N-Heterocyclic Carbene-Catalyzed Atroposelective Annulation for Access to Thiazine Derivatives with C?N Axial Chirality

Article abstract of DOI:10.1002/anie.202010606

A catalytic atroposelective cycloaddition reaction between thioureas and ynals is developed. This reaction features the first NHC-catalyzed addition of thioureas to acetylenic acylazolium intermediates to eventually set up C?N axial chirality with excellent optical purities. The obtained axially chiral thiazine derivative products bear multiple functional groups and are feasible for further transformations.

Full text of DOI:10.1002/anie.202010606

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Communications
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 9362–9367
International Edition:
German Edition:
doi.org/10.1002/anie.202010606
doi.org/10.1002/ange.202010606
Organocatalysis
N-Heterocyclic Carbene-Catalyzed Atroposelective Annulation for
ꢀ
Access to Thiazine Derivatives with C N Axial Chirality
Tingting Li+, Chengli Mou+, Puying Qi, Xiaolin Peng, Shichun Jiang, Gefei Hao, Wei Xue,
Song Yang, Lin Hao, Yonggui Robin Chi, and Zhichao Jin*
Abstract: A catalytic atroposelective cycloaddition reaction
between thioureas and ynals is developed. This reaction
features the first NHC-catalyzed addition of thioureas to
ꢀ
acetylenic acylazolium intermediates to eventually set up C N
axial chirality with excellent optical purities. The obtained
axially chiral thiazine derivative products bear multiple func-
tional groups and are feasible for further transformations.
T
hiazine is an important heterocyclic structural motif that
accounts for bioactivities with significant applications in
medicines[1] and agricultural chemicals[2] (Figure 1a). For
example, cephalosporins such as Cefradine contain thiazine
fragments and have found wide uses as human drugs to cure
and / or prevent bacterial infections.[1a,b] Omonasteine is
a simple carboxylic acid bearing a hydrothiazine moiety and
can be used in the treatment of respiratory diseases.
Buprofezin[2a] is a commercially available and extensively
used pesticide for the protection of crops from various insects.
Therefore, many thiazine derivatives, either in achiral or
enantiomerically enriched forms, have received considerable
attentions in synthetic chemistry and relevant fields.[3] To
date, most of the chiral thiazine derivatives are obtained
through the introduction of central chirality.[3d–f,h] On the
other hand, it has been well established that molecules with
axial chirality show exceptional performance in a broad range
of areas such as catalysis[4] and medicines.[5]
Here we report an N-heterocyclic carbene (NHC) cata-
lytic approach for atroposelective access to axially chiral
thiazine derivatives (Figure 1b). The nitrogen atom of the
Figure 1. Bioactive thiazine derivatives and NHC-catalyzed atroposelec-
tive heteroatom cycloaddition reaction.
ꢀ
thiazine moiety is directly installed as part of chiral C N axis
via a face-selective process. It is worth noting that the
ꢀ
atroposelective synthesis with C N chiral axes is an important
[*] T. Li,[+] P. Qi, X. Peng, S. Jiang, Prof. Dr. G. Hao, Prof. Dr. W. Xue,
Prof. Dr. S. Yang, Prof. Dr. Y. R. Chi, Prof. Dr. Z. Jin
Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University
Guiyang 550025 (China)
topic in synthetic chemistry.[6] For instance, Miller,[6e–g]
Gustafson[6k] and co-workers developed organocatalytic atro-
poselective bromination reactions for the formation of chiral
[6a,b]
ꢀ
C N axes. Jørgensen,
Tan,[6h] Zhang,[6j] and Yang[6l]
reported the syntheses of axially chiral N-aryl compounds
through organocatalytic atroposelective Friedel–Crafts ami-
nation reactions. The N-nucleophilic reactions promoted by
chiral Lewis acids or bases have also been used in the
E-mail: zcjin@gzu.edu.cn
Dr. C. Mou[+]
School of Pharmacy, Guizhou University of Traditional Chinese
Medicine
ꢀ
preparations of axially chiral compounds containing C N
Guiyang 550025 (China)
chiral axes.[6c,d,i] In the field of NHC catalysis, to the best of our
knowledge, reported reactions are mainly used to prepare
central chiral molecules.[7] The rather limited examples of
axially chiral products via NHC catalysis are based on
forming C-C chiral axes, as disclosed by Zhao, Wang, Zhu
and others.[8] In a larger content, NHC-catalyzed atropose-
lective annulation reactions involving heteroatom-centered
nucleophiles remain undeveloped.
Dr. L. Hao, Prof. Dr. Y. R. Chi
Division of Chemistry & Biological Chemistry, School of Physical &
Mathematical Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202010606.
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Key steps of our reaction involve NHC-catalyzed addition
here were not effective for this atroposelective annulation
of a thiourea (2a)[9] to ynal (1a)-derived acetylenic acylazo-
reaction (entry 6). Solvent also had significant impact on the
reaction yields (entries 7 to 9). To our delight, the yield of the
product 3a could be dramatically increased when using furan
as the solvent (entry 9). Lewis acids have proven to be
effective additives for improving the chemo- and stereoselec-
tivities in NHC organocatalytic reactions.[15] In this scenario,
Sc(OTf)3 could serve as an efficient additive to improve the
reaction yield of 3a without diminishing the product er value
(entry 10 vs. entry 9). Finally, the product (3a) could be
obtained in 63% isolated yield and 99:1 er when using an
excess amount of ynal 1a in the presence of 5 ꢀ MS and
Sc(OTf)3 as the additives (entry 11).
Having established an optimal reaction condition for the
atroposelective annulation reaction (Table 1, entry 11), we
then examined the substrate scope using various substituted
ynals (Scheme 1). Both electron-donating and electron-with-
drawing substituents could be installed on each position of the
b-benzene rings of the ynal 1, with the atropisomeric thiazine
products afforded in moderate to good yields with excellent
optical purities (3b to 3i). The b-benzene ring of the ynal 1a
could be switched to a 1-napthyl group, with the product 3j
2
lium intermediate (I)[8c,10] to form a new C(sp ) S bond
ꢀ
(intermediate II). Subsequent catalyst-controlled face-selec-
tive intramolecular lactam formation of II gives atropisomeric
thiazine derivative 3a with a 99:1 enantiomeric ratio. Lewis
acid (Sc(OTf)3) additive[7d,11] was found to facilitate the
reaction with an appreciable improvement on the product
yield with retention of the optical purity. The axially chiral
thiazine derivative products from our reactions are rich in
functionalities and are feasible for further transformations.
We initially tested the atroposelective annulation reaction
between alkynyl aldehyde 1a and benzoylthiourea 2a using
various NHC catalysts in the presence of the DQ[12] as an
oxidant at 308C (Table 1, entries 1 to 5). NHC catalysts
bearing N-mesityl groups could give the desired products (3a)
in promising yields with good to excellent enantioselectivities
(entries 1, 4, 5).[13] No target products could be observed when
using the NHC catalysts with N-Ph or N-C6F5 substituents
(entries 2 & 3).[14] We then used the aminoindanol-derived
NHC pre-catalyst A[13a] for additional condition optimiza-
tions. Organic or inorganic bases other than DMAP examined
Table 1: Optimization of reaction conditions.[a]
[c]
Entry NHC Base
Solvent Additive Yield
[%][b]
Er
1
2
3
4
5
6
A
B
C
D
E
DMAP
DMAP
DMAP
DMAP
THF
THF
THF
THF
THF
THF
31
97:3
<5
<5
26
20
<5
91:9
91:9
DMAP
A
Et3N/ Cs2CO3/
DABCO etc.
DMAP
DMAP
DMAP
7
8
9
A
A
A
A
A
EtOAc
CHCl3
furan
furan
furan
31
<5
43
96:4
97:3
97:3
99:1
10
DMAP
DMAP
Sc(OTf)3 55
Sc(OTf)3 63
11[d]
[a] Unless otherwise specified, the reactions were carried using 1a
(0.20 mmol), 2a (0.10 mmol), DQ (0.20 mmol), NHC (0.02 mmol), base
(0.10 mmol), 4 ꢀ MS (150 mg), solvent (2.0 mL) at 308C for 12 h. The
absolute configurations of the products were estimated based on the X-
ray analysis on the single crystals of 3a (CCDC 2009386). [b] Isolated
yield of 3a. [c] The er values were determined via UPLC on chiral
stationary phase. [d] 1a (0.30 mmol), 2a (0.10 mmol), DQ (0.30 mmol),
A (0.02 mmol), DMAP (0.10 mmol), 5 ꢀ MS (150 mg), Sc(OTf)3
(0.02 mmol), furan (2.0 mL), 308C, 12 h.
Scheme 1. Scope of ynals 1.[a] [a] Reaction conditions as stated in
Table 1, entry 11. Yields are isolated yields after purification by column
chromatography. Er values were determined by HPLC or UPLC on
chiral stationary phase.
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afforded in 53% yield as a single atropisomer. Aliphatic ynal
substrates led to complex reaction mixtures in this NHC
organocatalytic process without any identifiable products
formed.
The acylthiourea substrate 2 also showed good tolerance
to various substituents and substitution patterns (Scheme 2).
Substituents could be installed on each position of the
benzene ring of the benzoyl group regardless of their
electronic properties, with the corresponding products
afforded in moderate yields and excellent enantioselectivities
(3k to 3v). The R1 group of the acyl unit could be switched to
a heteroaromatic furanyl group without erosion on the
product yield and er value (3w). The R1 group could also be
replaced with an alkyl group, although the product yield and
er value dropped under the current catalytic conditions (3x).
The 2-isopropyl group on the N-benzene rings of the
substrate 2 is crucial to the atroposelectivities of the NHC-
catalyzed annulation reaction, since it blocks the rotation of
ꢀ
the N-phenyl groups around the C N axis of the thiazine
products. Substituents were well tolerated on the 4- and 5-
positions of the N-phenyl group of the substrate 2, with the
target products afforded in excellent optical purities (4a to
4d). Replacing the 2-isopropyl group on the N-benzene ring
of the substrate 2a with a less bulky 2-phenyl or 2-methyl
group led to slight drops in the product er values (e.g., 4e, 4 f).
It is worth noting that the er value of the product 4 f can be
gradually decreased under our current catalytic conditions.
The stereochemical stabilities of the atroposelective
thiazine products were evaluated through both experimental
and computational methods.[16] The er value of 3a was stable
at 508C, but severely dropped to 55:45 after stirring at 1008C
in mesitylene for 24 h (Table 2, entry 1). The chiral product 4e
was less stable than 3a at 508C, and the er value of 4e
dropped a lot after stirring for 12 h at 758C in mesitylene
(entry 2). As a sharp contrast, the er value of 4 f deteriorated
significantly even at 508C and became racemic after stirring
for 12 h at 758C (entry 3).
The barrier to rotation for 3a was measured at 1008C in
¼
mesitylene (Table 2, 3a, DG = 29.5 kcalmolꢀ1), and the
¼
result is in accordance with the value (DG = 30.4 kcalmolꢀ1)
calculated through density functional theory (DFT). Simi-
larly, the barriers to rotations for 4e and 4 f were measured
¼
experimentally at 758C in mesitylene (4e, DG = 28.4 kcal
¼
molꢀ1; 4 f, DG = 26.9 kcalmolꢀ1). The results clearly show
that the size of the 2-substituents on the N-phenyl moieties of
the thiazine products play significant roles in both chirality
inductions and stereochemical stabilities of the axially chiral
thiazine molecules. Thiazines bearing the 2-isopropyl groups
on the N-phenyl moieties (e.g., 3a) can generally be formed in
excellent enantioselectivities and the products are stable at
our reaction conditions. In contrast, the lower er value
obtained with the product 4 f bearing a N-(2-methyl)phenyl
group was believed to be resulted from both weaker steric
controls during the atroposelective reaction and the less
stability of the afforded chiral thiazine product.
The thiazine molecules bearing axial chirality can be
further functionalized through simple protocols (Scheme 3).
The a-sp2 carbon of the lactam moiety of 3a can be
halogenated under mild conditions to give the products
(e.g., 5 and 6) in moderate yields without obvious erosions on
the optical purities. The a-brominated product 6 can be
coupled with alkynes and give the atroposelective cross-
coupling alkyne product 7 in a good yield with an excellent
enantioselectivity. The TMS group of 7 can be efficiently
removed to give the chiral terminal alkyne 8 in an excellent
Scheme 2. Scope of acylthioureas 2.[a] [a] Reaction conditions as stated
in Table 1, entry 11. Yields are isolated yields after purification by
column chromatography. Er values were determined by HPLC or UPLC
on chiral stationary phase.
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Table 2: Stereochemical stabilities of the thiazine products 3a, 4e and
observed. The Boc protecting group on the product 4d can be
4 f[a] and their rotation barriers.
removed under acidic conditions and the afforded atropose-
lective aniline product 10 can be further transformed to a urea
11 or a thiourea 12 with retention of the optical purities. It is
worth noting that ureas and thioureas are rich in function-
alities and have been widely used in both catalytic and
biological research.[19]
[b]
Entry
Thiazine
er0
er (508C)
er (758C)
er (1008C)
1[c]
2
3
3a
4e
4 f
99:1
93:7
91:9
98:2
88:12
76:24
92:8
55:45
50:50
55:45
51:49
50:50
In summary, we have developed an NHC-catalyzed
atroposelective cycloaddition reaction for the synthesis of
ꢀ
enantiomerically enriched thiazine derivatives. Chiral C N
axis is readily constructed for the first time through NHC
organic catalysis. Our reaction tolerates various functional-
ities, with the axially chiral products generated in excellent
optical purities. The thiazine derivatives obtained from our
method are rich in functionalities and can be transformed to
ꢀ
various functional molecules containing chiral C N axes with
[a] Unless otherwise specified, the chiral thiazine product (0.05 mmol)
was disolved in mesitylene (1 mL) and stirred at the corresponding
temperature for 12 h. [b] Er0 indicates the initial er values of the thiazine
products. [c] Thiazine 3a was stirred at the corresponding temperatures
for 24 h.
retention of the optical purities. Further studies on atropo-
selective synthesis with applications in agricultural chemicals
are being pursued in our laboratories.
Acknowledgements
We acknowledge financial support from the National Natural
Science Foundation of China (21772029, 21801051, 21961006,
22071036), The 10 Talent Plan (Shicengci) of Guizhou
Province ([2016]5649), the Guizhou Province Returned Over-
sea Student Science and Technology Activity Program
[(2014)-2], the Science and Technology Department of
Guizhou Province ([2018]2802, [2019]1020), the Program of
Introducing Talents of Discipline to Universities of China
(111 Program, D20023) at Guizhou University, Frontiers
Science Center for Asymmetric Synthesis and Medicinal
Molecules, Department of Education, Guizhou Province
[Qianjiaohe KY (2020)004], the Guizhou Province First-
Class Disciplines Project [(Yiliu Xueke Jianshe Xiangmu)-
GNYL(2017)008], Guizhou University of Traditional Chi-
nese Medicine, and Guizhou University (China). Singapore
National Research Foundation under its NRF Investigator-
ship (NRF-NRFI2016-06), the Ministry of Education, Singa-
pore, under its MOE AcRF Tier 1 Award (RG108/16, RG5/
19, RG1/18), MOE AcRF Tier 3 Award (MOE2018-T3-1-
003), the Agency for Science, Technology and Research
(A*STAR) under its A*STAR AME IRG Award
(A1783c0008, A1783c0010), GSK-EDB Trust Fund, Nanyang
Research Award Grant, Nanyang Technological University.
Conflict of interest
Scheme 3. Synthetic transformations of the Axially Chiral Thiazine
Products.
The authors declare no conflict of interest.
ꢀ
Keywords: atroposelective reaction · chiral C N axis ·
N-heterocyclic carbenes · organocatalysis
yield. Note that, the terminal alkynyl group in 8 is a versatile
functional group that can be used as linkers for macro-
molecule modification[17] and in various small molecular
synthetic transformations.[18] The nitro group existed in the
axially chiral product 3t can be efficiently reduced to a free
amino group (9), although a slight drop in the er value was
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Manuscript received: August 4, 2020
Accepted manuscript online: February 2, 2021
Version of record online: March 17, 2021
Angew. Chem. Int. Ed. 2021, 60, 9362 –9367
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