Amberlite IR-120H as an efficient and versatile solid phase catalyst for nucleophilic substitution of propargylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2013.04.120

A highly efficient Amberlite IR-120H resin mediated nucleophilic substitution of the hydroxyl group of propargylic alcohols with a wide range of nucleophiles is reported. The reactions were achieved under very mild conditions in excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.04.120

Tetrahedron Letters 54 (2013) 3550–3553
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Amberlite IR-120H as an efficient and versatile solid phase catalyst for
nucleophilic substitution of propargylic alcohols
⇑
Satheesh Gujarathi, Howard P. Hendrickson, Guangrong Zheng
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient Amberlite IR-120H resin mediated nucleophilic substitution of the hydroxyl group of
propargylic alcohols with a wide range of nucleophiles is reported. The reactions were achieved under
very mild conditions in excellent yields.
Received 5 April 2013
Revised 11 April 2013
Accepted 26 April 2013
Available online 3 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amberlite IR-120H
Nucleophilic substitution
Propargylic alcohols
Solid phase catalyst
Regioselectivity
A challenging yet important goal in organic synthesis is to max-
imize synthetic efficiency in transforming starting materials to the
target molecules. Readily available starting materials and reagents,
high yield, high selectivity, mild reaction conditions, and high atom
economy are characteristics of an efficient synthetic method. Prop-
argylic substitution reactions of activated or unactivated propargy-
lic alcohols or propargylic esters with C-nucleophiles and
heteroatom centered nucleophiles have recently been extensively
explored. These reactions are generally achieved through activa-
tion of the acetylene moiety by forming cobalt complexes (Nicho-
las reaction)1 or through the catalysis of rhenium,2 ruthenium,3 or
gold4 metal complexes. However, these reactions suffer from the
high cost of reagents and catalysts. Alternative catalysts, including
FeCl3,5 BiCl3,6 [bmim]PF6/Bi(NO3)3,7 PMA-silica gel,8 I2,9 InCl3,10a
used after activation or even without activation, making the pro-
cess economically viable. Herein, we report simple and
straightforward method using Amberlite IR-120H ion-exchange re-
sin as a catalyst for the nucleophilic substitution of propargylic
alcohols with various nucleophiles in excellent yields under very
mild reactions conditions.
Using 1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-ol (1a) and
indole (2a) as model reactants, it was observed that the reaction
proceeded smoothly in CH3CN at room temperature in the pres-
ence of Amberlite IR-120H resin (Scheme 1). Amberlite IR-120H
a
NH
OH
AmberliteIR-120H resin
+
13
N
InBr3,10b Sc(OTf)3,11 Yb(OTf)3,12 Al(OTf)3, CeCl3,14 Pd-Sn,15 and
CH3CN, rt
Ph
H
MeO
PTSA,16 have been introduced for these reactions; however, many
of them involve either large amount of catalyst or limited to selec-
tive nucleophiles. Thus, highly efficient, inexpensive reaction sys-
tems with good selectivity for these transformations are still
highly desirable.
Heterogeneous catalysis has played a central role in various
organic transformations. Among heterogeneous catalysts,
ion-exchange resins are widely used owing to their low cost, reus-
ability, wide range of acid/base strength, ease of handling, environ-
mental compatibility, and low toxicity. Moreover, they can be
easily recovered from reaction mixtures by filtration and can be re-
Ph
2a
1a
3a
MeO
Scheme 1. Substitution of the OH group in propargylic alcohol with indole.
Table 1
Optimization of the reaction conditionsa
Entry
Amberlite IR-120H
(mg/mmol)
Timeb (min)
Yieldc (%)
1
2
3
50
150
300
120
60
30
45
70
93
a
b
c
All reactions were carried out with 1a (1 mmol), and 2a (1.2 mmol) in CH3CN at rt.
Reaction time before filtration; both 1 and 2 were incomplete.
Isolated yield.
⇑
Corresponding author. Tel.: +1 501 526 6787; fax: +1 501 526 5945.
E-mail address: gzheng@uams.edu (G. Zheng).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.120

S. Gujarathi et al. / Tetrahedron Letters 54 (2013) 3550–3553
3551
Table 2
Amberlite IR-120H resin promoted substitution of the hydroxyl group in propargylic alcohols with various nucleophilesa
Entry
Alcohol
Nucleophile
Productb
Time (min)c
Temperature (°C)
Yield (%)d
OH
NH
N
H
3a
3c
Ph
a
30
rt
93
87
90
MeO
Ph
MeO
OH
NH
N
H
3b
b
c
30
30
60
Ph
Ph
OH
NH
N
H
Ph
rt
MeO
HO
Ph
MeO
HN
Ph
Ph
N
H
3d
d
120
rt
87
OMe
OMe
HO
H
N
Ph
N
H
Ph3e
e
90
rt
87
N
Ts
N
Ts
OH
NH
N
H
3f
Ph
f
180
60
83
F
Ph
F
OH
OH
HO
3g
g
h
i
60
rt
93
90
90
Ph
MeO
Ph
MeO
HO
OH
OH
OH
3h
90
60
60
Ph
Ph
OH
HO
3i
180
Ph
F
Ph
F
OH
O
O
O
O
3j
j
120
rt
90
Ph
MeO
Ph
MeO
(continued on next page)

3552
S. Gujarathi et al. / Tetrahedron Letters 54 (2013) 3550–3553
Table 2 (continued)
Entry
k
Alcohol
Nucleophile
Productb
Time (min)c
Temperature (°C)
Yield (%)d
OH
O
O
O
O
3k
120
60
87
Ph
Ph
O
OH
O
O
O
3l
l
150
180
rt
rt
86
90
Ph
MeO
Ph
MeO
Ph
Ph
O
HO
3m
O
O
O
m
OMe
OMe
HO
MeO
Ph
Ph
3n
n
o
MeOH
180
180
rt
rt
90
83
N
Ts
N
Ts
OH
OH
OH
HO
O
Ph
Ph
MeO
MeO
3o
Ph
MeO
MeO
OH
OMe
Ph
p
180
rt
87
3p
OMe
OH
O
O
NH2
HN
3q
q
r
180
180
60
60
90
87
Ph
Ph
OH
TMS
3r
O
O
O
O
Ph
Ph
a
b
c
All reactions were carried out with alcohol/nucleophile in a molar ration of 1:1.2 in CH3CN in the presence of 300 mg/mmol of Amberlite IR-120H.
Products were characterized by 1H NMR, 13C NMR, and MS.
Time required for complete consumption of propargylic alcohol (monitored by TLC and GC–MS).
Isolated yield.
d
is a gel type, strongly acidic, cation exchange resin of the sulfo-
nated polystyrene type. It has excellent physical, chemical, and
thermal stability and has been used for various organic transfor-
mations.17 The rate of the reaction is correlated with the amount
of resin used. Various quantities of Amberlite IR-120H per mmol
of 1a (mg/mmol) were tested in the reaction (examples listed in
Table 1); with 300 mg/mmol of resin, the reaction completed with-
in 30 min at room temperature to give 3-(1-(4-methoxyphenyl)-3-
phenylprop-2-yn-1-yl)-1H-indole 3a in 93% yield (Table 1, entry
3).
absorption of 3a on the resin. On the other hand, no reaction was
observed when Amberlite IR-120H was replaced by Amberlite
CG-50 or Amberlite IRC-50, likely due to the decreased acidity of
these resins.
The scope of the application of this reaction system was then
investigated. Initially, a variety of propargylic alcohols were trea-
ted with indole (Table 2, entries b and d–f) or 2-methyl indole (Ta-
ble 2, entry c).18 When the p-MeO (entries a and c) on the phenyl
ring at the benzylic position of the propargylic alcohol was re-
moved (entry b) or replaced by an electron-withdrawing group
(fluoro, entry f), elevated temperature (60 °C) was needed for com-
pletion of the reactions. Regardless of the reaction temperature, all
reactions were in excellent yields (Table 2, entries b–f). A variety
While the rate of reaction seemed slightly increased (suggested
by TLC analysis) when increasing the amount of resin, the yield
was decreased, possibly due to decomposition of 3a and/or higher

S. Gujarathi et al. / Tetrahedron Letters 54 (2013) 3550–3553
3553
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4537–4542.
of nucleophiles, including 2-naphthol, 1,3-cyclohexanedione,
acetylacetone, methanol, ethylene glycol, anisole, amide, and
allyltrimethylsilane, were then tested under these reaction condi-
tions. Similarly, electron-donating p-MeO group on the phenyl ring
at the benzylic position of the propargylic alcohol was found to
have beneficial effects on reactivity compared to H atom and elec-
tron-withdrawing F atom on the same position (Table 2, entry g vs
entries h and i; entry j vs entry k). Complete regioselectivity was
observed with nucleophiles containing more than one electron-
rich carbon (2-naphthol, 1,3-cyclohexanedione, acetylacetone,
and anisole). In all cases, C-substitution was on the carbon with
the highest electron density, that is, C-1 for 2-naphthol, C-2 for
1,3-cyclohexanedione and acetylacetone, and C-4 for anisole.
In summary, we have developed a novel, efficient, and general
method for the direct nucleophilic substitution of the hydroxyl
group of propargylic alcohols with various nucleophiles using
Amberlite IR-120H resin as a catalyst. The method features short
reaction times, mild reaction conditions, simplicity in operation,
zero aqueous waste generation, complete regioselectivity, and a
clean reaction profile. Moreover, the resin is inexpensive, stable,
noncorrosive, easy to handle, and potentially reusable.
16. Sanz, R.; Miguel, D.; Mart´ınez, A.; AÄ lvarez-Gutie´rrez, J. M.; Rodrıguez, F. Org.
´
Lett. 2007, 9, 727–730.
17. (a) Madhusudana Reddy, M. B.; Aatika, N.; Pasha, M. A. Chin. J. Catal. 2010, 31,
518–520; (b) Vinod, K. T.; Neetu, T.; Diksha, K.; Rama, P. T. Monatsh. Chem.
2007, 138, 1297–1302; (c) Pasha, M. A.; Aatika, N. J. Saudi Chem. Soc. 2012, 16,
237–240; (d) Neetu, T.; Diksha, K.; Vinod, K. T.; Rama, P. T. Tetrahedron Lett.
2003, 44, 6639–6642; (e) Krstenansky, J. L.; Cotterill, I. Curr. Opin. Drug. Disc.
Dev. 2000, 4, 454–461.
18. General experimental procedure: to a stirred mixture of arylpropargy alcohol 1
(1 mmol) and nucleophile (1.2 mmol) was added Amberlite IR-120H resin
(0.3 g) in acetonitrile (5 mL). The mixture was stirred at rt À60 °C (Table 1) for
an appropriate time. When the reaction was complete (GC and TLC analyses),
the mixture was filtered and evaporated to dryness in vacuo to yield the crude
product, which was purified by silicagel column chromatography (EtOAc-
hexane).
Acknowledgments
The authors would like to thank the College of Pharmacy of Uni-
versity of Arkansas for Medical Sciences for financial support and
Dr. Lin Song for the HRMS and HPLC analyses.
Spectral data for selected products: 3-(1-(4-methoxynaphthalen-1-yl)-3-
phenylprop-2-ynyl)-1H-indole (3d): solid; mp 150–152 °C; 1H NMR
(400 MHz, CDCl3): d 8.33 (bt, 1H), 8.19 (bt, 1H), 7.97 (s, 1H), 7.64 (dd, J = 8.0,
16.0 Hz, 2H), 7.41–7.49 (m, 4H), 7.36 (d, J = 8.0 Hz, 1H), 7.26 (br s, 3H), 7.19 (t,
J = 8.0 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.08
(s, 1H), 4.02 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): d 154.9, 136.7, 131.7,
128.2, 128.1, 127.7, 126.5, 126.4, 126.1, 124.9, 124.0, 123.3, 122.6, 122.2, 119.8,
119.6, 116.6, 111.2, 103.3, 90.7, 55.5, 32.2 ppm; HRMS (ESI): m/z calcd for
References and notes
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C
28H20NO [MÀH] 386.1545; found 386.1563. 3-(1-(1H-indol-3-yl)-3-
phenylprop-2-ynyl)-1-tosyl-1H-indole (3e): solid; mp: 129–131 °C; 1H NMR
(400 MHz, CDCl3): d 8.03 (br s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz,
2H), 7.64 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.49 (br s, 1H), 7.39–7.45
(m, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.24–7.31 (m, 4H), 7.14–7.20 (m, 5H), 7.04 (t,
J = 8.0 Hz, 1H), 5.59 (s, 1H), 2.27 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): d
144.8, 136.7, 135.7, 135.1, 131.7, 129.8, 129.7, 128.2, 128.0, 126.8, 125.9, 124.7,
124.3, 123.3, 123.1, 122.7, 122.3, 120.4, 119.5, 119.4, 114.2, 113.8, 111.4, 88.8,
82.7, 27.0, 21.5 ppm; HRMS (ESI): m/z calcd for C32H23N2O2S [MÀH] 499.1480;
found 499.1496. 1-(1-(4-methoxyphenyl)-3-phenylprop-2-ynyl)naphthalen-
2-ol (3g): solid; mp: 62–64 °C 1H NMR (400 MHz, CDCl3):
d 8.02 (d,
J = 8.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.21–7.45 (m,
9H), 7.13 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.3 Hz, 2H), 6.52 (s, 1H), 6.21 (s, 1H),
3.72 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): d 158.5, 152.2, 132.3, 131.8,
131.5, 129.7, 129.6, 128.8, 128.4, 128.3, 128.2, 126.8, 123.3, 123.0, 122.6, 119.1,
117.7, 114.0, 88.7, 85.7, 55.2, 32.9 ppm; HRMS (ESI): m/z calcd for C26H19O2
[MÀH] 363.1385; found 363.1381. 2-(1-(4-methoxynaphthalen-1-yl)-3-
phenylprop-2-ynyl)cyclohexane-1,3-dione (3m): solid; mp: 87–89 °C; 1H
NMR (400 MHz, CDCl3): d 8.31 (d, J = 8.0 Hz, 1H,), 8.05 (d, J = 8.0 Hz, 1H), 7.71
(d, J = 8.0 Hz, 1H), 7.38–7.59 (m, 5H), 7.24–7.33 (m, 2H), 6.77 (d, J = 8.0 Hz, 1H),
6.21 (s, 1H), 3.99 (s, 3H), 2.39–2.60 (m, 4H), 1.84–2.12 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3): d 196.2, 174.2, 155.5, 131.8, 131.7, 128.4, 128.3, 127.1,
126.7, 126.5, 125.5, 123.8, 123.8, 122.6, 122.6, 115.3, 102.8, 88.5, 88.4, 55.5,
36.5, 29.5, 27.9, 20.4 ppm; HRMS (ESI): m/z calcd for
C
26H21O3 [MÀH]
4. Georgy, M.; Boucard, V.; Campagne, J.-M. J. Am. Chem. Soc. 2005, 127, 14180–
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5. (a) Zhan, Z.-P.; Yu, J.-L.; Liu, H.-J.; Cui, Y.-Y.; Yang, R.-F.; Yang, W.-Z.; Li, J.-P. J.
Org. Chem. 2006, 71, 8298–8301; (b) Peng, S.; Wang, L. J. Org. Biomol. Chem.
2012, 10, 225–228.
381.1490; found 381.1492. N-(1,3-diphenylprop-2-ynyl)-4-methylbenzamide
(3q): solid; mp: 146–148 °C; 1H NMR (100 MHz, CDCl3): d 7.72 (d, J = 8.0 Hz,
2H), 7.64 (d, J = 8.0 Hz, 2H), 7.23–7.48 (m, 8H), 7.21 (d, J = 7.6 Hz, 2H), 6.73 (d,
J = 8.4 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H), 2.38 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): d 166.2, 142.4, 139.2, 131.9, 131.0, 129.3, 128.8, 128.6, 128.4, 128.2,
127.2, 122.5, 87.1, 85.0, 45.6, 21.5 ppm; HRMS (ESI): m/z calcd for C23H18NO
[MÀH] 324.1389; found 324.1372.
6. Zhan, Z.-P.; Yang, W.-Z.; Yang, R.-F.; Yu, J.-L.; Li, J.-P.; Liu, H.-J. Chem. Commun.
2006, 3352–3354.