Synthesis of isoquinolines through the coupling of Fischer carbene complexes with o-alkynylpyridine carbonyl derivatives

Article abstract of DOI:10.1016/j.jorganchem.2009.08.019

The reaction of Fischer carbene complex with o-alkynylpyridine carbonyl derivatives has been investigated. This involves the generation of furo[3,4-c]pyridine as transient intermediates through the coupling of o-alkynylpyridine carbonyl derivatives with carbene complex and subsequent Diels-Alder trapping with suitable dienophiles resulted in the formation of isoquinoline derivatives and the entire sequence can be run in one pot. When an olefinic tether was present, intramolecular Diels-Alder cycloaddition occurred followed by ring opening to yield tricyclic alcohols.

Full text of DOI:10.1016/j.jorganchem.2009.08.019

Journal of Organometallic Chemistry 694 (2009) 4100–4106
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthesis of isoquinolines through the coupling of Fischer carbene complexes
with o-alkynylpyridine carbonyl derivatives
*
Soumita Mukherjee, Gouranga P. Jana, Binay K. Ghorai
Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah 711 103, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 June 2009
Received in revised form 10 August 2009
Accepted 12 August 2009
Available online 20 August 2009
The reaction of Fischer carbene complex with o-alkynylpyridine carbonyl derivatives has been investi-
gated. This involves the generation of furo[3,4-c]pyridine as transient intermediates through the coupling
of o-alkynylpyridine carbonyl derivatives with carbene complex and subsequent Diels–Alder trapping
with suitable dienophiles resulted in the formation of isoquinoline derivatives and the entire sequence
can be run in one pot. When an olefinic tether was present, intramolecular Diels–Alder cycloaddition
occurred followed by ring opening to yield tricyclic alcohols.
Keywords:
Fischer carbene
Isoquinoline
Ó 2009 Elsevier B.V. All rights reserved.
Azaisobenzofuran
Diels–Alder reaction
Heterolignan
1. Introduction
offer an incredible level of diversity for the production of diverse
structural entities from a few simple components. As part of our
Isoquinoline is an important heterocyclic template which pos-
sesses diverse biological activities owing to its presence in variety
of natural products [1] and pharmaceuticals [2–5]. Isoquinoline
species are also utilized as chiral ligands for transition metal cata-
lysts [6–9], and their iridium complexes are used in organic light-
emitting diodes [10–13]. Numerous elegant synthesis have been
developed for isoquinolines [14–34], however the exploration of
diversity-oriented synthetic routes for this class of compounds still
remains a challenge. One of the important pathways for synthesis
of these compounds involves the use of Diels–Alder reaction [27–
34]. The method depends critically on the availability of the appro-
priate dienes. Heterocyclic o-quinodimethanes and their stable
analogs have been utilized in this regard [32–36]. On the other
hand, the use of heteroaromatic isobenzofurans [37–39] as dienes
is emerging as a powerful alternative to the above method.
Furo[3,4-c]pyridine intermediate is one of the interesting member
of the heteroaromatic isobenzofurans and important building
block for the synthesis of isoquinoline derivatives such as hetero-
cyclic analogues of 1-arylnaphthalene lignans [32]. The generation
of this intermediate include (i) thermal retro Diels–Alder reaction
of 1,4-epoxides [40], (ii) lithiation and subsequent o-silylation of
pyridine–phthalides [41], (iii) the Hamaguchi–Ibata reaction of o-
aminodiazocarbonyl precursors [33,39], and (iv) sequential Pum-
merer–Diels–Alder route [32]. Multicomponent coupling reactions
continuing interest in the chemistry of azaisobenzofurans [42],
we wish to describe a multicomponent coupling approach to the
synthesis of isoquinoline derivatives by using Fischer carbene
chemistry. Our strategy towards isoquinoline synthesis is based
on the pioneering work of Herndon and coworkers [43–48] as out-
lined in Scheme 1. This involves the generation of furo[3,4-c]pyri-
dine as transient intermediates through the coupling of
o-alkynylpyridine carbonyl derivatives 1 with Fischer carbene
complex 2, and subsequent Diels–Alder trapping with suitable
dienophiles resulted in the formation of isoquinoline derivatives
5. The full details of our efforts in this area are described herein.
2. Results and discussion
Requisite alkynyl carbonyl derivatives 1 required for the syn-
thesis of isoquinolines were readily prepared from the commer-
cially available 3-bromo-4-pyridine carboxaldehyde (6) [49]
(Scheme 2). The Sonogashira coupling of 6 with trimethylsilylacet-
ylene afforded alkyne aldehyde 1a in 80% yield, which on treat-
ment with
a phenyl-Grignard reagent in diethyl ether and
subsequent oxidation with PDC gave the corresponding alkyne car-
bonyl derivative 1b in 60% yield.
In the first phase of the studies, tandem carbene–alkyne
coupling – furo[3,4-c]pyridine intermediate formation – intermo-
lecular Diels–Alder reactions were examined using N-methylmalei-
mide/N-phenylmaleimide as dienophile. Coupling of carbene
complex 2 with alkyne 1 in refluxing THF in presence of electron
* Corresponding author. Tel.: +91 33 26684561; fax: +91 33 26682916.
E-mail address: bkghorai@yahoo.co.in (B.K. Ghorai).
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.08.019

S. Mukherjee et al. / Journal of Organometallic Chemistry 694 (2009) 4100–4106
4101
Cr(CO)5
Cr(CO)5
R1
O
O
O
O
Me OMe
Me OMe
R1
R1
R1
2
2
N
Cr(CO)4
N
N
N
OMe
Me
OMe
Me
SiMe3
SiMe3
Me3Si
Me3Si
1
1
3
9
E1
E2
R1
Cr(CO)3
O
R1
O
N
N
Cr(CO)4
R1
R1
OMe
Me
OMe
Me
DBU or H3O+
H
E1
E2
O
Me3Si
Me3Si
10
E1
E2
O
N
N
11
H
O
Me
Me
O
5
4
NR2
O
R1
R1
1.
2.
O
O
H
Scheme 1.
O
N R2
N R2
O
N
N
H3O+
-H2O
H
O
O
O
Me
O
CHO
Br
CHO
N
a
b
Ph
SiMe3
Me
N
N
8
7
SiMe3
1b
1a
6
Scheme 3.
Scheme 2. Reagents and conditions: (a) trimethylsilylacetylene, (Ph3P)2PdCl2, PPh3,
CuI, THF, Et3N, rt, 80%; (b) (i) PhMgBr; (ii) CrO3, 2Py, 60%.
line derivative 8C on treatment with DBU in refluxing toluene
[42,52].
Formation of the products in Table 1 most likely occurs via the
reaction pathway in Scheme 3. Initial coupling affords the vinylcar-
bene complex 9, which undergoes ylide formation to afford the
azaisobenzofuran intermediate 11. The Diels–Alder reaction
should initially provide the bridged structure 7; however in most
of the examples tested this intermediate rapidly undergoes dehy-
dration to afford the isoquinoline ring systems 8 except the exam-
ple (entry C, Table 1). Compounds 8C and 8D may be viewed as
heterocyclic analogues of 1-arylnaphthalene lignans [32].
In the second phase of the studies for the synthesis of isoquin-
oline derivatives, the coupling of 3-trimethylsilylethynylpyridine-
deficient dienophiles led to the synthesis of isoquinoline deriva-
tives (see Table 1). This reaction pathway was general, and in all
cases this type of coupling led to the synthesis of isoquinoline
derivatives 8 through the tandem generation of azaisobenzofuran
intermediate and subsequent trapping with Diels–Alder dienophile
followed by acid/base catalyzed aromatization. In case of alkynyl
ketones 1b (entry C), in addition to isoquinoline derivative 8C, an
oxa-bridged adduct 7C was also isolated. The stereochemistry of
the oxa-bridge adduct is exo which can be anticipated from the
chemical shifts of Ha and Hb (<4 ppm) [43,50,51]. This oxa-bridged
adduct 7C can be readily converted to the corresponding isoquino-
Table 1
Synthesis of isoquinoline through tandem furo[3,4-c]pyridine formation – Diels–Alder reaction.
R1
O
R1
O
O
O
Ha
O
R1
Cr(CO)5
Me OMe
2
THF, reflux, 12 h
1.
N R2
N R2
O
NR2
O
+
+
+
N
N
N
2. H3O+
Hb
O
SiMe3
O
O
Me
Me
1a, R=H
1b, R=Ph
7
8
Entry
R1
R2
Yield 7a
Yield 8a
A
B
C
D
H
H
Ph
Ph
Ph
Me
Ph
–
–
20
–
44
41
40
52
Me
a
Isolated yield in %.

4102
S. Mukherjee et al. / Journal of Organometallic Chemistry 694 (2009) 4100–4106
O
THF, reflux, 12 h
1.
R1
CO2Me
CO2Me
Cr(CO)5
+
N
Me OMe
2. H3O+
SiMe3
2
1a, R=H
1b, R=Ph
R1
R1
R1
H
CO2Me
CO2Me
CO2Me
+
+
O
N
N
N
O
O
CO2Me
O
CO2Me
H
O
Me
Me
Me
14b, R1=Ph
13a, R1=H
13b, R1=Ph
12a, R1=H
12b, R1=Ph
Scheme 4.
4-carboxaldehyde (1a), methyl-carbene complex 2 and dimethyl-
maleate was tested (Scheme 4). In this reaction, initially formed
Diels–Alder adduct 12a is not stable under reaction conditions
and readily converted to the isoquinoline derivative 13a in 24%
yield. In the coupling of alkynyl ketones 1b with 2 and dimethyl-
maleate, oxa-bridged adduct 12b was isolated along with pyridine
fused isocoumarin derivative 14b. In this case, isoquinoline deriv-
ative 13b was not isolated; it readily converted into 14b under the
reaction condition. Treatment of the oxa-bridged adduct 12b with
DBU in refluxing toluene afforded isocoumarin derivative 14b in
45% yield, presumably via formation of isoquinoline derivative
13b, followed by enolate generation at the more acidic benzylic po-
sition [53]. Partial conversion of 12b to 14b also took place on
treatment with 10% aqueous hydrochloric acid.
In order to improve the yield of the products by the one-pot
coupling reaction process, we have studied the coupling reaction
of alkynyl aldehyde 1a, carbene complex 2 and N-phenylmaleim-
ide under two different conditions: (i) under refluxing dioxane
and (ii) by separate and simultaneous addition of the carbene com-
plex and dienophile to the refluxing solution of the alkynyl alde-
hyde 1a in THF. In the first case the yield of the product was
slightly improved from 44% to 49%. No improvement of yield was
observed in the later case.
H
H
O
O
H
H
N
N
Me3Si
Me3Si
17a'
OMe
OMe
17a
-45.20 kcal/mol
Ph
-52.67 kcal/mol
Ph
O
O
H
H
N
N
Me3Si
Me3Si
17b'
-16.88 kcal/mol
OMe
OMe
17b
-23.74 kcal/mol
Fig. 1. Heats of formation for compounds 17a, 17a0, 17b, 17b0.
(Scheme 5). Formation of 18 likely occurs via the desired reaction
pathway involving formation of furo[3,4-c]pyridines 16, followed
by intramolecular Diels–Alder reaction and subsequent ring open-
ing of the strained oxanorbornene system.
Six-membered-ring-forming intramolecular Diels–Alder reac-
tions of isobenzofurans normally proceed with exo stereochemistry
[50,55–58]. Comparison of energies calculated using the PM3
semi-empirical single point molecular orbital method with
10 ꢀ 10 configuration space for the most stable conformations
(MM+ optimize followed by PM3 optimizations) of exo and endo
Diels–Alder adducts reveals that the exo products are the most sta-
The final phase of these studies involve the use of c,d-unsatu-
rated Fischer carbene complex 15 [54], in order to establish the
feasibility of an intramolecular Diels–Alder cycloaddition in the
furo[3,4-c]pyridines. The coupling of alkynyl carbonyl derivatives
1 with carbene complex 15 afforded tricyclic products 18 in one
pot. In these cases, the only product was an oxanorbornene ring
opening product 18 and not the initial Diels–Alder adduct 17
Cr(CO)5
R1
R1
O
R1
O
OMe
R1 OH
15
THF, reflux
O
H
H
N
N
Me3Si
N
N
SiMe3
Me3Si
Me3Si
OMe
OMe
O
1
16
18a, R1=H (44%)
17
18b, R1=Ph (54%)
Scheme 5.

S. Mukherjee et al. / Journal of Organometallic Chemistry 694 (2009) 4100–4106
4103
ble products in both cases (Fig. 1). Calculation shows that 17a is
more stable than 17a0 by 7.47 kcal/mol and 17b is more stable than
17b0 by 6.86 kcal/mol.
(15 mL) for 1.5 h at room temperature] and stirred at room tem-
perature for 4 h. The mixture was then diluted with Et2O (15 mL)
and passed through a bed of silica gel (10 g). After evaporation of
the solvent, the crude product was purified by column chromatog-
raphy (silica gel, ethyl acetate/petroleum ether, 1:9) to give ketone
1b (450 mg, 60%) as colourless thick liquid. Rf (10% EtOAc/petro-
leum ether) 0.42; IR (CHCl3, cmꢁ1): 2162, 1672; 1H NMR
(500 MHz, CDCl3): d 8.77 (s, 1H), 8.67 (d, 1H, J = 4.80 Hz), 7.79 (d,
2H, J = 7.5 Hz), 7.61 (t, 1H, J = 7.5 Hz), 7.47 (t, 2H, J = 7.5 Hz), 7.34
(d, 1H, J = 4.80 Hz), -0.05 (s, 9H); 13C NMR (125 MHz, CDCl3): d
194.8, 153.1, 148.9, 148.8, 135.8, 133.8, 130.0 (2C), 128.5 (2C),
121.2, 117.4, 104.4, 98.92, -0.75 (3C); MS: m/e (relative intensity):
281(MH++1, 28), 280 (MH+, 100); Anal. Calc. for C17H17NOSi: C,
73.08; H, 6.13; N, 5.01. Found: C, 72.85; H, 6.31; N, 4.83%.
3. Conclusion
The results presented herein demonstrate the potential of the
tandem carbene–alkyne coupling – furo[3,4-c]pyridine intermedi-
ate formation – inter/intramolecular Diels–Alder sequence leading
to the synthesis of isoquinoline derivatives in one pot. Our results
clearly indicate that the tandem-cascade process provides a rapid
entry into heteroaromatic azaisobenzofurans. This area of research
is currently being pursued in more detail in our laboratory.
4. Experimental
4.4. General procedure 1 – coupling of carbene complex with alkynyl
pyridine carbonyl derivatives and maleimides/dimethylmaleate
4.1. General
A solution of carbene complex 2 (1.1 mmol) in THF (10 mL) was
added dropwise to a refluxing solution of alkynyl carbonyl deriva-
tives 1 (1 mmol) and maleimide/dimethylmaleate (1.1 mmol) in
THF (5 mL) over a period of 1 h. After the addition was complete,
the mixture was heated to reflux for a period of 12 h. The mixture
was allowed to cool to room temperature. After removal of the sol-
vent, EtOAc (20 mL) was added and the residue was filtered
through Celite (1.0 g). The solvent was removed, and the crude
products were dissolved in ether (20 mL). To this solution of crude
product in ether was added aqueous HCl (1:1) (0.5 mL) and the
mixture was stirred for 6 h at room temperature. The organic layer
was separated. The aqueous layer was neutralized with saturated
NaHCO3 solution (3 mL) and extracted with ethyl acetate
(3 ꢀ 10 mL). The combined organic layer (diethyl ether layer and
ethyl acetate layer) was washed with water (3 mL) and brine
(3 mL), and dried over anhydrous Na2SO4. Evaporation of solvent
and purification by column chromatography gave the pure
products.
All melting points are uncorrected. Unless otherwise noted, all
reactions were carried out under an inert atmosphere in flame
dried flasks. Solvents and reagents were dried and purified by dis-
tillation before use as follows: tetrahydrofuran, diethyl ether from
sodium benzophenone ketyl; dichloromethane and chloroform
from P2O5; DMF and diisopropylamine from CaH2; triethylamine
and pyridine from solid KOH. After drying, organic extracts were
evaporated under reduced pressure and the residue was column
chromatographed on silica gel (Spectrochem, particle size 100–
200 mesh), using an ethyl acetate–petroleum ether (60–80 °C)
mixture as eluent unless specified otherwise.
4.2. 3-Trimethylsilylethynylpyridine-4-carboxaldehyde (1a) [49]
A
mixture of 3-bromo-4-carboxaldehyde (6) (600 mg,
3.2 mmol), Pd(PPh3)2Cl2 (115 mg, 0.16 mmol), PPh3 (21 mg,
0.08 mmol), trimethylsilylacetylene (475 mg, 4.8 mmol) and tri-
ethylamine (490 mg, 4.8 mmol) in THF (15 mL) was stirred for
20 min at room temperature, and then CuI (10 mg, 0.05 mmol)
was added. The reaction mixture was stirred for 14 h at room tem-
perature. After removal of the solvent, the residue was treated with
dichloromethane and filtered through a bed of Celite (2.0 g). After
evaporation of the solvent, the crude product was purified by col-
umn chromatography (silica gel, ethyl acetate/petroleum ether,
1:9) to yield aldehyde 1a (525 mg, 80%) as low melting solid. IR
(neat, cmꢁ1): 2853, 2156, 1710; 1H NMR (500 MHz, CDCl3): d
10.50 (s, 1H), 8.86 (s, 1H), 8.69 (d, 1H, J = 5.0 Hz), 7.65 (d, 1H,
J = 5.0 Hz), 0.28 (s, 9H); 13C NMR (125 MHz, CDCl3): d 190.7,
154.8, 149.4, 140.8, 121.1, 118.8, 105.9, 96.8, ꢁ0.60 (3C); MS: m/
e (relative intensity): 204 (MH+, 100), 176 (7).
4.4.1. Coupling of carbene complex 2 with 3-
trimethylsilylethynylpyridine-4-carboxaldehyde (1a) and N-
phenylmaleimide (Table 1, entry A)
General procedure 1 was followed using alkynyl aldehyde 1a
(150 mg, 0.74 mmol), carbene complex 2 (202 mg, 0.81 mmol)
and N-phenylmaleimide (141 mg, 0.81 mmol). The crude product
was purified using column chromatography (silica gel, ethyl ace-
tate/petroleum ether 2:3) to yield the isoquinoline derivative 8A
(107 mg, 44%) as white solids. Mp 210–212 °C (decomposed); Rf
(50% EtOAc/petroleum ether) 0.24; IR (KBr, cmꢁ1): 1765, 1708;
1H NMR (400 MHz, CDCl3): d 9.98 (s, 1H), 8.76 (d, 1H, J = 5.6 Hz),
8.59 (s, 1H), 8.44 (d, 1H, J = 5.6 Hz), 7.65–7.40 (m, 5H), 5.16 (s,
2H), 2.55 (s, 3H); 13C NMR (125 MHz, CDCl3): d 203.4, 167.1,
165.7, 150.5, 146.2, 138.7, 134.7, 131.3, 131.1, 129.8, 129.2 (2C),
128.5, 126.6 (2C), 125.6, 123.2, 122.6, 41.1, 30.4; MS: m/e (relative
intensity): 331 (MH+, 100), 289 (14); HRMS: Anal. Calc. for
C20H15N2O3 (MH+): 331.1083. Found: 331.1078.
4.3. Phenyl-(3-trimethylsilylethynylpyridine-4-yl)methanone (1b)
A solution of phenylmagnesium bromide (0.6 M, 5 mL, 3 mmol)
in diethyl ether [prepared from bromobenzene (650 mg, 4.2 mmol)
and magnesium (120 mg, 5 mmol) in 15 mL diethyl ether] was
added dropwise to a stirred solution of aldehyde 1a (550 mg,
2.7 mmol) in diethyl ether (10 mL) over a period of 20 min at
0 °C. After 3 h stirring the mixture was allowed to come at room
temperature and then quenched with saturated aqueous NH4Cl
(5 mL). The organic layer was separated and the aqueous layer
was extracted with diethyl ether (3 ꢀ 10 mL). The combined or-
ganic layer was washed with brine (5 mL) and dried over anhy-
drous Na2SO4. After removal of the solvent, the crude alcohol
was dissolved in dry CH2Cl2 (5 mL) and added to a red solution
of CrO3ꢂ2Py [prepared from vigorously stirred suspension of CrO3
(800 mg, 8 mmol) and pyridine (1.26 g, 16 mmol) in CH2Cl2
4.4.2. Coupling of carbene complex 2 with 3-
trimethylsilylethynylpyridine-4-carboxaldehyde (1a) and N-
methylmaleimide (Table 1, entry B)
General procedure 1 was followed using alkynyl aldehyde 1a
(150 mg, 0.74 mmol), carbene complex 2 (202 mg, 0.81 mmol)
and N-methylmaleimide (90 mg, 0.81 mmol). The crude product
was purified using column chromatography (silica gel, ethyl ace-
tate/petroleum ether 1:1) to yield the isoquinoline derivative 8B
(81 mg, 41%) as white solids. Mp 160–162 °C (decomposed); Rf
(50% EtOAc/petroleum ether) 0.21; IR (KBr, cmꢁ1): 1762, 1705;
1H NMR (500 MHz, CDCl3): d 9.46 (s, 1H), 8.75 (d, 1H, J = 5.5 Hz),

4104
S. Mukherjee et al. / Journal of Organometallic Chemistry 694 (2009) 4100–4106
8.25 (s, 1H), 7.86 (d, 1H, J = 5.6 Hz), 4.92 (s, 2H), 3.24 (s, 3H), 2.45 (s,
3H); 13C NMR (125 MHz, CDCl3): d 203.4, 168.1, 166.8, 150.4, 146.0,
138.6, 133.8, 131.5, 129.5, 126.2, 122.7, 122.5, 41.1, 30.3, 24.3; MS:
m/e (relative intensity): 269 (MH+, 100), 242 (5); Anal. Calc. for
C15H12N2O3: C, 67.16; H, 4.51; N, 10.44. Found: C, 66.96; H, 4.59;
N, 10.39%.
(s, 1H), 8.70 (d, 1H, J = 5.5 Hz), 8.45 (s, 1H), 7.77 (d, 1H,
J = 5.5 Hz), 4.31 (s, 2H), 3.97 (s, 6H), 2.32 (s, 3H); 13C NMR
(125 MHz, CDCl3): d 203.6, 168.8, 165.8, 149.7, 144.9, 135.5,
131.4, 129.9, 129.8, 128.5, 128.2, 121.5, 53.0 (2C), 43.8, 29.7; MS:
m/e (relative intensity): 303 (MH++1, 18), 302 (MH+, 100), 286
(25), 279 (15), 270 (15); Anal. Calc. for C16H15NO5: C, 63.78; H,
5.02; N, 4.65. Found: C, 63.45; H, 5.19; N, 4.76%.
4.4.3. Coupling of carbene complex 2 with phenyl-(3-
trimethylsilylethynylpyridine-4-yl)methanone (1b) and N-
4.4.6. Coupling of carbene complex 2 with phenyl-(3-
phenylmaleimide (Table 1, entry C)
trimethylsilylethynylpyridine-4-yl)methanone (1b) and dimethyl
maleate (Scheme 4)
General procedure 1 was followed using alkynyl ketone 1b
(150 mg, 0.54 mmol), carbene complex 2 (148 mg, 0.59 mmol)
and N-phenylmaleimide (103 mg, 0.59 mmol). The crude product
was purified using column chromatography (silica gel, ethyl ace-
tate/petroleum ether 2:3) to yield the isoquinoline derivative 8C
(87 mg, 40%) as gummy solid and the oxa-bridged compound 7C
(45 mg, 20%) as yellowish thick liquid. Compound 8C: Rf (50%
EtOAc/petroleum ether) 0.58; IR (KBr, cmꢁ1): 1768, 1714; 1H
NMR (300 MHz, CDCl3): d 9.57 (s, 1H), 8.70 (bs, 1H), 7.80–7.00
(m, 11H), 5.06 (s, 2H), 2.51 (s, 3H); 13C NMR (75 MHz, CDCl3): d
203.8, 167.0, 165.2, 139.1, 133.8, 132.9, 131.3, 129.8 (2C), 129.2,
129.0 (3C), 128.8, 128.6, 128.4 (3C), 126.8, 126.5 (2C), 126.4,
126.0, 125.9, 41.0, 28.4; FABMS: m/e (relative intensity): 407
(MH+, 35), 107 (100); HRMS: Anal. Calc. for C26H19N2O3 (MH+):
407.1396. Found: 407.1396. Compound 7C: Rf (50% EtOAc/petro-
leum ether) 0.39; IR (CHCl3, cmꢁ1): 1778, 1713; 1H NMR
(400 MHz, CDCl3): d 8.64 (s, 1H), 8.53 (bs, 1H), 7.60 (d, 2H,
J = 7.6 Hz), 7.50 (t, 2H, J = 7.6 Hz), 7.46–7.30 (m, 4H), 7.16 (d, 1H,
J = 4.4 Hz), 7.12 (d, 2H, J = 7.6 Hz), 3.77 (d, 1H, J = 6.8 Hz), 3.71 (d,
1H, J = 18.0 Hz), 3.50 (d, 1H, J = 18.0 Hz), 3.49 (d, 1H, J = 6.8 Hz),
2.45 (s, 3H); 13C NMR (75 MHz, CDCl3): d 204.9, 173.5, 171.7,
156.0, 149.3, 142.5, 132.3, 131.4, 129.2 (2C), 129.0, 128.7 (2C),
128.5 (2C), 126.4, 126.2 (2C), 125.7 (2C), 90.6, 86.0, 52.3, 50.8,
44.7, 30.6; FABMS: m/e (relative intensity): 425 (MH+, 72), 252
(100), 208 (38); Anal. Calc. for C26H20N2O4: C, 73.57; H, 4.75; N,
6.60. Found: C, 73.23; H, 4.87; N, 6.42%.
General procedure 1 was followed using alkynyl ketone 1b
(178 mg, 0.64 mmol), carbene complex 2 (175 mg, 0.7 mmol) and
dimethyl maleate (100 mg, 0.7 mmol). The crude product was puri-
fied using column chromatography (silica gel, ethyl acetate/petro-
leum ether 1:1) to yield the oxa-bridged compound 12b (63 mg,
25%) as gummy yellow solids and isoquinoline–lactone 14b
(65 mg, 30%) as a yellow solid. Compound 12b: Rf (50% EtOAc/
petroleum ether) 0.31; IR (KBr, cmꢁ1): 1734; 1H NMR (500 MHz,
CDCl3): d 8.60 (s, 1H), 8.50 (d, 1H, J = 4.8 Hz), 7.69–7.62 (m, 2H),
7.50–7.40 (m, 3H), 7.06 (d, 1H, J = 4.8 Hz), 4.25 (d, 1H, J = 4.6 Hz),
3.75 (s, 3H); 3.55 (d, 1H, J = 17.6 Hz), 3.50 (d, 1H, J = 4.6 Hz), 3.49
(s, 3H), 3.33 (d, 1H, J = 17.6 Hz), 2.30 (s, 3H); 13C NMR (125 MHz,
CDCl3): d 203.7, 172.6, 172.3, 162.5, 153.3, 145.5, 140.7, 128.5
(2C), 128.2, 126.5, 126.2 (2C), 121.2, 99.5, 77.2, 53.0, 52.4, 50.3,
47.6, 44.4, 20.3; MS: m/e (relative intensity): 396 (MH+, 37), 378
(MH+-H2O, 7), 252 (100), 209 (14); Anal. Calc. for C22H21NO6: C,
66.83; H, 5.35; N, 3.54. Found: C, 66.57; H, 5.51; N, 3.34%. Com-
pound 14b: Mp 112 °C; Rf (50% EtOAc/petroleum ether) 0.51; IR
(KBr, cmꢁ1): 1744, 1643; 1H NMR (500 MHz, CDCl3): d 9.76 (s,
1H), 8.68 (d, 1H, J = 6.0 Hz), 7.53–7.45 (m, 3H), 7.42 (d, 1H,
J = 6.0 Hz), 7.38–7.28 (m, 2H), 7.23 (s, 1H), 3.68 (s, 3H), 2.48 (s,
3H); 13C NMR (125 MHz, CDCl3): d 167.9, 160.6, 158.9, 148.6,
147.5, 138.5, 137.9, 136.3, 134.6, 134.5, 130.1, 129.0, 128.7, 128.4
(2C), 122.0, 119.9, 113.9, 98.1, 52.6, 20.3; MS: m/e (relative inten-
sity): 346 (MH+, 100), 320 (80), 252 (60); Anal. Calc. for C21H15NO4:
C, 73.03; H, 4.38; N, 4.06. Found: C, 73.36; H, 4.11; N, 4.23%.
4.4.4. Coupling of carbene complex 2 with phenyl-(3-
trimethylsilylethynylpyridine-4-yl)methanone (1b) and N-
methylmaleimide (Table 1, entry D)
4.4.7. Coupling of carbene complex 2 with 3-
trimethylsilylethynylpyridine-4-carboxaldehyde (1a) and N-
phenylmaleimide
General procedure 1 was followed using alkynyl aldehyde 1a
(100 mg, 0.49 mmol) carbene complex 2 (135 mg, 0.54 mmol)
and N-phenylmaleimide (93 mg, 0.54 mmol) with the exception
that the reaction was carried out in refluxing dioxane instead of
THF. The crude product was purified using column chromatogra-
phy (silica gel, ethyl acetate/petroleum ether 2:3) to give the iso-
quinoline derivative 8A (78 mg, 49%).
General procedure 1 was followed using alkynyl ketone 1b
(150 mg, 0.54 mmol), carbene complex 2 (148 mg, 0.59 mmol)
and N-methylmaleimide (65 mg, 0.59 mmol). The crude product
was purified using column chromatography (silica gel, ethyl ace-
tate/petroleum ether 2:3) to yield the isoquinoline derivative 8D
(96 mg, 52%) as yellowish thick liquid. Rf (50% EtOAc/petroleum
ether) 0.50; IR (CHCl3, cmꢁ1): 1762, 1704; 1H NMR (400 MHz,
CDCl3): d 9.48 (s, 1H), 8.65 (d, 1H, J = 5.0 Hz), 7.60 (d, 1H,
J = 5.0 Hz), 7.59–7.50 (m, 3H), 7.40–7.30 (m, 2H), 4.99 (s, 2H),
3.13 (s, 3H), 2.49 (s, 3H); 13C NMR (125 MHz, CDCl3): d 203.8,
168.0, 166.3, 150.1, 146.1, 139.0, 138.3, 132.9, 132.8, 129.8 (3C),
128.9, 128.4 (3C), 127.1, 126.1, 41.0, 30.3, 24.1; MS: m/e (relative
intensity): 346 (MH++1, 20), 345 (MH+, 100), 301 (20), 294 (25),
163 (30); HRMS: Anal. Calc. for C21H17N2O3 (MH+): 345.1239.
Found: 345.1232.
4.4.8. Coupling of carbene complex 2 with 3-
trimethylsilylethynylpyridine-4-carboxaldehyde (1a) and N-
phenylmaleimide
General procedure 1 was followed using alkynyl aldehyde 1a
(100 mg, 0.49 mmol) carbene complex 2 (135 mg, 0.54 mmol)
and N-phenylmaleimide (93 mg, 0.54 mmol), but in this case the
carbene and dienophile were added separately and simultaneously
to the aldehyde in refluxing THF. The crude product obtained after
acid treatment was purified using column chromatography (silica
gel, ethyl acetate/petroleum ether 2:3) which gave the isoquinoline
derivative 8A (72 mg, 45%).
4.4.5. Coupling of carbene complex 2 with 3-
trimethylsilylethynylpyridine-4-carboxaldehyde (1a) and dimethyl
maleate (Scheme 4)
General procedure 1 was followed using alkynyl aldehyde 1a
(150 mg, 0.74 mmol) carbene complex 2, (202 mg, 0.81 mmol)
and dimethyl maleate (116 mg, 0.81 mmol). The crude product
was purified using column chromatography (silica gel, ethyl ace-
tate/petroleum ether 1:1) to yield the isoquinoline derivative 13a
(53 mg, 24%) as thick liquid. Rf (50% EtOAc/petroleum ether)
0.42; IR (CHCl3, cmꢁ1): 1730; 1H NMR (500 MHz, CDCl3): d 9.39
4.5. Methyl 3-methyl-1-oxo-9-phenyl-1H-2-oxa-6-azaphenanthrene-
10-carboxylate (14b)
To a stirred solution of oxa-bridged compound 12b (50 mg,
0.13 mmol) in toluene (1 mL), DBU (198 mg, 1.3 mmol) was added

S. Mukherjee et al. / Journal of Organometallic Chemistry 694 (2009) 4100–4106
4105
[3] U.R. Mach, A.E. Hackling, S. Perachon, S. Ferry, C.G. Wermuth, J.-C. Schwartz, P.
Sokoloff, H. Stark, ChemBioChem. 5 (2004) 508–518.
[4] D.E. Muscarella, K.A. O’Brian, A.T. Lemley, S.E. Bloom, Toxicol. Sci. 74 (2003)
66–73.
[5] F. Dzierszinski, A. Coppin, M. Mortuaire, E. Dewally, C. Slomianny, J.-C.
Ameisen, F. Debels, S. Tomavo, Antimicrob. Agents Chemother. 46 (2002)
3197–3207.
dropwise at room temperature. The mixture was heated at reflux
for 1.5 h. After cooling to room temperature, the mixture was
washed with 10% aqueous HCl (1 mL) and dried over anhydrous
Na2SO4. After evaporation of the solvent, the crude product was
purified by column chromatography (silica gel, ethyl acetate/petro-
leum ether, 1:1) to give lactone 14b (20 mg, 45%) as yellow solid.
[6] F. Durola, J.-P. Sauvage, O.S. Wenger, Chem. Commun. (2006)
171–173.
[7] B.A. Sweetman, H. Müller-Bunz, P.J. Guiry, Tetrahedron Lett. 46 (2005) 4643–
4646.
[8] C.W. Lim, O. Tissot, A. Mattison, M.W. Hooper, J.M. Brown, A.R. Cowley, D.I.
Hulmes, A.J. Blacker, Org. Process Res. Dev. 7 (2003) 379–384.
[9] N.W. Alcock, J.M. Brown, G.I. Hulmes, Tetrahedron: Asymmetry 4 (1993) 743–
756.
4.6. 5-Hydroxy-10-trimethylsilyl-5,6,7,8-tetrahydro-6aH-
benzo[h]isoquinoline-9-one (18a)
To a solution of alkynyl aldehyde 1a (162 mg, 0.8 mmol) in THF
(4 mL) at reflux was added a solution of c,d-unsaturated carbene
[10] K.-H. Fang, L.-L. Wu, Y.-T. Huang, C.-H. Yang, I.-W. Sun, Inorg. Chim. Acta 359
(2006) 441–450.
complex 15 [54] (255 mg, 0.88 mmol) in THF (10 mL) over a period
of 1 h. After the addition was complete, the mixture was heated at
reflux for 18 h. The reaction mixture was cooled to room tempera-
ture. The THF was removed under reduced pressure, ethyl acetate
(10 mL) was added and the residue was filtered through Celite
(1.0 g). After evaporation of the solvent, the crude product was
purified by column chromatography (silica gel, ethyl acetate/petro-
leum ether, 1:1) to yield a white solid alcohol 18a (100 mg, 44%).
Mp 122 °C; Rf (50% EtOAc/petroleum ether) 0.26; IR (KBr, cmꢁ1):
3442, 1632; 1H NMR (500 MHz, CDCl3): d 8.63 (d, 1H, J = 5.0 Hz),
8.55 (s, 1H), 7.46 (d, 1H, J = 5.0 Hz), 4.97 (dd, 1H, J = 8.5, 5.0 Hz),
2.69 (m, 1H), 2.50 (ddd, 1H, J = 17.1, 3.8, 3.0 Hz), 2.42 (dt, 1H,
J = 13.2, 5.2 Hz), 2.32 (ddd, 1H, J = 17.1, 15.0, 5.0 Hz), 2.17 (m,
1H), 1.85–1.70 (m, 2H), 1.65 (bs, 1H), 0.10 (s, 9H); 13C NMR
(125 MHz, CDCl3): d 202.7, 164.5, 151.4, 150.5, 149.1, 139.3,
131.2, 121.1, 68.1, 41.0, 38.3, 36.8, 28.7, 1.6 (3C); MS: m/e (relative
intensity): 288 (MH+, 17), 258 (20), 220 (16), 188 (100); HRMS:
Anal. Calc. for C16H22NO2Si (MH+): 288.1420. Found: 288.1416.
[11] S.-J. Liu, Q. Zhao, R.-F. Chen, Y. Deng, Q.-L. Fan, F.-Y. Li, L.-H. Wang, C.-H. Huang,
W. Huang, Chem. Eur. J. 12 (2006) 4351–4361.
[12] Q. Zhao, S. Liu, M. Shi, C. Wang, M. Yu, L. Li, F. Li, T. Yi, C. Huang, Inorg. Chem. 45
(2006) 6152–6160.
[13] A. Tsuboyama, H. Iwawaki, M. Furugori, T. Mukaide, J. Kamatani, S. Igawa, T.
Moriyama, S. Miura, T. Takiguchi, S. Okada, M. Hoshino, K. Ueno, J. Am. Chem.
Soc. 125 (2003) 12971–12979.
[14] M. Balasubramanian, J.G. Keay, Isoquinoline Synthesis, in: A.E. McKillop, A.R.
Katrizky, C.W. Rees, E.F.V. Scrivem (Eds.), In Comprehensive Heterocyclic
Chemistry II, vol. 5, Elsevier, Oxford, 1996, pp. 245–300.
[15] For a review on the synthesis of isoquinoline alkaloid, see: M. Chrzanowska,
M.D. Rozwadowska, Chem. Rev. 104 (2004) 3341–3370.
[16] Z. Huo, Y. Yamamoto, Tetrahedron Lett. 50 (2009) 3651–3653.
[17] Y.-N. Niu, Z.-Y. Yan, G.-L. Gao, H.-L. Wang, X.-Z. Shu, K.-G. Ji, Y.-M. Liang, J. Org.
Chem. 74 (2009) 2893–2896.
[18] Y.-Y. Yang, W.-G. Shou, Z.-B. Chen, D. Hong, Y.-G. Wang, J. Org. Chem. 73 (2008)
3928–3930.
[19] D. Fischer, H. Tomeba, N.K. Pahadi, N.T. Patil, Z. Huo, Y. Yamamoto, J. Am.
Chem. Soc. 130 (2008) 15720–15725.
[20] M. Movassaghi, M.D. Hill, Org. Lett. 10 (2008) 3485–3488.
[21] T. Blackburn, Y.K. Ramtohul, Synlett 8 (2008) 1159–1164.
[22] G. Pandey, M. Balakrishnan, J. Org. Chem. 73 (2008) 8128–8131.
[23] S. Su, J.A. Porco, Org. Lett. 9 (2007) 4983–4986.
[24] M. Mori, H. Wakamatsu, K. Tonogaki, R. Fujita, T. Kitamura, Y. Sato, J. Org.
Chem. 70 (2005) 1066–1069.
4.7. 5-Hydroxy-5-phenyl-10-trimethylsilyl-5,6,7,8-tetrahydro-6aH-
benzo[h]isoquinoline-9-one (18b)
[25] Z. Xiang, T. Luo, K. Lu, J. Cui, X. Shi, R. Fathi, J. Chen, Z. Yang, Org. Lett. 6 (2004)
3155–3158.
[26] Q. Huang, R.C. Larock, J. Org. Chem. 68 (2003) 980–988.
[27] B.K. Ghorai, S. Duan, D. Jiang, Synthesis (2006) 3661–3669.
[28] F. Palacios, C. Alonso, M. Rodríguez, E.M. de Marigorta, G. Rubiales, Eur. J. Org.
Chem. (2005) 1795–1804.
The procedure described for 18a was employed using alkynyl
ketone 1b (140 mg, 0.5 mmol) and c,d-unsaturated carbene com-
[29] F. Palacios, C. Alonso, G. Rubiales, M. Villegas, Tetrahedron 61 (2005) 2779–
2794.
[30] P.R. Carly, S.L. Cappelle, F. Compernolle, G.J. Hoornaert, Tetrahedron 52 (1996)
11889–11904.
[31] J.A.R. Rodrigues, G.C. Leiva, J.D.F. de Sousa, Tetrahedron Lett. 36 (1995)
59–62.
[32] T.K. Sarkar, N. Panda, S. Basak, J. Org. Chem. 68 (2003) 6919–6927.
[33] P.R. Carly, T.C. Govaerts, S.L. Cappelle, F. Compernolle, G.J. Hoornaert,
Tetrahedron 57 (2001) 4203–4212.
[34] T.K. Sarkar, S.K. Ghosh, T.J. Chow, J. Org. Chem. 65 (2000) 3111–3115.
[35] T.K. Sarkar, S. Basak, I. Wainer, R. Moaddel, R. Yamaguchi, K. Jozwiak, H.-T.
Chen, C.-C. Lin, J. Med. Chem. 47 (2004) 6691–6701.
[36] For reviews, see: T.-S. Chou, Rev. Heteroat. Chem. 8 (1993) 65–104.
[37] For a review on heteroisobenzofurans, see: S. Basak, S.K. Ghosh, T.K. Sarkar, J.
Indian Inst. Sci. 81 (2001) 431–452.
[38] A. Padwa, Chem. Commun. (1998) 1417–1424.
[39] T.K. Sarkar, S. Basak, Z. Slanina, T.J. Chow, J. Org. Chem. 68 (2003)
4206–4214.
plex 15 (160 mg, 0.55 mmol). Purification was effected by column
chromatography (silica gel, ethyl acetate/petroleum ether 4:6) to
yield the alcohol 18b (98 mg, 54%) as a white solid. Mp 168–
169 °C; Rf (30% EtOAc/petroleum ether) 0.42; IR (KBr, cmꢁ1):
3426, 1659; 1H NMR (400 MHz, CDCl3): d 8.64 (s, 1H), 8.59 (d,
1H, J = 5.2 Hz), 7.38–7.28 (m,3H), 7.20–7.13 (m, 2H), 7.11(d, 1H,
J = 5.2 Hz), 2.63 (m, 1H), 2.5 (bs, 1H, exchangeable with D2O),
2.52–2.40 (m, 2H), 2.28 (m, 1H), 2.11 (dd, 1H, J = 13.2, 9.6 Hz),
2.00 (m, 1H), 1.72 (m, 1H), 0.12 (s, 9H); 13C NMR (125 MHz, CDCl3):
d 202.8, 164.6, 152.1, 151.4, 150.1, 145.1, 139.7, 131.9, 128.4 (2C),
127.9, 126.2 (2C), 121.5, 75.2, 48.0, 37.1, 37.0, 28.9, 1.6 (3C); MS:
m/e (relative intensity): 364 (MH+, 30), 284 (100); HRMS: Anal.
Calc. for C22H26NO2Si (MH+): 364.1733. Found: 364.1728.
[40] U.E. Wiersum, C.D. Eldred, P. Vrijhof, H.C. Ven der Plas, Tetrahedron Lett. 18
(1977) 1741–1742.
Acknowledgements
[41] M. Iwao, H. Inoue, T. Kuraishi, Chem. Lett. 13 (1984) 1263–1266.
[42] G.P. Jana, B.K. Ghorai, Tetrahedron 63 (2007) 12015–12025.
[43] D. Jiang, J.W. Herndon, Y.-F. Lam, Org. Lett. 2 (2000) 1267–1269.
[44] B.K. Ghorai, J.W. Herndon, Org. Lett. 3 (2001) 3535–3538.
[45] Y. Luo, J.W. Herndon, F. Cervantes-Lee, J. Am. Chem. Soc. 125 (2003) 12720–
12721.
[46] B.K. Ghorai, J.W. Herndon, Organometallics 22 (2003) 3951–3957.
[47] A. Camacho-Davila, J.W. Herndon, J. Org. Chem. 71 (2006) 6682–6685.
[48] Y. Chen, S. Ye, L. Jiao, Y. Liang, D.K. Sinha-Mahapatra, J.W. Herndon, Z.-X. Yu, J.
Am. Chem. Soc. 129 (2007) 10773–10784.
Financial support from CSIR
[No. 01 (2215)/08-EMR-II],
Government of India is gratefully acknowledged. The UGC, New
Delhi, is also thanked for the award of Junior Research Fellowship
to S.M. We are also thankful to CPIPL, Kolkata; IICB, Kolkata for
providing us NMR facility and Professor S.K. Chattopadhyay,
Department of Chemistry, BESUS for his assistance in PM3
calculations.
[49] Compound
bromopyridine with LDA at ꢁ78 °C followed by quenching with DMF,
according to literature procedure. A. Numata, Y. Kondo, T. Sakamoto,
6 was prepared by the regioselective ortho-lithiation of 3-
a
References
Synthesis (1999) 306–311.
[50] D. Tobia, B. Rickborn, J. Org. Chem. 52 (1987) 2611–2615.
[51] A.D. Payne, D. Wege, Org. Biomol. Chem. 1 (2003) 2383–2387.
[52] T.K. Sarkar, S. Basak, N. Panda, Tetrahedron Lett. 43 (2002) 1341–1344.
[1] K.W. Bentley, The Isoquinoline Alkaloids, vol. 1, Hardwood Academic,
Amsterdam, 1998.
[2] D. Kletsas, W. Li, Z. Han, V. Papadopoulos, Biochem. Pharmacol. 67 (2004)
1927–1932.

4106
S. Mukherjee et al. / Journal of Organometallic Chemistry 694 (2009) 4100–4106
[53] S. Duan, D.K. Sinha-Mahapatra, J.W. Herndon, Org. Lett. 10 (2008) 1541–
1544.
[56] Y. Yamaguchi, H. Yamada, K. Hayakawa, K. Kanematsu, J. Org. Chem. 52 (1987)
2040–2046.
[54] Compound 15 was prepared from carbene complex 2 via deprotonation using
n-BuLi at ꢁ78 °C followed by addition of an excess allylic bromide according to
a literature procedure. Ref. [47].
[57] S. Menon, D. Sinha-Mahapatra, J.W. Herndon, Tetrahedron 63 (2007) 8788–
8793.
[58] Y. Luo, J.W. Herndon, Organometallics 24 (2005) 3099–3103.
[55] S.K. Meegalla, R. Rodrigo, Synthesis (1989) 942–944.