Organocatalyzed cascade reactions of cyclic β-enamino esters and α,β-unsaturated aldehydes leading to indoloquinolizidines and benzoquinolizidines

Article abstract of DOI:10.1002/ejoc.201101105

Organocatalyzed cascade reactions between cyclic β-enamino esters and α,β-unsaturated aldehydes have been developed. They provide highly substituted indolo[2,3-a]quinolizidines and benzo[a]quinolizidines in moderate to good yields and with good to excelle

Full text of DOI:10.1002/ejoc.201101105

FULL PAPER
DOI: 10.1002/ejoc.201101105
Organocatalyzed Cascade Reactions of Cyclic β-Enamino Esters and α,β-
Unsaturated Aldehydes Leading to Indoloquinolizidines and Benzoquinolizidines
Xiaoyu Wu,*[a] Linlin Nie,[a] Huihui Fang,[a] Jie Chen,[a] Weiguo Cao,*[a] and Gang Zhao*[b]
Keywords: Organocatalysis / Conjugate addition / Domino reactions / Cyclization / Nitrogen heterocycles
Organocatalyzed cascade reactions between cyclic β-en- yields and with good to excellent enantioselectivities. Both
amino esters and α,β-unsaturated aldehydes have been de-
veloped. They provide highly substituted indolo[2,3-a]quin-
olizidines and benzo[a]quinolizidines in moderate to good
aromatic and aliphatic α,β-unsaturated aldehydes react read-
ily with enamino esters to furnish the desired products.
Unlike enamides and enecarbamates, enamino esters,
which are also derivatives of enamines, had never been used
as nucleophiles in asymmetric catalysis until very recently.[5]
In 2010, though, Takemoto et al. described reactions be-
tween β-enamino esters and α,β-unsaturated aldehydes pro-
moted by a Brønsted acid/thiourea co-catalyst, affording
functionalized 1,4-dihydropyridines with ee values of up to
80%.[5a,5b] Kanger and co-workers developed a cascade
protocol catalyzed by prolinol TMS ether with enaminones
or enamino esters as nucleophiles and α,β-unsaturated alde-
hydes as electrophiles, yielding 1,4-dihydropyridines with
good enantioselectivities.[5c] On the other hand, β-enamino
esters are a class of highly versatile building blocks in or-
ganic synthesis.[6] In particular, cyclic β-enamino esters have
been used in the synthesis of a number of natural products
such as indolizidines, quinolizidines, and other alkaloids.[6]
For the past several years we have been engaged in a
research program directed towards efficient and enantiose-
lective synthesis of highly substituted quinolizidines by a
cascade strategy.[7] Here we report some new results from
our work, leading to the multiply substituted quinolizidines
5 (Scheme 1) and 8 (Table 3, below) through asymmetric
cascade reactions, catalyzed by a prolinol TMS ether deriv-
Introduction
Enamine-based organocatalysis has been intensively in-
vestigated during the past few years. The mechanism of ca-
talysis of this type involves the in situ formation of an en-
amine from an amine catalyst and an aldehyde or ketone as
a key intermediate, this acting as a nucleophile in a catalytic
cycle to provide chiral induction.[1] The employment of
stable enamine derivatives (Figure 1), such as enamides and
enecarbamates, as nucleophiles in asymmetric catalytic re-
actions has been reported less frequently.[2–4] Kobayashi
and co-workers have recently demonstrated chiral Lewis-
acid-catalyzed enantioselective additions of enamides to a
series of electron-deficient reactants.[2] Chiral Brønsted
acids have also been successfully utilized in place of Lewis
acids to promote addition reactions of enamides or ene-
carbamates to electron-deficient reactants.[3] Wang et al. de-
scribed cascade cyclization reactions between α,β-unsatu-
rated aldehydes and enamides catalyzed by chiral secondary
amines.[4a] Using a similar strategy, Hayashi and co-workers
reported a cascade sequence utilizing enecarbamates as nu-
cleophiles.[4b]
Figure 1. Structures of enamine derivatives.
[a] Department of Chemistry, Shanghai University,
99 Shangda Rd, Shanghai 200444, P. R. China
Fax: +86-21-66134856
E-mail: wuxy@shu.edu.cn, wgcao@staff.shu.edu.cn
[b] Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Instititute of Organic Chemistry, Chinese Academy
of Sciences,
345 Lingling Lu, Shanghai 200032, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101105.
Scheme 1. Concept of the cascade reactions between 1 and 2.
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X. Wu, L. Nie, H. Fang, J. Chen, W. Cao, G. Zhao
FULL PAPER
ative,[8] between the cyclic enamino esters 1 or 7 and the delighted to find, however, that no formation of N-adduct
α,β-unsaturated aldehydes 2.[9] Indoloquinolizidines or was observed in an initial reaction between 1a and 2a as-
benzoquinolizidines can be obtained from enamino esters sisted by catalysis by α,α-diphenylprolinol TMS ether (6a,
attached to indolyl or phenyl functionalities, respectively.
10 mol-%) and benzoic acid (10 mol-%) at –10 °C in DCM.
Our initial proposal for the cascade reactions between The indoloquinolizidine 5a was isolated with moderate
the cyclic enamino esters 1 and the α,β-unsaturated alde- yield and enantioselectivity (Table 1, Entry 1). In an at-
hydes 2 is shown in Scheme 1.[10] Conjugate addition of the tempt to improve the chiral induction, the secondary amine
enamino esters 1 to the enals 2 is promoted through the catalysts 6b–e were also screened. Better results could not
activation of the enals by formation of iminium intermedi- be obtained by use of the less bulky 6b or the free α,α-
ates to afford the intermediates 3 after release of the cata- diphenylprolinol derivatives 6c or 6d, however, whereas the
lyst.[1] The aldehydes 3 spontaneously undergo cyclization MacMillan catalyst 6e was ineffective in this reaction, with
to afford the hemiaminals 4.[11] After dehydration of the no conversion of the starting materials being observed
intermediates 4 in the presence of acid additive, the cyclized (Table 1, Entries 2–5).
products 5 are obtained enantioselectively.
The enantioselectivity of the reaction appears to be
strongly dependent on the solvent. With methanol as the
solvent, the enantioselectivity was comparable to that ob-
served in DCM, but the yield was much lower (Table 1, En-
try 6). In THF almost no product was formed (Table 1, En-
try 7), whereas use of acetonitrile led both to lower yield
and to poorer enantioselectivity than use of DCM (Table 1,
Entry 8). Better results were obtained in chloroform and
toluene, and the latter proved to be the best solvent
(Table 1, Entries 9 and 10).
We next examined the influence of temperature (Table 1,
Entries 10–12). The reaction gave a higher yield and better
enantioselectivity at –20 °C, although with a longer reaction
time needed to achieve full conversion of 1a (Table 1, En-
try 12).
Results and Discussion
To test the feasibility of this cascade approach, a model
reaction between the enamino ester 1a and cinnamaldehyde
(2a) was examined under a broad set of conditions
(Table 1). We were concerned that there might be regio-
chemical selectivity issues, arising from competing N- and
C-1,4-addition, in the designed cascade sequence. We were
Table 1. Screening studies of the cascade reaction between the en-
amino ester 1a and cinnamaldehyde (2a).[a]
Furthermore, acid additives were also screened as
sources of counterions for iminium intermediates. A signifi-
cant dependence of enantioselectivity on the natures of the
acids was revealed in the course of our study (Table 1, En-
tries 12–16). It turned out that benzoic acid (A1) was the
most effective in terms of yield and enantioselectivity.
Lower enantioselectivities were observed when stronger ac-
ids were used: TFA and 3,5-dinitrobenzoic acid, for exam-
ple, were found to be the least effective.
With the optimized reaction conditions established
(Table 1, Entry 12), the scope of this cascade reaction was
studied next (Table 2). Initially, we investigated the cascade
sequences with the α,β-unsaturated aldehydes 2a–i as elec-
trophiles and the indole-tethered enamino ester 1a as nu-
cleophile (Table 2, Entries 1–9). As shown in Table 2, the
domino reactions proceeded well both for aromatic and for
aliphatic α,β-unsaturated aldehydes, providing the cyclized
products 5a–i in moderate to good yields. Good enantio-
selectivities were achieved in all cases except for that of 2e,
which gave only 61% ee (Table 2, Entry 5). Next, the en-
amino esters 1b and 1c, with substituents on the indole moi-
ety, and the ethyl enamino ester 1d were examined (Table 2,
Entries 10–17). All the reactions proceeded to give the cor-
responding cyclized products 5j–q in moderate to good
yields and with ee values ranging from 72 to 89%. The en-
amino ester 1d gave higher enantioselectivities than 1a
(Table 2, Entry 16 vs. Entry 2, and Entry 17 vs. Entry 5).
The superior levels of enantioselectivities exhibited by 1d
could be explained in terms of the increased steric encum-
brance created by substituents on the ethyl group.
Entry Cat. Additive Solvent T [°C] t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
6a
6b
6c
6d
6e
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
A1
A1
A1
A1
A1
A1
A1
A1
A1
A1
A1
A1
A2
A3
A4
A5
DCM
DCM
DCM
DCM
DCM
CH3OH –10
THF –10
CH3CN –10
CHCl3 –10
toluene –10
–10
–10
–10
–10
–10
15
15
22
22
37
43
43
43
23
15
15
40
40
40
40
40
53
60
61
51
–
39
17
30
11
–
25
–
37
–
36
70
69
71
72
48
37
39
62
17
53
77
51
86
1
11
65
75
toluene
0
toluene –20
toluene –20
toluene –20
toluene –20
toluene –20
[a] General conditions: 1a (0.1 mmol), 2a (0.12 mmol), 6 (10 mol-
%), and additive (10 mol-%) in solvent (0.6 mL). Additives: A1:
BzOH; A2: 3,5-(O2N)2C6H3CO2H; A3: TFA; A4: 4-O2NC6H4-
CO2H; A5: AcOH. [b] Yields refer to isolated pure products. [c] En-
antiomeric excesses were determined by chiral HPLC analysis.
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Cascade Reactions Leading to Indoloquinolizidines and Benzoquinolizidines
Table 2. Asymmetric cascade reactions of the enamino esters 1a–d rated substituted phenyl systems generally gave the cyclized
and the α,β-unsaturated aldehydes 2a–i.[a]
products with higher enantioselectivities than the enamino
esters 1 containing incorporated indolyl systems.
Table 3. Further expansion of substrate scope.[a]
Entry
R1, R2, 1
R3, 2
5
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H, Me, 1a
H, Me, 1a
H, Me, 1a
H, Me, 1a
H, Me, 1a
H, Me, 1a
H, Me, 1a
H, Me, 1a
H, Me, 1a
MeO, Me, 1b
Me, Me, 1c
MeO, Me, 1b
Me, Me, 1c
MeO, Me, 1b
Me, Me, 1c
H, Et, 1d
C6H5, 2a
p-BrC6H4, 2b
p-FC6H4, 2c
o-MeOC6H4, 2d 5d
p-MeC6H4, 2e
Me, 2f
5a
5b
5c
72
77
51
55
54
68
55
72
74
71
87
63
63
74
41
51
60
86
81
81
71
61
80
83
73
82
82
89
77
69
86
81
89
72
Entry R1, 7
R2, 2
8
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
Me, 7a
Me, 7a
Me, 7a
Me, 7a o-MeOC6H4, 2d
Me, 7a p-MeC6H4, 2e
C6H5, 2a
p-BrC6H4, 2b
p-FC6H4, 2c
8a
8b
8c
8d
8e
8f
8g
8h
8i
65
71
74
54
56
54
58
53
63
74
81
57
87
92
95
93
91
91
95
93
95
93
93
91
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
Et, 2g
nPr, 2h
Me, 7a
Me, 7a
Me, 7a
Me, 2f
Et, 2g
nPr, 2h
CH3(CH2)6, 2i
p-BrC6H4, 2b
p-BrC6H4, 2b
p-MeC6H4, 2e
p-MeC6H4, 2e
CH3(CH2)6, 2i
CH3(CH2)6, 2i
p-BrC6H4, 2b
p-MeC6H4, 2e
Me, 7a CH3(CH2)6, 2i
10
11
12
Et, 7b
Et, 7b
Et, 7b
C6H5, 2a
p-BrC6H4, 2b
p-MeC6H4, 2e
8j
8k
8l
[a] See footnote in Table 1 for reaction conditions; reaction time:
20–48 h. [b] Yields refer to isolated pure products. [c] Enantiomeric
excesses were determined by chiral HPLC analysis.
H, Et, 1d
[a] See footnote in Table 1 for reaction conditions; reaction time:
20–48 h. [b] Yields refer to isolated pure products. [c] Enantiomeric
excesses were determined by chiral HPLC analysis.
The collective results shown above (Tables 2 and 3) indi-
cated that this cascade sequence could tolerate a broad
spectrum of substrates. This asymmetric catalyzed cascade
To illustrate the power of this catalytic enantioselective sequence, leading to multiply substituted indoloquinolizid-
cascade reaction further, the cyclic enamino esters 7a and ines and benzoquinolizidines, which are prevalent structural
7b (Table 3), containing incorporated dimethoxyphenyl sys- motifs in alkaloids,[12] should be useful in syntheses of alka-
tems, were examined under the same reaction conditions as loids of these types.
for 1a–d. In all cases the enamino esters 7 reacted smoothly
The stereochemical outcome of this cascade sequence
both with aromatic and with aliphatic α,β-unsaturated alde- was determined unambiguously by single-crystal X-ray dif-
hydes 2 to afford the cyclized benzoquinolizidines 8 in mod- fraction analysis of 5p (Figure 2).[13] The absolute configu-
erate to good yields with excellent enantioselectivities. It is rations of other cyclized products could be assigned by
notable that the cyclic enamino esters 7 containing incorpo- analogy. The stereochemistry at C-2 of 5p is that resulting
Figure 2. X-ray structure of 5p.
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X. Wu, L. Nie, H. Fang, J. Chen, W. Cao, G. Zhao
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Figure 3. Relative stereochemistry of 5hЈ.
from conjugate addition of the enamino ester 1d to the α,β- erate to good yields and with good to excellent enantio-
unsaturated iminium intermediate (Scheme 1) from the less selectivities.
hindered re-face.
To explore the synthetic potential of our current method,
the polycyclic compounds 5a and 5h were chosen for fur-
Experimental Section
ther manipulation (Scheme 2). Reduction of the dihydropyr-
General Information: Thin-layer chromatography (TLC) was car-
idine moieties in 5a and 5h to piperidines, with the creation
ried out on 0.25 mm silica gel plates with visualization with UV
of two new stereochemical centers, was explored. The re-
light and/or by staining with ethanolic phosphomolybdic acid
(PMA) or iodine. Flash column chromatography was performed on
silica gel H (10–40 μm). NMR spectra were recorded with a Bruker
duction reactions were carried out with NaBH4 as reduct-
ant at 0 °C in THF as solvent in the presence of AcOH.[14]
Interestingly, in each case only one out of the four possible
diastereomers was predominantly obtained in moderate
yield after column chromatography separation. The relative
stereochemistry of the reduced products was assigned by
single-crystal X-ray diffraction analysis of 5hЈ (Figure 3).[13]
AM 500 instrument (500 MHz). Chemical shifts (δ) are given in
ppm relative to TMS, coupling constants (J) in Hz. Optical rota-
tions were recorded with a JASCO P1030 instrument. High-resolu-
tion mass spectra were recorded with a Bruker ApeXIII 7.0 TESLA
FTMS instrument. Enantiomeric excesses were determined by chi-
ral HPLC with Waters or Shimadzu instruments.
Syntheses of the Cyclic Enaminoesters 1a–d and 7a–b: These sub-
strates were prepared according to a literature procedure[9] and
purified by silica gel column chromatography with elution with
hexane/ethyl acetate.
Methyl 2-(3,4-Dihydro-2H-pyrido[3,4-b]indol-1(9H)-ylidene)acetate
(1a):[15a] 1H NMR (CDCl3, 500 MHz): δ = 8.30 (s, 1 H), 8.14 (s, 1
H), 7.57 (d, J = 8.0 Hz, 1 H), 7.38 (d, J = 8.2 Hz, 1 H), 7.31–7.26
(m, 1 H), 7.18–7.11 (m, 1 H), 4.90 (s, 1 H), 3.71 (s, 3 H), 3.57 (td,
J = 6.8, 2.6 Hz, 2 H), 3.00 (t, J = 6.8 Hz, 2 H) ppm.
Scheme 2. Further transformation of 5a and 5h.
Methyl
2-{6-Methoxy-3,4-dihydro-2H-pyrido[3,4-b]indol-1(9H)-
ylidene}acetate (1b): 1H NMR (CDCl3, 500 MHz): δ = 8.30 (s, 1
H), 8.02 (s, 1 H), 7.30–7.26 (m, 1 H), 6.95 (dt, J = 8.7, 2.4 Hz, 2
H), 4.87 (s, 1 H), 3.89–3.84 (m, 3 H), 3.70 (s, 3 H), 3.57 (td, J =
6.8 and 2.6 Hz, 2 H), 2.96 (t, J = 6.8 Hz, 2 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 171.1, 154.5, 150.9, 132.5, 128.5, 126.4,
115.7, 115.5, 112.6, 100.6, 55.8, 50.5, 40.6, 20.7 ppm. HRMS (ESI):
calcd. for C15H17N2O3 273.1233; found 273.1242.
Conclusions
We have demonstrated that cyclic enamino esters can be
also employed as nucleophiles in asymmetric iminium or-
ganocatalysis. Conjugate additions of cyclic enamino esters
to α,β-unsaturated aldehydes were catalyzed by chiral sec-
ondary amines in the presence of acid additives. After re-
lease of the catalyst from the intermediate and subsequent
cyclization, a series of highly substituted indoloquinolizid-
Methyl
2-{6-Methyl-3,4-dihydro-2H-pyrido[3,4-b]indol-1(9H)-yl-
1
idene}acetate (1c): H NMR (CDCl3, 500 MHz): δ = 8.29 (s, 1 H),
ines and benzoquinolizidines were easily obtained in mod- 8.02 (s, 1 H), 7.35 (d, J = 0.7 Hz, 1 H), 7.28 (s, 1 H), 7.11 (dd, J =
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Cascade Reactions Leading to Indoloquinolizidines and Benzoquinolizidines
8.4, 1.3 Hz, 1 H), 4.87 (s, 1 H), 3.70 (s, 3 H), 3.56 (td, J = 6.8,
NMR (CDCl3, 500 MHz): δ = 12.23 (s, 1 H), 7.56 (d, J = 8 Hz, 1
2.5 Hz, 2 H), 2.96 (t, J = 6.8 Hz, 2 H), 2.45 (s, 3 H) ppm. 13C H), 7.43 (d, J = 8 Hz, 1 H), 7.25–7.20 (m, 3 H), 7.11 (t, J = 8 Hz,
NMR (CDCl3, 125 MHz): δ = 171.1, 150.9, 135.6, 129.7, 127.8,
126.5, 119.1, 115.7, 111. 3, 50.5, 40.6, 21.5, 20.7 ppm. HRMS
(ESI): calcd. for C19H22NO4 257.1285; found 257.1287.
1 H), 6.94 (t, J = 9 Hz, 2 H), 6.16 (d, J = 7 Hz, 1 H), 5.12 (t, J =
7 Hz, 1 H), 4.72 (d, J = 7 Hz, 1 H), 3.73–3.81 (m, 1 H), 3.71 (s, 3
H), 3.66–3.71 (m, 1 H), 2.95–3.13 (m, 2 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 170.3, 143.0, 142.9, 136.3, 130.4, 128.5,
128.4, 127.0, 125.0, 124.4, 119.7, 119.0, 115.8, 115.2, 115.1, 112.3,
107.1, 96.2, 51.8, 51.3, 39.2, 20.9 ppm. HRMS (ESI): calcd. for
C23H18FN2O2 373.1347; found 373.1359. HPLC (Phenomenex am-
ylose-2, hexane/2-propanol 10:1, flow rate 1.00 mLmin–1, λ =
220 nm): tR = 8.10 min (minor enantiomer), tR = 11.46 min (major
enantiomer).
Ethyl 2-{3,4-Dihydro-2H-pyrido[3,4-b]indol-1(9H)-ylidene}acetate
(1d):[15b] 1H NMR (CDCl3, 500 MHz): δ = 8.30 (s, 1 H), 8.13 (s, 1
H), 7.57 (d, J = 7.9 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.29 (dd,
J = 11.7, 4.6 Hz, 1 H), 4.89 (s, 1 H), 4.17 (q, J = 7.1 Hz, 2 H), 3.57
(td, J = 6.8, 2.5 Hz, 2 H), 2.99 (t, J = 6.8 Hz, 2 H), 1.30 (t, J =
7.1 Hz, 3 H) ppm.
Methyl 2-[6,7-Dimethoxy-3,4-dihydroisoquinolin-1(2H)-ylidene]acet-
1
Methyl (S)-2-(2-Methoxyphenyl)-2,6,7,12-tetrahydroindolo[2,3-a]-
quinolizine-1-carboxylate (5d): [α]2D5 = –274.64 (c = 0.63, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 12.37 (s, 1 H), 7.57 (d, J = 8 Hz,
1 H), 7.47 (d, J = 8 Hz, 1 H), 7.24–7.29 (m, 1 H), 7.09–7.18 (m, 3
H), 6.81–6.85 (m, 2 H), 6.04 (d, J = 7 Hz, 1 H), 5.28 (t, J = 7 Hz,
1 H), 5.11 (d, J = 7 Hz, 1 H), 3.88 (s, 3 H), 3.68–3.73 (m, 1 H),
3.64 (s, 3 H), 3.60–3.63 (m, 1 H), 2.99–3.10 (m, 2 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 170.8, 155.7, 143.9, 136.3, 135.5,
130.2, 127.5, 127.3, 127.1, 125.1, 124.2, 120.9, 119.7, 118.9, 115.5,
112.4, 110.5, 106.9, 94.0, 55.5, 51.9, 51.1, 33.9, 20.9 ppm. HRMS
(ESI): calcd. for C24H21N2O3 385.1547; found 385.1557. HPLC
(Phenomenex amylose-2, hexane/2-propanol 10:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 9.30 min (minor enantiomer), tR
= 12.44 min (major enantiomer).
ate (7a): H NMR (CDCl3, 500 MHz): δ = 9.00 (s, 1 H), 7.11 (s, 1
H), 6.66 (s, 1 H), 5.05 (s, 1 H), 3.90 (d, J = 9.9 Hz, 6 H), 3.70 (s,
3 H), 3.42 (td, J = 6.4, 3.2 Hz, 2 H), 2.83 (t, J = 6.4 Hz, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 171.47, 156.49, 151.07, 147.83,
130.00, 121.52, 110.61, 108.01, 56.05, 55.97, 50.24, 38.93,
28.53 ppm.
Ethyl 2-[6,7-Dimethoxy-3,4-dihydroisoquinolin-1(2H)-ylidene]acet-
ate (7b):[15c] 1H NMR (CDCl3, 500 MHz): δ = 9.03 (s, 1 H), 7.12
(s, 1 H), 6.65 (s, 1 H), 5.05 (s, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 3.89
(d, J = 8.4 Hz, 6 H), 3.42 (td, J = 6.4, 3.2 Hz, 2 H), 2.82 (t, J =
6.4 Hz, 2 H), 1.30 (t, J = 7.1 Hz, 3 H) ppm.
Typical Asymmetric Organocatalyzed Cascade Reaction Procedure:
The α,β-unsaturated aldehyde 2a (0.12 mmol, 1.2 equiv.) was added
under Ar with stirring to a solution of the cyclic enamino ester 1a
(0.1 mmol, 1.0 equiv.) in toluene (0.6 mL). After the mixture had
been cooled to –20 °C, the catalyst 6a (0.1 mmol, 0.1 equiv.) and
benzoic acid (0.1 mmol, 0.1 equiv.) were added. The reaction was
monitored by TLC. After complete consumption of 1a, the reaction
mixture was loaded directly onto a silica gel column and eluted
with hexane/ethyl acetate to afford 5a as a white solid in 72% yield
with 86% ee.
Methyl (S)-2-(p-Tolyl)-2,6,7,12-tetrahydroindolo[2,3-a]quinolizine-1-
carboxylate (5e): [α]2D5 = –89.42 (c = 0.57, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 12.26 (s, 1 H), 7.56 (d, J = 8 Hz, 1 H), 7.44
(d, J = 8 Hz, 1 H), 7.27–7.25 (m, 1 H), 7.17 (d, J = 8 Hz, 2 H),
7.10–7.14 (m, 1 H), 7.08 (d, J = 8 Hz, 2 H), 6.14 (d, J = 7 Hz, 1
H), 5.14 (t, J = 7 Hz, 1 H), 4.71 (d, J = 7 Hz, 1 H), 3.74–3.80 (m,
1 H), 3.71 (s, 3 H), 3.65–3.70 (m, 1 H), 2.98–3.12 (m, 2 H), 2.30 (s,
3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.6, 145.1, 142.8,
136.3, 135.8, 130.2, 129.2, 127.3, 126.9, 125.1, 124.2, 119.7, 118.9,
115.7, 112.3, 107.5, 96.3, 51.8, 51.3, 39.4, 21.1, 20.9 ppm. HRMS
(ESI): calcd. for C24H21N2O2: 369.1598; found 369.1610. HPLC
(Phenomenex amylose-2, hexane/2-propanol 10:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 7.48 min (minor enantiomer), tR
= 9.50 min (major enantiomer).
Methyl (S)-2-Phenyl-2,6,7,12-tetrahydroindolo[2,3-a]quinolizine-1-
carboxylate (5a): [α]2D5 = –79.29 (c = 1.13, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 12.24 (s, 1 H), 7.54 (d, J = 8 Hz, 1 H), 7.41
(d, J = 8 Hz, 1 H), 7.21–7.25 (m, 5 H), 7.13–7.17 (m, 1 H), 7.10 (t,
J = 8 Hz, 1 H), 6.13 (d, J = 7 Hz, 1 H), 5.13 (t, J = 7 Hz, 1 H),
4.73 (d, J = 7 Hz, 1 H), 3.78–3.73 (m, 1 H), 3.69 (s, 3 H), 3.64–3.67
(m, 1 H), 3.00–3.09 (m, 2 H) ppm. 13C NMR (CDCl3, 125 MHz): δ
= 170.6, 148.0, 143.0, 136.3, 130.3, 128.5, 127.2, 127.0, 126.3, 125.0,
124.3, 119.7, 118.9, 115.7, 112.3, 107.3, 96.2, 51.8, 51.3, 39.9,
20.9 ppm. HRMS (ESI): calcd. for C23H19N2O2 355.1441; found
355.1457. HPLC (Phenomenex amylose-2, hexane/2-propanol 10:1,
flow rate 1.00 mLmin–1, λ = 220 nm): tR = 8.64 min (minor enantio-
mer), tR = 12.19 min (major enantiomer).
Methyl (R)-2-Methyl-2,6,7,12-tetrahydroindolo[2,3-a]quinolizine-1-
carboxylate (5f): [α]2D5 = –43.33 (c = 0.33, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 12.27 (s, 1 H), 7.54 (d, J = 8 Hz, 1 H), 7.44
(d, J = 8 Hz, 1 H), 7.25 (t, J = 8 Hz, 1 H), 7.11 (t, J = 8 Hz, 1 H),
6.08 (d, J = 7 Hz, 1 H), 5.03 (t, J = 7 Hz, 1 H), 3.80 (s, 3 H), 3.73–
3.76 (m, 1 H), 3.61–3.68 (m, 1 H), 3.48–3.56 (m, 1 H), 2.89–3.10
(m, 2 H), 1.02 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 170.6, 143.1, 136.2, 130.6, 127.6, 125.1, 124.1, 119.6,
118.9, 115.1, 112.3, 108.5, 97.7, 51.8, 50.9, 28.5, 23.6, 20.9 ppm.
HRMS (ESI): calcd. for C18H17N2O2 293.1285; found 293.1294.
HPLC (Phenomenex amylose-2, hexane/2-propanol 10:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 6.10 min (minor enantiomer), tR
= 8.63 min (major enantiomer).
Methyl (S)-2-(4-Bromophenyl)-2,6,7,12-tetrahydroindolo[2,3-a]quin-
olizine-1-carboxylate (5b): [α]2D5 = –75.79 (c = 1.03, CHCl3). 1H
NMR (CDCl3, 500 MHz): δ = 12.24 (s, 1 H), 7.56 (d, J = 8 Hz, 1
H), 7.44 (d, J = 8 Hz, 1 H), 7.38 (d, J = 9 Hz, 2 H), 7.27 (t, J =
8 Hz, 1 H), 7.15 (d, J = 9 Hz, 2 H), 7.12 (t, J = 8 Hz, 1 H), 6.15
(d, J = 7 Hz, 1 H), 5.11 (t, J = 7 Hz, 1 H), 4.71 (d, J = 7 Hz, 1 H),
3.78–3.73 (m, 1 H), 3.71 (s, 3 H), 3.68–3.65 (m, 1 H), 3.05–2.95 (m,
2 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.3, 147.0, 143.1,
136.3, 131.5, 130.5, 128.8, 127.0, 125.0, 124.4, 120.0, 119.8, 119.0,
115.9, 112.3, 106.8, 95.7, 51.8, 51.3, 39.5, 21.7 ppm. HRMS (ESI):
calcd. for C23H18BrN2O2 433.0546; found 433.0566. HPLC (Phe-
nomenex amylose-2, hexane/2-propanol 10:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 9.63 min (minor enantiomer), tR
= 12.82 min (major enantiomer).
Methyl
(R)-2-Ethyl-2,6,7,12-tetrahydroindolo[2,3-a]quinolizine-1-
carboxylate (5g): [α]2D5 = –166.85 (c = 0.28, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 12.27 (s, 1 H), 7.53 (d, J = 8 Hz, 1 H), 7.44
(d, J = 8 Hz, 1 H), 7.24 (t, J = 8 Hz, 1 H), 7.12 (t, J = 8 Hz, 1 H),
6.13 (d, J = 7 Hz, 1 H), 5.02 (t, J = 7 Hz, 1 H), 3.79 (s, 3 H), 3.77–
3.74 (m, 1 H), 3.68–3.61 (m, 1 H), 3.47 (m, 1 H), 3.01–3.07 (m, 1
H), 2.93–2.98 (m, 1 H), 1.28–1.22 (m, 2 H), 0.86 (t, J = 7 Hz, 3 H)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.8, 143.3, 136.1, 131.1,
127.5, 125.1, 124.0, 119.6, 118.8, 115.1, 112.3, 106.6, 96.1, 51.7,
Methyl (S)-2-(4-Fluorophenyl)-2,6,7,12-tetrahydroindolo[2,3-a]quin-
olizine-1-carboxylate (5c): [α]2D5 = –229.35 (c = 0.58, CHCl3). 1H
Eur. J. Org. Chem. 2011, 6755–6763
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6759

X. Wu, L. Nie, H. Fang, J. Chen, W. Cao, G. Zhao
FULL PAPER
50.8, 34.7, 30.4, 20.8, 9.4 ppm. HRMS (ESI): calcd. for
C19H19N2O2 307.1441; found 307.1451. HPLC (Phenomenex amyl-
ose-2, hexane/2-propanol 10:1, flow rate 1.00 mLmin–1, λ =
Methyl (S)-9-Methoxy-2-(p-tolyl)-2,6,7,12-tetrahydroindolo[2,3-a]-
1
quinolizine-1-carboxylate (5l): [α]2D5 = –83.43 (c = 0.83, CHCl3). H
NMR (CDCl3, 500 MHz): δ = 12.26 (s, 1 H), 7.35 (d, J = 10 Hz,
220 nm): tR = 5.90 min (minor enantiomer), tR = 8.32 min (major 1 H), 7.19 (d, J = 8.5 Hz, 2 H), 7.10 (d, J = 8.5 Hz, 2 H), 6.93–
enantiomer).
6.98 (m, 2 H), 6.16 (d, J = 7 Hz, 1 H), 5.16 (t, J = 7 Hz, 1 H), 4.72
(d, J = 7 Hz, 1 H), 3.89 (s, 3 H), 3.76–3.79 (m, 1 H), 3.72 (s, 3 H),
3.66–3.72 (m, 1 H), 2.97–3.11 (m, 2 H), 2.32 (s, 3 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 170.6, 145.1, 143.0, 135.8, 131.6,
130.2, 129.9, 129.2, 128.6, 127.8, 126.9, 125.1, 115.4, 115.1, 113.3,
107.5, 99.5, 55.8, 51.8, 51.3, 39.4, 21.1, 20.9 ppm. HRMS (ESI):
calcd. for C25H23N2O3 399.1703; found 399.1695. HPLC
(Phenomenex amylose-2, hexane/2-propanol 10:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 14.37 min (minor enantiomer),
tR = 17.82 min (major enantiomer).
Methyl (R)-2-Propyl-2,6,7,12-tetrahydroindolo[2,3-a]quinolizine-1-
carboxylate (5h): [α]2D5 = –162.50 (c = 0.28, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 12.27 (s, 1 H), 7.53 (d, J = 8 Hz, 1 H), 7.44
(d, J = 8 Hz, 1 H), 7.24 (t, J = 8 Hz, 1 H), 7.10 (t, J = 8 Hz, 1 H),
6.11 (d, J = 7 Hz, 1 H), 5.04 (t, J = 7 Hz, 1 H), 3.79 (s, 3 H), 3.78–
3.72 (m, 1 H), 3.63 (m, 1 H), 3.52 (m, 1 H), 2.85–3.10 (m, 2 H),
1.32–1.39 (m, 2 H), 1.25–1.32 (m, 4 H), 0.88 (t, J = 7 Hz, 3 H)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.7, 143.2, 136.1, 130.9,
127.5, 125.1, 124.0, 119.6, 118.8, 115.0, 112.3, 107.1, 96.5, 51.7,
50.8, 40.3, 33.1, 20.9, 18.1, 14.2 ppm. HRMS (ESI): calcd. for
C20H21N2O2 321.1598; found 321.1601. HPLC (Phenomenex Chi-
ralpak amylose-2, hexane/2-propanol 10:1, flow rate 1.00 mLmin–1,
λ = 220 nm): tR = 5.63 min (minor enantiomer), tR = 8.32 min
(major enantiomer).
Methyl
(S)-9-Methyl-2-(p-tolyl)-2,6,7,12-tetrahydroindolo[2,3-a]-
quinolizine-1-carboxylate (5m): [α]2D5 = –116.42 (c = 0.67, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 12.14 (s, 1 H), 7.30–7.35 (m, 2
H), 7.16 (d, J = 8 Hz, 2 H), 7.05–7.10 (m, 3 H), 6.13 (d, J = 7 Hz,
1 H), 5.13 (t, J = 7 Hz, 1 H), 4.70 (d, J = 7 Hz, 1 H), 3.79–3.72
(m, 1 H), 3.70 (s, 3 H), 3.69–3.61 (m, 1 H), 3.09–2.89 (m, 2 H),
2.45 (s, 3 H), 2.29 (s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ
= 170.6, 145.2, 143.0, 135.8, 134.7, 130.2, 129.2, 128.9, 127.3, 126.9,
126.1, 125.2, 118.3, 115.2, 112.0, 107.4, 96.0, 64.3, 51.7, 51.3, 39.4,
21.6, 21.1 ppm. HRMS (ESI): calcd. for C25H23N2O2 383.1754;
found 383.1766. HPLC (Phenomenex amylose-2, hexane/2-propa-
nol 10:1, flow rate 1.00 mLmin–1, λ = 220 nm): tR = 7.81 min
(minor enantiomer), tR = 10.92 min (major enantiomer).
Methyl (R)-2-Heptyl-2,6,7,12-tetrahydroindolo[2,3-a]quinolizine-1-
carboxylate (5i): [α]2D5 = –125.67 (c = 0.93, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 12.29 (s, 1 H), 7.54 (d, J = 8 Hz, 1 H), 7.45
(d, J = 8 Hz, 1 H), 7.25 (t, J = 8 Hz, 1 H), 7.10 (t, J = 8 Hz, 1 H),
6.11 (d, J = 7.5 Hz, 1 H), 5.05 (t, J = 7.5 Hz, 1 H), 3.79 (s, 3 H),
3.72–3.78 (m, 1 H), 3.61–3.65 (m, 1 H), 3.47–3.53 (m, 1 H), 3.02–
3.05 (m, 1 H), 2.92–2.99 (m, 1 H), 1.42–1.15 (m, 12 H), 0.85 (t, J
= 7.4 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.8,
143.2, 136.2, 130.9, 127.5, 125.1, 124.0, 119.6, 118.8, 115.0, 112.3,
107.2, 96.6, 51.7, 50.8, 38.0, 33.3, 32.0, 29.7, 29.4, 25.0, 22.7, 20.9,
14.2 ppm. HRMS (ESI): calcd. for C24H29N2O2 377.2224; found
377.2234. HPLC (Phenomenex amylose-2, hexane/2-propanol 10:1,
flow rate 1.00 mLmin–1, λ = 220 nm): tR = 4.97 min (minor
enantiomer), tR = 7.87 min (major enantiomer).
Methyl
(R)-2-Heptyl-9-methoxy-2,6,7,12-tetrahydroindolo[2,3-a]-
quinolizine-1-carboxylate (5n): [α]2D5 = –256.61 (c = 0.61, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 12.25 (s, 1 H), 7.34 (d, J = 10 Hz,
1 H), 6.90–6.95 (m, 2 H), 6.10 (d, J = 7 Hz, 1 H), 5.04 (t, J = 7 Hz,
1 H), 3.86 (s, 3 H), 3.78 (s, 1 H), 3.71–3.77 (m, 1 H), 3.59–3.66 (m,
1 H), 3.48–3.53 (m, 1 H), 2.94–3.01 (m, 1 H), 2.89–2.92 (m, 1 H),
1.36–1.19 (m, 12 H), 0.87 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 170.7, 154.1, 143.2, 131.5, 130.9, 128.0,
125.2, 115.1, 114.5, 113.2, 107.2, 99.5, 96.3, 55.8, 51.7, 50.9, 38.0,
33.2, 32.0, 29.7, 29.4, 25.0, 22.7, 20.9, 14.2 ppm. HRMS (ESI):
calcd. for C25H31N2O3 407.2329; found 407.2344. HPLC (Phe-
nomenex amylose-2, hexane/2-propanol 10:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 8.52 min (minor enantiomer), tR
= 13.06 min (major enantiomer).
Methyl
(S)-2-(4-Bromophenyl)-9-methoxy-2,6,7,12-tetrahydro-
indolo[2,3-a]quinolizine-1-carboxylate (5j): [α]2D5 = –192.18 (c = 1.1,
1
CHCl3). H NMR (CDCl3, 500 MHz): δ = 12.21 (s, 1 H), 7.37 (d,
J = 8.5 Hz, 2 H), 7.33 (d, J = 8 Hz, 1 H), 7.14 (d, J = 8.5 Hz, 2
H), 6.91–6.96 (m, 2 H), 6.14 (d, J = 7 Hz, 1 H), 5.10 (t, J = 7 Hz,
1 H), 4.70 (d, J = 7 Hz, 1 H), 3.87 (s, 3 H), 3.71–3.76 (m, 1 H),
3.69 (s, 3 H), 3.63–3.67 (m, 1 H), 2.98–3.01 (m, 2 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 170.3, 154.2, 147.0, 143.2, 132.4,
131.5, 130.5, 129.8, 129.0, 128.8, 127.5, 125.1, 120.0, 115.4, 113.3,
106.8, 99.5, 55.8, 51.8,51.3, 39.4, 20.9 ppm. HRMS (ESI): calcd.
for C24H20BrN2O3 463.0652; found 463.0671. HPLC (Phenomenex
amylose-2, hexane/2-propanol 10:1, flow rate 1.00 mLmin–1, λ =
220 nm): tR = 17.47 min (minor enantiomer), tR = 22.07 min
(major enantiomer).
Methyl (R)-2-Heptyl-9-methyl-2,6,7,12-tetrahydroindolo[2,3-a]quin-
olizine-1-carboxylate (5o): [α]2D5 = –325.27 (c = 0.61, CHCl3). 1H
NMR (CDCl3, 500 MHz): δ = 12.17 (s, 1 H), 7.35 (d, J = 8.5 Hz,
1 H), 7.30 (s, 1 H), 7.07 (d, J = 8.5 Hz, 1 H), 6.10 (d, J = 7.5 Hz,
1 H), 5.04 (t, J = 7.5 Hz, 1 H), 3.78 (s, 3 H), 3.71–3.77 (m, 1 H),
3.62–3.66 (m, 1 H), 3.48–3.53 (m, 1 H), 2.45 (s, 3 H), 1.34–1.21 (m,
12 H), 0.87 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz):
δ = 170.7, 143.3, 134.6, 130.9, 128.8, 127.6, 125.9, 125.3, 118.2,
114.6, 111.9, 107.1, 96.3, 51.6, 50.9, 38.0, 33.3, 32.0, 29.7, 29.4,
25.0, 22.7, 21.6, 20.9, 14.2 ppm. HRMS (ESI): calcd. for
C25H31N2O2 391.2380; found 391.2392. HPLC (Phenomenex
amylose-2, hexane/2-propanol 10:1, flow rate 1.00 mLmin–1, λ =
220 nm): tR = 5.08 min (minor enantiomer), tR = 8.50 min (major
enantiomer).
Methyl
(S)-2-(4-Bromophenyl)-9-methyl-2,6,7,12-tetrahydro-
indolo[2,3-a]quinolizine-1-carboxylate (5k): [α]2D5 = –220.46 (c =
0.73, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 12.14 (s, 1 H),
7.38 (d, J = 8.5 Hz, 2 H), 7.31–7.35 (m, 2 H), 7.15 (d, J = 8.5 Hz,
2 H), 7.08–7.12 (m, 1 H), 6.14 (d, J = 7 Hz, 1 H), 5.10 (t, J = 7 Hz,
1 H), 4.70 (d, J = 7 Hz, 1 H), 3.73–3.77 (m, 1 H), 3.70 (s, 3 H),
3.65–3.68 (m, 1 H), 2.97–3.02 (m, 2 H), 2.46 (s, 3 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 170.3, 147.1, 143.2, 134.8, 131.5,
130.6, 129.1, 128.8, 127.0, 126.4, 125.2, 120.0, 118.3, 115.5, 112.0,
Ethyl (S)-2-(4-Bromophenyl)-2,6,7,12-tetrahydroindolo[2,3-a]quinol-
izine-1-carboxylate (5p): [α]2D5 = –89.46 (c = 0.52, CHCl3). 1H NMR
106.7, 100.0, 95.4, 51.8, 51.4, 39.5, 21.6, 20.9 ppm. HRMS (ESI): (CDCl3, 500 MHz): δ = 12.29 (s, 1 H), 7.56 (d, J = 8 Hz, 1 H), 7.43
calcd. for C24H20BrN2O2 447.0703; found 447.0720. HPLC (Phe-
nomenex amylose-2, hexane/2-propanol 10:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 8.79 min (minor enantiomer), tR
= 12.28 min (major enantiomer).
(d, J = 8 Hz, 1 H), 7.38 (d, J = 8.5 Hz, 2 H), 7.27 (t, J = 8 Hz, 1
H), 7.16 (d, J = 8.5 Hz, 2 H), 7.12 (t, J = 8 Hz, 1 H), 6.15 (d, J =
7 Hz, 1 H), 5.07 (t, J = 7 Hz, 1 H), 4.73 (d, J = 7 Hz, 1 H), 4.08–
4.22 (m, 2 H), 3.73–3.80 (m, 1 H), 3.65–3.71 (m, 1 H), 2.97–3.19 (m,
6760
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6755–6763

Cascade Reactions Leading to Indoloquinolizidines and Benzoquinolizidines
2 H), 1.23 (t, J = 7 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ
= 169.9, 147.3, 142.8, 136.3, 131.4, 130.5, 129.0, 127.1, 125.0, 124.4,
120.0, 119.8, 118.9, 115.8, 112.3, 106.7, 96.3, 60.6, 51.4, 39.8, 20.9,
14.2 ppm. HRMS (ESI): calcd. for C24H20BrN2O2 447.0703; found
447.0720. HPLC (Phenomenex amylose-2, hexane/2-propanol 10:1,
flow rate 1.00 mLmin–1, λ = 220 nm): tR = 8.24 min (minor
enantiomer), tR = 8.75 min (major enantiomer).
flow rate 1.00 mLmin–1, λ = 220 nm): tR = 11.24 min (minor en-
antiomer), tR = 9.10 min (major enantiomer).
Methyl (S)-9,10-Dimethoxy-2-(2-methoxyphenyl)-6,7-dihydro-2H-
pyrido[2,1-a]isoquinoline-1-carboxylate (8d): [α]2D5 = –201.21 (c =
1
0.71, CHCl3). H NMR (CDCl3, 500 MHz): δ = 7.22 (dd, J = 7.5,
1.5 Hz, 1 H), 7.16 (td, J = 7.5, 1.5 Hz, 1 H), 7.08 (s, 1 H), 6.89 (t,
J = 7.5 Hz, 1 H), 6.87 (d, J = 7.5 Hz, 1 H), 6.67 (s, 1 H), 5.96 (d,
J = 7.5 Hz, 1 H), 5.13 (d, J = 7.5 Hz, 1 H), 4.93 (d, J = 7.5 Hz, 1
H), 3.93 (s, 3 H), 3.87 (s, 3 H), 3.82 (s, 3 H), 3.49 (s, 3 H), 3.43–
3.48 (m, 1 H), 3.33–3.43 (m, 1 H), 2.95–3.04 (m, 1 H), 2.68 (dt, J
= 15, 4 Hz, 1 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.3,
155.6, 150.4, 146.7, 146.2, 136.1, 130.4, 129.2, 127.9, 127.1, 122.3,
121.0, 114.2, 110.6, 109.8, 105.8, 92.3, 56.2, 56.0, 55.6, 50.9, 48.9,
34.8, 29.5 ppm. HRMS (ESI): calcd. for C24H24NO5 406.1649;
found 406.1661. HPLC (Phenomenex amylose-2, hexane/2-prop-
anol 2:1, flow rate 1.00 mLmin–1, λ = 220 nm): tR = 11.57 min
(minor enantiomer), tR = 9.67 min (major enantiomer).
Ethyl (S)-2-(p-Tolyl)-2,6,7,12-tetrahydroindolo[2,3-a]quinolizine-1-
carboxylate (5q): [α]2D5 = –128.17 (c = 0.61, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 12.31 (s, 1 H), 7.56 (d, J = 8 Hz, 1 H), 7.43
(d, J = 8 Hz, 1 H), 7.24 (t, J = 8 Hz, 1 H), 7.19 (d, J = 7.5 Hz, 2
H), 7.11 (t, J = 8 Hz, 1 H), 7.07 (d, J = 7.5 Hz, 2 H), 6.14 (d, J =
7 Hz, 1 H), 5.11 (t, J = 7 Hz, 1 H), 4.73 (d, J = 7 Hz, 1 H), 4.07–
4.25 (m, 2 H), 3.73–3.82 (m, 1 H), 3.64–3.72 (m, 1 H), 2.97–3.14
(m, 2 H), 2.30 (s, 3 H), 1.25 (t, J = 7 Hz, 3 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 170.2, 145.4, 142.4, 136.2, 135.8, 130.1,
129.1, 127.3, 127.1, 125.1, 124.1, 119.6, 118.9, 115.5, 112.3, 107.4,
97.0, 60.5, 51.3, 39.7, 21.1, 21.0, 14.2 ppm. HRMS (ESI): calcd. for
C25H23N2O2 383.1754; found 383.1766. HPLC (Daicel Chiralpak
ADH, hexane/2-propanol 4:1, flow rate 0.7 mLmin–1, λ = 220 nm):
tR = 6.89 min (minor enantiomer), tR = 7.66 min (major enantio-
mer).
Methyl (S)-9,10-Dimethoxy-2-(p-tolyl)-6,7-dihydro-2H-pyrido[2,1-
a]isoquinoline-1-carboxylate (8e): [α]2D5 = –285.45 (c = 0.57, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 7.24 (d, J = 8 Hz, 2 H), 7.11 (t,
J = 8 Hz, 2 H), 6.94 (s, 1 H), 6.64 (s, 1 H), 6.09 (d, J = 7.5 Hz, 1
H), 5.00 (dd, J = 7.5, 6.5 Hz, 1 H), 4.47 (d, J = 6.5 Hz, 1 H), 3.91
(s, 3 H), 3.77 (s, 3 H), 3.50–3.55 (m, 1 H), 3.49 (s, 3 H), 3.41–3.48
(m, 1 H), 2.95–3.03 (m, 1 H), 2.68 (dt, J = 15, 3.5 Hz, 1 H), 2.37
(s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.3, 150.3,
146.6, 145.6, 145.1, 135.8, 130.3, 129.3, 129.2, 127.0, 122.3, 114.3,
109.7, 106.0, 94.7, 56.2, 56.0, 50.9, 49.0, 40.7, 29.5, 21.1 ppm.
HRMS (ESI): calcd. for C24H24NO4 390.1700; found 390.1701.
HPLC (Phenomenex amylose-2, hexane/2-propanol 2:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 15.01 min (minor enantiomer),
tR = 9.28 min (major enantiomer).
Methyl (S)-9,10-Dimethoxy-2-phenyl-6,7-dihydro-2H-pyrido[2,1-a]-
isoquinoline-1-carboxylate (8a): [α]2D5 = –257.76 (c = 0.97, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 7.35 (d, J = 7.5 Hz, 2 H), 7.30
(t, J = 7.5 Hz, 2 H), 7.19 (t, J = 7.5 Hz, 1 H), 6.92 (s, 1 H), 6.65
(s, 1 H), 6.11 (d, J = 7 Hz, 1 H), 5.02 (t, J = 7 Hz, 1 H), 4.52 (d,
J = 7 Hz, 1 H), 3.91 (s, 3 H), 3.77 (s, 3 H), 3.50–3.55 (m, 1 H),
3.49 (s, 3 H), 3.48–3.41 (m, 1 H), 2.95–3.05 (m, 1 H), 2.69 (dt, J =
14.8, 3.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.3,
150.4, 148.4, 146.7, 145.2, 130.4, 129.5, 128.5, 127.2, 126.3, 122.3,
114.3, 109.7, 105.8, 94.5, 56.2, 56.0, 50.9, 49.0, 41.0, 29.5 ppm.
HRMS (ESI): calcd. for C23H23NNaO4 400.1519; found 400.1531.
HPLC (Phenomenex amylose-2, hexane/2-propanol 2:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 17.22 min (minor enantiomer),
tR = 13.19 min (major enantiomer).
Methyl
(R)-9,10-Dimethoxy-2-methyl-6,7-dihydro-2H-pyrido[2,1-
a]isoquinoline-1-carboxylate (8f): [α]2D5 = –14.38 (c = 0.51, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 6.91 (s, 1 H), 6.61 (s, 1 H), 5.98
(d, J = 7.4 Hz, 1 H), 4.86 (dd, J = 7.4, 6.2 Hz, 1 H), 3.90 (s, 3 H),
3.83 (s, 3 H), 3.54 (s, 3 H), 3.48 (td, J = 12.5, 3 Hz, 1 H), 3.43–
3.36 (m, 1 H), 3.37–3.42 (m, 1 H), 3.27–3.34 (m, 1 H), 2.88–2.97
(m, 1 H), 2.62 (dt, J = 15, 3.5 Hz, 1 H), 1.10 (d, J = 6 Hz, 3 H)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.6, 150.1, 146.6, 130.2,
129.6, 122.5, 114.0, 109.7, 106.7, 93.9, 56.1, 55.9, 50.8, 48.9, 30.0,
29.5, 24.4 ppm. HRMS (ESI): calcd. for C18H20NO4 314.1387;
found 314.1387. HPLC (Phenomenex amylose-2, hexane/2-prop-
anol 2:1, flow rate 1.00 mLmin–1, λ = 220 nm): tR = 8.29 min
(minor enantiomer), tR = 7.00 min (major enantiomer).
Methyl (S)-2-(4-Bromophenyl)-9,10-dimethoxy-6,7-dihydro-2H-pyr-
ido[2,1-a]isoquinoline-1-carboxylate (8b): [α]2D5 = –210.45 (c = 0.92,
CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 7.40 (d, J = 8 Hz, 2 H),
7.23 (d, J = 8 Hz, 2 H), 6.86 (s, 1 H), 6.64 (s, 1 H), 6.13 (d, J =
7.5 Hz, 1 H), 4.97 (t, J = 7.5 Hz, 1 H), 4.47 (d, J = 7.5 Hz, 1 H),
3.91 (s, 3 H), 3.77 (s, 3 H), 3.52 (dd, J = 12.5, 3 Hz, 1 H), 3.49 (s,
3 H), 3.42–3.48 (m, 1 H), 3.03–2.95 (m, 1 H), 2.68 (dt, J = 12.5,
3 Hz, 1 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.2, 150.5,
147.4, 146.7, 145.3, 131.5, 130.4, 129.8, 129.1, 122.1, 120.0, 114.2,
109.8, 105.2, 94.1, 56.2, 56.0, 50.9, 49.0, 40.5, 29.4 ppm. HRMS
(ESI): calcd. for C23H21BrNO4 454.0649; found 454.0665. HPLC
(Phenomenex amylose-2, hexane/2-propanol 2:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 20.64 min (minor enantiomer),
tR = 12.18 min (major enantiomer).
Methyl (R)-2-Ethyl-9,10-dimethoxy-6,7-dihydro-2H-pyrido[2,1-a]-
isoquinoline-1-carboxylate (8g): [α]2D5 = –189.40 (c = 0.28, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 6.95 (s, 1 H), 6.64 (s, 1 H), 6.07
(d, J = 7.5 Hz, 1 H), 4.88 (dd, J = 7.5, 6 Hz, 1 H), 3.93 (s, 3 H),
3.85 (s, 3 H), 3.56 (s, 3 H), 3.37–3.53 (m, 2 H), 3.24–3.29 (m, 1 H),
2.91–3.01 (m, 1 H), 2.64 (dt, J = 15, 3.5 Hz, 1 H), 1.40–1.55 (m, 2
H), 0.92 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz):
δ = 170.6, 150.1, 146.6, 145.5, 130.2, 130.1, 122.5, 114.1, 109.7,
104.9, 93.9, 56.1, 55.9, 50.8, 48.8, 36.0, 30.8, 29.5, 9.1 ppm. HRMS
(ESI): calcd. for C19H22NO4 328.1543; found 328.1553. HPLC
(Phenomenex amylose-2, hexane/2-propanol 2:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 7.74 min (minor enantiomer), tR
= 6.69 min (major enantiomer).
Methyl (S)-2-(4-Fluorophenyl)-9,10-dimethoxy-6,7-dihydro-2H-pyr-
ido[2,1-a]isoquinoline-1-carboxylate (8c): [α]2D5 = –329.13 (c = 0.79,
CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 7.30 (dd, J = 8.5,
4.5 Hz, 2 H), 6.96 (t, J = 8.5 Hz, 2 H), 6.87 (s, 1 H), 6.64 (s, 1 H),
6.12 (d, J = 7.5 Hz, 1 H), 4.99 (t, J = 7.5 Hz, 1 H), 4.49 (d, J =
6.2 Hz, 1 H), 3.91 (s, 3 H), 3.77 (s, 3 H), 3.52 (td, J = 12.5, 3 Hz,
1 H), 3.49 (s, 3 H), 3.42–3.48 (m, 1 H), 2.95–3.04 (m, 1 H), 2.68
(dt, J = 12.5, 3.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 125 MHz): δ Methyl (R)-9,10-Dimethoxy-2-propyl-6,7-dihydro-2H-pyrido[2,1-a]-
= 170.3, 150.5, 146.7, 145.1, 144.2, 130.4, 129.6, 128.7, 128.6, 122.2,
115.2, 114.2, 109.8, 105.6, 94.6, 56.2, 56.0, 50.9, 48.9, 40.3,
29.5 ppm. HRMS (ESI): calcd. for C23H21FNO4 394.1449; found
394.1463. HPLC (Phenomenex amylose-2, hexane/2-propanol 2:1,
isoquinoline-1-carboxylate (8h): [α]2D5 = –177.35 (c = 0.46, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 6.91 (s, 1 H), 6.61 (s, 1 H), 6.02
(d, J = 7 Hz, 1 H), 4.88 (dd, J = 7, 6.5 Hz, 1 H), 3.90 (s, 3 H), 3.83
(s, 3 H), 3.37–3.52 (m, 2 H), 3.24–3.29 (m, 1 H), 2.90–2.99 (m, 1
Eur. J. Org. Chem. 2011, 6755–6763
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6761

X. Wu, L. Nie, H. Fang, J. Chen, W. Cao, G. Zhao
FULL PAPER
H), 2.61 (dt, J = 15, 3.5 Hz, 1 H), 1.32–1.47 (m, 4 H), 0.91 (t, J =
7 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.6, 150.1,
146.6, 145.5,130.1, 130.0, 122.5, 114.1, 109.7, 105.5, 94.1, 56.1,
55.9, 50.8, 48.8, 40.7, 34.5, 29.5, 18.0, 14.4 ppm. HRMS (ESI):
calcd. for C20H24NO4 342.1700; found 342.1715. HPLC (Phe-
nomenex amylose-2, hexane/2-propanol 2:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 7.49 min (minor enantiomer), tR
= 6.22 min (major enantiomer).
1.00 mLmin–1, λ = 220 nm): tR = 16.75 min (minor enantiomer),
tR = 8.33 min (major enantiomer).
Procedure for Reduction of 5a and 5h: Sodium borohydride (34 mg,
0.855 mmol) and AcOH (0.6 mL) were added at 0 °C to a suspen-
sion of 5a (63 mg, 0.177 mmol) in THF (2 mL). The reaction mix-
ture was stirred at 0 °C for 2 h. The reaction was quenched with
aqueous saturated NH4Cl solution (5 mL) and the mixture ex-
tracted with EtOAc (3ϫ10 mL). The organic layers were combined
and dried with anhydrous Na2SO4. After concentration under re-
duced pressure, the residue was purified by flash silica gel
chromatography with elution with hexane/ethyl acetate to afford
5aЈ as a white solid in 59% yield.
Methyl (R)-2-Heptyl-9,10-dimethoxy-6,7-dihydro-2H-pyrido[2,1-a]-
isoquinoline-1-carboxylate (8i): [α]2D5 = –22.21 (c = 0.37, CHCl3). 1H
NMR (CDCl3, 500 MHz): δ = 6.91 (s, 1 H), 6.61 (s, 1 H), 6.02 (d,
J = 7 Hz, 1 H), 4.88 (dd, J = 7, 6.5 Hz, 1 H), 3.90 (s, 3 H), 3.82 (s,
3 H), 3.53 (s, 3 H), 3.48 (td, J = 12, 3 Hz, 1 H), 3.40 (dt, J = 12,
4 Hz, 1 H), 3.25 (q, J = 6 Hz, 1 H), 2.90–2.97 (m, 1 H), 2.61 (dt,
J = 15, 3 Hz, 1 H), 1.46–1.37 (m, 3 H), 1.32–1.20 (m, 9 H), 0.85
(t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.5,
150.1, 146.6, 145.4, 130.1, 130.0, 122.5, 114.1, 109.7, 105.4, 94.3,
56.1, 55.9, 50.8, 48.8, 38.4, 34.7, 32.0, 29.8, 29.5, 29.4, 24.8, 22.7,
14.2 ppm. HRMS (ESI): calcd. for C24H32NO4 398.2326; found
398.2338. HPLC (Phenomenex amylose-2, hexane/2-propanol 2:1,
flow rate 1.00 mLmin–1, λ = 220 nm): tR = 6.83 min (minor
enantiomer), tR = 5.90 min (major enantiomer).
Methyl
(1S,2R,12bR)-2-Phenyl-1,2,3,4,6,7,12,12b-octahydroind-
olo[2,3-a]quinolizine-1-carboxylate (5aЈ): [α]2D5 = –96.15 (c = 0.13,
CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 7.88 (s, 1 H), 7.48 (d, J
= 7.5 Hz, 1 H), 7.28–7.36 (m, 5 H), 7.21–7.26 (m, 1 H), 7.07–7.16
(m, 2 H), 3.67–3.71 (m, 1 H), 3.43 (t, J = 4 Hz, 1 H), 3.33–3.39
(m, 1 H), 3.25 (dd, J = 11, 5.0 Hz, 1 H), 3.16 (s, 3 H), 2.97–3.12
(m, 3 H), 2.67–2.75 (m, 1 H), 2.50–2.63 (m, 2 H), 1.81–1.87 (m, 1
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.6, 142.2, 136.5,
132.0, 128.5, 127.4, 127.3, 126.9, 121.6, 119.5, 118.3, 111.0, 110.2,
62.7, 56.1, 53.9, 51.3, 49.8, 44.2, 25.9, 21.4 ppm. HRMS (ESI):
calcd. for C23H25N2O2 361.1911; found 361.1921. HPLC (Phe-
nomenex Chiralpak amylose-2, hexane/2-propanol 2:1, flow rate
1.00 mLmin–1, λ = 220 nm): tR = 9.96 min (minor enantiomer), tR
= 11.54 min (major enantiomer).
Ethyl (S)-9,10-Dimethoxy-2-phenyl-6,7-dihydro-2H-pyrido[2,1-a]iso-
1
quinoline-1-carboxylate (8j): [α]2D5 = –457.30 (c = 0.93, CHCl3). H
NMR (CDCl3, 500 MHz): δ = 7.33–7.38 (m, 2 H), 7.29 (t, J =
8 Hz, 2 H), 7.17 (t, J = 8 Hz, 1 H), 6.95 (s, 1 H), 6.64 (s, 1 H), 6.11
(d, J = 7 Hz, 1 H), 5.00 (dd, J = 7, 6 Hz, 1 H), 4.53 (d, J = 6 Hz,
1 H), 3.93–4.02 (m, 2 H), 3.90 (d, J = 5.0 Hz, 3 H), 3.77 (s, 3 H),
3.41–3.54 (m, 1 H), 2.94–3.03 (m, 1 H), 2.70 (dt, J = 15, 4 Hz, 1
H), 1.01 (t, J = 7 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ
= 169.9, 150.3, 148.5, 146.6, 144.9, 130.3, 129.5, 128.4, 127.3, 126.2,
122.4, 114.5, 109.7, 105.6, 95.1, 59.6, 56.1, 56.0, 49.0, 41.2, 29.5,
14.1 ppm. HRMS (ESI): calcd. for C24H24NO4 390.1700; found
390.1702. HPLC (Phenomenex amylose-2, hexane/2-propanol 2:1,
flow rate 1.00 mLmin–1, λ = 220 nm): tR = 13.55 min (minor en-
antiomer), tR = 10.46 min (major enantiomer).
Methyl
(1S,2R,12bR)-2-Propyl-1,2,3,4,6,7,12,12b-octahydroind-
olo[2,3-a]quinolizine-1-carboxylate (5hЈ): [α]2D5 = –588.2 (c = 0.17,
CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 9.68 (br., 1 H), 7.48 (d,
J = 8 Hz, 1 H), 7.39 (d, J = 8 Hz, 1 H), 7.17 (t, J = 8 Hz, 1 H),
7.10 (t, J = 8 Hz, 1 H), 4.49–4.69 (br., 1 H), 3.80 (s, 3 H), 3.15–
3.35 (m, 2 H), 2.98–3.07 (m, 1 H), 2.95 (dd, J = 11, 3.5 Hz, 1 H),
2.85 (td, J = 12, 3.5 Hz, 1 H), 2.61–2.72 (m, 2 H), 1.69–1.91 (m, 2
H), 1.31–1.44 (m, 3 H), 1.08–1.23 (m, 2 H), 0.87 (t, J = 6.5 Hz, 3
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 175.6, 135.6, 130.1,
126.6, 121.8, 119.3, 118.0, 111.5, 107.9, 56.0, 52.5, 51.8, 51.0, 35.4,
32.6, 29.7, 22.0, 19.4, 17.1, 14.2 ppm. HRMS (ESI): calcd. for
C20H27N2O2 327.2067; found 327.2074. HPLC (AS-H column, hex-
Ethyl (S)-2-(4-Bromophenyl)-9,10-dimethoxy-6,7-dihydro-2H-pyr-
ido[2,1-a]isoquinoline-1-carboxylate (8k): [α]2D5 = –235.23 (c = 0.37,
ane/2-propanol 19:1, flow rate 0.5 mLmin–1, λ = 220 nm): tR
=
1
CHCl3). H NMR (CDCl3, 500 MHz): δ = 7.40 (d, J = 7.5 Hz, 2
11.49 min (minor enantiomer), tR = 16.62 min (major enantiomer).
H), 7.23 (d, J = 7.5 Hz, 2 H), 6.90 (s, 1 H), 6.64 (s, 1 H), 6.12 (d,
J = 7.5 Hz, 1 H), 4.96 (dd, J = 7.5, 6.5 Hz, 1 H), 4.48 (d, J =
6.5 Hz, 1 H), 3.91–4.02 (m, 2 H), 3.90 (s, 3 H), 3.76 (s, 3 H), 3.42–
3.53 (m, 2 H), 2.96–3.02 (m, 1 H), 2.68 (td, J = 15, 4 Hz, 1 H),
1.01 (t, J = 7 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ =
169.8, 150.4, 147.6, 146.6, 145.1, 131.4, 130.3, 129.8, 129.1, 122.2,
112.0, 114.5, 109.8, 105.0, 94.7, 59.7, 56.1, 56.0, 49.0, 40.6, 29.5,
14.1 ppm. HRMS (ESI): calcd. for C24H23BrNO4 468.0805; found
468.0823. HPLC (Phenomenex amylose-2, hexane/2-propanol 2:1,
flow rate 1.00 mLmin–1, λ = 220 nm): tR = 20.44 min (minor en-
antiomer), tR = 10.60 min (major enantiomer).
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of 1a–d and 7a–b; NMR spectra and HPLC
analysis of the products.
Acknowledgments
The generous financial support from the National Natural Science
Foundation of China (No. 20802043 and No. 21072125) and the
Foundations of Education Commission of Shanghai Municipality
(No. J50102) is gratefully acknowledged. Dr. Hanwei Hu at Shang-
hai Medicilon is also gratefully acknowledged for helpful dis-
cussions.
Ethyl (S)-9,10-Dimethoxy-2-(p-tolyl)-6,7-dihydro-2H-pyrido[2,1-a]-
isoquinoline-1-carboxylate (8l): [α]2D5 = –235.45 (c = 0.65, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 7.24 (d, J = 8 Hz, 2 H), 7.10 (d,
J = 8 Hz, 2 H), 6.95 (s, 1 H), 6.64 (s, 1 H), 6.09 (d, J = 7 Hz, 1 H),
4.99 (dd, J = 7, 6 Hz, 1 H), 4.48 (d, J = 6 Hz, 1 H), 3.92–4.02 (m,
2 H), 3.91 (s, 3 H), 3.77 (s, 3 H), 3.41–3.55 (m, 2 H), 2.95–3.03 (m,
1 H), 2.68 (dt, J = 15, 3.5 Hz, 1 H), 2.31 (s, 3 H), 1.02 (t, J = 7 Hz,
3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 170.0, 150.3, 146.5,
145.8, 144.8, 135.7, 130.3, 129.4, 129.2, 127.1, 122.4, 114.5, 109.7,
105.9, 95.2, 59.6, 56.1, 56.0, 49.0, 40.7, 29.6, 21.1, 14.1 ppm.
HRMS (ESI): calcd. for C25H26NO4 404.1856; found 404.1868.
HPLC (Phenomenex amylose-2, hexane/2-propanol 2:1, flow rate
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6762
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6755–6763

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Received: July 29, 2011
Published Online: September 21, 2011
[8] For examples of conjugate additions promoted by prolinol
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Eur. J. Org. Chem. 2011, 6755–6763
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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