Diastereoselective Michael addition of (S)-mandelic acid enolate to 2-arylidene-1,3-diketones: enantioselective diversity-oriented synthesis of densely substituted pyrazoles

Article abstract of DOI:10.1016/j.tet.2006.06.009

A diversity-oriented approach to enantiomerically pure densely substituted pyrazoles, α-aryl-α-pyrazolylatrolactic acid and α-aryl-α-pyrazolylacetophenones has been developed. The approach utilises the conjugated addition of the lithium enolate of the (2S

Full text of DOI:10.1016/j.tet.2006.06.009

Tetrahedron 62 (2006) 8069–8076
Diastereoselective Michael addition of (S)-mandelic acid enolate
to 2-arylidene-1,3-diketones: enantioselective diversity-oriented
synthesis of densely substituted pyrazoles
a
Gonzalo Blay, Isabel Fernandez, Eva Molina, M. Carmen Mun˜oz, Jose R. Pedro
a
a
b
a,
*
ꢀ
ꢀ
and Carlos Vilaa
a
´
ꢁ
´
ꢁ
ꢁ
Departament de Quımica Organica, Facultat de Quımica, Universitat de Valencia, E-46100-Burjassot (Valencia), Spain
b
´
Departamento de Fısica Aplicada, Universidad Politecnica de Valeꢁncia, E-46071 Valeꢁncia, Spain
´
Received 8 May 2006; revised 30 May 2006; accepted 2 June 2006
Available online 27 June 2006
Abstract—A diversity-oriented approach to enantiomerically pure densely substituted pyrazoles, a-aryl-a-pyrazolylatrolactic acid and
a-aryl-a-pyrazolylacetophenones has been developed. The approach utilises the conjugated addition of the lithium enolate of the (2S,5S)-
cis-1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalaldehyde to several 2-arylidene-1,3-diketones, which pro-
ceeds readily to give the corresponding Michael adducts in good yields and diastereoselectivities. The cyclocondensation of the 1,3-diketone
moieties present in Michael adducts with several hydrazines leads to enantiomerically pure densely substituted pyrazoles. Subsequent basic
hydrolysis of the dioxolanone moiety present in these products leads to enantiomerically pure a-aryl-a-pyrazolylatrolactic acids. Finally, ox-
idative decarboxylation of these using oxygen, pivalaldehyde and the Co(III)–Me2opba complex as catalyst gives a-aryl-a-pyrazolylaceto-
phenones. In this approach four points of diversity are introduced, one of them is the configuration of the (S)-mandelic acid, which acts as an
umpoled chiral equivalent of the benzoyl anion.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
non-steroidal anti-inflammatory drugs (NSAIDs).1 Due to
the importance of these pharmacological properties, signifi-
cant efforts toward the synthesis of this kind of compounds
have been carried out in the last years.2 However, to the
best of our knowledge, preparation of optically active
substituted pyrazoles has never been reported, despite chiral
compounds could be used in pharmacological studies to ex-
plore the receptor topology.3 In this paper we wish to report
a general and diversity-oriented approach towards the syn-
theses of these compounds, including the construction of
a stereogenic centre in the side chain.
Substituted pyrazoles constitute an important class of hetero-
cyclic compounds because this ring system is present in
numerous compounds of therapeutic importance, including
a number of marketed drugs, such as Celecoxib (CelebrexÒ)
or Deracoxib (Fig. 1). These compounds are used with
success for the treatment of inflammatory diseases with the
advantage they present low ulcerogenic side effects com-
monly associated with the chronic use of other non-selective
CF3
CHF2
Our approach to the synthesis of densely substituted pyra-
zoles, i.e., a-aryl-a-pyrazolylacetophenones, is shown in
Figure 2. The pyrazole ring can be obtained by a variety of
synthetic methods, including the 1,3-dipolar cycloaddition
of diazo compounds onto triple bonds and the cycloconden-
sation of hydrazines with 1,3-difunctionalized compounds.
This last procedure is the most commonly used strategy be-
cause of the availability of 1,3-difunctionalized compounds,
and it is the one we used in our approach. According to this,
we disconnected our target molecules into a hydrazine (frag-
ment D) and a chiral 1,3-dicarbonyl component, which can
be prepared from a 1,3-diketone (fragment C), an aromatic
aldehyde (fragment B), and mandelic acid (fragment A).
F
N
N
N
N
H3C
H3CO
SO2NH2
Celecoxib
Figure 1. Some pyrazole-based marketed drugs.
SO2NH2
Deracoxib
* Corresponding author. Tel.: +34 963544329; fax: +34 963544328; e-mail:
jose.r.pedro@uv.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.009

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G. Blay et al. / Tetrahedron 62 (2006) 8069–8076
Aromatic
Aldehyde
R1
H
R1
H
Ar
Ar
Hydrazine
Cyclocondensation
NH2
Ph
Ph
+
HN
R
O
N
O
O
N
R1
O
O
R1
(D)
R
Mandelic
acid
1,3-diketone
Ar R1
R1
O
H
Ph
Ph
CO2H
OH
(A)
Ar
O
+
+
O
R1
O
O
R1
(B)
(C)
Figure 2. Retrosynthetic analysis.
Therefore, up to four points of diversity are possible in this
scheme: R, R1, Ar and the configuration of the stereogenic
centre, which depends on mandelic acid.
with a LDA solution at ꢀ78 ꢁC in THF and then Michael ac-
ceptor 3a was added to the resulting enolate solution. How-
ever, these conditions provided 4a only with moderate
yield and low diastereoselectivity (Table 1, entry 1). Next,
the effect of the enolate aggregation state was examined. In
most cases, the use of HMPA as an additive appreciably
increases the reactivity as well as substantially modifies the
selectivity. However, when 3 equiv of HMPAwas used (entry
2) an important drop of the reaction yield was observed. The
reaction was also examined in the presence of a crown ether
as cation sequestering agent. When we carried out the
reaction in the conditions reported recently by Dixon10 for
Michael addition to arylidene malonate esters, using 18-
crown-6 and KHMDS as the base, the yield of 4a was again
very low (entry 3). However a change in the order of addition
of the reagents brought about a spectacular increase in yield
(90%) with a moderately good diastereoselectivity (77:23)
(entry 4). Finally, the change of potassium to sodium
The key step in the preparation of the chiral 1,3-dicarbonyl
component is the conjugate addition of the enolate of (S)-
mandelic acid to a 2-arylidene-1,3-diketone. Recently, we
have described a highly diastereoselective Michael reaction
of the enolate of (S)-(+)-mandelic acid to enones and the
transformation of the resulting products into highly enantio-
enriched 2-substituted-1,4-diketones.4
2. Results and discussion
Our synthetic methodology is summarised in Scheme 1. The
key step involves a Michael addition of the (S)-(+)-mandelic
acid enolate to 2-arylidene-1,3-diketones 3, which are easily
prepared from aromatic aldehydes and pentane-2,4-dione
via a Knoevenagel reaction.5 These compounds are excellent
Michael acceptors due to the strong anion-stabilising effect
of the two carbonyl groups. Although the formation of the
mandelic acid enolate leads to loss of chirality at the stereo-
genic centre, it is possible to regenerate the chiral informa-
tion if (S)-(+)-mandelic acid (1) is previously transformed
into (2S,5S)-cis-2-tert-butyl-5-phenyl-1,3-dioxolan-4-one
(2), according to the principle of self-regeneration of stereo-
centres,6 as shown by Seebach7 and us.4,8,9
Table 1. Michael addition of (2S,5S)-cis-2-tert-butyl-5-phenyl-1,3-dioxo-
lan-4-one (2) and 3-benzylidene-2,4-pentanedione 3a (optimisation of the
conditions)
Entry
Additive
Base
4a Yield (%)a
4a drb
1c
2c
3d
4e
5e
None
HMPA
18-Crown-6
18-Crown-6
18-Crown-6
LDA
LDA
KHMDS
KHMDS
NaHMDS
60
26
19
90
84
60:40
62:38
80:20
77:23
94:6
a
Yield of the major adduct after column chromatography.
Determined by 1H NMR of the mixture prior purification.
Our early protocol. See Ref. 4.
Dixon’s protocol. See Ref. 10.
Our present protocol. See Section 3.
The initial conditions tested for the Michael addition of 2 to
3-benzylidene-2,4-pentanedione 3a were identical to those
previously established by us for the addition of 2 to simple
a,b-unsaturated ketones.4 Compound 2 was deprotonated
b
c
d
e
Ar
O
Ar
3
O
O
t
H
H
H
Bu CHO
H
O
O
O
HO2C
HO
O
O
O
t
H+
Bu
t
NaHMDS, 18-crown6
THF, -78 °C
Ph
Ph
Bu
Ph
O
4
2
1
Ar
Ar
Ar
HO2C
Ph
O
1. KOH
2. HCl
Co complex
H
RNHNH2
H+
5
O
O
N
HO
N
t
N
O
N
Bu CHO, O2
t
Ph
N
Ph
Bu
N
R
6
8
R
7
R
Scheme 1. Synthesis of compounds 4–8.

G. Blay et al. / Tetrahedron 62 (2006) 8069–8076
8071
hexamethyldisilazanide as the base increased the diastereo-
selectivity to 94:6, maintaining a good yield of 4a (entry 5).
cyclocondensation11 of the 1,3-diketone moiety present in
the Michael adducts 4 with different hydrazines 5. Reaction
of diketones 4a, 4b and 4e with either phenylhydrazine (5a),
or p-nitrophenylhydrazine (5c) using concd H2SO4 as cata-
lyst in ethanol at reflux11a afforded pyrazoles 6aa and 6ac,
6ba and 6bc, 6ea and 6ec, respectively, with good yields
(Table 3). The same diketones reacted with methylhydrazine
(5b) at dioxane reflux in the presence of catalytic acetic
acid11b to give pyrazoles 6ab, 6bb and 6eb with acceptable
yields (93–56%).
The Michael addition reaction with the enolate of 2 was car-
ried out with several 2-arylidene-1,3-diketones 3 under these
optimised conditions. In all cases the corresponding adducts
4 were obtained in good to excellent yields (81–94%) and
diastereomeric ratios (from 89:11 to 97:3) (Table 2). It is im-
portant to note that the Michael adducts were obtained as
only two diastereomers out of the four possible ones attend-
ing to the configuration of the two newly created stereogenic
centres, one of the diastereomers being strongly predomi-
nant. The stereochemical structures of the major Michael
adducts 4 were elucidated by NOE experiments. These
experiments showed for all major diastereomers 4 a cis-rela-
tionship between the t-Bu group and the phenyl group from
the original (S)-mandelic acid. The absolute configuration
of the newly formed quaternary carbon atom was then as-
signed to be S, upon the consideration that the absolute con-
figuration of the dioxolanone C-2 carbon atom bearing the
tert-butyl group in 2 is S and remains unaltered from 2 to 4.
Furthermore, in the case of the p-chlorophenyl substituted
adduct 4b, the absolute stereochemistry of the major dia-
stereomer was unambiguously determined by single X-ray
diffraction (Fig. 3). According to the crystal structure the
tertiary chiral carbon in 4b had the S configuration. These
results indicate that the major reaction pathway involves
the approach of the Re-face of the 2-arylidene-1,3-diketone
3 to the Re-face of the lithium enolate of 2 (relative topicity
like), in good agreement with the results reported by See-
bach7 and us4,8,9 in related reactions.
Table 3. Preparation of pyrazoles 6 from 1,3-diketones 4 and hydrazines 5
Entry
4 (Ar)
5 (R)
Pyrazoles 6
(Yield %)
1
2
3
4
5
6
7
8
9
4a (Ph)
4a (Ph)
4a (Ph)
4b (p-ClC6H4)
4b (p-ClC6H4)
4b (p-ClC6H4)
4e (p-MeOC6H4)
4e (p-MeOC6H4)
4e (p-MeOC6H4)
5a (Ph)
5b (Me)
5c (p-O2NC6H4)
5a (Ph)
5b (Me)
5c (p-O2NC6H4)
5a (Ph)
5b (Me)
6aa (77)
6ab (93)
6ac (74)
6ba (86)
6bb (62)
6bc (74)
6ea (86)
6eb (56)
6ec (56)
5c (p-O2NC6H4)
The next step in our synthetic sequence was the cleavage of
the 1,3-dioxolan-4-one moiety present in compound 6,
which was achieved upon basic hydrolysis with ethanolic
KOH and reprotonation to give the corresponding hydroxy
acids, a-aryl-a-pyrazolylatrolactic acids 7, with good yields
(Table 4).
The second step in our synthetic sequence was the prepara-
tion of the pyrazole ring system, which involves the
Table 4. Hydrolysis of the 1,3-dioxolan-4-one moiety in compounds 6 and
oxidative decarboxylation of the hydroxy acid in compounds 7
Table 2. Michael reaction of (2S,5S)-cis-2-tert-butyl-5-phenyl-1,3-dioxo-
lan-4-one (2) with 2-arylidene-1,3-diketones 3
Entry
6
6,7,8 Ar
6,7,8 R
7 (Yield %) 8 (Yield %)
1
2
3
4
5
6
7
6aa Ph
6ab Ph
6ac Ph
6ba p-Cl–C6H4
6bb p-Cl–C6H4
Ph
Me
7aa (94)
7ab (77)
p-O2NC6H4 7ac (73)
8aa (66)
8ab (87)
8ac (—)
8ba (62)
8bb (61)
8ea (58)
8eb (74)
Entry 3 (Ar)
4 (Ar)
4 Yield (%)a 4 drb
1
2
3
4
5
3a (Ph)
4a (Ph)
84
84
81
78
94:6
91:9
89:11
97:3
95:5
Ph
Me
7ba (88)
7bb (86)
7ea (99)
7eb (93)
3b (p-ClC6H4)
3c (p-BrC6H4)
3d (p-MeC6H4)
4b (p-ClC6H4)
4c (p-BrC6H4)
4d (p-MeC6H4)
6ea p-MeO–C6H4 Ph
6eb p-MeO–C6H4 Me
3e (p-MeOC6H4) 4e (p-MeOC6H4) 94
a
Yield of the major adduct after column chromatography.
Determined by 1H NMR of the mixture prior purification.
b
Finally, the oxidative decarboxylation of the a-hydroxy acid
moiety present in 7 to carbonyl compounds 8 was carried out
by using a catalytic system developed in our laboratory that
employs oxygen as terminal oxidant in the presence of piv-
alaldehyde and a catalytic amount of the Co(III)–Me2opba
complex (Fig. 4).12 Under these conditions a-aryl-a-pyrazo-
lylacetophenones 8 were obtained in good yields from
a-aryl-a-pyrazolylatrolactic acids 7, except in the case of
the N-(p-nitrophenyl)pyrazole 7ac that gave rise to a com-
plex reaction mixture (Table 4).
C(11)
C(9)
O(30)
O(29)
C(10)
C(8)
C(6)
C(7)
C(25)
C(12)
O(2)
O(1)
C(5)
C(13)
C(26)
C(14)
C(17)
C(16)
C(24)
C(4)
C(18)
C(15)
-
O(3)
C(27)
C(19)
Cl(31)
O
O
O
O(28)
C(23)
C(20)
N
N
N
N
+
Co
NMe4
C(22)
O
C(21)
Me Me
Figure 3. ORTEP drawing for compound 4b.14
Figure 4. Co(III) ortho-phenylene-bis(N0-methyloxamidate) complex.

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G. Blay et al. / Tetrahedron 62 (2006) 8069–8076
In summary, a practical, efficient and diversity-oriented
synthesis of enantiomerically pure densely substituted pyra-
zoles, a-aryl-a-pyrazolylatrolactic acids and a-aryl-a-
pyrazolylacetophenones has been developed. The key step
in this synthesis is the conjugate addition of the lithium eno-
late of the (2S,5S)-cis-2-tert-butyl-5-phenyl-1,3-dioxolan-
4-one to 2-arylidene-1,3-diketones, which proceeds readily
to give the corresponding Michael adducts in good yields
and diastereoselectivities. The cyclocondensation of the
1,3-diketone moieties present in these adducts with several
hydrazines leads to substituted pyrazoles. Subsequent basic
hydrolysis of the 1,3-dioxolan-4-one moiety present in these
products leads to enantiomerically pure a-aryl-a-pyrazolyl-
atrolactic acids. Finally, oxidative decarboxylation of these
using oxygen, pivalaldehyde and the Co(III)–Me2opba com-
plex as catalyst gives a-aryl-a-pyrazolylacetophenones. In
this synthetic sequence four points of diversity, including
the configuration of the stereogenic centre of the side chain,
are introduced. Furthermore, it should be noted that by using
other substituted mandelic acids as starting materials,13
a fifth point of diversity could be introduced (the substituent
of the benzoyl group). In this synthetic sequence (S)-
mandelic acid acts as an umpoled chiral equivalent of the
benzoyl carbanion determining the configuration of the
stereogenic centre of the side chain.
The reaction was kept at this temperature until consumption
of the 2-arylidene-1,3-diketone 3 as indicated by TLC. The
reaction was then quenched with glacial acetic acid (80 mL,
2 mmol) via syringe at ꢀ78 ꢁC. Once the mixture reached
room temperature, water (15 mL) was added and extracted
with diethyl ether (3ꢂ15 mL). The combined organic ex-
tracts were washed with brine, dried (MgSO4), filtered and
evaporated. The residue was flash chromatographed on silica
gel (hexane–diethyl ether) to afford adduct 4.
3.2.1. Michael adduct 4a. White crystals; mp 177–178 ꢁC
(from hexane–diethyl ether); [a]2D5 +296.9 (c 0.79, CHCl3);
1H NMR (300 MHz, CDCl3) d 0.83 (9H, s), 1.61 (3H, s),
2.25 (3H, s), 4.45 (1H, d, J¼11.4 Hz), 4.53 (1H, d,
J¼11.4 Hz), 4.92 (1H, s), 7.20–7.35 (10H, m); 13C NMR
(75 MHz, CDCl3) d 23.2 (q), 26.9 (q), 30.5 (q), 34.6 (q),
51.8 (d), 70.2 (d), 82.4 (s), 107.8 (d), 126.9 (d), 127.6 (d),
128.0 (d), 128.2 (d), 128.6 (d), 133.7 (s), 134.2 (s), 170.4
(s), 201.1 (s), 202.0 (s); HRMS (CI) m/z 409.2015 (M++1,
62, C25H29O5 required 409.2015), 323 (83), 220 (51), 147
(75), 105 (100).
3.2.2. Michael adduct 4b. White crystals; mp 197–198 ꢁC
(from hexane–diethyl ether); [a]2D5 +286.3 (c 1.20, CHCl3);
1H NMR (300 MHz, CDCl3) d 0.84 (9H, s), 1.64 (3H, s),
2.28 (3H, s), 4.44 (2H, s), 5.01 (1H, s), 7.2–7.35 (9H, m);
13C NMR (75 MHz, CDCl3) d 23.2 (q), 27.0 (q), 30.6 (q),
34.6 (q), 51.2 (d), 70.0 (d), 82.0 (s), 107.9 (d), 126.9 (d),
127.7 (d), 128.2 (d), 128.8 (d), 132.7 (s), 133.3 (s), 134.3
(s), 170.3 (s), 200.8 (s), 201.7 (s); HRMS (CI) m/z
443.1682 (M++1, 13, C25H28ClO5 required 443.1625), 445
(4), 359 (15), 357 (43), 220 (68), 219 (61), 105 (100).
3. Experimental
3.1. General
All melting points are uncorrected. Column chromatography
was performed on silica gel (Merck, silica gel 60, 230–
400 mesh). Commercial reagents and solvents were of ana-
lytical grade or were purified by standard procedures, prior
to use. All reactions involving air or moisture sensitive mate-
rials were carried out under nitrogen atmosphere. Optical ro-
tations were determined on a Perkin–Elmer 243 polarimeter.
NMR spectra were recorded on a Bruker Advance 300 DPX
spectrometer (1H at 300 MHz and 13C at 75 MHz) or a Varian
Unity 400 (1H at 400 MHz and 13C at 100 MHz) and refer-
enced to TMS as internal standard. The carbon type was
determined by DEPT experiments. In the case of some
pyrazoles 6 the 13C NMR was registered in DMSO-d6 at
70 ꢁC in order to observe all the expected signals. Mass spec-
tra were run by electron impact at 70 eV, by chemical ionisa-
tion using methane as ionising gas, or FAB+ on a VG
Autospec spectrometer (VG Analytical, Micromass Instru-
ments). All new compounds were determined >95% pure
by 1H NMR spectroscopy.
3.2.3. Michael adduct 4c. White crystals; mp 202–203 ꢁC
(from hexane–diethyl ether); [a]2D5 +272.3 (c 0.67, CHCl3);
1H NMR (300 MHz, CDCl3) d 0.84 (9H, s), 1.64 (3H, s),
2.28 (3H, s), 4.41 (1H, d, J¼11.4 Hz), 4.45 (1H, d,
J¼11.7 Hz), 5.01 (1H, s), 7.25–7.40 (9H, m); 13C NMR
(75 MHz, CDCl3) d 23.2 (q), 27.0 (q), 30.5 (q), 34.6 (q),
51.2 (d), 70.0 (d), 81.9 (s), 107.9 (d), 122.5 (s), 126.8 (d),
127.7 (d), 128.8 (d), 131.1 (d), 131.2 (s), 133.2 (s), 170.2
(s), 200.8 (s), 201.6 (s); HRMS (CI) m/z 487.1147 (M++1,
1, C25H28BrO5 required 487.1120), 489 (1), 403 (9), 401
(9), 220 (41), 219 (34), 105 (100).
3.2.4. Michael adduct 4d. White solid; mp 164–165 ꢁC;
[a]2D5 +299.2 (c 0.66, CHCl3); 1H NMR (300 MHz, CDCl3)
d 0.84 (9H, s), 1.61 (3H, s), 2.25 (3H, s), 2.30 (3H, s), 4.41
(1H, d, J¼11.1 Hz), 4.48 (1H, d, J¼11.4 Hz), 4.95 (1H, s),
7.20–7.35 (9H, m); 13C NMR (75 MHz, CDCl3) d 21.1
(q), 23.1 (q), 26.8 (q), 30.5 (q), 34.5 (q), 51.3 (d), 70.2 (d),
82.3 (s), 107.6 (d), 126.9 (d), 127.5 (d), 128.5 (d), 128.6
(d), 130.9 (d), 133.6 (s), 137.9 (s), 170.4 (s), 201.2 (s),
202.0 (s); HRMS (CI) m/z 423.2268 (M++1, 69, C26H31O5
required 423.2171), 337 (93), 220 (38), 203 (76), 161
(100), 105 (5).
3.2. General procedure for the preparation of Michael
adducts 4
A solution of 18-crown-6 (0.8 mmol) in dry THF (0.8 mL)
was added to a solution of NaHMDS (1.0 mmol) in dry
THF (10 mL) at ꢀ78 ꢁC. The reaction mixture was then
stirred for 15 min at ꢀ78 ꢁC before a solution of (2S,5S)-
cis-2-tert-butyl-5-phenyl-1,3-dioxolanone (2)7a (0.8 mmol)
in dry THF (4.5 mL) was dropwise added. Stirring was main-
tained for 30 min at ꢀ78 ꢁC before a solution of 2-arylidene-
1,3-diketone 3 (0.67 mmol) in dry THF (5 mL) was added.
3.2.5. Michael adduct 4e. White solid; mp 128–130 ꢁC;
[a]2D5 +272.0 (c 0.78, CHCl3); 1H NMR (300 MHz, CDCl3)
d 0.84 (9H, s), 1.62 (3H, s), 2.25 (3H, s), 3.78 (3H, s), 4.40
(1H, d, J¼11.4 Hz), 4.45 (1H, d, J¼11.4 Hz), 4.96 (1H, s),
7.20–7.30 (9H, m); 13C NMR (75 MHz, CDCl3) d 23.2

G. Blay et al. / Tetrahedron 62 (2006) 8069–8076
8073
(q), 26.7 (q), 30.6 (q), 34.5 (q), 50.9 (d), 55.1 (q), 70.3 (d),
82.4 (s), 107.7 (d), 113.2 (d), 113.3 (d), 125.9 (s), 126.9
(d), 127.5 (d), 128.5 (d), 159.3 (s), 170.5 (s), 201.2 (s),
202.1 (s); HRMS (CI) m/z 339.1614 (M++1ꢀC5H7O2, 9,
C21H23O4 required 339.1596), 219 (25), 177 (100), 105 (5).
3.3.5. Pyrazole 6ac. Yellow oil; [a]2D5 +241.0 (c 0.72,
CHCl3); H NMR (300 MHz, CDCl3) d 1.03 (9H, s), 2.13
1
(3H, br s), 2.54 (3H, br s), 4.97 (1H, s), 5.01 (1H, s), 7.05–
7.20 (5H, m), 7.29 (3H, t, J¼7.5 Hz), 7.65 (2H, d,
J¼8.7 Hz), 7.84 (2H, d, J¼7.5 Hz), 8.33 (2H, d, J¼9 Hz);
1H NMR (400 MHz, DMSO-d6) d 1.00 (9H, s), 2.15 (3H,
s), 2.45 (3H, s), 5.03 (1H, s), 5.06 (1H, s), 7.03 (1H, t,
J¼7.4 Hz), 7.12 (2H, t, J¼7.4 Hz), 7.21 (1H, t, J¼7.2 Hz),
7.32 (2H, t, J¼7.8 Hz), 7.36 (2H, d, J¼7.6 Hz), 7.77 (2H,
d, J¼8.8 Hz), 7.85 (2H, dd, J¼8.4, 1.2 Hz), 8.32 (2H, d,
3.3. General procedure for the preparation of
pyrazoles 6
3.3.1. Procedure A (reaction with arylhydrazines). To
a solution of compound 4 (0.24 mmol) in absolute EtOH
(3 mL), acidified with a drop of concd H2SO4, was dropwise
added a solution of arylhydrazine 5 (PhNHNH2 or
p-NO2PhNHNH2) (0.48 mmol) in absolute EtOH (2 mL).
The reaction mixture was heated at reflux temperature until
complete transformation of compound 4 into pyrazole 6, as
shown by TLC. Then, the reaction mixture was neutralised
with saturated aqueous NaHCO3, extracted with CH2Cl2,
washed with brine, dried over Na2SO4, concentrated and
flash chromatographed on silica gel (hexane–diethyl ether)
to afford pyrazoles 6.
13
J¼9.2 Hz); C NMR (100 MHz, DMSO-d6, 70 ꢁC) d 11.1
(q), 12.6 (q), 23.0 (q), 34.3 (q), 48.4 (d), 86.0 (s), 109.4
(d), 116.9 (s), 124.0 (d), 124.1 (d), 125.3 (d), 125.6 (d),
127.0 (d), 127.2 (d), 127.3 (d), 129.5 (d), 137.2 (s), 137.3
(s), 138.0 (s), 144.0 (s), 145.3 (s), 148.9 (s), 172.3 (s);
HRMS (FAB+) m/z 526.2383 (M++1, 70, C31H32N3O5 re-
quired 526.2342), 306 (100), 260 (15), 105 (14).
3.3.6. Pyrazole 6ba. Colourless oil; [a]2D5 +228.9 (c 0.75,
CHCl3); H NMR (300 MHz, CDCl3) d 0.95 (9H, s), 2.03
1
(3H, s), 2.35 (3H, s), 4.85 (1H, s), 4.94 (1H, s), 7.00 (2H, d,
J¼8.4 Hz), 7.12–7.41 (10H, m), 7.73 (2H, d, J¼7.5 Hz),
1H NMR (400 MHz, DMSO-d6) d 1.00 (9H, s), 2.15 (3H,
s), 2.30 (3H, s), 5.00 (1H, s), 5.04 (1H, s), 7.16 (2H, d, J¼
8.8 Hz), 7.22 (1H, td, J¼7.4, 1.2 Hz), 7.33 (2H, t, J¼
8.4 Hz), 7.37 (2H, d, J¼8.8 Hz), 7.43–7.39 (3H, m), 7.51
(2H, t, J¼7.6 Hz), 7.82 (2H, dd, J¼8.4, 1.2 Hz); 13C NMR
(100 MHz, DMSO-d6, 70 ꢁC) d 10.7 (q), 12.5 (q), 23.0 (q),
29.5 (s), 47.9 (d), 86.0 (s), 109.5 (d), 124.4 (d), 125.2 (d),
126.9 (d), 127.0 (d), 127.3 (d), 127.4 (d), 128.6 (d), 130.3
(s), 131.3 (d), 136.5 (s), 137.2 (s), 137.3 (s), 139.0 (s),
146.9 (s), 172.1 (s); HRMS (FAB+) m/z 515.2119 (M++1,
15, C31H32ClN2O3 required 515.2101), 517 (5), 297 (34),
296 (44), 295 (86), 267 (15), 221 (46), 147 (100).
3.3.2. Procedure B (reaction with methylhydrazine). A
solution of compound 4 (0.49 mmol), methylhydrazine 5b
(0.98 mmol) and CH3CO2H (56 mL, 0.98 mmol) in dioxane
(8 mL), was heated at reflux temperature until complete
transformation of compound 4 into pyrazole 6, as shown by
TLC (in some cases additional amounts of reagent were
added). Then, the dioxane was removed in vacuo, and the
residue was diluted with water, extracted with EtOAc,
washed with saturated aqueous NaHCO3 and with brine,
dried over Na2SO4, concentrated and flash chromatographed
on silica gel (hexane–diethyl ether) to afford pyrazoles 6.
3.3.3. Pyrazole 6aa. Yellow oil; [a]2D5 +253.0 (c 0.78,
CHCl3); H NMR (300 MHz, CDCl3) d 1.03 (9H, s), 2.15
1
3.3.7. Pyrazole 6bb. Colourless oil; [a]2D5 +260.1 (c 1.03,
CHCl3); H NMR (300 MHz, CDCl3) d 1.01 (9H, s), 2.00
1
(3H, br s), 2.41 (3H, br s), 4.97 (1H, s), 5.03 (1H, s), 7.06–
7.45 (13H, m), 7.83 (2H, d, J¼7.2 Hz); 1H NMR
(400 MHz, DMSO-d6) d 1.00 (9H, s), 2.13 (3H, s), 2.29
(3H, s), 5.01 (1H, s), 5.03 (1H, s), 7.02 (1H, tt, J¼7.4,
1.4 Hz), 7.12 (2H, t, J¼7.6 Hz), 7.20 (2H, dt, J¼7.6, 1.2 Hz),
7.31 (2H, d, J¼8 Hz), 7.35 (2H, d, J¼7.6 Hz), 7.40 (2H, d,
J¼8 Hz), 7.41 (1H, d, J¼7.2 Hz), 7.5 (2H, t, J¼7.8 Hz),
7.83 (2H, d, J¼8 Hz); 13C NMR (100 MHz, DMSO-d6,
70 ꢁC) d 10.7 (q), 12.5 (q), 23.0 (q), 34.3 (q), 48.5 (d), 86.2
(s), 109.4 (d), 115.0 (s), 124.4 (d), 125.3 (d), 125.5 (d),
126.9 (d), 127.0 (d), 127.2 (d), 127.3 (d), 128.5 (d), 129.4
(d), 137.2 (s), 137.4 (s), 137.5 (s), 139.1 (s), 147.0 (s), 172.4
(s); HRMS (FAB+) m/z 481.2497 (M++1, 33, C31H33N2O3
required 481.2491), 262 (36), 261 (100), 147 (15).
(3H, s), 2.34 (3H, s), 3.71 (3H, s), 4.81 (1H, s), 4.95 (1H,
s), 7.03 (2H, d, J¼8.4 Hz), 7.18–7.30 (5H, m), 7.78 (d,
J¼7.2 Hz); 13C NMR (75 MHz, CDCl3) d 10.1 (q), 14.2
(q), 23.8 (q), 35.1 (s), 36.2 (q), 49.1 (d), 86.9 (s), 110.6
(d), 113.6 (s), 125.7 (d), 127.7 (d), 127.9 (d), 128.0 (d),
131.3 (d), 131.7 (s), 137.60 (s), 137.63 (s), 146.3 (s), 173.0
(s); HRMS (FAB+) m/z 453.1951 (M++1, 49, C26H30ClN2O3
required 453.1945), 455 (16), 235 (33), 233 (100), 147 (44).
3.3.8. Pyrazole 6bc. Yellow oil; [a]2D5 +236.2 (c 0.75,
CHCl3); H NMR (300 MHz, CDCl3) d 1.03 (9H, s), 2.10
1
(3H, br s), 2.55 (3H, br s), 4.92 (1H, s), 5.00 (1H, s), 7.1
(2H, d, J¼8.7 Hz), 7.23 (3H, t, J¼6.9 Hz), 7.31 (2H, t,
J¼7.5 Hz), 7.66 (2H, d, J¼8.7 Hz), 7.81 (2H, d, J¼9 Hz),
8.34 (2H, d, J¼9 Hz); 1H NMR (400 MHz, DMSO-d6)
d 1.00 (9H, s), 2.17 (3H, s), 2.46 (3H, s), 5.02 (1H, s), 5.07
(1H, s), 7.17 (2H, d, J¼8.8 Hz), 7.23 (1H, tt, J¼7.4,
1.2 Hz), 7.34 (2H, t, J¼7.6 Hz), 7.38 (2H, d, J¼8.4 Hz),
7.77 (2H, d, J¼9.2 Hz), 7.84 (2H, dd, J¼8.8, 1.2 Hz), 8.32
(2H, d, J¼9.1 Hz); 13C NMR (100 MHz, DMSO-d6, 70 ꢁC)
d 11.1 (q), 12.6 (q), 22.9 (q), 34.3 (q), 47.8 (d), 85.8 (s),
109.5 (d), 116.3 (s), 124.1 (d), 124.2 (d), 125.3 (d), 127.0
(d), 127.39 (d), 127.42 (d), 130.4 (s), 131.3 (d), 136.2 (s),
137.0 (s), 138.1 (s), 143.9 (s), 145.3 (s), 148.8 (s), 172.0
(s); HRMS (FAB+) m/z 560.1956 (M++1, 81, C31H31ClN3O5
required 560.1952), 562 (33), 342 (42), 340 (100), 169 (38).
3.3.4. Pyrazole 6ab. Colourless oil; [a]2D5 +270.4 (c 0.71,
CHCl3); H NMR (300 MHz, CDCl3) d 1.01 (9H, s), 2.01
1
(3H, br s), 2.33 (3H, br s), 3.67 (3H, s), 4.85 (1H, s), 4.97
(1H, s), 6.96 (1H, t, J¼7.2 Hz), 7.05 (2H, t, J¼7.8 Hz),
7.13 (1H, t, J¼7.2 Hz), 7.25 (2H, m), 7.81 (2H, dd, J¼7.5,
1.2 Hz); 13C NMR (75 MHz, CDCl3) d 10.1 (q), 13.6 (q),
23.8 (q), 35.1 (q), 36.1 (q), 49.6 (d), 87.0 (s), 110.5 (d),
114.0 (s), 125.7 (d), 125.8 (d), 127.4 (d), 127.6 (d), 127.8
(d), 129.9 (d), 137.5 (s), 137.9 (s), 138.0 (s), 146.4 (s),
173.8 (s); HRMS (FAB+) m/z 419.2341 (M++1, 34,
C26H31N2O3 required 419.2335), 281 (12), 221 (13), 199
(100), 147 (71).

8074
G. Blay et al. / Tetrahedron 62 (2006) 8069–8076
3.3.9. Pyrazole 6ea. Yellow oil; [a]2D5 +270.8 (c 0.77,
CHCl3); H NMR (300 MHz, CDCl3) d 1.03 (9H, s), 2.14
(300 MHz, CDCl3) d 2.04 (3H, s), 2.25 (3H, s), 5.10 (1H,
s), 6.93–6.97 (3H, m), 7.06–7.18 (10H, m), 7.60 (2H, d,
J¼7.2 Hz); 13C NMR (75 MHz, CDCl3) d 12.1 (q), 12.4
(q), 47.3 (d), 81.3 (s), 117.8 (s), 125.6 (d), 126.5 (d), 127.0
(d), 127.48 (d), 127.78 (d), 128.0 (d), 128.78 (d), 128.83
(d), 130.0 (d), 138.0 (s), 139.34 (s), 139.99 (s), 141.7 (s),
148.0 (s), 176.2 (s); HRMS (FAB+) m/z 413.1875 (M++1,
5, C26H25N2O3 required 413.1865), 282 (22), 261 (100),
147 (74).
1
(3H, br s), 2.40 (3H, br s), 3.68 (3H, s), 4.91 (1H, s), 5.02
(1H, s), 6.63 (2H, d, J¼8.7 Hz), 7.15–7.3 (5H, m), 7.35–
7.48 (5H, m), 7.82 (2H, d, J¼7.5 Hz); 1H NMR (400 MHz,
DMSO-d6) d 1.00 (9H, s), 2.15 (3H, s), 2.29 (3H, s), 3.64
(3H, s), 4.97 (1H, s), 5.01 (1H, s), 6.68 (2H, d, J¼9.2 Hz),
7.21 (1H, tt, J¼8.6, 1.4 Hz), 7.26 (2H, d, J¼8.4 Hz), 7.32
(2H, t, J¼7.6 Hz), 7.37–7.43 (3H, m), 7.47–7.53 (2H, m),
7.82 (2H, dd, J¼8.4, 1.2 Hz); 13C NMR (100 MHz, DMSO-
d6, 70 ꢁC) d 10.7 (q), 12.5 (q), 23.0 (q), 34.2 (q), 47.8 (d), 54.4
(q), 86.3 (s), 109.4 (d), 112.6 (d), 115.3 (s), 124.4 (d), 125.2
(d), 126.9 (d), 127.1 (d), 127.3 (d), 128.5 (d), 129.5 (s), 130.5
(d), 137.0 (s), 137.5 (s), 139.1 (s), 147.0 (s), 156.9 (s), 172.4
(s); HRMS (FAB+) m/z 511.2584 (M++1, 70, C32H35N2O4
required 511.2597), 291 (100), 169 (12).
3.4.2. Compound 7ab. White solid; mp 255–257 ꢁC (from
1
chloroform–methanol); [a]2D5 +261.0 (c 1.8, CH3OH); H
NMR (300 MHz, CDCl3) d 2.15 (3H, s), 2.49 (3H, s), 3.58
(3H, s), 5.23 (1H, s), 6.98–7.04 (3H, m), 7.16–7.27 (5H,
m), 7.76 (2H, d, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3–
MeOH-d4) d 10.5 (q), 11.9 (q), 34.9 (q), 46.8 (d), 80.8 (s),
115.5 (s), 125.0 (d), 126.1 (d), 126.8 (d), 127.0 (d), 127.5
(d), 129.6 (d), 138.6 (s), 139.4 (s), 141.0 (s), 146.1 (s),
176.1 (s); HRMS (FAB+) m/z 351.1711 (M++1, 41,
C21H23N2O3 required 351.1709), 281 (36), 221 (45), 199
(38), 147 (100).
3.3.10. Pyrazole 6eb. Colourless oil; [a]2D5 +246.9 (c 0.82,
CHCl3); H NMR (300 MHz, CDCl3) d 0.94 (9H, s), 1.97
1
(3H, br s), 2.25 (3H, br s), 3.59 (3H, s), 3.63 (3H, s), 4.72
(1H, s), 4.89 (1H, s), 6.52 (2H, d, J¼9.0 Hz), 7.09 (1H, t,
J¼6.9 Hz), 7.10 (2H, d, J¼9 Hz), 7.19 (2H, d, J¼7.5 Hz),
7.72 (2H, d, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d 10.2 (q), 14.1 (q), 23.9 (q), 35.1 (q), 36.1 (q), 48.9 (d),
54.9 (q), 87.2 (s), 110.5 (d), 112.8 (d), 114.3 (s), 125.7 (d),
127.6 (d), 127.9 (d), 130.2 (s), 130.9 (d), 137.4 (s), 138.0
(s), 146.4 (s), 157.4 (s), 173.9 (s); HRMS (FAB+) m/z
449.2447 (M++1, 11, C27H33N2O4 required 449.2440), 281
(40), 229 (18), 221 (54), 147 (100).
3.4.3. Compound 7ac. Oil; [a]2D5 ꢀ150.0 (c 1.0, CH3OH);
1H NMR (300 MHz, CDCl3) d 2.08 (3H, s), 2.20 (3H, s),
5.12 (1H, s), 6.90–7.00 (3H, m), 7.10–7.30 (7H, m), 7.57
(2H, d, J¼7.2 Hz), 7.93 (2H, d, J¼8.4 Hz); 13C NMR
(75 MHz, CDCl3) d 12.7 (q), 12.8 (q), 47.0 (d), 81.3 (s),
119.4 (s), 124.4 (d), 124.9 (d), 125.9 (d), 126.3 (d), 127.4
(d), 127.6 (d), 128.0 (d), 129.9 (d), 138.6 (s), 140.0 (s),
141.2 (s), 143.5 (s), 146.0 (s), 150.2 (s), 176.2 (s); HRMS
(FAB+) m/z 458.1711 (M++1, 7, C26H24N3O5 required
458.1716), 412 (8), 281 (32), 147 (100).
3.3.11. Pyrazole 6ec. Yellow oil; [a]2D5 +288.4 (c 0.70,
CHCl3); H NMR (300 MHz, CDCl3) d 1.02 (9H, s), 2.13
1
(3H, br s), 2.54 (3H, br s), 3.69 (3H, s), 4.90 (1H, s), 5.00
(1H, s), 6.65 (2H, d, J¼6.9 Hz), 7.20 (3H, t, J¼7.2 Hz),
7.30 (2H, t, J¼7.6 Hz), 7.66 (2H, d, J¼8.7 Hz), 7.82 (2H,
d, J¼7.5 Hz), 8.33 (2H, d, J¼9.3 Hz); 1H NMR (400 MHz,
DMSO-d6, 70 ꢁC) d 1.00 (9H, s), 2.16 (3H, s), 2.45 (3H, s),
3.64 (3H, s), 4.99 (1H, s), 5.02 (1H, s), 6.68 (2H, d,
J¼8.8 Hz), 7.22 (1H, t, J¼7.2 Hz), 7.26 (2H, d, J¼8.8 Hz),
7.33 (2H, t, J¼7.6 Hz), 7.77 (2H, d, J¼9.2 Hz), 7.83 (2H,
d, J¼7.6 Hz), 8.32 (2H, d, J¼8.8 Hz); 13C NMR
(100 MHz, DMSO-d6, 70 ꢁC) d 11.2 (q), 12.6 (q), 23.0 (q),
34.3 (q), 47.6 (d), 54.4 (q), 86.2 (s), 109.4 (d), 112.6 (d),
117.2 (s), 124.1 (d), 124.1 (d), 125.3 (d), 127.2 (d), 127.3
(d), 129.1 (s), 130.5 (d), 137.4 (s), 137.9 (s), 144.0 (s),
145.2 (s), 148.9 (s), 157.0 (s), 172.3 (s). HRMS (FAB+)
m/z 556.2436 (M++1, 71, C32H34N3O6 required 556.2448),
336 (100), 238 (27), 169 (62).
3.4.4. Compound 7ba. White solid; mp 240–243 ꢁC (from
1
chloroform–methanol); [a]2D5 +201.8 (c 1.2, CH3OH); H
NMR (300 MHz, CDCl3) d 2.10 (3H, s), 2.24 (3H, s), 5.11
(1H, s), 6.99 (2H, d, J¼8.1 Hz), 7.10–7.25 (10H, m), 7.64
(2H, d, J¼6.6 Hz); 13C NMR (75 MHz, CDCl3) d 12.1 (q),
12.3 (q), 46.8 (d), 81.1 (s), 115.3 (d), 117.2 (s), 125.6 (d),
126.4 (d), 127.6 (d), 127.9 (d), 128.9 (d), 129.5 (d), 131.4
(d), 137.9 (s), 139.9 (s), 141.3 (s), 147.9 (s), 155.9 (s),
176.1 (s); HRMS (FAB+) m/z 447.1495 (M++1, 20,
C26H24ClN2O3 required 447.1475), 449 (5), 294 (44), 281
(29), 154 (100).
3.4.5. Compound 7bb. Pale yellow solid; mp 230–232 ꢁC
1
(from ether–methanol); [a]2D5 +202.1 (c 1.4, CHCl3); H
NMR (300 MHz, CDCl3) d 2.04 (3H, s), 2.33 (3H, s), 3.44
(3H, s), 5.09 (1H, s), 6.93 (2H, d, J¼9.0 Hz), 7.05–7.19
(5H, m), 7.66 (2H, d, J¼6.9 Hz); 13C NMR (75 MHz,
CDCl3) d 11.4 (q), 11.6 (q), 34.9 (q), 46.6 (d), 81.2 (s),
116.5 (s), 126.4 (d), 127.14 (d), 127.64 (d), 127.95 (d),
131.24 (d), 131.32 (s), 138.3 (s), 140.3 (s), 141.8 (s), 145.1
(s), 177.2 (s); HRMS (FAB+) m/z 385.1316 (M++1, 9,
C21H22ClN2O3 required 385.1319), 387 (3), 281 (40), 221
(40), 207 (45), 147 (100).
3.4. General procedure for the hydrolysis of the
1,3-dioxolan-4-one moiety in compound 6
Compound 6 (0.5 mmol) was treated with 5% ethanolic
KOH (1.1 mL, 1 mmol) at 60 ꢁC until complete reaction of
the starting material (TLC). The reaction mixture was
poured into ice and acidified with 1 M HCl until pH w2.
The aqueous mixture was extracted with EtOAc
(4ꢂ25 mL), and the organic layers were washed with brine
(2ꢂ15 mL), dried (NaSO4), filtered and concentrated under
reduced pressure to give a-hydroxy acids 7.
3.4.6. Compound 7ea. Pale yellow solid; mp 248–251 ꢁC
1
(from ether–methanol); [a]2D5 +164.8 (c 1.0, CH3OH); H
NMR (300 MHz, CDCl3-25% CD3OD) d 2.14 (3H, s), 2.24
(3H, s), 3.57 (3H, s), 5.09 (1H, s), 6.51 (2H, d, J¼8.4 Hz),
7.07–7.31 (10H, m), 7.65 (2H, d, J¼7.8 Hz); 13C NMR
(75 MHz, CDCl3-25% CD3OD) d 12.4 (q), 12.5 (q), 46.7 (d),
3.4.1. Compound 7aa. White solid; mp 225–227 ꢁC (from
1
ether–methanol); [a]2D5 +179.6 (c 0.77, CHCl3); H NMR

G. Blay et al. / Tetrahedron 62 (2006) 8069–8076
8075
54.9 (q), 81.3 (s), 112.8 (d), 117.5 (s), 124.4 (d), 125.4 (d),
127.1 (d), 127.6 (d), 128.8 (d), 130.45 (d), 130.90 (d), 131.5
(s), 138.5 (s), 139.1 (s), 141.3 (s), 148.5 (s), 157.1 (s), 176.5
(s); HRMS (FAB+) m/z 443.1944 (M++1, 25, C27H27N2O4
required 443.1971), 281 (92), 207 (100), 147 (100).
3.5.4. Compound 8bb. Yellow oil; [a]2D5 ꢀ35.4 (c 1.2,
1
CHCl3); H NMR (300 MHz, CDCl3) d 2.05 (3H, s), 2.13
(3H, s), 3.69 (3H, s), 5.77 (1H, s), 7.04 (2H, d, J¼8.7 Hz),
7.28 (2H, d, J¼8.7), 7.41 (2H, t, J¼7.5 Hz), 7.53 (1H, tt,
J¼7.8, 1.5 Hz), 7.92 (2H, dd, J¼7.2, 1.5 Hz); 13C NMR
(75 MHz, CDCl3) d 10.1 (q), 12.2 (q), 36.0 (q), 49.4 (d),
112.6 (s), 128.47 (d), 128.55 (d), 128.63 (d), 130.2 (d),
130.3 (s), 132.7 (s), 133.2 (d), 136.5 (s), 137.1 (s), 145.6
(s), 197.8 (s); HRMS (EI) m/z 338.1168 (M+, 2,
C20H19ClN2O required 338.1186), 247 (15), 233 (100).
3.4.7. Compound 7eb. Pale yellow solid; mp 230–231 ꢁC
1
(from ether–methanol); [a]2D5 +203.9 (c 1.6, CHCl3); H
NMR (300 MHz, CDCl3) d 2.13 (3H, s), 2.38 (3H, s), 3.49
(3H, s), 3.66 (3H, s), 5.14 (1H, s), 6.58 (2H, d, J¼8.7 Hz),
7.08–7.26 (5H, m), 7.76 (2H, d, J¼6.6 Hz); 13C NMR
(75 MHz, CDCl3) d 11.3 (q), 11.7 (q), 34.9 (q), 46.4, (d),
54.9 (q), 81.5 (s), 112.8 (d), 117.2 (s), 126.5 (d), 126.9 (d),
127.8 (d), 130.8 (d), 131.8 (s), 140.1 (s), 142.3 (s), 145.2
(s), 157.2 (s), 177.7 (s); HRMS (FAB+) m/z 381.1823
(M++1, 54, C22H25N2O4 required 381.1814), 281 (86), 229
(83), 207 (63), 147 (100).
3.5.5. Compound 8ea. Pale yellow oil; [a]2D5 ꢀ52.2 (c 0.7,
1
CHCl3); H NMR (300 MHz, CDCl3) d 2.04 (3H, s), 2.13
(3H, s), 3.72 (3H, s), 5.78 (1H, s), 6.80 (2H, d, J¼8.7 Hz),
7.02 (2H, d, J¼9.3 Hz), 7.23–7.38 (7H, m), 7.45 (1H, tt,
J¼7.8, 1.5 Hz), 7.91 (2H, d, J¼8.7 Hz); 13C NMR
(75 MHz, CDCl3) d 11.4 (q), 12.6 (q), 49.4 (d), 55.2 (q),
113.9 (d), 115.2 (s), 125.2 (d), 127.5 (d), 128.6 (d), 128.9
(d), 130.0 (d), 130.4 (d), 133.0 (d), 136.8 (s), 137.3 (s),
139.6 (s), 147.9 (s), 158.5 (s), 198.4 (s); HRMS (EI) m/z
396.1847 (M+, 1, C26H24N2O2 required 396.1838), 336
(11), 291 (100).
3.5. General procedure for the oxidative decarboxyl-
ation of a-hydroxy acid moiety of compound 7
A solution of compound 7 (0.22 mmol), Co(III)–Me2opba
complex (5.3 mg, 0.013 mmol) and pivalaldehyde (74 mL,
0.66 mmol) in acetonitrile (1.5 mL) and DMF (0.2 mL)
was stirred under an oxygen atmosphere until consumption
of the starting material (TLC). Water was added, the mixture
was extracted with ethyl ether (3ꢂ20 mL) and the organic
layer was washed with saturated aqueous NaHCO3
(10 mL), brine (2ꢂ10 mL) and dried (MgSO4). The reaction
products were purified by flash chromatography on silica gel
(hexane–ethyl acetate) to afford compound 8.
3.5.6. Compound 8eb. Pale yellow oil; [a]2D5 ꢀ70.5 (c 1.7,
1
CHCl3); H NMR (300 MHz, CDCl3) d 2.05 (3H, s), 2.13
(3H, s), 3.69 (3H, s), 3.77 (3H, s), 5.77 (1H, s), 6.84 (2H, d,
J¼8.7 Hz), 7.04 (2H, d, J¼8.7 Hz), 7.40 (2H, t, J¼7.2 Hz),
7.51 (1H, t, J¼7.5 Hz), 7.94 (2H, d, J¼7.2 Hz); 13C NMR
(75 MHz, CDCl3) d 10.1 (q), 12.2 (q), 35.9 (q), 49.2 (d),
55.2 (q), 113.5 (s), 113.8 (d), 128.52 (d), 128.54 (d), 129.8
(d), 130.6 (s), 132.9 (d), 136.7 (s), 137.3 (s), 145.6 (s),
158.4 (s), 198.4 (s); HRMS (EI) m/z 334.1678 (M+, 1,
C21H22N2O2 required 334.1681), 244 (21), 149 (63).
3.5.1. Compound 8aa. Orange oil; [a]2D5 ꢀ34.8 (c 0.8,
1
CHCl3); H NMR (300 MHz, CDCl3) d 2.12 (3H, s), 2.22
(3H, s), 5.92 (1H, s), 7.19 (2H, d, J¼6.6 Hz), 7.55–7.26
(13H, m), 8.00 (2H, d, J¼7.2 Hz); 13C NMR (75 MHz,
CDCl3) d 11.5 (q), 12.5 (q), 50.0 (d), 125.2 (d), 125.5 (d),
126.7 (d), 127.6 (d), 128.5 (d), 128.89 (d), 128.94 (d),
129.2 (d), 133.2 (d), 136.1 (s), 136.7 (s), 137.6 (s), 138.4
(s), 139.4 (s), 147.9 (s), 198.1 (s); HRMS (FAB+) m/z
367.1829 (M++1, 100, C25H23N2O required 367.1810), 277
(20), 261 (64).
Acknowledgements
Financial supports from the Spanish Government MEC
(BQU2001-3017) and from Generalitat Valenciana (Grupos
03/168 and GV05/10) are acknowledged.
References and notes
3.5.2. Compound 8ab. Yellow oil; [a]2D5 ꢀ71.0 (c 1.2,
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Spindler, J. F.; Taillefer, M. Eur. J. Org. Chem. 2004, 695–
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(3H, s), 3.70 (3H, s), 5.83 (1H, s), 7.11 (2H, d, J¼6.6 Hz),
7.55–7.25 (8H, m), 7.95 (2H, d, J¼7.2 Hz); 13C NMR
(75 MHz, CDCl3) d 10.1 (q), 12.1 (q), 27.1 (q), 35.9 (q),
49.9 (d), 126.9 (d), 128.30 (s), 128.4 (d), 128.6 (d), 128.9
(d), 130.0 (s), 133.0 (d), 136.7 (s), 138.6 (s), 145.7 (s),
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1
CHCl3); H NMR (300 MHz, CDCl3) d 2.12 (3H, s), 2.21
(3H, s), 5.86 (1H, s), 7.11 (2H, d, J¼8.4 Hz), 7.30–7.37
(5H, m), 7.41–7.47 (4H, m), 7.56 (1H, t, J¼7.4 Hz), 7.98
(2H, d, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3) d 11.4 (q),
12.5 (q), 49.5 (d), 111.3 (s), 114.5 (s), 125.2 (d), 127.7 (d),
128.6 (d), 128.7 (d), 129.0 (d), 130.3 (d), 132.9 (s), 133.3
(s), 136.5 (s), 136.9 (s), 137.5 (s), 147.7 (s), 197.7 (s);
HRMS (EI) m/z 400.1317 (M+, 2, C25H21ClN2O required
400.1342), 297 (33), 295 (100).

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