Access to dihydropyridinones and spirooxindoles: Application of N-heterocyclic carbene-catalyzed [3+3] annulation of enals and oxindole-derived enals with 2-aminoacrylates

Article abstract of DOI:10.1039/c7cc02753b

A strategy for the NHC-catalyzed synthesis of dihydropyridinones and spirooxindoles has been developed via [3+3] annulation reactions of enals or isatin-derived enals with 2-aminoacrylates under oxidative conditions. In this efficient strategy, the 2-aminoacrylates served as nucleophiles. Modifying the standard base switched the carbon-carbon double bond formation from 5,6-positions to 3,4-positions to generate 5,6-dihydropyridinones and 3,4-dihydropyridinones, respectively. Meanwhile, a diverse set of spirooxindole derivatives were also synthesized in good to excellent yields.

Full text of DOI:10.1039/c7cc02753b

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Access to Dihydropyridinones and Spirooxindoles: Application of
N‑Heterocyclic Carbene-Catalyzed [3 + 3] Annulation of Enals and
Oxindole-Derived Enals with 2-Aminoacrylates
Received 00th January 20xx,
Accepted 00th January 20xx
Liang-Liang Zhaoa, Xing-Shuo Lia, Li-Li Caoa, Rui Zhanga, Xiao-Qian Shia, and Jing Qi* a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A strategy for the NHC-catalyzed synthesis of dihydropyridinones
and spirooxindoles has been developed via [3+3] annulation
reactions of enals or isatin-derived enals with 2-aminoacrylates
under oxidative condition. In this efficient strategy, the 2-
aminoacrylates served as nucleophiles. Modifying the standard
base switched the carbon-carbon double bonds formation from
5,6-position to 3,4-position to generate 5,6-dihydropyridinones
and 3,4-dihydropyridinones respectively. Meanwhile, a diverse set
of spirooxindoles derivatives were also synthesized in good to
excellent yields.
Dihyropyridinone core is one of the characteristic structural
motifs present in a variety of biologically active natural
products and numerous pharmaceuticals.1 Moreover, the
spirooxindole motif is also an important scaffolds in clinical
pharmaceuticals and natural products.2 Consequently, many
approaches have been developed for the efficient synthesis of
these core motifs.3 Although considerable progress has been
described toward their synthesis, development of a novel
method to efficiently synthesis these two dihyropyridinones
core structure remains valuable.
N-Heterocyclic carbene (NHC) catalysis has been developed
extensively for various chemical transformations over the past
decade, due to their unique properties to reverse the polarity
of aldehydes and modes of reactivity.4 Beyond their traditional
a1-d1 umpolung5 and a3-d3 umpolung6 reactive modes, the
NHC-catalyzed generation of α,β-unsaturated acyl azolium
from enals, ynals, 2-bromoenal and ester has becomes an
interesting alternative for the construction of useful
compounds.7 The pioneering investigation was completed by
Studer and co-workers by combining α,β-unsaturated acyl
triazoliums with 1,3-dicarbonyl compounds to construct dihyro
Scheme 1. NHC-Catalyzed [3 + 3] annulation of enals and oxindole-derived enals
with 2-aminoacrylates
pyranones.8 In 2012, Bode and co-workers reported NHC-
catalyzed [3+3] annulation of cyclic ketimines with enals under
oxidative condition to give tricylic dihydropyridinones.9 In 2015,
Ye and co-workers reported an excellent work of NHC-
catalyzed [3+3] cyclocondensation of bromoenals and
aldimines for the construction of dihydropyridiones.10 Very
recently, Zhong’s group reported an elegant work that using
oxindole-derived enals to generate formal Michael acceptor
with NHC catalyst, and then through [3+3] cycloaddition with
imines to synthesis spirooxindoles.11 However, most of the
reports mentioned above was limit to active 1,3-dicarbonyl
compounds, ketimines, aldimines and imines. The NHC-
catalyzed corresponding reaction direct with 2-aminoacrylates
still unexplored, possibly due to its relative weak nucleophilic
towards electrophiles. In 2010, Glorius and co-worker reported
an elegant work of a carbene-mediated asymmetric Stetter
reaction of starting from aldehydes and 2-aminoacrylates to
construct
-amino acid derivatives, in which the 2-
aminoacrylates act as Michael acceptors.12 However, 2-
aminoacrylates as potential nucleophiles and application in
organic synthesis were long ignored. Herein, we report our
results on this NHC-catalyzed [3+3] annulation of enals and
isatin-derived enals with 2-aminoacrylates for the construction
of dihydropyridinones and spirooxindoles. Moreover, two
different dihydropyridinones were generated from this novel
a. Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and
Environmental Science, Hebei University, Baoding 071002, People’s Republic of
China
.
Email: qijinghbu2013@126.com
b. Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry
of Education, Hebei University, Baoding 071002, People’s Republic of China
.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 1. Optimization of the reaction conditions a
products in acceptable yields respectively (Table 2, entries 1-5).
However, there is a significant exception that when the
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DOI: 10.1039/C7CC02753B
aromatic enals 1f and 1g were used under the condition
A
and
B, both of the two conditions only afford the carbon-carbon
double bonds migration products (3f, 3g) (Table 2, entries 6-7).
Aromatic enals with a meta-substituent, ortho-substituted, or
meta, meta-disubstituted aryl substrates showed no negative
effect on the reaction (3i-3n, 4h-4n) (Table 2, entries 9-16).
Interestingly, when the 2-methyl substituted aromatic enal 1h
was examined the 5,6-dihydropyridinone 4h was generated as
the major product under the two reaction conditions (Table
2,entry 8). Heteroaromatic enals, such as 3-thieny-substituted
enal 1o, 3-furyl-substituted enal 1p were also worked well in
these useful methodology (Table 2, entries 17-18).
Furthermore, the naphthyl-derived enal 1q was also tolerated,
but the yield of conjugated product 3q was a little lower in
that case (Table 2, entry 19). However, the reaction of dienal
1r with 2-aminoacrylate 2a worked smoothly under the
optimal reaction conditions (Table 2, entry 20). Changing the
ester group of 2-aminoacrylate from ethyl to methyl delivered
the desired 3s in 80% yield and 4s in 75% yield, which were
similar to the results for 1a (Table 2, entry 21).
Entry Catalyst
Slovent
THF
THF
THF
THF
THF
THF
Toluene
DCM
CH3CN
Base
Products Yield (%) b
1
2
3
A
B-D
E
DABCO
DABCO
DABCO
DBU
3a
Trace
3a
8
-
80
60
15
66
74
58
56
65
75
83
4
E
3a
3a
3a
3a
5
E
K2CO3
6
E
DMAP
DABCO
DABCO
DABCO
7
E
8
E
3a
3a
9
E
10
11
12c
E
E
E
1,2-dioxane DABCO
3a
4a
6a
To emphasize the generality of our approach, the
THF
THF
LiOAc
LiOAc
applicability of the NHC catalyst with isatin-derived enals
5 to
generate spirooxindoles was also examined. In our strategy a
6
a
Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), catalyst (20 mol %),
base (1.5 equiv.), oxidant (2.0 equiv.), solvent (2.0 mL), 12 h. b Isolated yield.
c Reaction conditions: 5a (0.2 mmol), 2a (0.3 mmol), catalyst (20 mol %), 20
mol % LiOAc was used as the base. DABCO = 1,4-Diazabicyclo[2.2.2]octane;
Table 2. Substrate scope for the synthesis of dihydropyridinones a
DBU
= 1,8-diazabicyclo[5.4.0]undec-7-ene; TBD = 1,5,7-triazabicyclo
[4.4.0]dec-5-ene; DMAP = 4-dimethylaminopyridine;
strategy by employed different bases and
a series of
spirooxindoles derivatives were also synthesized with
moderate to good yields (Scheme 1).
To investigate the unprecedented [3+3] cycloaddition of
enal and 2-aminoacrylates, we first surveyed the commercial
available cinnamaldehyde 1a and N-tos-protected 2-
Entry
1
2
3
4
5
6
7
8
R
R1
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Condition A b
3a, 80%
3b, 78%
3c, 10%
3d, 65%
3e, 72%
Condition B b
1a, Ph
4a, 75 %
4b, 66%
1b, 4-MeC6H4
1c, 4-MeOC6H4
1d, 4-ClC6H4
1e, 4-BrC6H4
1f, 4-FC6H4
1g, 4-CF3C6H4
1h, 2-MeC6H4
1i, 2-BrC6H4
1j, 3-MeC6H4
1k, 3-FC6H4
1l, 3,5-FC6H4
1m, 3-Br,4-FC6H4
1n, 3,4-MeC6H3
1o, 3- thienyl
1p, 2-furyl
3c:4c = 1:3, 35% d,e
4d, 29%
aminoacrylate 2a as the starting materials and quinone
7 was
used as the oxidant. The precatalyst promoted the reaction
A
4e, 41%
3f, 60%
3g, 35%
and gave the 3,4-dihyropyridinone 3a as the only product in 8%
yield in the presence of DABCO. However, the precatalyst B, C
3f, 65%
3g, 66% (78%)c
and
D
did not work for this reaction (Table 1, entry 2). To our
as the precatalyst
3h:4h=1:5, 50%d 3h:4h = 1:10, 80%d,e
great delight, employing the triazolium salt
E
9
3i, 64%
3j, 65% (73%)c
3k, 74%
4i, 84%
4j, 82%
4k, 61%
sufficiently improved the yield to 80% (Table 1, entry 3).
However, no improvement of yield was observed for the
reaction by screening different bases and solvents (Table 1,
entries 4-10). Notably, when LiOAc was used as the base the
5,6-dihydropyridinones was obtained as the product with 75%
yield (Table 1, entry 11). To further emphasize this novel
strategy, the application of the NHC-catalysis with isatin-
derived enals 5a to generate spirooxindoles was examined
using LiOAc as the base, and the corresponding product 6a was
obtained in 83% yield (Table 1, entry 16).
10
11
12
15
16
17
18
19
20
21
3l, 69%
4l, 57%
3m, 75%
3n, 61%
3o, 55%
3p, 28%
3q, 27%
3r, 49%
4m, 50%
4n, 63%
3o:4o=1:4, 44%d,e
4p, 54%
1q, 1-Naphth
1r, styryl
4q, 68%
4r, 41%
4s, 75%
1s, Ph
3s, 80%
All reactions were performed on a 0.2 mmol scale. Yield of isolated product. c
Toluene was used as the solvent.
experiments were carried out to further reduce the isomerisation from 4 to 3, for
detail please see supporting information.
a
b
With these two acceptable reaction conditions in hand, we
next explored the generality of this strategy. Both electron-
donating and electron-withdrawing groups on the para-
position of aromatic enals were tolerated and give the desired
d
e
Yield of isolated product.
Several
2 | J. Name., 2012, 00, 1-3
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Scheme 2. Substrate scope for the synthesis of spirooxindoles
Scheme 4. Proposed catalytic pathway
broad range of different isatin-derived enals bearing
electron-
donating, and -withdrawing substituents on the aromatic ring
were examined, giving the corresponding spirooxindoles
products (6a-6k) with moderate to excellent yields. Enal
substrates with varied N-substituents such as methyl and allyl
also worked well in this annulations procedure and afford the
intermediate IV. The tautomerization of IV forms
undergoes lactam formation to yield product
V
or
, which
3
6
and
regenerate the NHC catalyst. Meanwhile, when the reaction
utilizes DABCO as the base, the product transformed to
product via carbon-carbon double bond migration pathway.
3
4
However, the 1,4-addition of-unsaturated acyl azolium
intermediate II with 2-aminoacrylate 2a followed by
intramolecular acylation could also liberate the NHC catalyst
and give the ultimate product (path b). And this reaction
pathway cannot be totally ruled out.
To further explore the reaction mechanism, several control
experiments were then carried out. Treatment of chiral 5,6-
dihydropyridinone 4aa in the presence of 50 mol% DABCO
affording the 3,4-dihydropyridinone 3aa in 65% yield and the
high enantiomeric excess was retained. The Ts group of 4aa
could be removed by DBU, meanwhile the dehydrogenation
reaction also occurred to afford 8a as the product in 70% yield
(Scheme 5, Eqn 1). From this observation, we demonstrated
that the transformation begin with deprotonation of 4aa at
corresponding products in excellent yields (6i
, 6j). The
structures of compounds 6a were unambiguously confirmed
by X-ray crystallographic analysis.13 (Scheme 2)
To further investigate this novel strategy, a preliminary
study on the asymmetric catalytic version of this methodology
was carried out. In the presents of 20 mol% chiral triazolium
salt F, the reaction of enal 1a and 2-aminoacrylates 2a using
lithium acetate as the base to afford 4aa as the product in 67%
yield with 99% ee. Interestingly, when the reaction carried out
using DABCO as the base and chiral triazolium F as the catalyst,
3,4-dihydropyridinone 3aa was generated in 83% yield with 99%
ee (Scheme 3, Eqn 1). Similarly, the spirooxindoles 6a was also
prepared with good yield and excellent enantiomeric excess
(Scheme 3, Eqn 2). And these results serve as a proof of
concept for developing a highly efficient asymmetric version of
the current reaction.
C(4)–H, which facilitated by the adjacent C(4)–aryl and -
position of -unsaturated ester units, and subsequently
undergoes protonation at C(6) from the less hindered side to
afford intermediate 9a and then rapidly undergoes the second
carbon-carbon double bonds migration to give 3aa as the
product. We also found that racemic 4a could transformed to
A postulated reaction pathway for this reaction is shown in
Scheme 4. The addition of the NHC catalyst to enals
derived enals to generate the Breslow intermediates
rapidly undergoes oxidative reaction to afford the 
unsaturated acyl azolium intermediate II According to
1
or isatin-
5
I
, which
-
3,4-dihydropyridinone 3a in the presence of chiral NHC F, but
no enantioselectivity was observed (Scheme 5, Eqn 2). This
.
previous work reported by Bode and co-workers, 1,2-addition
of 2-aminoacrylate 2a to intermediate II followed by a Claisen
rearrangement affords intermediate III (path a).14 Then the
tautomerization of intermediate III leads to the formation of
Scheme 3. Enantioselective studies of this methodology
Scheme 5. Control Experiments.
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Angew. Chem. Int. Ed. 2007, 46, 2988; (c) A. T. Biju, N.
result illustrated that the NHC catalyst did not participate in
this transformation. Furthermore, the combination of 2-
bromoenal 10a and ynal 11a with 2-aminoacrylates 2a could
also afford those two dihydropyridinones with different
View Article Online
Kuhl, F. Glorius, Acc. Chem. Res.D2O0I1: 110,.14043,9/1C178C2C;0(2d7)53VB.
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bases.15 And this result demonstrated that the generated 
-
unsaturated acyl azolium III as the key intermediate in the
reaction pathway.
Conclusions
In summary, we have described a rapid access to 5,6-
dihydropyridinones, 3,4-dihydropyridinones and spiro-
oxindoles via NHC-catalyzed [3+3] annulation of 2-
aminoacrylates with enals and oxindole-derived enals. In this
unique strategy, 2-aminoacrylates served as nucleophiles.
Utilize of different bases played important roles for the
carbon-carbon bonds formation. In addition, a preliminary
study on the asymmetric synthesis of 3,4-dihydropyridinones,
5,6-dihydropyridinone and spirooxindoles were also achieved.
Furthermore, the applications of 2-aminoacrylates as
nucleophiles in other organic transformation are currently
underway in our laboratory.
5
6
Some selected recent examples of a1-d1 umpolung: (a)
G. Wen, Y. Su, G. Zhang, Q. Lin, Y. Zhu, Q. Zhang, X.
Fang, Org. Lett., 2016, 18, 3980; (b) P. Haghshenas, J.
W. Quail, M. Gravel, J. Org. Chem., 2016, 81, 12075; (c)
G. Wang, X. Chen, Y. Zhang, W. Yao, C. Ma, Org. Lett.,
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Chem. Commun., 2017, 53, 3338.
Some selected recent examples of a3-d3 umpolung: (a) J.
Xu, S. Hu,; Y. Lu, Y. Dong, W. Tang, T. Lu, D. Du, Adv.
Synth. Catal., 2015, 357, 923; (b) Y. Zhang, X. Wu, L.
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R. Chi, Org. Chem. Front., 2017, 4, 467; (c) C. Guo, D.
Janssen-Müller, M. Fleige, A. Lerchen, C. G. Daniliuc, F.
Glorius, J. Am. Chem. Soc., 2017, 139, 4443; (d) C. Guo,
M. Fleige, D. anssen-M ller, C. G. Daniliuc, F. Glorius, J.
Am. Chem. Soc., 2016, 138, 7840. (e) L. Yang, B. Tan, F.
Acknowledgment
Wang, G. Zhong, J. Org. Chem., 2009, 4, 1744.
7
(a) X. Wu, B. Liu, Y. Zhang, M. Jeret, H. Wang, P. Zheng,;
S. Yang, B.-A. Song, Y. R. Chi, Angew. Chem. Int. Ed.,
2016, 55, 12280; (b) S. Hu, B. Wang, Y. Zhang, W. Tang,
We thank the National Natural Science Foundation of China
(21402037), Natural Science Foundation of Hebei Province
(B2015201175), and the Foundation of Hebei Education
Department (QN2014106) for financial support.
M. Fang, T. Lu, D. Du, Org. Biomol. Chem., 2015, 13
4661; (c) C. Zhang, J. F. Hooper, D. W. Lupton, ACS
Catal., 2017, 2583; (d) J. Kaeobamrung, J.
,
7
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7CC02753B
Ph
N
O
O
N
Ph
Ts
N
N
ClO4
Ts
N
Ph
H
O
CO2R1
R
CO2R1
NHC
Ts
O
O
Base : LiOAc
N
R2
O
R
H
HN
O
Ts
N
N
CO2R1
NHC, Base, [O]
THF, 45 oC, 12 h
NHC, LiOAc, [O]
THF, 45 oC, 12 h
R2
Spiro-oxindoles
R
CO2R1
Base : DABCO
Dihydropyridinones
A strategy for the NHC-catalyzed synthesis of dihydropyridinones and spirooxindoles has been
developed via [3+3] annulation reactions of enals or isatin-derived enals with 2-aminoacrylates
under oxidative condition.