond fission to give a methyl radical by the
loss of one molecule of ketone. The methyl radical reacts
with various electrophilic substrates or other radicals to
produce the relevant C-, N-, or O-methylation products
(Scheme 14).[12]
In this section, I highlight the recent advances of four fre-
quently used peroxides in methylation chemistry (Schemes
13– 16): dicumyl peroxide (DCP), tert-butyl peroxybenzoate
(TBPB), di-tert-butyl peroxide (DTBP), and tert-
butylhydroperoxide (TBHP).
The application of DCP in Scheme 15 includes: 1) 2-
methylation of pyridines 137 achieved through the reduction
of 2-methylated pyridine oxides 136;[85] 2) in the absence of
metal cat-
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tions opens up a new possibility for the synthesis of the
methyl Heck products 144.[91] Compared with other proto-
cols,[92] in which 2.5 equivalents of Me3SiCH2MgCl and
catalytic cobalt are used, the reaction conditions using
TBPB are mild, clean, and easy to handle. No additive is
needed, and no haz- ardous waste is generated.
The application of DTBP in Scheme 17 is summarized
here:
1) synthesis of 144 is demonstrated by an iron-catalyzed
decarboxylative methylation of a,b-unsaturated acids in
the absence of ligands;[93] 2) by using Cu(OAc)2 as the
catalyst, N-methylation of sulfoximines 145 was
developed with good functional group tolerance;[94] 3) a
facile and straightforward route to the synthesis of 3-
methylcoumarins 146 was achieved through the radical
reaction of coumarins with DTBP catalyzed by CuCl;[95]
4) two different methods of amidic N-methylation of amides
147 and sulfonamides 148 were developed by Li and Cai.
Under the conditions, the methylation selectively occurs on
the amidic nitrogen.[87,96] As a comparison, in Scheme 15,
in the presence of Pd(OAc)2, the methylation takes place at
the ortho position (139, 140).
Sulfonyl hydrazides as the sulfonyl precursor in the
presence of TBHP have been well developed in recent
years.[97] However, the direct S-methylation of sulfonyl
hydrazides with TBHP for the synthesis of methyl sulfones
149 has rarely been reported. As shown in Scheme 18, the
synthesis of 149 can be smoothly
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Scheme 16. Recent advances of methylation by using peroxide TBPB.
The addition of effective ligands has been a

useful strategy in methylation when using MBA as
the reagent. By using BrettPhos, Buchwald et al.
reported the synthesis of the methylated products
153–155 in high yields from the relevant tosylates
or mesylates.[103]
Optimization of the palladium catalyst is another
useful approach for methylation. Di(2-
pyridyl)methylamine-based palladium dichloride
complex 156 was selected for the synthesis of 157
Scheme 17. Recent advances of methylation by using peroxide DTBP.
in aqueous solvents under aerobic conditions.
In addition to screening different palladium cata-
lysts, a catalyst switch from palladium to copper
turned out to be successful. For instance, in 2009,
Cruces et al. for the first time reported the selective
monomethylation of anilines through a Chan–Lam
coupling by using Cu(OAc)2 as the catalyst
(products 158–160).[104] Recently, Cu(OAc)2 has
Scheme 18. Recent advances of methylation by using peroxide TBHP. been applied in the N-methylation of sulfoximines
(products 161– 163).[105] The Chan–Lam reaction
has been applied in O-methylation of carboxylic
carried out in water without the addition of ligand or additive. acids by using catalytic
The copper catalyst in water can be recycled by a simple CuCO3·Cu(OH)2 (164–166).[106] Recently, a Cu(ClO4)2 catalyzed
phase separation and reused several times without aromatic C@H methylation was reported (product 167).[107]
significant loss of catalytic activity. [98] To prepare 85, methyl
esterification of oxygenates such as benzyl alcohols, aryl 2.10.2. Methylation through methyl radical approaches
aldehydes, and aryl carboxylic acids was carried out by
employing copper and copper/palladium based nanoparticle MBA has been also used as the methyl source in free radical
catalysts and by using TBHP as the oxidizing and pathways. Owing to its high energy and reactivity, the methyl
methylating agent.[99] radical as a methylation source is challenging, particularly
2.10. Methyl boronic acid (MBA) by using Ag2CO3 (1 equiv) together with KF (3 equiv) (152).[102]
2.10.1.Methylation through metal-catalyzed
cross- coupling
MBA as the methyl source has been used in a
metal- catalyzed cross-coupling approach. This
section high- lights the interesting results obtained
through the addition of auxiliaries (inorganic salts or
ligands) and the application of different catalysts
(Figure 5).
It was found that AgI salts can significantly en-
hance Suzuki cross-couplings of n-alkyl boronic
acids. For instance, in the presence of Ag2O
(2.5 equiv), product 150 was prepared from the
relevant vinyl iodide.[100] The ortho-methylated
product
151 was synthesized through C@H
functionalization
by using 1 equivalent of Ag2CO3 as the base for
coupling.[101] C-2 indole methylation was achieved
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Figure 5. Selected methylated products by using MBA as the

methylation reagent.
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under photocatalytic reaction conditions.[108] Conditions using In cases where MeBF3K is used for the methylation of
methyl radicals created from MBA in a Minisci-type reaction arenes, several inorganic oxidants have been applied to
have not been well developed under photocatalytic condi- promote
tions.[51, 109]
Acetoxybenziodoxole (BI-OAc; Scheme 19), a hypervalent
iodine oxidant has been used for a decarboxylative alkenyla-
tion of alkyl trifluoroborates with vinyl carboxylic acids under
Ru photoredox catalysis.[110] However, methylation with MBA
by photocatalysis has been underexplored, with only one
paper being published to date. Under the specified
conditions, product 169 was prepared from 168 in good
yield (Scheme 19).[111]
Scheme 19. Minisci-type C@H methylation with MBA.
2.11. Trimethylboroxine (TMB)

TMB is the anhydride form of MBA. Both are often examined
in parallel for the same substrate but with different Pd
catalysts to find optimal reaction conditions.[112] Owing to the
advantage of both boiling point (78–80 8C) and excellent
solubility in non-
nucleophilic solvents, TMB has been a useful replacement for
MBA.[113] Since the first reported methylation of aryl halides
using TMB as a partner for the palladium-catalyzed Suzuki–
Miyaura coupling,[114] it has been frequently applied in medici-
nal chemistry as a result of its wide substrate scope and
excellent functional group tolerance.
In general, methylation occurs on an activated substrate
such as C-halides (Cl, [115] Br),[116] C-OTf,[117] C-OSO2C6F5,[118] and
halogenated acrylates.[119] In many cases, methylation is
carried out on late-stage intermediates, and more
interestingly, owing to the excellent functional group
tolerance, TMB-mediated methylation chemistry is often
published in journals relevant to medicinal chemistry, in
which functional groups, such as secondary amine, [120]
oxetane,[121] acetal,[122] aldehyde,[123] ketone,[124] imidazole,[123]
aniline,[123] thiol ether,[125] indole,[126] ester,[127] and amide[128] are
often designed into pharmaceutical molecules or their
corresponding intermediates.
2.12. Potassium methyltrifluoroborate (MeBF3K)

In 2009, Molander et al. described the application of MeBF3K
as a methylating reagent, which is more convenient to
prepare and handle than boronic acids/esters.[129] In general,
it is air- stable, more atom-economical than most
organoborons, and water soluble.[112] More importantly, by
virtue of an sp3 hybrid- ized boron, MeBF3K can avoid
undesired deborylation, a common side reaction under
Suzuki conditions when using MBA.[130]
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methylation under mild conditions. Recently disclosed
inorganic oxidants include: 1) MnF 3 in Pd-catalyzed
pyridine and amide-directed C@H methylations;[131] 2) AgF
in the RhIII-cata-
lyzed pyridine, pyrimidine, oxime, and amide-directed C@H
methylations;[132] 3) AgF in the RhII-catalyzed pyridine-
directed C@H methylations;[133] 4) Ag2O in the RhIII-
catalyzed thiazole-directed C@H methylations.[134]
Similarly to MBA, methylation with MeBF3K under
photoredox conditions have been rarely explored.
Recently, Molander et al. used Fukuzumi’s organo
photocatalyst (9-mesityl-10- methylacridinium ion) and a
mild oxidant (K2S2O8) to function- alize heteroaromatics by
using alkyltrifluoroborates. However, such a metal-free
method is primarily limited to simple alkyl groups (e.g.,
methyl, ethyl). Notably, compared with other alkylboron
reagents, alkyltrifluoroborates, in general, have excellent
redox properties under photoredox conditions.[135] So far,
only one successful experiment has been reported in this
respect (product 136, R = ortho-Me, yield 38 %). The
reaction conditions are very similar to the ones that work
for MBA as shown in Scheme 19.[136]
2.13. Other alkylboron reagents
In addition to MBA, TMB, and MeBF3K, another two boron

reagents, lithium methyltriolborate (LMTB)[137] and B-
methyl-N- methyliminodiacetyl (B-methyl MIDA) boronate,
[130]
have been developed as methylation reagents.
In 2013, Yamamoto et al. prepared LMTB and used this
air- stable material in Pd-catalyzed sp3–sp2 Suzuki–
Miyaura cross- coupling reaction with aryl halides in the
presence of RuPhos and the absence of bases to prepare
the methylated products (Table 12).[137]
Recently, the synthesis of B-methyl MIDA boronate (177,
Scheme 20) has been reported.[138] This tetrahedral
boronate is less prone to transmetallation than MeBF3K
under Suzuki conditions.[138] Selective cross-coupling of
177 with aryl bromides to afford 178 and 179 (Scheme 20)
was reported, in which only 1.1 equivalent of MIDA
boronate was used.[130]
Table 12. Preparation and application of LMTB.
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enables sequential direct alkylation/methylation of 2,2’-bipyri-

dine N-oxide to form the asymmetric product 193.
2.15. Dimethyl carbonate (DMC)
DMC is an environmentally friendly substitute for DMS and

methyl halides in methylation reactions. Owing to its non-tox-
icity and biodegradability, it has been used both as a “green”
Scheme 20. Preparation and application of B-methyl MIDA boronate.
solvent[141] and a “green” replacement for toxic intermediates
such as phosgene.[10b,c] The conversion of CO2 into DMC has
been commercialized. Such a utilization of CO2 makes DMC
2.14. gem-bis[(Pinacolato)boryl]methane (BpinCH2Bpin) a true “green” solvent/reagent.[10e] Given that Tundo and
others have summarized the general application of this
Recently, gem-diborylalkanes have attracted much attention reagent in C- methylation, O-methylation, and
as versatile building blocks and fundamental intermediates in methoxycarbonylation,[10,142] here recent advances in N-
organic synthesis.[139] In the absence of a transition-metal methylation, particularly mono N- methylation, are highlighted
catalyst, the Cho research group developed a new method owing to its importance in the functionalization of drug
for preparing alkylated pyridines by using the base- molecules in medicinal chemistry.
promoted debory- lative alkylation of pyridine N-oxides by One successful example of mono N-methylation of anilines
using 1,1-diborylalkanes as the alkyl sources.[140] Alkylation is the utilization of DMC in the presence of X- or Y-type zeo-
of a wide range of pyridine N-oxides with BpinCH2Bpin lites.[10c] However, the reaction has to be operated at high
affords the desired methylated products (Table 13). temperature (130–150 8C) because methoxycarbonylation
Mechanistic studies suggest that the a-borylcarbanion as the
intermediate 181, which is generated through mono side reaction usually occurs at 90 8C. Additionally, the reaction
deborylation of 180, attacks the pyridine N- oxide to form time is usually long (2–14 h).[10b] Thus, efforts to find milder N-
species 182. The subsequent migration of the boryl group methylation conditions have been a challenge. Here, I briefly
from the carbon to the N-oxide through the five- membered summarize several recently developed approaches in this re-
intermediate 182, followed by intramolecular proton transfer spect.
and a second deborylation furnish the desired methylated In 2008, Wang et al. reported the methylation of 1,2,3,4-
products (Table 13). Interestingly, the reaction also tet- rahydropyrimidine-2-thione (THPT), a Biginelli
compound, which was promoted by MgO and
tetrabutylammonium bromide (TBAB) under microwave
Table 13. Use of BpinCH2Bpin for N-methylated pyridines. heating in the absence of a strong base (Scheme 21).[143]
Scheme 21. Methylation of Biginelli compounds.
Among several solid oxide bases (MgO, ZnO, ZrO2, CeO2,

CaO, and Al2O3), MgO was selected by the Bhanage group
for the methylation of indoles and phenols under microwave
conditions (170 8C, 30 min). The protocol works well for
the N-
methylation of imidazole, but no products are formed on the
aliphatic N-containing heterocycles.[144]
In 2009, Laurila et al. demonstrated an N-methylation of
electron-deficient pyrroles by using DMC both as reagent
and solvent, plus catalytic 1,4-diazabicyclo[2.2.2]octane
(DABCO), and DMF as co-solvent. It is noteworthy that the
method works well even at 90 8C and gives, in general, high
to excel-
lent yields (Scheme 22).[145]
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Dong et al. examined the N-methylation of 5-substituted
1 H-tetrazoles with DMC in DMF under different
temperatures. When the reaction was conducted at 958C,
only a trace of the
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Scheme 22. Methylation of electron-deficient pyrroles.
methylated products (203, 204) were isolated, whereas the

car- bamates 201 and 202 were the major products. At 130
8C, the yields of the methylated products dramatically
increased,
which indicates that decarboxylation of 201 and 202 is
favored at high temperature. Interestingly, in the presence of Scheme 24. Mechanism of DBU-promoted mono N-methylation of
catalytic DABCO, chemoselectivity was observed for alkyl- anilines with DMC.
and aryl-substituted substrates (Scheme 23).[146]
In many cases, the addition of an excess of DMC often
presence of PhSiH3 in DMC at 100 8C. Different from earlier
leads to the formation of dimethylated products, which is a
methodologies, in which the methyl group in DMC acts as
potential issue if mono N-methylated products are expected.
the methyl C source, in this reductive methylation, the C1
To circum- vent this problem, Jamison et al. developed a
building
practical protocol in which 1,8-diazabicyclo[5.4.0]undec-7-ene
blocks are the carbonyl moieties of the carbonate in DMC.
(DBU) was used for the selective mono N-methylation of
Therefore, other di-alkyl carbonates can be used as C1
anilines with DMC in continuous flow. The selective mono N-
building blocks under reductive methylation conditions.
methylation is achieved through an in situ
Compared with other dialkyl carbonates, DMC has been
protection/deprotection pathway (Scheme 24). First, in the
most used with respect to methylation owing to its
presence of DBU, 4-chloroaniline reacts with DMC to form
availability.
the carbamate 205, which further reacts with DMC to afford
By searching commercially available hydrosilanes and
the methylated carbamate 206 by the release of MeOH and
carbonates from Aldrich, Beller et al. predicted in 2015 that
CO2(g). The intermediate 206 in the reaction mixture
there were > 10 000 combinations of methylation methods.
decomposes on heating to afford the monomethylated [152]
After screening metal catalysts and solvents, followed by
product 207.[147]
the selection of ligands, and the examination of different
Recently, ionic liquids have been used as solvents to pro-
silanes, optimal conditions for methylation were discovered,
mote methylation with DMC. Quan et al. reported a
which are summarized in Scheme 25.
convenient and efficient S-methylation of mercaptans or
The N-methylated aryl anilines (105, 106, 208, and 209)
thiophenols in room temperature ionic liquids (RTILs),[148]
described in Beller’s paper[152] were synthesized at room
such as 1-butyl-3- methylimidazolium chloride ([Bmim]Cl).[149]
temperature in good to excellent yields. For aliphatic
In 2012, Holbrey, Kappe, and co-workers applied the basic
secondary amines, high temperature is needed to achieve
ionic liquid tributyl- methylammonium methylcarbonate as the
high yields (210, 112). The moderate and high yields for 128
catalyst under continuous-flow conditions to methylate a
and 211 demonstrate good tolerance towards functional
variety of different indoles, phenols, thiophenols, and aryl
groups such as alkene and alcohol. From a chemoselectivity
carboxylic acid substrates.[150]
perspective, the monomethylated product 212 was obtained
In 2014, the first synthetic protocol describing a reductive
from the heterocyclic diamine, whereas only traces of the
methylation of amines with DMC was published by Darcel
other monomethylated isomer were observed. In addition, a
and co-workers.[151] A combination of catalysis by
domino reduction/methylation sequence using formamide
[CpFe(CO)2(IMes)]I and visible light irradiation was used to
213 as the substrate resulted in the methylated product 112
convert secondary amines including di-arylamines into N-
with 77 % isolated yield.
methyl amines in the
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Scheme 23. Chemoselective methylation of tetrazole 197 and its tautomeric form 198.
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Scheme 25. Reductive methylation of amines with DMC.
In Scheme 24, the methyl moieties in the products Table 14. Methylation of Ar-I and Ar-Br with in situ formed MeZnI.
originate from the methyl group in DMC. However, under
reductive methylation conditions, as shown in Scheme 25,
the methyl moieties in the final products are the carbonyl
moieties in DMC. Instead of using silanes as the reductants,
the Beller group applied molecular hydrogen as the reducing
reagent and performed the reductive methylation in the
presence of an in situ formed ruthenium/Triphos complex
catalyst to synthesize N-methylated tertiary aromatic and
aliphatic amines in good to excellent yields.[153] However, the
high pressure of H2 (60 bar), the high reaction temperature
(150 8C), and the long
reaction time (18 h) may limit the wider application of this pro-
tocol.
2.16. Methyl iodide (MeI) and its derivatives dimethylsulfonamides

in 4 min reaction time and in high yield (up to 92 %). The ad-
MeI is a common methylation reagent in organic synthesis. vantages of such a solvent-free reaction include simplicity, gen-
As the iodide is a very good leaving group, methyl iodide is
an excellent substrate for SN2 reactions.[154] Additionally,
owing to the “softness” of the iodide anion, methylation with
MeI usually occurs at the “softer” end of an ambident
nucleophile. For instance, alkylation of enolates with alkyl
halides mainly affords C-alkylated products.[154,155] Since MeI
as the direct methylation reagent has been widely applied in
organic chemistry,[154,156] in this section only indirect
approaches, that is, where the toxic MeI is used as the
methyl group precursor, are summarized.
Recently, Liao et al. disclosed a nickel-catalyzed
methylation of aryl halides with the in situ formed complex of
MeZnI[NaI]n (n = 0, 1, 2) by mixing MeI and Zn in the
presence of NaI.[157] The reaction can be conducted at room
temperature, and the yields are up to 99 %. In addition, this
method particularly suits the syntheses of CD3-containing
products owing to the readily available and cheap CD3I
(Table 14).
Trimethylsulfoxonium iodide (TMSO-I), prepared from DMSO
and MeI,[158] was used for the methylation of alkyl and arylsul-
fonamides in the presence of KOH.[159] Typically, a mixture of
the appropriate sulfonamide, TMSO-I (2 equiv), and KOH
(2 equiv) was loaded on alumina. This mixture was irradiated
with microwaves (130 8C), forming N,N-
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erality, rapidity, and avoidance of toxic or expensive

catalysts and solvents.
TMSO-I has been used as the precursor to
dimethyloxosulfo- nium methylide (DIMSOY), the so-called
Corey–Chaykovsky reagent, which is usually prepared by
the reaction of TMSO-I with a strong base (NaH) in an
appropriate solvent (DMSO) without drying or further
purification. Besides epoxidation, DIMSOY has been used
for methylation.[160] Recently, Ganguly, Chakraborty, and co-
workers reported the C-methylation at the 2-position of 2-
carboxy-4-chromanones by using freshly prepared
DIMSOY.[161] The reaction was performed through a very
mild and simple approach: first, DIMSOY was prepared
from TMSO-I in DMSO with cooling in an ice bath; second,
to the DIMSOY solution was added chromone-2-carboxylates.
The reaction took 4–12 h at room temperature to afford
the C2-methylated products in 47–83 % yields.
Aryltrimethylammonium salts as arylation reagents are
often used to replace aryl halides in Ni0-catalyzed cross-
coupling reactions.[162] In the presence of a NiII catalyst,
the Ph@N bond in phenyltrimethylammonium iodide does
not undergo oxidative addition to the substrate. Instead,
the 8-aminoquinoline moiety in the substrate acts as the
directing group to facilitate the methylation of C(sp2)@H
bonds as shown in Table 15.[163] In-
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Table 16. C-Methylation of carbonyl chlorides and alkyl bromides with MeOTs.
Table 15. NiII-catalyzed methylation of amides with phenyltrimethylammonium salts.
terestingly, this protocol works well for the synthesis of 142 h

from the relevant aliphatic amide.
It is noteworthy that under similar conditions as described
in Table 15, such NiII catalysts have been recently applied to
the C-alkylation and C-benzylation of aryl and a,b- Besides alkyl halides, aryl bromides were also used by the
unsaturated amides that bear the 8-aminoquinoline moiety Gong group as substrates for methylation with MeOTs.[175]
as the directing group, by using alkyl halides and The optimal reaction conditions were comprised of a
benzyltrimethylammonium salts.[164] combination of NiI2/ligand/MgCl2/TBAI/Zn in DMA delivered
the methylated products in good to excellent yields with good
functional group tolerance (Table 17).
2.17. Methyl sulfonates
Table 17. C-Methylation of aryl bromides with MeOTs.
Methyl tosylate (MeOTs), methyl p-nitrobenzenesulfonate
(MeONs), and methyl triflate (MeOTf) are three common
methyl sulfonates that are used as methylation reagents.
MeOTf and its perfluoro analogs such as methyl nona-fluoro-
butyl-1-sulfonate (MeONf) are powerful reagents for methyla-
tion and are more reactive by a factor of approximately 104
than methyl iodide and Me2SO4.[165] In many cases, they are
used as N-,[20,166] O-,[167,168] or S-methylation[169] reagents under
basic conditions. The literature on the uses of these methyl
sulfonates as methylation reagents are very profuse.[165a,170]
How- ever, reviews on C-methylation using these methylation
reagents are rare.[17] Here, I summarize the relevant works,
particularly the usage of MeOTs in methylation.
In 1980, the Booth group pioneered C-methylation by
using methyl sulfonates.[171] However, the application of
methyl or other alkyl sulfonates for C-methylation has been
underexplored.[165a,172] In 2014, Gong et al. developed a Ni-
catalyzed reductive cross-coupling strategy for the
methylation of inactivated alkyl halides and carbonyl Another example of NiII-catalyzed methylation by using
chlorides by using MeOTs as the methylation reagent. As MeOTs was disclosed by the Chatani group.[164a] The protocol
shown in Table 16, under mild conditions, moderate to works with good regioselectivity, that is, the less hindered
excellent coupling yields were achieved with good functional C@H bonds were exclusively methylated under the
group tolerance.[173] Both MeBr and MeI were tested as conditions (Table 18). Compared with the results in Table 15,
methylation reagents in the reductive cross- coupling the addition of NaI in the protocol leads to slightly better
reactions with alkyl halides but the reactions failed owing to yields.
fast dimerization of the methyl halides.[174] Thus, the use of
MeOTs proved to be critical probably owing to the slow
2.18. Dimethyl sulfate (DMS) and dimethyl sulfite (DMSi)
generation of the relevant methyl halides under reaction con-
ditions. Consequently, the low concentration of MeX in the In 2001, Merriman described a short review of DMS in O-
reaction mixture avoids its rapid dimerization.[173] methylation, N-methylation, S-methylation, and C-
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methylation.[176]
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Table 18. ortho-C-Methylation of aryl amides with MeOTs. Table 19. Synthesis of methylated ether 257.
philicity, DMS can rapidly react with substrates to afford N-

methylated products. Thus, DMS is frequently used in DNA-
methylation studies, for example, methylation of the 7-
nitrogen of guanine in the major DNA groove and 3-nitrogen
However, owing to the extreme toxicity and high of adenine in the minor groove.[179]
carcinogenic- ity, DMS is not a preferred reagent for Compared with DMS, the sulfite form (DMSi) is less
methylation, particularly in large-scale production. In the reactive. The methylation with DMSi usually needs catalysis.
small-scale synthesis of the HIV integrase inhibitor raltegravir So far, DMSi as the methyl reagent has only been reported
potassium (256, Scheme 26), the phenolic OH of the key for the synthesis of methylated ethers. For example, Lemaire
intermediate hydroxypyrimidinone 249 was protected as a et al. found that under an argon flow, in the presence of the
benzoate ester (250), then N-methylation with DMS gave acidic aluminium oxide (Al2O3; entry 2, Table 19), the
251. However, from a large-scale production perspective, methylation of the alcohol gave the best conversion and high
this protection/deprotection strategy should be avoided. ratio of the methylated product 257. However, without an
Thus, a direct N-methylation of 249 with DMS was examined. aluminium catalyst (entry 1), the conversion was low. The
Unfortunately, a mixture of N- and O-methylation products results of entry 2 and entry 3 indicate that without argon flow
(252, 253) in the ratio of 70:30 was obtained. Finally, the (entry 3), the formation of 257 is slow, and the sulfite 258 is
chemoselectivity issue was solved by using MeI and the major product. A possible approach for the formation of
Mg(OMe)2 in DMSO to form 255.[177] However, MeI is still 257 is via SO2 extrusion from 258. Indeed, the treatment of
toxic. Further improvement in the synthesis of 256 will be the isolated O-sulfoxyme-
discussed in Section 2.21. thylated product 258 in the gas phase (200 8C) in the
Taking methylation efficiency, chemical safety, and costs presence of acidic Al2O3 produced 257 in 95 % yield.[180]
into account, Selva and Perosa have evaluated DMC, MeI,
DMS, and methanol based on atom economy and mass 2.19. Trimethyloxonium tetrafluoroborate (Me3OBF4) and
index.[178] From 33 different procedures in the literature, they diazomethane (CH2N2)
concluded that methanol and DMC are more favorable
reagents owing to a significant decrease of the overall flow of Diazomethylation is a well-known approach for the N-methyla-
materials (reagents, catalysts, solvents, etc.). Owing to the tion of a-amino acids because of its mild conditions, high
extremely strong electro-
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Scheme 26. DMS and MeI in the synthesis of 256.
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yields, and low racemization risk. However, CH2N2 has to be
2.21.1.MeLi
used with great caution because of its explosive and toxic
nature and should be avoided in large-scale synthesis.
In the 1960s, the reaction of nicotine with MeLi was reported.
Recent advances in the generation of diazomethane in a
Three methyl derivatives, namely, 2-methylnicotine (261), 4-
safer manner from its precursor have been reviewed from an
methylnicotine (262), and 6-methylnicotine (78), have been
industrial perspective.[181] It is well known that N-
isolated (Figure 6). The yields of the three isomers depend
arylsulfonylation is a common protection strategy for a-amino
on the reaction conditions, such as temperature, solvent, and
acids. The diazomethylation of N-arylsulfonylated
the concentration of MeLi. Interestingly, the reaction of
substrates gave variable yields, which depends on the acidity
nicotine N-
of the N-H (Table 20).[182] With the 4-NO2 substituent, the yield
oxide with MeMgBr in THF at @70 8C gave 2- and 6-methylni-
was quantitative (entry 1). A halide (F, Cl) atom in the 4-
cotine in moderate yields, but no 4-methylnicotine product
position gave low yields (entries 2, 3), whereas with an
was formed.[186]
electron-donating substituent (Me, OMe), the yields were
poor (entries 4, 5). To achieve high yields, Me3OBF4 was
used, and quantitative isolated yields can be obtained in
15–110 min of reaction (entries 7–12).
Table 20. Synthesis of N-arylsulfonyl-N-methyl (S)-analine methyl esters.

Figure 6. Structures of three methylated nicotines.
In 2017, Mart&nez-Lamenca, Oehlrich, and co-workers report-

2.20. Dimethyl phosphite, trimethyl phosphite, and
ed for the first time the preparation of N-alkyl-S-methyl-
trimethyl phosphate
trifluor- omethyl-sulfoximines through the reaction of the
In the presence of catalytic In(OTf) 3 (5 mol %), dimethyl relevant CF3cross-coupling
Table 21. Fast - sulfonimidoyl fluorides with
of arylbromides MeLi at @78 8C.
with MeLi.
phosphite was used both as methylation reagent and the The protocol provided a novel method for the synthesis of
solvent for the mono N-methylation of primary aliphatic and methylated CF3-sulfoximines.[187]
aromatic amines under microwave irradiation.[183] In 2017, Feringa et al. reported an ultrafast cross-coupling
In the presence of phosphorus oxychloride (POCl3, 2 of alkyl- and aryllithium reagents with a range of aryl
equiv), the reaction of 2-mercaptobenzimidazole derivatives bromides in the presence of both catalytic palladium
with trimethyl phosphite (2 equiv) in xylene afforded the S- nanoparticles and O2.[188] The cross-coupling of arylbromides
methylated products in moderate to high isolated yields.[184] with MeLi gave good to excellent yields with good functional
group tolerance (Table 21). It is noteworthy that CD3Li can be
generated in situ by using deuterated MeI and tBuLi. Under
analogous conditions, deuterated 175 was obtained in 65 %
2.21. Methyl organometals
yield.
Methyl organometals, such as MeLi, Me4Sn, Me3Al, MeMgX
(X= Cl, Br, I), Me2Zn, and MeZnBr have been used as
methylation reagents. So far, only one review on using Me3Al
as the methylation reagent has been published.[185] Owing to
the wide application of methyl organometals in methylation,
I mainly summarize recent advances in this respect.
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2.21.2.Me4Sn Figure 7. Methyl transformation of ArOTf/Ar-X with Me 4Sn.
Me4Sn as the methylation reagent has been used for transi-

tion-metal mediated conversion of carbonyl chlorides to
methyl ketones,[189] and aryl halides/aryl mesylates to aryl
methyl ketones in the presence of CO.[190] Despite its volatility
and toxicity, Me4Sn has still been widely used with care in the
laboratory owing to the advantages of mild reaction condi-
tions, wide functional group tolerance, and lack of sensitivity
to moisture and oxygen. In cross-coupling catalysis, Stille
coupling is still a widely used method.[191] In this section, I
high-
light the recent applications of Me4Sn in C@C formation by
using aryl triflates[192] and aryl halides (Ar-I,[193] Ar-Br,[194] and
Ar- Cl)[195] as the electrophile substrates. Figure 7 showcases
selected C-methylated products and different key
conditions.
Based on previous reports, Espinet et al. updated the
mechanism of the Stille reaction to include the role of LiCl in
different solvents.[196] The results in Figure 7a show that the
addition of LiCl salt is crucial to achieving high yields.[192b]
With the aid of the heterogeneous catalyst Pd@PDEB,
which was prepared from a one-step self-encapsulation
cross-linking polymerization of 1,3-diethynylbenzene (DEB)
with Pd(OAc)2/ triphenylphosphine/methanesulfonic acid,
Suzuki–Miyaura reactions can be carried out with a Pd
loading level of 1– 100 mol ppm. At high Pd loadings
(1000 or 5000 mol ppm), almost quantitative conversions
were achieved in the reactions
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with the more challenging 2-chloropyridine. With this
catalyst, product 282 was obtained in excellent yield (93
%).[195b]
2.21.3.Me3Al
The gem-dimethyl moiety is a structural feature that is fre-

quently found in many natural products.[197] Among different
synthetic methods that are used to install a gem-dimethyl
group, the reagent of “Me3Al-TMSOTf” (TMSOTf =
trimethylsilyl trifluoromethanesulfonate), which was
reported in 1994, transforms a carbonyl moiety into a
geminal dimethyl functionali- ty.[198] Scheme 27 shows
another example in which the same reagent was used to
transform the lactol acetate 283 into a- methyl
tetrahydropyran 284 as a single stereoisomer in 75 % yield
(Scheme 27).[199]
Scheme 27. Transformation of lactol acetate 283 with Me 3Al.
In Sections 2.9 and 2.16, both DCP[89] (Scheme 15) and

PhMe3NI[163] (Table 15) were used as the ortho-methylation
reagent for the synthesis of the products 142. Recently,
two papers have been published for the synthesis of 142
analogs by using Me3Al as the methylation reagent and
2,3-dichlorobu- tane (DCB) as the oxidant in the presence
of a FeIII or a CoIII catalyst.
In 2015, Ilies, Nakamura, and Shang used the
substrates bearing an 8-aminoquinoline (NH-Q) group and
a picolinoyla- mide (PA) group for the synthesis of 142
analogs (Table 22) and products 285 a–f (Table 23) in the
presence of a FeIII catalyst under similar conditions on a
gram scale.[200]
In 2016, Xu et al. used Co(acac)3 as the catalyst and
PPh3 as the ligand. Under the analogous conditions shown
in Table 23, products 142 were obtained in high to
excellent yields (Table 24).[201]
Table 22. Iron-catalyzed ortho-methylation by using Me3Al.
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Table 23. Iron-catalyzed methylation by using Me3Al. reagent can be challenging, in particular when an excess of
the Grignard reagent is applied. One efficient solution to the
problem is to transform the carbonyl chloride into the
Weinreb amide before it reacts with the Grignard reagent.
This approach has been widely applied in medicinal
chemistry since it was introduced in 1981 by Weinreb and
Nahm.[202] Another solution is to convert the carbonyl
chloride into the azetidinyl amide 286, a non-planar amide
with a large ring strain. Upon the nucleophilic addition by
organometallics, such as organolithium and Grignard
reagents, the amide undergoes acid- mediated elimination
through the stable tetrahedral intermediate 287 to produce
Table 24. Cobalt-catalyzed ortho-methylation by using Me3Al.
the ketone product 12 (Scheme 28).[203]
Scheme 28. Synthesis of methyl ketones through N-acylazetidine.
Similarly, as discussed in Section 2.21.1, in which MeLi is

used in metal-catalyzed cross-couplings, Grignard reagents
have been used in the presence of different metal catalysts
for
functional group transformation,[204] stereospecific ring-open-
ing of aryl-substituted tetrahydrofurans,[205] and C@H activa-
2.21.4.MeMgCl, MeMgBr, MeMgI tion[206] (Scheme 29).
MeMgCl and MeMgBr have been used as the methyl anion

2.21.5.Me2Zn
reagents for the preparation of gem-dimethyl products in
medicinal chemistry. The reactions can be performed in the Compared with Grignard reagents, alkyl zinc reagents
presence/absence of Lewis acids (TiCl4, ZrCl4).[197] It is well usually provide better functional group tolerance.[205] In 2012,
known that ketone synthesis from a carbonyl chloride with a Jarvo et al. reported the synthesis of 291 by using MeMgI as
Grignard the methylation reagent.[204c] Instead of MeMgI, Me2Zn was
applied
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Scheme 29. C@C formation with methylmagnesium halides.
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by the same research group in the synthesis of a-methylated Table 27. Transformation of sulfonyl chlorides into thioethers.
benzylic products through Negishi nickel-catalyzed
stereospecific cross-coupling reaction of secondary
benzylic esters (Table 25).[207]
Table 25. Cross-coupling reaction of benzylic esters with Me2Zn.
cently, Me2Zn has been used to transform aryl sulfonyl chlor-

ides into aryl methyl thioethers (302 ; Table 27).[208]
2.21.6.MeZnBr/MeZnBr·LiCl
It is well known that R-ZnX can be prepared through the ZnX2
mediated transmetalation of a Grignard or an organolithium
reagent.[204b,208–209] The methyl analogs of such zinc reagents
In the presence of the NiII catalyst, the ring-opening product are commercially available. In this section, recent
292 was obtained in 93% yield when MeMgI was used applications on functional group transformation are
(Scheme 29). In the same paper, the cross-coupling reaction summarized in Scheme 30, including the transformation of
of chiral lactones (300) with Me2Zn affords highly Ar-Cl,[209,210] Ar- Br,[211] and Ar-OTf[212] into methylated products.
stereoselective ring-opening products (301) in high yields
(Table 26).[205] Re-
2.22. Borane dimethylamine complex/N,N-dimethylforma-
mide (Me2NH-BH3/DMF)
Table 26. Cross-coupling reaction of lactones with Me2Zn. Recently, Wang et al. developed a new a-monomethylation
strategy by using a borane dimethylamine complex/N,N-
dimethylformamide (R3N-BH3/DMF) system.[213] Mechanistic
studies indicate that DMF is the source of the methyl group,
and the amine-borane is subjected to hydride reduction. A
proposed mechanism is illustrated in Scheme 31.
2-Arylacetonitrile 308 is first deprotonated by tBuONa. The
resulting carboanion 309 reacts with DMF to afford the
hemiaminal 310. Removal of the hydroxyl group gives the
intermediate 311, which is reduced by the borane reagent
to give a-di- methylaminomethyl-substituted intermediate
312. Under basic
Scheme 30. C@C formation with MeZnX.
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methylating re-
Scheme 31. Mechanism of a-monomethylation with Me2NH-BH3/DMF.
conditions, an E1cB elimination of Me2NH occurs to afford

acrylonitrile 313, which undergoes a further hydride reduction
to furnish the methylated product 314.
A few representative products are shown in Figure 8. In
general, the a-monomethylated products are obtained in
high to excellent yields. Functional groups such as electron-
donating groups (314 b), electron-withdrawing groups (314
c), heterocycles (314 d), free aryl amines (314 e), and free
acids (314 f), are tolerated. Product 314 g was not obtained
under the conditions, instead 96% of the relevant starting
material was recov- ered. Notably, a remarkable advantage
of this methylation protocol lies in the control of the
numbers of deuterium atoms in the methyl group. For
instance, the usage of fully deuterated DMF gives the mono-
deuterated product (314 i), whereas the application of BD3
affords the di-deuterated product (314 j).
Figure 8. Products of a-monomethylation using borane dimethylamine

complex/DMF.
3. Monomethylation
In Section 2, the key methylation conditions with different
methylation reagents is highlighted. Sometimes the formation
of a monomethylated product is challenging. For instance, in
Table 5, when primary amines were used, only the N,N-dime-
thylated products (66–69) were formed.[43] In Table 7, both
the monomethylated product 81 and the dimethylated
product 82 were formed when isonicotinonitrile was used as
the substrate.[46] In Scheme 11, both the monomethylated
product 108 and the dimethylated product 109 were obtained.
[58a]
The monomethylation has been challenging because the
monomethylated product can further react to afford the
dimethylated byproduct, particularly when an excess of
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agents is used. In this section, the recent efforts and aromatic sulfonamides are used
advances on selective monomethylation are highlighted.
3.1. Mono C-methylation

Tables 22–24 demonstrate the application of Me 3Al in the
mono selective ortho-C@H functionalization of
carboxamides in the presence of [Fe] or [Co] catalysts.[200–
201]
In 2015, Chen et al. applied MeI as the methylation
reagent in mono-selective ortho-C@H functionalization of
the substrate 315 to prepare the methylated product 142 o.
Interestingly, the mono- or di- selectivity of the reaction is
controlled by the amount of NaHCO3 incorporated in the
reaction. Using 1.5 equivalents of NaHCO3 and 0.3
equivalents of (BnO)2PO2H (BP) provided 75 % isolated
yield of 142 o and 16% of the dimethylated byproduct 316;
whereas when 3.5 equivalents of NaHCO3 was applied
with 0.3 equivalents of BP, only 5% of 142 o was obtained,
but
316 was isolated in 82 % yield (Scheme 32).[156b]
Scheme 32. Mono- and dimethylation of 315.
3.2. Mono N-methylation
Compared with mono C-methylation, mono N-methylation

has attracted more attention in the chemistry community,
and particularly in medicinal chemistry.[214] However, in
cases where excess amounts of methylation reagents are
applied, the control of monomethylation can be
challenging. For instance, when methanol is used in Table
4[39] and Table 5,[43] or when DMSO/FA is used in Scheme
11,[58a] or when CO2 is used in Table 11,[79] only the
corresponding dimethylated products are formed. Here,
methylation reagents that have been successful- ly applied
in mono N-methylation are summarized.
3.2.1. DMC for monomethylation
In 1997, Selva et al. reported selective mono N-

methylation of primary aromatic amines by DMC (both as
the solvent and reagent) over zeolites.[215] The reaction
was run in a stainless- steel autoclave at 120–150 8C by
treating a mixture of aniline/
DMC (1:74 mole ratio) in the presence of X- and Y-type zeo-
lites. Although GLC analysis showed high conversion (94–
99 %) and high selectivity of monomethylation (up to 44:1
in favor of monomethylation), the application of the zeolites
in N- methylation has been underexplored. The research
group has published excellent reviews on methylation
using DMC[10b,216] and the study of kinetics and selectivity.
[217]
In 2016, Tu et al. accomplished mono N-methylation of

poorly nucleophilic aromatic amines with DMC under the
conditions illustrated in Table 28. The protocol works
nicely for less hindered substrates. However, it mainly
affords N,N-dimethylated products (319–321) when
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Table 28. Mono N-methylation with DMC. Table 30. Mono N-methylation of anilines by Chan–Lam cross-coupling.
under the same conditions.[218] A possible solution to the mon-

omethylation of sulfonamides is presented in Section 3.2.4.
In 2017, Jamison et al. achieved selective
monomethylation of anilines under continuous-flow
conditions by using DMC in the presence of DBU. The
continuous-flow regime with short reaction times (5–20 min) 3.2.3. MeI for monomethylation
safely induces monomethylation in
the superheated solvent (NMP, 250 8C) at high pressure. The
It is well known that direct mono N-methylation of primary
method was applicable to a broad range of primary aniline
amines with MeI is challenging mainly because of further
substrates including ortho-, meta-, and para-substituted ani-
methylation of the monomethylated product to generate the
lines, and electron-rich or electron-deficient anilines
(Table 29).[147] undesired dimethylated product. To tackle this issue,
Dalcanale and Yebeutchou applied an effective
sequestrating agent Tiiii as the host to form a complex 334
Table 29. Mono N-methylation with DMC in flow chemistry. with the HI ammonium salt of the monomethylated product
(Scheme 33).[214] By using such
3.2.2. MeB(OH)2 for monomethylation
In 2009, Cruces et al. reported a selective mono N-

methylation of anilines by Cu(OAc)2-promoted Chan–Lam
cross-coupling with MeB(OH)2 with good functional group
tolerance (Table 30).[104]
The main byproduct under the conditions is the dimethylat-
ed product, which is favored at longer reaction times. To ach-
ieve high conversion to the desired monomethylated product,
the copper catalyst must be added first and an incubation
period (10–15 min) is needed before the addition of
MeB(OH)2. Table 30 shows that ketone groups, esters, and
methylthiol groups are well tolerated. However, the Scheme 33. Tiiii-mediated mono N-methylation.
preparation of 328 was unsuccessful. Other heteroaromatic
amines, such as ami- noquinolines can be methylated, a host–guest sequestration approach, they gained highly
although the yields are moderate (products 331 and 332). selective monomethylation. Despite using 3 equivalents of
MeI, only the monomethylated product was formed in
excellent GC yields (96–100 %). Several advantages, such
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as the synthetic feasibility of preparing Tiiii from
resorcinarene,[219] the broad scope of guests (from linear
primary amines to aromatic primary amines), easy
isolation of monomethylated product (through water
extraction), and the possibility of re-use of the host through
filtration from the water suspension, makes such a host–
guest sequestration approach attractive in mono N-
methylation synthesis.
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3.2.4. MeOH for monomethylation Table 32. Mono N-methylation by using the ligand-installed Ir catalyst
341.
In 2005, Takebayashi et al. discovered that aniline is easily installed catalyst 341 is applicable for the benzylic sulfonamide
N- methylated in supercritical methanol without catalyst at (344) and aliphatic sulfonamide (345). Compared with the
350 8C to give mono N-methylaniline with high selectivity.[220] conditions in Table 31, the conditions in Table 32 are milder:
Howev- er, the required high temperature may prevent the the reactions
application
of this protocol in organic synthesis.
In 2007, Gopinath et al. achieved mono N-methylation of
aniline by running the reaction in vapor-phase reaction condi-
tions on Cu1@xZnxFe2O4 systems.[221] However, the reaction still
needs high temperatures (up to 300 8C) to achieve high
yields
(+ 95 %). Additionally, vapor-phase reaction conditions and
the
preparation of the Cu-Zn-Fe catalyst may limit the application
of this method.
In 2012, Li et al. developed a method of direct N-monome-
thylation of aromatic primary amines, including arylamines,
ar- ylsulfonamides, and amino-azoles in the presence of a
[Cp*IrCl2]2/NaOH system (Cp*= 1,2,3,4,5-pentamethylcyclopen-
tadiene).[222] The method is well known as the hydrogen-bor-
rowing strategy. The method works well for aliphatic primary
amines, but only affords dimethylated products because ali-
phatic amines are more nucleophilic than aromatic amines.
Table 31 demonstrates that this method is highly attractive
for N-monomethylation of aromatic primary amines because
of low catalyst loading, broad substrate scope, and excellent
yields.
Table 31. Mono N-methylation by using the [Cp*IrCl2]2 catalyst.
In 2017, the Li group developed a new type of Cp*Ir com-

plex bearing a functional 2,2’-dibenzimidazole ligand (341)
for the N-methylation of a variety of amines in the presence
of a weak base (0.3 equiv of Cs2CO3).[223] The ligand-installed
cata-
lyst 341 can be readily prepared, and representative
methylated products are shown in Table 32.
The yields of 336, 340, and 148 a–c in Table 31 and Table
32 are similar. However, the approach of using the ligand-
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can be conducted at a lower temperature (120 8C) in the

presence of a weak base (Cs2CO3) under air.
In 2017, Obora et al. used self-prepared DMF-stabilized
Ir nanoclusters (Ir NCs) as a catalyst in the hydrogen-
borrowing reaction for mono N-methylation of anilines
(Table 33).[224]
Table 33. Mono N-methylation by using the Ir NCs catalyst.
In 2017, Tu et al. carried out mono N-methylation of

anilines by using self-prepared N-heterocyclic carbene
iridium (NHC-Ir) polymer (347) as the catalyst in excellent
yields (Table 34). Under optimized conditions, aryl
sulfonamide can be monomethylated.[225]
In addition to iridium catalysis, the ruthenium-catalyzed
N- methylation of amines has also been explored. Seayad
et al. used the in situ generated complex from [RuCp*Cl 2]2
and the
Table 34. Mono N-methylation by using the NHC-Ir polymer.
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dpePhos ligand as an efficient catalyst for the N-methylation
of amines when using methanol. Through a Ru-catalyzed
hydrogen-borrowing strategy, mono N-methylation of
substituted primary anilines and sulfonamides was obtained
in high to excellent yields (Table 35).[226] Owing to the
catalytic amount of
Table 35. Mono N-methylation by using the hydrogen-borrowing strategy (Ru catalyst).
Figure 9. Mono N-methylated products from nitroarenes.
base, functional groups such as ester and nitrile, are tolerated.

In 2017, Kundu et al. reported a novel method of mono N-
As shown in Table 36, the dimethylated 126 was formed
methylation from nitro compounds through a tandem reduc-
from the corresponding aliphatic amine. The authors tried to
tion/methylation transformation.[227] First, in the presence of
synthesize it from the relevant nitro compound.
the phenpy-OMe preinstalled Ru catalyst 352, various
Unfortunately, under the conditions shown in Table 36 but
aromatic amines were converted into the corresponding
with 5 mol % of 352, only the dimethylated product 126 was
mono N-methylated amines in good to excellent yields, while
formed. Interest- ingly, under the optimal conditions, the
the benzylic amine and the aliphatic amine furnish
monomethylated amine 358 was formed from the a,b-
dimethylated products
(126, 355 ; Table 36). unsaturated starting material (Figure 10), probably because
the secondary amine (358) is less nucleophilic than the
Second, N-methylation of a variety of nitroarenes bearing
saturated analog, which further reacts to afford the
both electron-donating and electron-withdrawing groups was
dimethylated product 357.
explored. Under the same conditions as in Table 36 but by
using 5 mol % of 352, the monomethylated products were
prepared with excellent results and good functional group
tolerance (330 and 356; Figure 9).
Figure 10. Mono N-methylated products from aliphatic and a,b-

unsaturated nitro compounds.
Table 36. Mono N-methylation of amines by using the Ru catalyst 352. The Kundu group used the 352 analogous catalysts 363
and 364 (Figure 11) for the N-methylation of aromatic or
aliphatic nitriles.[228] However, only N,N-dimethylated amines
were obtained. It can be reasoned that the mono aliphatic
methylated intermediate amines are prone to be further
methylated to afford the tertiary amines. To achieve N-
monomethylation, the group recently developed the catalyst
365 (Figure 11) and a one-pot strategy using bromide
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derivatives as the starting materials. First, bromides are
converted to azides, and the latter
Figure 11. Representative [Ru] catalysts for methylation by the Kundu

group.
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are further transformed to N-monomethylated products in
good yields. Table 37 demonstrates that monomethylation
selectivity in the protocol is easily controlled by applying
different reaction times, for instance, 2 h reaction time leads
to the monomethylated product 366, whereas 24 h reaction
time affords the dimethylated product 367.[229]
Table 37. N-Monomethylation from bromides.
Figure 12. Monomethylated products by using methanol, 370, and H 2.
An additional recent study on selective N-monomethylation

was reported by Hong and Choi. By using the novel Ru nol as solvent, and a 40 bar H2 atmosphere. Some products
catalyst 370 (Scheme 34), they achieved monomethylation of were transformed into Boc-protected forms as shown in
amines by using methanol as the C1 source and hydrogen Figure 12.
gas as the reducing agent. A possible mechanism is The results in Figure 12 show that the method is suitable
shown in Scheme 34.[230] for both aromatic and aliphatic primary amines. The high
isolated yields of 346, 385, and 386 demonstrate excellent
chemoselectivity preferably towards primary amines when
both a secondary amine and a primary amine are present
in one molecule. Manganese pincer complexes are another
efficient and selective catalysts that have been recently
applied in the hydrogen-borrowing strategy for N-
methylation of amines as demonstrated in the work from
the Beller group[231] and the Sortais
group [232]
(Figure 13).
Scheme 34. Mechanism of N-monomethylation.
The hemiaminal 371 is formed from a primary amine and Figure 13. Recent manganese catalysts for mono N-methylation.
the aldehyde, which is formed from methanol by a hydrogen-
borrowing approach. Hydrogen gas (H2) is used to retard the
dehydrogenation of 371, thus the formation of 374 is not fa- Under optimized conditions, all three catalysts work well
vored. On the other hand, H2 could facilitate the hydrogena- for mono N-methylation. Representative products with the
tion of imine 372, which is formed by dehydration of 371. It isolated yields or the NMR yields are summarized in Table
was envisioned that the formation of the charged iminium in- 38. In general, many functional groups are tolerated with
termediate 375 could have a higher activation barrier than these three catalysts, such as heterocycles, a,b-unsaturated
that of neutral imine 372. As a result, the N,N-dimethylation arenes, methyl thioether, methyl ketone, halogenated arenes,
is not favored. Similarly, the formation of 376 is not favored nitroarenes, aryl nitriles, aryl esters, aryl amides, aliphatic
when H2 is applied. Consequently, the monomethylated prod- and aromatic sulfonamides.
uct is the main product in this protocol. Monomethylated Recently, the Sortais group reported a rhenium-catalyzed
amines were prepared with excellent results and good func- se- lective mono N-methylation of anilines with methanol.[233]
tional group tolerance by using 2% of 370 as catalyst, Cata- lyst 420 was selected, and the monomethylated
metha- products were obtained in good to excellent yields (Table 39).
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In a recent work by Liu et al., Co(acac)2 was used as the
catalyst for mono N-methylation.[234] Under the optimal
conditions, as shown in Table 40, the dimethylated products
were formed from benzylic and aliphatic amines, whereas
the aromatic amines formed monomethylated products.
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Table 38. Selected N-methylated products by using catalysts 387–389.

Table 40. N-Methylation of amines by using Co(acac)2 as the catalyst.
Table 41. In(OTf)3-catalyzed mono N-methylation of amines with dimethyl phosphite.
Table 39. Selective mono N-methylation of anilines by using the [Re] catalyst 397.
In 2017, Sajiki, Sawama, and co-worker published a

convenient procedure for selective mono N-alkylation of
alkyl and aryl amides by using trimethyl phosphate as the
methylation reagent and cyclopentyl methyl ether (CPME)
as the solvent. The use of NaOH significantly leads to the
formation of the desired monomethylated products in good to
high yields (Table 42).[235]
Table 42. Mono N-methylation of primary amides by using trimethyl phosphate.
3.2.5. Dimethyl phosphite and trimethyl phosphate for mono-

methylation
In 2013, Kundu, Majee, and Mitra used indium(III) triflate

(In(OTf)3) as a catalyst for selective mono N-alkylation of pri-
mary amines by using dialkyl phosphite as the alkylating
agent and solvent under microwave irradiation conditions.
When dimethyl phosphite was used, this method afforded
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mono N-methylated products in high yields (Table 41).[183]
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3.2.6. Peroxides for monomethylation
drawing and electron-donating substituents, as well as
aliphatic primary and secondary amines. Table 45 shows
As mentioned in Section 2.9, DTBP has been used in the
three examples of mono N-methylation of aliphatic primary
mono N-methylation of primary amides and sulfonamides.
[87,96] amines.
In 2017, Maruoka et al. reported the CuI-catalyzed
synthesis of 147 a by using methylsilyl peroxides (Table 43),
however, the use of benzene as the solvent is a clear Table 45. Mono N-methylation of aliphatic primary amines.
drawback.[236]
Table 43. CuI-catalyzed mono N-methylation of primary amides with peroxides.
4. Common Strategies for Selective N-Methyla-

3.2.7. HCHO for monomethylation
tion of Amino Acids and Peptides
In 2007, Bieber et al. reported the mono N-methylation of ali-
In 2004, Hughes et al. published an elegant review on the
phatic amines with HCHO and zinc in an aqueous medium.
synthetic preparation of N-methyl-a-amino acids.[31] In 2016,
Under optimized conditions, including pH, reaction stoichiom-
Lig- uori and co-workers presented a short review on the
etry, and time, the selected monomethylated products were
synthesis and biological activity of N-methylated amino acids
obtained in excellent yields (Table 44).[68] However, there is
and peptides.[7c] In general, an indirect methylation strategy
no a general protocol for selective monomethylation. For
for the mono N-methylation of amino acids has been used for
instance, the synthesis of 406 and 407 was conducted under
decades. The primary amine group is first activated through
the same conditions but only one equivalent of NaH2PO4 was
a substitution with an electron-withdrawing group. The proton
needed for the synthesis of 406.
on the N atom becomes more acidic and thus can be easily
Recently, the Shi group has devised a mono N-methylation
deprotonated. Second, reaction of the resulting N anion with
procedure using paraformaldehyde and H2 in the presence of
electrophilic methylation reagents, such as MeI,[237] CH2N2,[238]
a CuAlOx catalyst.[74] The protocol works well for a variety of
Me2SO4,[239] etc., followed by a deprotection step to remove
amines, including primary anilines with both electron-with-
the activating group gives the mono N-methylated products.
This method has been widely applied in the synthesis of N-
methyl amino acids, which are then used in the synthesis of
peptides bearing N-methyl group(s).[4m,240] Alternatively, in the
second step, a Mitsunobu reaction is performed to make
the N-methylated products after removal of activating groups.
[239a,241]
When Na-Fmoc lysine is the substrate, mono Ne-
methylation can be achieved through another indirect ap-
proach (benzylation/methylation/debenzylation) as shown in
Scheme 35.[242]
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Scheme 35. Na-Fmoc Ne-(Boc, methyl) lysine.
Peptides, especially cyclic peptides, as a rejuvenated chemis-

try modality have drawn the attention of medicinal chemists
in drug discovery. Peptide therapeutics are expected to
address unmet medical needs in a variety of therapeutic
areas, and can be an excellent complement or even
preferable alternative to small-molecule and biological
therapeutics.[4i,243] However,
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owing to the liabilities associated with peptide-like molecules, Mono N-methylation of aromatic primary amines has been
N-methylation of the N@Ca peptide bond is a well-known well explored. However, N-methylation of primary aliphatic
strategy to overcome these problems.[4b,k,7] In general, N- amines (or amino acids) by using HCHO and a suitable reduc-
methylation of peptides can lead to conformational changes
from a structural perspective. Such three-dimensional
modifications can lead to changes in physicochemical and
biological proper-
ties, such as solubility,[4p] permeability,[4c,244] stability,[245] affinity,
selectivity,[4s] and bioavailability,[1a,4g,j,246] etc.
From a synthetic perspective, the direct synthesis of N-me-
thylated peptides is still challenging, mainly owing to poor
site selectivity when multiple amide bonds can be subjected
to methylation. Therefore, a specific mono N-methylated
amino acid or a short N-methylated peptide is usually
prepared before the synthesis of the full-length peptide.
[166,239a,240,241,247]
This method has been applied in a “peptide
methyl scan”, a method to study the methylation effect of a
peptide by incor- porating an N-methylated amino acid into a
peptide.[248]
Lokey, Jacobson, and co-workers have devised a method
for the selective, on-resin N-methylation of cyclic peptides to
generate compounds with drug-like membrane permeability
and oral bioavailability.[4m] In their work, the selectivity of
methylation depended on the hydrogen-bond environment
of the cyclic peptide. In other words, a hydrogen bond in R-
CON-H- O=C acts as a protecting group, preventing N-
methylation, whereas the other “free” NHs are methylated.
Figure 14 dem-
Figure 14. Selective N-methylation of cyclic peptides.
onstrates two methylated cyclic peptides. The difference

between these two substrates is the use of D-Leu
(colored in blue). Owing to the hydrogen bonding difference
in these two
substrates, product 414 is tri-methylated, whereas 415 is
tetra- methylated.
5. Summary and Perspective

This review summarizes the wide range of options for
methylation reagents that organic chemists have at their
disposal. It can be used as a guide for chemists wanting to
apply the best methylation conditions in their work. Despite
the fact that only methylation chemistry is covered in this
review, certain methods also work well for accessing other
alkyl groups, such as cyclic (cyclopropyl, -pentyl, and -hexyl)
alkyl groups, benzylation, etc.[16b, 35, 45, 88, 156b, 204b, 231a, 235, 249]
Revie
tant, that is, a direct reductive amination strategy, usually 6, 437 – 443; c) U. K. Marelli, O. Ovadia, A. O. Frank, J. Chatterjee, C.
Gilon, A. Hoffman, H. Kessler, Chem. Eur. J. 2015, 21, 15148–
leads to poor selectivity since N,N-dimethylation is more
15152 ; d) N.
thermody- namically favorable in many cases.[68] So far,
only a few reports are available in which selective formation
of mono N-methylated products from primary aliphatic
amines is demonstrated (Tables 44 and 45). As discussed
in Section 3.2, mono N-methylation of aliphatic primary
amines by using DMC, MeB(OH)2, MeI, MeOH, dimethyl
phosphite and trimethyl phosphate, peroxides, and HCHO
as the methyl source is very challenging. Two significant
breakthroughs in this respect are exemplified in Table
37[229] and Figure 12.[230] Indeed, the demand for a simple,
convenient, straightforward, and highly selective mono N-
methylation of aliphatic primary amines is still much
desired. N-Methylation of amino acids has been well
explored, and many N-methylated amino acids are
commercially available. Figure 14 showcases the selective
multiple methylation of cyclic peptides through an
intermolecular hydrogen-bonding design. However,
regarding direct N-methylation of peptides, available
synthetic approaches do not meet the increasing
demand for desired variations. For instance, the
regioselectivity among multiple methylation sites in the
peptide backbone is
still highly challenging.
Acknowledgments
The author thanks Dr. Daniel Pettersen and Dr. Martin A.

Hayes for valuable comments and suggestions on the
manuscript. The author thanks his family (Jia, Erik, and
Viktor) for their continuous support.
Conflict of interest
The authors declare no conflict of interest.
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Recent Advances in Methylation: A Guide For Selecting Methylation Reagents

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DOI: 10.1002/chem.

Recent Advances in Methylation:

Chem. Eur. J. 2019, 25, 3405 – 3439

Methylation as a popular structural modification has been

Figure 1. Representative examples of methylated drugs.

Stegobinone and its diastereomeric form, that is, epi-

[a] Dr. Y. Chen

Figure 2. Chemical structure of stegobinone and epi-stegobinone.

Owing to the importance of methylation in medicinal

2. Methylation by Using Conventional

Scheme 2. Two pathways for methylation of 8-oxoadenosine.

Fairley et al. at AstraZeneca used DMF-DMA for the

Yantao Chen ( ) received his

Table 2. Rh-catalyzed methylation of ketones.

Mechanistically, oxidation of DMF by persulfate affords the

hydrogenation–hydrogenolysis of enaminones 14, 15 to

2.2. N,N-Dimethylformamide (DMF)

Table 3. Multicomponent synthesis of a-branched methylated ketones.

Scheme 5. An additional proposed mechanism of the formation of 29.

Methanol, the simplest alcohol, has often been used as a C 1

Scheme 6. Representative pathway for a general metal-catalyzed hydrogen-

or an amide to give the intermediate 36; 3) formation of 37

as an alkylation approach. For recent advances of

Historically, photoalkylation of heteroarenes was reported

2.3.2. Methanol in hydrogenolytic deprotection/hydrogenation

2.3.3. Methanol in metal-free photoinduced reactions

In 2017, Li et al. described a simple photoinduced

Scheme 8. [Cu]-catalyzed decarboxylative methylation of aryl acids.

First, PhI(OAc)2 (83) decomposes to yield acetoxy radicals

Scheme 9. Photoredox approach to methylation of heteroarenes.

situ oxidatively quenches the excited photocatalyst by a

2.6. Formic acid (FA)

In Scheme 11, FA acts as a reducing reagent to transfer the

Scheme 11. Methylation of amines with DMSO/FA.

Scheme 12. O-Methylation of aryl acids with DMSO.

Table 9. FA as methylation reagent.

HCHO has been used in Eschweiler–Clarke reactions, in

2.8. Carbon dioxide (CO )

Besides organocatalysts, metals are also efficient catalysts

alysts, methylated pyrimidinones and pyridinones 138 were

In the work by Lin, Fu and colleagues, only two

Scheme 16. Recent advances of methylation by using peroxide TBPB.

The addition of effective ligands has been a

Figure 5. Selected methylated products by using MBA as the

Scheme 19. Minisci-type C@H methylation with MBA.

2.11. Trimethylboroxine (TMB)

2.12. Potassium methyltrifluoroborate (MeBF3K)

2.13. Other alkylboron reagents

In addition to MBA, TMB, and MeBF3K, another two boron

Table 12. Preparation and application of LMTB.

enables sequential direct alkylation/methylation of 2,2’-bipyri-

2.15. Dimethyl carbonate (DMC)

DMC is an environmentally friendly substitute for DMS and

Scheme 21. Methylation of Biginelli compounds.

Among several solid oxide bases (MgO, ZnO, ZrO2, CeO2,

Scheme 22. Methylation of electron-deficient pyrroles.

methylated products (203, 204) were isolated, whereas the

Scheme 25. Reductive methylation of amines with DMC.

2.16. Methyl iodide (MeI) and its derivatives dimethylsulfonamides