Mandelic Acid as Synthetic Equivalent of Benzoyl Carbanion. Synthesis of Nitrobenzophenones

Article abstract of DOI:10.1055/s-2003-42123

Nitrobenzophenones are prepared from a mandelic acid dioxolanone. The sequence starts with the aromatic nucleophilic substitution of the enolate of the dioxolanone onto p-fluoronitrobenzenes, followed by hydrolysis of the acetal moiety and oxidative decarboxylation of the resulting α-hydroxyacids. The whole sequence involves the use of mandelic acid as synthetic equivalent of the benzoyl carbanion.

Full text of DOI:10.1055/s-2003-42123

LETTER
2325
Mandelic Acid as Synthetic Equivalent of Benzoyl Carbanion. Synthesis of
Nitrobenzophenones
S
ynthesis of
N
itrob
o
enzophenon
n
es zalo Blay, Luz Cardona, Isabel Fernández, Raquel Michelena, José R. Pedro,* Teresa Ramírez,
Rafael Ruiz-García
Departament de Química Orgànica, Facultat de Química, Universitat de València, Dr. Moliner 50, 46100 Burjassot (València), Spain
Fax +34(96)3544328; E-mail: jose.r.pedro@uv.es.
Received 12 July 2003
The starting materials in our synthesis were commercially
Abstract: Nitrobenzophenones are prepared from a mandelic acid
available aromatic nitrocompounds having a leaving
dioxolanone. The sequence starts with the aromatic nucleophilic
group in either the ortho or para position with respect to
the nitro group.
substitution of the enolate of the dioxolanone onto p-fluoroni-
trobenzenes, followed by hydrolysis of the acetal moiety and oxida-
tive decarboxylation of the resulting a-hydroxyacids. The whole
sequence involves the use of mandelic acid as synthetic equivalent
of the benzoyl carbanion.
The aromatic nucleophilic substitution was first tested
with p-halonitrobenzenes in order to optimise the reaction
conditions (Scheme 2, Table 1). Compound 1 was depro-
tonated with a LDA solution at –78 °C in THF, and then
p-chloronitrobenzene 2a (X = Cl) was added to the result-
ing enolate solution. Under these conditions none of the
expected product was obtained (entry 1). Instead, com-
pound 6 was obtained in 40% yield and 30% of the start-
ing material was recovered. Compound 6 is the aldol
product of dioxolanone (1) and pivalaldehyde. The pres-
ence of pivalaldehyde in the reaction mixture is not com-
pletely clear, but since formation of compound 6 is only
Key words: acetals, nucleophilic aromatic substitutions, ketones,
oxygen, oxidations, decarboxylation
The presence of the benzophenone scaffold in the frame-
work of natural and synthetic compounds with important
physiological activities, such as antimalaria,1 antiinflam-
matory,2 anticancer3 or antibiotic,4 continues to spur syn-
thetic efforts regarding their preparation.5 Most of the
classical synthetic protocols for benzophenones involve
Friedel–Crafts benzoylations between an aromatic sub-
strate and an electrophilic reagent. These reactions are ca-
talysed by acidic catalysts (generally used in excess of
molar amounts) and do not proceed successfully with ar-
omatic substrates having electron-withdrawing groups.6
An alternative route involves the substitution on the arene
by the action of an appropriate nucleophilic species. Re-
cently, we have reported the use of different mandelic acid
derivatives as synthetic equivalents of benzoyl carban-
ion.7 In this communication we describe a new application
of this strategy in the synthesis of benzophenones 5. Our
synthesis started with aromatic nucleophilic substitution
of the enolate of (S,S)-dioxolanone (1) onto aromatic nitro
compounds 2, followed by hydrolysis of the acetal moiety
present in 3 and oxidative decarboxylation of the resulting
bis-aryl-a-hydroxyacids 4 (Scheme 1).
O
O
H
H
O
Ar
Ph
H
O
LDA
+
Ar-F
O
O
But
But
THF-HMPA
Ph
1
2
3
O
OH
Ar
HO2C
Ph
Co complex
1. KOH
2. H3O+
Ph
Ar
O2, pivalaldehyde
4
5
NO2
b Ar =
a Ar =
c Ar =
e Ar =
O2N
O2N
O2N
MeO
Me
Aromatic nucleophilic substitution with carbanions can
be achieved by a number of procedures, such as the nu-
cleophilic substitution to arene-transition metal carbonyl
complexes,8 transition metal catalysed aromatic nucleo-
philic substitution of aryl halides,9 and aromatic substitu-
tion via nucleophilic addition to electron-deficient arenes
(including vicarious10 and ipso11).
d Ar =
O2N
CF3
CH2OMEM
f Ar = O2N
NO2
Cl
h Ar = O2N
g Ar = O2N
SYNLETT 2003, No. 15, pp 2325–2328
0
1
.1
2
.2
0
0
3
Advanced online publication: 07.11.2003
DOI: 10.1055/s-2003-42123; Art ID: G17003ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

2326
G. Blay et al.
LETTER
Table 1 Reaction of 1,3-Dioxolan-4-one (1) with p-Halonitrobenzenes 2a
Entry
2a (X)
Solvent
THF
THF
THF
THF
THF
THF
DMF
Additive
Base
3a (Yield)
6 (Yield)
1
2
3
4
5
6
7
Cl
Cl
F
–
LDA
40% (30%)a
40%
HMPA (3 equiv)
HMPA (3 equiv)
HMPA (3 equiv)
HMPA (3 equiv)
LDA
30%
85%
27%
50%
LDA
Br
F
LDA
30%
t-BuLi
NaHMDS
NaH
b
F
–
F
35%
a Recovered 1 in brackets.
b Enolate decomposition.
observed after the addition of the nitrocompound, we oronitrobenzene (entry 4) and 2-trifluoromethyl-4-fluo-
believe that it most likely results from a redox process ronitrobenzene (entry 5). The reaction was also carried
between the enolate of 1 and the nitro group,11b,12 which out with p-fluoronitrobenzenes substituted in the ortho
would take place faster than the addition of the enolate to position with respect the fluorine atom in order to deter-
the aromatic ring (Scheme 2). As a matter of fact, the use mine possible steric effects (entries 6–8). Again, the reac-
of 3 equivalents of HMPA, an additive that increases the tion proceeded readily in all the cases, including the bulky
reactivity of enolates toward nucleophilic substitution,13 MEM-protected benzyl alcohol group (entry 6), without
allowed to obtain the desired product 3a in 30% yield, al- much influence of the electron-donating (entries 6 and 7)
though accompanied with 40% of 6 (entry 2). The forma- or electron-withdrawing (entry 8) features of the addition-
tion of compound 6 could be prevented only when p- al substituent.
fluoronitrobenzene 2a (X = F) was used as arylating re-
agent (entry 3) while the use of p-bromonitrobenzene 2a
(X = Br) did not provide satisfactory results (entry 4).
O2N
Ph
X
2a
O
O
H
The use of tert-butyllithium instead of LDA gave poorer
results. Sodium bases gave also disappointing results.
Thus, NaHDMS in THF (entry 6) brought about decom-
position of the enolate, even at –78 °C, while the combi-
nation NaH–DMF11b (entry 7) gave low yields of the
expected product. It was also observed the tendency of
compound 3a to decompose upon prolonged reaction
times or higher temperatures. Accordingly, a short reac-
tion time (5–10 min) and quenching at –78 °C was estab-
lished as the best experimental protocol. p-Cyano- and p-
trifluoromethyl fluorobenzenes were also tested as arylat-
ing reagents. However none of these electron-withdraw-
ing groups was able to induce nucleophilic substitution
with the enolate of 1 under the optimised conditions
(LDA–THF–HMPA).
H
H
H
O
O
Base
O
O
But
But
Ph
1
O
H
O
O
redox
SNAr
PhCOCO2
O
O
But
But
Ph
enolate
aldol reaction
OH
3a
O
H
O
But
O
But
Ph
6
Scheme 2
The nucleophilic aromatic substitution reaction with the
enolate of 1 was carried out with a number of fluoroni-
trobenzenes 2 under similar conditions (Table 2). In the
case of o-fluoronitrobenzene (2b) (entry 2) the reaction
proceeded but only with modest yield. Therefore we cen-
tered our study with p-substituted fluoronitrobenzenes.
The presence of an additional group on the aromatic ring
was also studied. When this group was in meta position
respect the fluorine atom, the reaction worked well re-
gardless of its electronic nature. Thus, fair to good yields
of the corresponding compounds 3 were obtained with 2-
methyl-4-fluoronitrobenzene (entry 3), 2-methoxy-4-flu-
Although irrelevant for the synthesis of benzophenones, it
is worth remarking that the nucleophilic aromatic substi-
tution reaction here described is completely diastereose-
lective, the nitro aromatic ring being exclusively
introduced anti to the t-butyl group of the dioxolanone
ring.16
The next step in the synthetic sequence was the cleavage
of the acetal moiety, which was achieved upon basic hy-
drolysis with ethanolic KOH and reprotonation to give the
corresponding hydroxyacids 4, with good yields. In the
case of the dinitroderivative 3h, benzophenone 5h was
Synlett 2003, No. 15, 2325–2328 © Thieme Stuttgart · New York

LETTER
Synthesis of Nitrobenzophenones
2327
Nucleophilic Substitution.18 A solution of dioxolanone (S,S)-116a
(220 mg, 1 mmol) in 1.5 mL of dry THF was added to a –78 °C pre-
cooled solution prepared from 0.625 mL of a 2 M commercial solu-
tion 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
p-fluoronitrobenzene (2a, 0.133 mL, 1.25 mmol) in 0.5 mL of THF
was added dropwise, and 10 min after, the reaction was quenched
with the addition of 2–3 drops of H2O and silica gel. Once the mix-
ture reached r.t., the solvent was removed and the resulting powder
chromatographed on silica gel to give compound 3a (291 mg, 85%):
oil; [a]D25 +44.1 (c 2.60, CHCl3). MS (EI): m/z (%) = 297 (100) [M+
– CO2], 280 (30), 228 (48), 211 (58), 165 (58). HRMS found
Table 2 Synthesis of Nitrobenzophenones 5 from Dioxolanone (1)
and Fluoronitrobenzenes 2
Entry
2 (X = F)
3 (Yield)
85%
4 (Yield)
94%
78%
87%
93%
64%
80%
81%
–
5 (Yield)
82%a
90%a
87%b
80%b
95%
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
37%
82%
75%
1
75%
297.1374, C18H19NO3 required 297.1365. H NMR (CDCl3): d =
1.00 (9 H, s), 5.13 (1 H, s), 7.27 (3 H, m), 7.36 (2 H, m), 7.72 (2 H,
d, J = 9.0 Hz), 8.17 (2 H, d, J = 9.0 Hz). 13C NMR (CDCl3): d = 23.6
(q), 34.0 (s), 83.7 (s), 108.3 (d), 124.1 (d), 126.3 (d), 127.5 (d),
128.7 (d), 129.0 (d), 137.8 (s), 143.8 (s), 148.2 (s), 171.1 (s).
80%
65%
2g
2h
66%
91%
90%
63%c,d
Cleavage of the Acetal Moiety.18 Compound 3a (170 mg, 0.5
mmol) was treated with 5% ethanolic KOH (1.1 mL, 1 mmol) at r.t.
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, the organic layers
washed with brine, dried, filtered and concentrated under reduced
pressure to give compound 4a (128 mg, 94%): oil; [a]D25 –45.6 (c
0.84, MeOH). MS (EI): m/z (%) = 227 (25) [M+ – CO2H2], 197 (12),
150 (7). HRMS found 227.0566, C13H9NO3 required 227.0582. 1H
NMR (CDCl3): d = 7.10 (2 H, br s), 7.37 (5 H, br s), 7.66 (2 H, d,
J = 8.5 Hz), 8.14 (2 H, d, J = 8.5 Hz). 13C NMR (CDCl3): d = 80.7
(s), 123.2 (d), 126.9 (d), 128.6 (d), 128.7 (d), 129.0 (d), 140.6 (s),
147.7 (s), 147.8 (s), 176.9 (s).
a Identical to a commercially available sample.
b Ref.14
c Ref.15
d Product obtained during hydrolysis of 3h.
directly obtained from the reaction mixture. In this case,
the presence of two strongly electron-withdrawing nitro
groups facilitates decarboxylation of the a-hydroxyacid
4h because of mesomeric stabilisation by the nitro groups
at ortho and para positions of the resulting hydroxybenzyl
carbanion, which is then oxidised by oxygen to ketone 5h
under the hydrolysis conditions.11c,17
Oxidative Decarboxylation of a-Hydroxyacids.18 A solution of a-
hydroxyacid 4a (60 mg, 0.22 mmol), Co(III) complex 7 (5.3 mg,
0.013 mmol) and pivalaldehyde (74 mL, 0.66 mmol) in 0.9 mL of
acetonitrile was stirred under an oxygen atmosphere until consump-
tion of the a-hydroxyacid 4a as indicated by TLC. Water was add-
ed, the mixture extracted with Et2O, and the organic layer washed
with brine and dried. The reaction products were purified by flash
chromatography to give nitrobenzophenones 5a (40 mg, 82%): oil;
MS (EI): m/z (%) = 227 (63) [M+], 150 (15), 105 (100). HRMS
found 227.0527, C13H9NO3 required 227.0582. 1H NMR (CDCl3) d
= 7.51 (2 H, t, J = 8.0 Hz), 7.64 (1 H, t, J = 8.0 Hz), 7.78 (2 H, d,
For the decarboxylation of the rest of the hydroxyacids 4
we used a catalytic system developed in our laboratory
which employs oxygen as terminal oxidant in the presence
of pivalaldehyde and a catalytic amount of a Co(III) com-
plex 7 (Figure 1).7 Under these conditions, benzophe-
nones
5 were obtained with good yields from
hydroxyacids 4.
J = 8.0 Hz), 7.91 (2 H, d, J = 8.5 Hz), 8.31 (2 H, d, J = 8.5 Hz). 13
C
In summary, we present here a new method for the synthe-
sis of nitrobenzophenones. The overall sequence eventu-
ally involves mandelic acid as an ‘umpoled’ equivalent of
the benzoyl anion, and it is an alternative to the electro-
philic Friedel–Crafts benzoylation of electron-deficient
nitrobenzenes which normally does not work well. It is
also convenient to note that, unlike in the Friedel–Craft
reaction, in this case the carbonyl group is provided by the
nucleophilic component of the reaction.
NMR (CDCl3) d = 123.5 (d), 128.7 (d), 130.1 (d), 130.7 (d), 133.5
(d), 136.3 (s), 142.9 (s), 149.8 (s), 194.8 (s).
Acknowledgement
This work was financially supported by the Spanish Government
(MCYT, project BQU 2001-3017) and in part by Generalitat Valen-
ciana. RR (Ramón y Cajal program) thanks MCYT for a grant.
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Synlett 2003, No. 15, 2325–2328 © Thieme Stuttgart · New York

2328
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LETTER
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Synlett 2003, No. 15, 2325–2328 © Thieme Stuttgart · New York