Isothiourea-Catalyzed Atroposelective N-Acylation of Sulfonamides

Article abstract of DOI:10.1021/acs.orglett.0c02266

We report herein an atroposelective N-acylation of sulfonamides using a commercially available isothiourea catalyst, (S)-HBTM, with a simple procedure. The N-sulfonyl anilide products can be obtained in good to high enantiopurity, which represents a new axially chiral scaffold. The application of the product as a chiral iodine catalyst is also demonstrated for the asymmetric α-oxytosylation of propiophenone.

Full text of DOI:10.1021/acs.orglett.0c02266

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Letter
Isothiourea-Catalyzed Atroposelective N‑Acylation of Sulfonamides
Jun-Yang Ong,⊥ Xiao Qian Ng,⊥ Shenci Lu,* and Yu Zhao*
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ABSTRACT: We report herein an atroposelective N-acylation of
sulfonamides using a commercially available isothiourea catalyst,
(S)-HBTM, with a simple procedure. The N-sulfonyl anilide
products can be obtained in good to high enantiopurity, which
represents a new axially chiral scaffold. The application of the
product as a chiral iodine catalyst is also demonstrated for the
asymmetric α-oxytosylation of propiophenone.
(Scheme 1b). However, the strategy of atroposelective N-
acylation of these substrates remains elusive in the literature.
Enantioselective acylation of alcohols and phenols has been
developed as a powerful tool in asymmetric catalysis.8 In
contrast, asymmetric acylation of amine-based nucleophiles is
significantly more challenging due to the higher nucleophilicity
of nitrogen, resulting in stronger background reactivity. In
recent years, great advancement in this topic of research has
been made by the groups of Fu,9 Seidel,10 and Bode11 in the
kinetic resolution of amines. The Birman group,12 the Bolm
group,13 and the Miller group14 also developed catalytic
asymmetric N-acylation of lactams, sulfoximines, and (thio)-
formamides, respectively. We report herein an unprecedented
atroposelective N-acylation of sulfonamides by the use of a
simple procedure catalyzed by commercially available iso-
thiourea (S)-HBTM (Scheme 1c).15 The chiral N-sulfonyl
anilides accessed in this study represent a new axially chiral
scaffold bearing a C−N bond axis. Notably, our products
typically bear an iodine substituent, the utility of which for
asymmetric iodine catalysis was demonstrated in an asymmeric
α-oxytosylation of propiophenone.
tropoisomerism, a form of chirality arising from restricted
Arotation around a bond axis, has been a topic of great
interest to chemists since its discovery in 1922.1 One particular
class of compounds containing atropoisomerism along a C−N
bond axis, namely, tertiary anilides and sulfonamides, has
received more attention in the past decades due to the
discovery of their roles in medicinal and agricultural chemistry
(Scheme 1a).2 Because of their intrinsic value, many
asymmetric catalytic reactions had been developed for the
synthesis of these tertiary anilides and sulfonamides, including
but not limited to conjugate addition,3 oxidation,4 cyclo-
addition,5 bromination,6 and N-alkylation or arylation7
Scheme 1. Atropoisomeric Anilides and Sulfonamides
Our group has been interested in the enantioselective
acylation of alcohols and phenols with the use of N-
heterocyclic carbenes as the catalyst.16 Very recently, together
with the Kurti group, we have also successfully achieved the
first atroposelective N-alkylation of sulfonamides (such as 1a in
Scheme 2) to prepare axially chiral N-alkyl sulfonamides.7j In
an effort to access new variations of this intriguing axially chiral
scaffold, we decided to examine asymmetric acylation of this
sulfonamide instead, which was unprecedented for this class of
N-based nucleophiles. Initial investigation involved the
Received: July 8, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02266
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
Scheme 2. Screening of Various Catalysts for
Atroposelective N-Acylation of Sulfonamide 1
Table 1. Optimization of Atroposelective Acylation
b
c
entry
catalyst
base
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
C1
C2
C3
C2
C2
C2
C2
C2
C2
C2
C2
−
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
KOtBu
DIPEA
Na2CO3
Na2CO3
CH2Cl2
CH2Cl2
CH2Cl2
THF
toluene
MeCN
CPME
CPME
CPME
CPME
CPME
CPME
CPME
87
92
97
53
95
89
83
36
76
36
80
81
15
84
85
80
62
82
−
d
85 (73 )
9
97
97
80
3
10
11
12
e
13
C2
23
76
a
reaction of sulfonamide 1a with trans-cinnamaldehyde 2 under
oxidative NHC catalysis conditions (Scheme 2a), which
unfortunately resulted in minimal reactivity with no
enantioselectivity for product 4a. We then switched to the
more classical asymmetric acylation using an anhydride 3a as
the reagent (Scheme 2b). Early efforts using cinchona alkaloid-
based nucleophilic amine catalysts, planar chiral DMAP, and
amidine type all proved to be futile. To our delight, the
promising reactivity and enantioselectivity for 4a (87% yield
and 36% ee) were finally obtained when an isothiourea
catalyst,17 (R)-BTM first developed by the Birman group,18
was used.
The reaction was conducted using 1 (1.0 equiv), 3a (1.5 equiv), a
catalyst (10 mol %), a base (2.0 equiv), and 4 Å molecular sieves in
b
solvent (0.075 M) under N2 at 25 °C, unless stated otherwise. 1H
NMR yield using 1,3,5-trimethoxybenzene as an internal standard.
c
d
Determined by HPLC with a chiral stationary phase. Isolated yield.
Conducted at 0 °C instead.
e
With the optimal conditions in hand, the scope of various
substituted anhydrides 3 for the reaction with 1a was examined
first (Scheme 3). Similar to model product 4a, both electron-
donating methoxy (OMe) and electron-withdrawing fluorine
a
We then proceeded with the screening of various parameters
to further optimize the reaction (Table 1). The use of other
commercially available isothiourea catalysts, (S)-HBTM and
HyperBTM developed by the groups of Birman19 and Smith,20
respectively, afforded better yields (entries 2 and 3,
respectively), but only (S)-HBTM could give an improved
enantioselectivity of 76% (entry 2).21 Screening of the solvents
revealed that cyclopentyl methyl ether (CPME) was the
optimal choice (entries 4−7), giving a slightly improved 84%
ee. The use of Na2CO3 furnished the product in a good 85%
yield (73% isolated yield) and 85% ee (entry 8), while the use
of strong inorganic bases such as Cs2CO3 and KOtBu gave
almost quantitative yields but decreased ee values (entries 9
and 10, respectively). The use of a weak organic base, DIPEA,
did not improve the experimental results further (entry 11). A
control reaction (entry 12) showed that background reaction,
although low, is still present despite the use of a strongly
electron-withdrawing nosyl protecting group, thus hindering
our efforts to improve the enantioselectivity further. Finally, in
an attempt to eliminate the background reaction, we tried to
decrease the reaction temperature to 0 °C (entry 13), but that
led to a drastic decrease in the yield of the product and a mild
erosion of enantioselectivity, likely due to the decrease in the
reactivity of the catalyst. We then decided to adopt the set of
reaction conditions in entry 8 as the optimal conditions for
further investigation.
Scheme 3. Substrate Scope for Various Anhydrides 3
a
See the Supporting Information for the detailed procedure.
Performed with 20 mol % catalyst. Reaction time of 96 h.
b
c
B
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substituents on the phenyl ring were well tolerated to yield 4b
and 4c with similar levels of enantioselectivities. Fused 1-
naphthyl-substituted 4d was also accessed with high efficiency
and enantioselectivity. Anhydrides with an alkyl chain or
heteroaromatic ring at the β position also participated in the
reaction with an excellent level of reactivity but suffered an
erosion in enantioselectivity to 65% and 72% for 4e and 4f,
respectively. Reaction with benzoic anhydride produced 4g
with a good level of enantioselectivity, but the reaction was
sluggish and required a reaction time of 96 h, possibly due to
the greater steric bulk of the phenyl ring. Alkyl anhydrides were
also tested, which successfully yielded 4h and 4i with good
levels of reactivity and enantioselectivity (80−88% ee). The
desired products could be obtained in an enantiopure form
after recrystallization as demonstrated by 4c and 4i (Scheme
3). The absolute configuration of 4c was unambiguously
assigned by single-crystal X-ray analysis. The configurations of
other products in Scheme 3 were assigned by analogy.
worked out well to deliver 4o and 4p in high yield and good
ee’s of 81−84%. These compounds can serve as a versatile
springboard for accessing other valuable analogues by cross
coupling. Finally, when the nosyl protecting group on the
nitrogen atom was changed to one with either the meta-nitro
or the para-chloro substituent, the reaction proceeded with
similar levels of reactivity and selectivity for 4q and 4r.
Additionally, we were happy to observe that a substrate with a
small mesyl protecting group also worked well in this reaction
to yield 4s in 84% ee.
To demonstrate the practical utility of the method, the
reaction of 1a and 3a was carried out at a larger scale of 0.5
mmol. To our satisfaction, 4a was isolated with an improved ee
of 90% albeit in a slightly lower yield of 60%.
It is noteworthy that during the investigation of the substrate
scope, several limitations were discovered (Scheme 4). First,
changing the iodine to a small chlorine atom yielded the
desired product 4t that has no stable atropoisomerism,
suggesting that the chlorine atom is too small to provide a
sufficient rotation barrier along the C−N axis. Second, we
discovered by achiral 4u and 4v that both the ortho positions of
the substrate are needed to provide a rotation barrier that is
sufficiently high for both atropoisomers to exist.
We then turned our attention to the scope of substituted
sulfonamides 1 (Scheme 4). By changing the para substituent
a
Scheme 4. Substrate Scope for Various Sulfonamides 1
To demonstrate the synthetic utility of our methodology, we
tested products 4 as a potential enantioselective iodine catalyst
for the asymmetric α-oxytosylation of propiophenone,22 which
was previously attempted as an application from the group of
Li and Cheng.7h As illustrated by selected data in Scheme 5,
Scheme 5. Use of Product 4 as an Iodine Catalyst
compared to the benchmark of 21% enantiospecificity (e.s.)
from the use of iodine 6, a simple switch of the N-alkyl
substituent to nosyl as in 4g led to a similar level of 24% e.s.
More attempts showed that the identity of the N-acyl unit had
an important influence on enantioselectivity. The use of 4i and
4c bearing an ethyl or a styrenyl group improved the
enantioselectivity of 7 to 40% and 52% e.s., respectively.
This serves as an important proof of concept that our product
could be used as an iodine catalyst with catalytic turnover and
moderate enantioselectivity.
In conclusion, we have developed an efficient and
atroposelective acylation of sulfonamides to yield N-sulfonyl
anilides with a novel axially chiral scaffold. The reaction was
facilitated by a commercially available isothiourea catalyst, (S)-
HBTM, and the potential of the product as an iodine catalyst
was also demonstrated. The development of other novel axially
chiral entities is currently underway in our laboratory.
a
See the Supporting Information for the detailed procedure.
b
Performed with 20 mol % catalyst.
of the aryl unit to either phenyl or other halogens, we
produced products 4j−4m with good to high efficiency. The
level of enantioselectivities for this series of products, however,
decreased to 71−79%. Not surprisingly, keeping one of the
ortho substituents on the aryl unit as a small methyl gorup was
needed for the good enantioselectivity. For ethyl-substituted
product 4n, a much lower ee of 49% was obtained, which was
probably due to the diminished size difference between the
two ortho substituents in this substrate (Me/I vs Et/I). To our
gratification, changing the ortho iodine substituent to bromine
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02266.
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CCDC 2015027 contains the supplementary crystallographic
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AUTHOR INFORMATION
Corresponding Authors
■
Shenci Lu − Department of Chemistry, National University of
Singapore, Republic of Singapore 117543; Shaanxi Key
Laboratory of Flexible Electronics, Northwestern Polytechnical
University, Xi’an 710072, China; Email: iamsclu@
nwpu.edu.cn
Yu Zhao − NUS Graduate School for Integrative Sciences &
Engineering (NGS) and Department of Chemistry, National
University of Singapore, Republic of Singapore 119077; Joint
School of National University of Singapore and Tianjin
University, Binhai New City, Fuzhou 350207, China;
orcid.org/0000-0002-2944-1315; Email: zhaoyu@
nus.edu.sg
Authors
Jun-Yang Ong − NUS Graduate School for Integrative Sciences
& Engineering (NGS) and Department of Chemistry, National
University of Singapore, Republic of Singapore 119077
Xiao Qian Ng − Department of Chemistry, National University
of Singapore, Republic of Singapore 117543
(8) (a) Li, X.; Jiang, H.; Uffman, E. W.; Guo, L.; Zhang, Y.; Yang, X.;
Birman, V. B. J. Org. Chem. 2012, 77, 1722−1737. (b) Taylor, J. E.;
Bull, S. D.; Williams, J. M. Chem. Soc. Rev. 2012, 41, 2109−2121.
(c) Zell, D.; Schreiner, P. R. In Comprehensive Organic Synthesis II;
2014; pp 296−354. (d) Lu, S.; Poh, S. B.; Ong, J. Y.; Zhao, Y. In N-
Heterocyclic Carbenes in Organocatalysis; Biju, A. T., Ed.; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, Germany, 2019; pp 287−
308.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02266
Author Contributions
⊥J.-Y.O. and X.Q.N. contributed equally to this work.
Notes
(9) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem., Int. Ed.
2001, 40, 234−236.
The authors declare no competing financial interest.
(10) (a) De, C. K.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009,
131, 17060−17061. (b) Klauber, E. G.; De, C. K.; Shah, T. K.; Seidel,
D. J. Am. Chem. Soc. 2010, 132, 13624−13626. (c) De, C. K.; Seidel,
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2012, 14, 3084−3087. (g) Seidel, D. Synlett 2014, 25, 783−794.
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2011, 133, 19698−19701. (b) Kreituss, I.; Murakami, Y.; Binanzer,
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ACKNOWLEDGMENTS
■
The authors are grateful for the generous financial support
from the Ministry of Education of Singapore (R-143-000-A94-
112) and the National University of Singapore (R-143-000-
A57-114) to Y.Z., Natural Science Basic Research Plan in
Shaanxi Province of China (2020JM-107) to S.L., and the
NUS Graduate School for Integrative Sciences & Engineering
(NGS) for a scholarship to J.-Y.O.
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