ZrCl4 mediated cyclization between epoxides and homopropargylic alcohols: synthesis of 4-chloro-5,6-dihydro-2H-pyran derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.06.063

Epoxides undergo cyclization with homopropargylic alcohols in the presence of zirconium tetrachloride under mild conditions to afford the corresponding dihydropyran derivatives in excellent yields under mild conditions.

Full text of DOI:10.1016/j.tetlet.2006.06.063

Tetrahedron Letters 47 (2006) 6149–6151
ZrCl mediated cyclization between epoxides
4
and homopropargylic alcohols: synthesis
of 4-chloro-5,6-dihydro-2H-pyran derivatives
I
J. S. Yadav, K. Rajasekhar and M. S. R. Murty*
Division of Organic Chemistry-I, Discovery Laboratory, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 27 January 2006; revised 30 May 2006; accepted 8 June 2006
Abstract—Epoxides undergo cyclization with homopropargylic alcohols in the presence of zirconium tetrachloride under mild con-
ditions to afford the corresponding dihydropyran derivatives in excellent yields under mild conditions.
Ó 2006 Elsevier Ltd. All rights reserved.
6
1
. Introduction
and homoallylic alcohols. In continuing our research
on the synthesis of pyran ring systems, in this report
we further extend the work on the synthesis of dihydro-
pyran derivatives through the cyclization between epox-
ides and homopropargylic alcohols using zirconium
tetrachloride.
Substituted dihydropyrans are key intermediates for the
synthesis of many natural products. The olefin function
1
particularly has great synthetic value for further func-
tionalization to obtain polysubstituted tetrahydropyrans
2
from dihydropyrans. Despite their potential impor-
tance to construct structurally complex molecules, the
synthesis of dihydropyrans remains under utilized.
Although other methods are available,3 their impor-
tance prompted us to study extensively the synthesis of
dihydropyran derivatives. However, the development
of efficient and versatile catalytic methods would be a
preferable approach. Epoxides are convenient starting
materials because of their ease of formation, wide reac-
In order to delineate the standard operating conditions,
a mixture of styrene oxide and 3-butyn-1-ol was treated
with zirconium tetrachloride in dry methylene chloride.
The mixture was stirred at room temperature for
30 min and after work-up, the crude product was puri-
fied over silica gel to provide the product in 70% yield.
By spectroscopic analysis the product was confirmed
3
b
as 3a by comparing with the literature data (Scheme
tivity and ability to undergo regioselective ring-opening
1).
4
reactions. ZrCl has been used for various epoxide ring-
4
5
opening reactions giving the products in good yield.
With these encouraging results, the reaction was per-
formed with a wide range of epoxides and all reacted
smoothly with 3-butyn-1-ol under similar conditions to
Recently, we reported the formation of tetrahydropy-
rans through the cyclization reaction between epoxides
Cl
O
R
ZrCl4
DCM, r.t.
+
R = H or Aryl
Ph
OH
O
1
2a
3
R
Scheme 1.
q
IICT Communication No. 060523.
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40 27160512; e-mail: msrmurty@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.063

6150
J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 6149–6151
Table 1. ZrCl
4
mediated cyclization of epoxides with homopropargylic alcohols
Epoxide Alcohol
a
b
Entry
Products
Yield (%)
Cl
O
1
OH
80
Ph
2a
O
3
1a
a
Cl
O
OH
2
3
68
65
Ph
Ph
O
2b
1
a
3b
Cl
O
O
OH
OH
2
a
O
1b
3c Ph
Cl
4
5
77
2
a
O
1c
3d
Cl
O
OH
67
65
2
a
O
1d
3e
Cl
O
OH
6
2
b
O
1d
3f
a
1
All the products were characterized by H NMR and mass spectroscopy.
Isolated yields after column chromatography.
b
afford the corresponding dihydropyran derivatives in
good yields ranging from 65–80% (Table 1). In all cases,
the reactions proceeded efficiently at ambient tempera-
ture under mild conditions showing the generality of
the reaction. The reaction also proceeded well with the
cyclic epoxide 1,2-dihydronaphthalene oxide to give
the corresponding spiro dihydropyran in good yield (en-
try 4).
tetrachloride followed by the migration of hydrogen (in
the case of 1a, 1c and 1d) or the phenyl group (in the
case of 1b) to generate the carbenium species, which is
attacked by the homopropargylic alcohol and cyclized
to the dihydropyran carbenium species. This is further
attacked by the chloride nucleophile to give the 4-
chloro-5,6-dihydro-2H-pyran derivative (Scheme 2).
In summary, we have described a simple and highly effi-
cient protocol for the preparation of dihydropyran
derivatives through the reaction between epoxides and
The mechanism for dihydropyran formation can be
explained by opening of the epoxide ring with zirconium
ZrCl3
R
Cl
O
O
O
ZrCl3
ZrCl3
R
R
HO
R
R
R
O
O
O
Cl-
Cl
Scheme 2.

J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 6149–6151
6151
homopropargylic alcohols using zirconium tetra-
chloride.
78 (10). Anal. Calcd for C H ClO (234): C, 71.64; H,
14 15
6.44%. Found: C, 71.72; H, 6.48%.
1
Compound 3f: H NMR (200 MHz, CDCl ) d: 4.24 (d,
3
J = 4.53 Hz, 1H), 3.94–4.02 (m, 1H), 3.71–3.81 (m,
2
. Representative procedure
1H), 2.71–2.81 (m, 1H), 2.45–2.58 (m, 1H), 2.07–2.09
(
m, 3H), 1.55–1.92 (m, 5H), 1.41–1.51 (m, 1H), 1.03–
To a stirred solution of styrene oxide (240 mg, 2 mmol)
and 3-butyn-1-ol (140 mg, 2 mmol) in dry methylene
chloride (10 mL) was added zirconium tetrachloride
1
3
1
2
1
8
.33 (m, 5H). C NMR (50 MHz, CDCl ) d: 27.70,
3
9.32, 28.63, 34.25, 38.40, 43.10, 64.22, 79.83, 125.20,
+
29.12. EIMS: m/z: 214 (10) M , 179 (15), 131 (100),
(
466 mg, 2 mmol) at room temperature. The mixture
3 (10), 67 (40), 55 (20), 41 (40), 39 (20). Anal. Calcd
was stirred under a nitrogen atmosphere for 30 min.
After work-up, the solution was concentrated and the
crude mixture was separated by column chromato-
graphy over silica gel to give dihydropyran 3 (ethyl
acetate–hexane, 3–7).
for C H ClO (214): C, 67.12; H, 8.92%. Found: C,
6
12 19
7.21; H, 8.98%.
Acknowledgements
K.R.S. thanks CSIR, New Delhi, for the award of a
fellowship.
3. Spectral data
1
Compound 3b: H NMR (200 MHz, CDCl ) d: 7.18–
3
References and notes
7
6
2
5
4
.28 (m, 5H), 4.22–4.29 (m, 1H), 3.83 (dt, J = 1.51 and
.79 Hz, 2H), 3.04 (dd, J = 3.77 and 10.57 Hz, 1H),
.84 (dd, J = 7.55 and 6.79 Hz, 1H), 2.00–2.12 (m,
1
. (a) Oishi, T.; Ohtsuka, Y. In Studies in Natural Products
Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
1989; Vol. 3, p 73; (b) Yet, L. Chem. Rev. 2000, 100,
2963–3007.
2. (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309; (b) Coppi,
L.; Ricci, A.; Taddei, M. J. Org. Chem. 1988, 53, 911; (c) Li,
C.-J.; Zhang, W.-C. Tetrahedron 2000, 56, 2403; (d)
Schmidt, B.; Westhus, M. Tetrahedron 2000, 56, 2421.
3. (a) Dobbs, A. P.; Martinovic, S. Tetrahedron Lett. 2002, 43,
1
3
H). C NMR (50 MHz, CDCl ) d: 30.95, 36.13,
3
2.29, 67.17, 81.89, 126.40, 128.30, 129.28, 129.84.
+
EIMS: m/z: 222 (10) M , 187 (10), 131 (25), 103 (100),
9
7
1 (50), 77 (15). Anal. Calcd for C H ClO (222): C,
0.11; H, 6.79%. Found: C, 70.18; H, 6.72%.
13 15
1
Compound 3c: H NMR (200 MHz, CDCl ) d: 7.17–
3
7
055; (b) Miranda, P. O.; Diaz, D. D.; Padron, J. I.;
7
4
2
6
1
1
.37 (m, 10H), 5.69–5.73 (m, 1H), 4.79–4.89 (m, 1H),
.34–4.46 (m, 1H), 3.89–4.07 (m, 2H), 2.49–2.69 (m,
H). C NMR (50 MHz, CDCl ) d: 33.01, 56.35,
4.17, 77.58, 125.53, 126.63, 126.92, 128.84, 128.70,
28.52. EIMS: m/z: 284 (10) M , 249 (15), 167 (100),
53 (10), 139 (20), 117 (15), 105 (60), 77 (50). Anal.
Bermejo, J.; Martin, V. S. Org. Lett. 2003, 5, 1979; (c) Yu,
C.-M.; Shin, M.-S.; Cho, E.-Y. Bull. Korean Chem. Soc.
2004, 25, 1625.
. (a) Ollevier, T.; Lavie-Compin, G. Tetrahedron Lett. 2004,
45, 49; (b) Baltork, M.; Aliyan, H. Synth. Commun. 1998,
28, 3943; (c) Baltork, M.; Tangestaninejad, S.; Aliyan, H.;
Mirkhani, V. Synth. Commun. 2000, 30, 2365; (d) Baltork,
M.; Khosropour, A. R.; Aliyan, H. Synth. Commun. 2001,
1
3
3
4
+
Calcd for C H ClO (284): C, 75.92; H, 6.02%. Found:
C, 75.98; H, 6.13%.
1
8
17
3
1, 3411; (e) Swamy, N. R.; Kondaji, G.; Nagaiah, K.
1
Synth. Commun. 2002, 32, 2307; (f) Ollevier, T.; Lavie-
Compin, G. Tetrahedron Lett. 2002, 43, 7891.
. (a) Giovanni, V.; Stephen, B.; Jamal, E. M.; Marcella, B.;
Guiseppe, Z. Tetrahedron Lett. 2002, 43, 2687; (b) Chak-
raborti, A. K.; Kondaskar, A. Tetrahedron Lett. 2003, 44,
Compound 3d: H NMR (200 MHz, CDCl ) d: 7.03–
3
7
5
1
2
1
.13 (m, 4H), 5.85 (t, J = 1.75 Hz, 1H), 3.92 (t, J =
.26 Hz, 2H), 2.70–3.14 (m, 4H), 2.38–2.47 (m, 2H),
.80–2.09 (m, 2H). C NMR (50 MHz, CDCl ) d:
5.77, 32.22, 33.04, 39.59, 59.49, 73.10, 125.90, 126.02,
28.55, 129.31, 129.75. EIMS: m/z: 234 (10) M , 199
80), 155 (20), 141 (20), 130 (10), 129 (15), 104 (100),
5
1
3
3
8
315.
+
6. Yadav, J. S.; Rajasekhar, K.; Murty, M. S. R. Tetrahedron
Lett. 2005, 46, 2311.
(