Facile synthesis of pyrido[2,1- a ]isoindoles via iron-mediated 2-arylpyridine C-H bond cleavage

Article abstract of DOI:10.1055/s-0032-1318495

An iron-catalyzed reaction of 2-arylpyridine C-H bond with 2-bromoacetophenone is achieved, providing pyrido[2,1-a]-isoindoles in moderate to good yields. The regioselectivity stems from the domination of hindrance on the regioselective ortho-functionalization of 2-arylpyridines C-H bond. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318495

LETTER
▌847
letter
Facile Synthesis of Pyrido[2,1-a]isoindoles via Iron-Mediated 2-Arylpyridine
C–H Bond Cleavage
Facile Synthesis of Pyrido[2,1-a]isoindoles
Shan Liu, Xingen Hu, Xinhua Li, Jiang Cheng*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325000, P. R. of China
Fax +86(577)569989 39; E-mail: jiangcheng@cczu.edu.cn; E-mail: jiangcheng@wzu.edu.cn
Received: 15.01.2013; Accepted after revision: 05.03.2013
tion-metal-catalyzed ortho C–H functionalization of 2-ar-
Abstract: An iron-catalyzed reaction of 2-arylpyridine C–H bond
ylpyridine, the regioselectivity is highly dominated by
with 2-bromoacetophenone is achieved, providing pyrido[2,1-a]-
steric hindrance, thus, the reaction takes place at the less
isoindoles in moderate to good yields. The regioselectivity stems
from the domination of hindrance on the regioselective ortho-func-
congested ortho C–H bond.7 In light of this, we envisaged
tionalization of 2-arylpyridines C–H bond.
to construct this moiety via the 2-arylpyridine C–H bond
Key words: iron, 2-arylpyridine, C–H bond cleavage, pyridoisoin-
dole, regioselectivity
Table 1 Screening the Optimized Reaction Conditionsa
O
O
N
N
Br
Pyrido[2,1-a]isoindoles are useful structural motifs in an-
titumor batracilin,1 dyes,2 and some fluorescent materi-
als.3 The free radical cyclization is a powerful strategy to
construct these motifs.4 However, either harsh reaction
conditions or multiple steps were required, which would
greatly diminish the practicality for such transformation.
Thus, the development of a facile method remains a high-
ly desired goal for organic chemists. In 2008, Zhang and
Huang reported the synthesis of pyrido[2,1-a]isoindoles
via a three-component assembly involving benzynes.5
These novel procedures involved cycloaddition of ben-
zyne to the 1,3-dipolar compound, which was an elegant
strategy to construct benzo five-membered rings.6 How-
ever, Zhang and Huang’s method may be troublesome for
preparing the pyrido[2,1-a]isoindoles having different
groups on the 3 and 4 positions, which is mostly due to the
low selectivity of benzyne during the cycloaddition (path
a, Scheme 1). To circumvent this problem, a new strategy
achieving the cyclization with high selectivity is required.
+
1a
2a
3a
Entry
Catalyst
Additive (equiv) Yield (%)a
1
2
PdCl2
Pd(OAc)2
Pd(dba)2
CuI
CsI (1.25)
CsI (1.25)
CsI (1.25)
CsI (1.25)
CsI (1.25)
CsI (1)
CsI (1)
CsI (1)
CsI (1)
CsI (1)
CsI (1.25)
CsI (1.25)
KI
8
6
3
10
4
15
5
CuBr
Fe(acac)3
FeCl3
FeCl2
FeBr2
FeI2
16
6
<5
7
24
8
31
9
29
O
10
11
12
13
14
15
16
17
32
N
R3
O
N
O
N
FeI2
60 (53)b (15)c (55)d
path b
R1
path a
R1
M
R3
R3
FeI2
36e (<5)f
FeI2
42
43
20
21
22
R1
R2
R2
R1 ≠ R2
R2
FeI2
CuI
R1 ≠ R2
hindrance-dominated regioselectivity
this work
low selectivity
previous work
FeI2
AgI
FeI2
CuBr
Scheme 1 New strategy to pyrido[2,1-a]isoindoles
FeI2
–
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), iron (25
mol%), additive with indicated equivalents, toluene–NMP (15:1, 1.5
mL), 130 °C, 48 h.
The development of organometallic chemistry provides a
potential possibility to solve this problem. In the transi-
b The reaction was carried out at 140 °C.
c The reaction was carried out at 120 °C.
d The amount of iron used was 50 mol%.
e Solvent used: toluene (1.5 mL).
SYNLETT 2013, 24, 0847–0850
Advanced online publication: 15.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318495; Art ID: ST-2013-W0049-L
© Georg Thieme Verlag Stuttgart · New York
f Solvent used: NMP (1.5 mL).

848
S. Liu et al.
LETTER
cleavage (path b, Scheme 1). Herein, we report our study creased to 60% by increasing the amount of CsI to 1.25
leading to pyrido[2,1-a]isoindoles based on this new strat- equivalents in the presence of 25 mol% of FeI2. However,
egy.
when the catalyst loading was increased to 50 mol%, a
lower yield resulted. The efficiency of the reaction also
decreased at 120 °C or 140 °C. Further studies revealed
CsI was the best among the iodides tested. The iodide was
crucial for this reaction since the yield dramatically de-
creased to 22% in the absence of any iodides. Meanwhile,
reaction in toluene or NMP decreased the reaction effi-
ciency (entry 12, Table 1).
We initiated our investigation by examining the reaction
of 2-phenylpyridine with 2-bromoacetophenone (Table
1). Iodide was added as an additive for the potential halo-
gen exchange to increase the reactivity. Palladium and
copper showed low efficiency for this reaction (entries 1–
5, Table 1). Gratifyingly, the cyclization took place when
some iron salts were used as catalyst (entries 6–10, Table
1). The desired product was obtained in 31% yield with With the established optimized reaction conditions, the re-
the combination of 1a, 2a, CsI and FeCl2 in toluene–NMP action scope of 2-arylpyridines was tested, as shown in
at 130 °C (entry 8, Table 1). FeI2 showed comparable ac- Scheme 2.
tivity for this transformation.8 Fortunately, the yield in-
As expected, a series of substituted 2-arylpyridines were
compatible with the reaction conditions. Notably, bromo
and chloro groups remained untouched in the procedure.
O
N
N
Importantly, thanks to the new strategy, no isomers were
produced during the formation of 3b, 3e, and 3h–k. More-
over, owing to the high selectivity during the functional-
ization of the 2-arylpyridine ortho C–H bond, no isomers
were detected by 1H NMR and GC–MS for products such
as 3c and 3f. Thus, this procedure complements the [3+2]
cyclization. However, benzo[h]quinoline did not work
under the standard procedure, which was at least partly
owing to the introduced highly rigid phenyl ring.
O
+
Br
Ph
Ph
R
R
1
2
3
O
N
O
N
O
N
Ph
Ph
Ph
To gain some preliminary insight into the reaction, the po-
tential intermediate 4 was prepared9 and subjected to the
procedure. Pyrido[2,1-a]isoindole was isolated in 42%
yield (Scheme 3).
3a 60%
3b 54%
3c 40%
O
N
O
N
O
N
Br
O
Ph
Ph
O
Ph
N
N
Ph
standard procedure
MeO
Ph
OMe
3d 45%
3e 59%
3f 39%
42%
4
O
O
N
N
O
N
Scheme 3 Reaction of the potential intermediate in the standard pro-
cedure
Ph
Ph
MeO
Ph
Next, the intramolecular kinetic isotope effect was stud-
ied, as shown in Scheme 4. The ratio of kH and kD was
found to be 1.0. This result confirmed that the cleavage of
the ortho C–H bond in the 2-arylpydidine was not the rate-
determining step.
t-Bu
F
3g 44%
3h 48%
3i 32%
O
N
N
O
O
N
Ph
Ph
O
Ph
N
N
O
Ph
51% d
Cl
+
H
D
Ph
H
Br
3j 37%
3k 40%
3l NR
Br
3a + 3a–d
yield: 45%
Scheme 2 The reaction of 2-arylpyridine with 2-bromoacetophe-
none. Reagents and conditions: 1a (0.2 mmol), 2a (0.24 mmol), FeI2
(25 mol%), CsI (0.25 mmol), toluene–NMP (15:1, 1.5 mL), 130 °C,
48 h.
1-d
Scheme 4 Intramolecular kinetic isotope effect
Synlett 2013, 24, 847–850
© Georg Thieme Verlag Stuttgart · New York

LETTER
Facile Synthesis of Pyrido[2,1-a]isoindoles
849
A proposed mechanism is illustrated in Scheme 5. Firstly,
electrophilic attack of the 2-arylpyridine ortho C–H bond
by iron(II) species takes place to form intermediate A.10
Secondly, the reaction of 2-bromoacetophenone with the
pyridine moiety generates intermediate B. Thirdly, inter-
mediate C is formed by attack of the α-carbon of 2-bromo-
acetophenone. Finally, the reductive elimination of C
provides D, which releases a proton to give the final prod-
uct. The iron(0) species is oxidized to iron(II) by air to ful-
fill the catalytic cycle. In addition, an alternative
mechanism could be proposed via nucleophilic substitu-
tion of the nitrogen to α-bromo acetophenone followed by
deprotonation, cyclization and dehydrogenated aromati-
zation.
Acknowledgment
We thank the National Natural Science Foundation of China (No.
21272028 and No. 21073132), and the Natural Science Foundation
of Zhejiang Province (No. R4110294) for financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
(1) (a) Wang, S.; Cao, L.; Shi, H.; Dong, Y.; Sun, J.; Hu, Y.
Chem. Pharm. Bull. 2005, 53, 67. (b) Peese, K. M.; Gin, D.
Y. J. Am. Chem. Soc. 2006, 128, 8734. (c) Orlemans, E. O.
M.; Verboom, W.; Scheltinga, M. W.; Reinhoudt, D. N.;
Lelieveld, P.; Fiebig, H. H.; Winterhalter, B. R.; Double, J.
A.; Bibby, M. C. J. Med. Chem. 1989, 32, 1612. (d) Diana,
P.; Martorana, A.; Barraja, P.; Montalbano, A.; Dattolo, G.;
Cirrincione, G.; Dall’Acqua, F.; Salvador, A.; Vedaldi, D.;
Basso, G.; Viola, G. J. Med. Chem. 2008, 51, 2387.
FeII
BrCH2R
R = COPh
(e) Lübbers, T.; Angehrn, P.; Gmünder, H.; Herzig, S.
Bioorg. Med. Chem. Lett. 2007, 17, 4708. (f) Martínez-
Viturroa, C. M.; Domínguez, D. Tetrahedron Lett. 2007, 48,
4707. (g) Simone, F. D.; Gertsch, J.; Waser, J. Angew.
Chem. Int. Ed. 2010, 49, 5767.
N
N
A
H
(2) Romanov, N. N. Ukr. Khim. Zhur. 1981, 1280.
R
N
(3) (a) Mitsumori, T.; Bendikov, M.; Dautel, O.; Wudl, F.;
Shioya, T.; Sato, H.; Sato, Y. J. Am. Chem. Soc. 2004, 126,
16793. (b) Vlahovici, A.; Andrei, M.; Druta, I. J. Lumin.
2002, 96, 279. (c) Voitenko, Z. V.; Pocholenko, O. A.;
Chkarov, O. O.; Shishkin, O. V.; Shishkina, S. V.; Dall’Ava,
A.; Vedrenne, M.; Sanchez, M.; Wolf, J.-G. Eur. J. Org.
Chem. 2001, 7, 1401. (d) Vlahovici, A.; Druta, I.; Andrei,
M.; Cotlet, M.; Dinica, R. J. Lumin. 1999, 82, 155.
N
FeII
RH2C
FeII
FeII
B
(4) (a) Schiesser, C. H.; Wille, U.; Matsubara, H.; Ryu, I. Acc.
Chem. Res. 2007, 40, 303. (b) Dix, I.; Doll, C.; Hopf, H.;
Jones, P. G. Eur. J. Org. Chem. 2002, 15, 2547. (c) Burner,
S.; Canesso, R.; Widmer, U. Heterocycles 1994, 37, 239.
(d) RajanBabu, T. V. Acc. Chem. Res. 1991, 24, 139.
(5) (a) Xie, C.; Zhang, Y.; Xu, P. Synlett 2008, 3115. (b) Huang,
X.; Zhang, T. Tetrahedron Lett. 2009, 50, 208.
N
R
Fe0
FeII
C
(6) (a) Liu, Z.; Shi, F.; Martinez, P. D. G.; Raminelli, C.;
Larock, R. C. J. Org. Chem. 2008, 73, 219. (b) Huang, X.-
C.; Liu, Y.-L.; Liang, Y.; Pi, S.-F.; Wang, F.; Li, J.-H. Org.
Lett. 2008, 10, 1525. (c) Jin, T.; Yamamoto, Y. Angew.
Chem. Int. Ed. 2007, 46, 3323. (d) Raminelli, C.; Liu, Z.;
Larock, R. C. J. Org. Chem. 2006, 71, 4689.
R
R
N
N
N
H
H
R
(7) For selected examples, see: (a) Peng, X.; Zhu, Y.; Ramirez,
T. A.; Zhao, B.; Shi, Y. Org. Lett. 2011, 13, 5244. (b) Li, B.;
Wu, Z.-H.; Gu, Y.-F.; Sun, C.-L.; Wang, B.-Q.; Shi, Z.-J.
Angew. Chem. Int. Ed. 2011, 50, 1109. (c) Chen, Q.; Ilies,
L.; Yoshikai, N.; Nakamura, E. Org. Lett. 2011, 13, 3232.
(d) Xiao, F.; Shuai, Q.; Zhao, F.; Baslé, O.; Deng, G.; Li, C.-
J. Org. Lett. 2011, 13, 1614. (e) Jia, X.; Zhang, S.; Wang,
W.; Luo, F.; Cheng, J. Org. Lett. 2009, 11, 3120. (f) Wang,
W.; Pan, C.; Chen, F.; Cheng, J. Chem. Commun. 2011, 47,
3978. (g) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2011,
133, 400. (h) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2011, 133, 1248.
D
Scheme 5 Proposed mechanism
In conclusion, we have developed a new strategy leading
to pyrido[2,1-a]isoindoles. The functionalization of 2-ar-
ylpyridine ortho C–H bond controls the selectivity. Thus,
high selectivities were obtained for analogues with sub-
stituents on the phenyl rings. This procedure represents an
exceedingly attractive alternative to the traditional [3+2]
cyclization method.11
(i) Kitahara, M.; Umeda, N.; Hirano, K.; Satoh, T.; Miura,
M. J. Am. Chem. Soc. 2011, 133, 2160. (j) Ackermann, L.;
Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org. Lett. 2010,
12, 5032. (k) Gao, K.; Lee, P.-S.; Fujita, T.; Yoshikai, N. J.
Am. Chem. Soc. 2010, 132, 12249. (l) Li, M.; Ge, H. Org.
Lett. 2010, 12, 3464. (m) Kim, J.; Chang, S. J. Am. Chem.
Soc. 2010, 132, 10272. (n) Luo, N.; Yu, Z. Chem. Eur. J.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 847–850

850
S. Liu et al.
LETTER
Nakamura, E. J. Am. Chem. Soc. 2008, 130, 5858.
(c) Yoshikai, N.; Asako, S.; Yamakawa, T.; Ilies, L.;
Nakamura, E. Chem. Asian J. 2011, 6, 3059.
2010, 16, 787. (o) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am.
Chem. Soc. 2010, 132, 3648. (p) Jia, X.; Yang, D.; Wang,
W.; Luo, F.; Cheng, J. J. Org. Chem. 2009, 74, 9470.
(q) Ackermann, L.; Vicente, R. Org. Lett. 2009, 11, 4922.
(r) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Org. Lett. 2009,
11, 4716. (s) Ye, Z.; Wang, W.; Luo, F.; Zhang, S.; Cheng,
J. Org. Lett. 2009, 11, 3974. (t) Yu, W.-Y.; Sit, W. N.; Zhou,
Z.; Chan, A. S.-C. Org. Lett. 2009, 11, 3174. (u) Kakiuchi,
F.; Kochi, T.; Mutsutani, H.; Kobayashi, N.; Urano, S.; Sato,
M.; Nishiyama, S.; Tanabe, T. J. Am. Chem. Soc. 2009, 131,
11310. (v) Zhao, X.; Dimitrijevic, E.; Dong, V. M. J. Am.
Chem. Soc. 2009, 131, 3466. (w) Kochi, T.; Urano, S.; Seki,
H.; Mizushima, E.; Sato, M.; Kakiuchi, F. J. Am. Chem. Soc.
2009, 131, 2792. (x) Kalyani, D.; Deprez, N. R.; Desai, L.
V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330.
(11) General Experimental Details: Under an air atmosphere, a
reaction tube was charged with 2-arylpyridine (0.2 mmol),
2-bromo-1-phenylethanone (0.24 mmol), FeI2 (25 mol%),
CsI (0.25 mmol) and toluene–NMP (15:1, 1.5 mL). The
mixture was stirred at 130 °C for 48 h in a sealed tube. After
the completion of the reaction, as monitored by TLC, the
solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography on
silica gel to give the product.
(10-Methylpyrido[2,1-a]isoindol-6-yl)(phenyl)-
methanone (3d): 1H NMR (500 MHz, CDCl3): δ = 10.70 (d,
J = 7.0 Hz, 1 H), 8.37 (d, J = 8.5 Hz, 1 H), 7.67–7.68 (m, 2
H), 7.51–7.55 (m, 4 H), 7.37 (d, J = 7.0 Hz, 1 H), 7.12–7.15
(m, 1 H), 7.00 (d, J = 7.0 Hz, 1 H), 6.71 (d, J = 8.5 Hz, 1 H),
2.88 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 183.8, 142.2,
137.9, 135.1, 132.6, 131.9, 130.5, 128.6, 128.2, 127.7,
125.3, 122.9, 120.2, 118.6, 118.0, 117.0, 114.1, 26.8. IR
(prism): 1716, 1578, 1558, 1485, 1473, 1439, 1416, 1297,
1264, 1228, 1165, 1148, 1108, 1043, 1017, 972, 865, 848,
803, 775, 753, 736, 710, 701, 682, 656 cm–1. HRMS (EI):
m/z [M + H]+ C20H16NO: 286.1232; found: 286.1225.
(8) The ICP test confirmed that FeI2 contained copper (830
ppm) and palladium (3 ppm). However, as shown in Table 1,
copper and palladium exhibited low activity for this
transformation.
(9) (a) Bradsher, C. K.; Beavers, L. E. J. Am. Chem. Soc. 1955,
77, 453. (b) Mousseau, J. J.; Fortier, A.; Charette, A. B. Org.
Lett. 2010, 12, 516.
(10) (a) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111,
1293. (b) Norinder, J.; Matsumoto, A.; Yoshikai, N.;
Synlett 2013, 24, 847–850
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.