N-Heterocyclic Carbene Catalyzed [3+2] Cycloaddition of Enals with β,γ -Unsaturated α -Ketimino Esters for the Synthesis of Multisubstituted Cyclopentanone

Article abstract of DOI:10.1002/adsc.201901144

A convenient strategy of N-heterocyclic carbene catalyzed [3+2] cycloaddition of enals with β,γ-unsaturated α-ketimino esters is developed. This effective protocol features mild reaction conditions and broad substrate scope, which enables the rapid assembly of various benzoxazinone derived cyclopentanone scaffolds in good to high yields with excellent diastereoselectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.201901144

Title: N-Heterocyclic Carbene Catalyzed [3+2] Cycloaddition of Enals
with β,γ-Unsaturated α-Ketimino Esters for the Synthesis of
Multisubstituted Cyclopentane
Authors: Jing Qi, Xiao-Qian Shi, Meng-Die Dong, Xiao-Yong Duan, and
Teng-Liang Cao
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901144
Link to VoR: http://dx.doi.org/10.1002/adsc.201901144

10.1002/adsc.201901144
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
N-Heterocyclic Carbene Catalyzed [3+2] Cycloaddition of Enals
with  -Unsaturated  -Ketimino Esters for the Synthesis of
Multisubstituted Cyclopentane
Xiao-Qian Shi, a Meng-Die Dong, a Xiao-Yong Duan, a,b,* Teng-Liang Cao, a Jing Qi a,b,*
a
Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science,
Hebei University
b
Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University
qijinghbu2013@126.com, duanxy05@126.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A convenient strategy of N-heterocyclic
carbene catalyzed [3+2] cycloaddition of enals with -
unsaturated -ketimino esters is developed. This
effective protocol features mild reaction conditions and
broad substrate scope, which enables the rapid assembly
of various benzoxazinone derived cyclopentanone
scaffolds in good to high yields with excellent
diastereoselectivities.
Keywords: N-heterocyclic carbene; -unsaturated -
ketimino esters; cyclopentanone.
The benzoxazinone skeleton is one of the most
important classes of organic scaffold that can be found
in numerous biologically active natural products and
pharmaceuticals.[1] Meanwhile, the functionalized
cyclopentanone as an important chemical building
block has attracted a lot of attention in the past few
decades.[2] Owing to their unique biological activities
and valuable applications in the field of natural
Scheme 1. NHC-Catalyzed Cycloaddition of Enals with
-Unsaturated Imines and Our Synthetic Design.
products and drug molecules synthesis, many
synthetic approaches have been extensively developed
for the rapid construction of these core motifs.[3] In aim
to develop new methods for the efficient synthesis of
functional molecules, we have demonstrated a novel
excellent work on NHC-catalyzed reactions of cis-
enals and-unsaturated imines to afford chiral
strategy for the quick access of benzoxazinone bearing
cyclopentanones products.[6] The asymmetric formal
a cyclopentanone moiety via N-heterocyclic carbene
[3+2] cycloadditions of enals with heterocyclic
Michael acceptors were achieved by Glorius et al. and
(NHC) catalyzed [3+2] cycloaddition of enals with
-unsaturated -ketimino esters.
Ender’s group respectively in recent years.[7]
Meanwhile, Enders’ group discovered a switchable
annulation strategy for the selective synthesis of
spirocyclopentane oxindoles and enaminones.[8]
Impressively, the enantioselective synthesis of adipic
acid derivatives was reported by the same group in
2017. In this efficient NHC-catalyzed formal [3+2]
cycloaddition strategy, the masked cinnamates were
used as linear Michael acceptors. Based on previous
In the last two decades , NHC has been developed
as a powerful tool for the rapid construction of various
organic molecules based on their unique polarity
reversal strategy.[4] In 2007, Nair’s group synthesized
spirocyclopentanes from a NHC-catalyzed [3+2]
annulation reaction between enals and cyclic Michael
acceptors.[5] In 2013, Chi and co-workers reported an
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901144
Advanced Synthesis & Catalysis
reports, we focused our attentions on explore NHC-
catalyzed [3+2] cycloadditions with unconventional
substrates. Recently, -unsaturated -ketimino ester
has been used as an excellent electrophile to construct
functionalized indoles.[9] However, the application of
-unsaturated-ketimino esters in NHCs catalyzed
annulation strategy has not been developed, probably
due to their relatively weak electrophilicity towards
nucleophiles. Herein we report our results on the
NHC-catalyzed [3+2] cycloaddition of enals with -
unsaturated-ketimino esters for the rapid
construction of multisubstituted cyclopentanones
(Scheme 1).
We began our investigation by using -
unsaturated -ketimino ester 1a and cinnamaldehyde
2a as the model substrates and DBU was chosen as the
base, while THF was initially employed as the solvent.
Screening of catalysts revealed that the triazolium-
based catalyst C with an N-mesityl substituent played
best catalytic activity compared to the other catalysts
(Table 1, entries 1-7). Other commonly used bases,
such as TBD, DIPEA, K2CO3 and Cs2CO3 were far less
effective, furnished the desired product in reduced
yields (Table 1, entries 8−11). A variety of organic
solvents were also screened for this reaction, and the
results showed that the yields were generally lower
than in THF (Table 1, entries 12−15). Finally, the
optimal conditions were identified, using NHC C as
the catalyst, DBU as the base and THF as the solvent,
with the desired multisubstituted cyclopentanones 3a
formed in 80 % yield (Table 1, entry 3). It was worthy
to note that the trans-isomers were generated as a
single diastereomer during the optimization process.
After establishing the optimal reaction conditions,
we next examined the substrate scope. With -
unsaturated-ketimino ester 1a as the model substrate
(Scheme 2), enals derived from aryl aldehydes bearing
various electron-withdrawing or electron-donating
substituents all worked well, afforded the
corresponding [3+2] cycloaddition adducts 3a−m with
good to excellent yields (up to 99% yield). When the
-phenyl substituent of enals replaced by heterocyclic
units, such as thienyl and furyl were also worked well
in this strategy (3n-o). Moreover, the indole derived
enal was compatible in this reaction with lower
diastereoselectivity (3p). Enals containing a sterically
demanding group such as 1-naphthyl was well
tolerated, thus affording the corresponding product in
Table 2. Substrate Scopea), b), c)
Table 1. Optimization of Reaction Conditiona)
entry
1
NHC
A
base
slovent
THF
yield (%)b
37
DBU
DBU
DBU
DBU
DBU
DBU
DBU
TBD
2
THF
trace
80
B
3
THF
C
4
THF
trace
76
D
5
THF
E
6
THF
13
F
7
THF
60
G
C
8
THF
58
9
DIPEA
K2CO3
Cs2CO3
DBU
DBU
DBU
DBU
THF
32
C
10
11
12
13
14
15
THF
47
C
THF
68
C
DCM
CH3CN
1,4-dioxane
DME
66
C
55
C
71
C
66
C
a)Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.2
mmol, 2.0 equiv), NHC (20 mol %), base (20 mol %),
b)
solvent (1.0 mL), room temperature, 12 h. Isolated yield
a) 1 (0.1 mmol), 2 (0.2 mmol), catalyst (20 mol %), base (20
after
flash
chromatography.
DBU
DIPEA
=
1,8-
mol %). Yields given are for the isolated products following
diazabicyclo[5.4.0]-undec-7-ene,
=
N,N-
b)
column chromatography.
Unless otherwise noted dr >
diisopropylethylamine, Mes = mesityl, DME = 1,2-
Dimethoxyethane.
20:1. c) Diastereomers ratios were determined by HNMR
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901144
Advanced Synthesis & Catalysis
excellent yield (3r, 94% yield). When -alkyl and -
vinyl substituted enals were used as the starting
materials under the standard conditions, the reactions
processed smoothly to afford the corresponding
products in moderate yields (3r-s), while the
diastereoselectivities were reduced. Placing a vinyl
no obvious loss of yield was observed. Then, further
synthetic transformation of 3a was performed as
shown in Scheme 2. Under oxidative cleavage with
ozone, 3a could easily transformed to 2-hydroxy
cyclopentenone 4. Interestingly, reduction of 3a by
NaBH4 gave the acetal 5 as the product. Moreover,
substituent on the enal -carbon was also tolerated (3s). protecting the N-atom of 3a with tosyl group afforded
With enal 2a as the model substrate, the scope of -
unsaturated -ketimino esters was also examined. Not
surprisingly, different aryl substituents on the-
unsaturated -ketimino esters were all well tolerated
(3t-3aa). When the benzoxazinone unit bore an
electron-withdrawing or electron-donating substituent
(3ab, 3ac), the reaction afforded their corresponding
products in high yields. Notably, the benzoxazinone
part could be replace by a quinoxalinone unit (3ad).
the compound 6. Ring opening reaction was
subsequently carried out in methanol, and
cyclopentenone 7 was generated as essentially a single
diastereomer (Scheme 2).
The proposed reaction pathway for the [3+2]
cycloaddition of -unsaturated -ketimino esters 1a
and enal 2a is illustrated in Scheme 3. Addition of
NHC C to enal 2a led to the formation of NHC–
homoenolate I. Then the intermediate I undergo a
Michael/tautomerization reaction to -unsaturated
-ketimino esters 2a to create a new carbon−carbon
bond and the intermediate II was generated. The
intermediate II is in equilibrium with its tautomer III.
Table 3. Enantioselective studies of this methodology
Scheme 2. Scale-up synthesis and further transformations .
Figure 1. ORTEP diagram of 3a’.
To further investigate this strategy, we next turned
our attention to the asymmetric catalytic version of this
reaction. Unfortunately, all the reaction conditions led
to unsatisfactory ee values or yields.[10] Finally, the
acceptable reaction conditions were identified, using
chiral triazolium salt H as the catalyst, Et3N as the base
and a mixture of DMSO/THF (1:2, v/v) as the solvent,
afforded the desired product in 63% yield with 87% ee
(3a’, Table 3). Then, we roughly screened the substrate
scope, and the results showed that all the examples
afforded low to moderate yields with acceptable ee
values (3b’-3i’).
The absolute configuration (2R, 3R) of the
stereogenic centers in compound 3a’ were
unambiguously determined by X-ray crystallographic
analysis (Figure 1). [11]
In order to further demonstrate the practicality of
this strategy, a gram-scale synthesis of 3a was carried
out under the standard condition. To our great delight,
Scheme 3. Proposed Reaction Pathways.
Then after an aza-Dieckmann-type cyclization and
final tautomerization, the product 3a was generated
and NHC catalyst was released to enter next catalytic
cycle (Scheme 3).
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901144
Advanced Synthesis & Catalysis
In conclusion, the NHC-catalyzed [3+2]
Biomol. Chem., 2017, 15, 2609-2628; e) J. Yang, N. Li,
G. Li, W. Wang, A. Wang, X. Wang, Y. Cong, and T.
Zhang, Chem. Commun., 2014, 50, 2572-2574; f) S. D.
Penrose, A. J. Stott, P. Breccia, A. F. Haughan, R. W.
Bürli, R. E. Jarvis, and C. Dominguez, Org. Lett., 2015,
17, 1401–1404.
cycloadditions of enals with -unsaturated -
ketimino esters were developed. This unique and
effective strategy features mild reaction conditions and
broad substrate scope, which enables the rapid
assembly of various benzoxazinone derived
cyclopentanone scaffolds in good to high yields with
excellent diastereoselectivities. Other investigations
concerning the construction of relevant targets, as well
as the asymmetric study are currently underway in our
laboratory.
[4] Reviews on NHC catalysis: a) D. Enders, O. Niemeier,
and A. Henseler, Chem. Rev., 2007, 107, 5606−5655; b)
N. Marion, S. Díez-Gonzalez, and S. P. Nolan, Angew.
Chem., 2007, 119, 3046-3058; Angew. Chem. Int. Ed.,
2007, 46, 2988−3000; c) V. Nair, S. Vellalath, and B. P.
Babu, Chem. Soc. Rev., 2008, 37, 2691−2698; (d) T.
Rovis, Chem. Lett., 2008, 37, 2−7; e) A. T. Biju, N. Kuhl,
and F. Glorius, Acc. Chem. Res., 2011, 44, 1182−1195;
f) V. Nair, R. S. Menon, A. T. Biju, C. R. Sinu, R. R.
Paul, A. Jose, and V. Sreekumar, Chem. Soc. Rev., 2011,
40, 5336−5346; g) K. Hirano, I. Piel, and F. Glorius,
Chem. Lett., 2011, 40, 786−791; h) J. Izquierdo, G. E.
Hutson, D. T. Cohen, and K. A. Scheidt, Angew. Chem.,
2012, 124, 11854-11866; Angew. Chem., Int. Ed., 2012,
51, 11686−11698; i) J. Douglas, G. Churchill, and A. D.
Smith, Synthesis, 2012, 44, 2295−2309; j) X.-Y. Chen,
and Y. Song, Synlett, 2013, 24, 1614−1622; k) S. J. Ryan,
L. Candish, and D. W. Lupton, Chem. Soc. Rev., 2013,
19, 4664 − 4678; l) S. De Sarkar, A. Biswas, R. C.
Samanta, and A. Studer, Chem. - Eur. J., 2013, 19, 4664-
4678; m) J. Mahatthananchai, and J. W. Bode, Acc.
Chem. Res., 2014, 47, 696−707; n) M. N. Hopkinson, C.
Richter, M. Schedler,and F. Glorius, Nature, 2014, 510,
485−496; o) D. M. Flanigan, F. Romanov-Michailidis,
N. A. White, and T. Rovis, Chem. Rev., 2015, 115, 9307
−9387; p) M. H. Wang, and K. A. Scheidt, Angew.
Chem., 2016, 128, 15134-15145; Angew. Chem., Int. Ed.,
2016, 55, 14912−14922; q) X. Bugaut, and F. Glorius,
Chem. Soc. Rev., 2012, 41, 3511−3522; r) S. Mondal, S.
R. Yetra, S. Mukherjee, and A. T. Biju, Acc. Chem. Res.,
2019, 52, 425−436; s) K. J. R. Murauski, A. A. Jaworski,
and K. A. Scheidt, Chem. Soc. Rev., 2018, 47, 1773-
1782; t) X.-Y. Chen, Q. Liu, P. Chauhan, and D. Enders,
Angew. Chem. Int. Ed., 2018, 57, 3862 – 3873; u) C.
Zhang, J. F. Hooper, and D. W. Lupton, ACS Catal.,
2017, 7, 2583−2596; w) X.-Y. Chen, S. Li, F. Vetica, M.
Kumar, and D. Enders, iScience, 2018, 2, 1-26.
Experimental Section
A dry 25 mL Schlenk tube with stir bar was charged with
-unsaturated -ketimino ester 1a (25 mg, 0.1 mmol, 1.0
equiv), NHC C (6.3 mg, 0.01 mmol, 20 mol %), DBU (3 mg,
0.02 mmol, 20 mol %). The tube was evacuated, and refilled
with nitrogen. Then enals 2a (26.4 mg, 0.2 mmol, 2.0 equiv)
was added and the mixture was dissolved with newly
distilled THF (1 mL). The mixture was stirred at room
temperature for 12 hours when the substrate was consumed
completely (monitored by TLC). The reaction mixture was
concentrated under vacuum and purified by column
chromatography on silica gel using Petroleum ether/EtOAc
(15:1) as eluent to afford desired product 3a as yellow solid
(30.5 mg, 80% yield).
Acknowledgements
We acknowledge financial support by the National Natural
Science Foundation of China (21402037), the Natural
Science Foundation of Hebei Province (B2015201175,
B2019201081, B2019201101), and the Foundation of Hebei
Education Department (QN2014106), the Project of
Introduction of Overseas Personnel in Hebei Province in
2019 (C20190503), the Advanced Talents Incubation
Program of the Hebei University (801260201299).
References
[1] a) P. S. Akula, B. C. Hong, and G. H. Lee, RSC Adv.,
2018, 8, 19580-19584; b) C. Huo, J. Dong, Y. Su, J.
Tang, and F. Chen, Chem. Commun., 2016, 52, 13341-
13344; (c) J. J. Mason, J. Bergman, and T. Janosik, J.
Nat. Prod., 2008, 71, 1447-1450; (d) S. Xia, J.-Q. Liu,
X.-H. Wang, Y. Tian, Y. Wang, J. H. Wang, L. Fang,
and H. Zuo, Bioorg. Med. Chem. Lett., 2014, 24, 1479-
1483; e) C. Liu, J.-L. Tan, S.-Y. Xiao, J.-F. Liao, G.-R.
Zou, X.-X. Ai, J.-B. Chen, Y. Xiang, Q. Yang, and H.
Zuo, Chem. Pharm. Bull., 2014, 62, 915-920.
[5] V. Nair, B. P. Babu, S. Vellalath and E. Suresh, Chem.
Commun., 2008, 747-749.
[6] X. Chen, X. Fang, and Y. R. Chi, Chem. Sci., 2013, 4,
2613-2618.
[7] a) C. Guo, M. Schedler, C. G. Daniliuc, and F. Glorius,
Angew. Chem. Int. Ed., 2014, 53, 10232-10236; b) L.
Wang, S. Li, P. Chauhan, D. Hack, A. R. Philipps, R.
Puttreddy, K. Rissanen, G. Raabe, and D. Enders, Chem.
Eur. J., 2016, 22, 5123-5127 c) S. Li, L. Wang, P.
Chauhan, K. Rlssanen, and D. Enders, Synthesis, 2017,
49, 1808-1815.
[2] a) K. Trisuwan, N. Khamthong, V. Rukachaisirikul, S.
Phongpaichit, S. Preedanon, and J. Sakayaroj, J. Nat.
Prod., 2010, 73, 1507–1511; b) X.-M. Zhang, Y.-Q. Tu,
F.-M. Zhang, Z.-H. Chen, and S.-H. Wang, Chem. Soc.
Rev., 2017, 46, 2272-2305; c) Z. Xu, Q. Wang, and J.
Zhu, Chem. Soc. Rev., 2018, 47, 7882-7898.
[3] For selected articles, see: a) X. Huang, and L. Zhang, J.
Am. Chem. Soc., 2007, 129, 6398 – 6399; b) B.-L.
Zhao,and D.-M. Du, Org. Lett., 2017, 19,1036–1039; c)
R. Guo, X. Mo, and G. Zhang, Org. Lett., 2019, 21,
1263–1267; d) A. E. Shiely, C. N. Slattery, A. Ford, K.
S. Eccles, S. E. Lawrencea, and A. R. Maguire, Org.
[8] L. Wang, S. Li, M. Blümel, R. Puttreddy, A. Peuronen,
K. Rissanen, and D. Enders, Angew. Chem., 2017, 129,
8636-8641; Angew. Chem. Int. Ed., 2017, 56, 8516 -
8521.
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901144
Advanced Synthesis & Catalysis
[9] a) B. Bi, Q.-X. Lou, Y.-Y. Ding, S.-W. Chen, S.-S.
Zhang, W.-H. Hu, and J.-L. Zhao, Org. Lett., 2015, 17,
540–543; b) Y.-Y. Ding, D.-F. Xu, S.-S. Meng, Y. Li,
and J.-L. Zhao, Adv. Synth. Catal., 2018, 360, 664-669.
[11] Single crystal X-ray analysis of 3a’ using CuK
radiation with oxygen as the heavy atom for absolute
stereochemistry (CCDC 1964949). These data are
available free of charge from the Cambridge
Crystallographic Data Centre.
[10] For the detail of optimization of enantioselective please
see the supporting information.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901144
Advanced Synthesis & Catalysis
COMMUNICATION
N-Heterocyclic Carbene Catalyzed [3+2]
Cycloaddition of Enals with -Unsaturated -
Ketimino Esters for the Synthesis of
Multisubstituted Cyclopentane
Adv. Synth. Catal. Year, Volume, Page – Page
Xiao-Qian Shi, Meng-Die Dong, Xiao-Yong
Duan,* Teng-Liang Cao, Jing Qi *
6
This article is protected by copyright. All rights reserved.