Nucleophilic substitution of propargyl alcohols with aliphatic alcohols, aliphatic amines and heterocycles catalyzed by 4-nitrobenzenesulfonic acid: A scalable and metal-free process

Article abstract of DOI:10.1016/j.tetlet.2014.02.086

It is aimed to provide a cost effective p-NBSA catalyzed nucleophilic substitution of propargyl alcohols with alcohols, amines and heterocycles, without employing corrosive and costly metal catalysts, toxic solvents and column chromatography for purification. A systematic study of CC, CN and CO bond formation and efficacy of the scalability have also been confirmed.

Full text of DOI:10.1016/j.tetlet.2014.02.086

Accepted Manuscript
Nucleophilic substitution of propargyl alcohols with aliphatic alcohols, aliphatic
amines and heterocycles catalyzed by 4-nitrobenzenesulfonic acid: A scalable
and metal-free process
S. Antony Savarimuthu, D.G. Leo Prakash, S. Augustine Thomas
PII:
S0040-4039(14)00338-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.02.086
TETL 44273
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 November 2013
22 February 2014
24 February 2014
Please cite this article as: Antony Savarimuthu, S., Leo Prakash, D.G., Augustine Thomas, S., Nucleophilic
substitution of propargyl alcohols with aliphatic alcohols, aliphatic amines and heterocycles catalyzed by 4-
nitrobenzenesulfonic acid: A scalable and metal-free process, Tetrahedron Letters (2014), doi: http://dx.doi.org/
10.1016/j.tetlet.2014.02.086
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Nucleophilic substitution of propargyl alcohols with
aliphatic alcohols, aliphatic amines and heterocycles
catalyzed by 4-nitrobenzenesulfonic acid: A scalable and
metal-free process
S. Antony Savarimuthu1*, D.G. Leo Prakash2, S. Augustine Thomas1
p-NBSA (5mol%),
Nu-H
ACN, rt,
0.5 to 1.5 hrs
Nu
R1
HO
R1
R2
R2
H2O
+
R1 = aryl, alkyl, heterocycle
R2 = aryl
Nu-H = nucleophile

1
Tetrahedron Letters
journal hom epage: www.elsevier.com
Nucleophilic substitution of propargyl alcohols with aliphatic alcohols, aliphatic
amines and heterocycles catalyzed by 4-nitrobenzenesulfonic acid: A scalable
and metal-free process
S. Antony Savarimuthu1*, D.G. Leo Prakash2, S. Augustine Thomas1
1Department of Chemistry, St.Xavier’s College, Palayamkottai, Tamil Nadu-627 002, India
2Materials Research Center, School of Engineering, University of Swansea, Swansea SA2 8PP, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
It is aimed to provide a cost effective p-NBSA catalyzed nucleophilic substitution of propargyl
alcohols with alcohols, amines and heterocycles, without employing corrosive and costly metal
catalysts, toxic solvents and column chromatography for purification. A systematic study of C-
C, C-N and C-O bond formation and efficacy of the scalability have also been confirmed.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Propargyl alcohol
Propargyl ether
Propargyl amine
Heterocycles
Sulfonic acids
Bond forming reactions are most widely attempted
transformations in organic synthesis. Formations of carbon-
carbon and carbon-heteroatom bonds, in particular C-N and C-O,
have received much focus as these linkages are constituent of
numerous bioactive molecules,1 pharmaceutical targets2 and
materials. These transformations often require transition metal
catalysts3 facing severe limitations as they are expensive and also
generate toxic metal waste.4 As a consequence, low cost and
metal-free methods have received great interest in recent years.
dichloride for C-C bond formation.11Sc(OTf)3has been used for
propargylation of indoles at 3-postion in dichloroethane
(DCE)12solvent at 80°C and also in nitromethane13 solvent at
15
60°C. The use of Al(OTf)314 and FeCl3 for such a C-C bond
forming reaction is also reported. In contrast to C-O bond
formation, C-N16 bond forming reaction of a propargyl alcohol
with an amine17 is very limited. Almost all these reported
synthetic methods have used either costly or corrosive catalysts
or toxic solvents (DCE and nitro methane) at reflux temperature
(40 to 80°C), proving a major drawback in commercial aspects.
In general, the pharma industry prefers to avoid where possible
the use of metal catalysts because of their costs and toxicity.
Furthermore, in industrial scales, reactions under harsh
conditions and the product purification through traditional
column chromatography are not desired due to high cost
associated with them. This urges an economically viable
approach to synthesize propargyl derivatives whilst avoiding the
undesirable elements that are corrosive metal catalysts and toxic
solvents at reflux temperatures.
Propargyl alcohol is an important moiety which has been
routinely used as a scaffold for the synthesis of various
heterocyclic compounds5 of biological interest. Furthermore, it
has been used as a potential source for carbon dioxide fixation6
and also a valuable source for the synthesis of allene7 derivatives.
In particular, the hydroxyl group in the substituted propargyl
alcohols can act as a good leaving group and can be displaced by
various nucleophiles (Scheme 1).
p-NBSA (5mol%),
Nu-H
ACN, rt,
0.5 to 1.5 hrs
Nu
R1
HO
R1
R2
R2
H2O
+
In this context, the target of this research is to achieve
nucleophilic substitution of hydroxyl group in substituted
propargyl alcohols with nucleophiles such as aliphatic alcohols,
aliphatic amines and heterocycles by introducing a protic acid
such as 4-nitrobenzenesulfonic acid (p-NBSA) a catalyst; this
reagent is cheap and commercially available and also C-C, C-N
and C-O bond forming reactions using catalytic protic acids at
room temperature are not previously reported. An added
advantage of this scalable process is easy purification without the
aid of traditional column chromatography. Besides, this work
does not include any costly or corrosive catalysts and toxic
solvents.
R1 = aryl, alkyl, heterocycle
R2 = aryl
Nu-H = nucleophile
Scheme 1: Nucleophilic substitution of propargyl alcohols
Metal catalyzed8 nucleophilic substitutions of hydroxyl group
in substituted propargyl alcohols were previously reported, and in
the recent years, metal chlorides (FeCl3, BiCl3, InCl3 and TiCl4) 9-
10
have been used as catalysts. Yang et al. used titanocene

2
Tetrahedron Letters
In order to find out the effectiveness of protic acid catalysts,
1.2
10
seven protic acids in acetonitrile (ACN), tetrahydrofuran (THF)
and dichloromethane (DCM) solvents were screened. The details
are listed in Table 1. Aliphatic sulfonic acid catalysts used in
ACN led to charring of the reaction mass with below average
yield (Table 1; Entries 3-4). With regard to aromatic sulfonic
acids, the use of p-toluenesulfonic acid (p-TSA) with 1,3-
diphenyl-prop-2-yn-1-ol (1a) offered inconsistent result while
benzenesulfonic acid (BSA) resulted in a slight increase in yield
(Table 1; Entry 5). The results also confirm that 5 mol% of 4-
nitrobenzenesulfonic acid in ACN provided very good yields
with the stated nucleophiles, methanol (Entry 7), allyl amine
(Entry 10) and furan (Entry 11). The experimental condition in
Table 1, entry 7 was adjudged the optimum reaction condition.
The reactions involving C-C, C-N and C-O bond formations in
Table 2 were performed under the optimum reaction condition.18
5
ACN
ACN
ACN
THF
CH3OH /
1.2
C6H5SO3H /
10
0.5 h 72
0.5 h 52
0.5 h 89
2.0 h 45
0.5 h 52
0.5 h 92
6
CH3OH /
1.2
p-TSA / 10
p-NBSA / 5
p-NBSA / 5
p-NBSA / 5
p-NBSA / 5
7
CH3OH /
1.2
8
CH3OH /
1.2
9
DCM
ACN
CH3OH /
1.2
10
Allyl
amine /
1.2
Table 1: Optimization of reaction conditions with 1a
Entry Solvent Nu-H/ Eq. Catalyst /
mol %
Time
%
yield
11
ACN
Furan / 1.2 p-NBSA / 5
0.5 h 93
* Nu-H: nucleophile, Eq.: Equivalent. Reaction condition: room temperature
(rt)
1
2
3
4
ACN
ACN
ACN
ACN
CH3OH /
1.2
CH3COOH / 2.0 h
10
0
Considering the process involving carbon-oxygen bond
formation (shown in Table 2), 1,3-diphenyl-prop-2-yn-1-ol (1a)
was treated with both primary and secondary alcohols, which
gave excellent yields of the corresponding products containing
alkynic linkage (Table 2; Entries 1-3). Similar trials with allyl
and propargyl alcohols also afforded 88% of 2d and 85% of 2e
(Table 2; Entries 4-5), respectively, whereas benzyl alcohol
CH3OH /
1.2
CF3COOH /
10
2.0 h 23
0.5 h 35
0.5 h 54
CH3OH /
1.2
CH3SO3H /
10
CH3OH /
CF3SO3H /
yielded
79%
of
2f
(Table
2;
Entry
6).
Table 2: Nucleophilic substitution of propargyl alcohols with nucleophiles
Entry
Substrate
Nucleophile
Time
Product
% yield
89
HO
CH3OH
1
0.5 h
O
1a
2a
HO
HO
HO
2
3
0.5 h
0.5 h
90
92
O
1a
1a
2b
HO
HO
O
O
O
2c
HO
4
0.5 h
88
1a
2d
HO
HO
OH
5
6
0.5 h
0.5 h
85
79
1a
1a
2e
HO
O
2f
HO
CH3OH
7
0.5 h
82
O
F
F
1b
2g

3
Entry
8
Substrate
Nucleophile
Time
0.5 h
Product
% yield
82
HO
CH3OH
O
F
F
1c
F
F
2h
HO
CH3OH
9
0.5 h
83
O
F
F
F
1d
F
2i
F
HO
O
CH3OH
CH3OH
10
11
0.5 h
0.5 h
81
85
F
F
F
1e
F
F
2j
HO
O
1f
Cl
Cl
2k
HO
CH3OH
O
12
0.5 h
86
O2N
O2N
1g
Cl
Cl 2l
HO
CH3OH
CH3OH
O
13
14
0.5 h
0.5 h
80
87
F
F
1h
Br
F
2m
Br
F
HO
O
1i
Br
Br
2n
HO
CH3OH
CH3OH
15
16
0.5 h
0.5 h
89
94
O
F
F
F
F
1j
OMe
OMe
2o
HO
O
1k
2p
O
O
O
O
HO
CH3OH
O
17
1.5 h
84
Br
Br
1l
N
N
2q
HO
CH3OH
CH3OH
18
19
20
1.0 h
1.0 h
0.5 h
81
84
81
O
1m
2r
HO
O
F
F
1n
2s
HO
HO
HN
HN
NH2
H2N
1a
1a
2t
21
0.5 h
92
2u

4
Tetrahedron
Entry
Substrate
Nucleophile
H2N
Time
Product
% yield
86
HO
22
0.5 h
HN
1a
1a
2v
HO
23
0.5 h
93
O
O
2w
AcO
HO
HO
24
25
0.5 h
0.5 h
90
89
O
AcO
O
1a
1a
2x
N
Br
H
N
H
Br
2y
*Reaction condition: Substrate (1 mmol), Nu-H (1.2 mmol) and p-NBSA (5 mol %) in ACN at room temperature (rt).
Since yields in this category involving 1a are exceptional,
trials with thirteen substituted internal propargyl alcohols (1b-1n)
were carried out. The reactions of methanol with propargyl
alcohols, 1b and 1c, resulted in very good yields of the expected
products (Table 2; Entries 7, 8). Methanol reacted separately with
1-(2,5-difluoro-phenyl)-3-phenyl-prop-2-yn-1-ol (1d) and 1-(2,5-
centers i.e., 2- and 5-positions, its reaction with 1,3-diphenyl-
prop-2-yn-1-ol (1a) resulted in selective monopropargylation
(Table 2; Entry 23). The treatment of the 2-substituted furan, i.e.,
acetic acid furan-2-ylmethyl ester with 1a afforded an excellent
yield of acetic acid 5-(1,3-diphenyl-prop-2-ynyl)-furan-2-
ylmethyl ester (2x) (Table 2; Entry 24). In addition, 6-
bromoindole on treatment with 1a, yielded 89% of 6-bromo-3-
(1,3-diphenyl-prop-2-ynyl)-1H-indole (2y) (Table 2; Entry 25).
As with C-O bond formation, the reactions involving C-N and C-
C bond formation, through the suggested synthetic route, also
offered exceptional yields.
difluoro-phenyl)-3-(4-fluoro-phenyl)-prop-2-yn-1-ol
(1e)
producing 83% of 2i (Table 2; Entry 9) and 81% of 2j (Table 2;
Entry 10), respectively. 1f and 1g, carrying electron withdrawing
(Cl, NO2) groups, offered very good yields of 2k (Table 2; Entry
11) and 2l (Table 2; Entry 12), respectively. Also, both ortho (1i)
and para (1h) substituted bromobenzene propargyl alcohols
(Table 2; Entries 14, 13) afforded very good yields. The electron
donating group carrying, 1j (Table 2; Entry 15) gave 89% of 2o.
1k, obtained by esterification of 3-formyl-benzoic acid with
methanol and subsequent treatment of the resulting ester with 4-
fluorophenyl acetylene in presence of n-BuLi at < -70°C, was
treated with methanol (Table 2; Entry 16) to get superior yield of
2p. Furthermore, 1-(5-bromo-pyridin-3-yl)-3-phenyl-prop-2-yn-
1-ol (1l) was successfully reacted with methanol to obtain very
good yield of 2q (Table 2; Entry 17). Thereafter, alkyl aryl
substituted internal propargyl alcohols, i.e., 4-methyl-1-phenyl-
pent-1-yn-3-ol (1m) and 1-(4-fluoro-phenyl)-4-methyl-pent-1-yn-
3-ol (1n), were treated with methanol to obtain 81% of 2r (Table
2; Entry 18) and 84% of 2s (Table 2; Entry 19), respectively.
These results clearly highlight that the proposed synthetic route is
much productive regarding the C-O bond formation.
CH3
OH
O
OH
S
O
O
protonation
H
de-protonation
NO2
O
H
CH3
H
O
O
S
O
O
NO2
methanol insertion
water elimination
H2O
CH3OH
C
Three reactions were carried out with 1,3-diphenyl-prop-2-
yn-1-ol (1a) as the substrate to explore the carbon-nitrogen19
bond formation using both primary and secondary amines as
nucleophiles. The first reaction with tert-butyl amine under
optimum reaction condition produced 81% of the desired product
(Table 2; Entry 20). The second reaction with allyl amine and
third reaction with cyclopropyl-methyl amine yielded 92% of 2u
(Table 2; Entry 21) and 86% of 2v, respectively (Table 2; Entry
22).
Scheme 2: proposed reaction mechanism
In the feasible reaction mechanism proposed in Scheme 2,
first, the hydroxyl group of 1,3-diphenyl-prop-2-yn-1-ol is
protonated by p-NBSA. Subsequently water is eliminated to form
secondary carbocation, which may be in equilibrium with allene
carbocation (not observed). Afterwards, CH3OH substituted into
the secondary carbocation undergoes de-protonation to form
propargyl ether. The eliminated proton is captured by sulfonium
anion to form p-NBSA. Thus the reaction proceeds by SN1 type
mechanism. Use of a homochiral alcohol on the substrate would
Finally, the carbon-carbon20 bond formation was first tested
with furan21 as nucleophile. Although furan has two active

5
give rise to an achiral ether following this SN1 reaction
mechanism.
catalytic 4-nitrobenzenesulfonic acid assisted nucleophilic
substitution of substituted propargyl alcohols with aliphatic
alcohols, aliphatic amines and heterocycles. Most importantly,
this method does not employ any costly or corrosive metal
catalysts and toxic solvents, and also avoids the traditional
column chromatographic purification. The results confirm that
the product yields are exceptional in all stated C-C, C-N and C-O
bond forming reactions. Furthermore, this synthetic route makes
it possible for widespread applications in synthetic chemistry,
particularly in the formations of C-C, C-N and C-O bonds, as
these linkages are constituent of numerous bioactive molecules,
pharmaceutical targets and materials.
The scalability of the substitution process was tested on gram
scale in the cases of six moieties, 2d, 2e, 2o, 2u, 2x and 2y as
presented in Table 3.
Table 3: Scalability of this process was tested in six compounds
Entry
Substrate /
Product /
Yield (%)
Quantity (g)
Quantity (g)
1
2
3
4
5
6
1a / 1.2
1a / 1.5
1j / 1.1
1a / 2.0
1a / 1.0
1a / 1.5
2d / 1.26
2e / 1.51
2o / 1.03
2u / 2.19
2x / 1.43
2y / 2.47
88
85
89
92
90
89
Supplementary data
The general synthetic procedure and the details of NMR and
Mass spectra, associated with this article, are given in the
supplementary data, available in the online version.
References
*Reaction condition: Substrate (1 mol), Nu-H (1.2 mol) and p-NBSA (5 mol
%) in ACN (10 volume) at room temperature (rt).
Click here to remove instruction text...
In conclusion, we have found a metal-free economically
viable and scalable new synthetic protocol for making a variety
of compounds containing linkages C-C, C-N and C-O by
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