Multicomponent reactions of pyridines, α-bromo carbonyl compounds and silylaryl triflates as aryne precursors: a facile one-pot synthesis of pyrido[2,1-a]isoindoles

Article abstract of DOI:10.1016/j.tetlet.2008.10.118

Multicomponent reactions (MCRs) involving pyridines, α-bromo ketones, and silylaryl triflates as aryne precursors were investigated. The reactions could also be extended to isoquinoline or α-bromo ethyl acetate. Substituted pyrido[2,1-a]isoindoles or isoi

Full text of DOI:10.1016/j.tetlet.2008.10.118

Tetrahedron Letters 50 (2009) 208–211
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Tetrahedron Letters
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Multicomponent reactions of pyridines,
a
-bromo carbonyl compounds
and silylaryl triflates as aryne precursors: a facile one-pot synthesis
of pyrido[2,1-a]isoindoles
a
Xian Huang a,b, , Tiexin Zhang
*
a Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, PR China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Multicomponent reactions (MCRs) involving pyridines,
precursors were investigated. The reactions could also be extended to isoquinoline or
acetate. Substituted pyrido[2,1-a]isoindoles or isoindolo[2,1-a]isoquinolines could be obtained from this
routine, which may have potential applications in antitumor drugs and fluorescent material fields.
Ó 2008 Elsevier Ltd. All rights reserved.
a
-bromo ketones, and silylaryl triflates as aryne
-bromo ethyl
Received 2 September 2008
Revised 22 October 2008
Accepted 24 October 2008
Available online 30 October 2008
a
Keywords:
Multicomponent reaction
Aryne
One-pot synthesis
Pyrido[2,1-a]isoindole
Azomethine ylide
Pyrido[2,1-a]isoindole, as the analogue of antitumor batracilin,1
the parent compound of many dyes,2 and the structural unit of
some highly fluorescent materials,3 is of marked interest for its
versatility. Although some accesses to this skeleton and its deriva-
tives have progressed in decades,4,5 some flaws have been in con-
comitance with them, namely as limitations in scopes,4a,b need of
unhealthy radiation,4c demand for strict experimental conditions
when transition metal catalysts were used,4d or the loss of yields
in multi-steps routines.5 So it is essential to develop more facile,
atom economical, and reliable routes to prepare pyrido[2,1-a]iso-
indoles. In recent years, multicomponent reactions (MCRs) have
been extensively studied due to their efficiency, atom economy
and convenience in construction of multiple new bonds in one-
pot processes, which played powerful roles in approach to complex
structures and promoted the ‘green chemistry’.6
Arynes are useful organic intermediates, and the relative re-
ports mushroomed since the employment of (trimethylsilyl)phenyl
triflates as aryne precursors due to the mild and tolerable condi-
tions to generate arynes7 and a variety of MCRs involving arynes
have been developed in recent years.8 It is well known that the
cycloaddition of arynes could lead to formation of benzo rings
which are not easy to synthesize by other methods.9 Moreover,
1,3-dipolar cycloadditions are useful way to construct five-
membered rings,10 so the 1,3-dipolar cycloaddition of aryne could
be a potential method to construct benzo five-membered rings.9i–m
Based on the continuous interest on MCRs and aryne chemistry,8f,11
Table 1
Optimization of conditions for the one-pot synthesis of
phenyl-pyrido[2,1-a]isoindol-6-yl-methanone 4aa
O
O
N
TMS
OTf
conditions
Br
+
+
N
1a
2a
Solvent
3a
4a
Entry
Base
Temperature (°C)
1a/2a/3a
Yieldb (%)
1
2
3
4
5
6
7
8
9
NaH
Et3N
K3PO4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
DME
DME
DME
DME
60
60
60
60
60
60
60
rt
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:0.8
1:1:1.5
28
41
43
39
50
Trace
54
K2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
33
85
85
85
60
10
11
59c
55
DME
a
Reactions were carried out on a 0.3 mmol scale (based on
a-bromo carbonyl
compounds) and monitored by TLC (eluent/petroleum ether).
b
Isolated yield based on 1a.
Isolated yield based on 3a.
* Corresponding author. Fax: +86 571 88807077.
E-mail address: huangx@mail.hz.zj.cn (X. Huang).
c
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.118

X. Huang, T. Zhang / Tetrahedron Letters 50 (2009) 208–211
209
Table 2 (continued)
Table 2
The MCRs utilizing various pyridines,
a-bromo carbonyl compounds, and different
Entry
1
2
3
Product
Yield
(%)b
aryne precursorsa
R1
O
R2
R1
N
TMS
OTf
O
N
O
Na2CO3 / CsF
DME, 85 o
R3
+
+
8
1a
2c
3a
40
37
Br
R2
C
CH3
N
4h
R3
1
2
4
3
1a: R1 = H;
1d: 2-C2H5-3-CH3-Pyridine;
2a: R2 = C6H5 ; 2b: R2 = p-Cl-C6H4 ; 2c: R2 = CH3 ; 2d: R2 = OC2H5 ;
1b: R1 = 4-CH3 ;
1c: R1 = 3-CH3 ;
O
O
N
C2H5
9
1a
2d
3a
3a: R3 = H;
3b: 4-CH3-5-CH3-Triflate;
3c: R3 = 4-CH3
Entry
1
2
3
Product
Yield
(%)b
4i
a
Reactions were carried out on a 0.3 mmol scale and monitored by TLC.
b
c
Isolated yield based on 1a.
The total yield of inseparable mixture of 8-methyl and 9-methyl products at a
O
N
ratio of 1:1; the ratio of the mixture was identified by 1H NMR.
d
1
1a
2a 3a
2a 3b
2a 3c
60
The total yield of inseparable mixture of 1-methyl and 3-methyl products at a
ratio of 1:1; the ratio of the mixture was identified by 1H NMR.
4a
we would like to report a facile one-pot synthesis of pyrido[2,1-a]-
isoindoles via 1,3-dipolar cycloaddition of arynes utilizing pyr-
O
N
idines,
three components.
a-bromo carbonyl compounds, and silylaryl triflates as
2
1a
49
The initial examination using pyridine 1a, a-bromo phenyl eth-
anone 2a, and aryne precursor 3a at a ratio of 1:1:1.2 was con-
ducted in dried CH3CN. After refluxing overnight, 1.5 equiv of
NaH and 4.0 equiv of CsF were added and the mixture was stirred
under 60 °C. When the reaction terminated (monitored by TLC), the
expected product phenyl-pyrido[2,1-a]isoindol-6-yl-methanone
4a was affored in a yield of 28% (Table 1, entry 1). We then focused
on optimizing the reaction conditions. Different bases were ini-
tially tested. The use of organic base Et3N could enhance the yield
to 41% (Table 1, entry 2). Some weak inorganic bases were also ap-
plied to the optimization (e.g., a clear reaction induced by K3PO4
with a yield of 43%) (Table 1, entries 3–5), and Na2CO3 was chosen
as the proper base for the higher yield (Table 1, entry 5). Then, sev-
eral solvents ordinarily used in reactions of aryne were checked. In
THF, we only got trace amount of 4a probably due to the poor sol-
ubility of CsF in THF (Table 1, entry 6). An improved yield was ob-
served in DME (Table 1, entry 7). Our further study demonstrated
that the relatively remarkable factor was the temperature when
cycloaddition happened. The yield rose to 60% at 85 °C, but de-
creased dramatically to 33% at rt (Table 1, entries 8 and 9). Next,
different ratios of starting materials were compared, and the ratio
1:1:1.2 (1a:2a:3a) was proven to be the favored one (Table 1, en-
tries 9–11). Therefore, the optimized reaction condition was that
H C
3
CH
N
4b
3
N
O
O
+
3
1a
52
(1:1)c
H3C
H3C
CH
3
4c
4c’
O
N
N
4
1b
2a 3a
51
4d
H3C
O
5
1b
2b 3a
58
1.0 equiv of pyridines, 1.0 equiv of a-bromo carbonyl compounds,
and 1.2 equiv of aryne precursors were refluxed in DME overnight,
then the reaction proceeded at 85 °C after addition of 1.5 equiv of
Na2CO3 and 4.0 equiv of CsF.15,16
With the optimized conditions in hand, the scope of the reac-
tion was investigated, and the typical results are summarized in
Table 2. The corresponding pyrido[2,1-a]isoindoles were obtained
smoothly in yields from 54% to 60% using symmetrically substi-
4e
Cl
CH3
N
H C
3
N
O
O
6
1c
2a 3a
59
+
(1:1)d
tuted pyridines,
a-bromo aryl ethanones and symmetrical arynes
4f
4f’
(Table 2. entries 1, 2, 4, and 5). When the unsymmetrically substi-
tuted pyridine 1c was employed, 1:1 mixture of 1-methyl and 3-
methyl substituted products was obtained in a total yield of 59%
(Table 2, entry 6), and we gained only one compound without
other isomers from unsymmetrical 1d due to the ethyl group
attaching to the nitrogen-neighbored carbon atom of pyridine from
one side (Table 2, entry 7). If the unsymmetrical 4-methyl triflate
3c participated in the reaction, the ratio of the 1:1 inseparable mix-
CH3
N
C2H5
O
7
1d 2a 3a
43
4g

210
X. Huang, T. Zhang / Tetrahedron Letters 50 (2009) 208–211
Table 3
Further scope expansion of the MCR: the new approach to isoindolo[2,1-a]isoquinolinesa
O
TMS
OTf
N
O
Na CO / CsF
2
3
2
3
R
R
+
+
Br
2
o
N
R
DME, 85
C
5
3
6
2
3
R
Entry
2
3
Product
Yieldb (%)
N
N
O
O
1
2a
3a
3b
42
6a
6b
2
2a
49
H3C
CH3
N
O
3
2b
3a
48
Cl
6c
a
Reactions were carried out on a 0.3 mmol scale and monitored by TLC.
Isolated yield based on 5.
b
ture of 8-methyl and 9-methyl products implied the aryne reaction
mechanism12 (Table 2, entry 3). Besides the
-bromo aryl ethanon-
es, the -bromo alkyl ethanone 2c was conducted into the MCRs
and a slightly lower yield of corresponding product 4h was ob-
tained (Table 2, entry 8). Using -bromo ethyl acetate 2d instead
of -bromo ketones, we successfully got the aimed product 4i in
a yield of 37% (Table 2, entry 9). As can be seen from Table 2, by
utilizing various substituted pyridines, -bromo carbonyl com-
1
TMS
OTf
R
O
3
a
R
Br
2
a
R
N
2
3
1
F
a
a
1
1
R
R
a
N
Br
O
N
-HBr
Base
pounds, and different aryne precursors, multiple substituted
groups were introduced to parent structure of pyrido[2,1-a]isoin-
dole, and moderate yields were obtained.
O
3
2
2
R
R
R
7
8
9
For further scope expansion of this MCR, other nitrogen-bearing
heterocyclic compounds were employed to take the place of pyri-
dines. Isoquinoline was found to have good acceptance and the
corresponding products isoindolo[2,1-a]isoquinolines, as the
analogues of antitumor drugs, were afforded in moderate yields13
(Table 3).
O
1
R
N
2
R
On the basis of relative reports,14 a plausible mechanism of the
3
4
R
MCR is shown in Scheme 1. The pyridine 1 and the
bonyl compound 2 produce the pyridium salt 7,14a then the base
captures an activated proton from carbon of carbonyl group of
a-bromo car-
Scheme 1. The plausible mechanism of formation of pyrido[2,1-a]isoindoles.
a
7 and generates azomethine ylide 8. Next, the 1, 3-dipolar cycload-
dition reaction between 8 and aryne intermediate 9 induced by
fluoride occurs. We might envision that the resulting cycloaddition
product is unstable and easily oxidized by the air in the absence of
any other oxidants to obtain the stable aromatized product 4
(Scheme 1).14b,c
occurrence of their analogues in drugs and materials. The details of
mechanism and synthetic applications of this methodology are
being further studied in our laboratory.
Acknowledgments
In conclusion, we have disclosed a facile synthesis of pyrido[2,1-
a]isoindoles based upon MCRs of pyridines,
silylaryl triflates as aryne precursors, which could be extended to
employ isoquinoline or -bromo ethyl acetate as substrates. The
products of the MCRs would be potentially useful due to the wide
a-bromo ketones, and
We are grateful to the National Natural Science Foundation of
China (Project Nos. 20672095 and 20732005) and CAS Academi-
cian Foundation of Zhejiang Province for financial support.
a

X. Huang, T. Zhang / Tetrahedron Letters 50 (2009) 208–211
211
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G.; Raminelli, C.; Larock, R. C. J. Org. Chem. 2008, 73, 219; (j) Huang, X.-C.; Liu,
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Supplementary data
The relevant spectroscopic data of all the new compounds
mentioned in the Letter. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/j.tetlet.
2008.10.118.
References and notes
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(2a, 0.3 mmol) and (trimethylsilyl)phenyl triflate (3a, 0.36 mmol) were mixed
in 3 mL of dried DME and the solution was stirred at reflux overnight, then
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carried out at 85 °C and monitored by TLC (7:1 P.E./EtOAc eluent). After total
conversion of the triflate (about 0.8 h later), the reaction mixture was filtrated
through a short pad of silica gel to remove indiscerptible materials, and then
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16. Selected data for 4a: Yellow solid, mp: 101–105 °C. IR (neat): 3055, 1633, 1582,
1560, 1475, 1450, 1430, 1319, 1295, 1247, 1230, 1210, 1120, 943, 756, 728,
702, 655 cmÀ1 1H NMR (400 MHz, CDCl3): d 10.61 (d, J = 6.9 Hz, 1H), 8.17 (d,
.
J = 8.4 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 6.8 Hz, 2H), 7.57–7.48 (m,
4H), 7.34 (t, J = 6.9 Hz, 1H), 7.26–7.19 (m, 2H), 6.83 (d, J = 8.1 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 114.1, 117.2, 118.5, 119.2, 119.7, 120.0, 121.4, 125.5,
128.1, 128.3, 128.6, 129.4, 130.2, 132.6, 135.0, 142.4, 183.1. MS (EI, 70 eV): m/z
(%) = 272 (37) [M++1], 271 (100) [M+], 270 (100) [M+À1]. HRMS (EI+): calcd for
[C19H13NO]+: m/z 271.0997. Found 271.1004.