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Ketene dithioacetals III: the conjugate addition of ketene dithioacetal anions to cyclic α,β-unsaturated ketones
.
KETENEDITHIOACETALSIII': THE CONJUGATEADDITIONOF KETENE DITHIOACETALANIONS TO CYCLICoc,B-UNSATURATED KETONES
Frederick
E. Ziegler*
Sterling
and Coretta Chan Tam
Chemistry
Yale University,
Laboratory
New Haven, CT
06520
Abstract: The reilutiveamounts of 1,2 to 1,4 addition products of severa ketene dithioacetal anions to cycZic a,B-unsaturatedketones have been determined. The influence of solvent and counterion is reported.
Methods anions
have been reported
to a,@unsaturated
equivalents,
lents4
of these anions
Deprotonation isopropylamide deprotonated
(-15"C, THF, 0.5h) while
of deprotonation
is readily
material
2 (18%). additions
or alkylation
these lithium
anions
were effected
of the resultant
in THF and/or THF-HMPA
(A), cyclopentenone@I),
concerning
achieved
conditions.
the conjugate
with lithium di-
(3 equiv)-THF
enolates.
and E-methylcyclopentenone
4717
anions,
by warming
salts
(5) is outlined
which
starting
to 25'C and eventual
The regioselectivity
or their cuprous
of
for 0.5 h at 0°C.
(82%) and undeuterated
at -78'C followed
is 54%
Deprotonation
by GC-MS of the D20 quenched
2-deuterio-2-isopropylidene-1,3-dithiane
The conjugate
acyl anion equiva-
2-isopropylidene-1,3-dithiane(2)
using LDA-HMPA
was determined
of functioning
ketones.
(LDA, THF, -15' to -5"C, 0.75h) under similar be achieved
of dithiane
anions serve as acyl anion
or u,B-unsaturated
of Z-ethylidene-1,3-dithiane(U5
(LDA)
1,4 addition
have the potential
in this Letter our results
provided
protonation
anions,
to several a,b-unsaturated
the extent of 82% could
The degree
While dithiane
and ketones3.
(y-substitution)
We report
.
which permit the aprotic
ketene dithioacetal
anion equivalents
(a-substitution)
addition
Lto
lactones2
their vinylogs,
as B-propionate
recently
of the reaction
in THF with cyclohexenone in the Table.
of
MO. 49
Tablea
Entry
KeteneDithioacetal
Rxn Conditions
&
Products (rel %)
Distilled Yield %
3
LDA, THF
2
3
LDA, THF CuI'(Me0)3P
3
5
LDA, THF
4
5
LDA, THF CUI'(M~O)~P
9a (98) iji;i- (2)
54
5
5
LDA, THF HMPA
-9a (100)
66
6
4
LDA, THF
7
5
8
5
9
5
1) LDA,THF,HMPA 2) CH2=CHCH2Br
68
10
5
1) LDA,THF,HMPA 2) CH2=CH-CH2Br
67
1
a)
1
L (71) 6 (20) 132 (9) ; 1;;) E I!$ r2 (24)
1) LDA,THF,HMPA 2) CH31 LUA, THF HMPA
68 67 82
44 70
71
all new compounds were identified by elemental analysis, FMR, GC-MS and IR.
The lithium anion of 2-ethylidene-1,3-dithianeshows regioselectivity (entries 1, 3, 6) for 1,4-v substitution. The v/a ratio of the 1,2 products has not been determined. A significant reversal of selectivity is observed by using 3 equiv. of HMPA (entries 5 and 8) or the cuprous salt of the anion (entries 2 and 4), generated by addition of CuI'(Me0)3P to the lithium anion, providing the 1,4-a product as the dominant isomer. When the conjugate addition of entry 2 was conducted at -78°C for 0.25 h and then quenched with methanol at -78'C, the 1,4-a product was obtained along with unreacted cyclohexenone, indicating, in this
0
Lb h+y,,.%. u R1
R2
S
s
s
%
S
a
S
ga,
1.
J
R1=CH3,
R2=H
b, Rl=R2=H
2 a, R,=CH3,
R2_4=H
b, R,_4=H
0
c, R,=R2=CH3,
R1 R2
R4 %
s
d, R,=R2=R4=CH3, e, R,=R3=CH3,
R2=R4=H
\
f, R,=R3=CH3,
R2=C3H5,
g, R,=R3=CH3,
R2=R4=C3H5
's
that the 1,4 product
The enolates using methyl
generated
iodide
sf and Bare
R3=H
R3
U
instance,
R3=R4=H
h, R,=CH3,
R2=C3H5,
i, R,=CH3,
R2=R4=C3H5,
additions
(entry 9) or ally1 bromide
homogeneous
R3=R4=H
does not arise upon warming
in the conjugate
substances
R,=H .J
to 25%.
can be regioselectively
(entries
and are assumed
R4=H
10 and 11).
alkylated
The allylated
to have the bulky dithianyl
products
group trans
to the ally1 residue6. A typical
experimental
procedure
of LDA in 3.0 mL of dry THF at -2O'C 1.0 mL of THF and the mixture solution
(N2) was added a solution
was stirred
THF solution
1.5 equivalents
of a solution
of cuprous
A solution
THF was added at -78Y. tional 0.5 h, then cooled
was cooled
iodide-trimethylphosphite
at -78°C and stirred
to -78"C,
was warmed
to 0°C over
of 1 in
To the deep red to -78% complex
for 0.5 h forming
of 75 mg (0.77 tnnol) of 2-methylcyclopentenone
The mixture
of 0.77 mmole
of 114 mg (0.77 mmol)
of HMPA and the mixture
was added to the deep red solution
suspension).
To a solution
at -20' to -1O'C for 0.5 h.
at -1O'C was added 0.4 mL (2.3 mmol)
(alternatively,
yellow
(entry 7) is as follows:
in
a
(5) in 1 rd_ of
1 h, stirred at 0“C for an addi-
and 0.07 mL (1.2 mnol) of neat methyl
iodide was added.
The reaction mixture drying
mixture
was allowed
to warm to 25°C over 3 h and stirred
was taken up in hexane and washed (MgS04) of the hexane solution
was distilled contained 160°C).
(Kugelrohr,
successively
and concentration
llO"C, 0.02 mm) to afford
89% -9c (70% yield), The vpc collected
MHz) 6 1.00 (3H, s), 1.21
5% -9a and 6% s,
materials
as determined
properties:
(6H, m), 2.50-2.63
and 5.88 (lH, dd, Jtrans mass spectrum Anal. a:
q
1.72 Hz, Jcis = 10.2 Hz);
product
(1.5% OV-101, SC:
(CCl4, 270
(lH, m), 2.79-2.84
5.42 (lH, dd, Jcis = 10.2 Hz, Jgem = 1.5 Hz), 5.50 (lH, dd, Jtrans
After
liquid which
by vpc analysis
spectral
brine.
the crude reaction
155 mg of a pale yellow
had the following
(3H, s), 1.72-2.37
with water and saturated in vacua,
The
at 25'C for 13 h.
(4H, m),
= 17.2 Hz, Jgem = 1.5 Hz),
ir (CC14) 1745(s) and 1625(w) cm
-1
;
(70 eV) m/e (rel int) 256 (54, M+), 145 (loo), 106 (33), and 71 (37).
Calcd
for C13H200S2:
mass spectrum
C, 60.89;
H, 7.86.
Found:
C, 60.97;
H, 7.78.
(70 eV) m/e (rel int) 270 (15, M+), 256 (23), 145 (loo), 106 (34), and
71 (22). @:
identical
in all respects
ACKNOWLEDGMENTS:We and Hoffmann-LaRoche ment was supported Division
express
to the major component
our thanks
(Nutley) for financial by National
of Research
Institutes
obtained
to the National support
Institutes
of this work.
of Health Research
in entry 5.
of Health
The Bruker
(CA 16432)
270 MHz
Grant No. l-PO7-PRO0798
instrufrom the
Sources.
REFERENCESAND NOTES: 1.
Part II:
2.
F.E. Ziegler
3.
P.C. Ostrowski and V.V. Kane, Tetrahedron Yamaichi, Chem. Commun., 100 (1979).
4.
D. Seebach and M. Kolb, Justus Liebigs Ann. Chem., 811 (1977) and E.J. Corey and A.P. Kozikowski, Tetrahedron Lett., 925 (1975).
5.
F.E. Ziegler
6.
M.F. Semmelhack, 5566 (1978). (Heceived
F.E. Ziegler
and C.C. Tam, J. Org. Chem., 44, 0000 (1979).
and J.A. Schwartz,
J. Org. Chem., Q, Lett.,
and C.M. Chan, J. Org. Chem., g, A. Yamashita,
J.C. Tomesch,
in US& 1-1 Se?tenlber 1979)
985 (1978) and ref. cited therein. 3549
(1977);
C.A. Brown and A.
3065 (1978). and K. Hirotsu,
J. Am. Chem. Sot.,
100,
KETENEDITHIOACETALSIII': THE CONJUGATEADDITIONOF KETENE DITHIOACETALANIONS TO CYCLICoc,B-UNSATURATED KETONES
Frederick
E. Ziegler*
Sterling
and Coretta Chan Tam
Chemistry
Yale University,
Laboratory
New Haven, CT
06520
Abstract: The reilutiveamounts of 1,2 to 1,4 addition products of severa ketene dithioacetal anions to cycZic a,B-unsaturatedketones have been determined. The influence of solvent and counterion is reported.
Methods anions
have been reported
to a,@unsaturated
equivalents,
lents4
of these anions
Deprotonation isopropylamide deprotonated
(-15"C, THF, 0.5h) while
of deprotonation
is readily
material
2 (18%). additions
or alkylation
these lithium
anions
were effected
of the resultant
in THF and/or THF-HMPA
(A), cyclopentenone@I),
concerning
achieved
conditions.
the conjugate
with lithium di-
(3 equiv)-THF
enolates.
and E-methylcyclopentenone
4717
anions,
by warming
salts
(5) is outlined
which
starting
to 25'C and eventual
The regioselectivity
or their cuprous
of
for 0.5 h at 0°C.
(82%) and undeuterated
at -78'C followed
is 54%
Deprotonation
by GC-MS of the D20 quenched
2-deuterio-2-isopropylidene-1,3-dithiane
The conjugate
acyl anion equiva-
2-isopropylidene-1,3-dithiane(2)
using LDA-HMPA
was determined
of functioning
ketones.
(LDA, THF, -15' to -5"C, 0.75h) under similar be achieved
of dithiane
anions serve as acyl anion
or u,B-unsaturated
of Z-ethylidene-1,3-dithiane(U5
(LDA)
1,4 addition
have the potential
in this Letter our results
provided
protonation
anions,
to several a,b-unsaturated
the extent of 82% could
The degree
While dithiane
and ketones3.
(y-substitution)
We report
.
which permit the aprotic
ketene dithioacetal
anion equivalents
(a-substitution)
addition
Lto
lactones2
their vinylogs,
as B-propionate
recently
of the reaction
in THF with cyclohexenone in the Table.
of
MO. 49
Tablea
Entry
KeteneDithioacetal
Rxn Conditions
&
Products (rel %)
Distilled Yield %
3
LDA, THF
2
3
LDA, THF CuI'(Me0)3P
3
5
LDA, THF
4
5
LDA, THF CUI'(M~O)~P
9a (98) iji;i- (2)
54
5
5
LDA, THF HMPA
-9a (100)
66
6
4
LDA, THF
7
5
8
5
9
5
1) LDA,THF,HMPA 2) CH2=CHCH2Br
68
10
5
1) LDA,THF,HMPA 2) CH2=CH-CH2Br
67
1
a)
1
L (71) 6 (20) 132 (9) ; 1;;) E I!$ r2 (24)
1) LDA,THF,HMPA 2) CH31 LUA, THF HMPA
68 67 82
44 70
71
all new compounds were identified by elemental analysis, FMR, GC-MS and IR.
The lithium anion of 2-ethylidene-1,3-dithianeshows regioselectivity (entries 1, 3, 6) for 1,4-v substitution. The v/a ratio of the 1,2 products has not been determined. A significant reversal of selectivity is observed by using 3 equiv. of HMPA (entries 5 and 8) or the cuprous salt of the anion (entries 2 and 4), generated by addition of CuI'(Me0)3P to the lithium anion, providing the 1,4-a product as the dominant isomer. When the conjugate addition of entry 2 was conducted at -78°C for 0.25 h and then quenched with methanol at -78'C, the 1,4-a product was obtained along with unreacted cyclohexenone, indicating, in this
0
Lb h+y,,.%. u R1
R2
S
s
s
%
S
a
S
ga,
1.
J
R1=CH3,
R2=H
b, Rl=R2=H
2 a, R,=CH3,
R2_4=H
b, R,_4=H
0
c, R,=R2=CH3,
R1 R2
R4 %
s
d, R,=R2=R4=CH3, e, R,=R3=CH3,
R2=R4=H
\
f, R,=R3=CH3,
R2=C3H5,
g, R,=R3=CH3,
R2=R4=C3H5
's
that the 1,4 product
The enolates using methyl
generated
iodide
sf and Bare
R3=H
R3
U
instance,
R3=R4=H
h, R,=CH3,
R2=C3H5,
i, R,=CH3,
R2=R4=C3H5,
additions
(entry 9) or ally1 bromide
homogeneous
R3=R4=H
does not arise upon warming
in the conjugate
substances
R,=H .J
to 25%.
can be regioselectively
(entries
and are assumed
R4=H
10 and 11).
alkylated
The allylated
to have the bulky dithianyl
products
group trans
to the ally1 residue6. A typical
experimental
procedure
of LDA in 3.0 mL of dry THF at -2O'C 1.0 mL of THF and the mixture solution
(N2) was added a solution
was stirred
THF solution
1.5 equivalents
of a solution
of cuprous
A solution
THF was added at -78Y. tional 0.5 h, then cooled
was cooled
iodide-trimethylphosphite
at -78°C and stirred
to -78"C,
was warmed
to 0°C over
of 1 in
To the deep red to -78% complex
for 0.5 h forming
of 75 mg (0.77 tnnol) of 2-methylcyclopentenone
The mixture
of 0.77 mmole
of 114 mg (0.77 mmol)
of HMPA and the mixture
was added to the deep red solution
suspension).
To a solution
at -20' to -1O'C for 0.5 h.
at -1O'C was added 0.4 mL (2.3 mmol)
(alternatively,
yellow
(entry 7) is as follows:
in
a
(5) in 1 rd_ of
1 h, stirred at 0“C for an addi-
and 0.07 mL (1.2 mnol) of neat methyl
iodide was added.
The reaction mixture drying
mixture
was allowed
to warm to 25°C over 3 h and stirred
was taken up in hexane and washed (MgS04) of the hexane solution
was distilled contained 160°C).
(Kugelrohr,
successively
and concentration
llO"C, 0.02 mm) to afford
89% -9c (70% yield), The vpc collected
MHz) 6 1.00 (3H, s), 1.21
5% -9a and 6% s,
materials
as determined
properties:
(6H, m), 2.50-2.63
and 5.88 (lH, dd, Jtrans mass spectrum Anal. a:
q
1.72 Hz, Jcis = 10.2 Hz);
product
(1.5% OV-101, SC:
(CCl4, 270
(lH, m), 2.79-2.84
5.42 (lH, dd, Jcis = 10.2 Hz, Jgem = 1.5 Hz), 5.50 (lH, dd, Jtrans
After
liquid which
by vpc analysis
spectral
brine.
the crude reaction
155 mg of a pale yellow
had the following
(3H, s), 1.72-2.37
with water and saturated in vacua,
The
at 25'C for 13 h.
(4H, m),
= 17.2 Hz, Jgem = 1.5 Hz),
ir (CC14) 1745(s) and 1625(w) cm
-1
;
(70 eV) m/e (rel int) 256 (54, M+), 145 (loo), 106 (33), and 71 (37).
Calcd
for C13H200S2:
mass spectrum
C, 60.89;
H, 7.86.
Found:
C, 60.97;
H, 7.78.
(70 eV) m/e (rel int) 270 (15, M+), 256 (23), 145 (loo), 106 (34), and
71 (22). @:
identical
in all respects
ACKNOWLEDGMENTS:We and Hoffmann-LaRoche ment was supported Division
express
to the major component
our thanks
(Nutley) for financial by National
of Research
Institutes
obtained
to the National support
Institutes
of this work.
of Health Research
in entry 5.
of Health
The Bruker
(CA 16432)
270 MHz
Grant No. l-PO7-PRO0798
instrufrom the
Sources.
REFERENCESAND NOTES: 1.
Part II:
2.
F.E. Ziegler
3.
P.C. Ostrowski and V.V. Kane, Tetrahedron Yamaichi, Chem. Commun., 100 (1979).
4.
D. Seebach and M. Kolb, Justus Liebigs Ann. Chem., 811 (1977) and E.J. Corey and A.P. Kozikowski, Tetrahedron Lett., 925 (1975).
5.
F.E. Ziegler
6.
M.F. Semmelhack, 5566 (1978). (Heceived
F.E. Ziegler
and C.C. Tam, J. Org. Chem., 44, 0000 (1979).
and J.A. Schwartz,
J. Org. Chem., Q, Lett.,
and C.M. Chan, J. Org. Chem., g, A. Yamashita,
J.C. Tomesch,
in US& 1-1 Se?tenlber 1979)
985 (1978) and ref. cited therein. 3549
(1977);
C.A. Brown and A.
3065 (1978). and K. Hirotsu,
J. Am. Chem. Sot.,
100,