3-Amino-2-arylpropanoic acids by electrophilic substitution of 2-arylethylamines at the benzylic position

Article abstract of DOI:10.1016/0040-4039(91)85013-U

A reaction sequence consisting of N-pivaloylation, lithiation at the benzylic position, carboxylation and deprotection allows to convert 2-arylethylamines into 3-amino-2-arylpropanoic acids with good yields.

Full text of DOI:10.1016/0040-4039(91)85013-U

Tctrahedron Letters, Vo132, No.17, pp 1963 1964, 1991
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3-AMINO-2-ARYLPROPANOIC ACIDS
BY ELECTROPHILIC SUBSTITUTION OF 2-ARYLETHYLAMINES
AT THE BENZYLIC POSITION
Gyula SIMIG and Manfred SCHLOSSER*
Institut de Chimie organique de l'Universit6
Rue de la Barre 2, CH-1005 Lausanne, Switzerland
Summary :
A reaction sequence consisting of N-pivaloylatinn, lithiation at the
benzylic position, carboxylation and deprotection allows to convert 2-arylethylamines
into 3-amino-2-arylpropanoic acids with good yields.
When treated with butyllithium in diethyl ether or hexane, N,N-dimcthylaniline I1] and N,N-dimethylbenzyl-
amine [2] slowly undergo hydrogen/lithium exchange at an ortho position. The metalation promoting effect
vanishes with increasing distance between the complexing group and the reaction center. Actually, only 7% of
the ortho substituted derivative were obtained after N,N-dimetbyl-2-phenylethylamine had been submitted to
consecutive metalation with butyllithium and trapping with benzophenone [3] The principal reaction pathway was
postulated to be a lithiation at the benzylic position followed by E-elimination of lithium dimetbylamide and
subsequent polymerization of the resulting styrene. However, N,N-dimethyl-2-mcthyl-2-phenylpropylamine as a
substrate gave only a slightly increased yield (17%) of the ortho derivative [31.
~
~ N(CH3}2
"El
N(CH3} 2 ~ "
"-~.
[ ~ L L NICH3}2
v
L i.
~
N(CH3}2
We wish to report now that the deprotonated N-pivaloylamino [4] moiety provides more powerful and more
specific neighboring group assistance to mctalation than does the dimcthylamino group. In this way, perfect
control over the reaction outcome can be achieved :
With tert-butyllithium as the metalating reagent, clean mctalation at the benzylic position takes place. The
introduction of methoxy substituents into the aromatic ring does not alter this regioselectivlty (see Table),
while N,N-dimethyl- or N-(trimethylsilyl)-2-(4-alkoxyphenyl)cthylamines are invariably attacked at an
aromatic position [51.
•
The organometalfic intermediates are stable towards elimination. They efficiently react with clectrophiles,
in particular with carbon dioxide (see Table).
1963

1964
After carboxylation, the N-pivaloyl moiety can be removed by acid hydrolysis. Thus, 2-arylethylamines can
be indirectly converted into 3-amino-2-arylpropanoic acids with good yields (see Table).
COOH
C O O H
x
~
C
H
,
C H 2 - N H 2 - - X ~ - C H 2 CH2-NH-CO-R
[CO-R
x ~ C H - O H 2 - N H - C O R - - x ~ C H - C H 2 - N H 2
=
CO-C(CH313]
Table.
Synthesis of 3-(N-pivaloylamino)-2-arylpropanoic acids a) and 3-amino-2-
arylpropanoic acid hydrochlorides a) : yields and melting ranges tq.
COOH
COOH
®
®
X"
~
-
C
H - CH2- N- C- C(CH3}3
X " ~ - CH-CH2-NH3 CI
x x
X/
'X
H
O
X'
X
yield
melting range
yield
melting range
1Z.7 - 1Z.8 °C e}
X"
X'
H
X
N
76%
53%
228
212
-
22g°cgl
213°C hI
72%
H
-
77% c}
77% dl
179 - 180 °C e}
138 - 139 °C fl
132 - 133 °ca}
H
H
)CH
N
3CH3
75%
63%
5 7 %
227- 228°C il
211.- 215°C ~}
232 - 233 °Cil
H
H
H
H
CH:
79%
78%
168
-
169°C el
OH )OH
(a) Standard working procedures : A 1.5 M solution of tert-butyllithium (30 mmol) in
pentane was added to the 2-aryl-N-pivaloylethylaraine (10 mmol) in tetrahydrofuran
(50 mL) at -75 °C. After 3 h at -50 °C the mixture was poured on dry ice. The organic
layer was extracted with water (1 x 30 and 2 x 5 mL). Upon acidification of the aqueous
phase the 3-(N-pivaloyl)-2-arylpropanoic acid precipitated. It was either immediately
collected or isolated by extraction with dichloromethane. The products (3 mmol) were
suspended in 20% hydrochloric acid (12 mL) heated 8 h under reflux. The hot solution
was f'dtered; upon cooling the 3-amino-2-arylpropanoic acid hydrochlorides settled out.
(b) The hydrocblorides melt under decomposition. (c) Metalation during 6 h at -75 °C.
(d) Metalation during 3 h at -75 *C. (e) Crystallized from ethyl acetate. (0 Crystallized
from toluene. (g) Crystallized from ethanol. (h) Crystallized from a mixture of iso-
propanol and diethylether. (i) Crystallized from aqueous ethanol.
REFERENCES
[1]
A.R. Lepley, W.A. Khan, A.B. Giumanini, A.G. Giumanini, J. Org. Chem. 31 (1966), 2047; R.E. Ludt,
G.P. Growther, C.R. Hauser, Z Org. Chem. 35 (1970), 1288; D.W. Slocum, G. Back, C.A. Jennings,
Tetrahedton Left. I1 (1970), 3443.
[2]
[3]
F.N. Jones, R.L. Vaalx, C.R. Hauser, J. Org. Chem. 28 (1963), 3461.
D.W. Slocum, T.R. Engelmann, C.A. Jennings, Austr. Z Chem. 21 (1968), 2319; see also : R.L. Vaulx,
F.N. Jones, C.R. Hauser, Z Org. Chem. 30 (1965), 58; N.S. Narasimhan, A.C. Ranade, Tetrahedron Lett. 7
(1966), 603.
[4]
[5]
Metalation of N-pivaloylbenzylamines : Gy. Simig, M. Schlosser, Tetrahedron Lett. 29 (1988), 4277.
D.W. Sloeum, C.A. Jennings. Z Org. Chem. 41 (1976), 3653; C.D. Liang, Tetrahedron Lett. 27 (1986), 1971;
C. Lamas, L Castedo, D. Domhaguez, Tetrahedron Lett. 29 (1988), 3865.
(Received in France 31 January 1991)