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A novel reducing agent derived from formic acid and two equivalents of a grignard reagent: Chemoselective reduction of aldehydes
Tetrahedron Letters Vol. 22, pp 621 - 622 OPergamon Press Ltd. 1981. Printed in Great Sritain
A NOVEL REDUCING
AGENT DERIVED
TWO EQUIVALENTS CHEMOSELECTIVE James Department
H.
REDUCTION
Babler*
of
and
Chemistry,
Chicago,
:
Summary addition solution.
F.
addition
the
Sato of
tetrahydrofuran that
and
two
presumed
coworkers
some
decided
to
examine
its
(1)
formic
citra13
potential by acid (2:’
afforded,
as
successful starting
by
aldehyde.
indicated
THF as of
of
(1,
Chicago
in
the
product
X=Br)
in
these
Using
initial the
absence
and
resulted
alcohol of
any in
results,
standard 7
in
94%
a 75% distilled
of given
stirring
the
manner and
we examined
conditions
unreacted
to
a solution
reaction room
which
procedure and
5
preparation
of
aldehydes
of
formic
mixture.
in
that acid
They
temperature.
intermediate
equivalents
the
reagent obtained by the acid in tetrahydrofuran quite slowly.
also
Since
the
a Cannizzaro
in-
in indicated latter 2
reaction,
we
donor to carbonyl compounds. 0 REOMgX + R’CH20MgX
R=CH3CH2, molar
the
THF at
proposed
a,
stereoisomers)
of
in
a hydride
two
described E:Z
p-methylbenzyl the
the
for
reagent of
(3,7-dimethyl-2,6-octadien-l-o17)
Encouraged
afforded
agent
isolation
alcohol
decyl
of
USA
a method
stable
RC(OMgX)2 I! -1
addition
mixture
to
potential
reducing the in
after
desired
lnvergo
University
a Grignard
was
resemblance
HCOOH + 2RMgX THF,
of
J.
60626
by acidification
intermediate
bears
prepared
of
followed
(I) -
The
Loyola
reported’
equivalents
(THF),
species
was
OF ALDEHYDES
Benedict
Illinois
AND
REAGENT:
Aldehydes are reduced at a moderate rate by use of a novel of two molar equivalents of ethylmagnesium bromide to formic Under similar conditions the reduction of ketones proceeds
Recently volved
FROM FORMIC ACID
OF A GRIGNARD
(35
yield.
yield
The of
at
aldehyde
in
reactions 2O’C)
3
mixture
of 9
of decyl of
88%
with
outlined
NMR analysis
reduction
a 9:’
initial
studies to
a solution
Subsequent addition of 4 for 20 minutes at roan temperature 6 of outlined below, a 3:’ mixture
similar
min.
for
bromide
below.
unreduced
IR and
aldehyde.
we selected
ethylmagnesium
distilled
p-tolualdehyde
below, the
the yield.
reaction
aIdehyde
I-decanol
and
-p-tolualdehyde3 product8 was
7
and
also
unreacted
material.
Procedure: To a solution of 0.25 mL (6.6 moles) of formic acid ” [assay (HCOOH):min. 98%] in 8 mL of anhydrous THF at O°C under a nitrogen atmos here was added dropwise slowly over 20 min. 4 mL of a 3 3 solution of ethylmagnesium bromide ! (12 mmoles) in ethyl ether. This mixture was subsequently stirred at room temperature for 30 min. before adding dropwise over 2 min. a solution of 3.3 mmoles of the carbonyl compound in 2 mL of anhydrous THF. After being stirred for 35 min. at 20°C, this mixture was cooled to O’C and subsequently acidified by dropwise addition of 6 mL of 2 M aq. HCI. The reaction mixture was then poured into 60 mL of saturated brine and extracted wTth solvent ether (Ix40 mL). The organic phase was washed successively with 50 mL portions of brine and saturated aqueous NaHC03 solution.” The organic layer was then dried (MgS04), the solvent removed in vacua, and the product purified by evaporative (Kugelrohr) distillation.
621
622
When the proceeded for this of and
se1 ect ive novel “RI’
procedure
slowly reduct
type
are
results
above
very
of
ion
be
and
was
shown
13
reducing
changed, will
as
its
reported
of
utilized
by the
aldehydes agent
in
(I_),
the
with
a future
Material
%Yielda
representative
Table
presence its
other
I.
This
of
ketones.
properties
functional
A more as
the
groups
is
reduct
therefore detailed
solvent presently
ionI
offers
promise
study
and
the
being
of
nature initiated
I
(Distilled
Product)
Ratiob of Ketone to Alcohol
93
propiophenone 4-phenyl-2-butanone cycloheptanone
ketones,3
method
article. TABLE
Starting
several in
including
reactivity in
for
results
91:9 go:10 81:19
aVPC analy is indicated the ketone g mixture. This ratio was determined tent ion times: alcohol > ketone. structures.
and corresponding by VPC analysis IR and NMR spectra
reduction
product to comprise >98% of the 2f% Carbowax 20M column). Reconsistent with the assigned
(6’x1/8” were
REFERENCES 1. 32: 4. 5. 6. 7. 8. 9. 10. 11.
12.
13.
F. Sato, K. Ogura, H. Watanabe, and M. Sato, Tetrahedron Lett., 21, 2869 (1980). For a review, see T.A. Geissman, Org. React., 2, 94-113 (1944). Available from Aldrich Chemical Co., Milwaukee, Wis. U.S.A. After a reaction time of 40 minutes, the product was a 9:l mixture of alcohol and the corresponding aldehyde. No citronella1 or citronellol, products obtainable by 1,4-reduction of citral, could be detected by NMR analysis of this mixture. This ratio was determined by NMR analysis (CH20H vs. CHO signals). IR and NMR spectra were identical to those ej;hibited by the authentic compound sold by Aldrich Chemical Co. NMR analysis failed to detect the presence of any p-tolylethylcarbinol, a by-product expected in the presence of excess ethylmagnesium bromide. This ratio was determined by VPC analysis (6’x1/8” 24% Carbowax 20M column, 185’C). The alcohol and aldehyde comprised >95% of this mixture. Among the suppliers of “anhydrous” formic acid are Fluka (purum anhydrous HCOOH, 98% min.) and Eastman Organic Chemicals (formic acid, 97% min.). If this wash was not done, the crude product was contaminated with a minor amount of propionic acid (the formation of which is consistent with our proposed mechanism for the reduction). Although its reduction was quite Anomalous results were obtained using cyclohexanone. slow, ~75% of the isolated material was a mixture of products derived from aldol-type condensations. For orevious methods to effect such a transformation see: P.A. Risbood and D.M. Ruthven. J. Org. Chem ., 9, 3969 (1979); G.C. Andrews, Tetrahedron Lett., 2, 697 (1980) and references in footnote 3 in that paper.
(Received in USA
26
August 1980)
A NOVEL REDUCING
AGENT DERIVED
TWO EQUIVALENTS CHEMOSELECTIVE James Department
H.
REDUCTION
Babler*
of
and
Chemistry,
Chicago,
:
Summary addition solution.
F.
addition
the
Sato of
tetrahydrofuran that
and
two
presumed
coworkers
some
decided
to
examine
its
(1)
formic
citra13
potential by acid (2:’
afforded,
as
successful starting
by
aldehyde.
indicated
THF as of
of
(1,
Chicago
in
the
product
X=Br)
in
these
Using
initial the
absence
and
resulted
alcohol of
any in
results,
standard 7
in
94%
a 75% distilled
of given
stirring
the
manner and
we examined
conditions
unreacted
to
a solution
reaction room
which
procedure and
5
preparation
of
aldehydes
of
formic
mixture.
in
that acid
They
temperature.
intermediate
equivalents
the
reagent obtained by the acid in tetrahydrofuran quite slowly.
also
Since
the
a Cannizzaro
in-
in indicated latter 2
reaction,
we
donor to carbonyl compounds. 0 REOMgX + R’CH20MgX
R=CH3CH2, molar
the
THF at
proposed
a,
stereoisomers)
of
in
a hydride
two
described E:Z
p-methylbenzyl the
the
for
reagent of
(3,7-dimethyl-2,6-octadien-l-o17)
Encouraged
afforded
agent
isolation
alcohol
decyl
of
USA
a method
stable
RC(OMgX)2 I! -1
addition
mixture
to
potential
reducing the in
after
desired
lnvergo
University
a Grignard
was
resemblance
HCOOH + 2RMgX THF,
of
J.
60626
by acidification
intermediate
bears
prepared
of
followed
(I) -
The
Loyola
reported’
equivalents
(THF),
species
was
OF ALDEHYDES
Benedict
Illinois
AND
REAGENT:
Aldehydes are reduced at a moderate rate by use of a novel of two molar equivalents of ethylmagnesium bromide to formic Under similar conditions the reduction of ketones proceeds
Recently volved
FROM FORMIC ACID
OF A GRIGNARD
(35
yield.
yield
The of
at
aldehyde
in
reactions 2O’C)
3
mixture
of 9
of decyl of
88%
with
outlined
NMR analysis
reduction
a 9:’
initial
studies to
a solution
Subsequent addition of 4 for 20 minutes at roan temperature 6 of outlined below, a 3:’ mixture
similar
min.
for
bromide
below.
unreduced
IR and
aldehyde.
we selected
ethylmagnesium
distilled
p-tolualdehyde
below, the
the yield.
reaction
aIdehyde
I-decanol
and
-p-tolualdehyde3 product8 was
7
and
also
unreacted
material.
Procedure: To a solution of 0.25 mL (6.6 moles) of formic acid ” [assay (HCOOH):min. 98%] in 8 mL of anhydrous THF at O°C under a nitrogen atmos here was added dropwise slowly over 20 min. 4 mL of a 3 3 solution of ethylmagnesium bromide ! (12 mmoles) in ethyl ether. This mixture was subsequently stirred at room temperature for 30 min. before adding dropwise over 2 min. a solution of 3.3 mmoles of the carbonyl compound in 2 mL of anhydrous THF. After being stirred for 35 min. at 20°C, this mixture was cooled to O’C and subsequently acidified by dropwise addition of 6 mL of 2 M aq. HCI. The reaction mixture was then poured into 60 mL of saturated brine and extracted wTth solvent ether (Ix40 mL). The organic phase was washed successively with 50 mL portions of brine and saturated aqueous NaHC03 solution.” The organic layer was then dried (MgS04), the solvent removed in vacua, and the product purified by evaporative (Kugelrohr) distillation.
621
622
When the proceeded for this of and
se1 ect ive novel “RI’
procedure
slowly reduct
type
are
results
above
very
of
ion
be
and
was
shown
13
reducing
changed, will
as
its
reported
of
utilized
by the
aldehydes agent
in
(I_),
the
with
a future
Material
%Yielda
representative
Table
presence its
other
I.
This
of
ketones.
properties
functional
A more as
the
groups
is
reduct
therefore detailed
solvent presently
ionI
offers
promise
study
and
the
being
of
nature initiated
I
(Distilled
Product)
Ratiob of Ketone to Alcohol
93
propiophenone 4-phenyl-2-butanone cycloheptanone
ketones,3
method
article. TABLE
Starting
several in
including
reactivity in
for
results
91:9 go:10 81:19
aVPC analy is indicated the ketone g mixture. This ratio was determined tent ion times: alcohol > ketone. structures.
and corresponding by VPC analysis IR and NMR spectra
reduction
product to comprise >98% of the 2f% Carbowax 20M column). Reconsistent with the assigned
(6’x1/8” were
REFERENCES 1. 32: 4. 5. 6. 7. 8. 9. 10. 11.
12.
13.
F. Sato, K. Ogura, H. Watanabe, and M. Sato, Tetrahedron Lett., 21, 2869 (1980). For a review, see T.A. Geissman, Org. React., 2, 94-113 (1944). Available from Aldrich Chemical Co., Milwaukee, Wis. U.S.A. After a reaction time of 40 minutes, the product was a 9:l mixture of alcohol and the corresponding aldehyde. No citronella1 or citronellol, products obtainable by 1,4-reduction of citral, could be detected by NMR analysis of this mixture. This ratio was determined by NMR analysis (CH20H vs. CHO signals). IR and NMR spectra were identical to those ej;hibited by the authentic compound sold by Aldrich Chemical Co. NMR analysis failed to detect the presence of any p-tolylethylcarbinol, a by-product expected in the presence of excess ethylmagnesium bromide. This ratio was determined by VPC analysis (6’x1/8” 24% Carbowax 20M column, 185’C). The alcohol and aldehyde comprised >95% of this mixture. Among the suppliers of “anhydrous” formic acid are Fluka (purum anhydrous HCOOH, 98% min.) and Eastman Organic Chemicals (formic acid, 97% min.). If this wash was not done, the crude product was contaminated with a minor amount of propionic acid (the formation of which is consistent with our proposed mechanism for the reduction). Although its reduction was quite Anomalous results were obtained using cyclohexanone. slow, ~75% of the isolated material was a mixture of products derived from aldol-type condensations. For orevious methods to effect such a transformation see: P.A. Risbood and D.M. Ruthven. J. Org. Chem ., 9, 3969 (1979); G.C. Andrews, Tetrahedron Lett., 2, 697 (1980) and references in footnote 3 in that paper.
(Received in USA
26
August 1980)