Decarboxylative elimination of enol triflates as a general synthesis of acetylenes.

Article abstract of DOI:10.1039/b401435a

The enol trifluoromethanesulfonates 4, 8, 12, 17 and 20 of tert-butyl beta-ketodiesters and beta-ketoesters can be hydrolysed to the corresponding carboxylic acids by dissolution in trifluoroacetic acid. The dicarboxylic acids undergo mild decarboxylative elimination to give the acetylenic acids 4 and 9 in aqueous sodium bicarbonate solution at room temperature. Similarly, the monocarboxylic acids give the terminal and mid-chain acetylenes 13, 18, 21, and 24 by refluxing in acetone with potassium carbonate. One of the substituents on the acetylenes can be methyl, primary alkyl, secondary alkyl or ethynyl, and the other can be a carboxylic acid, hydrogen or primary alkyl, but the enol trifluoromethanesulfonates could not be prepared when one of the substituents was tert-butyl, nor when both substituents on the precursor to the acetylene were secondary alkyl.

Full text of DOI:10.1039/b401435a

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Decarboxylative elimination of enol triflates as a general synthesis
of acetylenes†
Ian Fleming* and Chandrashekar Ramarao
Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK.
E-mail: if10000@cam.ac.uk; Fax: ϩ44 (0)1223 336362; Tel: ϩ44 (0)1223 336372
Received 2nd February 2004, Accepted 19th March 2004
First published as an Advance Article on the web 21st April 2004
The enol trifluoromethanesulfonates 4, 8, 12, 17 and 20 of tert-butyl β-ketodiesters and β-ketoesters can be
hydrolysed to the corresponding carboxylic acids by dissolution in trifluoroacetic acid. The dicarboxylic acids
undergo mild decarboxylative elimination to give the acetylenic acids 4 and 9 in aqueous sodium bicarbonate
solution at room temperature. Similarly, the monocarboxylic acids give the terminal and mid-chain acetylenes
13, 18, 21 and 24 by refluxing in acetone with potassium carbonate. One of the substituents on the acetylenes can
be methyl, primary alkyl, secondary alkyl or ethynyl, and the other can be a carboxylic acid, hydrogen or primary
alkyl, but the enol trifluoromethanesulfonates could not be prepared when one of the substituents was tert-butyl,
nor when both substituents on the precursor to the acetylene were secondary alkyl.
a ρ value of 1.76 has been measured for the ionisation of
Introduction
1-adamantyl arenesulfonates.7 Putting these facts together
implied that enol triflates would undergo decarboxylative
elimination significantly faster than enol arenesulfonates, and
quite possibly fast enough to work for those cases that had
failed before.
We established long ago in a series of papers1,2 that enol arene-
sulfonates 1 derived from acylmalonates underwent concerted
decarboxylative elimination in water at room temperature to
give acetylenic acids 2, provided that the group R was cation-
stabilising (Scheme 1). As a measure of how cation-stabilising
Results and discussion
We optimised the sequence in Scheme 2, fully characterising all
the intermediates. We used the Rathke procedure for making
the acetylmalonate 3,8 one of the standard methods using triflic
anhydride with triethylamine for making the enol triflate 4,9 and
dissolution in trifluoroacetic acid to cleave the tert-butyl esters
to give the dicarboxylic acid 5. When we dissolved this acid in
aqueous sodium bicarbonate solution, and kept the solution
overnight, it cleanly gave tetrolic acid 6, showing that the
biggest limitation in our earlier work had been overcome. The
dicarboxylic acid 5 was a sensitive compound, and it proved to
be easier not to isolate it. Dissolving the enol triflate 4 in tri-
fluoroacetic acid, evaporating the solution after thirty minutes,
and dissolving the residue in sodium bicarbonate solution gave
tetrolic acid 6 in 66% overall yield, with the decarboxylative
elimination complete within four hours.
Scheme 1
the group R needed to be, we found that the ρ value from chang-
ing the substituents on a phenyl group R, was Ϫ3.12.2 This
value showed that a substantial positive charge was developing
at the carbon atom carrying the nucleofugal group, but not a
full positive charge. In more detail, when the substituent was a
para-nitro group, the rate of decarboxylative elimination was so
slow that hydrolysis of the enol sulfonate took place, giving
p-nitroacetophenone, at a comparable rate. Thus the reaction
only worked if the group R was aryl, as long it was not
inappropriately substituted, and it also worked if the group R
was vinyl or cyclopropyl. The reaction did not work if R was
alkyl or ethynyl, a severe limitation which deterred us at the
time from investigating the synthetic potential of this reaction
any further. In the meantime, better sulfonate leaving groups
have been developed,3 and so we returned to this remarkably
mild reaction, and reported in a preliminary communication4
that it could be made into a more general synthesis of acetyl-
enes using enol trifluoromethanesulfonates (triflates) in place of
enol arenesulfonates. We now report our results in full.
As indications of how much better a triflate might be, we
knew that 1-adamantyl triflate undergoes SN1 solvolysis 105 to
106 times faster than the corresponding toluene-p-sulfonate
(tosylate),5 and ethyl triflate undergoes SN2 solvolysis in acetic
acid 104 faster than ethyl tosylate.6 Furthermore, the ρ value for
Scheme 2 Reagents: i, CH2(CO2But)2, Et3N, MgCl2, MeCN, rt 12 h;
ii, Tf2O, Et3N, CH2Cl2, 0 ЊC, 1 h; iii, TFA, rt, 30 min; iv, NaHCO3, H2O,
rt, 4 h.
the decarboxylative elimination 1
2 with a range of p-substi-
tuted benzenesulfonates was 1.16,2 which indicated that the
elimination was sensitive to how good the leaving group was,
but, as expected, less sensitive than an SN1 reaction, for which
A similar sequence (Scheme 3) with other alkyl groups, and
minor variations in the details, such as using sodium hydride as
the base in the formation of the enol triflates,10 gave the corre-
sponding acetylenic acids 9, including one diacetylenic acid 9c.
We now have success with R as a methyl group, a primary alkyl
† We dedicate this paper to the memory of Dr John Harley-Mason,
1920–2003.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 0 4 – 1 5 1 0
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
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catalysed condensation between tert-butyl acetoacetate and
benzaldehyde. Hydrogenation of 15a–c and 19 gave the alkyl-
ated β-ketoesters, and the decarboxylative elimination of the
enol triflates 17 and 20 using potassium carbonate in acetone as
the base gave the acetylenes 18 and 21. Some of the enol tri-
flates appeared to be pairs of stereoisomers in varying propor-
tions from run to run, but we were unable to separate them, in
order to investigate the stereochemistry of the elimination.
Finally we prepared a small range of acetylenes 24 with
a branched chain derived either by conjugate addition to
the Knoevenagel product 19 or by hydrogenation of the
Knoevenagel product 22 (Scheme 6). In contrast, we were
unable to prepare an enol triflate with branched alkyl groups
on both sides of the intended triple bond—neither of the
β-ketoesters 25 (Scheme 7) gave an enol triflate, even though we
were successful with examples having branched chains separ-
ately on each side in Schemes 5 and 6.
Scheme 3 Reagents: i, Tf2O, Et3N, CH2Cl2, 0 ЊC
rt, 3 h; ii, NaH,
Et2O, 0 ЊC, 1 h, then Tf2O, 0 ЊC, then rt, 1 h; iii, TFA, rt, 30 min;
iv, NaHCO3, H2O, rt, 12 h.
group and a secondary alkyl group, but we were unable to
prepare the enol triflate 8d with a tertiary alkyl group.
With a more general reaction now at our disposal, we investi-
gated whether the second carboxylic acid group was necessary.
It had always been possible that the second carboxylate ion,
present in all our earlier reactions, had accelerated the decarb-
oxylative elimination by a Coulombic repulsion. We prepared
the enol triflate 12 (Scheme 4). On treatment successively with
trifluoroacetic acid and base this gave the terminal acetylene 13,
showing that the second carboxyl group was unnecessary. In
this case, potassium carbonate in refluxing acetone proved to be
better for the decarboxylative elimination step than aqueous
sodium bicarbonate solution.
Scheme 6 Reagents: i, Ph2CuLi or Me2CuLi, THF, Ϫ78 ЊC, 1 h; ii, H2,
Pd/C, MeOH, rt, 16 h; iii, NaH, Et2O, 0 ЊC, 1 h; iv, Tf2O, 0 ЊC 1 h, rt,
1 h; v, TFA, rt, 30 min; vi, K2CO3, Me2CO, reflux, 4–5 h.
Scheme 4 Reagents: i, CDI, THF, rt 1 h; ii, LiCH2CO2But, THF,
Ϫ78 ЊC, 1 h; iii, NaH, Et2O, 0 ЊC, 1 h; iv, Tf2O, 0 ЊC, 1 h, rt, 1 h; v, TFA,
rt, 30 min; vi, K2CO3, Me2CO, reflux, 4 h.
We also prepared a small range of acetylenes 18a–c and 21
with linear alkyl groups derived from an aldehyde using
Knoevenagel condensation and hydrogenation (Scheme 5). We
prepared the unsaturated ketoesters 15 using Lehnard’s condi-
tions, and the known unsaturated ketoester 19 by piperidine-
Scheme 7 Reagents: i, Me2CuLi, THF, Ϫ78 ЊC, 1 h; ii, NaH, Et2O,
0 ЊC, 1 h followed by Tf2O; iii, Ph2NTf.
Except for these limitations, we now have a fairly general
synthesis of acetylenes based on a β-ketoester system (Scheme
8), with a wide variety of methods for incorporating or attach-
ing the groups R1 and R2 on each side of the ketone group,11
some of which are illustrated by the standard but far from
optimised methods we used in Schemes 3–7. The overall
transformation is similar to that achieved by earlier routes
from β-keto acid derivatives by way of heterocyclic intermedi-
ates,12 and especially by Zard’s intriguing reaction,13 in which
β-ketoesters are treated successively with hydroxylamine and
with sodium nitrite and iron() sulfate, but the pathway
described here is mechanistically more straightforward, and
probably less apt to give byproducts. In particular, as he has
pointed out, our method works for the synthesis of terminal
acetylenes, which his does not. It also bears some resem-
blance to a fragmentation reaction of an enol triflate studied
by Kuwajima, in which the electrofugal group is a tertiary
carbocation stabilised by a β-trimethylsilyl group.14 Both our
reaction, with an electrofugal carbon dioxide, and his are com-
pletely regioselective in favour of the formation of acetylenes,
whereas base-induced elimination of enol triflates derived from
ketones can give allenes as well.15 The success of our reaction
Scheme 5 Reagents: i, Meldrum’s acid, Py, CH2Cl2, rt, 1 h; ii, ButOH,
toluene, reflux, 3 h; iii, Ph(CH2)2CHO, TiCl4, Py, THF, rt, 16 h; iv, H2,
Pd/C, MeOH, rt, 12 h; v, NaH, Et2O, 0 ЊC, 1 h; vi, Tf2O, 0 ЊC 1 h, rt, 1 h;
vii, TFA, rt, 30 min; viii, K2CO3, Me2CO, reflux, 4–5 h.
Scheme 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 0 4 – 1 5 1 0
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also suggests that the enol triflates of cyclic β-diketones
might undergo fragmentation on treatment with hydroxide or
alkoxide ions, analogous to the Eschenmoser fragmentation,16
provided that conjugate addition leading to hydrolysis can be
suppressed.
MHz; CDCl3) 7.30–7.10 (5 H, m, Ph), 2.66 (2 H, t, J 7.3,
PhCH2), 2.40 (2 H, t, J 7.4, CH2CH2CH2Ph), 1.96 (2 H, m,
CH2CH2CH2), 1.50 (9 H, s, But) and 1.46 (9 H, s, But); m/z (EI)
306 (11%, M Ϫ C4H8), 250.1 [78, M Ϫ (C4H8)2] and 57 (80,
C4H9) (Found: Mϩ Ϫ C4H8, 306.1466. C21H30O5 requires M Ϫ
C4H8, 306.1467).
Experimental
Di-tert-butyl isobutyrylmalonate 7b (87%). Rf(EtOAc–light
petroleum, 1 : 9) 0.6; νmax(film)/cmϪ1 1725 (C᎐O); δ (250 MHz;
General
᎐
H
CDCl3) 2.80 (1 H, m, Me2CH ), 1.48 (18 H, s, But) and 1.14
(6 H, m, Me2CH); m/z (EI) 230 (40%, M Ϫ C4H8), 174 [72, M Ϫ
(C4H8)2] and 57 (100, C4H9) (Found: Mϩ Ϫ C4H8, 230.1156.
C15H6O5 requires M Ϫ C4H8, 230.1154).
Infrared spectra were recorded on a Perkin-Elmer 297 or FT-IR
1620 spectrophotometer and wave numbers measured relative
to polystyrene (1603 cmϪ1), using sodium chloride plates or
1
sodium chloride solution cells (0.1 mm path length). H- and
13C-NMR spectra were recorded on Bruker NMR spectro-
meters (DRX 500, AM 400, DPX 250, AC 250, AC 200). Chem-
ical shifts were measured relative to tetramethylsilane (δ 0.00)
or chloroform (δ 7.25) as internal standards. The coupling
constants J are expressed in Hertz. In 13C attached proton test
(APT) spectra, ϩ denotes a signal in the same direction as the
solvent signal. Mass spectra were recorded on AE1 MS 89,
Kratos MS 50 or HP 5988A spectrometers and carried out by
technical staff. Flash column chromatography was carried out
using Merck Kieselgel 60 (230–400 mesh ASTM). Thin layer
chromatography (TLC) was performed on glass plates coated to
a thickness of 1 mm with Kieselgel 60 PF254. Melting points
were determined using a Gallenkamp melting point apparatus
and stand uncorrected. Tetrahydrofuran (THF) and ether were
freshly distilled from lithium aluminium hydride under argon.
Dichloromethane, carbon tetrachloride, acetonitrile, methanol,
light petroleum, hexane, and toluene were freshly distilled from
calcium hydride under argon. Light petroleum refers to the
fraction boiling in the region 40–60 ЊC. Other solvents and
reagents where appropriate were purified before use.
Di-tert-butyl phenylpropioloylmalonate 7c (89%). Rf(EtOAc–
light petroleum, 1 : 9) 0.65; νmax(film)/cmϪ1 2208 (C᎐C) and
᎐
᎐
1730 (C᎐O); δ (250 MHz; CDCl ) 7.60–7.30 (5 H, m, Ph) and
᎐
H
3
1.58 (18 H, s, But); m/z (EI) 288 (50%, M Ϫ C4H8), 232 [30, M Ϫ
(C4H8)2] and 57 (100, C4H9) (Found: Mϩ Ϫ C4H8, 288.0997.
C20H24O5 requires M Ϫ C4H8, 288.0998).
Di-tert-butyl pivaloylmalonate 7d (84%). Rf(EtOAc–light
petroleum, 1 : 9) 0.67; νmax(film)/cmϪ1 1734 (C᎐O); δ (250 MHz;
᎐
H
CDCl3) 1.46 (18 H, s, But) and 1.10 (9 H, s, Me). m/z (EI) 301
(20%, M ϩ H) and 57 (100, C4H9) (Found: Mϩ ϩ H, 301.2012.
C16H28O5 requires M ϩ H, 301.2014).
tert-Butyl 3-oxo-7-phenylheptanoate 11
tert-Butyl acetate (2.14 g, 18.4 mmol) was added to lithium
N,N-diisopropylamide (LDA) (18.4 mmol) in THF (15 cm3)
under argon at Ϫ78 ЊC and the mixture kept for 1 h. Carbonyl
diimidazole (CDI) (1.6 g, 10 mmol) and 5-phenylvaleric acid
(1.5 g, 8.4 mmol) were stirred in THF (15 cm3) under argon for
1 h at room temperature, and then transferred by cannula to the
solution of tert-butyl lithioacetate at Ϫ78 ЊC over 10 min. The
mixture was stirred for 1 h and quenched with saturated aque-
ous ammonium chloride solution. The aqueous layer was
extracted with ether (2 × 30 cm3). The combined organic layers
Di-tert-butyl acetylmalonate 3
Following Rathke and Cowan,8 triethylamine (1.96 g, 19.4
mmol) was added to di-tert-butyl malonate (2.00 g, 9.3 mmol)
and magnesium chloride (0.95 g, 10 mmol) in dry acetonitrile
(15 cm3) under argon, and the mixture was stirred for 15 min at
0 ЊC. Acetyl chloride (0.81 g, 10 mmol) was added dropwise, the
mixture was stirred at 0 ЊC for 1 h, and at room temperature for
12 h. The mixture was quenched with saturated aqueous
ammonium chloride solution (20 cm3), and the aqueous layer
was extracted with ether (3 × 20 cm3). The combined organic
fractions were washed with brine (40 cm3), dried (MgSO4)
and concentrated under reduced pressure. The residue was
chromatographed (SiO2, EtOAc–hexane, 2 : 98) to give the acyl-
malonate (2.05 g, 87%); Rf(EtOAc–light petroleum, 1 : 9) 0.6;
νmax(film)/cmϪ1 3300–2500 br (OH), 1720 (C᎐O) and 1625 (C᎐C
were washed with hydrochloric acid solution (3 mol dmϪ3
,
30 cm3), brine (30 cm3), dried (MgSO4) and concentrated under
reduced pressure. The residue was chromatographed (SiO2,
EtOAc–light petroleum, 4 : 96) to give the ester as an oil (1.85 g,
80%); Rf(EtOAc–light petroleum, 2 : 8) 0.73; νmax(film)/cmϪ1
1736 (C᎐O), 1714 (C᎐O) and 1642 (Ph); δ (250 MHz; CDCl )
᎐
᎐
H
3
7.30–7.10 (5 H, m, Ph), 3.32 (2 H, s, COCH2CO), 2.62 (2 H, t,
J 7.4, PhCH2), 2.55 (2 H, t, J 7.3, CH2CH2CO), 1.71–1.60 [4 H,
m, PhCH2(CH2)2] and 1.48 (9 H, s, But); m/z (EI) 277 (38%,
M ϩ H), 202 (100, M Ϫ ButOH) and 161 [20, Ph(CH2)4CO]
(Found: Mϩ ϩ H, 277.1811. C17H24O3 requires M Ϫ H,
277.1803).
᎐
᎐
of enol); δH(250 MHz; CDCl3) 2.1 and 2.28 (3 H total, s, MeCO
of keto and enol forms) and 1.48 (18 H, s, But) (Found: C,
60.72; H, 8.64. C13H22O5 requires C, 60.45; H. 8.58%).
The ꢀ-keto esters 14
Following Oikawa et al.,18 pyridine (207 mmol) was added to a
stirred solution of Meldrum’s acid19 (69.4 mmol) in dry di-
chloromethane (50 cm3) at 0 ЊC. The acid chloride (90.0 mmol)
was added dropwise, and the mixture was stirred at 0 ЊC for 1 h
and at room temperature for 1 h. The mixture was quenched
with saturated aqueous ammonium chloride solution (50 cm3).
The mixture was extracted with dichloromethane (3 × 50 cm3).
The combined organic fractions were washed with aqueous
hydrochloric acid (3 mol dmϪ3, 3 × 50 cm3) and brine (50 cm3),
dried (MgSO4), and concentrated under reduced pressure. The
residue, which was refluxed in a mixture of toluene (50 cm3) and
tert-butanol (207 mmol) for 3 h. The mixture was poured into
water (50 cm3), and extracted with ether (2 × 50 cm3). The
combined organic fractions were washed with brine (50 cm3),
dried (MgSO4), and concentrated under reduced pressure. The
residue was chromatographed (SiO2, EtOAc–light petroleum,
4 : 96) to give the esters.
The other acylmalonates
Typically, following Breslow, Baumgarten and Hauser,17 di-tert-
butyl malonate (9.3 mmol) was added slowly to a stirred mix-
ture of magnesium ethoxide (11 mmol) in dry ether (15 cm3)
and refluxed for 20 min. The acid chloride (11 mmol) was added
dropwise to the mixture, and refluxing continued for 20 min.
The mixture was cooled and quenched with saturated aqueous
ammonium chloride solution (15 cm3). The mixture was
extracted with ether (3 × 20 cm3) The combined organic frac-
tions were washed with brine (30 cm3), dried (MgSO4), and
concentrated under reduced pressure. Chromatography (SiO2,
EtOAc–hexane, 2 : 98) gave the acylmalonate.
The following acylmalonates were prepared by this method.
Di-tert-butyl 5-phenylvalerylmalonate 7a (91%). Rf(EtOAc–
light petroleum, 1 : 9) 0.64; νmax(film)/cmϪ1 1724 (C᎐O); δ (250
᎐
H
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 0 4 – 1 5 1 0
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The following esters were prepared by this method.
(Found: Mϩ Ϫ C4H8, 218.0942. C17H22O3 requires M Ϫ C4H8,
218.0942).
tert-Butyl 3-oxo-6-phenylhexanoate 14b (82%). Rf(EtOAc–
light petroleum, 2 : 8) 0.70; νmax(film)/cmϪ1 1738 and 1715
(E and Z )-tert-Butyl 3-oxo-6-phenyl-2-(3-phenylpropylidene)-
hexanoate 15b (82%). Rf (EtOAc–light petroleum, 2 : 8) 0.76
(one isomer) and 0.72 (other isomer); νmax(film)/cmϪ1 1720 br
(C᎐C); δ (250 MHz; CDCl ) 7.30–7.10 (5 H, m, Ph), 3.31 (2 H,
᎐
H
3
s, COCH2CO), 2.63 (2 H, t, J 7.4, PhCH2), 2.53 (2 H, t, J 7.3,
CH2CH2CO) and 1.93 (2 H, qn, J 7.3, CH2CH2CH2); m/z (EI)
262 (5%, Mϩ), 206 (50, M Ϫ C4H8), 188 [45, M Ϫ (C4H8 ϩ
H2O)], 91 (80, PhCH2) and 57 (100, C4H9) (Found: Mϩ,
262.1561. C16H22O3 requires M, 262.1568).
(C᎐O); δ (250 MHz; CDCl ) 7.30–7.10 (10 H, m, Ph), 6.84
᎐
H
3
(1 H, t, J 7.8, C᎐CH, one isomer), 6.74 (1 H, t, J 7.7, C᎐CH,
᎐
᎐
other isomer), 2.77 (2 H, m, C᎐CHCH , one isomer), 2.83 (2 H,
᎐
2
m, C᎐CHCH , other isomer), 2.62 (2 H, t, J 7.8, PhCH , one
᎐
2
2
isomer), 2.51–2.43 (4 H, m, PhCH2 and CH2CO, one isomer),
2.70–2.52 (6 H, m, PhCH2 and CH2CO, other isomer), 1.98
(2 H, quintet, CH2CH2CH2, one isomer), 1.89 (2 H, quintet,
J 7.4, CH2CH2CH2, other isomer), 1.46 (9 H, s, But, one isomer)
and 1.54 (9 H, s, But, other isomer); m/z (EI) 305 (15%, M Ϫ
C4H9O) (Found: Mϩ Ϫ C4H9O, 305.1541. C25H30O3 requires
M Ϫ C4H9O, 305.1541).
tert-Butyl 4-methyl-3-oxo-pentanoate 14c20 (55%). Rf(EtOAc–
light petroleum, 2 : 8) 0.61; νmax(film)/cmϪ1 1720 and 1713
(C᎐C); δ (250 MHz; CDCl ) 3.38 (2 H, s, COCH CO), 2.70
᎐
H
3
2
(1 H, septet, J 7.0, Me2CH ), 1.44 (9 H, s, But), 1.12 (3 H, d,
J 7.0, CHMeAMeB) and 1.11 (3 H, d, J 7.0, CHMeAMeB).
tert-Butyl 3-cyclohexyl-3-oxo-propionate 14d21 (84%). Rf(Et-
OAc–light petroleum, 2 : 8) 0.75; νmax(film)/cmϪ1 1738 and 1709
(E and Z )-tert-Butyl 2-isobutyryl-5-phenylpent-2-enoate 15c
(74%). Rf (EtOAc–light petroleum, 1 : 5) 0.63 (one isomer) and
(C᎐C); δ (250 MHz; CDCl ) 3.36 (2 H, s, COCH CO), 1.88–
᎐
H
3
2
1.75 (6 H, m, cyclohexyl), 1.44 (9 H, s, But) and 1.36–1.23 (5 H,
m, cyclohexyl); m/z (EI) 226 (20%, Mϩ), 170 (50, M Ϫ C4H8)
and 54 (100, C4H9) (Found: Mϩ, 226.1568. C13H22O3 requires
M, 226.1569).
0.66 (other isomer); νmax(film)/cmϪ1 1717 and 1697 (C᎐O);
᎐
δH(250 MHz; CDCl3) 7.40–7.10 (5 H, m, Ph), 6.86 (1 H, t, J 7.8,
CH᎐C, one isomer), 6.69 (1 H, t, J 7.6, CH᎐C, other isomer),
᎐
᎐
3.02 (1 H, septet, J 6.8, Me2CH, one isomer), 2.90–2.34 (5 H, m,
PhCH2 and PhCH2CH2, both isomers and Me2CH, other iso-
mer), 1.52 (9 H, s, But, one isomer) and 1.48 (9 H, s, But, other
isomer); m/z (EI) 302 (5%, Mϩ), 246 (65, M Ϫ C4H8), 91 (100,
PhCH2) and 57 (100, C4H9) (Found: Mϩ, 302.1893. C19H26O3
requires M, 302.1882).
(E and Z )-tert-Butyl 2-benzylidene-3-oxobutanoate22
tert-Butyl acetoacetate (5 g, 31.6 mmol), benzaldehyde (3.35 g,
31.6 mmol), piperidine (1 cm3) and ethanol (1 cm3) were kept at
5 ЊC for 24 h. Ether (50 cm3) was added. The organic layer was
washed with aqueous hydrochloric acid solution (3 mol dmϪ3
,
50 cm3), brine (50 cm3), dried (MgSO4) and concentrated under
reduced pressure. The residue was chromatographed (SiO2,
EtOAc–light petroleum 4 : 96) to give the ester (3.81 g, 50%,
2 : 1 mixture of geometrical isomers) as needles, mp 84–85 ЊC
(from EtOAc) (lit.,22 84–85 ЊC); Rf(EtOAc–light petroleum,
2 : 8) 0.74 (one isomer) and 0.58 (other isomer); νmax(Nujol)/
(Z )-tert-Butyl
2-(cyclohexanecarbonyl)-5-phenylpent-2-
enoate 15d (82%, predominantly one isomer). Rf(EtOAc–light
petroleum, 2 : 8) 0.69; νmax(film)/cmϪ1 1720 and 1697 (C᎐O);
᎐
δH(250 MHz; CDCl3) 7.30–7.10 (5 H, m, Ph), 6.68 (1 H, t, J 7.6,
C᎐CH), 2.83–2.72 (2 H, m, PhCH CH ), 2.63 (2 H, t, J 6.9,
᎐
2
2
PhCH2), 1.80–1.77 (5 H, m, cyclohexyl), 1.52 (9 H, s, But) and
1.32–1.23 (6 H, m, cyclohexyl); m/z (EI) 342 (5%, Mϩ), 91 (100,
PhCH2) and 57 (80, C4H9) (Found: Mϩ, 342.2194. C22H30O3
requires M, 342.2195).
cmϪ1 1723, 1655 (C᎐O) and 1575 (Ph); δ (250 MHz; CDCl )
᎐
H
3
7.50–7.30 (5 H, m, Ph, both isomers), 7.26 (1 H, s, PhCH, both
isomers), 2.41 (3 H, s, MeCO, one isomer), 2.19 (3 H, s, MeCO,
other isomer), 1.52 (9 H, s, But, one isomer) and 1.12 (9 H, s,
But, other isomer).
Hydrogenation of the unsaturated ꢀ-keto esters
Typically, palladium on carbon (10% w/w, 140 mg) was stirred
with the α-alkylidene ester (4.6 mmol) in methanol (10 cm3)
for 24 h at room temperature under hydrogen delivered from a
balloon. The mixture was filtered through Celite, dried
(MgSO4) and concentrated under reduced pressure to give the
α-substituted β-keto ester.
The other unsaturated ꢀ-ketoesters
Typically, following Lehnert,23 the ester (18.8 mmol) and alde-
hyde (18.8 mmol) in THF (10 cm3), followed by pyridine
(75 mmol) in THF (10 cm3), were added dropwise to titanium
tetrachloride (1 mol dmϪ3 in CH2Cl2, 37.6 mmol) in dry THF
(35 cm3) under argon at 0 ЊC over 30 min, and the mixture
stirred at room temperature for 16 h. The mixture was
quenched with saturated aqueous ammonium chloride solution
and extracted with ether (3 × 50 cm3). The combined organic
fractions were washed with aqueous hydrochloric acid (3 mol
dmϪ3, 2 × 50 cm3) and brine (10 cm3), dried (MgSO4) and con-
centrated under reduced pressure. The residue was chromato-
graphed (SiO2, EtOAc–hexane, 4 : 96) to give the α-alkylidene
esters as ca. 1.5 : 1 mixtures of geometrical isomers.
The following esters were prepared by this method.
tert-Butyl 2-benzyl-3-oxobutanoate24 (87%). Rf(EtOAc–light
petroleum, 2 : 8) 0.70; νmax(film)/cmϪ1 1731 and 1715 (C᎐C) and
᎐
1604 (Ph); δH(250 MHz; CDCl3) 7.30–7.10 (5 H, m, Ph), 3.68
(1 H, t, J 7.9, COCHCO), 3.10 (2 H, d, J 8.0, PhCH2), 2.2 (3 H,
s, MeCO) and 1.38 (9 H, s, But).
tert-Butyl 2-acetyl-5-phenylpentanoate 16a (90%). Rf(EtOAc–
light petroleum, 2 : 8) 0.6; νmax(film)/cmϪ1 1731 and 1713 (C᎐O);
The following esters were prepared by this method.
᎐
δH(250 MHz; CDCl3) 7.30–7.10 (5 H, m, Ph), 3.31 (1 H, t, J 7.4,
COCHCO), 2.74 (2 H, t, J 7.6, PhCH2), 2.18 (3 H, s, MeCO),
1.95–1.80 (2 H, m, CHCH2), 1.70–1.53 (2 H, m, PhCH2CH2)
and 1.44 (9 H, s, But); m/z (TES) 299 (100%, M ϩ Na) (Found:
Mϩ ϩ Na, 299.1652. C17H24O3 requires M ϩ Na, 299.1623).
(E and Z )-tert-Butyl 2-acetyl-5-phenylpent-2-enoate 15a
(62%). Rf(EtOAc–light petroleum, 2 : 8) 0.51 (one isomer) and
0.43 (other isomer); νmax(film)/cmϪ1 1722 and 1697 (C᎐O);
᎐
δH(250 MHz; CDCl3) 7.30–7.10 (5 H, m, Ph), 6.83 (1 H, t, J 7.8,
CH᎐C, one isomer), 6.76 (1 H, t, J 7.5, CH᎐C other isomer),
᎐
᎐
2.81 (2 H, t, J 8.0, PhCH2, one isomer), 2.76 (2 H, t, J 7.8,
PhCH2, other isomer), 2.65 (2 H, q, J 7.8, PhCH2CH2, one
isomer), 2.53 (2 H, q, J 7.6, PhCH2CH2, other isomer), 2.27
(3 H, s, MeCO, one isomer), 2.17 (3 H, s, MeCO, other isomer),
1.52 (9 H, s, But, one isomer) and 1.48 (9 H, s, But, other iso-
mer); m/z (EI) 218 (60%, M Ϫ C4H8) and 91 (100, PhCH2)
tert-Butyl 3-oxo-6-phenyl-2-(3-phenylpropyl)hexanoate 16b
(90%). Rf(EtOAc–light petroleum, 2 : 8) 0.78; νmax(film)/cmϪ1
1733 and 1717 (C᎐O); δ (250 MHz; CDCl ) 7.30–7.10 (10 H,
᎐
H
3
m, Ph), 3.31 (1 H, t, J 7.2, COCHCO), 2.61–2.46 [8 H, m, 2 ×
PhCH2, CHCH2 and CH2CO], 1.93–1.80 (4 H, m, CH2CH2CO
and CHCH2CH2) and 1.40 (9 H, s, But); m/z (EI) 322 (50%,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 0 4 – 1 5 1 0
1507

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M Ϫ C4H9) and 233 (100, M Ϫ C4H8 Ϫ PhCH2) (Found: Mϩ Ϫ
C4H9, 322.1587. C25H32O3 requires M Ϫ C4H9, 322.1568).
(50, M Ϫ C4H8 Ϫ H2O Ϫ MeCO) (Found: Mϩ Ϫ C4H8,
206.0948. C16H22O3 requires M Ϫ C4H8, 206.0947).
tert-Butyl 4-methyl-3-oxo-2-(3-phenylpropyl)pentanoate 16c
(94%). Rf(EtOAc–light petroleum, 2 : 8) 0.66; νmax(film)/cmϪ1
tert-Butyl 4-methyl-3-oxo-2-(4-phenylbut-2-yl)pentanoate 25c
Methyllithium (1.6 mol dmϪ3 solution in ether, 6.2 cm3, 10
mmol) was added dropwise to a suspension of copper() cyan-
ide (0.44 g, 5.0 mmol) in THF (5 cm3) under argon at 0 ЊC and
stirred for 1 h. The mixture was cooled to Ϫ78 ЊC and the enone
15c (1.13 g, 3.3 mmol) in THF (5 cm3) was added dropwise, and
the mixture stirred for 1 h. Basic aqueous saturated ammonium
chloride solution was added, and the mixture extracted with
ether (2 × 20 cm3). The combined organic fractions were
washed with brine (25 cm3), dried (MgSO4) and concentrated
under reduced pressure. The residue was chromatographed
(SiO2, EtOAc–hexane, 4 : 96) to give the ester (0.958 g, 91%) as
a 1 : 1 mixture of diastereoisomers; Rf(EtOAc–light petroleum,
2 : 8) 0.76; νmax(film)/cmϪ1 1738 and 1712 (C᎐O); δ (250 MHz;
1739 and 1712 (C᎐O); δ (250 MHz; CDCl ) 7.40–7.10 (5 H, m,
᎐
H
3
Ph), 3.52 (1 H, t, J 7.1, COCHCO), 2.78 (1 H, septet, J 6.9,
Me2CH ), 2.63 (2 H, td, J 7.5 and 3.2, CH2CHCO), 2.18 (2 H, t,
J 7.5, PhCH2), 1.85 (2 H, m, PhCH2CH2), 1.43 (9 H, s, But),
1.10 (3 H, d, J 6.6, CHMeAMeB) and 1.08 (3 H, d, J 7,
CHMeAMeB); m/z (EI) 304 (10%, Mϩ), 248 (85, M Ϫ C4H8),
91 (85, PhCH2) and 57 (100, C4H9) (Found: Mϩ, 304.2027.
C19H28O3 requires M, 304.2038).
tert-Butyl 2-cyclohexyl-3-oxobutanoate 23c (63%). Rf(Et-
OAc–light petroleum, 1 : 9) 0.5; νmax(film)/cmϪ1 1709 br (C᎐O);
᎐
δH(250 MHz; CDCl3) 3.07 (1 H, d, J 9.7, COCHCO), 2.14 (3 H,
s, MeCO), 1.69–1.56 (5 H, m, cyclohexyl), 1.40 (9 H, s, But) and
1.30–0.85 (6 H, m, cyclohexyl); m/z (EI) 241 (20%, Mϩ ϩ H)
and 185 (80, M Ϫ C4H8 ϩ H) (Found: Mϩ ϩ H, 241.1808.
C14H24O3 requires M ϩ H, 241.1803).
᎐
H
CDCl3) 7.27–7.10 (5 H, m, Ph), 3.44 (1 H, d, J 9.5, COCHCO),
2.81–2.28 (6 H, m, PhCH2, PhCH2CH2, MeCH, and Me2CH ),
1.45 (9 H, s, But, one isomer), 1.42 (9 H, s, But, other isomer),
1.10 (3 H, d, J 6.9, CHMeAMeB one isomer), 1.09 (3 H, d, J 6.9,
CHMeAMeB, other isomer), 1.07 (3 H, d, J 7.0, CHMeAMeB,
one isomer) (the CHMeAMeB signal for the other isomer was
obscured), 1.03 (3 H, d, J 7.6, MeCH, one isomer) and 0.95
(3 H, d, J 6.7 MeCH, other isomer). This compound was not
fully characterised.
tert-Butyl 2-diphenylmethyl-3-oxobutanoate 23a
Phenyllithium (1.3 mol dmϪ3 solution in hexane, 18.75 cm3,
24.39 mmol) was added dropwise to a suspension of copper()
cyanide (1.08 g, 12.2 mmol) in THF (10 cm3) under argon at
0 ЊC and the mixture stirred for 1 h. The mixture was cooled to
Ϫ78 ЊC and the enone 19 (2 g, 8.13 mmol) in THF (10 cm3) was
added dropwise, and the mixture stirred for 1 h. Saturated basic
aqueous ammonium chloride solution was added, and the
mixture was extracted with ether (2 × 20 cm3). The combined
organic fractions were washed with brine (50 cm3), dried
(MgSO4) and concentrated under reduced pressure. The residue
was chromatographed (SiO2, EtOAc–hexane, 4 : 96) to give the
ester (1.23 g, 47%) as needles, mp 117–120 ЊC (from Et2O);
Rf(EtOAc–light petroleum, 2 : 8) 0.66; νmax(CHCl3)/cmϪ1 1736
tert-Butyl 2-(cyclohexanecarbonyl)-3-methyl-5-phenyl-
pentanoate 25d
Similarly, the enone 15d (2.5 g, 7.3 mmol) gave the ester (2.21 g,
84%) as a 1 : 1 mixture of diastereoisomers; Rf(EtOAc–light
petroleum, 2 : 8) 0.76; νmax(film)/cmϪ1 1739 and 1709 (C᎐O);
᎐
δH(250 MHz; CDCl3) 7.32–7.10 (5 H, m, Ph), 3.43 (1 H, d, J 9.3,
COCHCO, one isomer), 3.42 (1 H, d, J 9.3, COCHCO, other
isomer), 2.78–2.25 (5 H, m, PhCH2, PhCH2CH2 and MeCH ),
1.79–1.76 (6 H, m, cyclohexyl), 1.44 (9 H, s, But, one isomer),
1.41 (9 H, s, But, other isomer), 1.23 (5 H, m, cyclohexyl), 1.02
(3 H, d, J 6.7, MeCH, one isomer) and 0.94 (3 H, d, J 6.7
MeCH, other isomer); m/z (EI) 358 (20%, Mϩ), 302 (85, M Ϫ
C4H8), 91 (80 PhCH2) and 57 (100, C4H9) (Found: Mϩ,
358.2512. C23H34O3 requires M, 358.2507).
and 1708 (C᎐O); δ (250 MHz; CDCl ) 7.50–7.00 (10 H, m, Ph),
᎐
H
3
4.68 (1 H, d, J 12.2, COCHCO), 4.43 (1 H, d, J 12.2 PhCHPh),
4.33 (1 H, s, PhCHPh, of enol form), 2.10 and 1.74 (3 H, s,
MeCO, of keto and enol forms), 1.18 and 1.02 (9 H, s, But, of
keto and enol forms) (Found: C, 77.28; H, 7.47; Mϩ ϩ Na,
347.1621. C21H24O3 requires C, 77.75; H, 7.46%; M ϩ Na,
347.1623).
The enol triflates
tert-Butyl 3-oxo-2-(1-phenylethyl)butanoate 23b
Method A. Typically the di-tert-butyl acylmalonate (1.96
mmol) was dissolved in dry dichloromethane (10 cm3) and
cooled to 0 ЊC. Trifluoromethanesulfonic (triflic) anhydride
(2.35 mmol) was added slowly, followed by triethylamine (3.92
mmol). The mixture was stirred for 1 h at 0 ЊC and allowed to
warm to room temperature. Saturated aqueous ammonium
chloride solution was added, and the mixture was extracted
with dichloromethane (3 × 10 cm3). The combined organic frac-
Methyllithium (1.4 mol dmϪ3 solution in ether, 71.4 cm3, 0.101
mol) was added dropwise to a suspension of copper() iodide
(19.3 g, 0.101 mol) in THF (100 cm3) under argon at 0 ЊC and
the mixture stirred for 1 h. The mixture was cooled to Ϫ78 ЊC
and the enone 19 (10 g, 0.04 mol) in THF (50 cm3) was added
dropwise, and the mixture stirred for 1 h. Basic saturated
ammonium chloride solution was added, and the mixture
extracted with ether (2 × 100 cm3). The combined organic
fractions were washed with brine (50 cm3), dried (MgSO4) and
concentrated under reduced pressure. The residue was chrom-
atographed (SiO2, EtOAc–light petroleum, 4 : 96) to give the
ester (7.73 g, 82%) as a 1.8 : 1 mixture of diastereoisomers;
Rf(EtOAc–light petroleum, 2 : 8) 0.75; νmax(film)/cmϪ1 1737 and
tions were washed with hydrochloric acid solution (3 mol dmϪ3
,
50 cm3) and brine (50 cm3), dried (MgSO4) and concentrated
under reduced pressure. The residue was chromatographed
(SiO2, EtOAc–light petroleum, 2 : 98) to give the enol triflate.
Method B. Typically the di-tert-butyl acylmalonate or the
α-substituted β-keto ester (1.96 mmol) in dry ether (5 cm3) was
added dropwise to a prewashed suspension of sodium hydride
(60% dispersion in mineral oil, 2.94 mmol) in dry ether (10 cm3)
at 0 ЊC and stirred for 1 h. Triflic anhydride (2.35 mmol) was
added and the mixture was stirred for 1 h at 0 ЊC and 1 h at
room temperature. The mixture was worked up in the same as
for Method A.
The following enol triflates were prepared by either or both
of these methods. The enol triflates were unstable, and, except
for the first, were not fully characterised before being used in
the next step.
1708 (C᎐O); δ (250 MHz; CDCl ) 7.40–7.20 (5 H, m, Ph), 3.70
᎐
H
3
(1 H, d, J 7.9, COCHCO, one isomer), 3.68 (1 H, d, J 8.1,
COCHCO, other isomer), 3.48 (1 H, m, PhCHMe, both iso-
mers), 2.29 (3 H, s, MeCO, one isomer), 1.94 (3 H, s, MeCO,
other isomer), 1.48 (9 H, s, But, one isomer), 1.27 (3 H, d, J 6.8,
PhCHMe, one isomer), 1.17 (3 H, d, J 6.9, PhCHMe, other
isomer) and 1.12 (9 H, s, But, other isomer); δC(CDCl3) 202.6ϩ,
167.7ϩ, 167.2ϩ, 143.5ϩ, 143.4ϩ, 128.6Ϫ, 128.3Ϫ, 127.6Ϫ,
127.3Ϫ, 126.7Ϫ, 126.6Ϫ, 82.0ϩ, 81.6ϩ, 68.6Ϫ, 68.0Ϫ, 39.8Ϫ,
39.7Ϫ, 29.5Ϫ, 29.1Ϫ, 27.9Ϫ, 27.4Ϫ, 20.8Ϫ, 20.5Ϫ; m/z (EI)
206 (20%, Mϩ Ϫ C4H8), 188 (100, M Ϫ C4H8 Ϫ H2O) and 145
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 0 4 – 1 5 1 0
1508

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1,1-Di-tert-butoxycarbonylpropen-2-yl
trifluoromethane-
3-tert-Butoxycarbonyl-3-cyclohexylprop-2-en-2-yl trifluoro-
methanesulfonate (48% by method B). Rf(EtOAc–light petrol-
eum, 2 : 8) 0.63; δH(250 MHz; CDCl3) 2.40–2.20 (1 H, m,
sulfonate 4 (89% by method A, 85% by method B). Rf(EtOAc–
light petroleum, 1 : 9) 0.65; νmax(film)/cmϪ1 1720 (C᎐O); δ (250
᎐
H
MHz; CDCl3) 2.48 (3 H, s, Me) and 1.50 (18 H, s, 2 × But);
δC(CDCl3) 161.4ϩ, 161.1ϩ, 156.7ϩ, 83.8ϩ, 83.6ϩ, 27.9Ϫ,
27.7Ϫ and 17.8Ϫ; m/z (EI) 391 (15%, M ϩ H), 335 (70, M ϩ H
Ϫ 2But) and 57 (100, C4H9) (Found: Mϩ ϩ H, 391.1045.
C14H21F3O7S requires M ϩ H, 391.1038).
cyclohexyl CH), 2.15 and 2.05 (3 H, s, MeC᎐C), 1.85–1.58
᎐
(11 H, m, cyclohexyl) and 1.45 (9 H, s, But).
3-tert-Butoxycarbonyl-4-phenylpent-2-en-2-yl
trifluoro-
methanesulfonate (85% by method B). Rf(EtOAc–light petrol-
eum, 2 : 8) 0.77; νmax(film)/cmϪ1 1721 (C᎐O) and 1602 (Ph);
᎐
δH(250 MHz; CDCl3) 7.30–7.20 (5 H, m, Ph), 3.96 and 3.86
1,1-Di-tert-butoxycarbonyl-5-phenylpenten-2-yl
trifluoro-
(1 H, q, J 7.3, PhCH ), 2.12 and 2.10 (3 H, s, MeC᎐C), 1.57
methanesulfonate 8a (70% by method A). Rf(EtOAc–light
᎐
(3 H, d, J 7.2, MeCH) and 1.31 (9 H, s, But).
petroleum, 1 : 9) 0.69; νmax(film)/cmϪ1 1729 (C᎐O); δ (250 MHz;
᎐
H
CDCl3) 7.30–7.10 (5 H, m, Ph), 2.68 (2 H, t, J 7.5, CH2CH2-
CH2Ph), 2.56 (2 H, t, J 7.5, PhCH2), 1.94 (2 H, qn, J 7.7,
CH2CH2CH2), 1.52 (9 H, s, But) and 1.48 (9 H, s, But).
2-tert-Butoxycarbonyl-1,1-diphenylbut-2-en-3-yl
trifluoro-
methanesulfonate (73% by method B). One isomer; Rf(EtOAc–
light petroleum, 2 : 8) 0.7; νmax(film)/cmϪ1 1717 (C᎐O); δ (250
᎐
H
MHz; CDCl3) 7.50–7.00 (10 H, m, Ph), 5.15 (1 H, s, PhCHPh),
1,1-Di-tert-butoxycarbonyl-3-methylbuten-2-yl
trifluoro-
2.06 (3 H, s, MeC᎐C) and 1.13 (9 H, s, But) (Found: Mϩ ϩ H,
᎐
methanesulfonate 8b (72% by method A). Rf(EtOAc–light
petroleum, 1 : 9) 0.65; νmax(film)/cmϪ1 1731 (C᎐O); δ (250 MHz;
457.1318. C20H27F3O5S requires M ϩ H, 457.1297).
᎐
H
CDCl3) 3.17 (1 H, septet, J 7.2, CHMe2), 1.47 (18 H, s, 2 × But)
and 1.26 (3 H, d, J 7.1, MeCH).
1-Trifluoromethanesulfonyloxyethylidenemalonic acid 5
Triflate 4 (0.3 g, 0.76 mmol) was dissolved in trifluoroacetic acid
(5 cm3) and stirred for 20 min at room temperature. The excess
trifluoroacetic acid was removed under reduced pressure, and
the residue crystallised from ether–light petroleum to give the
dicarboxylic acid (0.162 g, 76%), mp 80–82 ЊC (from Et2O-light
1,1-Di-tert-butoxycarbonyl-4-phenylbuten-3-yn-2-yl trifluoro-
methanesulfonate 8c (73% by method A). Rf(EtOAc–light
petroleum, 1 : 9) 0.65; νmax (film)/cmϪ1 2208 (C᎐C) and 1732
᎐
᎐
(C᎐O); δ (250 MHz; CDCl ) 7.60–7.30 (5 H, m, Ph) and 1.58
᎐
H
3
(18 H, s, But).
petroleum); νmax(Nujol)/cmϪ1 3449 (COOH) and 1761 (C᎐O);
᎐
δH(250 MHz; CDCl3) 2.05 (3 H, s, Me) (Found: C, 25.84; H,
1.74. C6H5F3O7S requires C, 25.91; H, 1.81%). The diacid is
unstable and decomposes in a few hours.
1-tert-Butoxycarbonyl-6-phenyl-hexen-2-yl trifluoromethane-
sulfonate 12 (72% by method B). One isomer; Rf(EtOAc–light
petroleum, 2 : 8) 0.76; νmax(film)/cmϪ1 1725 (C᎐O) and 1676
᎐
(C᎐C); δ (250 MHz; CDCl ) 7.30–7.10 (5 H, m, Ph), 5.63 (1 H,
The acetylenic acids
᎐
H
3
s, C᎐CH), 2.64 (2 H, t, J 7.2, PhCH ), 2.36 (2 H, t, J 7.2, CH C᎐
᎐
᎐
2
2
Typically, the enol triflate (0.75 mmol) was stirred in trifluoro-
acetic acid (5 cm3) at room temperature for 30 min. The excess
trifluoroacetic acid was removed under reduced pressure. The
residue was dissolved in saturated aqueous sodium hydrogen
carbonate (10 cm3) and was stirred for 4 h. The mixture was
washed with ether (5 cm3), and the aqueous layer was carefully
acidified with concentrated hydrochloric acid solution. The
mixture was extracted with ether (3 × 10 cm3). The combined
organic fractions were washed with brine (30 cm3), dried
(MgSO4), and concentrated under reduced pressure to give the
acetylenic acid.
CH), 1.7–1.5 (4 H, m, CH2CH2CH2Ph) and 1.49 (9 H, s, But).
3-tert-Butoxycarbonyl-6-phenylhex-2-en-2-yl trifluoro-
methanesulfonate 17a (71% by method B). Rf(EtOAc–light
petroleum, 2 : 8) 0.64; νmax(film)/cmϪ1 1714 (C᎐C); δ (250 MHz;
᎐
H
CDCl3) 7.30–7.10 (5 H, m, Ph), 2.67 and 2.65 (2 H, t, J 7.5,
PhCH ), 2.42–2.18 (2 H, m, C᎐CCH ), 2.06 and 1.98 (3 H, s,
᎐
2
2
MeCO), 1.92–1.70 (2 H, m, PhCH2CH2) and 1.50 (9 H, s, But);
m/z (EI) 335 (80%, M Ϫ C4H8 Ϫ 16) and 91 (75, PhCH2) and
57 (100, C4H9) (Found: Mϩ Ϫ C4H8, 335.0564. C18H23F3O5S
requires M Ϫ C4H8O, 335.0559).
The following compounds were prepared by this method.
5-tert-Butoxycarbonyl-1,8-diphenyloct-4-en-4-yl
trifluoro-
2-Butynoic acid 6 (66%). [0.043 g, 66% from enol triflate 5
(0.3 g)], mp 75–76 ЊC (from light petroleum) (lit.,25 78–80 ЊC);
methanesulfonate 17b (86% by method B). νmax(film)/cmϪ1 1722
νmax(Nujol)/cmϪ1 2918 (COOH), 2246 (C᎐C) and 1711 (C᎐O);
(C᎐O); δ (250 MHz; CDCl ) 7.30–7.10 (10 H, m, Ph), 2.60
᎐
᎐
H
3
᎐
᎐
(4 H, t, J 7.4 2 × PhCH ), 2.44–2.18 (4 H, m, 2 × C᎐CCH ),
᎐
2
2
δH(250 MHz; CDCl3) 2.11 (3 H, s, Me).
1.94–1.66 (4 H, m, 2 × CH2CH2CH2) and 1.51 and 1.40 (9 H, s,
But); m/z (EI) 455 (10%, M Ϫ C4H9), 91 (100, PhCH2) and
57 (80, C4H9) (Found: Mϩ Ϫ C4H9, 455.1129. C26H31F3O5S
requires M Ϫ C4H9, 455.1139).
6-Phenylhex-2-ynoic acid 9a (56%). νmax (film)/cmϪ1 2236
᎐
(C᎐C) and 1720 (C᎐O); δ (250 MHz; CDCl ) 7.30–7.10 (5 H,
᎐
᎐
H
3
m, Ph), 2.74 (2 H, t, J 7.3, PhCH2), 2.36 (2 H, t, J 7.1,
CH2CH2CH2Ph) and 1.92 (2 H, qn, J 7.3, CH2CH2CH2);
δC(CDCl3) 158.2ϩ, 140.7ϩ, 128.5Ϫ, 126.2Ϫ, 112.6Ϫ, 91.8ϩ,
73.2ϩ, 34.6ϩ, 28.9ϩ and 18.1ϩ; m/z (EI) 188.1 (34%, Mϩ),
170.1 (55, M Ϫ H2O) and 91 (100, PhCH2) (Found: Mϩ,
188.0835. C12H12O2 requires M, 188.0837).
4-tert-Butoxycarbonyl-2-methyl-7-phenylhept-3-en-3-yl
tri-
fluoromethanesulfonate 17c (92% by method B). Rf(EtOAc–light
petroleum, 2 : 8) 0.71; νmax(film)/cmϪ1 1722 (C᎐O); δ (250 MHz;
᎐
H
CDCl3) 7.40–7.10 (5 H, m, Ph), 2.82 and 2.78 (1 H, 2 × septets,
J 6.9, Me2CH ), 2.68 and 2.66 (2 H, 2 × t, J 7.4, PhCH2), 2.43–
4-Methylpent-2-ynoic acid 9b26 (54%). νmax(film)/cmϪ1 2979
2.30 (2 H, m, C᎐CCH ), 1.90–1.73 (2 H, m, CH CH CH ),
᎐
2
2
2
2
1.49 and 1.30 (9 H, 2 × s, But), 1.15 and 1.13 (3 H, 2 × d,
J 6.9, CHMe2) (Found: Mϩ Ϫ C4H9O, 363.0876. C20H27F3O5S
requires M Ϫ C4H9O, 363.0872).
᎐
(COOH), 2231 (C᎐C) and 1693 (C᎐O); δ (250 MHz; CDCl )
᎐
᎐
H
3
2.72 (1 H, septet, J 6.9, CHMe2) and 1.24 (6 H, d, J 6.9
CHMe2); δC(CDCl3) 158.7, 97.3, 71.8, 29.7, and 21.6; m/z (EI)
111 (50%, M Ϫ H), 97 (56, M Ϫ H Ϫ Me) and 67 (100, M Ϫ H
Ϫ CO2) (Found: Mϩ Ϫ H, 111.0446. C6H8O2 requires M Ϫ H,
111.0446).
2-tert-Butoxycarbonyl-1-phenylbut-2-en-3-yl
trifluoro-
methanesulfonate 20 (87% by method B). Rf(EtOAc–light pet-
roleum, 2 : 8) 0.74; νmax(film)/cmϪ1 1723 (C᎐C); δ (250 MHz;
᎐
H
CDCl3) 7.30–7.10 (5 H, m, Ph), 3.75 and 3.66 (2 H, s, PhCH2),
5-Phenylpenta-2,4-diynoic acid 9c27 (71%). mp 142–144 ЊC
(from Et2O–hexane) (lit.,27 143–144 ЊC); νmax(film)/cmϪ1 3445
2.24 and 2.17 (3 H, s, MeCO) and 1.34 (9 H, s, But).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 0 4 – 1 5 1 0
1509

View Article Online
᎐
(COOH), 2226 (C᎐C) and 1732 (C᎐O); δ (250 MHz; CDCl )
1-Cyclohexylpropyne 24c31 (84%). Rf(EtOAc–light petrol-
᎐
᎐
H
3
7.60–7.30 (5 H, m, Ph); δC(CDCl3) 157.4ϩ, 133.2Ϫ, 130.8Ϫ,
128.7Ϫ, 85.1ϩ, 73.9ϩ, and 70.9ϩ.
eum, 2 : 8) 0.85; νmax(film)/cmϪ1 no characteristic peaks; δH(250
᎐
MHz; CDCl ) 2.25 (1 H, m, C᎐CCH), 1.77 (3 H, d, J 2.4,
᎐
3
᎐
MeC᎐C) and 1.67–1.23 (11 H, m, cyclohexyl); δ (CDCl )
᎐
C
3
The other acetylenes
83.7ϩ, 75.0ϩ, 33.1ϩ, 29.2Ϫ, 25.9ϩ, 25.0ϩ, 3.45Ϫ.
Typically, the enol triflate (2.29 mmol) was stirred in trifluoro-
acetic acid (5 cm3) at room temperature for 30 min. The excess
trifluoroacetic acid was removed under reduced pressure. The
residue was dissolved in anhydrous acetone (20 cm3), potassium
carbonate (6.87 mmol) was added and the mixture refluxed for
4 h. The mixture was cooled, poured into water and extracted
with ether (2 × 20 cm3). The combined organic fractions were
washed with brine (30 cm3), dried (MgSO4), and concentrated
under reduced pressure. The residue was chromatographed
(SiO2, EtOAc–hexane, 2 : 98) to give the acetylene.
References
1 I. Fleming and J. Harley-Mason, Proc. Chem. Soc., 1961, 245;
I. Fleming and J. Harley-Mason, J. Chem. Soc., 1963, 4771–4778;
E. J. D. Brown and J. Harley-Mason, J. Chem. Soc., 1966, 1390;
I. Fleming and C. R. Owen, J. Chem. Soc. (C), 1971, 2013.
2 I. Fleming and C. R. Owen, J. Chem. Soc. (B), 1971, 1293.
3 T. W. Bentley, in The Chemistry of Sulfonic Acids, Esters and their
Derivatives, S. Patai and S. Rappoport, eds., Wiley, Chichester, 1991,
pp. 671––696.
4 I. Fleming and C. Ramarao, Chem. Commun., 1999, 1113.
5 K. Takeuchi, K. Ikai, T. Shibata and A. Tsugeno, J. Org. Chem.,
1988, 53, 2852.
6 A. Streitwieser, Jr., C. L. Wilkins and E. Kiehlmann, J. Am. Chem.
Soc., 1968, 90, 1598. See also: M. G. Ahmed, R. W. Alder, G. H.
James, M. L. Sinnott and M. C. Whiting, J. Chem. Soc., Chem.
Commun., 1968, 1533; D. N. Kevill and G. M. Lin, Tetrahedron
Lett., 1978, 949; J. F. Garrity and J. W. Prodolliet, Tetrahedron Lett.,
1982, 23, 417.
The following compounds were prepared by this method.
6-Phenylhexyne 13 (68%). Rf(EtOAc–light petroleum, 2 : 8)
0.87; νmax(film)/cmϪ1 3300 C᎐C-H) and 2238 (C᎐C); δ (250
᎐
᎐
᎐
᎐
H
MHz; CDCl3) 7.30–7.10 (5 H, m, Ph), 2.64 (2 H, t, J 7.3,
᎐
᎐
2
PhCH ), 2.22 (2 H, td, J 7.0 and 2.6, CH C᎐C), 1.94 (1 H, t,
2
᎐
J 2.6, C᎐CH), 1.75 (2 H, m, PhCH CH ) and 1.57 (2 H, m,
᎐
2
2
᎐
CH CH C᎐C); m/z (EI) 157 (10%, M Ϫ H) and 91 (12, PhCH )
᎐
2
2
2
7 D. N. Kevill, K. C. Kolwyck, D. M. Shold and C.-B. Kim, J. Am.
Chem. Soc., 1973, 95, 6022.
(Found: Mϩ Ϫ H, 157.1014. C12H14 requires M Ϫ H, 157.1017).
8 M. W. Rathke and P. J. Cowan, J. Org. Chem., 1985, 50, 2622.
9 P. J. Stang, M. Hanack and L. R. Subramanian, Synthesis, 1982,
85.
10 A. García Martinez, R. Martínez Alvarez, M. Madueño Casado,
L. R. Subramanian and M. Hanack, Tetrahedron, 1987, 43, 275.
11 S. Benetti, R. Romagnoli, C. De Risi, G. Spalluto and V. Zanirato,
Chem. Rev., 1995, 95, 1065.
12 E. C. Taylor, R. L. Robey and A. McKillop, Angew. Chem., Int. Ed.
Engl., 1972, 11, 48; P. J. Kocienski, J. M. Ansell and B. E. Norcross,
J. Org. Chem., 1976, 41, 3650; C. Wentrup and W. Reichen,
Helv. Chim. Acta, 1976, 59, 2615; C. Wentrup and H.-W. Winter,
Angew. Chem., Int. Ed. Engl., 1976, 17, 609.
13 J. Boivin, L. ElKaim, P. G. Ferro and S. Z. Zard, Tetrahedron Lett.,
1991, 32, 5321; J. Boivin, S. Huppé and S. Z. Zard, Tetrahedron Lett.,
1995, 36, 5737; J. Boivin, S. Huppé and S. Z. Zard, Tetrahedron
Lett., 1996, 37, 8735; S. Huppé, H. Rezaei and S. Z. Zard,
Chem. Commun., 2001, 1894 reviewed in S. Z. Zard, Chem.
Commun., 2002, 1555.
14 M. Sugai, K. Tamino and I. Kuwajima, Synlett, 1997, 461.
15 K. M. Brummond, K. D. Gesenberg, J. L. Kent and A. D. Kerekes,
Tetrahedron Lett., 1998, 39, 8613.
16 A. Eschenmoser, D. Felix and G. Ohloff, Helv. Chim. Acta, 1967, 50,
708.
17 D. S. Breslow, E. Baumgarten and C. R. Hauser, J. Am. Chem. Soc.,
1944, 66, 1286.
18 Y. Oikawa, T. Yoshioka, K. Sugano and O. Yonemitsu, Org. Synth.,
1990, Coll. Vol. VII, 359.
6-Phenylhex-2-yne 18a28 (73%). Rf(EtOAc–light petroleum,
1 : 9) 0.72; νmax(film)/cmϪ1 1603 (Ph); δH(250 MHz; CDCl3)
7.30–7.10 (5 H, m, Ph), 2.72 (2 H, t, J 7.8, PhCH2), 2.16 (2 H,
᎐
᎐
m, C᎐CCH ) and 1.84–1.78 (5 H, m, MeC᎐C and PhCH CH );
᎐
᎐
2
2
2
m/z (EI) 158 (95%, Mϩ), 143 (95, M Ϫ Me) and 91 (100, Ph)
(Found: Mϩ, 158.1088. C12H14 requires M, 158.1096).
1,8-Diphenyloct-4-yne 18b (60%). Rf(EtOAc–light petroleum,
1 : 9) 0.85; νmax(film)/cmϪ1 1602 (Ph); δH(250 MHz; CDCl3)
7.30–7.10 (10 H, m, Ph), 2.76 (4 H, t, J 7.4, 2 × PhCH2), 2.22
᎐
(4 H, t, J 7.0, 2 × CH C᎐C) and 1.84 (4 H, qn, J 6.9, 2 ×
᎐
2
PhCH2CH2); δC(CDCl3) 141.8ϩ, 128.5Ϫ, 128.3Ϫ, 125.8Ϫ,
80.3ϩ, 34.8ϩ, 30.7ϩ and 18.2ϩ; m/z (EI) 262 (25%, Mϩ), 171
(10, M Ϫ PhCH2) and 91 (100, PhCH2) (Found: Mϩ, 262.1721.
C20H22 requires M, 262.1721).
2-Methyl-7-phenylhept-3-yne 18c (86%). Rf(EtOAc–light
petroleum, 2 : 8) 0.80; νmax(film)/cmϪ1 1603 (Ph); δH(250 MHz;
CDCl3) 7.40–7.10 (5 H, m, Ph), 2.72 (2 H, t, J 7.3, PhCH2), 2.55
(1 H, septet t, J 6.8 and 2.1, Me2CH ), 2.18 (2 H, td J 7.3 and
᎐
2.1, C᎐CCH ), 1.8 (2 H, qn, J 7.3, PhCH CH ) and 1.17 (6 H, d,
᎐
2
2
2
J 6.8, Me2CH); δC(CDCl3) 141.9ϩ, 128.5Ϫ, 128.2Ϫ, 125.7Ϫ,
86.6ϩ, 78.8ϩ, 34.7ϩ, 31.4Ϫ, 30.7ϩ, 23.4Ϫ, 20.5– and 18.1ϩ;
m/z (EI) 186 (35%, Mϩ), 171 (40, M Ϫ Me) and 91 (70, PhCH2)
(Found: Mϩ, 186.1408. C14H18 requires M, 186.1409).
19 D. Davidson and S. A. Bernhard, J. Am. Chem. Soc., 1948, 70,
3426.
20 W. L. Meyer, M. J. Brannon, C. da G. Burgos, T. E. Goodwin and
R. W. Howard, J. Org. Chem., 1985, 50, 438.
21 R. V. Hoffman and J. E. Saenz, Tetrahedron Lett., 1997, 49,
8469.
22 S.-O. Lawesson, E. H. Larsen, G. Sundström and H. J. Jakobsen,
Acta Chem. Scand., 1963, 17, 2216.
23 W. Lehnert, Synthesis, 1974, 667.
1-Phenylbut-2-yne 229 (69%). Rf(EtOAc–light petroleum,
2 : 8) 0.85; νmax(film)/cmϪ1 2204 (C᎐C); δ (250 MHz; CDCl )
᎐
᎐
H
3
7.40–7.10 (5 H, m, Ph), 3.55 (2 H, q, J 2.6, PhCH2) and 1.85
(3 H, t, J 2.6, Me).
24 S.-O. Lawesson, S. Gronwall and M. Andersson, Ark. Kemi, 1961,
17, 457; S.-O. Lawesson, M. Dahlen and C. Frisell, Acta Chem.
Scand., 1962, 16, 1191.
1,1-Diphenylbut-2-yne 24a (60%). Rf(EtOAc–light petroleum,
1 : 9) 0.76; νmax(film)/cmϪ1 no characteristic peaks; δH(250 MHz;
25 F.-M. Simmross and P. Weyerstahl, Synthesis, 1981, 72.
26 G. Haaima, M.-J. Lynch, A. Routledge and R. T. Weavers,
Tetrahedron, 1993, 49, 4229.
27 W. Chodkiewicz, Ann. Chim. (Paris), 1957, 2(13), 819 (Chem. Abstr.,
1958, 52, 14565c).
28 J. Wolinsky, G. W. Clark and P. C. Thorstenson, J. Org. Chem., 1976,
41, 745.
29 J.-L. Derocque and F.-B. Sundermann, J. Org. Chem., 1974, 39,
1736.
30 J. C. Gilbert, D. H. Giamalva and U. Weerasooriya, J. Org. Chem.,
1983, 48, 5251.
31 B. Grédy, C. R. Acad. Sci., 1934, 199, 153 (Chem. Abstr., 1934, 28,
6117); G. Zweifel, G. M. Clark and N. L. Polston, J. Am. Chem.
Soc., 1971, 93, 3395.
CDCl3) 7.46–6.98 (10 H, m, Ph), 4.96 (1 H, br s, PhCHPh) and
᎐
1.92 (3 H, d, J 2.4, MeC᎐C); δ (CDCl ) 142.3ϩ, 128.4ϩ,
᎐
C
3
127.8ϩ, 126.6ϩ, 80.3ϩ, 79.6ϩ, 43.2Ϫ and 3.79Ϫ; m/z (EI) 206
(35%, Mϩ) and 77 (32, C6H5) (Found: Mϩ, 206.1095. C16H14
requires M, 206.1095).
4-Phenylpent-2-yne 24b30 (91%). Rf(EtOAc–light petroleum,
2 : 8) 0.85; νmax(film)/cmϪ1 1596 (Ph); δH(250 MHz; CDCl3)
7.40–7.20 (5 H, m, Ph), 3.72 (1 H, m, PhCH ), 1.88 (3 H, d,
᎐
J 2.5, MeC᎐C) and 1.47 (3 H, d, J 7.2, MeCH); δ (CDCl )
᎐
C
3
144ϩ, 128.4Ϫ, 126.8Ϫ, 126.4Ϫ, 82.0ϩ, 77.5ϩ, 31.9Ϫ, 24.6Ϫ
and 3.6Ϫ.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 0 4 – 1 5 1 0
1510