Palladium-catalyzed cyclization of 3-bromopyridine-4-carbaldehyde with carbon monoxide and carboxylic acids

Article abstract of DOI:10.1002/jhet.5570450523

(Chemical Equation Presented) 3-Bromopyridine-4-carbaldehyde is cyclized with carboxylic acids in acetonitrile at 100° under carbon monoxide pressure in the presence of a catalytic amount of a palladium catalyst along with a base to afford the corresponding 3-oxo-1,3-dihydrofuro[3,4-c]pyridine-1-yl alkanoates in moderate to good yields.

Full text of DOI:10.1002/jhet.5570450523

Sep-Oct 2008
1397
Palladium-Catalyzed Cyclization of 3-Bromopyridine-4-
carbaldehyde with Carbon Monoxide and Carboxylic Acids
Chan Sik Cho* and Jun Uk Kim
Department of Applied Chemistry, College of Engineering, Kyungpook National University,
Daegu 702-701, Korea
Received February 28, 2008
O
O
Br
O
PdCl2(PPh3)2
Et3N, CO
CHO
R
+
RCOOH
O
N
N
3-Bromopyridine-4-carbaldehyde is cyclized with carboxylic acids in acetonitrile at 100° under carbon
monoxide pressure in the presence of a catalytic amount of a palladium catalyst along with a base to afford
the corresponding 3-oxo-1,3-dihydrofuro[3,4-c]pyridine-1-yl alkanoates in moderate to good yields.
J. Heterocyclic Chem., 45, 1397 (2008).
INTRODUCTION
and carboxylic acids under carbon monoxide pressure.
The starting 3-bromopyridine-4-carbaldehyde (2) was
prepared by the treatment of 3-bromopyridine (1) with
LDA and DMF by known method (Scheme 1) [8].
Generally, 2 was subjected to the reaction with two
equivalents of a carboxylic acid 3 in acetonitrile at 100° in
It is well known that many heterocyclic compounds
play an important role as a basic unit for the design of
many pharmacologically and biologically active
compounds. Palladium-catalyzed carbonylation followed
by cyclization process has been recognized as a useful
straightforward synthetic tool for heterocycles containing
carbonyl moiety [1]. As part of our continuing studies
directed towards transition metal-catalyzed cyclization
reactions, we also reported on the synthesis of several
heterocycles such as isoindolinones [2], ꢀ-lactams [3] and
phthalides [4] using such an intrinsic palladium-catalyzed
carbonylation followed by cyclization [5,6]. Among them,
in connection with this report, 2-bromobenzaldehyde was
found to be cyclized with carboxylic acids in the presence
of a palladium catalyst under carbon monoxide pressure
to afford 3-oxo-1,3-dihydro-1-isobenzofuranyl alkanoates
[7]. This protocol led us to extend to the reaction with 3-
bromopyridine-4-carbaldehyde, which is readily prepared
from 3-bromopyridine via reported method (Scheme 1)
[8]. Herein, this report describes a palladium-catalyzed
cyclization of 3-bromopyridine-4-carbaldehyde with
carbon monoxide and carboxylic acids leading to 1,3-
dihydro-3-oxofuro[3,4-c]pyridine-1-yl alkanoates [9].
the
presence
of
dichlorobis(triphenylphosphine)-
palladium(II) along with triethylamine under carbon
monoxide pressure (10 atm) to afford 3-oxo-1,3-
dihydrofuro[3,4-c]pyridin-1-yl alkanoates 4. The reaction
was monitored until 2 had disappeared on TLC, which
occurred within 1 hour.
The reaction of 2 with various carboxylic acids 3 was
screened in order to investigate the reaction scope and
several representative results are summarized in Table 1.
Compound 2 was cyclized with an array of aliphatic
carboxylic acids 3a-e having straight and branched alkyl
chains to give the corresponding 3-oxo-1,3-dihydro-
furo[3,4-c]pyridin-1-yl alkanoates 4a-e in the range of 51-
73% isolated yields without any identifiable side
products. The straight chain length and branching of
aliphatic carboxylic acids had no relevance to the product
yield. Lower reaction rate and yield were observed with
phenylacetic acid (3f). From the reactions between 2 and
ꢁ,ꢀ-unsaturated carboxylic acid 3g, the corresponding
cyclized product 4g was also formed and the product yield
was lower than that when compared to the reaction with
aliphatic carboxylic acids. The reaction proceeds likewise
with aromatic carboxylic acid 3h to give 3-oxo-1,3-
dihydrofuro[3,4-c]pyridin-1-yl benzoate (4h) in 59%
yield.
Scheme 1
O
O
Br
Br
O
RCOOH (3)
PdCl2(PPh3)2
CHO
R
1. LDA, THF
2. DMF
O
Et3N, CO
N
N
N
1
2
4
The present reaction, consistent with the product
formed, seems to proceed via a pathway shown in Scheme
2. Oxidative addition of a carbon-bromide bond of 2 to
palladium(0) produces an arylpalladium(II) intermediate 5
where carbon monoxide coordination to palladium and
then aryl migration from palladium to the carbon of
carbon monoxide occurs to give an aroylpalladium(II)
RESULTS AND DISCUSSION
The present reaction was intrinsically carried out with
similar catalytic system based on our recent report on
palladium-catalyzed synthesis of 3-oxo-1,3-dihydro-1-
isobenzofuranyl alkanoates from 2-bromobenzaldehyde

1398
C. S. Cho and J. U. Kim
Vol 45
Table 1
known on palladium-catalyzed cyclization of (Z)-ꢀ-
iodoenones with carbon monoxide leading to ꢁ-lactones
[10,11].
Palladium-Catalyzed Cyclization of 2 with Carbon Monoxide and 3
Leading to 4 [a]
Carboxylic acid 3
O
Product 4
O
O
Yield
73
Scheme 2
Br
O
OH
CHO
O
O
O
O
Pd
N
N
R
N
O
2
3a
4a
O
4
N
O
O
72
51
71
69
30
46
59
PdBr
O
Et3NHBr
CHO
CO
OH
O
RCOONHEt3
Et3N
N
5
3b
4b
O
O
O
O
O
O
N
PdBr
CHO
O
RCOOH
3
OH
PdBr
O
N
N
7
3c
4c
O
O
6
O
O
OH
O
In summary, it has been shown that 3-bromopyridine-4-
carbaldehyde undergoes palladium-catalyzed cyclization
with carboxylic acids under carbon monoxide pressure to
afford 3-oxo-1,3-dihydrofuro[3,4-c]pyridine-1-yl alka-
noates in moderate to good yields. The present reaction
provides a new entry for phthalide analogue exhibiting
biological activity.
N
3d
4d
O
O
O
O
OH
O
N
3e
4e
O
O
O
O
Ph
EXPERIMENTAL
Ph
OH
O
1H and 13C NMR (400 and 100 MHz) spectra were recorded
on a Bruker Avance Digital 400 spectrometer using Me4Si as an
internal standard. Melting points were determined on a Thomas-
Hoover capillary melting points apparatus and are uncorrected.
The isolation of pure products was carried out via thin layer
(silica gel 60 GF254, Merck) chromatography. Commercially
available organic and inorganic compounds were used without
further purification except for the solvent, which was distilled by
standard methods before use.
N
3f
4f
O
O
O
O
OH
O
N
3g
4g
O
O
O
O
Ph
General Procedure for Palladium-Catalyzed Cyclization
of 3-Bromopyridine-4-carbaldehyde (2) with Carbon
Monoxide and Carboxylic Acids 3. To a 50 mL stainless steel
autoclave were added 3-bromopyridine-4-carbaldehyde 2 (93
mg, 0.5 mmol), carboxylic acid 3 (1 mmol), PdCl2(PPh3)2 (18
mg, 0.025 mmol), Et3N (253 mg, 2.5 mmol) and MeCN (5 mL).
After the system was flushed and then pressurized with carbon
monoxide to 10 atm, the reaction mixture was allowed to react at
100° for 1 hour. The reaction mixture was filtered through a
short silica gel column (ethyl acetate-hexane mixture) to
eliminate inorganic salts. Removal of the solvent left a crude
mixture, which was separated by thin layer chromatography
(silica gel, ethyl acetate-hexane mixture) to give cyclized
product 4. All products prepared by the above procedure were
characterized spectroscopically as shown below.
Ph
OH
O
N
3h
4h
[a] Reaction conditions: 2 (0.5 mmol), 3 (1 mmol), PdCl2(PPh3)2
(0.025 mmol), Et3N (2.5 mmol), MeCN (5 mL), CO (10 atm), 100°,
for 1 hour. [b] Isolated yield.
ꢀ
intermediate 6. Subsequent intramolecular addition of
aroylpalladium bond of 6 to neighboring formyl C=O
produces cyclized alkylpalladium species 7. This is
followed by the reaction with ammonium alkanoate to
give 4. A similar catalytic process has already been
proposed in palladium-catalyzed cyclization of 2-bromo-
benzaldehyde with carbon monoxide and nucleophiles [4].
The mechanistic acylpalladium addition to ketones is
3-Oxo-1,3-dihydrofuro[3,4-c]pyridin-1-yl acetate (4a). This
1
compound was obtained as an oil; H nmr (CDCl3): ꢂ 2.23 (s,
3H), 7.45 (s, 1H), 7.62 (d, J = 5.0 Hz, 1H), 8.99 (d, J = 5.0 Hz,
1H), 9.23 (s, 1H); 13C nmr (CDCl3): ꢂ 21.05, 92.35, 118.71,

Sep-Oct 2008
Palladium-Catalyzed Cyclization
1399
122.81, 148.42, 152.76, 154.93, 166.42, 169.35. Anal. Calcd.
For C9H7NO4: C, 55.96; H, 3.65; N, 7.25. Found: C, 55.75; H,
3.60; N, 7.27.
7.5 Hz, 1H), 7.69 (d, J = 5.0 Hz, 1H), 7.70 (s, 1H), 8.05 (d, J =
7.5 Hz, 2H), 9.01 (d, J = 5.0 Hz, 1H), 9.27 (s, 1H); 13C nmr
(CDCl3): ꢀ 93.01, 118.91, 122.93, 128.16, 129.14, 130.63,
134.85, 148.53, 152.97, 155.05, 165.04, 166.51. Anal. Calcd.
For C14H9NO4: C, 65.88; H, 3.55; N, 5.49. Found: C, 65.78; H,
3.45; N, 5.44.
3-Oxo-1,3-dihydrofuro[3,4-c]pyridin-1-yl propionate (4b).
This compound was obtained as a solid, mp 64-65° (hexane-
chloroform); 1H nmr (CDCl3): ꢀ 1.22 (t, J = 7.5 Hz, 3H), 2.49 (q,
J = 7.5 Hz, 2H), 7.47 (s, 1H), 7.60 (d, J = 5.0 Hz, 1H), 8.99 (d, J
= 5.0 Hz, 1H), 9.23 (s, 1H); 13C nmr (CDCl3): ꢀ 9.00, 27.69,
92.34, 118.69, 122.86, 148.45, 152.89, 154.92, 166.48, 172.91.
Anal. Calcd. For C10H9NO4: C, 57.97; H, 4.38; N, 6.76. Found:
C, 57.80; H, 4.29; N, 6.75.
Acknowledgement. This work was supported by the Korea
Research Foundation Grant funded by the Korea Government
(MOEHRD, Basic Research Promotion Fund) (KRF-2007-359-
C00021).
3-Oxo-1,3-dihydrofuro[3,4-c]pyridin-1-yl butyrate (4c).
This compound was obtained as an oil; 1H nmr (CDCl3): ꢀ 1.00
(t, J = 7.5 Hz, 3H), 1.68-1.77 (m, 2H), 2.44 (t, J = 7.5 Hz, 2H),
7.47 (s, 1H), 7.60 (d, J = 5.0 Hz, 1H), 8.99 (d, J = 5.0 Hz, 1H),
9.23 (s, 1H); 13C nmr (CDCl3): ꢀ 13.88, 18.39, 36.04, 92.29,
118.67, 122.87, 148.45, 152.92, 154.92, 166.49, 172.06. Anal.
Calcd. For C11H11NO4: C, 59.73; H, 5.01; N, 6.33. Found: C,
59.59; H, 4.88; N, 6.27.
3-Oxo-1,3-dihydrofuro[3,4-c]pyridin-1-yl hexanoate (4d).
This compound was obtained as an oil; 1H nmr (CDCl3): ꢀ 0.91
(t, J = 7.0 Hz, 3H), 1.31-1.36 (m, 4H), 1.65-1.73 (m, 2H), 2.44
(t, J = 7.5 Hz, 2H), 7.46 (s, 1H), 7.58 (d, J = 5.0 Hz, 1H), 8.98
(d, J = 5.0 Hz, 1H), 9.23 (s, 1H); 13C nmr (CDCl3): ꢀ 14.24,
22.60, 24.53, 31.45, 34.22, 92.31, 118.63, 122.88, 148.48,
152.93, 154.90, 166.46, 172.24. Anal. Calcd. For C13H15NO4: C,
62.64; H, 6.07; N, 5.62. Found: C, 62.34; H, 6.00; N, 5.65.
3-Oxo-1,3-dihydrofuro[3,4-c]pyridin-1-yl 3-methylbutan-
oate (4e). This compound was obtained as an oil; 1H nmr
(CDCl3): ꢀ 1.00 (d, J = 7.0 Hz, 6H), 2.10-2.21 (m, 1H), 2.34 (d,
J = 7.0 Hz, 2H), 7.48 (s, 1H), 7.60 (d, J = 5.0 Hz, 1H), 8.99 (d, J
= 5.0 Hz, 1H), 9.23 (s, 1H); 13C nmr (CDCl3): ꢀ 22.66, 25.94,
43.10, 92.25, 118.64, 122.86, 148.44, 152.94, 154.92, 166.50,
171.44. Anal. Calcd. For C12H13NO4: C, 61.27; H, 5.57; N, 5.95.
Found: C, 61.02; H, 5.48; N, 5.94.
REFERENCES AND NOTES
[1] Handbook of Organopalladium Chemistry for Organic
Synthesis, Negishi, E. Ed, Wiley, New York, 2002, Vol II, pp 2309-
2712; Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V.
Carbonylation: Direct Synthesis of Carbonyl Compounds, Plenum Press,
New York, 1991.
[2] Cho, C. S.; Lee, J. W.; Lee, D. Y.; Shim, S. C.; Kim, T. J.
Chem. Commun. 1996, 2115; Cho, C. S.; Chu, D. Y.; Lee, D. Y.; Shim,
S. C.; Kim, T.-J.; Lim, W. T.; Heo, N. H. Synth. Commun. 1997, 27,
4141; Cho, C. S.; Jiang, L. H.; Shim, S. C. Synth. Commun. 1998, 28,
849; Cho, C. S.; Jiang, L. H.; Lee, D. Y.; Shim, S. C.; Lee, H. S.; Cho,
S.-D. J. Heterocycl. Chem. 1997, 34, 1371.
[3] Cho, C. S.; Jiang, L. H.; Shim, S. C. Synth. Commun. 1999,
29, 2695; Cho, C. S.; Park, J. C.; Jiang, L. H.; Kim, T.-J.; Shim, S. C.;
Kim, M. C. Bull. Korean Chem. Soc. 2000, 21, 541.
[4] Cho, C. S.; Baek, D. Y.; Shim, S. C. J. Heterocycl. Chem.
1999, 36, 363; Cho, C. S.; Baek, D. Y.; Shim, S. C. J. Heterocycl. Chem.
1999, 36, 1101; Cho, C. S.; Lim, D. K.; Kim, T.-J.; Shim, S. C. J. Chem.
Res. (S) 2002, 550.
[5] For our recent report on palladium-catalyzed cyclization
using 2-bromobenzaldehydes, ꢁ-bromovinyl aldehydes and 3-
bromopyridine-4-carbaldehyde, see: Cho, C. S.; Lim, D. K.; Heo, N. H.;
Kim, T.-J.; Shim, S. C. Chem. Commun. 2004, 104; Cho, C. S.; Patel, D.
B. Tetrahedron 2006, 62, 6388; Cho, C. S.; Lim, D. K.; Zhang, J. Q.;
Kim, T.-J.; Shim, S. C. Tetrahedron Lett. 2004, 45, 5653; Cho, C. S.;
Patel, D. B.; Shim, S. C. Tetrahedron 2005, 61, 9490; Cho, C. S.; Patel,
D. B. J. Mol. Cat. A: Chem. 2006, 260, 105; Cho, C. S.; Shim, H. S.
Tetrahedron Lett. 2006, 47, 3835.
[6] For an annulation using 2-bromobenzaldehydes, see: Larock,
R. C.; Doty, M. J. J. Org. Chem. 1993, 58, 4579; Gevorgyan, V.; Quan,
L. G.; Yamamoto, Y. Tetrahedron Lett. 1999, 40, 4089; Dyker, G.;
Grundt, P. Tetrahedron Lett. 1996, 37, 619; Terao, Y.; Satoh, T.; Miura,
M.; Nomura, M. Tetrahedron 2000, 56, 1315.
3-Oxo-1,3-dihydrofuro[3,4-c]pyridin-1-yl 2-phenylacetate
(4f). This compound was obtained as a solid, mp 127-128°
1
(hexane-chloroform); H nmr (CDCl3): ꢀ 3.73 (d, J = 15.6 Hz,
1H), 3.78 (d, J = 15.6 Hz, 1H), 7.26-7.36 (m, 5H), 7.43 (s, 1H),
7.51 (d, J = 5.0 Hz, 1H), 8.96 (d, J = 5.0 Hz, 1H), 9.23 (s, 1H);
13C nmr (CDCl3): ꢀ 41.16, 92.63, 118.64, 122.80, 128.12,
129.25, 129.66, 132.56, 148.51, 152.68, 155.00, 166.37, 170.15.
Anal. Calcd. For C15H11NO4: C, 66.91; H, 4.12; N, 5.20. Found:
C, 66.68; H, 4.04; N, 5.19.
[7] Cho, C. S.; Baek, D. Y.; Kim, H. Y.; Shim, S. C.; Oh, D. H.
Synth. Commun. 2000, 30, 1139.
(E)-3-Oxo-1,3-dihydrofuro[3,4-c]pyridin-1-yl but-2-enoate
(4g). This compound was obtained as a solid, mp 89-90°
(hexane-chloroform); H nmr (CDCl3): ꢀ 1.95 (dd, J = 2.0 and
1
[8] Numata, A.; Kondo, Y.; Sakamoto, T. Synthesis 1999, 306.
[9] For our recent report on palladium catalysis, see: Cho, C. S.
J. Mol. Cat. A: Chem. 2005, 240, 55; Cho, C. S. J. Organomet. Chem.
2005, 690, 4094; Cho, C. S.; Kim, J. U. Tetrahedron Lett. 2007, 48,
3775.
[10] Copéret, C.; Sugihara, T.; Wu, G.; Shimoyama, I.; Negishi,
E. J. Am. Chem. Soc. 1995, 117, 3422.
[11] For intramolecular nucleophilic addition of aryl- and
vinylpalladiums to ketones and aldehydes, see: Quan, L. G.; Gevorgyan,
V.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 3545; Quan, L. G.;
Lamrani, M.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 4827.
7.0 Hz, 3H), 5.90 (dq, J = 15.6 and 2.0 Hz, 1H), 7.17 (dq, J =
15.6 and 7.0 Hz, 1H), 7.52 (s, 1H), 7.61 (d, J = 5.0 Hz, 1H), 8.98
(d, J = 5.0 Hz, 1H), 9.24 (s, 1H); 13C nmr (CDCl3): ꢀ 18.83,
92.47, 118.78, 120.92, 122.93, 148.44, 149.81, 153.06, 154.89,
164.44, 166.53. Anal. Calcd. For C11H9NO4: C, 60.27; H, 4.14;
N, 6.39. Found: C, 60.01; H, 4.08; N, 6.35.
3-Oxo-1,3-dihydrofuro[3,4-c]pyridin-1-yl benzoate (4h).
This compound was obtained as a solid, mp 147-148° (hexane-
chloroform); 1H nmr (CDCl3): ꢀ 7.46-7.50 (m, 2H), 7.65 (t, J =