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Carbamate dianions: Generation and alkylation of α-oxo carbanions
Tetrahedron Letters,Vo1.30,No.40,pp Printed in Great Britain
CARBAMATE
GENERATION
DIANIONS:
oo40-4039/89 $3.00 Pergamon Press plc
5413-5416,1989
AND
AIXYLATION
OF
a-OX0
+ -00
CARBANIONS
Bruce A. Barrier* and R.S. Mani Department
of Chemistry
University
of Wyoming
Laramie,
WY
82071
summary :
Dianions from simple N-tbutyl benzylic-type carbamates are readily alkylation with a variety of formed with alkyllithium bases and undergo Both secondary and tertiary a-0x0 carbanions are easily electrophiles. DIBAL cleavage of the carbamate provides a high yield, general accessible. synthesis of alkylated benzylic alcohols.
The
ability
to generate
receive
widespread
classic
examples recent
silicon, area in
of
this
hydroxymethyl commonly direct
anion
primary
by
alcohols alcohol
toward
the
l), we have
proton
are
subject
synthetic
asymmetric completed
numbers
and a-alkoxy stannanes
reports upon
been
that
an initial l(eq 2).
1.
Base (2 eq)
2.
Electrophile
study
in
simple
Our rationale
of endeavors
in
thus
specialized esters
providing
carbamate
in using
of are
although
aromatic
achiral
a-ox0
species
with our efforts
utilizing
in the
preparation
described
In conjunction
of alcohols
and
exchange,
hindered
to metallation/alkylation,
equivalent.6
sulfur,
Such
tin/lithium
has
to
concerning the
carbanions.4
by
to
addition
particularly
the vitality
of
continues
In
phosphorus,
emphasis
demonstrated
synthesis
tbutyl benzylcarbamate
to
chemistry,1
to demonstrate
abstraction
has
carbanions
application.
adjacent
particular
a-alkoxy
Beak
Indeed,
lithio
with
a-hetero and
carbanion
serve
equivalents3
from
lithiation
systems.5
centers
Increasing
field.
appearing,
prepared
research
in u-amino
synthesis,2
expanding are
in
carbanionic
advances
of asymmetric
carbanions
and homologate
attention
directed
dianions
(eq
using
systems
tbutylamine E
of
an a-
N-
(1" amine)
Cleavage
(eq 1)
in the
preparation
of
our
model
nitrogen-containing
chiral
process
available
are readily
Benzylcarbamate benzyl to 1
chloroformate (THF,-78'C),
dianion
1 was
conveniently
2
guided
prepared
solution
underwent
5413
by
the
as candidates
of primary
Upon addition
red-colored
Dianion
was
viewed
by reduction
in CH2C12.
a deep
formation.
carbamate
auxiliaries
fact
a-amino
in 92% with
was produced,
many
acids. tbutylamine
of 2.2 equivalents
alkylation
that
in our asymmetric
characteristic
with
a
and
of set-BuLi
variety
of of
5414
electrophiles
in excellent
Alkyd
1.7
chlorides
temperatures
(-50°C)
experiments
with
Mono
1.
tosylates
with
the
unactivated
been unsuccessful
Table
or
the results
yields,
and
failed
addition
to date in the metallation
of
2.2
eq s-BuLi
H
higher similar
ethylcarbamate)
1.
(eq 2)
l. E1ectrophile- %,K,R,, 2. Hz0 I H
3
Electrophile
%
R
a
Yield
a.
Me1
- Me
91
b.
PhCH2Br
- CH2Ph
82
- CH2CH=CH2
86
C.
have
step.
2
Entry
CH2=CHCH2Br
d.
CH2=C(CH2C1)2
e.
ClCH2CH=CHCH$l
- CH2C(CH2Cl)=CH2
89
- CH2CH=CHCH2Cl
81
f.
Br(CH2)3Cl
- (CH2)3Cl
86
g. h.
Br(CH2)4Cl
- (CH2)4Cl
82
Me3SiCl
- SiMe3
85
1.
PhCHO
- CH(OH)Ph
3. k.
ICH2C(CH3)2CHO
- CH(OH)C(CH3)2CH21
CH3CHBrCH2CH2Br
'
8ac 87C
- CH2CH2CHBrCH3
a2=
Dried and distilled prior to use except for MeI. b. Purified yields following silica gel chromatography. c. Approximately 1:l mixture of diastereomers. Having
ascertained
monoalkylated dialkylated
problem
in most
addition
tertiary
cases
a-oxo
studied.
for example,
of the
metallated/alkylated material.
dialkylation
there
Table
experiments.
good
to note
a variety 2
to extend
carbanions,
of 3a with
lists
this
approach this
was a question
Dianion
electrophile,
under
of
we sought
Initially
It is of interest
obtained.
feasibility
benzylcarbamates,
upon treatment,
starting
the
carbamates.
be able to generate
ing
TMEDA.
addition,
‘Bu 1
a.
In
in Table at
Li
+*A,,
THF, -78OC
I
even
2,
N-tButyl-benzylcarbamate Lb3
tBulNAOePh
of
are depicted
alkylate
(e.g. N-tbutyl
carbamates
Alkylation
of which
to
however
formation
that
of
carbamate
of conditions, representative
method
providing
as applied
as to whether this proved
occurred
2.2 equivalents yields
in
3h
with
not to be a
readily
of set-BuLi.
dialkylated
complete
results
at
-78'C
Follow-
material
(R=SiMe3)
to
we would
were
could not be recovery
obtained
in
of the
5415
Table
2.
Second
of
Alkylation
~13,,J&
l* 2.
li
Carbamate
Tertiary
2*2 eq S-BuLi_
~BJJ(,
Electrophile
(eq 3)
H 4
a.
Electrophile
R
- Me
MeI
- Me
MegSiCl
-
CH2Ph
a
79
- Me
82
d.
- CH2CH=CH2
Me1
- Me
69
- Me
Br(CH2)3Cl
- CH2(CHz)zCl
77
Dried and distilled prior to use except for MeI. b. gel chromatography. In order we
functionality. Table
3.
to
achieve
required
an
Hydrolytic
Generation
of
one
of our
initial
efficient
method
cleavage
Purified yields following silica
goals for
by
Carbamate
in the
Reductive 4
R2
HO x
Ph
3rd Entry
Carbamate
of
extensively
DIBAL, 2.1 eq THF, O'C, 2 hrs
study
cleavage
was investigated
Alcohols
b
80
- SiMe3
Me1
Yield
e.
dianions,
a.
%
R'
- Me
a. b. C.
Carbanions.
I
3 Entry
QOxo
of carbamate the
carbamate
under numerous Cleavage.
(es 4)
5 Rl
R2
a.
3c
-H
b.
3d
-H
- CH2C(CH2Cl)=CH2
- CH$H=CHz
% Yield 91 90
C.
3e
-H
- CH2CH=CHCH$l
84
d.
3f
-H
- (CH213Cl
89
e.
3s
-H
- (CH2)4C1
89
f.
3h
-H
- SiMe3
81 64
g.
3j
-H
- CH(OH)C(CH3)2CHzI
h.
3k
-H
- CH2CH2CHBrCH3
1.
4e
- Me
- (CH2)3Cl
Purified yields following silica gel chromatography.
88 -73
L
5416
however
conditions, more
expedient
giving
effective, Table
our
summary,
development benzylic
excellent
Noteworthy
3. In
long reaction
procedure.
of
a
heterocycles
times
yields
interest
Further
and the asymmetric
in THF
of alcohols
necessitated
(O'C) has proven
(5) within
2 hours
finding
a
to be most as shown
in
in CHzCl2 failed to cleave the carbamates.
in
high
and poor yields
(2.1 eq)
is that DIBAL
general,
alcohols.
DIBAL
a-oxo yield
studies synthesis
carbanion synthesis
chemistry of
addressing of alcohols
has
secondary
the
synthesis
led
and of
to
the
tertiary various
are in progress.
We are grateful to the National Science Foundation (EPSCoR Acknowledgment. RII-8610680) and the American Cancer Society (IN 160A) for support of our work. References and Notes Beak, P.; Zajdel, W.J.; Reitz, D.B. Chem. Rev. 1984, 84, 411. 1. Hay, D.R.; Song, 2.; Smith, S.G.; Beak, P. J. Am. Chem. Sac. 1988, 110, 8145. Meyers, A.I. Aldrichimica Acta 1985, 18(3j ,519. Seebach, D.; Huber, I.M.P.; Syfrig, M.A. Helv. Chim. Acta 1987, 70, 1357. 2. Meyers, A.I.; Miller, D.B.; White, F.H. J. Am. Chem. Sot. 1988, 110, Gawley, R.E. ibid 1987, 109, 1265. 4718, and references cited. Corey, 3. Katritzky, A.R.; Sengupta, S. Tetrahedron Lett. 1987, 28, 1847. E.J.; Eckrich, T.M. ibid 1983, 24, 3165. Seebach, D.; Meyer, N. Ar1gew. Chem., Int. Ed. Engl. 1976, 15, 438. Magnus, P .; 4. Corey, E.J.; Eckrich, T.M. Tetrahedron Lett. 1983, 24, 3163. Still, W.C. J. Am. Chem. Sot. 1982, 1, 553. Roy, G. Orqanometallics Linderman, R.J.; Godfrey, A.; Horne, K. Tetrahedron 1978, 100, 1481. Lett. 1987, 28, 3911. 5. Still, W.C.; Macdonald, T.L. J. Am. Chem. Sot. 1974, 96, 5560. Evans, D.A.;.Andrews, G.C.; Buckwalter, B. ibid 1974, 96, 5561; Katritzky, A.R.; Fan, W.-Q.; Akutagawa, K. Synthesis 1987, 415. N,N-dialkyl Hanko, R.; Hoppe, D. Angew. allylcarbamates as homoenolate equivalents: Chem., Int. Ed. Engl. 1981, 20, 127; HoPpe, D. ibid 1984, 23, 932. N,N-dialkyl benzylcarbamate monoanions are known, generated with n-B&i and TMEDA: Hoppe, D.; Bronneke, A. Synthesis 1962, 1045. 6. Beak, P.; Carter, L.G. J. Org. Chem. 1981, 46, 2363. (IH- and 13C-NMR, 7. All new compounds exhibited spectral characteristics IR, MS) and microanalytical data (C,H,N or HRMS) consistent with their assigned structures. A representative alkylation procedure is as A flame-dried 100mL round bottom flask under an argon atmosfollows: phere charged with benzylcarbamate 1 (1.029, 4.82mmol) in dry tetrahydrofuran (40mL) was cooled to -78'C and treated with a 1.16 M solution of set-BuLi (9.10mL, 10.16mmol) dropwise over 10 min with continuous stirring. After 1 hr, benzyl bromide fO.91g, 5.31mmol) was added neat dropwise to the red-colored solution, and stirring was continued at -78OC for an additional 1 hr. The reaction was quenched by the addition of 5mL of saturated aqueous NH4Cl and 5mL water, and the product extracted into The extract was washed with 5mL water followed ethyl acetate (3 x 25mL). by 5mL brine, and was dried over anhydrous Na2.504. Following filtration and concentration in vacua, the residue was chromatographed on silica gel (10% EtOAc in hexane) giving 1.179 (82%) of carbamate 3b as white fluffy crystals. Recrystallized from hexane: mp 58-59'C. IR (solid film) 3314, 1699, 1603, 1534, 1274, 1090, 756, 698 cm-l. IH-NMR (CDC13, 270 MHz) 8 7.3-7.0 (m, lOH), 5.84 (m, lH), 4.66 (s, lH, Nfl), 3.10 (=X. ZH, A~\IAB= 41.2 Hz, JA'~=13.7, Jm'6.8, 13C-NMR (CDC13, J~x=6.8 Hz), 1.23 (s, 9H). 67.8 MHz) 6 154.0, 140.6, 137.1, 129.5, 128.1, 128.0, 127.6, 126.4, 126.3, 76.1, 50.2, 43.2, 28.9. Anal. Calcd. for CrgH23N02: C, 76.74; H, 7.80; N, 4.71, Found: C, 76.86; H, 8.00; N, 4.70. (Received
in USA
15 June
1989)
CARBAMATE
GENERATION
DIANIONS:
oo40-4039/89 $3.00 Pergamon Press plc
5413-5416,1989
AND
AIXYLATION
OF
a-OX0
+ -00
CARBANIONS
Bruce A. Barrier* and R.S. Mani Department
of Chemistry
University
of Wyoming
Laramie,
WY
82071
summary :
Dianions from simple N-tbutyl benzylic-type carbamates are readily alkylation with a variety of formed with alkyllithium bases and undergo Both secondary and tertiary a-0x0 carbanions are easily electrophiles. DIBAL cleavage of the carbamate provides a high yield, general accessible. synthesis of alkylated benzylic alcohols.
The
ability
to generate
receive
widespread
classic
examples recent
silicon, area in
of
this
hydroxymethyl commonly direct
anion
primary
by
alcohols alcohol
toward
the
l), we have
proton
are
subject
synthetic
asymmetric completed
numbers
and a-alkoxy stannanes
reports upon
been
that
an initial l(eq 2).
1.
Base (2 eq)
2.
Electrophile
study
in
simple
Our rationale
of endeavors
in
thus
specialized esters
providing
carbamate
in using
of are
although
aromatic
achiral
a-ox0
species
with our efforts
utilizing
in the
preparation
described
In conjunction
of alcohols
and
exchange,
hindered
to metallation/alkylation,
equivalent.6
sulfur,
Such
tin/lithium
has
to
concerning the
carbanions.4
by
to
addition
particularly
the vitality
of
continues
In
phosphorus,
emphasis
demonstrated
synthesis
tbutyl benzylcarbamate
to
chemistry,1
to demonstrate
abstraction
has
carbanions
application.
adjacent
particular
a-alkoxy
Beak
Indeed,
lithio
with
a-hetero and
carbanion
serve
equivalents3
from
lithiation
systems.5
centers
Increasing
field.
appearing,
prepared
research
in u-amino
synthesis,2
expanding are
in
carbanionic
advances
of asymmetric
carbanions
and homologate
attention
directed
dianions
(eq
using
systems
tbutylamine E
of
an a-
N-
(1" amine)
Cleavage
(eq 1)
in the
preparation
of
our
model
nitrogen-containing
chiral
process
available
are readily
Benzylcarbamate benzyl to 1
chloroformate (THF,-78'C),
dianion
1 was
conveniently
2
guided
prepared
solution
underwent
5413
by
the
as candidates
of primary
Upon addition
red-colored
Dianion
was
viewed
by reduction
in CH2C12.
a deep
formation.
carbamate
auxiliaries
fact
a-amino
in 92% with
was produced,
many
acids. tbutylamine
of 2.2 equivalents
alkylation
that
in our asymmetric
characteristic
with
a
and
of set-BuLi
variety
of of
5414
electrophiles
in excellent
Alkyd
1.7
chlorides
temperatures
(-50°C)
experiments
with
Mono
1.
tosylates
with
the
unactivated
been unsuccessful
Table
or
the results
yields,
and
failed
addition
to date in the metallation
of
2.2
eq s-BuLi
H
higher similar
ethylcarbamate)
1.
(eq 2)
l. E1ectrophile- %,K,R,, 2. Hz0 I H
3
Electrophile
%
R
a
Yield
a.
Me1
- Me
91
b.
PhCH2Br
- CH2Ph
82
- CH2CH=CH2
86
C.
have
step.
2
Entry
CH2=CHCH2Br
d.
CH2=C(CH2C1)2
e.
ClCH2CH=CHCH$l
- CH2C(CH2Cl)=CH2
89
- CH2CH=CHCH2Cl
81
f.
Br(CH2)3Cl
- (CH2)3Cl
86
g. h.
Br(CH2)4Cl
- (CH2)4Cl
82
Me3SiCl
- SiMe3
85
1.
PhCHO
- CH(OH)Ph
3. k.
ICH2C(CH3)2CHO
- CH(OH)C(CH3)2CH21
CH3CHBrCH2CH2Br
'
8ac 87C
- CH2CH2CHBrCH3
a2=
Dried and distilled prior to use except for MeI. b. Purified yields following silica gel chromatography. c. Approximately 1:l mixture of diastereomers. Having
ascertained
monoalkylated dialkylated
problem
in most
addition
tertiary
cases
a-oxo
studied.
for example,
of the
metallated/alkylated material.
dialkylation
there
Table
experiments.
good
to note
a variety 2
to extend
carbanions,
of 3a with
lists
this
approach this
was a question
Dianion
electrophile,
under
of
we sought
Initially
It is of interest
obtained.
feasibility
benzylcarbamates,
upon treatment,
starting
the
carbamates.
be able to generate
ing
TMEDA.
addition,
‘Bu 1
a.
In
in Table at
Li
+*A,,
THF, -78OC
I
even
2,
N-tButyl-benzylcarbamate Lb3
tBulNAOePh
of
are depicted
alkylate
(e.g. N-tbutyl
carbamates
Alkylation
of which
to
however
formation
that
of
carbamate
of conditions, representative
method
providing
as applied
as to whether this proved
occurred
2.2 equivalents yields
in
3h
with
not to be a
readily
of set-BuLi.
dialkylated
complete
results
at
-78'C
Follow-
material
(R=SiMe3)
to
we would
were
could not be recovery
obtained
in
of the
5415
Table
2.
Second
of
Alkylation
~13,,J&
l* 2.
li
Carbamate
Tertiary
2*2 eq S-BuLi_
~BJJ(,
Electrophile
(eq 3)
H 4
a.
Electrophile
R
- Me
MeI
- Me
MegSiCl
-
CH2Ph
a
79
- Me
82
d.
- CH2CH=CH2
Me1
- Me
69
- Me
Br(CH2)3Cl
- CH2(CHz)zCl
77
Dried and distilled prior to use except for MeI. b. gel chromatography. In order we
functionality. Table
3.
to
achieve
required
an
Hydrolytic
Generation
of
one
of our
initial
efficient
method
cleavage
Purified yields following silica
goals for
by
Carbamate
in the
Reductive 4
R2
HO x
Ph
3rd Entry
Carbamate
of
extensively
DIBAL, 2.1 eq THF, O'C, 2 hrs
study
cleavage
was investigated
Alcohols
b
80
- SiMe3
Me1
Yield
e.
dianions,
a.
%
R'
- Me
a. b. C.
Carbanions.
I
3 Entry
QOxo
of carbamate the
carbamate
under numerous Cleavage.
(es 4)
5 Rl
R2
a.
3c
-H
b.
3d
-H
- CH2C(CH2Cl)=CH2
- CH$H=CHz
% Yield 91 90
C.
3e
-H
- CH2CH=CHCH$l
84
d.
3f
-H
- (CH213Cl
89
e.
3s
-H
- (CH2)4C1
89
f.
3h
-H
- SiMe3
81 64
g.
3j
-H
- CH(OH)C(CH3)2CHzI
h.
3k
-H
- CH2CH2CHBrCH3
1.
4e
- Me
- (CH2)3Cl
Purified yields following silica gel chromatography.
88 -73
L
5416
however
conditions, more
expedient
giving
effective, Table
our
summary,
development benzylic
excellent
Noteworthy
3. In
long reaction
procedure.
of
a
heterocycles
times
yields
interest
Further
and the asymmetric
in THF
of alcohols
necessitated
(O'C) has proven
(5) within
2 hours
finding
a
to be most as shown
in
in CHzCl2 failed to cleave the carbamates.
in
high
and poor yields
(2.1 eq)
is that DIBAL
general,
alcohols.
DIBAL
a-oxo yield
studies synthesis
carbanion synthesis
chemistry of
addressing of alcohols
has
secondary
the
synthesis
led
and of
to
the
tertiary various
are in progress.
We are grateful to the National Science Foundation (EPSCoR Acknowledgment. RII-8610680) and the American Cancer Society (IN 160A) for support of our work. References and Notes Beak, P.; Zajdel, W.J.; Reitz, D.B. Chem. Rev. 1984, 84, 411. 1. Hay, D.R.; Song, 2.; Smith, S.G.; Beak, P. J. Am. Chem. Sac. 1988, 110, 8145. Meyers, A.I. Aldrichimica Acta 1985, 18(3j ,519. Seebach, D.; Huber, I.M.P.; Syfrig, M.A. Helv. Chim. Acta 1987, 70, 1357. 2. Meyers, A.I.; Miller, D.B.; White, F.H. J. Am. Chem. Sot. 1988, 110, Gawley, R.E. ibid 1987, 109, 1265. 4718, and references cited. Corey, 3. Katritzky, A.R.; Sengupta, S. Tetrahedron Lett. 1987, 28, 1847. E.J.; Eckrich, T.M. ibid 1983, 24, 3165. Seebach, D.; Meyer, N. Ar1gew. Chem., Int. Ed. Engl. 1976, 15, 438. Magnus, P .; 4. Corey, E.J.; Eckrich, T.M. Tetrahedron Lett. 1983, 24, 3163. Still, W.C. J. Am. Chem. Sot. 1982, 1, 553. Roy, G. Orqanometallics Linderman, R.J.; Godfrey, A.; Horne, K. Tetrahedron 1978, 100, 1481. Lett. 1987, 28, 3911. 5. Still, W.C.; Macdonald, T.L. J. Am. Chem. Sot. 1974, 96, 5560. Evans, D.A.;.Andrews, G.C.; Buckwalter, B. ibid 1974, 96, 5561; Katritzky, A.R.; Fan, W.-Q.; Akutagawa, K. Synthesis 1987, 415. N,N-dialkyl Hanko, R.; Hoppe, D. Angew. allylcarbamates as homoenolate equivalents: Chem., Int. Ed. Engl. 1981, 20, 127; HoPpe, D. ibid 1984, 23, 932. N,N-dialkyl benzylcarbamate monoanions are known, generated with n-B&i and TMEDA: Hoppe, D.; Bronneke, A. Synthesis 1962, 1045. 6. Beak, P.; Carter, L.G. J. Org. Chem. 1981, 46, 2363. (IH- and 13C-NMR, 7. All new compounds exhibited spectral characteristics IR, MS) and microanalytical data (C,H,N or HRMS) consistent with their assigned structures. A representative alkylation procedure is as A flame-dried 100mL round bottom flask under an argon atmosfollows: phere charged with benzylcarbamate 1 (1.029, 4.82mmol) in dry tetrahydrofuran (40mL) was cooled to -78'C and treated with a 1.16 M solution of set-BuLi (9.10mL, 10.16mmol) dropwise over 10 min with continuous stirring. After 1 hr, benzyl bromide fO.91g, 5.31mmol) was added neat dropwise to the red-colored solution, and stirring was continued at -78OC for an additional 1 hr. The reaction was quenched by the addition of 5mL of saturated aqueous NH4Cl and 5mL water, and the product extracted into The extract was washed with 5mL water followed ethyl acetate (3 x 25mL). by 5mL brine, and was dried over anhydrous Na2.504. Following filtration and concentration in vacua, the residue was chromatographed on silica gel (10% EtOAc in hexane) giving 1.179 (82%) of carbamate 3b as white fluffy crystals. Recrystallized from hexane: mp 58-59'C. IR (solid film) 3314, 1699, 1603, 1534, 1274, 1090, 756, 698 cm-l. IH-NMR (CDC13, 270 MHz) 8 7.3-7.0 (m, lOH), 5.84 (m, lH), 4.66 (s, lH, Nfl), 3.10 (=X. ZH, A~\IAB= 41.2 Hz, JA'~=13.7, Jm'6.8, 13C-NMR (CDC13, J~x=6.8 Hz), 1.23 (s, 9H). 67.8 MHz) 6 154.0, 140.6, 137.1, 129.5, 128.1, 128.0, 127.6, 126.4, 126.3, 76.1, 50.2, 43.2, 28.9. Anal. Calcd. for CrgH23N02: C, 76.74; H, 7.80; N, 4.71, Found: C, 76.86; H, 8.00; N, 4.70. (Received
in USA
15 June
1989)