Highly diastereoselective arylation of (S)-mandelic acid enolate: Enantioselective synthesis of substituted (R)-3-hydroxy-3-phenyloxindoles and (R)-benzylic acids and synthesis of nitrobenzophenones

Article abstract of DOI:10.1021/jo0402069

An easy access to substituted (R)-3-hydroxy-3-phenyloxindoles, (R)-benzylic acids, and benzophenones is described. The reaction of the lithium enolate of the (2S,5S)-cis-1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalaldehyde with several o- and p-halonitrobenzenes proceeds readily to give the corresponding arylation products in good yields and diastereoselectivities. The reduction of the nitro group with Zn/HCl/EtOH in the o-nitro arylation products with concomitant intramolecular aminolysis of the dioxolanone moiety leads directly to enantiomerically pure (R)-3-hydroxy-3- phenyloxindoles. On the other hand the basic hydrolysis of the dioxolanone moiety in all the arylation products (ortho and para) leads to enantiomerically pure substituted (R)-benzylic acids. The oxidative decarboxylation of these latter with oxygen as terminal oxidant in the presence of pivalaldehyde and the Co(III)-Me₂opba complex as catalyst gives substituted nitrobenzophenones.

Full text of DOI:10.1021/jo0402069

High ly Dia ster eoselective Ar yla tion of (S)-Ma n d elic Acid En ola te:
En a n tioselective Syn th esis of Su bstitu ted
(R)-3-Hyd r oxy-3-p h en yloxin d oles a n d (R)-Ben zylic Acid s a n d
Syn th esis of Nitr oben zop h en on es#
Santiago Barroso, Gonzalo Blay, Luz Cardona, Isabel Ferna´ndez, Begon˜a Garc´ıa, and
J ose´ R. Pedro*
Departament de Quı´mica Orga`nica, Facultat de Quı´mica, Universitat de Vale`ncia, Dr. Moliner 50,
E-46100 Burjassot, Vale`ncia, Spain
jose.r.pedro@uv.es
Received J une 1, 2004
An easy access to substituted (R)-3-hydroxy-3-phenyloxindoles, (R)-benzylic acids, and benzophe-
nones is described. The reaction of the lithium enolate of the (2S,5S)-cis-1,3-dioxolan-4-one derived
from optically active (S)-mandelic acid and pivalaldehyde with several o- and p-halonitrobenzenes
proceeds readily to give the corresponding arylation products in good yields and diastereoselec-
tivities. The reduction of the nitro group with Zn/HCl/EtOH in the o-nitro arylation products with
concomitant intramolecular aminolysis of the dioxolanone moiety leads directly to enantiomerically
pure (R)-3-hydroxy-3-phenyloxindoles. On the other hand the basic hydrolysis of the dioxolanone
moiety in all the arylation products (ortho and para) leads to enantiomerically pure substituted
(R)-benzylic acids. The oxidative decarboxylation of these latter with oxygen as terminal oxidant
in the presence of pivalaldehyde and the Co(III)-Me2opba complex as catalyst gives substituted
nitrobenzophenones.
Recently, we have reported a highly diastereoselective
Michael reaction of the (S)-mandelic acid enolate using
R,â-unsaturated carbonyl compounds1 and nitroalkenes2
as acceptors and the transformation of the corresponding
adducts into highly enantioenriched 2-substituted 1,4-
dicarbonyl compounds1 and R-hydroxy-R,â-diaryl-γ-lac-
tams,2 respectively. In both syntheses the strategy em-
ployed to exert stereochemical control in the newly
created stereogenic centers involved the use of (S)-
mandelic acid (1) as the source of chiral information
through its previous conversion into (2S,5S)-cis-2-tert-
butyl-5-phenyl-1,3-dioxolan-4-one (2) by reaction with
pivalaldehyde (Seebach principle of self-regeneration of
stereocenters).3
In this paper we wish to report an extension of this
methodology4 to a diastereoselective arylation of (S)-
mandelic acid enolate with o- and p-fluoronitrobenzenes
3 and the transformation of the corresponding products
4 into enantiomerically pure substituted (R)-3-hydroxy-
3-phenyloxindoles 5 and (R)-benzylic acids 6. We will also
describe the aerobic oxidative decarboxylation of benzylic
acids 6 to give substituted benzophenones 7.
number of marketed drugs.6 Their biological activities
and their role as essential intermediates in the total
synthesis of other indole alkaloids make these compounds
attractive targets in medicinal and synthetic organic
chemistry. Of particular interest are 3-hydroxyoxindoles,7
specially 3-aryl-3-hydroxyoxindoles and their 3-fluoro
derivatives (Figure 1). Very recently, chemists at Sumi-
tomo Pharmaceuticals have reported the growth hormone
secretagogue activity of the nonpeptidyl oxindole deriva-
tive SM-130686,8 and researchers at Brystol-Myers Squibb
(4) For some examples of the use of (2S,5S)-cis-2-tert-butyl-5-phenyl-
3-dioxolan-4-one (2) for the synthesis of biologically important mol-
ecules see: (a) Mase, T.; Houpis, I. N.; Akao, A.; Dorziotis, I.; Emerson,
K.; Hoang, T.; Iida, T.; Itoh, T.; Kamei, K.; Kato, S.; Kato, Y.; Kawasaki,
M.; Lang, F.; Lee, J .; Lynch, J .; Maligres, P.; Molina, A.; Nemoto, T.;
Okada, S.; Reamer, R.; Song, J . Z.; Tschaen, D.; Wada, T.; Zewge, D.;
Volante, R. P.; Reider, P. J .; Tomimoto, K. J . Org. Chem. 2001, 66,
6775-6786. (b) Grover, P. T.; Bhongle, N. N.; Wald, S. A.; Senanayake,
C. H. J . Org. Chem. 2000, 65, 6283-6287. (c) Mitsuya, M.; Ogino, Y.;
Ohtake, N.; Mase, T. Tetrahedron 2000, 56, 9901-9907 and references
therein.
(5) (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2003, 20, 216-242.
(b) Hibino, S.; Choshi, T. Nat. Prod. Rep. 2002, 19, 148-180 and
previous articles of this series.
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A.; Zorn, S. H.; Maloney, P. R.; Ewing, F. E.; Newman, M. E.; Schmidt,
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Oxindoles (2-indolinones) are a class of heterocyclic
compounds found in many natural products5 and in a
#
This paper is dedicated to Professor J ose´ L. Soto on occasion of
his retirement.
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60, 165-170.
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10.1021/jo0402069 CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/03/2004
J . Org. Chem. 2004, 69, 6821-6829
6821

Barroso et al.
R-alkylation of chiral glycolic acid equivalents being
among the most commonly used.14e,16 However, to the best
of our knowledge, no examples of arylation of mandelic
acids to benzylic acids have been reported so far. The
clinical application of this kind of compounds is under
study, and for example, 3-quinuclidinyl 4-halobenzylates
show a high affinity for muscarinic acetyl choline recep-
tors17 and their radioactive halogen counterparts are
useful as tomography imaging agents.18 Nevertheless, the
syntheses of optically active substituted benzylic acids
are limited to organometallic additions to benzoylformate
with 8-phenylmenthol as a chiral auxiliary.19
Finally, the presence of the benzophenone scaffold in
the framework of natural and synthetic compounds with
important physiological activities, such as antimalaria,20
antiinflammatory,21 anticancer,22 or antibiotic,23 contin-
ues to spur synthetic efforts regarding their prepara-
tion.24 Most of the classical synthetic protocols for ben-
zophenones involve Friedel-Crafts benzoylations between
an aromatic substrate and an electrophilic reagent.
However, these reactions, which are catalyzed by acidic
catalysts (generally used in excess of molar amounts),
do not proceed successfully with aromatic substrates
having electron-withdrawing groups.25 An alternative
route involves the substitution on the aromatic substrate
by the action of an appropriate nucleophilic species, such
as a synthetic equivalent of benzoyl carbanion.1,26
F IGURE 1. Examples of bioactive oxindoles.
laboratories have prepared and tested several 3-aryl-3-
hydroxy-9 and 3-aryl-3-fluorooxindoles which culminated
in the discovery of BMS-204352 (MaxiPost), a potent
opener of Maxi-K channels of application in the treatment
of stroke.10 Interest in the synthesis of 3-aryl-3-hydroxy-
oxindoles lies not only in its intrinsic biological activity
but also in the fact that they are used as intermediates
for the synthesis of the corresponding 3-fluorooxin-
doles.10,11 Racemic 3-phenyl-3-hydroxyoxindoles have been
prepared by cyclization of benzoylformic acid aryl amides,12
radical oxidation of oxindoles,13 or addition of Grignard
reagents to isatin.10 An extension of this last method has
allowed the preparation of enantiomerically enriched
3-aryl-3-hydroxyoxindoles by asymmetric hydroxylation
of the 3-aryloxindoles prepared by dehydroxylation of the
Grignard-isatin adducts.9 However, the preparation of
the starting isatins required for these syntheses needs
long synthetic sequences and/or presents regioselectivity
problems.
Optically active R-hydroxy acids are structural units
present in many biologically and pharmacologically
important compounds.14 In addition R-hydroxy acid de-
rivatives are important intermediates for asymmetric
synthesis.15 Consequently a number of useful synthetic
methods for R-hydroxy acids have been developed over
the years, the R-alkylation of optically active natural
R-hydroxy acids such as lactic or mandelic acids, or the
Resu lts a n d Discu ssion
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6822 J . Org. Chem., Vol. 69, No. 20, 2004

Diastereoselective Arylation of (S)-Mandelic Acid Enolate
TABLE 1. Rea ction of (2S,5S)-cis-1,3-Dioxola n -4-on e (2)
w ith p-Ha lon itr oben zen es 3a
SCHEME 1
3a
4a (yield, 8 (yield,
entry (X) solvent
additive
base
LDA
%)
%)
1
2
3
4
5
6
7
Cl
Cl
F
Br
F
THF
THF
THF
THF
THF
THF
DMF
40 (30)a
40
HMPA (3 equiv) LDA
HMPA (3 equiv) LDA
HMPA (3 equiv) LDA
HMPA (3 equiv) t-BuLi
30
85
27
50
b
30
F
F
NaHMDS
NaH
35
a
b
Recovered 2 in parentheses. Enolate decomposition.
philic substitution to arene-transition metal carbonyl
complexes,29 the transition metal catalyzed aromatic
nucleophilic substitution of aryl halides,30 and the aro-
matic substitution via nucleophilic addition to electron-
deficient arenes (including vicarious31 and ipso28a,32) are
the most interesting ones.
SCHEME 2
The starting materials in our synthesis were com-
mercially available aromatic nitro compounds having a
leaving group in either the ortho or para position with
respect to the nitro group. The aromatic nucleophilic
substitution was first tested with different p-haloni-
trobenzenes in order to optimize the reaction conditions
(Scheme 2, Table 1).33
Compound 2 was deprotonated with a LDA solution
at -78 °C in THF, and then p-chloronitrobenzene 3a (X
) Cl) was added to the resulting enolate solution. Under
these conditions none of the expected product was
obtained (Entry 1). Instead, compound 8 was obtained
in 40% yield besides 30% of recovered starting material.
Compound 8 is the aldol product of the 1,3-dioxolan-4-
one 2 enolate and pivalaldehyde.34 The presence of
pivalaldehyde in the reaction mixture is not completely
clear, but since formation of compound 8 is only observed
after the addition of the nitrobenzene compound, we
believe that it most likely results from a redox process
between the 1,3-dioxolan-4-one enolate and the nitro
group,28 which would take place faster than the addition
of the enolate to the aromatic ring (Scheme 3). As a
matter of fact, the use of 3 equiv of HMPA, an additive
benzophenones from (S)-(+)-mandelic acid and o- and
p-fluoronitrobenzenes is based on retrosynthetic Scheme
1.
According to this analysis, the first synthetic step
should involve an aromatic nucleophilic substitution with
the (S)-(+)-mandelic acid enolate onto a halonitroben-
zene. Although the formation of the mandelic acid enolate
leads to loss of chirality at the stereogenic center, it
should be possible to regenerate that chiral information
if (S)-(+)-mandelic acid (1) is previously transformed
into (2S,5S)-cis-2-tert-butyl-5-phenyl-1,3-dioxolanone (2)
(Scheme 2), according to the principle of self-regeneration
of stereocenters,3 as shown by Seebach16a,27 and us.1,2
Although the nucleophilic substitution of oxygen and
nitrogen nucleophiles onto halonitrobenzenes is a stan-
dard reaction in organic synthesis, there are not many
successful methods to carry out the aromatic nucleophilic
substitutions with enolates, in part because the nitro
group often reacts with carbanions by electron-transfer
processes.28 Among the described procedures, the nucleo-
(29) (a) Ku¨ndig, E. P.; Desobry, V.; Simmons, D. P.; Wenger, E. J .
Am. Chem. Soc. 1989, 111, 1804-1814. (b) Rose-Munch, F.; Rose, E.;
Semra, A. J . Chem. Soc., Chem. Commun. 1987, 942-943. (c) Rose-
Munch, F.; Rose, E.; Semra, A.; J eannin, Y.; Rober, F. J . Organomet.
Chem. 1988, 353, 53-64. (d) Rose-Munch, F.; Rose, E.; Semra, A.;
Mignon, L.; Garcia-Oricain, J .; Knobler, C. J . Organomet. Chem. 1989,
363, 297-309.
(30) (a) Zhang, T. Y.; Zhang, H. B. Tetrahedron Lett. 2002, 43, 1363-
1365. (b) Ahman, J .; Wolfe, J . P.; Troutman, M. V.; Palucki, M.;
Buchwald, S. L. J . Am. Chem. Soc. 1998, 120, 1918-1919. (c) Freund,
R.; Mederski, W. W. K. R. Helv. Chim. Acta 2000, 83, 1247-1255. (d)
Palucki, M.; Buchwald S. L. J . Am. Chem. Soc. 1997, 119, 11108-
11109. (e) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37,
3387-3388.
(31) (a) Lawrence, N. J .; Liddle, J .; J ackson, D. A. Synlett 1996, 55-
56. (b) Makosza, M. Synthesis 1991, 103-111.
(32) (a) Selvakumar, N.; Azhagan, A. M.; Srinivas, D.; Krishna, G.
G. Tetrahedron Lett. 2002, 43, 9175-9178. (b) Gurjar, M.; Reddy, D.
S.; Murugaiah, A.; Murugaiah, S. Synthesis 2000, 1659-1661.
(33) These results have been reported in a previous communica-
tion: Blay, G.; Cardona, L.; Ferna´ndez, I.; Michelena, R.; Pedro, J . R.;
Ramirez, T.; Ruiz-Garc´ıa, R. Synlett 2003, 2325-2328.
(27) (a) Calderari, G.; Seebach, D. Helv. Chim. Acta 1985, 68, 1592-
1604. (b) Seebach, D.; Golinski, J . Helv. Chim. Acta 1981, 64, 1413-
1423.
(28) (a) Selvakumar, N.; Reddy, B. Y.; Kumar, G. S.; Iqbal, J .
Tetrahedron Lett. 2001, 42, 8395-8398. (b) Comprehensive Carbanion
Chemistry, Part A; Durst, T., Ed.; Elsevier: Amsterdam, The Neth-
erlands, 1980. (c) Bjorsvik, H. R.; Liguori, L.; Merinero, J . A. V. J .
Org. Chem. 2002, 67, 7493-7500.
(34) (a) Battaglia, A.; Barbaro, G.; Giorgianni, P.; Guerrini, A.;
Bertucci, C.; Geremia, S. Chem. Eur. J . 2000, 6, 3551-3557. (b) Data
for compound 8: 1H NMR (CDCl3) δ 0.77 (9H, s), 1.01 (9H, s), 2.47
(1H, br s), 4.12 (1H, d, J ) 5.6 Hz), 5.59 (1H, S), 7.32 (3H, m), 7.71
(2H, dd, J ) 8.1, 1.1 Hz); 13C NMR (CDCl3) δ 23.7 (CH3), 27.4 (CH3),
34.7 (C), 36.9 (C), 83.8 (CH), 87.1 (C), 110.7 (CH), 125.6 (CH), 126.5
(CH), 127.9 (CH), 137.0 (C), 174.4 (C).
J . Org. Chem, Vol. 69, No. 20, 2004 6823

Barroso et al.
SCHEME 3
TABLE 2. Rea ction of Ar yla tion of (2S,5S)-cis-1,3-
Dioxola n -4-on e 2 w ith F lu or on itr oben zen es 3 (X ) F )'
obtained with 3-methyl-4-nitrofluorobenzene 3c (Entry
3), 3-methoxy-4-nitrofluorobenzene 3d (Entry 4), and
3-trifluoromethyl-4-nitrofluorobenzene 3e (Entry 5). The
reaction was also carried out with p-fluoronitrobenzenes
substituted in the ortho position with respect to the
fluorine atom in order to determine possible steric effects
(Entries 6-8). Again, the reaction proceeded readily in
all cases, including the bulky MEM-protected benzyl
alcohol group (Entry 6), without much influence of the
electron-donating (Entries 6 and 7) or electron-withdraw-
ing (Entry 8) features of the additional substituent.
entry
3 and 4
NO2
R
4 (yield, %)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
a
b
c
d
e
f
g
h
i
j
k
l
m
n
4-NO2
2-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
H
H
85
37
82
75
75
80
66
94
88
66
80
77
60
90
3-Me
3-OMe
3-CF3
2-CH2OMEM
2-Cl
2-CN
5-Me
5-OMe
4-CF3
Despite the low yield obtained with o-fluoronitroben-
zene we decided to examine the reaction with substituted
o-fluoronitrobenzenes 3i-n and we were very pleased to
observe that in these cases the reaction proceeded with
fair to good yields to give the expected nucleophilic
aromatic substitution products 4i-n (Table 2, Entries
9-14). The reaction proceeded well regardless of the
location of the additional substituent, although the
presence of strong electron-donating groups on the
aromatic ring slightly decreased the yield of the reaction
(Entries 10 and 13).
4-CO2Me
4-N(Me)COPh
4-NO2
that increases the reactivity of enolates toward nucleo-
philic substitution,35 allowed us to obtain the desired
product 4a in 30% yield, although still accompanied by
40% of 8 (Entry 2). The formation of compound 8 could
be prevented only when p-fluoronitrobenzene 3a (X ) F)
was used as arylating reagent (Entry 3) while the use of
p-bromonitrobenzene 3a (X ) Br) did not provide satis-
factory results (Entry 4). The use of tert-butyllithium
instead of LDA gave poorer results (Entry 5). Sodium
bases also gave disappointing results. Thus, NaHDMS
in THF (Entry 6) brought about decomposition of the
enolate, even at -78 °C, while the combination NaH-
DMF28a (Entry 7) gave low yields of the expected product.
The tendency of compound 4a to decompose upon pro-
longed reaction times or higher temperatures was also
observed. Accordingly, a short reaction time (5-10 min)
and quenching at -78 °C was established as the best
experimental protocol. Other electron-deficient fluoroben-
zenes such as p-cyano- and p-trifluoromethylfluoroben-
zene were also tested as arylating reagents. However,
none of these electron-withdrawing groups was able to
induce nucleophilic substitution with the enolate of 2
under the optimized conditions (LDA, THF-HMPA).
The nucleophilic aromatic substitution reaction with
the enolate of 2 was carried out with a number of
fluoronitrobenzenes 3 (X ) F) under similar conditions
(Table 2). In the case of o-fluoronitrobenzene 3b (Entry
2) the reaction proceeded but only with modest yield. The
presence of an additional group on the aromatic ring was
also studied. In the case of substituted p-fluoronitroben-
zenes the reaction worked well if the additional group
was in the meta position with respect to the fluorine
atom, regardless of its electronic nature. Thus, fair to
good yields of the corresponding compounds 4 were
In all cases, the reaction was stereoselective either with
o- or p-fluoronitrobenzene compounds and only one
stereoisomer out of the two possible was obtained. The
stereochemical structures of compounds 4 were eluci-
dated by NOE experiments. These experiments showed
in all of the cases the cis relationship between the tert-
butyl group and the phenyl group from the original (S)-
(+)-mandelic acid. The absolute configuration of the
newly formed quaternary carbon atom was then assigned
to be R, upon the consideration that the absolute config-
uration of the dioxolanone C-2 carbon atom bearing the
tert-butyl group in 2 is S and remains unaltered from 2
to 4. These results indicate that compounds 4 are
obtained from the exclusive approach of the fluoroni-
trobenzene reagent anti to the tert-butyl group, in good
agreement with the results reported by Seebach3,16a,27 and
us1,2 in related reactions.
The second step in the synthetic sequence to oxindoles
involved the reduction of the aromatic nitro group in the
o-nitro arylation products 4b,i-m (Scheme 2). This
reaction was carried out with Zn/HCl/EtOH. The reduc-
tion of the nitro group to amine took place with concomi-
tant intramolecular aminolysis of the dioxolanone ring
to afford the corresponding (R)-3-hydroxy-3-phenyloxin-
doles 5 with high yields (Table 3). The resulting (R)-3-
hydroxy-3-phenyloxindoles 5b,i-m were enantiomeri-
1
cally pure (ee>99%) as was proven by H NMR experi-
ments with the chiral lanthanide shift reagent Eu(hfc)3
under conditions previously optimized for racemic mix-
tures prepared from (()-mandelic acid dioxolanone,
indicating no sign of epimerization at C-3 during the
(35) Handbook of Reagents for Organic Synthesis. Acidic and Basic
Reagents; Reich, J . H., Rigby, J . H., Eds.; J ohn Wiley and Sons:
Chichester, UK, 1999; pp 160-166.
6824 J . Org. Chem., Vol. 69, No. 20, 2004

Diastereoselective Arylation of (S)-Mandelic Acid Enolate
TABLE 3. Syn th esis of (R)-3-Hyd r oxy-3-p h en yloxin d oles
5 fr om o-Ar yla tion P r od u cts 4
entry
4 and 5
5 (R)a
5 (yield, %)
1
2
3
4
5
6
b
i
j
k
l
m
H
5-Me
5-OMe
6-CF3
6-CO2Me
6-N(Me)COPh
79
99
95
89
72
98
F IGURE 2. Structure of the Co(III)-Me2opba complex.
a
For numbering of oxindole compounds 5 see Scheme 2.
of the resulting hydroxybenzyl carbanion, which is then
oxidized by oxygen to ketone 7n and 7h under the
hydrolysis conditions.32b,36 In the case of 7h , this com-
pound is obtained as the hydroxy phthalide tautomer37
after concomitant hydrolysis of the cyano group.
SCHEME 4
Finally, the oxidative decarboxylation of the rest of the
benzylic acids 6 to benzophenones 7 (Scheme 4) was
carried out by using a catalytic system developed in our
laboratory that employs oxygen as terminal oxidant in
the presence of pivalaldehyde and a catalytic amount of
a Co(III)-Me2opba complex (Figure 2).26 Under these
conditions, nitrobenzophenones 7 were obtained with
good yields from benzylic acids 6 (Table 4).
In summary, concise, regio- and enantioselective syn-
theses of (R)-3-hydroxy-3-phenyloxindoles and substi-
tuted (R)-benzylic acids starting from (S)-mandelic acid
are presented. The syntheses are advantageous over
other available syntheses since they are shorter, avoid
problems of regioselectivity in the functionalization of the
aromatic ring, and do not require the use of expensive
chiral reagents nor difficult racemic resolution. Enan-
tiomerically enriched substituted mandelic acids are
readily available via asymmetric Friedel-Crafts reac-
tions with glyoxylates,38 which will allow extending the
scope of this methodology to the preparation of 3-aryl-
3-hydroxyoxindoles and benzylic acids substituted in both
aromatic rings. Finally a new method for the synthesis
of nitrobenzophenones is presented. The overall sequence
involves mandelic acid as an “Umpoled” equivalent of the
benzoyl carbanion, and it is an alternative to the elec-
trophilic Friedel-Crafts benzoylation of electron-deficient
nitrobenzenes
TABLE 4. Rea ction of Hyd r olysis of th e 1,3-Dioxola n -
4-on e Moiety 4 a n d Oxid a tive Deca r boxyla tion of
Ben zylic Acid s 6
entry
4, 6, and 7
6 (yield, %)
7 (yield, %)
1
2
3
4
5
6
7
8
9
10
11
12
13
a
b
c
d
e
f
g
h
i
94
78
87
93
64
80
81
82
90
87
80
95
65
91
77a
90
88
84
56
63a
79
73
84
70
j
k
m
n
Exp er im en ta l Section
a
Gen er a l P r oced u r e for th e Ar yla tion of (2S,5S)-cis-2-
ter t-Bu tyl-5-p h en yl-1,3-d ioxola n -4-on e (2) w ith F lu or on i-
tr oben zen es 3. A solution of (S,S)-cis-2-tert-butyl-5-phenyl-
1,3-dioxolan-4-one16a 2 (220 mg, 1 mmol) in 1.5 mL of dry THF
was added to a -78 °C precooled solution prepared from 0.625
mL of a 2 M commercial solution of LDA in heptane-THF-
ethylbenzene (1.25 mmol), 0.56 mL of HMPA (3 mmol), and 4
mL of THF. After 30 min, a solution of fluoronitrobenzene 3
(1.25 mmol) in 0.5 mL of THF was added dropwise, and 10
min later, the reaction was quenched with the addition of 2-3
drops of water and silica gel. Once the mixture reached room
temperature, the solvent was evaporated under reduced pres-
sure and the resulting powder chromatographed on silica gel
to give compounds 4.
Product obtained during hydrolysis of compound 4.
acidic reductive treatment of the o-nitro arylation prod-
ucts 4b,i-m .
The second step in the synthetic sequence to substi-
tuted (R)-benzylic acids was the cleavage of the 1,3-
dioxolan-4-one moiety in compounds 4, which was achieved
upon basic hydrolysis with ethanolic KOH and reproto-
nation to give the corresponding hydroxy acids 6, with
good yields (Scheme 4, Table 4). The resulting (R)-
benzylic acids 6a -g,i-k ,m were enantiomerically pure
1
(ee >99%) as was proven by H NMR experiments with
(2S,5R)-2-ter t-Bu tyl-5-(4-n itr op h en yl)-5-p h en yl-1,3-d i-
oxola n -4-on e (4a ): 85% yield; pale yellow powder; mp 100-
the chiral lanthanide shift reagent Eu(hfc)3. In the cases
of the arylation products 4h and 4n , which bear two
strongly electron-withdrawing groups, benzophenones 7h
and 7n were directly obtained from the reaction mixture.
In both cases, the presence of the two strongly electron-
withdrawing groups facilitates decarboxylation of the
R-hydroxy acids 6h and 6n because of the mesomeric
stabilization by these groups at ortho and para positions
102 °C (hexane-diethyl ether); [R]25 +44.1 (c 2.60, CHCl3);
D
(36) Bull, D. J .; Fray, M. J .; Mackenny, M. C.; Malloy, K. A. Synlett
1996, 647-648.
(37) Fabian, W. M. F.; Bowden, K. Eur. J . Org. Chem. 2001, 2, 303-
309.
(38) Gathergood, N.; Zhuang, W.; J orgensen, K. A. J . Am. Chem.
Soc. 2000, 122, 12517-12522.
J . Org. Chem, Vol. 69, No. 20, 2004 6825

Barroso et al.
1H NMR (CDCl3) δ 1.00 (9H, s), 5.13 (1H, s), 7.27 (3H, m),
7.36 (2H, m), 7.72 (2H, d, J ) 9.0 Hz), 8.17 (2H, d, J ) 9.0
Hz); 13C NMR (CDCl3) δ 23.6 (CH3), 34.0 (C), 83.7 (C), 108.3
(CH), 124.1 (CH), 126.3 (CH), 127.5 (CH), 128.7 (CH), 129.0
(CH), 137.8 (C), 143.8 (C), 148.2 (C), 171.1 (C). HRMS (EI)
m/z 297.1374 (M+ - CO2, 100) (C18H19NO3 requires 297.1365),
280 (30), 228 (48), 211 (58), 165 (58).
mp 136-137 °C (hexane-diethyl ether); [R]25D +178.5 (c 4.29,
CHCl3); 1H NMR (CDCl3) δ 1.11 (9H, s), 5.24 (1H, s), 7.46 (5H,
m), 8.10 (1H, d, J ) 8.7 Hz), 8.45 (1H, dd, J ) 8.7, 2.3 Hz),
8.58 (1H, d, J ) 2.3 Hz); 13C NMR (CDCl3) δ 23.4 (CH3), 34.6
(C), 83.2 (C), 108.7 (CH), 113.0 (C), 115.0 (C), 126.1 (CH), 127.0
(CH), 128.7 (CH), 129.3 (CH), 130.8 (CH), 135.5 (C), 146.5 (C),
147.6 (C), 169.5 (C); HRMS (EI) m/z 322.1330 (M+ - CO2, 37)
(C19H18 N2O3 requires 322.1317), 253 (100), 190 (41), 70 (64).
(2S,5R)-2-ter t-Bu tyl-5-(2-n itr op h en yl)-5-p h en yl-1,3-d i-
oxola n -4-on e (4b): 37% yield; oil; [R]25 +402.2 (c 1.50,
(2S,5R)-2-ter t-Bu tyl-5-(5-m eth yl-2-n itr oph en yl)-5-ph en -
yl-1,3-d ioxola n -4-on e (4i): 88% yield; slightly pale yellow
crystals; mp 104-105 °C (hexane-diethyl ether); [R]25D +526.9
D
1
CHCl3); H NMR (CDCl3) δ 1.02 (9H, s), 5.06 (1H, s), 7.25-
7.50 (5H, m), 7.55-7.64 (3H, m), 7.91 (1H, d, J ) 7.5 Hz); 13
C
1
NMR (CDCl3) δ 23.5 (CH3), 34.3 (C), 83.7 (C), 108.5 (CH), 124.3
(CH), 126.1 (CH), 127.8 (C), 128.4 (CH), 128.8 (CH), 129.3
(CH), 130.2 (CH), 131.1 (CH), 137.2 (C), 149.4 (C), 170.6 (C);
HRMS (EI) m/z 341.1279 (M+, 0.1) (C19H19NO5 requires
341.1263), 284 (7), 256 (49), 211 (66), 194 (46), 167 (100).
(2S,5R)-2-ter t-Bu tyl-5-(3-m eth yl-4-n itr oph en yl)-5-ph en -
(c 0.42, CHCl3); H NMR (CDCl3) δ 1.03 (9H, s), 2.46 (3H, s),
5.05 (1H, s), 7.20-7.50 (7H, m), 7.69 (1H, s); 13C NMR (CDCl3)
δ 21.5 (CH3), 23.5 (CH3), 34.3 (C), 83.9 (C), 108.4 (CH), 124.4
(CH), 126.2 (CH), 127.7 (C), 128.3 (CH), 128.8 (CH), 129.6
(CH), 130.6 (CH), 137.3 (C), 142.1 (C), 147.4 (C), 170.8 (C);
HRMS (EI) m/z 355.1403 (M+, 3) (C20H21NO5 requires 355.1420),
331 (7), 270 (42), 225 (50), 208 (45), 180 (100).
yl-1,3-d ioxola n -4-on e (4c): 82% yield; oil; [R]25 +111.4 (c
D
1.80, CHCl3); 1H NMR (CDCl3) δ 1.06 (9H, s), 2.60 (3H, s), 5.18
(1H, s), 7.33-7.44 (5H, m), 7.54 (1H, s), 7.57 (1H, d, J ) 8.0
Hz), 7.98 (1H, d, J ) 8.0 Hz); 13C NMR (CDCl3) δ 20.6 (CH3),
23.5 (CH3), 34.5 (C), 83.6 (C), 108.1 (CH), 125.0 (CH), 125.2
(CH), 126.3 (CH), 128.6 (CH), 128.9 (CH), 130.6 (CH), 134.3
(C), 137.8 (C), 141.8 (C), 149.3 (C), 171.2 (C); HRMS (EI) m/z
311.1532 (M+ - CO2, 100) (C19H21NO3 requires 311.1521), 294
(26), 242 (58), 225 (85), 178 (37), 164 (19), 152 (15).
(2S ,5R )-2-t er t -Bu t yl-5-(5-m e t h oxy-2-n it r op h e n yl)-5-
p h en yl-1,3-d ioxola n -4-on e (4j): 66% yield; pale yellow crys-
tals; mp 99-101 °C (hexane-diethyl ether); [R]25 +584.5 (c
D
0.54, CHCl3); 1H NMR (CDCl3) δ 1.02 (9H, s), 3.87 (3H, s), 5.03
(1H, s), 6.95 (1H, dd, J ) 9.0, 2.7 Hz), 7.40-7.50 (6H, m), 7.57
(1H, d, J ) 9.0 Hz); 13C NMR (CDCl3) δ 23.5 (CH3), 34.5 (C),
56.0 (CH3), 84.0 (C), 108.6 (CH), 114.4 (CH), 114.8 (CH), 126.1
(CH), 126.7 (CH), 128.3 (CH), 128.8 (CH), 131.0 (C), 137.3 (C),
142.9 (C), 161.2 (C), 170.8 (C); HRMS (EI) m/z 371.1386 (M+,
0.3) (C20H21NO6 requires 371.1369), 314 (2), 286 (23), 224 (33),
182 (100).
(2S ,5R )-2-t er t -Bu t yl-5-(3-m e t h oxy-4-n it r op h e n yl)-5-
p h en yl-1,3-d ioxola n -4-on e (4d ): 75% yield; oil; [R]25D +109.1
1
(c 1.80, CHCl3); H NMR (CDCl3) δ 1.07 (9H, s), 3.92 (3H, s),
5.18 (1H, s), 7.24-7.42 (7H, m), 7.86 (1H, d, J ) 8.4 Hz); 13C
NMR (CDCl3) δ 23.5 (CH3), 34.5 (C), 56.6 (CH), 83.8 (C), 108.2
(CH), 111.6 (CH), 118.1 (CH), 126.1 (CH), 126.5 (CH), 128.7
CH), 129.1 (CH), 137.7 (C), 139.7 (C), 143.0 (C), 153.1 (C), 171.3
(C); HRMS (EI) m/z 371.1373 (M+, 10) (C20H21NO6 requires
371.1369), 327 (100), 258 (59), 165 (35), 105 (47).
(2S,5R)-2-ter t-Bu tyl-5-(2-n itr o-4-tr iflu or om eth ylph en yl)-
5-p h en yl-1,3-d ioxola n -4-on e (4k ): 80% yield; pale yellow
crystals; mp 110-111 °C (hexane-diethyl ether); [R]25D +356.4
1
(c 0.88, CHCl3); H NMR (CDCl3) δ 1.01 (9H, s), 5.08 (1H, s),
7.35-7.50 (5H, m), 7.77 (1H, d, J ) 1.5 Hz), 7.84 (1H, dd, J )
8.3, 1.5 Hz), 8.09 (1H, d, J ) 8.3 Hz); 13C NMR (CDCl3) δ 23.4
(CH3), 34.4 (C), 83.3 (C), 109.0 (CH), 121.6 (CH, q, J C-F ) 3.4
Hz), 122.4 (CH, q, J C-F ) 271.3 Hz), 126.0 (CH), 127.8 (CH, q,
J C-F ) 3.4 Hz), 128.6 (CH), 129.2 (CH), 130.4 (CH), 132.2 (C),
132.8 (C, q, J C-F ) 34.8 Hz), 136.5 (C), 149.4 (C), 170.1 (C);
HRMS (EI) m/z 331.0681 (M+ - C6H6, 100) (C14H12NO5F3
requires 331.0668), 262 (63), 245 (63).
(2S,5R)-2-ter t-Bu tyl-5-(4-n itr o-3-tr iflu or om eth ylph en yl)-
5-p h en yl-1,3-d ioxola n -4-on e (4e): 75% yield; oil; [R]25D +76.2
(c 1.96, CHCl3); 1H NMR (CDCl3) 1.06 (9H, s), 5.22 (1H, s),
7.34-7.45 (5H, m), 7.90 (1H, d, J ) 8.2 Hz), 7.98 (1H, dd, J )
8.2, 1.8 Hz), 8.04 (1H, d, J ) 1.8 Hz); 13C NMR (CDCl3) δ 23.5
(CH3), 34.7 (C), 83.0 (C), 108.6 (CH), 121.6 (C, q, J C-F ) 272.1
Hz), 124.4 (C, q, J C-F ) 34.4 Hz), 125.7 (CH, q, J
) 5.0
(2S,5R)-2-ter t-Bu tyl-5-(4-m eth oxyca r bon yl-2-n itr op h e-
n yl)-5-p h en yl-1,3-d ioxola n -4-on e (4l): 77% yield; slightly
pale yellow crystals; mp 114-116 °C (hexane-diethyl ether);
C-F
Hz), 125.6 (CH), 126.1 (CH), 129.0 (CH), 129.3 (CH), 131.0
(CH), 137.0 (C), 142.7 (C), 148.0 (C, q, J C-F ) 3.5 Hz), 171.0
(C); HRMS (EI) m/z 365.1245 (M+ - CO2, 41) (C19H18F3NO3
requires 365.1239), 314 (36), 269 (45), 254 (100).
[R]25 +281.2 (c 0.09, CHCl3); 1H NMR (CDCl3) δ 1.01 (9H, s),
D
3.95 (3H, s), 5.06 (1H, s), 7.30-7.50 (5H, m), 8.00 (1H, d, J )
8.3 Hz), 8.15 (1H, d, J ) 1.7 Hz), 8.23 (1H, dd, J ) 8.3, 1.7
Hz); 13C NMR (CDCl3) δ 23.4 (CH3), 34.4 (C), 52.8 (CH3), 83.5
(C), 108.8 (CH), 125.3 (CH), 126.0 (CH), 128.5 (CH), 129.0
(CH), 129.7 (CH), 131.7 (CH), 132.3 (C), 132.4 (C), 136.7 (C),
149.4 (C), 164.2 (C), 170.2 (C); HRMS (EI) m/z 368.1129 (M+
- MeO, 10) (C20H18NO6 requires 368.1134), 314 (60), 269 (100).
(2S,5R)-2-ter t-Bu t yl-5-(2-m et h oxyet h oxym et h oxym e-
th yl-4-n itr op h en yl)-5-p h en yl-1,3-d ioxola n -4-on e (4f): 80%
yield; oil; [R]25 +168.1 (c 0.91, CHCl3); 1H NMR (CDCl3) δ
D
1.08 (9H, s), 3.31 (3H, s), 3.36-3.39 (2H, m), 3.47-3.55 (2H,
m), 4.35 (1H, d, J ) 14.7 Hz), 4.58 (1H, d, J ) 6.6 Hz), 4.64
(1H, d, J ) 14.7 Hz), 4.66 (1H, d, J ) 6.6 Hz), 5.00 (1H, s),
7.33 (5H, m), 7.81 (1H, d, J ) 8.7 Hz), 8.17 (1H, dd, J ) 8.7,
2.4 Hz), 8.57 (1H, d, J ) 2.4 Hz); 13C NMR (CDCl3) δ 23.6
(CH3), 34.3 (C), 58.9 (C), 65.5 (CH2), 66.9 (CH2), 71.5 (CH2),
76.4 (CH2), 85.8 (C), 95.3 (CH2), 107.7 (CH), 121.7 (CH), 124.2
(CH), 126.2 (CH), 128.5 (CH), 128.7 (CH), 129.2 (CH), 136.2
(C), 138.7 (C), 141.4 (C), 148.7 (C), 170.7 (C); HRMS (EI) m/z
353.1247 (M+ - C4H10O3, 5) (C20H19NO5 requires 353.1263),
284 (16), 267 (96), 240 (100), 165 (62), 105 (15), 89 (99).
(2S,5R)-2-ter t-Bu tyl-5-(2-ch lor o-4-n itr op h en yl)-5-p h en -
(2S,5R)-2-ter t-Bu tyl-5-[4-(N-ben zoyl-N-m eth yla m in o)-
2-n itr oph en yl]-5-ph en yl-1,3-dioxolan -4-on e (4m ): 60% yield;
pale yellow-orange powder; mp 140-142 °C (hexanes-EtOAc);
[R]25 +326.3 (c 0.58, CHCl3); 1H NMR (CDCl3) δ 0.94 (9H, s),
D
3.44 (3H, s), 4.93 (1H, s), 7.14-7.35 (12H, m), 7.65 (1H, d, J )
8.4 Hz); 13C NMR (CDCl3) δ 23.4 (CH3), 34.3 (C), 38.0 (CH3),
83.4 (C), 108.7 (CH), 121.5 (CH), 125.0 (CH), 126.1 (CH), 128.3
(CH), 128.38 (CH), 128.4 (CH), 128.43 (CH), 129.0 (CH), 130.6
(CH), 134.8 (C), 137.0 (C), 146.2 (C), 149.6 (C), 170.4 (C), 170.6
(C); HRMS (EI) m/z 474.1769 (M+, 10) (C27H26N2O6 requires
474.1791), 389 (3), 344 (5), 222 (2), 105 (100).
yl-1,3-d ioxola n -4-on e (4g): 66% yield; oil; [R]25 +247.0 (c
D
0.13, CHCl3); 1H NMR (CDCl3) 1.10 (9H, s), 5.10 (1H, s), 7.37
(5H, m), 7.81 (1H, d, J ) 8.5 Hz), 8.17 (1H, dd, J ) 8.5, 2.4
Hz), 8.28 (1H, d, J ) 2.4 Hz); 13C NMR (CDCl3) δ 23.7 (CH3),
34.5 (C), 85.1 (C), 108.4 (CH), 121.2 (C), 126.2 (CH), 127.5 (CH),
128.5 (CH), 128.9 (CH), 130.4 (CH), 135.9 (C), 136.3 (C), 140.2
(C), 148.2 (C), 170.4 (C); HRMS (EI) m/z 331.0958 (M+ - CO2,
100) (C18H18NO3Cl requires 331.0975), 333 (32), 275 (19), 262
(55), 245 (54), 164 (23).
(2S,5R)-2-ter t-Bu tyl-5-(2,4-d in itr op h en yl)-5-p h en yl-1,3-
d ioxola n -4-on e (4n ): 90% yield; yellow crystals; mp 144-145
1
°C (hexane-diethyl ether); [R]25 +355.4 (c 0.83, CHCl3); H
D
NMR (CDCl3) 1.02 (9H, s), 5.11 (1H, s), 7.42 (5H, m), 8.19 (1H,
d, J ) 8.7 Hz), 8.37 (1H, d, J ) 2.2 Hz), 8.67 (1H, dd, J ) 8.7,
2.2 Hz); 13C NMR (CDCl3) δ 23.4 (CH3), 34.5 (C), 83.1 (C), 109.3
(CH), 119.7 (CH), 125.4 (CH), 126.0 (CH), 128.8 (CH), 129.4
(CH), 130.9 (CH), 135.0 (C), 136.2 (C), 148.1 (C), 149.3 (C),
169.8 (C); HRMS (EI) m/z 329.0414 (M+ - C4H9, 6.1) (C15H19
(2S,5R)-2-ter t-Bu tyl-5-(2-cya n o-4-n itr op h en yl)-5-p h en -
yl-1,3-d ioxola n -4-on e (4h ): 94% yield; pale yellow crystals;
6826 J . Org. Chem., Vol. 69, No. 20, 2004

Diastereoselective Arylation of (S)-Mandelic Acid Enolate
N2O7 requires 329.0410), 301 (73), 273 (13), 256 (100), 239 (62),
210 (16), 195 (24).
m), 7.62 (1H, br d, J ) 1.4 Hz), 7.80 (1H, dd, J ) 7.8, 1.4 Hz),
7.80 (1H, br s); 13C NMR (DMSO-d6, 100 MHz) δ 52.7 (CH3),
77.6 (C), 114.7 (CH), 124.0 (CH), 125.4 (CH), 125.8 (CH), 128.1
(CH), 128.7 (CH), 130.9 (C), 139.3 (C), 141.1 (C), 142.8 (C),
Gen er a l P r oced u r e for th e r ed u ction of o-Nitr o Ar y-
la tion Com p ou n d s 4 to Oxin d oles 5. Zn dust (256 mg, 2.56
mmol) and concentrated HCl (0.28 mL) were added to a
solution of compound 4 (0.35 mmol) in 3.3 mL of EtOH-H2O
(4:1). The mixture was heated at reflux temperature until
complete transformation of compound 4 into oxindole 5, as
shown by TLC. In some cases, additional amounts of Zn and
HCl were required. The mixture was cooled, filtered, diluted
with EtOAc, and washed with water, and the aqueous layer
was re-extracted with EtOAc. The combined organic layer was
washed with brine and dried over MgSO4. After filtration, the
solvent was removed under reduced pressure to afford oxin-
doles 5.
166.3 (C), 178.6 (C); HRMS (EI) m/z 283.0841 (M+, 53) (C16H13
-
NO4 requires 283.0845), 255 (77), 154 (100), 252 (9), 178 (16),
105 (11), 77 (11).
(R)-3-Hyd r oxy-6-(N-ben zoyl-N-m eth yla m in o)-3-p h en -
yl-2-oxin d ole (5m ): 98% yield; white crystals; mp 225-227
°C dec (EtOAc); [R]25D +7.1 (c 0.92, CH3OH); 1H NMR (DMSO-
d6) δ 3.36 (3H, s), 6.62 (1H, s), 6.68 (1H, d, J ) 1.7 Hz), 6.73
(1H, dd, J ) 7.9, 1.7 Hz), 6.95 (1H, d, J ) 7.9 Hz), 7.10-7.40
(10H, m), 10.37 (1H, s); 1H NMR (CDCl3, 400 MHz) δ 3.49 (3H,
s), 6.67 (1H, d, J ) 1.9 Hz), 6.81 (1H, dd, J ) 8.0, 1.9 Hz),
7.16 (1H, d, J ) 8.0 Hz), 7.20-7.40 (11 H, m), 7.88 (1H, br s);
13C NMR (DMSO-d6) δ 38.3 (CH3), 77.3 (C), 109.1 (CH), 121.2
(CH), 125.6 (CH), 125.7 (CH), 127.9 (CH), 128.1 (CH), 128.4
(CH), 128.5 (CH), 129.9 (CH), 132.0 (C), 136.6 (C), 141.6 (C),
142.8 (C), 145.7 (C), 169.7 (C), 178.6 (C); HRMS (EI) m/z
358.1325 (M+, 53) (C22H18N2O3 requires 358.1317), 330 (18),
329 (6), 118 (13), 105 (100), 77 (37).
(R)-3-Hydr oxy-3-ph en yl-2-oxin dole (5b): 79% yield; white
crystals; mp 230-233 °C dec (EtOAc); [R]25D -12.3 (c 0.91, CH3-
1
OH); H NMR (DMSO-d6, 400 MHz) δ 6.68 (1H, s), 6.95 (1H,
d, J ) 7.5 Hz), 7.02 (1H, t, J ) 7.5 Hz), 7.15 (1H, d, J ) 7.5
1
Hz), 7.45-7.25 (6H, m), 10.46 (1H, s); H NMR (CDCl3, 400
MHz) δ 3.25 (1H, br s), 6.95 (1H, br d, J ) 7.8 Hz), 7.09 (1H,
td, J ) 7.6, 0.8 Hz), 7.29-7.40 (5H, m), 7.43-7.46 (2H, m),
7.63 (1H, br s); 13C NMR (DMSO-d6) δ 77.6 (C), 110.2 (CH),
122.4 (CH), 125.1 (CH), 125.7 (CH), 127.7 (CH), 128.5 (CH),
129.6 (CH), 134.1 (C), 141.9 (C), 142.3 (C), 142.3 (C), 178.8
(C); HRMS (EI) m/z 225.0801 (M+, 44) (C14H11NO2 requires
225.0790), 197 (60), 196 (100), 120 (17), 77 (14).
Gen er a l P r oced u r e for th e Hyd r olysis of th e 1,3-
Dioxola n -4-on e Moiety. Compound 4 (0.5 mmol) was treated
with 5% ethanolic KOH (1.1 mL, 1 mmol) at room temperature
until complete reaction of the starting material (TLC). The
solution was poured into ice and acidified with 1 M HCl until
pH ∼2. The aqueous mixture was extracted with EtOAc, and
the organic layers were washed with brine, dried, filtered, and
concentrated under reduced pressure to give compound 6.
(R)-3-Hyd r oxy-5-m eth yl-3-p h en yl-2-oxin d ole (5i): 99%
yield; white crystals; mp 175-178 °C dec (MeOH); [R]25D -51.3
1
(c 1.21, CH3OH); H NMR (DMSO-d6, 400 MHz) δ 2.21 (3H,
(R)-4-Nitr oben zylic a cid (6a ): 94% yield; oil; [R]25D -45.6
s), 6.57 (1H, s), 6.79 (1H, d, J ) 7.9 Hz), 6.90 (1H, br s), 7.05
1
(c 0.84, MeOH); H NMR (CDCl3) δ 7.10 (2H, br s), 7.37 (5H,
1
(1H, br d, J ) 7.9 Hz), 7.25-7.35 (5H, m), 10.29 (1H, s); H
br s), 7.66 (2H, d, J ) 8.5 Hz), 8.14 (2H, d, J ) 8.5 Hz); 13C
NMR (CDCl3) δ 80.7 (C), 123.2 (CH), 126.9 (CH), 128.6 (CH),
128.7 (CH), 129.0 (CH), 140.6 (C), 147.7 (C), 147.8 (C), 176.9
(C); HRMS (EI) m/z 227.0566 (M+ - CO2H2, 25) (C13H9NO3
requires 227.0582), 197 (12), 150 (7), 105 (100).
NMR (CDCl3, 400 MHz) δ 2.30 (3H, s), 3.25 (1H, br s), 6.84
(1H, d, J ) 8.0 Hz), 7.09 (1H, br s), 7.10 (1H, br d, J ) 8.0
Hz), 7.30-7.40 (3H, m), 7.43-7.47 (2H, m), 7.69 (1H, br s);
13C NMR (DMSO-d6, 100 MHz) δ 21.1 (CH3), 77.9 (C), 110.0
(CH), 125.7 (CH), 125.8 (CH), 127.8 (CH), 128.5 (CH), 129.8
(CH), 131.3 (C), 134.3 (C), 139.9 (C), 142.1 (C), 179.0 (C);
HRMS (EI) m/z 239.0948 (M+, 58) (C15H13NO2 requires
239.0946), 211 (65), 210 (100), 134 (14) 105 (11), 77 (15).
(R)-2-Nitr oben zylic a cid (6b): 78% yield; yellow powder;
mp 147-151 °C (EtOAc); [R]25D -278 (c 0.28, MeOH); 1H NMR
(CDCl3) δ 6.94 (1H, d, J ) 7.6 Hz), 7.40-7.46 (5H, m), 7.59-
7.61 (2H, m), 7.84 (1H, dd, J ) 7.6, 1.2 Hz); 13C NMR (CDCl3)
δ 79.9 (C), 125.0 (CH), 126.9 (CH), 128.7 (CH), 129.3 (CH),
130.5 (CH), 131.7 (CH), 132.5 (CH), 136.1 (C), 138.7 (C), 149.0
(C), 176.0 (C); HRMS (EI) m/z 228.0650 (M+ - CO2H, 65)
(C13H10NO3 requires 228.0661), 167 (79), 152 (81), 105 (64),
77 (100).
(R)-3-Hydr oxy-5-m eth oxy-3-ph en yl-2-oxin dole (5j): 95%
yield; white crystals; mp 173-175 °C dec (EtOAc); [R]25D -75.3
1
(c 1.14, CH3OH); H NMR (DMSO-d6, 400 MHz) δ 3.66 (3H,
s), 6.63 (1H, br s), 6.70 (1H, br s), 6.83 (2H, br s), 7.25-7.35
(5H, m), 10.22 (1H, s); 1H NMR (CDCl3, 400 MHz) δ 3.25 (1H,
br s), 3.76 (3H, s), 6.67 (1H, dd, J ) 8.6, 2.2 Hz), 6.86 (1H, br
s), 6.88 (1H, t, J ) 1.5 Hz), 7.33-7.39 (3H, m), 7.43-7.45 (2H,
m), 7.56 (1H, br s); 13C NMR (DMSO-d6, 100 MHz) δ 55.9
(CH3), 78.2 (C), 110.8 (CH), 111.8 (CH), 114.4 (CH), 125.9 (CH),
127.9 (CH), 128.5 (CH), 135.4 (C), 135.5 (C), 142.0 (C), 155.6
(C), 178.8 (C); HRMS (EI) m/z 255.0917 (M+, 100) (C15H13NO3
requires 255.0895), 227 (69), 226 (51), 212 (29), 194 (10), 105
(10), 77 (14).
(R)-3-Meth yl-4-n itr oben zylic a cid (6c): 87% yield; pale
yellow powder; mp 118-124 °C (EtOAc); [R]25 -43.2 (c 0.81,
D
1
MeOH); H NMR (CDCl3) δ 2.54 (3H, s), 7.34-7.39 (5H, m),
7.43 (1H, dd, J ) 8.6, 1.6 Hz), 7.49 (1H, br s), 7.89 (1H, d, J )
8.6 Hz); 13C NMR (CDCl3) δ 20.5 (CH3), 80.7 (C), 124.4 (CH),
126.1 (CH), 127.0 (CH), 128.7 (CH), 128.9 (CH), 131.7 (CH),
133.5 (C), 140.6 (C), 145.8 (C), 148.9 (C), 176.6 (C); HRMS (EI)
m/z 242.0827 (M+ - CO2H, 95) (C14H12NO3 requires 242.0817),
224 (46), 164 (37), 150 (15), 105 (100), 77 (48).
(R )-3-H yd r oxy-3-p h e n yl-6-t r iflu or om e t h yl-2-oxin -
d ole (5k ): 89% yield; white crystals; mp 206-208 °C dec
(EtOAc); [R]25 +11.4 (c 0.70, CH3OH); 1H NMR (DMSO-d6,
(R)-3-Meth oxy-4-n itr oben zylic a cid (6d ): 93% yield; oil;
D
1
[R]25 -44.1 (c 0.55, MeOH); H NMR (CDCl3) δ 3.85 (3H, s),
D
400 MHz) δ 6.85 (1H, s), 7.12 (1H, s), 7.25-7.35 (7H, m), 10.70
1
7.13 (1H, dd, J ) 6.5, 1.2 Hz), 7.32-7.41 (6H, m), 7.75 (1H, d,
J ) 6.5 Hz); 13C NMR (CDCl3) δ 56.5 (CH3), 80.6 (C), 112.8
(CH), 119.6 (CH), 125.3 (CH), 127.0 (CH), 128.6 (CH), 128.9
(CH), 139.0 (C), 140.7 (C), 147.5 (C), 152.7 (C), 176.5 (C);
HRMS (EI) m/z 258.0761 (M+ - CO2H, 46) (C14H12NO4
requires 258.0766), 257 (36), 241 (26), 227 (21), 180 (16), 150
(16), 105 (100), 77 (44).
(1H, br s); H NMR (CDCl3, 400 MHz) δ 3.40 (1H, br s), 7.20
(1H, br s), 7.35-7.45 (7H, m), 7.77 (1H, br s); 13C NMR (DMSO-
d6) δ 77.3 (C), 106.5 (CH, q, J C-F ) 4.0 Hz), 119.5 (CH, q, J C-F
) 4.0 Hz), 124.3 (C, q, J C-F ) 271.8 Hz), 125.6 (CH), 125.9
(CH), 128.1 (CH), 128.6 (CH), 130.0 (C, q, J C-F ) 31.6 Hz),
138.4 (C), 140.8 (C), 143.2 (C), 178.5 (C); HRMS (EI) m/z
293.0668 (M+, 37) (C15H10F3NO2 requires 293.0664), 274 (6),
265 (54), 264 (100), 188 (15), 105 (13), 77 (13).
(R)-4-Nitr o-3-tr iflu or om eth ylben zylic a cid (6e): 64%
yield; pale yellow powder; mp 121-124 °C (EtOAc); [R]25
(R)-3-H yd r oxy-6-m et h oxyca r b on yl-3-p h en yl-2-oxin -
d ole (5l): 72% yield; white crystals; mp 223-225 °C dec
D
-60.2 (c 0.71, MeOH); 1H NMR (CDCl3) δ 7.38 (5H, br s), 7.81
(1H, d, J ) 8.5 Hz), 7.85 (1H, dd, J ) 8.5, 1.5 Hz), 8.07(1H, br
s); 13C NMR (CDCl3) δ 80.3 (C), 121.9 (C, q, J C-F ) 272 Hz),
123.4 (C, q, J C-F ) 34 Hz), 124.7 (CH), 126.7 (CH), 127.0 (CH,
q, J C-F ) 5.5 Hz), 129.0 (CH), 129.3 (CH), 132.4 (CH), 140.4
(C), 146.2 (C), 147.6 (C), 175.4 (C); HRMS (EI) m/z 296.0539
(EtOAc); [R]25 +24.5 (c 0.95, CH3OH); 1H NMR (DMSO-d6,
D
400 MHz) δ 3.86 (3H, s), 6.83 (1H, s), 7.27-7.35 (5H, m), 7.25
(1H, d, J ) 7.7 Hz), 7.43 (1H, d, J ) 1.5 Hz), 7.62 (1H, dd, J
) 7.7, 1.5 Hz), 10.64 (1H, s); 1H NMR (CDCl3, 400 MHz) δ
3.40 (1H, br s), 3.94 (3H, s), 7.30-7.40 (4H, m), 7.42-7.45 (2H,
J . Org. Chem, Vol. 69, No. 20, 2004 6827

Barroso et al.
(M+ - CO2H, 69) (C14H9NO3F3 requires 296.0535), 295 (100),
276 (33), 265 (49), 249 (11), 188 (14).
4-Nitr oben zop h en on e (7a ): 82% yield; pale yellow pow-
der; mp 133-135 °C (hexanes-EtOAc); 1H NMR (CDCl3) δ
7.51 (2H, t, J ) 8.0 Hz), 7.64 (1H, t, J ) 8.0 Hz), 7.78 (2H, d,
J ) 8.0 Hz), 7.91 (2H, d, J ) 8.5 Hz), 8.31 (2H, d, J ) 8.5 Hz);
13C NMR (CDCl3) δ 123.5 (CH), 128.7 (CH), 130.1 (CH), 130.7
(CH), 133.5 (CH), 136.3 (C), 142.9 (C), 149.8 (C), 194.8 (C);
HRMS (EI) m/z 227.0527 (M+, 63) (C13H9NO3 requires
227.0582), 150 (15), 105 (100).
(R)-2-Meth oxyeth oxym eth oxym eth yl-4-n itr oben zylic
a cid (6f): 80% yield; oil; [R]25D +19.3 (c 0.60, MeOH); 1H NMR
(CDCl3-CD3OD 9:1) δ 3.31 (3H, s), 3.47 (2H, d, J ) 3.8 Hz),
3.59 (2H, d, J ) 3.8 Hz), 4.63 (4H, m), 7.26-7.30 (4H, m), 7.44
(2H, m), 7.91 (1H, d, J ) 8.7 Hz), 8.40 (1H, br s); 13C NMR
(CDCl3-CD3OD 9:1) δ 58.7 (CH3), 66.2 (CH2), 66.8 (CH2), 71.6
(CH2), 81.2 (C), 95.0 (CH2), 121.3 (CH), 123.5 (CH), 126.8 (CH),
128.2 (CH), 129.4 (CH), 140.5 (C), 141.4 (C), 147.2 (C), 147.5
(C), 175.9 (C); HRMS (EI) m/z 346.1303 (M+ - CO2H, 0.2)
(C18H20NO6 requires 346.1291), 240 (100), 226 (49), 194 (31),
105 (18), 77 (19).
2-Nitr oben zop h en on e (7b): 90% yield; pale yellow pow-
1
der; mp 105-106 °C (CH2Cl2); H NMR (CDCl3) δ 7.42-7.51
(3H, m), 7.59 (1H, tt, J ) 7.6, 1.1 Hz), 7.68 (1H, td, J ) 8.2,
1.3 Hz), 7.73-7.81 (3H, m), 8.23 (1H, dd, J ) 8.2, 1.3 Hz); 13
C
NMR (CDCl3) δ 124.4 (CH), 128.7 (CH), 128.9 (CH), 129.2
(CH), 130.5 (CH), 133.8 (CH), 134.1 (CH), 135.9 (C), 136.2 (C),
146.7 (C), 193.4 (C); HRMS (EI) m/z 227.0580 (M+, 29) (C13H9-
NO3 requires 227.0582), 152 (22), 150 (18), 134 (81), 105 (100).
3-Meth yl-4-n itr oben zop h en on e (7c): 87% yield; oil; 1H
NMR (CDCl3) δ 2.63 (3H, s), 7.50 (2H, t, J ) 7.5 Hz), 7.62
(1H, t, J ) 7.5 Hz), 7.60-7.79 (4H, m), 7.99 (1H, d, J ) 8.3
Hz); 13C NMR (CDCl3) δ 20.2 (CH3), 124.5 (CH), 128.2 (CH),
128.6 (CH), 130.1 (CH), 133.3 (CH), 133.7 (C), 133.9 (CH),
136.4 (C), 141.3 (C), 151.2 (C), 194.9 (C); HRMS (EI) m/z
241.0727 (M+, 79) (C14H11NO3 requires 241.0739), 224 (66), 164
(24), 105 (100).
(R)-2-Ch lor o-4-n itr oben zylic a cid (6 g): 81% yield; pale
yellow powder; mp 169-172 °C (EtOAc); [R]25 -62.4 (c 0.60,
D
1
MeOH); H NMR (CDCl3-CD3OD 9:1) δ 7.00 (1H, d, J ) 8.4
Hz), 7.29 (3H, br s), 7.57 (2H, br s), 7.80 (1H, d, J ) 8.4 Hz),
8.15 (1H, br s); 13C NMR (CDCl3-CD3OD 9:1) δ 80.4 (C), 121.1
(CH), 125.7 (CH), 126.7 (CH), 128.7 (CH), 129.2 (CH), 131.5
(CH), 135.3 (C), 137.8 (C), 145.9 (C), 147.9 (C), 176.9 (C);
HRMS (EI) m/z 261.0185 (M+ - CO2H2, 33) (C13H8NO3Cl
requires 261.0193), 263 (10.2), 231 (11), 154 (17), 105 (100),
77 (39).
(R)-5-Meth yl-2-n itr oben zylic a cid (6i): 79% yield; pale
3-Meth oxy-4-n itr oben zop h en on e (7d ): 80% yield; oil; 1H
NMR (CDCl3) δ 3.98 (3H, s), 7.33 (1H, dd, J ) 8.4, 1.8 Hz),
7.47-7.52 (3H, m), 7.63 (1H, tt, J ) 7.8, 1.5 Hz), 7.78 (2H, dd,
J ) 7.8, 1.5 Hz), 7.85 (1H, d, J ) 8.4 Hz); 13C NMR (CDCl3) δ
56.8 (CH3), 114.5 (CH), 121.8 (CH), 125.1 (CH), 128.6 (CH),
130.0 (CH), 133.3 (CH), 136.4 (C), 141.8 (C), 142.3 (C), 152.7
(C), 194.6 (C); HRMS (EI) m/z 257.0681 (M+, 76) (C14H11NO4
requires 257.0688), 226 (2), 211 (2), 180(15), 105 (100), 77 (35).
4-Nitr o-3-tr iflu or om eth ylben zoph en on e (7e): 95% yield;
yellow powder; mp 162-169 °C (EtOAc); [R]25D -290.8 (c 0.73,
1
MeOH); H NMR (CDCl3) δ 2.24 (3H, s), 6.75 (1H, br s), 7.22
(1H, d, J ) 8.1 Hz), 7.38 (3H, m), 7.57 (2H, m), 7.76 (1H, d, J
) 8.1 Hz); 13C NMR (CDCl3) δ 21.6 (CH3), 80.0 (C), 125.3 (CH),
126.8 (CH), 128.6 (CH), 128.9 (CH), 129.8 (CH), 132.3 (CH),
136.2 (C), 138.7 (C), 144.0 (C), 146.7 (C), 175.7 (C); HRMS (EI)
m/z 242.0835 (M+ - CO2H, 66) (C14H12NO3 requires 242.0817),
208 (59), 180 (100), 164 (43), 152 (46), 105 (59), 77 (72).
(R)-5-Meth oxy-2-n itr oben zylic a cid (6j): 73% yield; oil;
1
[R]25 -245.9 (c 0.66, MeOH); 1H NMR (CDCl3) δ 3.64 (3H, s),
oil; H NMR (CDCl3) δ 7.53 (2H, t, J ) 7.5 Hz), 7.67 (1H, t, J
D
) 7.5 Hz), 7.77 (2H, d, J ) 7.5 Hz), 7.95 (1H, d, J ) 8.1 Hz),
8.08 (1H, dd, J ) 8.1, 1.0 Hz), 8.21 (1H, br s); 13C NMR (CDCl3)
δ 121.5 (C, q, J C-F ) 272.0 Hz,), 124.0 (C, q, J C-F ) 34.0 Hz),
125.0 (CH), 128.9 (CH), 129.2 (CH, q, J C-F ) 5.0 Hz), 130.1
(CH), 133.9 (CH), 134.2 (CH), 135.8 (C), 149.7 (C), 193.2 (C);
HRMS (EI) m/z 295.0459 (M+, 100) (C14H8NO3F3 requires
295.0456), 218 (8), 105 (100), 77 (26).
6.43 (1H, br s), 6.83 (1H, dd, J ) 9.2, 2.4 Hz), 7.36 (3H, br s),
7.57 (2H, br s), 7.95 (1H, d, J ) 9.2 Hz); 13C NMR (CDCl3) δ
55.7 (CH3), 80.2 (C), 113.0 (CH), 118.2 (CH), 126.8 (CH), 128.1
(CH), 128.6 (CH), 129.0 (CH), 138.5 (C), 139.5 (C), 141.8 (C),
162.9 (C), 175.5 (C); HRMS (EI) m/z 258.0773 (M+ - CO2H,
100) (C14H12NO4 requires 258.0766), 224 (23), 182 (45), 154
(21), 105 (30), 77 (40).
2-Me t h oxye t h oxym e t h oxym e t h yl-4-n it r ob e n zop h e -
n on e (7f): 65% yield; oil; 1H NMR (CDCl3) δ 3.31 (3H, s), 3.45
(2H, m), 3.57 (2H, m), 4.63 (2H, s), 4.70 (2H, s), 7.44-7.50 (3H,
m), 7.61 (2H, tt, J ) 7.6, 1.2 Hz), 7.74 (2H, dd, J ) 7.6, 1.2
Hz), 8.19 (1H, dd, J ) 8.4, 2.1 Hz), 8.43 (1H, d, J ) 2.1 Hz);
13C NMR (CDCl3) δ 58.9 (CH3), 66.4 (CH2), 67.2 (CH2), 71.6
(CH2), 95.4 (CH2), 122.1 (CH), 123.4 (CH), 128.7 (CH), 129.1
(CH), 130.0 (CH), 134.0 (CH), 136.2 (C), 139.6 (C), 143.3 (C),
(R)-2-Nitr o-4-tr iflu or om eth ylben zylic a cid (6k ): 84%
yield; yellow powder; mp 161-163 °C (EtOAc); [R]25 -222.1
D
(c 1.01, MeOH); 1H NMR (CDCl3-CD3OD 9:1) δ 7.12-7.14 (3H,
m), 7.18 (1H, d, J ) 8.4 Hz), 7.35-7.38 (2H, m), 7.43 (1H, d,
J ) 8.4 Hz), 7.72 (1H, br s); 13C NMR (CDCl3-CD3OD 9:1) δ
81.2 (C), 120.8 (CH, q, J C-F ) 3.5 Hz), 122.6 (C, q, J C-F ) 271.3
Hz), 126.9 (CH), 127.6 (CH, q, J C-F ) 3.5 Hz), 127.9 (CH), 128.0
(CH), 130.5 (C, q, J C-F ) 34 Hz), 133.1 (CH), 141.7 (C), 141.9
148.7 (C), 195.8 (C); HRMS (EI) m/z 345.1220 (M+, 0.2) (C18H19
-
(C), 149.3 (C), 176.5 (C); HRMS (EI) m/z 295.0437 (M+
CO2H2, 2) (C14H8NO3F3 requires 295.0456), 279 (40), 264 (89),
235 (44), 201 (45), 149 (68), 105 (65), 77 (100).
-
NO6 requires 345.1212), 299 (0.4), 270 (8), 240 (100), 194 (26),
165 (29), 105 (9), 77 (13).
2-Ch lor o-4-n itr oben zop h en on e (7g): 91% yield; oil; 1H
NMR (CDCl3) δ 7.51 (2H, t, J ) 7.5 Hz), 7.57 (1H, d, J ) 8.5
Hz), 7.66 (1H, t, J ) 7.5 Hz), 7.77 (2H, dd, J ) 7.5, 1.1 Hz),
8.24 (1H, dd, J ) 8.5, 2.0 Hz), 8.35 (1H, d, J ) 2.0 Hz); 13C
NMR (CDCl3) δ 121.9 (CH), 125.2 (CH), 128.9 (CH). 129.6
(CH), 129.9 (CH), 132.5 (C), 134.5 (CH), 135.2 (C), 144.4 (C),
148.8 (C), 193.2 (C); HRMS (EI) m/z 261.0182 (M+, 85) (C13H8-
NO3Cl requires 261.0193), 263 (29), 184 (20), 105 (100), 77 (34).
Hyd r oxyp h th a lid e (7h ): 77% yield from 4h ; oil; 1H NMR
(DMSO-d6) δ 7.33-7.41 (3H, m), 7.51 (2H, dd, J ) 8.1, 1.3 Hz),
7.57 (1H, d, J ) 8.4 Hz), 8.31 (1H, d, J ) 2.1 Hz), 8.38 (1H,
dd, J ) 8.4, 2.1 Hz), 9.71 (1H, s); 13C NMR (DMSO-d6) δ 87.6
(C), 118.1 (CH), 124.8 (CH), 125.9 (CH), 128.2 (CH), 128.7
(CH), 128.8 (CH), 132.4 (C), 141.0 (C), 148.9 (C), 156.6 (C),
166.5(C); HRMS (EI) m/z 253.0361 (M+ - H2O, 20) (C14H7NO4
requires 253.0376), 206 (11), 193 (30), 175 (11), 105 (16).
5-Meth yl-2-n itr oben zop h en on e (7i): 90% yield; mp 96-
97 °C (hexane-diethyl ether); 1H NMR (CDCl3) δ 2.48 (3H,
s), 7.24 (1H, d, J ) 1.0 Hz), 7.40-7.45 (3H, m), 7.56 (1H, tt, J
) 7.7, 1.0 Hz), 7.73 (2H, dd, J ) 7.7, 1.0 Hz), 8.12 (1H, d, J )
(R)-4-(N-Ben zoyl-N-m eth yla m in o)-2-n itr oben zylic a cid
1
(6m ): 70% yield; oil; [R]25 -164.3 (c 0.67, MeOH); H NMR
D
(CDCl3) δ 3.46 (3H, s), 6.76 (1H, d, J ) 8.6 Hz), 7.00 (1H, dd,
J ) 8.6, 2.0 Hz), 7.16-7.35 (8H, m), 7.49 (2H, br s), 7.56 (1H,
br s); 13C NMR (CDCl3) δ 38.3 (CH3), 79.6 (C), 122.0 (CH), 126.8
(CH), 128.2 (CH), 128.5 (CH), 128.7 (CH), 129.4 (CH), 130.5
(CH), 132.3 (CH), 134.1 (C), 134.4 (C), 139.4 (C), 144.9 (C),-
149.0 (C), 171.2 (C), 175.1 (C); HRMS (EI) m/z 360.1106 (M+
- CO2H2, 5) (C21H16N2O4 requires 360.1110), 344 (10), 328 (10),
105 (100), 77 (43).
Gen er a l P r oced u r e for th e Oxid a tive Deca r boxyla tion
of r-Hyd r oxy Acid Moiety. A solution of R-hydroxy acid 6
(0.22 mmol), Co(III)-Me2opba complex (5.3 mg, 0.013 mmol),
and pivalaldehyde (74 µL, 0.66 mmol) in 0.9 mL of acetonitrile
was stirred under an oxygen atmosphere until consumption
of the R-hydroxy acid 6 as indicated by TLC. Water was added,
the mixture was extracted with ethyl ether, and the organic
layer was washed with brine and dried. The reaction products
were purified by flash chromatography to give nitrobenzophe-
nones 7.
6828 J . Org. Chem., Vol. 69, No. 20, 2004

Diastereoselective Arylation of (S)-Mandelic Acid Enolate
8.5 Hz); 13C NMR (CDCl3) δ 21.5 (CH3), 124.5 (CH), 128.7 (CH),
129.1 (CH), 130.9 (CH), 133.7 (CH), 136.0 (C), 136.3 (C), 144.4
(C), 145.9 (C), 193.7 (C); HRMS (EI) m/z 241.0743 (M+, 25)
(C14H11NO3 requires 241.0739), 164 (31), 148 (100), 105 (87),
77 (37).
(CH), 128.6 (CH), 128.8 (CH), 129.1 (CH), 129.5 (CH), 130.7
(CH), 131.5 (CH), 133.9 (CH), 133.1 (C), 134.7 (C), 135.7 (C),
146.8 (C), 147.1 (C), 170.7 (C), 192.6 (C); HRMS (EI) m/z
360.1168 (M+, 22) (C21H16N2O4 requires 360.1110), 105 (100),
77 (37).
5-Meth oxy-2-n itr oben zop h en on e (7j): 88% yield; oil; 1H
NMR (CDCl3) δ 3.90 (3H, s), 6.86 (1H, d, J ) 2.7 Hz), 7.06
(1H, dd, J ) 9.1, 2.7 Hz), 7.42 (2H, td, J ) 7.5, 1.5 Hz), 7.56
(1H, tt, J ) 7.5, 1.5 Hz), 7.73 (2H, dd, J ) 7.5, 1.5 Hz), 8.22
(1H, d, J ) 9.1 Hz); 13C NMR (CDCl3) δ 56.2 (CH3), 113.3 (CH),
115.3 (CH), 127.0 (CH), 128.7 (CH), 139.1 (CH), 133.7 (CH),
135.7 (C), 138.8 (C), 139.3 (C), 164.2 (C), 193.2 (C); HRMS (EI)
m/z 257.0693 (M+, 47) (C14H11NO4 requires 257.0688), 211
(21.2), 180 (10), 105 (100), 77 (47).
2-Nitr o-4-tr iflu or om eth ylben zoph en on e (7k): 84% yield;
oil; 1H NMR (CDCl3) δ 7.45 (2H, t, J ) 7.5 Hz), 7.61 (1H, t, J
) 7.5 Hz), 7.63 (1H, d, J ) 8.0 Hz), 7.72 (2H, dd, J ) 7.5, 1.3
Hz), 8.02 (1H, d, J ) 8.0 Hz), 8.49 (1H, s); 13C NMR (CDCl3)
δ 121.9 (CH, q, J C-F ) 3.8 Hz), 122.5 (C, q, J C-F ) 271.0 Hz),
129.0 (CH), 129.3 (CH), 129.9 (CH), 130.8 (CH, q, J C-F ) 3.4
Hz), 133.0 (C, q, J C-F ) 34.0 Hz), 134.3 (CH), 135.2 (C), 139.4
(C), 146.7 (C), 191.9 (C); HRMS (EI) m/z 295.0457 (M+, 31)
(C14H8NO3F3 requires 295.0456), 218 (8), 202 (59), 172 (25),
105 (100), 77 (43).
2,4-Din itr oben zop h en on e (7n ): 63% yield from 4n ; yel-
low-orange powder; mp 146-147 °C (hexanes-EtOAc); 1H
NMR (CDCl3) δ 7.45 (2H, t, J ) 7.8 Hz), 7.62 (1H, tt, J ) 7.8,
1.6 Hz), 7.77 (2H, dd, J ) 7.8, 1.6 Hz), 7.86 (1H, d, J ) 8.1
Hz), 8.11 (1H, d, J ) 2.3 Hz), 8.65 (1H, dd, J ) 8.1, 2.3 Hz);
13C NMR (CDCl3) δ 110.1 (CH), 128.6 (CH), 128.9 (CH), 129.6
(CH), 130.3 (CH), 134.5 (CH), 136.4 (C), 142.0 (C), 149.0 (C),
160.5 (C), 194.0 (C); HRMS (EI) m/z 272.0453 (M+, 3.0)
(C13H8N2O5 requires 272.0433), 256 (42), 240 (26), 193 (29),
166 (39), 105 (79), 77 (100).
Ack n ow led gm en t. This work was financially sup-
ported by the Spanish Government (MCYT, project
BQU2001-3017) and by Generalitat Valenciana (AV-
CYT, Grupos 03/168).
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal methods description and H NMR and 13C NMR spectra of
4-(N-Ben zoyl-N-m et h yla m in o)-2-n it r ob en zop h en on e
(7m ): 56% yield; oil; 1H NMR (CDCl3) δ 3.58 (3H, s), 7.26-
7.39 (7H, m), 7.42 (2H, tt, J ) 7.2, 2.1 Hz), 7.57 (1H, tt, J )
7.2, 1.2 Hz), 7.65 (2H, dd, J ) 7.2, 1.5 Hz), 7.94 (1H, d, J )
2.1, Hz); 13C NMR (CDCl3) δ 38.2 (CH3), 121.5 (CH), 128.4
compounds 4a -n , 5b, 5i-m , 6a -g, 6i-k , 6m , 7a -k , and
7m -n . This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0402069
J . Org. Chem, Vol. 69, No. 20, 2004 6829