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Directed metalation of tertiary benzamides.
Tetrahedron Letters,Vol.23,No.l6,pp Printed in Great Britain
DIRECTED
1647-1650,1982
METALATION
SHORT SYNTHESES M.
0040-4039/82/161647-04$03.00/O 01982 Pergamon Press Ltd.
OF TERTIARY
OF HYDRANGENOL
BENZAMIDES.
AND PHYLLODULCIN
Watanabe,*aM. Sahara,aS. Furukawa,aR. Billedeau, b and V. Snieckus*b a Faculty of Pharmaceutical Bunkyo-machi, b
Guelph-Waterloo University
Sciences, Nagasaki,
Centre
852
for Graduate
of Waterloo,
Nagasaki Japan
Work
Waterloo,
in Chemistry,
Canada
Summary: Brief syntheses of isocoumarin natural products hydrangenol via ortho-lithiated benzamide intermediates are described. '?? The directed construction
benzoquinones,
subsequent methods.
of tertiary
of polysubstituted
verse alkaloids,
of Cl-units
metalation
aromatics,
naturally-occurring
and polycyclic
at various
states
has evolved
phthalides,
anthraquinones,
aromatic
oxidation
chain extension
benzamides
hydrocarbons
several
condensed
and ring elaboration
phyllodulcin
($, major constituent ($, sweet principle
offer advantages
of brevity
of Hydrangea of H. serrata
and efficiency
(3) and phyllodulcin
classes
carbocyclic
Seringe
Stend var. otakusa
to those previously
1
1647
expedient
var. thunbergii
R1=OH,R2=H (Hydrangenol)
2
R1=OMe,R2=OH (Phyllodulcin)
394
L allows
by classical
syntheses
of
Maxim)3'4a
Sugimoto)
reported.
2
introduction
intermediates
to systems not easily prepared
opuloides
di-
and heterocyclic
The regiospecific
provides
for the
of biogenetically
ortho-lithiated
In this Letter, we show that such methodology
hydrangenol
N2L 361
as a useful strategy
(PAH's)."~
into substituted
University,
and
3,4b-d,'
which
1648
LDA
1.
t THF/-78OC Mel
2.
THF/-78OC
6
,$
R=H
5
R=Me
[#I&J;]
Hk:;MkR2
I?'
7 Ah
Me0
2
R'=OMe,R'=H
2
R' = OMe, R* = CH20Ph
0
1. 50% aq NaOH/EtOH
BBr2/CH2Cl2 *Cl
O
2.H+
R2
\ I @xx
/
212 -78OC
I?'
R'=OMe,R*=H
s
-
11 R' = OMe , R* = 0CH2Ph Mm The syntheses lithiation
of hydrangenol
(2) and phyllodulcin equiv. TMEOA/THF/-78°C)
(2.4 equiv I-BuLi/2.4
by treatment
with methyl
iodide
(2.0 equiv./-78°C)
lation of $ with LDA (1.6 equiv. of a burgundy-red
solution
with e-anisaldehyde, converted
into the isocoumarin
in 35% overall yield.
n-BuLi/l.6
of the metalated
provided
(2) are outlined
g7
of g
gave the g-toluamide
ortho-toluamide
by base-catalyzed
The preparation
of N-methyl-g-anisamide
equiv. _i-Pr*NH/THF/-78OC)
the amide alcohol ?J 8.
in m.
t6 followed
$, in 80% yield.7 resulted
Meta-
in the formation
species ,8 7 which, when quenched
Compound ,Q was not isolated hydrolysis
was abbreviated
Ortho
but directly
(50% aq. NaOH/EtOH/reflux
by a one-pot
sequence
8 h)
as follows.
1649
Compound
and the resulting
MeI),
(1.2 equiv. s-BuLi/l.2
2 was lithiated'
excess methyl
solution
iodide, cooled
1.6 equiv. i-Pr2NH/TMEDA), isolated
hydroxyamide
45% overall
yield.
(,$), mp 181-182°C Application mediacy
in 45% yield. These
(lit.3 mp 181°C)
starting
u
(excess to remove
treated with LDA (1.6 equiv. s-BuLi/
(1.6 equiv).
Alkaline
as described
hydrolysis
above afforded + RT) produced
BBr3/CH2CL2/-78°C
of the un-
compound
&Q in
(+)-hydrangenol
in 94% yield." on Q using o-benzylisovanillin
(32% overall
yield).7
with the dimethylamide
demethylation
2 by the one-pot
and debenzylation
lh * RT/l2 h) to provide
Isocoumarin
(+)-phyllodulcin
of u
12 a
gave, via the interwas also obtained
procedure
was achieved
(2), mp 128-130°C
described
in
for
with BBr3 (2 equiv/ (lit.4 130-132°C)
11
constitute
the utility
References
(8 equiv.
short routes to hydrangenol
respectively further
Demethylation
methylated
(6O'C) under a stream of nitrogen
and sequentially
,Q under the same conditions
Selective
CH2CL2/-78"C,
(-6O"C),
of the same sequence
yield
hydrangenol.
of { was warmed
and p-anisaldehyde
of 2, the isocoumarin
21% overall
equiv. TMEDA/THF/-90°C),
(<) and phyllodulcin
the most efficient
of the directed
syntheses
metalation
(2) in 42% and 14% overall yields
of these natural
reaction
in synthesis.
products
and augment
13
and Footnotes
1. Snieckus,
V. Heterocycles,
l%,
l4_, 1649.
2.
'I,
103, 4247.
3. a) Structure: Asahina, Y.; Asano, J. Chem. Ber. ls, 62, 171, ibid. lm, Absolute configuration: Arakawa, H. Bull.Chem. Sot. Jpn. la, 33_, 200.
63, 429; b)
4. Synthesis:
a) Naoi, Y.; Higuchi, S.; Nakano, T.; Sakai, K.; Nishi, A.; Sano. S. Qn. (~6% overall yield); b) Takeuchi, N.; Ochi, K.; Murase, M.;ToEnaqa, lw, 593 (14% overall yield); c) Takeuchi, N.; Murase, M.; Ochi; K.;Tobinaga, S. Chem. Pharm. Bull. Jpn. la, 28, 3013 (0.5% overall yield); d) Naoi, Y.; Higuchi, S.; Ito, H.; Nakano, T.; Sakai, K.; Matsui, T.; Wagatsuma, S,; Nishi, A.; Sano, S. Org. Prep. Proc. Int. la, 7, 129 (11% overall yield).
5. Japanese name: Amacha (sweet tea). This is served during the Hanamatsuri(Flower Festival). Phyllodulcin is 400 x as sweet as sucrose: Yamato, M.; Hashigaki, K.; Mite, K.; Koyama, T. Chem. Pharm. Bull. Jpn. 9, 2&, 2321. 6. Faust, J.A.;
Jules,
L.H.; Sahyun,
M. J. Amer.
Pharm. Assoc.
lz,
45, 514.
1650
7. All new compounds show analytical and spectral data in accord with their structures. Only salient physical and spectral features follow: : bp 95-97"C/O.l mm; IR (neat) v max 1630 cm-'; NMR (CD&) 6 2.2, 2.43, 3.08, 3.73 Ji4 x s, 12 H);MS m/e 193 (M+). 1 : mp + 5 Hz), 152'C (lit3a 151'C); IR (KBr) v max 1725 cm-'; NMR (CDCk3) 6 2.93 (q, 1 H, J = 6, 3.30 (q, 1 H, J = 10, 15 Hz), 5.33 (q, 1 H, J q 6,lO Hz); MS m/e 284 (M+). 1 : mp l&J121“C; IR (KBr) v max 1723 cm-'; NMR (CDCI13) 6 2.95 (q, 1 H, J = 5,16 Hz), 3.+ 8 (q, 1 H, J = 12,16 Hz), 5.27 (q, 1 H, J = 5,12 Hz); MS m/e 390 (M+). 8. Deprotonation of methyl groups ortho to other directed metalation functions is a protocol deserving greater exploitation: Gschwend, H.W.; Rodriguez, H.R. Org. Reactions, m, 3, 1 (see p. 17); Wakefield, B.J. "The Chemistry of Organolithium Compounds" Pergamon Press, New York, 1974, p. 30. 9. Since N,N-dimethylbenzamidessuffer displacement of Me2NH by s-BuLi'O, N,N-diethylbenzamides The successful ortho metalation have been always used to generate ortho metalated species. of 5 (first achieved bv M. Iwao. these laboratories) suaaests a steric effect to nucleo__ phi%; attack from the"OMe group. 10.
Iwao,M.; Reed, J.N.; Snieckus, V., unpublished R.A. J. Org. Chem. lx, 42, 1823.
observations.
See also Beak, P.; Brown,
and awere shown to be identical (IR, NMR, MS) with authentic 11. Synthetic samples hydrangenol and (+? -phyllodulcin kindly provided by Professor M. Yamato, Okayama University. 12. Robinson,
R.; Sugasawa,
S. J. Chem. Sot. 12,
(+I-
3163.
13. We are grateful to NSERC of Canada for financial support (to R.B., V.S.) and to Professor M. Yamato for copies of spectra of (+)-hydranqenol and (+)-phyllodulcin.
(Received in USA 5 January 1982)
DIRECTED
1647-1650,1982
METALATION
SHORT SYNTHESES M.
0040-4039/82/161647-04$03.00/O 01982 Pergamon Press Ltd.
OF TERTIARY
OF HYDRANGENOL
BENZAMIDES.
AND PHYLLODULCIN
Watanabe,*aM. Sahara,aS. Furukawa,aR. Billedeau, b and V. Snieckus*b a Faculty of Pharmaceutical Bunkyo-machi, b
Guelph-Waterloo University
Sciences, Nagasaki,
Centre
852
for Graduate
of Waterloo,
Nagasaki Japan
Work
Waterloo,
in Chemistry,
Canada
Summary: Brief syntheses of isocoumarin natural products hydrangenol via ortho-lithiated benzamide intermediates are described. '?? The directed construction
benzoquinones,
subsequent methods.
of tertiary
of polysubstituted
verse alkaloids,
of Cl-units
metalation
aromatics,
naturally-occurring
and polycyclic
at various
states
has evolved
phthalides,
anthraquinones,
aromatic
oxidation
chain extension
benzamides
hydrocarbons
several
condensed
and ring elaboration
phyllodulcin
($, major constituent ($, sweet principle
offer advantages
of brevity
of Hydrangea of H. serrata
and efficiency
(3) and phyllodulcin
classes
carbocyclic
Seringe
Stend var. otakusa
to those previously
1
1647
expedient
var. thunbergii
R1=OH,R2=H (Hydrangenol)
2
R1=OMe,R2=OH (Phyllodulcin)
394
L allows
by classical
syntheses
of
Maxim)3'4a
Sugimoto)
reported.
2
introduction
intermediates
to systems not easily prepared
opuloides
di-
and heterocyclic
The regiospecific
provides
for the
of biogenetically
ortho-lithiated
In this Letter, we show that such methodology
hydrangenol
N2L 361
as a useful strategy
(PAH's)."~
into substituted
University,
and
3,4b-d,'
which
1648
LDA
1.
t THF/-78OC Mel
2.
THF/-78OC
6
,$
R=H
5
R=Me
[#I&J;]
Hk:;MkR2
I?'
7 Ah
Me0
2
R'=OMe,R'=H
2
R' = OMe, R* = CH20Ph
0
1. 50% aq NaOH/EtOH
BBr2/CH2Cl2 *Cl
O
2.H+
R2
\ I @xx
/
212 -78OC
I?'
R'=OMe,R*=H
s
-
11 R' = OMe , R* = 0CH2Ph Mm The syntheses lithiation
of hydrangenol
(2) and phyllodulcin equiv. TMEOA/THF/-78°C)
(2.4 equiv I-BuLi/2.4
by treatment
with methyl
iodide
(2.0 equiv./-78°C)
lation of $ with LDA (1.6 equiv. of a burgundy-red
solution
with e-anisaldehyde, converted
into the isocoumarin
in 35% overall yield.
n-BuLi/l.6
of the metalated
provided
(2) are outlined
g7
of g
gave the g-toluamide
ortho-toluamide
by base-catalyzed
The preparation
of N-methyl-g-anisamide
equiv. _i-Pr*NH/THF/-78OC)
the amide alcohol ?J 8.
in m.
t6 followed
$, in 80% yield.7 resulted
Meta-
in the formation
species ,8 7 which, when quenched
Compound ,Q was not isolated hydrolysis
was abbreviated
Ortho
but directly
(50% aq. NaOH/EtOH/reflux
by a one-pot
sequence
8 h)
as follows.
1649
Compound
and the resulting
MeI),
(1.2 equiv. s-BuLi/l.2
2 was lithiated'
excess methyl
solution
iodide, cooled
1.6 equiv. i-Pr2NH/TMEDA), isolated
hydroxyamide
45% overall
yield.
(,$), mp 181-182°C Application mediacy
in 45% yield. These
(lit.3 mp 181°C)
starting
u
(excess to remove
treated with LDA (1.6 equiv. s-BuLi/
(1.6 equiv).
Alkaline
as described
hydrolysis
above afforded + RT) produced
BBr3/CH2CL2/-78°C
of the un-
compound
&Q in
(+)-hydrangenol
in 94% yield." on Q using o-benzylisovanillin
(32% overall
yield).7
with the dimethylamide
demethylation
2 by the one-pot
and debenzylation
lh * RT/l2 h) to provide
Isocoumarin
(+)-phyllodulcin
of u
12 a
gave, via the interwas also obtained
procedure
was achieved
(2), mp 128-130°C
described
in
for
with BBr3 (2 equiv/ (lit.4 130-132°C)
11
constitute
the utility
References
(8 equiv.
short routes to hydrangenol
respectively further
Demethylation
methylated
(6O'C) under a stream of nitrogen
and sequentially
,Q under the same conditions
Selective
CH2CL2/-78"C,
(-6O"C),
of the same sequence
yield
hydrangenol.
of { was warmed
and p-anisaldehyde
of 2, the isocoumarin
21% overall
equiv. TMEDA/THF/-90°C),
(<) and phyllodulcin
the most efficient
of the directed
syntheses
metalation
(2) in 42% and 14% overall yields
of these natural
reaction
in synthesis.
products
and augment
13
and Footnotes
1. Snieckus,
V. Heterocycles,
l%,
l4_, 1649.
2.
'I,
103, 4247.
3. a) Structure: Asahina, Y.; Asano, J. Chem. Ber. ls, 62, 171, ibid. lm, Absolute configuration: Arakawa, H. Bull.Chem. Sot. Jpn. la, 33_, 200.
63, 429; b)
4. Synthesis:
a) Naoi, Y.; Higuchi, S.; Nakano, T.; Sakai, K.; Nishi, A.; Sano. S. Qn. (~6% overall yield); b) Takeuchi, N.; Ochi, K.; Murase, M.;ToEnaqa, lw, 593 (14% overall yield); c) Takeuchi, N.; Murase, M.; Ochi; K.;Tobinaga, S. Chem. Pharm. Bull. Jpn. la, 28, 3013 (0.5% overall yield); d) Naoi, Y.; Higuchi, S.; Ito, H.; Nakano, T.; Sakai, K.; Matsui, T.; Wagatsuma, S,; Nishi, A.; Sano, S. Org. Prep. Proc. Int. la, 7, 129 (11% overall yield).
5. Japanese name: Amacha (sweet tea). This is served during the Hanamatsuri(Flower Festival). Phyllodulcin is 400 x as sweet as sucrose: Yamato, M.; Hashigaki, K.; Mite, K.; Koyama, T. Chem. Pharm. Bull. Jpn. 9, 2&, 2321. 6. Faust, J.A.;
Jules,
L.H.; Sahyun,
M. J. Amer.
Pharm. Assoc.
lz,
45, 514.
1650
7. All new compounds show analytical and spectral data in accord with their structures. Only salient physical and spectral features follow: : bp 95-97"C/O.l mm; IR (neat) v max 1630 cm-'; NMR (CD&) 6 2.2, 2.43, 3.08, 3.73 Ji4 x s, 12 H);MS m/e 193 (M+). 1 : mp + 5 Hz), 152'C (lit3a 151'C); IR (KBr) v max 1725 cm-'; NMR (CDCk3) 6 2.93 (q, 1 H, J = 6, 3.30 (q, 1 H, J = 10, 15 Hz), 5.33 (q, 1 H, J q 6,lO Hz); MS m/e 284 (M+). 1 : mp l&J121“C; IR (KBr) v max 1723 cm-'; NMR (CDCI13) 6 2.95 (q, 1 H, J = 5,16 Hz), 3.+ 8 (q, 1 H, J = 12,16 Hz), 5.27 (q, 1 H, J = 5,12 Hz); MS m/e 390 (M+). 8. Deprotonation of methyl groups ortho to other directed metalation functions is a protocol deserving greater exploitation: Gschwend, H.W.; Rodriguez, H.R. Org. Reactions, m, 3, 1 (see p. 17); Wakefield, B.J. "The Chemistry of Organolithium Compounds" Pergamon Press, New York, 1974, p. 30. 9. Since N,N-dimethylbenzamidessuffer displacement of Me2NH by s-BuLi'O, N,N-diethylbenzamides The successful ortho metalation have been always used to generate ortho metalated species. of 5 (first achieved bv M. Iwao. these laboratories) suaaests a steric effect to nucleo__ phi%; attack from the"OMe group. 10.
Iwao,M.; Reed, J.N.; Snieckus, V., unpublished R.A. J. Org. Chem. lx, 42, 1823.
observations.
See also Beak, P.; Brown,
and awere shown to be identical (IR, NMR, MS) with authentic 11. Synthetic samples hydrangenol and (+? -phyllodulcin kindly provided by Professor M. Yamato, Okayama University. 12. Robinson,
R.; Sugasawa,
S. J. Chem. Sot. 12,
(+I-
3163.
13. We are grateful to NSERC of Canada for financial support (to R.B., V.S.) and to Professor M. Yamato for copies of spectra of (+)-hydranqenol and (+)-phyllodulcin.
(Received in USA 5 January 1982)