One-pot synthesis of furo[2,3-h]quinoline and furo[2,3-h]isoquinoline derivatives using Fischer carbene complex

Article abstract of DOI:10.1016/j.tetlet.2010.11.044

A new route for the synthesis of furo[2,3-h]quinoline and furo[2,3-h]isoquinoline derivatives have been explored through the coupling of carbene complexes with pyridine-bridged enynes. This reaction process, involving the annulation of both furan and benzene ring on to a pre-existing pyridine ring is highly efficient in the presence of triphenylphosphine as ligand additive.

Full text of DOI:10.1016/j.tetlet.2010.11.044

Tetrahedron Letters 52 (2011) 251–253
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of furo[2,3-h]quinoline and furo[2,3-h]isoquinoline
derivatives using Fischer carbene complex
⇑
Priyabrata Roy, Binay K. Ghorai
Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah 711103, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new route for the synthesis of furo[2,3-h]quinoline and furo[2,3-h]isoquinoline derivatives have been
explored through the coupling of carbene complexes with pyridine-bridged enynes. This reaction process,
involving the annulation of both furan and benzene ring on to a pre-existing pyridine ring is highly effi-
cient in the presence of triphenylphosphine as ligand additive.
Received 9 October 2010
Revised 29 October 2010
Accepted 4 November 2010
Available online 29 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Furo[2,3-h]quinoline
Furo[2,3-h]isoquinoline
Carbene complex
Benzannulation
Nitrogen-containing heterocycles are abundant in nature and
have continued to attract significant interest from synthetic and
medicinal chemists alike partly because of their diverse biological
activities, which allow their utility as research tools in pharmacol-
ogy, but also because they provide challenging targets for testing
new synthetic methodologies.1 Furo[2,3-h]quinoline derivatives
are of particular interest as they appear to be very promising phot-
ochemotherapeutic agents due to some of its properties, such as
high antiproliferative activity, very poor genotoxicity and lack of
skin phototoxicity.2 Furo[2,3-h]isoquinoline, a versatile core con-
tained in several naturally occurring alkaloids have been impli-
cated as moderate inhibitors of eosinophil function and as
possible anti-inflammatory agents.3 These heterocyclic ring sys-
tems are most commonly assembled by the annulation of a furan
ring onto a pre-existing quinoline/isoquinoline ring.2,4 However,
the literature search revealed that construction of these ring sys-
tems by the annulation of benzofuran rings onto pre-existing pyr-
idine rings surprisingly remained unexplored so far. This letter
focuses on the successful execution of the latter transformation
through the simultaneous construction of both furan and benzene
rings by the coupling of Fischer carbene complexes 2 with pyri-
dine-bridged enyne systems 1 (Scheme 1). This process is mecha-
nistically related to the Dötz benzannulation reaction5 in that a
chromium carbene-generated ketene complex 3 cyclizes to a phe-
nol derivative 4, which finally converts to the furoquinoline/iso-
quinoline derivatives 5, upon treatment with acid.
Cr(CO)5
OMe
R2
R2
R1
OMe
Cr(CO)3
X
X
2
Y
Y
C
O
R1
1
3
OMe
R2
R2
O
X
H+
X
OH
R1
Y
Y
R1
5
4
X=N, Y=CH: Furo[2,3-h]quinoline series
X=CH, Y=N: Furo[2,3-h]isoquinoline series
Scheme 1. Synthetic plan towards furoquinoline/isoquinoline derivatives.
TMS
CHO
R1
R2
X
X
X
Br
a
b
Y
Y
Y
CHO
1, R1=SiMe3
8, R1=H
7
6
⇑
Corresponding author. Tel.: +91 33 26684561; fax: +91 33 26682916.
E-mail address: bkghorai@yahoo.co.in (B.K. Ghorai).
Scheme 2. Reagents and conditions: (a) trimethylsilylacetylene, (Ph3P)2PdCl2, CuI,
THF, Et3N, rt; (b) Ph3P@CHR2, THF, rt.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.044

252
P. Roy, B. K. Ghorai / Tetrahedron Letters 52 (2011) 251–253
Table 1
lene at room temperature afforded alkynyl aldehyde 7, which on
treatment with appropriate Wittig reagent afforded the desired
enyne derivatives 1 in good yield. Wittig reactions with reactive
or semistabilized ylides gave exclusively desilylated terminal al-
kynes 8.
Effect of reaction conditions on the coupling of 8a and carbene complex 2a
Cr(CO)5
H
OMe
O
2
N
N
To test the viability of the proposed benzannulation reaction,
we have first considered the coupling reaction of enyne derivative
8a (R2 = CO2Me) with a carbene complex 2. Thus, exposure of 8a to
a carbene complex 2 in refluxing tetrahydrofuran (THF) for 20 h
followed by treatment with catalytic sulphuric acid gave furoquin-
oline 9a in 49% yield (entry 1, Table 1). The isolation of 9a as the
sole product suggests that no competitive reaction takes place
other than CO insertion (Scheme 1).7,8 Decrease of reaction time
did not improve the product yield (entry 2). Since competing liga-
tion of the sp2 nitrogen might be a factor in the reduced yield in
this system, the reaction was tested in the presence of triphenyl-
phosphine as a ligand additive9 and the yield of the product was
improved to 73% (entry 3).10 The yield of the product was consid-
erably lower in dilute solution (entry 4). This is consistent with the
allelochemical effect previously described by Wulff and co-work-
ers,11 in that CO insertion is suppressed in dilute solution since
co-ordination of a second alkyne ligand is crucial for the CO inser-
tion event. The yield of the reaction did not improve with the use of
other solvents, for example, 1,4-dioxane, acetonitrile and acetone.
Having prepared the furo[2,3-h]quinoline derivative success-
fully, we decided to explore the scope and generality of this reac-
tion in the synthesis of other analogues especially varying the
substituent at C-6. Accordingly a variety of enyne derivatives 1/8
were reacted with the Fischer carbene complex 2 under optimized
conditions (entry 3 of Table 1) and the results are summarized in
Table 2. In all cases, formation of furoquinoline/furoisoquinoline
derivatives was the exclusive pathway. In reactions in entries b
and c, a slightly lower yield of the product was observed as the
pure cis isomer was employed.7 The benzannulation process was
also efficient for silylated alkynes (entries d and g), which afford
the same products as the terminal alkyne after desilylation using
catalytic sulphuric acid. However, the presence of steric bulk
group, that is, trimethylsilyl group as an alkyne substituent (en-
tries i and j) slightly lower yield was observed compared to their
terminal analogues (entries a and h).
CO2Me
CO2Me
8a
9a
Entry
Solvent
Time (h)
Concnb (M)
Yieldc (%)
1
2
3
4
5
6
7
THF
THF
THF
THF
20
10
20
20
20
20
20
0.4
0.4
0.4
0.1
0.4
0.4
0.4
49
31
73d
52d
64d
58d
56d
1,4-Dioxane
Acetonitrile
Acetone
a
b
c
All reaction were conducted at the reflux temperature.
Concentration of carbene and enyne in respective solvents.
Isolated yields.
d
1.0 equiv PPh3 used.
Pyridine-bridged enyne derivatives required for our studies
were easily obtained from the corresponding bromoaldehyde 66
(Scheme 2). Sonogashira reaction of 6 with (trimethylsilyl)acety-
Table 2
Synthesis of furo[2,3-h]quinoline and furo[2,3-h]isoquinoline derivatives through the
coupling of Fischer carbene complexes with pyridine-bridged enynesa
Cr(CO)5
R1
R1
R1
R2
OMe
O
OMe
O
X
X
X
2
Y
Y
Y
+
R2
R2
9
1/ 8
10
Entry
X
Y
R1
R2
Yield 9 (%)
Yield 10 (%)
a
b
c
d
e
f
g
h
i
N
N
N
N
CH
CH
CH
CH
N
CH
CH
CH
CH
N
N
N
N
CH
N
H
H
H
CO2Me
CH3
Ph
CO2Et
H
CH3
CO2Me
Ph
CO2Me
Ph
73
0
0
78
7c
4c
71
0
0
61 (55)d
67 (62)d
TMSb
H
0
60
58
0
65
0
An unusual benzannulation product 12 was obtained from the
coupling of carbene complex 2 and enyne derivative 11 (Scheme
3). This product is more likely derived from electrocyclization of
aromatic enyne 11 and not the alternative benzannulation product
15 based on the absence of fused furan ring. A proposed mecha-
nism depicted in Scheme 3 explains the unusual formation of acri-
dine. Catalytic amount of Cr(CO)6, which is generally present in
Fischer carbene complexes as impurity or is generated in the reac-
tion mixture,12 reacts with THF to form Cr(CO)5ÁTHF in situ. This
H
TMSb
H
TMSb
TMSb
64
0
j
CH
55
a
b
c
Purified trans isomer was used as the starting material.
In the product, R1 is H.
Tentatively identified by 1H NMR, IR, mass spectroscopy.
d
The number in parentheses is the yield using the purified cis isomer as the
starting material.
Cr(CO)5ÁTHF initially forms an alkyne-Cr(CO)5
p-complex with 11,
N
N
N
(Cr(CO)6 + THF)
Cr(CO)5 THF
H
O
11
12 (85%)
NOT OBSERVED
15
Cr(CO)5
C
N
N
Cr(CO)5
14
13
Scheme 3.

P. Roy, B. K. Ghorai / Tetrahedron Letters 52 (2011) 251–253
253
3. (a) Kohno, J.; Hiramatsu, H.; Nishio, M.; Sakurai, M.; Okuda, T.; Komatsubara, S.
Tetrahedron 1999, 55, 11247–11252; (b) Slack, G. J.; Puniani, E.; Frisvad, J. C.;
Samson, R. A.; Miller, J. D. Mycol. Res. 2009, 113, 480–490.
4. Xie, L.; Qian, X.; Cui, J.; Xiao, Y.; Wang, K.; Wu, P.; Cong, L. Bioorg. Med. Chem.
2008, 16, 8713–8718.
5. Dötz, K. H.; Tomuschat, P. Chem. Soc. Rev. 1999, 28, 187–198.
6. Bromoaldehydes 6 were prepared by the regioselective ortho-lithiation of 2-
bromopyridine/3-bromopyridine followed by quenching with DMF, according
to a literature procedure. Numata, A.; Kondo, Y.; Sakamoto, T. Synthesis 1999,
306–311.
7. For benzannulation through CO insertion, see: Zhang, Y.; Candelaria, D.;
Herndon, J. W. Tetrahedron Lett. 2005, 46, 2211–2214.
8. CO insertion is a minor reaction pathway during the coupling reaction of
ethynylstyrene derivatives with carbene complexes: (a) Jackson, T. J.; Herndon,
J. W. Tetrahedron 2001, 57, 3859–3868; (b) Zhang, L.; Herndon, J. W.
Organometallics 2004, 23, 1231–1235.
which gradually isomerizes to the vinylidene intermediate 13. 6p-
Electrocyclization of 13 gives a carbene intermediate 14, which is
readily converted to acridine (12) by 1,2-hydrogen migration with
the regeneration of Cr(CO)5ÁTHF.13
In conclusion, we have demonstrated a new route for the syn-
thesis of furo[2,3-h]quinoline and furo[2,3-h]isoquinoline deriva-
tives by the coupling of appropriate enyne derivatives with
Fischer carbene complexes. The reaction appears to be quite gen-
eral involving a simultaneous one-pot construction of both the fur-
an and benzene ring, which occurs in conjunction with the
formation of three carbon–carbon bonds and one carbon–oxygen
bond.
9. Zhang, J.; Zhang, Y.; Schnatter, W. F. K.; Herndon, J. W. Organometallics 2006, 25,
1279–1284.
Acknowledgements
10.
A typical procedure for coupling of enyne derivatives with Fischer carbene
complex: A 0.4 M solution of carbene complex 2 (201 mg, 0.80 mmol) in THF
was added dropwise over a period of 1 h to a refluxing 0.4 M solution of
enyne 8a (100 mg, 0.534 mmol) and PPh3 (140 mg, 0.534 mmol) in THF.
After the addition was complete, the mixture was heated to reflux for a
period of 20 h. The reaction mixture was allowed to cool to room
temperature and concentrated on a rotary evaporator. EtOAc (20 mL) was
added and the residue was filtered through Celite (1.0 g). After removal of
the solvent on a rotary evaporator, dichloromethane (10 mL) and sulfuric
acid (0.1 mL) were added and the solution was stirred at room temperature
for 5 h. Additional dichloromethane (20 mL) was added and was washed
with saturated aqueous NaHCO3 solution (3 mL). Evaporation of solvent and
purification by column chromatography (silica gel, ethyl acetate/petroleum
ether 3:7) afforded the pure product 9a (94 mg, 73% yield). Mp: 104 °C; IR
(neat, cmÀ1): 1721, 1705, 1618; 1H NMR (500 MHz, CDCl3): d 9.01 (dd, 1H,
J = 4.3, 1.7 Hz), 8.35 (s, 1H), 8.32 (dd, 1H, J = 8.2, 1.7 Hz), 7.45 (dd, 1H, J = 8.2,
4.3 Hz), 7.19 (d, 1H, J = 1.0 Hz), 4.07 (s, 3H), 2.65 (d, 3H, J = 1.0 Hz); 13C NMR
(125 MHz, CDCl3): d 165.1, 156.6, 151.7, 151.5, 144.5, 137.7, 127.6, 126.9,
124.1, 120.4, 116.2, 102.2, 52.5, 14.4; MS: m/e (relative intensity): 243
(MH++1, 15), 242 (MH+, 100); HRMS calcd for C14H12NO3 [M+H]+: 242.0817;
found: 242.0813.
Financial support from the CSIR [no. 01 (2215)/08-EMR-II], Gov-
ernment of India is gratefully acknowledged. We thank Gouranga
Prasad Jana for experimental assistance. We thank the CPIPL, Kolk-
ata and IICB, Kolkata for providing us NMR facility. The CSIR, New
Delhi, is also thanked for the award of Senior Research Fellowship
to P.R.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.044.
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