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Synthesis of α-aminoketones via selective reduction of acyl cyanides
Tetrahedron Printed in
Letters,Vol.25,No.28,pn Great Britain
SYNTHESIS
2977-2980,1984
OF a-AMINOKETONES
Andreas
Laboratorium
VIA SELECTIVE
Pfaltz*
fiir Organische CH-8092
0040-4039/84 $3.00 + .oo 01984 Peraamon Press Ltd.
REDUCTION
OF ACYL CYANIDES
and Saeed Anwar
Chemie
Zurich,
der ETH, ETH-Zentrum,
Switzerland
Abstract: Reduction of acyl cyanides with zinc in acetic acid in the presence of excess acetic anhydride leads to N-acetyl-cr-aminoketones in good yields. An efficient three-step synthesis of 5-aminolevulinic acid by this method is described.
a-Aminoketones
are versatile
difunctional
compounds.
They have found a wide range of
heteroapplications in organic synthesis, e.g. as building blocks for nitrogen-containing 1 cycles. We report here an efficient procedure for the preparation of a-aminoketones from carboxylic
acids,
based on the selective
In connection the reduction precursor
interest chemical
of methyl
succinyl
of 4, provided
amine without labelled
reduction of acyl cyanides. 13 with the synthesis of C-labelled 5-aminolevulinic
affecting
succinate,
cyanide 2. Compound
that the nitrile
Starting
acid 4 we have studied
be an ideal,
group could be selectively
the keto and ester groups.
readily
transformed
from labelled
cyanide
available to R primal-y or from
introduced by this route, which would be of 13 considering the numerous applications of C-labelled 5-aminolevulinic acids in bio2 and structural studies of natural porphyrins and corrins.
An example Stuckwisch3,
isotope
2 would
of conversion
who studied
corresponding an analogous
labels could be easily
of an acyl cyanide
the Stephen
amino-acetophenones. transformation
reduction
(SnC12/HC1)
Our experiments
is also feasible
to an a-aminoketone
has been reported
of aroyl cyanides
with methyl
in the aliphatic
succinyl
leading
by
to the
cyanide 2 showed
that
series. We found that compound
is cleanly
reduced at the nitrile group with zinc in acetic acid in the presence of excess 4 Concomitant acetylation leads to the relatively stable N-acetyl derivative 5 2 of 5-aminolevulinic acid methyl ester, obtained as a crystalline compound in high yield. acetic
anhydride.
Subsequent isolated allows
hydrolysis
a convenient
available
in aqueous
as the hydrochloride
methyl
well suited
three-step
succinyl
hydrochloric
acid affords
-4 in essentially
quantitative
preparation
yield
(cf. Scheme
1). This route
of 5-aminolevulinic acid 4 from commercially 6 Our synthesis is particularly -1 in ca. 60 % overall yield. 13 of a C-label at C-5 starting from relatively inexpensive
chloride
to the introduction 7 [13C]-sodium cyanide.
the free amino acid, which can be
2977
2
2978
Table
1. Reduction
of Acyl Cyanides
Entry
with Zinc in Acetic Acid /Acetic
Anhydride
Reactiona
12
Yieldb
__
0
0
(I)
NHAc
CN
(2)
QJ,
(3)
dCN
75 %
-
~NHAC
71 %
w
&NHAC
74 % -!!
(‘I
H,COOC
C
CN
83 %
H3COOCANHAC
2
3 0
70%
(5) +CN 0
0
OH (-30 %I=
(61 -
CN
(-20%)”
&NHAC
-1
12
(7)
ANHAC
i-1 O%T
17 -
aAll reactions
were done at 40 "C as described
of methyl
succinyl
chlorides
and CuCN
tography
procedure
for the reduction
The acyl cyanides were prepared from the corresponding acyl cyanide 2. 10 pure products after chromaor Me3Sik:P"l. bYields of spectroscopically
and recrystallization.
ducts obtained
in the experimental
in preliminary
'Approximate experiments.
yields
of chromatographed
(non-crystalline)
pro-
2979
Scheme
Zn/AcOH AqO 140’
I:
H$OOC-CN
zinc in acetic
the scope of the method,
and selective;
The results
acyl cyanides
a different
course
C=O double ponding hydrin
bond was observed.
of benzaldehyde.
are summarized the method
are obtained
conditions
types of acyl cyanides in Table
in good yields.
with
1. With the excep-
seems to be generally
(cf. entries
applicable,
The reagent
is mild
3, 4 and 5).
acyl cyanide __I 15 not unexpectedly,
(entry 7). In addition
group a non-specific
acetamido-ketone
various
bonds like the vinyl group in 2, as well as ester and keto functions
under the reaction
In the case of the a,P-unsaturated
acetamido-methyl
we have treated
N-acetyl-o-aminoketones
C=C double
are not affected
anhydride.
and a,P-unsaturated
and the corresponding
H$OOCLNHAC 3
acid /acetic
tion of aromatic
*
(83%)
2
To evaluate
1
to the usual transformation
reduction
Zinc reduction
the reaction
of the nitrile
of the enone system at either
of benzoyl
(entry 6); the only product,
cyanide
isolated
took
to an
the C=C or the
did not lead to the corresin low yield, was the cyano-
8
In recent years a number of efficient methods for the preparation of acyl cyanides have 9 The most general routes start from the corresponding carboxylic acids and 10 9,ll involve the reaction of an acyl halide with cuprous cyanide or trimethylsilyl cyanide .
been developed.
The reduction to established
of acyl cyanides described here can thus be considered methods 196 for the synthesis of aminomethyl-ketones.
Acknowledgement. Federal
Government
Rudolf Wettstein
We thank Prof. A. Eschenmoser
Fellowship' for valuable
for the support
to Saeed Anwar is gratefully technical
assistance.
an attractive
alternative
of this work. A 'Swiss
acknowledged.
We also thank Mr.
2980
References
1.
2.
D. Mayer
in "Houben-Weyl,
(Thieme,
Stuttgart
Methoden
and Notes
der Organischen
See e.g.: A.I. Scott, Pure Appl. Chem. 2, "ti12",
Chemie",
4th. Ed., Vol. 7/2c, p. 2251
1977). 1215 (1981); A.R. Battersby,
E. McDonald
in
D. Dolphin Ed., Vol. 1, p. 107 (Wiley, New York 1982); A. Pfaltz, 6. Jaun, A.
Fassler,
A. Eschenmoser;
R. Jaenchen,
H.H. Gilles,
G. Diekert,
R.K. Thauer,
!-:elv.Chim.
Acta 41, 823 (1982). 3.
C.G. Stuckwisch, phenones
K.H. Werner, 4.
J. Org. Chem. 21, 318 (1972). According
can also be prepared DDR-Pat.
The reduction
Catalytic
65929 (1969); C.A. 11,
amide
formation
hydrogenation
of 5-aminolevulinic
Sot. Chem. Commun.
1978, 753; G. Schulz,
Ed.,Vol.VI,
8.
In contrast
9.
S. Hiinig, R. Schaller,
A. Fassler,
obtained
W. Steglich,
Press,
J.F. Normant, K. Herrmann,
G. Simchen,
C. Piechucki,
R. Schaller,
Chem. Ber. 115,
Experimental
Procedure:
the addition,
MeOH
A solution
(Received
solid
1979, 204; U. Hertenstein,
of methyl
in
Germany
is converted
to
Ed. 1,
36 (1982).
S. Hiinig, H. Reichelt,
succinyl
cyanide 2 (3.0 g, 21 mmol)
(4 ml) was added dropwise
solid was washed
1984)
in of acti-
(30 ml) under nitrogen.
was kept at 40 'C. After
mixture
wa s cooled
with methylene
to rooir terpera-
chloride.
The solvents
cm silica gel column
solidified
upon drying
gave 3.3 g (83 X) of acetamido-ketone
“cj.
5 April
to a suspension
anhydride
on a 3x15
oil (Rf = 0.31), which
from toluene
(sp. 52-53
cyanide
with SnC12/HC1.3
90 min at 40 "C, the reaction
a yellowish
torr. Recrystallization crystalline
benzoyl
1 (1982); Angew. Chem.,Int.
at 0.01 torr. Flash chromatography
1O:l) afforded
D. Dolphin
261 (1982).
lhe remaining
ture and filtered.
J. Chem.
787 (1980) and
in "The Porphyrins",
which took ca. 10 min, the temperature
for additional
were removed
Chem. Ber. 113,
Bull. Sot. Chim. Fr. 1972, 2402.
Synthesis
acid (4 ml) / acetic anhydride
stirring
gave
(40 - 65 %).
New York 1979).
vated zinc dust (12 g) in acetic acid (30 ml) / acetic During
1 atm. H2; AcOH/Ac20)
yield
in
and the acyl cyanide.
(in preparation).
with Zn/AcOH/Ac20,
Angew. Chem. 94,
11.
acetic
aminoketone
cyanide 1 (Pd-C;
in 67 % yield by reduction
10.
(H. Brachwitz, 1, p. 2516).
of a large excess of acetic anhydride
& A. Valasinas
Helv. Chim. Acta
to the results
cY-amino-acetophenone
of aroyl cyanides
acid cf.: D.A. Evans, P.J. Sidebottom,
B. Frydman
Part A, p. 12 (Academic
A. Pfaltz,
to a patent cu-amino-aceto-
(1969); cf. reference
the resulting
succinyl
For other syntheses
7.
123965s
in lower and less reproducible
the review of R.B. Frydman,
12.
between
of methyl
the same product 2 albeit 6.
hydrogenation
has to be done in the presence
order to prevent 5.
by catalytic
(EtOAc/
at 0.01
2 as a white
Letters,Vol.25,No.28,pn Great Britain
SYNTHESIS
2977-2980,1984
OF a-AMINOKETONES
Andreas
Laboratorium
VIA SELECTIVE
Pfaltz*
fiir Organische CH-8092
0040-4039/84 $3.00 + .oo 01984 Peraamon Press Ltd.
REDUCTION
OF ACYL CYANIDES
and Saeed Anwar
Chemie
Zurich,
der ETH, ETH-Zentrum,
Switzerland
Abstract: Reduction of acyl cyanides with zinc in acetic acid in the presence of excess acetic anhydride leads to N-acetyl-cr-aminoketones in good yields. An efficient three-step synthesis of 5-aminolevulinic acid by this method is described.
a-Aminoketones
are versatile
difunctional
compounds.
They have found a wide range of
heteroapplications in organic synthesis, e.g. as building blocks for nitrogen-containing 1 cycles. We report here an efficient procedure for the preparation of a-aminoketones from carboxylic
acids,
based on the selective
In connection the reduction precursor
interest chemical
of methyl
succinyl
of 4, provided
amine without labelled
reduction of acyl cyanides. 13 with the synthesis of C-labelled 5-aminolevulinic
affecting
succinate,
cyanide 2. Compound
that the nitrile
Starting
acid 4 we have studied
be an ideal,
group could be selectively
the keto and ester groups.
readily
transformed
from labelled
cyanide
available to R primal-y or from
introduced by this route, which would be of 13 considering the numerous applications of C-labelled 5-aminolevulinic acids in bio2 and structural studies of natural porphyrins and corrins.
An example Stuckwisch3,
isotope
2 would
of conversion
who studied
corresponding an analogous
labels could be easily
of an acyl cyanide
the Stephen
amino-acetophenones. transformation
reduction
(SnC12/HC1)
Our experiments
is also feasible
to an a-aminoketone
has been reported
of aroyl cyanides
with methyl
in the aliphatic
succinyl
leading
by
to the
cyanide 2 showed
that
series. We found that compound
is cleanly
reduced at the nitrile group with zinc in acetic acid in the presence of excess 4 Concomitant acetylation leads to the relatively stable N-acetyl derivative 5 2 of 5-aminolevulinic acid methyl ester, obtained as a crystalline compound in high yield. acetic
anhydride.
Subsequent isolated allows
hydrolysis
a convenient
available
in aqueous
as the hydrochloride
methyl
well suited
three-step
succinyl
hydrochloric
acid affords
-4 in essentially
quantitative
preparation
yield
(cf. Scheme
1). This route
of 5-aminolevulinic acid 4 from commercially 6 Our synthesis is particularly -1 in ca. 60 % overall yield. 13 of a C-label at C-5 starting from relatively inexpensive
chloride
to the introduction 7 [13C]-sodium cyanide.
the free amino acid, which can be
2977
2
2978
Table
1. Reduction
of Acyl Cyanides
Entry
with Zinc in Acetic Acid /Acetic
Anhydride
Reactiona
12
Yieldb
__
0
0
(I)
NHAc
CN
(2)
QJ,
(3)
dCN
75 %
-
~NHAC
71 %
w
&NHAC
74 % -!!
(‘I
H,COOC
C
CN
83 %
H3COOCANHAC
2
3 0
70%
(5) +CN 0
0
OH (-30 %I=
(61 -
CN
(-20%)”
&NHAC
-1
12
(7)
ANHAC
i-1 O%T
17 -
aAll reactions
were done at 40 "C as described
of methyl
succinyl
chlorides
and CuCN
tography
procedure
for the reduction
The acyl cyanides were prepared from the corresponding acyl cyanide 2. 10 pure products after chromaor Me3Sik:P"l. bYields of spectroscopically
and recrystallization.
ducts obtained
in the experimental
in preliminary
'Approximate experiments.
yields
of chromatographed
(non-crystalline)
pro-
2979
Scheme
Zn/AcOH AqO 140’
I:
H$OOC-CN
zinc in acetic
the scope of the method,
and selective;
The results
acyl cyanides
a different
course
C=O double ponding hydrin
bond was observed.
of benzaldehyde.
are summarized the method
are obtained
conditions
types of acyl cyanides in Table
in good yields.
with
1. With the excep-
seems to be generally
(cf. entries
applicable,
The reagent
is mild
3, 4 and 5).
acyl cyanide __I 15 not unexpectedly,
(entry 7). In addition
group a non-specific
acetamido-ketone
various
bonds like the vinyl group in 2, as well as ester and keto functions
under the reaction
In the case of the a,P-unsaturated
acetamido-methyl
we have treated
N-acetyl-o-aminoketones
C=C double
are not affected
anhydride.
and a,P-unsaturated
and the corresponding
H$OOCLNHAC 3
acid /acetic
tion of aromatic
*
(83%)
2
To evaluate
1
to the usual transformation
reduction
Zinc reduction
the reaction
of the nitrile
of the enone system at either
of benzoyl
(entry 6); the only product,
cyanide
isolated
took
to an
the C=C or the
did not lead to the corresin low yield, was the cyano-
8
In recent years a number of efficient methods for the preparation of acyl cyanides have 9 The most general routes start from the corresponding carboxylic acids and 10 9,ll involve the reaction of an acyl halide with cuprous cyanide or trimethylsilyl cyanide .
been developed.
The reduction to established
of acyl cyanides described here can thus be considered methods 196 for the synthesis of aminomethyl-ketones.
Acknowledgement. Federal
Government
Rudolf Wettstein
We thank Prof. A. Eschenmoser
Fellowship' for valuable
for the support
to Saeed Anwar is gratefully technical
assistance.
an attractive
alternative
of this work. A 'Swiss
acknowledged.
We also thank Mr.
2980
References
1.
2.
D. Mayer
in "Houben-Weyl,
(Thieme,
Stuttgart
Methoden
and Notes
der Organischen
See e.g.: A.I. Scott, Pure Appl. Chem. 2, "ti12",
Chemie",
4th. Ed., Vol. 7/2c, p. 2251
1977). 1215 (1981); A.R. Battersby,
E. McDonald
in
D. Dolphin Ed., Vol. 1, p. 107 (Wiley, New York 1982); A. Pfaltz, 6. Jaun, A.
Fassler,
A. Eschenmoser;
R. Jaenchen,
H.H. Gilles,
G. Diekert,
R.K. Thauer,
!-:elv.Chim.
Acta 41, 823 (1982). 3.
C.G. Stuckwisch, phenones
K.H. Werner, 4.
J. Org. Chem. 21, 318 (1972). According
can also be prepared DDR-Pat.
The reduction
Catalytic
65929 (1969); C.A. 11,
amide
formation
hydrogenation
of 5-aminolevulinic
Sot. Chem. Commun.
1978, 753; G. Schulz,
Ed.,Vol.VI,
8.
In contrast
9.
S. Hiinig, R. Schaller,
A. Fassler,
obtained
W. Steglich,
Press,
J.F. Normant, K. Herrmann,
G. Simchen,
C. Piechucki,
R. Schaller,
Chem. Ber. 115,
Experimental
Procedure:
the addition,
MeOH
A solution
(Received
solid
1979, 204; U. Hertenstein,
of methyl
in
Germany
is converted
to
Ed. 1,
36 (1982).
S. Hiinig, H. Reichelt,
succinyl
cyanide 2 (3.0 g, 21 mmol)
(4 ml) was added dropwise
solid was washed
1984)
in of acti-
(30 ml) under nitrogen.
was kept at 40 'C. After
mixture
wa s cooled
with methylene
to rooir terpera-
chloride.
The solvents
cm silica gel column
solidified
upon drying
gave 3.3 g (83 X) of acetamido-ketone
“cj.
5 April
to a suspension
anhydride
on a 3x15
oil (Rf = 0.31), which
from toluene
(sp. 52-53
cyanide
with SnC12/HC1.3
90 min at 40 "C, the reaction
a yellowish
torr. Recrystallization crystalline
benzoyl
1 (1982); Angew. Chem.,Int.
at 0.01 torr. Flash chromatography
1O:l) afforded
D. Dolphin
261 (1982).
lhe remaining
ture and filtered.
J. Chem.
787 (1980) and
in "The Porphyrins",
which took ca. 10 min, the temperature
for additional
were removed
Chem. Ber. 113,
Bull. Sot. Chim. Fr. 1972, 2402.
Synthesis
acid (4 ml) / acetic anhydride
stirring
gave
(40 - 65 %).
New York 1979).
vated zinc dust (12 g) in acetic acid (30 ml) / acetic During
1 atm. H2; AcOH/Ac20)
yield
in
and the acyl cyanide.
(in preparation).
with Zn/AcOH/Ac20,
Angew. Chem. 94,
11.
acetic
aminoketone
cyanide 1 (Pd-C;
in 67 % yield by reduction
10.
(H. Brachwitz, 1, p. 2516).
of a large excess of acetic anhydride
& A. Valasinas
Helv. Chim. Acta
to the results
cY-amino-acetophenone
of aroyl cyanides
acid cf.: D.A. Evans, P.J. Sidebottom,
B. Frydman
Part A, p. 12 (Academic
A. Pfaltz,
to a patent cu-amino-aceto-
(1969); cf. reference
the resulting
succinyl
For other syntheses
7.
123965s
in lower and less reproducible
the review of R.B. Frydman,
12.
between
of methyl
the same product 2 albeit 6.
hydrogenation
has to be done in the presence
order to prevent 5.
by catalytic
(EtOAc/
at 0.01
2 as a white