The reaction of prop-2-ynylsulfonium salts and sulfonyl-protected β-amino ketones to epoxide-fused 2-methylenepyrrolidines and S-containing pyrroles

Article abstract of DOI:10.1039/d0cc07745c

A novel divergent domino annulation reaction of prop-2-ynylsulfonium salts with sulfonyl-protected β-amino ketones has been developed, affording various epoxide-fused 2-methylenepyrrolidines and S-containing pyrroles in moderate to excellent yields. Prop-2-ynylsulfonium salts act as C₂synthons in the reactions providing a promising epoxide-fused skeleton in a single operation with readily accessible starting materials.

Full text of DOI:10.1039/d0cc07745c

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
The reaction of prop-2-ynylsulfonium salts
and sulfonyl-protected b-amino ketones to
epoxide-fused 2-methylenepyrrolidines and
S-containing pyrroles†
Cite this: Chem. Commun., 2021,
57, 2657
Received 26th November 2020,
Accepted 3rd February 2021
Tingting Jia,ab Gongruixue Zeng,a Chong Zhang,a Linghui Zeng,a Wenya Zheng,a
DOI: 10.1039/d0cc07745c
ab
Siyao Li,a Keyi Wu,a Jiaan Shao,*ab Jiankang Zhang*ab and Huajian Zhu
*
rsc.li/chemcomm
A novel divergent domino annulation reaction of prop-2-ynylsulfonium advances using propargyl sulfur ylides as C2 synthons.8 According
salts with sulfonyl-protected b-amino ketones has been developed, to their research, propargyl sulfur ylides can transform into allenic
affording various epoxide-fused 2-methylenepyrrolidines and sulfonium salts and be attacked by a nucleophile at the b-carbon
S-containing pyrroles in moderate to excellent yields. Prop-2- atom, providing a zwitterionic intermediate, which can further go
ynylsulfonium salts act as C2 synthons in the reactions providing a through intramolecular annulation to obtain complex heterocyclic
promising epoxide-fused skeleton in a single operation with readily products (Scheme 2b). On the basis of the proposed working model
accessible starting materials.
of prop-2-ynylsulfonium salts as C2 synthons, we are eager to find a
versatile synthon that can react with propargyl sulfur ylides to
Five-membered nitrogenated heterocycles, pyrrolidines and provide valuable chemical entities. Here we report a novel divergent
pyrroles, are privileged structures for a large number of natural domino annulation reaction of prop-2-ynylsulfonium salts with
products and biologically active molecules (Scheme 1).1,2 sulfonyl-protected b-amino ketones,9 providing facile access to
Epoxide-fused 2-methylenepyrrolidine, in particular, is a pro- epoxide-fused 2-methylenepyrrolidines and S-containing pyrroles.
mising skeletal structure which is potentially useful for the
Our investigation commenced with prop-2-ynylsulfonium
rapid construction of densely substituted pyrrolidines and salt 1a and N-sulfonyl-b-amino-1-phenylethanone 2a as model
pyrrolidinones for use in natural product synthesis.3 To the substrates. As shown in Table 1, prop-2-ynylsulfonium salt 1a
best of our knowledge, only Borhan’s group have reported a strategy was allowed to react with N-sulfonyl-b-amino-1-phenylethanone
enabling construction of an epoxide-fused 2-methylenepyrrolidine 2a in the presence of Cs2CO3 (1.5 equiv.) in CH3CN at 20 1C
unit via a one-pot tandem aza-Payne/hydroamination reaction.4 (Table 1, entry 1). The reaction gave the sequential [3+2]- and
Thus, development of a novel strategy for the construction of these [2+1]-annulation product 3a in 45% yield as well as S-containing
epoxide-fused 2-methylenepyrrolidines would enable facile access to pyrrole in 3% yield. A range of bases and solvents were screened
a relatively underexplored chemical space.
Propargyl sulfur ylide, which can be easily obtained by the
reaction of propargyl bromide and dimethyl sulfide, that can be
readily transformed into an allenic sulfonium salt.5 According
to previous reports, it can be viewed as a C1 synthon and reacts with
2-(1H-indol-2-yl)phenols6 and sulfonyl-protected o-amino aromatic
aldimines7 to afford indole-fused 4H-benzo[e][1,3]oxazines and
hexahydropyrrolo[3,2-b]indoles, respectively (Scheme 2a). Beyond
the application of C1 synthons, Huang’s group has also made great
a School of Medicine, Zhejiang University City College, Hangzhou, 310015,
P. R. China. E-mail: zhuhj@zucc.edu.cn, zjk0125@yeah.net, shaoja@zucc.edu.cn
b College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058,
P. R. China
† Electronic supplementary information (ESI) available: Experimental procedures,
compound characterization data, NMR spectra, and X-ray crystal structure of 3f and
Scheme 1 Representative biologically active molecules containing pyrrolidine
4g. CCDC 2040979 and 2040984. For ESI and crystallographic data in CIF or other
and pyrrole scaffolds.
electronic format see DOI: 10.1039/d0cc07745c
This journal is The Royal Society of Chemistry 2021
Chem. Commun., 2021, 57, 2657ꢀ2660 | 2657

View Article Online
Communication
ChemComm
used as a base (Table 1, entry 5). Screening of the loading of
Cs2CO3 and synthon 1a revealed that 2.0 equivalents of Cs2CO3
and 1a gave a small improvement in the yield (Table 1, entries
11 and 12). Temperature also affected the reaction significantly:
the yield increased from 62% to 86% as the temperature
decreased from 20 1C to 0–10 1C (Table 1, entry 14). Interestingly,
unexpected product 4a was obtained in 66% yield when 9.0
equivalents of prop-2-ynylsulfonium salt 1a reacted with 2a in
the presence of 3.0 equivalents of triethylamine (TEA) in THF at
30 1C (Table 1, entry 21). It is worth mentioning that the reaction
feeding order has an effect on the yield of product 4a.
Having established the optimal reaction conditions, we
explored the substrate scope of these sequential [3+2]- and [2+1]-
annulation reactions in the presence of Cs2CO3. As illustrated in
Scheme 3, the reactions of N-sulfonyl-b-amino-1-phenylethanone
3 bearing either electron-rich or weakly electron-deficient sub-
stituents at the para-position on the benzene ring of R2 produced
the desired products (3a–3c, 3g–3h) in good to high yields
(82–96%), but bromine is the exception (3d), which had a
reduced yield (50%). In the case of strong electron-withdrawing
groups at the para-position of the benzene ring of R2, reduced
yields were obtained in 63% and 51%, respectively (3e and 3f).
Furthermore, substrates 2 with bromo- and methoxy-substituted
phenyl rings at the meta-position were transformed into the desired
products (3i, 3g) in moderate yields (63%), while substrate 2 with a
strong electron donating group at the ortho-position of the benzene
ring could afford the product 3k in 78% yield. Further investigation
demonstrated that N-sulfonyl-b-amino-1-phenylethanones bearing
Scheme 2 Applications of prop-2-ynylsulfonium salt and this work.
Table 1 Screening of the reaction conditionsa
Yieldb [%]
3a
4a
Entry
Solvent
Base
T (1C)
1a/2a/base
1
2
3
4
5
6
7
8
CH3CN
DMSO
THF
Acetone
DCM
DCM
DCM
DCM
DCM
THF
DCM
DCM
DCM
DCM
DCM
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DBU
DIPEA
TEA
TEA
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
TEA
20
20
20
20
20
20
20
20
20
20
20
20
0
0–10
30
20
20
20
20
20
30
50
1.5 : 1 : 1.5
1.5 : 1 : 1.5
1.5 : 1 : 1.5
1.5 : 1 : 1.5
1.5 : 1 : 1.5
1.5 : 1 : 1.5
1.5 : 1 : 1.5
1.5 : 1 : 1.5
1.5 : 1 : 1.5
1.5 : 1 : 1.5
2 : 1 : 2
3 : 1 : 3
2 : 1 : 2
2 : 1 : 2
2 : 1 : 2
5 : 1 : 1.5
9 : 1 : 1.5
15 : 1 : 1.5
9 : 1 : 3
9 : 1 : 4
9 : 1 : 3
45
42
12
20
56
52
47
32
38
6
62
57
59
86
65
11
9
3
4
37
33
8
27
4
30
36
40
4
2
3
9
10
11
12
13
14
15
16c
17c
18c
19c
20c
21c
22c
2
5
44
54
53
62
61
66
42
THF
THF
THF
THF
THF
THF
TEA
TEA
TEA
TEA
TEA
TEA
10
9
11
8
9 : 1 : 3
10
a
The reaction was carried out with 1a, 2a (0.1 mmol), base and solvent
b
c
(1 mL). HPLC yields. THF (2 mL).
Scheme 3 Substrate scope of epoxide-fused 2-methylenepyrrolidines.
Reactions were carried out with 1 (1.0 mmol), Cs2CO3 (1.0 mmol) and
2 (0.5 mmol) in DCM (5 mL) at 0–10 1C. Isolated yields are given.
to optimize the yield of 3a (Table 1, entries 1–9). The reaction
conducted in DCM gave a better yield of 56% when Cs2CO3 was
2658 | Chem. Commun., 2021, 57, 2657ꢀ2660
This journal is The Royal Society of Chemistry 2021

View Article Online
ChemComm
Communication
Scheme 4 The influence of sulfonium salts for the yields of 3a. Reactions
were carried out at 1 (1.0 mmol), Cs2CO3 (1.0 mmol) and 2a (0.5 mmol) in
DCM (5 mL) at 0–10 1C. Isolated yields are given.
a thiophene ring and phenethyl were also efficient for the trans-
formation, generating the annulation products (3l and 3m) in
high yields (81% and 94%). To our delight, 3-methylprop-2-yn-
1-yldimethylsulfonium bromide and 3-phenylprop-2-yn-1-yldimethy-
lsulfonium bromide10 also reacted with 2a smoothly, giving the
corresponding products 3n and 3o in excellent yields (92% and
91%). Lastly, sulfonium salts 1a–1c (Scheme 4) were tested under
optimal conditions, which indicated that the yield of 3a dropped
sharply when tetrahydrothiophene sulfonium salt 1c was employed
in the reaction, but diethyl prop-2-ynylsulfonium bromide 1b made
no difference to the yield of 3a. The structure of 3f was characterized
by single-crystal X-ray analysis (CCDC 2040979†).
We then examined the scope of the reaction for S-containing
pyrrole derivatives in the presence of TEA. As shown in
Scheme 5, 2,3-dihydro-1H-pyrrol-3-ol (4aa) was observed in
the reaction of model substrates in 68% yield and could be
further transformed into 4a (66% yield). It is noteworthy to
point out that the hydroxyl group of the 2,3-dihydro-1H-pyrrol-
3-ol derivatives tended to be eliminated spontaneously when
electron-donating substituents were on the benzene ring of R2,
and the desired products (4f, 4g, 4i) could be obtained in
moderate yields (48–68%). By contrast, relatively stable 2,3-
dihydro-1H-pyrrol-3-ol derivatives (4ba, 4da, 4ea, 4ha) were
Scheme 5 Substrate scope of S-containing pyrroles. a Reaction conditions:
1 (4.5 mmol) was added to a stirred solution of 2 (0.5 mmol) in THF (10 mL)
slowly. Subsequently, TEA was added to the reaction mixture and stirred at
30 1C. Isolated yields are given. b Substrate 1 was ethyl methyl prop-2-
ynylsulfonium bromide.
successfully isolated in 37–75% yields with an electron- observed. The structure of 4g was unambiguously confirmed by
withdrawing group (except for Cl atom) on the benzene ring X-ray crystallography (CCDC 2040984†).
of R2, but the elimination reaction could also be conducted in
According to our experimental results, we proposed a plausible
the presence of MsCl and TEA in over 90% conversion. How- mechanism for the domino annulation reactions (Scheme 6).
ever, the ortho-substituents of R2 bearing a methoxy group Under the treatment of base, prop-2-ynylsulfonium salt 1a iso-
failed to furnish the desired products 4j and 4ja, presumably merizes into allenic sulfonium salt 1a0 which is attacked by the
because the methoxy group sterically hindered the formation of N anion of 2a, generating intermediate A. For path I, intermediate
stable intermediate B under standard conditions (Scheme 6). A then undergoes an intramolecular nucleophilic addition to form
Surprisingly, the generality of this methodology was also intermediate B in which the O anion conjugated with cesium to
demonstrated by using electron-rich groups of R2, such as constitute ‘‘naked anions’’.11 Finally, the desired product 3a is
thiophene and phenethyl, and the corresponding eliminated obtained by an intramolecular nucleophilic addition. In the reac-
products 4k and 4l can be obtained in 48% and 31% yields, tion process of 3n and 3o, favored intermediate B1 tended to be
respectively. Furthermore, different sulfonium salts were formed because of the steric- hindrance (Scheme 6). For path II,
employed in the reaction. When ethyl methyl prop-2-ynylsulf- the O anion of intermediate B would capture a proton immediately,
onium bromide and diethyl prop-2-ynylsulfonium bromide followed by a double-bond isomerization affording the inter-
were chosen as substrates, the same product 4m was obtained mediate C. Then, the Br anion attacked the Me2S sulfonium to
in 76% and 86% yields, respectively. Meanwhile, tetrahy- yield the product 4aa. Finally, the hydroxyl group of 4aa is
drothiophene sulfonium salt was also compatible with the eliminated to obtain product 4a. It is worth noting that MsCl
transformation (4n and 4na). However, when a H atom of R1 and TEA can speed up the departure of a hydroxyl when the
was substituted by phenyl and alkyl, no desired products were benzene ring of substrate 2 has electron-withdrawing substituents.
This journal is The Royal Society of Chemistry 2021
Chem. Commun., 2021, 57, 2657ꢀ2660 | 2659

View Article Online
Communication
ChemComm
Rep., 2008, 25, 139; (c) M. Cooper, A. Llinas, P. Hansen, M. Caffrey,
A. Ray, S. Sjodin, I. Shamovsky, H. Wada, T. J. Jensen, U. Sivars,
L. Hultin, U. Andersson, S. Lundqvist, K. Gedda, L. Jinton,
N. Krutrok, R. Lewis, P. Jansson and C. Gardelli, J. Med. Chem.,
2020, 63, 9705; (d) D. Habel, D. S. Nair, Z. Kallingathodi, C. Mohan,
S. M. Pillai, R. R. Nair, G. Thomas, S. Haleema, C. Gopinath,
R. V. Abdul, M. Fritz, A. R. Puente, J. L. Johnson, P. L. Polavarapu
and I. Ibnusaud, J. Nat. Prod., 2020, 83, 2178; (e) T. W. Lyons,
T. A. Martinot, C. Q. He, J. Qi and G. X. Shao, Org. Process Res. Dev.,
2020, 24, 1457; ( f ) Z. H. Pei, X. F. Li, K. Longenecker, T. W. von
Geldern, P. E. Wiedeman, T. H. Lubben, B. A. Zinker, K. Stewart,
S. J. Ballaron, M. A. Stashko, A. K. Mika, D. W. A. Beno, M. Long,
H. Wells, A. J. Kempf-Grote, D. J. Madar, T. S. McDermott,
L. Bhagavatula, M. G. Fickes, D. Pireh, L. R. Solomon, M. R. Lake,
R. Edalji, E. H. Fry, H. L. Sham and J. M. Trevillyan, J. Med. Chem.,
2006, 49, 3520; (g) R. A. Pilli and M. de Oliveira, Nat. Prod. Rep., 2000,
17, 117; (h) D. Crich and A. Banerjee, Acc. Chem. Res., 2007, 40, 151.
2 (a) D. L. Boger, C. W. Boyce, M. A. Labroli, C. A. Sehon and Q. Jin,
J. Am. Chem. Soc., 1999, 121, 54; (b) D. O’Hagan, Nat. Prod. Rep.,
2000, 17, 435; (c) A. Furstner, Angew. Chem., Int. Ed., 2003, 42, 3582;
(d) H. Fan, J. N. Peng, M. T. Hamann and J. F. Hu, Chem. Rev., 2008,
108, 264; (e) V. Bhardwaj, D. Gumber, V. Abbot, S. Dhiman and
P. Sharma, RSC Adv., 2015, 5, 15233; ( f ) M. Z. Wang, H. Xu, T. W. Liu,
Q. Feng, S. J. Yu, S. H. Wang and Z. M. Li, Eur. J. Med. Chem., 2011,
46, 1463; (g) K. H. van Pee and J. M. Ligon, Nat. Prod. Rep., 2000,
17, 157; (h) T. Antonucci, J. S. Warmus, J. C. Hodges and D. G. Nickell,
Antiviral Chem. Chemother., 1995, 6, 98; (i) K. Muralirajan,
R. Kancherla and M. Rueping, Angew. Chem., Int. Ed., 2018, 57, 14787.
3 (a) L. W. Wang, H. J. Su, S. Z. Yang, S. J. Won and C. N. Lin, J. Nat.
Prod., 2004, 67, 1182; (b) Y. K. T. Lam, O. D. Hensens, R. Ransom,
R. A. Giacobbe, J. Polishook and D. Zink, Tetrahedron, 1996, 52, 1481;
(c) A. J. Humphrey and D. O’Hagan, Nat. Prod. Rep., 2001, 18, 494;
(d) H. Gholami, A. Kulshrestha, O. K. Favor, R. J. Staples and
B. Borhan, Angew. Chem., Int. Ed., 2019, 58, 10110; (e) S. Mizutani,
K. Komori, T. Taniguchi, K. Monde, K. Kuramochi and K. Tsubaki,
Angew. Chem., Int. Ed., 2016, 55, 9553.
4 (a) A. Kulshrestha, J. M. Schomaker, D. Holmes, R. J. Staples,
J. E. Jackson and B. Borhan, Chem. – Eur. J., 2011, 17, 12326;
(b) J. M. Schomaker, A. R. Geiser, R. Huang and B. Borhan, J. Am.
Chem. Soc., 2007, 129, 3794; (c) A. Kulshrestha, N. S. Marzijarani,
K. D. Ashtekar, R. Staples and B. Borhan, Org. Lett., 2012, 14, 3592.
5 M. Aso, M. Sakamoto, N. Urakawa and K. Kanematsu, Heterocycles,
1990, 31, 1003.
6 P. H. Jia and Y. Huang, Adv. Synth. Catal., 2018, 360, 3044.
7 P. H. Jia, Q. L. Zhang, Q. M. Ou and Y. Huang, Org. Lett., 2017, 19, 4664.
8 (a) M. Aso, A. Ojida, G. Yang, O. J. Cha, E. Osawa and K. Kanematsu,
J. Org. Chem., 1993, 58, 3960; (b) A. Ojida, F. Tanoue and
K. Kanematsu, J. Org. Chem., 1994, 59, 5970; (c) P. H. Jia,
Q. L. Zhang, H. X. Jin and Y. Huang, Org. Lett., 2017, 19, 412;
(d) S. J. Shen, Y. L. Yang, J. Y. Duan, Z. H. Jia and J. Y. Liang, Org.
Biomol. Chem., 2018, 16, 1068.
Scheme 6 Plausible reaction mechanism.
In conclusion, we have developed a novel divergent domino
annulation reaction of prop-2-ynylsulfonium salts and sulfonyl-
protected b-amino ketones, generating epoxide-fused 2-methyl-
enepyrrolidines and S-containing pyrroles in moderate to
excellent yields under mild conditions. In this [3+2] annulation
reaction, prop-2-ynylsulfonium salts were utilized as C2 synthons.
We believe that the novel annulation reaction will be promising to
be used in the synthesis of natural products and pharmaceuticals.
We are grateful for the financial support from the National
Natural Science Foundation of China (21702183 and 81803432),
Agricultural and Social Development Fund of Hangzhou
Science and Technology Committee (20191203B50) and The
Second Round of Excellent Innovation Team of Hangzhou
Municipal University in 2019 for L.-H. Zeng.
9 (a) M. Gunther, J. Lategahn, M. Juchum, E. Doring, M. Keul, J. Engel,
H. L. Tumbrink, D. Rauh and S. Laufer, J. Med. Chem., 2017,
60, 5613; (b) I. V. Magedov, G. Luchetti, N. M. Evdokimov,
M. Manpadi, W. F. A. Steelant, S. Van Slambrouck, P. Tongwa,
M. Y. Antipin and A. Kornienko, Bioorg. Med. Chem. Lett., 2008,
18, 1392; (c) X. D. Li, M. Chen, X. Xie, N. Sun, S. Li and Y. H. Liu, Org.
Lett., 2015, 17, 2984; (d) P. J. Wang, Y. Xiong, Y. Q. Qin, J. J. Zhang,
N. N. Yi, J. N. Xiang and W. Deng, Catal. Commun., 2019, 131, 7.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 (a) E. Fattorusso and O. Taglialatela-Scafati, Modern Alkaloids: 10 P. W. Davies, N. Martin and N. Spencer, Beilstein J. Org. Chem., 2011, 7, 839.
Structure, Isolation, Synthesis and Biology, Wiley-VCH Verlag GmbH 11 S. I. Kim, F. X. Chu, E. E. Dueno and K. W. Jung, J. Org. Chem., 1999,
& Co. KGaA, Weinheim, Germany, 2007; (b) J. P. Michael, Nat. Prod.
64, 4578.
2660 | Chem. Commun., 2021, 57, 2657ꢀ2660
This journal is The Royal Society of Chemistry 2021