Synthesis of novel 3-bromo-2H-chromene derivatives: Palladium-mediated intramolecular cyclization of aryl propargyl ethers

Article abstract of DOI:10.1055/s-0029-1217563

Aryl propargyl ethers were cyclized in the presence of catalytic amount of Pd(OAc)₂ in conjunction with stoichiometric amount of CuBr ₂ and LiBr to the corresponding 3-bromo-2H-chromene derivatives in good yields. The protocol was fu

Full text of DOI:10.1055/s-0029-1217563

LETTER
2079
Synthesis of Novel 3-Bromo-2H-chromene Derivatives: Palladium-Mediated
Intramolecular Cyclization of Aryl Propargyl Ethers
Synthesis of
N
ove
u
l
3-Bromo-2
H
r
-chrom
u
ene
D
erivativ
n
e
s
athan Savitha, Kulandhai Felix, Paramasivan T. Perumal*
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received 31 March 2009
chromene derivatives could be synthesized from aryl pro-
Abstract: Aryl propargyl ethers were cyclized in the presence of
catalytic amount of Pd(OAc)2 in conjunction with stoichiometric
amount of CuBr2 and LiBr to the corresponding 3-bromo-2H-
chromene derivatives in good yields. The protocol was further ex-
pargyl ethers in the presence of catalytic amount of Pd(II)
along with stoichiometric amount of CuBr2. We envi-
sioned that activation of the alkyne will takes place by co-
tended to synthesize 3-bromo-benzofused 2H-chromene deriva- ordination to Pd(II) followed by a rapid intramolecular
tives.
nucleophilic attack by the arene. Subsequent halogen-
transfer reaction assisted by CuBr2 will furnish the corre-
sponding 3-bromo-2H-chromene derivatives (Scheme 1).
Herein we wish to report the results of our investigations
on the Palladium-mediated cyclization of aryl propargyl
ethers to novel 3-bromo-2H-chromene derivatives.
Key words: palladium-mediated
chromenes, aryl propargyl ethers, LiBr, CuBr2
cyclization,
3-bromo-2H-
2H-1-Benzopyrans, commonly known as 2H-benzopy-
rans or 2H-chromenes, are key structural units of a variety
of biologically important compounds, many of which are
pharmaceutically significant. The 2H-benzopyran dau-
richromenic acid is known to exhibit anti-HIV properties,1
while coutareagenin possesses antidiabetic activity.2 De-
rivatives of 3,4-diphenylchromans are known to have es-
trogenic activity.3 Numerous derivatives of 2H-
benzopyrans are useful for the treatment of proliferative
skin disorders and microbial infections4 and show potent
antifungal activity.5 Derivatives of 2H-benzopyrans, like
2,4-diphenyl-2H-benzopyran and 2,2,4-triphenyl-2H-
benzopyran, have been studied for their photochromic be-
havior.6 Owing to their biological and pharmaceutical im-
portance, there has been a constant research in the
development of new methodologies for the synthesis of
2H-chromene derivatives.7
R
R
Br
cat. Pd(OAc)2
CuBr2
O
O
Scheme 1
We initially focused our efforts on the cyclization of the
aryl propargyl ether 1a to the corresponding 3-bromo-2H-
chromene derivative. After a series of trials, the aryl pro-
pargyl ether 1a underwent cyclization in the presence of 5
mol% Pd(OAc)2 in conjunction with 2.5 equivalents of
CuBr2 and 1 equivalent of LiBr in acetic acid at room tem-
perature to give the expected 3-bromo-4-ethyl-2H-
chromene in 68% yield after purification through column
chromatography (Scheme 2, Table 1).15
To contribute to this area of research, we are interested in
developing a methodology that provides facile access to
2H-chromene derivatives. Our methodology towards the
synthesis of 2H-chromene derivatives involves the cy-
clization of aryl propargyl ethers using catalytic amount
of Pd(OAc)2 in the presence of CuBr2 and LiBr.
R
R
Br
5 mol% Pd(OAc)2
1 equiv LiBr
2.5 equiv CuBr2
O
O
AcOH
Henry and co-workers have reported that CuBr2 and
CuCl2 can facilitate the palladium(II)-catalyzed enantio-
selective intermolecular dibromination and chlorohydra-
tion of olefins.8–10 In these reactions, halogen transfer
occurs more rapidly than hydride elimination, a common
terminating event in Pd(II)-catalyzed reactions.11–13 Man-
zoni et al. have carried out intramolecular amino bromina-
tion of olefins by using catalytic amount of Pd(II) in
conjunction with stoichiometric amount of CuBr2.14
Based on these reports we supposed that 3-bromo-2H-
2a–e
1a–e
R = Me, Et, 4-MeC6H4, Pr, C5H11
Scheme 2
In the 1H NMR spectrum of compound 2a, the presence of
only four protons in the aromatic region confirmed the cy-
clization of the aryl propargyl ether 1a to the correspond-
ing 3-bromo-4-ethyl-2H-chromene 2a. Further the
absence of the alkynyl carbon signals in the 13C NMR
spectrum confirmed the formation of the chromene deriv-
ative 2a. Finally, mass spectral studies supported the for-
mation of 2a.16
SYNLETT 2009, No. 13, pp 2079–2082
Advanced online publication: 15.07.2009
x
x
.x
x
.2
0
0
9
DOI: 10.1055/s-0029-1217563; Art ID: G08909ST
© Georg Thieme Verlag Stuttgart · New York

2080
G. Savitha et al.
LETTER
R
It was found that the reaction did not proceed in the ab-
sence of either Pd(OAc)2 or CuBr2, thereby illustrating
their significant role in the reaction, and with the use of
LiBr the reaction was clean and proceeded to completion
in short reaction times.
R
O
Br
5 mol% Pd(OAc)2
1 equiv LiBr
2.5 equiv CuBr2
O
AcOH
Having established the optimum conditions for the reac-
tion, a variety of aryl propargyl ethers 1b–e were cyclized
following similar procedure (Scheme 2). In all the cases
the reaction proceeded smoothly within 10 minutes fur-
nishing the corresponding 3-bromo-2H-chromene deriva-
tives in good yields. The results are summarized in
Table 1.
2f–i
R = Et, Me, 4-OMeC6H4, 4-MeC6H4
1f–i
Scheme 3
R
O
R
5 mol% Pd(OAc)2
1 equiv LiBr
Br
Table 1 Synthesis of 3-Bromo-2H-chromene Derivatives
2.5 equiv CuBr2
O
AcOH
Entry Aryl propargyl
3-Bromo-2H-
chromene 2
Time Yield
(min) (%)a
2j–l
1j–l
ether 1
R = Et, 4-OMeC6H4, 4-MeC6H4
Et
Et
Scheme 4
Br
Br
Br
Br
1
5
5
6
6
68
70
63
72
Table 2 Synthesis of 3-Bromo Benzofused 2H-Chromene
Derivatives
O
O
2a
1a
Entry Aryl propargyl ether 1 Product 2
Time Yield
(min) (%)a
Me
Me
2
Et
Et
O
Br
O
O
2b
1
10
15
72
69
1b
Pr
O
Pr
3
2f
1f
Me
O
Me
O
O
2c
Br
1c
C5H11
C5H11
2
O
4
5
O
2g
O
1g
2d
1d
OMe
OMe
Me
Me
3
15
68
Br
10
75
Br
O
O
O
O
2e
1e
a Isolated yield.
2h
1h
Me
Me
Encouraged by this, we further extended the protocol to
prepare various 3-bromo benzofused 2H-chromene deriv-
atives from the corresponding naphthyl propargyl ethers
under optimized reaction conditions (Scheme 3 and
Scheme 4).
4
15
65
Br
O
O
In all the cases the reaction proceeded smoothly affording
the corresponding cyclized product in moderate to good
yields, and the results are summarized in Table 2.
2i
1i
Synlett 2009, No. 13, 2079–2082 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel 3-Bromo-2H-chromene Derivatives
2081
Table 2 Synthesis of 3-Bromo Benzofused 2H-Chromene Deriva-
tives (continued)
ganometallic intermediate i. This intermediate may be
converted into the palladium(IV) species ii, which may
decompose through reductive elimination to give the
product 2. Formation of Pd(IV) species and their subse-
quent reductive elimination reactions were supported by
Canty and co-workers.18–20
Entry Aryl propargyl ether 1 Product 2
Time Yield
(min) (%)a
Et
O
The product 2 can also be formed from i via intermediate
iii following an alternative mechanism analogous to that
proposed by Henry and co-workers in his olefin dibromi-
nation and chlorohydration reactions,8–10 in which cop-
per(II) assists in ligand transfer and also retaining
palladium in its +2 oxidation state.
5
10
15
72
71
Br
Br
Et
O
O
2j
1j
Me
The role of LiBr can be explained from the structures of
the intermediate i and ii in which palladium is coordinated
to bromide and acetate ions. The use of LiBr increases the
bromide ion concentration thereby increases the ratio of
the number of bromide ions to that of acetate ions coordi-
nated to palladium in the intermediate i and ii and thus fa-
cilitating the reaction to proceed smoothly to furnish the
product 2 in shorter reaction times.
6
Me
O
O
2k
1k
OMe
In conclusion we have developed an efficient methodolo-
gy which gives rise to 3-bromo-2H-chromene derivatives
in good yields from the easily accessible starting materials
under mild reaction conditions. The methodology was
also applied to synthesize 3-bromo benzofused 2H-
chromene derivatives. We believe that this simple proto-
col will find further application in the palladium-mediated
synthesis of various cyclic frameworks.
Br
7
15
73
OMe
O
2l
1l
a Isolated yield.
The structure of the compounds 2f–l was confirmed
Acknowledgment
1
through H and 13C NMR spectroscopic analysis and
mass-spectrometry.17
One of the authors, G.S., expresses her gratitude to the Council of
Scientific and Industrial Research, New Delhi, for a research fel-
lowship.
A plausible mechanism for the formation of 3-bromo-2H-
chromene derivatives from the corresponding aryl propar-
gyl ethers is given in Scheme 5.
References and Notes
The mechanism involves the cyclization of the aryl prop-
argyl ether via carbopalladation, wherein activation of the
alkyne by coordination to Pd(II) is followed by intramo-
lecular nucleophilic attack by the arene furnishing the or-
(1) (a) Zhendong, J.; Ying, K. WO 2004058738, 2004.
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L
L
L
R
O
L
R
O
R
L
PdIV
R
2 CuX2
2 CuX
PdII
X
X
cat. PdII
CuX2
PdII
X
L
X
L
ii
••
i
O
O
– PdII
1
reductive
elimination
X = Br
L = Br, OAc
L
R
R
PdII
X
Br
– PdII
L
CuII
O
O
iii
2
II-assisted reductive elimination
Cu
Scheme 5
Synlett 2009, No. 13, 2079–2082 © Thieme Stuttgart · New York

2082
G. Savitha et al.
LETTER
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chromene Derivatives 2a–l
To a stirred mixture of the aryl propargyl ether 1a–l (1
mmol) in AcOH, Pd(OAc)2 (5 mol%), LiBr (1 mmol), and
CuBr2 (2.5 mmol) were added at r.t. The reaction mixture
was stirred until completion of the reaction as monitored by
TLC. A sat. solution of NaHCO3 was then added to
neutralize the reaction mixture, which was then extracted
with EtOAc (3 × 10 mL). The organic layer was dried over
anhyd Na2SO4. Removal of the solvent under reduced
pressure gave the crude product, which was purified by
column chromatography on silica gel using hexane as eluent
to afford the pure product.
(16) 3-Bromo-4-ethyl-2H-chromene (2a, Table 1, Entry 1)
Colorless oily liquid. IR (KBr): nmax = 3062, 2966, 2851,
2354, 1629, 1467 cm–1.1H NMR (500 MHz, CDCl3): d =
1.14 (t, 3 H, J = 7.5 Hz), 2.65 (q, 2 H, J = 7.5 Hz), 4.86 (s, 2
H), 6.86 (d, 1 H, J = 8.0 Hz), 6.95 (t, 1 H, J = 7.5 Hz), 7.16
(t, 1 H, J = 7.5 Hz), 7.22 (d, 1 H, J = 8.0 Hz). 13C NMR (125
MHz, CDCl3): d = 12.4, 23.8, 70.8, 112.9, 116.3, 121.9,
122.6, 123.6, 129.1, 134.6, 153.3. ESI-MS: m/z = 239 [M+ +
1], 241 [M+ + 3]. Anal. Calcd (%) for C11H11BrO: C, 55.26;
H, 4.65. Found: C, 55.31; H, 4.71.
(17) 3-Bromo-4-ethyl-2H-benzo[h]chromene (2f, Table 2,
Entry 1)
Colorless oily liquid. IR (KBr): nmax = 3062, 2956, 1738,
1642, 1561, 1466 cm–1.1H NMR (500 MHz, CDCl3): d =
1.96 (t, 3 H, J = 7.7 Hz), 2.75 (q, 2 H, J = 7.7 Hz), 5.06 (s, 2
H), 7.38 (d, 1 H, J = 8.2 Hz), 7.45–7.49 (m, 3 H), 7.76–7.8
(m, 1 H), 8.17–8.19 (m, 1 H). 13C NMR (125 MHz, CDCl3):
d = 12.6, 24.1, 71.3, 110.7, 117.3, 121.2, 121.4, 122.2, 124.6,
125.9, 126.8, 127.6, 134.0, 135.3, 149.1. ESI-MS: m/z = 289
[M+ + 1], 291 [M+ + 3]. Anal. Calcd (%) for C15H13BrO: C,
62.30; H, 4.53. Found: C, 62.21; H, 4.65.
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