Efficient Fe/I2/NaI mediated synthesis of alkenyl iodides through direct coupling of alcohols and alkynes

Article abstract of DOI:10.1016/j.tetlet.2011.11.037

A new and efficient method for the synthesis of alkenyl iodides through direct coupling of alcohols and alkynes has been developed in the presence of iron powder, I₂, and NaI. This methodology not only provides an attractive approach to alkenyl

Full text of DOI:10.1016/j.tetlet.2011.11.037

Tetrahedron Letters 53 (2012) 317–319
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient Fe/I2/NaI mediated synthesis of alkenyl iodides through direct
coupling of alcohols and alkynes
Ming-Ming Li a,b, Qiang Zhang a,b, Hui-Lan Yue a,b, Lei Ma c, Jian-Xin Ji a,
⇑
a Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
b Graduate University of the Chinese Academy of Sciences, Beijing 100049, China
c Center for Drug Evaluation, State Food and Drug Administration, Beijing 100038, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and efficient method for the synthesis of alkenyl iodides through direct coupling of alcohols and
alkynes has been developed in the presence of iron powder, I2, and NaI. This methodology not only provides
an attractive approach to alkenyl iodides, but also expands the application of iron in synthetic chemistry.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 2 August 2011
Revised 28 October 2011
Accepted 8 November 2011
Available online 15 November 2011
Keywords:
Iron powder
Iodine
Alkenyl iodides
Alkynes
Alcohols
Alkenyl iodides are highly valuable structural motifs and widely
serve as important intermediates in the synthesis of various natural
products, pharmaceuticals, and polymers.1 The iodide moiety is
commonly regarded as the key element which provides simple
and convenient avenues for further structural elaboration through
transition-metal-catalyzed cross-coupling reactions, such as Heck,
Suzuki, Stille, Sonogashira, and Negishi reactions.1b,2 In general,
the strategies for the construction of alkenyl iodides are mostly
based on iodination or hydroiodination of alkynes,3 allenes,4 propar-
gylic alcohols, and their derivatives5 with iodinating reagents such
as HI, I2, or N-iodosuccinimide. From a synthetic standpoint,
iodoalkylationof alkynes could supply more versatile functionalized
alkenyl iodides. So far, various methods have been developed over
the past decades.6–9 Typically, the iodoalkylation of alkynes was
achieved through two steps (i) the addition of organometallic re-
agents or unsaturated compounds such as vinyl ether to alkynes
mediated by Zr, Ti, or Ni salts for the preparation of alkenyl organo-
metallics, and (ii) treatment of the alkenyl organometallics with I2
generated alkenyl iodides.6 Alternative procedures including intra-
molecular electrophilic cyclization of complicated alkynes such as
1,5-diynes or 1,5-enynes,7 AIBN or zinc powder mediated radical
addition of perfluoroalkyl iodides to alkynes,8 and the use of ketones
and aldehydes reacted with activated alkynes and iodide salts to ac-
cess alkenyl iodides have also been developed.9 Nevertheless, most
of these methods suffer from limitations such as the need of extra
steps to prepare active starting materials, drastic reaction condi-
tions, and the use of expensive and toxic metal catalysts. Therefore,
the development of simple and efficient methods for the iodoalkyla-
tion of alkynes is still highly desirable.
Iron as an abundant, cheap, and environmentally benign metal,
has displayed excellent reactivity for the formation of carbon–car-
bon and carbon–heteroatom bonds.10 Recently, a new synthetic
strategy for preparing alkenyl chlorides and alkenyl bromides
through coupling reaction of benzyl alcohols and alkynes has been
developed, in which FeCl3 and FeBr3 were employed not only as
promoters to accomplish the formation of chemical bonds but also
as halide sources (Eq. 1).11a–c However, alkenyl iodides could not
be afforded by this procedure due to the highly labile feature of
FeI3.12 Herein, we report a new and efficient iron powder, I2, and
NaI mediated method for the synthesis of alkenyl iodides from al-
kynes and alcohols under
ð1Þ
ð2Þ
⇑
Corresponding author. Tel.: +86 28 82855463; fax: +86 28 82855223.
E-mail address: jijx@cib.ac.cn (J.-X. Ji).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.037

318
M.-M. Li et al. / Tetrahedron Letters 53 (2012) 317–319
Table 2
mild conditions (Eq. 2).
In an initial experiment, benzhydrol 1a and phenylacetylene 2a
Results for reactions of alkynes with various alcoholsa,b
were chosen as model substrates to examine the activity of various
iron and iodinating reagents including FeI2, iron powder/HI, iron
powder/NaI, and iron powder/I2 in 1,2-dibromoethane (DBE)13 at
55 °C. No desired product 3a was detected in the presence of iron
powder/HI and iron powder/NaI (Table 1, entries 2 and 3). To our
delight, the desired alkenyl iodide 3a was produced in 28% and
32% yields by the promotion of FeI2 and iron powder/I2, respec-
tively, (Table 1, entries 1 and 4). Considering iron powder and I2
are cheaper and easily available reagents, further optimization of
the reaction using iron powder and I2 was conducted. The results
suggested that the increase of iron powder and I2 loading greatly
improved this iodoalkylation reaction, and good yield of 3a was ob-
tained when NaI was employed as the additive (Table 1, entries 5–
10). Further investigation showed that solvents had a strong effect
on this process, halogenated solvents such as 1,2-dichloroethane,
DBE, and dichloromethane worked more efficiently for this trans-
formation than non-halogenated solvents, and DBE was found to
be the most effective (Table 1, entries 9, 11–15). After an extensive
screening, the best yield (88%) was obtained by employing iron
powder (1 equiv), I2 (1 equiv), and NaI (2 equiv) in DBE at 55 °C
(Table 1, entry 9).
Under the optimal reaction conditions, the generality of the pro-
cess was tested by using various alcohols with alkynes and the re-
sults are summarized in Table 2. In general, the desired products
were produced with E isomers as the main products, which can be
explained from the preferred trans attack of the iodide ion to the
alkenyl carbocation. Dibenylmethanols with either electron-donat-
ing or -withdrawing groups attached to the benzene ring were suit-
able for this protocol, and the corresponding products were
obtained in good to excellent yields (3a–e). Benzylic alcohols could
also be used in the reaction to give the expected alkenyl iodides (3f
and 3g). In addition, allylic alcohols such as (E)-1,3-diphenylprop-2-
en-1-ol, cyclohex-2-enol, and 4,4-dimethyl-cyclohex-2-enol re-
acted smoothly with alkynes, affording 1-iodo-1,4-diene deriva-
tives in good yields (3h–l). With respect to alkynes, electron-rich
3a (88%), E:Z (86:14)
3b (91%), E:Z (82:18)
3c (89%), E:Z (77:23)
3d (66%), E:Z (81:19)
3f (90%), E:Z (86:14)
3e (90%), E:Z (91:9)
3g (61%), E:Z (84:16)
3h (72%), E:Z (82:18)
3j (81%), E:Z (80:20)
3i (83%), E:Z (77:23)
3k (72%), E:Z (84:16)
Table 1
3l (86%), E:Z (84:16)
Screening of the reaction conditionsa,b
3m (90%), E:Z (83:17)
3o (61%), E:Z (87:13)
3q (65%), E:Z (91:9)
3n (83%), E:Z (85:15)
3p (72%), E:Z (89:11)
Entry
Iron/iodinating reagents (equiv)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
FeI2 (0.5)
Fe (0.5)/HI (1)
Fe (0.5)/NaI (1)
Fe (0.5)/I2 (0.5)
Fe (0.5)/I2 (0.75)
Fe (0.75)/I2 (0.75)
Fe (1)/I2 (1)
Fe (1)/I2 (1)/NaI (1)
Fe (1)/I2 (1)/NaI (2)
Fe (1)/I2 (1)/NaI (3)
Fe (1)/I2 (1)/NaI (2)
Fe (1)/I2 (1)/NaI (2)
Fe (1)/I2 (1)/NaI (2)
Fe (1)/I2 (1)/NaI (2)
Fe (1)/I2 (1)/NaI (2)
Fe (1)/I2 (1)/KI (2)
Fe (1)/I2 (1)/HI (2)
DBE
DBE
DBE
DBE
DBE
DBE
DBE
DBE
28
0c
0
32
29
45
56
68
88
57
79
77
39
0
DBE
DBE
ClCH2CH2Cl
CH2Cl2 (reflux)
Toluene
CH3OH
CH3CN
DBE
3r (60%), E:Z (98:2)
a
Reaction conditions: alcohols 1 (0.5 mmol), alkynes 2 (1.5 mmol), I2 (0.5 mmol),
iron powder (0.5 mmol), NaI (1.0 mmol), DBE (1.0 mL), 55 °C, 8–12 h.
Isolated yields of the E:Z mixtures; the E:Z ratio was determined by 1H NMR
b
0
spectroscopy.
60
DBE
74c
a
Reaction conditions: benzhydrol 1a (0.5 mmol), phenylacetylene 2a (1.5 mmol),
aromatic alkynes generally exhibited better reactivity than elec-
tron-deficient ones (3m–p). Notably, internal aromatic alkynes such
as 1-phenyl-1-propyne and 1-phenyl-1-butyne were also tolerated
iron/iodinating reagents, solvent (1.0 mL), 55 °C, 8 h.
b
Isolated yields of the E:Z mixtures.
c
47% aqueous HI was used.

M.-M. Li et al. / Tetrahedron Letters 53 (2012) 317–319
319
iodides, but also expands the application of iron in synthetic chem-
istry. Further investigation of the detailed reaction mechanism and
synthetic applications are ongoing.
Acknowledgment
We are grateful for the financial support from the National Nat-
ural Science Foundation of China (20802072).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.037.
Scheme 1. Postulated reaction pathways.
in this process, leading to the corresponding products in moderate
yields (3q and 3r). Nevertheless, when aliphatic alkynes were used
as the substrates, none of the desired products were detected.
In the course of our investigation on the mechanism of this
reaction, dimeric ether 4a was observed and isolated together with
the product 3a when the reaction of benzhydrol 1a and phenyl-
acetylene 2a was conducted in the presence of iron powder, I2,
and NaI (Eq. 3). Furthermore, the product 3a was obtained in an
81% isolated yield when a separate experiment was performed be-
tween dimeric ether 4a and phenylacetylene 2a under the standard
conditions (Eq. 4). These results suggested that dimeric ether 4
might be an intermediate in this iodoalkylation reaction. Neverthe-
less, the direct iodoalkylation of alkynes with alcohols and iodinat-
ing reagents could not be excluded at present stage.11c–e
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ð3Þ
ð4Þ
Although the detailed mechanism is unclear, based on the
above results and previous studies,11 we proposed two postulated
pathways of this reaction shown in Scheme 1. One pathway was a
direct alkylation of alkyne 2 with alcohol 1 to generate alkenyl cat-
ion 5, which was attacked by iodide ion to form alkenyl iodides 3.
In another probable pathway, the starting alcohol 1 was firstly con-
verted to the corresponding dimeric ether 4. Then, the alkylation of
alkyne 2 by dimeric ether 4 was proceeded to give alkenyl cation 5.
Finally, the iodination of alkenyl cation 5 delivered the desired
product 3.
In summary, we have successfully developed a convenient and
efficient method for the synthesis of alkenyl iodides through direct
coupling of various alcohols with alkynes in the presence of iron
powder, I2, and NaI under mild conditions. The present protocol
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