Stereoselective synthesis of 1,3-dienes from propargylic alcohols by LiAlH4/AlCl3

Article abstract of DOI:10.1080/00397911.2012.711881

Herein we report that LiAlH₄/AlCl₃ is a very efficient reagent for the reductive dehydration of aryl propargylic alcohols in tetrahydrofuran solvent at reflux to give 1,3-dienes with good yields and high E selection. The reaction con

Full text of DOI:10.1080/00397911.2012.711881

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Stereoselective Synthesis of 1,3-Dienes
from Propargylic Alcohols by LiAlH4/AlCl3
Dong-Mei Cui a , Kai Zhu a , Li Chen a , Lang-Jun Qi a , Cheng-Zhu
Zhang a & Chen Zhang b
a College of Pharmaceutical Science, Zhejiang University of
Technology , Hangzhou , China
b College of Pharmaceutical Sciences, Zhejiang University ,
Hangzhou , China
Accepted author version posted online: 20 Mar 2013.Published
online: 03 Jun 2013.
To cite this article: Dong-Mei Cui , Kai Zhu , Li Chen , Lang-Jun Qi , Cheng-Zhu Zhang & Chen Zhang
(2013): Stereoselective Synthesis of 1,3-Dienes from Propargylic Alcohols by LiAlH4/AlCl3 , Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:17, 2380-2384
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Synthetic Communications1, 43: 2380–2384, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.711881
STEREOSELECTIVE SYNTHESIS OF 1,3-DIENES
FROM PROPARGYLIC ALCOHOLS BY LiAlH4/AlCl3
Dong-Mei Cui,1 Kai Zhu,1 Li Chen,1 Lang-Jun Qi,1
Cheng-Zhu Zhang,1 and Chen Zhang2
1College of Pharmaceutical Science, Zhejiang University of Technology,
Hangzhou, China
2College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
GRAPHICAL ABSTRACT
Abstract Herein we report that LiAlH4/AlCl3 is a very efficient reagent for the reductive
dehydration of aryl propargylic alcohols in tetrahydrofuran solvent at reflux to give
1,3-dienes with good yields and high E selection. The reaction conditions are mild and easy
to operate, and a variety of aryl functional groups, such as bromo, fluoro, butyl, and meth-
oxyl groups, are tolerated. With our protocol, useful (E,E)-1,3-dienes can be synthesized.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Dehydration; 1,3-diene; propargylic alcohol; reduction; stereoselection
INTRODUCTION
Olefin metathesis is an important method for C-C double bond formation in
organic synthesis.[1] In particular, the Diels–Alder reaction of 1,3-dienes has been
utilized to construct a diverse set of organic molecules.[2] A wide variety of methods
exists for the construction of stereodefined 1,3-dienes. These include Wittig,[3]
Julia–Kocienski,[4] Suzuki cross coupling,[5] and other reactions.[6] Despite their
advantages, several drawbacks remain associated with such reactions, including poor
stereoselectivity, the generation of by-products, and the use of stereodefined coup-
ling partners and expensive transition-metal catalysts. Thus, the development of
new methods for their stereoselective synthesis is still needed.
On the other hand, lithium aluminum hydride (LiAlH4) is used for the reduction
of various functionalities and also acts as a highly selective reducing agent for pro-
Received March 11, 2012.
Address correspondence to Dong-Mei Cui, College of Pharmaceutical Science, Zhejiang University
of Technology, Hangzhou 310014, China. E-mail: cuidongmei@zjut.edu.cn
2380

SYNTHESIS OF 1,3-DIENES
2381
pargylic alcohols.[7] We have envisaged that LiAlH4-catalyzed E-selective reduction of
propargylic alcohols followed by Lewis acid–catalyzed dehydration could be a valuable
and complementary synthetic method for one-pot conversion of propargylic alcohols
into conjugated (E)-dienes.[8] Therefore, in this article, we report a facile one-pot prep-
aration of (E)-dienes from propargylic alcohols by LiAlH4=AlCl3.
RESULTS AND DISCUSSION
Our studies began with the use of acetone-derived 2-methyl-4-phenylbut-
3-yn-2-ol (1a) as the substrate for reductive=dehydrative reaction. The reaction mix-
ture consisting of 1a, LiAlH4 (2 equiv), and AlCl3 (3 equiv) was heated to reflux in
tetrahydrofuran (THF) to produce exclusively (E)-1-(3-methylbuta-1,3-dienyl)ben-
zene (2a) at 79% isolated yield (Table 1, entry 1). Formation of 2a was closely related
with the amount of LiAlH4 and AlCl3 used in the reaction: When 1a was treated with
2 equiv of LiAlH4 to yield 2a and dehydrative product 3a at a 65:35 mixture, AlCl3
was reduced to 1 equiv, and the yield of diene derivative 2a became considerably
lower (entries 3 and 6). Importantly, only dehydrative product 3a or reductive pro-
duct 4a was obtained in the absence of LiAlH4 or AlCl3 (entries 4 and 7). Different
solvents were screened, and THF was found to be the best one (entries 8 and 9).
Other Lewis acids such as ZnCl2, InCl3, and FeCl3 failed to give the corresponding
diene. The C-C double bond configuration was confirmed by the coupling constant
1
of the protons in H NMR studies.
Given our optimized conditions, we investigated the scope of this one-pot
reaction sequence using various aryl- and furan-substituted propargylic alcohols
(Table 2). Therefore, both electron-rich and electron-deficient aryl-substituted
tertiary propargylic alcohols were evaluated, yielding the corresponding 1,3-dienes in
good to excellent yields with high E selectivity (Table 2, entries 1–5). The
a
Table 1. Reductive dehydration of propargylic alcohol 1a by LiAlH4=AlCl3
Entry
AlCl3 (eq.)
LiAlH4 (eq.)
Solvent
Yield (%) of (2a=3a=4a)b
1
2
2
2
2
1
3
1
0
2
2
2
3
4
2
0
3
3
3
3
3
3
THF
THF
THF
79 (100=0=0)
35 (100=0=0)
82 (65=35=0)
87 (0=100=0)
76 (100=0=0)
58 (100=0=0)
50 (0=0=100)
71 (48=52=0)
trace
3
4
THF
THF
5
6
THF
THF
7
8
ether
(CH2Cl)2
dioxane
9
10
trace
aThe reactions were performed with 1a (1 mmol), AlCl3 (0–3 mmol), and LiAlH4 (0–4 mmol) in solvent
(2 mL) at 70 ꢀC for 5 h.
bIsolated yields. The ratios of 2a, 3a, and 4a were determined by GC.

2382
D.-M. CUI ET AL.
Table 2. Reaction scope for one-pot synthesis of (E)-dienes from propargylic alcoholsa
Entry
1
Acetylenic alcohol
1
Diene
2
Yield (%)b
75
1b: R1 ¼ 4-BrPh
2b
2
3
4
5
6
7
1c: R1 ¼ 3-FPh
1d: R1 ¼ 4-n-BuPh
1e: R1 ¼ 4-MeOPh
1f: R1 ¼ 3,4-MeOPh
2c
2d
2e
2f
90
65
92
87
67
88
1g: R1 ¼ 3-futanyl
2g
2h
1
=
1h: R ¼ E-PhCH CH
8
9
1i
1j
2i
2j
79
85
10
11
1k
1l
2k
2l
75
65
12c
13
1m
1n
2m
95
2n1 þ 2n2
71 (1:1)d
aThe reactions were performed with 1.0 mmol of 1a, 2 mmol of AlCl3, and 3 mmol of LiAlH4 in 2 mL of
THF at 70 ꢀC for 5 h.
bIsolated yields.
cThe reactions were performed with 1.0 mmol of 1a and 3 mmol of LiAlH4 in 2 mL of THF at 70 ꢀC for
5 h and then with AlCl3 (2 mmol) at 70 ꢀC for 3 h.
dThe ratio of 2n1 and 2n2 was determined by 1H NMR.
furan-substituted propargylic alcohol 1g was also a suitable reaction partner (Table 2,
entry 6). When acetone and (E)-1-(but-1-en-3-ynyl)benzene-derived propargylic alcohol
1h was used as the substrate, the desired (E,E,E)-triene 2h was obtained stereoselectively
(Table 2, entry 4). Even bulky cyclohexanone- and tetralone-derived tertiary propargylic
alcohols 1i and 1j gave good product yields, and acetophenone-derived propargylic

SYNTHESIS OF 1,3-DIENES
2383
alcohol 1m provided a good yield of product (Table 2, entries 8, 9, and 12). Furthermore,
aldehyde-derived secondary aryl propargylic alcohol tended to give (E,E)-1,3-diene 2k
with high stereoselectivity, and the sterically hindered propargylic alcohol 1l was also
tolerated (Table 2, entries 10 and 11). With different alkyl groups (R2, R3) occupied
on the aryl propargylic alcohol 1n, the reaction proceeded smoothly, giving 2n1 and
2n2 as a 50:50 mixture (Table 2, entry 13).
In summary, the present study illustrates the feasibility and broad applicability
of LiAlH4=AlCl3-catalyzed reduction=dehydration of aryl propargylic alcohols.
Moreover, reaction setup and execution of the two-step, one-pot sequence are sim-
ple, and the method provides the target 1,3-dienes in excellent yields with good
stereoselectivity. Additionally, this transformation tolerates a wide range of func-
tional groups on the aryl-substituted part, and a series of secondary or tertiary pro-
pargylic alcohols could be applied.
EXPERMENTAL
General Procedure for Dienes 2a–2n
To a mixture of LiAlH4 (3 mmol), and AlCl3 (2 mmol) in anhydrous THF
(4 mL) was added propargylic alcohol (1 mmol). The mixture was then stirred at
70 ꢀC until the starting propargylic alcohol was consumed as judged by thin-layer
chromatography. The mixture was quenched with saturated solution of NH4Cl
and then extracted with ethyl acetate (20 mL ꢁ 3). The organic layer was washed with
brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography (silica gel) to yield product in an analytically pure form.
(E)-1-Fluoro-3-(3-methylbutA-1, 3-dien-1-yl)benzene (2c)
1
Pale yellow oil; H NMR (500 MHz, CDCl3): d 7.29–7.24 (m, 1H), 7.18–7.16
(m, 1H), 7.14–7.11 (m, 1H), 6.93–6.89 (m, 1H), 6.87 (d, J ¼ 16.0 Hz, 1H), 6.48 (d,
J ¼ 16.0 Hz, 1H), 5.14 (s, 1H), 5.11 (s, 1H), 1.96 (s, 3H).13C NMR (125 MHz,
CDCl3): d 163.2 (d, J ¼ 242.5 Hz), 141.7, 139.8 (d, J ¼ 8.8 Hz), 133.0, 130.0 (d,
J ¼ 8.8 Hz), 127.5 (d, J ¼ 1.2 Hz), 122.4, 118.3, 114.2 (d, J ¼ 22.5 Hz), 112.7 (d,
J ¼ 21.3 Hz), 18.5. IR (KBr, cmꢂ1): 3417, 2994, 1761, 1756, 1636, 1384, 1246,
1051. HRMS (EI) ([M]þ) calcd. for C11H11F: 162.0845; found 162.0842.
Complete experimental details are available online in the Supporting
Information.
ACKNOWLEDGMENT
We thank the Zhejiang Scienece Foundation (No. Y4100558) for financial
support.
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2384
D.-M. CUI ET AL.
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