A solvent-free method for the direct synthesis of Cbz-protected β-amino ketones using triphenylphosphine dibromide

Article abstract of DOI:10.1016/j.tetlet.2013.04.105

Triphenylphosphine dibromide (TPPDB) has been found to be a very effective catalyst for the one pot three-component Mannich reactions of aryl aldehyde, acetophenone, and benzyl carbamate under solvent-free condition at room temperature. The advantageous f

Full text of DOI:10.1016/j.tetlet.2013.04.105

Tetrahedron Letters xxx (2013) xxx–xxx
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Tetrahedron Letters
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A solvent-free method for the direct synthesis of Cbz-protected b-amino
ketones using triphenylphosphine dibromide
⇑
Pori Buragohain, Partha Pratim Saikia , Nabin C. Barua
Natural Products Chemistry Division, CSIR-North-East Institute of Science & Technology, Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Triphenylphosphine dibromide (TPPDB) has been found to be a very effective catalyst for the one pot
three-component Mannich reactions of aryl aldehyde, acetophenone, and benzyl carbamate under
solvent-free condition at room temperature. The advantageous features of this methodology are
operational simplicity, shorter reaction time, cost-effectiveness, and excellent yields. The catalyst
possesses distinct advantages over other catalysts used for this conversion.
Received 11 February 2013
Revised 25 April 2013
Accepted 28 April 2013
Available online xxxx
Ó 2013 Published by Elsevier Ltd.
Keywords:
Multicomponent reaction
Mannich reaction
b-Keto carbamate
Solvent-free
Triphenylphosphine dibromide
Chemical transformations are experiencing a deep change to
meet sustainability criteria imposed by the Green Chemistry prin-
ciples. In this context, the solventless approach is simple with
amazing versatility. Organic reactions under solvent-free condi-
tions are advantageous because of their enhanced selectivity and
efficiency, ease of manipulation, and cleaner product formation,
as toxic or volatile solvents are avoided.1
Multicomponent coupling reactions (MCRs) are emerging as
useful tools for the carbon–carbon and carbon heteroatom bond-
forming reactions and for the synthesis of small drug-like mole-
cules with several degrees of structural diversity.2 Additionally,
MCRs are often environmentally benign and atom economic as
well as they avoid time-consuming and costly purification
processes and protection–deprotection steps. The Mannich reac-
tion is one such multicomponent reaction and is the most widely
utilized chemical transformation for construction of b-amino
ketones and other b-amino carbonyl compounds, which in turn
are important synthetic intermediates for various pharmaceuticals,
natural products, and so forth.3 Procedures exist in the literature
for MCR synthesis of Cbz-protected b-amino ketones,4 but most
of them require solvents as reaction media, employ costly catalysts
and reagents or toxic metal salts. They also suffer from drawbacks
such as the use of a high catalyst loading and low yields.5 Addition-
ally, most of these methods use anilines or benzyl amine as
nitrogen source and hence deprotection of the resulting amino-
compound is difficult. Thus, the development of alternative
efficient methods for the synthesis of b-amino ketones is highly
desirable.
Triphenylphosphine dibromide (Ph3PBr2)6 is a readily accessi-
ble, cheap, and highly effective reagent, as well as a catalyst for
various organic transformations, such as bromination of alcohols,
phenols, and enols, cleavage of ethers and acetals to alkyl
O
O
O
NHCbz
R2
TPPDB
rt
CbzNH2
+
+
R
R1
R2
H
R
R= alkyl, aryl
R1= Me
R2= aryl, heteroaryl
Scheme 1.
Table 1
Catalytic systems for the synthesis of Cbz-protected b-amino ketones
O
O
O
NHCbz
Catalyst
CbzNH2
+
+
Ph
Me
Ph
H
Ph
Ph
Entry
Catalyst
Time (h)
Solvent
Yield (%)
Refs.
⇑
Corresponding author.
E-mail address: ncbarua2000@yahoo.co.in (N.C. Barua).
1
2
3
AuCl3-PPh3 (5 mol%)
I2 (10 mol%)
PPh3Br2 (5 mol%)
24
24
12
CH3CN
CH3CN
—
82
78
80
4a
4a
Present address: Department of Chemistry, NNS College, Titabar 785630, Assam,
India.
This work
0040-4039/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.04.105
Please cite this article in press as: Buragohain, P.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.04.105

2
P. Buragohain et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Table 2
TPPDB catalyzed Mannich reaction for the synthesis of Cbz-protected b-amino ketones
O
O
O
NHCbz
R2
TPPDB
rt
CbzNH2
+
+
R
R1
R2
R1-
H
R
Entry
R-
R2-
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
Phenyl-
4-Bromo-phenyl-
Phenyl-
Phenyl-
Phenyl-
Me-
Me-
Me-
Me-
Me-
Me-
Me-
Me-
Me-
Me-
Me-
Me-
Me-
Phenyl-
4-MeO-phenyl-
2,4-Dichloro-phenyl-
3,4-Dichloro-phenyl-
4-Bromo-phenyl-
2-Napthyl-
4-Benzyloxy-phenyl-
Phenyl-
4-MeO-phenyl-
4-Benzyloxy-phenyl-
2-Napthyl-
12
10
13
13
10
10
13
12
12
12
13
14
12
10
10
10
12
10
12
12
10
80
85
79
75
80
80
75
70
80
80
75
75
79
80
80
75
75
85
80
85
80
Phenyl-
Phenyl-
4-Bromo-phenyl-
4-Chloro-phenyl-
4-Bromo-phenyl-
4-Bromo-phenyl-
4-Chloro-phenyl-
Phenyl-
-Cyclohepta-
-Cyclohexa-
-Cyclohexa-
-Cyclohepta-
4-Me-phenyl-
4-Chloro-phenyl-
Phenyl-
9
10
11
12
13
14
15
16
17
18
19
20
21
2-Napthyl-
4-Nitro-phenyl-
4-MeO-phenyl-
4-MeO-phenyl-
Phenyl-
Phenyl-
4-Methyl-phenyl-
Phenyl-
Me-
Me-
Me-
Me-
4-MeO-phenyl-
2-Thiophen-
Phenyl-
a
Isolated yield and products were characterized by IR, NMR, and elemental analysis.
bromides, cyclization of b- and
c
-amino alcohols to aziridines7 and
In conclusion, we have demonstrated the efficacy and generality
of triphenylphosphine dibromide as a versatile reagent for the syn-
thesis of b-amino carbonyl compounds under solvent-free condi-
tion. It is worth mentioning that this metal-free method is faster,
cost effective, and simpler than most of the existing methods and
likely to attract attention of organic as well as medicinal chemists.
azetidines, conversion of carboxylic acid derivatives into acyl bro-
mides, bromination or dehydration of carboxamides groups, or
epoxide opening to vicinal dibromides, esterification of carboxylic
acids,8 preparation of nitrosamines and azides from the corre-
sponding amines and hydrazines, deoxygenation of sulfoxides to
the corresponding sulfides, synthesis of b-haloamines through
the ring opening of aziridines etc. In the context of our study aimed
at improving the ecocompatibility of certain organic processes, we
report herein a mild, efficient, and simple procedure for the
direct synthesis of Cbz-protected b-amino ketones using
triphenylphosphine dibromide (TPPDB) as catalyst under solvent-
free conditions at room temperature (Scheme 1).
Acknowledgement
We are grateful to the Director, NEIST, Jorhat, for providing
facilities to carry out this work. P.B. thanks CSIR, New Delhi for
research fellowships.
References and notes
We have observed that upon simple mixing of aldehyde
(1 mmol), acetophenone (1 mmol), benzylcarbamate (1.2 mmol),
and triphenylphosphine dibromide (5 mol%) quantitative conver-
sion to b-keto carbamate was observed with excellent isolated
yields. For comparison, the reaction was also carried out in organic
solvents, such as CH2Cl2, THF, diethyl ether, CH3CN, DMF, nitro-
methane, and methanol. Good yields of products were also formed
in organic solvents such as CH3CN and CH2Cl2 after 1–2 h of stirring
at room temperature. In the absence of TPPBD, the reaction failed
to provide the desired product even after stirring for longer dura-
tion. On the contrary, we observed that under solvent-free condi-
tions at room temperature, the reaction proceeded to completion
in one-pot, affording the b-keto carbamate in excellent yield.
The efficacy and generality of the catalyst TPPDB with some re-
ported catalyst such as AuCl3-PPh3 and I2 for the synthesis of Cbz-
protected b-amino ketones can be gauged by comparison (Table 1).
It is found that TPPDB was faster, cost-effective, and simpler than
the existing methods.
A variety of structurally diverse aromatic aldehydes underwent
the one-pot reaction smoothly without using any solvent to afford
the corresponding b-keto carbamates in excellent yields.9 The re-
sults are summarized in Table 2. Aromatic aldehydes bearing func-
tional groups such as –CH3, –OMe, –Cl, –Br, and –NO2 as well as
heteroatom containing aldehydes reacted efficiently to give the
corresponding b-keto carbamates in high yields irrespective of
the substituent position on the aromatic ring (Table 2).
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9. Experimental section:
(a) General experimental procedure: Triphenylphosphine dibromide (5 mol%) was
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P. Buragohain et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
added to
a
mixture of benzaldehyde (1 mmol), carbamate (1 mmol), and
J2 = 6 Hz, 1H); 13C (75 MHz, CDCl3): 197.4, 155.8, 141.9, 136.2, 136.1, 135.8,
133.7, 132.6, 131.3, 130.5, 128.8, 128.5, 128.3, 128.2, 128.1, 125.9, 60.4, 50.7,
43.5; Anal. Calcd for C23H19NO3: C 64.50%, H 4.47%, N 3.27%. Found: C 64.51%,
H4.48%, N 3.29%.
1-(4-Benzyloxy-phenyl)-3-oxo-3-phenyl-propyl-carbamic acid benzyl ester
(entry 7): White solid; Mp 94–103 °C; IR (CHCl3) cmÀ1: 3335, 2918, 2850,
1686, 1596, 1290, 1039, 771; 1H NMR (300 MHz, CDCl3): 7.87 (d, J = 9 Hz, 2H),
7.42 (m, 15H), 6.91(d, J = 6 Hz, 2H), 5.79 (br s, 1H), 5.28 (m, 1H), 5.08 (s, 2H),
5.01 (s, 2H), 3.66 (d, J = 12 Hz, 1H), 3.38 (dd, J1 = 6 Hz, J2 = 9 Hz, 1H); 13C
(75 MHz, CDCl3): 198.0, 158.1, 155.7, 136.9, 136.6, 136.4, 133.4, 128.7, 128.6,
128.5, 128.1, 128.0, 127.6, 127.5, 114.9, 70.0, 66.8, 51.3, 43.6; Anal. Calcd for
acetophenone (1 mmol), and the reaction mixture was stirred at room
temperature. The progress of the reaction was monitored by TLC. After
completion of the reaction, the reaction mixture was extracted with EtOAc
(2 Â 10 mL), dried over anhydrous Na2SO4, and concentrated and purified by
column chromatography on silica gel (60–120 mesh) with petroleum ether–
EtOAc as eluent.
(b) General experimental procedure for solid substances: Triphenylphosphine
dibromide (5 mol%) was added to a mixture of aldehyde (1 mmol), carbamate
(1 mmol), and ketone (1 mmol) in a mortar. The reaction mixture was ground
with a pestle to produce a homogeneous powder, and the mixture was left at
room temperature. The progress of the reaction was monitored by TLC. After
completion of the reaction, to the solid was added 5 mL of water and the
reaction mixture was extracted with EtOAc (2 Â 10 mL), dried over Na2SO4, and
concentrated and purified by column chromatography on silica gel (60–120
mesh) with petroleum ether–EtOAc as eluent.
C
30H27NO4: C 77.40%, H 5.85%, N 3.01%. Found: C 77.41%, H 5.88%, N 3.0%.
3-(4-Chloro-phenyl)-1-naphthalen-2-yl-3-oxo-propyl-carbamic
acid
benzylester (entry 12): Pale yellow solid; Mp 151 °C; IR (CHCl3) cmÀ1: 3332,
3059, 1691, 1588, 1241, 1044.2, 696; 1H NMR (300 MHz, CDCl3): 7.81 (m, 6H),
7.40 (m, 10H), 5.89 (s, 1H), 5.46 (m, 1H), 5.1 (s, 2H), 3.74 (d, J = 15.4 Hz, 1H), 3.48
(dd, J1 = 5.2 Hz, J2 = 5.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): 196.6, 155.8, 139.9,
136.3, 134.8, 133.2, 132.7, 129.5, 129.0, 128.6, 128.5, 128.1, 128.0, 127.6, 126.3,
126.0, 125.2, 124.4, 66.9, 51.9, 43.9; Anal. Calcd for C27H22ClNO3: C 73. 05%, H
5.00%, N 3.16%. Found: C 73.04%, H 5.01%, N 3.15%.
3-(4-Bromo-phenyl)-1-(4-methoxy-phenyl)-3-oxo-propyl-carbamic
acid
benzyl ester (entry 2): White solid; Mp 142–143 °C; IR (CHCl3) cmÀ1: 2921,
2852, 1702, 1583, 1396, 1029, 695; 1H NMR (300 MHz, CDCl3): 7.9 (d, J = 8.3 Hz,
2H), 7.55 (d, J = 8.4 Hz, 2H), 7.23–7.33 (m,7H), 6.82 (d, J = 8.6 Hz, 2H), 5.68 (br s,
1H), 5.23 (m, 1H), 5.08 (s, 2H), 3.76 (s, 3H), 3.65 (d, J = 14.8 Hz, 1H), 3.34 (dd,
J1 = 6.6 Hz, J2 = 6.6 Hz, 1H); 13C (75 MHz, CDCl3): 196.9, 158.9, 155.6, 136.3,
135.3, 133.0, 131.9, 129.6, 128.6, 128.5, 128.1, 127.6, 114.0, 66.8, 55.2, 51.4,
44.1; Anal. Calcd for C24H22NO4: C 74.21%, H 5.71%, N 3.61%. Found: C 74.20%, H
5.72%, N 3.59%.
3-Oxo-3-phenyl-1-thiophen-2-yl-propyl-carbamic acid benzyl ester (entry 21):
Yellow oil; IR (CHCl3) cmÀ1: 3323, 3064, 1686, 1220, 1041; 1H NMR (300 MHz,
CDCl3): 7.90 (d, J = 7.44 Hz, 2H), 7.24–7.84 (m, 8H), 7.15 (d, J = 4.8 Hz, 1H), 6.88
(m, 2H), 5.98 (d, J = 8.4 Hz, 1H), 5.55 (m, 1H), 5.11 (s, 2H), 3.73 (d, J = 13.8 Hz,
1H), 3.47 (dd, J1 = 5.9 Hz, J2 = 5.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): 197.6,
155.6, 145.0, 136.5, 136.3, 133.5, 133.3, 128.7, 128.5, 128.1, 128.0, 126.8, 124.5,
66.9, 47.9, 43.5; Anal. Calcd for C21H19NO3S: C 69.02%, H 5.24%, N 3.83%. Found:
C 69.00%, H 5.27%, N 3.80%.
1-(3,4-Dichloro-phenyl)- 3-oxo-propyl-carbamic acid benzyl ester (entry 4):
White solid; Mp 140–163 °C; IR (CHCl3) cmÀ1: 3455, 2924, 2853, 1681, 1597,
1385, 1074, 689; 1H NMR (300 MHz, CDCl3): 7.89 (d, 2H), 7.43 (m, 11H), 6.0 (br
s, 1H), 5.23 (m, 1H), 5.09 (s, 2H), 3.65 (d, J = 10 Hz, 1H), 3.40 (dd, J1 = 6 Hz,
Please cite this article in press as: Buragohain, P.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.04.105