Copper(i) iodide catalyzed synthesis of primary propargylic alcohols from terminal alkyne

Article abstract of DOI:10.1039/c4ra12719f

A highly efficient and practical method for the synthesis of primary propargylic alcohols has been developed using CuI as catalyst and paraformaldehyde as the formaldehyde source. The reaction was performed under mild reaction conditions offering the desired products in good to excellent yields with a variety of terminal alkynes.

Full text of DOI:10.1039/c4ra12719f

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Copper(I) iodide catalyzed synthesis of primary
propargylic alcohols from terminal alkyne†
Cite this: RSC Adv., 2015, 5, 13220
a
a
b
*
*
Shrishnu Kumar Kundu, Kanchan Mitra and Adinath Majee
Received 19th October 2014
Accepted 19th January 2015
DOI: 10.1039/c4ra12719f
www.rsc.org/advances
A highly efficient and practical method for the synthesis of primary moisture sensitive reagents and strong base thus making
propargylic alcohols has been developed using CuI as catalyst and the procedures operationally complex and economically
paraformaldehyde as the formaldehyde source. The reaction was restrictive.
performed under mild reaction conditions offering the desired prod-
ucts in good to excellent yields with a variety of terminal alkynes.
Alkynylation of aldehydes is one of the most important reac-
tions widely used in organic synthesis which lead to the
production of propargylic alcohols.1 Among the various alde-
hydes, alkynylation of formaldehyde has drawn signicant
attention as it forms primary propargylic alcohols. These
primary alcohols have a wide range of applicability. They are
useful building blocks in all types of organic synthesis, partic-
ularly for that of different heterocyclic scaffolds2 (Fig. 1) and
complex compounds3 (Fig. 2).
There are several methods in literature for synthesis of
secondary and tertiary propargylic alcohols from terminal
alkynes4 but synthesis of primary propargylic alcohols from
the alkyne and formaldehyde is still a challenge because
Fig. 1 Synthesis of heterocyclic scaffolds.
formaldehyde is not easily accessible from the polymeric
forms. Primary propargylic alcohols are usually synthesized by
reaction of phenyl acetylene and formaldehyde. Literature
survey has yielded three general methods of synthesis: (i)
passing of gaseous formaldehyde which is generated by the
thermal depolymerisation of paraformaldehyde5 or 1,3,5-tri-
oxane6 over the alkynyl Grignard reagent by a current of dry
nitrogen, (ii) the reaction of ethereal solution or suspension of
lithium acetylide with in situ generated formaldehyde from
dry paraformaldehyde7 and (iii) reaction of alkynyl Grignard
reagents with the in situ generated formaldehyde from its
linear polymer.8 All of these methods require low temperature,
aDepartment of Chemistry, Jhargram Raj College, Midnapore (West), Jhargram,
WB-721507, India. E-mail: shrishnuk@gmail.com
bDepartment of Chemistry, Visva-Bharati (A Central University), Santiniketan-731235,
India. E-mail: adinath.majee@visva-bharati.ac.in
† Electronic supplementary information (ESI) available: Experimental details, MS
and 1HNMR and 13CNMR for all products. See DOI: 10.1039/c4ra12719f
Fig. 2 Synthesis of complex compounds.
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The limitations of the general methods prompted us to synthesis of primary propargylic alcohols was done from the
search and develop an alternative method to construct primary work of M. Shibasaki and his group,11 where Cu-catalyst has
propargylic alcohols from terminal alkynes.
been used in the form of Cu(I) alkoxide for alkynylation of
During preliminary investigations, reaction between phenyl triuoromethyl ketones to form CF3-substituted tertiary
acetylene and paraformaldehyde was examined as model propargyl alcohol. Initially, we were interested about the
system using different reaction conditions (Tables 1–3). In all possibility of Cu-based catalysts for transformation of form-
the reactions Cu-salts were used as catalysts since they are aldehyde and terminal alkyne to prepare primary propargylic
known to play a vital catalytic role in modern organic alcohols since the mechanism of both the reaction should be
synthesis.9 Among the Cu-salts, CuI in particular reacts with similar.
terminal alkynes to form copper acetylynic complex10 which
At rst, the reaction was performed in presence of CuI and
acts as a good nucleophile. The use of CuI as catalyst in our triethyl amine without potassium hydroxide, where 71% of
homocoupling product (Table 1, entry 1) was isolated. However,
introduction of potassium hydroxide gave our desired product,
primary propargylic alcohols in good yield (Table 1, entry 2). As
Table 1 Screening of bases in reaction conditions
the amount of potassium hydroxide was increased, the yield of
propargylic alcohols increased with decrease of the homocou-
pling products. Preliminary screening of the reaction condi-
tions prompted us to select CuI (5 mol%) as catalyst, and KOH
(1 equiv.) as the base. We examined different organic bases such
as triethyl amine, pyridine and triphenyl phosphine in the
reaction. Among these, triethyl amine is more environmentally
Inorganic
base
friendly and also proved better than others in terms of yield of
the desired products.
Entrya
Organic base
Yieldsb (%) 3a
Yieldsb (%) 4a
The reaction in absence of triethylamine did not proceed
(entry 10, Table 1). Thus, preliminary observations (Table 1)
have shown that both KOH and Et3N were essential for this
transformation. Next our goal was to search for optimum
temperature and the proper ratio of KOH and Et3N to obtain
primary propargylic alcohol as the sole product.
Results presented in Table 2, showed 100 ꢀC as the optimum
temperature and 1 : 1 ratio of KOH and Et3N with respect to
phenyl acetylene was the best conditions for this trans-
formation (Table 2, entry 5).
1
2
3
4
5
6
7
8
9
10
Et3N
Et3N
Pyridine
PPh3
DMAP
Pyridine
Pyridine
Pyridine
Et3N
—
KOH
—
—
—
KOH
NaOH
K2CO3
NaOH
NaOH
—
86
—
—
—
75
59
31
79
—
71
—
81
56
61
—
—
26
—
c
—
—
a
Reaction conditions: 0.5 mmol of 1, 1 mmol of 2, 2 mL DMSO, organic
b
base 0.5 mmol, inorganic bases 0.5 mmol, 100 ꢀC (oil bath). Isolated
Subsequently, we directed our attention in choosing a suit-
able solvent and in examining the effect of other copper salts as
yields aer chromatography on silica gel. c Yellowish suspension.
Table 2 Optimization of the reaction temperature and ratios of bases
Catalyst loading
(mol%)
Et3N
(equiv.)
Entrya
Temp. (ꢀC)
KOH (equiv.)
Yieldsb (%) 3a
Yieldsb (%) 4a
1
2
3
4
5
6
7
8
9
5
5
5
5
0.1
0.5
1
1
1
1
1
1
1
100
100
100
100
100
100
100
120
80
1
1
0.1
0.5
1
1
1
1
1
22
25
6
46
86
79
77
62
57
12
5
70
26
—
—
—
—
—
5
10
15
10
10
a
Reaction conditions: 0.5 mmol of 1, 1 mmol of 2, 2 mL DMSO. b Isolated yields aer chromatography on silica gel.
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Table 3 Optimization of solvent and catalyst
Table 4 Substrates scope of the reaction
Entrya
Solvent
Catalyst
Yieldsb (%) 3a
Yieldsb (%) 4a
Entrya
1
Substrates
Products
Time (h)
Yieldsb
91
1
2
3
4
5
6
7
8
9
10
DMF
CuI
CuI
CuI
CuI
CuBr
Cu(OAc)2
NiCl2
ZnI2
FeCl3
CoCl3
55
7
40
75
79
—
70
82
46
35
22
56
1,2-DCE
1,4-Dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
<5
91
20
—
25
15
15
20
3a
4
8
2
3b
77
3
4
5
3c
3d
3e
7
8
5
75
00c
77
a
Reaction conditions: 0.5 mmol of 1, 1 mmol of 2, 2 mL solvent, Et3N
0.5 mmol, KOH 0.5 mmol, catalyst 5 mol%, 100 ꢀC (oil bath).
b
Isolated yields aer chromatography on silica gel.
catalyst for the above transformation. We have experimented
with some high boiling solvents like DMSO, DMF, 1,2-DCE etc.
and CuI, CuBr, Cu(OAc)2 as catalysts. To examine the role of
other metal salt we have performed the same experiment using
DMSO as solvent and NiI2, ZnI2, FeCl3 and CoCl3 as catalyst
(entry 7–10) and isolated very low yield. But only CuI as catalyst
in DMSO solvent yielded the desired product primary prop-
argylic alcohols without any byproducts. In all other cases it was
observed that homocoupling products were major or sole
products.
6
7
3f
4
4
86
85
3g
8
9
3h
3i
5
5
00c
78
Aer optimizing the reaction conditions, transformation
was examined with a variety of terminal alkyne systems. Phenyl
acetylene and its different derivatives were found to react
satisfactorily to give the corresponding primary propargylic
alcohols in good yields. Furthermore electron-releasing (Table
4, entries 2 & 5) and electron-withdrawing substituent (Table 4,
entry 6) on the phenyl ring were almost equally effective during
the transformation with good to excellent yields. Moreover,
this method was not only effective for simple aliphatic
terminal alkyne with yields ranging from 74% to 84% (Table 4,
entry 9–13) but also alkyne with highly strained cyclopropane
ring (Table 4, entry 10). Unfortunately, it was found that the
compounds like 4-ethynylbenzonitrile and 2-ethynylpyridine
(Table 4, entries 4 & 8) fails to react in the following trans-
formations. An important advantage of this method is that the
primary amine group remains unchanged which has been
substantiated by deuterium exchange experiment. To explore
the reaction for other aldehyde, we have examined benzalde-
hyde and butyraldehyde but no expected product was
observed.
10
3j
5
85
11
12
3k
3l
5
5
74
80
13
3m
5
84
14
15
3n
3o
5
4
84
82
16
3p
8
45
a
Reaction conditions: 1 mmol of 1, 2 mmol of 2, 3 mL DMSO, Et3N 1
b
mmol, KOH 1 mmol, CuI 5 mol%, 100 ꢀC (oil bath). Isolated yields
aer chromatography on silica gel. c Starting material isolated.
In this context it is worthy to mention that when propargylic
ether underwent the reaction, depropargylation of propargylic
ether was found as the sole product (Scheme 1).
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Scheme 1 Depropargylation of propargylic ether.
Conclusions
In conclusion, we have developed a simple, efficient, mild and
good alternative catalytic method for the synthesis of primary
propargylic alcohols from terminal alkyne. This procedure is far
superior with respected to the established methods in terms of
(i) simplicity of operation (ii) higher quantity of yields and (iii)
faster rate of reaction. We believe that the present methodology
for synthesis of primary propargylic alcohols has immense
potential for application in both academic and industrial elds.
Acknowledgements
We are grateful to Dr Gurucharan Mukhopadhyay and Dr
Samrajnee Dutta, Jhargram Raj College for their immense
support to carry out this work. S. K. Kundu and A. Majee are
pleased to acknowledge nancial support from UGC, Govt. of
India (UGC-MRP, no. F. PSW-171/11-12).
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