Novel synthesis of medium-sized oxa-heterocycles by palladium-catalyzed intramolecular Heck reaction

Article abstract of DOI:10.1016/j.tetlet.2007.08.121

An efficient and high yielding method for the synthesis of eight-membered heterocyclic skeletons has been developed via palladium-catalyzed intramolecular Heck reaction.

Full text of DOI:10.1016/j.tetlet.2007.08.121

Tetrahedron Letters 48 (2007) 7633–7636
Novel synthesis of medium-sized oxa-heterocycles
by palladium-catalyzed intramolecular Heck reaction
K. C. Majumdar,* B. Chattopadhyay and K. Ray
Department of Chemistry, University of Kalyani, Kalyani 741235, India
Received 11 June 2007; revised 20 August 2007; accepted 30 August 2007
Available online 4 September 2007
Abstract—An efficient and high yielding method for the synthesis of eight-membered heterocyclic skeletons has been developed via
palladium-catalyzed intramolecular Heck reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
Over the past decade, palladium-catalyzed cyclization
processes have proven to be an extremely powerful
and useful tool for the construction of carbon–carbon,
as well as carbon–heteroatom bonds.1–3 Furthermore,
palladium is typically used in catalytic amounts and tol-
erates a wide variety of functional groups, thus neatly
avoiding protection group chemistry. Generally, many
natural products, drugs and preclinical leads contain
medium-sized heterocycles fused to aryl rings, for exam-
ple, naphthoxepin derivatives such as A and B which are
used as antipsychotic drugs4 (Fig. 1).
compounds from readily available a- and b-naphthol
and resorcinol based on the thermal Claisen rearrange-
ment, followed by phosphine-free,6 palladium-catalyzed
intramolecular Heck reaction.7
Entropy8 plays an important role in intramolecular
Heck reactions for the formation of cyclized products.
In the majority of cases, the reaction proceeds in the
exo-trig mode which is far less sterically demanding.
The endo-trig mode of cyclization requires the olefinic
bond to be positioned inside the intermediate p-com-
plex. This requires a flexible tether between the olefinic
bond and the aromatic ring for it to be able to bend into
the proper conformation (Scheme 1) and is highly
improbable due to geometric reasons.9
However, a general synthesis of this type of medium-
sized heterocyclic compound is lacking. The synthesis
of medium-sized ring compounds, mainly seven- and
eight-membered, was reported5 based on ring closing
metathesis reactions. Herein, we report a simple ap-
proach to the synthesis of eight-membered heterocyclic
The Heck precursors 5a–d required for our present
study were synthesized in 70–80% yields by refluxing
a- and b-naphthols 3a,b with either 2-bromobenzyl bro-
mide 4a or 2-bromo-3-methoxybenzyl bromide 4b in dry
acetone in the presence of anhydrous potassium carbon-
ate and a small amount of sodium iodide10 (Scheme 2).
Naphthols 3a,b in turn were prepared in good to excel-
lent yields by the reaction of a- and b-naphthols 1a,b
X
O
A, X = O
B, X = N-methylcyclohexane
Exo
Pd
Figure 1. Naphthoxepin derivatives used as antipsychotic drugs.
Pd
Endo
Keywords: Palladium catalyst; Medium-sized ring; Claisen rearrange-
ment; 8-exo-Trig; 9-endo-Trig; Intramolecular Heck reaction.
Pd
Pd
*
Corresponding author. Tel.: +91 033 25827521; fax: +91 033 582
8282; e-mail: kcm_ku@yahoo.co.in
Scheme 1. exo and endo mode of cyclization.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.121

7634
K. C. Majumdar et al. / Tetrahedron Letters 48 (2007) 7633–7636
OH
1a
allyl bromide
acetone, NaI
K2CO3, reflux
Br
Br
O
OH
Br
O
DCB
acetone, K2CO3
NaI, reflux
R
+
R
R
2a
3a
3b
5a,b
4a,b
4a,b
Br
Br
O
OH
O
Br
acetone, K2CO3
NaI, reflux
DCB
+
R
2b
5c,d
5a, R = H, 84%
5b, R = OMe, 79%
5c, R = H, 71%
allyl bromide
acetone, NaI
K2CO3, reflux
5d, R = OMe, 78%
OH
1b
Scheme 2.
with allyl bromide followed by a Claisen rearrangement
in refluxing dichlorobenzene (DCB) for about 8–9 h.
in Table 2. We then extended the reaction to the readily
available, inexpensive starting material resorcinol.
When the intramolecular Heck reaction was carried out
with 5a in the presence of 10 mol % of Pd(OAc)2 as a
catalyst and KOAc (2.75 equiv) as a base and tetrabutyl-
ammonium bromide as a promoter11 in DMF at 120 °C
for 4–6 h, the 8-exo cyclized product 6a12 was obtained
as the major product in 78% yield, along with the 9-endo
cyclized 7 as a minor product in 20% yield. The use of
Pd(PPh3)2Cl2 as a catalyst was also found to be effective
but the nine-membered endo-Heck product was com-
pletely absent and the yield of the eight-membered
exo-Heck product was low (49%). We have examined
the effects of various bases, and experimentally, it was
found that Et3N (4 equiv) and K2CO3 (2 equiv) were
also effective but the yield of the 8-exo cyclized products
were lower than for the above-mentioned catalytic sys-
tems. The effect of temperature plays an important role
in this reaction. When the reaction was performed with
the low-boiling solvent acetonitrile the reaction did not
proceed at all, probably due to the unactivated allylic
system. Continuing the reaction for a long time at ele-
vated temperature rapidly decreased the yield due to
decomposition of the cyclized product. Other catalytic
systems such as PdCl2 yielded a number of unidentified
products along with unreacted starting material. The
results are summarized in Table 1.
Resorcinol 1c on reaction with allyl bromide in the pres-
ence of acetone, K2CO3 and NaI gave the O,O-dialky-
lated product 2c. The dialkylated product on refluxing
in o-DCB for 20–25 h afforded the rearranged product
3c, which on treatment with 2-bromobenzyl bromide
Table 1. Cyclizationa of compound 5a to 6a and 7
Br
9
8
O
O
O
+
7
6a
5a
Entry
Catalystb
Basec
Solvent
Yield of 6a:7 (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PdCl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
KOAc
K2CO3
Et3N
Et3N
Et3N
KOAc
KOAc
Et3N
—
DMF
DMF
DMF
DMF
DMF
MeCN
DMF
MeCN
DMF
DMF
78:20
58:0
NR
NR
40:0
NR
NR
NR
49:0
NR
10
Et3N
Substrates 5b–d were reacted under the conditions de-
scribed in entry 1, Table 1, to afford the eight-membered
exo-cyclic ring products. The 9-endo Heck products were
not obtained, probably in these cases due to the instabil-
ity of the endo-Heck product; the results are summarized
a Tetrabutylammonium bromide (TBAB) was used as a promoter. All
the reactions were performed at 120 °C for 4–6 h.
b 10 mol % of catalyst was used.
c 2.75 equiv of base was used. NR = No reaction.

K. C. Majumdar et al. / Tetrahedron Letters 48 (2007) 7633–7636
Table 2. Summarized results of the Heck reaction with 5a–d
7635
Entry
Substrate
Product
Yield (%) of 6
Br
9
O
8
1
78
72
81
77
O
O
O
5a
7
6a12
OMe
Br
O
8
2
3
4
OMe
5b
6b
Br
Br
O
O
8
5c
6c
OMe
O
O
8
OMe
5d
6d
afforded the corresponding Heck precursor 5e (Scheme
3).
6–9, Table 1. Only one of the allylic groups underwent
cyclization to form the eight-membered heterocyclic
compound 6e. We also failed to cyclize preformed 6e
to the doubly cyclized Heck product 8 (Scheme 4).
When the reaction of 5e was performed using the condi-
tions described in entry 1, Table 1, for 4 h at 120 °C, the
8-exo cyclized product (69%) and starting material
(21%) were isolated. Increasing the reaction time caused
considerable decomposition of the cyclized product. At
elevated temperature (>160 °C) extensive decomposition
also occurred. When the reaction was carried out using
the conditions described in entries 2, 5 and 10, Table 1,
the same product was obtained as under the conditions
described in entry 1, Table 1, but the yields were lower
(44%, 41% and 29%, respectively). There was no reac-
tion under the conditions described in entries 3, 4 and
The formation of the 8-exo trig product13 is quite
reasonable due to the less sterically demanding
environment. Formation of product 7, that is, the
nine-membered ring by the 9-endo-trig mode of cycliza-
tion, is quite interesting and follows a pathway that is
not common in cyclization chemistry.14
In summary, we have developed an efficient method for
the synthesis of eight-membered heterocyclic ring com-
pounds. This method may be applicable to other hetero-
allyl bromide,
acetone, K2CO3
NaI, reflux, 20 h
HO
O
OH
O
O
O
2c
1c
DCB
reflux
2-bromobenzyl bromide,
acetone, K2CO3
NaI, reflux, 20 h
HO
OH
Br
Br
5e
3c
Scheme 3.

7636
K. C. Majumdar et al. / Tetrahedron Letters 48 (2007) 7633–7636
Br
Br
O
O
O
O
8
8
Br
O
O
6e
5e
8
8
Scheme 4.
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the synthesis of a heterocyclic library is underway and
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Acknowledgement
We thank the CSIR (New Delhi) for financial assistance
and two of us (B.C. and K.R.) are grateful to the CSIR
(New Delhi) for their fellowships.
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