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472
Chemistry Letters Vol.36, No.12 (2007)
Heteropoly Acid-catalyzed Direct Substitution of 2-Propynyl Alcohols with Sulfonamides
Ã
J. S. Yadav, B. V. Subba Reddy, T. Srinivasa Rao, B. Bala. M. Krishna, and G. G. K. S. Narayana Kumar
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received August 23, 2007; CL-070904; E-mail: yadavpub@iict.res.in)
OH
Direct substitution of the hydroxy group in 2-propynyl
NHTs
alcohols with sulfonamides has been achieved using 5 mol %
of phosphomolybdic acid supported on silica gel (PMA/SiO2)
under mild reaction conditions to produce 2-propynyl amides
in excellent yields and with high selectivity.
5 mol % PMA/SiO
DCE, r.t.
2
+
Ts NH2
3A
Scheme 1.
NHSO Ph
OH
2
Aryl amines are found in a number of drug molecules such
as cetirizine hydrochloride (histamine H1-receptor), SNC80 (an
5 mol % PMA/SiO2
DCE, r.t.
+
2 2
PhSO NH
1
,2
opioid receptor agonist) and sertraline (anti-depressant). The
nucleophilic substitution of alcohols by amines is one of the
direct and most important methods for carbon–nitrogen bond
formation. However, the catalytic activation of alcohols is
difficult due to the poor leaving ability of the hydroxy group.
Consequently, hydroxy groups are generally transformed into
the corresponding halides, carboxylates, carbonates, phospho-
3N
Scheme 2.
NHTs
CH
OH
CH
5
mol % PMA/SiO
2
3
3
+ Ts NH2
DCE, r.t.
3
3O
nates, or related compounds. However, such processes inevita-
bly produce stoichiometric amounts of salt waste and also substi-
tution with halides requires a stoichiometric amount of base
which limits their use in large scale synthesis. Therefore, the
development of catalytic methods for the synthesis of amines
Scheme 3.
pynyl alcohols. Interestingly, various 2-propynyl alcohols such
as 1-(2,5-dimethoxyphenyl)-3-phenyl-2-propyn-1-ol, 1-(2-naph-
thyl)-2-nonyn-1-ol, 1-(4-nitrophenyl)-2-nonyn-1-ol, and 3-phen-
yl-1-(2-thienyl)-2-propyn-1-ol reacted readily with sulfon-
amides to provide the corresponding propargylic amides in
excellent yields (Entries B–L, Table 1). In addition, doubly
activated (E)-1,5-diphenyl-1-penten-4-yn-3-ol underwent facile
nucleophilic substitution with sulfonamides to furnish the
respective 2-propynyl amide (Entries M and N, Scheme 2,
Table 1).
The 2-propynyl alcohols reacted regioselectively at the 2-
propynyl position. No allenic products were detected as a result
of amide attack at the triple bond. Interestingly, allyl alcohols al-
so reacted rapidly with TsNH2 at room temperature to afford the
corresponding allylic amides (Entries O and P, Scheme 3,
Table 1).
In cases of allyl alcohols (Entries M–P, Table 1), no allylic
rearrangement was observed which was confirmed by NMR
spectrum of the crude product. Furthermore, secondary cyclic
sulfonamide, saccharin also reacted easily with 2-propynyl alco-
hol (Entry D, Table 1). Other sulfonamides such as methanesul-
fonamide and benzenesulfonamide were also effective substrates
for this conversion. However, carbamates and carboxamides
were not so effective coupling partners for this reaction. In all
cases, the reactions proceeded in excellent yields with high se-
lectivity and were complete within 4.0–8.0 h. In the absence of
PMA/SiO2, no reaction was observed. This method is compati-
ble with alkene, alkyne, ester, nitro, and ether functionalities. To
know the effect of the solvent, the reaction was carried out in
various solvents such as dichloroethane, acetonitrile, tetrahydro-
furan, and ethanol. However, dichloroethane was the solvent of
choice. The effects of various silica supported acid catalysts such
as HClO4/SiO2, H2SO4/SiO2, and NaHSO4/SiO2 were tested
4
,5
continues to be a challenging and active area of research.
However, little has been explored on nucleophilic substitution
6
,7
of 2-propynyl alcohols with amides. In most cases, either a
high reaction temperature or a promoter is required to enhance
the leaving ability of the hydroxy group. Thus, the direct catalyt-
ic substitution of alcohols with amides using an efficient, cost-
effective, and recyclable catalyst is highly desirable.
Recently, the use of heteropoly acids, HPAs, as environmen-
tally friendly and economically viable solid acids, is increasing
continuously owing to their ease of handling, high catalytic ac-
8
tivities, and reactivities. These compounds possess unique
properties, such as well-defined structure, Brønsted acidity, pos-
sibility to modify their acid–base and redox properties by chang-
ing their chemical composition (substituted HPAs), ability to ac-
9
cept and release electrons, high proton mobility, etc. In view of
green chemistry, the substitution of harmful liquid acids by reus-
able solid HPAs as catalysts in organic synthesis is the most
1
0
promising application of these acids. Among them, phospho-
molybdic acid (PMA, H3PMo12O40) is one of the less expensive
1
1
and commercially available catalysts.
In continuation of our efforts to explore the synthetic utility
1
2
of phosphomolybdic acid supported on silica gel (PMA–SiO2),
we herein report a direct and efficient nucleophilic substitution
of 2-propynyl alcohols with sulfonamides. Initially, we attempt-
ed the amidation of 1,3-diphenyl-2-propyn-1-ol (1) with TsNH2
(2) in the presence of 5 mol % of PMA/SiO2. The reaction went
to completion at room temperature over 6.0 h to give the product,
N-(1,3-diphenyl-2-propynyl)-4-methyl-1-benzenesulfonamide
(3A) in 86% yield (Scheme 1).
This remarkable catalytic activity of PMA/SiO2 provided
the incentive for further study of reactions with different 2-pro-
Copyright Ó 2007 The Chemical Society of Japan
Yadav
