Novel synthesis of pyrido[2,1-a]isoindoles via a three-component assembly involving benzynes

Article abstract of DOI:10.1055/s-0028-1087417

A novel three-component assembly involving benzynes has been developed for the synthesis of pyrido[2,1-a]isoindoles in moderate yields. Reaction conditions have been optimized and the scope of the reaction has been studied. A plausible mechanism has been proposed to account for the three-component reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087417

LETTER
3115
Novel Synthesis of Pyrido[2,1-a]isoindoles via a Three-Component Assembly
Involving Benzynes
Novel Synthesis
h
u
-
a
]isoindole
n
s
song Xie,a,b Yuhong Zhang,*a Peixin Xua
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87953244; E-mail: yhzhang@zju.edu.cn
b
Center for Biomedicine and Health, Hangzhou Normal University, Hangzhou 310012, P. R. of China
Received 12 July 2008
We initiated our experiments by using benzyne, which
was generated in situ from the elimination of o-trimethyl-
silyl phenyltriflate induced by CsF, reacting with 2-bro-
mo-1-phenylethanone and pyridine in MeCN at 80 °C for
24 hours. Several products were observed and the main
product was easily isolated by silica gel column chroma-
tography. After the characterization of the main product
Abstract: A novel three-component assembly involving benzynes
has been developed for the synthesis of pyrido[2,1-a]isoindoles in
moderate yields. Reaction conditions have been optimized and the
scope of the reaction has been studied. A plausible mechanism has
been proposed to account for the three-component reaction.
Key words: three component, benzyne, aryne, pyrido[2,1-a]iso-
indole
1
by H NMR, 13C NMR and HRMS, the exact structure
was still ambiguous. We finally identified the exact struc-
ture by the X-ray diffraction analysis of the single crystal
of the product (Figure 1 and see the supplementary infor-
mation).13 It appears that the resonance structure 1B con-
tributed more to the NMR data of the product (Scheme 1),
which led to the chemical shifts of proton on carbon next
to nitrogen emerging in very low-field range.
Pyrido[2,1-a]isoindoles are important core structures of
many pharmaceuticals1 and functional materials.2 In spite
of the wide applications, the synthetic methods of this
framework are quite scarce. The most frequently used
method to construct these motifs is the free radical cy-
clization strategies.3 However, these methods generally
require strict reaction conditions and involve multistep re-
actions.
Multicomponent reactions have attracted a lot of attention
in recent years 4 due to their rapid elaboration of complex
structure in a highly efficient and modular manner, and
the formation of several bonds in one single step is highly
compatible with the goals of ‘green chemistry’ and atom
economy. The application of this strategy in the syntheses
of heterocycles has become an attractive field in recent
years5–7 in light of the paramount role of these targets in
the natural products, pharmaceuticals and functional ma-
terials.
Arynes are one of the most important organic species and
have been frequently used as intermediates in a variety of
reactions.8 Recently, multicomponent reactions involving
arynes have attracted much attention.9 For example,
Yamamoto and his co-workers have reported the palladi-
um-catalyzed co-cyclizations of arynes, alkenes and
alkynes.10 Moreover, Wang and his co-workers have de-
veloped a three-component cascade reaction involving
arynes, aldehydes and amines.11 During our continuous
explorations on new reactions involving arynes,12 we
found that a kind of betaine structure like 1B
(Scheme 1) can be accessed in a single step via a three-
component reaction of benzynes, pyridines, and a-haloge-
nated ketones.
Figure 1 Representation of the X-ray crystal structure of product 1
O
O–
N
N+
1B
1A
SYNLETT 2008, No. 20, pp 3115–3120
1
6
.1
2
.2
0
0
8
Advanced online publication: 27.11.2008
DOI: 10.1055/s-0028-1087417; Art ID: W11108ST
Scheme 1 The resonance of 1A and 1B
© Georg Thieme Verlag Stuttgart · New York

3116
C. Xie et al.
LETTER
Table 1 The Optimization Studiesa
We next optimized the reaction conditions of this three-
component assembly and the results are summarized in
Table 1. Solvents frequently used in aryne chemistry such
as toluene, THF, DME and MeCN were employed as the
reaction media at their respective refluxing temperatures,
and the best result was obtained when MeCN was used
(Table 1, entries 1–4). Lowering the reaction temperature
from 80 °C to room temperature led to the decrease in the
yields (Table 1, entries 5–7). When the reaction was car-
ried out in refluxing MeCN for two hours, a comparable
yield was obtained to that for 24 hours (Table 1, entry 8).
Further shortening of the reaction time led to lower yields
(Table 1, entries 9 and 10). The best result was obtained
when the reaction was conducted in refluxing MeCN for
two hours, leading to a 56% yield of pyrido[2,1-a]isoin-
dole product.
O
OTf
+
O
N
CsF
CCH2Br +
solvents
T, time
TMS
N
Entry
Solvent
Toluene
THF
T (°C)b
110
67
Time (h)
Yield (%)c
1
2
24
24
24
24
24
24
24
2
Trace
8
3
DME
80
39
57
50
40
36
56
52
38
4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
80
5
60
With the optimized reaction conditions in hand, we turned
to investigate the scope of the three-component reaction
and some typical results are summarized in Table 2. Un-
der the standard reaction conditions, various substituted 2-
bromo-1-phenylethanones underwent the reaction
smoothly, while 2-bromo-1-phenylethanones bearing
electron-donating groups gave better yields than those
bearing electron-withdrawing groups (Table 2, entries 3,
5, 7 and 9). It had to be noted that benzyne with two sym-
metric methyl groups could also take part in the three-
component reaction efficiently and afforded products in
moderate yields (Table 2, entries 2, 4, 6, 8 and 10). More-
over, good results were also obtained when substituted
pyridine like 4-picoline underwent the reaction (Table 2,
entries 11 and 12). Other nitrogen-containing heterocycle
such as isoquinoline could also react with 2-bromo-1-
phenylethanone and benzynes to afford the corresponding
products efficiently (Table 2, entries 13 and 14).
6
40
7
25
8
80
9
80
1
10
80
0.5
a Reaction conditions: 2-bromo-1-phenylethanone (0.6 mmol), pyri-
dine (1.0 mmol), benzyne precursor (0.5 mmol), CsF (1.5 mmol), sol-
vents (5.0 mL).
b Bath temperature.
c Isolated yields.
Table 2 Scope of the Reactiona
R
O
R2
R1
R1
OTf
O
N
CsF
R
CCH2Br
+
+
MeCN, 80 °C, 2 h
R2
R1
TMS
N
R1
Entry
1
R
R1
H
R2
H
Product
Yield (%)b
O
H
H
56
N
O
2
Me
H
47
N
Synlett 2008, No. 20, 3115–3120 © Thieme Stuttgart · New York

LETTER
Novel Synthesis of Pyrido[2,1-a]isoindoles
3117
Table 2 Scope of the Reactiona (continued)
R
O
R2
N
R1
R1
OTf
O
N
CsF
R
CCH2Br
+
+
MeCN, 80 °C, 2 h
R2
R1
TMS
R1
Entry
R
R1
H
R2
H
Product
Yield (%)b
MeO
O
3
4
5
6
7
8
MeO
MeO
Et
60
N
MeO
O
O
O
Me
H
H
H
H
H
47
57
45
41
35
N
O
Et
H
N
Et
Et
Me
N
O
Cl
Cl
H
N
Cl
Cl
Me
N
Synlett 2008, No. 20, 3115–3120 © Thieme Stuttgart · New York

3118
C. Xie et al.
LETTER
Table 2 Scope of the Reactiona (continued)
R
O
R2
N
R1
R1
OTf
O
N
CsF
R
CCH2Br
+
+
MeCN, 80 °C, 2 h
R2
R1
TMS
R1
Entry
R
R1
H
R2
H
Product
Yield (%)b
O2N
O
9
10
11
12
NO2
NO2
H
36
31
56
53
N
O2N
O
Me
H
N
O
H
4-Me
N
O
H
Me
4-Me
N
O
13
14
H
H
H
isoquinoline
isoquinoline
N
51
45
O
Me
N
a Reaction conditions: 2-bromo-1-phenylethanones (0.6 mmol), pyridines (1.0 mmol), benzyne precursors (0.5 mmol), CsF (1.5 mmol), MeCN
(5.0 mL), 80 °C (bath temperature), 2 h.
b Isolated yields.
Synlett 2008, No. 20, 3115–3120 © Thieme Stuttgart · New York

LETTER
Novel Synthesis of Pyrido[2,1-a]isoindoles
3119
O
O
O
Br–
–
OTf
Br
N
B
CsF
N+
N
+
TMS
HBr
II
I
O
N
O
– 2 H
N
III
Scheme 2 Proposed mechanism
K. M.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 8734.
Based on the above results, a plausible reaction mecha-
nism is proposed (Scheme 2). The initial step involved the
generation of a cationic species I from the reaction of 2-
bromo-1-phenylethanone with pyridine, which then elim-
inated one molecular HBr to form the 1,3-diplor interme-
diate II. The subsequent cycloaddition between the
intermediate II and benzyne species, which was generated
in situ from the fluoride induced 1,2-elimination of o-tri-
methylsilyl phenyltriflate, produced the annulation prod-
uct III. A dehydrogenated aromatization of III then
liberated the final pyrido[2,1-a]isoindole product.
(d) Wang, S. Z.; Cao, L. Y.; Shi, H. J.; Dong, Y. M.; Sun,
J. W.; Hu, Y. F. Chem. Pharm. Bull. 2005, 53, 67.
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In conclusion, a novel three-component assembly involv-
ing benzynes, which can be used for the syntheses of py-
rido[2,1-a]isoindole structure, has been developed in our
laboratory.14,15 The exact structure of the product has been
identified by the X-ray crystallographic analysis. The re-
action conditions have been optimized and the scope of
the reaction has been investigated. Further mechanism ex-
ploration and application studies of the products are cur-
rently ongoing in our laboratory.
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Acknowledgment
We thank the support of the Zhejiang Provincial Natural Science
Foundation of China (R407106) and the Natural Science Foundati-
on of China (No. 20571063).
References and Notes
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Synlett 2008, No. 20, 3115–3120 © Thieme Stuttgart · New York

3120
C. Xie et al.
LETTER
(13) The CCDC number of the X-ray structure is 701719.
(14) (a) All the reactions were carried out under the nitrogen
atmosphere in oven-dried flasks. MeCN was distilled from
CaH2 using benzophenone as the indicator. 2-Bromo-1-(4-
methoxyphenyl)ethanone, 2-bromo-1-(4-ethylphenyl)-
ethanone, 2-bromo-1-(4-nitrophenyl)ethanone, 2-bromo-1-
(4-chlorophenyl)ethanone were prepared according to the
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Tanious, F. A.; Wilson, W. D.; Boykin,
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purification. 1H NMR spectra were recorded at 400 MHz
using TMS as internal standard. 13C NMR spectra were
recorded at 100 MHz using TMS as internal standard. Mass
spectroscopy data of the reaction product were collected on
an HRMS (EI) instrument.
(15) General Procedure of the Three-Component Reaction:
An oven-dried flask was charged with 2-bromo-1-phenyl-
ethanone (0.6 mmol), pyridine (1.0 mmol), CsF (1.5 mmol)
and MeCN (3 mL). Benzyne precursor (0.5 mmol) in MeCN
(2 mL) was added dropwise under the protection of N2. The
reaction mixture was then allowed to react at 80 °C for 2 h.
After the completion of the reaction, the mixture was cooled
to r.t. and filtered through a pad of celite. The solvent was
then removed in vacuum, and the final product was obtained
by flash chromatography on a silica gel column as a yellow
powder.
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