Asymmetric intramolecular Friedel–Crafts reaction catalyzed by a spiropyrrolidine organocatalyst: Enantioselective construction of indolizine and azepine frameworks

Article abstract of DOI:10.1016/j.tetlet.2018.09.061

The asymmetric intramolecular Friedel–Crafts type Michael reaction of α,β-unsaturated aldehyde with pyrrole, catalyzed by a spiropyrrolidine (SP)-type organocatalyst, has been accomplished, which allows the construction of a series of azepine and indolizi

Full text of DOI:10.1016/j.tetlet.2018.09.061

Accepted Manuscript
Asymmetric intramolecular Friedel–Crafts reaction catalyzed by a spiro-pyrro-
lidine organocatalyst: enantioselective construction of indolizine and azepine
frameworks
Yi-Hang Zhang, Yong-Hai Yuan, Shu-Yu Zhang, Yong-Qiang Tu, Jin-Miao
Tian
PII:
S0040-4039(18)31165-1
https://doi.org/10.1016/j.tetlet.2018.09.061
TETL 50300
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Reference:
Tetrahedron Letters
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21 September 2018
25 September 2018
Please cite this article as: Zhang, Y-H., Yuan, Y-H., Zhang, S-Y., Tu, Y-Q., Tian, J-M., Asymmetric intramolecular
Friedel–Crafts reaction catalyzed by a spiro-pyrrolidine organocatalyst: enantioselective construction of indolizine
and azepine frameworks, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.09.061
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Tetrahedron Letters
Asymmetric intramolecular Friedel–Crafts reaction catalyzed by a spiro-pyrrolidine
organocatalyst: enantioselective construction of indolizine and azepine frameworks
Yi-Hang Zhang a, Yong-Hai Yuan b, Shu-Yu Zhang a, Yong-Qiang Tu a,b,*, Jin-Miao Tian a,*
a School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
b State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The asymmetric intramolecular Friedel–Crafts type Michael reaction of α,β-unsaturated
aldehyde with pyrrole, catalyzed by a spiro-pyrrolidine (SP)-type organocatalyst, has been
accomplished, which allows the construction of a series of azepine and indolizine frameworks
with high to excellent enantioselectivities (up to 98% ee). Moreover, the substrate scope could
be extended to generate a quaternary center in indolizine frameworks (up to 96% ee).
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Friedel–Crafts
spiro-pyrrolidine organocatalyst
enantioselective
indolizine and azepine
excellent property and our interest in the synthesis of above
frameworks, herein, we have successfully accomplished
asymmetric intramolecular Friedel-Crafts type7 Michael addition
of α, β-unsaturated aldehyde with pyrrole using SPD
1. Introduction
The azepine and indolizine frameworks exist widely in natural
products such as stenine and rhazinal and so on (Figure 1).1
Therefore, great attention has been focused on developing
effective methods to construct these targets via asymmetric
catalysis.2 To date, several catalysis systems, including
Pd/NBE,2a Au/PHOX,2b Cu/BOX,2c,d CPA2e and secondary
amine,2f-h have been reported by Gu, Carreira et al, albeit with
limited examples. Therefore, a more general and effective
strategy with a broad of substrates is still desirable.
organocatalyst
2. Results and discussion
Initially, we began to investigate the asymmetric
intramolecular Friedel-Crafts cyclization using 2a as the model
substrate for constructing azepine framework (Table 1).
Pleasingly, the reaction proceeded smoothly to give the designed
product 3a with 96% ee and 81% yield under the similar
condition of our previous work (entry 1).6a Screening solvents
with DCM, Et2O, THF and so on, could not give better results
(entries 2-6). To our surprise, the property of additives could
seriously affect the result. For example, the reaction slowed
down sharply (almost needed 7 day) without PhCO2H as an
additive, along with a slightly lower 92% ee (entry 7). Moreover,
almost no product 3a was detected when PhCO2H was replaced
by NaOAc (entry 8). A better result was got when additive N-
(tert-butoxycarbonyl)-D-phenylalanide (Boc-D-Phe-OH) was
used (98% ee and 90% yield, entry 9). Lowering the reaction
temperature to 0 °C would also decrease the rate of reaction
(entry 10, about 8% of 2a was recovered). At last, the steric
hindrance effect of catalyst was investigated, the result showed
that the larger steric hindrance was, the better the
enantioselectivity was (entries 9, 11 and 12). These facts
demonstrate further the excellent property of the sterically
hindered SPD-type organocatalyst. As a result, entry 9 was
chosen as the standard condition for the following substrate
scope expansion.
Figure 1. Selected natural products containing indolizine and
azepine frameworks.
Chiral spirocyclic ligand and organocatalyst have played
more and more important role in asymmetric catalysis.3-5
Compared with chiral spirocyclic ligand-equipped metal
catalysts,4 study on chiral spirocyclic organocatalyst5 is reported
less. Recently, our group has developed a spiro-pyrrolidine
(SPD)-backbone-based organocatalyst, which could promote the
asymmetric Michael addition reaction as well as its cascade
reaction in excellent enantioselectivity.6 In consideration of this

2
Table 1
Table 2
Optimization for the asymmetric Friedel-Crafts reactiona
Substrate scope of intramolecular Friedel-Crafts reactiona
Entry Catalyst Solvent
Additive
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
-
t (h) Yieldb (%) eec (%)
T (℃)
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
toluene
DCM
Et2O
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
6
81
24
76
NR
15
20
41
ND
90
75
85
82
96
93
88
-
10
10
24
24
24
7d
24
5
3
4
THF
5
MeCN
DMF
58
60
92
-
6
7
toluene
toluene
8
NaOAc
9
toluene Boc-D-Phe-OH
98
95
94
69
10
11
12
toluene
toluene
toluene
Boc-D-Phe-OH
Boc-D-Phe-OH
Boc-D-Phe-OH
24
5
rt
rt
5
a The reaction was carried out with 2a (0.1 mmol, 1 equiv), 1 (0.2 equiv),
additive (0.2 equiv) in 1.0 mL of solvent and stirred for the appointed time.
Then NaBH4 (1.2 equiv) was added at 0 °C and stirred for 5 min.
b Isolated yield.
c Determined by HPLC.
Under the optimal condition, the substrate scope was further
investigated toward this cyclization. Almost all of the substrates
screened gave high to excellent enantioselectivities (87-98% ee)
and modest to high yields (49-86% yield) (Table 2). As for
azepine framework construction (Table 2, 2b-2k), first, the C2-
substituted and C3-substituted pyrrole substrates were well
tolerated in this reaction, although the C2-substituted pyrrole
gave lower yields than that of the C3-substituted ones (3b vs 3d,
3c vs 3e). Second, the yield could be decreased as the ability of
electron-withdrawing at C3-substituted aryl group was increased
(3e-3i). Furthermore, varying the substituentsʹ position at C3-
phenyl group could affect the results slightly (3i-3k).
Considering of the utility of indolizine skeleton in natural
product rhazinal and others, then we turned to assemble
indolizine framework (Table 2, 2l-2n). To our disappointment,
however, the substrates 2l and 2m could not be got in pure form
due to their instability which hindered further attempt. But C3-
arylsubstituted-pyrrole-enal 2n with electron-withdrawing group
(Cl) could proceed smoothly well to give satisfactory result (80%
yield and 87% ee). Their absolute configurations of 3a-3l were
unambiguously confirmed by X-ray analysis of 3eʹ,8 which was
derived from 3e (Figure 2).
a
The reaction was carried out with 2b-2n (0.1 mmol, 1 equiv), 1a (0.2
equiv), Boc-D-Phe-OH (0.2 equiv) in 1.0 mL of toluene and stirred until the
2b-2n was disappeared via TLC detection. Then NaBH4 (1.2 equiv) was
added at 0 °C and stirred for 5 min.
b Isolated yield.
c Determined by HPLC.
At last, we turned our attention to construct indolizine skeleton
with quaternary center. Under the standard condition, the
substrate 4a could work well and the expected product 5a was
obtained with 81% ee and 72% yield. After lowering the
temperature to -10 °C and simply screening solvent, an
acceptable result was obtained with 90% ee and 86% yield in
Et2O. Under the same condition, 4b-4d could also work well to
give the corresponding products with better ees with 93%-96%,
albeit with a little lower yield (33-61% yield).
Figure 2. Preparation and X-ray structure of compound 3eʹ
3. Conclusion
In conclusion, the SP organocatalyst was again proved to be
effective to the asymmetric intramolecular Friedel-Crafts type
Michael cyclization reaction of enal-chained pyrroles. It could be
used to construct not only azepine and indolizine frameworks
with tertiary carbon center in up to 98% ee, but also the
indolizine skeleton with all-carbon quaternary center in up to
96% ee. This achievement once again has demonstrated the
distant β-positionʹs enantiocontrol ability of SP type-
organocatalyst. Further study including natural product synthesis
using this method as key step is ongoing in our group.

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a
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a
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Acknowledgments
We are grateful for financial support provided by the National
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4
1) Asymmetric Friedel-Crafts reaction using our
SPD-type organocatalyst.
2) Construction of azepine and indolizine
frameworks in excellent ee.
3) All-carbon quaternary center in indolizine
frameworks was generated.