InBr3-Et3N promoted alkynylation of aldehydes and N,O-acetals under mild conditions: Facile and simple preparation of propargylic alcohols and amines

Article abstract of DOI:10.1016/S0040-4039(03)00931-6

The use of a novel InBr₃-Et₃N reagent system to promote addition reactions of 1-alkynes not only with a variety of aromatic or bulky aliphatic aldehydes but also with N,O-acetals is described. The corresponding propargylic alcohols or amines are produced in good to excellent yields.

Full text of DOI:10.1016/S0040-4039(03)00931-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4171–4174
InBr3–Et3N promoted alkynylation of aldehydes and N,O-acetals
under mild conditions: facile and simple preparation of
propargylic alcohols and amines
Norio Sakai,* Maki Hirasawa and Takeo Konakahara*
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science, Noda,
Chiba 278-8510, Japan
Received 18 March 2003; revised 9 April 2003; accepted 10 April 2003
Abstract—The use of a novel InBr3–Et3N reagent system to promote addition reactions of 1-alkynes not only with a variety of
aromatic or bulky aliphatic aldehydes but also with N,O-acetals is described. The corresponding propargylic alcohols or amines
are produced in good to excellent yields. © 2003 Elsevier Science Ltd. All rights reserved.
The synthesis of propargylic alcohols has been exten-
sively studied because a number of their derivatives
constitute basic units in natural products and related
biologically active substances.1 The nucleophilic addi-
tion of alkynylmetals containing Ce,2 B,3 V4 and Al5 to
carbonyl compounds has been typically used for this
purpose in the past. However, these methods are not
straightforward, because most of these alkynylmetals
must be generated by the transmetalation of Li, Na, or
Mg acetylides,6 and low temperature condition is
required to stabilize the metal acetylides which may
undergo side reactions such as the base-induced forma-
tion of by-products. Hence, development of alkynyla-
tion of carbonyl compounds without such strong bases
that can be used under mild conditions would be highly
desirable in terms of simplifying with the reaction pro-
cesses. After some trials, a practical manner in which
the combined use of a Lewis acid, such as Sn(OTf)2,7
highly efficient and widely applicable alkynylation of
carbonyl compounds using an indium(III) halide and
Lewis base. We report herein that a novel InBr3–Et3N
reagent system effectively promotes the alkynylation of
aldehydes leading to the corresponding propargylic
alcohols under relatively mild conditions. We also dis-
close herein that, unlike conventional alkynylations
using enamines,12 aminals,13 and imines,9a,14 this
reagent system can be used in alkynylation reaction of
N,O-acetals, which function as imine equivalents,
directly producing propargylic amines in excellent
yields.
We initially examined the reaction of phenylacetylene
(1a) with benzaldehyde (2a) in the presence of indium
trichloride. Thus, when the acetylene (1.5 equiv.) was
treated with Et3N (1.5 equiv.) and InCl3 (1.5 equiv.) at
room temperature for an hour, followed by the addi-
tion of benzaldehyde, the corresponding propargyl
alcohol 3a was produced in 21% yield (run 1).15 To
optimize the alkynylation, we then ran the reaction
using several different solvents and other indium tri-
halides. The results are summarized in Table 1. Conse-
quently, we found that when Et2O was used instead of
CH2Cl2, the product yield was improved to 50% yield
(run 3). In contrast, in the cases of THF and PhMe, the
yields decreased (runs 4 and 5). It is particularly note-
worthy that, when InBr3 was used as a promoter, the
reaction proceeded smoothly and the yield of 3a was
dramatically improved to a near quantitative yield (run
7). On the other hand, an amine, such as trihexylamine,
and InI3 were not effective for this reaction (runs 6 and
8). It was also found that 2 equiv. of these reagents
GaI3,8 Zn(OTf)2,9a and ZnCl2 and a Lewis base, such
9b
as an amine promotes or catalyzes the alkynylation of
carbonyl compounds, was developed. On the other
hand, indium(III) halide has attracted considerable
attention in synthetic organic chemistry due to its low
toxicity in the laboratory, high stability under aqueous
conditions, and strong tolerance to oxygen- and nitro-
gen-containing functional groups.10,11 Hence, we
became interested in developing a method for the
Keywords: indium tribromide; alkynylation; propargylic alcohol;
propargylic amine; N,O-acetal.
* Corresponding author. Tel.: +81-4-7124-1501; fax: +81-4-7123-9890;
e-mail: sakachem@rs.noda.tus.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00931-6

4172
N. Sakai et al. / Tetrahedron Letters 44 (2003) 4171–4174
Table 1. Examination of indium trihalide and reaction conditionsa
Run
InX3 (equiv.)
Amine (equiv.)
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
InCl3 (1.5)
InCl3 (2)
InCl3 (2)
InCl3 (2)
InCl3 (2)
InCl3 (2)
InBr3 (2)
InI3 (2)
Et3N (1.5)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Hex3N (2)
Et3N (2)
Et3N (2)
Et3N (1.2)
Et3N (2)
CH2Cl2
CH2Cl2
Et2O
THF
PhMe
Et2O
Et2O
Et2O
Et2O
Et2O
24
24
24
24
24
18
3
24
6
10
21
33
50
4
Trace
11
98 (94)c
26
9
10
InBr3 (1.2)
None
61
NDd
a Reaction was carried out using phenylacetylene 1a (1.2–2 equiv. per 2a), benzaldehyde 2a (0.4 mmol), and indium trihalide (1.2–2 equiv. per 2a).
See Typical procedure in Ref. 15.
b NMR yields based on benzaldehyde 2a.
c Isolated yield was in parenthesis.
d ND=not detected.
(acetylene, InBr3, and amine) per aldehyde 2 was
required for this reaction; if not, the product yield is
reduced and the reaction time is prolonged (run 9).
Needless to say, in the absence of indium trihalide, no
alkynylation took place (run 10).
gylic alcohol derivatives. Consequently, the present
method could be applied to alkynylation reactions
using aromatic aldehydes other one with a benzene
skeleton (runs 1–9). In particular, unlike previous
reports,2–5,7,8 when acetylene 1a was treated with het-
eroaromatic aldehydes containing pyridine, thiophene,
and furan skeletons, the corresponding heterocyclic
propargylic alcohols were also obtained in satisfactory
yields. In contrast, the alkynylation of ketones, such as
cyclohexanone was rather sluggish (48 h), and the
product yield (48%) was low. Furthermore, a reaction
using acetophenone and acetone was not successful,
due to enolization of the ketone.
To clarify the general applicability of this alkynylation,
the reaction of various benzaldehyde derivatives and
aliphatic aldehydes with phenylacetylene (1a) was car-
ried out under the above optimized conditions, the
results of which are listed in Table 2. The use of
benzaldehyde derivatives having an electron-withdraw-
ing substituent, such as halogens, cyano, and nitro
groups required only a short for a complete reaction,
and the corresponding propargyl alcohols 3b–e were
produced in excellent yields ranging from 87 to 97%
(runs 1–4). Similarly, benzaldehydes containing an elec-
tron-donating group also underwent the expected
alkynylation in good yields (runs 5 and 6). In the case
of p-methoxybenzaldehyde, however, reflux conditions
were required to obtain a satisfactory yield (run 5). This
is due to the low electrophilicity of p-methoxybenzalde-
hyde. When aliphatic aldehydes were used, the alkynyl-
ation of bulky aldehydes such as pival- and
isobutyraldehyde gave the corresponding alcohols in
good to moderate yields (runs 7 and 8). However, an
easily enolizable aldehyde, such as butyraldehyde pro-
duced a small amount of the alkynylated product 3j
along with a 22% yield of the side-reaction product,
formed by aldol condensation of the aldehyde (run 9).
This result shows that the abstraction of an a-hydrogen
on the aldehyde by the in-situ formed anionic interme-
diate proceeds faster than the nucleophilic addition of
the intermediate to the aldehyde, thus leading to eno-
lization of the aldehyde.
Table 2. Reaction of phenylacetylene with various alde-
hydes leading to propargylic alcohols
Run
Aldehyde 2
Time (h)
Yield of 3 (%)a
R2
1
2
3
4
5
6
7
8
9
p-Cl-Ph
2b
2c
2d
2e
2f
2g
2h
2i
5
5
3b
90
92
97
87
70b
80
88b
44
11
p-F-Ph
p-CN-Ph
p-NO2-Ph
p-MeO-Ph
p-Me-Ph
t-Bu
3c
3d
3e
3f
3g
3h
3i
1.5
0.5
24
15
24
24
24
i-Pr
n-Pr
2j
3j
a Isolated yields based on aldehyde 2.
b Reaction was carried out at 40°C (bath temperature).
Table 3 shows some results of reactions of other 1-alky-
nes with aromatic aldehydes leading to various propar-

N. Sakai et al. / Tetrahedron Letters 44 (2003) 4171–4174
4173
Table 3. Reaction of terminal alkynes with aldehydes leading to propargylic alcohols
Run
Acetylene 1
Aldehyde 2
Time (h)
Yield of 3 (%)a
R1
R2
1
2
3
4
5
6
7
8
9
C6H13
t-Bu
Me3Si
Ph
Ph
Ph
C6H13
Ph
Ph
1b
1c
1d
1a
1a
1a
1b
1a
1a
p-CN-Ph
Ph
2d
2a
2d
2k
2l
2m
2m
2n
2o
18
24
24
24
20
1
12
24
12
3k
3l
99
67
93b
61
46
99
40
57
93
p-CN-Ph
1-Naphthyl
PhCHꢀCH
3-Pyridyl
3-Pyridyl
2-Thienyl
2-Furyl
3m
3n
3o
3p
3q
3r
3s
a Isolated yields based on aldehyde 2.
b Reaction was carried out at 40°C (bath temperature).
Table 4. Reaction of terminal alkynes with N,O-acetals leading to propargylic amines
Run
Acetylene 1
N,O-Acetal 4
Time (min)
Yield of 5 (%)a
R1
R2
R3
1
2
3
4
Ph
1a
1b
1d
1a
Ph
Ph
Ph
H
Et
Et
Et
SiMe3
4a
4a
4a
4b
<5
<10
10
5a
5b
5c
5d
94
78
54
C6H13
Me3Si
Ph
<60
68 (R3=H)
a Isolated yields based on N,O-acetal 4.
Finally, on the basis of our previous work,16 we applied
the present reaction to the preparation of propargylic
amine derivatives, the skeletons of which were widely
distributed in natural products and biologically active
substances,1 with N,O-acetals.17 Thus, the reaction of
three types of 1-alkynes with appropriate N,O-acetals
was carried out under optimized conditions and the
results are shown in Table 4. It should be especially
noted that the alkynylation of N,O-acetals proceeds
faster than that of aldehydes to produce the expected
propargylic amines in good to excellent yields, demon-
strating the generality of this procedure.
with a variety of aldehydes under mild conditions lead-
ing to the corresponding propargylic alcohols in good
to excellent yields. In addition, we also found that,
unlike conventional alkynylations using Al and Ga, this
reagent system can be used in alkynylation reaction of
heteroaromatic aldehydes producing the corresponding
heterocyclic propargylic alcohols in excellent yields, and
can be applied to the smooth preparation of propar-
gylic amine derivatives with N,O-acetals. Further inves-
tigation into the mechanism of this reaction is now in
progress.
Although, there is no clear explanation for the reaction
intermediate at present, we assume that a nucleophilic
intermediate such as a dibromoindium acetylide, which
is similar to that reported by Baba et al.11 would be
formed.
Acknowledgements
This work was partially supported by a grant from the
Japan Private School Promotion Foundation and a
grant for High Technology Research Centers of Private
Universities.
Thus far, we have demonstrated that the InBr3–Et3N
reagent system promotes the facile reaction of 1-alkynes

4174
N. Sakai et al. / Tetrahedron Letters 44 (2003) 4171–4174
14. (a) Li, C.-J.; Wei, C. Chem. Commun. 2002, 268; (b)
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