Synthesis of 2,5-disubstituted tetrahydrofurans from organozinc halides and lactones

Article abstract of DOI:10.1016/j.cclet.2009.12.026

2,5-Disubstituted tetrahydrofurans were obtained from lactones and organozinc halides in moderate to high yield in the presence of Lewis acids.

Full text of DOI:10.1016/j.cclet.2009.12.026

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Chinese Chemical Letters 21 (2010) 511–514
www.elsevier.com/locate/cclet
Synthesis of 2,5-disubstituted tetrahydrofurans from organozinc
halides and lactones
*
Dan Feng Huang , Hai Feng Wang, Chang Ming Xu, Teng Niu, Yu Lai Hu
*
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, China
Received 7 September 2009
Abstract
,5-Disubstituted tetrahydrofurans were obtained from lactones and organozinc halides in moderate to high yield in the presence
2
of Lewis acids.
2009 Dan Feng Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
#
Keywords: Organozinc halides; Lactones; Lactols; 2,5-Disubstituted tetrahydrofurans; Lewis acid
2,5-Disubstituted tetrahydrofurans are often found in many biologically active natural products such as acetogenins
1] and polyether antibiotics [2]. Thus, there has been a long-standing interest in the preparation of 2,5-disubstituted
[
tetrahydrofurans and a variety of methods have been achieved [3]. Among them conversion of lactols to 2,5-
disubstituted tetrahydrofurans by organometallic reagents is an efficient method. For example, organosilane has been
extensively investigated [4]. Organoaluminium, organostanne [5], Grignard reagents [6], and enolates [7] are also used
as nucleophiles to convert lactols to 2,5-disubstituted tetrahydrofurans. As for the organozinc reagents, only
Reformatsky reagents [8] and dialkylzinc (R Zn) [5,9] are used in this transformation. There are no reports for the
2
formation of 2,5-disubstituted tetrahydrofurans from organozinc halides (FG-RZnX). As it is known, organozinc
halides are more convenient to be prepared, and more useful in organic synthesis because they can tolerate a broad
range of functionalities, but can react with various electrophiles to give multi-functional molecules [10]. Lots of work
on organozinc halides has been done in our group [11]. Thus, we wondered if organozinc halides would be able to
convert lactols to 2,5-disubstituted tetrahydrofurans. If so, functionalized 2,5-disubstituted tetrahydrofurans can be
obtained and further incorporated into the natural products through the functional group. Firstly, allylzinc bromide was
used. As expected, the reaction occurred. We will report here that the allylzinc and propargylzinc bromides can react
with lactols prepared in situ or their acetoxy derivatives to give the 2,5-disubstituted tetrahydrofurans in the presence
of Lewis acids.
Initially, we got lactol 2 from lactone 1, which was not separated from reaction mixture and used directly in the next
step. Allylzinc bromide was then reacted with lactol 2 in the presence of BF ꢀEt O. Unfortunately, the desired product
3
2
3
a was obtained only in 19% yield, the ring opening diol 4 was major product in 76% yield (Scheme 1). We envisioned
*
Corresponding authors.
E-mail addresses: huangdf@nwnu.edu.cn (D.F. Huang), huyl@nwnu.edu.cn (Y.L. Hu).
1001-8417/$ – see front matter # 2009 Dan Feng Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.12.026

512
D.F. Huang et al. / Chinese Chemical Letters 21 (2010) 511–514
Scheme 1.
Scheme 2.
that the hemiacetal 2 maybe too reactive. So we captured the aluminium hemiacetal intermediate 5 in situ with Ac O to
2
give acetoxy derivative 6 (Scheme 2), which was then reacted with allylzinc bromide. To our delight, the reaction gave
the expected product 3a in 64% yield.
To investigate the applicability of the method, various substituted lactones were further employed. As shown in
Table 1, the reaction with allylzinc bromides gave the desired 2,5-disubstituted tetrahydrofurans (Table 1, entries 1–3).
The reaction with propargylzinc bromides also produced the corresponding 2,5-disubstituted tetrahydrofurans
(Table 1, entries 4–5). In addition, when the hendered lactone with substituents at 3-position was used, the reaction
also afforded the product 3f in 82% yield (Table 1, entry 6).
Table 1
Preparation of 2,5-disubstituted tetrahydrofurans from lactons and organozinc bromides using BF
3
ꢀEt
2
O as Lewis acid.
0
a
b
Entry
1
Lactone
R ZnBr
Product
Yield (%)
Ratio of trans/cis
3a
3b
64
57/43
2
69
56/44
3
4
3c
77
63
37/63
53/47
3d
5
6
3e
3f
58
82
55/45
50/50
a
Isolated yield [12].
b
The ratio of trans/cis was determined by GC.

D.F. Huang et al. / Chinese Chemical Letters 21 (2010) 511–514
513
Table 2
Effects of different Lewis acids on the reaction.
a
Entry
Lewis acid
Isolated yield 3a (%)
Ratio of trans/cis
1
2
3
4
5
ZnBr
ZnCl
BF
ꢀEt
SnCl
CeCl
2
59
88
64
59
91
56/44
50/50
57/43
57/43
46/54
2
3
2
O
4
3
a
The ratio of trans/cis was determined by GC.
Table 3
3
Preparation of 2, 5-disubstituted tetrahydrofurans from lactones and organozinc boromides using CeCl as lewis acid.
.
0
a
Entry
R
R
Product
Isolated yield (%)
Ratio of trans/cis
1
2
3
4
5
n-C
n-C
Ph
7
H
H
15
Allyl
3a
3b
3c
3d
3e
91
86
90
76
71
46/54
47/53
39/61
40/60
55/60
4
9
Allyl
Allyl
n-C
n-C
7
H
H
15
Proparyl
Proparyl
4
9
a
The ratio of trans/cis was determined by GC.
In order to improve the yield, we examined the reaction with various Lewis acids using 5-heptanyllactone as
representative substrate (Table 2). The model reaction proceeded smoothly in the presence of ZnBr , ZnCl , BF ꢀEt O,
2
2
3
2
SnCl or CeCl , respectively. Among them, CeCl showed the best reactivity and the yield of the product reached 91%
3
4
3
(Table 2, entry 5). Based on the optimized reaction conditions, we tried the reaction with different substrates using
CeCl as Lewis acid. Compared with the results in Table 1, the yields of all products were greatly improved (Table 3).
3
1
. Experimental
The solution of lactone (2.5 mmol) in THF (10 mL) was cooled to ꢁ78 8C and DIBAL (5 mL, 1 mol/L) was added
dropwise in 15 min under nitrogen. The mixture was then stirred for 45 min at ꢁ78 8C. A solution of pyridine
(
7.5 mmol) and DMAP (5 mmol) in CH Cl (8 mL) was added into the mixture, and then Ac O (15 mmol) was added.
2 2 2
After being stirred for 12 h, the mixture was allowed to warm to 0 8C, and then saturated aqueous NH Cl (20 mL) and
4
potassium sodium tartrate (10 mL) were added. The mixture was stirred at 0 8C for 30 min and extracted with CH Cl
2
2
(10 mL ꢂ3). The combined organic layers were dried and concentrated to afford acetoxy derivative which was used
directly in the next step.
Organozinc halides (7.5 mmol) (prepared following Knochel’s procedure) [13] in THF (5 mL) was added at
78 8C dropwise into the solution of acetoxy derivative of lactol prepared above in CH Cl (6 mL) under nitrogen.
ꢁ
2
2
The mixture was stirred for 10 min, and then anhydrous CeCl (5 mmol) was added. The mixture was stirred at ꢁ78 8C
3
for 3 h. After completion of the reaction, the reaction mixture was warmed to room temperature and saturated aqueous
NH Cl (15 mL) was added. The mixture was stirred for 10 min and then extracted with CH Cl (15 mL ꢂ3). The
4
2
2
combined organic layers were dried over MgSO and concentrated in vacuum. The pure products were obtained by
4
column chromatography on silica gel using petroleum–ethylacetate as eluent.
In conclusion, an efficient method for synthesis of 2,5-disubstituted tetrahydrofurans from organozinc halides and
lactones via lactols or their acetoxy derivatives has been developed. Allylzinc and propargylzinc bromides can react
with lactols or their acetoxy derivatives prepared in situ from lactones to give the 2,5-disubstituted tetrahydrofurans in
high yield in the presence of Lewis acids. CeCl is the best Lewis acid. Acetoxy derivatives of lactols give better results
3
than the corresponding lactols.

514
D.F. Huang et al. / Chinese Chemical Letters 21 (2010) 511–514
Acknowledgments
The work was supported by the National Natural Science Foundation of China (No. 20472068), Specialized
Research Fund for the Doctoral Program of Higher Education (No. 200807360001), Key Laboratory of Eco-
Environment-Related Polymer Materials of Ministry of Education (Northwest Normal University).
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ꢁ
1 1
[
[
12] Compound 3a: colorless oil. IR (KBr): 3074, 2926, 2857, 1644, 1082, 998, 912 cm . H NMR (400 MHz, CDCl
3
): d 5.85–5.76 (m, 1H), 5.10–
.03 (m, 2H), 4.02–3.78 (m, 2H), 2.39–1.88 (m, 4H), 1.66–1.28 (m, 14H), 0.93–0.86 (t, 3H). C NMR (100 MHz, CDCl ): d 135.1, 116.6, 79.6,
9.0, 78.4, 77.8, 40.5, 40.4, 36.1, 36.0, 31.9, 31.8, 31.4, 30.9, 30.4, 29.7, 29.3, 26.2, 22.6, 14.1. HRMS (ESI, Pos.) m/z calcd. for C14 30NO
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3
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7
3
H
+
[M+NH
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