Nucleophilic benzoylation using lithiated methyl mandelate as a synthetic equivalent of the benzoyl carbanion. Oxidative decarboxylation of α-hydroxyacids

Article abstract of DOI:10.1016/S0040-4020(00)01097-8

The synthesis of alkyl aryl ketones using lithiated methyl mandelate as a synthetic equivalent of the benzoyl carbanion is reported (Umpolung). The methodology involves alkylation of methyl mandelate, hydrolysis of the ester group and oxidative decarboxylation of the resulting α-hydroxyacids. The last step is carried out in a catalytic aerobic way using a Co(III) complex in the presence of pivalaldehyde under very mild and advantageous conditions. The procedure is also applied to methyl mandelates substituted on the aromatic ring.

Full text of DOI:10.1016/S0040-4020(00)01097-8

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1075±1081
Nucleophilic benzoylation using lithiated methyl mandelate as a
synthetic equivalent of the benzoyl carbanion. Oxidative
decarboxylation of a-hydroxyacids
p
Gonzalo Blay, Isabel Fernandez, Pilar Formentin, Belen Monje, Jose R. Pedro and Rafael Ruiz
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Departament de Quõmica Organica, Facultat de Quõmica, Universitat de Valencia, E-46100 Burjassot (Valencia), Spain
Received 8 August 2000; revised 6 November 2000; accepted 23 November 2000
AbstractÐThe synthesis of alkyl aryl ketones using lithiated methyl mandelate as a synthetic equivalent of the benzoyl carbanion is
reported (Umpolung). The methodology involves alkylation of methyl mandelate, hydrolysis of the ester group and oxidative decarboxyl-
ation of the resulting a-hydroxyacids. The last step is carried out in a catalytic aerobic way using a Co(III) complex in the presence of
pivalaldehyde under very mild and advantageous conditions. The procedure is also applied to methyl mandelates substituted on the aromatic
ring. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
inversion. These protocols are normally referred to as
`Umpolung'. Because of the importance of the carbonyl
group in organic chemistry, it is not surprising that many
of these `Umpolung' methods have been aimed at tempo-
rarily reversing the characteristic reactivity of this group.
Dithianes and dithiolanes,1 TosMIC,2 enol ethers3 and vinyl
sul®des4 are among classical acyl anion equivalents. Other
recent examples involve the use of a-aminonitriles,5 cyano-
hydrins,6 SAMP-hydrazones7 or heterocycles.8
Carbon±carbon bond forming reactions are very important
processes in synthetic organic chemistry. Normally, these
reactions require the interaction between carbon atoms of
opposite polarity, i.e. electron donor and electron acceptor
carbons. In some occasions, it is convenient to invert the
`normal' reactivity of a carbon atom and therefore organic
chemists have developed several protocols to achieve this
In a previous communication we reported on the aerobic
oxidative decarboxylation of a-hydroxyacids catalysed by
a Co(III) complex 1 (Fig. 1) under very mild conditions and
advanced the use of methyl mandelate as a masked
d1-synthon for nucleophilic benzoylation.9 In this paper
we describe in full our results on the application of this
reaction in the synthesis of aryl alkyl ketones through
Scheme 1, which involves alkylation of the methyl mande-
late, hydrolysis of the ester group and oxidative decarboxyl-
ation of the resulting a-hydroxyacids.
Figure 1.
Scheme 1.
Keywords: decarboxylation; catalysts; Umpolung; cobalt; complexes.
Corresponding author. Tel.: 134-963864329; fax: 134-963864328; e-mail: jose.r.pedro@uv.es
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01097-8

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G. Blay et al. / Tetrahedron 57 (2001) 1075±1081
Table 1. Oxidative decarboxylation of a-alkylated mandelic acids
2. Results and discussion
or carboxyester. Also alkyl or benzyl dihalides underwent
dialkylation allowing the formation of dihydroxydiesters.
The effective C-alkylation of methyl mandelate 2 has been
described in the literature.10,11 The procedure involves the use
of 2 equiv. of LDA and 1 equiv. of an alkyl bromide or iodide,
and gives good yields for primary and secondary halides but
lower yields for tertiary halides. Following this method we
prepared a range of a-alkylated methyl mandelates 3 bearing
primary or secondary alkyl groups, allyl or benzyl groups, and
other additional groups or functionalities such as bromide, ether
The a-alkylated methyl mandelates obtained in this way
were transformed into the corresponding a-hydroxyacids
4 upon basic hydrolysis in almost quantitative yields.
The key step in the sequence was the ®nal oxidative decar-
boxylation of these hydroxyacids to give the corresponding
aryl alkyl ketones 5. This transformation was achieved

G. Blay et al. / Tetrahedron 57 (2001) 1075±1081
1077
Table 2. Oxidative decarboxylation of a-alkylated substituted mandelic acids
using a catalytic procedure developed recently in our
laboratory which employs oxygen as terminal oxidant in
the presence of pivalaldehyde and of a catalytic amount of
the Co(III) ortho-phenylene-bis(N0-methyloxamidate)
complex 1, (NMe4)Co(III)Me2opba´2H2O´CH3CN (Fig.
1).12 Although the oxidative decarboxylation of a-hydroxy-
acids or hydroxyesters may be achieved with various oxi-
dizing reagents, such as lead tetraacetate,13 periodates,14
N-halogenosuccinimides,15 copper(II) bromide±lithium
tert-butoxide16 or by ¯ash vacuum pyrolysis of its ethyl
esters,10 our method presents the advantages of mildness,
simplicity and the use of a cheap and environmental accep-
table oxidant such as molecular oxygen.
hexanedioic acid gave the corresponding d-ketoacid in
good yield (77%). However, oxidative decarboxylation of
2-hydroxy-2-phenylbutanedioic acid could only be opti-
mized up to 50% yield carrying out the reaction at 2458C
to give the corresponding b-ketoacid besides other uniden-
ti®ed by-products apparently bearing a lactone or an anhy-
dride moiety.
Finally we have studied the extension of this methodology
to other methyl mandelate esters substituted on the aromatic
ring (Table 2). Thus compounds 4m±4p were prepared from
methyl p-bromo- and p-methoxymandelate, and subjected
to oxidative decarboxylation with our catalytic system. The
yields were comparable to those obtained with the unsub-
stituted mandelates. Also, in the cases where an additional
double bond was present, the reaction had to be brought
about at 08C in order to avoid epoxidation and/or migration
of the double bond to the conjugated position with the
carbonyl group.
The results for the oxidative decarboxylation of a-substi-
tuted mandelic acids 4 are shown in Table 1. Good to excel-
lent yields were obtained with substrates bearing primary or
secondary alkyl groups (entries a±d). Also substrates with
benzyl or allyl groups, which gave low or null yields by a
recently described ¯ash vacuum pyrolysis procedure, were
decarboxylated with very good yields (entries e±g). The
selective decarboxylation in the presence of a double bond
or a vinyl bromide could be achieved when the reaction
was carried out at 08C (entries f, g). In a similar way an
a-hydroxyacid having an additional phenolic ether group
gave the expected ketone in good yield at 08C while the
same substrate gave a complex mixture at room temperature
(entry h). Double oxidative decarboxylation of bis-a-
hydroxyacids allowed dicarbonyl compounds to be obtained
(entries i, j). The yield was dependent on the link between
both hydroxyacid groups. Thus, a high yield (85%) was
obtained when they were linked with a saturated alkyl
chain (entry i) while the yield was lower (40%) when the
link was a p-phenylenemethylene group (entry j). Finally,
the presence of an additional carboxylic acid was tested in
entries k and l. Decarboxylation of 2-hydroxy-2-phenyl-
In summary, we present an alternative procedure for the use
of methyl mandelates as masked d1-synthons for the benzoyl
group (Umpolung), in which the key step is the aerobic
oxidative decarboxylation with oxygen in the presence of
pivalaldehyde and a Co(III) complex 1, under very mild
conditions. Our procedure shows some advantages with
regard to other described procedures and it is compatible
with the presence in the molecule of other oxidizable groups.
3. Experimental section
3.1. General
All melting points are uncorrected. Column chroma-
tography was performed on silica gel (Merck, silica gel

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G. Blay et al. / Tetrahedron 57 (2001) 1075±1081
60, 230±400 mesh). IR spectra were recorded as liquid ®lm
in NaCl for oils and as KBr discs for solids. NMR spectra
3.1.6. Methyl 2-hydroxy-2-phenyl-4-pentenoate (3f). Oil;
1H NMR (d, CDCl3) 7.63 (2H, dd, Jˆ7.9, 1.3 Hz), 7.28 (3H,
m), 5.85 (1H, ddt, Jˆ17.3, 9.8, 6.5 Hz), 5.20 (1H, brd, Jˆ
17.4 Hz), 5.11 (1H, brd, Jˆ9.9 Hz), 4.09 (1H, s), 3.65 (3H,
s), 3.00 (1H, dd, Jˆ13.9, 7.7 Hz), 2.78 (1H, dd, Jˆ13.9,
6.6 Hz); 13C NMR (d, CDCl3) 174.4 (s), 140.5 (s), 131.7
(d), 127.6 (d), 127.2 (d), 124.8 (d), 118.7 (t), 77.4 (s), 52.5
(q), 43.4 (t); MS m/z 207 (M111, 2), 206 (M1, 0.1), 166
(13), 147 (25), 105 (66), 91 (6), 77 (76); HRMS m/z found
207.1026, C12H15O3 required 207.1021.
1
were run at 200 MHz for H and at 50.3 MHz for 13C, and
referenced to the solvent as internal standard. The carbon
type was determined by DEPT experiments. Mass spectra
were run by electron impact at 70 eV. Complex 1 was
prepared according to the literature.12
3.1.1. Alkylation of methyl mandelates. Methyl mandelate
2 was alkylated following procedures described in the litera-
ture.10,11 To a solution of diisopropylamine (1.8 ml,
13.7 mmol) in dry THF (20 ml) was added dropwise
8.6 ml of a solution of 1.6 M n-BuLi in hexane (13.7
mmol) at 08C under argon. After 30 min, the solution was
cooled at 2788C and a solution of the methyl mandelate 2
(6.1 mmol) in THF was added. The resulting solution was
stirred at 2788C during 15 min and alkyl bromide or iodide
(6.1 mmol) in THF (5 ml) was added. The reaction mixture
was stirred at this temperature for 15 min and then at room
temperature until the reaction was complete. After this time,
the reaction mixture was poured into 1 M HCl (30 ml),
extracted with ether (3£30 ml), washed with 1 M HCl
(2£35 ml) and brine until neutral pH, and dried with
MgSO4. After removal of the solvent the resulting product
3 was puri®ed by column chromatography on silica gel.
3.1.7. Methyl 4-bromo-2-hydroxy-2-phenyl-4-penteno-
1
ate (3g). Oil; H NMR (d, CDCl3) 7.60 (2H, dd, Jˆ6.4,
1.8 Hz), 7.33 (3H, m), 5.73 (1H, d, Jˆ1.3 Hz), 5.61 (1H,
d, Jˆ1.3 Hz), 3.91 (1H, s), 3.80 (3H, s), 3.48 (1H, d,
Jˆ15.7 Hz), 3.11 (1H, d, Jˆ15.7 Hz); 13C NMR (d,
CDCl3) 174.4 (s), 140.8 (s), 128.3 (d), 128.1 (d), 126.1
(d), 125.4 (d), 122.0 (t), 53.4 (q), 50.3 (t); MS m/z 287
(M111, 0.1), 285 (M111, 0.1), 227 (5), 225 (5), 165
(71), 105 (100), 77 (37); HRMS m/z found 287.0127 and
285.0133, C12H14BrO3 required 287.0106 and 285.0126.
3.1.8. Methyl 2-hydroxy-4-phenoxy-2-phenylbutanoate
(3h). Mp 74±768C; H NMR (d, CDCl3) 7.66 (2H, dd,
1
Jˆ8.4, 1.7 Hz), 7.32 (5H, m), 6.95 (1H, t, Jˆ8.0 Hz), 6.87
(2H, d, Jˆ8.4 Hz), 4.23 (1H, m), 4.14 (1H, s), 4.12 (1H, m),
3.79 (3H, s), 2.95 (1H, m), 2.46 (1H, m); 13C NMR (d,
CDCl3) 175.3 (s), 158.4 (s), 141.6 (s), 129.4 (d), 128.3 (d),
127.8 (d), 125.3 (d), 120.8 (d), 114.3 (d), 99.5 (s), 63.4 (t),
53.2 (q), 38.5 (t); MS m/z 286 (M1, 23), 228 (15), 227 (87),
193 (64), 161 (39), 133 (58), 105 (100), 77 (53); HRMS m/z
found 286.1206, C17H18O4 required 286.1205.
3.1.2. Methyl 2-hydroxy-2-phenyltetradecanoate (3b).
1
Mp 38±408C; H NMR (d, CDCl3) 7.58 (2H, dd, Jˆ7.8,
1.2 Hz), 7.30 (3H, m), 3.76 (3H, s), 2.12 (2H, m), 1.26
(20H, m), 0.88 (3H, t, Jˆ5.9 Hz); 13C NMR (d, CDCl3)
175.9 (s), 141.9 (s), 128.2 (d), 127.6 (d), 125.5 (d), 78.4
(s), 53.2 (q), 39.7±22.7 (t, overlapped signals), 14.1 (q);
MS 334 (M1, 0.2), 276 (100), 165 (9), 105 (51), 77 (12);
HRMS m/z found 334.2507, C21H34O3 required 334.2508.
3.1.9. Dimethyl 2,9-dihydroxy-2,9-diphenyldecanedioate
(3i). Mp 86±888C; H NMR (d, CDCl3) 7.57 (4H, dd,
1
3.1.3. Methyl 2-hydroxy-3-methyl-2-phenylbutanoate
(3c). Mp 41±438C; H NMR (d, CDCl3) 7.71 (2H, dd,
Jˆ8.4, 1.7 Hz), 7.29 (6H, m), 3.75 (6H, s), 2.11 (2H, m),
1.95 (2H, m), 1.25 (8H, m); 13C NMR (d, CDCl3) 175.8 (s),
141.8 (s), 128.1 (d), 127.6 (d), 125.4 (d), 78.4 (s), 53.1 (q),
39.6 (t), 29.4 (t), 23.5 (t); MS m/z 355 (M12CO2Me, 25),
337 (74), 305 (66), 277 (30), 259 (25), 133 (90), 105 (100),
77 (21); HRMS m/z found 355.1908, C22H27O4 required
355.1909.
1
Jˆ8.7, 1.5 Hz), 7.30 (3H, m), 3.89 (1H, s), 3.71 (3H, s),
2.67 (1H, m, Jˆ6.8 Hz), 1.03 (3H, d, Jˆ6.6 Hz), 0.76
(3H, d, Jˆ6.6 Hz); 13C NMR (d, CDCl3) 176.1 (s), 141.0
(s), 127.9 (d), 127.3 (d), 125.8 (d), 80.9 (s), 53.1 (q), 35.7
(d), 17.1(q), 15.6 (q); MS m/z 208 (M1, 3), 165 (17), 105
(100), 77 (45); HRMS m/z found 208.1099, C12H16O3
required 208.1099.
3.1.10. p-Bis(2-hydroxy-2-methoxycarbonyl-2-phenylethyl)-
benzene (3j). Mp 212±2148C; H NMR (d, CDCl3) 7.65
1
3.1.4. Methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate
(4H, dd, Jˆ8.0, 1.3 Hz), 7.34 (6H, m), 7.10 (4H, s), 3.71
(6H, s), 3.54 (2H, d, Jˆ13.6 Hz), 3.15 (2H, d, Jˆ13.6 Hz);
13C NMR (d, CDCl3) 141.9 (s), 134.8 (s), 130.7 (d),128.8
(d), 128.4 (d), 126.2 (d), 79.3 (Cd), 53.6 (2q), 46.1 (t); MS
m/z 434 (M1, 0.2), 357 (4), 329 (6), 270 (11), 252 (100), 193
(41), 165 (21), 105 (91), 77 (21); HRMS m/z found
434.1712, C26H26O6 required 434.1729.
1
(3d). Mp 49±518C; H NMR (d, CDCl3) 7.67 (2H, d, Jˆ
7.3 Hz), 7.32 (3H, m), 3.76 (3H, s), 2.26 (1H, m), 1.13±1.84
(10H, m); 13C NMR (d, CDCl3) 176.0 (s), 140.6 (s), 127.9
(d), 127.2 (d), 125.9 (d), 80.9 (s), 53.1 (q), 45.6 (s), 27.3 (t),
26.2 (t), 26.1 (t), 25.3 (t); MS m/z 248 (M1, 1), 189 (100),
166 (53), 107 (36), 105 (63), 91 (14), 77 (19); HRMS m/z
found 248.1419, C15H20O3 required 248.1412.
3.1.11. Ethyl 5-hydroxy-5-methoxycarbonyl-5-phenyl-
pentanoate (3k). Mp 82±848C; H NMR (d, CDCl3) 7.60
1
3.1.5. Methyl 2-hydroxy-2,3-diphenylpropanonate (3e).
1
Mp 80±828C; H NMR (d, CDCl3) 7.65 (2H, dd, Jˆ6.7,
(2H, m), 7.30 (3H, m), 4.08 (2H, q, Jˆ7.3 Hz), 3.74 (3H, s),
2.28 (2H, t, Jˆ7.3 Hz), 2.11 (2H, m), 1.66 (2H, m), 1.20
(3H, t, Jˆ 7.3 Hz); 13C NMR (d, CDCl3) 175.3 (s), 158.3 (s),
141.6 (q), 129.3 (d), 128.3 (d), 127.8 (d), 125.3 (d), 120.8
(d), 114.8 (d), 76.2 (s), 63.4 (t), 53.2 (ZOCH3), 38.4 (q); MS
m/z 221 (M12CO2Me, 2), 175 (11), 128 (100), 107 (33),
105 (9), 86 (100); HRMS m/z found 221.1179, C13H17O3
required 221.1178.
1.2 Hz), 7.35 (3H, m), 7.23 (5H, m), 3.72 (3H, s), 3.60
(1H, d, Jˆ13.3 Hz), 3.19 (1H, d, Jˆ13.5 Hz); 13C NMR
(d, CDCl3) 174.7 (s), 141.5 (s), 135.7 (s), 130.4 (d), 128.3
(d), 128.1 (d), 127.9 (d), 127.0 (d), 125.7 (d), 78.8 (s), 53.1
(q), 45.9 (t); MS m/z 256 (M1, 1), 197 (27), 165 (55), 105
(100), 91 (24), 77 (31); HRMS m/z found 256.1108,
C16H16O3 required 256.1099.

G. Blay et al. / Tetrahedron 57 (2001) 1075±1081
1079
3.1.12. Dimethyl 2-hydroxy2-phenylbutanedioate (3l).
Mp 61±638C; H NMR (d, CDCl3) 7.60 (2H, m), 7.35
brine until neutrality, dried, ®ltered and concentrated
under vacuum to give the a-alkylated mandelic acid 4.
1
(3H, m), 4.40 (1H, s), 3.80 (3H, s), 3.75 (3H, s), 3.50 (1H,
d, Jˆ16 Hz), 2.95 (1H, d, Jˆ16 Hz); 13C NMR (d, CDCl3)
174.1 (s), 171.4 (s), 140.0 (s), 128.4 (d), 128.1 (d), 124.9 (d),
67.8 (s), 53.2 (q), 51.9 (q), 44.2 (t); MS m/z 239 (M111,
0.1), 179 (100), 147 (18), 105 (100), 77 (24); HRMS m/z
found 239.0915, C12H15O5 required 239.1909.
3.1.18. 2-Hydroxy-2-phenyltetradecanoic acid (4b). Mp
98±1008C; 1H NMR (d, DMSO) 7.60 (2H, dd, Jˆ7.8,
1.4 Hz), 7.31 (3H, m), 2.16 (2H, m), 1.22 (20H, m), 0.86
(3H, t, Jˆ6.3 Hz).
3.1.19. 2-Hydroxy-3-methyl-2-phenylbutanoic acid (4c).
Mp 142±1448C; 1H NMR (d, DMSO) 7.63 (2H, dd, Jˆ7.2,
1.6 Hz), 7.33 (3H, m), 2.63 (1H, m, Jˆ6.5 Hz), 1.03 (3H, d,
Jˆ6.6 Hz), 0.69 (3H, d, Jˆ6.6 Hz).
3.1.13. Methyl 2-(40-bromophenyl)-2-hydroxy-3-methyl-
butanoate (3m). Mp 94±968C; H NMR (d, CDCl3) 7.52
1
(2H, d, Jˆ8.6 Hz), 7.43 (2H, d, Jˆ8.5 Hz), 3.75 (3H, s),
2.54 (1H, m, Jˆ6.5, 0.8 Hz), 0.94 (3H, dd, Jˆ6.4,
0.8 Hz), 0.67 (3H, dd, Jˆ6.4, 0.8 Hz); 13C NMR (d,
CDCl3) 175.6 (s), 140.1 (s), 131.1 (d), 127.8 (d), 121.6
(d), 80.6 (s), 53.3 (q), 35.8 (d), 17.0 (q), 15.5 (q); MS m/z
288 (M1, 3), 286 (M1, 3), 245 (22), 243 (22), 229 (97), 227
(100), 185 (91), 183 (92), 105 (38); HRMS m/z found
288.0182 and 286.0206, C12H15BrO3 required 288.0184
and 286.0205.
3.1.20. 2-Cyclohexyl-2-hydroxy-2-phenylacetic acid (4d).
Mp 169±1718C; 1H NMR (d, DMSO) 7.52 (2H, d,
Jˆ7.6 Hz), 7.47 (3H, m), 3.23 (1H, m), 1.90±1.06 (10H, m).
3.1.21. 2-Hydroxy-2,3-diphenylpropanoic acid (4e). Mp
1
164±1668C; H NMR (d, DMSO) 7.75 (2H, dd, Jˆ7.8,
1.5 Hz), 7.30 (8H, m), 3.60 (1H, d, Jˆ13.6 Hz), 3.2 (1H,
d, Jˆ13.6 Hz).
3.1.14. Methyl 2-(40-bromophenyl)-2-hydroxy-4-penteno-
ate (3n). Mp 37±398C; H NMR (d, CDCl3) 7.45 (4H, s),
1
3.1.22. 2-Hydroxy-2-phenyl-4-pentenoic acid (4f). Mp
1
106±1088C; H NMR (d, DMSO) 7.61 (2H, dd, Jˆ7.8,
5.74 (1H, ddd, Jˆ17.8, 10.0, 6.8 Hz), 5.12 (1H, d,
Jˆ17.8 Hz), 5.10 (1H, d, Jˆ10.0 Hz), 3.73 (3H, s), 2.90
(1H, ddd, Jˆ13.8, 6.5, 1.2 Hz), 2.69 (1H, ddd, Jˆ13.8,
6.7, 0.9 Hz); 13C NMR (d, CDCl3) 174.3 (s), 140.1 (s),
131.6 (d), 131.1 (d), 127.3 (d), 121.8 (s), 119.4 (t), 77.7
(s), 53.1 (q), 44.0 (t); MS m/z 286 (M1, 0.2), 284 (M1,
0.2), 269 (1), 267 (1), 245 (70), 243 (70), 185 (98), 183
(100), 157 (28), 155 (28); HRMS m/z found 286.0054 and
284.0053, C12H13BrO3 required 286.0028 and 284.0048.
1.2 Hz), 7.40 (3H, m), 5.85 (1H, ddt, Jˆ19.2, 10.6,
7.2 Hz), 5.30 (1H, d, Jˆ19.2 Hz), 5.2 (1H, d, Jˆ10.6 Hz),
3.00 (1H, dd, Jˆ14.5, 7.2 Hz), 2.98 (1H, dd, Jˆ14.3,
7.4 Hz).
3.1.23. 4-Bromo-2-hydroxy-2-phenyl-4-pentenoic acid
(4g). Mp 72±748C; H NMR (d, DMSO) 7.62 (2H, dd,
1
Jˆ7.8, 1.9 Hz), 7.33 (3H, m), 5.74 (1H, d, Jˆ1.5 Hz),
5.62 (1H, d, Jˆ1.5 Hz), 3.51 (1H, d, Jˆ15.4 Hz), 3.15
(1H, d, Jˆ15.4 Hz).
3.1.15. Methyl 2-hydroxy-2-(40-methoxyphenyl)-3-methyl-
butanoate (3o). Mp 70±738C; H NMR (d, CDCl3) 7.52
1
3.1.24. 2-Hydroxy-4-phenoxy-2-phenylbutanoic acid
(4h). Mp 109±1128C; H NMR (d, DMSO) 7.66 (2H, dd,
(2H, d, Jˆ8.6 Hz), 6.85 (2H, d, Jˆ8.6 Hz), 3.78 (3H, s),
3.75 (3H, s), 2.55 (1H, m, Jˆ6.6 Hz), 0.94 (3H, d,
Jˆ6.6 Hz), 0.69 (3H, d, Jˆ6.6 Hz); 13C NMR (d, CDCl3)
175.7 (s), 158.2 (d), 132.4 (s), 126.4 (d), 112.7 (d), 80.0 (s),
54.5 (q), 52.5 (q), 35.0 (t), 16.5 (q), 15.0 (q); MS m/z 238
(M1, 13), 195 (61), 179 (71), 135 (100), 77 (17); HRMS m/z
found 238.1205, C13H18O4 required 238.1205.
1
Jˆ7.9, 1.9 Hz), 7.35 (5H, m), 6.93 (1H, t, Jˆ7.5 Hz), 6.80
(2H, d, Jˆ7.3 Hz), 4.60 (1H, s, ZOH), 4.15 (2H, t,
Jˆ5.1 Hz), 2.86 (1H, dt, Jˆ14.7, 5.9 Hz), 2.53 (1H, dt,
Jˆ14.6, 5.0 Hz).
3.1.25. 2,9-Dihydroxy-2,9-diphenyldecanedioic acid (4i).
Mp 176±1778C; 1H NMR (d, DMSO) 7.51 (4H, d,
Jˆ7.2 Hz), 7.27 (6H, m), 3.34 (1H, s, ZOH), 2.02 (4H,
m), 1.82 (4H, m), 1.18 (4H, m).
3.1.16. Methyl 2-hydroxy-2-(40-methoxyphenyl)-4-penteno-
1
ate (3p). Oil; H NMR (d, CDCl3) 7.49 (2H, dd, Jˆ8.8,
2.9 Hz), 6.87 (2H, dd, Jˆ8.8, 2.9 Hz), 5.77 (1H, ddt,
Jˆ17.5, 9.4, 7.1 Hz, H4), 5.14 (1H, dd, Jˆ17.5, 1.6 Hz),
5.12 (1H, dd, Jˆ9.4, 1.9 Hz), 3.78 (3H, s), 3.74 (3H, s),
2.93 (1H, dd, Jˆ14.1, 7.5 Hz), 2.72 (1H, ddd, Jˆ13.9,
6.6, 1.3 Hz); 13C NMR (d, CDCl3) 175.3 (s), 159.1 (s),
133.3 (d), 132.4 (d), 126.8 (d), 119.3 (t), 113.6 (d), 77.7
(d), 55.2 (q), 53.1 (q), 44.1 (t); MS m/z 236 (M1, 1), 219
(1), 195 (100), 177 (17), 135 (71), 107 (8), 92 (19), 77
(24); HRMS m/z found 236.1038, C13H16O4 required
236.1048.
3.1.26. p-Bis(2-carboxy-2-hydroxy-2-phenylethyl)ben-
zene (4j). Mp .2508C; H NMR (d, DMSO) 7.54 (4H, d,
1
Jˆ 7.7 Hz), 7.27 (6H, m), 3.35 (2H, d, Jˆ13.6 Hz), 3.05
(2H, d, Jˆ13.6 Hz).
3.1.27. 2-Hydroxy-2-phenylhexanedioic acid (4k). Mp
1
131±1328C; H NMR (d, DMSO) 7.50 (2H, dd, Jˆ6.6,
1.4 Hz), 7.32 (3H, m), 6.70 (1H, s, ZOH), 2.17 (2H, t, Jˆ
7.5 Hz), 1.97 (2H, m), 1.44 (2H, q, Jˆ7.6 Hz).
3.1.17. Hydrolysis of a-alkylated methyl mandelates.
The a-alkylated methyl mandelate 3 (1 mmol) was treated
with 5% ethanolic KOH (2.5 ml, 2 mmol) at room tempera-
ture until complete reaction of the starting material (TLC).
The solution was poured into ice and acidi®ed with 1 M HCl
until pH<2. The aqueous mixture was extracted with
EtOAc (3£60 ml), the organic layers were washed with
3.1.28. 2-Hydroxy-2-phenylbutanedioic acid (4l). Mp
1
200±2018C; H NMR (d, DMSO) 7.55 (2H, d, Jˆ7.1 Hz),
7.32 (3H, m), 3.33 (1H, d, Jˆ16.0 Hz), 2.65 (1H, d,
Jˆ16.0 Hz).
3.1.29. 2-(40-Bromophenyl)-2-hydroxy-3-methylbutanoic
acid (4m). Mp 143±1468C; 1H NMR (d, DMSO) 7.52 (4H,

1080
G. Blay et al. / Tetrahedron 57 (2001) 1075±1081
m), 2.57 (1H, m, Jˆ6.7, 2.6 Hz), 2.04 (1H, d, Jˆ2.7 Hz),
1.01 (3H, dd, Jˆ6.5, 2.6 Hz), 0.68 (3H, dd, Jˆ6.6, 2.5 Hz).
3.1.38. Allyl phenyl ketone (5f). Oil; IR n 2925, 1680,
1
1635 cm21; H NMR (d, CDCl3) 7.95 (2H, dd, Jˆ7.0,
1.7 Hz), 7.44 (3H, m), 6.00 (1H, ddt, Jˆ18.2, 10.0,
6.9 Hz), 5.22 (1H, dd, Jˆ18.2, 1.5 Hz), 5.20 (1H, dd,
Jˆ10.0, 1.5 Hz), 3.75 (2H, dd, Jˆ6.9, 1.4 Hz); 13C NMR
(d, CDCl3) 197.9 (s), 136.3 (s), 133.0 (d), 130.8 (d), 128.4
(d), 128.1 (d), 118.5 (t), 43.2 (t); MS m/z 146 (M1, 8), 105
(100), 77 (48), 51 (14); HRMS m/z found 146.0726,
C10H10O4 required 146.0732.
3.1.30. 2-(40-Bromophenyl)-2-hydroxy-4-pentenoic acid
(4n). Mp 94±968C; H NMR (d, DMSO) 7.48 (4H, m),
1
5.66 (1H, m), 5.03 (1H, d, Jˆ14.4 Hz), 4.98 (1H, d,
Jˆ9.8 Hz), 2.80 (1H, dd, Jˆ13.9, 6.9 Hz), 2.64 (1H, dd,
Jˆ13.9, 6.6 Hz).
3.1.31. 2-Hydroxy-2-(40-methoxyphenyl)-3-methylbuta-
noic acid (4o). Mp 146±1488C; H NMR (d, DMSO) 7.60
1
3.1.39. 3-Bromo-1-phenyl-3-buten-1-one (5g). Oil; IR n
1
(2H, d, Jˆ18.1 Hz), 6.89 (2H, d, Jˆ7.9 Hz), 3.77 (3H, s),
2.62 (1H, m, Jˆ6.6 Hz), 1.01 (3H, d, Jˆ6.6 Hz), 0.67 (3H,
d, Jˆ6.6 Hz).
3.1.32. 2-Hydroxy-2-(40-methoxyphenyl)-4-pentenoic acid
(4p). Mp 80±828C; 1H NMR (d, DMSO) 7.51 (2H, d,
Jˆ8.8 Hz), 6.87 (2H, d, Jˆ8.8 Hz), 5.73 (1H, m), 5.19
(1H, d, Jˆ 18.7 Hz), 5.17 (1H, d, Jˆ9.3 Hz), 3.78 (3H, s),
2.97 (1H, dd, Jˆ14.1, 7.3 Hz), 2.75 (1H, dd, Jˆ14.0, 7.0 Hz).
1688, 1598 cm21; H NMR (d, CDCl3) 7.97 (2H, m), 7.46
(3H, m), 5.75 (1H, d, Jˆ1.8 Hz), 5.69 (1H, d, Jˆ1.8 Hz),
4.12 (2H, s); 13C NMR (d, CDCl3) 136.1 (s), 133.6 (d),
128.7 (d), 128.4 (d), 124.8 (s), 121.5 (t), 50.3 (t); MS m/z
226 (M1, 11), 224 (M1, 13), 149 (15), 147 (74); HRMS m/z
found 225.9827 and 223.9819, C10H9BrO required 225.9816
and 223.9837.
3.1.40. 3-Phenoxy-1-phenyl-1-propanone (5h). Mp 57±
1
598C; IR n 2935, 1680, 1248, 1210 cm21; H NMR (d,
3.1.33. Catalytic aerobic decarboxylation of a-hydroxy-
acids 4. A solution of a-hydroxyacid 4 (0.11 mmol) in
0.2 ml of acetonitrile was added to a stirred mixture of
Co(III) complex 1 (6.5£1023 mmol) and pivalaldehyde
(0.33 mmol) in 0.2 ml of acetonitrile under a dioxygen
atmosphere. The mixture was stirred at the indicated
temperature until consumption of the starting a-hydroxy-
acid as indicated by TLC. The reaction products 5 were
puri®ed by ¯ash column chromatography.
CDCl3) 8.00 (2H, d, Jˆ6.9 Hz), 7.47 (3H, m), 7.27 (2H,
m), 6.94 (3H, m), 4.42 (2H, t, Jˆ6.5 Hz), 3.46 (2H, t,
Jˆ6.6 Hz); 13C NMR (d, CDCl3) 158.6 (s), 136.8 (s),
133.3 (d), 129.4 (d), 128.6 (d), 128.1 (d), 120.9 (d), 114.5
(d), 63.1 (t), 38.1 (t); MS m/z 226 (M1, 30), 133 (48), 105
(100), 77 (45); HRMS m/z found 226.0997, C15H14O2
required 226.0994.
3.1.41. 1,8-Diphenyl-1,8-octanedione (5i). Mp 82±848C;
1
IR n 2932, 1684, 1446 cm21; H NMR (d, CDCl3) 7.94
3.1.34. Dodecyl phenyl ketone (5b). Mp 39±418C; IR n
2924, 2853, 1688 cm21; 1H NMR (d, CDCl3) 7.94 (2H, dd,
Jˆ8.4, 1.6 Hz), 7.47 (3H, m), 2.94 (2H, t, Jˆ7.3 Hz), 1.24
(20H, s), 0.86 (3H, t, Jˆ6.2 Hz); 13C NMR (d, CDCl3) 200.5
(4H, dd, Jˆ8.0, 1.1 Hz), 7.45 (6H, m), 2.95 (4H, t,
Jˆ7.1 Hz), 1.74 (4H, m), 1.43 (4H, m); 13C NMR (d,
CDCl3) 200.0 (s), 137.0 (s), 132.7 (d), 128.5 (d), 127.9
(d), 38.4 (t), 29.1 (t), 24.1 (t); MS m/z 294 (M1, 3), 276
(33), 252 (12), 189 (5), 175 (78), 133 (17), 120 (84), 105
(100); HRMS m/z found 294.1623, C20H22O2 required
194.1620.
0
(s), 137.0 (s), 132.8 (C4 ), 128.5 (d), 128.0 (d), 38.6 (t), 31.8
(t), 29.6 (t), 29.4 (t), 29.3 (t), 24.3 (t), 22.6 (t), 14.1 (q); MS
m/z 274 (M1, 14), 120 (100), 105 (60), 77 (21), 55 (4);
HRMS m/z found 274.2291, C19H30O required 274.2297.
3.1.42. p-Bis(phenacyl)benzene (5j). Mp 187±1898C; IR n
1
3.1.35. Isopropyl phenyl ketone (5c). Oil; IR n 2800,
;
2925, 1686 cm21; H NMR (d, CDCl3) 8.02 (4H, m), 7.48
1680 cm21
1H NMR (d, CDCl3) 7.94 (2H, dd, Jˆ8.2,
(10H, m), 4.27 (4H, s); 13C NMR (d, CDCl3) 197.6 (s),
137.0 (d), 133.2 (d), 129.7 (d), 128.6 (d), 45.0 (t); MS m/z
314 (M1, 8), 223 (9), 105 (100), 77 (40); HRMS m/z found
314.1321, C22H18O2 required 314.1307.
1.3 Hz), 7.49 (3H, m), 3.55 (1H, m, Jˆ6.9 Hz), 1.18 (6H,
d, Jˆ6.8 Hz); 13C NMR (d, CDCl3) 136.7 (s), 133.3 (d),
129.1 (d), 128.8 (d), 35.8 (d), 19.7 (q); MS m/z 148 (M1,
10), 105 (100), 77 (25); HRMS m/z found 148.0891,
C10H12O required 148.0888.
3.1.43. 5-Oxo-5-phenylpentanoic acid (5k). Oil; IR n
2927, 2873, 2856, 1731, 1685 cm21; H NMR (d, CDCl3)
1
3.1.36. Cyclohexyl phenyl ketone (5d). Mp 558C; IR n
2925, 1638 cm21 1H NMR (d, CDCl3) 7.94 (2H, dd,
;
7.95 (2H, dd, Jˆ6.7, 1.3 Hz), 7.47 (3H, m), 3.06 (2H, t,
Jˆ7.1 Hz), 2.49 (2H, t, Jˆ7.1 Hz), 2.07 (2H, q,
Jˆ7.0 Hz); 13C NMR (d, CDCl3) 199.3 (s), 178.8 (s),
136.7 (s), 133.1 (d), 128.6 (d), 128.0 (d), 37.3 (t), 33.0 (t),
29.6 (t); MS m/z 192 (M1, 64), 120 (56), 105 (100), 77 (86),
52 (48); HRMS m/z found 192.0787, C11H12O3 required
192.0786.
Jˆ8.2, 1.5 Hz), 7.41 (3H, m), 3.26 (1H, m), 1.90±1.24
(10H, m); 13C NMR (d, CDCl3) 136.1 (s), 132.7 (d),
128.5 (d), 128.2 (d), 45.6 (d), 29.4 (t), 25.9 (t), 25.8 (t);
MS m/z 188 (M1, 15), 105 (100), 77 (65); HRMS m/z
found 188.1189, C13H16O required 188.1201.
3.1.37. Deoxybenzoin (5e). Mp 48±518C; IR n 1685 cm21
;
3.1.44. 3-Oxo-3-phenylpropanoic acid (5l). Oil; IR n
1H NMR (d, CDCl3) 8.01 (2H, dd, Jˆ6.5, 1.1 Hz), 7.48 (3H,
m), 7.28 (5H, m), 4.28 (2H, s); 13C NMR (d, CDCl3) 197.7
(s), 136.2 (s), 134.3 (s), 133.2 (d), 129.6 (d), 128.7 (d), 126.9
(d), 45.6 (t); MS m/z 197 (M111, 10), 196 (M1, 27), 105
(100), 91 (21), 77 (60), 52 (15); HRMS m/z found 196.0894,
C14H12O required 196.0888.
2963, 2927, 2855, 1684, 1642 cm21; H NMR (d, CDCl3)
1
10.50 (1H, s), 7.94 (2H, d, Jˆ7.4 Hz), 7.41 (3H, m), 3.50
(2H, s); 13C NMR (d, CDCl3) 134.2 (s), 133.6 (d), 128.9 (d),
128.2 (d), 46.1 (t); MS m/z 164 (M1, 4), 120 (59), 105 (100),
79 (82); HRMS m/z found 164.0473, C9H8O3 required
164.0471.

G. Blay et al. / Tetrahedron 57 (2001) 1075±1081
1081
3.1.45. 4-Bromophenyl isopropyl ketone (5m). Oil; IR n
2965, 2927, 1687, 1H NMR (d, CDCl3) 7.81 (2H, d,
Jˆ7.0 Hz), 7.60 (2H, d, Jˆ7.2 Hz), 3.49 (1H, m,
Jˆ6.4 Hz), 1.23 (6H, d, Jˆ6.4 Hz); 13C NMR (d, CDCl3)
203.3 (s), 134.8 (s), 131.8 (d), 129.8 (d), 127.8 (d), 35.3 (d),
19.0 (q); MS m/z 228 (M1, 11), 226 (M1, 12), 185 (63), 183
(66), 157 (24), 155 (26), 76 (89), 74 (51); HRMS m/z
227.9979 and 226.0002, C10H11BrO required 227.9973
and 225.9993.
gratefully acknowledged. B. M. and R. R. thank the
Â
Ministerio de Educacion y Ciencia for predoctoral and post-
doctoral grants, respectively.
References
1. (a) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231.
(b) Seebach, D. Synthesis 1969, 17.
3.1.46. Allyl 4-bromophenyl ketone (5n). Oil; IR n 2900,
2. (a) van Leusen, D.; van Leusen, A. M. Recl. Trav. Chim. Pays-
Bas 1991, 110, 393. (b) Moskal, J.; van Leusen, A. M.
Tetrahedron Lett. 1984, 25, 2585. (c) Blay, G.; Schrijvers,
R.; Wijnberg, J. B. A.; de Groot, A. J. Org. Chem. 1995, 60,
2188.
1726, 1584 cm21 1H NMR (d, CDCl3) 7.81 (2H, d,
;
Jˆ8.6 Hz), 7.58 (2H, d, Jˆ8.6 Hz), 6.04 (1H, ddt,
Jˆ17.3, 10.3, 6.7 Hz), 5.22 (1H, dd, Jˆ17.3, 1.4 Hz), 5.18
(1H, dd, Jˆ10.0, 1.4 Hz), 3.70 (2H, dd, Jˆ6.5, 1.3 Hz); 13C
NMR (d, CDCl3) 196.6 (s), 135.0 (s), 131.7 (d), 130.4 (d),
129.6 (d), 128.2 (d), 118.8 (t), 43.2 (t); MS m/z 226 (M1, 7),
224 (M1, 8), 185 (98), 183 (100), 157 (26), 155 (26), 76
(12), 74 (4), 57 (8); HRMS m/z found 225.9812 and
223.9840, C10H9BrO required 225.9816 and 223.9837.
È
3. Hartmann, J.; Stahle, M.; Schlosser, M. Synthesis 1974, 888.
4. (a) Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097.
(b) Carey, F. A.; Court, A. S. J. Org. Chem. 1972, 37, 939.
5. (a) Fabrice, P.; Enders, D. Tetrahedron Lett. 1999, 40, 531.
(b) Enders, D.; Mannes, D.; Raabe, G. Synlett 1992, 837.
6. Schrader, T. Chem. Eur. J. 1997, 3, 1273.
3.1.47. Isopropyl 4-methoxyphenyl ketone (5o). Oil; IR n
Â
7. Enders, D.; Syrig, R.; Raabe, G.; Fernandez, R.; Gasch, C.;
1
1706 cm21; H NMR (d, CDCl3) 7.93 (2H, d, Jˆ8.7 Hz),
Lassaleta, J.-M.; Llera, J.-M. Synthesis 1996, 48.
8. (a) Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Spalluto,
G.; Zanirato, V. Tetrahedron 1996, 52, 4719. (b) Katritzky,
A. R.; Oniciu, D. C.; Ghiviriga, I.; Soti, F. J. Org. Chem. 1998,
63, 2110.
6.91 (2H, d, Jˆ8.8 Hz), 3.84 (3H, s), 3.49 (1H, m, Jˆ
6.8 Hz), 1.18 (6H, d, Jˆ6.7 Hz); 13C NMR (d, CDCl3)
203.1 (s), 165.2 (s), 130.5 (d), 129.1 (s), 113.7 (d), 55.4
(q), 34.9 (d), 19.3 (q); MS m/z 178 (M1, 9), 135 (100),
107 (4); HRMS m/z found 178.0998, C11H14O2 required
178.0994.
Â
Â
9. Blay, G.; Fernandez, I.; Formentin, P.; Pedro, J. R.; Rosello,
A. L.; Ruiz, R.; Journaux, Y. Tetrahedron Lett. 1998, 39,
3327.
3.1.48. Allyl 4-methoxyphenyl ketone (5p). Oil; IR n
10. (a) Aitken, R. A.; Thomas, A. W. Synlett 1997, 293.
(b) Aitken, R. A.; Thomas, A. W. Synlett 1998, 102.
11. Ciochetto, L. J.; Bergbreiter, D. E.; Newcomb, M. J. Org.
Chem. 1977, 42, 2948.
Â
12. Estrada, J.; Fernandez, I.; Pedro, J. R.; Ruiz, R.; Journaux, Y.
Tetrahedron Lett. 1997, 38, 2377.
1
2900, 1674, 1600, 1259 cm21; H NMR (d, CDCl3) 7.93
(2H, d, Jˆ8.9 Hz), 6.91 (2H, d, Jˆ8.8 Hz), 6.05 (1H, ddt,
Jˆ17.2, 10.8, 6.6 Hz), 5.20 (1H, dd, Jˆ17.2, 1.3 Hz), 5.18
(1H, d, Jˆ10.7 Hz), 3.84 (3H, s), 3.69 (2H, d, Jˆ6.6 Hz);
13C NMR (d, CDCl3) 196.5 (s), 163.4 (s), 131.3 (d), 130.4
(d), 129.5 (d), 118.3 (t), 113.6 (d), 55.3 (q), 43.1 (t); MS m/z
176.0841 (M1, 4), 135 (100), 107 (6), 77 (13), 64 (5);
HRMS m/z found 176.0841, C11H12O required 176.0837.
13. Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 279.
14. Ferraboschi, P.; Azadani, M. N.; Santaniello, E.; Trave, S.
Synth. Commun. 1986, 16, 43.
15. Beebe, T. R.; Boyd, L.; Fonkeng, S. B.; Horn, J.; Mooney,
T. M.; Saderholm, M. J.; Skidmore, M. V. J. Org. Chem. 1996,
60, 6602.
Acknowledgements
16. Takeda, T.; Yamauchi, S.; Fujiwara, T. Synthesis 1996, 600.
Â
Financial support from Direccion General de EnsenÄanza
Superior e Investigacion Cientõ®ca (grant PB 97-1411) is
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