Intramolecular cyclization reaction - Palladium(0)-catalyzed cyclization is more effective than tin hydride mediated reaction

Article abstract of DOI:10.1139/V08-023

Intramolecular CH arylation of pyrone, pyridone, uracil, imidazole, and benzimidazole derivatives are carried out in the presence of a Pd catalyst to form potentially bioactive fused heterocyclic compounds, whereas the n-Bu ₃SnH-mediated aryl radical cyclization of the precursors 3 afforded mainly halogen-reduced uncyclized products.

Full text of DOI:10.1139/V08-023

325
Intramolecular cyclization reaction —
Palladium(0)-catalyzed cyclization is more
effective than tin hydride mediated reaction
Krishna C. Majumdar, Pradip Debnath, Abu Taher, and Amarta K. Pal
Abstract: Intramolecular CH arylation of pyrone, pyridone, uracil, imidazole, and benzimidazole derivatives are carried
out in the presence of a Pd catalyst to form potentially bioactive fused heterocyclic compounds, whereas the n-
Bu3SnH-mediated aryl radical cyclization of the precursors 3 afforded mainly halogen-reduced uncyclized products.
Key words: Pd(0) catalyst, CH arylation, intramolecular cyclization, regioselectivity.
Résumé : Opérant en présence d’un catalyseur de palladium, on a réalisé l’arylation intramoléculaire du CH de dérivés
de la pyrone, de la pyridone, de l’uracile, de l’imidazole et du benzimidazole pour former des composés hétérocycli-
ques condensés potentiellement bioactifs alors que la cyclisation des précurseurs 3 à l’aide de radicaux aryles, catalysée
par le n-Bu3SnH, fournit principalement des produits non cyclisés desquels les halogènes ont été réduits.
Mots-clés : catalyseur de Pd(0), arylation du CH, cyclisation intramoléculaire, régiosélectivité.
Majumdar et al. 332
Introduction
try, it has been rapidly applied in an intramolecular sense to
the synthesis of carbocyclic (8) and heterocyclic (9) com-
pounds. The main advantage is that the reagent is non-toxic
and involves an easy workup procedure, and hence can suc-
cessfully be applied for the synthesis of bioactive molecules.
Recently, there is much interest in the synthesis of 2-
pyrone derivatives due to their diverse pharmacological
properties (10). Several natural (11) and synthetic (12)
2-pyrones exhibit remarkable biological activity. 3-
Deazauridine, a pyridone-based compound, is currently un-
dergoing clinical trials as an anticancer agent (13), and it is
also effective against tumor growth (14). Some [1,2-a] fused
imidazoles are also known to have anti-ulcer, antidepressant,
and antimicrobial activity (15). Several [1,2-a]fused
benzimidazoles have antitumor activity (16). Although Pd-
catalyzed intramolecular cyclization is a well-known pro-
cess, its application on pyrone, pyridone, uracil, imidazole,
and benzimidazole systems is much less documented. Re-
cently, the palladium-mediated three component synthesis of
2,3-fused furo-pyridones has been reported (17). An unsuc-
cessful attempt to synthesize the 5-membered fused
heterocycles by intramolecular aromatic substitution by an
imidazol-2-yl radical has been reported (18). However,
Dubois and co-workers (19) reported the synthesis of
bioactive 5H-imidazol[2,1-a]isoindoles by the Pd-catalyzed
intramolecular arylation of N-benzyl-2-iodoimidazole.
Recently, we have successfully demonstrated the radical re-
action (20) and a Pd-catalyzed Heck reaction (21) on
The synthesis of heteroaromatic compounds by intra-
molecular cyclizations has received increasing attention in
organic chemistry, since a wide variety of such molecules
show potential biological activities as pharmaceutical and
agrochemical compounds (1). Several intramolecular reac-
tions have been discovered, and their applications in organic
chemistry have also been well documented in the literature.
The most important ones include the Claisen rearrangement
(2), free radical reactions (3), Pd(0)-catalyzed insertion reac-
tions (4), etc. Free radical reactions are one of the most
straightforward ways for carbon–carbon bond formation in
organic synthesis. Several methods have been devised to
effect such radical cyclizations, with n-Bu3SnH- or n-
Bu3SnCl-mediated reactions being the most explored. The
highly toxic nature of the tin reagent, the difficulties associ-
ated with the removal of toxic tin from the reaction products,
and reduction of the intermediate carbon centered radical by
n-Bu3SnH are frequently highlighted as reasons to avoid
these reagents (5). The disadvantages associated with these
reagents have led synthetic organic chemists to find alterna-
tive methods and (or) reagents to accomplish such reactions.
Reagents such as less toxic silanes and germanes have been
used as substitutes for n-Bu3SnH and n-Bu3SnCl (6). In re-
cent years, palladium-catalyzed (7) cyclization reactions
have been shown to be a highly effective and practical
method in organic synthesis. Having established this chemis-
Received 14 November 2007. Accepted 30 January 2008. Published on the NRC Research Press Web site at canjchem.nrc.ca on
10 March 2008.
K.C. Majumdar,1 P. Debnath, A. Taher, and A.K. Pal. Department of Chemistry, University of Kalyani, Kalyani 741235, WB,
India
1Corresponding author (e-mail: kcm_ku@yahoo.co.in).
Can. J. Chem. 86: 325–332 (2008)
doi:10.1139/V08-023
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Can. J. Chem. Vol. 86, 2008
Scheme 1. Reagents and conditions: (i) dry acetone, K2CO3, re-
flux, 6 h.
benzannulated analogues of pyrone and pyridone. Here, we
describe a comparative study of radical and Pd(0)-catalyzed
cyclizations as a synthetic method to access pyron-, pyridon-,
imidazol-, benzimidazol-, and uracil-annulated heterocycles
of biological interest.
Results and discussion
For our initial investigation, we have selected compounds
3a–3l as starting materials. These ethers were prepared
by the alkylation of 4-hydroxypyrone, 4-hydroxypyridones,
5-hydroxyuracil, imidazole, and benzimidazole with 2-
bromobenzyl bromide and 2-bromo-5-methoxybenzyl bro-
mide. Compounds 3a–3b were prepared in 80% and 84%
yields, respectively, by using a classical alkylation procedure
from 4-hydroxypyrone (1) and 2-bromobenzyl bromide (2a)
or 2-bromo-5-methoxybenzyl bromide (2b) in refluxing ace-
tone in the presence of K2CO3 (Scheme 1). The compounds
3a–3b were characterized by their elemental analyses and
spectroscopic data. Similarly, other substrates 3c–3l were
also prepared.
As our goal was to synthesize new heterocycles by C–C
bond formation, we first considered n-Bu3SnCl-mediated
radical cyclization conditions. The substrate 3a was sub-
jected to optimal reaction conditions (20), i.e., n-Bu3SnCl,
Na(CN)BH3, AIBN in dry toluene under nitrogen atmo-
sphere at 80 °C for 4 h. A single product, solid, mp 92–
94 °C, was isolated by column chromatography. The 1H
NMR spectrum of the product revealed that cyclization did
not occur. Only the halogen-reduced product 4a was ob-
tained. We then tried to carry out the cyclization reaction in
the presence of n-Bu3SnH, instead of n-Bu3SnCl, in
refluxing toluene. But we again failed to achieve the radical
cyclization. However, radical cyclization between the precur-
sors 3c–3f and n-Bu3SnH gave the cyclized products 5c–5f
in poor yields (4%–7%) with uncyclized reduced products
4c–4f (64%–83%). The use of a stoichiometric amount (22)
of radical initiator gave improved yields 5a (20%), 5b
(17%), 5c (29%), 5d (25%), 5e (27%), and 5f (31%) respec-
tively, with halogen-reduced products 4a–4f (44%–56%)
(Scheme 2).
Aryl radical cyclization onto the benzannulated analogues
of these compounds (20), namely coumarins, quinolones,
and uracil derivatives (precursors 3g–3h) gave better yields
of cyclized product with no reduced product. This may be
due to the better stabilization of radical intermediates in the
benzannulated series. Aryl radicals are nucleophilic, and
electron-withdrawing and (or) radical-stabilizing groups im-
prove the cyclization. The formation of six-membered ring
heterocycles at C-3 (not at C-5) may easily be explained by
the generation of aryl radical 6, followed by a 6-endo trig
cyclization to give allyl radical intermediate 7 (Scheme 2).
The oxidative elimination of hydrogen from intermediate 7
may afford 5. The regioselective formation of compounds 5
from substrates 3 may be attributed to the stability of the in-
termediate allylic radical 7. Otherwise, a 6-endo attack at C-
5 position would give a α-oxo radical (8), which is unstable.
Attempted five-membered ring aryl radical cyclizations
with the azole, imidazole, and benzimidazole radical precur-
sors 3i and 3k using n-Bu3SnH gave only reduced
uncyclized products 4i and 4j, respectively, even with slow
addition of the tin reagent (Scheme 3). It is also important to
note that attempts to effect the five-membered ring
cyclization with a stoichiometric amount of the initiator did
not divert the reaction away from dehalogenation. Since rad-
ical precursors 3i and 3k gave only the reduced products, we
did not proceed further with the precursors 3j and 3l.
Cyclizations onto five-membered ring azoles is less fa-
vored due to the strain of formation of products with two
five-membered rings, one of which is a heteroarene (23).
Bowmen and co-workers (24) showed that alkyl radical
cyclization onto imidazoles and benzimidazoles, 6-
membered ring cyclization, gave better yields than five-
membered ring cyclization, whereas aryl radical cyclization
gave only reduced products in the case of five-membered
ring cyclizations.
To increase the yield of cyclized products, we then uti-
lized Pd(0)-catalyzed cyclization reactions. We have exam-
ined the influence of factors such as the nature of the base,
the ligand, the solvent, and the reaction temperature, which
might influence the efficiency of the reaction. The Heck re-
action was carried out at 100 °C in DMF with 10 mol% of
Pd(OAc)2, tri-2-tolylphosphine as ligand, and K2CO3 as the
base with substrate 3a. Only one product was obtained after
6 h, in 25% yield, along with a large amount of starting ma-
terial (62%). Increasing the reaction temperature (up to
150 °C) and also the reaction time did not improve the yield
of the reaction due to extensive decomposition of the start-
ing material. We have also examined the influence of bases
like Cs2CO3, KOAc, organic bases like triethylamine, and
the ligands triphenylphosphine and tri-4-tolylphosphine.
Potassium acetate proved to be the best base with the tri-2-
tolylphosphine ligand for this cyclization, improving the
yield to 42%. Changing the solvent (DMSO, CH3CN) did
not provide any improvement in the yield. However, the best
results were achieved under Jeffery’s two phase conditions
(25). The reaction conditions for this transformation in-
volved dissolving compound 3a (0.34 mmol) in dry DMF,
followed by the addition of Pd(OAc)2 (10 mmol%), TBAB
(0.34 mmol), KOAc (0.85 mmol), and stirring the reaction
mixture for 4 h at 95 °C under an inert atmosphere. The re-
action was monitored by TLC and an appreciable change
was observed. Isolation of the product by flash column chro-
matography furnished a solid in 87% yield. The product was
characterized by elemental analysis and spectral data. Com-
pounds 3b–3l, on similar treatment, furnished compounds
5b–5l in 61%–96% yields (Table 1).
The palladium(0)-catalyzed reaction affords better yields
than the tin hydride protocol, except in the case of uracil
derivatives, where the yields are comparable with the tin
hydride-mediated reaction.
The coupling of the precursors 3a–3f occurs regio-
selectively at C-3 as in the case of the radical cyclization re-
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Majumdar et al.
327
Scheme 2. Reagents and conditions: (i) n-Bu3SnH, AIBN, toluene, reflux, 4–7 h.
Scheme 3. Radical reactions of imidazole and benzimidazole.
Scheme 4.
actions. Mori and co-workers (26) also regioselectively
synthesized compound 5i by utilizing PdCl2-2PPh3 in
DMSO at 140 °C, but we have achieved better results using
Jeffery’s protocol in a short reaction time and at a lower
temperature.
The proposed mechanism for this annulation process is
shown in Scheme 4. Initially, the oxidative addition of com-
pound 3 to palladium may form the arylpalladium intermedi-
ate 9. Complex 9 may then add to the double bond to give a
σ–alkylpalladium intermediate 10, and finally β–hydrogen
elimination from intermediate 10 may provide products 5.
Similar mechanisms for the Pd-catalyzed CH-arylation of π-
excessive heteroarenes have been reported in the literature
(27). Recently, the mechanism of the Pd-catalyzed Heck re-
action has been reviewed (28).
corded on a Bruker-300, Bruker DPX-400, and Bruker DRX-
500 spectrometers in CDCl3 (chemical shift in δ) with TMS
as internal standard. Silica gel [(60–120, 230-400 mesh),
Spectrochem, India] was used for chromatographic separa-
tion. Silica gel G [E-Merck (India)] was used for TLC.
Petroleum ether refers to the fraction boiling between 60 and
80 °C.
Conclusion
In conclusion, we have successfully extended the Pd(0)-
catalyzed intramolecular Heck reaction to the regioselective
synthesis of potentially bioactive heterocyclic compounds.
The process is quite simple, practical, and affords good to
excellent yields of the desired products and is far superior to
the toxic tin hydride methodology. The mildness of the reac-
tion conditions and the high level of chemoselectivity allow
this annulation process to serve as a powerful synthetic tool
for the preparation of complex aromatic heterocycles.
General procedure for the preparation of compounds
3a–3l
A mixture of 4-hydroxy-6-methyl pyrone (1a, 0.20 g,
1.59 mmol) 2-bromobenzyl bromide (2a, 0.475 g, 1.90 mmol)
or 2-bromo-5-methoxybenzyl bromide (2b, 0.530 g,
1.90 mmol) and anhydrous potassium carbonate (3 g) were
refluxed in dry acetone (75 mL) on a water bath for 5–6 h.
The reaction mixture was cooled, filtered, and the solvent
was removed. The residual mass was extracted with CH2Cl2
(3 × 30 mL). The CH2Cl2 extract was washed with water (3 ×
30 mL) and dried (Na2SO4). The residual mass, after re-
moval of CH2Cl2, was subjected to column chromatography
over silica gel (60–120 mesh) using petroleum ether – ethyl
acetate as the eluant to give compounds 3a–3b. Similarly,
the substrates 3c–3l were prepared from pyridone, uracil,
imidazole, and benzimidazole, respectively. All solid com-
pounds were recrystalized from an acetonitrile–methanol mixture.
Experimental
General
Melting points were determined in open capillaries and
are uncorrected. IR spectra were recorded on a PerkinElmer
L 120-000A spectrometer (γmax in cm–1) using samples as
neat liquids, and solid samples were recorded in KBr disks.
1H NMR (300 MHz, 400 MHz, 500 MHz) spectra were re-
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Can. J. Chem. Vol. 86, 2008
Table 1. Pd-catalyzed cyclization of compounds 3a–31.
1H NMR (CDCl3, 400 MHz, ppm) δH: 2.29 (s, 3H), 3.44 (s,
3H), 5.01 (s, 2H), 5.86 (s, 1H), 5.89 (s, 1H), 7.15 (t, J =
7.6 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz,
1H), 7.54 (d, J = 8.0 Hz, 1H). MS m/z: 307, 309 (M+). Anal.
calcd. for C14H14BrNO2: C 54.56, H 4.58, N 4.55; found: C
54.43, H 4.72, N 4.61.
4-[(2-Bromobenzyl)oxy]-6-methyl-2H-pyran-2-one (3a)
Yield 80%, colorless solid, mp 135–137 °C (acetonitrile–
methanol). IR (KBr, cm–1) υ: 2924, 1726, 1248, 1033. H
1
NMR (CDCl3, 400 MHz, ppm) δH: 2.20 (s, 3H), 5.01 (s,
2H), 5.48 (d, J = 2.0 Hz, 1H), 5.83 (t, J = 0.8 Hz, 1H), 7.36-
7.44 (m, 4H). MS m/z: 294, 296 (M+). Anal. calcd. for
C13H11BrO3: C 52.91, H 3.76; found: C 53.02, H 3.72.
4-[(2-Bromo-5-methoxybenzyl)oxy]-1,6-dimethyl-1,2-
dihydropyridin-2-one (3d)
4-[(2-Bromo-5-methoxybenzyl)oxy]-6-methyl-2H-pyran-
2-one (3b)
Yield 85%, colorless solid, mp 148 to 149 °C
(acetonitrile–methanol). IR (KBr, cm–1) υ: 2959, 1655, 1238.
1H NMR (CDCl3, 400 MHz, ppm) δH: 2.30 (s, 3H), 3.45 (s,
3H), 3.78 (s, 3H), 4.98 (s, 2H), 5.87 (d, J = 2.2 Hz, 1H),
5.90 (d, J = 2.7 Hz, 1H), 6.72 (dd, J = 3.0, 8.7 Hz, 1H), 6.98
(d, J = 2.8 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H). MS m/z: 337,
339 (M+). Anal. calcd. for C15H16BrNO3: C 53.27, H 4.77, N
4.14; found: C 53.53, H 4.86, N 4.26.
Yield 84%, colorless solid, mp 125 to 126 °C
(acetonitrile–methanol). IR (KBr, cm–1) υ: 2940, 1733, 1245,
1
1013. H NMR (CDCl3, 400 MHz, ppm) δH: 2.22 (s, 3H),
3.79 (s, 3H), 5.02 (s, 2H), 5.47 (d, J = 2.4 Hz, 1H), 5.85 (t,
J = 0.8 Hz, 1H), 6.75 (dd, J = 2.4, 6.6 Hz, 1H), 6.93 (d, J =
2.1 Hz, 1H) 7.44 (d, J = 6.3 Hz, 1H). MS m/z: 324, 326
(M+). Anal. calcd. for C14H13BrO4: C 51.71, H 4.03; found:
C 51.95, H 3.87.
4-[(2-Bromobenzyl)oxy]-1-ethyl-6-methyl-1,2-
dihydropyridin-2-one (3e)
4-[(2-Bromobenzyl)oxy]-1,6-dimethyl-1,2-
dihydropyridin-2-one (3c)
Yield 78%, colorless solid, mp 102–104 °C (acetonitrile–
1
Yield 77%, colorless solid, mp 134 to 135 °C
methanol). IR (KBr, cm–1) υ: 2924, 1645, 1241. H NMR
(acetonitrile–methanol). IR (KBr, cm–1) υ: 2952, 1658, 1201.
(CDCl3, 400 MHz, ppm) δH: 1.26 (t, J = 6.8 Hz, 3H), 2.35
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Majumdar et al.
329
Table 1 (concluded).
Note: Compound 3 (0.34 mmol), Pd(OAc)2 (10 mol%), TBAB (0.34 mmol), KOAc (0.85 mmol), DMF (25 mL).
aIsolated yeilds of the Pd(0)-catalyzed cyclized products.
(s, 3H), 4.0 (q, J = 7.2 Hz, 2H), 5.03 (s, 2H), 5.84 (d, J =
2.8 Hz, 1H), 5.90 (d, J = 2.4 Hz, 1H), 7.18–7.22 (m, 1H),
7.30-7.59 (m, 3H). MS m/z: 321, 323 (M+). Anal. calcd. for
C15H16BrNO2: C 55.92, H 5.01, N 4.35; found: C 55.71, H
5.12, N 4.28.
1-(2-Bromobenzyl)-1H-imidazole (3i)
See ref. 26.
1-(2-Bromo-5-methoxybenzyl)-1H-imidazole (3j)
Yield 86%, colorless solid, mp 118–120 °C (EtOAc – pe-
troleum ether). IR (KBr, cm–1) υ: 2936, 1594, 1241, 729. H
1
4-[(2-Bromo-5-methoxybenzyl)oxy]-1-ethyl-6-methyl-1,2-
dihydropyridin-2-one (3f)
NMR (CDCl3, 400 MHz, ppm) δH: 3.71 (s, 3H), 5.17 (s,
2H), 6.44 (d, J = 2.8 Hz, 1H), 6.73 (dd, J = 3.2, 8.8 Hz, 1H),
6.96 (s, 1H), 7.12 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.62 (s,
1H). MS m/z: 266, 268 (M+). Anal. calcd. for C11H11BrN2O:
C 49.46, H 4.15, N 10.49; found: C 49.70, H 4.12, N 10.52.
Yield 71%; gummy mass. IR (KBr, cm–1) υ: 2936, 1651,
1
1242. H NMR (CDCl3, 400 MHz, ppm) δH: 1.25 (t, J =
7.1 Hz, 3H), 2.34 (s, 3H), 3.78 (s, 3H), 3.99 (q, J = 7.1 Hz,
2H), 4.97 (s, 2H), 5.84 (d, J = 2.2 Hz, 1H), 5.89 (d, J =
2.6 Hz, 1H), 6.72 (dd, J = 3.0, 8.8 Hz, 1H), 6.97 (d, J =
3.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H). MS m/z: 351, 353
(M+). Anal. calcd. for C16H18BrNO3: C 54.56, H 5.15, N
3.98; found: C 54.59, H 5.13, N 4.19.
1-(2-Bromobenzyl)-1H-benzo[d]imidazole (3k)
Yield 79%, colorless solid, mp 108–110 °C (acetonitrile–
methanol). IR (KBr, cm–1) υ: 3055, 1613, 749. H NMR
1
(CDCl3, 400 MHz, ppm) δH: 5.43 (s, 2H), 6.77-6.81 (m,
1H), 7.15-7.31 (m, 5H), 7.61-7.85 (m, 2H), 7.95 (s, 1H). MS
m/z: 286, 288 (M+). Anal. calcd. for C14H11BrN2: C 58.56, H
3.86, N 9.76; found: C 58.73, H 3.91, N 9.69.
Compounds 3g and 3h
See ref. 20a.
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Can. J. Chem. Vol. 86, 2008
1-(2-Bromo-5-methoxybenzyl)-1H-benzo[d]imidazole (3l)
4-[(3-Methoxybenzyl)oxy]-1,6-dimethyl-1,2-
dihydropyridin-2-one (4d)
Yield 75%, colorless solid, mp 94–96 °C (acetonitrile–
1
methanol). IR (KBr, cm–1) υ: 2963, 1614, 739. H NMR
Eluted from the column with 60% ethyl acetate – petro-
leum ether mixture as a colorless solid (56%), mp 128–
130 °C (acetonitrile–methanol). IR (KBr, cm–1) υ: 2931,
(CDCl3, 400 MHz, ppm) δH: 3.60 (s, 3H), 5.38 (s, 2H), 6.34
(d, J = 2.6 Hz, 1H), 6.71 (dd, J = 2.7, 8.7 Hz, 1H), 7.27-7.32
(m, 3H), 7.49 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H),
7.95 (s, 1H). MS m/z: 316, 318(M+). Anal. calcd. for
C15H13BrN2O: C 56.80, H 4.13, N 8.83; found: C 57.09, H
4.18, N 8.97.
1
1719, 1233, 1011. H NMR (CDCl3, 400 MHz, ppm) δH:
2.29 (s, 3H), 3.43 (s, 3H), 3.75 (s, 3H), 4.99 (s, 2H), 5.88 (d,
J = 2.2 Hz, 1H), 5.90 (d, J = 2.7 Hz, 1H), 6.67-7.19 (m, 3H),
7.43 (d, J = 8.6 Hz, 1H). MS m/z: 259 (M+). Anal. calcd. for
C15H17NO3: C 69.48, H 6.61, N 5.40; found: C 69.45, H
6.66, N 5.33.
General procedure for the radical reaction of
compounds 3a–3i and 3k
4-Benzyloxy-1-ethyl-6-methyl-1,2-dihydropyridin-2-one
(4e)
A
deoxygenated solution of n-Bu3SnH in toluene
(0.12 ml, 0.40 mmol) was added dropwise to a magnetically
stirred solution of the precursors 3 (0.34 mmol) and
azobis(isobutyro)nitrile (0.056 gm) in dry toluene (10 mL)
under a nitrogen atmosphere. The mixture was refluxed for
4–7 h. After completion of the reaction, the solvent was re-
moved under reduced pressure. The residue was dissolved in
CH2Cl2 (10 mL) and stirred with 10% aq. KF solution
(10 mL) for 1 h. The aqueous phase was extracted with
CH2Cl2 (3 × 25 mL). The combined CH2Cl2 extracts were
washed with water (2 × 20 mL), brine solution (1 × 20 mL),
and dried (Na2SO4). The solvent was evaporated under re-
duced pressure. The crude products were purified by column
chromatography over silica gel using petroleum ether – ethyl
acetate mixture as eluant. All solid compounds were crystal-
lized from an acetonitrile–methanol mixture.
Eluted from the column with 55% ethyl acetate – petro-
leum ether mixture as a colorless solid (47%), mp 156 to
157 °C (acetonitrile–methanol). IR (KBr, cm–1) υ: 2970,
1
1723, 1228. H NMR (CDCl3, 400 MHz, ppm) δH: 1.24 (t,
J = 7.0 Hz, 3H), 2.32 (s, 3H), 3.98 (q, J = 7.1 Hz, 2H), 4.94
(s, 2H), 5.80 (d, J = 2.5 Hz, 1H), 5.88 (d, J = 2.6 Hz, 1H),
7.32-7.37 (m, 5H). MS m/z: 243 (M+). Anal. calcd. for
C15H17NO2: C 74.05, H 7.04, N 5.76; found: C 74.24, H
7.14, N 5.94.
1-Ethyl-4-[(3-methoxybenzyl)oxy]-6-methyl-1,2-
dihydropyridin-2-one (4f)
Eluted from the column with 55% ethyl acetate – petro-
leum ether mixture as a colorless solid (56%), mp 173 to
174 °C (acetonitrile–methanol). IR (KBr, cm–1) υ: 2945,
1
1727, 1222. H NMR (CDCl3, 300 MHz, ppm) δH: 1.25 (t,
J = 7.0 Hz, 3H), 2.33 (s, 3H), 3.81 (s, 3H), 3.99 (q, J =
7.1 Hz, 2H), 4.94 (s, 2H), 5.83 (d, J = 1.9 Hz, 1H), 5.89 (d,
J = 2.4 Hz, 1H), 6.86-6.96 (m, 3H), 7.26 (dd, J = 1.3,
7.7 Hz, 1H). MS m/z: 273 (M+). Anal. calcd. for C16H19NO3:
C 70.31, H 7.01, N 5.12; found: C 70.19, H 6.83, N 5.30.
The precursors 3g and 3h did not give any reduced
uncyclized products (20a).
4-Benzyloxy-6-methyl-2H-pyran-2-one (4a)
Eluted from the column with 20% ethyl acetate – petro-
leum ether mixture as colorless solid (53%), mp 92–94 °C
(acetonitrile-methanol). IR (KBr, cm–1) υ: 2923, 1728, 1244,
1
1035. H NMR (CDCl3, 400 MHz, ppm) δH: 2.20 (s, 3H),
4.99 (s, 2H), 5.48 (d, J = 2.1 Hz, 1H), 5.82 (t, J = 0.8 Hz,
1H), 7.34-7.42 (m, 5H). MS m/z: 216 (M+). Anal. calcd. for
C13H12O3: C 72.21, H 5.59; found: C 72.03, H 5.48.
1-Benzyl-1H-imidazole (4i)
Eluted from the column with 40% ethyl acetate – petro-
leum ether mixture as a gummy mass (57%). IR (KBr, cm–1)
4-[(3-Methoxybenzyl)oxy]-6-methyl-2H-pyran-2-one (4b)
1
υ: 2919, 1233. H NMR (CDCl3, 400 MHz, ppm) δH: 5.08
Eluted from the column with 20% ethyl acetate – petro-
leum ether mixture as colorless solid (55%), mp 121 to
122 °C (acetonitrile–methanol). IR (KBr, cm–1) υ: 2943,
(s, 2H), 6.87 (s, 1H), 7.06 (s, 1H), 7.11 (d, J = 6.5 Hz, 2H),
7.27-7.35 (m, 3H), 7.51 (s, 1H). MS m/z: 158 (M+). Anal.
calcd. for C10H10N2: C 75.92, H 6.37, N 17.71; found: C
75.99, H 6.33, N 17.82.
1
1731, 1245, 1012. H NMR (CDCl3, 400 MHz, ppm) δH:
2.24 (s, 3H), 3.79 (s, 3H), 5.03 (s, 2H), 5.48 (d, J = 2.2 Hz,
1H), 5.84 (t, J = 0.8 Hz, 1H) 6.82-7.41 (m, 4H). MS m/z:
246 (M+). Anal. calcd. for C14H14O4: C 68.28, H 5.73;
found: C 68.41, H 5.81.
1-Benzyl-1H-benzo[d]imidazole (4j)
Eluted from the column with 40% ethyl acetate – petro-
leum ether mixture as a colorless solid (64%), mp 110–
112 °C (acetonitrile–methanol). IR (KBr, cm–1) υ: 2919,
1
4-Benzyloxy-1,6-dimethyl-1,2-dihydropyridin-2-one (4c)
1265. H NMR (CDCl3, 400 MHz, ppm) δH: 5.31 (s, 2H),
7.13 (d, J = 7.5 Hz, 2H), 7.19-7.32 (m, 6H), 7.79 (d, J =
7.5 Hz, 1H), 7.90 (s, 1H). MS m/z: 208(M+). Anal. calcd. for
C14H12N2: C 80.74, H 5.81, N 13.45; found: C 80.88, H
5.92, N 13.50.
Eluted from the column with 60% ethyl acetate – petro-
leum ether mixture as a colorless solid (44%), mp 138–
140 °C (acetonitrile–methanol). IR (KBr, cm–1) υ: 2912,
1
1724, 1244, 1035. H NMR (CDCl3, 400 MHz, ppm) δH:
2.28 (s, 3H), 3.42 (s, 3H), 5.00 (s, 2H), 5.86 (s, 1H), 5.88 (s,
1H), 6.99-7.54 (m, 5H). MS m/z: 229 (M+). Anal. calcd. for
C14H15NO2: C 73.34, H 6.59, N 6.11; found: C 73.13, H
6.48, N 5.88.
General procedure for the Heck type of reaction for
compounds 3a–3l
To a mixture of 3a–3l (0.34 mmol), Bu4NBr (0.113 g,
© 2008 NRC Canada

Majumdar et al.
331
0.34 mmol), and KOAc (0.083 g, 0.85 mmol) in dry and de-
gassed DMF (25 mL) in a screw-cap sealed tube was added
Pd(OAc)2 (0.008 g, 10 mol%) under an inert atmosphere,
and the sealed tube was placed in a preheated oil bath at 80–
120 °C (Table 1) with stirring for 1.5–12 h (Table 1, for
each reaction). The reaction mixture was cooled and diluted
with water (50 mL). This was extracted with ethyl acetate (3
× 20 mL). The organic extract was washed with hydrochlo-
ric acid (1N, 20 mL), water (3 × 30 mL), and saturated brine
solution (25 mL), and dried (Na2SO4). The solvent was dis-
tilled off. The crude products were purified by column chro-
matography over silica gel (60–120 mesh) using petroleum
ether – ethyl acetate mixture as the eluant to give com-
pounds 5a–5l. All solid compounds were recrystalized from
dichloromethane–petroleum ether (60–80 °C).
2.33 (s, 3H), 3.54 (s, 3H), 3.81 (s, 3H), 5.07 (s, 2H), 5.87 (s,
1H), 6.60 (d, J = 2.5 Hz, 1H), 6.86 (dd, J = 2.6, 8.7 Hz, 1H),
8.73 (d, J = 8.8 Hz, 1H). MS m/z: 257 (M+). Anal. calcd. for
C15H15NO3: C 70.02, H 5.88, N 5.44; found: C 70.19, H
5.95, N 5.38.
2-Ethyl-3-methyl-2,6-dihydro-1H-isochromen[4,3-
c]pyridin-1-one (5e)
Eluted from the column with 45% ethyl acetate – petro-
leum ether mixture as a colorless solid (78%), mp 113 to
114 °C (dichloromethane–petroleum ether). IR (KBr, cm–1)
1
υ: 2982, 1644, 1246. H NMR (CDCl3, 400 MHz, ppm) δH:
1.32 (t, J = 6.9 Hz, 3H), 2.39 (s, 3H), 4.09 (q, J = 7.1 Hz,
2H), 5.09 (s, 2H), 5.85 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H),
7.18-7.36 (m, 2H), 8.77 (d, J = 8.0 Hz, 1H). 13C NMR
(125 MHz, ppm) δC: 14.2, 20.8, 39.7, 69.3, 100.8, 106.1,
124.0, 124.7, 127.0, 128.5, 128.8, 129.1, 146.0, 162.0,
3-Methyl-1H,6H-pyran[4,3-c]isochromen-1-one (5a)
Eluted from the column with 20% ethyl acetate – petro-
leum ether mixture as a colorless solid (87%), mp 110–
113 °C (dichloromethane–petroleum ether). IR (KBr, cm–1)
+
162.9. HRMS calcd, for C15H16O2 (MH): 242.1172; found
242.1184. Anal. calcd. for C15H15NO2: C 74.67, H 6.27, N
5.81; found: C 74.62, H 6.04, N 5.99.
1
υ: 2924, 1705, 1240, 1042. H NMR (CDCl3, 400 MHz,
2-Ethyl-8-methoxy-3-dimethyl-2,6-dihydro-1H-
isochromen[4,3-c]pyridin-1-one (5f)
ppm) δH: 2.26 (s, 3H), 5.22 (s, 2H), 5.90 (d, J = 0.6 Hz, 1H),
7.03 (d, J = 7.6 Hz, 1H), 7.22-7.26 (m, 1H), 7.33 (t, J =
8.0 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H). MS m/z: 214 (M+).
Anal. calcd. for C13H10O3: C 72.89, H 4.71; found: C 72.82,
H 4.75.
Eluted from the column with 45% ethyl acetate–petroleum
ether mixture as a colorless solid (81%), mp 105–107 °C
(dichloromethane–petroleum ether). IR (KBr, cm–1) υ: 2917,
1
1643, 1215. H NMR (CDCl3, 400 MHz, ppm) δH: 1.30 (t,
J = 7.0 Hz, 3H), 2.37 (s, 3H), 3.80 (s, 3H) 4.09 (q, J =
7.0 Hz, 2H), 5.06 (s, 2H), 5.84 (s, 1H), 6.59 (d, J = 2.5 Hz,
1H), 6.86 (dd, J = 2.6, 8.7 Hz, 1H), 8.73 (d, J = 8.7 Hz, 1H).
MS m/z: 271 (M+). Anal. calcd. for C16H17NO3: C 70.83, H
6.32, N 5.16; found: C 71.05, H 6.33, N 5.20.
8-Methoxy-3-methyl-1H,6H-pyran[4,3-c]isochromen-1-
one (5b)
Eluted from the column with 20% ethyl acetate – petro-
leum ether mixture as a colorless solid (94%), mp 122 to
123 °C (dichloromethane–petroleum ether). IR (KBr, cm–1)
1
υ: 2920, 1704, 1246, 1045. H NMR (CDCl3, 400 MHz,
Compounds 5g and 5h
See ref. 20a.
ppm) δH: 2.24 (s, 3H), 3.80 (s, 3H), 5.19 (s, 2H), 5.89 (s,
1H), 6.58 (d, J = 2.5 Hz, 1H), 6.86 (dd, J = 2.6, 8.72 Hz,
1H), 8.39 (d, J = 8.7 Hz, 1H). 13C NMR (CDCl3, 125 MHz,
ppm) δC: 20.4, 55.7, 69.5, 100.2, 100.6, 110.4, 113.7, 119.4,
126.0, 129.0, 159.5, 161.8, 162.2, 165.0. HRMS calcd. for
5H-Imidazole[5,1-a]isoindole (5i)
See ref. 26.
+
C14H13O4 (MH): 245.0814, found 245.0807. Anal. calcd. for
C14H12O4: C 68.85, H 4.95; found: C 69.08, H 4.89.
8-Methoxy-5H-imidazole[5,1-a]isoindole (5j)
Eluted from the column with 40% ethyl acetate – petro-
leum ether mixture as a colorless solid (84%), mp 141 to
142 °C (dichloromethane–petroleum ether). IR (KBr, cm–1)
2,3-Dimethyl-2,6-dihydro-1H-isochromeno[4,3-c]pyridin-
1-one (5c)
1
υ: 2932, 1703, 1041. H NMR (CDCl3, 400 MHz, ppm) δH:
Eluted from the column with 45% ethyl acetate – petro-
leum ether mixture as a colorless solid (88%), mp 100–
102 °C (dichloromethane–petroleum ether). IR (KBr, cm–1)
3.83(s, 3H), 4.96 (s, 2H), 6.88 (dd, J = 2.2, 8.4 Hz, 1H),
6.94 (d, J = 2.2 Hz, 1H), 7.06 (s, 1H), 7.43 (d, J = 8.3 Hz,
1H), 7.67 (s, 1H). 13C NMR (CDCl3, 125 MHz, ppm) δC:
49.0, 56.0, 110.3, 114.3, 117.1, 121.3, 123.8, 132.4, 138.9,
142.6, 159.2. MS m/z: 186 (M+). Anal. calcd. for
C11H10N2O: C 70.95, H 5.41, N 15.04; found: C 70.88, H
5.47, N 15.16.
1
υ: 2916, 1643, 1239. H NMR (CDCl3, 400 MHz, ppm) δH:
2.35 (s, 3H), 3.55 (s, 3H), 5.09 (s, 2H), 5.89 (s, 1H), 7.04 (d,
J = 7.4 Hz, 1H), 7.19-7.37 (m, 2H), 8.77 (d, J = 7.5 Hz, 1H).
13C NMR (125 MHz, ppm) δC: 16.2, 25.9, 63.9, 95.2, 100.5,
118.6, 119.4, 121.7, 123.1, 123.5, 123.7, 141.2, 157.2,
157.6. MS m/z: 227 (M+). Anal. calcd. for C14H13NO2: C
73.99, H 5.77, N 6.16; found: C 74.20, H 5.69, N 6.29.
11H-Benzo[4,5]imidazo[2,1-a]isoindole (5k)
See ref. 24b.
8-Methoxy-2,3-dimethyl-2,6-dihydro-1H-isochromen[4,3-
c]pyridin-1-one (5d)
2-Methoxy-11H-benzo[4,5]imidazol[2,1-a]isoindole (5l)
Eluted from the column with 40% ethyl acetate – petro-
leum ether mixture as a colorless solid (61%), mp 122 to
123 °C (dichloromethane–petroleum ether). IR (KBr, cm–1)
Eluted from the column with 45% ethyl acetate – petro-
leum ether mixture as a colorless solid (83%), mp 98 to
99 °C (dichloromethane–petroleum ether). IR (KBr, cm–1) υ:
1
1
υ: 2920, 1624, 1265. H NMR (CDCl3, 400 MHz, ppm) δH:
2916, 1644, 1251. H NMR (CDCl3, 400 MHz, ppm) δH:
© 2008 NRC Canada

332
Can. J. Chem. Vol. 86, 2008
(1996); (c) K. Kagechika and M. Shibasaki. J. Org. Chem. 56,
4093 (1991); (d) C. S. Nylund, J.M. Klopp, and S.M. Weinreb.
Tetrahedron Lett. 35, 4287 (1994); (e) S. Nukul, M. Sodeoka,
3.89 (s, 3H), 5.02 (s, 2H), 7.02 (d, J = 8.0 Hz, 1H), 7.09 (s,
1H), 7.24-7.79 (m, 4H), 8.01 (d, J = 8.2 Hz, 1H). MS m/z:
236 (M+). Anal. calcd. for C15H12N2O: C 76.25, H 5.12, N
11.86; found: C 76.01, H 5.26, N 11.85.
and M. Shibasaki. Tetrahedron Lett. 34, 4965 (1993).
9. (a) D.J. Hart and Y.M. Tsai. J. Org. Chem. 47, 4403 (1982);
(b) K. Kondo, M. Sodeoka, and M. Shibasaki. J. Org. Chem.
60, 4322 (1995); (c) S.P. Maddaford, N.G. Andersen, W.A.
Cristofoli, and B.A. Keay. J. Am. Chem. Soc. 118, 10766
(1996); (d) R.V. Rozhkov, and R.C. Larock. Org. Lett. 5, 797
(2003); (e) S. Gracon, S. Vassiliou, M. Cavicchioli, B.
Hartmann, N. Monteiro, and G. Balme. J. Org. Chem. 66,
4069 (2001).
Acknowledgements
We thank the Council of Scientific and Industrial Re-
search (CSIR, New Delhi) for financial assistance. AKP, PD
and AT are thankful to the CSIR for their fellowships. We
also thank the Department of Science and Technology (DST,
New Delhi) for providing UV–vis and IR spectrometers un-
der the DST-FIST program.
10. (a) W.B. Mors, O.R. Gollilieb, and C. Dierassi. J. Am. Chem.
Soc. 79, 4507 (1957); (b) W. J. McGahren, G.A. Ellestad, G.O.
Morton, M.P. Kunstman, and P. Mullen. J. Org. Chem. 38,
3542 1973); (c) S.A. Sparace, J.B. Mudd, B.A. Bruke, and A.J.
Aasan. Phytochemistry, 23, 2693 (1984); (d) R.J. Capon and
D.J.J. Faulkner. J. Org. Chem. 45, 2506 (1984).
11. S. Omura, H. Ohno, T. Saheki, Y. Masakazu, and A.
Nakagawa. Biochem. Biophy. Res. Commun. 83, 704 (1978).
12. W.C. Groutas, M.A. Stanga, M.J. Brubakar, T.L. Huang, M.K.
Moi, and R.J. Carrol. J. Med. Chem. 28, 1106 (1985).
13. P. J. Creaven, Y. Rustum, R. Catane, E.S. Henderson, and E.
Mihich. 10th International Congress of Chemotherapy, Zurich,
18–23 Sept. 1977. Abstract No. 540. 1977.
References
1. Comprehensive heterocyclic chemistry. Vols. 1-8. Edited by
A.R. Katritzky, C.W. Rees, E.F.V. Scriven. Pergamon Press,
Oxford, UK. 1996.
2. (a) R.P. Lutz. Chem. Rev. 84, 205 (1984); (b) U. Kazmaier and
A. Krebs. Angew. Chem Int. Ed. Engl. 34, 2012 (1995);
(c) T.P. Yoon, V.M. Dong, and D.W.C. MacMillan. J. Am.
Chem. Soc. 121, 9726 (1999); (d) K.C. Majumdar and S.K.
Chattopadhyay. Can. J. Chem. 84, 469 (2006).
14. M.J. Robins and B.L. Currie. Chem. Commun. 1547 (1968).
15. D.Y. Hua, F. Zhang, J. Chen, and P.D. Robinson. J. Org.
Chem. 59, 5084 (1994).
3. (a) B. Giese. Radicals in organic synthesis: Formation of car-
bon–carbon bonds. Pergamon, New York, 1986; (b) K.C.
Majumdar, P.K. Basu, and P.P. Mukhopadhyay. Tetrahedron
60, 6239 (2004); (c) K.C. Majumdar and S. Alam. Org. Lett.
8, 4059 (2006); (d) K.C. Majumdar, A. Biswas, and P.P.
Mukhopadhyay. Synthesis, 2385 (2003); (e) K.C. Majumdar,
P.P. Mukhopadhyay, and A. Biswas. Tetrahedron Lett. 46,
6655 (2005); (f) K.C. Majumdar and P.P. Mukhopadhyay. Syn-
thesis, 920 (2003).
4. (a) R.F. Heck. J. Am. Chem. Soc. 90, 518 (1968); (b) For the
first example using aryl and vinylic halides, see: T. Mizoroki,
K. Mori, and A. Ozaki. Bull. Chem. Soc. Jpn. 44, 44158
(1971); (c) T. Mizutani, S. Honzawa, S.U. Tosaki, and K.
Shibasaki. Angew. Chem., Int. Ed. 41, 4680 (2002).
5. (a) For a detailed report on the toxicity of tin reagents, see:
Occupational exposure to organotin compounds, US Depart-
ment of Health, Education and Welfare, Washington. Nov.
1976; (b) I. J. Boyer. Toxicology, 55, 253 (1989); (c) S. Lee
and G. Robinson. Process development: Fine chemicals from
grams to kilograms. Oxford University Press, Oxford, UK.
1995.
6. (a) D.C. Harrowven, B.J. Sutton, and S. Coulton. Org. Biomol.
Chem. 1, 4047 (2003); (b) W. Zhang and G. Pugh. Tetrahe-
dron, 59, 3009 (2003).
7. (a) L.F. Tietze and A. Modi. Eur. J. Org. Chem. 1959 (2000);
(b) A.D. Lebsack, J.T. Link, L. E. Overman, and B.A. Stearns.
J. Am. Chem. Soc. 124, 9008 (2002); (c) N.E. Carpenter, D.J.
Kucera, and L.E. Overman. J. Org. Chem. 54, 5846 (1989).
8. (a) M. Shibasaki, T. Mase, and S. Ikegami. J. Am. Chem. Soc.
108, 2090 (1986); (b) T. Ohshima, K. Kagechika, M. Adachi,
M. Sodeoka, and M. Shibasaki. J. Am. Chem. Soc. 118, 7108
16. E.B. Skibo, I. Islam, W.G. Schulz, R. Zhou, L. Bess, and R.
Boruah. Synlett. 297 (1996).
17. E. Bossharth, P. Desbordes, N. Monteiro, and G. Balme. Org.
Lett. 5, 2441 (2003).
18. M.A. Clyne and F. Aldabbagh. Org. Biomol. Chem. 4, 268
(2006).
19. R.M. de. Figueiredo, S. Thoret, C. Huet, and J. Dubois. Syn-
thesis, 529 (2007).
20. (a) K.C. Majumdar, P.K. Basu, P.P. Mukhopadhyay, S. Sarkar,
S.K. Ghosh, and P. Biswas. Tetrahedron, 59, 2151 (2003);
(b) K.C. Majumdar and P.P. Mukhopadhyay. Synthesis, 97 (2003).
21. K.C. Majumdar, A.K. Pal, A. Taher, and P. Debnath. Synthe-
sis, 1707 (2007).
22. A.L.J. Beckwith, V.W. Bowry, W.R. Bowman, E. Mann, J.
Parr, and J.M.D. Storey. Angew. Chem. Int. Ed. 43, 95 (2004).
23. (a) F. Aldabbagh, W.R. Bowman, E. Mann, and A.M.Z.
Slawin. Tetrahedron Lett. 40, 8111 (1999); (b) F. Aldabbagh,
W.R. Bowman, and E. Mann. Tetrahedron Lett. 38, 7937 (1997).
24. (a) S.M. Allin, W.R. Bowman, M.R.J. Elsegood, V. McKee,
and R. Karim. Tetrahedron, 61, 2689 (2005); (b) S.M. Allin,
W.R. Bowman, R. Karim, and S.S. Rahman. Tetrahedron, 62,
4306 (2006).
25. T. Jeffery. Tetrahedron Lett. 26, 2667 (1985).
26. N. Arai, M. Takahashi, M. Mitani, and A. Mori. Synlett. 3170
(2006).
27. S. Pivsa-Art, T. Satoh, Y. Kawamura, M. Miura, and M.
Nomura. Bull. Chem. Jpn. 71, 467 (1998).
28. C. Amatore and A. Jutand. Acc. Chem. Res. 33, 314 (2000)
© 2008 NRC Canada