Organocatalytic sequential Hetero-Diels-Alder and Friedel-crafts reaction: Constructions of fused heterocycles with scaffold diversity

Article abstract of DOI:10.1021/ol202492x

A highly enantioselective aza-Diels-Alder and Friedel-Crafts reaction sequence of N-sulfonyl-1-aza-1,3-butadienes and aliphatic aldehydes tethered to an arene motif has been developed, affording the fused chiral piperidine frameworks with a versatile scaf

Full text of DOI:10.1021/ol202492x

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5874–5877
Organocatalytic Sequential
Hetero-DielsÀAlder and FriedelÀCrafts
Reaction: Constructions of Fused
Heterocycles with Scaffold Diversity
Si-Li Zhou,† Jun-Long Li,† Lin Dong,† and Ying-Chun Chen*,†,‡
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education
Ministry, Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China, and State Key Laboratory of Biotherapy,
West China Hospital, Sichuan University, Chengdu, China
ycchenhuaxi@yahoo.com.cn
Received September 14, 2011
ABSTRACT
A highly enantioselective aza-DielsÀAlder and FriedelÀCrafts reaction sequence of N-sulfonyl-1-aza-1,3-butadienes and aliphatic aldehydes
tethered to an arene motif has been developed, affording the fused chiral piperidine frameworks with a versatile scaffold diversity. A similar
strategy has been applied for the construction of complex chiral tetrahydroquinoxaline structures.
The chiral fused piperidine structures have been widely
embedded in natural alkaloids.1 They are also the “privi-
leged” skeletons in numerous pharmaceutically important
compounds that exhibit broad biological activities as
exemplified in Figure 1.2 Not surprisingly, the develop-
ment of efficient protocols to access enantioenriched fused
piperidine frameworks has always attracted much atten-
tion in both synthetic and medicinal chemistry communi-
ꢀ
3
ties. Notably, Franzen and co-workers presented a very
† West China School of Pharmacy.
effective one-pot organocatalytic reaction to complex qui-
nolizidine derivatives, in which anintramolecularFriedelÀ
Crafts reaction of an in situ formed acyliminium ion was
utilized to complete the fused ring production.4 Subse-
quently, Zhao et al. successfully expanded such a synthetic
strategy.5 Nevertheless, highly electron-rich 3-indolyl or
3,4-dimethoxyphenyl motifs usually have to be applied
in the FriedelÀCrafts sequence, which would significantly
limit the structural diversity constructions.6
‡ West China Hospital.
(1) For a review, see: Rubiralta, M.; Giralt, E.; Diez, A. Piperidine:
Structure, Preparation and Synthetic Applications of Piperidine and its
Derivatives; Elsevier: Amsterdam, 1991.
(2) For selected examples, see: (a) Brewster, W. K.; Nichols, D. E.;
Riggs, R. M.; Mottola, D. M.; Lovenberg, T. W.; Lewis, M. H.; Mailman,
R. B. J. Med. Chem. 1990, 33, 1756. (b) Cannon, J. G.; Lee, T.; Goldman,
H. D.; Long, J. P.; Flynn, J. R.; Verimer, T.; Costall, B.; Naylor, R. J.
J. Med. Chem. 1980, 23, 1. (c) Augstein, J.; Ham, A. L.; Leeming, P. R.
J. Med. Chem. 1972, 15, 466. (d) Kunstmann, R.; Fischer, G. J. Med.
Chem. 1984, 27, 1312. (e) Cook, C. E.; Wani, M. C.; Jump, J. M.; Lee,
Y.-W.; Fail, P. A.; Anderson, S. A.; Gu, Y.-Q.; Petrow, V. J. Med. Chem.
1995, 38, 753. (f) Rampin, O.; Jerome, N.; Susandeau, C. Life Science
2003, 72, 2329.
(3) For selected examples, see: (a) Akiyama, T.; Morita, H.; Fuchibe,
K. J. Am. Chem. Soc. 2006, 128, 13070. (b) Dickmeiss, G.; Jensen, K. L.;
Worgull, D.; Franke, P. T.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2011, 50, 1580. (c) Yamashita, M.; Yamada, K.-i.; Tomioka, K. J. Am.
Chem. Soc. 2004, 126, 1954. (d) Sarkar, N.; Banerjee, A.; Nelson, S. G.
J. Am. Chem. Soc. 2008, 130, 9222. (e) Xie, M.; Chen, X.; Zhu, Y.; Gao,
B.; Lin, L.; Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2010, 49, 3799.
(f) Pepe, A.; Pamment, M.; Georg, G. I.; Malhotra, S. V. J. Org. Chem.
2011, 76, 3527.
ꢀ
(4) (a) Franzen, J.; Fisher, A. Angew. Chem., Int. Ed. 2009, 48, 787.
ꢀ
(b) Zhang, W.; Franzen, J. Adv. Synth. Catal. 2010, 352, 499.
(5) (a) Wu, X. Y.; Dai, X. Y.; Nie, L. L.; Fang, H. H.; Chen, J.; Ren,
Z. J.; Cao, W. G.; Zhao, G. Chem. Commun. 2010, 46, 2733. (b) Fang, H.;
Wu, X.; Nie, L.; Dai, X.; Chen, J.; Cao, W.; Zhao, G. Org. Lett. 2010, 12,
5366. (c) Wu, X.; Dai, X.; Fang, H.; Nie, L.; Chen, J.; Cao, W.; Zhao, G.
Chem.;Eur. J. 2011, 17, 10510.
(6) For a recent study on N-acyliminium ion chemistry, see: Othman,
~
R. B.; Affani, R.; Tranchant, M.-J.; Antoniotti, S.; Dalla, V.; Dunach,
E. Angew. Chem., Int. Ed. 2010, 49, 776.
r
10.1021/ol202492x
Published on Web 10/13/2011
2011 American Chemical Society

Table 1. Screening Studies of Sequential Aza-DielsÀAlder and
FriedelÀCrafts Reactiona
temp
t
yieldb
(%)
eec
Figure 1. Selected fused piperidine systems showing broad bio-
logical activity.
entry
acid
TFA
equiv
(°C)
(h)
(%)
1d
2
1
1
rt
24
24
24
24
24
16
1
<10
À
HCl
À25
<10
À
3
HCl
1
rt
decomp.
decomp.
<10
À
Recently, we developed an asymmetric inverse-electron-
demand aza-DielsÀAlder reaction of N-sulfonyl-1-aza-
1,3-butadienes and aliphatic aldehydes catalyzed by a
chiral secondary amine, which delivered almost enantio-
pure piperidine derivatives containing a hemiaminal func-
tionality.7 As illustrated in Scheme 1, we envisaged that an
electrophilic iminium ion would be generated from the
hemiaminal intermediate under proper acidic conditions;
consequently, an intramolecular FriedelÀCrafts reaction
with a tethered arene system would proceed to give the
fused piperidine derivatives with high molecular com-
plexity.8 The iminium ion bears a strongly electron-with-
drawing N-sulfonyl group, which would be expected to
enhance the electrophilicity and might enable the utiliza-
tion of simple aromatic systems in FriedelÀCrafts cycliza-
tion step.
4
H2SO4
TFA
TFA
TFA
TFA
0.2
5
rt
À
5
rt
À
6
10
20
10
rt
75
>99
>99
>99
7
rt
67
8
À78Àrt
48
70
a Unless noted otherwise, reactions were performed with 1-azadiene
2a (0.1 mmol), aldehyde 3a (0.2 mmol), cat. 1 (0.01 mmol), and benzoic
acid (0.01 mmol) in MeCN/H2O (10:1, 0.5 mL) at rt for 2 h. Then solvent
was removed, and DCM (1.0 mL) and acid were added. The conditions
in the table (temp and t) refer to the FC step. b Isolated yield of two steps.
c Determined by chiral HPLC analysis. d FC reaction was conducted in
MeCN/H2O solution.
1-azadiene 2a9 and 3-(3,4-dimethoxyphenyl)propanal 3a
by the catalysis of R,R-diphenylprolinol O-TMS ether 110
under the established conditions.7a The aza-DielsÀAlder
reaction proceeded smoothly at room temperature, cleanly
affording the expected hemiaminal intermediate 4a. Thus
we set out to explore the intramolecular FriedelÀCrafts
reaction to generate an indeno[1,2-b]piperidine system
without the isolation of 4a. A very sluggish reaction was
observed by directly adding trifluoroacetic acid (TFA) to
the mixture (Table 1, entry 1). The desired FriedelÀCrafts
reaction also did not occur in DCM at À25 °C by using a
solution of HCl in ethyl acetate as the promoter (entry 2),4
and the decomposition of 4a happened at room tempera-
ture (entry 3). Concentrated H2SO4 was not successful too
(entry 4). Nevertheless, it seems that TFA might be an
optimal selection because it does not destruct hemiaminal
4a even in the presence of excess TFA (entry 5). To our
gratification, the reaction was greatly accelerated when 10
equiv of TFA were used, and indeno[1,2-b]piperidine deri-
vative 5a was isolated in good yield in an enantio- and
diastereomerically pure manner (entry 6).4a The reac-
tion time could be dramatically shortened by employing
a larger amount of TFA, but a slightly diminished yield
Scheme 1. Proposed Sequential Aza-DielsÀAlder/FriedelÀ
Crafts Reaction to the Fused Piperidines
Based on the above considerations, the initial inves-
tigation was conducted with readily available N-Tos
(7) (a) Han, B.; Li, J.-L.; Ma, C.; Zhang, S.-J.; Chen, Y.-C. Angew.
Chem., Int. Ed. 2008, 47, 9971. (b) He, Z.-Q.; Han, B.; Li, R.; Wu, L.;
Chen, Y.-C. Org. Biomol. Chem. 2010, 8, 755. (c) Li, J.-L.; Zhou, S.-L.;
Han, B.; Wu, L.; Chen, Y.-C. Chem. Commun. 2010, 46, 2665.
(8) For an excellent review, see: Albrecht, Ł.; Jiang, H.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2011, 50, 8492.
(9) (a) Boger, D. L.; Kasper, A. M. J. Am. Chem. Soc. 1989, 111,
1517. (b) Clark, R. C.; Pfeiffer, S. S.; Boger, D. L. J. Am. Chem. Soc.
2006, 128, 2587. (c) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc.
2006, 128, 8418.
(10) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen,
K. A. Acc. Chem. Rec. 2011, 44, DOI: 10.1021/ar200149w.
Org. Lett., Vol. 13, No. 21, 2011
5875

Scheme 2. Substrate Scope Studiesa
Scheme 3. A Hetero-DielsÀAlder and FriedelÀCrafts Sequence
to the Fused Tetrahydroquinoxalinesa
a Reactions were performed with diimide 6 (0.1 mmol), aldehyde 3 (0.2
mmol), cat. 1 (0.01 mmol), and benzoic acid (0.01 mmol) in THF/H2O
(10:1, 0.5 mL) at rt. After completion, the solution was concentrated, and
DCM (1.0 mL) and TFA (10 equiv) were added at rt. Reaction time and
yield refer to two steps; dr >99:1 by 1H NMR analysis.
skeleton; thus the more complex heterocyclic architectures
5lÀ5n were smoothly constructed, though longer reaction
times were required. Moreover, the heteroaryl motifs, the
3-thienyl or 3-indolyl group, were also smoothly employed in
the FriedelÀCrafts reaction, and the cyclic products 5o and
5p were produced, respectively, with outstanding results.
In addition, this sequential reaction strategy has been
expanded to construct other fused heterocyclic systems. As
outlined in Scheme 3, a diimide substrate11 6 could effec-
tively react with 3-(3,4-dimethoxyphenyl)propanal or 3-
(phenylthio)propanal to generate the chiral hemiaminal
intermediates 7 by the catalysis of chiral amine 1.12 Then
the similar TFA-mediated intramolecular FriedelÀCrafts
reaction was conducted to deliver the fused tetrahydro-
quinoxaline13 derivatives 8a or 8b, respectively, also in
excellent diastereo- (>99:1) and enantioselectivity and
good yields.14
a Reactions were performed with 1-azadiene 2 (0.1 mmol), aldehyde 3
(0.2 mmol), cat. 1 (0.01 mmol), and benzoic acid (0.01 mmol) in MeCN/
H2O (10:1, 0.5 mL) at rt. After completion, the solution was concen-
trated, and DCM (1.0 mL) and TFA (10 equiv) were added at rt. Reac-
tion time and yield refer to two steps; dr >99:1 by H NMR analysis.
bThe absolute configuration of 5c was determined by X-ray analysis, see
the Supporting Information. The others were assigned by analogy.
1
was obtained (entry 7). The reaction has been tested at
lower temperature, but the results could not be further
improved (entry 8).
In conclusion, we have developed an organocatalytic
and asymmetric sequential reaction to construct chiral
heterocyclic scaffolds with high molecular complexity,
which may have potential in medicinal chemistry. This
method relies on the chiral secondary amine-catalyzed aza-
DielsÀAlder of N-sulfonyl-1-aza-1,3-butadienes and ali-
phatic aldehydes via enamine catalysis, followed by the
intramolecular FriedelÀCrafts reaction of the hemiaminal
functionalgroup with a tetheredarene motif in the presence
of TFA. A spectrum of enantioenriched piperidines with
Subsequently, we explored an array of N-sulfonyl-1-aza-
1,3-butadienes and aliphatic aldehydes tethered to an aryl
or heteroaryl group. As shown in Scheme 2, for the
reactions of 3-(3,4-dimethoxyphenyl)propanal, in general,
N-Tos 1-azadienes carrying a diversely substituted aryl or
heteroaryl group could be well tolerated, giving the tricyc-
lic piperidine derivatives 5aÀ5h in good isolated yield and
excellent diastereo- (>99:1) and enantioselectivity, except
that a modest yield was obtained for an ortho-bromophe-
nyl substrate (5b). Good results were also attained for
1-azadienes with a differently substituted pattern (5i and
5j). On the other hand, we paid much attention on the
scope and limitations of the aldehyde counterpart, which
would allow the formation of the fused piperidines with
more scaffold diversity. Pleasingly, 4-phenylbutanal could
be efficiently applied, and a polyhydrobenzo[h]quinoline
5k was obtained in remarkable enantioselectivity and yield.
It was noteworthy that the simple phenyl group also ex-
hibited high reactivity in the FriedelÀCrafts step owing to
the strong activation effects of the N-Tos group.4,5 More
importantly, we found that the heteroatoms, such as S, O,
and N, could be successfully incorporated into the aldehyde
(11) Abraham, C. J.; Paull, D. H.; Scerba, M. T.; Grebinski, J. W.;
Lectka, T. J. Am. Chem. Soc. 2006, 128, 13370.
(12) Li, J.-L.; Han, B.; Jiang, K.; Du, W.; Chen, Y.-C. Bioorg. Med.
Chem. Lett. 2009, 19, 3952.
(13) For limited examples with the fused hydroquinoxaline struc-
tures, see: (a) Gavara, L.; Saugues, E.; Anizon, F.; Moreau, P. Tetra-
hedron 2011, 67, 1663. (b) Morley, J. S. J. Chem. Soc. 1952, 4008.
(c) Pearson, B. D.; Mitsch, R. A.; Cromwell, N. H. J. Org. Chem. 1962,
27, 1674. For asymmetric synthesis of chiral tetrahydroquinoxalines,
see:(d) Chen, Q.-A.; Wang, D.-S.; Zhou, Y.-G.; Duan, Y.; Fan, H.-J.;
Yang, Y.; Zhang, Z. J. Am. Chem. Soc. 2011, 133, 6126 and references
cited therein.
(14) The stereochemistry of products 5 and 8 has been assigned by
X-ray and NOE studies. For more discussion on the formation of cis-
fused 5 and trans-fused 8, see the Supporting Information.
5876
Org. Lett., Vol. 13, No. 21, 2011

fused frameworks were produced in a highly efficient and
economical manner. In addition, the fused chiral tetrahy-
droquinoxaline skeletons have been similarly constructed.
Currently, more explorations on these chiral heterocyclic
systems were underway, and the results will be presented in
due course.
of China (20972101 and 21021001) and National Basic
Research Program of China (973 Program, 2010CB-
833300).
Supporting Information Available. Experimental pro-
cedures, structural proofs, NMR spectra and HPLC
chromatograms of the products, cif file of enantiopure
5c. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
Acknowledgment. We are grateful for the financial
support from the National Natural Science Foundation
Org. Lett., Vol. 13, No. 21, 2011
5877