Asymmetric (4 + 3) and (4 + 1) Annulations of Isatin-derived Morita-Baylis-Hillman Carbonates to Construct Diverse Chiral Heterocyclic Frameworks

Article abstract of DOI:10.1021/acs.orglett.0c01283

A chiral tertiary amine-catalyzed asymmetric γ-regioselective (4 + 3) annulation reaction of isatin-derived Morita-Baylis-Hillman carbonates and 1-azadienes was developed, delivering chiral azepane spirooxindoles with excellent stereoselectivity. In addition, by tuning the substituents of Morita-Baylis-Hillman carbonates, the switchable γ-(4 + 3) or α-(4 + 1) annulation reaction with o-quinone methides was observed to furnish benzo[b]oxepines or 2,3-dihydrobenzofurans, respectively, under similar catalytic conditions.

Full text of DOI:10.1021/acs.orglett.0c01283

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Letter
Asymmetric (4 + 3) and (4 + 1) Annulations of Isatin-derived Morita−
Baylis−Hillman Carbonates to Construct Diverse Chiral Heterocyclic
Frameworks
Ru-Jie Yan, Bao-Xin Liu, Ben-Xian Xiao, Wei Du, and Ying-Chun Chen*
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ABSTRACT: A chiral tertiary amine-catalyzed asymmetric γ-regioselective (4 + 3) annulation reaction of isatin-derived Morita−
Baylis−Hillman carbonates and 1-azadienes was developed, delivering chiral azepane spirooxindoles with excellent stereoselectivity.
In addition, by tuning the substituents of Morita−Baylis−Hillman carbonates, the switchable γ-(4 + 3) or α-(4 + 1) annulation
reaction with o-quinone methides was observed to furnish benzo[b]oxepines or 2,3-dihydrobenzofurans, respectively, under similar
catalytic conditions.
Scheme 1. Diverse (4 + 3) Annulations of MBH Carbonates
he seven-membered N-heterocyclic motif is a privileged
Tscaffold in diverse bioactive natural products and
pharmaceuticals,1 and thus the development of effective
protocols to construct these architectures has attracted
growing interest for synthetic chemists.2 Nevertheless,
compared with five- or six-membered rings via classic [3 +
2] or [4 + 2] cycloadditions or (3 + 3) annulations, the
formation of seven-membered hetero- or carbocycles,
especially via asymmetric catalysis, is more challenging, as
harsh conditions are usually required to overcome entropic and
enthalpic penalties.3 The asymmetric (4 + 3) annulation
reaction has been regarded as one of the most efficient
approaches to access these compounds, and highly reactive
three-atom components are usually utilized. As a result, the
current protocols mainly rely on employing active 1,3-poles,
including nitrones,4 azomethine imines,5 in-situ-generated
homoenolates6 or acyl azoliums7 via N-heterocyclic carbene
(NHC) catalysis and palladium-trimethylenemethane (Pd-
TMM) intermediates.8
The Morita−Baylis−Hillman (MBH) carbonates could
generate zwitterionic allylic ylide species in the presence of
Lewis base catalysts, acting as good three-atom synthons with
suitable electrophilic reagents in various stereoselective (3 + n)
annulation reactions.9 In particular, the Lu group disclosed the
first (4 + 3) reaction of benzaldehyde-derived MBH
carbonates and methyl coumalate catalyzed by phosphines
(Scheme 1a, 1).10 Later, a few four-atom units, including 1-
azadienes and o-quinone methides, were utilized to furnish
different (4 + 3) annulations with MBH derivatives (Scheme
1a, 2−4).11 Unfortunately, no asymmetric version has been
Received: April 12, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01283
© XXXX American Chemical Society
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uncovered despite the significant progress in this field. Very
recently, an asymmetric (4 + 3) annulation reaction with γ-
regio-, chemo-, and stereoselectivity was disclosed by our
group, in which two types of zwitterionic species were
generated from MBH carbonates and functionalized allylic
carbonates, respectively, under the cooperative catalysis of
tertiary amines and chiral iridium complexes (Scheme 1b).12
Nevertheless, the asymmetric version achieved by a single
chiral Lewis base organocatalyst, as a more atom-economical
and convenient approach, is still desirable. Here we report an
asymmetric (4 + 3) annulation reaction between isatin-derived
MBH carbonates and 1-azadienes under the catalysis of chiral
tertiary amines, producing fused azepane spirooxindoles with
excellent stereoselectivity (Scheme 1c).
Table 1. Screening Conditions of (4 + 3) Annulations of
MBH Carbonates 1 and 1-Azadienes 2
a
b
c
entry
C
1
solvent
yield (%)
ee (%)
Because 2-benzylenebenzofuran-3(2H)-one-based 1-aza-
diene 2a has been successfully utilized as a four-atom partner
in (4 + 3) annulation with a simple MBH carbonate,11c,13 we
first explored the assembly of 2a and isatin-derived MBH
carbonate 1a under the catalysis of DABCO (10 mol %). As
expected, the (4 + 3) annulation reaction proceeded efficiently
in toluene at room temperature, and the γ-regioselective
azepane product 3a was obtained in an excellent yield with
exclusive diastereoselectivity after 5 h (Table 1, entry 1). As a
result, we explored the asymmetric version with chiral tertiary
amines. Although a spectrum of catalytic parameters were
explored, only moderate enantioselectivity for chiral 3a was
attained in a fair yield in CHCl3 under the catalysis of α-IC C1
(Table 1, entry 2).14 Because a much higher reactivity was
observed by using the 2-benzylenebenzo[b]thiophen-3(2H)-
one-derived 1-azadiene 2b (Table 1, entry 3),15 we then
explored the catalytic conditions for the assembly of MBH
carbonate 1 and 1-azadiene 2b. A few cinchona-derived tertiary
amine catalysts were evaluated (Table 1, entries 4−7),
indicating that β-ICD C3 derived from quinidine provided
the best enantioselectivity (Table 1, entry 5). Other solvents
were briefly screened but with inferior data (Table 1, entries
8−11). The reaction proceeded smoothly at lower temper-
ature, and less MBH carbonate 1a was required (Table 1, entry
12). We further modified the substitution pattern of the MBH
carbonate partner (Table 1, entries 13−15), and better
enantioselectivity was gained when MBH carbonate 1b or 1d
was used (Table 1, entries 13 and 15). In addition, adding 4 Å
MS was slightly beneficial for enantioselectivity (Table 1, entry
16).14 To improve the enantiocontrol, the 2′-methylated β-
ICD C6 was used for the reaction of MBH carbonates 1b and
2b, and an outstanding ee value was pleasingly achieved (Table
1, entry 17). Importantly, the annulation still proceeded
effectively with 2 mol % C6, furnishing retained high yield and
stereoselectivity at room temperature (Table 1, entry 18). The
asymmetric reaction also took place on a larger scale, and
similar excellent data were gained (Table 1, entry 19).
d
1
DABCO
C1
C1
C2
C3
C4
C5
C3
C3
C3
C3
C3
C3
C3
C3
C3
C6
C6
C6
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1b
1b
1b
1b
toluene
CHCl3
toluene
toluene
toluene
toluene
toluene
PhCF3
CHCl3
THF
CH3CN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
3a, 92
3a, 43
3b, 93
3b, 84
3b, 93
3b, 87
3b, 90
3b, 90
3b, 96
3b, 96
3b, 60
3b, 95
3c, 96
3d, 95
3e, 95
3c, 95
3c, 94
3c, 96
3c, 92
d
2
3
4
5
6
7
8
9
−66
−40
−50
70
60
40
65
67
50
40
70
80
70
83
82
98
98
98
10
11
12
13
14
15
16
17
18
19
ef
,
ef
,
ef
,
ef
,
ef g
, ,
ef g
, ,
eg h
, ,
eg hi
,
, ,
a
Unless otherwise noted, the reaction was performed with MBH
carbonate 1 (0.1 mmol, 2.0 equiv), 1-azadiene 2b (0.05 mmol, 1.0
equiv), and C (10 mol %) in solvent (0.05 mL) at rt for 5 h. Isolated
yield. Determined by HPLC analysis on a chiral stationary phase; dr
>19:1 by H NMR analysis. 2a was used. MBH carbonate 1 (0.06
mmol, 1.2 equiv) was used. At 5 °C for 12 h. 4 Å MS (20.0 mg) was
added. With C (2 mol %) at room temperature for 12 h. On a 1.0
b
c
d
e
1
f
g
h
i
mmol scale.
data (Table 2, entry 13). On the contrary, a number of
benzothiophene-derived 1-azadienes 2 bearing different
substituents were explored in the reactions with MBH
carbonate 1b under the same catalytic conditions, and
outstanding data were generally produced (Table 2, entries
14−22). It should be note that the MBH carbonate 4a (Table
3, R1 = H) derived from acrylate was inert in the reaction with
1-azadiene 2b under identical conditions.14
Consequently, the substrate scope and limitations of this γ-
regioselective asymmetric (4 + 3) annulation reaction were
investigated under the optimal catalytic conditions. As shown
in Table 2, most reactions proceeded smoothly, affording the
corresponding azepane spirooxindoles in high yields with
excellent diastereo- and enantioselectivity. Specifically, the
different N-substitutions of the MBH carbonates 1 had
inappreciable effects on the reactions (Table 2, entries 1−4).
In addition, the MBH carbonates 1 bearing electron-donating
or -withdrawing groups on the aryl ring were well tolerated in
the reactions with 1-azadiene 2b (Table 2, entries 5−12). The
MBH carbonate derived from 7-azaisatin also delivered good
In 2019, the Du group developed an efficient Lewis-base-
catalyzed γ-regioselective (4 + 3) annulation reaction of o-
quinone methides (o-QMs) and isatin-based MBH carbonates,
and a series of valuable benzo[b]oxepine derivatives incorpo-
rating a spirooxindole motif were produced in moderate to
excellent yields with good diastereoselectivity but without
achieving any asymmetric success.11d Pleasingly, the asym-
metric γ-regioselective (4 + 3) annulation reaction of MBH
carbonates 4 from methyl acrylate and o-QMs 5 could be
realized under our catalytic conditions. After screenings,14 the
chiral product 6a was obtained in 83% yield with 77% ee under
the catalysis of amine C2 (Table 3, entry 1). The substrate
B
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scope and limitations of the γ-regioselective (4 + 3)
annulations were briefly explored, and an array of chiral
oxepane spirooxindole frameworks 6 could be constructed in
good yields with moderate enantioselectivity (Table 3, entries
2−7). In addition, the enantiopurity of the cycloadducts could
be significantly improved after simple recrystallization (Table
3, entries 4 and 5, data in parentheses).
Table 2. Substrate Scope and Limitations of (4 + 3)
Annulations for MBH Carbonates 1 and 1-Azadienes 2
a
During the exploration for the substrate scope of the MBH
carbonates 4, it was found that the γ-regioselective (4 + 3)
annulation pattern was dominantly switched to an α-
regioselective (4 + 1) version by using the MBH carbonates
7 from t-butyl acrylate under the identical catalytic
conditions.16 To the best of our knowledge, this is the first
example of the chiral tertiary amine-catalyzed asymmetric α-
regioselective (4 + 1) annulation reaction of isatin-derived
MBH carbonates.17 The 2,3-dihydrobenzofuran 8a having a
tetrasubstituted alkene moiety was isolated in 77% yield with
98% ee catalyzed by amine C2 in PhCF3 (Table 4, entry 1),14
b
c
entry
R
R1, R2
H, Ph
H, Ph
H, Ph
H, Ph
5-Me, Ph
5-MeO, Ph
5,7-Me2, Ph
5-F, Ph
5-Cl, Ph
7-Cl, Ph
5-Br, Ph
5-I, Ph
yield (%)
ee (%)
1
2
3
4
5
6
7
8
Bn
3b, 94
3c, 95
3d, 95
3e, 95
3f, 96
3g, 89
3h, 90
3i, 95
3j, 95
3k, 97
3l, 94
3m, 96
3n, 97
3o, 97
3p, 95
3q, 97
3r, 96
3s, 93
3t, 99
3u, 84
3v, 99
3w, 96
>99
d
Me
MOM
Boc
Bn
Bn
Bn
Bn
Bn
Bn
Bn
98
98
98
98
92
98
98
99
99
92
98
98
97
97
97
96
98
98
98
98
>99
9
10
11
12
Table 4. Substrate Scope of α-Regioselective (4 + 1)
Bn
a
Annulations for MBH Carbonates 7 and o-QM 5b
e
13
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H, Ph
14
15
16
17
18
19
20
21
22
H, 4-FC6H4
H, 4-ClC6H4
H, 3-BrC6H4
H, 4-BrC6H4
H, 3-MeC6H4
H, 4-MeC6H4
H, 4-MeOC6H4
H, 2-naphthyl
H, 2-thienyl
b
c
entry
1
R
R1
yield (%)
ee (%)
Me
Bn
Bn
Me
Me
Me
Me
Bn
H
H
8a, 71
8b, 64
8c, 58
8d, 73
8e, 61
8f, 63
99
99
95
>99
95
95
d
2
3
d
5-MeO
5-Me
5-F
5-Cl
5-I
a
Unless otherwise noted, the reactions were performed with MBH
carbonate 1 (0.12 mmol, 1.2 equiv, X = CH), 1-azadiene 2 (0.1 mmol,
1.0 equiv), 4 Å MS (40.0 mg), and C6 (2 mol %) in toluene (1.0 mL)
4
5
6
b
c
at rt for 5−24 h. Isolated yield. Determined by HPLC analysis on a
e
f
d
chiral stationary phase; dr >19:1 by 1H NMR analysis. Absolute
7
dg
,
8g, 76 (67)
8h, 64
97 (97)
89
8
H
configuration of enantiopure 3c was determined by X-ray analysis.
The other products were assigned by analogy. X = N.
e
a
Unless otherwise noted, the reactions were performed with MBH
carbonate 7 (0.12 mmol, 1.2 equiv, X = CH), o-QM 5b (0.1 mmol,
1.0 equiv), 4 Å MS (40.0 mg), and amine C2 (10 mol %) in PhCF3
Table 3. Substrate Scope of γ-Regioselective (4 + 3)
Annulations of MBH Carbonates 4 and o-QMs 5
b
c
a
(1.0 mL) at −10 °C or rt for 10−36 h. Isolated yield. Determined
by HPLC analysis on a chiral stationary phase; dr >19:1 by 1H NMR
d
e
analysis. MBH carbonate 7 (0.15 mmol, 1.5 equiv) was used. Data
f
in parentheses were obtained on a 1.0 mmol scale. Absolute
configuration of enantiopure 8g was determined by X-ray analysis.
g
The other products were assigned by analogy. X = N.
indicating that the steric hindrance of the ester group of 7 plays
a key role in achieving the switched regio- and chemo-
selectivity. As summarized in Table 4, an array of assemblies of
MBH carbonates 7 and o-QM 5b were explored, and the
corresponding products 8b−h were obtained in moderate
yields with excellent enantioselectivity (Table 4, entries 2−8).
In addition, high levels of stereoselectivity could also been
attained on a larger scale, albeit in a slightly decreased yield
(Table 4, entry 7, data in parentheses).
Product 3c possessing multiple functional groups could
undergo selective transformations. As illustrated in Scheme 2,
the cyano group was smoothly hydrogenated and subsequently
protected as an N-Boc derivative in the presence of Raney Ni
and (Boc)2O, giving the product 9 in a high yield with the
retained ee value. Importantly, a highly diastereoselective 1,3-
dipolar cycloaddition reaction of the crowded tetrasubstituted
alkene moiety of compound 8g could still be efficiently
b
c
entry
R1, 5
H, 5a
5-Me, 5a
5-MeO, 5a
5-Cl, 5a
5-I, 5a
yield (%)
ee (%)
73
67
66
1
2
3
4
5
6
6a, 83
6b, 75
6c, 70
d
d
6d, 60 (32)
6e, 63 (39)
6f, 79
75 (98)
76 (98)
73
7-F, 5a
H, 5b
e
7
6g, 81
58
a
Unless otherwise noted, the reactions were performed with MBH
carbonate 4 (0.15 mmol, 1.5 equiv, added in two potions), o-QM 5
(0.1 mmol, 1.0 equiv), 4 Å MS (40.0 mg), and amine C2 (20 mol %)
b
c
in PhCF3 (1.0 mL) at −20 °C for 12 h. Isolated yield. Determined
by HPLC analysis on a chiral stationary phase; dr >19:1 by 1H NMR
d
analysis. Data in parentheses were obtained after recrystallization.
e
At rt.
C
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Authors
Scheme 2. Synthetic Transformations of Cycloadducts
Ru-Jie Yan − Key Laboratory of Drug-Targeting and Drug
Delivery System of the Ministry of Education and Sichuan
Research Center for Drug Precision Industrial Technology, West
China School of Pharmacy, Sichuan University, Chengdu
610041, China
Bao-Xin Liu − Key Laboratory of Drug-Targeting and Drug
Delivery System of the Ministry of Education and Sichuan
Research Center for Drug Precision Industrial Technology, West
China School of Pharmacy, Sichuan University, Chengdu
610041, China
Ben-Xian Xiao − Key Laboratory of Drug-Targeting and Drug
Delivery System of the Ministry of Education and Sichuan
Research Center for Drug Precision Industrial Technology, West
China School of Pharmacy, Sichuan University, Chengdu
610041, China
Wei Du − Key Laboratory of Drug-Targeting and Drug Delivery
System of the Ministry of Education and Sichuan Research
Center for Drug Precision Industrial Technology, West China
School of Pharmacy, Sichuan University, Chengdu 610041,
China
conducted with sarcosine and paraformaldehyde,18 furnishing
the separable spirooxindole product 10 with four contiguous
stereogenic centers in excellent yield.
In conclusion, we have developed a chiral tertiary amine-
catalyzed asymmetric γ-regioselective (4 + 3) annulation
reaction between isatin-derived MBH carbonates and 2-
alkylenebenzo[b]thiophen-3(2H)-one-derived 1-azadienes. An
array of chiral azepane spirooxindole frameworks were
efficiently constructed in good yields with excellent diastereo-
and enantioselectivity. Moreover, the asymmetric γ-regiose-
lective (4 + 3) annulation reaction between MBH carbonates
from acrylate and o-quinone methides was realized, and a
switchable α-regioselective (4 + 1) annulation reaction was
observed by simply tuning the ester group of MBH carbonates
under similar catalytic conditions, producing oxepane spiroox-
indoles or 2,3-dihydrobenzofuran derivatives, respectively, with
moderate to excellent stereocontrol. The investigation of the
further applications of these heterocycles with structural
diversity is underway.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01283
Funding
We are grateful for the financial support from the NSFC
(21931006 and 21921002).
Notes
The authors declare no competing financial interest.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01283.
More screening conditions, complete experimental
procedures and characterization of new products,
NMR and HRMS spectra, HPLC chromatograms, and
crystallographic information (PDF)
Accession Codes
́
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emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
Ying-Chun Chen − Key Laboratory of Drug-Targeting and
Drug Delivery System of the Ministry of Education and Sichuan
Research Center for Drug Precision Industrial Technology, West
China School of Pharmacy, Sichuan University, Chengdu
610041, China; College of Pharmacy, Third Military Medical
University, Shapingba, Chongqing 400038, China;
orcid.org/0000-0003-1902-0979; Email: ycchen@
scu.edu.cn
D
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Letter
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Hui, X.-P. Org. Lett. 2017, 19, 5380. (b) Shi, Q.; Wang, Y.; Wang, Y.;
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(12) Chen, Z.-C.; Chen, Z.; Yang, Z.-H.; Guo, L.; Du, W.; Chen, Y.-
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(13) For an early example, see: Rong, Z.-Q.; Wang, M.; Chow, C. H.
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(14) For more details, see the Supporting Information.
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