An efficient FeCl3-catalyzed amidation reaction of secondary benzylic and allylic alcohols with carboxamides or p-toluenesulfonamide

Article abstract of DOI:10.1016/j.tetlet.2007.11.176

A simple, inexpensive, environmentally friendly and high yielding amidation reaction of benzylic and allylic alcohols with primary amides using a catalytic amount of FeCl₃ (5 mol %) is described. Direct substitution of various amides such as be

Full text of DOI:10.1016/j.tetlet.2007.11.176

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 858–862
An efficient FeCl3-catalyzed amidation reaction of secondary benzylic
and allylic alcohols with carboxamides or p-toluenesulfonamide
Umasish Jana *, Sukhendu Maiti, Srijit Biswas
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
Received 19 September 2007; revised 21 November 2007; accepted 28 November 2007
Available online 4 December 2007
Abstract
A simple, inexpensive, environmentally friendly and high yielding amidation reaction of benzylic and allylic alcohols with primary
amides using a catalytic amount of FeCl3 (5 mol %) is described. Direct substitution of various amides such as benzamide, sulfonamide,
acetamide and acrylamide is reported, and this method also works on a large scale in high yield.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Ferric chloride; Amidation reactions; Alcohols; Atom-economical; Inexpensive
C–N bond formation is an important reaction in organic
synthesis. Hence, the development of simple, efficient and
environmentally friendly C–N bond forming reactions is
of paramount importance in organic synthesis. Among
the various methods for the construction of C–N bonds,1
transition metal catalyzed substitution reactions of deriva-
tives of alcohols with nitrogen nucleophiles such as amines/
amides is one of the most efficient and reliable methods.2
However, these methods produce stoichiometric amounts
of salt waste both in derivatization of the alcohols and
the C–N bond formation steps. Thus, in view of the
demand for efficient, economic and environmentally viable
processes for the direct catalytic substitution of alcohols3
with nitrogen nucleophiles, a method for the formation
of C–N bonds, which is salt-free, highly atom-economic,4
environmentally friendly with water as the only byproduct
is highly desirable. Although a number of C–N bond form-
ing reactions by direct substitution of alcohols with amines
catalyzed by transition metals have been reported,5 the use
of weak nitrogen nucleophiles such as amides which are
easily available are extremely rare and require high temper-
atures.6 Moreover, amide-containing compounds are very
useful in organic synthesis and in biology.7
To our knowledge, only a few Lewis acid catalyzed ami-
dation reactions of alcohols with primary amides have been
described in the literature using NaAuCl4,8a H–Montmoril-
8c
3a
lonite,8b MoCl5 and a combination of Bi(OTf)3 with
KPF6 as additive. However, the use of expensive and toxic
catalysts limit the practical utility of these methods in the
large scale synthesis of differently substituted benzylic
and allylic amides, despite the importance of the corres-
ponding benzylic and allylic amines in fine chemicals and
pharmaceutical industries.9 Furthermore, the substrate
generality is limited. Therefore, development of a more
practical and economical method for direct substitution
of primary amides with benzylic or allylic alcohols is highly
desirable for the synthesis of such compounds.
Recently, we reported two very efficient methods for the
direct catalytic substitution of alcohols with various nucleo-
philes using the inexpensive and environmentally friendly
Lewis acid FeCl3.10 Herein, we report the FeCl3-catalyzed
direct substitution of benzylic and allylic alcohols with var-
ious carboxamides or p-toluenesulfonamide (Scheme 1).
To establish the reaction conditions we initially exam-
ined C–N bond formation between benzyl amide 2 and
benzhydrol 1 in the presence of FeCl3.11 The reaction
*
Corresponding author. Tel.: +91 33 2414 6223; fax: +91 33 2414 6584.
E-mail address: jumasish2004@yahoo.co.in (U. Jana).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.176

U. Jana et al. / Tetrahedron Letters 49 (2008) 858–862
859
NH-R2
R1
proceeded in the presence of a catalytic amount of FeCl3
(5 mol %) in nitromethane under reflux and the desired
substituted amide 3a was obtained in 98% yield, without
the removal of moisture and air. We investigated this reac-
tion with several solvents including acetonitrile, tetrahydro-
furan, dichloroethane, nitromethane and methylene
chloride; however, the reaction did not proceed in methyl-
ene chloride and tetrahydrofuran even under refluxing
OH
R1
FeCl3 (5 mol%)
CH3NO2
R2-NH2
H2O
+
+
2
1
3
R1 = alkyl, aryl or allyl
2 = PhCO, Ts, CH3CO or CH2=CHCO
R
Scheme 1. FeCl3-catalyzed amidation of benzylic/allylic alcohols.
Table 1
FeCl3-catalyzed substitution of various alcohols 2 with amides 1a
Entry
Nucleophile
Alcohol
Product
Time (h)
1
Temp (°C)
Yieldb (%)
98
OH
Ph
O
O
Ph
Ph
1
Reflux
NH
NH
NH2
3a
1a
2a
O
OH
Ph
2
3
4
1a
1
2
3
Reflux
Reflux
rt
98
55
85
MeO
3b
2b
OMe
O
OH
Me
Me
Me
NH
NH
1a
1a
2c
3c
O
OH
Me
MeO
3d
O
2d
OMe
OH
Me
NH
NH
Me
5
1a
1a
3
Reflux
65
3e
Cl
2e
Cl
O
OH
Me
Me
S
6
7
1
2
80
56
98
S
3f
2f
Ph
Ph
SO2NH2
SO2NH
2a
2b
Reflux
1b
3g
SO2NH
8
1b
1
Reflux
82
3i
OMe
(continued on next page)

860
U. Jana et al. / Tetrahedron Letters 49 (2008) 858–862
Table 1 (continued)
Entry
Nucleophile
Alcohol
Product
Time (h)
Temp (°C)
Yieldb (%)
84
Me
Me
9
1b
2c
1
Reflux
SO2NH
3j
SO2NH
10
1b
2d
1
rt
84
96
94
85
3k
OMe
Me
SO2NH
11
12
1b
2e
2a
2a
2
4
3
Reflux
Reflux
Reflux
3l
Cl
O
O
HN
Ph
NH2
1c
3m
O
NH2
HN
13
O
Ph
1d
3n
a
Reaction condition: nucleophile 1 (1 mmol), alcohol 2 (1 mmol), FeCl3 (0.5 mmol), nitromethane (3.5 mL).
The yield refers to pure isolated product characterized from spectral data.
b
conditions. The reactions did proceed in dichloroethane
was highly efficient for secondary benzylic alcohols, benzyl
alcohol itself did not react under these conditions even on
prolonged heating. In all cases, selective monosubstitution
of the amide occurred even when using excess alcohols. We
also investigated this reaction on a large scale (5.43 mmol)
synthesis of 3a, which afforded the product in a similar 97%
yield.11
and acetonitrile at reflux, but they were very sluggish. The
best results were achieved using nitromethane in terms of
time and yields.
Encouraged by these initial results, we next investigated
the amidation reactions of a number of amides including
benzamide, p-toluenesulfonamide, acetamide and acrylamide
with several structurally diverse benzylic alcohols. The
results are summarized in Table 1. In general, the reactions
proceeded efficiently with various substituted secondary
benzylic alcohols and primary amides in very good to
excellent yields within very short period of time. The pres-
ent method was equally effective for benzylic alcohols bear-
ing electron-donating and weak electron-withdrawing
groups such as methoxy and chloride (Table 1, entries 2,
4, 5, 8, 9 and 11). Aliphatic primary amides such as acryl-
amide and acetamide also underwent smooth amidation
with benzhydrol 2a and gave the desired products in 85%
and 94% yields, respectively (Table 1, entries 12 and 13),
which have not been reported previously by other meth-
ods.8 Furthermore, this reaction was also applied to thio-
phene derivative 2f (Table 1, entry 6), but a slightly lower
yield of product was obtained. Various functional groups
such as methoxy, chloride, tosyl, acetyl, benzoyl and acryl
tolerated the reaction conditions. Although this reaction
To extend the scope of this methodology, the direct sub-
stitution of structurally varied allylic alcohols with amides
was investigated. All the reactions proceeded smoothly in
the presence of 5 mol % FeCl3 in nitromethane at room
temperature (Table 2) in good yields with complete selec-
tivity within a short period of time. Amide 1a reacted under
similar reaction conditions with two regio-isomeric allylic
alcohols 4b and 4c and furnished the single product 5b
regioselectively in good yield (Table 2, entries 2 and 3).
This clearly reflects the formation of the same, delocalized
allylic cation intermediate from each of the alcohols,
followed by nucleophilic attack by the amide to produce
product 5b (SN1 mechanism involved). Both steric and elec-
tronic factors are responsible for the regioselective forma-
tion of 5b. Similar regioselectivity was also observed in
the reactions of p-toluenesulfonamide with alcohols 4b
and 4c to afford the corresponding aminated product 5e
in good yields (Table 2, entries 6 and 7). So, the present

U. Jana et al. / Tetrahedron Letters 49 (2008) 858–862
861
Table 2
FeCl3-catalyzed substitution of various allylic alcohols 4 with amides 1a
Entry
Nucleophile
Alcohol
Product
Time (h)
2
Temp (°C)
Yieldb (%)
85
O
OH
Ph
O
1
rt
NH
NH
NH2
Ph
Ph
1a
4a
5a
O
HO
Ph
2
3
4
5
6
1a
1.5
rt
rt
rt
rt
rt
68c
48c
50c
60
4b
5b
OH
1a
1a
5b
3
4c
O
HO
NH
Ph
3
Cl
Cl
4d
5c
NHTs
Ph
SO2NH2
4a
4b
2
1b
5d
NHTs
1b
1b
1
65c
5e
7
8
4c
4a
5e
2.5
3
rt
rt
80
76
O
O
NH
Ph
O
NH2
1c
1d
5f
NH
Ph
O
9
4a
3
rt
67
NH2
5g
a
Reaction conditions: nucleophile 1 (1 mmol), alcohol 2 (1 mmol), FeCl3 (0.5 mmol), nitromethane (3.5 mL) and the product was extracted with ethyl
acetate.
b
The yield refers to pure isolated product characterized from spectral data.
The reaction was performed using 1.5 equiv of amide.
c
method is also useful for the synthesis of structurally varied
allylic amides.
mechanism is uncertain at this moment, we have observed
that the benzylic alcohols were first converted to the corres-
ponding dimeric ether (catalyzed by FeCl3) and then acti-
vated by the Lewis acid to produce the final product by
nucleophilic substitution with the amide. Formation of
an ether was not observed for allylic ethers. However,
experimental observation can only be explained by consid-
ering the SN1 mechanism operating for allylic alcohols.
Further investigation on the reaction mechanism and the
Thus, we have demonstrated a simple FeCl3-catalyzed
direct amidation of benzylic and allylic alcohols with struc-
turally varied primary amides under neutral reaction con-
ditions in the presence of air and moisture. A thiophene
system survived under these reaction conditions. No side
products were isolated in any of the reactions. The reaction
did not proceed at all without FeCl3. Although the exact

862
U. Jana et al. / Tetrahedron Letters 49 (2008) 858–862
7. (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317,
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scope of this reaction are currently underway in our
laboratory.
The notable advantages of this method are the opera-
tional simplicity, direct use of alcohols and inexpensive
and non-toxic FeCl3 catalyst (5 mol %) which render this
method an important alternative to previously reported
methods. Moreover, this method can also be useful for
the large scale synthesis of benzylic and allylic amide
derivatives.
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Acknowledgements
We are pleased to acknowledge the financial support
from Jadavpur University. S.B. is also thankful to UGC,
New Delhi, India for his fellowship.
10. Direct substitution of alcohols, see: (a) Jana, U.; Biswas, S.; Maiti, S.
Tetrahedron Lett. 2007, 48, 4065–4069; (b) Jana, U.; Maiti, S.; Biswas,
S. Tetrahedron Lett. 2007, 48, 7160–7163.
11. Representative experimental procedure: To
a stirred solution of
References and notes
benzamide 1a (128 mg, 1 mmol) and benzhydrol 2a (185 mg, 1 mmol)
in dry nitromethane (3.5 mL) was added anhydrous FeCl3 (8 mg,
0.05 mmol). The resulting reaction mixture was refluxed for 1 h. The
reaction mixture was then concentrated under reduced pressure and
loaded onto a silica gel column and chromatographed with petroleum
ether/ ethyl acetate (4:1) to afford product 3a (282 mg, 0.98 mmol,
98%) as a white solid, mp 170 °C (lit.12 170 °C); 1H NMR (300 MHz,
CDCl3) d 6.46 (d, J = 7.7 Hz, 1H), 6.68 (br s, 1H), 7.26–7.55 (m,
13H), 7.83 (d, J = 7.5 Hz, 2H).
Large scale synthesis of 3a: A mixture of 1a (1.00 g, 5.43 mmol), 2a
(658 mg, 5.43 mmol) and FeCl3 (44 mg, 0.27 mmol) in nitromethane
(6 mL) was refluxed for 1.5 h. Usual work-up and purification
afforded a white solid 3a (1.51 g, 5.27 mmol, 97%). Spectral data for
new compounds are given below:
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15173.
N-(4-Chlorophenylbut-3-en-2yl)benzamide (5c): White solid, mp
;
140 °C; IR (KBr) 3302, 1636, 1526 cmÀ1 1H NMR (300 MHz,
CDCl3) d 1.45 (d, J = 3.3 Hz, 3H), 4.95–5.00 (m, 1H), 6.11 (br s, 1H),
6.25 (dd, J = 16.0, 5.3 Hz, 1H), 6.54 (d, J = 16.0 Hz, 1H), 7.26–7.32
(m, 4H), 7.43–7.54 (m, 3H), 7.80 (d, J = 7.5 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 20.8, 47.0, 127.0, 127.8, 128.7, 128.8, 128.9, 131.7,
133.4, 134.7, 135.3, 166.8; HRMS: m/z calcd for C17H16ClNONa:
308.0818; found, 308.0776.
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N-(1,3-Diphenylprop-2-en-1-yl)acrylamide (5g): White solid, mp
123 °C; IR (KBr) 3238, 3055, 1656, 1614, 1547; 1H NMR
(300 MHz, CDCl3) d 5.70 (d, J = 11 Hz, 1H), 5.88–5.96 (m, 2H),
6.11–6.21 (m, 1H), 6.33–6.41 (m, 2H), 6.57 (d, J = 16, 1H), 7.22–7.38
(m, 10H); 13C NMR (75 MHz, CDCl3) d 55.0, 126.7, 127.3, 127.4,
127.9, 128.7, 129.0, 130.7, 131.7, 136.5, 140.8, 164.7; MS m/z: calcd
for C18H17NONa, 286.1208; found, 286.0687.
6. Pd-catalyzed allylation of amides at high temperature, see: (a) Qu, Y.;
¨
Ishimura, Y.; Nagato, N. Nippon Kagaku Kaishi 1996, 256–259;
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