A catalyst-free N-benzyloxycarbonylation of amines in aqueous micellar media at room temperature

Article abstract of DOI:10.1016/j.tetlet.2008.05.010

N-Benzyloxycarbonylation of amines was carried out in aqueous micellar media. Aliphatic (open and cyclic), aromatic and heteroaromatic amines react with Cbz-Cl to give excellent yields of products. The reactions were carried out in water and at room temperature.

Full text of DOI:10.1016/j.tetlet.2008.05.010

Tetrahedron Letters 49 (2008) 4799–4803
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Tetrahedron Letters
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A catalyst-free N-benzyloxycarbonylation of amines in aqueous micellar
media at room temperature
*
Janhavi J. Shrikhande, Manoj B. Gawande, Radha V. Jayaram
Department of Chemistry, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Benzyloxycarbonylation of amines was carried out in aqueous micellar media. Aliphatic (open and
cyclic), aromatic and heteroaromatic amines react with Cbz-Cl to give excellent yields of products. The
reactions were carried out in water and at room temperature.
Received 14 February 2008
Revised 26 April 2008
Accepted 3 May 2008
Available online 9 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
N-Benzyloxycarbonylation
Amines
Micellar media
Catalyst-free
1. Introduction
chemoselective protection of amines in the presence of
La(NO3)3ÁH2O,20 or in the presence of an aqueous phase and
Allyloxycarbonyl (Alloc), tert-butoxycarbonyl (Boc) and benzyl-
oxycarbonyl (Cbz) are amongst the most useful protecting groups
for alcohols, amines and, to a lesser extent, thiols.1 Amongst these,
the Cbz group is used extensively, as it can be introduced easily by
acylation with allyl2 or benzyl chloroformate in the presence of a
base,3 and removed when needed, by catalytic hydrogenation,
using Pd–fibroin (Pd/Fib),4 lithium-mediated naphthalene-cata-
lyzed reductive cleavage5 or tetrabutylammonium fluoride.6
The use of the Cbz group as a protecting agent for amines is of
much interest in the pharmaceutical industry, for the synthesis
of novel HIV second-generation protease inhibitors,7 and toxins
related to Alzheimer’s and Parkinson’s diseases and dementia.8
Cbz-protection is also used in the preparation of chiral ligands that
form complexes with gadolinium which are used for in vivo diag-
nostics.9 Certain surface modified dendrimers for drug delivery
systems also involve this Cbz-protection step in their synthesis.10
The benzyloxycarbonyl group also has application in the syn-
thesis of peptides,11 nucleotides,12 carbohydrates13 and antibio-
tics.14,15 The other applications of Cbz-protection include C–C
bond formation reactions16 and synthesis of biodegradable
copolymers.17
b-cyclodextrin,21 reaction on a solid surface,22 and the use of
molecular iodine.23
Due to the growing importance and awareness about environ-
mental protection, there has been a significant impetus in the field
of green chemistry. Various techniques such as microwave24 and
ultrasonic25 promoted synthesis have been widely explored. As
water is the most abundant and environmentally acceptable sol-
vent, organic reactions in aqueous media have attracted much
attention. Thus, attempts are being made to replace organic
solvents, with water.26
Recently, we reported on the chemoselective N-benzyloxycarb-
onylation of amines at room temperature using silica sulfuric
acid.27 In continuation of our efforts in green chemistry28 and to
explore the applicability of aqueous micelles as reaction med-
ium,29 we tested the applicability of this medium for the Cbz-pro-
tection reaction. Here, we describe the N-benzyloxycarbonylation
of various amines in micellar medium (Scheme 1). To our surprise,
we observed that the Cbz-protection reactions occurred in water in
R
H
R
Various methods are available for the N-benzyloxycarbonyl-
Cbz-Cl
ation of amines, which include selective protection of
L-arginine
N
Cbz
NH
RT, CTAB-H2O
at the Na-position in a NaHCO3–NaOH buffered solution,18 use of
polymer-bound 1-hydroxybenzotriazole for immobilization,19
H
R = alkyl, aryl
* Corresponding author. Tel.: +91 22 24145616; fax: +91 22 24145614.
E-mail address: rvjayaram@udct.org (R. V. Jayaram).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.010

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J. J. Shrikhande et al. / Tetrahedron Letters 49 (2008) 4799–4803
the presence of surfactants without any catalyst. To the best of our
NHCbz
NH2
knowledge, this is the first report on the Cbz-protection of amines
in micellar medium in the absence of a catalyst.
The model reaction studied in the present case was the N-ben-
zyloxycarbonylation of 4-fluoroaniline (Scheme 2).
Cbz-Cl
RT(30 oC), surfactant-H2O
F
F
10 min
Scheme 2.
When the reaction was carried out in water, without any surfac-
tant no product formation was observed (Table 1, entry 1). In order
to study the effect of surfactant we investigated the reaction in
aqueous surfactant solutions of cationic, anionic and non-ionic sur-
factants. The solutions in consideration were taken well above
their critical micellar concentrations (CMC). The yield observed
in the case of SDS was only 23% at a concentration of 50 mM (Table
1, entry 2), whilst with Triton X-114, no product formation
occurred at the same concentration (Table 1, entry 3). However,
when the reaction was carried out in the presence of the cationic
surfactant tetradecyl trimethylammonium bromide (TTAB), the
yield was 71% in 50 mM solution (Table 1, entry 4). When the
cationic surfactant, cetyltrimethylammonium bromide (CTAB)
was used, we observed product formation in 45% yield at only
25 mM concentration (Table 1, entry 5). Using higher concentra-
tions of CTAB led to a considerable increase in the yield. In the
presence of 50 mM surfactant solution, 82% yield was achieved
(Table 1, entry 6). On further increasing the surfactant concentra-
Table 1
Effect of surfactant on the yield of N-Cbz producta
Entry
Surfactant
Concentration (mM)
Yieldb (%)
1
2
3
4
5
6
7
None
SDS
Triton X-114
TTAB
CTAB
—
NRc
23
50
50
50
25
50
75
NRc
71
45
82
83
CTAB
CTAB
a
Reaction conditions: 4-fluoroaniline (2.5 mmol) was added to the surfactant
solution according to the given concentration and the reaction stirred for 2–3 min.
To this stirring solution Cbz-Cl (2.5 mmol) was added slowly dropwise and the
reaction stirred until a solid product formed.
b
Isolated yield.
No reaction.
c
Table 2
N-Benzyloxycarbonylation of various amines in the presence of CTAB-H2O at room temperaturea
Entry
Amine
Productb
Time (min)
10
Yieldc (%)
80
NH2
H
N
Cbz
1
H
N
NH2
Cbz
2
3
4
10
30
10
82
87
88
F
F
H
N
NH2
F
Cbz
F
H
N
NH2
Cbz
Cl
Cl
H
N
NH2
Cbz
5
6
5
5
85
82
Br
Br
H
N
NH2
Cbz
HOOC
HOOC
H
N
NH2
Cbz
7
10
80

J. J. Shrikhande et al. / Tetrahedron Letters 49 (2008) 4799–4803
4801
Table 2 (continued)
Entry
Amine
Productb
Time (min)
30
Yieldc (%)
95
Cbz
NH2
N
H
8
Cbz
HN
NH2
9
10
65
Cbz
HN
NH2
Cl
Cl
10
15
83
Cl
Cl
Cbz
H2N
CF3
CF3
HN
11
12
10
10
88
91
Cbz
N
H
N
Cbz
NH2
HN
13
10
95
14
15
15
15
80
82
N
N
H
Cbz
N
N
H
Cbz
Cbz
NH
N
16
17
10
10
83
O
O
Cbz
H
N
75
N
(continued on next page)

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J. J. Shrikhande et al. / Tetrahedron Letters 49 (2008) 4799–4803
Table 2 (continued)
Entry
Amine
Productb
Time (min)
10
Yieldc (%)
76
Cbz
18
N
H
NH2
Cbz
19
20
5
5
88
82
N
H
NH2
PhH2C-N
HO
NH
PhH2C-N
HO
N
Cbz
Cbz
21
10
83
N
NH2
H
a
Reaction conditions: 4-fluoroaniline (2.5 mmol) was added to CTAB solution (10 mL, 50 mM) and stirred for 2–3 min. To this Cbz-Cl (2.5 mmol) was added slowly
dropwise and stirred the reaction at room temperature.
b
All products are well characterized by IR and 1H NMR.
Isolated yield.
c
tion (75 mM), no significant increase in the yield was observed
(Table 1, entry 7).
Thus, CTAB at a concentration of 50 mM was used as the reac-
tion medium for further studies.
Encouraged by these results we performed the reaction using
various aliphatic (open chain and cyclic), aromatic and heteroaro-
matic amines (Table 2).
The reaction thus carried out at room temperature afforded
excellent yields of the products (65–95%). In the case of an amino
alcohol (Table 2, entry 21), chemoselectivity was observed and
the N-Cbz derivative was obtained as the sole product, without
competitive formation of the O-Cbz product.
When the reactant concentration was increased 40 times, the
activity and selectivity remained the same. The micellar media
proved to be an efficient reaction medium on 100 mmol scale. To
400 mL of a solution of CTAB in distilled water (50 mM) was added
4-methylaniline(100 mmol). This solution was stirred for
15–20 min and Cbz-Cl (100 mmol) was slowly added dropwise
with constant stirring. Vigorous stirring was continued for 1 h
and then the reaction mixture was allowed to stand for 15 min.
The resulting solid was filtered and washed with water, affording
a 72% yield of product.
1710, 1600, 1506, 1412, 1291, 1043, 750 cmÀ1; Anal. Calcd for
C
14H12O2NF: C, 68.57; H, 4.90; N, 5.71. Found C, 68.12; H, 4.71;
N, 5.38; EIMS m/z 245 (M+).
Entry 5: 1H NMR (400 MHz, CDCl3): d = 7.42–7.32 (m, 4H), 7.29–
7.26(m, 5H), 5.19 (s, 2H), 6.66 (s, 1H); IR (KBr): m 3308, 2800, 2613,
2421, 1725, 1497, 1207, 1051 cmÀ1; Anal. Calcd For C14H12O2NBr:
C, 54.90; H, 3.92; N, 4.57. Found C, 54.35; H, 3.97; N, 4.23; EIMS
m/z 306 (M+).
Entry 7: 1H NMR (400 MHz, CDCl3): d = 2.29 (s, 3H), 5.18 (s, 2H),
6.64 (s, 1H), 7.40–7.08 (m, 9H); IR (KBr): m 3368, 2810, 1730, 1560,
1199, 1029 cmÀ1; Anal. Calcd For C15H15O2N: C, 74.68; H, 6.22; N,
5.81. Found C, 74.31; H, 6.30; N, 5.89; EIMS m/z 241 (M+).
Entry 13: 1H NMR (400 MHz, CDCl3): d = 7.30–7.36 (m, 5H), 5.08
(s, 2H), 4.65 (s, 1H), 1.72–1.66 (m, 4H), 1.32–1.39 (m, 4H), 1.17–
1.11 (m, 2H); IR (KBr): m 3535, 3326, 2826, 2360, 1922, 1689,
1282, 1065 cmÀ1 Anal. Calcd for C14H19O2N: C, 72.10; H, 7.72; N,
6.00. Found C, 71.92; H, 7.33; N, 5.80; EIMS m/z 233 (M+).
Acknowledgement
M.B.G is thankful to CSIR, New Delhi, India, for the senior
research fellowship.
In summary, we have developed an efficient method for N-benz-
yloxycarbonylation of amines in a micellar medium at room tem-
perature. The method affords high yields of N-Cbz protected
products.
References and notes
1. (a) Kunz, H.; Waldman, H. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6; (b) Greene, T. W.; Wuts, P. G.
M. Protective Groups in Organic Synthesis; Wiley: New York, 1999; (c) Jarowicki,
K.; Kocienski, P. J. Chem. Soc., Perkin Trans. 1 1999, 1589–1615.
2. Paquette, L. A. In Encyclopedia of Reagents for Organic Synthesis; Wiley:
Chichester, 1995; Vol. 1, pp 95–96.
2. General experimental procedure for the
N-benzyloxycarbonylation of amines
To a 10 mL solution of CTAB in distilled water (50 mM) in a
round-bottomed flask was added amine (2.5 mmol), and the mix-
ture was stirred for 5–10 min. To this stirring solution, Cbz-Cl
(2.5 mmol) was added slowly dropwise and the stirring continued
until the reaction was complete as indicated by TLC. The resulting
product, if solid, was separated by simple filtration and washed
with water. In the case of liquid products, the reaction mixture
was extracted using ethyl acetate, and concentrated under reduced
pressure to give a crude product which was further purified by
column chromatography (hexane:ethyl acetate, 9:1).
3. Paquette, L. A. In Encyclopedia of Reagents for Organic Synthesis; Wiley:
Chichester, 1995; Vol. 1, pp 323–326.
4. Ikawa, T.; Sajiki, H.; Hirota, K. Tetrahedron 2005, 61, 2217–2231.
5. Behloul, C.; Guijarro, D.; Yus, M. Tetrahedron 2005, 61, 9319–9324.
6. Jacquemard, U.; Beneteau, V.; Lefoix, M.; Routier, S.; Merour, J.-Y.; Coudert, G.
Tetrahedron 2004, 60, 10039–10047.
7. Recuero, V.; Gonzalo, G.; Brieva, R.; Gotor, V. Eur. J. Org. Chem. 2006, 18, 4224–
4230.
8. Moura, S.; Pinto, E. Tetrahedron Lett. 2007, 48, 2325–2327.
9. Harre, M.; Nickisch, K.; Schulz, C.; Weinmann, H. Tetrahedron Lett. 1998, 39,
2555–2558.
10. Fuchs, S.; Kapp, T.; Otto, H.; Schoeneberg, T.; Franke, P.; Gust, R.; Schlueter, A.
D. Chem. Eur. J. 2004, 10, 1167–1192.
11. (a) Bodanszky, M. Peptide Chemistry; Springer: Berlin, 1988; (b) Bergeron, R. J.;
Ludin, C.; Muller, R.; Smith, R. E.; Phanstiel, O. J. Org. Chem. 1997, 62, 3285–
3290.
2.1. Spectral data of selected compounds
12. (a) Amarnath, V.; Broom, A. D. Chem. Rev. 1977, 77, 183–217; (b) Watkins, B. E.;
Rapoport, H. J. Org. Chem. 1982, 47, 4471–4477; (c) Myers, A. G.; Gin, D. Y.;
Rogers, D. H. J. Am. Chem. Soc. 1994, 116, 4697–4718.
Entry 3: 1H NMR (400 MHz, CDCl3): d = 8.11 (s, 1H), 7.42–7.32
(m, 4H), 6.97–7.25 (m, 5H), 5.85 (s, 2H); IR (KBr): m 3310, 3095,

J. J. Shrikhande et al. / Tetrahedron Letters 49 (2008) 4799–4803
4803
13. (a) Saito, H.; Nishimura, Y.; Kondo, S.; Umezawa, H. Chem. Lett. 1987, 799–802;
(b) Teshima, T.; Nakajima, K.; Takahashi, M.; Shiba, T. Tetrahedron Lett. 1992,
33, 363–366; (c) Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A.
Tetrahedron Lett. 2000, 41, 9305–9309.
14. Saito, H.; Yamada, T.; Okumura, K.; Yonezawa, Y.; Shin, C.-G. Chem. Lett. 2002,
11, 1098–1099.
15. Durand, P.; Richard, P.; Renaut, P. J. Org. Chem. 1998, 63, 9723–9727.
16. Matsuo, J.-I.; Tanaki, Y.; Ishibashi, H. Org. Lett. 2006, 8, 4371–4374.
17. Won, C.-Y.; Chu, C.-C.; Lee, J. D. Polymer 1998, 39, 6677–6681.
18. Moynihan, H. A.; Yu, W. P. Synth. Commun. 1998, 28, 17–23.
19. Dendrinos, K. G.; Kalivretenos, A. G. J. Chem. Soc., Perkin Trans. 1 1998, 1463–
1464.
21. Pavan Kumar, V.; Somi Reddy, M.; Narender, M.; Surendra, K.; Nageswar, Y. V.
D.; Rama Rao, K. Tetrahedron Lett. 2006, 47, 6393–6396.
22. Yadav, V. K.; Babu, K. G. J. Org. Chem. 2004, 69, 577–580.
23. Varala, R.; Enugala, R.; Adapa, S. R. J. Iran Chem. Soc. 2007, 4, 370–374.
24. Dollinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563–2591.
25. Mason, T. J. Sonochemistry; Oxford Univ. Press: Oxford, 1999.
26. Herrerias, C. I.; Yao, X.; Li, Z.; Li, C. J. Chem. Rev. 2007, 107, 2546–2562.
27. Gawande, M. B.; Polshettiwar, V.; Varma, R. S.; Jayaram, R. V. Tetrahedron Lett.
2007, 48, 8170–8173.
28. (a) Gawande, M. B.; Deshpande, S. S.; Sonavane, S. U.; Jayaram, R. V. J. Mol.
Catal. A: Chem. 2005, 241, 151–155; (b) Gawande, M. B.; Jayaram, R. V. Catal.
Commun. 2006, 7, 931–935.
20. Mahesh, K. C.; Narasimhulu, M.; Reddy, T. S.; Suryakiran, N.; Venkateswarlu, Y.
Tetrahedron Lett. 2007, 48, 55–59.
29. Shrikhande, J. J.; Gawande, M. B.; Jayaram, R. V. Catal. Commun. 2007, 9, 1010–
1016.