A mild and efficient chemoselective: N-benzyloxycarbonylation of amines using TBAB a catalyst under solvent-free conditions

Article abstract of DOI:10.1139/V08-169

We describe a mild and efficient method for the chemoselective N-benzyloxycarbonylation of amines by treatment amines and aminoesters with benzyloxycarbonyl chloride (Cbz-Cl) in the presence of TBAB under solvent-free in excellent yields. The method is ge

Full text of DOI:10.1139/V08-169

393
A mild and efficient chemoselective
N-benzyloxycarbonylation of amines using TBAB
as a catalyst under solvent-free conditions
Kothamasu Suresh Babu, Vidadala Rama Subba Rao, Ravu Ranga Rao,
Sakhamuri Sivaram Babu, and Janaswami Madhusudana Rao
Abstract: We describe a mild and efficient method for the chemoselective N-benzyloxycarbonylation of amines by treat-
ment of amines and aminoesters with benzyloxycarbonyl chloride (Cbz-Cl) in the presence of TBAB under solvent-free
conditions in excellent yields. The method is general for the preparation of a wide variety of N-Cbz derivatives of ali-
phatic, aromatic amines, and aminoesters.
Key words: amines, green chemistry, benzyloxycarbonyl chloride, TBAB, solvent-free conditions.
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Resume : On decrit une methode douce et efficace de N-benzyloxycarbonylation chimio-selective des amines par traite-
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ment des amines ou des aminoesters par du chlorure de benzyl-oxy-carbonyle (Cbz-Cl), en presence de TBAB, dans des
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conditions sans solvant et avec d’excellents rendements. La methode est generale et elle s’applique a une grande variete
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de derives d’amines ou d’aminoesters aliphatiques ou aromatiques portant un groupe benzyloxycarbonyle (CBZ).
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Mots-cles : amines, chimie verte, chlorure de benzyloxycarbonyle, TBAB, conditions sans solvant.
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[Traduit par la Redaction]
Introduction
Scheme 1.
The protection and deprotection of amines is a common
event in multistep organic syntheses. Among protecting
groups of amines, the N-benzyloxycarbonyl (Cbz) group is
very important and provides a useful functionality for the
protection of amines because N-Cbz is stable in the presence
of a wide range of nucleophiles in alkaline and also in aque-
ous acidic conditions. It is easily removable by catalytic hy-
drogenation, without any side reactions, to get the parent
amine. In addition, it also serves as a stable protecting group
in peptide chemistry.1 There are several methods available
for the protection of amino groups as N-Cbz derivatives,
with aryl and (or) alkyl amine and benzyloxycarbonyl chlor-
ide (Cbz-Cl) in the presence of 4-(dimethylamino)pyridine
(DMAP) being the most commonly employed method.1 Re-
cently, LiHMDS in THF-HMPA2 and b-cyclodextrin in
aqueous medium have been reported for this transforma-
tion.3,4 However, the utility of a catalyst having quaternar-
yammonium salt for the preparation of N-Cbz derivatives
has not been thoroughly investigated.
in the absence of solvent are also attracting the attention of
chemists because of their ease of processing and environ-
mentally friendly nature. Tetra-alkylammonium bromides
(NR4)+Br– have a molecular structure similar to that of the
cationic surfactants previously employed,6 the main differ-
ence being the absence of the long hydrophobic tail that pre-
vents the formation of any organised structure (micelle) and
thereby the partition of the substrate. These salts are promis-
ing additives, as different alkyl residues in the (R4N)+
ammonium cation lead to different charge density and hy-
drophobicity. In continuation of our work to develop new
organic transformations,7 we have observed the N-benzylox-
ycarbonylation of amines and (or) aminoesters with Cbz-Cl
using TBAB as a mild and efficient catalyst under solvent-
free conditions at room temperature (RT) (Scheme 1).
Organic reactions using mild water tolerant catalysts have
received much attention in recent years, as they can conven-
iently be handled and removed from the reaction mixture,
making the experimental procedure simple and eco-
friendly.5 On the other hand, organic reactions carried out
Results and discussion
In the present method, we describe a mild, efficient, and
high yielding protocol for the N-benzyloxycarbonylation of
amines and (or) aminoesters. In general, all the reactions
were carried out by the addition of amines and (or) amino-
esters (1 mmol) to Cbz-Cl (1.2 mmol) in the presence of
TBAB under solvent-free conditions at RT to give the corre-
sponding N-benzyloxycarbamates in excellent yields
(Table 1, 75%–99%). The times required for derivatization
were comparatively very short (5–35 min). This method
Received 9 July 2008. Accepted 15 October 2008. Published on
the NRC Research Press Web site at canjchem.nrc.ca on
17 December 2008.
K.S. Babu, V.R.S. Rao, R.R. Rao, S.S. Babu,1 and J.M. Rao.
Organic Chemistry Division-I, Indian Institute of Chemical
Technology, Uppal Road, Hyderabad 500-007, India.
1Corresponding author (e-mail: sivarambabu_anu@yahoo.co.in).
Can. J. Chem. 87: 393–396 (2009)
doi:10.1139/V08-169
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394
Can. J. Chem. Vol. 87, 2009
Table 1. A mild and efficient chemoselective N-benzyloxycarbonylation of amines using TBAB
as a catalyst.
S.
No
Time
(min)
Yield
(%)b
Substrate
Producta8–11
1
2
3
4
5
10
20
20
20
10
90
95
90
95
90
6
7
20
15
92
90
8
20
91
9
20
20
25
95
94
85
10
11
12
23
96
13
14
10
5
95
98
15
16
5
99
90
20
17
18
5
98
79
35
19
20
25
25
82
80
1
aAll products were characterized by IR, H NMR and mass spectral analysis.
bYields refer to pure isolated products.
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Babu et al.
395
was compatible with various amines including aliphatic, aro-
matic, heteroaromatic, and some aminoesters. Amino groups
with different chemical natures further demonstrated the
chemoselectivity of the reaction. Similarly, in the cases of
an amino phenol (Table 1, entry 14) and an amino alcohol
(Table 1, entry 15), only the amino groups were protected.
In the case of a mixture of aliphatic and aromatic amines
(1 mmol), only the aliphatic amine was derivatized in the
reaction with Cbz-Cl (1 mmol) in the presence of TBAB.
Aromatic amines containing electron-withdrawing groups
also gave the desired derivatives in good yields. Chiral sub-
strates were resistant to racemization and labile functional-
ities, such as esters, were compatible in this conversion.
The protocol is highly chemoselective, involves simple ex-
perimental procedures, mild reaction conditions, and gives
excellent yields of Cbz-protected amines.
Entry 2
Mp and recrystallization in EtOH 72–74 8C. IR (KBr,
cm–1): 3425, 1733, 1529, 1461, 125, 1208, 1047, 745. H
1
NMR (200 MHz, CDCl3) d: = 3.98 (s, 3H), 5.21 (s, 2H),
6.80n (b s, 1H), 7.00 (m, 2H), 7.20 (dd, 1H, J = 8.50 and
2.81 Hz), 7.40 (m, 5H), 8.19 (dd, 1H, J = 8.00 and
2.80 Hz). EIMS (M + 1) m/z: 258.
Entry 3
Mp and recrystallization in EtOH 65–66 8C. IR (KBr,
cm–1): 3291, 3073, 2938, 1694, 1555, 1515, 1254, 1216,
1062, 834, 739, 694. 1H NMR (200 MHz, CDCl3). d: =
5.18 (s, 2H), 6.60 (br s, 1H), 6.90–6.95 (m, 2H), 7.25–
7.40 (m, 7H). EIMS (M + 1) m/z: 246.
Entry 4
Mp and recrystallization in EtOH 73–75 8C. IR (KBr,
1
cm–1): 3415, 1699, 1616, 1241, 1100, 1055, 619. H NMR
In conclusion, we have described a mild and efficient
method for the protection of amines and (or) aminoesters as
their N-benzyloxycarbonyl derivatives in the presence of
catalytic amount of TBAB under solvent-free conditions at
RT in excellent yields of the corresponding products. In the
absence of TBAB, the reaction takes more time to complete
and leads to a laborious process. The advantages of the
method are reduced reaction times, simple experimental
work-up procedures, and high product yields, making it a
useful addition to the existing methodologies.
(200 MHz, CDCl3) d = 5.20 (s, 2H), 6.78 (br s, 1H), 6.85–
7.00 (m, 2H), 7.35–7.40 (m, 5H), 8.10 (br s, 1H). EIMS
(M + 1) m/z: 264.
Entry 5
Mp and recrystallization in EtOH 55–57 8C. IR (KBr,
cm–1): 3324, 3059, 3022, 2979, 1680, 1537, 1256, 1055,
1
1025, 756, 697. H NMR (200 MHz, CDCl3) d: = 0.90 (t,
3H, J = 7.00 Hz), 1.20–1.40 (m, 2H) 1.60–1.80 (m, 2H),
4.60 (br s, 1H), 5.01 (d, 1H, J = 12.80), 5.03 (d, 1H, J =
12.80 Hz), 4.97 (m, 1H), 7.15–7.40 (m, 10H). EIMS (M +
1) m/z: 284.
Experimental
IR spectra were recorded on a PerkinElmer FT-IR 240-c
1
spectrometer using KBr optics. H NMR spectra were re-
Entry 6
corded on a Gemini-200 spectrometer in CDCl3 using TMS
as internal standard. Mass spectra were recorded on an Agi-
lent 1200 spectrometer. Starting materials were obtained
commercially from Sigma-Aldrich and Lancaster, and were
used without purification.
Mp and recrystallization in EtOH 47–48 8C. 1H NMR
(200 MHz, CDCl3) d: = 1.50 (d, 3H, J = 6.60), 4.80 (m,
1H), 4.90 (br s, 1H), 5.10 (s, 2H), 7.20–7.40 (m, 10H).
EIMS (M + 1) m/z: 256.
Entry 7
Typical experimental procedure
Mp and recrystallization in EtOH 47–50 8C. IR (KBr,
cm–1): 2859, 1702, 1427, 1241, 1119, 769. 1H NMR
(200 MHz, CDCl3) d: = 3.45 (t, 4H, J = 4.50 Hz), 3.65 (t,
4H, J = 4.00 Hz), 5.15 (s, 2H), 7.30–7.38 (m, 5H). 13C
NMR (75 MHz, CDCl3) d: = 44.1, 66.5, 67.2, 128.0,
128.1, 128.5, 136.4, 155.2. EIMS (M + 1) m/z: 222.
To a mixture of amine and (or) aminoesters (1 mmol) and
benzyloxycarbonyl chloride (Cbz-Cl) (1.2 mmol) was added
TBAB (5 mol %), and the reaction was stirred under sol-
vent-free conditions at RT for an appropriate amount of
time (Table 1). After completion of the reaction as moni-
tored by TLC, saturated sodium bicarbonate was added to
the reaction mixture, and the product was extracted into
ethyl acetate (3 Â 20 mL). The combined organic layer was
washed with brine, dried over anhydrous sodium sulphate,
and concentrated under reduced pressure to give a crude
product that was purified by silica gel column chromatogra-
phy to afford the corresponding N-benzyloxycarbonyl-
protected amines or aminoesters. Spectral data for selected
compounds are given below.
Entry 8
Mp and recrystallization in EtOH 49–50 8C. IR (KBr, cm–1):
3422, 2122, 2733, 1722, 1590, 1301, 1248, 1169, 1081, 1053,
695. 1H NMR (200 MHz, CDCl3) d: = 5.32 (s, 2H), 6.80 (d, 1H,
J = 4.30 Hz), 7.20 (d, 1H, J = 4.30 Hz), 7.38–7.40 (m, 5H).
EIMS (M + 1) m/z: 235.
Entry 9
Mp and recrystallization in EtOH 41–43 8C. IR (KBr,
cm–1) 3431, 2929, 1692, 1405, 1260, 1208, 1147, 1058,
Entry 1
Mp and recrystallization in EtOH 70–71 8C. 1H NMR
(200 MHz, CDCl3) d: = 2.28 (s, 3H), 5.15 (s, 2H), 6.68 (br
s, 1H), 7.08 (d, 2H, J = 8.55 and 2.80 Hz), 7.25 (d, 2H, J =
8.55 and 2.80 Hz), 7.30–7.40 (m, 5H). EIMS (M + 1) m/z:
242.
1
743, 697. H NMR (200 MHz, CDCl3) d: = 1.65 (m, 2H),
3.28 (m, 2H), 3.65 (t, 2H, J = 5.20 Hz) 5.18 (s, 2H), 5.20
(br s, 1H), 7.28–7.38 (m, 5H). 13C NMR (75 MHz, CDCl3)
d: = 27.0, 29.0, 46.0, 62.0, 67.1, 127.3, 128.5, 136.1,
157.2. EIMS (M + 1) m/z: 210.
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Can. J. Chem. Vol. 87, 2009
Entry 10
Entry 20
1
Mp and recrystallization in EtOH 52–53 8C. IR (KBr,
A pale yellow oil. H NMR (300 MHz, CDCl3) d: = 0.89
(d, 3H, J = 6.79 Hz), 0.96 (d, 3H, J = 6.79 Hz), 2.19 (m,
1H), 3.66 (s, 3H), 4.34 (m, 1H), 5.08 (s, 2H), 5.68 (d, NH,
J = 9.0 Hz), 7.31 (m, 5H). 13C NMR (75 MHz, CDCl3) d: =
17.1, 18.7, 30.8, 58.7, 66.6, 127.8, 128.2, 135.9, 156.4,
175.3. EIMS (M + 1) m/z: 266.
cm–1): 3031, 2930, 1702, 1453, 1402, 1219, 1140, 698; H
1
NMR (200 MHz, CDCl3) d: = 2.89 (s, 3H), 4.50 (s, 2H),
5.15 (s, 2H), 7.20–7.40 (m, 5H). EIMS (M + 1) m/z: 256.
Entry 13
Mp and recrystallization in EtOH 68–69 8C. IR (KBr,
cm–1): 3323, 3146, 3058, 3028, 2950, 1709, 1601, 1538,
1445, 1314, 1220, 1054, 754, 695. 1H NMR (300 MHz,
CDCl3) d: = 5.25 (s, 2H), 6.76 (br s, 1H), 7.08 (t, 1H,
J = 8.0 Hz,), 7.20–7.45 (m, 9H). EIMS (M + 1) m/z:
228.
Acknowledgement
The authors thank University Grants Commission, New
Delhi, India, for the financial support and to the Director,
Indian Institute of Chemical Technology, for his encourage-
ment.
Entry 15
References
Mp and recrystallization in EtOH 75–76 8C. 1H NMR
(200 MHz, CDCl3) d: = 1.53–1.62 (m, 4H), 2.90 (br s, 1H,
-OH), 3.13–3.25 (m, 2H), 3.60–3.66 (m, 2H), 4.99 (br s,
NH),5.06 (s, 2H), 7.22–7.36 (m, 5H). 13C NMR (75 MHz,
CDCl3) d: = 29.7, 40.5, 62.1, 66.5, 127.6, 128.0, 135.7,
156.3. EIMS (M + 1) m/z: 224.
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Entry 16
Mp and recrystallization in EtOH 79–81 8C. IR (KBr,
cm–1), 3315, 3065, 2975, 1687, 1540, 1452, 1255, 1073,
1
1040, 695. H NMR (300 MHz, CDCl3) d: = 1.16 (d, 3H,
J = 6.80 Hz), 2.44 (brs, 1H), 3.53 (dd, 1H, J = 5.3,
9.8 Hz), 3.66 (d, 1H, J = 9.8 Hz), 3.84 (m, 1H), 4.94 (br
s, 1H), 5.07 (s, 2H), 7.39 –7.28 (m, 5H). EIMS (M + 1)
m/z: 210.
Entry18
1
A pale yellow oil. H NMR (300 MHz, CDCl3) d: = 1.40
(d, 3H, J = 7.17 Hz) 3.70 (s, 3H), 4.38 (m, 1H), 5.05 (s,
2H), 5.39 (br s, NH), 7.30–7.27 (m, 5H). 13C NMR
(75 MHz, CDCl3) d: = 18.7, 48.7, 52.5, 67.0, 128.5, 127.0,
136.2, 156.8, 174.8. EIMS (M + 1) m/z: 238.
´
(10) Hernandez, J. N.; Martin, V. S. J. Org. Chem. 2004, 69,
Entry 19
3591.
A pale yellow oil. IR (KBr, cm–1): 2955, 2888, 1714,
(11) Schlessinger, R. H.; Iwanowicz, E. J. Tetrahedron Lett.
1987, 28, 2083 and refs. cited therein. doi:10.1016/S0040-
4039(00)96049-0.
1
1456, 1380, 1345, 1214, 1064. H NMR (300 MHz, CDCl3)
d: = 3.47 (s, 1H), 3.65 (s, 3H), 3.83 (dq, 2H, J = 11.0 Hz,
3 Hz), 4.35 (br s, 1H), 5.04 (s, 2H), 6.08 (br s, 1H), 7.25
(m, 5H). 13C NMR (75 MHz, CDCl3) d: = 52.4, 56.0, 68.0,
67.0, 128.0, 128.0, 128.3, 136.0, 156.3, 171.1. EIMS (M +
1) m/z: 254.
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