C?H Methylation of Iminoamido Heterocycles with Sulfur Ylides**

Article abstract of DOI:10.1002/anie.202010958

The direct methylation of N-heterocycles is an important transformation for the advancement of pharmaceuticals, agrochemicals, functional materials, and other chemical entities. Herein, the unprecedented C(sp²)-H methylation of iminoamido heterocycles as nucleoside base analogues is described. Notably, trimethylsulfoxonium salt was employed as a methylating agent under aqueous conditions. A wide substrate scope and excellent level of functional-group tolerance were attained. Moreover, this method can be readily applied to the site-selective methylation of azauracil nucleosides. The feasibility of gram-scale reactions and various transformations of the products highlight the synthetic potential of the developed method. Combined deuterium-labeling experiments aided the elucidation of a plausible reaction mechanism.

Full text of DOI:10.1002/anie.202010958

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: C–H Methylation of Iminoamido Heterocycles with Sulfur Ylides
Authors: Prithwish Ghosh, Na Yeon Kwon, Saegun Kim, Sangil Han,
Suk Hun Lee, Won An, Neeraj K Mishra, Soo Bong Han, and
In Su Kim
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202010958
Link to VoR: https://doi.org/10.1002/anie.202010958

10.1002/anie.202010958
Angewandte Chemie International Edition
COMMUNICATION
C–H Methylation of Iminoamido Heterocycles with Sulfur Ylides
Prithwish Ghosh,[a,†] Na Yeon Kwon,[a,†] Saegun Kim,[a] Sangil Han,[a] Suk Hun Lee,[a] Won An,[a] Neeraj
Kumar Mishra,[a] Soo Bong Han,[b,c] and In Su Kim*[a]
Abstract: The direct methylation of N-heterocycles is an important
transformation for the advancement of pharmaceuticals,
agrochemicals, functional materials, and other chemical entities.
Herein, the unprecedented C(sp2)–H methylation of iminoamido
heterocycles as nucleoside base analogues is described. Notably,
trimethylsulfoxonium salt was employed as a methylating agent
under aqueous conditions. A wide substrate scope and excellent
level of functional group tolerance were attained. Moreover, this
method can be readily applied to the site-selective methylation of
azauracil nucleosides. The feasibility of gram-scale reactions and
various transformations of the products highlight the synthetic
potential of the developed method. Combined deuterium-labeling
experiments aided the elucidation of a plausible reaction mechanism.
carbanion center has been studied for the metal-free C–H
methylation for nitroarenes and N-heteroaromatic compounds by
Makosza.[12] In this process, the nature of the leaving group (X)
provides the possibility of its elimination as HX from the
intermediate σ-complex (Scheme 1B). However, this protocol
presents intrinsic drawbacks, namely, the deficiency of site-
selectivity and the need of additional carbanion stabilizing
groups such as SO2Ph. Although sulfur ylides were also used as
carbanion nucleophiles in vicarious nucleophilic substitution,
these examples have been only limited in the methylation of
nitro(hetero)arenes.[13]
A. Classification of N-heterocycle alkylation
Conventional cross-coupling
X = halogens; R-[M]
Methylation is one of vital processes in biological systems
because DNA and histone methylation is responsible for gene
expression without affecting the gene sequence.[1] For example,
the C(sp2)–H methylation of uracil of deoxyuridine-5’-
monophosphate (dUMP) by thymidylate synthase is a well-
known metabolic process for DNA biosynthesis and RNA post-
translational modification.[2] In addition, methylation of cysteine
can affect signaling pathways by disrupting ubiquitin-chain
sensing in NF-κB activation.[3] Methylation is also an important
modification in medicinal chemistry and drug discovery, as
physical and pharmacological properties of lead candidates can
be favorably or adversely affected with the mere addition of a
methyl group.[4] To address this challenge, number of synthetic
strategies have been explored to install a methyl group on N-
heterocyclic molecules.[5] In particular, methylation beyond
monoazines, i.e., that of diazines and triazines, has emerged as
a hot topic in this area due to the relevance of a number of
bioactive molecules.[6]
Minisci-type reaction
Het
R
Het
X
alkyl radicals by oxidants & photoredox
Metal-catalyzed C-H functionalization
alkyl halides, unsaturates
B. Vicarious nucleophilic substitution using stabilized carbanions
NO2
H
NO2
NO2
CH2
R
R
R
HC SO2Ph
X
+
Y
SO2Ph
Y
H
Y
HX
X
Y = C, N
SO2Ph
-complex
R1
N
C. Methylation of iminoamido heterocycles with sulfoxonium ylide
O
O
R1
a
R1
N
X
b
N
O
N
O
H
B
O
O
H
O
Corey-Chaykovsky
aziridine (not observed)
+
X
H2C SMe2
X
N
SMe2
O
N
R1
a
X = C, NR2
The conventional approach is the transition-metal-catalyzed
cross-coupling reactions between halogenated N-heterocycles
and organometallic reagents (Scheme 1A).[7] Minisci-type
alkylations using alkyl radicals[8] and metal-catalyzed C–H
alkylations[9] of N-heterocycles constitute the current established
protocols. Alternative routes including the metal-free C–H
alkylations of preactivated N-heterocycles have been also
developed.[10] For examples, our group recently described the
reductive C2-alkylation of heteroaromatic N-oxides using
phosphonium ylides.[11] Vicarious nucleophilic substitution (VNS)
using carbanions with leaving groups (e.g., Cl and PhS) at the
H2O
b
O
N
O
X
N
Me
this work
Scheme 1. C–H methylation of N-heterocycles.
Since the landmark discovery by Johnson, Corey, and
Chaykovsky in the 1960s,[14] sulfoxonium ylides have been
widely employed as methylene surrogates in epoxidations,
cyclopropanations, and aziridinations via intermolecular
nucleophilic addition into electron-deficient π-unsaturated
compounds, such as carbonyls, α,β-unsaturated compounds,
and imines.[15] However, there are no reports on the direct and
selective alkylation of iminoamido N-heterocyclic compounds as
non-N-heteroaromatic compounds using alkyl sulfoxonium ylides.
Moreover, previous reports related to sulfoxonium ylides
predominantly rely on the use of organic solvents,[16] which
preclude them as environmentally benign processes. Herein, we
describe the unprecedented C(sp2)–H alkylation of iminoamido
diazines and triazines as nucleoside base analogues with alkyl
sulfoxonium salts. Of particular importance is the mechanistic
pathway for the imino alkylation in aqueous media, which can
[a]
Dr. P. Ghosh, N. Y. Kwon, S. Kim, Dr. S. Han, Dr. S. H. Lee, W. An,
Dr. N. K. Mishra, Prof. Dr. I. S. Kim
School of Pharmacy, Sungkyunkwan University, Suwon 16419,
Republic of Korea
E-mail: insukim@skku.edu
[b]
[c]
Dr. S. B. Han
Division of Bio & Drug Discovery, Korea Research Institute of
Chemical Technology, Daejeon 34114, Republic of Korea
Department of Medicinal and Pharmaceutical Chemistry, University
of Science and Technology, Daejeon 34113, Republic of Korea
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/anie.202010958
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of reaction conditions.[a]
provide novel insights into Corey-Chaykovsky reagents (Scheme
1C). Moreover, the amenability of this protocol to the
pharmaceutical industry is attributed to the use of H2O and ROH
as the greenest solvents and economical inorganic bases.
Optimization of reaction conditions commenced with the
coupling between pyrazinone 1a and trimethylsulfoxonium iodide
(2a), as shown in Table 1. The formation of C3-methylated
pyrazinone 3a was achieved with the use of KOtBu in THF at
entry
base (equiv.)
solvent
yield[b]
1
KOtBu (3)
KOtBu (3)
KOtBu (3)
KOtBu (3)
KOH (3)
THF
43
58
78
84
91
88
90
87
80
65
45
o
100 C (entry 1). This reaction could likewise be performed in
2
DME
protic solvents, such as MeOH (entry 3). Surprisingly, aqueous
media accelerated the coupling reaction to afford 3a in 84%
yield within 2 h (entry 4). It should be noted that the aziridine
compound generated from the imine functionality by the Corey-
Chaykovsky aziridination was not observed in all cases,
suggesting that the reaction pathways of the Corey-Chaykovsky
reaction and the C(sp2)–H methylation reported herein are
distinct. More importantly, this reaction was successful with the
use of KOH, a cost-efficient base, to provide 3a in 91% yield
(entry 5). Comparable yields were obtained in EtOH and
H2O/EtOH solvents (entries 6 and 7). Screening of other bases
yielded inferior results (entries 8 and 9). Control experiments
revealed that the loading amount of KOH and reaction
temperature were crucial for increasing the yield of 3a (entries
10 and 11). It is noted that phosphonium salt (MePPh3I) and
sulfonium salt (Me3SI) were unreactive in this transformation.
3
MeOH
H2O
4
5
H2O
6
KOH (3)
EtOH
H2O/EtOH (1:1)
H2O
7
KOH (3)
8
NaOH (3)
K2CO3 (3)
KOH (2)
9[c]
10
11[d]
H2O
H2O
KOH (3)
H2O
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), base (quantity
noted), solvent (1 mL) under air at 100 oC for 2 h in reaction tubes. [b] Yield
by flash column chromatography. [c] 10 h. [d] 60 oC for 2 h. THF =
tetrahydrofuran. DME = 1,2-dimethoxyethane.
R1
R1
O
N
O
R
N
O
H
X
R
KOH, H2O
100 oC, 2 h
S
R
+
R
R2
N
R2
N
[b]
3a 3z
-
, %
1a 1w
-
2a 2e
-
R
CN
MeO
Me
N
O
F
O
N
O
N
N
O
N
N
O
N
O
N
O
N
O
N
O
Ph
N
Me
Ph
N
Me
Ph
Me
Ph
3c
Me
Ph
N
Me
Ph
N
Me
Ph
3e
N
Me
Ph
N
Me
[c]
3h
3i
, 54% (R = CF3)
[c]
[d]
[e]
[c]
3a
3b
3d
3f
3g
, 89%
, 91%
R
, 82%
, 75%
MeO
, 76%
, 80%
, 73%
, 45%[e], 80%[f] (R = CN)
F
Me
N
Me
N
O
Me
Me
O
N
OMe
Ph
Ph
N
O
N
N
O
N
N
O
N
Me
N
N
O
N
O
N
Me
N
O
N
Me
Me
Me
Ph
Me
Ph
N
Me
R
N
Me
[d]
3j
, 77% (R = OMe)
, 27%[e], 78%[g]
[d]
, 32%[e], 68%[f]
, 87%
, 83%
[c]
NO2
3o
, 65% (R = CF3)
3l
3n
3q
, 73%
3r
3s
, 72%
3k
, 43%[e], 60%[h]
[d]
3m
3p
, 95% (R = Br)
(R = NO2)
Me
O
Me
Me
CO2Et
Me
Br
Me
Me
N
Johnson's reagents
N
O
N
O
O
O
N
N
O
N
O
N
N
O
R S Ph
BF4
NMe2
Ph
N
Ph
N
Ph
N
N
N
O
Me
Me
Ph
Me
N
Me
Ph
Me
2d
2e
(R = cyclopropyl)
(R = Me)
Ph
Me
3t
3u, 40%[g]
3v, 65%[g]
3w, 61%[i]
3x
3y
, 77%
3z, 45%[j]
, 78%
, 70%
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10.1002/anie.202010958
Angewandte Chemie International Edition
COMMUNICATION
Scheme 2. Substrate scope for methylation and alkylation of pyrazinones. [a] Reaction conditions: 1a–1w (0.2 mmol), 2a–2e (0.6 mmol), KOH (3 equiv.), H2O (1
mL) under air at 100 oC for 2 h in reaction tubes. [b] Yield by flash column chromatography. [c] H2O/EtOH (1:1, 1 mL). [d] H2O/EtOH (5:1, 1 mL). [e] KOMe (3
equiv.), i-PrOH (1 mL). [f] K2CO3 (3 equiv.), i-PrOH (2 mL) at 80 oC for 3 h. [g] K2CO3 (3 equiv.), i-PrOH (2 mL) at 100 oC for 4 h. [h] K2CO3 (3 equiv.), i-PrOH (2
mL) at 100 oC for 8 h. [i] K2CO3 (3 equiv.), EtOH (2 mL) at 100 oC for 2 h. [j] EtOH (1 mL) at 100 oC for 6 h.
With the optimized reaction conditions in hand, the substrate
scope of pyrazinones was examined (Scheme 2). A wide range
of N-alkylated and N-benzylated pyrazinones 1b–1f were found
to be suitable substrates for this transformation, providing the
corresponding C3-methylated pyrazinones 3b–3f in high yields.
In addition, we observed the successful methylation of N-
arylated pyrazinones 1g–1l. It is noted that electron-deficient N-
aryl pyrazinones (1i, 1k and 1l) containing cyano, nitro, and 2-
pyridyl groups provided increased yields by using K2CO3 and i-
PrOH. The electronic effect on this transformation was likewise
observed for the C4-arylated pyrazinones 1m–1p. The complete
site-selective methylation was detected on nitroarene-containing
pyrazinones 1k and 1m, which would undergo vicarious
nucleophilic substitution (VNS) on electrophilic nitrobenzene ring.
Moreover, tri-substituted pyrazinone adduct 3q was formed
smoothly in 73% yield. Furthermore, the site-selective
methylation of 1r–1t was successfully achieved under the
standard reaction conditions, affording the corresponding
products 3r–3t in high yields. To highlight the synthetic value of
the developed method, the scope of functional group tolerance
was subsequently examined. To our delight, alkyl halide (1u),
enolizable carbonyl (1v), and ester (1w) groups were compatible
under the current reaction conditions. The tolerance of CN, NO2,
Br, ketone, and ester moieties presents valuable opportunities
for further versatile synthetic transformation. Having established
the broad scope of pyrazinones, sulfoxonium salts 2b–2e was
additionally evaluated. In the case of ethylation and propylation,
trialkyl sulfoxonium chlorides were employed as alkylating
agents to afford the corresponding products 3x (70%) and 3y
(77%). The current protocol could be implemented using
Johnson’s sulfoxonium salts[17] 2d and 2e, furnishing
cyclopropylated pyrazinone 3z (45%) and methylated
pyrazinone 3a (35%), respectively. In case of the reactions of
Johnson’s sulfoxonium salts, the starting material 1a was
recovered in 50% and 55% yields, respectively.
R1
N
R1
N
O
S
O
H
O
X
R
KOH, H2O
100 oC, 2 h
R2
R2
+
R
R
N
4a 4l
N
Me
[b]
2a, 2b and 2d
5a 5n
- , %
-
Ph
N
Me
N
R
Me
N
O
N
O
Cl
O
O
N
Me
N
Me
N
Me
N
Me
5a
5b
5c
5d
, 97%
5e
, 94%
, 100%
, 99% (R = n-Bu)
, 95% (R = i-Bu)
R
Me
Me
N
O
N
N
O
N
N
O
N
N
O
O2N
N
Me
Me
Me
Me
, 32%[c], 91%[d]
, 100% (R = OEt)
, 75%[d] (R = NO2)
, 97%
5f
5g
5i
5j
, 88%
5h
Me
Me
Me
Me
N
N
N
O
N
N
O
N
N
N
O
N
N
O
Me
Me
Me
5k, 42%[c], 75%[e]
5l, 78%
5m, 98%
5n, 60%
Scheme 3. Substrate scope of methylation and alkylation of quinoxalinones.
[a] Reaction conditions: 4a–4l (0.2 mmol), 2a, 2b and 2d (0.6 mmol), KOH (3
equiv.), H2O (1 mL) under air at 100 oC for 2 h in reaction tubes. [b] Yield by
flash column chromatography. [c] KOMe (3 equiv.), i-PrOH (1 mL). [d] K2CO3
(3 equiv.), i-PrOH (2 mL) at 100 oC for 3 h. [e] K2CO3 (3 equiv.), i-PrOH (2 mL)
at 80 oC for 3 h.
Azauracil, an azapyrimidinone analogue of uracil, is of
interest in medicinal chemistry due to its potential to inhibit
various species of microorganisms. The ribonucleosides of 6-
azauracil have been shown to display diverse biological profiles
such as antiviral, antitumor, and antifungal activities.[18] Based
on the methylation of uracil in nature, we envisioned the direct
alkylation of 6-azauracils and 6-azauracil nucleosides (Scheme
4). N,N’-Disubstituted azauracil 6a was smoothly alkylated with
2a–2c to afford the corresponding products 7a–7c in satisfactory
yields. In addition, triazinones 6b–6e were compatible with this
process. It is noteworthy that hydroxyl and 2-pyranosyl groups in
7e and 7g were also tolerable. Direct C(sp2)–H methylation of
azauracil ribonucleoside 6f was successfully achieved by using
K3PO4 as a base, providing 7h in 91% yield. Moreover, 2’-deoxy-
6-azauridine nucleoside 6g was also coupled with 2a–2c to
afford the corresponding nucleoside derivatives 7i–7k in good to
high yields.
Meanwhile, the scope of quinoxalinones 4a–4l was explored,
as shown in Scheme 3. N-Alkylated quinoxalinones 4a–4c and
N-benzylated quinoxalinone 4d were successfully reacted with
2a to provide C3-methylated quinoxalinone adducts 5a–5d in
excellent yields. Additionally, quinoxalinones 4e and 4f were
coupled with 2a to afford 5e (94%) and 5f (32%). As the reaction
of electron-deficient pyrazinones, the use of milder base, K2CO3,
provided the significantly increased formation of 5f in 91% yield
without the methylation on nitroarene ring. The reaction also
readily proceeded with N-arylated quinoxalinones 4g–4k,
furnishing the corresponding products 5g–5k in high yields.
Pyrido-pyrazinone 4l also participated in the methylation
reaction to provide 5l in 78% yield. Furthermore, N-butylated
quinoxalinone 4b was subjected to ethylation and
cyclopropylation, affording the corresponding products 5m
(98%) and 5n (60%), respectively.
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10.1002/anie.202010958
Angewandte Chemie International Edition
COMMUNICATION
R1
R1
N
A. Gram-scale reactions
O
O
N
O
H
O
O
Me
Me
X
R
KOMe, i-PrOH
S
R
+
O
R
N
O
N
O
H
80 oC, 2 h
N
N
I
KOH (3 equiv)
R2
R2
N
6a 6g
-
N
R
[b]
S
+
Me
Me
H2O, 100 oC, 2 h
2a 2c
7a 7k
-
-
, %
Me
Ph
N
Me
Ph
1a
N
2a
(2 g, 10.8 mmol)
Ph
(3 equiv)
3a
, 90%
Ph
Ph
Et
Ph
O
N
O
O
N
O
O
N
N
O
O
N
N
O
N
O
Ph
N
HO
N
I
KOH (3 equiv)
Me
N
R
N
Me
Me
S
+
Me
Me
H2O, 100 oC, 2 h
7a
7b
7c
, 75% (R = Me)
, 25%[c], 67%[d]
O
Me
[c]
7d
7e
, 54%
N
H
N
Me
[c]
, 64% (R = Et)
5d
[c]
, 95%
4d
2a
(1 g, 4.2 mmol)
(3 equiv)
, 62% (R = n-Pr)
Me
N
Me
Me
Me
N
B. Synthetic transformations
N
O
N
O
O
O
Me
O
N
OH
Me
O
N
O
N
O
N
BnO
N
Me
N
Me
N
O
NiBr2, KOtBu
+
EtO
Ph
N
OBn OBn
1,10-Phen, toluene
[e]
[e]
[f]
Ph
Ph
N
Me
7f
7g
7h
, 91%
, 69%
, 62%
Ar
NMe2
Me
8a
, 82%
O
N
O
N
Me
O
3a
Ar = Ph(m-NMe2)
Me
Me
Me
Me
N
N
N
O
N
N
N
O
O
Me
N
O
N
Me
O
O
N
NH
O
O
1) SeO2, 1,4-dioxane (78%)
BnO
BnO
BnO
N
2) 1-adamantylamine
NaBH3CN, CH2Cl2
OBn
OBn
N
Me
OBn
7k
Ph
[f]
[f]
[f]
3a
7i
7j
, 72%
, 94%
, 60%
Me
8b
, 40%
N
O
Scheme 4. Substrate scope for methylation and alkylation of azauracils and
nucleosides. [a] Reaction conditions: 6a–6g (0.2 mmol), 2a–2c (0.6 mmol),
KOMe (3 equiv.), i-PrOH (1 mL) under air at 80 oC for 2 h in reaction tubes. [b]
Yield by flash column chromatography. [c] 8 h. [d] K2CO3 (3 equiv.), i-PrOH (2
mL) at 100 oC for 24 h. [e] KOtBu (0.4 mmol), i-PrOH (2 mL), 5 min. [f] 2a–2c
(0.8 mmol), K3PO4 (0.6 mmol), i-PrOH (2 mL) at 100 oC for 24 h.
O
1) NBS, DCE (66%)
N
H
H
H
5a
2) estrone, K2CO3
MeCN
8c
, 50%
Me
O
Ar
O
S O
O
1) TFA, CH2Cl2 (90%)
2) NaH, DMF
α,β-Unsaturated ketones have been widely employed for the
cyclopropanation using Corey-Chaykovsky reagents in polar
organic solvents such as DMSO and MeCN. To further
demonstrate the chemoselectivity between iminoamido
heterocycles and α,β-unsaturated ketones, we performed the
intermolecular competition experiments of quinoxalinone 4a with
benzylideneacetone in aqueous media. Gratifyingly, sulfoxonium
ylide selectively reacted with 4a to provide 5a in 55% yield, and
100% of benzylideneacetone was recovered (Scheme 5).
Similar results were observed by using pyrazinone 1a and ethyl
cinnamate as an α,β-unsaturated ester (see the Supporting
Information for the details).
N
O
N
O
Ph
N
Me
Ph
N
Me
ClO2S
CF3
8d
, 60%
Ar = Ph(p-CF3)
3d
Scheme 6. Gram-scale reactions and synthetic transformations. 1,10-Phen =
1,10-phenanthroline. NBS = N-bromosuccinimide. DCE = 1,2-dichloroethane.
TFA = trifluoroacetic acid. DMF = dimethylformamide.
To illustrate the synthetic potential of the developed protocol,
gram-scale experiments were first performed (Scheme 6A). The
reaction of pyrazinone 1a (2 g, 10.8 mmol) with 2a afforded 3a in
90% yield. In addition, a gram-scale reaction of quinoxalinone
4d was also successfully performed, providing 5d in 95% yield.
It is noteworthy that both products 3a and 5d were isolated by
simple filtration instead of column chromatography, indicating
the capability of the developed method in process chemistry.
Next, various transformations of the synthesized C3-methylated
products were performed (Scheme 6B). The Ni(II)-catalyzed
cross-coupling reaction between 3a and benzyl alcohol gave 8a
in 82% yield. Benzylic oxidation of 3a with SeO2 followed by
reductive amination with 1-adamantylamine provided 8b in 40%
yield. In addition, benzylic bromination of 5a and subsequent O-
nucleophilic substitution with estrone furnished 8c in 50% yield.
To demonstrate the utility of the N-protecting group, the
Me
Me
N
O
H
N
O
4a
(42%)
recovered
2a
(1 equiv.)
+
N
4a
K2CO3 (1 equiv.)
H2O, 100 oC, 2 h
N
Me
5a
, 55%
+
O
O
+
Ph
Me
Ph
Me
100% recovered
benzylideneacetone
Scheme 5. Intermolecular competition experiment for chemoselectivity.
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10.1002/anie.202010958
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Scheme 7. [D]-Labeling experiments and proposed reaction mechanism.
tetrahydropyranoyl group on 3d was removed under acidic
conditions to provide the free-(NH)-pyrazinone adduct in 90%
yield, which further reacted with arylsulfonyl chloride to deliver
8d in 60% yield.
Based on the deuterium-labeling experiment results and
previous literature related to sulfoxonium ylides,[14,15] we propose
a plausible reaction mechanism (Scheme 7B). Sulfoxonium ylide
A, derived from 2a and KOH, undergoes nucleophilic addition
onto the imine moiety of 1a, generating intermediate B. Under
basic aqueous conditions, protonation of the nitrogen anion and
E2 elimination of intermediate B spontaneously occur to deliver
intermediate C and DMSO. The release of DMSO was detected
by GC-MS analysis of the crude reaction mixture.[20] Finally,
protonation of the exo-olefin in C occurs to afford the C3-
methylated pyrazinone 3a.
To garner mechanistic insights into this process, a series of
deuterium-labeling experiments were performed (Scheme 7A).
Treatment of 1a with KOH in the presence of D2O resulted in
45% and 94% deuterium incorporation at the C3 and C6
positions, respectively. Partial deuteration (20%) on the N–Me
group was also observed. These results indicate that
a
hydroxide anion possibly undergo nucleophilic addition onto
imino functionality of pyrazinone 1a to generate a nitrogen anion
intermediate, which can undergo a deuteration/deprotonation
equilibrium reaction at the C3 and C6 positions (see the
Supporting Information for the proposed mechanism). The
reaction of 1a with 2a in the presence of D2O under otherwise
identical reaction conditions provided 93% deuteration at the
benzylic CH3 moiety as well as 73% deuteration at the C6
position, suggesting C3-methylation by sulfoxonium ylide on 1a
followed by subsequent deproto-deuteration at the benzylic
position. Benzylic deuteration was further confirmed by the
reaction of 3a in aqueous KOH solution. To evaluate the unique
reactivity of pyrazinones as cyclic iminoamides, control
experiments were performed with N-aryl 2-pyridone and 2H-
benzo[b][1,4]oxazin-2-one.[19] No formation of methylated
adducts under the standard reaction conditions was observed,
revealing that the cyclic iminoamide backbone is crucial for the
C(sp2)–H methylation (see the Supporting Information for the
details).
To further demonstrate the utility of the developed
methodology, the sequential transformation of N-benzylated
pyrazinone 9a was performed (Scheme 8). Pyrazinone 9a was
smoothly methylated with 2a to provide 9b in 82% yield.
Removal of the benzyl group of 9b followed by treatment with
PhPOCl2 afforded chloropyrazine 9c in 79% yield. Finally,
Suzuki cross-coupling reaction between 9c and 2-thiophene
boronic acid under Pd(II) catalysis provided tetra-substituted
pyrazine 9d in 70% yield.
A. Deuterium-labeling experiments
94%
20%
CH3
N
CD3
N
O
D
O
D
KOH (1 equiv)
D2O, 100 oC, 12 h
45%
Ph
Ph
N
Ph
N
1a
deuterio-1a
, 90%
Scheme 8. Synthesis of tetra-substituted pyrazine. dppf
bis(diphenylphosphino)ferrocene.
=
1,1′-
73%
69%
CH3
N
CH3
2a
(3 equiv)
O
D
N
O
KOH (3 equiv)
D2O, 100 oC, 2 h
N
93%
Ph
N
CD3
In conclusion, we presented an unprecedented protocol for
the direct C–H alkylation of iminoamido N-heterocycles,
including pyrazinones, quinoxalinones, and azauracils, using
sulfoxonium salts as the alkylating agents. The use of aqueous
solvent in the coupling reaction and the selective methylation of
azauracil nucleosides under the developed reaction conditions
are noteworthy. The synthetic applicability of this method was
demonstrated by successful gram-scale reactions and valuable
synthetic transformations of the methylated products, as well as
by the synthesis of a tetra-substituted pyrazine via sequential
transformations. The findings of this study are expected to be of
significant interest to organic and medicinal chemists because of
the synthetic simplicity, broad substrate scope, high efficiency,
excellent chemoselectivity, and environmentally benign nature of
the developed methodology.
1a
deuterio-3a
, 96%
CH3
CH3
N
D
N
O
O
KOH (1.5 equiv)
D2O, 100 oC, 2 h
95%
OH
Ph
N
CD3
Ph
N
CH3
deuterio-3a'
, 95%
3a
B. Proposed reaction mechanism
Me
N
O
O
H
O
KOH
I
Me
1a
S
S
H2C
O
Me
Me
H2O
Ph
N
Me
Me
SMe2
H2O
O
2a
E2
DMSO
A
B
Me
N
Me
N
protonation
O
H2O
Ph
N
H
Ph
N
Me
C
3a
OH
Acknowledgements
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10.1002/anie.202010958
Angewandte Chemie International Edition
COMMUNICATION
K. Mishra, Y. H. Jung, S. J. Chung, I. S. Kim, Org. Lett. 2019, 21,
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This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MSIP)
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Heterocycles • Sulfur ylides.
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Entry for the Table of Contents
Key Topic: Methylation using sulfur ylides
COMMUNICATION
Prithwish Ghosh, Na Yeon Kwon,
Saegun Kim, Sangil Han, Suk Hun Lee,
Won An, Neeraj Kumar Mishra, Soo
Bong Han, and In Su Kim*
Page No. – Page No.
C–H Methylation of Iminoamido
Heterocycles with Sulfur Ylides
Text for Table of Contents
Sulfur ylides as C–H alkylation surrogates: An unprecedented methylation of various
iminoamido heterocycles using Corey-Chaykovsky reagents is described. The use of
aqueous solvent in the coupling reaction and the selective methylation and alkylation of
azauracil nucleosides are highlighted.
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