Molybdenum(V) chloride-catalyzed amidation of secondary benzyl alcohols with sulfonamides and carbamates

Article abstract of DOI:10.1016/j.tetlet.2007.07.204

A general and selective method for the direct amidation of secondary benzyl alcohols with both sulfonamides and carbamates is described. This method has been applied to a variety of substrates and the reaction proceeded smoothly at room temperature in the

Full text of DOI:10.1016/j.tetlet.2007.07.204

Tetrahedron Letters 48 (2007) 7169–7172
Molybdenum(V) chloride-catalyzed amidation of secondary
benzyl alcohols with sulfonamides and carbamatesI
Ch. Raji Reddy,* P. Phani Madhavi and A. Syamprasad Reddy
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 13 June 2007; revised 23 July 2007; accepted 30 July 2007
Available online 2 August 2007
Abstract—A general and selective method for the direct amidation of secondary benzyl alcohols with both sulfonamides and car-
bamates is described. This method has been applied to a variety of substrates and the reaction proceeded smoothly at room tem-
perature in the presence of 5 mol % molybdenum(V) chloride to give the desired products in good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Benzylic amines are of medicinal potential1 and are
found in a number of biologically active compounds
such as sertraline (antidepressant), cetirizine hydrochlo-
ride (histamine H-receptor) and SNC80 (an opioid
receptor agonist).1c–e Literature methods for the synthe-
sis of such compounds include introduction of an amine
via reductive amination of ketones2 or the addition of an
organometallic compound to an imine.3,4 Alternatively,
substitution of a hydroxyl group is also known with
amine nucleophiles, which generally require pre-activa-
tion of the hydroxyl group due to their poor leaving
ability.5 Most of these methods also work equally well
for non-benzylic alcohols. Therefore, the selective and
direct substitution of alcohols with amine nucleophiles
is an attractive goal.
the presence of 5 mol % of molybdenum(V) chloride11
that augments existing methods for the transformations
(Scheme 1).
As a first example, benzylic alcohol 1a was treated with
p-toluenesulfonamide (TsNH2) in the presence of
catalytic molybdenum(V) chloride (5 mol %) in dichlo-
romethane at room temperature to give the correspond-
ing amidated product 2a in 90% yield within 5 h (Table
1, entry 1). The reaction of 1a with benzenesulfonamide
was also successful (Table 1, entry 2). With this success,
we were interested to test the nucleophilic substitution
reaction with benzyl carbamate (CbzNH2). Thus, the
reaction of 1a with CbzNH2 in the presence of
5 mol % MoCl5 in CH2Cl2 proceeded easily to provide
the corresponding Cbz-protected amine 2c in 90% yield
(Table 1, entry 3). Similarly, the catalytic system was
also effective for the amidation of 1a with t-butyl carba-
mate (BocNH2) (Table 1, entry 4). To further explore
this MoCl5-catalyzed direct amidation of benzylic alco-
hols, various substrates were studied and the results are
summarized in Table 1. Benzylic alcohols such as benz-
hydrol 1b and 1-phenylethanol 1c were reacted with
both p-toluenesulfonamide and benzyl carbamate under
the described reaction conditions to provide the corre-
sponding amide products 2e–h in good yields (Table 1,
In recent years, benzylic alcohols and their derivatives
have received considerable attention as carbon electro-
philes capable of reacting with various carbon, oxygen
and sulfur nucleophiles.6 To the best of our knowledge
there is a very limited number of examples known with
less nucleophilic nitrogen nucleophiles such as sulfona-
mides and carbamates. The catalysts/reagents employed
for these examples are NaAuCl4,7 H–montmorillonite,8
9
Bi(OTf)3/KPF6 amongst others.6a,10 Herein we report
a simple procedure for the direct amidation of secondary
benzylic alcohols with sulfonamides or carbamates in
OH
NH-X
R
X-NH2
R
Keywords: Molybdenum(V) chloride; Amidation; Benzyl alcohol;
Sulfonamide; Carbamate.
MoCl5 (5 mol%)
CH2Cl2, rt
q IICT Communication No. 070607.
R= alkyl or aryl or alkynyl; X= PhSO2 or Ts or Cbz or Boc
*
Corresponding author. Tel.: +91 40 27193128; fax: +91 40
27160512; e-mail: rajireddy@iict.res.in
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.204

7170
Ch. R. Reddy et al. / Tetrahedron Letters 48 (2007) 7169–7172
Table 1. MoCl5-catalyzed amidation of secondary benzyl alcohols
Entry
1
Benzyl alcohol
Carbamate/sulfonamide
TsNH2
Reaction time (h)
5
Producta
Yieldb (%)
90
NHTs
OH
2a
NHSO2Ph
2b
1a
MeO
MeO
2
3
4
5
6
7
1a
PhSO2NH2
CbzNH2
BocNH2
TsNH2
6
88
90
85
84
89
82
MeO
MeO
MeO
NHCbz
1a
5
2c
NHBoc
1a
8
2d
OH
NHTs
10
12
10
2e
1b
NHCbz
NHTs
1b
CbzNH2
TsNH2
2f
OH
2g
1c
NHCbz
NHTs
8
9
1c
CbzNH2
TsNH2
8
84
70
2h
OH
2i
12
Cl
Cl
Cl
1d
Cl
NHCbz
2j
10
11
1d
CbzNH2
TMSN3
10
72
92
Cl
Cl
OH
N3
4
2k
2l
1b
OH
NHTs
12
13
TsNH2
TsNH2
24
24
0c
0c
1e
OH
NHTs
2m
1f
a All the products were characterized by 1H, 13C NMR and mass spectra.
b Isolated yields.
c No reaction either at room temperature or at 40 °C.
entries 5–8). Entries 9 and 10 (Table 1) demonstrate
the conversion of alcohol 1d to sertraline derivatives 2i
and 2j. In addition, we observed that the reaction of
benzhydrol with azidotrimethylsilane (TMSN3) was also
successful furnishing the corresponding azide 2k in 92%
yield (Table 1, entry 11). However, the reaction of pri-

Ch. R. Reddy et al. / Tetrahedron Letters 48 (2007) 7169–7172
7171
mary benzyl alcohol 1e or non-benzylic alcohol 1f with
p-toluenesulfonamide was unsuccessful (Table 1, entries
12 and 13).
hols generated from aromatic aldehydes, and not with
the propargyl alcohols generated from aliphatic alde-
hydes. This may be due to the benzylic nature of the for-
mer alcohols.13
Next, we sought to extend this methodology to the di-
rect amidation of propargyl alcohols an important
transformation.6b,c,9,12 Accordingly, the reaction of
propargylic alcohol 3a with sulfonamides and carba-
mates, namely, TsNH2, PhSO2NH2, CbzNH2 and
BocNH2 in the presence of MoCl5 (5 mol %) gave the
corresponding amide derivatives 4a–d in good yields
(Table 2, entries 1–4). Similarly, propargylic substrates
3b and 3c also underwent facile nucleophilic substitution
with TsNH2 and CbzNH2 (Table 2, entries 5–8). How-
ever, the reaction of propargylic alcohol 3d with p-tolu-
enesulfonamide failed to give the desired product 4i after
24 h at room temperature or at 40 °C (Table 2, entry 9).
The results from the above reactions clearly demonstrate
that the direct amidation with sulfonamides or carba-
mates was successful only in the case of propargyl alco-
As described above, molybdenum(V) chloride (5 mol %)
in CH2Cl2 presents itself as an effective catalyst for the
direct amidation of benzylic alcohols with sulfonamides
and carbamates. In addition to good yields, mild reac-
tion conditions and an operational simplicity makes this
newly developed method of broad synthetic utility.
General experimental procedure: To a stirred solution of
benzylic alcohol (1 mmol) in dichloromethane (5 mL)
was added sulfonamide or carbamate (1 mmol) and
5 mol % MoCl5. The reaction mixture was stirred at
room temperature and the reaction progress was moni-
tored by TLC analysis. After the reaction was complete
(for reaction time, see Tables 1 and 2), the mixture was
evaporated in vacuo. The residue was purified by
Table 2. MoCl5-catalyzed amidation of secondary benzyl/propargyl alcohols
Entry
Benzyl alcohol
Carbamate/sulfonamide
Reaction time (h)
Producta
NHTs
Yieldb (%)
88
OH
1
TsNH2
8
3a
4a
NHSO2Ph
NHCbz
2
3
3a
PhSO2NH2
CbzNH2
10
8
86
85
4b
4c
3a
NHBoc
4
3a
BocNH2
12
82
4d
OH
NHSO2Ph
5
6
PhSO2NH2
TsNH2
10
7
86
89
F
F
F
3b
4e
4f
NHTs
3b
NHCbz
7
8
9
3b
CbzNH2
CbzNH2
TsNH2
9
87
78
0c
F
4g
OH
NHCbz
8
4h
4
4
MeO
MeO
3c
OH
OH
24
4
4
4i
3d
a All the products were characterized by 1H, 13C NMR and mass spectra.
b Isolated yields.
c No reaction either at room temperature or at 40 °C.

7172
Ch. R. Reddy et al. / Tetrahedron Letters 48 (2007) 7169–7172
10. (a) Garcia, A.; Castedo, L.; Dominguez, D. Synlett 1993,
271–272; (b) Tillack, A.; Hollmann, D.; Michalik, D.;
Beller, M. Tetrahedron Lett. 2006, 47, 8881–8883.
11. Molybdenum pentachloride is a widely available and
inexpensive reagent, which is not fully explored as a Lewis
acid catalyst. For examples of C–C bond forming
reactions using MoCl5, see: (a) Kramer, B.; Waldvogel,
S. R. Angew. Chem., Int. Ed. 2004, 43, 2446–2449; (b)
Kramer, B.; Frohlich, R.; Waldvogel, S. R. Eur. J. Org.
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Huang, D.; Holman, T. R.; Toste, F. D. Org. Lett. 2005,
7, 2501–2504.
column chromatography on silica gel using ethyl acetate
and hexanes as eluent to give the corresponding
amidated products.14
Acknowledgements
C.R.R. thanks Dr. J. S. Yadav, Director, IICT, for his
support and is grateful to Dr. S. Chandrasekhar for
his encouragement and useful discussions. P.P.M. and
A.S.R. thank the CSIR, New Delhi, for financial
assistance.
References and notes
13. A close look at the literature reveals the fact that, the
hydroxyl substrates, which successfully participated
were also flanked on one side by a phenyl group
and on the other side with an acetylenic group. See
Refs. 6a,c,9,13.
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P. M. J. Comb. Chem. 2005, 7, 99–108.
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2006, 128, 9998–9999; (b) Nishimura, T.; Yasuhara, Y.;
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Vasse, J.-L.; Szymoniak, J. Synthesis 2005, 2075–2079; (d)
Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.;
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14. Spectral data for representative new products; (2a): 1H
NMR (CDCl3, 300 MHz): d 7.53 (d, J = 8.3 Hz, 2H), 7.1
(d, J = 8.3 Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.61 (d,
J = 8.3 Hz, 2H), 5.57–5.43 (m, 1H), 5.04–4.96 (m, 2H),
4.27 (dd, J = 6.8, 13.6 Hz, 1H), 3.71 (s, 3H), 2.51–2.39 (m,
2H), 2.37 (s, 3H); 13C NMR (75 MHz, CDCl3): d 159.0,
143.1, 137.7, 133.4, 132.6, 129.4 (2C), 127.9 (2C), 127.3
(2C), 119.1, 113.8 (2C), 56.9, 55.3, 42.0, 21.6; HRMS (ESI)
calcd for C18H21NO3SNa: 354.1139 [M+Na]+, found:
1
354.1153 [M+Na]+. Compound 2b: H NMR (300 MHz,
CDCl3): d 7.64 (d, J = 7.55 Hz, 2H), 7.45–7.4 (m, 1H),
7.34–7.28 (m, 2H), 6.92 (d, J = 8.3 Hz, 2H), 6.61 (d,
J = 8.3 Hz, 2H), 5.58–5.44 (m,1H), 5.3 (d, J = 6.79 Hz,
1H), 5.04 (d, J = 6.04 Hz, 1H), 4.99 (s, 1H), 4.31 (dd,
J = 7.55, 14.35 Hz, 1H), 3.71 (s, 3H), 2.51–2.35 (m, 2H);
13C NMR (75 MHz, CDCl3): d 159.1, 140.7, 133.4, 132.5
(2C), 128.9 (2C), 127.9 (2C), 127.3 (2C), 119.4, 113.9 (2C),
56.9, 55.4, 42.0; HRMS (ESI) calcd for C17H19NO3SNa:
340.0983 [M+Na]+, found: 340.0984 [M+Na]+. Com-
1
pound 2c: H NMR (300 MHz, CDCl3): d 7.33–7.21 (m,
5H), 7.13 (d, J = 8.3 Hz, 2H), 6.78 (d, J = 8.3 Hz, 2H),
5.71–5.56 (m, 1H), 5.12–5.0 (m, 4H), 4.69 (br s, 1H), 3.75
(s, 3H), 2.54–2.44 (m, 2H); 13C NMR (75 MHz, CDCl3): d
158.0, 155.8, 136.6, 134.2, 134.0, 128.6 (2C), 128.3 (3C),
127.6 (2C), 118.5, 114.1 (2C), 66.9, 55.4, 54.2, 41.2; HRMS
(ESI) calcd for C19H21NO3Na: 334.1419 [M+Na]+, found:
4. For alternative methods see: (a) Lebel, H.; Huard, K. Org.
Lett. 2007, 9, 639–642; (b) Pelletier, G.; Powell, D. A. Org.
Lett. 2006, 8, 6031–6034; (c) Bensal, N.; Pevere, V.;
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Lett. 1999, 40, 879–882; (d) Kim, S. Y.; Yoon, N. M. Bull.
Korean. Chem. Soc. 1998, 19, 891–893.
1
334.1411 [M+Na]+. Compound 2d: H NMR (200 MHz,
CDCl3): d 7.15 (d, J = 9.14 Hz, 2H), 6.80 (d, J = 8.3 Hz,
2H), 5.78–5.53 (m, 1H), 5.16–4.98 (m, 2H), 4.90–4.73 (m,
1H), 4.70–4.53 (m, 1H), 3.78 (s, 3H), 2.49 (br t, J =
5.81 Hz, 2H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3):
d 158.8, 155.0, 134.5, 134.3, 127.5 (2C), 118.2, 114.0 (2C),
79.6, 55.4, 55.3, 41.4, 28.5 (3C); HRMS (ESI) calcd for
C16H23NO3Na: 300.1575 [M+Na]+, found: 300.1574
5. Mayr, H.; Gorath, G.; Bauer, B. Angew. Chem., Int. Ed.
Engl. 1994, 33, 788–789.
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1
[M+Na]+. Compound 4c: H NMR (200 MHz, CDCl3):
d 7.53 (d, J = 6.59 Hz, 2H), 7.46–7.39 (m, 3H), 7.35–7.24
(m, 10H), 5.91 (d,J = 8.7 Hz, 1H), 5.28 (br d, J = 7.8 Hz,
1H), 5.12 (s, 2H); 13C NMR (75 MHz, CDCl3): d 155.5,
139.4, 136.3, 131.9 (2C), 128.9 (2C), 128.7, 128.7 (2C),
128.5, 128.4 (2C), 128.3 (2C), 127.1 (3C), 122.5, 87.1, 85.2,
67.3, 47.6; HRMS (ESI) calcd for C23H19NO2Na:
364.1313 [M+Na]+, found: 364.1308 [M+Na]+. Com-
1
pound 4d: H NMR (300 MHz, CDCl3): d 7.68–7.19 (m,
7. Terrasson, V.; Marque, S.; Georgy, M.; Campagne, J.-M.;
Prim, D. Adv. Synth. Catal. 2006, 348, 2063–2067.
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4617–4620.
10H), 5.85 (br d, J = 8.3 Hz, 1H), 5.01 (br d, J = 7.55 Hz,
1H), 1.47 (s, 9H); 13C NMR (75 MHz, CDCl3): d 154.9,
139.7, 131.9 (2C), 128.8 (2C), 128.6, 128.4 (2C), 128.1,
127.1 (2C), 122.7, 87.6, 84.9, 80.3, 47.0, 28.5 (3C); HRMS
(ESI) calcd for C20H21NO2Na: 330.1469 [M+Na]+, found:
330.1474 [M+Na]+.
9. Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M.
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