Palladium-catalyzed one-pot synthesis of pyrrole-annulated coumarin, quinolone, and 7-aza-indole derivatives

Article abstract of DOI:10.1055/s-0030-1260312

An efficient one-pot approach for the synthesis of highly substituted pyrrolocoumarin, quinolone, and pyrrolopyridine derivatives has been achieved by palladium acetate catalyzed reaction in DMF through initially formed enamine from cyclic and acyclic ketones and 6-amino-5-bromocoumarin, 6-amino-5-bromo-1-methyl quinolone, and 2-amino-3,5-dibromopyridine, respectively. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260312

LETTER
2369
Palladium-Catalyzed One-Pot Synthesis of Pyrrole-Annulated Coumarin,
Quinolone, and 7-Aza-indole Derivatives
P
yrrole-Annulated
.
C
oumarin,
Q
C
uinolone, and 7-
.
Aza-indole
D
M
erivative
s
ajumdar,*a,b Sintu Ganai,a Buddhadeb Chattopadhyay,a Krishanu Raya
a
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Department of Chemical Sciences, Tezpur University, Napaam, Tezpur 784028, India
Fax +91(33)25828282; E-mail: kcm_ku@yahoo.co.in
b
Received 9 June 2011
pyridine derivatives by palladium-catalyzed intramolecu-
lar Heck reaction starting from easily available bromo
derivatives of the corresponding heterocyclic amines and
ketones using a ligand-free protocol. To achieve the opti-
Abstract: An efficient one-pot approach for the synthesis of highly
substituted pyrrolocoumarin, quinolone, and pyrrolopyridine deriv-
atives has been achieved by palladium acetate catalyzed reaction in
DMF through initially formed enamine from cyclic and acyclic ke-
tones and 6-amino-5-bromocoumarin, 6-amino-5-bromo-1-methyl mized reaction conditions we first attempted the palladi-
quinolone, and 2-amino-3,5-dibromopyridine, respectively.
um-catalyzed intramolecular Heck reaction with the
substrates 6-amino-5-bromo quinolone (1a) and cyclo-
hexanone (2a). Initially, the reaction was performed in an-
hydrous N,N-dimethylformamide (DMF) using 10 mol%
palladium acetate, 1.5 equivalents DABCO under nitro-
gen atmosphere at 85 °C for four hours. However, even
after long reaction times there was no indication for the
formation of any desired product. After several attempts it
was observed that the reaction proceeds with a minimum
of three equivalents of DABCO at 120 °C affording a
product in 91% yield. The spectral analyses of the com-
pound revealed the formation of the product 3a22
(Scheme 1).
Key words: pyrrolocoumarin, pyrroloquinolone, pyrrolopyridine,
palladium acetate
Coumarin and quinolone moieties are found in a large
number of natural products, which have a broad spectrum
of biological activity.1 In particular, pyrroloquinolone de-
rivatives are also important as they can act as phosphodi-
esterase 5 inhibitors,2 shows analgesic activity,3 and are
important precursors for the antibiotic martinelline.4 Fur-
thermore, pyrrolocoumarin derivatives exhibit several bi-
ological activity.5–9 They also act as ideal dyes for various
modern fluorescent imaging technologies such as
FRET.10 Pyrrolocoumarin derivatives are important pre-
cursors for the construction of two biologically active ma-
rine alkaloids, namely, ningalin B and lamellarin D.11,12
Moreover, pyranoindole bearing heterocycles and pyrrol-
opyridines have attracted much attention in both synthetic
and medicinal chemistry due to their potential biological
activities.13–16 Therefore, we have focused much attention
on the development of an efficient one-step protocol for
synthesizing substituted pyrrolocoumarin, pyrroloqui-
nolone, and pyrrolopyridine derivatives. So far we have
used different methodologies for the synthesis of such bi-
ologically active heterocycles including aza-Claisen rear-
Br
O
NH2
+
NH
(i)
O
N
O
N
Me
Me
3a
1a
2a
Scheme 1 Reagents and conditions: (i) Pd(OAc)2 (10 mol%),
DABCO (3 equiv), DMF, 120 °C, N2 atmosphere, 4 h.
Further increase of catalyst loading, amount of base or re-
action temperature did not improve the yield of the prod-
uct. We have also examined the effect of different
catalysts [Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2] and bases
[KOAc, NaOAc, Et3N], but investigation on the palladi-
um source and bases revealed that palladium acetate and
DABCO were the most effective reagents to perform the
cyclization. The use of DMF as solvent is crucial for the
success of the reaction, other solvents such as acetonitrile,
toluene, and 1,4-dioxane were ineffective (Table 1). Sim-
ilar treatment of substrates 1a–c with different cyclic ke-
tones under the above-mentioned optimized reaction
conditions [Pd(OAc)2 (10 mol%), DABCO (3 equiv),
DMF, 120 °C, 4 h, N2 atm.] gave the products 3b–j in
good yields, except in the case of 1c. Substrate 1c failed
to produce any cyclized product with the cyclic ketones
2a–c, even after longer reaction times. However, when the
rangement,17
gold-catalyzed
cycloisomerisation,18
palladium-catalyzed Heck reaction,19 Pd(0)-mediated
cross-coupling followed by Cu(I)-catalyzed heteroannu-
lation reaction,20 to name a few. All the above-mentioned
reactions proceed in two or more steps. Recently Chen et
al. have reported the indole synthesis using a palladium-
catalyzed annulation between o-iodoanilines and ke-
tones.21
In order to further explore the scope of this methodology
we wish to report a one-pot synthesis of such biologically
active pyrrolocoumarin, pyrroloquinolone, and pyrrolo-
SYNLETT 2011, No. 16, pp 2369–2373
x
x
.x
x
.2
0
1
1
Advanced online publication: 13.09.2011
DOI: 10.1055/s-0030-1260312; Art ID: B10511ST
© Georg Thieme Verlag Stuttgart · New York

2370
K. C. Majumdar et al.
LETTER
same reactions were conducted at 140 °C for eight hours
while keeping the other parameters unchanged products
3h–j were formed in 65–72% yields. At the same time the
bromine atom at the 5-position of the pyridine ring under-
went debromination in both the products as indicated by
the spectral data. Further variation of any other parame-
ters did not improve the yield of the products 3h–j. The re-
sults are summarized in Table 2. The optimized reaction
conditions also failed in the cases of substrates 1d and 1e.
Table 1 Optimization of the Palladium-Catalyzed Intramolecular
Heck Reactiona
Entry Catalyst (10 mol%) Base (3 equiv) Solvent
Yield (%)b
91
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)2Cl2
PdCl2
DABCO
KOAc
DMF
DMF
n.r.
3
NaOAc
Et3N
DMF
n.r.
4
DMF
n.r.
In case of 1d debromination occurred, and 1e remained
unaffected even after prolonged reaction times (Table 2).
Again, 1a did not react with the seven-membered cyclic
ketone 2e (Table 2, entry 13). The plausible mechanism
for the formation of the products 3a–j from the substrates
1a–c is depicted in Scheme 2.
5
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DMF
52
6
DMF
<20
n.r.
7
DMF
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
MeCN
toluene
dioxane
n.r.
First, substrates 1a–c condense with cyclic ketones 2a–d
to generate I and produce the enamines II in the presence
of base. The formed enamines subsequently underwent in-
tramolecular palladium-catalyzed Heck reaction to afford
the products 3a–j.
9
n.r.
10
n.r.
a The reactions were carried out at 120 °C.
b Isolated yields; n.r. = no reaction.
Table 2 Summarized Results of the Intramolecular Heck Reaction
Entry
Substrate
Ketone
Product
Yield (%)c
Br
O
NH2
1a
91
NH
O
N
Me
O
N
2a
Me
1a
3a
Br
O
NH2
NH
2a
86
O
N
Me
O
N
2b
Me
1a
3b
O
Br
NH2
3a
89
82
NH
O
N
Me
O
N
1a
2c
Me
3c
Br
O
NH2
NH
4a
O
N
Me
O
N
2d
Me
1a
3d
Synlett 2011, No. 16, 2369–2373 © Thieme Stuttgart · New York

LETTER
Pyrrole-Annulated Coumarin, Quinolone, and 7-Aza-indole Derivatives
2371
Table 2 Summarized Results of the Intramolecular Heck Reaction (continued)
Entry
5a
Substrate
Ketone
Product
Yield (%)c
Br
O
NH2
NH
83
80
O
O
O
O
2a
1b
3e
Br
O
NH2
6a
NH
O
O
2b
O
O
1b
3f
O
Br
NH2
7a
82
NH
O
O
1b
O
O
2c
3g
O
Br
Br
8b
72
65
N
NH2
N
H
N
N
1c
2a
3h
O
Br
Br
9b
N
N
NH2
N
H
1c
2b
3i
O
Br
Br
10b
70
NH2
N
H
N
1c
2c
3j
O
Br
d
d
11a
12b
–
–
O
O
NH2
2a
1d
O
NH2
Br
–
–
n.r.
n.r.
Br
N
1e
2a
Br
O
NH2
13a
O
N
Me
2e
1a
a Pd(OAc)2 (10 mol%), DABCO (3 equiv), DMF, 120 °C, 4 h, N2 atm.
b Pd(OAc)2 (10 mol%), DABCO (3 equiv), DMF, 140 °C, 8 h, N2 atm.
c Isolated yield.
d Debromination occurred, n.r. indicates no reaction.
Synlett 2011, No. 16, 2369–2373 © Thieme Stuttgart · New York

2372
K. C. Majumdar et al.
LETTER
O
Supporting Information for this article is available online at
X
X
N
http://www.thieme-connect.com/ejournals/toc/synlett.
condensation
+
Het
Het
n = 1,2
Pd (OAc)2, DMF
NH2
n = 1,2
Acknowledgment
1a–c
2a–d
I
We thank the CSIR (New Delhi) and the DST (New Delhi) for fi-
nancial assistance. Three of us (S.G., B. C., and K. R) are grateful
to the CSIR (New Delhi) for their research fellowships. We also
thank the DST (New Delhi) for providing Bruker NMR (400 MHz),
Perkin-Elmer CHN Analyser, FTIR, and UV-vis spectrometer.
Base
X = PdBr
X = Br
n = 1,2
X
Het
Het
n = 1,2
NH
N
H
References and Notes
II
3a–j
N
N
N
N
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⋅HBr
Scheme 2 Mechanism of the cyclization
The one-pot preparation of such important biologically
active compounds is a fundamental goal in organic syn-
thesis as it avoids the expensive purification that follows
the step-by-step synthesis. There are several reports in the
literature for the preparation of 7-aza indoles,23 but one-
pot synthesis by palladium-catalyzed intramolecular Heck
reaction is rare. The application of the Hegedus–Mori–
Heck reaction (intramolecular Heck reaction) to the syn-
thesis of 7-aza-indoles was investigated on enamines in
the presence of Pd(PPh3)4 and NaHCO3 in HMPA at
140 °C, but the reaction was not effective.24 Lachance et
al. have developed a one-pot microwave-assisted synthe-
sis of 7-aza-indoles by the formation of the enamines fol-
lowed by the Heck reaction of the enamines resulting
from the condensation.25 This approach was illustrated by
the in situ formation of (4-methylsulfonylphenyl)acetone
on 3-bromo-2-aminopyridine in the presence of tetra-
ethoxysilane, PPTS, and pyridine under microwave irra-
diation (heated successively for 20 min at 160 °C, 180 °C,
and 200 °C) followed by the addition of Pd(PPh3)4 (5
mol%) and Cy2NMe. The 2-(4-methylsulfonyl)phenyl-7-
aza-indole was obtained in only 41% yield. Recently, Jia
et al. reported a palladium-catalyzed synthesis of the 7-
aza-indole derivatives from 2-amino-3,5-dichloropyri-
dine and 2-amino-3-chloro-5-trifluoromethyl in the pres-
ence of a ligand.26 Spergel et al. also reported a one-pot
synthesis of aza-indoles via palladium-catalyzed het-
eroarylation of ketone enolates using (SIPr)Pd(allyl)Cl
and NaHMDS at 105 °C.27
(10) Chen, L.; Hu, T.-S.; Yao, Z.-J. Eur. J. Org. Chem. 2008,
6175.
(11) Chen, L.; Xu, M. H. Adv. Synth. Catal. 2009, 351, 2005.
(12) (a) Ridley, C. P.; Reddy, M. V. R.; Rocha, G.; Bushman,
F. D.; Faulknera, D. J. Bioorg. Med. Chem. 2002, 10, 3285.
(b) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J. H. Chem. Rev.
2008, 108, 264. (c) Yamaguchi, T.; Fukuda, T.; Ishibashi,
F.; Iwao, M. Tetrahedron Lett. 2006, 47, 3755. (d) Tardy,
C.; Facompré, M.; Laine, W.; Baldeyrou, B.; García-
Gravalos, D.; Francesch, A.; Mateo, C.; Pastor, A.; Jiménez,
J. A.; Manzanares, I.; Cuevasb, C.; Bailly, C. Bioorg. Med.
Chem. 2004, 12, 1697.
(13) Hiremath, S. P.; Badiger, G. R.; Jivanagi, A. S.; Purohit,
M. G. Indian J. Chem. 1992, 313, 583.
In summary, we have achieved an efficient route to the
synthesis of highly bioactive pyrrolocoumarin, pyrrolo-
quinolone, and 7-aza-indole derivatives starting from
readily available starting materials by palladium-cata-
lyzed intramolecular Heck reaction. The reaction condi-
tions are very simple and afford the products in moderate
to good yields in the absence of ligands, not requiring the
use of an amine protecting group. Further application of
this methodology for the synthesis of heterocyclic librar-
ies is under way and will be reported later.
(14) (a) Kuethe, J. T.; Wong, A.; Qu, C.; Smitrovich, J.; Davies,
I. W.; Hughes, D. L. J. Org. Chem. 2005, 70, 2555. (b) Van
Zandt, M. C.; Jones, M. L.; Gunn, D. E.; Geraci, L. S.; Jones,
J. H.; Sawicki, D. R.; Sredy, J.; Jacot, J. L.; Dicioccio, A. T.;
Petrova, T.; Mitschler, A.; Podjarny, A. D. J. Med. Chem.
2005, 48, 3141. (c) Faulkner, D. J. Nat. Prod. Rep. 1999, 16,
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(15) (a) Henry, J. R.; Rupert, K. C.; Dodd, J. H.; Turchi, I. J.;
Wadsworth, S. A.; Cavender, D. E.; Fahmy, B.; Olini, G. C.;
Davis, J. E.; Pellegrino-Gensey, J. L.; Schafer, P. H.;
Siekierka, J. J. J. Med. Chem. 1998, 41, 4196. (b) Henry,
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Synlett 2011, No. 16, 2369–2373 © Thieme Stuttgart · New York

LETTER
Pyrrole-Annulated Coumarin, Quinolone, and 7-Aza-indole Derivatives
2373
S. A.; Cavender, D. E.; Schafer, P. H.; Siekierka, J.
J. Bioorg. Med. Chem. Lett. 1998, 8, 3335.
(16) Peter, A. N.; Thomas, B.; Anna, K.; Tero, L.; Peter, S.
WO 2004016609, 2004; Chem. Abstr. 2004, 140, 217627.
(17) Majumdar, K. C.; Chattopadhyay, B. Synthesis 2008, 921.
(18) Majumdar, K. C.; Chattopadhyay, B.; Samanta, S. Synthesis
2008, 311.
(19) Majumdar, K. C.; Chakravorty, S.; Shyam, P. K.; Taher, A.
Synthesis 2009, 403.
(20) Majumdar, K. C.; Mondal, S. Tetrahedron Lett. 2009, 49,
2418.
Compound 3a
Yield 91%, solid, mp 254–256 °C. IR (KBr): 1637, 3305
cm–1. 1H NMR (400 MHz, CDCl3): d = 8.30 (d, 1 H, J = 9.5
Hz), 8.00 (s, 1 H), 7.48 (d, 1 H, J = 9.0 Hz), 7.13 (d, 1 H,
J = 9.0 Hz), 6.73 (d, 1 H, J = 9.5 Hz), 3.80 (s, 3 H), 3.00 (br
s, 2 H), 2.80 (br s, 2 H), 1.93 (br s, 4 H). 13C NMR (100 MHz,
DMSO): d = 22.17, 23.13, 23.18, 23.41, 29.57, 107.28,
108.69, 112.51, 114.75, 118.38, 122.47, 130.57, 134.79,
135.60, 136.82, 160.65; MS: m/z = 253 [M+ + H]. Anal.
Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10. Found: C,
76.34, H, 6.42, N, 11.27.
(21) Chen, C.-Y.; Lieberman, D. R.; Larsen, D. R.; Verhoeven,
T. R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676.
(22) General Procedure for the Synthesis of Compound 3a by
Heck Reaction
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Angew. Chem. Int. Ed. 2000, 39, 2488. (b) Koradin, C.;
Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P.
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Tetrahedron Lett. 2004, 45, 539. (d) Cacchi, S.; Fabrizi, G.;
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Schneider, C.; Lindenschmidt, A.; Will, D. W. Angew.
Chem. Int. Ed. 2004, 43, 4256. (f) Roy, P. J.; Dufresne, C.;
Lachance, N.; Leclerc, J.-P.; Boisvert, M.; Wang, Z.;
Leblanc, Y. Synthesis 2005, 2751.
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J.-P. Tetrahedron 1999, 55, 1959.
(25) Lachance, N.; April, M.; Joly, M.-A. Synthesis 2005, 2571.
(26) Xu, Z.; Hu, W.; Zhang, F.; Li, Q.; Lu, Z.; Zhang, L.; Jia, Y.
Synthesis 2008, 3981.
A mixture of 1a (100 mg, 0.395 mmol), cyclohexanone (2a,
77.5 mg, 0.79 mmol), and DABCO (132.7 mg, 1.185 mmol)
was taken in DMF (5 mL) under nitrogen atmosphere.
Pd(OAc)2 (10 mol%, 8.8 mg) was added and the reaction
mixture was stirred at 120 °C for 4 h. After completion of the
reaction as monitored by TLC, the reaction mixture was
cooled, H2O (20 mL) was added and extracted with EtOAc
(3 × 30 mL). The EtOAc extract was washed with H2O
(2 × 40 mL), followed by brine (30 mL). The organic layer
was dried (Na2SO4), and the solvent was evaporated to give
a crude product which was purified by column chromatog-
raphy over silica gel (230–400 mesh) using PE–EtOAc (3:2)
as eluent. Product 3a was isolated as a white solid in 91%
yield.
(27) Spergel, S. H.; Danielle, R.; Okoro, D. R.; Pitts, W. J. Org.
Chem. 2010, 75, 5316.
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