Synthesis of benzopyrrolizidinones by norrish-yang cyclization of 3-(acylmethyl)-2-alkylisoindol-1-ones

Article abstract of DOI:10.1055/s-0028-1088065

An efficient synthesis of 2-hydroxy-1,2,3,9b-tetrahydropyrrolo[2,1-a] isoindol-5-ones has been achieved by the Norrish-Yang cyclization of 3-(acylmethyl)-2-alkylisoindol-1-ones in benzene in moderate to high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088065

PAPER
1821
Synthesis of Benzopyrrolizidinones by Norrish–Yang Cyclization of
3-(Acylmethyl)-2-alkylisoindol-1-ones
S
ynthesis
i
of Be
n
n
zopyrrolizidi
g
nones fei Wu, Wei Zhang,* Cailin Wang
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8625657; E-mail: zhangwei6275@lzu.edu.cn
Received 25 November 2008; revised 12 February 2009
rivatives;7 tributyltin hydride mediated radical
cyclization;8 hydrogen fluoride catalyzed cyclization of
azomethine ylides produced from the addition of organo-
lithium to N-[(tributylstannyl)methyl]phthalimide;9 palla-
dium-catalyzed tandem cyclization of N-allyl-2-
iodobenzamides;10 flash vacuum pyrolysis of 1-[2-(meth-
oxycarbonyl)phenyl]pyrrole;11 base-catalyzed cyclization
and O-alkylation of N-phthalimido-substituted keto es-
ters;12 metal-mediated intramolecular Heck reactions;13
intramolecular Wittig reactions.14 Despite these advances,
room still exists for developing alternative approaches to
the synthesis of such compounds. We report herein a new
synthesis of benzopyrrolizidinones by Norrish–Yang cy-
clization of 3-(acylmethyl)-2-alkylisoindol-1-ones in ben-
zene solution (Scheme 1).
Abstract: An efficient synthesis of 2-hydroxy-1,2,3,9b-tetrahydro-
pyrrolo[2,1-a]isoindol-5-ones has been achieved by the Norrish–
Yang cyclization of 3-(acylmethyl)-2-alkylisoindol-1-ones in ben-
zene in moderate to high yields.
Key words: Norrish–Yang cyclization, 3-(acylmethyl)-2-alkyl-
isoindol-1-one, pyrrolo[2,1-a]isoindol-5-one, intramolecular ring
formation, C–C bond formation
The synthetic utility of the Norrish–Yang cyclization has
been studied extensively since Yang reported on an in-
triguing intramolecular C–C bond-forming reaction re-
sulting from intramolecular hydrogen abstraction by a
photoexcited ketone in 1958.1 The stereoselectivity of the
reaction has attracted considerable attention and has also
been closely studied in recent years in the photocycliza-
tion of ketone-amino acids.2,3 Different cyclic compounds
can be obtained by Norrish–Yang cyclization. From a
product-oriented point of view, the site of hydrogen ab-
straction determines the size of the resulting ring. The fac-
ile g-hydrogen abstraction, proceeding through a six-
membered transition state, affords four-membered rings
(cyclobutanes, oxetanes, azetidines, etc.).3 If there is no
hydrogen atom available in the g-position to the carbonyl
group, d- or e-hydrogen atom abstractions occur. The sub-
sequent cyclization results in five- or six-membered rings.
For example, Giese and Wyss reported the stereoselective
formation of substituted pyrrolidin-2-ones and piperidin-
2-ones by Norrish–Yang cyclization of N-(2-benzoyleth-
yl)glycinamides and N-(benzoylmethyl)glycinamides, re-
spectively.2–4
O
O
R3
R2
R3
R2
OH
hv
N
N
O
R1
X
X
H
R1
1a–d X = C, R1 = Ph
1e–h X = C, R1 = Me
1i,j X = C, R1 = CO2Me
1k,l X = N, R1 = Ph
2a–l
Scheme 1 Photocyclization of 3-(acylmethyl)-2-alkylisoindol-1-
ones
Our new synthetic method for the formation of benzopyr-
rolizidines reported in this paper is based on the construc-
tion of the pyrrolo[2,1-a]isoindol-5-one skeleton by
photocyclization of four kinds of ketone-amides such as
2-alkyl-3-(benzoylmethyl)isoindol-1-ones 1a–d, 3-
(acetylmethyl)-2-alkylisoindol-1-ones 1e–h, methyl 3-(2-
alkyl-3-oxoisoindol-1-yl)pyruvates 1i,j, and 7-(acetyl-
methyl)pyrrolo[3,4-b]pyridin-5-ones 1k,l.
We are interested in the intramolecular photocyclization
reactions of ketones with amides in relation to the synthe-
sis of alkaloid-like compounds benzopyrrolizidines be-
cause benzopyrrolizidines possess a wide range of
biological activities, such as potential kinase inhibitory,5a
antitumor, and antiviral activities.5b,c They could be used
as versatile key intermediates in the synthesis of alkaloid
gephyrotoxins.6 Hence the chemistry and synthesis of
these compounds have also received considerable atten-
tion. A literature survey shows that many methodologies
have been reported for the synthesis of benzopyrroliz-
idines, for example, photocyclization of phthalimide de-
Reactants 1a–d and 1i,j were synthesized by the coupling
reactions of carbonyl compounds [acetophenone (4a) and
methyl pyruvate (4b)] with 2-alkyl-3-hydroxyisoindol-1-
ones 3a–d15a under the catalysis of boron trifluoride–
diethyl ether complex at room temperature (Scheme 2);
reactants 1e–h were synthesized by a modified literature
method16 from the coupling reactions of ethyl acetoace-
tate (4c) with 2-alkyl-3-hydroxyisoindol-1-ones 3a–d
firstly under the catalysis of boron trifluoride–diethyl
ether complex at room temperature to give 5a–d and then
hydroxylation and decarboxylation (Scheme 3); 1k,l were
synthesized by the coupling reaction of acetophenone (4a)
SYNTHESIS 2009, No. 11, pp 1821–1828
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Advanced online publication: 27.04.2009
DOI: 10.1055/s-0028-1088065; Art ID: F23708SS
© Georg Thieme Verlag Stuttgart · New York

1822
J. Wu et al.
PAPER
Table 1 Photocyclization of 1a in Different Solvents
O
O
R3
R2
R3
Solvent
CH2Cl2
MeCN
Time (h)
Conversion (%) Yield (%)
BF3⋅OEt2
N
N
R2
+
MeCOR1
CH2Cl2
r.t.
O
48
32
20
35
75
81
32
37
45
OH
R1
3a R2 = R3 =H
4a R1 = Ph
1a-d R1 = Ph
1i,j R1 = CO2Me
3b R2 = R3 = Me
3c R2 –R3 = (CH2)5
3d R2 = H, R3 = Ph
4b R1 = CO2Me
benzene
The photoreactions of 1a–l showed high stereoselectivity.
Although two stereoisomers were produced in most cases,
only one isomer was the dominant product as depicted in
Table 2. In the case of 1g, two pure stereoisomers cis-2g
and trans-2g could be separated by repeated preparative
thin layer chromatography and their stereostructures were
evaluated by NOE correlation as shown in Figure 1. In
NOE correlation of cis-2g, the reciprocal interaction be-
tween H10 and protons of methyl group on C2 is ob-
served, which indicates that the configuration of H10 and
the methyl group on C2 is cis; while no reciprocal interac-
tion between H10 and protons of methyl group on C2 is
observed in the NOE correlation of trans-2g, indicating
that the configuration of H10 and the methyl group is
trans. The configurations of other products have also been
examined by NOE correlation. For example, no reciprocal
interaction between H10 and protons of phenyl group on
C2 in products 2a–d indicated that H10 and phenyl group
on C2 is trans; the reciprocal interaction between H10 and
protons of the methyl group on C2 in products 2e–h indi-
cate that H10 and methyl group on C2 are cis; no recipro-
cal interaction between H10 and protons of methoxy
group on C2 in products 2i,j indicate that H10 and CO2Me
group on C2 are trans. All these deduction are consistent
with the X-ray crystal structure analysis of 2a, 2h, and 2j
as shown in Figures 2– 4.
Scheme 2
O
R3
R2
O
R3
N
BF3⋅OEt2
N
R2
+ MeCOCH2CO2Et
O
CH2Cl2
r.t.
OH
O
OEt
3a R2 = R3 = H
3b R2 = R3 = Me
3c R2 –R3 = (CH2)5
3d R2 = H, R3 = Ph
5a–d
O
R3
R2
N
NaCl
O
DMSO–H2O
95 °C
1e–h
Scheme 3
O
O
N
80 °C
Ph
N
+
MeCOR1
Ph
O
CF3CO2H
N
N
OH
R1
4a R1 = Ph
4d R1 = Me
6
1k,l
Scheme 4
O
O
5
5
or acetone (4d) with 7-hydroxypyrrolo[3,4-b]pyridin-5-
one 615b in trifluoroacetic acid under heating (Scheme 4).
4
H
H
4
N
Me
3
Me
2
OH
2
N
3
10
10
9
9
Feasibility of the photocyclization reaction of 1a was in-
vestigated in three different solvents under irradiation in
Pyrex tubes with a high-pressure mercury lamp (500 W)
at ambient temperature and the results are shown in
Table 1. Obviously the photoreaction in benzene is more
efficient than those in acetonitrile and dichloromethane,
hence benzene was selected as solvent in the photoreac-
tions of all other reactants 1b–l (Table 2). The products
benzopyrrolizidines 2a–l were obtained by separation us-
ing silica gel column chromatography or repeated prepar-
ative layer chromatography (silica gel plate, acetone–
hexane, 1:10) and further purified by recrystallization. All
products were fully identified by 1H, 13C NMR, MS, and
NOE correlations (Figure 1) and the structures of 2a, 2h,
and 2j were further confirmed by the X-ray crystal struc-
tures as depicted in Figures 2–4.
1
1
H
H
Me
Ph
OH
2e
2b
5 O
5O
H
4
H
4
3
Me
N
N 3
OH
10
2
2
10
9
9
1
H
1
H
OH
Me
trans-2g
cis-2g
O
O
5
5
H
H
4
4
N
Ph
Ph
3
Me
CO2Me
N
3
10
10
2
2
9
9
1
1
H
H
H
H
OH
OH
2j
2h
Figure 1 NOE correlations of 2b, 2e, 2g, 2h, and 2j
Synthesis 2009, No. 11, 1821–1828 © Thieme Stuttgart · New York

PAPER
Synthesis of Benzopyrrolizidinones
1823
Figure 2 X-ray crystal structure (ORTEP drawing) of 2a
Figure 3 X-ray crystal structure (ORTEP drawing) of 2h
It could be observed from Table 2 that the acyl groups in
reactants 1a–l have a great effect on the stereoselectivity
of the photoreaction. For example, the photoreactions of
1a–d and 1k in which the acyl groups are all benzoyl
group give mainly the trans-isomers, in other words, the
configuration of the hydrogen atom on C10 and the hy-
droxy group on C2 is cis; but the photoreactions of 1e–j
and 1l in which the acyl groups are acetyl or methoxyox-
alyl groups afford mainly the cis-isomers in which the
configuration of the hydrogen atom on C10 and the hy-
droxy group on C2 is trans. Meanwhile, N-alkyl groups
have also effects on the structures of photocyclization
products. For example, the configuration of the hydrogen
atom on C10 and the phenyl group on C3 in products 2d,
2h, 2j, 2k, and 2l are all cis when the N-alkyl is the benzyl
group.
Figure 4 X-ray crystal structure (ORTEP drawing) of 2j
In summary, an efficient synthesis of 2-hydroxypyrro-
lo[2,1-a]isoindol-5-ones has been achieved by the Nor-
rish–Yang cyclization of 3-(acylmethyl)-2-alkylisoindol-
1-ones in benzene.
Table 2 Photocyclization of 3-(Acylmethyl)-2-alkylisoindol-1-ones and 6-Alkyl-7-(benzoylmethyl)pyrrolo[3,4-b]pyridin-5-ones
Entry
Substrate
Time
(h)
Conversion Producta
(%)
Yieldb
(%)
Mp
(°C)
O
O
O
O
O
Me
N
N
N
N
1
1a
20
20
18
24
81
76
85
74
2a
2b
2c
2d
45
42
56
39
141–142
253–254
269–270
197–199
N
N
N
N
Ph
O
OH
H
Ph
O
2
3
4
1b
1c
1d
Ph
O
OH
H
Ph
O
Ph
O
OH
H
Ph
O
H
Ph
Ph
Ph
O
OH
H
Ph
Synthesis 2009, No. 11, 1821–1828 © Thieme Stuttgart · New York

1824
J. Wu et al.
PAPER
Table 2 Photocyclization of 3-(Acylmethyl)-2-alkylisoindol-1-ones and 6-Alkyl-7-(benzoylmethyl)pyrrolo[3,4-b]pyridin-5-ones (continued)
Entry
5
Substrate
Time
(h)
Conversion Producta
(%)
Yieldb
(%)
Mp
(°C)
O
O
O
Me
1e
20
75
2e
51
149–150
N
N
N
OH
O
O
H
O
6
7
1f
20
18
68
80
2f
48
63
dense oil
242–243
N
N
OH
OH
H
O
O
N
1g
2g
O
H
(cis)
O
N
2g
2h
15
47
dense oil
218–219
OH
H
O
(trans)
O
O
H
Ph
N
N
8
9
1h
1i
26
18
62
65
Ph
O
N
N
OH
H
O
2i
2j
45
61
183–184
156–157
OH
O
CO2Me
H
CO2Me
O
O
O
O
H
Ph
N
N
N
Ph
O
10
1j
20
48
N
OH
CO2Me
H
CO2Me
O
H
H
Ph
Ph
Ph
O
11
12
1k
1l
18
18
93
82
2k
2l
87
78
130–131
166–168
N
N
N
N
OH
N
N
H
Ph
O
Ph
Ph
O
OH
H
a Isolated pure isomers.
b Yields based on conversion of 1a–l.
Synthesis 2009, No. 11, 1821–1828 © Thieme Stuttgart · New York

PAPER
Synthesis of Benzopyrrolizidinones
1825
All the reactions were monitored by TLC (silica gel coated TLC
plates). Silica gel 230–400 mesh was used for column chromatog-
raphy. EI-MS were recorded with a HP 5988 A mass spectrometer.
1H and 13C NMR spectra were recorded on a Bruker DRX-300
NMR spectrometers in CDCl3 and DMSO-d6 with TMS as an inter-
nal standard. Melting points were determined on a Yanagimoto
melting point apparatus. All solvents were dried and distilled before
use.
als were separated by column chromatography (silica gel, hexane–
acetone) to afford the coupling product ethyl 2-(2-cyclohexyl-3-
oxo-2,3-dihydro-1H-isoindol-1-yl)acetoacetate (5c). To a soln of 5c
(5 mmol) in DMSO (5 mL) was added NaCl (6.5 mmol) and H2O
(40 mL, 2.2 mmol). The mixture was heated at 100 °C for 5 h and
then H2O was added and the mixture was extracted with CH2Cl2 (4
× 20 mL). The combined organic phases were dried (anhyd Na2SO4)
and concentrated in vacuo. The residuals were separated by column
chromatography (silica gel, hexane–acetone) to afford the decar-
boxylated product 1g (1.2 g, 89%).
1H NMR (300 MHz, CDCl3): d = 1.18–1.29 (m, 1 H), 1.34–1.44 (m,
2 H), 1.69 (d, J = 12.3 Hz, 1 H), 1.77–1.97 (m, 5 H), 2.00–2.09 (m,
1 H), 2.22 (s, 3 H, CH3), 2.65–2.75 (m, 1 H), 3.21 (dd, J = 17.7 Hz,
1 H), 3.68–3.77 (m, 1 H), 5.10 (dd, J = 8.7, 3.6 Hz, 1 H), 7.31–7.34
(m, 1 H), 7.40–7.49 (m, 2 H), 7.77–7.80 (m, 1 H).
3-(Benzoylmethyl)-2-isopropyl-2,3-dihydro-1H-isoindol-1-one
(1b); Typical Procedure
To a stirred CH2Cl2 soln (100 mL) of 3-hydroxy-2-isopropylisoin-
dol-1-one 3b (0.01 mol) and acetophenone (0.015 mol) [or methyl
pyruvate (0.015 mol) for 1f] was added BF3·OEt2 (0.015 mol) at r.t.
The mixture was stirred for 24–36 h until 3b disappeared (moni-
tored by TLC). The mixture was washed with H2O (2 × 100 mL)
and the organic phase was dried (anhyd Na2SO4) and concentrated
in vacuo. The residuals were separated by column chromatography
(silica gel, hexane–acetone) to afford 1b (2.3 g, 78%).
1H NMR (300 MHz, CDCl3): d = 1.44–1.51 (m, 6 H, 2 CH3), 3.29
(dd, J = 17.7, 9.0 Hz, 1 H), 3.61 (dd, J = 17.7, 3.6 Hz, 1 H), 4.24 (m,
1 H), 5.38 (dd, J = 9.0, 3.6 Hz, 1 H), 7.35–7.39 (m, 1 H), 7.44 (m, 2
H), 7.47–7.52 (m, 2 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.81–7.84 (m, 1
H), 7.96 (d, J = 6.9 Hz, 2 H, 2 CH).
7-(Benzoylmethyl)-6-benzyl-6,7-dihydro-5H-pyrrolo[3,4-b]py-
ridin-5-one (1k)
1H NMR (300 MHz, CDCl3): d = 3.31 (dd, J = 18.0, 6.9 Hz, 1 H),
3.67 (dd, J = 18.0, 3.3 Hz, 1 H), 4.70 (d, J = 15.3 Hz, 1 H), 4.91 (d,
J = 15.0 Hz, 1 H), 5.32 (dd, J = 6.9, 3.6 Hz, 1 H), 7.08–7.17 (m, 4
H), 7.25 (d, J = 6.6 Hz, 2 H), 7.35–7.44 (m, 3 H), 7.53 (t, J = 7.2 Hz,
1 H), 7.73–7.76 (m, 1 H), 8.18 (d, J = 7.8 Hz, 1 H), 8.70 (d, J = 8.1
Hz, 1 H).
3-(Benzoylmethyl)-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one
(1c)
7-(Acetylmethyl)-6-benzyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyri-
din-5-one (1l)
1H NMR (300 MHz, CDCl3): d = 1.17–1.40 (m, 3 H), 1.67 (d,
J = 11.7 Hz, 1 H), 1.82–2.02 (m, 5 H), 2.03–2.16 (m, 1 H), 3.22–
3.32 (m, 1 H), 3.65 (dd, J = 17.4, 3.6 Hz, 1 H), 3.68–3.84 (m, 1 H),
5.37 (dd, J = 8.7, 3.3 Hz, 1 H), 7.29–7.40 (m, 3 H), 7.42–7.51 (m, 2
H), 7.58–7.63 (m, 1 H), 7.78–7.81 (m, 1 H), 7.94–7.96 (m, 2 H).
1H NMR (300 MHz, CDCl3): d = 1.81 (s, 3 H, CH3), 2.71 (dd,
J = 18.0, 7.5 Hz, 1 H), 3.13 (dd, J = 18.0, 3.6 Hz, 1 H), 4.72 (d,
J = 15.3 Hz, 1 H), 4.86 (d, J = 15.3 Hz, 1 H), 5.08 (dd, J = 7.2, 3.6
Hz, 1 H), 7.25–7.31 (m, 5 H), 7.41 (dd, J = 7.5, 4.5 Hz, 1 H), 8.16
(dd, J = 7.5, 1.4 Hz, 1 H), 8.70 (dd, J = 4.8, 1.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 25.4 (CH2), 26.0 (CH2), 26.1
(CH2), 30.8 (CH2), 31.2 (CH2), 43.2 (CH2), 54.0 (CH), 56.2 (CH),
122.7 (CH), 123.4 (C), 128.1 (2 CH), 128.3 (CH), 128.8 (2 CH),
131.5 (CH), 132.4 (C), 133.8 (CH), 146.2 (CH), 168.6 (C=O), 197.5
(C=O).
13C NMR (75 MHz, CDCl3): d = 29.8 (CH3), 45.0 (CH2), 45.0
(CH2), 57.3 (CH), 123.4 (CH), 125.5 (C), 127.5 (CH), 128.0 (2 CH),
128.6 (2 CH), 131.9 (CH), 137.1 (C), 152.6 (CH), 164.9 (C=O),
166.9 (C), 204.6 (C=O).
2-Hydroxy-2-phenyl-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-
a]isoindol-5-one (2a); Typical Procedure for Photochemical
Reactions
Methyl 3-(2-Cyclohexyl-3-oxo-2,3-dihydro-1H-isoindol-1-
yl)pyruvate (1i)
1H NMR (300 MHz, CDCl3): d = 1.13–1.28 (m, 1 H), 1.31–1.45 (m,
2 H), 1.61–1.78 (m, 1 H), 1.83–2.09 (m, 6 H), 3.18 (dd, J = 18.9, 8.7
Hz, 1 H), 3.61 (dd, J = 18.3, 3.0 Hz, 1 H), 3.71–3.80 (m, 1 H), 3.88
(s, 3 H, CH3), 5.11 (dd, J = 8.7, 3.6 Hz, 1 H), 7.31 (d, J = 6.3 Hz, 1
H), 7.50 (t, J = 6.3 Hz, 2 H, 2 CH), 7.81 (d, J = 6.3 Hz, 1 H).
To dry benzene (100 mL) was added 1a (1.0 mmol). The soln was
distributed into 5 20-mL quartz tubes and deaerated by bubbling ar-
gon for 30 min and irradiated with a high-pressure Hg lamp (500 W)
at r.t. for the appropriate time. The solvent was removed in vacuo
and the products were separated by column chromatography (silica
gel, hexane–acetone, 10:1) to afford 2a. The solid was further puri-
fied by recrystallization (hexane–acetone) to give pure 2a as color-
less needles.
1H NMR (300 MHz, CDCl3): d = 1.73 (t, J = 11.7 Hz, 1 H), 2.01 (s,
1 H, OH), 2.61 (dd, J = 12.3,5.4 Hz, 1 H), 3.75 (d, J = 12.9 Hz, 1
H), 4.10 (d, J = 12.3 Hz, 1 H), 5.32 (dd, J = 11.1, 5.4 Hz, 1 H), 7.24–
7.36 (m, 3 H), 7.41–7.51 (m, 4 H), 7.53–7.58 (m, 1 H), 7.81 (d,
J = 4.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 25.3 (CH2), 25.9 (CH2), 26.1
(CH2), 30.6 (CH2), 31.2 (CH2), 43.9 (CH2), 53.3 (CH), 53.9 (CH),
55.1 (CH3), 122.3 (CH), 123.5 (CH), 128.5 (CH), 131.5 (CH), 132.4
(C), 144.9 (C), 160.7 (C=O), 168.3 (C=O), 191.5 (C=O).
Methyl 3-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)pyru-
vate (1j)
1H NMR (300 MHz, CDCl3): d = 3.12 (dd, J = 18.3, 6.3 Hz, 1 H),
3.38 (dd, J = 18.9, 6.0 Hz, 1 H), 3.77 (s, 3 H, CH3), 4.55 (d, J = 15.3
Hz, 1 H), 4.98 (d, J = 11.7 Hz, 1 H, CH), 5.01 (d, J = 15.0 Hz, 1 H),
7.22–7.31 (m, 5 H), 7.35 (d, J = 6.3 Hz, 1 H), 7.47–7.55 (m, 2 H),
7.90 (d, J = 7.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 45.6 (CH2), 57.8 (CH2), 63.9 (CH),
80.8 (C), 122.8 (CH), 124.1 (CH), 124.9 (2 CH), 127.8 (CH), 128.4
(2 CH), 128.5 (CH), 131.8 (CH), 133.3 (C), 143.5 (C), 143.6 (C),
171.7 (C=O).
MS (EI, 70 eV): m/z (%) = 265 (M+, 15), 175 (65), 146 (76), 77
(100).
HRMS: m/z [M + H]+ calcd for C17H16NO2: 266.1176; found:
266.1170.
3-(Acetylmethyl)-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one
(1g); Typical Procedure
To a stirred CH2Cl2 soln (100 mL) of 2-cyclohexyl-3-hydroxyisoin-
dol-1-one 3c (0.01 mol) and ethyl acetoacetate (0.011 mol),
BF3·OEt2 (0.015 mol) was added at r.t. The mixture was stirred for
2 h until 3c disappeared (monitored by TLC). The mixture was
washed with H2O (2 × 100 mL)and the organic phase was dried (an-
hyd Na2SO4) and concentrated under reduced pressure. The residu-
X-ray crystal data for 2a: Recrystallized (acetone–hexane).
C17H15NO2, Mr = 265.30, monoclinic, a = 11.971(3) Å,
b = 10.876(3) Å, c = 11.991(3) Å, b = 118.643(4), V = 1370.2(6)
Å3, colorless plates, r = 1.286 g cm–3, T = 293(2) K, space group
Synthesis 2009, No. 11, 1821–1828 © Thieme Stuttgart · New York

1826
J. Wu et al.
PAPER
P2(1)/c, Z = 4, m (MoKa) = 0.085 mm–1, 2 qmax = 51°, 7039 reflec-
tions measured, 2555 unique (Rint = 0.0291), which were used in all
calculations. The final wR(F2) was 0.1144 (for all data),
R1 = 0.0413. CCDC file No. 707695.
13C NMR (75 MHz, CDCl3): d = 26.7 (CH3), 43.8 (CH2), 57.3
(CH2), 63.1 (C), 82.3 (CH), 122.5 (CH), 124.2 (CH), 128.2 (CH),
132.1 (CH), 132.6 (C), 147.6 (C), 173.3 (C=O).
MS (EI, 70 eV): m/z (%) = 203 (M+, 26), 174 (4), 160 (17), 145
(100).
3,3-Dimethyl-2-hydroxy-2-phenyl-1,2,3,9b-tetrahydro-5H-pyr-
rolo[2,1-a]isoindol-5-one (2b)
Colorless needles.
HRMS: m/z [M + H]+ calcd for C12H14NO2: 204.1090; found:
204.1020.
1H NMR (300 MHz, CDCl3): d = 1.18 (s, 3 H, CH3), 1.59 (s, 1 H,
OH), 1.71 (s, 3 H, CH3), 2.09 (dd, J = 14.1, 4.2 Hz, 1 H), 3.35 (dd,
J = 14.1, 10.5 Hz, 1 H), 5.11 (dd, J = 10.5, 4.8 Hz, 1 H), 7.30–7.47
(m, 5 H), 7.52–7.57 (m, 3 H), 7.81 (d, J = 7.5 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 17.4 (CH3), 25.8 (CH3), 59.9
(CH2), 68.6 (CH), 86.2 (C), 122.7 (CH), 122.9 (CH), 126.9 (2 CH),
127.0 (C), 127.4 (2 CH), 127.6 (CH), 131.7 (CH), 133.9 (C), 142.2
(C), 148.1 (C), 171.3 (C=O).
2-Hydroxy-2,3,3-trimethyl-1,2,3,9b-tetrahydro-5H-pyrro-
lo[2,1-a]isoindol-5-one (2f)
Pale dense oil.
1H NMR (400 MHz, CDCl3): d = 1.41 (s, 3 H, CH3), 1.42 (s, 3 H,
CH3), 1.61 (s, 3 H, CH3), 1.93 (dd, J = 12.8, 8.0 Hz, 1 H), 2.00 (s, 1
H, OH), 2.38 (dd, J = 12.8, 8.8 Hz, 1 H), 4.79 (t, J = 8.4 Hz, 1 H),
7.35 (d, J = 7.6 Hz, 1 H), 7.40 (t, J = 7.2 Hz, 1 H), 7.50 (t, J = 7.2
Hz, 1 H), 7.75 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 18.7 (CH3), 23.3 (CH3), 24.8
(CH3), 41.3 (CH2), 60.5 (C), 66.3 (C), 84.3 (CH), 122.1 (CH), 123.9
(CH), 128.1 (CH), 131.6 (CH), 134.5 (C), 146.5 (C), 171.0 (C=O).
MS (EI, 70 eV): m/z (%) = 293 (M+, 2), 250 (9), 173 (100).
HRMS: m/z [M + H]+ calcd for C19H20NO2: 294.1489; found:
294.1495.
MS (EI, 70 eV): m/z (%) = 231 (M+, 4), 196 (42), 173 (100).
HRMS: m/z [M + H]+ calcd for C14H18NO2: 232.1332; found:
2¢-Hydroxy-2¢-phenyl-1¢,9b¢-dihydrospiro[cyclohexane-1,3¢-
pyrrolo[2¢,1¢-a]isoindol]-5¢(2¢H)-one (2c)
Colorless needles.
232.1332.
1H NMR (300 MHz, CDCl3): d = 0.88–1.08 (m, 2 H), 1.10 (td,
J = 13.5, 4.2 Hz, 1 H), 1.18–1.36 (m, 1 H), 1.54–1.65 (m, 4 H),
1.72–1.77 (m, 1 H), 1.93–2.01 (m, 1 H), 2.25–2.34 (m, 1 H), 2.43–
2.89 (m, 1 H), 2.87 (d, J = 13.5 Hz, 1 H), 3.26 (t, J = 14.1 Hz, 1 H),
5.03 (dd, J = 10.5, 4.2 Hz, 1 H), 7.11–7.14 (m, 1 H), 7.33–7.48 (m,
4 H), 7.54–7.72 (m, 2 H), 7.73 (d, J = 5.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 22.2 (CH2), 23.8 (CH2), 24.6
(CH2), 25.3 (CH2), 33.5 (CH2), 40.7 (C), 59.9 (CH2), 73.6 (CH),
88.3 (C), 122.0 (CH), 123.9 (CH), 126.8 (2 CH), 127.5 (CH), 127.8
(2 CH),1 27.9 (CH), 131.8 (CH), 134.1 (C), 140.8 (C), 147.2 (C),
173.6 (C=O).
trans-2¢-Hydroxy-2¢-methyl-1¢,9b¢-dihydrospiro[cyclohexane-
1,3¢-pyrrolo[2¢,1¢-a]isoindol]-5¢(2¢H)-one (2g)
Pale dense oil.
1H NMR (400 MHz, CDCl3): d = 1.05 (s, 3 H, CH3), 1.35–1.39 (m,
2 H), 1.63–1.68 (m, 2 H), 1.71–1.78 (m, 2 H), 1.81–1.89 (m, 2 H),
2.25–2.29 (m, 2 H), 2.45 (dd, J = 12.8, 10.8 Hz, 1 H), 2.66 (d,
J = 13.6 Hz, 1 H), 4.89 (dd, J = 10.0, 5.6 Hz, 1 H), 7.37 (d, J = 7.6
Hz, 1 H), 7.43 (t, J = 7.2 Hz, 1 H),7.52 (t, J = 7.6 Hz, 1 H), 7.76 (d,
J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 22.4 (CH3), 24.2 (CH2), 25.6
(CH2), 26.3 (CH2), 26.5 (CH2), 31.6 (CH2), 41.5 (CH2), 59.0 (C),
69.5 (C), 82.6 (CH), 122.2 (CH), 123.8 (CH), 128.1 (CH), 131.7
(CH), 134.5 (C), 146.3 (C), 170.7 (C=O).
MS (EI, 70 eV): m/z (%) = 333 (M+, 2), 251 (3), 213 (100).
HRMS: m/z [M + H]+ calcd for C22H24NO2: 334.1802; found:
334.1798.
MS (EI, 70 eV): m/z (%) = 271 (M+, 11), 251 (19), 228 (5), 213
(100).
2-Hydroxy-2,3-diphenyl-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-
a]isoindol-5-one (2d)
Colorless needles.
HRMS: m/z [M + H]+ calcd for C17H22NO2: 272.1645; found:
272.1649.
1H NMR (300 MHz, CDCl3): d = 2.05 (s, 1 H, OH), 2.22 (d,
J = 13.5 Hz, 1 H), 3.08 (t, J = 10.5 Hz, 1 H), 5.47 (s, 2 H, 2 CH),
6.93–6.96 (m, 2 H), 7.11–7.19 (m, 8 H), 7.45–7.49 (m, 2 H), 7.53–
7.64 (m, 1 H), 7.91 (d, J = 6.5 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 39.5 (CH2), 63.2 (C), 73.4
(CH), 87.4 (CH), 123.3 (CH), 123.6 (CH), 126.5 (2 CH), 126.8
(CH), 127.4 (2 CH), 127.5 (2 CH), 127.6 (CH), 127.7 (2 CH), 128.1
(CH), 132.3 (CH), 132.5 (C), 138.5 (C), 142.2 (C), 150.1 (C), 174.4
(C=O).
cis-2¢-Hydroxy-2¢-phenyl-1¢,9b¢-dihydrospiro[cyclohexane-1,3¢-
pyrrolo[2¢,1¢-a]isoindol]-5¢(2¢H)-one (3g)
Colorless needles.
1H NMR (400 MHz, CDCl3): d = 1.31 (s, 3 H, CH3), 1.33–1.40 (m,
2 H), 1.61–1.64 (m, 2 H), 1.66–1.70 (m, 3 H), 1.93 (dd, J = 13.6, 4.8
Hz, 2 H), 2.36–2.43 (m, 2 H), 2.74 (dd, J = 13.2, 6.0 Hz, 1 H), 4.81
(dd, J = 10.4, 4.8 Hz, 1 H), 7.34 (d, J = 7.6 Hz, 1 H), 7.40 (t, J = 7.6
Hz, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.74 (d, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 22.5 (CH3), 22.7 (CH2), 24.0
(CH2), 25.1 (CH2), 25.8 (CH2), 33.6 (CH2), 41.4 (CH2), 60.0 (C),
72.4 (C), 85.4 (CH), 122.0 (CH), 123.9 (CH), 128.0 (CH), 131.8
(CH), 134.1 (C), 147.1 (C), 173.0 (C=O).
MS (EI, 70 eV): m/z (%) = 323 (M+ – H2O, 2), 221 (82), 57 (100).
HRMS: m/z [M + Na]+ calcd for C23H19NNaO2: 364.1308; found:
364.1305.
MS (EI, 70 eV): m/z (%) = 271 (M+, 11), 251 (13), 228 (16), 213
(100).
HRMS: m/z [M + H]+ calcd for C17H22NO2: 272.1645; found:
272.1651.
2-Hydroxy-3-methyl-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-
a]isoindol-5-one (2e)
Colorless needles.
1H NMR (300 MHz, CDCl3): d = 1.54 (s, 3 H, CH3), 1.82 (dd,
J = 12.3, 7.5 Hz, 1 H), 2.31 (dd, J = 12.3, 8.4 Hz, 1 H), 2.77 (s, 1 H,
OH), 3.22 (d, J = 12.3 Hz, 1 H), 3.90 (d, J = 12.6 Hz, 1 H), 4.80 (t,
J = 8.4 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 2 H, 2 CH), 7.51 (d, J = 7.2 Hz,
1 H), 7.75 (d, J = 7.8 Hz, 1 H).
2-Hydroxy-2-methyl-3-phenyl-1,2,3,9b-tetrahydro-5H-pyrro-
lo[2,1-a]isoindol-5-one (2h)
Colorless needles.
Synthesis 2009, No. 11, 1821–1828 © Thieme Stuttgart · New York

PAPER
Synthesis of Benzopyrrolizidinones
1827
1H NMR (300 MHz, CDCl3): d = 1.10 (s, 3 H), 1.58 (s, 1 H, OH),
1.87 (t, J = 11.7 Hz, 1 H), 2.45 (dd, J = 12.0, 6.0 Hz, 1 H), 4.92 (s,
1 H), 5.02 (dd, J = 12.3, 6.6 Hz, 1 H), 7.29–7.36 (m, 5 H), 7.46–7.57
(m, 2 H), 1.80 (t, J = 6.3 Hz, 1 H), 7.89 (d, J = 7.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 24.4 (CH3), 44.5 (CH2), 62.3 (CH),
69.4 (CH), 83.6 (C), 123.3 (CH), 123.4 (CH), 126.4 (2 CH), 126.9
(CH), 128.0 (2 CH), 128.3 (CH), 132.1 (CH), 132.3 (C), 139.5 (C),
147.8 (C), 172.0 (C=O).
8-Hydroxy-7,8-diphenyl-7,8,9,9a-tetrahydro-5H-pyrido[2,3-
a]pyrrolizin-5-one (2k)
Colorless needles.
1H NMR (300 MHz, CDCl3): d = 2.03 (t, J = 12.3 Hz, 1 H), 2.84
(dd, J = 12.6, 5.1 Hz, 1 H), 5.50 (s, 1 H), 5.58 (dd, J = 11.1, 5.1 Hz,
1 H), 7.07–7.10 (m, 2 H), 7.27–7.32 (m, 4 H), 7.33–7.47 (m, 5 H),
8.16 (dd, J = 7.8, 1.5 Hz, 1 H), 8.75 (dd, J = 4.8, 1.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 45.5 (CH2), 65.7 (CH), 70.1
(CH), 87.2 (C), 123.6 (C), 125.1 (2 CH), 126.9 (2 CH), 127.1 (C),
127.7 (CH), 128.2 (CH), 128.5 (2 CH), 128.7 (2 CH), 132.6 (CH),
134.9 (C), 142.5 (C), 152.9 (CH), 166.3 (CH), 170.2 (C=O).
MS (EI, 70 eV): m/z (%) = 279 (M+, 3), 236 (2), 221 (100).
HRMS: m/z [M + H]+ calcd for C18H17NNaO2: 302.1151; found:
302.1146.
MS (EI, 70 eV): m/z (%) = 342 (M+, 3), 237 (6), 84 (100).
HRMS: m/z [M + H]+ calcd for C22H18N2NaO2: 365.1260; found:
Crystal data for 2h: Recrystallized (acetone–hexane). C18H17NO2,
Mr = 279.33, monoclinic, a = 20.782(19) Å, b = 8.375(7) Å,
c = 16.846(14) Å, b = 94.00(3), V = 2925(4) Å3, colorless plates,
r = 1.269 g cm–3, T = 296(2) K, space group C2/c, Z = 8,
m(MoKa) = 0.083 mm–1, 2 qmax = 54.40°, 8312 reflections mea-
sured, 3212 unique (Rint = 0.0688), which were used in all calcula-
tions. The final wR(F2) was 0.1460 (for all data), R1 = 0.0926.
CCDC file No. 707696.
365.1254.
8-Hydroxy-8-methyl-7-phenyl-7,8,9,9a-tetrahydro-5H-pyri-
do[2,3-a]pyrrolizin-5-one (2l)
1H NMR (400 MHz, CDCl3): d = 1.15 (s, 3 H, CH3), 2.05 (dd,
J = 12.8, 8.0 Hz, 1 H), 2.54 (dd, J = 12.4, 7.6 Hz, 1 H), 5.07 (s, 1 H),
5.14 (t, J = 8.0 Hz, 1 H), 7.28–7.31 (m, 1 H), 7.32–7.39 (m, 4 H),
7.44 (dd, J = 7.6, 4.8 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 8.77 (d,
J = 4.0 Hz, 1 H).
Methyl 2¢-Hydroxy-5¢-oxo-1¢,2¢,5¢,9b¢-dihydrospiro[cyclohex-
ane-1,3¢-pyrrolo[2¢,1¢-a]isoindole]-2¢-carboxylate
(2i)
13C NMR (100 MHz, CDCl3): d = 26.5 (CH3), 43.0 (CH2), 65.3
(CH), 68.9 (CH), 83.6 (C), 123.6 (CH), 127.5 (2 CH), 128.4 (CH),
128.5 (C), 128.9 (2 CH), 132.7 (CH), 135.9 (C), 152.8 (C), 166.5
(C=O), 170.3 (C=O).
MS (EI, 70 eV): m/z (%) = 280 (M+, 23), 237 (21), 194 (37), 106
(100).
Colorless needles.
1H NMR (400 MHz, CDCl3): d = 1.12–1.28 (m, 2 H), 1.34–1.42 (m,
1 H), 1.59–1.66 (m, 2 H), 1.76 (d, J = 12.4 Hz, 1 H), 1.87–1.93 (m,
2 H), 1.94–2.05 (m, 1 H), 2.33–2.37 (m, 1 H), 2.86 (dd, J = 13.6, 3.2
Hz, 1 H), 3.19 (dd, J = 14.0, 10.4 Hz, 1 H), 3.85 (s, 3 H, CH3), 4.95
(dd, J = 10.4, 5.2 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.43 (t, J = 7.6
Hz, 1 H), 7.52 (m, 1 H), 7.75 (d, J = 3.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 22.3 (CH2), 23.9 (CH2), 25.4
(CH2), 25.5 (CH2), 34.1 (CH2), 37.7 (CH2), 52.9 (CH3), 60.2 (C),
72.6 (C), 88.5 (CH), 122.1 (CH), 123.9 (CH), 128.2 (CH), 132.0
(CH), 133.8 (C), 146.5 (C), 172.4 (C=O), 172.8 (C=O).
HRMS: m/z [M + H]+ calcd for C17H17N2O2: 281.1285; found:
281.1290.
Acknowledgment
We thank the National Natural Science Foundation of China
(20872056) for financial support.
MS (EI, 70 eV): m/z (%) = 315 (M+, 6), 227 (3), 213 (100).
HRMS: m/z [M + H]+ calcd for C18H22NO4: 316.1543; found:
316.1540.
References and Notes
Methyl 2-Hydroxy-5-oxo-3-phenyl-2,3,5,9b-tetrahydro-1H-
pyrrolo[2,1-a]isoindole-2-carboxylate (2j)
Colorless needles.
1H NMR (300 MHz, CDCl3): d = 1.92 (t, J = 11.7 Hz, 1 H), 2.80
(dd, J = 12.9, 6.3 Hz, 1 H), 3.33 (s, 3 H, CH3), 4.17 (s, 1 H, OH),
5.24 (s, 1 H), 5.43 (dd, J = 10.8, 6.3 Hz, 1 H), 7.25–7.46 (m, 5 H),
7.46–7.57 (m, 2 H), 7.60 (t, J = 6.6 Hz, 1 H), 7.88–7.91 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 41.3 (CH3), 52.6 (CH2), 64.1 (CH),
68.9 (C), 89.9 (CH), 122.6 (CH), 124.6 (CH), 125.6 (2 CH), 127.6
(CH), 128.2 (2 CH), 128.7 (CH), 132.3 (CH), 132.4 (C), 137.3 (C),
146.5 (C), 172.2 (C=O), 173.4 (C=O).
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324.1236.
Crystal data for 2j: Recrystallized (acetone–hexane). C19H17NO4,
Mr = 323.34, triclinic, a = 8.608(5) Å, b = 10.207(6) Å,
c = 10.802(5) Å, b = 107.91(3), V = 808.9(8) Å3, colorless plates,
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r = 1.327
g
cm–3, T = 296(2) K, space group P1, Z = 2,
m(MoKa) = 0.094 mm–1, 2 qmax = 54.40°, 3840 reflections mea-
sured, 2643 unique (Rint = 0.0284) which were used in all calcula-
tions. The final wR(F2) was 0.1460 (for all data), R1 = 0.0926.
CCDC file no. 722237.
Synthesis 2009, No. 11, 1821–1828 © Thieme Stuttgart · New York

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J. Wu et al.
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Synthesis 2009, No. 11, 1821–1828 © Thieme Stuttgart · New York