Palladium-catalyzed intramolecular 5-endo-trig oxidative Heck cyclization: a facile pathway for the synthesis of some sesquiterpene precursors

Article abstract of DOI:10.1016/j.tetlet.2007.09.052

An efficient and convenient method for the construction of substituted cyclopentenones via palladium-catalyzed intramolecular 5-endo-trig oxidative cyclization has been introduced as a powerful new strategy for the synthesis of sesquiterpenes.

Full text of DOI:10.1016/j.tetlet.2007.09.052

Tetrahedron Letters 48 (2007) 8005–8008
Palladium-catalyzed intramolecular 5-endo–trig oxidative
Heck cyclization: a facile pathway for the synthesis of
some sesquiterpene precursors
Devalina Ray, Sunanda Paul, Sulagna Brahma and Jayanta. K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 19 June 2007; revised 30 August 2007; accepted 7 September 2007
Available online 12 September 2007
Abstract—An efficient and convenient method for the construction of substituted cyclopentenones via palladium-catalyzed intra-
molecular 5-endo–trig oxidative cyclization has been introduced as a powerful new strategy for the synthesis of sesquiterpenes.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
1-bromopenta-1,4-dien-3-ols resulting in substituted
cyclopentenones. Based on the successful use of vinyl
halides or vinyl triflates as vinyl donors in palladium-
catalyzed reactions with olefinic systems8 and the known
behavior of allylic alcohols in palladium-catalyzed reac-
tions with organic halides, we thought that our method
would be a viable route toward the synthesis of cyclo-
pentenones related to natural product precursors.
endo-Cyclizations are relatively rare in comparison to
the exo mode of cyclization.9 Vinylated derivatives of
the b-bromovinylaldehydes were chosen as our substrate
because their reactions with aromatic analogues are very
sluggish and result in the formation of low yields of
products.
Transition metal-catalyzed intramolecular reactions of
alkenes are representative reactions in the organic chem-
istry of palladium1 which can continuously stimulate
research due to their immense synthetic potential.
Recently substituted cyclopentenones have been evalu-
ated as useful synthons for the synthesis of natural2
and unnatural3 products. As an extension of the palla-
dium-catalyzed intramolecular Heck cyclization for
the synthesis of substituted cyclopentenones, we have
already reported synthetic approaches starting from
allylated,4a propargylated,4b and methallylated4c deriva-
tives of a number of b-bromovinylaldehydes following
different pathways. Intermolecular Heck reactions of ha-
lides with allylic alcohols5 are widely known while the
intramolecular version6 is somewhat rare. The palla-
dium-catalyzed alkylation of thiopene at the 3-position
is accomplished by adopting the intermolecular coupling
of 3-bromothiopene with substituted allyl alcohols.7 As
part of our ongoing effort to expand the synthetic utility
of substituted cyclopentenones, we have been investigat-
ing palladium-catalyzed Heck reactions on substrates
possessing allylic alcohols.
The reactions are of preparative value for the synthesis
of sesquiterpene precursors. The structural skeleton 6b
is the core structure of ( )-a-cuparenone (6d) and lau-
rene (6e).10 Both sesquiterpenes can be obtained from
6b, which in turn can be prepared by our methodology
(Scheme 1).
The starting materials were synthesized by the addition
of vinylmagnesium bromide (1 mmol) to b-bro-
movinylaldehydes (1 mmol) in tetrahydrofuran (THF)
at 0 ꢁC to afford the bromo alcohols (1a–9a) (Table 1)
in good yield (Scheme 2).
In this context, we describe the intramolecular
palladium-catalyzed 5-endo–trig Heck cyclization of
Treatment of the substrates (1a–9a) (1 mmol) with
Pd(OAc)2 (5 mol %), PPh3 (0.5 equiv) and triethylamine
(1.2 equiv) in acetonitrile (8 mL) at 80 ꢁC yielded the
cyclized keto compounds (1b–9b) (Table 2) in moderate
Keywords: Intramolecular Heck cyclization; Sesquiterpenes; Vinylated
derivatives.
*
Corresponding author. Tel.: +91 3222 283326; fax: +91 3222
282252; e-mail: jkray@chem.iitkgp.ernet.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.052

8006
D. Ray et al. / Tetrahedron Letters 48 (2007) 8005–8008
O
O
6d
6e
6b
( )-α-cuparenone
Laurene
Scheme 1.
R1
R2
Br
Table 1. Vinylation of b-bromovinylaldehydes using vinylmagnesium
R1
R2
Br
bromidea
MgBr
Entry Substrate
Product
Yieldb
(%)
°
THF, 0 C, 1 h
CHO
OH
(1a-9a)
R1, R2 = - (CH2)n -. other fused rings
R1 = Ar, R2 = H
Br
Br
1
89
CHO
H
OH
Br
Scheme 2.
1a
to good yields (Scheme 3). These palladium-catalyzed
cyclizations have proceeded via a 5-endo–trig pathway.
Br
CHO
2
3
90
90
H
OH
2a
In an attempt to extend our methodology and apply it to
the synthesis of sesquiterpenes, we prepared a precursor
of ( )-a-cuparenone, which can be converted to the de-
sired natural product in a single step11 (Scheme 4). The
precursor (6c) was synthesized via 1,4-addition of 6b
with Me2CuLi.
Br
Br
CHO
H
OH
3a
Br
Br
In conclusion, we have developed a methodology for the
construction of five-membered rings with a,b unsatu-
rated keto functionality.
OH
CHO
4
85
H
4a
HO
H
2. Typical experimental procedure
CHO
Br
Br
5
6
92
89
2.1. General procedure for the palladium-catalyzed Heck
cyclization
5a
The appropriate vinylated derivative (1 mmol), Pd(OAc)2
(5 mol %), PPh3 (0.5 equiv) and Et3N (1.2 equiv) were
dissolved in acetonitrile. After degassifying with argon,
the solution was heated to 80 ꢁC for 8–10 h. The reaction
mixture was cooled, diluted with ice water and extracted
with diethyl ether. The solvent was evaporated after
drying (with Na2SO4) and the product was purified by
silica gel (60–120 mesh) column chromatography.
Br
Br
OH
CHO
H
6a
Br
Br
OH
CHO
7
8
90
90
H
7a
2.2. Spectral data of representative compounds
Br
Br
2.2.1. 1-(2-Bromo-cyclohex-1-enyl)prop-2-en-1-ol (1a).
1H NMR (400 MHz, CDCl3): d 1.58–1.69 (4H, m),
1.86 (1H, br s), 1.99–2.05 (1H, m), 2.19–2.27 (1H, m),
2.50–2.51 (2H, m), 5.18 (1H, d, J = 10.4 Hz), 5.31 (1H,
br s), 5.34 (1H, d, J = 17.2 Hz), 5.82–5.90 (1H, m).
13C NMR (100 MHz, CDCl3): d 22.04, 24.67, 25.24,
36.83, 74.77, 114.82, 120.66, 135.98, 137.02. Anal. Calcd
for C9H13OBr: C, 49.79; H, 6.03. Found: C, 48.99; H,
5.92.
OH
CHO
H3CO
H3CO
H3CO
H
8a
H3CO
Br
Br
OH
CHO
9
85
H
9a
a b-Bromovinylaldehyde (1 mmol), vinylmagnesium bromide (1 mmol),
THF (8 mL) at 0 ꢁC for 1 h.
The substituted vinyl alcohols were unstable, so mass spectra and
CHN analysis could not be obtained.
b Yields refer to isolated yields.

D. Ray et al. / Tetrahedron Letters 48 (2007) 8005–8008
Table 2. Palladium-catalyzed intramolecular 5-endo–trig cyclizationa
8007
2.2.3. 1-(2-Bromocyclooct-1-enyl)prop-2-en-1-ol (3a).
1H NMR (200 MHz, CDCl3): d 1.54 (4H, m), 1.58–
1.68 (4H, m), 2.21–2.28 (1H, m), 2.32–2.39 (1H, m),
2.69–2.72 (2H, m), 5.17 (1H, d, J = 10.4 Hz), 5.36–5.41
(2H, m), 5.84–5.92 (1H, m). 13C NMR (100 MHz,
CDCl3): d 25.52, 26.59, 27.34, 27.49, 31.29, 37.04,
75.75, 114.44, 123.03, 137.49, 138.41.
Substrate no.
Product
Yieldb (%)
1a
65
1b
O
2a
3a
70
73
2.2.4. 1-(1-Bromo-3,4-dihydronaphthalen-2-yl)prop-2-en-
1-ol (4a). 1H NMR (200 MHz, CDCl3): d 1.87 (1H, br
s), 2.34–2.57 (2H, m), 2.72–2.83 (2H, m), 5.23 (1H, d,
J = 10.6 Hz), 5.44 (2H, d, J = 17.0 Hz), 5.61 (1H, br
s), 5.88–6.02 (1H, m), 7.08–7.28 (3H, m), 7.66–7.69
(1H, m). 13C NMR (100 MHz, CDCl3): d 24.09, 28.00,
74.77, 115.37, 119.04, 126.64, 126.89, 127.12, 128.08,
133.72, 136.48, 136.53, 139.74. IR (CHCl3): mmax 3378,
1615, 1234, 942, 751 cmÀ1. Anal. Calcd for C13H13OBr:
C, 58.88; H, 4.94. Found: C, 58.99; H, 4.83.
O
O
2b
3b
O
4a
70
4b
O
2.2.5. 1-(2-Bromo-3,4-dihydronaphthalen-1-yl)prop-2-en-
1-ol (5a). 1H NMR (400 MHz, CDCl3): d 2.68–2.86
(4H, m), 5.18 (1H, d, Jcis = 11.6 Hz), 5.37 (1H, d,
Jtrans = 17.2 Hz), 5.72 (1H, d, J = 3.2 Hz), 6.04–6.12
(1H, m), 7.04–7.09 (3H, m), 7.61–7.63 (1H, m). 13C
NMR (100 MHz, CDCl3): d 29.56, 35.97, 74.44,
115.45, 125.27, 125.48, 126.15, 127.19, 127.53, 131.93,
135.20, 135.49, 137.96. Anal. Calcd for C13H13OBr: C,
58.88; H, 4.94. Found: C, 58.34; H, 4.91.
5a
6a
75
65
5b
O
6b
O
2.2.6. 1-Bromo-1-p-tolylpenta-1,4-dien-3-ol (6a). 1H
NMR (200 MHz, CDCl3): d 2.36 (3H, s), 5.20 (1H, br
s), 5.21 (1H, d, J = 9.8 Hz), 5.42 (1H, d, J = 17.1 Hz),
5.91–6.07 (1H, m), 6.22 (1H, d, J = 7.7 Hz), 7.13–7.47
(AB q, 4H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3):
d 22.60, 73.45, 104.16, 126.66, 127.47 (2 · C), 128.68,
128.94 (2 · C), 130.63, 137.31, 139.09. IR (CHCl3): mmax
7a
8a
9a
70
68
70
7b
O
H3CO
H3CO
8b
3367, 1610, 1224, 924, 774 cmÀ1
.
O
2.2.7. 1-Bromo-1-phenylpenta-1,4-dien-3-ol (7a). 1H
NMR (400 MHz, CDCl3): d 2.04 (1H, br s), 5.21–5.25
(1H, m), 5.24 (1H, d, J = 10.8), 5.44 (1H, d, J =
17.2 Hz), 5.95–6.04 (1H, m), 6.26 (1H, d, J = 7.6 Hz),
7.33–7.41 (3H, m), 7.53–7.55 (2H, m). 13C NMR
(100 MHz, CDCl3): d 73.46, 115.75, 116.08, 127.58,
128.35 (2 · C), 128.99, 129.06, 131.49, 133.95, 137.17.
9b
a All the reactions were carried out with 5 mol % of Pd(OAc)2,
0.5 equiv PPh3, 1.2 equiv of Et3N in acetonitrile (8 mL) at 80 ꢁC for
8–10 h.
b Yields refer to isolated yields after purification.
2.2.2. 1-(2-Bromocyclohept-1-enyl)prop-2-en-1-ol (2a).
1H NMR (200 MHz, CDCl3): d 1.36–1.76 (6H, m),
2.23 (2H, d, J = 9.1 Hz), 2.79 (2H, d, J = 7.9 Hz), 5.17
(1H, d, J = 11.0 Hz), 5.31 (1H, br s), 5.40 (1 H, br s),
5.73–5.89 (1H, m). 13C NMR (100 MHz, CDCl3): d
25.22, 26.50, 27.43, 31.53, 41.51, 76.11, 114.75, 123.98,
136.81, 141.17.
2.2.8. 1-Bromo-1-(3,4-dimethoxyphenyl)penta-1,4-dien-3-
ol (8a). 1H NMR (400 MHz, CDCl3): d 1.97 (1H, br s),
3.90 (3H, s), 3.91 (3H, s), 5.21 (1H, br s), 5.23 (1H, d,
J = 10.4 Hz), 5.43 (1H, d, J = 17.2 Hz), 5.91–6.04 (1H,
m), 6.18 (1H, d, J = 7.6 Hz), 6.83 (1H, d, J = 8.4 Hz),
7.07 (1H, d, J = 2.0 Hz), 7.13–7.15 (1H, dd,
J = 8.4 Hz, J = 2.4 Hz).
R1
R2
Br
R1
R2
Pd(OAc)2, PPh3
2.2.9.
1-Bromo-1-naphthalen-2-yl-penta-1,4-dien-3-ol
(9a). 1H NMR (400 MHz, CDCl3): d 5.15 (1H, d,
J = 10.0 Hz), 5.16 (1H, br s), 5.39 (1H, d, J =
17.2 Hz), 5.91–6.00 (1H, m), 6.33 (1H, d, J = 7.6 Hz),
7.41–7.47 (2H, m), 7.57–7.59 (dd, 1H, J = 8.8 Hz,
J = 2.0 Hz), 7.72–7.79 (3H, m), 7.97 (1H, s). 13C NMR
(100 MHz, CDCl3): d 73.56, 115.82, 124.10, 124.69,
126.59, 126.64, 126.79, 127.48 (2 · C), 127.79, 127.95,
128.39, 129.89, 131.85, 137.20.
°
Et3N, CH3CN, 80 C
O
OH
(1b-9b)
(1a-9a)
R1, R2 = - (CH2)n -, other fused rings
R1 = Ar, R2 = H
Scheme 3.

8008
D. Ray et al. / Tetrahedron Letters 48 (2007) 8005–8008
O
O
O
Me2CuLi, BF3.Et2O
Ether, 0 °C
Ref.11
6b
6d
6c
Scheme 4.
2. (a) Khan, F. A.; Dash, J.; Rout, B. Tetrahedron Lett. 2004,
45, 9285; (b) Venkata Ramana, G.; Venkateswara Rao, B.
Tetrahedron Lett. 2003, 44, 5103; (c) Khan, F. A.; Rout, B.
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1994, 59, 7915; (b) Denmark, S. E.; Jones, T. K. J. Am.
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1985, 41, 5855; For recent review: (d) Shore, N. E. In
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Vol. 40, Chapter 1.
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273; (b) Tamaru, Y.; Yamada, Y.; Yoshida, Z.-I. J. Org.
Chem. 1978, 43, 3396; (c) Frank, W. C.; Kim, Y. C.;
Heck, R. F. J. Org. Chem. 1978, 43, 2947; (d) Kasahara,
A.; Izumi, T.; Maemura, M. Bull. Chem. Soc. Jpn. 1977,
50, 1021.
2.2.10. 2,3,4,5-Tetrahydrocyclopenta[a]naphthalen-1-one
(5b).12 1H NMR (400 MHz, CDCl3): d 2.59–2.69 (6H,
m), 2.97 (2H, t, J = 8.0 Hz), 7.18–7.28 (3H, m), 8.25
(1H, d, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3): d
26.99, 27.55, 29.19, 35.82, 123.86, 126.67, 127.47,
127.75, 129.05, 134.36, 134.83, 175.05, 206.18; HRMS
(ESI, 70 eV): m/z = 185.0966 [M++H] (calculated mass
for C13H12O: 185.0966 [M++H]).
2.2.11. 3-(3,4-Dimethoxyphenyl)cyclopent-2-enone (8b).
1H NMR (400 MHz, CDCl3): d 2.57–2.60 (2H, m), 3.02–
3.04 (2H, m), 3.93 (3H, s), 3.94 (3H, s), 6.48 (1H, s), 6.92
(1H, d, J = 8.4 Hz), 7.14 (1H, d, J = 1.6 Hz), 7.27–7.30
(1H, dd, J = 8.4 Hz, J = 2.0 Hz). Anal. Calcd for
C13H14O3: C, 71.54; H, 6.46. Found: C, 71.67; H, 6.40.
2.2.12. 3-Naphthalen-2-yl-cyclopent-2-enone (9b). 1H
NMR (400 MHz, CDCl3): d 2.65–2.67 (2H, m), 3.19–
3.21 (2H, m), 6.71 (1H, s), 7.55–7.58 (2H, m), 7.75–
7.77 (1H, m), 7.87–7.91 (3H, m), 8.13 (1H, s). 13C
NMR (100 MHz, CDCl3): d 28.61, 35.26, 116.09,
123.90, 126.79, 126.84, 127.69, 127.75, 127.78, 128.60,
128.89, 132.95, 134.90, 173.73, 209.45. HRMS (ESI,
70 eV): m/z = 209.0907 [M++H] (calculated mass for
C15H12O: 209.0922 [M++H]).
6. (a) Gaudin, J.-M. Tetrahedron Lett. 1991, 32, 6113; (b)
Shi, L.; Narula, C. K.; Mak, K. T.; Kao, L.; Xu, Y.; Heck,
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1977, 38, 3365.
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1985, 50, 2302; (d) Cacchi, S.; Ciattini, P. G.; Morera, E.;
Ortar, G. Tetrahedron Lett. 1987, 28, 3039; (e) Pena, M.
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Ravindranathan, T.; Patil, S. S.; Dhondge, V. D.; Dantale,
S. W. Tetrahedron Lett. 1996, 37, 2629; (c) Srikrishna, A.;
Sundarababu, G. Tetrahedron 1991, 47, 481.
2.2.13. 3-Methyl-3-p-tolylcyclopentanone (6c).13 1H
NMR (400 MHz, CDCl3): d 1.29 (3H, s), 2.14–2.40
(4H, m), 2.23 (3H, s), 2.54–2.58 (2H, d, J = 17.6 Hz),
7.06–7.18 (4H, m); 13C NMR (100 MHz, CDCl3): d
20.87, 29.40, 35.86, 36.74, 43.46, 52.32, 125.32 (2 · C),
129.19 (2 · C), 135.85, 145.44, 218.83; HRMS (ESI,
70 eV): m/z = 189.1241 [M++H] (calculated mass for
C13H16O: 189.1235 [M++H]).
Compounds 1b, 2b, 3b, 4b, 6b, and 7b are reported in the
literature.14
11. Asaoka, M.; Takenouchi, K.; Takei, H. Tetrahedron Lett.
1998, 29, 325.
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2006, 128, 9348.
13. Honda, T.; Kimura, N.; Tsubuki, M. Tetrahedron: Asym-
metry 1993, 4, 21.
Acknowledgement
Financial support from CSIR (New Delhi) is gratefully
acknowledged.
14. (a) Gagnier, S. V.; Larock, R. C. J. Am. Chem. Soc. 2003,
125, 4804; (b) Fukuda, Y.; Negoro, T.; Tobe, Y.; Kimura,
K.; Odaira, Y. J. Org. Chem. 1979, 44, 4557; (c)
Yonezawa, N.; Koike, M.; Kameda, A.; Naito, S.; Hino,
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References and notes
1. (a) Burns, B.; Grigg, R.; Ratananukul, P.; Sridharan, V.;
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