Pd(0) catalyzed intramolecular Heck reaction: a versatile route for the synthesis of 2-aryl substituted 5-, 6-, and 7-membered O-containing heterocycles

Article abstract of DOI:10.1016/j.tetlet.2008.09.162

An efficient and convenient method for the synthesis of 2-aryl substituted tetrahydropyran, tetrahydrofuran, and oxepine derivatives via intramolecular palladium catalyzed cyclization is developed. The two exo-cyclic double bonds at adjacent carbon atoms

Full text of DOI:10.1016/j.tetlet.2008.09.162

Tetrahedron Letters 49 (2008) 7153–7156
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd(0) catalyzed intramolecular Heck reaction: a versatile route
for the synthesis of 2-aryl substituted 5-, 6-, and 7-membered
O-containing heterocycles
*
Shubhankar Samanta, Hemakesh Mohapatra, Rathin Jana, Jayanta K. Ray
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and convenient method for the synthesis of 2-aryl substituted tetrahydropyran, tetrahydro-
furan, and oxepine derivatives via intramolecular palladium catalyzed cyclization is developed. The two
exo-cyclic double bonds at adjacent carbon atoms in these ring systems could serve as potential dienes for
cycloaddition reactions.
Received 22 August 2008
Revised 25 September 2008
Accepted 27 September 2008
Available online xxxx
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Oxepine
Diene
Heterocyclic
Tetrahydropyran
1. Introduction
ene which yields the corresponding tetrahydropyran, oxepine,
and tetrahydrofuran, respectively. Herein, we report two modes
The intramolecular Heck reaction is a very useful approach for
the synthesis of various heterocyclic and carbocyclic rings.1 This
reaction is also important for the synthesis of natural products.
Substituted pyran, furan, and oxepine rings are common structural
components found in many natural products such as mycalamide,2
(+)-trans-kumasyne,3 and roglolenyne.4 Laulimide, a novel cancer-
therapy agent which contains two pyran rings can be synthesized
by nucleophilic attack on a carbopalladium complex.5 Morphine
contains a fused furan ring and has been synthesized via intramo-
lecular Heck reaction.6 Alternatively, an intermolecular Heck reac-
tion is used for the synthesis of (ꢀ)-strychnine, which contains an
oxepine subunit.7 These ring systems have been prepared by vari-
ous methods including radical cyclization,8 olefin metathesis9 and
metal catalyzed cyclization.10,11 Among these, palladium catalyzed
cyclization is a very powerful method due to its tolerance of a wide
variety of functional groups, thus neatly avoiding protection group
chemistry. Based on previous reports utilizing pyran, furan, and
oxepine ring systems as the subunit of many natural products,
we propose a general method for the synthesis of these ring sys-
tems via palladium catalyzed intramolecular Heck reaction.12–15
In this context, we describe the intramolecular Heck cyclization
of 4-(2-bromoallyloxy)-4-arylbut-1-ene, 4-(2-bromoallyloxy)-2-
methyl-4-arylbut-1-ene and 3-(2-bromoallyloxy)-3-arylprop-1-
of cyclization, one being the exo mode leading to substituted tetra-
hydropyran and tetrahydrofurans and the other being the endo
mode that leads to the substituted oxepines. The main feature of
the 2-aryl substituted tetrahyropyran and tetrahyrofuran rings
prepared herein is the presence of two adjacent double bonds that
can be utilized in cycloaddition reactions leading to 2-aryl substi-
tuted fused pyran and furan rings.16
First, the starting materials for the Heck reaction were prepared
by O-2-bromo-allylation of 1-arylbut-3-en-1-ol (2), 1-arylbut-3-
methyl-3-en-1-ol (3), and 1-arylprop-2-ene-1-ol (4). The alcohols
2 and 3 were synthesized by treating the appropriate aryl aldehyde
1 with indium metal, sodium iodide, and allyl bromide or methallyl
bromide in dimethylformamide at room temperature. The alcohols
4 were synthesized by treating aryl aldehydes with vinylmagne-
sium bromide in tetrahydrofuran at 0 °C followed by stirring at
room temperature (25–30 °C). Alcohols 2, 3, and 4 were reacted
with 2,3-dibromopropene in the presence of sodium hydride in
THF at 0 °C to give 4-(2-bromoallyloxy)-4-arylbut-1-ene (5), 4-
(2-bromoallyloxy)-2-methyl-4-arylbut-1-ene (6), and 3-(2-bromo-
allyloxy)-3-arylprop-1-ene (7), respectively, as the precursors for
the intramolecular Heck reaction, (Scheme 1).
Heck reaction precursors 5, 6, and 7 (1 mmol) with Pd(OAc)2
(5 mol %), PPh3 (0.5 equiv) and Cs2CO3 (1.2 equiv) in dimeth-
ylformamide (8 ml) at 80–85 °C yielded the desired 4,5-dimeth-
ylene-2-aryl-tetrahydropyrans 8a–h (Table 1, entries 1–8),
4-methyl6-methylene-2-aryl-2,3,6,7-tetrahydro-oxepines 9a–e
* Corresponding author. Tel.: +91 3222283326; fax: +91 3222282252.
E-mail address: jkray@chem.iitkgp.ernet.in (J. K. Ray).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.162

7154
S. Samanta et al. / Tetrahedron Letters 49 (2008) 7153–7156
Br
R
Br
O
OH
( )
R
Br
Br
In /
NaH/
THF, 0 ºC
O
Ar
H
Ar
n
NaI, DMF, r.t
( )
Ar
R
n
1
Mg Br
THF, 0 ºC
R = H, n = 1 (2)
R = Me, n = 1 (3)
R = H, n = 0 (4)
R = H, n = 1 (5)
R = Me, n = 1 (6)
R = H, n = 0 (7)
Scheme 1. Preparation of O-2-bromo-allylated derivatives.
Table 1
Pd-catalyzed cyclization of various 2-bromo-allylated derivativesa
Entry
Substrate
Product
Time (h)
Yield (%)
Br
1
1.83
1.75
1.5
80
O
O
5a
8a
Br
2
3
70
O
O
Cl
8b
Cl
5b
Br
65 + 10
MeO
MeO
MeO
O
O
O
5c
8c'
8c
Br
4
5
6
2.0
1.5
1.5
78
72
70
O
O
8d
MeO
Cl
MeO
Cl
5d
Br
O
O
5e
8e
Br
O
MeO
MeO
MeO
MeO
O
5f
8f
Br
7
8
1.5
2.0
82
65
S
S
O
O
8g
5g
Br
O
O
5h
O
O
8h

S. Samanta et al. / Tetrahedron Letters 49 (2008) 7153–7156
7155
Table 1 (continued)
Entry
Substrate
Product
Time (h)
1.0
Yield (%)
Br
9
10
11
12
80
75
68
70
O
O
6a
9a
Br
1.5
1.2
1.4
MeO
MeO
O
O
9b
6b
Br
O
O
6c
MeO
9c
MeO
Br
O
O
9d
6d
Cl
Cl
Br
13
2
60
O
O
9e
6e
Br
14
1.0
80
O
O
10a
7a
Br
15
16
1.30
72
70
O
O
7b
MeO
MeO
MeO
MeO
10b
Br
1.0
O
7c
O
10c
Br
Cl
17
1.5
75
Cl
O
O
7d
10d
a
Reagents and conditions: 5a–h, 6a–e, 7a–d (1 equiv), Pd(OAc)2 (5 mol %), Cs2CO3 (1.2 equiv), PPh3 (0.5 equiv), TBAC (1.5 equiv), DMF, 80–85 °C.
(Table 1, entries 9–13), and 3,4-dimethylene-2-aryl-tetrahydrofu-
rans 10a–d (Table 1, entries 14–17) in moderate to good yields
(Scheme 2). Exo-trig cyclization was observed with all the sub-
strates 5 and 7, yielding products with two adjacent exocyclic dou-
ble bonds, except in the case of 5c where two products 8c and 8c0
were obtained, one having an exocyclic double bond and the other
an endocyclic double bond due to isomerization. In the case of
compounds 6, endo-trig cyclization was observed to yield oxepine

7156
S. Samanta et al. / Tetrahedron Letters 49 (2008) 7153–7156
13CNMR (CDCl3, 50 MHz) d: 42.43, 55.27, 72.17, 79.64, 109.02,
110.04, 111.19, 113.44, 118.20, 129.45, 143.50, 143.68, 143.71,
159.17. MS-ESI: m/z = 217.1197 (100%) [M++H]. HRMS calcd for
C14H17O2 [M+ +H]: 217.123; found: 217.1197.
n = 1, R = H
n = 1, R = Me
n = 0, R = H
O
O
O
Ar
Ar
Br
8
9
Pd(OAc)2, PPh3
Cs2CO3, TBAC
DMF, 80 ºC
Compound 9b: Colorless liquid, 1H NMR (CDCl3, 400 MHz) d:
1.81 (3H, s), 2.50–2.74 (m, 2H), 3.81 (s, 3H) 4.39, 4.43, 4.60, 4.64
(AB-q, 2H, J = 14.4 Hz), 4.76–4.82 (m,1H), 4.91 (s, 1H), 4.92 (s,
1H), 6.08 (s, 1H), 6.79–6.81 (m, 1H), 6.91–6.93 (m, 2H), 7.22–
7.26 (m, 1H). 13C NMR (CDCl3, 50 MHz) d: 27.10, 44.10, 55.25,
73.50, 81.51, 110.14, 112.95, 114.00, 118.08, 127.33, 129.36,
136.90, 145.19, 145.70, 159.70. MS-ESI: m/z = 253.1181 (100%)
[M++Na]. HRMS calcd for C15H18O2Na [M+ +Na]: 253.1207, found:
253.1181.
O
( )
Ar
R
n
Me
R = H, n = 1 (5)
R = Me, n = 1 (6)
R = H, n = 0 (7)
Ar
10
Scheme 2. Pd-catalyzed cyclization of 2-bromo-allylated derivatives.
Compound 10d: Colorless liquid, 1H NMR (CDCl3, 400 MHz) d:
4.56, 4.53, 4.66, 4.69 (AB-q, 2H, J = 13.2 Hz), 4.71 (s, 1H), 5.03 (s,
1H) 5.34 (s, 1H) 5.48 (s, 1H) 5.53 (s, 1H) 7.24–7.29 (m, 1H) 7.34
(s, 1H) 7.54–7.51 (m, 1H) 7.69–7.71 (m, 1H). 13CNMR (CDCl3,
50 MHz) d: 71.56, 83.75, 103.18, 105.86, 125.39, 127.28, 128.13,
128.73, 128.78, 129.64, 130.83, 132.38.
derivatives in good yields. The reactions are suitable for substrates
possessing both electron donating and electron withdrawing sub-
stituents, except nitro groups. The reaction was also successful
using acetonitrile as solvent and K2CO3 as base.
In conclusion, we have developed a method for the synthesis of
various substituted tetrahydropyran, tetrahydrofuran, and oxepine
derivatives via palladium catalyzed intramolecular Heck reaction.
We expect that the two adjacent exocyclic double bonds in the
tetrahydropyrans and tetrahydrofurans can be utilized in cyclo-
addition reactions leading to various substituted fused pyran and
furan derivatives.
Acknowledgment
Financial support from CSIR (New Delhi) is gratefully
acknowledged.
References and notes
2. Typical experimental procedure for the Heck reaction
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Compound 5, 6, or
7 (1 equiv), Pd(OAc)2 (5 mol %), PPh3
(0.5 equiv), Cs2CO3 (1.2 equiv), tetrabutylammonium chloride
(1.5 equiv), and DMF (8 mL) were placed in a two-necked round-
bottomed flask. After degassing with N2, the mixture was heated
at 80–85 °C for 2 h. After cooling, the reaction mixture was diluted
with cold water and extracted with ether. The combined organics
were dried over anhydrous Na2SO4 and the solvent was evapo-
rated. The crude product was purified by preparative thin layer
chromatography.
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1680.
2.1. Spectral data of representative compounds
Compound 8c: Colorless liquid, 1H NMR (CDCl3, 400 MHz) d:
2.48–2.62 (m, 2H), 3.81 (s, 3H), 4.22 (d, 1H, J = 12.8 Hz) 4.47 (d,
2H, J = 12.8 Hz), 4.84 (s, 1H) 4.86 (s, 1H), 5.18 (s, 1H), 5.20 (s,
1H), 6.81–6.83 (m, 1H), 6.94–6.95 (m, 2H), 7.24–7.28 (m, 1H).
The substituted tetrahydrofuran derivatives were very unstable, as a result mass
spectra and CHN analysis could not be obtained.