Solid-phase synthesis of arylalkanolamines

Article abstract of DOI:10.1016/S0040-4039(01)01166-2

A versatile method for the solid-phase synthesis of differentially substituted arylalkanolamines has been developed using immobilized carbamates. The method has been successfully used for the synthesis of arylethanolamines and arylpropanolamines in high yields and purities.

Full text of DOI:10.1016/S0040-4039(01)01166-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5993–5995
Solid-phase synthesis of arylalkanolamines†
T. Srinivasan, P. Gupta and B. Kundu*
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 26 April 2001; revised 14 June 2001; accepted 28 June 2001
Abstract—A versatile method for the solid-phase synthesis of differentially substituted arylalkanolamines has been developed
using immobilized carbamates. The method has been successfully used for the synthesis of arylethanolamines and aryl-
propanolamines in high yields and purities. © 2001 Elsevier Science Ltd. All rights reserved.
The ability to synthesize large numbers of molecules
using the combinatorial approach requires the develop-
ment of methods to measure the diversity of such
collections of compounds. While large diverse libraries
remain a valuable source of novel lead molecules, the
overall efficiency of utilizing such compound collections
is usually lower than that for rationally designed,
directed or pharmacophore based libraries.1 In continu-
ation of our interest in pharmacophore based libraries,2
we targeted the solid-phase synthesis of arylalk-
anolamines as they are a class of therapeutically impor-
tant compounds. These prototypes are associated with
a wide range of biological activities ranging from
hypertension, asthma, obesity, diabetes, NMDA antag-
onism, anxiety and depression.
strategy in a manner so as to have at least two compo-
nents that can be independently and readily varied
(Scheme 1) for introducing diversity. Our solid-phase
synthesis of arylalkanolamines commences with the
preparation of immobilized carbamates 2 from Wang
resin and isocyanates 1 in the presence of an organic
base.5 Alternatively, carbamates 2 can be generated
using
carbonyldiimidazole6,7
or
4-nitrophenyl
chloroformate8,9 and amines, but the isocyanate
method resulted in higher loading and was also less
cumbersome to use. Next, the immobilized carbamates
2 were reacted with phenacyl bromides 3 to afford
N-alkylated carbamates 4 in quantitative yields. These
reactions were efficiently performed in DMF by activa-
tion of the NH group with NaH followed by addition
of the phenacyl bromides and heating at 80°C for 12 h.
The ketone was cleaved from the resin and character-
ized by NMR.10 The resulting immobilized ketones 4
were then smoothly reduced to the alcohols 5 using
sodium borohydride in a THF–alcohol mixture. The
cleavage of the final products from the resin 5 with 50%
TFA–DCM afforded the arylalkanolamines 6 as enan-
tiomeric mixtures in high yield ranging from 75 to 95%
and purities from 85 to 93%. Further, to investigate the
scope and limitation of our strategy, we synthesized a
library of 12 compounds using four isocyanates, two
bromoacetophenones and one 3-chloropropiophenone.
The compounds were obtained in good yields with
purities ranging from 85 to 93% (Table 1 and Ref. 10).
The compounds were characterized using HPLC, FAB
MS and NMR.10
Solid-phase syntheses of alkanolamines and arylalk-
anolamines have been reported in the literature.3,4
Purandre and Poss4 synthesized arylalkanolamines in
three steps, comprising reductive alkylation of resin
bound amines, alkylation of secondary amines with
structurally diverse chloroacetophenones and chloro-
propiophenones and, finally, reduction of the resulting
ketones to alcohols. However, side reactions such as
incomplete alkylation of the resin and partial quater-
nary salt formation, were encountered during their
solid-phase synthesis.
In this paper we present a versatile solid-phase synthe-
sis
of
arylalkanolamines
6,
in
particular,
arylethanolamines and arylpropanolamines, from resin
bound carbamates in high yields. We designed our
In summary, we have developed a versatile approach
for the solid-phase synthesis of arylalkanolamines from
polymer bound carbamates. It can be successfully used
for the generation of libraries of arylalkanolamines.
* Corresponding author. Tel.: 0091 522 212 411; fax: 0091 522 223
405; e-mail: bijoy kundu@yahoo.com
–
† CDRI Communication No. 6163.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01166-2

5994
T. Srini6asan et al. / Tetrahedron Letters 42 (2001) 5993–5995
Scheme 1. n=1, arylethanolamine and n=2, arylpropanolamine.
Table 1. Structures, yields and purity of the library compounds
Compound
R1
R2
n
Isolated yield (%)
HPLC purity (%)a
1
2
3
4
5
6
7
8
o-Tolyl
p-Tolyl
3-Chloro-4-methylphenyl
Benzyl
o-Tolyl
p-Tolyl
3-Chloro-4-methylphenyl
Benzyl
o-Tolyl
p-Tolyl
H
H
H
H
4-Br
4-Br
4-Br
H
H
H
1
1
1
1
1
1
1
2
2
2
2
82
92
81
78
75
75
81
79
88
85
82
89
88
90
86
87
90
86
85
90
89
93
9
10
11
3-Chloro-4-methylphenyl
H
a Whatmann C18 reversed-phase column (250×4.6 mm, 10 mm) with a linear gradient 10–98% CH3CN in water over 45 min, flow rate 0.5 ml/min,
and UV detection at 254 nm.
References
the benzylisocyanate (5 equiv., 0.35 mmol) and Et3N (10
equiv., 0.7 mmol). After shaking at 100°C for 16 h, the
solvent was drained and the resin washed with DMF
(5×3 min), DMF:H2O (1:1; 5×3 min), MeOH (5×3 min),
DCM (5×3 min) and dried in vacuo to give 2. Next, the
carbamate 2 was treated with NaH (60% in oil, 5 equiv.,
0.35 mmol) in DMF at rt for 1.5 h, followed by addition
of phenacyl bromide (10 equiv., 0.7 mmol) in DMF.
After shaking at 80°C for 16 h the resin was successively
washed with DMF (3×2 min), MeOH (3×2 min), DCM
(3×2 min) and finally dried in vacuo to give 4. Thereupon
resin 4 was treated with sodium borohydride (10 equiv.,
0.7 mmol) in a mixture of THF–ethanol (1.2 ml, 1:1) for
12 h. The resin was successively washed with THF (3×2
min), DMF (3×2 min), MeOH (3×2 min), DCM (3×2
min) and dried in vacuo to give resin 5. Finally resin 5
1. Dolle, R. E. J. Comb. Chem. 1999, 2, 383.
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5. General experimental procedure for 6: To a suspension of
Wang resin (100 mg, 0.07 mmol) in toluene was added

T. Srini6asan et al. / Tetrahedron Letters 42 (2001) 5993–5995
5995
was cleaved with a mixture of TFA–DCM (4 ml, 1:1) for
2 h and the resulting mixture was filtered and evaporated
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dissolving in t-BuOH–water (4:1) to give compound 6 as
the trifluoroacetate salt in 85% overall yield.
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(m, 2H, CH2), 4.02 (s, 2H, CH2), 4.32 (q, 1H, J=7.2 Hz,
CH), 6.86 (d, 2H, J=8.7 Hz, Ar-H), 7.36–7.42 (m, 5H,
Ar-H), 7.89 (d, 2H, J=8.4 Hz, Ar-H); RP-HPLC: tR=
15.6 min on a Whatmann C18 reversed-phase column
(250×4.6 mm, 10 mm) with a linear gradient 10–98%
CH3CN in water (v/v) over 45 min, flow rate 0.5 ml/min,
and UV detection at 254 nm.
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10. 2-(Benzylamino)-1-(4-bromophenyl)ethan-1-ol: FAB MS
307 (M+H); HPLC purity 95%; 1H NMR (300 MHz,
CDCl3): l 2.8 (brs, 1H, OH), 2.96 (brs, 1H, NH), 3.18
2-(Benzylamino)-1-(4-bromophenyl)ethan-1-one:
FAB
1
MS 305 (M+H); H NMR (300 MHz, CDCl3): l 4.03 (s,
2H, CH2), 5.47 (s, 2H, CH2), 6.89 (d, 2H, J=8.4 Hz,
Ar-H), 7.38–7.44 (m, 5H, Ar-H), 7.85 (d, 2H, J=8.4 Hz,
Ar-H); RP-HPLC: tR=23.6 min on a Whatmann C18
reversed-phase column (250×4.6 mm, 10 mm) with a
linear gradient 10–98% CH3CN in water over 45 min,
flow rate 0.5 ml/min, and UV detection at 254 nm.
.