One-step synthesis of substituted α-pyrones from cyclobutenediones and lithiated O-silyl cyanohydrins

Full text of DOI:10.1021/jo982271m

J . Org. Chem. 1999, 64, 2145-2148
2145
On e-Step Syn th esis of Su bstitu ted
r-P yr on es fr om Cyclobu ten ed ion es a n d
(2)
Lith ia ted O-Silyl Cya n oh yd r in s
Pamela Mingo, Shijie Zhang, and Lanny S. Liebeskind*,†
Sanford S. Atwood Chemistry Center, Emory University,
1515 Pierce Drive, Atlanta, Georgia 30322
Received November 16, 1998
In tr od u ction
phenols,22-43 ring-fused R-pyridones,44 and quinoline/
isoquinoline quinones.31,45 In an effort to extend this
highly versatile chemistry to the synthesis of substituted
R-pyrones, the addition of a lithiated O-silylated cyano-
hydrin to a cyclobutenedione with subsequent intra-
molecular 1,4-silyl migration and displacement of cyanide
was envisioned. This process would generate in situ a
4-acylcyclobutenone, which is known to undergo facile
rearrangement to a substituted 2-pyrone (eq 3).21
The R-pyrone unit1-5 is an important synthetic building
block6-10 that also is found in numerous biologically
active, naturally occurring compounds.11-19 Because of
the ease and efficiency with which they rearrange,20
4-acylcyclobutenones are strategically attractive precur-
sors to R-pyrones (eq 1). An acylcyclobutenone-based
(1)
method for the synthesis of substituted R-pyrones involv-
ing the palladium-catalyzed carbonylative coupling of
4-chlorocyclobutenones with organotin reagents was
previously disclosed (eq 2).21 Herein is described a
synthesis of 5-silyloxy-2-pyrones, which uses a highly
effective addition of a lithiated O-silyl cyanohydrin to a
cyclobutenedione followed by spontaneous silyl migration/
cyanide expulsion to generate the key acylcyclobutenone
(eq 3).
(3)
Resu lts a n d Discu ssion
O-tert-Butyldimethylsilyl cyanohydrins (1, Table 1)
The addition of unsaturated nucleophiles to cyclobutene-
diones provides access to, inter alia, quinones and
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L.; Patil, S.; Moore, H. W. J . Am. Chem. Soc. 1989, 111, 975.
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Org. Chem. 1990, 55, 1177.
† Tel no.: (404) 727-6604. FAX no.: (404) 727-0845. E-mail:
CHEMLL1@emory.edu.
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1988, 53, 3140.
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10.1021/jo982271m CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/02/1999

2146 J . Org. Chem., Vol. 64, No. 6, 1999
Ta ble 1. F or m a tion of Su bstitu ted r-P yr on es
Notes
expansion to give the desired product in good to excellent
yield.
Exp er im en ta l Section
Gen er a l Meth od s a n d Ma ter ia ls. All melting points were
performed in open capillary tubes using a Thomas-Hoover
melting point apparatus and are uncorrected. All reactions were
carried out under an inert atmosphere of nitrogen in flame-dried
flasks. All solvents and reagents were purchased from com-
mercial sources and were used as received, unless otherwise
noted. Acetonitrile and THF were dried over 4 Å molecular sieves
under an inert atmosphere. Flash chromatography was per-
formed with EM Science Silica Gel 60 (230-400 mesh) with
compressed air as the source of positive pressure. Analytical
thin-layer chromatography (TLC) was performed on Merck silica
gel 60F-254 glass-backed plates of 0.25 mm thickness which
were visualized with appropriate combinations of UV light,
phosphomolybdic acid stain (10% phosphomolybdic acid in
ethanol), and anisaldehyde stain (5 mL of p-anisaldehyde/95 mL
of ethanol). NaHCO3 refers to a saturated aqueous solution.
Elemental analyses were performed by Atlantic Microlab, Inc.,
Norcross, GA.
yield
no.
R1
R2
R3
no. (%)
1a 2-furyl
1b 2-fluorophenyl
1c 2-methyl-1-propenyl i-PrO
1d 4-chlorophenyl
1e N-methyl-2-pyrrolyl phenyl
1f phenyl
1g 3-pyridyl
1h phenyl
1i N-methyl-3-indolyl n-butyl
i-PrO
i-PrO
Et
i-PrO
a
i-PrO
i-PrO
2a 71
2b 61
2c 70
2d 50
2e 71
Et
a
phenyl
tert-butyl MeO
tert-butyl MeO
2f
86
2g 76
2h 78b
N, N-dimethylamino 2i
57b
R2,R3 ) benzo. Characterization and purification were fa-
cilitated by desilylation and then acetylization to provide the
5-acetoxypyrone
a
b
Sta r tin g Ma ter ia ls. The following compounds were prepared
by literature methods: 3-isopropoxy-4-phenyl-3-cyclobutene-1,2-
dione,48 4-tert-butyl-3-methoxy-3-cyclobutene-1,2-dione,48 3,4-
diisopropoxy-3-cyclobutene-1,2-dione,48 4-phenyl-3-isopropoxy-
3-cyclobutene-1,2-dione,48 4-n-butyl-3-(N,N-dimethylamino)-3-
cyclobutene-1,2-dione,49 3,4-diethyl-3-cyclobutene-1,2-dione,44 and
3,4-benzo-3-cyclobutene-1,2-dione.50,51
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Silyla t ed
Cya n oh yd r in s. Distinctive CN stretching absorptions were not
apparent in the infrared spectra of most of these cyanohydrins.
Very weak bands possibly attributable to the CN stretch were
seen between 2200 and 2300 wavenumbers.
ter t-Bu tyld im eth ylsilyloxy(2-fu r yl)a ceton itr ile, 1a . This
compound was prepared by a modification of a literature
procedure.46 To a room-temperature solution of 2-furancarbal-
dehyde (0.86 mL, 10.5 mmol, 1.00 equiv) in acetonitrile (60 mL)
were added potassium cyanide (2.70 g, 42.2 mmol, 4.02 equiv),
tert-butyldimethylsilyl chloride (1.91 g, 12.6 mmol, 1.20 equiv),
and zinc iodide (0.053 g, 0.17 mmol, 0.02 equiv). The reaction
mixture was stirred at room temperature for 18 h. The solvent
was removed in vacuo, diethyl ether (50 mL) was added, and
the organic layer was filtered, washed with water (2 × 25 mL),
dried over Na2SO4, filtered, and concentrated in vacuo to give
tert-butyldimethylsilyloxy-(2-furyl)acetonitrile as a colorless oil
(1.94 g, 8.17 mmol, 78%): TLC (silica gel, 4:1 hexane/ethyl
acetate, Rf ) 0.74); 1H NMR (CDCl3, 300 MHz) δ 7.45 (d, J )
1.0 Hz, 1 H), 6.53 (d, J ) 3.3 Hz, 1 H), 6.39-6.41 (m, 1 H), 5.56
(s, 1 H), 0.91 (s, 9 H), 0.17 (s, 3 H), 0.14 (s, 3 H); 13C NMR (CDCl3,
75.5 MHz) δ 148.4, 143.6, 117.1, 110.6, 109.3, 57.9, 25.3, 18.0,
-5.4. Anal. Calcd for C12H19NO2Si: C, 60.72; H, 8.07; N, 5.90;
O, 13.48; Si, 11.83. Found: C, 60.90; H, 8.15; N, 5.94.
were prepared by following the procedure of Cava.46 The
tert-butyldimethylsilyl protecting group was chosen be-
cause of its greater hydrolytic stability relative to that
of the trimethylsilyl group. The lithiated O-silyl cyano-
hydrins were generated by deprotonation with lithium
hexamethyldisilazide at -78 °C in THF. Addition of a
solution of the lithiated cyanohydrin via cannula into a
-78 °C solution of a cyclobutenedione in THF gave the
desired 2-pyrone, directly, after a low temperature quench
and workup. As shown in Table 1, a variety of highly
functionalized 5-silyloxy-2-pyrones (2a -i) were obtained
in good to excellent yields using this protocol.
Efficient formation of pyrone 2i required transmeta-
lation of the deprotonated cyanohydrin from lithium to
cerium in order to minimize competitive deprotonation
of the enolizable proton of the n-butyl group on the
cyclobutenedione. In addition, due to difficulty in the
purification of the corresponding silyl ether-protected
pyrone, this pyrone and 2h were desilylated and then
protected as the acetate for characterization purposes.
A particularly interesting aspect of this reaction is the
ability of the 4-acylcyclobutenone to rearrange to a
pyrone at or below room temperature, while most ring
expansions of 4-aryl- or 4-vinylcyclobutenones require
heating at temperatures in excess of 100 °C.34 A similar
result is seen when comparing the rates of cyclizations
of cis-trienes and cis-dienones,47 the latter of which
possess significantly lower activation energies. In each
case the more facile cyclization is attributed to greater
polarization of the carbonyl group compared to a carbon-
carbon double bond.
t er t -Bu t yld im e t h ylsilyloxy(2-flu or op h e n yl)a ce t on i-
tr ile, 1b. tert-Butyldimethylsilyloxy(2-fluorophenyl)acetonitrile,
a
colorless oil (2.67 g, 10.1 mmol, 91%), was analogously
prepared from 2-fluorobenzaldehyde (1.16 mL, 11.0 mmol, 1.00
equiv), potassium cyanide (2.90 g, 44.6 mmol, 4.05 equiv), tert-
butyldimethylsilyl chloride (1.98 g, 13.0 mmol, 1.18 equiv), and
zinc iodide (0.060 g, 0.19 mmol, 0.02 equiv): TLC (silica gel, 4:1
1
hexane/ethyl acetate, Rf ) 0.77); H NMR (CDCl3, 360 MHz) δ
7.67 (dt, J ) 7.6, 1.6 Hz, 1 H), 7.38-7.45 (m, 1 H), 7.26 (t, J )
7.9 Hz, 1 H), 7.10-7.15 (m, 1 H), 5.80 (s, 1 H), 0.96 (s, 9 H),
0.27 (s, 3 H), 0.17 (s, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ 160.8,
157.6, 131.1, 128.0, 124.0, 123.8, 118.2, 115.6, 115.3, 58.0, 25.3,
18.0, -5.4. Anal. Calcd for C14H20NOSiF: C, 63.36; H, 7.60; N,
5.28; O, 6.03; Si, 10.58; F, 7.16. Found: C, 63.43; H, 7.66; N,
5.18.
Con clu sion s
In conclusion, a method for the synthesis of highly
substituted R-pyrones using cyclobutenedione precursors
has been developed. Addition of an O-silylated cyanohy-
drin to a cyclobutenedione followed by 1,4-silyl migration
and cyanide displacement results in the formation of a
4-acylcyclobutenone which undergoes spontaneous ring
(48) Liebeskind, L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T. J .
Org. Chem. 1988, 53, 2482.
(49) Liebeskind, L. S.; Yu, M. S.; Fengl, R. W. J . Org. Chem. 1993,
58, 3543.
(50) Du¨rr, H.; Nickels, H.; Pacala, L. A.; J ones, M., J r. J . Org. Chem.
1980, 45, 973.
(46) Rawal, V. H.; Rao, J . A.; Cava, M. P. Tetrahedron Lett. 1985,
26, 4275.
(47) Marvell, E. N. Thermal Electrocyclic Reactions; Academic
Press: New York, 1980; Chapter 6.
(51) South, M. S.; Liebeskind, L. S. J . Org. Chem. 1982, 47, 3815.

Notes
ter t-Bu tyld im eth ylsilyloxy(2-m eth yl-1-p r op en yl)a ceto-
J . Org. Chem., Vol. 64, No. 6, 1999 2147
flash chromatography), was analogously prepared from 1-meth-
yl-3-indolecarboxaldehyde (1.59 g, 10.0 mmol, 1.00 equiv), potas-
sium cyanide (1.95 g, 30.0 mmol, 3.00 equiv), tert-butyldimeth-
ylsilyl chloride (1.51 g, 10.0 mmol, 1.00 equiv), and zinc iodide
(0.064 g, 0.20 mmol, 0.02 equiv): TLC (silica gel, 20% EtOAc in
hexane, Rf ) 0.35); chromatographic purification (flash column,
silica gel, 2 × 15 mm, 5% EtOAc in hexane); mp 74.0-76.0 °C;
1H NMR (CDCl3, 300 MHz) δ 7.74 (d, J ) 7.8 Hz, 1 H), 7.34-
7.17 (m, 4 H), 5.80 (s, 1 H), 3.75 (s, 3 H), 0.94 (s, 9 H), 0.22 (s,
3 H), 0.16 (s, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ 137.3, 127.6,
125.3, 122.5, 120.0, 119.5, 119.1, 110.8, 109.6, 57.9, 32.8, 25.5,
18.1, -5.1. Anal. Calcd for C17H24N2OSi: C, 67.95; H, 8.05; N,
9.32; O, 5.32; Si, 9.35. Found: C, 67.75; H, 8.12; N, 9.24.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-P yr on es.
5-ter t-Bu tyld im eth ylsilyloxy-3,4-d iisop r op oxy-6-(2-fu r yl)-
2-p yr on e, 2a . To a -78 °C solution of tert-butyldimethylsilyloxy-
(2-furyl)acetonitrile (0.200 g, 0.84 mmol, 1.05 equiv) in THF (4
mL) were added lithium hexamethyldisilazide, LiHMDS (1.80
mL, 1.00 M, 1.80 mmol, 2.24 equiv), by syringe. The solution
was stirred for 20 min at -78 °C and then added via cannula
into a solution of diisopropyl squarate (159 mg, 0.80 mmol, 1.00
equiv). After stirring for 20 min at -78 °C, the reaction was
quenched with a saturated solution of NaHCO3 (2 mL) and
warmed to room temperature. The solution was extracted with
diethyl ether (3 × 5 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. Chromatographic purification (flash
column, silica gel, 0-20% ethyl acetate in hexanes) gave 5-tert-
butyldimethylsilyloxy-3,4-diisopropoxy-6-(2-furyl)-2-pyrone, a
white solid (231 mg, 0.565 mmol, 70%): TLC (silica gel, 4:1
hexanes/ethyl acetate, Rf ) 0.51); mp 88-90 °C; IR (CH2Cl2, KCl,
cm-1) 1702 (m), 1634 (w); 1H NMR (CDCl3, 360 MHz) δ 7.44 (s,
1 H), 6.80 (d, J ) 3.4 Hz, 1 H), 6.46-6.47 (m, 1 H), 5.25 (hept,
J ) 6.2 Hz, 1 H), 4.67 (hept, J ) 6.2 Hz, 1 H), 1.30 (d, J ) 6.2
Hz, 6 H), 1.27 (d, J ) 6.2 Hz, 6 H), 0.95 (s, 9 H), 0.02 (s, 6 H);
13C NMR (CDCl3, 75.5 MHz) δ 159.8, 155.5, 145.4, 142.8, 136.8,
131.3, 129.3, 111.6, 111.4, 76.2, 74.1, 25.6, 22.4, 22.2, 18.3, -4.3.
Anal. Calcd for C21H32O6Si: C, 61.74; H, 7.89; O, 23.50; Si, 6.87.
Found: C, 61.93; H, 7.95.
n it r ile, 1c. tert-Butyldimethylsilyloxy(2-methyl-1-propenyl)-
acetonitrile, a pale yellow oil (2.12 g, 9.41 mmol, 86%), was
analogously prepared from 3,3-dimethylpropenal (1.06 mL, 11.0
mmol, 1.00 equiv), potassium cyanide (2.90 g, 44.0 mmol, 4.00
equiv), tert-butyldimethylsilyl chloride (1.98 g, 13.0 mmol, 1.18
equiv), and zinc iodide (0.060 g, 0.19 mmol, 0.02 equiv): TLC
(silica gel, 4:1 hexanes/ethyl acetate, Rf ) 0.74); IR (CH2Cl2, KCl,
cm-1) 673 (w); 1H NMR (CDCl3, 360 MHz) δ 5.31-5.34 (m, 1
H), 5.08 (d, J ) 8.5 Hz, 1 H), 1.77 (s, 3 H), 1.72 (s, 3 H), 0.90 (s,
9 H), 0.16 (s, 3 H), 0.13 (s, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ
138.7, 121.0, 119.2, 58.8, 25.3, 18.1, 17.9, -5.2. Anal. Calcd for
C12H23NOSi: C, 63.94; H, 10.28; N, 6.21; O, 7.10; Si, 12.46.
Found: C, 63.89; H, 10.27; N, 6.21.
t er t -B u t y ld im e t h y ls ily lo x y (4-c h lo r o p h e n y l)a c e t o -
n itr ile, 1d . tert-Butyldimethylsilyloxy(4-chlorophenyl)acetoni-
trile, a pale yellow oil (2.6 g, 9.22 mmol, 84%), was analogously
prepared from p-chlorobenzaldehyde (1.50 g, 11.0 mmol, 1.00
equiv), potassium cyanide (2.90 g, 44.0 mmol, 4.00 equiv), tert-
butyldimethylsilyl chloride (1.98 g, 13.0 mmol, 1.18 equiv), and
zinc iodide (0.060 g, 0.19 mmol, 0.02 equiv): TLC (silica gel, 4:1
hexanes/ethyl acetate, Rf ) 0.65); 1H NMR (CDCl3, 360 MHz) δ
7.40 (s, 4 H), 5.48 (s, 1 H), 0.94 (s, 9 H), 0.23 (s, 3 H), 0.16 (s, 3
H); 13C NMR (CDCl3, 75.5 MHz) δ 135.0, 134.8, 128.8, 127.2,
118.7, 63.0, 25.2, 17.8, -5.4. Anal. Calcd for C14H20NOClSi: C,
59.66; H, 7.15; N, 4.97; O, 5.68; Cl, 12.58; Si, 9.96. Found: C,
59.72; H, 7.19; N, 4.99; Cl, 12.50.
ter t-Bu tyld im eth ylsilyloxy(1-m eth yl-2-p yr r olyl)a ceton i-
t r ile, 1e. tert-Butyldimethylsiloxy(1-methyl-2-pyrrolyl)aceto-
nitrile, a yellow oil (1.92 g, 7.67 mmol, 77% after flash chroma-
tography), was analogously prepared from 1-methyl-2-pyrrole-
carboxaldehyde (1.09 g, 10.0 mmol, 1.00 equiv), potassium
cyanide (1.95 g, 30.0 mmol, 3.00 equiv), tert-butyldimethylsilyl
chloride (1.51 g, 10.0 mmol, 1.00 equiv), and zinc iodide (0.064
g, 0.20 mmol, 0.02 equiv): TLC (silica gel, 20% EtOAc in hexane,
Rf ) 0.50); chromatographic purification (flash column, silica
gel, 2 × 15 mm, 5% EtOAc in hexane); IR (CH2Cl2, KCl, cm-1
)
2306 (w); 1H NMR (CDCl3, 300 MHz) δ 6.69 (app t, J ) 1.8 Hz,
1 H), 6.23 (dd, J ) 3.3, 1.8 Hz, 1 H), 6.08 (app t, J ) 3.3 Hz, 1
H), 5.57 (s, 1 H), 3.79 (s, 3 H), 0.93 (s, 9 H), 0.15 (s, 3 H), 0.08
(s, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ 125.9, 125.3, 118.0, 110.3,
107.0, 57.7, 34.3, 25.4, 17.9, -5.3, -5.5. Anal. Calcd for C13H22N2-
OSi: C, 62.35; H, 8.86; N, 11.19; O, 6.39; Si, 11.22. Found: C,
62.47; H, 8.91; N, 11.17.
5-t er t -Bu t yld im e t h ylsilyloxy-3,4-d ie t h yl-6-(2-flu or o-
p h en yl)-2-p yr on e, 2b. 5-tert-Butyldimethylsilyloxy-3,4-diethyl-
6-(2-fluorophenyl)-2-pyrone, an off-white solid (0.163 g, 0.43
mmol, 60%), was analogously prepared from 3,4-diethyl-3-
cyclobutene-1,2-dione (0.099 g, 0.72 mmol, 1.00 equiv), tert-
butyldimethylsilyloxy(2-fluorophenyl)acetonitrile (0.200 g, 0.75
mmol, 1.05 equiv), and LiHMDS (1.6 mL, 1.13 mmol, 1.50
equiv): TLC (silica gel, 4:1 hexanes/ethyl acetate, Rf ) 0.43);
chromatographic purification (flash column, silica gel, 0-10%
ter t-Bu tyld im eth ylsilyloxy P h en yl Aceton itr ile, 1f. tert-
Butyldimethylsilyloxy phenyl acetonitrile, a colorless oil (4.60
g, 18.60 mmol, 93% after flash chromatography), was analo-
gously prepared from benzaldehyde (2.122 g, 20.0 mmol, 1.00
equiv), potassium cyanide (5.21 g, 80.0 mmol, 4.00 equiv), tert-
butyldimethylsilyl chloride (3.618 g, 24.0 mmol, 1.20 equiv), and
zinc iodide (0.115 g, 0.36 mmol, 0.02 equiv): TLC (silica gel, 10%
EtOAc/hexane, Rf ) 0.38); chromatographic purification (flash
column, silica gel, 2 × 15 mm, 5% EtOAc/hexane); 1H NMR
(CDCl3, 300 MHz) δ 7.48-7.40 (m, 5 H), 5.52 (s, 1 H), 0.94 (s, 9
H), 0.23 (s, 3 H), 0.15 (s, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ
136.4, 129.1, 128.8, 126.0, 119.2, 63.9, 25.5, 18.1, -5.2, -5.3.
Anal. Calcd for C14H21NOSi: C, 67.97; H, 8.56; N, 5.66; O, 6.47;
Si, 11.35. Found: C, 68.19; H, 8.62; N, 5.49.
ter t-Bu tyld im eth ylsilyloxy-3-p yr id in yla ceton itr ile, 1g.
tert-Butyldimethylsiloxy-3-pyridinylacetonitrile, a yellow oil
(2.71 g, 10.9 mmol, 73% after flash chromatography), was
analogously prepared from 3-pyridinecarboxaldehyde (1.61 g,
15.0 mmol, 1.00 equiv), potassium cyanide (2.93 g, 45.0 mmol,
3.00 equiv), tert-butyldimethylsilyl chloride (2.26 g, 15.0 mmol,
1.00 equiv), and zinc iodide (0.096 g, 0.30 mmol, 0.02 equiv):
TLC (silica gel, 20% EtOAc in hexane, Rf ) 0.14); chromato-
graphic purification (flash column, silica gel, 2 × 15 mm, 15%
EtOAc in hexane + 1% Et3N); 1H NMR (CDCl3, 300 MHz) δ 8.71
(d, J ) 1.8 Hz, 1 H), 8.66 (dd, J ) 7.8, 1.5 Hz, 1 H), 7.84 (dt, J
) 7.8, 1.8 Hz, 1 H), 7.39 (dd, J ) 7.8, 1.8 Hz, 1 H), 5.56 (s, 1 H),
0.94 (s, 9 H), 0.26 (s, 3 H), 0.18 (s, 3 H); 13C NMR (CDCl3, 75.5
MHz) δ 150.5, 147.5, 133.7, 132.2, 123.6, 118.3, 61.9, 25.3, 17.9,
-5.2, -5.4. Anal. Calcd for C13H20N2OSi: C, 62.86; H, 8.12; N,
11.28; O, 6.44; Si, 11.31. Found: C, 62.60; H, 8.18; N, 11.14.
ter t-Bu tyld im eth ylsilyloxy(1-m eth yl-3-in d olyl)a ceton i-
t r ile, 1i. tert-Butyldimethylsiloxy(1-methyl-3-indolyl)aceto-
nitrile, a white amorphous solid (2.95 g, 9.820 mmol, 98% after
ethyl acetate in hexanes); mp 78-80 °C; IR (CH2Cl2, KCl, cm-1
)
1701 (m), 1633 (s), 1551 (s); 1H NMR (CDCl3, 300 MHz) δ 7.50-
7.52 (m, 1 H), 7.30-7.36 (m, 1 H), 7.00-7.16 (m, 2 H), 2.51-
2.53 (m, 4 H), 1.10-1.16 (m, 6 H), 0.83 (s, 9 H), -0.36 (s, 6 H);
13C NMR (CDCl3, 75.5 MHz) δ 161.8, 161.5, 158.1, 153.5, 131.5,
131.4, 131.2, 126.3, 123.7, 123.7, 120.2, 120.0, 116.1, 115.8, 25.4,
21.1, 20.8, 17.9, 13.5, 13.3, -4.8. Anal. Calcd for C21H29O3SiF:
C, 66.99; H, 7.76; O, 12.75; Si, 7.46; F, 5.05. Found: C, 66.82;
H, 7.73.
5-ter t-Bu tyldim eth ylsilyloxy-3,4-diisopr opoxy-6-(2-m eth -
yl-1-p r op en yl)-2-p yr on e, 2c. 5-tert-Butyldimethylsilyloxy-3,4-
diisopropoxy-6-(2-methyl-1-propenyl)-2-pyrone, a pale yellow oil
(0.175 g, 0.44 mmol, 70%), was analogously prepared from
diisopropyl squarate (0.126 g, 0.63 mmol, 1.00 equiv), tert-
butyldimethylsilyloxy(2-methyl-1-propenyl)acetonitrile (0.150 g,
0.67 mmol, 1.05 equiv), and LiHMDS (1.00 mL, 1.00 M, 1.00
mmol, 1.58 equiv): TLC (silica gel, 4:1 hexanes/ethyl acetate,
Rf ) 0.62); chromatographic purification (flash column, silica
gel, 0-20% ethyl acetate in hexanes); IR (CH2Cl2, KCl, cm-1
)
1
1698 (s), 1643 (m); H NMR (CDCl3, 300 MHz) δ 6.01 (s, 1 H),
5.24 (hept, J ) 6.2 Hz, 1 H), 4.62 (hept, J ) 6.2 Hz, 1 H), 2.07
(s, 3 H), 1.89 (s, 3 H), 1.28 (m, 12 H), 0.98 (s, 9 H), 0.13 (s, 6 H);
13C NMR (CDCl3, 75.5 MHz) δ 160.8, 155.9, 145.3, 141.8, 131.7,
128.7, 113.4, 76.2, 74.3, 28.2, 26.1, 22.8, 22.6, 20.8, 18.7, -3.9.
Anal. Calcd for C21H36O5Si: C, 63.60; H, 9.15; O, 20.17; Si, 7.08.
Found: C, 63.66; H, 9.15.
3,4-B e n zo -5-t er t -b u t y ld im e t h y ls ily lo x y -6-(4-c h lo r o -
p h en yl)-2-p yr on e, 2d . 3,4-Benzo-5-tert-butyldimethylsilyloxy-
6-(4-chlorophenyl)-2-pyrone, a white solid (0.319 g, 0.82 mmol,
49%), was analogously prepared from 3,4-benzocyclobutene-1,2-

2148 J . Org. Chem., Vol. 64, No. 6, 1999
Notes
dione (0.223 g, 1.69 mmol, 1.00 equiv), tert-butyldimethylsily-
loxy(4-chlorophenyl)acetonitrile (0.500 g, 1.78 mmol, 1.05 equiv),
and LiHMDS (2.70 mL, 1.00 M, 2.70 mmol, 1.60 equiv): TLC
(silica gel, 4:1 hexanes/ethyl acetate, Rf ) 0.62); chromatographic
purification (flash column, silica gel, 0-20% ethyl acetate in
hexanes); mp 160-163 °C; IR (CH2Cl2, KCl, cm-1) 1724 (s), 1703
(w), 1626 (w); 1H NMR (CDCl3, 300 MHz) δ 8.29 (d, J ) 7.8 Hz,
1 H), 7.73-7.84 (m, 4 H), 7.54 (t, J ) 7.2 Hz, 1 H), 7.39 (d, J )
8.3 Hz, 2 H), 1.04 (s, 9 H), -0.26 (s, 6 H); 13C NMR (CDCl3, 75.5
MHz) δ 161.1, 141.8, 136.4, 134.9, 134.3, 132.5, 130.5, 129.9,
129.7, 128.5, 128.4, 122.4, 120.8, 25.8, 18.2, -4.2. Anal. Calcd
for C21H23O3SiCl: C, 65.18; H, 5.99; O, 12.40; Si, 7.26; Cl, 9.16.
Found: C, 65.30; H, 6.05; Cl, 9.22.
C
21H31NO4Si: C, 64.75; H, 8.02; N, 3.60; O, 16.43; Si, 7.21.
Found: C, 64.62; H, 8.03; N, 3.68.
5-Acetoxy-3-(ter t-bu tyl)-4-m eth oxy-6-ph en yl-2-pyr on e, 2h .
5-Acetoxy-3-(tert-butyl)-4-methoxy-6-phenyl-2-pyrone, a white
solid (0.494 g, 1.56 mmol, 78%), was analogously prepared from
(tert-butyldimethylsiloxy)phenylacetonitrile (0.55 g, 2.20 mmol,
1.10 equiv), LiHMDS (3.00 mL, 1.00 M, 3.00 mmol, 1.50 equiv),
and 3-tert-butyl-4-methoxy-3-cyclobutene-1,2-dione (0.34 g, 2.00
mmol, 1.00 equiv) with the following modification: The crude
product was treated in THF with acetic anhydride (0.31 g, 3.04
mmol, 1.52 equiv) and TBAF (0.55 g, 3.04 mmol, 1.05 equiv) for
30 min. After the usual workup, flash chromatography, and
recrystallization from CH2Cl2/hexane, the product was ob-
tained: TLC (silica gel, 20% EtOAc in hexane, Rf ) 0.12);
chromatographic purification (flash column, silica gel, 2 × 15
mm, 15% EtOAc in hexane); mp 110.5-111.8 °C (methylene
chloride/hexane); IR (CH2Cl2, KCl, cm-1) 1780 (s), 1717 (s), 1643
(m); 1H NMR (CDCl3, 300 MHz) δ 7.73-7.70 (m, 2 H), 7.39-
7.35 (m, 3 H), 3.77 (s, 3 H), 2.20 (s, 3 H), 1.41 (s, 9 H); 13C NMR
(CDCl3, 75.5 MHz) δ 167.5, 162.1, 161.4, 149.8, 130.2, 129.2,
128.4, 127.9, 127.1, 122.6, 61.5, 35.7, 29.7, 20.3. Anal. Calcd for
C18H20O5: C, 68.34; H, 6.37; O, 25.29. Found: C, 68.20; H, 6.39.
5-(ter t-Bu tyld im eth ylsiloxy)-4-isop r op oxy-6-(1-m eth yl-
2-p yr r olyl)-3-p h en yl-2-p yr on e, 2e. 5-(tert-Butyldimethyl-
siloxy)-4-isopropoxy-6-(1-methyl-2-pyrrolyl)-3-phenyl-2-pyrone,
a yellow solid (0.623 g, 1.42 mmol, 71%), was analogously
prepared from tert-butyldimethylsiloxy(1-methyl-2-pyrrolyl)-
acetonitrile (0.53 g, 2.10 mmol, 1.05 equiv), LiHMDS (3.00 mL,
1.00 M, 3.00 mmol, 1.50 equiv), and 3-isopropoxy-4-phenyl-3-
cyclobutene-1,2-dione (0.43 g, 2.00 mmol, 1.00 equiv): TLC (silica
gel, 20% EtOAc in hexane, Rf ) 0.30); chromatographic purifica-
tion (flash column, silica gel, 2 × 15 mm, 10% EtOAc in hexane);
mp 154.5-155.5 °C; IR (CH2Cl2, KCl, cm-1) 1695 (s), 1625 (m);
1H NMR (CDCl3, 300 MHz) δ 7.49-7.24 (m, 5 H), 6.70 (dd, J )
2.7, 1.8 Hz, 1 H), 6.59 (dd, J ) 3.6, 1.8 Hz, 1 H), 6.14 (dd, J )
3.6, 2.7 Hz, 1 H), 4.24 (hept, J ) 6.0 Hz, 1 H), 3.74 (s, 3 H), 1.06
(d, J ) 6.0 Hz, 6 H), 0.89 (s, 9 H), -0.07 (s, 6 H); 13C NMR
(CDCl3, 75.5 MHz) δ 163.0, 162.4, 142.9, 132.5, 132.4, 130.2,
127.9, 127.7, 125.5, 122.8, 114.5, 114.0, 108.1, 75.9, 35.7, 25.6,
22.0, 18.1, -4.9. Anal. Calcd for C25H33NO4Si: C, 68.30; H, 7.57;
N, 3.19; O, 14.56; Si, 6.39. Found: C, 68.17; H, 7.63; N, 3.13.
5-(ter t-Bu tyld im eth ylsiloxy)-3,6-d ip h en yl-4-isop r op oxy-
2-p yr on e, 2f. 5-(tert-Butyldimethylsiloxy)-3,6-diphenyl-4-iso-
propoxy-2-pyrone, a light yellow solid (0.753 g, 1.72 mmol, 86%),
was analogously prepared from (tert-butyldimethylsiloxy)-
phenylacetonitrile (0.55 g, 2.20 mmol, 1.10 equiv), LiHMDS (3.00
mL, 1.00 M, 3.00 mmol, 1.50 equiv), and 3-isopropoxy-4-phenyl-
3-cyclobutene-1,2-dione (0.43 g, 2.00 mmol, 1.00 equiv): TLC
(silica gel, 20% EtOAc in hexane, Rf ) 0.40); chromatographic
purification (flash column, silica gel, 2 × 15 mm, 5% EtOAc in
hexane); mp 156.8-158.5 °C; IR (CH2Cl2, KCl, cm-1) 1693 (s),
1620 (m), 1543 (s); 1H NMR (CDCl3, 300 MHz) δ 7.92-7.89 (m,
2 H), 7.51-7.31 (m, 8 H), 4.24 (hept, J ) 6.0 Hz, 1 H), 1.09 (d,
J ) 6.0 Hz, 6 H), 0.94 (s, 9 H), -0.07 (s, 6 H); 13C NMR (CDCl3,
75.5 MHz) δ 163.2, 162.6, 147.9, 133.0, 132.3, 131.2, 130.2, 129.5,
128.5, 128.1, 128.0, 127.9, 114.7, 76.0, 25.7, 22.0, 18.1, -4.5.
Anal. Calcd for C26H32O4Si: C, 71.52; H, 7.39; O, 14.66; Si, 6.43.
Found: C, 71.43; H, 7.39.
3-ter t-Bu t yl-5-(t er t -b u t yld im et h ylsiloxy)-4-m et h oxy-6-
(3-p yr id in yl)-2-p yr on e, 2g. 3-tert-Butyl-5-(tert-butyldimeth-
ylsiloxy)-4-methoxy-6-(3-pyridinyl)-2-pyrone, a light yellow solid
(0.589 g, 1.510 mmol, 76%), was analogously prepared from (tert-
butyldimethylsiloxy)-3-pyridinylacetonitrile (0.52 g, 2.10 mmol,
1.05 equiv), LiHMDS (3.00 mL, 1.00 M, 3.00 mmol, 1.50 equiv),
and 3-tert-butyl-4-methoxy-3-cyclobutene-1,2-dione (0.34 g, 2.00
mmol, 1.00 equiv): TLC (alumina, 20% EtOAc in hexane, Rf )
0.36); chromatographic purification (flash column, silica gel, 2
× 15 mm, (1) 200 mL 5% Et3N in hexane to treat silica gel, (2)
10% EtOAc in hexane + 1% Et3N); mp 116.0-118.0 °C; IR (CH2-
Cl2, KCl, cm-1) 1707 (s), 1630 (m), 1540 (s); 1H NMR (CDCl3,
300 MHz) δ 9.08 (br s, 1 H), 8.56 (br d, J ) 4.2 Hz, 1 H), 8.08
(dt, J ) 8.1, 1.8 Hz, 1 H), 7.33 (dd, J ) 8.1, 4.8 Hz, 1 H), 3.84 (s,
3 H), 1.42 (s, 9 H), 0.89 (s, 9 H), -0.15 (s, 6 H); 13C NMR (CDCl3,
75.5 MHz) δ 164.3, 161.6, 149.8, 149.3, 144.2, 134.9, 133.0, 127.4,
123.8, 123.1, 61.2, 35.8, 30.1, 25.7, 18.0, -4.8. Anal. Calcd for
5-Acetoxy 3-(n -bu tyl)-4-(d im eth yla m in o)-6-(1-m eth yl-3-
in d olyl)-2-p yr on e, 2i. CeCl3‚7H2O (1.27 g, 3.400 mmol, 1.70
equiv) was dried on the vacuum pump at 150-155 °C for 2 h
and cooled to room temperature, and then anhydrous THF (5
mL) was added. After stirring for 1 h under nitrogen at room
temperature, the slurry was cooled to -78 °C. A THF solution
of LiHMDS (3.00 mL, 1.00 M, 3.00 mmol, 1.50 equiv) was added
to a flask charged with (tert-butyldimethylsiloxy)(1-methyl-3-
indolyl)acetonitrile (0.90 g, 3.00 mmol, 1.50 equiv) in 5 mL of
THF at -78 °C under nitrogen. The mixture was stirred at -78
°C for 20 min and then transferred via cannula into the cold
slurry of CeCl3 in THF made above. After stirring for 20 min,
the cerium reagent was transferred to a solution of 3-n-butyl-
4-(N,N-dimethylamino)-3-cyclobutene-1,2-dione (0.36 g, 2.00
mmol, 1.00 equiv) in 5 mL of THF, which was precooled to -78
°C, and the reaction mixture was stirred for 1 h at -78 °C.
TMEDA (0.395 g, 3.40 mmol, 1.70 equiv) was added and stirring
was continued for 20 min. The reaction mixture was then
quenched with 10 mL of saturated NaHCO3, and the usual
workup was carried out. The crude product was treated in THF
for 30 min with acetic anhydride (0.41 g, 4.00 mmol, 2.00 equiv)
and TBAF (0.784 g, 3.00 mmol, 1.50 equiv). 5-Acetoxy-3-(n-
butyl)-4-(N,N-dimethylamino)-6-(1-methyl-3-indolyl)-2-pyrone was
isolated as a yellow foam (0.435 g, 1.14 mmol, 57%) after the
usual workup and flash chromatography: TLC (silica gel, 60%
EtOAc in hexane, Rf ) 0.31); chromatographic purification (flash
column, silica gel, 2 × 15 mm, (1) 30% EtOAc in hexane + 1%
Et3N, (2) 50% EtOAc in hexane + 1% Et3N); IR (CH2Cl2, KCl,
cm-1): 1772 (s), 1733 (m), 1686 (s), 1627 (s), 1543 (s); H NMR
1
(CDCl3, 300 MHz) δ 8.14 (dd, J ) 6.6, 1.8 Hz, 1 H), 7.51 (s, 1 H),
7.29-7.18 (m, 3 H), 3.73 (s, 3 H), 2.91 (s, 6 H), 2.53 (t, J ) 7.5
Hz, 2 H), 2.15 (s, 3 H), 1.55 (br pent, J ) 7.2 Hz, 2 H), 1.42
(pent, J ) 7.2 Hz, 2 H), 0.95 (t, J ) 7.2 Hz, 3 H); 13C NMR
(CDCl3, 75.5 MHz) δ 168.0, 164.1, 156.6, 148.2, 136.7, 130.7,
126.6, 124.9, 122.5, 122.0, 120.9, 110.5, 109.5, 105.6, 42.5, 33.1,
30.8, 26.9, 22.8, 20.5, 13.9. Anal. Calcd for C22H26N2O4: C, 69.09;
H, 6.85; N, 7.32; O, 16.73. Found: C, 68.89; H, 6.97; N, 7.25.
Ack n ow led gm en t. The National Cancer Institute,
DHHS, supported this investigation through Grant
CA40157.
J O982271M