Acid-catalyzed N-alkylation of tosylhydrazones using benzylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2009.07.093

N-Alkylation of tosylhydrazones in the presence of an acid catalyst is described for the first time. Tris(pentafluorophenyl) borane was found to be a mild and efficient catalyst when benzylic alcohols were used as the alkylating agents.

Full text of DOI:10.1016/j.tetlet.2009.07.093

Tetrahedron Letters 50 (2009) 5633–5635
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Tetrahedron Letters
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Acid-catalyzed N-alkylation of tosylhydrazones using benzylic alcohols
*
Ch. Raji Reddy , E. Jithender
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Alkylation of tosylhydrazones in the presence of an acid catalyst is described for the first time.
Tris(pentafluorophenyl) borane was found to be a mild and efficient catalyst when benzylic alcohols were
used as the alkylating agents.
Received 15 June 2009
Revised 14 July 2009
Accepted 17 July 2009
Available online 22 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
N-alkylation
Acid catalysis
Tosylhydrazones
Benzylic alcohols
Tris(pentafluorophenyl) borane
Ar1
N
R
In continuation of our earlier work in the alkylation of various
compounds such as sulfonamides1 and coumarins2 under acid
catalysis using benzylic alcohols, we were interested in exploring
the N-alkylation of tosylhydrazones. A careful literature survey re-
vealed that there is no precedent for the acid-catalyzed N-alkyl-
ation of tosylhydrazones. Commonly, N-alkylation is achieved
using alkyl halide/base3 and in the presence of phase transfer cat-
alyst.4 Recently, N-alkylation of tosylhydrazones was achieved
using alcohols under Mitsunobu reaction conditions (DEAD/
Ph3P).5 Furthermore, these N-alkylated hydrazones have various
applications in organic synthesis as useful synthons.6 Reductive
deoxygenation of alcohols can also be achieved via N-alkylation
of hydrazones.7 Thus, the development of new methods for N-
alkylation of tosylhydrazones is of significance.
OH
B(C6F5)3 (5 mol%)
CH2Cl2, rt
H
+
N
Ar1
R
Ar
N
Ts
N
Ar
Ts
Ar = aryl
Ar1 = aryl; R
= aryl, alkyl, H
Scheme 1. N-alkylation of tosylhydrazones.
Table 1
Acid-catalyzed N-alkylation of tosyl hydrazone 1a with alcohol 2a using acid catalysts
Entry
Acid (5 mol %)
Conditions
Time (h)
Yielda (%)
1
2
3
4
p-TSA
p-TSA
CH2Cl2/rt
CH2Cl2/reflux
CH2Cl2/rt
CH2Cl2/rt
CH2Cl2/rt
30
24
20
24
24
24
20
45
48
90
46
44
0b
B(C6F5)3
BF3Et2O
ZnCl2
PS-pTSA
PS-pTSA
In the light of above comments, herein we wish to report the re-
sults on N-alkylation of tosylhydrazones using benzylic alcohols as
alkylating agents under acidic conditions (Scheme 1).
5
6c
7c
CH2Cl2/reflux
CH3NO2/reflux
85d
Initially, the reaction of N0-benzylidene-4-methylbenzene
sulfonohydrazide (1a) with diphenyl methanol (2a) was carried out
in dichloromethane using p-toluenesulfonic acid (5 mol %) at room
temperature for 30 h, under which conditions the N-alkylation reac-
tion took place. However, this afforded the desired product, N-benz-
hydryl-N0-benzylidene-4-methylbenzenesulfonohy drazide (3a) in
only 45% yield (Table 1, entry 1). When, the same reaction was con-
ducted at reflux temperature for 24 h, there was no improvement in
the yield (Table 1, entry 2). Based on these results, the same reaction
was screened with different acid catalysts (5 mol %) to find the best
a
Isolated yield after purification.
No reaction.
50 mg/mmol catalyst used.
No reaction at rt.
b
c
d
catalyst for N-alkylation (Table 1). Among the catalysts screened
tris(pentafluorophenyl) borane [B(C6F5)3] gave good yields of the N-
alkylated product (Table 1, entry 3), whereas, ZnCl2 and BF3ꢀEt2O fur-
nished the product in low yields (Table 1, entries 4 and 5). However,
polystyrene-bound p-TSA (50 mg/mmol) in nitromethane under
refluxing conditions provided the product 3a in good yields (Table
1, entry 7), while there was no reaction either at room temperature
or in dichloromethane (Table 1, entries 6 and 7).
* Corresponding author. Tel.: +91 40 27191885; fax: +91 40 27160512.
E-mail address: rajireddy@iict.res.in (C.R. Reddy).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.093

5634
C. R. Reddy, E. Jithender / Tetrahedron Letters 50 (2009) 5633–5635
Under the optimized conditions, we next investigated the reaction
ofaldehydetosylhydrazoneswithbenzylicalcoholsunderthepresent
conditions. The results are summarized in Table 2. N-Alkylation of N0-
benzylidene-4-methylbenzenesulfonohydrazide (1a) with benzylic
Table 2
B(C6F5)3-catalyzed N-alkylation of aldehye tosylhydrazones using benzylic alcohols
Entry
Tosyl hydrazone
Benzylic alcohol
Reaction time (h)
20
Producta
Yieldb (%)
OH
Ph
N
Ph
N
Ts
Ph
Ts
Ph
Ph
N
Ts
N
N
N
3a
3b
1
90
H
Ph
Ph
2a
1a
Ph
Ph
OH
2
3
1a
1a
1a
1a
19
22
19
24
21
19
22
19
19
18
20
19
92
89
91
0c
Ph
2b
Ph
Ph
N
Ts
N
4 -OMeC6H4
2c
OH
3c
4 -MeOC6H4
OH
Ph
N
N
Ts
N
N
4
3d
2d
Ph
Ph
Ts
Ph
OH
3e
5
2e
4 -OMeC6H4
4 -OMeC6H4
N
Ts
4 -OMeC6H4
1b
N
Ts
N
N
N
3f
3g
3h
3i
6
2a
2b
2c
2d
2a
2b
2c
2d
89
89
87
90
91
92
87
91
H
Ph
Ph
N
N
Ts
Ph
7
1b
1b
Ph
4 -OMeC6H4
Ts
Ts
N
N
8
4 -MeOC6H4
4 -OMeC6H4
N
9
1b
2 -NO2C6H4
2 -NO2C6H4
N
Ts
2 -NO2C6H4
N
Ts
N
N
3j
10
11
12
H
1c
Ph
N
Ph
Ts
Ph
N
3k
3l
1c
1c
1c
Ph
2 -NO2C6H4
N
Ts
Ts
N
N
4 -OMeC6H4
2 -NO2C6H4
N
13
3m
a
All the products were characterized by 1H, 13C NMR and mass spectra.
Isolated yields.
No reaction either at room temperature or at 40 °C.
b
c

C. R. Reddy, E. Jithender / Tetrahedron Letters 50 (2009) 5633–5635
5635
Ph
N
Ts
Acknowledgements
OH
N
B(C6F5)3 (5 mol%)
Ph
N
Ts
+
N
H
We would like to thank DST, New Delhi for financial assistance
(GAP-0154) and are grateful to Dr. S. Chandrasekhar for his encour-
agement and useful discussions.
CH2Cl2, rt, 19 h
90%
1a
3d
R-2d
Scheme 2. N-alkylation with enantiopure alcohol R-2d.
References and notes
Ts
Ph
N
Ts
1. Reddy, Ch. R.; Madhavi, P. P.; Reddy, A. S. Tetrahedron Lett. 2007, 48, 7169–7172.
2. Reddy, Ch. R.; Srikanth, B.; Rao, N. N.; Shin, D.-S. Tetrahedron 2008, 64, 11666–
11672.
3. (a) Benstead, D. J.; Hulme, A. N.; McNab, H.; Wight, P. Synlett 2005, 1571–1574;
(b) He, R.; Lam, Y. Org. Biomol. Chem. 2008, 6, 2182–2186.
N
AgSbF6
N
Ph
N
Ph
Ph
CH2Cl2, rt
1 h, 85%
Ph
Ph
3b
4
4. Cahhi, S.; La Torre, F.; Mistiti, D. Synthesis 1977, 301–303.
5. (a) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scok, P. M.; Harris, G. D., Jr.;
Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709–5712; (b) Keith, J. M.; Gomez, L.
J. Org. Chem. 2006, 71, 7113–7116.
Scheme 3. Synthesis of pyrazole 4 from 3b.
6. (a) Kobayashi, S.; Hirabayashi, R. J. Am. Chem. Soc. 1999, 121, 6942–6943; (b)
Movassaghi, M.; Ahmed, O. K. Angew. Chem., Int. Ed. 2008, 47, 8909–8912; c
Buchwald, S. L.; Willoughby, C. A. Catalytic asymmetric and non-asymmetric
reduction of imines and oximines using metal catalysts. U.S. Cont.-in-part of U.S.
Ser. No. 698940, abandoned, US 5292893, 1994.; (d) Schantl, J. G.; Hebeisen, P.;
Karpellus, P. Synth. Commun. 1989, 19, 39–48; (e) Lee, Y. T.; Chung, Y. K. J. Org.
Chem. 2008, 73, 4698–4701; (f) Mundal, D. A.; Lutz, K. E.; Thomson, R. J. Org. Lett.
2009, 11, 465–468.
alcohols 2b to 2d in the presence of B(C6F5)3 in dichloromethane gave
the corresponding N-alkylated products 3b to 3d, respectively, in
good yields (Table 2, entries 2–4). However, the reaction of 1a with
3-phenyl-1-propanol (2e) did not proceed under the present reaction
conditions (Table 2, entry 5). This may be due to thenon-benzylicnat-
ure of the alcohol. However, the reaction of N0-(4-methoxybenzyli-
dene)-4-methylbenzenesulfonohydrazide (1b) and 4-methyl-N0-(-
2-nitrobenzylidene) benzenesulfonohydrazide (1c) with benzylic
alcohols 2a to 2d proceeded smoothly to give the corresponding N-
alkylated products 3f to 3m in good yields (Table 2, entries 6–13).
To check the configuration of enantiopure secondary benzylic
alcohols during the N-alkylation, the reaction of 1a with enantio-
pure 2d (R-2d) was carried out under the present reaction condi-
tions, which gave the corresponding N-alkylated product 3d with
loss of configuration.8 This may be due to the initial formation of
carbocation from benzylic alcohol followed by the reaction with
hydrazone (Scheme 2).
Furthermore, we have demonstrated the utility of the N-alkylated
hydrazone products in the synthesis of pyrazole products. The reac-
tion of N-alkylated tosylhydrazone 3b with silver hexafluoroantimo-
nate in dichloromethane at room temperature gave the 3,5-diphenyl-
1-(phenyl(tosyl) methyl)-1H-pyrazole 4 in 85% yield (Scheme 3).6e
In conclusion, we have developed an acid-catalyzed N-benzyla-
tion of tosylhydrazones using benzylic alcohols as alkylating
agents for the first time. The reaction conditions were mild and
efficient and provided the products in excellent yields. The applica-
bility of N-alkylated hydrazones has also been successfully demon-
strated for the synthesis of pyrazole.
7. (a) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492–4493; (b) Myers, A.
G.; Movassaghi, M.; Zheng, B. J. Am. Chem. Soc. 1997, 119, 8572–8573; (c)
Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007, 72, 1838–1841.
8. The enantioselectivity was checked using chiral HPLC: chiral pak IA 250 ꢁ 4.6 mm,
5
l, mobile phase: 5% iso-propanol in hexanes, flow rate: 1 mL/min., retention
time: 15.50 (47.4%), 23.15 (52.5%).
9. Spectral data of representative new products (3a): White solid; mp 149–153 °C;
1H NMR (300 MHz, CDCl3): d 8.16 (s, 1H), 7.48–7.38 (m, 3H), 7.29–7.19 (m, 14H),
7.07 (d, 2H, J = 8.1 Hz), 6.85 (s, 1H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3): d
151.7, 143.7, 138.2, 135.4, 134.4, 130.2, 128.5, 128.5, 128.5, 128.5, 128.5, 128.5,
128.5, 128.1, 128.1, 128.1, 128.1, 128.1, 128.1, 128.1, 127.4, 127.4, 127.4, 127.4,
127.4, 67.0, 21.5; IR (KBr):
m ;
3747, 3436, 3025, 1599, 1344, 1132, 697 cmꢂ1
HRMS-ESI calcd for C27H24N2O2SNa: 463.1456; found: 463.1435.
Compound (3b): Brown solid; mp 125–129 °C; 1H NMR (300 MHz, CDCl3): d 7.98
(d, 2H, J = 8.3 Hz), 7.82 (s, 1H), 7.75 (d, 2H, J = 8.1 Hz), 7.56–7.53 (m, 2H), 7.45 (t,
2H, J = 7.5 Hz), 7.38–7.23 (m, 9H), 7.12 (d, 2H, J = 8.1 Hz), 6.92 (s, 1H), 2.33 (s,
3H); 13C NMR (75 MHz, CDCl3): d 149.2, 144.3, 136.1, 134.8, 134.3, 131.7, 130.2,
129.9, 129.9, 129.5, 129.5, 129.1, 129.15, 128.9, 128.9, 128.8, 128.8, 128.7, 128.4,
128.3, 128.3, 127.6, 126.9, 126.9, 122.1, 89.4, 81.8, 54.5, 21.6; IR (KBr):
m
3423,
3024, 2917, 1967, 1598, 1359 cmꢂ1
487.1456; found: 487.1450.
; HRMS-ESI calcd for C29H24N2O2SNa:
Compound (3c): Light brown solid; mp 121–125 °C; 1H NMR (300 MHz, CDCl3): d
7.89 (d, 2H, J = 9.0 Hz), 7.52 (s, 1H), 7.38–7.23 (m, 8H), 7.11–7.03 (m, 3H), 5.86
(dd, 1H, J = 6.7, 4.5 Hz), 2.76 (m, 2H), 2.44 (s, 3H), 2.01 (m, 2H), 1.77 (m, 2H);
13CNMR (75 MHz, CDCl3): d 148.1, 144.0, 137.1, 136.4, 134.4, 134.3, 129.9, 129.7,
129.3, 129.3, 128.5, 128.5, 128.3, 128.3, 127.5, 127.2, 127.2, 127.2,126.8, 58.4,
29.4, 24.7, 22.4, 21.7; IR (KBr):
m 3434, 3063, 2947, 1911, 1601, 1397, 1162, 996,
695 cmꢂ1; HRMS-ESI calcd for C24H24N2O2SNa: 427.1456; found: 427.1435.
Compound (3d): Off-white solid; mp:130–133.5 °C; 1H NMR (300 MHz, CDCl3): d
7.84 (d, 2H, J = 8.3 Hz), 7.65 (s, 1H), 7.53–7.48 (m, 1H), 7.34–7.20 (m, 8H), 6.83
(d, 2H, J = 8.3 Hz), 4.73 (s, 2H), 3.78 (s, 3H), 2.44 (s, 3H) 13C NMR (75 MHz,
CDCl3): d 159.3, 147.4, 144.2, 134.8, 134.2, 130.3, 129.7, 129.7, 128.7, 128.7,
128.5, 128.5, 128.5, 127.6, 127.6, 127.5, 127.5, 114.5, 114.5, 55.4, 51.9, 21.7; IR
General experimental procedure for B(C6F5)3-catalyzed N-alkyl-
ation of aldehyde tosylhydrazones using benzylic alcohols: To a stirred
solution of benzylic alcohol 2 (1 mmol) in dichloromethane (5 mL)
were added tosyl hydrazone 1 (1 mmol) and 5 mol % B(C6F5)3. The
reaction mixture was stirred at room temperature and the reaction
progress was monitored by TLC analysis. After the completion of
the reaction (for reaction time, see Table 2), the mixture was evap-
orated in vacuo. The residue was purified by column chromatogra-
phy on silica gel using ethyl acetate and hexanes as eluent to give
the corresponding N-alkylated products.9
(KBr):
m 3737, 3023, 2917, 1606, 1407, 1171, 904, 661; HRMS-ESI calcd for
C22H22N2O3SNa: 417.1248; found: 417.1229.
Compound (4): Off-white solid; mp 172–175 °C; 1H NMR (300 MHz, CDCl3): d
7.82–7.74 (t, 4H, J = 6.9 Hz), 7.49–7.23 (m, 13H), 7.12 (d, 2H, J = 8.1 Hz), 6.61 (s,
1H), 6.25 (s, 1H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3): d 152.1, 147.8, 144.9,
133.1, 130.7, 130.7, 130.2, 129.8, 129.8, 129.2, 129.2, 129.2, 129.2, 128.9, 128.9,
128.7, 128.7, 128.7, 128.5, 128.5, 128.4, 128.4, 128.1, 126.9, 125.7, 125.7, 103.8,
80.8, 21.6; IR (KBr):
HRMS-ESI calcd for C29H24N2O2SNa: 487.1456; found: 487.1469.
m ;
3060, 2937, 1897, 1591, 1449, 1077, 814, 697 cmꢂ1