Published on the web December 18, 2010
111
Iron(III) Chloride-catalyzed Nucleophilic Substitution of Propargylic Alcohols:
A General and Efficient Approach for the Synthesis of 1,4-Diynes
Min Lin, Xin-liang Chen, Tao Wang, Ping Yan, Su-xia Xu, and Zhuang-ping Zhan*
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University,
Xiamen 361005, Fujian, P. R. China
(Received November 1, 2010; CL-100918; E-mail: zpzhan@xmu.edu.cn)
A wide variety of 1,4-diynes have been constructed via a
novel FeCl3-catalyzed coupling reaction of propargylic alcohols
with alkynylsilanes. This synthetic approach provides a general,
efficient, and economical route to 1,4-diynes.
Table 1. FeCl3-catalyzed nucleophilic substitution of various
propargylic alcohols with alkynylsilane 2aa
OH
5 mol% FeCl3
+
TMS
R1
CH3NO2, 25 °C, 5min
R2
R1
1,4-Diynes represent valuable building blocks owing to
their ability to serve as precursors for the synthesis of
pharmaceuticals, functional materials, polyunsaturated fatty
acids, and a wide variety of heterocyclic compounds.1 Histor-
ically, this motif has been constructed via the substitution of
propargyl(2-propynyl) halides with prepared alkynylide anions
or in situ generated metal acetylides under rigorous conditions.2
In these processes, a stoichiometric amount of strong base is
usually required to convert terminal alkynes to the correspond-
ing alkynylide anions, making base-sensitive substrates unsuit-
able for the traditional methods. Furthermore, the production of
large amounts of halide salts makes these methods less desirable.
Alternatively, halide by-products would be avoided if prop-
argylic alcohols could be employed as the electrophiles, making
the transformation more environmentally benign.
Compared with propargylic halides and esters, alcohols do
not react easily with nucleophiles by virtue of the poor leaving
ability of the hydroxy group. Very limited reports on the
preparation of 1,4-diynes via alkynylation of propargylic
alcohols have existed up to now. Kuninobu, Takai, et al.
recently demonstrated a rhenium-catalyzed smooth alkynylation
of propargylic alcohols with an alkynylsilane.3 Yadav and co-
workers described an efficient procedure for the substitution of
aryl propargylic alcohols with alkynylsilanes using molecular
iodine as the catalyst.4 However, more extensive use of these
methodologies is confined to some extent due to the high price
of the catalysts. Thus, the development of general, efficient and
economical methodologies for the synthesis of 1,4-diynes is still
highly demanding.
Lately, our research group has developed an acid-treated
K10 montmorillonite (H-K10 mont) catalyzed nucleophilic
substitution of propargylic alcohols with alkynylsilanes under
solvent-free condition.5 This approach provides a green and
rapid route to 1,4-diynes. Nevertheless, the scope of the
alkynylsilane component of the reaction has been limited to
terminal TMS-substituted aromatic alkynes. In our continued
effort to find novel approach for the synthesis of 1,4-diynes, we
sought to explore a more general synthetic strategy.
In recent years, iron catalysts have attracted significant
attention in synthetic organic chemistry, since iron is highly
abundant in nature and iron salts are inexpensive and environ-
mentally friendly.6,7 Our pioneering work has demonstrated the
use of FeCl3 for efficient activation of propargylic alcohols
toward various nucleophiles.8 We envisioned that the reaction
R2
2a
3
1
Entry
1: R1; R2
Product/Yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
1a: Ph; Ph
1b: Ph; n-Bu
3aa/93%
3ba/90%
3ca/85%
3da/86%
3ea/94%
3fa/92%
3ga/92%
3ha/86%
3ia/90%
3ja/89%
3ka/n.r.c
3la/89%
1c: Ph; cyclopropyl
1d: Ph; 1-cyclohexenyl
1e: Ph; TMS
1f: 1-naphthyl; TMS
1g: (trans)PhCH=CH; TMS
1h: Ph; H
1i: 4-Cl-C6H4; n-Bu
1j: 4-Br-C6H4; n-Bu
1k: 4-COOMe-C6H4; n-Bu
1l: 2-MeO-C6H4; n-Bu
1m: n-pentyl; Ph
3ma/36%, 79%d
aReaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), FeCl3
(0.025 mmol), CH3NO2 (2 mL), 25 °C. bIsolated yield. cn.r.:
No reaction. Reaction ran for 1 h at 25 °C, then for 24 h at
80 °C. dThe propargylic acetate was used instead of prop-
argylic alcohol as the substrate. Reaction ran at 80 °C for 2 h.
between propargylic alcohols and alkynylsilanes catalyzed by
FeCl3 would be feasible.
With this in mind, we initially investigated the FeCl3-
catalyzed substitution reaction of propargylic alcohol 1a with
alkynylsilane 2a. Gratifyingly, 5 mol % of FeCl3 in nitromethane
(CH3NO2) at 25 °C cleanly produced the desired 1,4-diyne 3aa
in 93% yield (Table 1, Entry 1). It is noteworthy that the
reaction finished within just 5 min, which is several-fold faster
than previous strategies.3-5 Our further study revealed that
various aryl- and alkyl-substituted propargylic alcohols effec-
tively underwent the FeCl3-catalyzed substitution.9 Typical
results are shown in Table 1. Employment of propargylic
alcohols bearing an alkyl chain at the terminal position of the
acetylene moiety smoothly afforded the desired products under
mild conditions (Table 1, Entries 2, 9, 10, and 12). Also, as
expected, 1,4-diyne 3ca was obtained from propargylic alcohol
1c in 85% yield, and no ring-opening of the cyclopropyl groups
was observed (Table 1, Entry 3). When R2 was replaced with an
unsaturated alkyl group, the reaction also led to the formation of
desired product in good yield (Table 1, Entry 4). Interestingly,
Chem. Lett. 2011, 40, 111-113
© 2011 The Chemical Society of Japan
Min, Lin
