Tandem C-C coupling - Intramolecular acetylenic Schmidt reaction under Pd/C-Cu catalysis

Article abstract of DOI:10.1039/b617823e

A new one-pot reaction for the regioselective construction of a six-membered fused N-heterocyclic ring leading to isoquinolones under Pd/C-Cu catalysis is described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b617823e

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Tandem C–C coupling – intramolecular acetylenic Schmidt reaction
under Pd/C–Cu catalysis{{
Venkateswara Rao Batchu,a Deepak Kumar Barange,a Dinesh Kumar,a Bukkapattanam R. Sreekanth,a
K. Vyas,a E. Amarender Reddyb and Manojit Pal*a
Received (in Cambridge, UK) 6th December 2006, Accepted 7th February 2007
First published as an Advance Article on the web 19th February 2007
DOI: 10.1039/b617823e
A new one-pot reaction for the regioselective construction of a
six-membered fused N-heterocyclic ring leading to isoquino-
lones under Pd/C–Cu catalysis is described.
Transition metal mediated synthesis of nitrogen containing
heterocycles via addition of an N–H bond across the C–C triple
bond has been one of the frontier areas in organic chemistry.1 This
Scheme 1
is exemplified by the synthesis of a large variety of structurally
diverse N-heterocycles and palladium is by far the most utilized
To this end, we have observed that treatment of 2-iodobenzoyl
metal in these catalytic processes. While the Pd-mediated synthesis
azide (1a) with 2-methylbut-3-yn-2-ol (2a) in the presence of a
of a number of N-heterocycles, especially indoles,2 has been
palladium catalyst, CuI and E3N produced the corresponding
studied extensively, only a few have been reported for the synthesis
3-substituted-1(2H)-isoquinolone (3a) as
a major product
of 1(2H)-isoquinolones.3 Nevertheless, this heterocycle is one of
the basic units found in a wide variety of plant alkaloids, bioactive
compounds and drugs.4 For example, 6-amino-7-chloro-
2-(5-methyl-3H-imidazol-4-ylmethyl)-2H-isoquinolone has been
identified as a novel orally active 5-HT3 antagonist4a and
2-{4-[(1-oxo-1,2-dihydroisoquinolin-7-ylmethyl)-prop-2-ynylamino]-
benzoylamino}succinic acid showed promising thymidylate
synthase (TS) inhibitory activity.4b Since TS inhibitors could
play a role as potential anticancer agents, we decided to
explore the synthesis and anticancer activities of a library of
small molecules based on an isoquinolone scaffold.
(entries 1–4, Table 1). Among the catalysts we examined, 10%
Pd/C–PPh3 in EtOH gave better results (entry 3, Table 1) although
the use of (PPh3)2PdCl2 or (PPh3)4Pd afforded 3a, albeit in low
yields. When the reaction was performed in the absence of CuI no
product was formed, indicating that the Cu-catalyst is needed for
the reaction to proceed. On the other hand the reaction gave
mainly five-membered ring product (4a) in the absence of Pd-
catalyst (entry 6, Table 1). Compound 4a was also isolated as the
only product when other solvents were used (entries 7–11, Table 1).
Isoquinolone 3a was distinguished from the isoindolinone 4a on
the basis of their IR spectra. The carbonyl absorption band
Recently, the union of terminal alkynes and organic azides5 in
the presence of transition metal catalysts to give 1,4-disubstituted
1,2,3-triazoles has shown remarkable applications in organic
synthesis.6 An intramolecular version of this [3 + 2] cycloaddition
afforded isoindoline fused with triazoles successfully under
appropriate reaction conditions.6d On the other hand the reactivity
of alkyl azides as nucleophiles toward gold(I)-activated alkynes in
an intramolecular cyclization process (acetylenic Schmidt reaction)
leading to pyrroles has been studied recently.7a The present
communication addresses several challenging issues related to the
use of acyl azides7b (Scheme 1) e.g. (i) their reactivity towards
transition metal-activated alkynes, (ii) regioselectivity and (iii) the
optimal catalyst system. We envisaged that the acyl group of acyl
azide might influence the reactivity pattern of azide favouring
expulsion of dinitrogen as the reaction proceeds (path a, Scheme 1).
Table 1 Pd-mediated coupling of 1a with terminal alkyne (2a)a
% Yieldb
Entry
Pd-catalyst
Solvent
3a
4a
1
2
3
Pd(PPh3)4
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
1,4-dioxane
THF
63
58
82
42
20
40
—
20
—
40
60
27
36
48
60
Pd(PPh3)2Cl2
10% Pd/C–PPh3
10% Pd/C
10% Pd/C–PPh3
PPh3
10% Pd/C–PPh3
10% Pd/C–PPh3
10% Pd/C–PPh3
10% Pd/C–PPh3
10% Pd/C–PPh3
4
5c
6
—
trace
nd
nd
nd
nd
nd
7
8
9
10
11
a
aDiscovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road,
Miyapur, Hyderabad 500049, India. E-mail: manojitpal@drreddys.com;
Fax: 91 40 2304 5438; Tel: 91 40 2304 5439
CH3CN
Toluene
DMF
bCustom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd.,
Bollaram Road, Miyapur, Hyderabad 500049, India
Reaction conditions: 1a (1.0 equiv.), 2a (1.0 equiv.), 10% Pd/C or
{ Electronic supplementary information (ESI) available: Experimental
procedures, spectral data for all new compounds (Table 2) and crystal-
lographic data for 3j. See DOI: 10.1039/b617823e
other Pd-catalyst (0.03 equiv.), PPh3 (0.12 equiv.), CuI (0.06 equiv.),
b
c
Et3N (2 equiv.) at 80 uC for 12 h under N2. Isolated yield. The
reaction was carried out without CuI. nd 5 not detected.
{ DRL publication number 634.
1966 | Chem. Commun., 2007, 1966–1968
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Table 2 Pd/C-mediated synthesis of 1(2H)-isoquinolonesa
Entry Haloenone Alkyne
1
Product
% Yieldb
82
3a
2a
1a
2
3
1a
3b
3c
85
60
2b
1a
2c
2d
4
1a
3d
82
5
6
1a
1a
3e
3f
55
44
Fig. 1 X-ray crystal structure of 3j (ORTEP diagram). Displacement
ellipsoids are drawn at 50% probability level for non-hydrogen atoms.
2e
3-substituted-1(2H)-isoquinolone 3 in good yields and isomeric
products such as isoindolinones were not detected (entries 1–12,
Table 2). The preparation of 3a is representative: A mixture of
2-iodobenzoyl azide (0.3 g, 1.09 mmol), 10% Pd/C (0.034 g, 0.033
mmol), PPh3 (0.034 g, 0.13 mmol), CuI (0.013 g, 0.065 mmol) and
triethylamine (0.22 g, 0.3 mL, 2.17 mmol) in ethanol (10 mL) was
stirred at 25 uC for 30 min under nitrogen. To this mixture was
added 2-methylbut-3-yn-2-ol (0.092 g, 1.09 mmol) slowly with
stirring. The reaction mixture was then stirred at 80 uC for 12 h,
cooled to room temperature, diluted with EtOAc (50 mL) and
filtered through Celite. The filtrate was collected and concentrated
under vacuum. The residue was purified by column chromato-
graphy (petroleum ether–EtOAc) to afford 3a in 82% yield. The
use of aryl alkynes afforded the desired products in low yield along
with other side products (entries 13–14, Table 2). Notably,
dimerization (homocoupling)8 of the terminal alkynes was
observed as a side reaction in a few cases especially when
arylalkynes were used (entries 13–14, Table 2). Perhaps this was
facilitated in the presence of Pd(II)8d generated in situ (see later for
mechanistic discussion). All the isoquinolones synthesized were
characterized by spectral9 and analytical data and this was
supported by the molecular structure of 3j being confirmed by
X-ray analysis (Fig. 1).§10
2f
7
8
9
1a
1a
3g
3h
3i
73
56
78
2g
2h
2d
1b
1b
10
11
2g
2f
3j
65
85
1b
1b
3k
12
13
2b
3l
84
1a
1a
3m 43c
2i
2j
A possible mechanism involving in situ generation of o-alkynyl
azido benzene
A via Pd/C-mediated Sonogashira coupling
14
3n
40d
followed by intramolecular acetylenic Schmidt reaction is shown
in Scheme 2. Presumably, Pd(II) generated11a from Pd(0) activates
the C–C triple bond11b which undergoes nucleophilic addition by
the proximal nitrogen of the azide. Subsequent loss of dinitrogen
a
Reaction conditions: 1 (1.0 equiv.), 2 (1.0 equiv.), 10% Pd/C
(0.03 equiv.), PPh3 (0.12 equiv.), CuI (0.06 equiv.), Et3N (2 equiv.)
b
c
in EtOH at 80 uC for 12 h under N2. Isolated yield. 3-Phenyl-4-
phenylethynyl-2H-isoquinolin-1-one was isolated as a side product.
3-p-Tolyl-4-tolylethynyl-2H-isoquinolin-1-one was isolated as a side
d
product.
appeared at 1736 cm21 for six-membered ring product 3a and at
1786 cm21 for five-membered ring product 4a.
We were pleased to find that tandem C–C coupling–
Schmidt reaction under Pd/C–Cu catalysis provided isoquinolones
with a variety of substitution patterns (Table 2). The reaction
proceeded well with a variety of terminal alkynes to give
Scheme 2 Possible mechanism for the formation of isoquinolone.
Chem. Commun., 2007, 1966–1968 | 1967
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produces the cationic intermediate B7a (stabilized by the electron
donation from palladium), which as a result of hydride shift
followed by the regeneration of Pd(0) finally affords the
isoquinolone 3. A mechanism involving generation of a nitrene-
like intermediate,7b although it cannot be fully ruled out, would
lead to the formation of a related product as a result of Curtius
rearrangement.11c Also the observation that o-alkynyl benzamide
is unreactive under the conditions studied (i.e. Pd/C–PPh3–CuI or
PPh3–CuI at 80 uC for 24 h) disfavours the intermediacy of this
amide that may be generated in situ. Nevertheless, a pathway
similar to that shown in Scheme 2 can also be proposed for the
formation of isoindolinone where nucleophilic addition of the
azide to the C–C triple bond followed by the loss of dinitrogen
produces the cationic intermediate corresponding to the five-
membered ring product.12
5 For the scope and limitations on the use of azides in industrial
production along with the implementation of safety measures, see:
J.-P. Hagenbuch, CHIMIA Int. J. Chem., 2003, 57, 773.
6 (a) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless,
Angew. Chem., Int. Ed., 2002, 41, 2596; (b) C. W. Tornøe, C. Christensen
and M. Meldal, J. Org. Chem., 2002, 67, 3057; (c) S. Kamijo, T. Jin,
Z. Huo and Y. Yamamoto, J. Am. Chem. Soc., 2005, 125, 7786; (d)
C. Chowdhury, S. B. Mandal and B. Achari, Tetrahedron Lett., 2005,
46, 8531.
7 (a) D. J. Gorin, N. R. Davis and F. D. Toste, J. Am. Chem. Soc., 2005,
127, 11260; (b) T. Bach, B. Schlummer and K. Harms, Synlett, 2000,
1330.
8 (a) N. G. Kundu, M. Pal and C. Chowdhury, J. Chem. Res. (S), 1993,
432; (b) A. Lei, M. Srivastava and X. Zhang, J. Org. Chem., 2002, 67,
1969; (c) S. Urgaonkar and J. G. Verkade, J. Org. Chem., 2004, 69,
5752; (d) A. S. Batsanov, J. C. Collings, I. J. S. Fairlamb, J. P. Holland,
J. A. K. Howard, Z. Lin, T. B. Marder, A. C. Parsons, R. M. Ward and
J. Zhu, J. Org. Chem., 2005, 70, 703; (e) Formation of 10–12% of
dimeric product was observed when arylalkynes were used.
9 Spectral data for selected compounds: 3a; brown solid; mp 88–90 uC;
nmax (KBr)/cm21 3284 and 1736; dH (400 MHz; CDCl3; Me4Si) 1.60
(6 H, s, 2 6 Me), 1.91 (1 H, br s, OH), 6.62 (1 H, s, CHLC), 7.43 (1 H,
d, J 6.8 Hz, ArH), 7.47 (1 H, t, J 6.8 Hz, ArH), 7.70 (1 H, t, J 7.5 Hz,
ArH) and 8.27 (1 H, d, J 7.5 Hz, ArH); dC (50 MHz; CDCl3; Me4Si)
28.2 (2C), 83.9, 99.9, 125.9, 126.4, 128.1, 129.5, 131.9, 134.9, 137.2 and
161.7; m/z (CI Mass) 205 (M + 1, 100%), 187 (M+ 2 18, 30%); 3g;
brown solid; mp 54–56 uC; nmax (KBr)/cm21 3423, 2243 and 1723; dH
(400 MHz; CDCl3; Me4Si) 2.14–2.07 (2 H, m, CH2), 2.51–2.42 (2 H, m,
CH2), 2.72 (2 H, t, J 7.2 Hz), 6.36 (1 H, s, CHLC), 7.38 (1 H, d, J 7.8 Hz,
ArH), 7.49 (1 H, t, J 7.8 Hz, ArH), 7.70 (1 H, t, J 7.3 Hz, ArH), 8.26
(1 H, d, J 7.3 Hz, ArH); dC (50 MHz; CDCl3; Me4Si) 16.3, 22.6, 32.1,
104.4, 120.2, 125.3, 128.1, 129.5 (2C), 134.9 (2C), 136.9 and 162.5; m/z
(CI Mass) 214 (M + 1,100%).
In summary, we have developed a simple method to afford
3-substituted 1(2H)-isoquinolones that are not easily available
from the previously known methodologies. The use of Pd/C–Cu
catalysis is the key of this new transformation. This mild process
was found to be general and highly regioselective, affording an
array of compounds of potential biological significance.13,14
We thank Dr R. Rajagopalan and Prof. J. Iqbal for their
encouragement and analytical group for spectral data. We also
thank Mr P. Annamalai for biological assays.
Notes and references
10 Crystallographic data for 3j: single crystal from methanol, C14H14N2O2,
˚
M 5 242.28, orthorhombic, space group Pca21, a 5 23.78(1) A,
§ CCDC 630060. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/b617823e
3
˚
˚
˚
b 5 4.560(3) A, c 5 11.134(7) A, V 5 1207(1) A and Z 5 4,
rcalc 5 1.333 Mg m23, T 5 298 K, m 5 0.907 cm21, 13936 processed
reflections, 1401 unique reflections, Rint 5 3.47% and final R
factor 5 0.067 (all data).
1 For general reviews, see: (a) M. E. Fakley, J. Organomet. Chem., 1985,
13, 345; (b) R. C. Larock and W. W. Leong, in Comprehensive Organic
Synthesis, ed. B. M. Trost and I. Fleming, Pergamon Press, Oxford,
1991, Vol. 4, p. 269; (c) Y. Yamamoto and U. Radhakrishnan, Chem.
Soc. Rev., 1999, 28, 199; (d) F. Alonso, I. P. Beletskaya and M. Yus,
Chem. Rev., 2004, 104, 3079.
11 (a) B. M. Trost and F. D. Toste, J. Am. Chem. Soc., 1996, 118, 6305.
For activation of triple bond by HPdX, see: (b) C. H. Oh, C. Y. Rhim,
H. H. Jung and S. H. Jung, Bull. Korean Chem. Soc., 1999, 20, 643; (c)
See for example, N. Briet, M. H. Brookes, R. J. Davenport, F. C. A.
Galvin, P. J. Gilbert, S. R. Mack and V. Sabin, Tetrahedron, 2002, 58,
5761.
2 S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105, 2873.
3 (a) T. Yao and R. C. Larock, J. Org. Chem., 2005, 70, 1432; (b)
M.-J. Wu, L.-J. Chang, L.-M. Wei and C.-F. Lin, Tetrahedron,
1999, 55, 13193; (c) H. Sashida and A. Kawamukai, Synthesis,
1999, 1145; (d) A. Nagarajan and T. R. Balasubramanian,
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 1989,
28, 67. For a review on other synthetic methods, see: (e)
V. A. Glushkov and Y. V. Shklyaev, Chem. Heterocycl. Compd.,
2001, 37, 663.
4 (a) T. Matsui, T. Sugiura, H. Nakui, S. Iguch, S. Shigeoka, H. Tukedu,
T. Odagaki, Y. Ushio, K. Ohmoto, M. Iwamani, S. Yamazaki, T. Arai
and M. Kawamura, J. Med. Chem., 1992, 35, 3307; (b) S. W. Li,
M. G. Nair, D. M. Edwards, R. L. Kisluick, Y. Gaument, I. K. Dev,
D. S. Duch, J. Humphreys, G. K. Smith and R. Ferone, J. Med. Chem.,
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256.
12 In an alternative mechanism, intermediate A adds HPdI to generate two
vinyl palladium intermediates. Intramolecular azide addition to the
double bond generates two triazines. Loss of nitrogen results in two
aziridines. The aziridines then open to give vinyl palladium intermediates
corresponding to the five- and six-membered ring products that finally
afford 3 and 4 in the presence of triethylamine (which perhaps acts as a
reducing agent). For intramolecular cycloaddition of an azide across a
double bond leading to an aziridine, see: A. Padwa, A. Ku, H. Ku and
A. Mazzu, J. Org. Chem., 1978, 43, 66 and G. Broggini, L. Garanti,
G. Molteni and T. Pilati, Tetrahedron: Asymmetry, 2001, 12, 1201.
13 Compound 3f showed anticancer activity with an average GI50 of 28.32
on a tested panel of cancer cell lines [e.g. HT29 (colon), H460 (lung),
LoVo (colon)] (see Electronic Supplementary Information).
14 For in vitro antitumour activity of compounds 3m–n against various cell
lines, see: W.-J. Cho, M.-J. Park, B.-H. Chung and C.-O. Lee, Bioorg.
Med. Chem. Lett., 1998, 8, 41.
1968 | Chem. Commun., 2007, 1966–1968
This journal is ß The Royal Society of Chemistry 2007