Gold-catalyzed benzannulation of electronically rich/rich and deficient/deficient oxoalkynes with alkynes

Article abstract of DOI:10.1055/s-0032-1318454

Two different strategies have been developed to perform the gold-catalyzed benzannulation of both electron-rich pyridine containing oxoalkynes with electron-rich alkynes as well as electron-deficient pyridine containing oxoalkynes with electron-deficient

Full text of DOI:10.1055/s-0032-1318454

PAPER
▌1227
pGapoerld-Catalyzed Benzannulation of Electronically Rich/Rich and Deficient/
Deficient Oxoalkynes with Alkynes
Benzannulation of Oxoalkynes with Alkynes
Biswajit Panda, Tarun K. Sarkar*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Fax +91(3222)2303; E-mail: tksr@chem.iitkgp.ernet.in
Received: 10.01.2013; Accepted after revision: 20.02.2013
from the reaction of electron-deficient oxoalkynes with
Abstract: Two different strategies have been developed to perform
electron-deficient alkynes (mismatching on the basis of
the gold-catalyzed benzannulation of both electron-rich pyridine
FMO). Indeed, the reaction of electron-rich oxoalkyne 1a
with phenylacetylene or diphenylacetylene does not fur-
containing oxoalkynes with electron-rich alkynes as well as elec-
tron-deficient pyridine containing oxoalkynes with electron-
deficient alkynes. The benzannulation between electron-rich nish the benzannulation products, for example, 3f or 3g;
oxoalkynes with electron-rich alkynes proceeds in the presence of
highly electron-deficient gold catalysts, whereas using catalytic
amount of alcohol benzannulation was performed efficiently be-
late does not furnish the benzannulation products 6d or 6e
tween electron-deficient oxoalkynes with electron-deficient al-
kynes.
similarly, the reaction of electron-deficient oxoalkyne 4
with dimethyl acetylenedicarboxylate or methyl propio-
(Scheme 1). In connection with our ongoing work on tran-
sition metal-catalyzed organic transformations,5,7 we now
Key words: gold catalysis, homogeneous catalysis, benzannula-
report two different strategies for the benzannulation of
tion, cycloaddition, Lewis acids
both rich/rich and deficient/deficient oxoalkynes with al-
kynes not available by our previously reported protocol.5
To extend our benzannulation methodology for rich/rich
The transition metal-catalyzed electrophilic activation of
systems our idea was to make electron-deficient azaiso-
alkynes towards intramolecular addition of heteronucleo-
benzopyrylium auric ate complexes via coordination of
philes has attracted increasing attention of the synthetic
electron-rich oxoalkynes with highly electron-deficient
community as a useful method for the preparation of di-
verse heterocyclic compounds.1 In particular, it has been
observed that AuCl3 catalyzes the formation of both car-
bon–carbon and carbon–hetero atom bonds thereby be-
having as an effective Lewis acid.2,3 One of the pioneering
examples of such reactions include benzannulation be-
tween o-alkynylbenzaldehydes and alkynes, and this has
been developed extensively by the research groups of
Yamamoto, Dyker, and others.4 As an extension of this
work, we have recently reported the homogeneous gold-
catalyzed formal [4+2] benzannulation between pyridine
containing oxoalkynes and alkynes, which leads to highly
substituted quinoline and isoquinoline derivatives.5
gold complexes. Gold salts having noncoordinating coun-
–
–
–
terions (like OTf–, BF4 , PF6 , SbF6 , etc.) are highly elec-
tron-deficient compared to gold chlorides.8 Thus, usage of
such highly electron-deficient gold salts might allow for-
mation of electron-deficient azaisobenzopyrilium auric
ate complexes from otherwise electron-rich oxoalkynes.
Table 1 Reaction of 1a with Phenylacetylene Under Various Cata-
lytic Systemsa
CHO
+
N
Ph
N
In the methodology described in that paper, it was ob-
served that the electron-rich azaisobenzopyrilium
intermediates6 generated from oxoalkynes 1a–d react
with electron-poor dienophiles, for example, dimethyl
acetylenedicarboxylate and methyl propiolate, and elec-
tron-poor azaisobenzopyrylium intermediates generated
from oxoalkyne 4 react with electron-rich dienophiles, for
example, phenylacetylene, 4-N,N-dimethylaminophenyl-
acetylene, etc., as would be expected on the basis of fron-
tier molecular orbital (FMO) considerations (Scheme 1).
From the synthetic point of view, one limitation of our
method is that it does not allow formation of benzannula-
tion products, which may be obtained from the reaction of
electron-rich oxoalkynes with electron-rich alkynes or
Ph
Ph
O
Ph
3f
1a
Entry
Catalytic system
Yield (%)b
1
2
3
4
5
6
AuCl3
0
11
74
37
45
0
AuCl3/AgOTf
AuCl3/AgSbF6
AuCl3/AgBF4
AuCl3/AgPF6
AgSbF6
a All reactions were performed using 1a (0.2 mmol) and phenylacet-
ylene (0.4 mmol) in the presence of a combination of AuCl3 (3 mol%)
and silver salt (9 mol%), except for entries 1 and 6, in 1,2-dichloro-
ethane (4 mL) at r.t. for 24 h.
SYNTHESIS 2013, 45, 1227–1234
Advanced online publication: 04.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1318454; Art ID: SS-2013-Z0027-OP
© Georg Thieme Verlag Stuttgart · New York
b Isolated yield.

1228
B. Panda, T. K. Sarkar
PAPER
R2
R2
R5
R5
R4
CHO
AuCl3 (3 mol%)
+
R3
N
R3
N
R4
R1
1
O
R1
2
3
1a, R1 = Ph, R2 = R3 = Me
3a, R1 = Ph, R2 = R3 = Me, R4 = R5 = CO2Me, 89%
3b, R1 = 4-Me2NC6H4, R2 = R3 = Me, R4 = R5 = CO2Me, 83%
3c, R1 = (CH2)3OBn, R2 = R3 = Me, R4 = R5 = CO2Me, 79%
3d, R1 = Ph, R2 = Me, R3 = Ph, R4 = R5 = CO2Me, 92%
3e, R1 = (CH2)3OBn, R2 = R3 = Me, R4 = H, R5 = CO2Me, 76%
3f, R1 = Ph, R2 = R3 = Me, R4 = Ph, R5 = H, 0%
1b, R1 = 4-Me2NC6H4, R2 = R3 = Me
1c, R1 = (CH2)3OBn, R2 = R3 = Me
1d, R1 = Ph, R2 = Me, R3 = Ph
3g, R1 = Ph, R2 = R3 = Me, R4 = R5 = Ph, 0%
Cl
Cl
R2
R2
CHO
N
N
AuCl3 (3 mol%)
+
Cl
R1
Cl
R1
Ph
O
Ph
5
6
4
6a, R1 = Ph, R2 = H, 86%
6b, R1 = 4-MeOC6H4, R2 = H, 91%
6c, R1 = 4-Me2NC6H4, R2 = H, 88%
6d, R1 = H, R2 = CO2Me, 0%
6e, R1 = CO2Me, R2 = CO2Me, 0%
Scheme 1 Gold-catalyzed benzannulation of pyridine containing oxoalkynes with alkynes
Under these conditions, the electron-deficient azaisoben- only catalysis does not give the desired product (entry 6,
zopyrilium auric ate complexes thus formed may react Table 1); decomposition of the starting oxoalkyne 1a was
with electron-rich alkynes following the inverse electron the result.
demand Diels–Alder reaction.
After finding the optimal conditions (Table 1), this meth-
To test the feasibility of our idea, compound 1a9 (electron- odology was then applied to a series of electronically rich
rich oxoalkyne) was subjected to benzannulation with oxoalkynes with alkynes as presented in Table 2. As can
phenylacetylene (electron-rich alkyne) under various cat- be seen from Table 2, like phenylacetylene, 4-methyl-
alytic systems. Thus, in the presence of 3 mol% of AuCl3 phenylacetylene (Table 2, entry 2) also participates in the
combined with 9 mol% of AgOTf as a catalytic system, reaction. Interestingly, strong electron donors, for exam-
the benzannulation product 3f was isolated in 11% yield ple, OMe or NMe2 on the aryl ring of phenylacetylene
(Table 1, entry 2). Interestingly, combination of AuCl3 speed up the reaction as would be expected based on FMO
with AgSbF6 as catalytic ensemble allowed formation of considerations (entries 3, 4).11 Other oxoalkynes, for ex-
the desired product in 74% yield (entry 3), whereas com- ample, 1d9 also reacts with phenylacetylene to afford de-
bination with other silver super halides (AgBF4, AgPF6) sired benzannulated product in high yield (entry 5).12
proves to be less efficient (entries 4 and 5). Thus, Looking at all the products from Table 2 [all potential che-
AuCl3/AgSbF6 catalytic system was found to be the most late ligands for the gold(III) square planar system], one
effective for such reactions (Table 1).10 Note that silver would have suspected product inhibition of the gold(III)
EWG
R2
11
R3OH
EWG
EWG
EWG
R2
CHO
EWG
R2
N
N
Au cat.
R3OH
+
+
EWG
R3O
EWG
R1
O
R1
12
13
14
Scheme 2 Possible benzannulation between electron-deficient oxoalkynes with electron-deficient alkynes
Synthesis 2013, 45, 1227–1234
© Georg Thieme Verlag Stuttgart · New York

PAPER
Benzannulation of Oxoalkynes with Alkynes
1229
catalyst, which seemingly is not the case.13 Note that all ether (compared to the starting alkyne). This species may
the reactions in Table 2 were tested using AuCl3 as cata- now react with an electron-deficient isobenzopyrylium
lyst and did not give any trace of the desired product.
auric ate complex and subsequent elimination of alcohol
(aromaticity-driven) leads to the desired benzannulated
product (Scheme 2). This idea though is not without a
snag. For example, the liberated alcohol present in the re-
action milieu can react with an azaiosobenzopyrylium au-
ric ate complex and may yield the addition product 15 as
by-product upon protodeauration (Scheme 3).14
After successful benzannulation of electron-rich
oxoalkynes with electron-rich alkynes, the next challenge
was to solve the benzannulation between electron-defi-
cient oxoalkynes with electron-deficient alkynes. In order
to facilitate the benzannulation between electron-deficient
oxoalkynes with electron-deficient alkynes, either the iso-
benzopyrylium auric ate complexes or the alkynes must One may consider that addition of alcohol to azaisobenzo-
be transformed into electron-rich species. In this context, pyrylium auric ate complexes is reversible, whereas pro-
our idea was to add an alcohol to an electron-deficient al- todeauration is not. Thus, to get away with the undesired
kyne so as to convert the latter into electron-rich enol alcohol addition reaction it is necessary to prevent the pro-
Table 2 Benzannulation for Rich/Rich Systemsa
AuCl3 (3 mol%)
CHO
AgSbF6 (9 mol%)
+
1,2-DCE, r.t.
R1
R3
R1
N
N
R3
R2
O
R2
Entry
Oxoalkyne
Time
Product
Yield (%)b
CHO
CHO
CHO
CHO
1
24 h
74
N
Ph
N
Ph
Ph
Ph
Ph
O
O
O
O
Ph
Ph
Ph
Ph
1a
3f
N
2
3
4
5
24 h
16 h
12 h
24 h
71
70
61
79
N
1a
7
N
N
OMe
1a
8
N
N
NMe2
1a
9
CHO
Ph
N
Ph
Ph
N
Ph
O
Ph
1d
10
a All reactions were performed using oxoalkynes (0.2 mmol) and alkynes (0.4 mmol) in the presence of a combination of AuCl3 (3 mol%) and
AgSbF6 (9 mol%) in 1,2-dichloroethane (4 mL) at r.t.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1227–1234

1230
B. Panda, T. K. Sarkar
PAPER
R
+
O
H
R
O
EWG
CHO
EWG
EWG
N
O
EWG
N
H
+
O
+ ROH
– ROH
N
N
O
AuX3
– AuX3
R1
EWG
R1
EWG
EWG
EWG
R1
R1
–AuX3
H
–AuX3
13
15
Scheme 3 Possible addition of alcohol to azaisobenzopyrylium auric ate complex
todeauration step in the first place. It is clear that basicity To bring this idea to fruition, enol ethers were prepared
and nucleophilicity of the carbon–gold bond is lower from electron-deficient alkynes by addition of alcohols.
when the gold centre is highly electron-deficient in nature Thus, reaction of the enol ether 1615 with electron-defi-
(tight binding). Notably, the azaisobenzopyrylium auric cient oxoalkyne 416 under AuCl3/AgSbF6 catalytic condi-
ate complexes generated via coordination of oxoalkynes tion at room temperature gave 25% of the desired product
with highly electron-deficient gold complex have lower 6d along with 46% of methanol addition product 17 (Ta-
LUMO thus reducing the HOMO-LUMO gap between ble 3, entry 1). Gratifyingly, the yield of the desired prod-
enol ethers and azaisobenzopyrylium auric ate complexes. uct 6d increased to 74% along with 9% debenzoylated
Therefore, in these cases a highly electron-deficient gold product 18 when the reaction temperature was raised to
complex should be the catalyst of choice.
50 °C. On the other hand, the product ratio was reversed
Table 3 Optimization Study for Benzannulation of an Oxoalkyne with an Enol Ether
Cl
Cl
Cl
OMe
O
Cl
CO2Me
+
CO2Me
CHO
N
AuCl3 (3 mol%)
CO2Me
N
N
+
+
N
AgSbF6 (9 mol%)
4 Å MS, 1,2-DCE
Cl
MeO
Ph
Cl
Cl
Cl
H
Ph
O
Ph
4
16
6d
17
18
Entry
Temp (°C)
Time (h)
Yield (%)b
6d
17
46
18
0
1
2
3
r.t.
50
80
24
12
3
25
74
23
trace
0
9
64
a All reactions were performed using oxoalkynes (0.2 mmol) and enol ether (0.4 mmol) in the presence of a combination of AuCl3 (3 mol%)
and AgSbF6 (9 mol%) in 1,2-dichloroethane (6 mL).
b Isolated yield.
R1
Cl
Ph
O
E
N
Cl
Au-cat
cycle I
Ph
Cl
R2
OMe
N
O
Au-cat
E
D
E
Cl
R1
cycle II
cycle III
MeOH
B
Au-cat
R2
A
E
Ph
O
Au-cat
R2
Cl
R2
E
C
N
Cl
R1
F
Scheme 4 Plausible mechanism for benzannulation of deficient/deficient systems
Synthesis 2013, 45, 1227–1234
© Georg Thieme Verlag Stuttgart · New York

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Benzannulation of Oxoalkynes with Alkynes
1231
under refluxing conditions: the debenzoylated product 18 A plausible mechanism for the gold-catalyzed19 formal
was obtained in 64% yield along with 23% of the desired [4+2] benzannulation (cf. Table 4) of electron-deficient
product 6d.17
pyridine containing oxoalkynes with electron-deficient al-
kynes is shown in Scheme 4. The reaction involves three
catalytic cycles. In cycle I, the coordination of the triple
bond of alkyne A to gold catalyst enhances the electrophi-
licity of the alkyne. Subsequently, the nucleophilic attack
of methanol to the electron-deficient alkyne complex C
followed by protodeauration leads to the formation of the
enol ether D and regeneration of the gold catalyst. On the
other hand, in cycle II, the coordination of the triple bond
of oxoalkyne B to gold catalyst enhances the electrophi-
licity of the triple bond. Subsequently, the nucleophilic at-
tack of the carbonyl oxygen to the activated triple bond
leads to the formation of the intermediate azaisobenzo-
pyrylium auric ate complex E. Now the Diels–Alder type
[4+2] cycloaddition of azaisobenzopyrylium auric ate
Our next goal was to perform this reaction in a one-pot
tandem and catalytic manner. Reaction of oxoalkyne 4
with methyl propiolate in the presence of catalytic amount
of methanol (10%) under gold catalytic conditions fur-
nished 32% of the desired product 6d. The yield of
benzannulation product 6d was improved to 62% by in-
creasing the amount of alcohol (30 mol%) (Table 4, entry
1). Reaction of 4 with DMAD or ethyl propiolate fur-
nished the desired products 6e and 19 in moderate yields
(Table 4, entries 2, 3). Other oxoalkynes, for example,
2016 also reacts with methyl propiolate to afford desired
benzannulated product 21 in good yield (entry 4). Note
that traces of corresponding methanol addition products
were found (TLC) in all the cases reported in Table 4.18
Table 4 Benzannulation of Deficient/Deficient Systemsa
Cl
R3
Cl
R3
CO2R2
CO2
R1
R2
AuCl3 (3 mol%)
AgSbF6 (9 mol%)
N
O
N
+
Cl
MeOH (30 mol%)
Cl
R1
Ph
1,2-DCE, 50 °C
24 h
O
Ph
Entry
Oxoalkyne
Product
Yield (%)b
Cl
Cl
CO2Me
H
CHO
N
N
N
N
N
1
62
Cl
Cl
Ph
O
O
O
O
Ph
Ph
Ph
Ph
4
6d
Cl
Cl
Cl
Cl
N
CO2Me
CO2Me
CHO
2
3
4
56
61
57
Cl
Cl
Ph
4
6e
Cl
N
CO2Et
H
CHO
Cl
Cl
Ph
4
19
Cl
N
CO2Me
H
O
Cl
Cl
Ph
20
21
a All reactions were performed using oxoalkynes (0.4 mmol) and alkynes (0.8 mmol) in the presence of a combination of AuCl3 (3 mol%),
AgSbF6 (9 mol%), and MeOH (30 mol%) in 1,2-dichloroethane (8 mL) at 50 °C.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1227–1234

1232
B. Panda, T. K. Sarkar
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HRMS (CI MS): m/z (M + H)+ calcd for C25H22NO: 352.1696;
found: 352.1696.
complex E with an enol ether D forms the intermediate
cycloadduct and consequent bond rearrangement gives
the isoquinoline derivatives F and regenerates the gold
catalyst and alcohol (cycle III).
[7-(4-Methoxyphenyl)-2,4-dimethylquinolin-8-yl]phenylmeth-
anone (8)
From 1a (0.05 g); yield: 0.054 g (70%); white solid; mp 136–
138 °C; Rf = 0.24 (10% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 8.06 (d, J = 8.4 Hz, 1 H), 7.65 (d,
J = 7.2 Hz, 2 H), 7.55 (d, J = 8.6 Hz, 1 H), 7.41–7.26 (m, 5 H), 7.08
(s, 1 H), 6.79 (d, J = 8.6 Hz, 2 H), 3.75 (s, 3 H), 2.70 (s, 3 H), 2.47
(s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 159.5, 159.3, 143.6, 139.8, 138.8,
132.7, 132.3, 130.7, 130.0, 129.6, 128.7, 128.3, 127.5, 125.3, 124.6,
123.5, 123.0, 114.0, 55.4, 25.6, 18.8.
In conclusion, we have successfully developed a new and
useful procedure for the benzannulation reaction between
electron-rich oxoalkynes with electron-rich alkynes using
highly electron-deficient gold catalysts. Additionally, us-
ing catalytic amount of methanol we have developed an
attractive procedure for the benzannulation reaction be-
tween electron-deficient oxoalkynes with electron-defi-
cient alkynes.
HRMS (CI MS): m/z (M + H)+ calcd for C25H22NO2: 368.1650;
found: 368.1654.
All melting points are uncorrected. 1H NMR and 13C NMR spectra
were recorded at the 400 MHz and 100 MHz or 200 MHz and 50
MHz in CDCl3 with residual CHCl3 (1H: 7.26 ppm, 13C: 77.2 ppm)
as an internal reference. The data are reported in the following or-
der: chemical shift in ppm (δ); multiplicity (standard abbreviations);
coupling constants in J (Hz). Analytical TLC was performed on sil-
ica gel 60 precoated plates with QF-254 indicator. Visualization
was accomplished by UV light, I2 vapor, or 2,4- dinitrophenylhy-
drazine solution. Column chromatography was performed on silica
gel (230–400 mesh) using EtOAc and petroleum ether (PE, bp 60–
80 °C) mixture as eluent. Unless otherwise stated, all reactions were
carried out under an argon atmosphere in flame-dried flasks. All re-
agents were commercially available and, where appropriate, puri-
fied prior to use, unless specified otherwise. Solvents were dried as
follows: MeCN and 1,2-dichloroethane (1,2-DCE) over P4O10. Af-
ter workup, anhyd Na2SO4 was used as the drying agent; organic ex-
tracts were evaporated under reduced pressure and the residue was
purified by column chromatography.
[7-(4-Dimethylaminophenyl)-2,4-dimethylquinolin-8-yl]phen-
ylmethanone (9)
From 1a (0.05 g); yield: 0.048 g (61%); yellow solid; mp 156–
158 °C; Rf = 0.21 (10% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 8.03 (d, J = 8.6 Hz, 1 H), 7.69 (d,
J = 7.7 Hz, 2 H), 7.58 (d, J = 8.6 Hz, 1 H), 7.41–7.23 (m, 5 H), 7.05
(s, 1 H), 6.61 (d, J = 8.8 Hz, 2 H), 2.89 (s, 6 H), 2.67 (s, 3 H), 2.45
(s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 200.0, 159.2, 150.0, 146.6, 143.5,
140.4, 139.0, 136.6, 132.5, 130.3, 129.6, 128.6, 128.2, 127.6, 124.9,
124.4, 122.6, 112.3, 40.4, 25.4, 18.7.
HRMS (FAB MS): m/z (M + H)+ calcd for C26H25N2O: 381.1967;
found: 381.1964.
(4-Methyl-2,7-diphenylquinolin-8-yl)phenylmethanone (10)
From 1d (0.06 g); yield: 0.063 g (79%); white solid; mp 136–
138 °C; Rf = 0.36 (10% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 8.14 (d, J = 8.6 Hz, 1 H), 7.82–
7.74 (m, 5 H), 7.65 (d, J = 8.6 Hz, 1 H), 7.48–7.42 (m, 3 H), 7.36–
7.28 (m, 8 H), 2.81 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 199.3, 156.4, 146.6, 144.6, 141.0,
139.8, 139.4, 139.0, 138.2, 132.7, 129.6, 129.5, 129.4, 128.7, 128.6,
128.4, 128.3, 127.9, 127.5, 126.2, 124.8, 119.4, 19.3.
Benzannulation of Both Electron-Rich Oxoalkynes with
Alkynes, General Procedure
AgSbF6 (6 mg, 0.018 mmol, 9 mol%) was added to a solution of
AuCl3 (2 mg, 0.006 mmol, 3 mol%) in 1,2-dichloroethane (3 mL).
After stirring at r.t. for 15 min, a mixture of respective oxoalkyne 1
(0.2 mmol) and respective alkyne (0.4 mmol) in 1,2-dichloroethane
(3 mL) was added dropwise and stirring was continued at r.t. for the
stated time in Table 2. After completion of the reaction (TLC, elu-
ent: 10% EtOAc–PE), solvent was removed, and the product puri-
fied by column chromatography over silica gel (Table 2).
HRMS (TOF MS): m/z (M + H)+ calcd for C29H22NO: 400.1701;
found: 400.1660.
Benzannulation of Both Electron-Deficient Oxoalkynes with
Alkynes; General Procedure
(2,4-Dimethyl-7-phenylquinolin-8-yl)phenylmethanone (3f)
From 1a (0.050 g); yield: 0.053g (74%); white solid; mp 148–
150 °C; Rf = 0.26 (10% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 1 H), 7.65 (d,
J = 6.0 Hz, 2 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.42–7.36 (m, 3 H),
7.29–7.21 (m, 5 H), 7.11 (s, 1 H), 2.71 (s, 3 H), 2.48 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 199.5, 159.6, 146.3, 143.6, 140.2,
139.9, 138.9, 137.6, 132.7, 129.6, 129.5, 128.4, 128.2, 127.7, 127.4,
125.5, 124.6, 123.2, 25.5, 18.8.
AgSbF6 (12 mg, 0.036 mmol, 9 mol%) was added to a solution of
AuCl3 (4 mg, 0.012 mmol, 3 mol%) in 1,2-dichloroethane (5 mL).
After stirring at r.t. for 15 min, a mixture of the appropriate alkyne
(0.8 mmol) and MeOH (4 mg, 30 mol%) in 1,2-dichloroethane (1
mL) (0.3 mL MeOH mixed with 50 mL 1,2-dichloroethane and
used as stock solution) was added dropwise and stirring was contin-
ued at r.t. for further 15 min. Then, oxoalkyne 4 or 20 (0. 4 mmol)
in 1,2-dichloroethane (2 mL) was added to the reaction mixture and
the reaction vessel was placed in a preheated oil bath at 50 °C and
stirring was continued for 24 h at that temperature. After completion
of the reaction (TLC, eluent: 10% EtOAc–PE), the solvent was re-
moved, and the product purified by column chromatography over
silica gel (Table 4).
HRMS (FAB MS): m/z (M + H)+ calcd for C24H20NO: 338.1545;
found: 338.1539.
(2,4-Dimethyl-7-p-tolylquinolin-8-yl)phenylmethanone (7)
From 1a (0.05 g); yield: 0.052 g (71%); white solid; mp 142–
144 °C; Rf = 0.30 (10% EtOAc–PE).
1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 8.4 Hz, 1 H), 7.66 (d,
J = 7.6 Hz, 2 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.41 (t, J = 7.4 Hz, 1 H),
7.29–7.25 (m, 4 H), 7.09–7.05 (m, 3 H), 2.70 (s, 3 H), 2.47 (s, 3 H),
2.28 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 199.7, 159.5, 146.4, 143.6, 140.1,
138.9, 137.5, 137.3, 136.9, 132.7, 129.7, 129.4, 129.2, 128.3, 127.5,
125.4, 124.6, 123.0, 25.5, 21.3, 18.8.
5-Benzoyl-1,3-dichloroisoquinoline-7-carboxylic Acid Methyl
Ester (6d)
From 4 (0.11 g); yield: 0.09 g (62%); white solid; mp 153–155 °C;
Rf = 0.26 (10% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 9.20 (s, 1 H), 8.43 (s, 1 H), 8.04
(s, 1 H), 7.82 (d, J = 8.2 Hz, 2 H), 7.68 (t, J = 7.1 Hz, 1 H), 7.52 (t,
J = 7.5 Hz, 2 H), 4.01 (s, 3 H).
Synthesis 2013, 45, 1227–1234
© Georg Thieme Verlag Stuttgart · New York

PAPER
Benzannulation of Oxoalkynes with Alkynes
1233
13C NMR (50 MHz, CDCl3): δ = 195.0, 165.2, 153.0, 147.5, 139.4,
136.9, 135.6, 134.5, 132.8, 132.2, 130.6, 129.1, 129.0, 125.9, 118.2,
53.2.
HRMS (CI MS): m/z (M + H)+ calcd for C11H8Cl2NO2: 255.9932;
found: 255.9899.
HRMS (CI MS): m/z (M + H)+ calcd for C18H12Cl2NO3: 360.0194;
found: 360.0141.
Acknowledgment
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, UK), Drs. S.
Djuric and S. Cepa (Abbott, Il), Prof. T.-J. Chow (Academia Sinica,
Taipei), and Prof. A. Sarkar (IACS, Kolkata) are thanked for conti-
nued help and support. We are also thankful to the referees for their
valuable suggestions.
5-Benzoyl-1,3-dichloroisoquinoline-6,7-dicarboxylic Acid Di-
methyl Ester (6e)
From 4 (0.11 g); yield: 0.093 g (56%); white solid; mp 162–163 °C;
Rf = 0.18 (10% EtOAc–PE).
1H NMR (400 MHz, CDCl3): δ = 8.99 (s, 1 H), 7.74 (d, J = 7.2 Hz,
2 H), 7.64 (m, 1 H), 7.50–7.46 (m, 3 H), 4.00 (s, 3 H), 3.58 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 194.3, 166.3, 165.4, 152.8, 147.5,
138.0, 137.0, 136.4, 135.0, 134.5, 130.8, 130.0, 129.5, 129.4, 129.2,
125.3, 118.2, 53.5, 53.2.
HRMS (CI MS): m/z (M + H)+ calcd for C20H14Cl2NO5: 418.0244;
found: 418.0247.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
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5-Benzoyl-1,3-dichloroisoquinoline-7-carboxylic Acid Ethyl
Ester (19)
References
From 4 (0.11 g); yield: 0.091 g (61%); white solid; mp 159–160 °C;
Rf = 0.24 (10% EtOAc–PE).
1H NMR (400 MHz, CDCl3): δ = 9.21 (s, 1 H), 8.44 (s, 1 H), 8.03
(s, 1 H), 7.84 (d, J = 7.4 Hz, 2 H), 7.69 (t, J = 7.3 Hz, 1 H), 7.53 (t,
J = 7.6 Hz, 2 H), 4.49 (q, J = 14.3, 7.0 Hz, 2 H), 1.45 (t, J = 7.0 Hz,
3 H).
13C NMR (100 MHz, CDCl3): δ = 194.8, 164.5, 152.7, 147.1, 139.1,
136.7, 135.4, 134.2, 132.5, 131.7, 130.4, 129.2, 128.8, 125.6, 117.9,
62.1.
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2004, 126, 7458. (e) Dyker, G.; Hildebrandt, D. J. Org.
Chem. 2005, 70, 6093. (f) Hildebrandt, D.; Huggenberg, W.;
Kanthak, M.; Ploger, T.; Muller, I. M.; Dyker, G. Chem.
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HRMS (CI MS): m/z (M + H)+ calcd for C19H14Cl2NO3: 374.0345;
found: 374.0349.
5-Benzoyl-1,3-dichloro-8-methylisoquinoline-7-carboxylicAcid
Methyl Ester (21)
From 20 (0.116 g); yield: 0.085 g (57%); white solid; mp 146–
148 °C; Rf = 0.26 (10% EtOAc–PE).
1H NMR (400 MHz, CDCl3): δ = 7.99 (s, 1 H), 7.97 (s, 1 H), 7.82
(d, J = 8.4 Hz, 2 H), 7.67 (t, J = 7.6 Hz, 1 H), 7.51 (t, J = 7.8 Hz, 2
H), 3.94 (s, 3 H), 3.18 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 195.2, 168.0, 151.2, 145.6, 142.1,
140.2, 137.1, 134.4, 133.5, 132.5, 132.4, 130.6, 129.1, 127.0, 118.1,
53.1, 22.9.
HRMS (CI MS): m/z (M + H)+ calcd for C19H14Cl2NO3: 374.0345;
found: 374.0349.
6,8-Dichloro-1-methoxy-3-phenyl-1H-pyrano[3,4-c]pyridine
(17)
Prepared following the experimental conditions reported in Table 3,
entry 1. From 4 (0.055 g); yield: 0.028 g (46%); white solid; mp
142–143 °C; Rf = 0.32 (10% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 7.84–7.79 (m, 2 H), 7.48–7.45 (m,
3 H), 7.06 (s, 1 H), 6.49 (s, 1 H), 6.36 (s, 1 H), 3.70 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 156.3, 150.6, 150.5, 148.0, 143.3,
133.0, 130.8, 129.0, 125.9, 118.8, 117.6, 97.2, 56.7.
HRMS (CI MS): m/z (M)+ calcd for C15H11Cl2NO2: 307.0167;
found: 307.0167.
1,3-Dichloroisoquinoline-7-carboxylic Acid Methyl Ester (18)
Prepared following the experimental conditions reported in Table 3,
entry 3. From 4 (0.055 g); yield: 0.033 g (64%); white solid; mp
146–148 °C; Rf = 0.42 (10% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 9.03 (s, 1 H), 8.35 (d, J = 8.6 Hz,
1 H), 7.84 (d, J = 8.6 Hz, 1 H), 7.72 (s, 1 H), 4.03 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 165.9, 152.6, 145.7, 141.4, 131.8,
130.5, 129.6, 127.0, 125.4, 119.9, 53.0.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1227–1234

1234
B. Panda, T. K. Sarkar
PAPER
(6) Yamamoto and co-workers4a have proposed that the gold-
catalyzed benzannulation takes place via the formation of
isobenzopyrylium auric ate complexes; indeed, we were able
to detect these species in our case by trapping experiments5
as well as UV and NMR studies; see the Supporting
Information.
(7) (a) Panda, B.; Sarkar, T. K. Tetrahedron Lett. 2010, 51, 301.
(b) Panda, B.; Sarkar, T. K. Chem. Commun. 2010, 46, 3131.
(c) Panda, B.; Sarkar, T. K. J. Org. Chem. 2013, 78, 2413.
(8) Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126, 13596.
(9) For full details of the preparation of this compound, see:
Panda, B.; Sarkar, T. K. Synthesis 2013, 45, 817.
(10) We cannot rule out the possibility of silver effect on gold
catalysis, as sometimes combination of gold salts with silver
salts leads to the formation of bimetallic clusters, see:
(a) Weber, D.; Gagne, M. R. Org. Lett. 2009, 11, 4962.
(b) Wang, D.; Cai, R.; Sharma, S.; Jirak, J.; Thummanapelli,
S. K.; Akhmedov, N. G.; Zhang, H.; Liu, X.; Petersen, J. L.;
Shi, X. J. Am. Chem. Soc. 2012, 134, 9012.
(11) For a successful utilization of alkynes with strong donor
ligands, see: (a) Hashmi, A. S. K.; Rudolph, M.; Huck, J.;
Frey, W.; Bats, J. W.; Hamzić, M. Angew. Chem. Int. Ed.
2009, 48, 5848. (b) Hashmi, A. S. K.; Pankajakshan, S.;
Rudolph, M.; Enns, E.; Bander, T.; Rominger, F.; Frey, W.
Adv. Synth. Catal. 2009, 351, 2855.
(12) Unfortunately, benzannulation of 1a with diphenylacetylene
or with alkylalkynes, for example, hex-1-yne does not give
any desired product(s) under these modified conditions.
(13) For observation of product inhibition by nitrogen-
containing, potentially chelating reaction products, see:
(a) Weyrauch, J. P.; Hashmi, A. S. K.; Schuster, A.; Hengst,
T.; Schetter, S.; Littmann, A.; Rudolph, M.; Hamzić, M.;
Visus, J.; Rominger, F. Chem. Eur. J. 2010, 16, 956. So far
this has been avoided by using gold(I), which has a low
affinity to nitrogen ligands, see: (b) Khin, C.; Hashmi, A. S.
K.; Rominger, F. Eur. J. Inorg. Chem. 2010, 1063.
(14) Handa, S.; Slaughter, L. M. Angew. Chem. Int. Ed. 2012, 51,
2912.
(15) Tellam, J. P.; Carbery, D. R. J. Org. Chem. 2010, 75, 7809.
(16) For the preparation of oxoalkynes 4 and 20, see the
Supporting Information.
(17) The reason for this change in product ratio in this case is not
clear to us.
(18) The presence of small amounts of debenzoylated products, if
any, in the crude reaction products was not checked.
(19) We also cannot rule out the possibility of autocatalysis by
the oxoalkynes, 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.
Synthesis 2013, 45, 1227–1234
© Georg Thieme Verlag Stuttgart · New York