Microwave-assisted direct addition of cycloethers to alkynes

Article abstract of DOI:10.1016/j.tetlet.2004.08.122

Under microwave conditions, tetrahydrofuran (THF), tetrahydropyran and 1,4-dioxane are added directly onto alkynes and generated various vinyl cycloethers.

Full text of DOI:10.1016/j.tetlet.2004.08.122

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7581–7584
Microwave-assisted direct addition of cycloethers to alkynes
a,b,
*
a
Yuhua Zhang and Chao-Jun Li
a
Department of Chemistry, Tulane University, New Orleans, LA 70118, USA
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, Canada H3A 2K6
b
Received 14 May 2004; revised 20 August2004; accep te d 20 August2004
Abstract—Under microwave conditions, tetrahydrofuran (THF), tetrahydropyran and 1,4-dioxane are added directly onto alkynes
and generated various vinyl cycloethers.
Ó 2004 Published by Elsevier Ltd.
2-Vinyl substituted heterocycles are the key structural
features of a large number of natural products that show
a wide range of biological activities. Therefore there has
microwave
n
n
R
+
O
1
O
R
been a sustained interest in developing methods for
forming such structures. Traditionally, 2-vinyl substi-
tuted heterocycles can be prepared by methods such as
the Horner–Emmons approach reacting alkyl(diphen-
n=1, 2
Scheme 1.
2
yl)phosphine oxide with a carbonyl compound, inter-
molecular hydroalkoxylation of alkynes catalyzed by
pyran to alkynes. Herein, we wish to report a direct
addition of cycloethers to various terminal alkynes un-
der microwave conditions (Scheme 1).
3
palladium/benzoic acid, and directsyn ht esis via zinc
4
chloride. Recently, it has been reported that the addi-
tion of a-heterosubstituted radicals to styryl sulfimides,
styryl triflone and b-nitrostyrenes can give such com-
pounds in good yields at ht e presence of AIBN or ben-
Within the last several years, microwave has become a
powerful method in organic synthesis. Many elegant
5
zoyl peroxide. However, all these methods require the
preparation of starting materials and involve an addi-
tion–elimination procedure, producing an equivalent
of side product at the same time.
Table 1. Optimization of the product formation
Entry
Molar
ratio
Temperature
(°C)
Time
(min)
Yield
a
(%)
(
alkyne/THF)
On the other hand, an overall addition reaction is an
atom economical and efficient way to construct more
complex structures from simpler units. As a general
1
2
3
4
5
6
7
8
9
1:15
1:20
165
180
180
200
10
10
5/6/89
6/7/87
6
1:10
1:25
10
30
<1%
6/7/87
<10%
effortin developing Ôgreener synthetic methodsÕ, we have
been interested in the direct functionalization of various
C–H bonds through various catalytic methods within
b
1:40
1:40
110
72h
72h
20
c
110
35/28/37
9/10/81
37/44/18
39/50/11
39/50/11
d
7
1:40
200
the last few years. One of these efforts is the develop-
ment of methods for synthesizing tetrahydrofuran and
1:100
1:200
1:200
1:200
200
200
200
200
1
20
20
8
tetrahydropyran derivatives. Conceivably, an efficient
method for forming such structures is the direct addition
of cyclic ether such as tetrahydrofuran and tetrahydro-
1
1
0
1
40
60
e
60%
a
Yields and ratios were based on H NMR of crude reaction mixtures
for the ratio of trans-isomer:cis-isomer:unreacted material).
Refluxing under oil bath.
(
b
c
Keywords: Alkyne–THF coupling; Atom-economy; Microwave; C–C
bond formation.
Refluxing under oil bath with AIBN added.
AIBN was added.
Isolated yield after chromatography.
d
e
*
Corresponding author. Tel.: +1 514 398 8457; fax: +1 514 398
797; e-mail: cj.li@mcgill.ca
3
0
040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.08.122

7582
Y. Zhang, C.-J. Li / Tetrahedron Letters 45 (2004) 7581–7584
9
studies have been reported in the literature. In particu-
lar, Leadbeater and Marco reported an efficient Suzuki-
type coupling without transition-metal catalyst under
microwave irradiation, we were surprised to find that
the corresponding addition product was produced in
almost all cases together with various by-products.
Subsequently, optimizing of the product was performed
by varying the amount of catalysts. It was found that the
best results were obtained without using any catalyst.
Then, the product formation was optimized in terms
of the microwave power, the reaction time and temper-
1
1
1
0
microwave conditions.
At the beginning of our investigation, we dissolved
phenylacetylene in tetrahydrofuran (THF) together with
various transition-metal catalysts. After subjected to
Table 2. Microwave-assisted direct addition of cycloethers to alkynes
a
b
Entry Alkyne
Cycloether Conditions (W/temp (°C)/time) Product
cis/trans-Ratio
Total yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
Ph
300/200/40min
300/200/120min
300/200/60min
300/200/80min
300/200/80min
300/200/120min
300/200/130min
300/200/120min
300/200/180min
300/200/180min
300/200/180min
300/200/120min
300/200/60min
300/200/120min
300/200/40min
300/200/40min
53:47
60
O
O
O
O
O
Ph
H2N
NH2
58:42
55:45
56:44
57:43
26:74
31:69
38:62
21:79
40:60
21:79
44:56
37:63
58:42
50:50
55:45
52
71
58
68
Br
O
O
O
O
Br
MeO
Me
O
OMe
Me
O
O
OH
c
42
HO
OH
56
47
38
37
38
43
26
22
34
57
HO
O
O
O
O
O
C8H17
OH
8
C H
17
OH
O
O
O
O
O
0
1
2
3
4
5
6
HO
O
OH
OH
O
O
OH
Si O
O Si
C6H13
O
O
6
C H
13
Me
Ph
Ph
O
O
O
O
O
Ph
D
D
O
O
Ph
a
b
c
1
cis/trans were determined by H NMR based on Ref. 5c.
Isolated yields were reported.
Only trans-isomer was isolated.

Y. Zhang, C.-J. Li / Tetrahedron Letters 45 (2004) 7581–7584
7583
ature and the conditions were summarized in Table 1.
As shown in Table 1, a 5mmol concentration of alkyne
in THF microwaved at200 °C in 60min produced the
desired addition product in good isolated yield as a mix-
ture of cis/trans geometrical isomers. The addition of
various additives, such as radical initiators (AIBN) or
Lewis acids and transition-metal catalysts, to the reac-
tion mixture decreased the yield of the product. Subse-
quently, the reaction of tetrahydrofuran with various
terminal alkynes were examined under similar condi-
tions (Table 2).
and synthetic application of this direct addition reaction
are under investigation.
The following procedure is representative: a mixture of
phenylacetylene (20.4mg, 0.2mmol) and THF
(3.25mL. 40mmol) in a sealed tube was placed in a
CEM microwave oven. The mixture was heated while
stirring under microwave (at 200°C with 300W operat-
ing power) for 40min. Upon cooling to room tempera-
ture, the reaction vial was taken out. After removal of
the solvent, the residue was separated by column chro-
matography on silica gel eluting with hexane/ethyl ace-
As shown in Table 2, aromatic alkynes appeared more
reactive than aliphatic alkynes under the same reaction
conditions. The presence of electron-withdrawing
groups on the aryl group of aromatic alkyne further
improved the reaction (entries 2, 3, 4 and 5). Alkynes
bearing hydroxyl groups and an amine can be used di-
rectly without the need of protection groups (entries 6,
tate (20:1) to give the desired compound (21mg, 60%).
1
H NMR (400MHz, CDCl ) d: 7.37–7.19 (m, 10H),
3
6.59–6.55 (t, 2H, J = 11.6, 6.4Hz), 6.22–6.14 (q, 1H,
J = 6.8, 9.2, 6.8Hz), 5.17–5.67 (t, 1H, J = 8.8, 11.6Hz),
4.68–4.62 (q, 1H, J = 7.6, 8, 7.6Hz), 4.48–4.43 (q, 1H,
J = 6.4, 6.8, 7.6Hz), 3.96–3.92 (m, 2H), 3.85–3.74 (m,
2H), 2.17–2.07 (m, 2H), 2.04–1.86 (m, 4H), 1.74–1.63
1
3
7, 9, 10 and 11); and no significant reactivity difference was
(m, 2H); C NMR (400MHz, CDCl ) d: 137.05,
3
observed between protected and unprotected propargyl
alcohol under the reaction conditions (compare entries
136.90, 133.05, 131.72, 130.71, 130.67, 129.05, 128.73,
128.38, 127.72, 127.34, 126.67, 79.90, 75.27, 68.41,
68.31, 33.15, 32.61, 26.62, 26.14; MS: m/z (%): 174
7
and 12). The reaction also proceeded well with tetra-
+
hydropyran and 1,4-dioxane. However, the yields were
lower with these compounds than those with THF;
and the required reaction temperatures were also higher.
(100) [M ], 157 (25), 131 (53), 115 (26), 104 (33); m/z
(%): 174 (100) [M ], 157 (25), 131 (50), 115 (22), 104
(31).
+
In conclusion, a direct addition of cycloethers to alkynes
was developed under microwave conditions to generate
various 2-vinyl substituted cyclic ether derivatives. A
tentative mechanism (Scheme 2) for the reaction was
proposed to involve the abstraction of the 2-hydrogen
of tetrahydrofuran by oxygen molecule to generate
tetrahydrofuran radicals. Then, a direct radical addition
to the terminal alkynes forms a C–C bond and a vinyl
radical, which undergoes subsequentradical ab sr ta ct
and regenerate new tetrahydrofuran radicals for further
reactions. Previously, tetrahydrofuran radical addition
to alkyne has been observed in the study of Bergman
Acknowledgements
We are grateful to NSF (No. 0207363) and NSF–EPA
Joint Program for a Sustainable Environment for partial
supportof our research.
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hydrofuran and tetrahydropyran to alkynes.

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