On the mechanism of the dimethyldioxirane oxidation of σ(H) adducts (Meisenheimer complexes) generated from nitroarenes and carbanions

Article abstract of DOI:10.1021/jo9915628

The mechanism of the novel dimethyldioxirane (DMD) oxidation of σ(H) adducts (Meisenheimer complexes) generated from nitroarenes and carbanions was elucidated. The proposed mechanism, which is akin to that of the oxidative Nef reaction, is supported by the isolation of the cyclohexadienone intermediate and the lack of a primary kinetic isotopic effect. Protic solvents (H₂O, MeOH) enhance the reactivity of DMD through intermolecular hydrogen bonding.

Full text of DOI:10.1021/jo9915628

J . Org. Chem. 2000, 65, 1099-1101
1099
On th e Mech a n ism of th e Dim eth yld ioxir a n e Oxid a tion of σH
Ad d u cts (Meisen h eim er Com p lexes) Gen er a ted fr om Nitr oa r en es
a n d Ca r ba n ion s
Waldemar Adam,*,†,‡ Mieczyslaw Makosza,*,§,| Cong-Gui Zhao,† and Marek Surowiec§
Institute of Organic Chemistry, University of Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany, and
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/ 52, 01-224 Warsaw, Poland
Received October 7, 1999
The mechanism of the novel dimethyldioxirane (DMD) oxidation of σH adducts (Meisenheimer
complexes) generated from nitroarenes and carbanions was elucidated. The proposed mechanism,
which is akin to that of the oxidative Nef reaction, is supported by the isolation of the
cyclohexadienone intermediate and the lack of a primary kinetic isotopic effect. Protic solvents
(H2O, MeOH) enhance the reactivity of DMD through intermolecular hydrogen bonding.
Sch em e 1. Dim eth yld ioxir a n e (DMD) Oxid a tion
of th e σH Ad d u cts Gen er a ted fr om Nitr oa r en es a n d
2-P h en ylp r op ion itr ile Ca r ba n ion
In tr od u ction
Nucleophiles add reversibly to the unsubstituted para
and ortho positions of nitroarenes to give anionic σH
adducts (Meisenheimer complexes).1 These σH adducts
may be converted into products of nucleophilic replace-
ment of hydrogen in several ways, of which the most
important are oxidation and vicarious nucleophilic sub-
stitution.1,2 For example, when the relatively long-lived
σH adducts 3, generated in situ from the nitroarenes 2
and the carbanion of 2-phenylpropionitrile (1) in liquid
ammonia at -70 °C, are treated with potassium per-
manganate, the substituted nitroarenes 4 are obtained
in high yields as the sole products.3 In contrast, when
the in-situ-generated σH adducts 3 in DMF-THF are
submitted to dimethyldioxirane (DMD) oxidation, the
substituted phenols 5 are formed as the major products;4
the previously3 observed nitroarenes 4 are formed in
small, if any amount (Scheme 1). This unprecedented
reaction constitutes the first direct synthesis of substi-
tuted phenols from nitroarenes, a novel oxidation of
preparative convenience for the synthesis of arenols,
which otherwise are cumbersome to obtain.
Sch em e 2. P r op osed Mech a n ism for DMD
Oxid a tion of σH Ad d u cts
To date, little if anything is known on the mechanism
of the unprecedented DMD oxidation of the σH adducts
3 to the corresponding phenols 5. On one hand, the
suggestion4 that the phenols 5 may arise from the
corresponding cyclohexadienone intermediate through
oxidative Nef reaction5 requires verification; on the other
hand, the pronounced water effect in enhancing the
efficiency of this oxidation process demands rationaliza-
tion.4 The present paper addresses these aspects and
provides experimental evidence for the mechanism of the
DMD oxidation of σH adducts proposed in Scheme 2.
* To whom correspondence should be addressed.
† University of Wu¨rzburg.
‡ Fax: +49-931-8884756; e-mail: adam@chemie.uni-wuerzburg.de;
http://www-organik.chemie.uni-wuerzburg.de.
§ Polish Academy of Sciences.
Resu lts a n d Discu ssion
Fax: +22-632 66 81; E-mail: icho-s@ichf.edu.pl.
(1) Makosza, M. Pol. J . Chem. 1992, 66, 3-23. (b) Makosza, M. Russ.
Chem. Bull. 1996, 45, 491-500. (c) Terrier, F. Nucleophilic Aromatic
Displacement; VCH: Weinheim, 1991.
(2) Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C.
Nucleophilic Aromatic Substitution of Hydrogen; Academic Press: San
Diego, 1994. (b) Makosza, M.; Winiarski, J . Acc. Chem. Res. 1987, 20,
282-289. (c) Makosza, M.; Wojciechowski, K. Liebigs Ann. Recueil
1997, 1805-1816.
(3) Makosza, M.; Stalinski, K.; Klepka, C. J . Chem. Soc., Chem.
Commun. 1996, 837-838. (b) Makosza, M.; Stalinski, K. Chem. Eur.
J . 1997, 3, 2025-2031.
(4) Adam, W.; Makosza, M.; Stalinski, K.; Zhao, C.-G. J . Org. Chem.
1998, 63, 4390-4391.
Isola tion of th e Cycloh exa d ien on e In ter m ed ia te.
To test the suggestion that the phenolic products 5 arise
from tautomerization of the corresponding 2,5-cyclohexa-
dienones,4 the para position in the starting nitroarene
should be blocked, to afford a cyclohexadienone which
should persist and become isolable. For this purpose,
p-nitrotoluene (2b) was chosen as the substrate, but
(5) Noland, W. E. Chem. Rev. 1955, 55, 137-155. (b) Pinnick, H.
W. Org. React. 1990, 38, 655-792.
10.1021/jo9915628 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/28/2000

1100 J . Org. Chem., Vol. 65, No. 4, 2000
Adam et al.
Ta ble 1. P r otic Solven t Effects on th e DMD a n d TF D
Oxid a tion of th e σH Ad d u ct 3a , Gen er a ted fr om
Nitr oben zen e (2a ) a n d th e 2-P h en ylp r op ion itr ile
Ca r ba n ion a
Sch em e 3. DMD Oxid a tion of σ Ad d u cts
Gen er a ted fr om 4-Nitr otolu en e a n d Bu Li
yield (%)b
H2O or MeOH
(equiv)
mass balance
(%)
entry
nitroarene 4a arenol 5a
1
0
0
6
47
traces
77
83
33
63
38
32
86
54d
91
100
84
2c
3e
4f
5e
6f
7h
8h
traces
4
6
5
4
10
9
1.0
1.0
1.0g
1.0g
0
90
unfortunately, it does not form sufficiently stable σH
adducts with the model carbanion of 1. Oxidation of a
mixture of 1 and 2b in liquid ammonia with KMnO4 gave
only 2,3-diphenyl-2,3-dicyanobutane, a product of the
oxidative dimerization of 1.3b Also the oxidation of such
mixture with DMD in THF-DMF did not give the
expected product. Presumably the desired σH adduct was
not formed due to steric reasons.
53i
49i
1.0
a
t
With 1.0 mmol of 1, 1.0 mmol of 2a , 1.1 mmol of BuOK, and
1.2 mmol of DMD in DMF/THF (1:20) under argon gas at -70 °C;
DMD solution was predried two times over fresh molecular sieves
b
for 2 days each. Yields of isolated materials after chromatogra-
phy. c DMD was dried over P2O5 and then over K2CO3. Poor mass
d
balance due to low recovery of 1. e H2O (MeOH) was added first
to the reaction mixture and 5 min later the DMD solution. f DMD
was added first to the reaction mixture and 5 min later the H2O
It is known from Bartoli’s work6 that the Grignard
reagents form relatively stable σH adducts with nitro-
arenes, which give alkylated nitroarenes when oxidized
with KMnO4. Analogously, in accord with the results of
Kienzle,7 we have found that alkyllithium reagents also
can add to nitroarenes; moreover, the latter σH adducts
may be oxidized by DMD to phenols.8 When p-nitrotolu-
ene (2b) was treated with BuLi and then oxidized with
DMD, indeed, cyclohexadienone 6 was isolated in a
modest yield (16%), along with 7% phenol 7 (Scheme 3).
The isolation of the cyclohexadienone 6 confirms that the
analogous intermediate C (Scheme 2) is the primary
product of this oxidation reaction, which subsequently
is tautomerized to the corresponding phenol.
Additional experimental evidence for the cyclohexa-
dienone intermediate provides the lack of a kinetic
isotope effect (KIE). A kH/kD value of 1.01 ( 0.01 was
found in the competitive DMD oxidation of the σH
adducts, generated from nitrobenzene and 4-deuterio-
nitrobenzene with the carbanion of 2-phenylpropionitrile.
Since the products of oxidation of σH and σD adducts are
identical, the mixture of recovered nitrobenzene and
deuteronitrobenzene was analyzed. The lack of a primary
kinetic isotope effect indicates that the C-H bond at the
para position remains intact during the oxidation. In
contrast, the KMnO4 oxidation of this σH adduct in liquid
g
h
(MeOH). MeOH was added instead of water.
1.2 mmol of
(trifluoromethyl)methyldioxirane (TFD) was added instead of
DMD.i Poor mass balance due to formation of some unidentified
products.
by Pb(OAc)4 gave 10,10-dialkylanthrones.10 Consequently,
DMD has been demonstrated herein as a good oxidant
for the oxidative Nef reaction,11 which establishes the link
between these two seemingly distinct reactions.
Th e Wa ter Effect on th e Oxid a tion P r ocess. The
results of the pronounced water effect in enhancing the
yield of the phenol product in the DMD oxidation of σH
adducts 34 are collected in Table 1. Oxidation of 3a with
a solution of DMD in acetone, prepared according to the
standard procedure,12 gave the phenol in a moderate yield
of 47% (entry 1). When 1 equiv of water was added to
the reaction mixture, either before or after the addition
of DMD, the yield of phenol 5a was almost doubled
(entries 3 and 4). When a rigorously dry DMD solution
was employed, the yield of the phenol diminished dra-
matically (entry 2). A similar water effect has also been
observed in the DMD oxidation of nitronate anions
(prepared by deprotonation of nitroalkanes) to carbonyl
products (the oxidative Nef reaction).11
One possible reason for the observed water effect is
that the σH adducts 3 might react with water to form the
protonated intermediate 3(H+), which could be more
ammonia at -70 °C displays a large KIE value (kH/kD
)
9.9), which indicates that CH-bond breaking is the rate-
limiting step.9 Thus, the slow step of the present DMD
oxidation is the formation of the cyclohexadienone inter-
mediate, which subsequently tautomerizes to the phenol.
Since the σH adducts 3 may be regarded as cyclohexa-
diene nitronate anions, this transformation is akin to the
oxidative Nef reaction,5 in which the nitronate anion
derived from a nitroalkane is converted to a carbonyl
group. For example, the formation of 4,4-disubstituted
cyclohexadienones was already observed, when the para
σH adducts of MeMgBr or BuMgBr with p-nitrotoluene
were acidified with aqueous HCl.6 Similarly, the addition
of an alkylmagnesium halide to 10-alkyl-9-nitroanthra-
cene and subsequent oxidation of the resulting σH adducts
prone to oxidation than the anion 3. To clarify this
possibility, the DMD oxidation of benzophenone oxime
(8) was conducted under neutral and basic conditions as
a model reaction (Scheme 4).
While the oxime 8 itself resisted oxidation by DMD to
benzophenone, in the presence of t-BuOK, a quantitative
conversion was achieved. Consequently, it appears that
the oxime anion 8- is oxidized first to the nitronate anion
(6) Bartoli, G.; Bosco, M.; Pezzi, G. J . Org. Chem. 1978, 43, 2932-
(10) Armillotta, N.; Bartoli, G.; Bosco, M.; Dalpozzo, R. Synthesis
1982, 836-839.
2933.
(7) Kienzle, F. Helv. Chim. Acta 1978, 61, 449-452.
(8) Adam, W.; Makosza, M.; Zhao, C.-G.; Surowiec, M. Unpublished
results.
(9) Makosza, M.; Stalinski, K. Tetrahedron Lett. 1998, 39, 3575-
3576.
(11) Adam, W.; Makosza, M.; Saha-Mo¨ller, C. R.; Zhao, C.-G. Synlett
1998, 1335-1336.
(12) Murray, R. W.; J eyaraman, R. J . Org. Chem. 1985, 50, 2847-
2853. (b) Adam, W.; Bialas, J .; Hadjiarapoglou, L. P. Chem. Ber. 1991,
124, 2377.

DMD Oxidation of σH Adducts from Nitroarenes and Carbanions
J . Org. Chem., Vol. 65, No. 4, 2000 1101
Sch em e 4. DMD Oxid a tion of th e Ben zop h en on e
Oxim e An ion
proved to be disadvantageous. Although the conversions
of the substrates were very high (>90%), the yields of
phenol 5a were low (32-38%), irrespective of whether
water was added or not (Table 1, entries 7 and 8).
Therefore, the DMD oxidation of the σH adducts 3 is a
chemoselective reaction, presumably because DMD pref-
erentially reacts with the more electron-rich CdN double
bond to give the cyclohexadienone. In contrast, the much
more reactive TFD apparently also oxidizes the cyclo-
hexadienone double bonds in the σH adduct 3, which leads
to a complex mixture of undefined products. The inherent
high reactivity of TFD is presumably also responsible
why no assistance by water is necessary.
Mech a n ism of DMD Oxid a tion of σH Ad d u cts. On
the basis of the above facts, we propose that the mech-
anism in Scheme 2 operates in the DMD oxidation of σH
adducts. On account of the enhanced reactivity through
hydrogen bonding with water, DMD oxidizes the σH
adducts 3 to the transient species A or B in the rate-
limiting step. Elimination of a nitrite ion (the nitrite ion
is expected to be oxidized to the nitrate ion under the
reaction conditions and does not accumulate for detec-
tion) from the A or B intermediates affords cyclohexa-
dienone C, which tautomerizes to the more stable phenols
5. This mechanism is analogous to that of the oxidative
9 and subsequently to benzophenone; in contrast, the
protonated nitronate 9(H+) survives further oxidation by
DMD. In view of the similarity between the oxidized
oxime species 9 and 9(H+) and the σH adducts 3 and
3(H+), these results suggest that the nitronate anion 3
(the σH adduct) and not the protonated intermediate
3(H+) is the likely species to be oxidized in the DMD
reaction of σH adducts. Additionally, the oxidation of the
protonated σH adduct 3(H+) is also ruled out because the
use of aqueous NH4Cl instead of water inhibits the DMD
oxidation. The possibility that water intervenes after the
oxidation step is discounted by the lack of a primary
kinetic isotope effect, which establishes that the removal
of the para hydrogen atom is not the rate-limiting step,
but presumably the oxidation of the σH adduct 3 to the
cyclohexadienone intermediate.
It is well-known in the literature that the protic
solvents water and MeOH accelerate DMD oxidations
through hydrogen bonding with the dioxiranes.13 Since
the σH adduct 3 is stabilized through conjugation, it is
quite resistant against oxidation by DMD. Water, how-
ever, enhances the reactivity of DMD through hydrogen
bonding and thus facilitates the oxidation process, and
the phenol yield is increased by circumvention of side
reactions of the σH adduct. Also MeOH serves as promoter
of this oxygen transfer, since the addition of 1.0 equiv of
MeOH (Table 1, entry 6) after DMD afforded a good yield
(63% versus 83% in H2O) of the phenol 5a (Table 1, entry
6); however, unlike in the case of water, the reverse
addition showed no effect for MeOH (Table 1, entry 5).
The use of the much more reactive (ca. 600 to 1000-
fold)14 methyl(trifluoromethyl)dioxirane (TFD) as oxidant
Nef reaction with KMnO4 or DMD11 as oxidants;
15
however, while KMnO4 has been successfully employed
in the Nef reaction to convert nitronate anions to carbonyl
products,15 in the present case it converts σH adducts 3
to the nitroarenes 4 instead of the arenols 5.3 Thus, the
DMD oxidation of the σH adducts of nitroarenes 2 to the
corresponding phenols is a unique process of preparative
value in aromatic substitution chemistry.
Ack n ow led gm en t . Generous financial support of
the Deutsche Forschungsgemeinschaft (Schwerpunkt-
programm: Peroxidchemie) and the Fonds der Chemis-
chen Industrie is appreciated. C.-G. Zhao thanks the
DAAD (Deutscher Akademischer Austauschdienst) for
a doctoral fellowship. M. Makosza thanks the Alex-
ander-von-Humboldt Foundation for a research award
to initiate these studies. We are grateful to the Peroxid-
Chemie GmbH (Ho¨llriegelskreuth, Germany) for a
generous gift of Curox (potassium monoperoxysulfate).
Su p p or tin g In for m a tion Ava ila ble: Experimental sec-
tion and GC-MS spectra. This material is available in the
Internet under http://pubs.acs.org.
(13) Baumstark, A. L.; Vasquez, P. C. J . Org. Chem. 1988, 53, 3437-
3439. (b) Murray, R. W.; Gu, D. J . Chem. Soc., Perkin Trans. 2 1993,
2203-2207. (c) Murray, R. W.; Gu, D. J . Chem. Soc., Perkin Trans. 2
1994, 451-453. (d) Adam, W.; Smerz, A. K. Tetrahedron 1995, 51,
13039-13044. (e) Adam, W.; Smerz, A. K. J . Org. Chem. 1996, 61,
3506-3510. (f) Buxton, P. C.; Ennis, J . N.; Marples, B. A.; Waddington,
V. L.; Boehlow, T. R. J . Chem. Soc., Perkin Trans. 2 1998, 265-268.
For a theoretical study see (g) Miaskiewicz, K.; Teich, N. A.; Smith,
D. A. J . Org. Chem. 1997, 62, 6493-6497.
J O9915628
(14) Adam, W.; Asensio, G.; Curci, R.; Gonza´lez-Nu´n˜ez, M. E.; Mello,
R. J . Org. Chem. 1992, 57, 953-955. (b) Murray, R. W.; J eyaraman,
R.; Mohan, L. J . Am. Chem. Soc. 1986, 108, 2470-2472.
(15) Schechter, H.; Williams, F. T., J r. J . Org. Chem. 1962, 27,
3699-3701.