Selective Methylation of Amides, N-Heterocycles, Thiols, and Alcohols with Tetramethylammonium Fluoride

Article abstract of DOI:10.1021/acs.orglett.9b04400

We herein disclose the use of tetramethylammonium fluoride (TMAF) as a direct and selective methylating agent of a variety of amides, indoles, pyrroles, imidazoles, alcohols, and thiols. The method is characterized by operational simplicity, wide scope, and ease of purification. Our computational studies suggest a concerted methylation-deprotonation as the preferred reaction pathway.

Full text of DOI:10.1021/acs.orglett.9b04400

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selective Methylation of Amides, N‑Heterocycles, Thiols, and
Alcohols with Tetramethylammonium Fluoride
Hong-Gang Cheng, Maoping Pu, Gourab Kundu, and Franziska Schoenebeck*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: We herein disclose the use of tetramethylammonium fluoride
(TMAF) as a direct and selective methylating agent of a variety of amides,
indoles, pyrroles, imidazoles, alcohols, and thiols. The method is
characterized by operational simplicity, wide scope, and ease of purification.
Our computational studies suggest a concerted methylation−deprotonation
as the preferred reaction pathway.
lthough the methyl group is the smallest alkyl group, its
incorporation can greatly modulate the solubility, hydro-
A
philicity, and conformation of polymers, proteins, drug
candidates, etc., thus leading to a drastic improvement of
their biological activity, pharmacokinetic profile, and physical
properties.1 This so-called “magic methyl effect” renders
methylation as one of the most popular structural modifica-
tions in medicinal chemistry. Indeed, a survey by Njarđarson
on the top-sold 200 pharmaceuticals in 2018 shows that over
70% of small-molecule drugs contain at least one methyl
group,2 with representative examples shown in Figure 1a.
Consequently, the development of efficient strategies for the
selective introduction of methyl groups into organic molecules
is of significant interest.
In this context, the methylation of amides is of particular
importance as these are ubiquitous motifs in a range of
medically important compounds.3 As such, substantial efforts
have been devoted to this field (see Figure 1).4 The
methylation of amides is traditionally done with frequently
unstable, volatile, or toxic methylating agents such as
iodomethane,5 dimethyl sulfate,6 or chloromethyldimethylsilyl
chloride7 and frequently requires an excess of a strong base.
Alternative strategies include the reductive methylation with
formaldehyde as a methylcarbon source8 or the transition-
metal-catalyzed methylation of amides with methanol.9 While
the former method requires an excess of reducing agents as
well as strong acids (e.g., trifluoroacetic acid), which limits
applicability, the latter suffers from relatively low conversion
and/or harsh reaction conditions. In the past decade, the
Figure 1. Representative drugs containing methyl groups (top) and
common methylation strategies of amides (bottom).
11
employment of peroxides10 or PO(OMe)3 as methylation
investigations with the methylation of N-phenylacetamide (1),
see Table 1. After extensive survey of the reaction
parameters,13 the optimal conditions were identified as
TMAF (2.5 equiv) in toluene (0.4 M) at 100 °C, wherein
the desired N-methyl-N-phenylacetamide (2) was obtained in
95% yield after 12 h (entry 1). A series of control experiments
was also conducted: decreasing the temperature to 80 °C led
to a slightly lower yield and required longer reaction times. At
reagents also gained popularity; these methods are in need of
specialized transition-metal catalysts, however, and display
relatively narrow scope.
As such, there is a continuing demand for a safe, practical,
and metal-free methylation methodology of amides, partic-
ularly paired with high chemoselectivity.
We herein report the efficient and chemoselective
methylation of amides as well as N-heterocycles, thiols, and
alcohols, employing tetramethylammonium fluoride
(TMAF)12 as the methyl group source. We started our
Received: December 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04400
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Scope of the Amides
b
entry
change from the standard conditions
yield (%)
c
1
2
3
4
5
6
7
8
9
none
95 (92)
d
80 °C instead of 100 °C
rt instead of 100 °C
93
d
0
NMP instead of toluene
DMF instead of toluene
CH3CN instead of toluene
Me4NCl instead of Me4NF
Me4NBr instead of Me4NF
Me4NCl and KF instead of Me4NF
95
70
57
d
0
d
0
d
0
a
b
Reactions were performed on a 0.2 mmol scale. Yields were
determined by GC analysis using dodecane as the internal standard.
c
d
Isolated yield is shown in parentheses. 24 h.
room temperature, no reaction took place (entries 2 and 3).
The polar solvent NMP proved to be as equally effective for
this reaction as toluene (entry 4). Moderate yields could also
be obtained when DMF or CH3CN were used as the solvent
(entries 5 and 6). Toluene was selected as the solvent due to
the added operational simplicity of the purification procedure,
as the excess TMAF and the only byproduct, Me3NHF, will
precipitate upon cooling to room temperature. This allows for
final purification via a simple filtration over a small pad of silica.
The fluoride anion in TMAF is critical for this process, as the
switching of fluoride to bromide or chloride both resulted in
no formation of desired product (entries 7 and 8).14
A
combination of tetramethylammonium chloride (Me4NCl, 2.5
equiv) and KF (2.5 equiv) instead of TMAF also failed to give
any product (entry 9).
With the optimized reaction conditions in hand, we
subsequently examined the substrate scope (Scheme 1).
Employing TMAF as the methylation reagent, an array of
amides, including acyclic amides (2−10, 14), cyclic amides
(11−13), and sulfonamide (15) were found to react efficiently,
providing the desired methylated amides in moderate to
excellent yields. Moreover, aliphatic, aromatic, and heterocyclic
substituents were tolerated. Notably, when 3-methylindolin-2-
one was employed as substrate, methylation occurred at both
N1 and C3 position (product 12), which demonstrates that
the method is also amenable for C−H methylation, provided
the site is sufficiently acidic.
We next investigated the potential of our method in late-
stage methylation of bioactive compounds. We successfully
methylated the anesthetic lidocaine (16),15 the drug
thalidomide (17),16 and anticancer agent enzalutamide (18).17
We subsequently explored the scalability and performed the
reaction on a 7.0 mmol scale, which led to the successful
preparation of product 3 in 1.1 g (88% yield).
We next tested the performance of TMAF to methylate
functional groups other than amides. As shown in Scheme 1, a
number of substituted 1H-indoles were efficiently methylated
to 19−30, independent of their respective substitution
patterns, tolerating substituents at C2 (20 and 21), C3 (22),
C4 (23), C5 (24−26), C6 (27 and 28), and C7 (29) of the
indole ring. A range of functional groups such as ester (21),
aldehyde (22), cyano (23), methoxy (24), iodo (25), bromo
a
Conditions: Substrate (0.4 mmol), TMAF (93.2 mg, 1.0 mmol), in
b
toluene (1.0 mL) at 100 °C. Isolated yields are shown. The reaction
was performed on a 7.0 mmol scale. 5.0 equiv of TMAF. NMP was
used instead of toluene. The reaction was performed on a 6.0 mmol
scale.
c
d
e
(26), chloro (27), and fluoro (28 and 29) were well-tolerated,
providing handles for further diversification.
B
DOI: 10.1021/acs.orglett.9b04400
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notably, a scale-up operation (6.0 mmol) of this
methylation procedure was successfully performed to obtain
1.13 g of product 20 (91% yield).
Moreover, pyrroles and imidazoles could also be converted
to the corresponding methylated products in 88−96% yields
(31−33). Similarly, methylations of phenol (34), alcohols (35
and 36), and thiols (37 and 38) proceeded equally smoothly
to give the corresponding methylated products in excellent
yields, highlighting the generality of this process.
We then turned our attention to substrates with multiple
potential reactive sites. To our delight, when attempting to
methylate substrates that contained both an amide and an
aromatic primary amine functionality (39 and 40 in Figure 2a),
a direct methyl cation transfer from TMAF. However, both
aromatic and alkyl amides show prohibitively high activation
free energy barriers (>45 kcal/mol) for transferring a CH3 to
NH.13
Notably, our control experiments (Table 1) showed that
fluoride plays a decisive role, as using the corresponding
chloride or bromide salts (i.e., TMACl or TMABr) resulted in
no reaction. Moreover, it has previously been shown that
fluoride can act as a base.20 Hence, in the search for an
alternative mechanism, we considered a concerted deprotona-
tion (by F−) and methyl transfer (from NMe4 ) (see Figure
+
2b). The corresponding activation free energy barrier
associated with this process is 30.9 kcal/mol. In this context,
we also considered that the amide could tautomerize to the
imidic acid, which is 3.4 kcal/mol higher in energy than the
amide. Interestingly, despite the free energy penalty for
tautomerization, overall, the concerted methylation/deproto-
nation is favored via the imidic acid tautomer by ΔΔG⧧ = 5.1
kcal/mol over direct reaction of the amide (see Figure 2b,
TS2). Moreover, the corresponding methylation at the primary
amine site (Figure 2b, TS3) is more than 8 kcal/mol higher
than methylation via TS2, which is in line with the observed
exclusive chemoselectivity.
In conclusion, we described the employment of tetramethy-
lammonium fluoride as a highly efficient, practical, direct, and
chemoselective methylation reagent.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04400.
1
Experimental procedures, characterization data, and H
and 13C NMR spectra of the new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: franziska.schoenebeck@rwth-aachen.de
ORCID
Figure 2. (a) Chemoselective methylations with TMAF. aConditions:
Substrate (0.4 mmol), TMAF (93.2 mg, 1.0 mmol), in toluene (1.0
mL) at 100 °C for 12−72 h. Isolated yields are shown. bNMP (1 mL)
at 160 °C. (b) Computational study. Energies refer to Gibbs free
energy activation barriers (in kcal/mol) calculated at the M06-2x/
def2-TZVP//M06-2x/6-31G(d,p) level of theory.
Franziska Schoenebeck: 0000-0003-0047-0929
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the RWTH Aachen University for funding.
Calculations were performed with computing resources
granted by JARA-HPC from RWTH Aachen University
under project “jara0091”.
the methylation exclusively occurred at the amide NH site,
regardless of the number of employed equivalents of TMAF,
giving products 39 and 40 in 90 and 88% yield, respectively.
For comparison, with conventional methodology, 40 was
previously prepared in a three-step sequence.18
Also in the cases of 41−44, the corresponding methylation
occurred at the indole NH site or hydroxyl site selectively in
high yields, leaving the primary or secondary amine site
completely untouched.
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DOI: 10.1021/acs.orglett.9b04400
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