Trimethylsilylethynyl ketones as surrogates for ethynyl ketones in the double Michael reaction

Article abstract of DOI:10.1021/jo0163086

Trimethylsilylethynyl ketones can be desilylated in the presence of a tethered carbon diacid and induced to undergo a double Michael reaction in situ. The trimethylsilylethynyl ketones can serve as surrogates of ethynyl ketones that are difficult to prepare or isolate.

Full text of DOI:10.1021/jo0163086

J . Org. Chem. 2002, 67, 3149-3151
3149
Sch em e 1
Tr im eth ylsilyleth yn yl Keton es a s
Su r r oga tes for Eth yn yl Keton es in th e
Dou ble Mich a el Rea ction
Derrick S. Holeman, Ravindra M. Rasne, and
Robert B. Grossman*
Department of Chemistry, University of Kentucky,
Lexington, Kentucky 40506-0055
rently be purchased for as little as $0.79 g-1), and its
isolation and purification does not present any special
difficulties or hazards.8,9 This paper describes our experi-
ments in this area.
rbgros1@uky.edu
Received November 21, 2001
Abstr a ct: Trimethylsilylethynyl ketones can be desilylated
in the presence of a tethered carbon diacid and induced to
undergo a double Michael reaction in situ. The trimethyl-
silylethynyl ketones can serve as surrogates of ethynyl
ketones that are difficult to prepare or isolate.
For our exploratory studies of the in situ desilylation-
double Michael reaction, we decided to use diethyl 2,6-
dicyanopimelate10 (1) as the tethered diacid (Scheme 1),
for several reasons. First, 1 was known to undergo a clean
and high-yielding double Michael reaction with 3-butyn-
2-one, and depending on the reaction conditions, either
kinetic or thermodynamic ratios of the three diastereo-
meric products, 2a -c, were obtained.1 We wanted to see
whether we could find comparable kinetic and thermo-
dynamic conditions for the in situ desilylation-double
Michael reaction. Second, 1 was very easily prepared.10
Third, the three diastereomeric double Michael adducts
2a -c were separated very well by GC.
We surveyed a wide variety of catalysts and solvents
for the in situ desilylation-double Michael reaction of 1
and 4-trimethylsilyl-3-butyn-2-one (Table 1). We found
that fluoride ion (either Bu4N+F- or KF‚2H2O) doubled
as a convenient base and desilylating agent. In most
cases, the products 2a -c were obtained quite cleanly,
with no byproducts visible by GC-MS unless the reaction
mixture was allowed to stir long past completion. The
diastereomeric ratios (dr’s) varied from as low as 4:4:1
(Table 1, entry 1) to as high as 15:6:1 2a :2b:2c (Table 1,
entry 5). By comparison, the double Michael reaction of
1 with 3-butyn-2-one gave dr’s that ranged from 4:4:1
(kinetic conditions: K2CO3, acetone, rt) to 5:1:0 (kinetic
conditions: NaH, THF, -78 °C to rt) up to 30:1:0
(thermodynamic conditions: t-BuOK, CH2Cl2, 0 °C).1,11
The in situ desilylation-double Michael reaction did not
proceed in the absence of any base (Table 1, entry 14) or
protic solvent (Table 1, entry 15); however, polar solvents
such as acetone contained enough water to allow the
reaction to proceed (Table 1, entries 11 and 12). Curi-
ously, under some conditions, the in situ desilylation-
double Michael reaction favored the asymmetric isomer
2b over the lower energy Cs-symmetric isomer 2a (Table
1, entries 2 and 4). In these cases, the dr’s may have
reflected the inherent energies of the TS-solvent com-
plexes under these (and not other) conditions or they may
have resulted from selective removal of 2a by a further
reaction. The dr’s sometimes changed upon extended
stirring of the reaction mixture (Table 1, entries 7 and
8), which may reflect equilibration of the isomers by a
Our group has been exploring the double Michael
reactions of “tethered diacids” (consisting of two carbon
acids connected by a tether) and 3-butyn-2-one, and we
have demonstrated the utility of these reactions for the
synthesis of densely functionalized and architecturally
complex compounds.1 A significant limitation to scale-
up of our methodology has been the limited availability
and high cost of 3-butyn-2-one (currently more than $8
g-1) from commercial sources. However, preparation of
this material ourselves is not an attractive prospect. The
method most widely used for its synthesis is J ones
oxidation of the alcohol, but this method is quite capri-
cious, with the original 1946 preparation reporting only
5% yield.2 The compound has also been prepared by
borax-catalyzed desilylation of 4-trimethylsilyl-3-butyn-
2-one in aqueous methanol3 or water,4 hydrolysis of
2-methoxy-1-buten-3-yne,5 by addition of NaAl(CtCH)4
to acetic anhydride,6 and by ozonolysis of 2-methyl-2-
buten-3-yne.7 All of these methods (including the J ones
oxidation) require a careful distillation of 3-butyn-2-one
at the end of the synthesis to separate it from solvent
(aqueous or organic) or unreacted 3-butyn-2-ol, and this
distillation presents a serious explosion hazard.
We reasoned that we might be able to avoid the
difficulty and hazard of distilling 3-butyn-2-one if we
could prepare it in situ from 4-trimethylsilyl-3-butyn-2-
one in the course of a double Michael reaction. The latter
compound is easily prepared in one step from acetic
anhydride and trimethylsilylacetylene (which can cur-
* To whom correspondence should be addressed. E-mail: rbgros1@
uky.edu.
(1) Grossman, R. B. Synlett 2001, 13.
(2) Bowden, K.; Heilbron, I. M.; J ones, E. R. H.; Weedon, B. C. L. J .
Chem. Soc. 1946, 39. Nemirovskii, V. D.; Chelpanova, L. F.; Petrov,
A. A. J . Gen. Chem. USSR (Engl. Transl.) 1961, 31, 2380. Landor, S.
R.; Miller, B. J .; Tatchell, A. R. J . Chem. Soc. C 1971, 2339. Reimann,
E.; Reitz, R. J ustus Liebigs Ann. Chem. 1976, 610.
(3) Bradshaw, C. W.; Fu, H.; Shen, G.-J .; Wong, C.-H. J . Org. Chem.
1992, 57, 1526.
(4) Hirao, K.; Yamashita, A.; Ando, A.; Hamada, T.; Yonemitsu, O.
J . Chem. Soc., Perkin Trans. 1 1988, 2913. An experimental procedure
was not provided.
(5) Petrov, A. A. J . Gen. Chem. USSR 1940, 10, 1682.
(6) Gawrilenko, V. V.; Ivanov, L. L.; Zakharkin, L. I. J . Gen. Chem.
USSR (Engl. Transl.) 1965, 35, 638.
(8) Komarov, N. V.; Yarosh, O. G. J . Gen. Chem. USSR (Engl.
Transl.) 1967, 37, 247.
(9) Walton, D. R. M.; Waugh, F. J . Organomet. Chem. 1972, 37, 45.
(10) Grossman, R. B.; Varner, M. A. J . Org. Chem. 1997, 62, 5235.
(11) Grossman, R. B.; Varner, M. A.; Skaggs, A. J . J . Org. Chem.
1999, 64, 340.
(7) Veysoglu, T.; Mitscher, L. A.; Swayze, J . K. Synthesis 1980, 807.
10.1021/jo0163086 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/05/2002

3150 J . Org. Chem., Vol. 67, No. 9, 2002
Notes
Ta ble 2. Com p a r ison of Dou ble Mich a el Rea ction s of
Ta ble 1. Dia ster eoselectivity of th e Dou ble Mich a el
Rea ction Dep icted in Sch em e 1
4-Tr im eth ylsilyl-3-bu tyn -2-on e a n d 3-Bu tyn -2-on e
entry
catalyst, solvent
TBAF, THF
TBAF, THF
TBAF, CH2Cl2
TBAF, DMF
TBAF (10 mol %),
KF‚2H2O, EtOH
TBAF (10 mol %),
KF‚2H2O, EtOH
TBAF (10 mol %),
CH2Cl2
T (°C), time
2a /2b/2ca
yield, dr of isolated materiala
(conditions)
1
2
3
4
5
0 °C to rt, 1 h
-78 °C to rt, 1 h
-78 °C to rt, 1 h
0 °C to rt, 1 h
-78 to 0 to
4:4:1
7:11:1
9.0:3.5:1
3.5:5.5:1
15:6:1
double
tethered Michael from 4-trimethylsilyl-
diacid adducts 3-butynone
from
3-butyn-2-one11,12
1
2a -c 68%, 7:3:1;b 36% 2a ,c
52% 2a ,b 11% 2bb
(NaH, THF, -78 °C)
20% 2bb
-78 °C, 1 hb
(10% TBAF, KF‚2H2O,
EtOH, 0 °C to rt)
6
7
8
9
-78 °C to rt, 1 h
7:3:1
3
5
7
4a ,b
55% 4a c
72%, 8:1b
rt, 1 h
rt, 1 d
5.4:3.7:1
8:5:1
(10% TBAF, KF‚2H2O, (NaH, THF, rt)
EtOH, rt, 14 d)
TBAF (10 mol %),
CH2Cl2
6a -c 57%, 4:4:1b
(TBAF, THF, rt)
63%, 1:1:0b
(t-BuOK, CH2Cl2,
0 °C)
Bu4N+ Br- (10 mol %), rt, 1 h
KF‚2H2O (solid),
5.8:3.5:1
CH2Cl2
Bu4N+ Br- (10 mol %), 0 °C, 1 h
KF‚2H2O, H2O and
NRd
8a ,b
66%, 60:1c
(KF‚2H2O, t-BuOH, rt)
10
c
CH2Cl2
a
b
Determined by GC-MS. Chromatographed material. c Re-
11
12
13
14
15
K2CO3, acetone
K2CO3, acetone
K2CO3, EtOH
EtOH
rt, 1 h
rt, overnight
rt, 1 h
rt, 2 d
-78 to 0 °C, 1 h
5:5:1
3:6:1
4:3:1
NRd
NRd
crystallized material.
Sch em e 3
t-BuOK, CH2Cl2
a
b
Determined by GC-MS. The alkynone and the salts were
combined at -78 °C, allowed to warm to 0 °C, and cooled to
-78 °C, and then 1 was added. c A two-phase mixture was used.
d
No reaction.
Sch em e 2
as 10 might be used to prepare rigid and functionalized
bicyclic nicotine analogues.
In conclusion, we have discovered that easily prepared
and purified trimethylsilylethynyl ketones can be sub-
stituted for ethynyl ketones as substrates for the double
Michael reaction. The yields and diastereoselectivities are
slightly lower when trimethylsilylethynyl ketones are
used, but this disadvantage must be balanced against the
loss of time and material sustained upon preparation and
purification of the corresponding ethynyl ketones. The
in situ desilylation-double Michael reaction is safe and
convenient, requires inexpensive and innocuous catalysts,
and proceeds under a wide variety of conditions. It will
not completely replace the standard double Michael
reaction, but it is a useful alternative when the ethynyl
ketone is not readily available or is prohibitively expen-
sive. Trimethylsilylethynyl ketones may also prove to be
useful surrogates for inaccessible ethynyl ketones in
other applications such as cycloadditions.
retro-Michael-Michael reaction or selective removal of
2b and 2c by a further reaction.
We then executed the in situ desilylation-double
Michael reaction of both 1 and other tethered diacids on
a preparatory scale (Scheme 2). In most cases, we used
the conditions that gave the best dr of 2 on a small
scale: 10% TBAF and 1 equiv of KF‚2H2O in THF. The
results were compared with the results obtained from the
conventional double Michael reaction with 3-butyn-2-one
(Table 2). The new method usually gave comparable but
slightly lower yields and dr’s, perhaps because it was
restricted to protic solvents and because it proceeded at
higher temperatures.
Exp er im en ta l Section
We had already been interested in extending the
double Michael reaction to substrates such as aryl
ethynyl ketones, but our progress had been hampered
by the instability of ethynyl ketones that contained
electron-poor aryl groups. In light of the above results,
we hypothesized that we might be able to use a trimeth-
ylsilylethynyl ketone as a surrogate for an unisolable
ethynyl ketone in the double Michael reaction. In the
event, we were unable to prepare ethynyl 3-pyridyl
ketone, but trimethylsilylethynyl 3-pyridyl ketone (pre-
pared from nicotinaldehyde in two high-yielding steps)
reacted with dicyano diester 910 in the presence of KF‚
2H2O in EtOH to afford double Michael adduct 10 in 71%
isolated yield (Scheme 3). Double Michael adducts such
The syntheses and characterization of 1-9 have been reported
elsewhere.10-12
4-Tr im eth ylsilyl-3-bu tyn -2-on e. This procedure was modi-
fied from the literature.8 A 2.0 M solution of ethylmagnesium
chloride in THF (0.30 L, 0.60 mol) under N2 was diluted with
THF (300 mL). The solution was cooled to 0 °C, and trimethyl-
silylacetylene (85 mL, 0.60 mol) was added slowly to the THF
solution (CAUTION: evolution of ethane gas). After the mixture
was stirred at 0 °C for a further 20 min, a solution of acetic
anhydride (113 mL, 1.20 mol) in dry THF (200 mL) was added
via cannula. The resulting reaction mixture was allowed to warm
to room temperature and allowed to stir overnight. The reaction
was quenched with water (100 mL), neutralized with 5% aqueous
(12) Grossman, R. B.; Rasne, R. M. Org. Lett. 2001, 3, 4027.

Notes
J . Org. Chem., Vol. 67, No. 9, 2002 3151
hydrochloric acid (100 mL), and allowed to stir for 3 h. The
organic layer was washed three times with saturated aqueous
NaHCO3 solution (75 mL each), three times with water (75 mL
each), and twice with brine (50 mL each), dried over MgSO4,
filtered, and evaporated. The remaining material was distilled
through a twelve-inch Vigreux column under reduced pressure
(aspirator), and the product was collected at 45-50 °C as a
colorless liquid (63.12 g, 450.0 mmol, 75% yield).
water (75 mL) and twice with brine (50 mL each), dried over
MgSO4, filtered, and evaporated to give the ketone (1.94 g, 9.69
mmol, 96% yield) as a light brown oil: 1H NMR (400 MHz,
CDCl3) δ 9.34 (dd, 0.9 Hz, 2.2 Hz, 1H), 8.81 (dd, 1.7 Hz, 4.8 Hz,
1H), 8.34 (ddd, 1.8 Hz, 2.2 Hz, 8.1 Hz, 1H), 7.44 (ddd, 0.9 Hz,
4.9 Hz, 8.1 Hz, 1H), 0.35 (s, 9H); 13C{H} NMR (50 MHz, CDCl3)
δ 176.0, 154.2, 151.5, 136.1, 131.7, 123.4, 102.5, 99.9, -0.9; IR
(neat) 2154, 1653, 1585, 1570 cm-1. C11H13NOSi.
Typical P r ocedu r e for P r epar ator y-Scale in Situ Dou ble
Mich a el R ea ct ion . A solution of tethered diacid (10 mmol),
TBAF (1 mmol), and KF‚2H2O (10 mmol) in EtOH (150 mL) was
cooled to 0 °C. A solution of 4-trimethylsilyl-3-butyn-2-one (15
mmol) in THF (10 mL) was added slowly by addition funnel.
After 1 h, all solvent was evaporated, and water (50 mL) was
added to the reaction mixture. The solution was extracted three
times with EtOAc (50 mL), and the organic layer was washed
three times with water (50 mL). All organic fractions were
combined, dried with brine and MgSO4, and concentrated to yield
a yellow oil. The products were purified by flash chromatography
and by recrystallization from hot ethanol.
Dieth yl 3,3-Dicya n o-2-(n icotin oylm eth yl)-1,1-cycloh ex-
a n ed ica r boxyla te (10). A solution of trimethylsilylethynyl
3-pyridyl ketone (1.05 g, 5.19 mmol) and diethyl (4,4-dicyanobu-
tyl)malonate (1.06 g, 3.98 mmol) in EtOH (120 mL) was treated
with a catalytic amount of KF‚2H2O and allowed to react
overnight. The solvent was evaporated, and EtOAc (100 mL) was
added. The organic layer was washed three times with water
(50 mL) and twice with brine (50 mL), dried over MgSO4, and
filtered and the solvent evaporated. The resulting solid was
purified by flash chromatography (eluant: 50% EtOAc in
petroleum ether) to give 10 (1.12 g, 2.82 mmol, 71% yield) as a
light yellow solid: mp 134 °C; 1H NMR (400 MHz, CDCl3) δ 9.22
(d, 1.6 Hz, 1H), 8.83 (dd, 1.6 Hz, 4.8 Hz, 1H), 8.31 (dt, J t ) 1.8
Hz, J d ) 8.1 Hz, 1H), 7.48 (ddd, 0.7 Hz, 5.0 Hz, 8.1 Hz, 1H),
4.34 (∼q, 7.1 Hz, 2H), 4.16 (dq, J q ) 7.1 Hz, J d ) 12.0 Hz, 1H),
4.11 (dq, J q ) 7.1 Hz, J d ) 12.0 Hz, 1H), 3.89 (dd, 2.4 Hz, 19.4
Hz, 1H), 3.81 (dd, 2.4 Hz, 6.6 Hz, 1H), 3.48 (dd, 6.6 Hz, 19.2 Hz,
1H), 2.62 (dm, J d ) 13.7 Hz, 1H), 2.52 (dm, J d ) 13.0 Hz, 1H),
2.20 (dt, J d ) 3.8 Hz, J t ) 13.4 Hz, 1H), 2.09 (qm, J q ) 13.7 Hz,
Tr im eth ylsilyleth yn yl 3-P yr id yl Ca r bin ol. A solution of
ethylmagnesium chloride in THF (24 mL, 2.0 M, 48 mmol) was
diluted with THF (50 mL), and trimethylsilylacetylene (6.75 mL,
43.8 mmol) was slowly added (CAUTION: evolution of ethane
gas). The flask was covered to exclude light, nicotinaldehyde
(4.50 mL, 47.7 mmol) was added, and the solution was allowed
to stir overnight. The reaction was quenched with saturated
aqueous NH4Cl (100 mL). Ether (100 mL) was added to the
organic layer. The organic layer was washed three times with
water (75 mL each) and twice with brine (50 mL each), dried
over MgSO4, and filtered and the solvent evaporated. The
product was collected as a brown solid (8.79 g, 43.0 mmol, 98%
yield): mp 71-72 °C; 1H NMR (400 MHz, CDCl3) δ 8.70 (d, 2.2
Hz, 1H), 8.51 (dd, 1.5 Hz, 4.8 Hz, 1H), 7.91 (dddd, 0.7 Hz, 1.8
Hz, 2.4 Hz, 7.6 Hz, 1H), 7.32 (ddd, 0.7 Hz, 4.8 Hz, 7.9 Hz, 1H),
5.45 (s, 1H), 3.95 (broad, 1H), 0.21 (s, 9H); 13C{H} NMR (100
MHz, CDCl3) δ 149.0, 148.0, 136.4, 134.8, 123.5, 103.9, 92.4, 62.5,
-0.3; IR (KBr) 3144, 2164, 1594, 1581 cm-1. Anal. Calcd for
1H), 1.96 (dm, J d ) 14.6 Hz, 1H), 1.75 (dt, J d ) 4.0 Hz, J t
)
13.2 Hz, 1H), 1.40 (t, 7.4 Hz, 3H), 1.18 (t, 7.2 Hz, 3H); 13C{H}
NMR (50 MHz, CDCl3) δ 194.0, 169.6, 168.0, 153.9, 149.5, 135.6,
131.4, 123.8, 115.0, 113.9, 62.6, 62.4, 56.5, 40.5, 39.6, 37.6, 35.5,
31.9, 19.0, 13.8, 13.8; IR (KBr) 2164, 1748, 1721, 1692, 1587
cm-1. Anal. Calcd for C21H23N3O3: C, 63.46; H, 5.83. Found: C,
63.43; H, 5.97.
Ack n ow led gm en t. We thank the National Science
Foundation (CAREER award to R.B.G., Grant No.
CHE-9733201) and the National Institutes of Health
(GM61002-02) for their generous support of this work.
NMR instruments used in this research were obtained
with funds from the CRIF program of the National
Science Foundation (CHE-997841) and the Research
Challenge Trust Fund of the University of Kentucky.
D.S.H. thanks the University of Kentucky for a Lyman
T. J ohnson Fellowship.
C
11H15NOSi: C, 64.34; H, 7.36. Found: C, 64.19; H, 7.49.
Tr im eth ylsilyleth yn yl 3-P yr id yl Keton e. A solution of
DMSO (1.70 mL, 24.0 mmol) in CH2Cl2 (3 mL) was added to a
solution of oxalyl chloride (1.00 mL, 5.41 mmol) in CH2Cl2 (25
mL) at -78 °C. A solution of trimethylsilylethynyl 3-pyridyl
carbinol (2.05 g, 10.13 mmol) in CH2Cl2 (5 mL) was then added.
After 15 min, triethylamine (7.00 mL, 50.2 mmol) was added,
and the reaction was allowed to stir for 5 min. The ice bath was
removed, and the reaction was allowed to reach room temper-
ature. Saturated aqueous NH4Cl (75 mL) was added to quench
the reaction, and the organic layer was washed three times with
J O0163086