One-pot synthesis of pyrrolidino- and piperidinoquinolinones by three-component aza-Diels-Alder reactions of in situ generated N-arylimines and cyclic enamides

Article abstract of DOI:10.1016/j.tetlet.2011.09.021

An efficient synthesis of hexahydropyrrolo[3,2-c]quinolin-2-ones and hexahydropyridino[3,2-c]quinolin-2-ones has been developed in moderate to high yields by one-pot two-step aza-Diels-Alder reactions of N-arylimines, formed in situ from anilines and benz

Full text of DOI:10.1016/j.tetlet.2011.09.021

Tetrahedron Letters 52 (2011) 6122–6126
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of pyrrolidino- and piperidinoquinolinones by
three-component aza-Diels–Alder reactions of in situ generated
N-arylimines and cyclic enamides
⇑
Wenxue Zhang, Yisi Dai, Xuerui Wang, Wei Zhang
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2011
Revised 29 August 2011
Accepted 6 September 2011
Available online 10 September 2011
An efficient synthesis of hexahydropyrrolo[3,2-c]quinolin-2-ones and hexahydropyridino[3,2-c]quinolin-
2-ones has been developed in moderate to high yields by one-pot two-step aza-Diels–Alder reactions of
N-arylimines, formed in situ from anilines and benzaldehydes, with cyclic enamides, formed in situ from
5-hydroxypyrrolidin-2-ones and 6-hydroxypiperidin-2-ones by BF3ÁOEt2-promoted dehydration in
dichloromethane at room temperature. The hexahydropyrrolo[3,2-c]quinolin-2-ones were formed as a
single exo-stereoisomer in most cases and hexahydropyridino[3,2-c]quinolin-2-ones were formed as a
mixture of exo- and endo-isomers favoring the endo-diastereomer.
Keywords:
Hexahydropyrrolo[3,2-c]quinolin-2-ones
Hexahydropyridino[3,2-c]quinolin-2-ones
Aza-Diels–Alder reactions
Three-component
Ó 2011 Elsevier Ltd. All rights reserved.
Cyclic enamides
The tetrahydroquinoline moiety is present in a number of natu-
ral products and many of these molecules have been found to pos-
sess a wide spectrum of biological activities, such as antitumoral,
antimicrobial, antibacterial, insecticide, analgesic, antipyretic, anti-
platelet, and cytotoxic activities.1 Owing to their relevant biologi-
cal properties, synthesis of new tetrahydroquinoline derivatives
is an active and rewarding research area. Among different ways
for constructing tetrahydroquinolines, aza-Diels–Alder reaction
between N-arylimines and dienophiles is an easy entry to these
compounds.2 Although numerous tetrahydroquinoline derivatives
have been afforded by this established method, reports about the
construction pyrrolidino- and piperidinoquinolinones are scarce.3
Pyrroloquinolines form the core structure unit in a number of bio-
logically interesting molecules, such as the natural products marti-
nelline and martinellic acid.4 Recently, Stevenson reported the
synthesis of hexahydropyrrolo[3,2-c]quinolines by indium trichlo-
ride catalyzed aza-Diels–Alder reactions of N-arylimines with
N-acyl-2,3-dihydropyrrole;5a and Lavilla reported the synthesis of
hexahydropyridino[3,2-c]quinolin-2-ones by Sc(OTf)3 catalyzed
aza-Diels–Alder reactions of N-arylimines with tetrahydropyrin-
2-one.5b Despite these achievements, more concise approaches
are still required. Recently, we reported a mild procedure for
the construction of isoindolo[2,1-a]quinolin-11-ones and
pyrrolidino[1,2-a]quinolin-1-ones by the [4+2] reactions of
N-acyliminium ions, produced from 3-hydroxy-2-arylisoindol-
1-one and 5-hydroxy-1-arylpyrrolidin-2-ones in the presence of
BF3ÁOEt2, with olefins.6 In this Letter, we report a concise approach
to the synthesis of pyrrolidino[3,2-c]quinolin-2-ones (5) and pip-
eridino[3,2-c]quinolin-2-ones (6) by the one-pot aza-Diels–Alder
reactions of arylimines, formed in situ from the condensation of
aniline (1) and benzaldehyde (2), with cyclic enamides, formed
in situ from 5-hydroxypyrrolidin-2-ones (3) and 6-hydroxypiperi-
din-2-ones (4) by BF3ÁOEt2 promoted dehydration (Scheme 1).
NH2
CHO
(1) 4 A MS, CH 2Cl2,
r.t. 2 hrs
n
+
+
O
OH
N
R3
(2) BF3.OEt2, 4 A MS,
CH2Cl2, r.t. 2 hrs
R1
R2
3 n = 1
4 n = 2
1
2
R3
R3
O
O
N
N
R1
R1
+
n
n
N
H
N
H
R2
R2
exo-5 n =1
exo-6 n = 2
endo-5 n = 1
endo-6 n = 2
⇑
Corresponding author. Tel.: +86 931 891 2582.
E-mail address: zhangwei6275@lzu.edu.cn (W. Zhang).
Scheme 1. One-pot three-component aza-Diels–Alder reactions.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.021

W. Zhang et al. / Tetrahedron Letters 52 (2011) 6122–6126
6123
Initially, we tried to synthesize hexahydropyrrolo[3,2-c]quino-
lin-2-one 5a by a one-pot reaction of 4-nitrobenzaldehyde, aniline,
and 5-hydroxypyrrolidin-2-one in the presence of a dehydration
agent and an acid catalyst, hoping that N-arylimine could be
formed in situ by the condensation of aniline (1a) and 4-nitrobenz-
aldehyde (2a) and the cyclic enamide could be generated in situ
by the dehydration of 3a and the subsequent cycloaddition of
N-arylimine and cyclic enamide catalyzed by the same acid to give
the product 5a. We found, however, the main product was not 5a
but 7, which appeared to be generated from coupling of 3a and
aniline (1a) under catalysis of either Lewis acids in the presence
of 4 Å molecular sieves or Brønsted acid with azeotropic
distillation dehydration (Scheme 2).
Then, we carried out the reaction by a one-pot two-step proce-
dure: N-arylimine was prepared by the condensation of aniline
(1a) and 4-nitrobenzaldehyde (2a) either in the presence of 4 Å
molecular sieves in anhydrous dichloromethane (DCM) at room
temperature for 2 h or in refluxing benzene (azeotropic distilla-
tion) for 2 h until the reaction was completed; next 3a and an acid
were added into the DCM solution and stirring was continued for
another 2 h at room temperature or 3a and an acid were added
to the benzene solution and azeotropic distillation was continued
for another 2 h. We found that 5a could be obtained in both cases
in different yields. Among various acid catalysts examined, such as
BF3ÁEt2O, Yb(OTf)3, InCl3, TsOH and TfOH, BF3ÁEt2O was found to
give the best result in DCM at room temperature (Table 1). How-
ever, in the absence of acid, the reactions did not proceed even
after long reaction times (12 h).
Under the optimized conditions, the reaction of N-arylimine
(formed in situ from anilines and 4-nitrobenzaldehydes in DCM)
with 3a in the presence of 0.8 equiv of BF3ÁOEt2 for 2 h at room
temperature in DCM afforded the corresponding pyrrolidino[3,2-
c]quinoline-2-ones 5a as a mixture of endo- and exo-5a isomers
in 82% total yield,7 favoring the exo-diastereomer.
The diastereomers could be easily separated by column chro-
matography on silica gel. In a similar manner, the reactions of
other N-arylimines (formed in situ from anilines 1a–c and aromatic
aldehydes 2a–d in DCM) were tested and it was found they could
be reacted smoothly with 5-hydroxypyrrolidin-2-ones 3a–c to
afford the corresponding pyrrolidino[3,2-c]quinolines 5a–o in
12–85% yield (Table 2, entries 1–15). In most cases, the product
was obtained as a single exo-stereoisomer. This high stereoselec-
tivity was much different from the InCl3-catalyzed results in which
the ratios of exo- and endo-isomers were nearly 1:1 as reported by
Stevenson.3a The results were listed in Table 2. All products were
fully identified by 1H, 13C NMR, and HRMS.7 The stereoconfigura-
tion of endo- and exo-5d was determined by NOE experiments
(Fig. 1)8 and the structure of exo-5b was further confirmed by X-
ray crystallography (Fig. 2).9
CHO
NH2
Encouraged by the results obtained with 5-hydroxypyrrolidin-
2-ones, we turned our attention to 6-hydroxypiperidin-2-one
under similar reaction conditions, the produced N-arylimines
reacted smoothly with 6-hydroxypiperidin-2-ones to produce
piperidin[3,2-c]quinolin-2-ones 6 in high yields. Similar to the
five-membered cyclic enamide intermediates, the reaction of
six-membered cyclic enamide intermediates with the preformed
N-arylimines also gave the products as a mixture of endo- and
exo-isomers. However, the reactions of six-membered cyclic ena-
mide favored endo-selectivity as compared with five-membered
cyclic enamides (Table 2).
+
Lewis acid, CH2Cl2
molecular sieve
NO2
2a
N
O
N
H
1a
or
TsOH or TfOH, C6H6
azeotropic distillation
+
Ph
7
O
OH
N
Ph
3a
Scheme 2. Acid-catalyzed coupling reaction of 1a with 3a.
Table 1
Optimization of reaction conditions for synthesis of 5a
CHO
NH2
O
O
Ph
Ph
+
N
N
(1) molecular sieve, CH2Cl2
(2) Lewis acid, CH2Cl2
NO2
+
2a
1a
N
H
N
H
or TsOH or TfOH, C6H6
azeotropic distillation
+
NO2
NO2
O
OH
N
endo-5a
exo-5a
Ph
3a
Entry
Solvent/additive
Catalyst
Time (h)
T (°C)
Yield of 5ac (%)
1
2
3
4
5
6
7
8
CH2Cl2/MSa
CH2Cl2/MSa
CH3CN/MSa
CH2Cl2/MSa
CH2Cl2/MSa
Benzeneb
0.5 equiv BF3ÁEt2O
0.8 equiv BF3ÁEt2O
0.8 equiv BF3ÁEt2O
0.8 equiv Yb(OTf)3
0.8 equiv InCl3
0.5 equiv TsOH
0.5 equiv CF3CO2H
0.5 equiv CF3SO3H
4
4
4
12
12
4
rt
rt
rt
rt
48
82
32
0
rt
0
Reflux
Reflux
Reflux
32
25
28
Benzeneb
4
4
Benzeneb
a
1.1 mmol 4-nitrobenzaldehyde and 1.0 mmol aniline were dissolved in anhydrous DCM, and 0.5 g 4 Å molecular sieves was added. The mixture was stirred at room
temperature for 2 h. Then 1.0 mmol 3a and 0.5–0.8 mmol Lewis acid were added, respectively. The mixture was stirred for 4–12 h.
b
1.1 mmol 4-nitrobenzaldehyde and 1.0 mmol aniline were dissolved in benzene. The mixture was refluxed with azeotropic distillation for 2 h. Then 1.0 mmol 3a and
0.5 mmol acid were added. The mixture was refluxed for another 2 h.
c
Yield of isolated product based on consumed 3a.

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W. Zhang et al. / Tetrahedron Letters 52 (2011) 6122–6126
Table 2
a
Synthesis of hexahydropyrrolo[3,2-c]quinolin-2-ones and hexahydropyridino[3,2-c]quinolin-2-ones by one-pot aza-Diels–Alder reaction catalyzed by BF3ÁOEt2
R3
O
O
R3
N
N
(1) 4 A MS, CH2Cl2,
r.t. 2 hrs
NH2
CHO
R1
R1
+
n
n
n
N
+
+
O
OH
.
(2) BF3 OEt2, 4 A MS,
N
H
N
H
R3
CH2Cl2, r.t. 2 hrs
R1
R2
R2
R2
3 n = 1
4 n = 2
exo-5 n =1
exo-6 n = 2
1
2
endo-5 n = 1
endo-6 n = 2
Entry
Substrate
R2
n
Time (h)
Yielda (%)
Ratio
R1
H
CH3
Cl
H
CH3
Cl
H
H
CH3
Cl
H
CH3
H
CH3
CH3
H
CH3
H
CH3
H
R3
exo/endo
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
1a
1b
1c
1a
1b
1c
1a
1a
1b
1c
1a
1b
1a
1b
1b
1a
1b
1a
1b
1a
1b
2a
NO2
NO2
NO2
CN
CN
CN
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3c
4a
4a
4a
4a
4a
4a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Bn
Bn
Bn
Bn
Bn
Bn
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
4
4
6
4
4
6
4
4
4
6
4
4
4
4
4
4
4
4
4
4
4
5a
5b
5c
5d
5e
5f
5g
5h
5i
82
85
57
72
80
37
30
60
80
45
72
77
36
12
55
75
84
73
82
40
28
10/1
1/-
1/-
7/1
1/-
1/-
1/-
1/-
1/-
1/-
1/-
1/-
1/-
1/-
1/1
1/1
1/4
1/1
1/2
1/1
1/3
2a
2a
2b
2b
2b
2c
2a
2a
2a
2b
2b
2c
2d
2a
2a
2a
2b
2b
2c
2d
H
NO2
NO2
NO2
CN
CN
H
OCH3
NO2
NO2
NO2
CN
5j
5k
5l
5m
5n
5o
6a
6b
6c
6d
6e
6f
CN
H
OCH3
CH3
a
Yield of isolated product based on consumed 3 or 4.
It was also observed from Table 2 that the substituents have great
influence to the cycloaddition reactions of N-arylimines formed
from 1 and 2 with 3 or 4. The electron-donating group on
aniline (R1 = Me) promoted the reactions and higher yields and
exo-selectivity of 5 could be reached; In contrast, the electron-
attracting group on aniline (R1 = Cl) retarded the reactions and the
yields of 5 decreased; Meanwhile, it was found that the yields of
5b, 5i, and 5o decreased gradually, indicating that R3 (R3 = Ph, Bn,
and Me) in 3 has great effect on the formation and reactivity of cyclic
enamides. On the other hand, R2 being an electron-withdrawing
group like nitro or cyano group in 2 was helpful to both the forma-
tion and stability of arylimines, and the yields of 5 and 6 formed from
these stable arylimines were relatively higher. Comparatively, reac-
tions of the unstable N-phenylimine from 1a and 2c (R1 = R2 = H)
with 3a, 3b, or 4a gave cyclization product 5g, 5m, or 6e in much
low yields, especially in the reactions of unstable N-arylimine
produced from 1b and electron-donating group-substituted benzal-
dehyde 2d with 3b or 4a, the yields of the products 5n and 6f were
decreased greatly. All these results were derived from the formation
of the coupling products like 7 from the reactions of N-acyliminium
O
O
H
H
N
N
H
H
H
H
H
H
N
N
H
H
H
H
H
H
CN
CN
exo-5d
endo-5d
Figure 1. NOE assignments for endo- and exo-5d.
n
n
.
n = 1
BF3 OEt2
O
OH
N
O
N
O
N
CH2Cl2
Bn
Bn
Bn
MS
r.t.
3b n = 1
4a n = 2
8
9
n = 1
n = 2
10
Figure 2. X-ray crystal structure of exo-5b.
Scheme 3. Dehydration reactions of 3b and 4a promoted by BF3ÁOEt2.

W. Zhang et al. / Tetrahedron Letters 52 (2011) 6122–6126
6125
NH2
O
+
O
Bn
O
N
Bn
N
(1) 4 A MS, CH2Cl2,
r.t. 2 hrs
N
Bn
10
or
n
1a
+
+
CHO
.
(2) BF3 OEt2, 4 A MS,
N
H
N
H
CH2Cl2, r.t. 2 hrs
NO2
NO2
+
O
N
exo-5h n = 1
exo-6a n = 2
endo-6a
Bn
NO2
2a
9
Scheme 4. Reactions of arylimine with cyclic enamides.
In conclusion, we have developed an efficient method for the
synthesis of hexahydropyrrolo[3,2-c]quinolin-2-ones and
CHO
NH2
.
MS
H
BF3 OEt2
+
hexahydropyridino[3,2-c]quinolin-2-ones by one-pot two-step
aza-Diels–Alder reactions of N-arylimines, produced in situ by the
condensation of anilines and benzaldehydes, with the cyclic ena-
mides, produced in situ from BF3ÁOEt2-promoted dehydration of
5-hydroxypyrrolidin-2-ones and 6-hydroxypiperidin-2-ones. The
reaction afforded hexahydropyrrolo[3,2-c]quinolin-2-ones as a sin-
gle exo-diastereomer in most cases and afforded hexahydropyridi-
no[3,2-c]quinolin-2-ones as a mixture of endo- and exo-isomers
favoring the endo-diastereomer.
N
C
CH2Cl2
r.t.
NO2
2a
1a
NO2
H
H
N
C
N
F3B
F3B
NO2
NO2
.
BF3 OEt2
O
OH
N
O
CH2Cl2
MS
r.t.
N
Acknowledgment
Ph
Ph
3a
We are grateful to the National Nature Science Foundation of
China (Grant No. 20872056) for the financial support.
O
Ph
O
O
Ph
Ph
N
N
-H+
N
Supplementary data
N
N
N
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.021.
H
H
BF3
NO2
NO2
NO2
5a
References and notes
Scheme 5. A plausible reaction mechanism of three-component aza-Diels–Alder
reaction promoted by BF3ÁOEt2 in DCM.
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ions with anilines produced by the hydrolysis of unstable N-
arylimine.
In order to confirm the formation of cyclic enamides, the dehy-
dration reactions of 3b and 4a promoted by BF3ÁOEt2 were per-
formed in anhydrous DCM at room temperature. It was found
that the cyclic enamides could be produced slowly under these
conditions. Differently, the cyclic enamide separated from the reac-
tion of 3b was 2,5-dihydropyrrol-2-one 10, but the cyclic enamide
separated from the reaction of 4a was 1,2,3,4-tetrahydropyridin-2-
one 9. (Scheme 3).
Next, the reactions of the separated 9 or 10 with in situ gener-
ated arylimine from 1a and 2a were examined in DCM at room
temperature in the presence of BF3ÁOEt2 (Scheme 4). It was found
that both exo-5h or endo- and exo-6a could be produced, but the
reaction of 10 was much slower (12 h) than the reaction of 9
(2 h). These results indicated that the isomerization of 10–8 was
reversible but difficult. Moreover, the one-pot reaction of 1a, 2a
with 10 was also much slower than the one-pot reaction of 1a,
2a with 3b (4 h) (Table 2).
According to these results, a plausible mechanism was proposed
for the formation of 5a by the one-pot reaction of aniline 1a and
benzaldehyde 2a with 3a (Scheme 5). Firstly, both N-arylimine
and cyclic enamide were produced in situ by molecular sieves-
promoted condensation of 1a and 2a, and by BF3ÁOEt2-promoted
dehydration; then the BF3ÁOEt2-catalyzed aza-Diels–Alder reaction
of the N-arylimine and cyclic enamide gave the product 5a.

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W. Zhang et al. / Tetrahedron Letters 52 (2011) 6122–6126
7. Synthesis of exo- and endo-5a: Anilines 1a (1.0 mmol) and aromatic aldehyde 2a
(1.1 mmol) were dissolved in anhydrous CH2Cl2 (20 mL), and 0.5 g 4 Å molecular
sieves was added. The mixture was stirred at room temperature for 2 h, and
1.0 mmol 3a and 0.8 mmol BF3ÁOEt2 were added, respectively. The mixture was
stirred for another 2 h. Upon completion monitored by TLC, 10 mL water was
added and the resulting mixture was extracted with CH2Cl2 (3 Â 20). The
organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was separated by flash chromatography (hexane/acetone 10:1 v/v) to
give the products. Compound enco-5a: mp 244–246 °C; 1H NMR (400 MHz,
CDCl3): d 8.24 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.36 (t, J = 6.8 Hz, 3H),
7.07 (d, J = 7.2 Hz, 3H), 6.64 (d, J = 8.0 Hz, 1H), 6.48–6.40 (m, 2H), 5.04 (d,
J = 5.6 Hz, 1H), 4.38 (d, J = 9.2 Hz, 1H), 4.31 (s, 1H), 2.83–2.79 (m, 1H), 2.72 (dd,
J = 7.6, 16.8 Hz, 1H), 2.34 (dd, J = 2.4, 16.8 Hz, 1H) ppm. 13C NMR (100 MHz,
CDCl3): d 173.2, 148.5, 147.9, 137.0, 131.8, 129.5, 129.2, 128.9, 128.2, 127.7,
124.0, 117.9, 116.5, 114.9, 50.5, 56.2, 38.7, and 34.9 ppm. ESI-HRMS: m/z Calcd
for C23H19N3O3+H+: 385.1500, found 385.1510. Compound exo-5a: mp 253–
255 °C; 1H NMR (400 MHz, CDCl3): d 8.28 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz,
2H), 7.43 (t, J = 8.0 Hz, 2H), 7.35 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 7.11–
7.07 (m, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.61–6.54 (m, 1H), 5.66 (d, J = 8.0 Hz, 1H),
4.75 (d, J = 2.4 Hz, 1H), 3.96 (s, 1H), 3.28–3.21 (m, 1H), 3.08 (dd, J = 11.6, 16 Hz,
1H), 2.02 (dd, J = 8.0, 16.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): d 172.4,
147.8, 147.8, 144.3, 138.3, 129.3, 128.9, 127.4, 126.4, 125.6, 124.2, 120.9, 119.6,
116.3, 59.9, 57.5, 40.6, and 30.5 ppm. ESI-HRMS: m/z Calcd for C23H19N3O3+H+:
385.1500, found 385.1512.
8. The NOE experiments were also performed for endo-6a.
9. Crystal data for exo-5b (recrystallized from acetone–hexane).
Mr = 399.44, monoclinic, space group P2 (1)/n, a = 6.881 (13), b = 15.11 (3),
c = 19.58 (4) Å, b = 98.67 (3)°, V = 2013 (7) Å3, colorless plates, Dc = 1.318 g cmÀ3
T = 296 (2) K, Z = 4,
(Mo-K ) = 0.71073 mmÀ1, 2hmax = 50.4°, 7313 reflections
C24H19 3O3,
,
l
a
measured, 3581 unique (Rint = 0.0741) which were used in all calculations. The
final wR(F2) was 0.1416 (for all data), R1 = 0.0687. CCDC 799818.