Palladium-copper catalysed heteroannulation of acetylenic compounds: An expeditious synthesis of isoindoline fused with triazoles

Article abstract of DOI:10.1016/j.tetlet.2005.10.006

A convenient and general method for the synthesis of isoindoline fused with triazoles from ortho-iodobenzyl azide and acetylenes through palladium-copper catalysis is described.

Full text of DOI:10.1016/j.tetlet.2005.10.006

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8531–8534
Palladium–copper catalysed heteroannulation of acetylenic
compounds: an expeditious synthesis of isoindoline
fused with triazolesI
Chinmay Chowdhury,a,* Sukhendu B. Mandalb and Basudeb Acharib
aCentral Institute of Medicinal and Aromatic Plants, Process and Product Development, Kukrail Picnic Spot Road,
P.O. CIMAP, Lucknow-226015, India
bIndian Institute of Chemical Biology, Medicinal Chemistry Division, 4, Raja S. C. Mullick Road, Kolkata-700032, India
Received 27 July 2005; revised 28 September 2005; accepted 4 October 2005
Abstract—A convenient and general method for the synthesis of isoindoline fused with triazoles from ortho-iodobenzyl azide and
acetylenes through palladium–copper catalysis is described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Developing new synthetic methods for novel nitrogen-
containing molecules has always been a frontier area
of organic synthesis.1 Among a large variety of com-
pounds, isoindoline derivatives are of particular interest
because of their diverse biological activities and clinical
applications. The core ring structure is present in many
heterocycles that have been shown to elicit a wide array
of biological effects including NMDA receptor antago-
nism,2a modulation of estrogen2b and dopamine D3
and D4 receptors,2c,d inhibition of selective serotonin
reuptake2e and anti-bacterial activity.2f Similarly, the
1,2,3-triazole nucleus is a structural motif found in large
number of compounds possessing activities, such as
anti-HIV,3a anti-microbial3b and anti-bacterial3c activi-
ties and has also found many applications in chemical
industries.3d Fused triazoles have also found widespread
use as anti-allergic agents4a and potent glycosidase
inhibitors4b amongst others.4c–e Although a variety of
approaches to isoindolines5 and triazoles6 have been de-
scribed, to our knowledge the synthesis of isoindoline
fused with triazoles which could perhaps be an impor-
tant building block (or a novel pharmacophore), has
not yet been reported.
As part of our continuing interest in the development of
novel heterocyclic ring structures7 of biological signifi-
cance, the (3+2) cycloaddition strategy has promoted
us to investigate the construction of isoindoline fused
with triazoles in a single operation under palladium–
copper catalysis. It is worth mentioning that the azido
group has emerged as a useful chemical handle in syn-
thetic chemistry and bioconjugate chemistry as well,
soon after the discovery of its (3+2) cycloaddition with
alkynes by Huisgen et al.8 This classic reaction is even
being carried out in living systems in order to under-
stand the chemical biology.9
Here, we report that treatment of ortho-iodobenzyl
azide10 1 with acetylene substrates 2a–j in DMF in
the presence of triethylamine and a catalytic amount
of bis(triphenylphosphine)palladium(II) chloride and
cuprous iodide furnished isoindolotriazoles 3a–j in good
yields (Scheme 1 and Table 1). Optimum yields were
obtained when the reaction mixture was stirred at room
temperature for 12 h followed by heating at 115 ꢁC for
10 h. Heating gave some polymeric products, thus
R
N
I
Pd(PPh3)2Cl2
N
+
N3
C
R
H
C
N
CuI /Et3N/DMF
115 oC, 10 h
Keywords: Palladium and copper catalyst; Isoindoline; Triazole.
q CIMAP Communication No. 2005-44J.
2a-j
1
3a-j
*
Corresponding author. Fax: +91 522 2357136; e-mail: cchinmay2@
yahoo.com
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.006

8532
C. Chowdhury et al. / Tetrahedron Letters 46 (2005) 8531–8534
Table 1. Palladium–copper catalysed heteroannulations of azides 1 with acetylenic compounds 2a–j leading to isoindoline fused with triazoles 3a–j
Entry
1
Acetylenes 2
Productsa 3
Yieldsb (%)
N
58
N
2a
N
3a
2
3
4
5
61
60
63
28
N
N
N
N
N
2b
3b
CH3
N
N
2c
CH3
3c
3d
CH2OMe
N
N
2d
CH2OMe
CHO
O
OHC
O
OMe
N
N
2e
OMe
N
3e
3f
N
N
6
7
CH3(CH2)3CꢀCH
66
31
N
2f
O
Ph
N
N
PhCH2OCH2CꢀCH
N
O
2g
3g
O
O
O
O
O
O
O
O
8
33
O
N
N
O
O
2h
N
N
3h
Me3Si
H
N
N
N
N
9c
Me3SiCꢀCH
57 (1:2)
N
+
2i
3i1
3i2
OTBS
N
N
10d
TBSOCH2CꢀCH
59
N
2j
3j
a Satisfactory spectroscopic (1H NMR, 13C NMR, IR and mass) and analytical data were obtained for all the compounds synthesised.
b The yields (based on o-iodobenzyl azide 1) are isolated yields of chromatographically pure materials.
c Partial desilylation took place under our reaction conditions.
d TBS represents tert-butyldimethylsilyl.

C. Chowdhury et al. / Tetrahedron Letters 46 (2005) 8531–8534
8533
lowering the product yields. Heating at lower tempera-
tures gave a mixture of the desired cyclised product 3
and the acyclic condensation product. The acyclic prod-
uct (A, Scheme 2) may be an intermediate in the forma-
tion of product 3. Bis(triphenylphosphine)palladium(II)
chloride was found to be the catalyst of choice. Cuprous
iodide was an essential co-catalyst. In the absence of
either palladium catalyst or cuprous iodide no product
was formed. This reaction was found to be equally
applicable to both aromatic and aliphatic acetylenes.
The acetylenic components 2 could also carry various
substituents like methyl, methoxy, formyl, ether, tert-
butyldimethylsilyl (TBS) and other moieties, without
affecting the heteroannulation process (entries 3–5and
10 in Table 1). The chiral sugar acetylene derivative 2h
was also found to be compatible (Table 1, entry 8).
Partial desilylation of 2i took place under our reaction
conditions (Table 1, entry 9). The yields were generally
found to be good except in the case of propargylated
acetylenes (entries 5, 7 and 8). Modest yields, observed
in these cases, could be attributable to a possible
depropargylation reaction.11
General procedure: A mixture of ortho-iodobenzyl azide
1 (2 mmol), (PPh3)2PdCl2 (0.07 mmol), CuI (0.14 mmol)
and triethylamine (12 mmol) was stirred in DMF (14 ml)
under an argon atmosphere for 1 h. The acetylenic com-
pound 2 (2.5mmol) was then added and the mixture
stirred at room temperature for 12 h followed by heating
at 115 ꢁC for another 10 h. DMF was evaporated under
reduced pressure and the residue was extracted with
ethyl acetate (3 · 40 ml). The combined organic layers
were dried (Na2SO4), filtered and the solvent removed
in vacuo. The residue was purified by chromatography
on silica gel (with 30–50% ethyl acetate in hexane as
eluent) to obtain the desired product 3. Thus, starting
with 1 (518 mg, 2 mmol), and hex-1-yne 2f (206 mg,
2.5mmol), a colourless solid product 3f (281 mg, 66%)
was isolated. mp: 75–78 ꢁC, 1H NMR (300 MHz,
CDCl3) dH 0.94 (t, J = 7.3 Hz, 3H), 1.39–1.51 (m, 2H);
1.76–1.86 (m, 2H), 2.99 (t, J = 7.3 Hz, 2H), 5.33 (s,
2H), 7.37–7.53 (m, 3H), 7.62 (d, J = 7.4 Hz, 1H); 13C
NMR (75MHz, CDCl 3) dC 13.66, 22.13, 25.41, 31.44,
50.74, 120.60, 123.96, 127.50, 128.30, 128.52, 139.17,
140.50; IR (KBr) mmax 3073, 2948, 2860, 1454, 1355,
1302 cmÀ1, mass spectrum (FAB): m/z = 214 (M+H)+,
198, 184, 170, 156, 142; Anal. Calcd for C13H15N3: C,
73.21; H, 7.09; N, 19.70. Found: C, 73.23; H, 7.12; N,
19.73.
The mechanism of the reaction may proceed according
to Scheme 2. The catalytic cycle begins with the forma-
tion of an active Pd(0) species7a,12 accompanied by the
formation of an acetylenic dimer.13 Next, coupling
through a Sonogashira reaction12 could lead to the for-
mation of acylic product A. Presumably, the acyclic
product A is converted to the cyclised product through
copper-coordinated intermediate species B.14 DMF, as
a dipolar aprotic solvent, may also facilitate the intra-
molecular [3+2] cycloaddition of B.15
Acknowledgements
C.C. thanks Dr. Suman P. S. Khanuja, director of
CIMAP, Lucknow, India, for constant encouragement
of this work.
Thus, we have described the first successful palladium–
copper catalysed reaction for the synthesis of isoindoline
fused with triazoles from readily available starting mate-
rials. This reaction relies on carbon–carbon bond forma-
tion followed by cycloaddition of azide to the internal
alkynes (generated in situ) under appropriate reaction
conditions. Notably, cycloadditions of azide to the
internal alkynes failed under click chemistry reaction
conditions.6a–c Our newly developed method is opera-
tionally simple and we believe that this method will find
applications in organic and medicinal chemistry as well.
References and notes
1. WohlerÕs synthesis of urea can be considered the birth of
organic synthesis: Wohler, F. Ann. Phys. Chem. 1828, 12,
253.
2. (a) Alanine, A.; Burner, S.; Buettelmann, B.; Heitz, N. M.;
Jaeschke, G.; Pinard, E.; Wyler, R. Eur. Pat. Appl., EP10
90917, 2001; Chem. Abstr. 2001, 134, 280719b; (b)
Bhagwat, S. S.; Gayo, L. M.; Stein, B.; Chao, Q.;
Gangloff, A.; Mckie, J.; Rice, K. PCT Int. Appl., WO
0055137, 2000; Chem. Abstr. 2000, 133, 252323d; (c)
Johnson, C. N.; Stemp, G. PCT Int. Appl., WO 0021950,
2000; Chem. Abstr. 2000, 132, 279110y; (d) Broughton, H.
B.; Kulagowski, J. J.; Leeson, P. D.; Mawer, I. M. PCT
Int. Appl., WO 9421628, 1994; Chem. Abstr. 1995, 122,
9863d; (e) Kapples, K. J.; Shutske, G. M. J. Heterocycl.
Chem. 1997, 34, 1335–1338; (f) Yamada, M.; Hamamoto,
S.; Hayashi, K.; Takaoka, K.; Matsukura, H; Yotsuji, M.;
Yonezawa, K.; Ojima, K.; Takamatsu, T.; Taya, K.;
Yamamoto, H.; Kiyoto, T.; Kotsubo, H. PCT Int. Appl.,
WO 9921849, 1999; Chem. Abstr. 1999, 130, 311706u.
3. (a) Alvarez, R.; Velazquez, S.; San, F.; Aquaro, S.; De-
Clercq, C.; Perno, C.-F.; Karlsson, A.; Balzarini, J.;
Camarasa, M. J. J. Med. Chem. 1994, 37, 4185–4194; (b)
Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn,
M. R.; Emmert, D. E.; Garmon, S. A.; Graber, D. R.;
Grega, K. C.; Hester, J. B.; Hutchinson, D. K.; Morris, J.;
Reischer, R. J.; Ford, C. W.; Zurenko, G. E.; Hamel, J.
CuI
Et3N
C)2R (Ph P) Pd0L
R-(C
(PPh3)2PdCl2 + 2 H
C
C
R
+
3
2
n
R
I
CuI
(PPh3)2Pd0Ln
Et3N
+
Pd0Ln
+
H
C C R
N
N
-
N3
N
+
2
A
1
CuI
R
R
CuI
N
CuI
..
N
N
N
N
N
-
+
B
3
Scheme 2. Proposed reaction mechanism.

8534
C. Chowdhury et al. / Tetrahedron Letters 46 (2005) 8531–8534
C.; Schaadt, R. D.; Stapert, D.; Yagi, B. H. J. Med. Chem.
7. (a) Chowdhury, C.; Kundu, N. G. Chem. Commun. 1996,
1067–1068; (b) Chowdhury, C.; Chaudhuri, G.; Guha, S.;
Mukherjee, A. K.; Kundu, N. G. J. Org. Chem. 1998, 63,
1863–1871; (c) Chaudhuri, G.; Chowdhury, C.; Kundu, N.
G. Synlett 1998, 1273–1275; (d) Achari, B.; Mandal, S. B.;
Dutta, P. K.; Chowdhury, C. Synlett 2004, 2449–2467.
8. (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2,
565–598; (b) Huisgen, R. In 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; pp 1–
176.
9. (a) Link, A. J.; Vink, M. K. S.; Tirrell, D. A. J. Am. Chem.
Soc. 2004, 126, 10598–10602; (b) Agard, N. J.; Prescher, J.
A.; Bertozzi, C. R. J. Am. Chem. Soc. 2004, 126, 15046–
15047; (c) Tian, F.; Tsao, M.-L.; Schultz, P. G. J. Am.
Chem. Soc. 2004, 126, 15962–15963.
2000, 43, 953–970; (c) Kume, M.; Kubota, T.; Kimura, Y.;
Nakashimizu, H.; Motokawa, K.; Nakano, M. J. Antibiot.
1993, 46, 177–192; (d) Fan, W.-Q.; Katritzky, A. R.. In
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Comprehensive Heterocyclic Chemistry II; Elsevier Sci-
ence: Oxford, 1996; Vol. 4, pp 1–126.
4. (a) Georgiev, V. S.; Loev, B.; Mack, R.; Musser, J. US
Patent, US 4,276, 292, 1981; Chem. Abstr. 1981, 95,
132905v; (b) Tatsuta, K.; Ikeda, Y.; Miura, S. J. Antibiot.
1996, 49, 836–838; (c) Roma, G.; Dibraccio, M.; Grossi,
G.; Mattioli, F.; Ghia, M. Eur. J. Med. Chem. 2000, 35,
1021–1035; (d) Krulle, T. M.; De la Fuente, C.; Pickering,
¨
L.; Aplin, R. T.; Tsitsanou, K. E.; Zographos, S. E.;
Oikonomakos, N. G.; Nash, R. J.; Griffiths, R. C.; Fleet,
G. W. Tetrahedron: Asymmetry 1997, 8, 3807–3820; (e)
Couty, F.; Durrat, F.; Prim, D. Tetrahedron Lett. 2004,
45, 3725–3728.
10. The starting material ortho-iodobenzyl azide
1 was
prepared by heating ortho-iodobenzyl bromide (1.5g,
5mmol) and sodium azide (400 mg, 6.2 mmol) at 100 ꢁC
for 8 h in dry DMF (12 ml). After work-up and purifica-
tion by chromatography on silica gel using 8% (v/v) ethyl
acetate in hexane as eluent, the desired azide 1 was
obtained in 82% yield.
5. (a) Gawley, R. E.; Chemburkar, S. R.; Smith, A. L.;
Anklekar, T. V. J. Org. Chem. 1988, 53, 5381–5383; (b)
Sun, Q.; Zhou, X.; Islam, K.; Kyle, D. J. Tetrahedron Lett.
2001, 42, 6495–6497; (c) Yamamoto, Y.; Nagata, A.; Itoh,
K. Tetrahedron Lett. 1999, 40, 5035–5038; (d) Mance, A.
D.; Borovicka, B.; Karaman, B.; Jakopcic, K. J. Hetero-
cycl. Chem. 1999, 36, 1337–1341; (e) Kukkola, P. J.; Bilci,
N. A.; Ikeler, T. J. Tetrahedron Lett. 1996, 37, 5065–5068;
(f) Grigg, R.; Scott, R.; Stevenson, P. J. Chem. Soc.,
Perkin Trans. 1 1988, 1357–1364.
11. Pal, M.; Parasuraman, K.; Yaleswarapu, K. R. Org. Lett.
2003, 5, 349–352.
12. (a) Sonogashira, K.; Tohda, Y.; Haghihara, N. Tetrahe-
dron Lett. 1975, 50, 4467–4470; (b) Sonogashira, K.. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon: Oxford, 1991; Vol. 3, pp 521–549.
6. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–
2599; (b) Krasinski, A.; Fokin, V. V.; Sharpless, K. B.
Org. Lett. 2004, 6, 1237–1240; (c) Tornoe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057–3064; (d) Katritzky, A. R.; Zhang, Y.; Singh, S. K.;
Steel, P. J. Arkivoc 2003(xv), 47–64; (e) Feldman, A. K.;
Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6, 3897–3899;
(f) Wang, Z.-X.; Qin, H.-L. Chem. Commun. 2003, 2450–
2451; (g) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.;
Vander Eycken, E. Org. Lett. 2004, 6, 4223–4225.
13. In a few cases, dimers were isolated and characterised
unambiguously by spectroscopic and analytical data.
14. Acyclic product A (R = CH2OTBS) was isolated by
carrying out the reaction at room temperature. Various
experiments were then carried with A under various
reaction conditions. Among them, the desired cycloaddi-
tion occurred when A was heated in DMF at 115 ꢁC in the
presence of triethylamine and a catalytic amount of
cuprous iodide only. Without cuprous iodide starting
material A was recovered.
15. Kadaba, P. K. J Org. Chem. 1976, 41, 1073–1075.