Sequential Claisen rearrangement and intramolecular Heck reaction as a route to medium-ring oxacycle-fused heterocycles

Article abstract of DOI:10.1055/s-2008-1072719

A synthetic strategy based on tandem application of Claisen rearrangement and intramolecular Heck reaction as key steps has been developed for the synthesis of various hitherto unknown benzoxocine- and benzoxonine-fused coumarin and quinolone derivatives.

Full text of DOI:10.1055/s-2008-1072719

LETTER
1137
Sequential Claisen Rearrangement and Intramolecular Heck Reaction as a
Route to Medium-Ring Oxacycle-Fused Heterocycles
Synthesis of
M
h
e
dium-Ring
i
O
xacy
t
c
le-F
u
a
sedHeteroc
l
ycles K. Chattopadhyay,* Kaushik Neogi, Sovan K. Singha, Rajat Dey
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Fax +91(33)25828282; E-mail: skchatto@yahoo.com
Received 17 September 2007
We have been engaged for some time in the synthesis of
Abstract: A synthetic strategy based on tandem application of
Claisen rearrangement and intramolecular Heck reaction as key
steps has been developed for the synthesis of various hitherto un-
known benzoxocine- and benzoxonine-fused coumarin and qui-
nolone derivatives.
medium-ring heterocycle-fused heterocyclic systems cul-
minating in the development of synthetic routes to hither-
to unknown oxepin- and oxocin-fused coumarins,8
quinolones,9 carbazole10 and naphthalene derivatives,11
based on tandem applications of Claisen rearrangement
and ring-closing diene- or enyne metathesis.12 The meth-
odology has found application13 in the synthesis of other
medium-ring heteroannulated compounds. Herein, we
report14 a new methodology for the synthesis of medium-
ring oxacycle-annulated heterocycles based on tandem
Claisen rearrangement15 and Heck-type arylation reaction
as key steps. In view of the known importance of furo- and
pyranocoumarins16 and their isosteric analogues furo- and
pyrano-2-quinolones17 we have chosen coumarin and 2-
quinolone as the heterocyclic frameworks for the explora-
tion in the present study.
Key words: Claisen rearrangement, Heck reaction, oxocine, oxo-
nine
Various normal-ring-size heterocycle-fused heterocyclic
systems display interesting properties and there has been
a continuous evolution of newer methodologies for the
synthesis of such ring systems.1 In contrast, medium-ring
heterocycle-annulated heterocyclic systems are less
known until recently when various metal-catalysed organ-
ic transformations made medium-sized rings more acces-
sible.2 The palladium-catalysed intramolecular Heck-type
arylation reaction has been extensively used for the syn-
thesis of heterocyclic rings of varying size and complexi-
ty.3 However, medium-ring formation through such a
procedure still poses challenges and therefore remains as
an explorable exercise. Whereas with activated olefins
(Michael-type olefinic fragments) only one mode of cycli-
sation (electronic controlled) is mostly observed,4 mix-
tures of endo- and exo-cyclisation products are usually
formed5 during medium-sized-ring formation from in-
tramolecular Heck reaction with unactivated olefins.6
This difference in regioselectivity has been explained by
the difficulties associated with the attainment of coplanar
eclipsed orientation of the relevant moieties during the
carbopalladation step (Figure 1). However, with the in-
crease in chain length exclusive endo-cyclisation leading
to nine- or ten-membered heterocyclic rings has also been
observed.7
Thus, Claisen rearrangement of 4,8-dimethyl-7-allyloxy-
coumarin (1) under our previously developed conditions8b
provided access to the rearranged phenol 2 (Table 1). The
latter on esterification with 2-iodobenzoic acid in the pres-
ence of dicyclohexylcarbodiimide smoothly led to the for-
mation of the Heck precursor 3. The crucial Heck
cyclisation of the latter was then studied under a range of
conditions reported for similar types of cyclisation but
with some modifications. The reaction proceeded best in
refluxing acetonitrile in the presence of palladium acetate
(10 mol%) as catalyst, tri-o-tolylphosphine (20 mol%) as
additive and triethylamine as base to form the cyclised
product 8 as the only isolable product but in disappoint-
ingly low yield (32%).
The formation of 8 from 3 could be explained if it is as-
sumed that the initially formed 8-exo cyclisation product
6 underwent in situ base-mediated isomerisation. The
amount or nature of the catalyst and base, higher temper-
ature or prolonged reaction time in different solvents at
different dilutions did not alter the course of the reaction
to any significant extent. Following our earlier success
with Jeffery’s two-phase protocol18 in other instances,19
we employed such conditions in the current effort. How-
ever, no significant improvement could be observed; al-
though undesired side products such as deiodinated
starting material were isolated in few cases indicating that
oxidative addition indeed took place. The difficulty asso-
ciated with the intramolecular Heck-type cyclisation of
the ester-tethered substrate may be explained in terms of
predominance of a favoured but unproductive Z-conform-
Pd
Pd
C
C
C
R
R
C
eclipsed
twisted
Figure 1
SYNLETT 2008, No. 8, pp 1137–1140
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072719; Art ID: D29007ST
© Georg Thieme Verlag Stuttgart · New York

1138
S. K. Chattopadhyay et al.
LETTER
er in the conformational equilibrium. For example, the Z bromide under conventional conditions. To our satisfac-
conformation in phenyl benzoate is preferred over E by 5– tion, cyclisation of 4 under conditions identical to that for
6 kcal/mol; with a rotation barrier of 10–13 kcal/mol.20 the conversion 3 into 8, led to the formation of the 8-exo
This led us to consider cyclisation of the corresponding cyclisation product 7 (51%) together with the isomerised
ether-tethered substrates.
product 9 (8%). Iodides are known to be better partners as
compared to bromides during medium-sized-ring forma-
tion through intramolecular Heck reaction. We thus pre-
We thus prepared the ether-tethered cyclisation precursor
4 by etherification of the phenol 2 with 2-bromobenzyl
Table 1 Claisen Rearrangement and Intramolecular Heck Reaction
Entry Starting ether
Rearranged phenol
(conditions, yield)
Heck precursora
(yield)
Productb
(yield)
O
O
X
O
6, X = CO
7, X = CH2 (62%)
Y
O
X
O
O
1
O
O
O
HO
O
O
1
2 (Ph2O, reflux, 3 h, 83%)
3, X = CO, Y = I (78%)
4, X = CH2, Y = Br (89%)
5, X = CH2, Y = I (91%)
O
O
X
O
8, X = CO (32%)
9, X = CH2 (8%)
O
O
O
O
O
O
2
HO
O
O
O
O
O
I
10
11 (Ph2O, reflux, 2 h, 79%)
13 (57%)
12 (85%)
O
O
O
O
O
O
HO
O
O
3
4
O
O
O
I
14
15 (Ph2O, reflux, 0.5 h, 76%)
17 (52%)
16 (89%)
I
O
O
OH
O
O
O
O
O
O
O
18
19 (PhCl, reflux, 12 h, 89%)
O
O
20 (91%)
21 (55%)
I
O
HO
5
O
O
N
O
N
O
O
N
Me
Me
N
O
Me
22
23 (PhNEt2, reflux, 10 h, 69%)
Me
24 (88%)
25 (62%)
a Reaction conditions: 2-BrC6H4CH2Br (or 2-IC6H4CH2Br; 1.4 equiv), K2CO3 (2 equiv), acetone, reflux, 12 h.
b Reaction conditions: Pd(OAc)2 (10 mol%), (o-tol)3P (20 mol%), MeCN (0.01 M), reflux, 16 h.
Synlett 2008, No. 8, 1137–1140 © Thieme Stuttgart · New York

LETTER
Synthesis of Medium-Ring Oxacycle-Fused Heterocycles
Outcome
1139
Table 2 Attempted Conditions for Intramolecular Heck Reaction
Entry
Substrate
Conditionsa
1
2
3
4
5
6
7
8
4
4
4
4
5
5
5
5
Pd(OAc)2, (o-tol)3P, Et3N, DMF, 110 ºC, 16 h
Pd(OAc)2, n-Bu4N+Br–, K2CO3, DMF, 80–110 °C, 16–48 h
Pd(OAc)2, n-Bu4N+Br–, KOAc, DMF, 110 ºC, 16 h
Pd(PPh3)2Cl2, Et3N, DMF, 100–110 ºC, 48 h
Pd(OAc)2, (o-tol)3P, Et3N, DMF, 110 ºC, 16 h
Pd(OAc)2, n-Bu4N+Br–, KOAc, DMF, 110 ºC, 16 h
Pd(PPh3)2Cl2, Et3N, MeCN, reflux, 48 h
7 (32%)
no reaction
7 (38%)
no reaction
7 (44%)
7 (49%)
no reaction
complex mixture
Pd(PPh3)2Cl2, KOAc, DMF, 110 ºC, 16 h
a Catalyst (10 mol%) was used in all cases.
pared the cyclisation precursor 5 by straightforward the rearranged phenol 19,8a underwent 8-exo cyclisation
etherification of the phenol 2 with 2-iodobenzyl bromide. under identical conditions leading to the formation of 21
Pleasingly, compound 5 also underwent 8-exo cyclisation as the only isolable product (55%). The product was char-
under identical conditions to provide the product 7 in an acterized by the characteristic appearance of the exocyclic
improved yield of 62%. We have examined other condi- methylene protons at d = 5.45 (d, J = 1.5 Hz, 1 H) and at
tions for the projected intramolecular Heck reaction by d = 5.21 (d, J = 1.1 Hz, 1 H) in its 1H NMR spectrum, and
changing the various parameters of the reaction and some from a methylenic carbon resonance at d = 115.2 in its
of the results thereof are summarised in Table 2. It was DEPT spectrum.
seen that the 8-exo cyclisation product was obtained con-
sistently under a range of conditions but in lower yields.
As bases, both Et3N and KOAc were effective. Catalyst
systems such as Pd(PPh3)2Cl2, PdCl2, Pd(PPh3)4 or
Pd2(dba)3 were found to be less effective. Use of higher
temperature or prolonged reaction time also had a delete-
rious effect on the outcome of the reaction.
In continuation of our earlier interest in medium-ring oxa-
cycle-fused quinolone derivatives,9 we then extended the
present study to the Heck precursor 24. The latter was pre-
pared by etherification of the rearranged phenol 239 with
2-iodobenzyl bromide. Pleasingly, compound 24 under-
went smooth cyclisation under the developed conditions
leading to the regioselective formation of the 8-exo cycli-
Similarly, starting from 7-allyloxy-4-methylcoumarin sation product 25 in good yield.
(10), the cyclisation precursor 12 was prepared by etheri-
In short, we have demonstrated that combined Claisen re-
arrangement and intramolecular Heck-type arylation reac-
fication of the rearranged phenol 118a with 2-iodobenzyl
bromide in an overall yield of 67% over two steps from
tion is a viable strategy for the synthesis of medium-ring
10. When compound 12 was subjected to cyclisation un-
annulated heterocyclic systems of interest. The cyclisa-
tion proceeded better with ether-tethered substrate com-
pared to ester-tethered substrate. Moreover, both possible
der the developed conditions, the 9-endo cyclisation prod-
uct 13 was obtained as the sole product (57%) along with
unchanged starting material (24%), the 8-exo cyclisation
8-exo and 9-endo modes of cyclisations have been ob-
not being observed. The product was easily characterised
served. The methodology developed may provide access
from its 1H NMR spectrum which displayed the presence
to other such heterocyclic systems and the compounds22
reported herein may also prove to be useful. Work will be
continued to study the scope of the present methodology
for the synthesis of other medium-ring heterocycle-annu-
of two olefinic protons belonging to the oxonine ring at d = 6.55
(d, J = 11.0 Hz, 1 H) and at d = 6.10 (dt, J = 8.5, 10.8 Hz,
1 H) with additional support from its 13C NMR and other
analytical data. Exclusive 9-endo cyclisation has been ob-
lated heterocyclic systems of interest.
served previously in medium-ring heterocycle formation
from substrates containing activated olefinic fragments.21
Acknowledgment
The regioselectivity in the present instance is therefore
noteworthy. Similarly, the iodobenzyl ether 16 (entry 3),
derived from the rearranged phenol 15, also underwent 9-
Financial assistance from DST, New Delhi (Grant No. SR/S1/OC-
51/2005) is gratefully acknowledged. One of us (S.S.) is thankful to
endo cyclisation under identical conditions to provide the CSIR, New Delhi, for a fellowship.
oxonine derivative 17 (52%) as a colourless solid together
with unreacted starting material. Efforts to increase the
yield of the oxonine derivatives 13 and 17 by increasing
the amount of catalyst or prolonging the reaction time un-
fortunately were unsuccessful. On the other hand, the
Heck precursor 20, prepared from 3-allyloxycoumarin via
References and Notes
(1) Katritzky, A. R.; Pozharaskii, A. F. Handbook of
Heterocyclic Chemistry; Pergamon: Oxford, 2003.
(2) For a review, see: Yet, L. Chem. Rev. 2000, 100, 2963.
Synlett 2008, No. 8, 1137–1140 © Thieme Stuttgart · New York

1140
S. K. Chattopadhyay et al.
LETTER
(17) (a) Yang, Z.-Y.; Xia, Y.; Xia, P.; Brossi, A.; Lee, K.-H.
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(18) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
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(22) All new compounds reported gave satisfactory spectroscopic
and/or analytical data. Compound 8: mp 265–266 °C. IR
(KBr): 1755, 1728, 1596, 1395, 1280, 1192, 1109, 1027 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.40 (m, 2 H), 7.29–
7.32 (m, 1 H), 7.14–7.24 (m, 1 H), 7.13 (s, 1 H), 6.67 (s, 1
H), 6.21 (s, 1 H), 2.38 (s, 3 H), 2.33 (d, J = 1.2 Hz, 3 H), 2.28
(d, J = 1.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 164.2
(s), 162.4 (s), 151.8 (s), 151.1 (s), 131.2 (s), 130.8 (d), 128.2
(s), 128.0(d), 127.2 (s), 127.1 (s), 126.6 (d), 126.3 (d), 126.1
(s), 122.6 (d), 121.6 (d), 118.2 (s), 117.3 (s), 114.7 (d), 24.5
(q), 18.7 (q), 9.6 (q). MS (EI, 70 eV): m/z (%) = 332 (10)
[M+], 224 (100). Anal. Calcd for C21H16O4: C, 75.89; H,
4.85. Found: C, 75.93; H, 5.01.
(9) Chattopadhyay, S. K.; Dey, R.; Biswas, S. Synthesis 2005,
403.
(10) Chattopadhyay, S. K.; Roy, S. P.; Ghosh, D.; Biswas, G.
Tetrahedron Lett. 2006, 47, 6895.
(11) (a) Chattopadhyay, S. K.; Biswas, T.; Maity, S. Synlett 2006,
2211. (b) Chattopadhyay, S. K.; Ghosh, D.; Neogi, K. Synth.
Commun. 2007, 37, 1535. (c)Chattopadhyay, S. K.; Paul, B.
K.; Maity, S. Chem. Lett. 2003, 32, 1190.
(12) For a recent review on medium ring heterocycle formation
by RCM, see: Chattopadhyay, S. K.; Karmakar, S.; Biswas,
T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron
2007, 63, 3919.
(13) (a) Pain, C.; Celanire, S.; Guillaument, G.; Joseph, B. Synlett
2003, 2089. (b) Kotha, S.; Mandal, K. Tetrahedron Lett.
2004, 45, 1391. (c) Majumdar, K. C.; Rahaman, H.; Muhuri,
S.; Roy, B. Synlett 2006, 466.
Compound 13: mp 205–206 °C. IR (KBr): 1710, 1624, 1588,
1379, 1275, 1078 cm–1. 1H NMR (300 MHz, CDCl3): d =
7.55 (d, J = 8.6 Hz, 1 H), 7.32–7.37 (m, 2 H), 7.24–7.26 (m,
2 H), 7.11 (d, J = 8.7 Hz, 1 H), 6.55 (d, J = 11.0 Hz, 1 H),
6.22 (s, 1 H), 6.10 (dt, J = 8.5, 10.8 Hz, 1 H), 5.29 (s, 2 H),
3.26 (d, J = 8.5 Hz, 2 H), 2.44 (s, 3 H). 13C NMR (75 MHz,
CDCl3): d = 161.5 (s), 160.1 (s), 152.4 (s), 138.5 (s), 137.4
(s), 136.2 (s), 132.4 (d), 130.6 (d), 129.2 (d), 128.7 (d), 126.4
(d), 125.2 (s), 124.2 (d), 118.4 (d), 116.2 (d), 115.2 (s), 113.1
(d), 75.5 (t), 35.6 (t), 18.9 (q). MS (TOFMS, ES+): m/z = 327
[M + Na]. Anal. Calcd for C20H16O3: C, 78.93; H, 5.30.
Found: C, 79.09; H, 5.26.
Compound 21: mp 168–169 °C. IR (KBr): 1710, 1605, 1451,
1299, 1147, 1107 cm–1. 1H NMR (300 MHz, CDCl3): d =
7.50 (dd, J = 1.2, 7.8 Hz, 1 H), 7.36–7.40 (m, 2 H), 7.23–7.24
(m, 1 H), 7.19–7.22 (m, 2 H), 7.13–7.18 (m, 2 H), 5.45 (d,
J = 1.5 Hz, 1 H), 5.43 (s, 2 H), 5.21 (d, J = 1.0 Hz, 1 H), 3.95
(s, 2 H). 13C NMR (75 MHz, CDCl3): d = 158.2 (s), 150.7 (s),
146.7 (s), 140.9 (s), 137.7 (s), 133.1 (s), 131.8 (s), 130.6 (s),
129.7 (d), 128.9 (d), 128.8 (d), 128.6 (d), 128.2 (d), 124.4
(d), 123.4 (d), 116.8 (d), 115.8 (t), 74.3 (t), 36.6 (t). MS
(TOFMS ES+): m/z = 313 [M + Na]. Anal. Calcd for
C19H14O3: C, 78.61; H, 4.86. Found: C, 78.80; H, 4.94.
(14) Taken in part from: Dey, R. PhD Dissertation; University of
Kalyani: India, 2005.
(15) For some recent reviews on Claisen rearrangement, see:
(a) Nubbemeyer, U. Synthesis 2003, 961. (b) Castro, A. M.
M. Chem. Rev. 2004, 104, 2939. (c) Blechert, S. Synthesis
1989, 71.
(16) (a) Larock, R. C.; Rozhkov, R. V. Org. Lett. 2003, 5, 797.
(b) Gonzalez-Gomez, J. C.; Uriarte, E. Synlett 2003, 2225.
(c) Zhang, S.-L.; Huang, Z.-S.; An, L.-K.; Bu, X.-Z.; Ma, L.;
Li, Y.-M.; Chan, A. S. C.; Gu, L.-Q. Org. Lett. 2004, 6,
4853. (d) Sekino, E.; Kumamoto, T.; Tanaka, T.; Ikeda, T.;
Ishikawa, T. J. Org. Chem. 2004, 69, 2760.
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