C2-Selective C-H methylation of heterocyclic N-oxides with sulfonium ylides

Article abstract of DOI:10.1021/acs.orglett.0c03403

A redox-neutral C2-selective methylation of heterocyclic N-oxides with sulfonium ylides is described herein. This report presents unprecedented findings for the utility of sulfonium ylides as the methylation source of N-heterocycles beyond the Corey-Chaykovsky reaction. Intriguingly, pyrrolidine plays a significant role in minimizing the reductive C2-methylation process. This method is characterized by its mild conditions, simplicity, and excellent site selectivity. The applicability of the developed protocol is showcased by the late-stage methylation and sequential transformations of complex drug molecules.

Full text of DOI:10.1021/acs.orglett.0c03403

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Letter
C2-Selective C−H Methylation of Heterocyclic N‑Oxides with
Sulfonium Ylides
Won An, Su Bin Choi, Namhoon Kim, Na Yeon Kwon, Prithwish Ghosh, Sang Hoon Han,
Neeraj Kumar Mishra, Sangil Han,* Sungwoo Hong,* and In Su Kim*
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ABSTRACT: A redox-neutral C2-selective methylation of heterocyclic N-oxides with sulfonium ylides is described herein. This
report presents unprecedented findings for the utility of sulfonium ylides as the methylation source of N-heterocycles beyond the
Corey−Chaykovsky reaction. Intriguingly, pyrrolidine plays a significant role in minimizing the reductive C2-methylation process.
This method is characterized by its mild conditions, simplicity, and excellent site selectivity. The applicability of the developed
protocol is showcased by the late-stage methylation and sequential transformations of complex drug molecules.
ulfur ylides are considered the privileged reagents for
carbon−carbon bond formation reactions in organic
In contrast to a strong P−O bond, our computational studies
revealed that the formation of aza-oxathiolanes was a
thermodynamically uphill process (>20 kcal/mol), whereas
the formation of corresponding aza-oxaphospholane was
observed to be exergonic (−5.3 kcal/mol), as shown in Scheme
1B.
S
synthesis. Since the pioneering work of Johnson, Corey, and
Chaykovsky in the 1960s,1 sulfur ylides have been extensively
utilized for cyclization reactions with electron-deficient π-
unsaturated compounds to afford a wide range of carbocyclic
and heterocyclic compounds.2 Mechanistically, the nucleophilic
addition of sulfur ylides into π-unsaturated compounds such as
carbonyl, imine, and α,β-unsaturated moieties leads to the
formation of betaine intermediates, which are decomposed by
O, N, and C anions via intramolecular nucleophilic substitution.
Recent advances have been made in the asymmetric synthesis of
oxiranes, aziridines, and cyclopropanes via organocatalysis,3
photocatalysis,4 Lewis acid catalysis,5 or transition-metal
catalysis.6 Asymmetric [2,3]-sigmatropic rearrangements of
sulfur ylides (Doyle−Kirmse reaction) have been also explored.7
Moreover, the applicability of sulfur ylides to the synthesis of
various natural products and pharmaceuticals has been ex-
plored.1,8 Sulfur-linked carbanions have been well studied in the
vicarious nucleophilic substitution (VNS) reaction on nitro-
arenes and N-heteroaromatic compounds, reported by
Makosza.9 Very recently, our group described the reductive
C2-alkylation of heterocyclic N-oxides using phosphonium
ylides.10 In this reaction, a concerted [3 + 2] cycloaddition
between a 1,3-dipolar fragment of heterocyclic N-oxides and
zwitterionic phosphonium ylides provides aza-oxaphospholane
intermediates, which subsequently undergo aromatization to
give reductive C2-alkylated N-heterocycles (Scheme 1A). A key
driving force in this protocol might be the formation of a strong
P=O bond (Ph3P=O bond dissociation energy = 529 kJ/mol).
Based on theoretical studies of the reactivity between
phosphonium and sulfonium ylides,11 we envisioned that the
reaction of heterocyclic N-oxides with sulfonium ylides can
generate betaine intermediates instead of aza-oxathiolanes
because of the weak S−O bond. These betaine intermediates
can undergo E2-elimination, followed by aromatization, to
furnish redox-neutral C2-methylated N-oxides. It is noteworthy
that a distinguished pathway between phosphonium ylides and
sulfonium ylides can be of significant advantage to organic and
medicinal chemists for the direct C−H functionalization of N-
heterocycles.12 Importantly, C2-functionalized heterocyclic N-
oxides derived from the reaction of sulfonium ylides can be
utilized for further transformations, e.g., Boekelheide rearrange-
ment and metal-catalyzed C8-functionalization of quinoline N-
oxides. Herein, we report the metal-free and redox-neutral C−H
methylation of heterocyclic N-oxides with sulfonium ylides.
Received: October 12, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03403
© XXXX American Chemical Society
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A

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screening of various bases and solvents, we found that the use of
KOtBu in THF promoted the coupling of 1a and 2a to provide a
separable mixture of redox-neutral and reductive C2-methylated
products 3a and 3aa in a combined yield (71%), albeit with
moderate selectivity (1.7:1 ratio), as shown in entry 1. After
further optimization, we found that pyrrolidine as an additional
base facilitated high levels of efficacy (91%) and selectivity (15:1
ratio) for the formation of 3a (entry 6). A control experiment
revealed that the combined use of KOtBu and pyrrolidine is
indispensable for the coupling of 1a and 2a (entry 9). In
addition, 3a was formed within 3 h in 95% yield with high
chemoselectivity (18:1), as shown in entry 10. Gratifyingly, this
transformation could also proceed under milder reaction
conditions (40 °C), providing 3a in 92% yield and with an
>20:1 ratio (entry 11). It is noted that and trimethylsulfoxonium
iodide (Me3SOI) was also reactive to provide 3a in 49% yield
with an >20:1 ratio, and 50% of starting material 1a was
recovered (entry 12). Moreover, this reaction could be carried
out on a 1 g scale to afford 3a in 84% yield with an almost
identical chemoselectivity of >20:1 (entry 13).
Scheme 1. C−H Methylation of Heterocyclic N-Oxides Using
Phosphonium vs. Sulfonium Ylides
The substrate scope of heterocyclic N-oxides under the
optimized reaction conditions was examined, as shown in
Scheme 2. Quinoline N-oxides (1b) could be smoothly coupled
with 2a to afford the redox-neutral C2-methylated product 3b in
78% yield along with a trace amount of reductive product 3ba. A
regioisomeric N-oxide, isoquinoline N-oxide (1c), also partici-
Notably, the late-stage methylation and sequential trans-
formations of complex bioactive molecules such as quinidine,
fasudil, and hydroquinidine demonstrate the applicability of the
developed methodology to drug discovery.
a
Scheme 2. Scope of Heterocyclic N-Oxides
We commenced our investigation by performing the coupling
reaction of 6-methoxyquinoline N-oxide (1a) and trimethylsul-
fonium iodide (2a). The results are listed in Table 1. After
a
Table 1. Selected Optimization of the Reaction Conditions
ratio (3a/
b
entry
base (equiv)
solvent
THF
1,4-dioxane
DMSO
THF
yield
3aa)
1
2
3
4
5
6
7
8
9
KOtBu (2)
71
25
1.7:1
3.1:1
-
3.3:1
2.7:1
15:1
-
8.8:1
-
18:1
>20:1
>20:1
>20:1
KOtBu (2)
KOtBu (2)
N.R.
85
KOtBu (2), DIPA (2)
KOtBu (2), Et3N (2)
THF
81
91
KOtBu (2), pyrrolidine (2) THF
KOtBu (2), pyridine (2)
KOtBu (2), pyrrolidine (1) THF
pyrrolidine (4) THF
THF
N.R.
95
N.R.
95
c
10
11
12
KOtBu (2), pyrrolidine (2) THF
KOtBu (2), pyrrolidine (2) THF
KOtBu (2), pyrrolidine (2) THF
KOtBu (2), pyrrolidine (2) THF
d
92
49
84
e
f
13
a
a
Reaction conditions: 1a (0.4 mmol), 2a (1.2 mmol), base (quantity
noted), and solvent (2 mL) at 80 °C in an oil bath for 16 h under air
Reaction conditions: 1b−n (0.4 mmol), 2a (1.2 mmol), KOtBu (0.8
mmol), pyrrolidine (0.8 mmol), and THF (2 mL) at 40 °C in an oil
bath for 16 h under air atmosphere in pressure tubes. Isolated yield
b
b
atmosphere in pressure tubes. Isolated yield by flash column
chromatography. The reaction was carried out for 3 h. The reaction
was carried out at 40 °C in an oil bath. Me3SOI (1.2 mmol) was used
instead of 2a. Gram-scale (1 g, 5.7 mmol) experiment. DIPA =
c
d
c
by flash column chromatography. Ratio between redox-neutral and
e
d
reductive products was determined by crude 1H NMR analysis. The
f
e
reaction was carried out at 80 °C in an oil bath for 3 h. The reaction
was carried out in t-BuOH at room temperature for 16 h.
diisopropylamine.
B
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pated in the C−H methylation reaction at 80 °C to exclusively
provide 3c in 74% yield. Complete site selectivity at the more
electrophilic C1-position was observed. This reaction was also
compatible with quinoxaline N-oxide (1d), a structural isostere
of 1b, delivering 3d in 80% yield. In the case of the sterically
congested 3,5-disubstituted pyrazine N-oxide, C2-selective
methylation of 1e occurred, presumably due to both steric and
electronic effects, and 60% of the starting material 1e was
recovered. Additionally, 5,6-benzoquinoline N-oxide (1f)
successfully reacted with 2a, furnishing the redox-neutral adduct
3f (76%) and reductive adduct 3fa (4%). In the case of 4-methyl
quinoline N-oxide (1g), a 2:1 ratio between 3g and 3ga was
observed. The reaction of 3,4-benzoquinoline N-oxide (1h)
provided the almost identical amount of redox-neutral product
3h (46%) and reductive adduct 3ha (46%). The incomplete
chemoselectivity for 3h could be rationalized by the competitive
aromatization over E2-elimination of the betaine intermediate.
Moreover, halogen substituents in 1i and 1j were tolerated
under the current reaction conditions. To our delight, C8-
substituted quinoline N-oxides 1k and 1l also underwent site-
selective and redox-neutral methylation reactions to give the
corresponding products. Surprisingly, unprotected 8-amino and
8-hydroxyl quinoline N-oxides 1m and 1n were found to be
good substrates for this transformation. Note that 8-amino-
quinoline is a pivotal core found in biologically relevant
molecules and bidentate ligands.13 Therefore, our developed
method would encourage organic and medicinal chemists to
attempt the C2-functionalization of 8-aminoquinoline deriva-
tives for preparing valuable medicinal and industrial compounds.
Having demonstrated the scope of heterocyclic N-oxides, we
performed the reaction of quinoxaline N-oxide (1d) with
diphenyl cyclopropylsulfonium salt 2b (Scheme 3). We were
Scheme 4. Late-Stage C−H Methylations of Bioactive
Molecules
Scheme 5. Sequential Transformation Using Hydroquinidine
Scheme 3. Cyclopropylation of Quinoxaline N-Oxide
methylation. The Boekelheide rearrangement14 of 6c afforded
the reductive C2-methylated hydroquinidine derivative 6d in
70% yield. These results can serve as a guide for the tentative
derivatization of quinine-based antimalarial and antiarrhythmic
agents in drug discovery.
Next, we carried out a series of transformations to
functionalize the benzylic and C8−C−H bonds of the
synthesized C2-methylated quinoline N-oxide 3b assisted by
an N-oxide group (Scheme 6). The reaction of 3b with 7a
derived from NSAID celecoxib under basic conditions resulted
in the formation of 8a (70%) via nucleophilic addition and a
subsequent dehydration reaction (eq 1). The Rh(III)-catalyzed
C−H arylation and Pd(II)-catalyzed C−H acylation of 3b with
diazo compound 7b and α-keto acid 7c afforded 8b (95%) and
8c (65%), respectively (eqs 2 and 3). The 8-aminated quinoline
adduct 3l was also obtained in 94% yield by the Ir(III)-catalyzed
C−H amination reaction,15 which can be an alternative route for
the synthesis of 8-aminoquinolines (eq 4).
To gain mechanistic insights into this transformation, we
performed the reaction of deuterium-labeled quinoline N-oxide
(deuterio-1b) with 2a under the standard reaction conditions
(Scheme 7). No deuterium incorporation at the benzylic
position was observed, suggesting that the intramolecular
deuterium 1,2-migration in the reaction pathway is completely
excluded (eq 1). To recognize the fate of sulfonium salts, we
performed the reaction of 1d with 1 equiv of 2b. Product 3o and
diphenyl sulfide 9a were obtained in almost identical yields,
pleased to observe the formation of cyclopropylated quinoxaline
N-oxide 3o in 91% yield. A trace amount of reductive C2-
cyclopropylated product 3oa was observed. However, linear
alkylsulfonium salts such as Et3SCl, EtPh2SBF4, and (n-Bu)3SI
were unreactive under the current reaction conditions.
The applicability of the developed protocol is highlighted by
the late-stage C−H methylation reaction of biologically
important N-heterocyclic molecules, as shown in Scheme 4.
For example, the antiarrhythmic O-methylated quinidine N-
oxide (4a) was readily methylated by using increased amounts
(5 equiv) of KOtBu, pyrrolidine, and 2a to afford 5a in 94% yield
(eq 1). It is noted that the reaction provided 5a in 42% yield and
starting material 4a in 46% yield under the standard reaction
conditions. In addition, a fasudil derivative as a RhoA/Rho
kinase inhibitor smoothly reacted with 2a to give the desired
product 5b in 77% yield (eq 2).
Subsequently, we performed the sequential transformation of
hydroquinidine (6a) to demonstrate the utility of the developed
method (Scheme 5). Treatment of 6a with m-CPBA followed by
the reduction of quinuclidine N-oxide furnished 6b in 90%
overall yield. The gram-scale methylation reaction of hydro-
quinidine N-oxide (6b) provided 6c in 92% yield. Interestingly,
the reaction resulted in both C2-methylation and O-
C
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Scheme 6. Synthetic Transformations of C2-Methylated
Quinoline N-Oxide
Figure 1. Free-energy profile for the redox-neutral C2-methylation of
heterocyclic N-oxides with sulfonium ylides. Red traces represent the
direct E2 pathway. Blue traces represent the pyrrolidine-assisted SN2
reaction, followed by the E2 pathway.
as a good leaving group in the nucleophilic substitution reaction
with pyrrolidine to form II′, which simultaneously engages in
E2-elimination reactions to ultimately yield intermediate III.
Our calculations indicate that the direct E2-elimination reaction
proceeds via transition state I-TS, leading to intermediate III
with an energy barrier of 18.2 kcal/mol. On the other hand, the
transition state I′-TS leading to the substitution pathway is
found to be 7.2 kcal/mol higher in free energy than I-TS,
suggesting that the most reasonable reaction pathway involves
the direct E2-elimination by pyrrolidine.
Scheme 7. Mechanistic Investigations
In conclusion, we have described the redox-neutral C2-
methylation of heterocyclic N-oxides with sulfonium ylides.
From a mechanistic perspective, sulfonium ylides can undergo
nucleophilic addition into 1,3-dipolar N-oxides to generate
betaine intermediates, which subsequently undergo E2-elimi-
nation and aromatization, providing redox-neutral C2-methy-
lated N-oxides. It is noteworthy that a distinguished pathway
between phosphonium ylides and sulfonium ylides would be
advantageous for the functionalization of heterocyclic N-oxides.
Excellent site-selectivity and broad functional group tolerance
were observed. In particular, the late-stage methylation and
sequential transformations of complex drug molecules highlight
the applicability of the developed method.
indicating that dimethylsulfide or diarylsulfide are generated by
C−S bond cleavage (eq 2).
As indicated by entries 6, 8, 10, and 11 in Table 1, the use of
pyrrolidine likely facilitates the redox-neutral C−H methylation
and minimizes the reductive C2-methylation process. To better
understand the role of pyrrolidine in the redox-neutral C2-
methylation, we carried out quantum chemical calculations
based on the density functional theory (DFT). The energy
profile is presented in Figure 1 (see the Supporting Information
for details).
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03403.
The reaction commences with the addition of a sulfonium
ylide to the heterocyclic N-oxide to generate betaine
intermediate I. As shown in Figure 1, two reaction modes can
be envisioned. We first investigated whether the direct E2-
elimination of dimethyl sulfide could proceed for the formation
of intermediate III. The betaine intermediate I makes a
hydrogen-bonding interaction with pyrrolidine, which gives a
slightly less stable intermediate at 1.5 kcal/mol (see Figure S1 in
the SI) followed by direct E2-elimination to afford III. Next,
aromatization furnishes the redox-neutral C2-methylated N-
oxide product 3b. Alternatively, the pathway through the
nucleophilic attack of pyrrolidine could proceed for the
formation of intermediate III. Indeed, dimethyl sulfide behaves
Experimental procedures, characterization data, computa-
1
tional details on DFT calculation, and H, 13C, and 19F
NMR spectra for all products (PDF)
FAIR data, including the primary NMR FID files, for
compounds 3a−o, 3aa, 3fa−ia, 5a,b, 6c,d, 8a−c, and
deuterio-1b (ZIP)
AUTHOR INFORMATION
Corresponding Authors
■
Sangil Han − School of Pharmacy, Sungkyunkwan University,
Suwon 16419, Republic of Korea; Email: win3wina@
naver.com
D
https://dx.doi.org/10.1021/acs.orglett.0c03403
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Letter
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Electrophilic Reactivities of α,β-Unsaturated Iminium Ions. Angew.
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P.; An, J.; Yao, C.-J.; Ming, Z.-H.; Xiao, W.-J. A New Entry to Cascade
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Sequentially Catalyzed by Thiourea and DMAP. J. Am. Chem. Soc.
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Sungwoo Hong − Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science (IBS), Daejeon
34141, Republic of Korea; Department of Chemistry, Korea
Advanced Institute of Science and Technology (KAIST), Daejeon
34141, Republic of Korea; orcid.org/0000-0001-9371-
1730; Email: hongorg@kaist.ac.kr
In Su Kim − School of Pharmacy, Sungkyunkwan University,
Suwon 16419, Republic of Korea; orcid.org/0000-0002-
2665-9431; Email: insukim@skku.edu
Authors
Won An − School of Pharmacy, Sungkyunkwan University, Suwon
16419, Republic of Korea
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Su Bin Choi − School of Pharmacy, Sungkyunkwan University,
Suwon 16419, Republic of Korea
Namhoon Kim − Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science (IBS), Daejeon
34141, Republic of Korea; Department of Chemistry, Korea
Advanced Institute of Science and Technology (KAIST), Daejeon
34141, Republic of Korea
Na Yeon Kwon − School of Pharmacy, Sungkyunkwan University,
Suwon 16419, Republic of Korea
Prithwish Ghosh − School of Pharmacy, Sungkyunkwan
University, Suwon 16419, Republic of Korea
Sang Hoon Han − School of Pharmacy, Sungkyunkwan
University, Suwon 16419, Republic of Korea
Neeraj Kumar Mishra − School of Pharmacy, Sungkyunkwan
University, Suwon 16419, Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03403
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by National Research Foundation of
Korea (NRF) grants funded by the Korea government (MSIT)
(Nos. 2019R1A4A2001451 and 2020R1A2C3005357) and the
Institute for Basic Science (IBS-R010-A2).
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