Synthesis of substituted isoquinolines via iminoalkyne cyclization using Ag(i) exchanged K10-montmorillonite clay as a reusable catalyst

Article abstract of DOI:10.1039/c4ra05026f

Monosubstituted isoquinolines are synthesized in good to excellent yields by the Ag(i)-exchanged K10-montmorillonite clay catalyzed ring closure of iminoalkynes. This silver catalyzed ring closure is highly effective in cyclizing aryl- and alkyl-substituted iminoalkynes at 100 °C and accommodates a variety of iminoalkynes, thus affording a convenient route to the synthesis of isoquinolines. The other salient features of this procedure are its reusability, environmentally benign nature, high yield, operational simplicity with fewer steps, easy separation, and minimization of metallic wastes. The reaction proceeds smoothly in moderate yields and tolerates various functional groups. The solid catalyst can be readily recovered and reused. Notably, no additional base or other co-catalysts are needed. A plausible mechanism is proposed in which isoquinolines are formed via simultaneous bifunctional acid-base catalysis by Ag(i) clay. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra05026f

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Synthesis of substituted isoquinolines via
iminoalkyne cyclization using Ag(I) exchanged K10-
Cite this: RSC Adv., 2014, 4, 38491
montmorillonite clay as a reusable catalyst†
a
ab
Received 28th May 2014
Accepted 18th August 2014
*
Mariappan Jeganathan and Kasi Pitchumani
DOI: 10.1039/c4ra05026f
www.rsc.org/advances
Monosubstituted isoquinolines are synthesized in good to excellent fractional crystallization of the acid sulfate. Weissgerber had
yields by the Ag(I)-exchanged K10-montmorillonite clay catalyzed ring developed a more rapid route in 1914 by selective extraction of
closure of iminoalkynes. This silver catalyzed ring closure is highly coal tar, exploiting the fact that isoquinoline is more basic than
effective in cyclizing aryl- and alkyl-substituted iminoalkynes at 100 ꢀC quinoline. Isoquinoline can then be isolated from the mixture
and accommodates a variety of iminoalkynes, thus affording a by fractional crystallization of the acid sulfate. Being an analog
convenient route to the synthesis of isoquinolines. The other salient of pyridine, isoquinoline is a weak base, with a pKb of 5.1. It
features of this procedure are its reusability, environmentally benign protonates to form salts upon treatment with strong acids, such
nature, high yield, operational simplicity with fewer steps, easy sepa- as HCl. It forms adducts with Lewis acids, such as BF3. Iso-
ration, and minimization of metallic wastes. The reaction proceeds quinolines have already been employed as useful intermediates
smoothly in moderate yields and tolerates various functional groups. in the synthesis of indenoisoquinolines,8 protoberberines,9 and
The solid catalyst can be readily recovered and reused. Notably, no dibenzoquinolizines10 and are also of interest in medicinal
additional base or other co-catalysts are needed. A plausible mecha- chemistry.11 Because of their biological and pharmacological
nism is proposed in which isoquinolines are formed via simultaneous importance, several methods have been reported for the
bifunctional acid-base catalysis by Ag(I) clay.
synthesis of isoquinolines. Isoquinoline species are also
utilized as chiral ligands for transition metal catalysts,12 and
their iridium complexes are used in organic light-emitting
diodes.13 For these reasons, the efficient synthesis of the iso-
quinoline ring system continues to attract the interest of
synthetic chemists.
A current trend in synthetic organic chemistry is to develop new
methodologies that afford products of greater structural
complexity with fewer synthetic steps,1 and of complex mole-
cules from relatively simple starting materials, employing
operationally simple, environmentally benign reaction condi-
tions while ensuring high yields. Isoquinoline derivatives are an
essential class of heterocycles and are found in many naturally
occurring compounds that demonstrate a variety of biological
activities such as antitumor, analgesic, antihistaminic and
antifertility activities.2 Their structures are integrated in several
alkaloids3 and other pharmacologically important compounds.4
Isoquinolines are used in the manufacture of dyes, paints,
insecticides, antifungal agents; as a solvent for the extraction of
resins and terpenes; and as a corrosion inhibitor.5,6
The traditional approaches for the synthesis of the iso-
quinoline ring system, include the Bischler-Napieralski,14 the
Pictet-Spengler15 and the Pomeranz-Fritsch16 reactions. These
methods play either strong acidic conditions for the ring
closure (Bischler-Napieralski and Pomeranz-Fritsch) or tedious
preparation of appropriately substituted phenylamines as
starting materials (Pictet–Spengler) to afford dihydro- and tet-
rahydroisoquinolines, respectively. An additional step involving
dehydrogenation is thus required to complete the synthesis of
isoquinoline. Recently, substituted isoquinolines have been
synthesized by employing palladium chemistry. Heck,17
Pfeffer18 and Widdowson19 have reported the palladium meth-
odology to synthesize substituted isoquinolines. These
approaches to isoquinolines suffer from major drawbacks as
they are stoichiometric with respect to palladium and a nal
pyrolysis step greatly limits the synthetic utility.
The rst isolation of isoquinolines was effected from coal tar
in 1885 by Hoogewerf and van Dorp.7 They isolated it by
aSchool of Chemistry, Madurai Kamaraj University, Madurai – 625 021, India. E-mail:
pit12399@yahoo.com
bCentre for Green Chemistry Processes, School of Chemistry, Madurai Kamaraj
In addition, the transition metal-catalyzed cyclization of
alkynes, which possesses a nucleophile in proximity to the triple
bond, by in situ coupling/cyclization reactions is an attractive
University, Madurai – 625 021, India
† Electronic supplementary information (ESI) available: See DOI:
10.1039/c4ra05026f
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 38491–38497 | 38491

View Article Online
RSC Advances
Communication
alternative.20 Isoquinoline derivatives have been synthesized via
base-catalyzed cyclization of terminal and disubstituted
alkynes. For example, Sharp, has reported the synthesis of N-
sulfonylimine isoquinolines in modest yield (40–70%) from the
base-induced cyclization of o-ethynylhydrazones.21 The transi-
tion metal chemistry focusing on isoquinoline synthesis has
also been extended by exploring other elements such as Cu,22
Ag,22b Rh,23 Zr,24 Ni25 and Pd complex.26 Later, Larock and co-
workers have developed methods to synthesize a wide variety
of 3,4-disubstituted isoquinolines.27 3-Substituted isoquino-
lines are formed by the reaction of o-ethynylbenzaldehydes and
ammonia in modest to excellent yields (45–95%).28 These
methods require longer reaction time and expensive metals.
A tremendous upsurge of interest is evident recently in
chemical transformations performed on solid supports,29 which
make the reaction processes convenient to perform (simple
isolation of reaction products by ltration), faster, more
economical, environmentally benign, and recyclable with
minimal metallic waste. Commercially available K10 montmo-
rillonite (K10 clay) clay is one such material that can fulll these
requirements. K10 clays are environmentally benign and
economically feasible solid catalysts that offer several advan-
tages, such as ease of handling, non-corrosiveness and low cost.
As a solid acid of moderate acid strength, its high surface area
(250 m2 gꢁ1) makes it an useful and active catalyst. In contin-
uation of our ongoing works on development of efficient,
reusable supports, and catalysts using clays30 which are readily
impregnated with metal ions, herein we report a simple, green,
and efficient protocol for the synthesis of 3-substituted iso-
quinolines with environmentally friendly AgI–K10 clay as a
novel catalyst. Although recent studies have shown that silver
species exhibited interesting catalytic activities functioning as a
transition metal catalyst,31 silver “catalysts” in a “transition
metal” sense are commonly considered to have low efficiency
and not as good as other late transition metals in synthesis of
heterocyclic compounds.32
Scheme 2 Synthesis of 3-phenylisoquinoline.
the electrophilic cyclization of iminoalkynes by electrophiles
other than organopalladium compounds in order to obtain 3-
substituted isoquinolines (Scheme 1). The requisite imi-
noalkynes are readily prepared in two steps from 2-hal-
obenzaldehyde and a terminal alkyne. The rst step is
Sonogashira coupling of the aryl halide and a terminal alkyne
catalyzed by 2 mol % PdCl2(PPh3)2 and 1 mol% CuI in Et3N at
50 ꢀC. The second step involves reaction of the 2-(1-alkynyl)
benzaldehyde and excess tert-butylamine at room temperature
Table 1 Optimization of reaction conditions for the synthesis of
3-phenylisoquinolinea
Entry
Catalyst
Solvent
Temp. (ꢀC)
RT
Yieldb (%)
1
2
—
—
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
Chlorobenzene
1,4-Dioxane
DMSO
Ethanol
Neat
—
4
—
10
12
69
20
39
100 ꢀ
RT
C
C
C
3c
4c
5d
6d
7
K10 clay
K10 clay
AgNO3
AgNO3
AgI–K10
AgI–K10
AgI–K10
AgI–K10
AgI–K10
AgI–K10
AgI–K10
AgI–K10
AgI–K10
AgI–K10
AgI–K10
AgI–K10
100 ꢀ
RT
100 ꢀ
RT
8
9
50 ꢀ
C
C
75 ꢀ
63
10e
11f
12
13
14
15
16
17
18
100 ꢀ
100 ꢀ
100 ꢀ
100 ꢀ
100 ꢀ
100 ꢀ
100 ꢀ
RT
C
C
C
C
C
C
C
93, 60, 28
93, 93, 93, 65
70
53
47
45
61
18
45
Due to the importance of isoquinoline derivatives in organic
chemistry, the development of new synthetic approaches with
various reaction conditions remains an active research area.
During the course of our studies using clays as heterogeneous
environmentally friendly catalysts, we were encouraged to study
Neat
100 ꢀ
C
a
Reaction conditions: Iminoalkyne (1 mmol), AgI–K10 (20 mg), Solvent
b
c
d
(5 mL). Isolated yield. 100 mg of K10 clay used. 10 mg of AgNO3
used. Reaction carried out in 6, 4, 2 h respectively. Reaction carried
out with 50, 30, 20, 10 mg of catalyst, respectively.
e
f
Scheme 1 Overall synthetic route for 3-substituted isoquinoline.
38492 | RSC Adv., 2014, 4, 38491–38497
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
Table 2 Synthesis of Substituted Isoquinolines via Cyclization of Table 2 (Contd.)
Iminoalkyne Catalyzed by AgI–K10 claya
Entry Iminoalkynea
Product
Yieldb (%)
Entry Iminoalkynea
Product
Yieldb (%)
9
4i
4j
91
85
1
4a 93
2
3
4
4b 88
4c 85
4d 86
10
11
4k 82
12
13
4l
80
4m 90
5
6
7
4e 85
4f 84
4g 92
14
4n 88
15
4o 92
a
Reaction conditions: Iminoalkyne (1 mmol), AgI–K10 (20 mg), DMF
b
(5 ml), 100 ꢀC, 6 h. Isolated yield.
8
4h 90
which proceeds well resulting in quantitative yields. Herein we
report the ring closure of iminoalkynes using AgI–K10 clay to
yield a wide variety of substituted isoquinolines (Scheme 2). The
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 38491–38497 | 38493

View Article Online
RSC Advances
Communication
silver exchanged clay was prepared by an ion exchange method entries 2–15). These results clearly establish that this method is
and was characterized by powder XRD, EDX and UV-DRS. The more advantageous in terms of ecofriendliness in the catalyst,
total silver content was found to be 4.57 atom% by EDX analysis much higher yield, reduced reaction time, and above all reus-
1
(ESI†). Other details of the various experimental protocols ability. All synthesized isoquinolines were characterized by H
including reagents, procedure and analysis as well as charac- and 13C NMR data and LC MS.
terisation technique are given in the ESI.†
As recyclability is important for industrial applications of a
Initially, the reaction parameters such as temperature, good catalyst, reuse performance of AgI–K10 was also investi-
time, identication of the optimum catalyst, quantity, and gated. The recovered catalyst was reused for consecutive runs
solvent for the synthesis of 3-phenylisoquinoline are exam- and it was observed that the catalyst afforded only slightly lower
ined by choosing unsubstituted iminoalkyne as a model yield than the fresh catalyst even aer ve runs (Table 3). The
substrate and the observed results are given in Table 1. reaction was performed under the optimized conditions as
Control experiments show that no desired product is obtained follows: the catalyst aer every use was recovered by ltration,
in the absence of catalyst at room temperature as well as at washed with excess acetone or ethyl acetate, and then dried in
100 ꢀC (Table 1, entries 1 and 2). The acidity of clay can be oven at 80 ꢀC. The catalyst was then employed for further
netuned using K10-clay, AgI–K10 clay, and AgNO3 as cata- reactions and the yield has decreased only marginally and
lysts for their activity in the synthesis 3-substituted iso- cyclization of iminoalkyne resulted in the desired product in
quinolines. AgNO3 has provided the desired product in low 85% yield aer the h cycle.
yield (Table 1, entries 5 and 6). However, the separation and
reuse of the AgNO3 pose problems due to its complete Sheldon test34 was performed to evaluate possible metal leach-
In order to verify the real heterogeneity of AgI–K10 clay,
dissolution in DMF.
ing. Iminoalkyne (1 mmol) in DMF (5 mL) was treated with 20
However, when compared to AgI–K10 clay, they exhibit mg of AgI–K10 at 100 ꢀC for 2 h. The reaction mixture at 100 ꢀC
reduced activity (Table 1, entries 3–10). It is thus established was cooled aer 2 h to room temperature and the catalyst was
that AgI–K10 clay is the catalyst of choice. An increase in the ltered. The ltrate was further heated to 100 C for an addi-
ꢀ
reaction temperature from room temperature to 50, 75 and 100 tional 4 h. Iminoalkyne was further added to the recovered solid
ꢀC accelerates the reaction to give the desired product in catalysts, and the reaction mixture was heated at 100 ꢀC for 6 h.
optimum yield (Table 1, entries 7–10). In the search for higher The obtained results clearly indicated that there is no appre-
yield, we varied the amount of AgI–K10 clay and interesting, ciable leaching of metal ions in the present reaction conditions
93% yield of 3-phenylisoquinoline was obtained when 20 mg of (Table 4).
clay was used. With further increase in the quantity of catalyst
ICP-OES analysis was carried out for the fresh AgI–K10 clay
to 30 and 50 mg, there is no improvement in yield (Table 1, entry and the reused one (aer the ve cycles) (ESI†). The results
11). The inuence of other experimental parameters such as reveal that the amount of silver in fresh AgI–K10 clay is 4.57%,
solvent are also optimized (Table 1, entries 11–16). Results show whereas the reused AgI–K10 clay contains 4.56% of silver, thus
that DMF is the suitable solvent for the synthesis of isoquino- conrming the absence of metal leaching from the catalyst even
line than toluene, chlorobenzene, 1,4-dioxane, DMSO, and aer the h run. Another strategy was also performed to
ethanol, whereas without solvent, the yield is low (Table 1, conrm the presence or absence of metal leaching. Iminoalkyne
entries 17 and 18).
(1 mmol) in DMF (5 mL) was treated with 20 mg of AgI–K10 at
Consequently the optimum reaction conditions for AgI–K10 100 ꢀC for 6 h and the catalyst was ltered, yielding 93% of the
clay catalyzed synthesis of 3-substitiuted isoquinolines are 100 product. Thus, the reaction mixture was ltered and the catalyst
ꢀC in DMF for 6 h.
was removed. Iminoalkyne (0.5 mmol) was further adꢀded to the
To understand the scope and generality of AgI–K10 clay ltrate, and the reaction mixture was heated at 100 C for 6 h
catalyzed cyclization reaction, various substituted alkynes were and the yield was found to be 70%. This suggests the absence of
also employed as substrates. As depicted in Table 2, in all the AgI ions leaching to the solution (Table 5). In addition, the
cases, the reactions were very clean and isoquinolines were absence of leaching was also conrmed from ICP-OES analysis
isolated in excellent yields under the optimized conditions.33 of the ltrate from the reaction mixture aer removing the
The best results are obtained with phenylacetylene containing catalyst which indicated that the presence of AgI is below the
an iminoalkyne precursor (Table 2, entry 1) than other detection limit (ESI†).
substituted phenylacetylene containing iminoalkynes (Table 2,
Table 4 Sheldon test with AgI–K10 clay catalyzed cyclization of
iminoalkynea
Table 3 Reusability of AgI–K10 clay catalyst in the synthesis of 3-
Yieldb (%)
phenylisoquinolinea
1st
2nd
92
3rd
90
4th
88
5th
85
Catalyst
2 h
2 + 4 h
29
Reused catalyst (6 h)
68
Run
AgI–K10
26
Yieldb (%)
93
a
Iminoalkyne (1 mmol), AgI–K10 (20 mg), DMF (5 ml) at 100 ꢀC. b HPLC
a
Reaction conditions: iminoalkyne (1 mmol), AgI–K10 (20 mg), DMF
b
(5 ml) 100 ꢀC, 6 h. Isolated yield.
yield (using 3a as an internal standard).
38494 | RSC Adv., 2014, 4, 38491–38497
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
Table 5 Leaching test with AgI–K10 clay catalyzed cyclization of
iminoalkyne
previous reports.22 The other notable advantages of the present
procedure are the ease of manipulation, good yields, milder
reaction conditions, lesser number of steps and the tolerance of
a wide range of functionalities.
Yieldc (%)
Catalyst
6 ha
6 + 6 hb
70
AgI–K10
93
Conclusions
a
Iminoalkyne (1 mmol), AgI–K10 (20 mg), DMF (5 ml) at 100 ꢀC.
In conclusion, we have developed an efficient method for the
synthesis of substituted isoquinolines via AgI–K10 clay cata-
lyzed cyclisation of iminoalkynes. A broad variety of function-
alized terminal alkynes participate in thus cyclization process
affording the desired nitrogen heterocycles in moderate to
excellent yields. The other salient features of this economical
procedure are its reusability, environmentally benign nature,
high yield, operational simplicity with fewer steps, easy sepa-
ration, and minimization of metallic waste. The reaction
proceeds smoothly in moderate yields and tolerates consider-
able functional groups. The solid catalyst can be readily recov-
ered and reused thus making this procedure more
environmentally acceptable. Notably, no additional base or
other co-catalysts are needed. A plausible mechanism involving
simultaneous bifunctional catalysis by Ag(I)–K10 clay is
proposed.
b
c
Filtrate, Iminoalkyne (0.5 mmol) at 100 ꢀC. HPLC yield (using 3a as
an internal standard).
On the basis of the above results, a plausible mechanistic
pathway for the present reaction is depicted in Scheme 3. AgI
bound to K10-clay coordinated readily to the alkyne, and this is
the dominant factor inuencing cyclization of iminoalkyne. The
clay bound AgI functioning as the active catalyst generates an
intial silver(I)-acetylide intermediate by the reaction between AgI
species in clay and the terminal alkyne with subsequent
cleavage of one of the oxo bridges in clay. The alkyne with a
resultant change in hybridization cyclizes readily producing a
tert-butylisoquinolinium salt. Subsequent proton removal by
the adjacent basic sites in clay, produces intermediate I, which
upon protonation forms isoquinoline as the end product, with
Ag(I) catalyst being released for further cycle of reactions.
In this internal alkyne annulation chemistry, AgI–K10 acts as
a bifunctional catalyst, functioning simultaneously as an elec-
trophile with Ag+ facililating annulation and as a base
promoting proton removal. The tert-butyl group apparently
fragments to relieve the strain resulting from interaction with
the substituent present in the 3-position. Other signicant
features of this study are the use of AgI–K10 clay as a simulta-
neous bifunctional catalyst, its reusability and absence of
incorporation of electrophile in the 4th position, unlike other
Acknowledgements
KP thanks Department of Science and Technology, New Delhi,
India for nancial assistance.
References and Notes
1 (a) B. M. Trost, Science, 1991, 254, 1471; (b) N. Hall, Science,
1994, 266, 32.
2 (a) The Chemistry of Heterocyclic Compounds: Isoquinolines,
ed. G. M. Coppola and H. F. Schuster, John Wiley & Sons,
New York, 1981, vol. 38, part 3; (b) G. Timari, T. Soos,
G. Hajos, A. Messmer, J. Nacsa and J. Molnar, Biol. Org.
Med. Chem. Lett., 1996, 23, 2831; (c) K. W. Bentley, The
isoquinoline Alkaloids, Hardwood Academic, Amsterdam,
The Netherlands, 1998, vol. 1.
3 (a) K. B. Bentley, Nat. Prod. Rep., 2000, 17, 247; (b)
O. Hoshino, inThe Alkaloids, ed. G. A. Cordell, AC press,
San Diego, 1998, vol. 51, p. 323.
4 G. Muller, Chem. Abstr., 1969, 71, 91735y.
5 J. D. Harris and W. J. Pope, J. Chem. Soc., 1922, 121, 1029.
6 Comprehensive Heterocyclic Chemistry II: A Review of the
Literature 1982-1995, ed. A. R. Katritsky, C. W. Rees and E.
F. Scriven, Elsevier, Tarrytown, NY, 1996, vol. 5.
7 S. Hoogewerf and W. A. van Dorp, Sur un isomere de la
quinoleine' (on an isomer of quinoline), Recueil des
Travaux Chemiques des Pays-Bas, Collection of Work in
Chemistry in the Netherlands, 1885, vol. 4, no. 4, pp. 125–
129.
8 (a) M. Jayaraman, B. M. Fox, M. Hollingshead, G. Koblhagen,
Y. Pommier and M. Cushman, J. Med. Chem., 2002, 45, 242;
(b) M. Cushman, M. Jayaraman, J. A. Vroman,
Scheme 3 Proposed mechanism for the formation of isoquinoline.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 38491–38497 | 38495

View Article Online
RSC Advances
Communication
A. K. Fukunaga, B. M. Fox, G. Koblhagen, D. Strumberg and
Y. Pommier, J. Med. Chem., 2000, 43, 3688.
1863; (e) S. Cacchi, G. Fabrizi and L. Moro, J. Org. Chem.,
1997, 62, 5327.
9 (a) E. Reimann, W. Erdle, C. Weigl and K. Polborn, Monatsh. 21 P. N. Anderson and J. T. Sharp, J. Chem. Soc., Perkin Trans. 1,
Chem., 1999, 130, 313; (b) R. N. Warrener, L. liu, R. A. Russell 1980, 1331.
and E. R. T. Tiekink, Synlett, 1998, 4, 387; (c) R. N. Warrener, 22 (a) B. Wang, B. Lu, Y. Jiang, Y. Zhang and D. Ma, Org. Lett.,
L. liu and R. A. Russell, Tetrahedron, 1998, 54, 7485; (d)
T. Vicente, E. Dominguez and M. J. Villa, Heterocycles,
1998, 48, 243.
2008, 10, 2761; (b) Q. Huang, A. H. Jack and R. C. Larock,
J. Org. Chem., 2002, 67, 3437.
23 S. G. Lim, J. H. Lee, C. W. Moon, J. B. Hong and C. H. Jun,
Org. Lett., 2003, 5, 2759.
10 I. Kaldor, P. L. Feldman, R. A. Mook, J. A. Ray, V. Samano,
A. M. Seer, J. B. Thompson, B. R. Travis and E. E. Boros, 24 T. V. V. Ramkrishna and P. R. Sharp, Org. Lett., 2003, 5, 877.
J. Org. Chem., 2001, 66, 3495. 25 R. P. Korivi and C. H. Cheng, Org. Lett., 2005, 7, 5179.
11 (a) R. J. Snow, M. G. Cardozo, T. M. Morwick, C. A. Busacca, 26 (a) Q. Huang and R. C. Larock, J. Org. Chem., 2003, 68, 980;
Y. Dong, R. J. Eckner, S. Jacober, S. Jakes, S. Kapadia, (b) G. Dai and R. C. Larock, J. Org. Chem., 2002, 67, 7042.
S. Lukas, M. Panzenbeck, G. W. Peet, J. D. Peterson, 27 (a) K. R. Roesch and R. C. Larock, J. Org. Chem., 1998, 63,
A. S. Prokopowicz, R. M. Sellati, M. A. schantz and
N. Moss, J. Med. Chem., 2002, 45, 3394; (b) G. J. Wells,
5306; (b) K. R. Roesch, H. Zhang and R. C. Larock, J. Org.
Chem., 2001, 66, 8042.
M. Tao, K. A. Josef and R. Bibovsky, J. Med. Chem., 2001, 28 (a) T. Sakamoto, Y. Kondo, N. Miura, K. Hayashi and
44, 3488.
H. Yamanaka, Heterocycles, 1988, 27, 2225; (b) A. Numata,
Y. Kondo and T. Sakamoto, Synthesis, 1999, 306.
12 (a) F. Durola, J. P. Sauvage and O. S. Wenger, Chem.
Commun., 2006, 171; (b) B. A. Sweetman, H. Muller-Bunz 29 M. Balogh and P. Laszlo, in Organic Chemistry Using Clays,
and P. J. Guiry, Tetrahedron Lett., 2005, 46, 4643; (c) Spring-Verlag, Berlin, 1993; and reference cited therein.
C. W. Lim, O. Tissot, A. Mattison, M. W. Hooper, 30 A. Dhakshinamoorthy and K. Pitchumani, Tetrahedron Lett.,
J. M. Brown, A. R. Cowley, D. L. Hulmes and A. J. Blacker, 2008, 49, 1818.
Org. Process Res. Dev., 2003, 7, 379; (d) N. W. Alcock, 31 (a) Y. Yamamoto, Chem. Rev., 2008, 108, 3199; (b)
J. M. Brown and G. I. Hulmes, Tetrahedron: Asymmetry,
1993, 4, 743.
J.-M. Weibal, A. Blanc and P. Pale, Chem. Rev., 2008, 108,
3149; (c) M. Alvarez-Corral, M. Nunoz-Dorado and
I. Rodriguez-Garcia, Chem Rev., 2008, 108, 3174; (d)
R. Umeda and A. Studer, Org. Lett., 2008, 10, 993; (e)
H. Mandai, K. Mandai, M. L. Snapper and A. H. Hoveyda,
J. Am. Chem. Soc., 2008, 130, 17961; (f) S. W. Youg and
J. I. Eom, J. Org. Chem., 2006, 71, 6705; (g) G. Y. Cho and
C. Bolm, Org. Lett., 2005, 7, 4983; (h) C.-G. Yang,
N. W. Reich, Z. Shi and C. He, Org. Lett., 2005, 7, 4553.
32 (a) X.-Z. Shu, X.-Y. Liu, K.-G. Ji, H.-Q. Xiao and Y.-M. Liang,
Chem.–Eur. J., 2008, 14, 5282; (b) K.-G. Ji, Y.-W. Shen,
X.-Z. Shu, H.-Q. Xiao, Y.-J. Bian and Y.-M. Liang, Adv.
Synth. Catal., 2008, 350, 1250; (c) L.-B. Zhao, Z.-H. Guan,
Y. Han, Y.-X. Xie, S. He and Y.-M. Liang, J. Org. Chem.,
2007, 72, 10276; (d) X.-Z. Shu, X.-Y. Liu, H.-Q. Xiao, K.-G. Ji,
L.-N. Guo, C.-Z. Qi and Y.-M. Liang, Adv. Synth. Catal.,
2007, 349, 2493; (e) X. Duan, X. Liu, L. Guo, M. Liao,
W. Liu and Y. Liang, J. Org. Chem., 2005, 70, 6980.
33 Typical procedure for synthesis of substituted isoquinolines:
(a) Step-1: General procedure for the preparation of 2-(1-alkynyl)
benzaldehyde: To a solution of 2-bromobenzaldehyde (1 eq.)
and alkyne (1.2 eq.) in Et3N (10 vol) was added PdCl2(PPh3)2
(2 mol%). The mixture was stirred for 5 min, and CuI
(1 mol%) was added. The resulting mixture was then heated
under a nitrogen atmosphere at 50ꢀ C for 4 h. The reaction
was monitored by TLC to establish completion. The reaction
mixture was allowed to cool to room temperature, and the
ammonium salt was removed by ltration. The solvent was
removed under reduced pressure, and the residue was
puried by column chromatography on silica gel using n-
hexane/ethyl acetate as an eluent to afford 2-(1-alkynyl)
benzaldehyde; (b) Step-2: General procedure for the preparation
of iminoalkynes: To a mixture of 2-(1-alkynyl)benzaldehyde
13 (a) S.-J. Liu, Q. Zhao, R.-F. Chen, Y. Deng, Q.-L. Fan, F.-Y. Li,
L.-H. Wang, C.-H. Huang and W. Huang, Chem.–Eur. J., 2006,
12, 4351; (b) Q. Zhao, S. Liu, M. Shi, C. Wang, M. Yu, L. Li,
F. Li, T. Yi and C. Huang, Inorg. Chem., 2006, 45, 6152; (c)
A. Tsuboyama, H. Iwawaki, M. Furugori, T. Mukaide,
J. Kamatani, S. Igawa, T. Moriyama, S. Miura, T. Takiguchi,
S. Okada, M. Hoshino and K. Ueno, J. Am. Chem. Soc.,
2003, 125, 12791.
14 (a) T. Ishikawa, K. Shimooka, T. Narioka, S. Noguchi,
T. Saito, A. Ishikawa, E. Yamazaki, T. Harayama, H. Seki
and K. Yamaguchi, J. Org. Chem., 2000, 65, 9143; (b)
N. Sotomayor and E. Dominguez, J. Org. Chem., 1996, 61,
4062.
15 (a) S. W. Youn, J. Org. Chem., 2006, 71, 2521; (b)
M. Chrzanowska and M. D. Rozwadowska, Chem. Rev.,
2004, 104, 3341; (c) E. D. Cox and J. M. Cook, Chem. Rev.,
1995, 95, 1797.
16 (a) M. Boudou and D. Enders, J. Org. Chem., 2005, 70, 9486;
(b) E. R. Walker, S. Y. Leung and A. G. M. Barrett, Tetrahedron
Lett, 2005, 46, 6537.
17 G. Wu, S. J. Geib, A. L. Rheingold and R. F. Heck, J. Org.
Chem., 1988, 53, 3238.
18 F. Maassarani, M. Pfeffer and G. Le Borgne, J. Chem. Soc.,
Chem. Commun., 1987, 8, 565.
19 I. R. Girling and D. A. Widdowson, Tetrahedron Lett., 1982,
23, 4281.
20 (a) S. Cacchi, G. Fabrizi and L. Moro, Tetrahedron Lett., 1998,
39, 5101; (b) G. Chaudhuri, C. Chowdhury and N. G. Kundu,
Synlett, 1998, 1273; (c) N. Montiero and G. Balme, Synlett,
1998, 746; (d) C. Chowdhury, G. Chaudhuri, S. Guha,
A. K. Mukkherjee and N. G. Kundu, J. Org. Chem., 1998, 63,
38496 | RSC Adv., 2014, 4, 38491–38497
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
(1 eq.) was added tert-butylamine (6 eq.). The mixture was then
stirred under an Ar atmosphere at room temperature for 24 h.
The resulting mixture was extracted with ether. The combined
organic layers were dried over Na2SO4 and ltered. Removal of
the solvent afforded an iminoalkyne; (c) Step-3: General
procedure for the cyclization of iminoalkynes: To a solution of
iminoalkyne (1 mmol) in DMF (5 mL) was added Ag(I)-K10
clay (20 mg) and the solution was ushed with nitrogen. The
300 K, TMS ¼ 0 ppm): d ¼ 7.41–7.45 (m, 1H), 7.50–7.58 (m,
2H), 7.60–7.62 (m, 1H), 7.69–7.73 (m, 1H), 7.78–7.90 (d, 1H),
8.00–8.02 (d, 1H), 8.08 (s, 1H), 8.13–8.15 (t, 2H), 9.36 (s, 1H)
ppm; 13C NMR (100 MHz, CDCl3, T ¼ 300 K, TMS ¼
0 ppm): d ¼ 116.5, 126.9, 127.0, 127.0, 127.5, 127.7, 128.5,
128.7, 130.5, 136.6, 139.5, 151.2, 152.3 ppm; LC MS (ESI-MS):
m/z calcd for C15H11N (M + H)+: 206.2; Found: 206.1 (M +
H)+(ii) 3-(2-Methylphenyl)isoquinoline (4b) (Table 2, entry 2):
Compound 4b was prepared according to the general
procedure and puried by column chromatography. Yellow
ꢀ
reaction mixture was heated to 100 C for 6 h. The reaction
mixture was cooled to room temperature, and then ltered
and concentrated. The crude product was puried through
column chromatography by using n-hexane/ethyl acetate as
an eluent to afford as substituted isoquinolines. The
recovered catalyst was thoroughly washed with ethyl acetate
and reused for next run. The puried products were
characterized by their 1H, 13C-NMR as well as by mass
spectral data(i) 3-Phenylisoquinoline (4a) (Table 2, entry 1):
Compound 4a was prepared according to the general
ꢀ
solid; m.p. 80.4-81.8 C. 1H NMR (400 MHz, CDCl3, T ¼ 300
K, TMS ¼ 0 ppm): d ¼2.43 (s, 3H),7.27–7.33 (q, 3H), 7.51–
7.52 (d, 1H), 7.61–7.65 (m, 1H), 7.71–7.75 (m, 1H), 7.76 (s,
1H), 7.86–7.88 (d, 1H), 8.02–8.04 (d, 1H), 9.36 (s, 1H) ppm;
13C NMR (100 MHz, CDCl3, T ¼ 300 K, TMS ¼ 0 ppm): d ¼
20.3, 120.0, 125.8, 126.6, 127.0, 127.1, 127.4, 128.0, 129.9,
130.4, 130.6, 136.07, 136.07, 136.1, 140.4, 151.7, 153.6 ppm;
LC MS (ESI-MS): m/z calcd for C16H13N (M + H)+: 220.1:
219.2; Found: 220.1 (M + H)+.
procedure and puried by column chromatography. Offwhite
ꢀ
solid; m.p. 103.4–104.4 C. 1H NMR (400 MHz, CDCl3, T ¼ 34 H. E. B. Lempers and R. A. Sheldon, J. Catal., 1998, 175, 62.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 38491–38497 | 38497