An approach to highly functionalized quinolines and isoquinolines via a gold-catalyzed benzannulation

Article abstract of DOI:10.1055/s-0030-1259555

The AuCl₃-catalyzed benzannulation of pyridine-containing oxo-alkynes with external as well as internal alkynes proceeds under mild conditions, and a variety of quinoline and isoquinoline derivatives are produced in good to excellent yields. Th

Full text of DOI:10.1055/s-0030-1259555

LETTER
689
An Approach to Highly Functionalized Quinolines and Isoquinolines via a
Gold-Catalyzed Benzannulation
A
pproach to High
i
ly Fun
s
ctionalize
w
d Quinolines and
I
a
soquinoline
j
s
it Panda, Jhuma Bhadra, Tarun K. Sarkar*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
E-mail: tksr@chem.iitkgp.ernet.in
Received 22 November 2010
carboxaldehyde via a Sonogashira coupling. When 1a
(0.5 mmol) was subjected to the benzannulation reaction3a
with dimethyl acetylene dicarboxylate (DMAD, 1.5
mmol) in the presence of AuCl3 (3 mol%) in 1,2-dichloro-
Abstract: The AuCl3-catalyzed benzannulation of pyridine-
containing oxo-alkynes with external as well as internal alkynes
proceeds under mild conditions, and a variety of quinoline and iso-
quinoline derivatives are produced in good to excellent yields. The
reaction proceeds through the formation of aza-isobenzopyrylium ethane (1.5 mL) at 80 °C, only traces of 2a were formed
auric ate complexes as evident from trapping experiments.
(entry 1, Table 1). This failure could be attributed to poly-
merization of DMAD (Michael acceptor) in the presence
of 1a (Michael donor).11 After some experimentation we
were able to find that working under dilute conditions and
at ambient temperature allowed obtention of 2a in high
yield (entry 2, Table 1).
Key words: gold, catalysis, benzannulation, quinolines, isoquino-
lines
Transition-metal-catalyzed electrophilic activation of
alkynes towards intramolecular addition of heteronucleo-
philes has attracted considerable attention as a useful
method for the preparation of heterocyclic compounds.1
In particular, it has been found that AuCl3 catalyzes the
formation of C–C and C–O bonds thus behaving as an ef-
fective Lewis acid catalytic system.2 One of the early ex-
amples of such reactions include benzannulation between
o-alkynylbenzaldehydes and alkynes as developed exten-
sively by the research groups of Yamamoto, Dyker, and
others.3 Surprisingly, use of hetero analogues like pyri-
dine-containing oxo-alkynes in these reactions has not
been documented,4 although the latter may offer an envi-
ronmentally benign and atom economic route to highly
functionalized quinoline and isoquinoline derivatives.
Table 1 Reaction of 1a with DMAD under Various Catalytic Sys-
temsa
CO2Me
CHO
CO2Me
CO2Me
+
N
N
CO2Me
Ph
O
Ph
1a
2a
Entry
Catalytic system
AuCl3
Yield of 2a (%)b
1
2
3
4
5
6
7
tracec
89
57
0
AuCl3
AuCl
Quinolines and isoquinolines are widespread in the alka-
loid family and generally constitute important structural
motifs in pharmaceuticals, agrochemicals, or even dye-
stuffs.5 In view of their substantial applicability, the syn-
theses of these species are extensively studied topics.6,7
However, in spite of their common properties and much
research on their preparation, a synthetic methodology
based on a single concept that is applicable to both ring
systems remains relatively underdeveloped.8,9 In connec-
tion with our ongoing work on transition-metal-catalyzed
organic transformations,10 we now report for the first time
the homogeneous gold-catalyzed benzannulation between
pyridine-containing oxo-alkynes with both external as
well as internal alkynes thereby producing highly func-
tionalized quinolines and isoquinolines in good to excel-
lent yields.
AuCl(PPh3)
AuCl(PPh3)/AgOTf
AuCl3/Ph3P
PtCl2
64
7
0
a All reactions were performed using 1a (0.2 mmol) and DMAD (0.4
mmol) in the presence of catalyst (3 mol%) in DCE (4 mL) at r.t. for
24 h.
b Isolated yield, average of two runs.
c The reaction was performed using 1a (0.5 mmol) and DMAD (1.5
mmol) in the presence of AuCl3 (3 mol%) in DCE (1.5 mL) at 80 °C
for 2 h.
We then studied this reaction in 1,2-dichloroethane with
different gold catalysts. AuCl catalyzes this reaction
though the yield is low (Table 1, entry 3), whereas other
gold(I) catalysts, for example, AuCl(PPh3) (entry 4,
Table 1) is completely inactive. Only when AuCl(PPh3)
was combined with AgOTf, the system catalyzes the reac-
tion and gave the desired product in moderate yield (entry
5, Table 1). As expected combination of AuCl3 with Ph3P
For our initial study we selected the oxo-alkyne 1a, readi-
ly available from the corresponding 2-chloro-3-pyridine-
SYNLETT 2011, No. 5, pp 0689–0693
x
x.
x
x.
2
0
1
1
Advanced online publication: 11.02.2011
DOI: 10.1055/s-0030-1259555; Art ID: G32910ST
© Georg Thieme Verlag Stuttgart · New York

690
B. Panda et al.
LETTER
gives traces of the desired product (Table 1, entry 6). tron-rich auric ate complexes (cf. 7, vide infra) formed
Triphenylphosphine might react with AuCl3 to destroy its from oxo-alkynes 1a–d12 react effectively with electron-
catalytic activity or Lewis acidity.3h At this stage we were poor dienophiles to yield variously substituted quinolines
also interested to use other carbophilic Lewis acids, such 2a–e in high yield. Notably, the reaction times are short
as PtCl23e which is known to catalyze the same kinds of re- when a strong electron donor, such as a p-dimethylanilino
actions, sometimes with even higher efficiency. However, group, is attached to the acetylenic end of the oxo-alkyne
when 1a was exposed to DMAD in 1,2-dichloroethane in as in entry 2, whereas the reactions are sluggish (entries 3
the presence of PtCl2 (Table 1, entry 7), no traces of 2a and 5) when a long carbon chain dangles from the acety-
could be detected from 1H NMR of the crude product.
lenic end due possibly to steric reasons in the transition
state of the reaction.
We then applied this methodology to a series of pyridine-
containing oxo-alkynes, and the results are presented in
Table 2. As can be seen from Table 2 (entries 1–5), elec-
Table 2 AuCl3-Catalyzed Benzannulation of Pyridine-Containing Oxo-Alkynes with Alkynesa
Entry
1
Oxo-alkyne
Product
Yield (%)b
CO2Me
CO2Me
CHO
89
N
N
Ph
O
Ph
1a
2a
CO2Me
CO2Me
CHO
N
83c
N
2
O
NMe2
NMe2
1b
1c
2b
CO2Me
CO2Me
CHO
3
4
79d
N
N
O
O
Ph
Ph
O
3
3
2c
CO2Me
CO2Me
CHO
92
Ph
N
Ph
N
Ph
O
Ph
1d
2d
CO2Me
CHO
5
6
76d
N
N
O
O
Ph
Ph
O
3
3
1c
1a
2e
CHO
0e
N
N
Ph
Ph
O
Ph
Synlett 2011, No. 5, 689–693 © Thieme Stuttgart · New York

LETTER
Approach to Highly Functionalized Quinolines and Isoquinolines
691
Table 2 AuCl3-Catalyzed Benzannulation of Pyridine-Containing Oxo-Alkynes with Alkynesa (continued)
Entry
7
Oxo-alkyne
Product
Yield (%)b
CHO
Ph
Ph
0e
N
N
Ph
O
Ph
1a
Ph
O
Ph
Cl
Cl
Ph
8
9
86
91
88
N
N
N
N
CHO
CHO
CHO
Cl
Cl
Cl
Cl
1e
2f
Ph
O
OMe
Ph
Cl
Cl
N
Cl
1e
2g
Ph
O
NMe2
Ph
Cl
Cl
10
N
N
Cl
1e
2h
Ph
Ph
Ph
Cl
Ph
Ph
Cl
11
12
13
72
0e
0e
N
CHO
CHO
CHO
Cl
Cl
Cl
Cl
2i
1e
Ph
Ph
O
Cl
Cl
CO2Me
CO2Me
N
N
Cl
1e
O
Cl
Cl
N
N
CO2Me
Cl
1e
a All reactions were performed using oxo-alkyne (0.2 mmol) and alkyne (0.4 mmol) in the presence of AuCl3 (3 mol%) in DCE (4 mL) at r.t.,
the reraction time being 24 h or otherwise noted.
b Isolated yield, average of two runs.
c Reaction time was 10 h.
d Reaction time was 48 h.
e Refluxing the reaction mixture does not give any trace of desired products.
On the other hand 1a does not react with electron-rich tron-poor auric ate complexes (cf. 7, vide infra) formed
alkynes, such as phenylacetylene or diphenylacetylene from oxo-alkynes, for example, 1e12 react nicely with
(entries 6 and 7). These results indicate that a Diels– electron-rich alkynes (entries 8–10) to give isoquinolines
Alder-type [4+2] cycloaddition may be operating in these 2f–h in high yields. The regioselectivity in entries 5 and
cases. This methodology was further extended for the syn- 8–10 is in accord with the observation made by Yamamoto
thesis of substituted isoquinolines. Thus, as expected elec- et al. in benzenoid systems.3a Incidentally, reaction of 1e
Synlett 2011, No. 5, 689–693 © Thieme Stuttgart · New York

692
B. Panda et al.
LETTER
with diphenyl acetylene followed a completely different
pathway to yield the isoquinoline 2i; such debenzoyla-
tions are known in the literature, although higher yields of
products are observed only using Cu(OTf)2.13 In contrast,
reactions of 1e with electron-poor dienophiles, for exam-
ple, DMAD or methyl propiolate did not yield any traces
of the desired isoquinolines (entries 12 and 13, Table 2).14
CHO
AuCl3 (3 mol%)
Ph2SO (1.2 equiv)
O
DCE, 5 h, r.t.
83 %
N
N
Ph
Ph
1a
AuCl3
7
After having success with intermolecular benzannulation
reaction on pyridine-containing oxo-alkynes, we then be-
came interested in the intramolecular version of this
reaction. Accordingly, the oxo-diyne 4 (Scheme 1) was
made via a Sonogashira coupling15 of 4,4-dicarboethoxy-
1,6-heptadiyne with iodo aldehyde 3, the latter being
available from the corresponding acid16 by esterification
(MeI, K2CO3, DMF) followed by DIBAL-H reduction.
When 4 was treated with AuCl3 (3 mol%) in 1,2-dichloro-
ethane at room temperature, the tricyclic ketone 5 was
formed in 92% yield as a white crystalline solid unaccom-
panied by even traces of the competing [3+2] cyclo-
isomerization product 6.17,18
Ph2SO
Ph
S
O
O
O
Ph
Ph
H
O
– Ph2S
N
Ph
N
AuCl3
8
Scheme 2 Oxidation of aza-isobenzopyrylium auric ate complex
In conclusion, this work shows that highly functionalized
quinolines and isoquinolines can be synthesized by a ho-
mogeneous gold-catalyzed benzannulation of pyridine-
containing oxo-alkynes with substituted alkynes in both
inter- and intramolecular fashion.
CO2Et
Cl
I
Cl
CO2Et
a
N
H
N
H
Cl
Cl
O
Cl
O
O
Supporting Information for this article is available online at
3
4
http://www.thieme-connect.com/ejournals/toc/synlett.
b
Acknowledgment
O
CO2Et
CO2Et
This work was supported by DST and CSIR, Government of India.
BP is grateful to CSIR, Government of India for a Senior Research
Fellowship. The NMR facility at IITKGP was supported by the
FIST program of the DST. Prof. T. Gallagher (Bristol), Drs. S.
Djuric and S. Cepa (Abbott, Il) are thanked for continued help and
support.
N
Cl
CO2Et
CO2Et
Cl
N
6
Cl
5
Scheme 1 Reagents and conditions: (a) 4,4-dicarboethoxy-1,6-
heptadiyne, PdCl2(PPh3)2 (2 mol%), DBMP, MeCN, r.t., 2 h, 56%; (b)
AuCl3 (3 mol%), DCE, r.t., 6 h, 92% [DBMP = 2,6-di-tert-butyl-4-
methylpyridine].
References and Notes
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Interestingly, the Thorpe–Ingold effect of the geminally
substituted carboethoxy groups which exerts its profound
influence in benzenoid systems leading to [3+2]-type
products is unable to effect chemoreversal in this case.
Yamamoto et al.3a has proposed that the gold-catalyzed
benzannulation takes place via the formation of isoben-
zopyrilium auric ate complexes.19 Indeed, we were able to
detect these species in our case by trapping experiments.
Thus when oxo-alkyne 1a was treated with 3 mol% AuCl3
in the presence of 1.2 equivalents of Ph2SO at room tem-
perature in 1,2-dichloroethane the aza-isocoumarin deriv-
ative 8 was isolated in 83% yield, thereby supporting the
formation of isobenzopyrylium complexes of type 7
(Scheme 2).20
(d) Hildebrandt, D.; Huggenberg, W.; Kanthak, M.; Ploger,
T.; Muller, I. M.; Dyker, G. Chem. Commun. 2006, 2260.
(e) Dyker, G.; Hildebrandt, D. J. Org. Chem. 2005, 70,
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Synlett 2011, No. 5, 689–693 © Thieme Stuttgart · New York

LETTER
Approach to Highly Functionalized Quinolines and Isoquinolines
693
5249. (g) Asao, N.; Sato, K. Org. Lett. 2006, 8, 5361.
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(11) Indeed 1a was found to react exothermally when brought in
contact with DMAD in DCE at a similar concentration.
(12) Oxo-alkynes 1a–d were prepared from the corresponding
pyridine-2-chloro aldehydes by Sonogashira coupling;
similarly, 1e was prepared from iodoaldehyde 3 by
Sonogashira coupling.
(4) (a) During the course of our work Organ et al. reported a few
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reactor under heterogeneous conditions, see: Shore, G.;
Tsimerman, M.; Organ, M. G. Beilstein J. Org. Chem. 2009,
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A.; Blacker, J.; Armstrong, A.; Cabral, J. T.; Blackmond,
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(6) Coffey, D. S.; Kolis, S. P.; May, S. A. In Progress in
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T. L., Eds.; Pergamon: Amsterdam, 2002, Chap. 6.1.
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Y.-N.; Yan, Z.-Y.; Gao, G.-L.; Wang, H.-L.; Shu, X.-Z.; Ji,
K.-G.; Liang, Y.-M. J. Org. Chem. 2009, 74, 2893.
(b) Dell’Acqua, M.; Abbiati, G.; Rossi, E. Synlett 2010,
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Vargas Méndez, L. Y.; Meléndez Gómez, C. M. Curr. Org.
Chem. 2005, 9, 141; and references therein. (d) Bose, D. S.;
Idrees, M.; Jakka, N. M.; Rao, J. V. J. Comb. Chem. 2010,
12, 100; and references therein.
(13) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 10921.
(14) An alkyne with an aryl and an ester substituent, e.g.,
PhC≡CCO2Me was found not to react either with the
electron-rich oxo-alkyne 1a or the electron-deficient oxo-
alkyne 1e; presumably in this case the HOMO–LUMO
energy difference is too high for both pairs of reactants.
(15) This Sonogashira coupling was unsuccessful (<10%) under
the classical conditions [PdCl2(PPh3)2/CuI] using a variety
of bases such as Et3N, i-Pr2NH, K2CO3, or NaHCO3.
(16) Marzi, E.; Bigi, A.; Schlosser, M. Eur. J. Org. Chem. 2001,
1371.
(17) Kim, N.; Kim, Y.; Park, W.; Sung, D.; Gupta, A. K.; Oh,
C. H. Org. Lett. 2005, 7, 5289.
(18) Even carrying out the reaction at a lower temperature (0–
15 °C) did not give any traces of the [3+2] product 6.
(19) For a discussion and computational analysis regarding [3+2]
vs. [4+2] cycloaddition of isobenzopyrylium 1,3-dipoles,
see: Straub, B. F. Chem. Commun. 2004, 1726.
(20) We also cannot rule out the possibility of autocatalysis by
the oxo-alkynes, as sometimes substrates might coordinate
and lead to the formation of even more efficient catalysts,
see: Hashmi, A. S. K.; Weyrauch, J. P.; Rudolph, M.;
Kurpejovic, E. Angew. Chem. Int. Ed. 2004, 43, 6545.
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