Novel synthesis of medium-sized heterocycles by palladium-catalyzed intramolecular Heck reaction via 9-endo-trig mode of cyclization

Article abstract of DOI:10.1055/s-0029-1217395

An efficient and high yielding method for the synthesis of nine-membered heterocyclic skeletons has been developed by palladium-catalyzed intramolecular Heck reaction via an unusual 9-endo-trig mode of cyclization. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217395

PAPER
2385
Novel Synthesis of Medium-Sized Heterocycles by Palladium-Catalyzed
Intramolecular Heck Reaction via 9-endo-trig Mode of Cyclization
S
ynthesis of Mediu
.
m-SizedHe
C
terocycles . Majumdar,* Buddhadeb Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Fax +91(33)25828282; E-mail: kcm_ku@yahoo.co.in
Received 8 February 2009; revised 23 March 2009
undertake an alternative ligand-free12 palladium-cata-
lyzed intramolecular Heck reaction sequence to synthe-
size coumarin- and uracil-annulated nine-membered
medium ring heterocycles.
Abstract: An efficient and high yielding method for the synthesis
of nine-membered heterocyclic skeletons has been developed by
palladium-catalyzed intramolecular Heck reaction via an unusual 9-
endo-trig mode of cyclization.
Key words: intramolecular Heck reaction, palladium acetate, 9- Recently, we have reported10c the synthesis of uracil-
endo-trig, nine-membered ring, Claisen rearrangement
annulated nine-membered oxa-heterocycles by the imple-
mentation of the intramolecular Heck reaction as shown in
Scheme 1. The reaction underwent an 9-endo-trig mode
of cyclization from an unactivated allylic system – a rare
The synthesis of medium-sized rings,1 in particular eight-
mode of cyclization. After achieving this success, we have
extended our developed protocol for the construction of
nine-membered oxa-heterocycles.
and nine-membered rings, has been and continues to be a
challenging and fascinating endeavor in synthetic organic
chemistry and this is due to unfavorable entropy and en-
thalpy factors that prevent the adaptation of traditional
methods of ring formations.2 Generally, eight- and nine-
membered heterocycles occupy a special place because of
the occurrence of these types of heterocyclic moieties in
various biologically active molecules possessing antipsy-
chotic,3 herbicidal,4 analgesic5 activities, etc. Besides,
many natural products such as naphthoxepin,6,3 rhazinil-
am,7 and its cogener rhazinal8 that contain medium-sized
heterocyclic moiety fused to aryl rings have attracted both
the biologists and synthetic organic chemists.9 Therefore,
due to remarkable biological activities of medium-sized
heterocyclic ring systems there has been enhanced interest
in the development of easy and simple protocols for the
synthesis of these molecules. Recently, we have synthe-
sized various types of heterocycles by the utilization of
various palladium complexes in our laboratory.6,10
O
O
O
Pd(OAc)2, KOAc
Me
O
Me
O
O
N
N
TBAB, DMF
100 °C, 2 h
90%
9
Br
N
N
Me
Me
Scheme 1
The Heck precursors 5a–d for our present investigation
were synthesized in excellent yields (81–91%) by reflux-
ing the compounds 3 with either 2-bromobenzyl bromide
(4a) or 2-bromo-5-methoxybenzyl bromide (4b) in anhy-
drous acetone in the presence of anhydrous potassium car-
bonate and a small amount of sodium iodide (Scheme 2).
Compounds 3a,b in turn were prepared in good yields by
the reaction of 3-hydroxycoumarin (1) with either allyl
bromide or crotyl bromide followed by a Claisen rear-
Among different types of organometallic catalysts, palla-
dium-catalyzed coupling reactions exemplify one of the
most important methods because they represent a power-
ful and popular strategy for the construction of carbon–
carbon bonds11. Significant innovations in this field have
been made in the modifications of traditional phosphine
ligands and in the discovery of novel phosphine sys-
tems.11 It is notable that, most of the phosphine ligands are
air and moisture sensitive with the conversion to phos-
phine oxides. This can inactivate the catalyst. Other prob-
lems frequently encountered in the use of phosphine
ligands in catalysis, such as cost, toxicity, labor involved
in the synthesis, and loss of catalyst during product extrac-
tion, have driven chemists to explore the alternatives.
Therefore, the above-mentioned findings prompted us to
R1
R1
OH
O
O
O
OH
O
(i)
(ii)
O
O
O
1
2a R1 = H
2b R1 = Me
3a R1 = H
3b R1 = Me
R1
Br
R1
Br
O
OH
O
Br
(iii)
R2
+
R2
O
O
O
3a R1 = H
3b R1 = Me
4a R2 = H
4b R2 = 4-MeO
5a R1 = Me, R2 = H
5b R1 = Me, R2 = 4-MeO
5c R1 = R2 = H
5d R1 = H, R2 = 4-MeO
Scheme 2 Reagents and conditions: (i) acetone, K2CO3, NaI, allyl
bromide or crotyl bromide, reflux; (ii) chlorobenzene, reflux; (iii)
acetone, K2CO3, NaI, reflux.
SYNTHESIS 2009, No. 14, pp 2385–2392
x
x.
x
x
.
2
0
0
9
Advanced online publication: 08.06.2009
DOI: 10.1055/s-0029-1217395; Art ID: Z02109SS
© Georg Thieme Verlag Stuttgart · New York

2386
K. C. Majumdar, B. Chattopadhyay
PAPER
Br
Br
O
Heck reaction
O
+
O
O
O
O
O
O
O
5a
7
6a
UNEXPECTED BUT FOUND
EXPECTED BUT NOT FOUND
Scheme 3
rangement in refluxing chlorobenzene for three to four the nine-membered cyclized product 6a was obtained re-
hours.
gioselectively in 61% yield under ligand-free conditions.
We have optimized the reaction conditions through a se-
ries of experiments by changing the catalyst, base, and
solvent. We found that the amount of catalyst plays an im-
portant role in this cyclization. If 10 mol% or more of the
catalyst is used, a number of unidentified products were
obtained instead of the nine-membered cyclized product.
Again if the catalyst mol% was reduced to less than 5
mol%, the rate of the reaction was rapidly decreased giv-
ing a poor yield of the cyclized product. Among the vari-
ous bases tried, such as KOAc, Cs2CO3, K2CO3, Ag2CO3,
and NaOAc, only anhydrous K2CO3 was effective in the
reaction. There was no reaction when organic bases such
as Et3N, pyridine etc. were used in the place of an inorgan-
ic base. The results are summarized in Table 1.
Based on the presence of one generalized intramolecular
reaction that has been successfully used for the synthesis
of heterocyclic compounds by treatment with Pd(OAc)2
as catalyst, KOAc as the base, TBAB as the additive, and
anhydrous DMF under nitrogen atmosphere, we have at-
tempted the cyclization of compound 5 via this estab-
lished protocol. However, only the isomerized product 7
was obtained under these conditions rather than the nine-
membered cyclized product10c 6a (Scheme 3).
Therefore, this negative observation led us to explore oth-
er alternative conditions.When the Heck reaction was per-
formed with 5a in a sealed tube in the presence of 5 mol%
Pd(OAc)2 as the catalyst, K2CO3 as base, and TBAB as
additive in anhydrous acetonitrile at 80 °C for two hours,
Table 1 Optimization of the Heck Cyclizationa of 5a to 6a
Entry
1d
Amount of catalyst
10 mol% Pd(OAc)2
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
10 mol% Pd(OAc)2
1 mol% Pd(OAc)2
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
1 mol% Pd(OAc)2
Baseb
Solvent
DMF
Yield (%)c of 6a
Yield (%)c of 7
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Ag2CO3
NaOAc
Et3N
0
0
96
93
0
2d
DMF
3e,f
4f
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
dioxane
THF
61
31
<5
0
–
5
–
6f
–
7f
0
–
8f
0
–
9f
0
–
10f
11
12
13
14
pyridine
K2CO3
K2CO3
K2CO3
K2CO3
0
–
16
39
11
<5
–
–
toluene
THF
–
–
a All reactions were carried out using TBAB (1.2 equiv) as an additive.
b Amount of base used: 2.75 equiv.
c Isolated yields.
d Temperature: 100–140 °C.
e Optimized reaction conditions.
f Temperature of the reaction is 80 °C and done in a sealed tube.
Synthesis 2009, No. 14, 2385–2392 © Thieme Stuttgart · New York

PAPER
Synthesis of Medium-Sized Heterocycles
2387
Similarly, other substrates 5b–d were subjected to the op-
timized conditions: Pd(OAc)2, K2CO3, TBAB, MeCN,
80 °C, to afford the corresponding nine-membered oxa-
heterocyclic products 6b–d.
O
O
O
Me
O
O
O
Me
O
N
conditions
N
O
9
I
N
N
Me
Me
Recently, Guy et al. reported13 the synthesis of seven- and
eight-membered heterocyclic compounds using the in-
tramolecular Heck reaction sequence. After synthesizing
these compounds, they also attempted to synthesize the
nine-membered oxa-heterocyles and nine-membered lac-
tone compounds employing the same protocol as used for
seven- and eight-membered heterocycles starting with the
highly activated Heck precursors (Scheme 4).
6e
5e
conditions A: Pd(OAc)2, TBAB, DMF, Et3N, 100–140 °C
conditions B: PdCl2, P(o-tolyl)3, DMF, Et3N, 100–140 °C
conditions C: Pd(OAc)2, Ph3P, DMF, Ag2CO3, 100–140 °C
conditions D: Pd(OAc)2, TBAB, DMF, Cs2CO3, 100–140 °C
conditions E: Pd(OAc)2, TBAB, K2CO3, DMF, 95 °C
O
O
O
Pd(OAc)2 (0.03 equiv)
O
Scheme 6
9
I
Cy2NMe, Et4NCl
DMA, 100 °C, 12 h
no reaction
COOEt
Again, the required Heck precursors 5g–k for our present
study were synthesized in 85–96% yields by refluxing 6-
allyl-substituted 5-hydroxy-1,3-dimethyluracils 8 and 914
with different benzyl bromides in anhydrous acetone for
about 2–3 hours in the presence of anhydrous potassium
carbonate and a small amount of sodium iodide (Finkel-
stein conditions15). The compounds 8 in turn were pre-
pared in good yields by the reaction of 5-hydroxyuracil
with allyl and crotyl bromide, respectively, followed by a
EtOOC
Scheme 4
However, their attempts to synthesize nine-membered
compounds failed. The synthesis of the Heck precursors
5e,f for this study is depicted in Scheme 5. The reaction of
acid chloride 4c (prepared from 2-iodobenzoic acid with
the oxalyl chloride in CH2Cl2 in the presence of a catalytic
amount of DMF) with 6-allyl-substituted 5-hydroxy-1,3-
dimethyluracils 3c,d in CH2Cl2–Et3N in the presence of a
catalytic amount of DMAP at 0 °C to room temperature
for four hours afforded the corresponding Heck precur-
sors 5e,f.
[3,3]
sigmatropic
rearrangement
in
refluxing
chlorobenzene15 for 1–1.5 hours (Scheme 7). In the case
of the compound 9, O-alkylation with cinnamyl bromide,
[3,3] sigmatropic rearrangement and double bond migra-
tion occur simultaneously in a single step in acetone at re-
fluxing conditions.
O
O
COCl
The intramolecular Heck reactions were performed in an-
hydrous DMF using potassium acetate as a base, tetrabu-
tylammonium bromide (TBAB) as a promoter,16 and
Pd(OAc)2 as catalyst under nitrogen atmosphere at 100 °C
for about 2–3.5 hours. All the reactions gave the endo-
Heck heterocyclic ring compounds 6g–k fused with aryl
ring and uracil moiety by the unusual 9-endo and 8-endo
cyclization mode exclusively in 88–96% yield except for
compound 5h. Compound 5h gave the 9-endo product 6h
(74%). The summarized results are shown in Table 2.
Me
O
OH
Me
O
O
R
I
N
N
(i)
O
+
I
N
N
Me
R
Me
4c
3c R = Me
3d R = H
5e R = Me
5f R = H
Scheme 5 Reagents and conditions: (i) CH2Cl2–Et3N, DMAP, 0 °C
to r.t., 4 h.
Atempted synthesis of the nine-membered lactone 6e
from the Heck precursor 5e using the optimized reaction
conditions as described in Table 1, failed and the entire
starting material remained unchanged in the reaction mix-
ture. Therefore, we have modified the reaction by using
the catalytic compositions as described in Scheme 6 (con-
ditions A–D). To our frustration, the desired nine-mem-
bered lactone 6e was not obtained at all. Subsequently, the
reaction was performed under the conditions E as de-
scribed in Scheme 6.
It is well documented11a that the intramolecular Heck re-
action may undergo cyclization through the exo- or endo-
mode of cyclization affording the corresponding Heck
product. According to a literature report,17 a large-sized
ring (~20) formation with a flexible tether generally fol-
lows endo-cyclization and a small to medium-sized ring
formation usually occur via exo-mode of cyclization since
the corresponding endo-cyclization is very much energy
demanding. Moreover, the medium-sized ring formation
may be possible through the endo-cyclization of the dou-
ble bond if connected with the Michael type of olefinic
fragment.11a Interestingly, in our present case, the endo-
Heck products were obtained exclusively by an unusual 9-
endo-trig mode of cyclization.
We were delighted to obtain the corresponding cyclized
nine-membered lactone 6e in 51% yield. We extended the
scope of this reaction by synthesizing another nine-mem-
bered lactone derivative 6f starting from the precursor 5f.
Synthesis 2009, No. 14, 2385–2392 © Thieme Stuttgart · New York

2388
K. C. Majumdar, B. Chattopadhyay
PAPER
O
O
N
Me
O
OH
Me
O
OH
allyl or crotyl bromide, K2CO3
acetone, NaI
N
N
PhCl, reflux
N
Me R2 R1
Me
8a R1 = R2 = H
7
8b R1 = H, R2 = Me
cinamyl bromide
K2CO3, acetone, NaI
reflux
2-bromobenzyl bromide
or 2-bromo-5-methoxybenzyl bromide
acetone, K2CO3, NaI
reflux
2-bromobenzyl bromide
or 2-bromo-5-methoxybenzyl bromide
acetone, K2CO3, NaI
reflux
O
R3
Me
O
OH
N
O
N
N
R1
R3
Me
O
N
Me R2
Br
O
O
9 R1 = Me, R2 = Ph
Me
O
O
Me R2 R1
N
5g R1 = H, R2 = Me, R3 = 4-MeO
5h R1 = R2 = R3 = H
5i R1 = R2 = H, R3 = 4-MeO
Br
N
R1
Me R2
5j R1 = Me, R2 = Ph, R3 = H
5k R1 = Me, R2 = Ph, R3 = 4-MeO
Scheme 7
Table 2 Summarized Results of the Heck Reaction (continued)
Table 2 Summarized Results of the Heck Reaction
Entry Substrate Product
Entry Substrate
Product
O
O
O
O
Me
N
O
Br
Me
O
N
6b
O
I
1a
O
O
N
O
N
O
O
Me
Me
O
O
6f (48%)
5f
5a
6a (61%)
OMe
Br
OMe
O
OMe
O
O
Br
Me
N
Me
O
O
7c
8c
9c
N
O
O
2a
OMe
O
N
O
O
N
Me
O
Me
6g (94%)
O
5b
5g
6b (63%)
O
O
O
Me
N
Me
O
O
Br
N
Br
O
O
3a
O
N
N
O
O
Me
Me
O
6h (74%)
5h
O
5c
OMe
Br
6c (70%)
OMe
O
O
O
OMe
Me
N
Me
O
O
Br
N
O
N
O
O
4a
N
OMe
Me
O
O
Me
O
6i (96%)
5i
O
5d
O
6d (62%)
O
N
O
Me
O
N
Me
O
O
O
O
N
10c
O
N
Me
N
O
Br
O
Me
N
Ph
Me
5b
Ph
O
I
Me
O
N
O
N
5j
6j (88%)
Me
Me
5e
6e (51%)
Synthesis 2009, No. 14, 2385–2392 © Thieme Stuttgart · New York

PAPER
Synthesis of Medium-Sized Heterocycles
2389
Table 2 Summarized Results of the Heck Reaction (continued)
5b
Yield: 81%; viscous liquid.
IR (neat): 1721 cm–1.
Entry Substrate
Product
OMe
Br
O
1H NMR (400 MHz, CDCl3): d = 1.35 (d, J = 7.2 Hz, 3 H, CH3),
3.76 (s, 3 H, OCH3), 4.27–4.29 (m, 1 H, CHCH3), 4.99 (dd, J = 9.8,
1.4 Hz, 1 H, CHaHb), 5.04 (dd, J = 17.0, 1.4 Hz, 1 H, CHaHb), 5.32
(s, 2 H, OCH2), 5.72–5.81 (m, 1 H, =CH), 6.73 (dd, J = 8.7, 3.0 Hz,
1 H, ArH), 7.15 (d, J = 2.8 Hz, 1 H, ArH), 7.24 (t, J = 7.8 Hz, 1 H,
ArH), 7.29 (d, J = 8.2 Hz, 1 H, ArH), 7.39 (d, J = 8.5 Hz, 2 H, ArH),
7.55 (d, J = 7.8 Hz, 1 H, ArH).
O
O
OMe
Me
O
N
Me
O
11c
N
N
O
N
Me
Ph
Ph
Me
6k (92%)
5k
a Reactions were carried out under the optimized conditions.
b Reactions were carried out under conditions E.
c Reactions were carried out with Pd(OAc)2, KOAc, TBAB, DMF,
100 °C.
MS: m/z = 414 (M+), 416 (M + 2).
Anal. Calcd for C21H19BrO4: C, 60.74; H, 4.61. Found: C, 60.89; H,
4.54.
5c
Yield: 91%; viscous liquid.
In conclusion, we have developed an easy and efficient
protocol for the synthesis of benz-annulated nine-mem-
bered oxa-heterocyclic ring systems as well as the nine-
membered lactone derivatives. The method is simple and
straightforward, and affords a convergent synthesis of tri-
cyclic compounds containing nine-membered ring sys-
tems by an unusual 9-endo-trig mode of cyclization via
the phosphine free intramolecular Heck reaction.
IR (neat): 1726 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.56–3.58 (m, 2 H, =CHCH2),
4.99 (dd, J = 9.8, 1.4 Hz, 1 H, =CHaHb), 5.02 (dd, J = 17.0, 1.4
Hz, 1 H, =CHaHb), 5.32 (s, 2 H, OCH2), 5.70–5.80 (m, 1 H, =CH),
7.18 (dt, J = 1.6, 7.7 Hz, ArH, 1 H), 7.23–7.35 (m, 4 H, ArH), 7.41–
7.45 (m, 1 H, ArH), 7.50–7.60 (m, 2 H, ArH).
MS: m/z = 370 (M+), 372 (M + 2).
Anal. Calcd for C19H15BrO3: C, 61.47; H, 4.07. Found: C, 61.23; H,
4.11.
Melting points were determined in open capillaries and are uncor-
rected. IR spectra were run for KBr discs (and neat for liquid sam-
ples) on a Perkin-Elmer 120-000A apparatus (cm–1) and NMR
spectra were determined for solutions in CDCl3 with TMS as inter-
nal standard at the Bose Institute, Indian Institute of Chemical Bio-
logy and Chembiotek Research International Pvt. Ltd., Calcutta.
Silica gel (60–120 mesh) was used for chromatographic separation.
Silica gel G [E-Merck (India)] was used for TLC.
5d
Yield: 83%; viscous liquid.
IR (neat): 1722 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.57–3.59 (m, 2 H, =CHCH2),
3.79 (s, 3 H, OCH3), 5.02 (dd, J = 10.2, 1.3 Hz, 1 H, =CHaHb), 5.06
(dd, J = 16.8, 1.3 Hz, 1H, =CHaHb), 5.26 (s, 2 H, OCH2), 5.74–5.83
(m, 1 H, =CH), 6.75 (dd, J = 2.9, 8.6 Hz, 1 H, ArH), 7.18 (d, J = 2.9
Hz, 1 H, ArH), 7.24–7.28 (m, 1 H, ArH), 7.34 (d, J = 8.2 Hz, 1 H,
ArH), 7.42–7.45 (m, 2 H, ArH), 7.56 (d, J = 7.9 Hz, 1 H, ArH).
Precursor Compounds 5a–d; General Procedure
A mixture of 3 (1.38 mmol), 2-bromobenzyl bromide 4 (1.38
mmol), and anhyd K2CO3 (2.0 g) in anhyd acetone (75 mL) in the
presence of NaI was refluxed for 4–5 h. After cooling, the reaction
mixture was filtered and the solvent was removed. The residual
mass was extracted with CHCl3 (3 × 30 mL), the combined organic
layers were washed with H2O (30 mL) followed by brine (20 mL),
and dried (Na2SO4). Removal of CHCl3 gave a crude product, which
was purified by chromatography over silica gel (60–120 mesh).
Elution of the column with hexanes–EtOAc (90%) gave compounds
5a–d.
MS: m/z = 400 (M+), 402 (M + 2).
Anal. Calcd for C20H17BrO4: C, 59.87; H, 4.27. Found: C, 60.13; H,
4.19.
Precursor 5e; Typical Procedure
DMAP (7 mg) and Et3N (1.5 mL) were added to 3c (300 mg, 1.44
mmol) in anhyd CH2Cl2 (20 mL) at ice-bath temperature. 2-Iodo-
benzoyl chloride (4c; 356 mg, 1.44 mmol, prepared from 2-iodo-
benzoic acid and oxalyl chloride) in anhyd CH2Cl2 (10 mL) was
added dropwise. The reaction mixture was stirred for 4 h at the same
temperature. The CH2Cl2 phase was then washed with H2O (3 × 15
mL) and brine (20 mL), and dried (Na2SO4). Evaporation of the
CH2Cl2 gave a crude mass, which was purified by chromatography
with 40% EtOAc–hexanes to afford 5e; yield: 585 mg (93%); vis-
cous liquid.
5a
Yield: 88%; viscous liquid.
IR (neat): 1723 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.35 (d, J = 7.2 Hz, 3 H, CH3),
4.28–4.31 (m, 1 H, CHCH3), 5.00 (dd, J = 9.8, 1.3 Hz, 1 H, CHaHb),
5.06 (dd, J = 16.8, 1.3 Hz, 1 H, CHaHb), 5.30 (s, 2 H, OCH2), 5.70–
5.80 (m, 1 H, =CH), 7.16 (dt, J = 1.6, 7.6 Hz, 1 H, ArH), 7.26–7.36
(m, 4 H, ArH), 7.42 (dt, J = 1.6, 7.3 Hz, 1 H, ArH), 7.52–7.58 (m, 2
H, ArH).
IR (neat): 1649, 1701, 1737 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.46 (d, J = 7.2 Hz, 3 H, CH3),
3.38 (s, 3 H, NCH3), 3.47 (s, 3 H, NCH3), 3.94–3.97 (m, 1 H, CH),
5.16–5.24 (m, 2 H, =CH2), 5.92–6.00 (m, 1 H, =CH), 7.20 (dt,
J = 7.8, 1.8 Hz, 1 H, ArH), 7.45 (dt, J = 7.7, 1.2 Hz, 1 H, ArH), 8.03
(dd, J = 8.1, 1.0 Hz, 1 H, ArH), 8.08 (dd, J = 7.8, 1.7 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 17.6, 34.3, 72.9, 100.2, 114.9,
117.0, 118.8, 123.8, 126.3, 127.6, 129.5, 129.9, 130.9, 132.8, 135.9,
139.2, 139.9, 143.9, 151.2, 158.1.
MS: m/z = 384 (M+), 386 (M + 2).
MS: m/z = 440 (M+).
Anal. Calcd for C20H17BrO3: C, 62.35; H, 4.45. Found: C, 62.43; H,
4.31.
Anal. Calcd for C17H17IN2O4: C, 46.38; H, 3.89; N, 6.36. Found: C,
46.57; H, 4.03; N, 6.22.
Synthesis 2009, No. 14, 2385–2392 © Thieme Stuttgart · New York

2390
5f
K. C. Majumdar, B. Chattopadhyay
PAPER
CH2=CH), 6.70–6.76 (m, 1 H, ArH), 7.14 (t, J = 3.4 Hz, 1 H, ArH),
7.38–7.42 (m, 1 H, ArH).
Compound 5f was prepared in an analogous manner.
Yield: 95%; viscous liquid.
MS: m/z = 394 (M+), 396 (M+ + 2).
IR (neat): 1648, 1700, 1736 cm–1.
Anal. Calcd for C17H19BrN2O4: C, 51.66; H, 4.85; N, 7.09. Found:
C, 51.69; H, 4.71; N, 7.19.
1H NMR (400 MHz, CDCl3): d = 3.34 (br s, 5 H, CH2 and NCH3
overlapped), 3.36 (s, 3 H, NCH3), 5.20–5.29 (m, 2 H, =CH2), 5.78–
5.88 (m, 1 H, =CH), 7.21 (dt, J = 7.7, 1.8 Hz, 1 H, ArH), 7.44 (t,
J = 7.9 Hz, 1 H, ArH), 8.01 (dd, J = 7.5, 1.0 Hz, 1 H, ArH), 8.05
(dd, J = 8.2, 1.2 Hz, 1 H, ArH).
5j
Yield: 91%; white solid; mp 103–104 °C.
IR (KBr): 1648, 1703 cm–1.
MS: m/z = 426 (M+).
1H NMR (400 MHz, CDCl3): d = 1.77 (d, J = 7.0 Hz, 3 H,
=CHCH3), 3.15 (s, 3 H, NCH3), 3.46 (s, 3 H, NCH3), 4.98 (s, 2 H,
OCH2), 6.48 (q, J = 7.0 Hz, 1 H, =CHCH3), 7.05 (t, J = 7.6 Hz, 1 H,
ArH), 7.17–7.23 (m, 3 H, ArH), 7.26–7.31 (m, 3 H, ArH), 7.40 (t,
J = 6.2 Hz, 2 H, ArH).
Anal. Calcd for C16H15IN2O4: C, 45.09; H, 3.55; N, 6.57. Found: C,
45.19; H, 3.71; N, 6.43.
Precursor Compounds 5g–k; General Procedure
A mixture of 3, 2-bromobenzyl bromide 4, and anhyd K2CO3 (2.0
g) in anhyd acetone (75 mL) in the presence of NaI was refluxed for
a period of 2–3 h. After cooling, the reaction mixture was filtered
and the solvent was removed. The residual mass was extracted with
CHCl3 (3 × 30 mL), the combined CHCl3 layers were washed with
H2O (30 mL) followed by brine (20 mL), and dried (Na2SO4). Re-
moval of CHCl3 gave a crude product, which was chromatographed
over silica gel (60–120 mesh). Elution of the column with hexanes–
EtOAc (2:1) gave compounds 5g–k.
MS: m/z = 440 (M+), 442 (M+ + 2).
Anal. Calcd for C22H21BrN2O3: C, 59.87; H, 4.80; N, 6.35. Found:
C, 60.03; H, 4.71; N, 6.29.
5k
Yield: 85%; white solid; mp 108–109 °C.
IR (KBr): 1649, 1700 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.77 (d, J = 7.0 Hz, 3 H,
=CHCH3), 3.16 (s, 3 H, NCH3), 3.43 (s, 3 H, NCH3), 3.78 (s, 3 H,
OCH3), 5.00 (s, 2 H, OCH2), 6.44 (q, J = 7.0 Hz, 1 H, =CHCH3),
6.61 (dd, J = 8.8, 3.0 Hz, 1 H, ArH), 6.97 (d, J = 3.0 Hz, 1 H, ArH),
7.17–7.21 (m, 2 H, ArH), 7.27–7.30 (m, 4 H, ArH).
5g
Yield: 89%; white solid; mp 98–99 °C.
IR (KBr): 1649, 1700 cm–1.
MS: m/z = 470 (M+), 472 (M+ + 2).
1H NMR (400 MHz, CDCl3): d = 1.24 (d, J = 7.2 Hz, 3
H, =CHCH3), 3.34 (s, 3 H, NCH3), 3.39 (s, 3 H, NCH3), 3.78 (s, 3
H, OCH3), 4.28–4.30 (m, 1 H, =CHCH3), 5.04 (dd, J = 2.1, 17.4 Hz,
1 H, =CHCHaHb), 5.10 (s, 2 H, OCH2), 5.15 (dd, J = 2.1, 12.2 Hz,
1 H, =CHCHaHb), 5.77–5.85 (m, 1 H, CH2=CH), 6.74 (dd, J = 3.0,
8.8 Hz, 1 H, ArH), 7.11 (d, J = 3.0 Hz, 1 H, ArH), 7.42 (d, J = 8.7
Hz, 1 H, ArH).
Anal. Calcd for C23H23BrN2O4: C, 58.61; H, 4.92; N, 5.94. Found:
C, 58.69; H, 5.01; N, 6.07.
Heck Reaction; Compound 6a; Typical Procedure
A mixture of 5a (0.26 mmol, 100 mg), Bu4NBr (0.31 mmol, 100.6
mg) and anhyd K2CO3 (0.72 mmol, 98 mg) was taken in anhyd
MeCN (10 mL) in a sealed tube. Pd(OAc)2 (5 mol%, 2.9 mg) was
added and the mixture was stirred in an oil bath at 80 °C for ~2 h.
The mixture was cooled, the MeCN removed under reduced pres-
sure, and H2O (3 mL) was added. The mixture was extracted with
EtOAc (3 × 20 ml), the combined EtOAc layers were washed with
H2O (2 × 20 mL), followed by brine (20 mL). The combined organ-
ic layers were dried (Na2SO4), and the solvent was distilled off to
furnish a viscous mass, which was purified by column chromatog-
raphy over silica gel. Elution of the column with 10% EtOAc–hex-
anes afforded the product 6a; yield: 73 mg (61%); viscous liquid.
MS: m/z = 408 (M+), 410 (M+ + 2).
Anal. Calcd for C18H21BrN2O4: C, 52.82; H, 5.17; N, 6.84. Found:
C, 52.87; H, 5.09; N, 6.94.
5h
Yield: 96%; white solid; mp 95–96 °C.
IR (KBr): 1650, 1699 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.36 (s, 3 H, NCH3), 3.39 (s, 3 H,
NCH3), 3.40–3.41 (m, 2 H, =CHCH2), 5.02 (dd, J = 1.0, 17.4 Hz, 1
H, =CHCHaHb), 5.10 (s, 2 H, OCH2), 5.13 (dd, J = 1.0, 12.2 Hz, 1
H, =CHCHaHb), 5.62–5.69 (m, 1 H, CH2=CH), 7.18 (dt, J = 1.6, 9.7
Hz, 1 H, ArH), 7.32 (dt, J = 1.0, 7.5 Hz, 1 H, ArH), 7.53–7.56 (m,
2 H, ArH).
IR (neat): 1736 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.48 (d, J = 7.2 Hz, 3 H, CH3),
4.30–4.32 (m, 1 H, CH), 4.82 (d, 1 H, J = 12.4 Hz, OCHaHb), 5.44
(d, J = 12.4 Hz, 1 H, OCHaHb), 6.25 (m, 1 H, =CHc), 6.46 (d,
J = 16.4 Hz, 1 H, =CHd), 7.26–7.28 (m, 2 H, ArH), 7.32–7.37 (m, 4
H, ArH), 7.46 (dt, J = 1.4, 7.4 Hz, 1 H, ArH), 7.71 (d, J = 7.9 Hz, 1
H, ArH).
13C NMR (125 MHz, CDCl3): d = 28.1, 30.1, 31.7, 73.3, 117.8,
123.3, 127.4, 129.5, 130.4, 130.6, 131.4, 132.4, 136.0, 143.3, 151.1,
159.5.
MS: m/z = 364 (M+), 366 (M+ + 2).
13C NMR (75 MHz, CDCl3): d = 19.2, 33.1, 76.3, 111.9, 113.7,
116.6, 119.9, 126.1, 127.7, 127.9, 129.8, 131.7, 134.8, 136.8, 144.9,
145.1, 145.7, 147.3, 152.6, 159.9.
Anal. Calcd for C16H17BrN2O3: C, 52.62; H, 4.69; N, 7.67. Found:
C, 52.71; H, 4.59; N, 7.77.
MS: m/z = 304 (M+).
5i
Yield: 87%; white solid; mp 99–100 °C.
Anal. Calcd for C20H16O3: C, 78.93; H, 5.30. Found: C, 78.88; H,
5.29.
IR (KBr): 1649, 1699 cm–1.
6b
Yield: 63%; viscous liquid.
1H NMR (400 MHz, CDCl3): d = 3.37 (s, 3 H, NCH3), 3.40 (s, 3 H,
NCH3), 3.41–3.43 (m, 2 H, =CHCH2), 3.79 (s, 3 H, OCH3), 5.04
(dd, J = 1.0, 17.4 Hz, 1 H, =CHCHaHb), 5.06 (s, 2 H, OCH2), 5.15
(dd, J = 1.0, 12.2 Hz, 1 H, =CHCHaHb), 5.63–5.69 (m, 1 H,
IR (neat): 1731 cm–1.
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Synthesis of Medium-Sized Heterocycles
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1H NMR (400 MHz, CDCl3): d = 1.50 (d, J = 7.2 Hz, 3 H, CH3),
3.81 (s, 3 H, OCH3), 4.29–4.31 (m, 1 H, CH), 4.81 (d, J = 12.4 Hz,
1 H, OCHaHb), 5.42 (d, 1 H, J = 12.4 Hz, OCHaHb), 6.24 (m, 1
H, =CHc), 6.43 (d, J = 16.4 Hz, 1 H, =CHd), 6.71 (d, J = 1.7 Hz, 1
H, ArH), 6.98 (t, J = 6.9 Hz, 1 h, ArH), 7.02 (d, J = 1.2 Hz, 1 H,
ArH), 7.12–7.14 (m, 2 H, ArH), 7.23 (d, J = 8.6 Hz, 1 H, ArH), 7.32
(d, J = 7.6 Hz, 1 H, ArH).
6h
Yield: 74%; white solid; mp 198–199 °C.
IR (KBr): 1650, 1701 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.25 (m, 2 H, =CHCH2), 3.34 (s,
3 H, NCH3), 3.39 (s, 3 H, NCH3), 4.75–4.77 (m, 1 H, =CHCH), 5.46
(d, J = 12.6 Hz, 1 H, OCHaHb), 5.83 (d, J = 12.6 Hz, 1 H, OCHaHb),
6.22–6.29 (m, 1 H, CH2CH), 7.25–7.35 (m, 4 H, ArH).
MS: m/z = 334 (M+).
MS: m/z = 284 (M+).
Anal. Calcd for C21H18O4: C, 75.43; H, 5.43. Found: C, 75.59; H,
5.29.
Anal. Calcd for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C,
67.68; H, 5.69; N, 9.79.
6c
Yield: 70%; solid; mp 94–95 °C.
6i
Yield: 96%; white solid; mp 195–196 °C.
IR (KBr): 1735 cm–1.
IR (KBr): 1650, 1701 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.69–3.71 (m, 2 H, =CHCH2),
4.82 (d, J = 12.4 Hz, 1 H, OCHaHb), 5.44 (d, J = 12.4 Hz, 1 H,
OCHaHb), 6.17 (m, 1 H, =CHc), 6.49 (m, 1 H, =CHd), 7.03 (dd,
J = 7.7, 1.7 Hz, 1 H, ArH), 7.15 (dt, J = 8.5, 1.7 Hz, 1 H, ArH),
7.20–7.25 (m, 3 H, ArH), 7.31–7.37 (m, 3 H, ArH).
1H NMR (400 MHz, CDCl3): d = 3.29 (s, 3 H, NCH3), 3.34 (s, 3 H,
NCH3), 3.35–3.37 (m, 2 H, =CHCH2), 3.77 (s, 3 H, OCH3), 4.74 (d,
J = 12.6 Hz, 1 H, OCHaHb), 5.41 (d, J = 12.6 Hz, 1 H, OCHaHb),
5.82 (dd, J = 1.4, 15.8 Hz, 1 H, =CCH), 6.29–6.38 (m, 1 H,
CH2CH=C), 6.72 (dd, J = 3.0, 8.7 Hz, 1 H, ArH), 7.13 (d, J = 2.8
Hz, 1 H, ArH), 7.38 (d, J = 7.8 Hz, 1 H, ArH).
MS: m/z = 290 (M+).
Anal. Calcd for C19H14O3: C, 78.61; H, 4.86. Found: C, 78.78; H,
5.01.
MS: m/z = 314 (M+).
Anal. Calcd for C17H18N2O4: C, 64.96; H, 5.77; N, 8.91. Found: C,
65.01; H, 5.83; N, 9.03.
6d
Yield: 62%; solid; mp 103–104 °C.
6j
Yield: 88%; viscous liquid.
IR (KBr): 1731 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.67–3.70 (m, 2 H, =CHCH2),
3.81 (s, 3 H, OCH3), 4.79 (d, J = 12.4 Hz, 1 H, OCHaHb), 5.41 (d,
J = 12.4 Hz, 1 H, OCHaHb), 6.21 (m, 1 H, =CHc), 6.47 (m, 1
H, =CHd), 6.82 (d, J = 1.6 Hz, 1 H, ArH), 7.05 (dd, J = 6.9, 1.4 Hz,
1 H, ArH), 7.09 (d, J = 1.4 Hz, 1 H, ArH), 7.16–7.19 (m, 2 H, ArH),
7.27 (dd, J = 7.8, 1.2 Hz, 1 H, ArH), 7.38 (d, J = 8.5 Hz, 1 H, ArH).
IR (neat): 1646, 1700 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.27 (s, 3 H, =CHCH3), 3.15 (s, 3
H, NCH3), 3.42 (s, 3 H, NCH3), 4.96 (s, 2 H, OCH2), 6.52 (dd,
J = 7.1, 1.6 Hz, 1 H, ArH), 7.15–7.23 (m, 3 H, ArH), 7.27–7.32 (m,
4 H, ArH), 7.47 (d, J = 7.6 Hz, 1 H, ArH).
MS: m/z = 360 (M+).
MS: m/z = 320 (M+).
Anal. Calcd for C22H20N2O3: C, 73.32; H, 5.59; N, 7.77. Found: C,
73.11; H, 5.66; N, 7.89.
Anal. Calcd for C20H16O4: C, 74.99; H, 5.03. Found: C, 75.13; H,
4.93.
6k
Yield: 92%; viscous liquid.
6e,f
Spectral data for the compounds 6e,f are not provided due to their
instability.
IR (neat): 1648, 1701 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.27 (s, 3 H, =CHCH3), 3.17 (s, 3
H, NCH3), 3.44 (s, 3 H, NCH3), 3.78 (s, 3 H, OCH3), 4.98 (s, 2 H,
OCH2), 6.47 (t, J = 7.3, 2.0 Hz, 2 H, ArH), 6.60 (d, J = 7.6 Hz, 1 H,
ArH), 7.10–7.21 (m, 4 H, ArH), 7.44 (s, 1 H, ArH).
Compounds 6g–k; Compound 6g; Typical Procedure
A mixture of the compound 5g (100 mg, 0.265 mmol), Bu4NBr (1.2
equiv), anhyd KOAc (2.75 equiv) was taken in anhyd DMF (10 mL)
under N2. The catalyst Pd(OAc)2 (10 mmol%, 5.92 mg) was then
added and the mixture was stirred in an oil bath at 100 °C for about
2–3.5 h. The mixture was cooled, H2O (3 mL) was added and ex-
tracted with EtOAc (3 × 10 mL). The combined EtOAc layers were
washed with H2O (2 × 10 mL) followed by brine (15 mL), and dried
(Na2SO4). Evaporation of EtOAc furnished a crude mass, which
was purified by column chromatography over silica gel. Elution of
the column with 10% EtOAc–hexanes afforded the product 6g;
yield: 146 mg (94%); white solid; mp 190–191 °C.
MS: m/z = 390 (M+).
Anal. Calcd for C23H22N2O4: C, 70.75; H, 5.68; N, 7.17. Found: C,
70.61; H, 5.83; N, 6.99.
Acknowledgment
We thank the DST (New Delhi) and CSIR (New Delhi) for financial
assistance. B.C. is grateful to the CSIR (New Delhi) for his fel-
IR (KBr): 1651, 1699 cm–1.
1
lowship. We also thank Dr. P. P. Mukhopadhyay for H and 13C
NMR spectra reported in this article.
1H NMR (400 MHz, CDCl3): d = 1.83 (s, 3 H, =CCH3), 3.23 (d,
J = 8.0 Hz, 2 H, =CCH2), 3.34 (s, 3 H, NCH3), 3.40 (s, 3 H, NCH3),
3.79 (s, 3 H, OCH3), 4.64 (d, J = 12.6 Hz, 1 H, OCHaHb), 5.33 (d,
J = 12.6 Hz, 1 H, OCHaHb), 5.84 (t, J = 8.0 Hz, 1 H, CH2CH), 6.82
(d, J = 2.7 Hz, 1 H, ArH), 6.85 (dd, J = 2.8, 8.3 Hz, 1 H, ArH), 7.22
(d, J = 8.3 Hz, 1 H, ArH).
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2392
K. C. Majumdar, B. Chattopadhyay
PAPER
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