N-hydroxyphthalimide/cobalt(II) catalyzed low temperature benzylic oxidation using molecular oxygen

Article abstract of DOI:10.1016/S0040-4020(00)00679-7

A variety of (substituted) aryl glyoxylates is formed in good to excellent yield under very mild conditions by direct oxidation of the corresponding arylacetic esters or mandelic acid esters with molecular oxygen and N-hydroxyphthalimide/cobalt(II) acetate as catalyst. Heteroaromatic analogs are more difficult to oxidize with this system. The effect of substitution in the aromatic ring of N-hydroxyphthalimide on the oxidation of ethylbenzene has been studied. Electron withdrawing substituents accelerate the oxidation of ethylbenzene and promote the formation of acetophenone. Electron donating substituents lead to decreased rates of oxidation and enhance the selectivity for 1-phenylethanol. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00679-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7797±7803
N-Hydroxyphthalimide/Cobalt(II) Catalyzed Low Temperature
Benzylic Oxidation Using Molecular Oxygen
Bastienne B. Wentzel,a Maurice P. J. Donners,a,b Paul L. Alsters,b Martinus C. Feitersa and
Roeland J. M. Noltea,
*
aDepartment of Organic Chemistry, NSR Center, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
bDSM Research, LS-CC, P.O. Box 18, 6160 MD Geleen, The Netherlands
Received 26 May 2000; revised 10 July 2000; accepted 27 July 2000
AbstractÐA variety of (substituted) aryl glyoxylates is formed in good to excellent yield under very mild conditions by direct oxidation of
the corresponding arylacetic esters or mandelic acid esters with molecular oxygen and N-hydroxyphthalimide/cobalt(II) acetate as catalyst.
Heteroaromatic analogs are more dif®cult to oxidize with this system. The effect of substitution in the aromatic ring of N-hydroxyphthalimide
on the oxidation of ethylbenzene has been studied. Electron withdrawing substituents accelerate the oxidation of ethylbenzene and
promote the formation of acetophenone. Electron donating substituents lead to decreased rates of oxidation and enhance the selectivity
for 1-phenylethanol. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
required in order to obtain acceptable selectivities. Such low
conversion processes are generally best carried out in
dedicated, continuous plants commonly found in the bulk
industry, but they are rarely compatible with the batch
production facilities that are common in the ®ne-chemical
industry. Thus, within the ®ne-chemical industry there is a
need for selective, high conversion dioxygen based oxy-
functionalizations that can be operated under mild
conditions.
The selective oxidation of organic substrates using dioxy-
gen (molecular oxygen) as the ultimate oxidant is a very
important synthetic and industrial goal. With respect to its
use in the manufacture of organic chemicals, catalytic
oxidation with dioxygen traditionally holds a very promi-
nent place in the petrochemical industry, where it is by far
the most important technology for the upgrading of hydro-
carbons.1 The dominant position of dioxygen as the oxidant
for bulk chemical oxy-functionalizations is due to the fact
that it is the only economically and environmentally feasible
oxidant for large scale processing. In contrast, even though
dioxygen is ideal from an economic and environmental
point of view and the need for the development of sustain-
able processes steadily increases, the ®ne-chemical business
is still heavily dependent on stoichiometric oxidants, such
as permanganate and dichromate. One of the reasons for
the lack of ®ne-chemical applications of catalytic oxy-
functionalizations is that the high molecular complexity of
®ne-chemical substrates is usually not compatible with the
rather forcing reaction conditions (high temperature and
pressure) required for traditional oxidations with dioxygen.
These processes are generally not very selective and accord-
ingly only suitable for the oxidation of relatively simple
substrates. Another problem associated with traditional
dioxygen oxidations which hampers its application in ®ne-
chemical manufacture is the low conversion that is usually
Recently, an ef®cient catalytic method for the low-tempera-
ture oxygenation of organic substrates with dioxygen was
developed by Ishii et al.2 using N-hydroxyphthalimide
(2-hydroxy-1H-isoindole-1,3-dione, NHPI, 1a) as a catalyst
and a metal salt as co-catalyst. With this system, organic
compounds containing suf®ciently reactive C±H bonds, e.g.
(cyclic) alkanes,3 sulfoxides,4 alkylbenzenes5 and aromatic
compounds containing benzylic functions2,6 have been
oxidized at moderate temperatures up to high conversion.
Keywords: oxidation; catalysis; N-imides; cobalt.
* Corresponding authors. Tel.: 131-24-365-2676; fax: 131-24-365-2929;
e-mail: nolte@sci.kun.nl
The cobalt salt/NHPI system of Ishii resembles the classical
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00679-7

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B. B. Wentzel et al. / Tetrahedron 56 (2000) 7797±7803
molecular oxygen were used in combination with hexa-
methylphosphoric triamide (HMPA) in THF to obtain the
corresponding glyoxylate in 63% yield, with concomitant
formation of 14% of the hydroxyketone. Finally, oxidations
of arylacetic esters to arylglyoxylic esters using hydro-
peroxides instead of molecular oxygen in combination
with for example a vanadium catalyst have been reported
in the literature.10 The yields of these oxidations vary from
24% (p-nitro substituted) to 88% (p-methoxy substituted)
glyoxylate.
Figure 1. Classical cobalt/bromide oxidation versus NHPI mediated oxida-
tion of hydrocarbons.
Co/Br2 catalyzed oxidation of hydrocarbons1 in the sense
that under oxidative conditions, NHPI is converted into its
corresponding radical phthalimide-N-oxyl (PINO 2), which,
like bromine atoms formed from bromide in the Co/Br
system, is able to abstract hydrogen from C±H bonds,
thus propagating the radical oxidation chain (Fig. 1).
However, in contrast to bromide catalysis, N-hydroxyphtha-
limide-based oxidation catalysis offers the possibility to
tune the catalyst performance by modifying NHPI via
introduction of substituents on the aryl ring. We have
investigated this possibility and report our ®ndings here.
In this paper, the oxidation of a variety of substrates
catalyzed by NHPI and cobalt(II) is described, followed
by a study in which different substituted NHPI catalysts
are tested. We end with a discussion of the reaction
mechanism.
Results
Oxidation of arylacetic esters
We investigated the aerobic oxidation of a range of arylacetic
esters, using NHPI/cobalt(II) acetate (Co(OAc)2´4H2O) as
the catalytic system. The results are presented in Table 1. It
can be seen from this table that the benzylic position of
arylacetic esters can be oxidized very ef®ciently. Remark-
ably, the conversion and selectivity towards glyoxylate
exceed those obtained with the NHPI/Co(acac)2 aided
system used by Matsunaka et al.8 It is important to note
that, while the reaction time is longer, the temperature is
much lower in our case (40 instead of 808C).
In addition to studying variations of the NHPI catalyst, we
wished to study different substrates in order to investigate
the scope and limitations of the oxidation procedure. We
started our research by studying the oxidation of substrates
that are challenging for industrial purposes such as benzylic
oxidation of phenylacetic esters and heteroaromatic
compounds. Around 1950 the preparation of phenyl-
glyoxalic acid by oxidation of methyl phenylacetate with
air and with the aid of a cobalt(II) salt, at 1108C was
reported in the Russian literature. After 36 h 86% of the
glyoxylate was obtained.7 Only very recently was NHPI in
combination with dioxygen used to oxidize ethyl phenyl-
acetate to ethyl phenylglyoxylate (ethyl 2-oxophenyl-
acetate).8 With n-Bu4NBr as additive, moderate
conversions (65%) were achieved. With bis(acetylaceto-
nato)cobalt(II) (Co(acac)2), a low conversion was reported.
Only one other example in which an arylacetate is oxidized
using molecular oxygen is known in the literature, viz. in
one of the steps of the synthesis of (^)-clavizepine.9 To
oxidize ethyl 2-[2(benzyloxy)phenoxy]-4,5-dimethoxy-
phenylacetate, lithium diisopropylamine (LDA) and
Yoshino et al. have investigated the possible in¯uence of
aryl substituents on the reactivity of the substrate.5 In the
reaction of substituted toluenes with 5% NHPI, 0.5% CoII
and molecular oxygen, they found that a p-Cl substituent
retards the oxidation with respect to unsubstituted toluene
(47% conversion after 24 h instead of 52%), whereas a
p-methoxy substituent greatly accelerates it (89% con-
version after 24 h). As can be seen in Table 1, also in this
study an electron donating substituent such as a methoxy
group at the para position of the substrate is shown to have a
positive effect on the yield of glyoxylate (entry 2 versus
entry 5). It is interesting to note that oxidation of 5a using
3-F-NHPI (1d) yields 6a in 81%, which is higher than with
NHPI itself (73%). An electron withdrawing substituent (i.e.
Br) in the para position of the substrate suppresses the
oxidation of the benzylic position very effectively (entries
3 and 4). Any substituent ortho with respect to the acetic
ester functionality inhibits oxidation completely. Steric
in¯uences are probably the reason for this effect, since
both electron withdrawing and donating substituents display
the same effect.1,11
Table 1. Benzylic oxidation of arylacetic esters by NHPI/CoII and O2
(Reaction conditions: 10 mmol substrate in 10 mL of acetic acid, 10%
NHPI, 0.5% CoII(OAc)2´4H2O, O2-®lled balloon, 408C)
Entry
Substrate
Product
Conversiona
Yielda
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
5a
5b
5c
5d
7b
7c
4a
4b
4c
4d
6a
6b
6c
6d
8b
8c
15
100
9
12
100
11
100
100
87
0
99
0
0
73b
0
99
64c
87
99
100
a Conversion and yields in % after 24 h, determined by GC.
b Yield calculated from 1H NMR spectra after isolation of the crude
product.
c Sole other product is (4-carboxyphenyl)acetic ester (36%).

B. B. Wentzel et al. / Tetrahedron 56 (2000) 7797±7803
7799
Table 2. Benzylic oxidation of heterocyclic acetic esters with NHPI/CoII
and O2
and may thus be intermediates in the oxidation of aryl
acetates towards these compounds.
Entry Substrate
Reaction conditionsa
Product
(Yield, %)
Oxidation of heteroaromatic substrates
1
2
3
4
9
0.8% CoII, 16% NHPI, 72 h
3% CoII, 15% NHPI, 48 h
0.5% CoII, 10% NHPI
±
±
Nitrogen or sulfur in a ®ve membered aromatic ring may be
regarded as an electron donating substituent, and facile
benzylic oxidation may be expected. In a six-membered
ring (e.g. pyridine), the electron withdrawing effect of the
heteroatom makes the ring positively polarized and hydro-
gen abstraction will be more dif®cult (see also the Dis-
cussion section). Since we were interested in expanding
the scope of the catalytic system, especially towards hetero-
aromatic compounds, four industrially relevant hetero-
aromatic substrates related to arylacetic esters (9±11 and
13) were chosen.
10
11
11
13
13
13
12 (18)
12 (22)
14 (21)
14 (14)
14 (6)
0.5% CoII, 20% NHPI
5b
6b
7b
3% CoII, 10% NHPI, 16 h, 408C
0.5% CoII, 10% NHPI, 16 h
0.5% CoII, 10% NHPI, 408C, 16 h
a The following general reaction conditions were applied: 10 mL of
acetic acid, 10 mmol of substrate, and the indicated of NHPI and
CoII(OAc)2´4H2O (in mol%) were vigourously stirred under an oxygen
atmosphere at 808C for 24 h.
b Other oxygen variations in reaction conditions were applied, but none
were successful in increasing the yield of the oxidized product from 13.
Virtually no difference was found in the reactivity of other-
wise identical methyl and ethyl esters (entries 2 and 7). A
methyl group on the aromatic ring can itself be oxidized but
entry 8 in Table 1 shows that the benzyl-CH2 in 5d is more
easily oxidized (64%) than the aromatic methyl substituent
(36%). Doubly oxidized products were not found.
The results of their reactions with NHPI/CoII/O2 are shown
in Table 2. It is indeed observed that a pyridine ring deac-
tivates the benzylic position to an extent that no conversion
takes place, as was predicted. The thiophene and thiazole
heterocycles, however, were also found to be relatively
unreactive towards benzylic oxidation when compared to
the carbocycles such as ethyl phenyl acetate. It is possible
Mandelic esters were also used as substrates to investigate
the oxidation of a possible side product or intermediate in
the formation of the glyoxylates. Entries 9 and 10 show that
mandelates can be oxidized very ef®ciently to glyoxylates,
Table 3. Oxidation of ethylbenzene by CoII and O2 in the presence of different N-hydroxy-phthalimides as co-catalysts (Reaction condition: 10 mmol
ethylbenzene, 0.5 mmol (5%) 1, 0.05 mmol (0.5%) CoII(OAc)2´ 4H2O, 10 mL of acetic acid, O2-®lled balloon, 808C, 24 h, vigorous stirring)
Entry
Catalyst
Conversion (%)
Yield of acetophenone (%)
Yield of 1-phenylethanol (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
94
95
93
96
82
80
10
7.5
85
87
82
88
68
59
3
2
2
3
2
4
5
0
2
1g
1h
4

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B. B. Wentzel et al. / Tetrahedron 56 (2000) 7797±7803
1-phenylethanol and acetophenone are formed in a 1:1 ratio
(ketone to alcohol ratio (K/A) of 1.0) in the ®rst 20 min of
the oxidation reaction (Fig. 2). This means that the ketone
does not only evolve from the oxidation of the alcohol (as
was shown by using mandelic esters as substrates, which
were oxidized to the corresponding glyoxylates, vide infra),
but is also formed directly. In a later stage of the reaction the
ketone is formed from 1-phenylethanol as can be concluded
from the decreasing amount of alcohol after about one hour
reaction time (Fig. 3). Secondly, the ¯uorinated NHPI is a
more active co-catalyst than the other NHPI's. With this co-
catalyst, acetophenone is produced at the cost of the yield of
1-phenylethanol.
Figure 2. Formation of acetophenone and 1-phenylethanol at low conver-
sions with two different NHPI catalysts. for reaction conditions see Table 3.
Explanation of symbols: (Ð) 1a as co-catalyst, ( - - -) 1e as co-catalyst, (A)
acetophenone, (K) 1-phenylethanol.
Overall, the electron withdrawing ¯uorine substituent
enhances the catalytic activity of the NHPI and thus the
rate of the reaction. On the other hand, the methoxy substi-
tuted NHPI's 1e and 1f decrease the reaction rate and at the
same time favor the formation of alcohol in the early stage
of the reaction. The mildly donating methyl substituent in
1b and in 1c slightly decreases the reaction rate with respect
to the unsubstituted catalyst, as expected.
that a nitroxide or sulfoxide is formed which deactivates the
substrate for oxidation. Also, coordination of the sulfur or
nitrogen atoms of the substrate to the cobalt catalyst can
occur, which will have a detrimental effect.
Catalytic activity of substituted NHPI's
The substituted N-hydroxyphthalimides 1a±h were used as
catalysts together with Co(II)(OAc)2´4H2O in the oxidation
of the model substrate ethylbenzene. In Table 3 the yields
of the reaction products after 24 h, when conversion is
essentially complete, are presented. It can be seen that the
NO2-substituted NHPI's are inactive. A possible explana-
tion may be the ability of a nitro group to act as a radical
scavenger. As the reaction is believed to be radical in nature
this quenches the oxidation. Similarly, Yoshino et al.5 have
observed a negative in¯uence of nitro groups on their reac-
tion system when substrates with NO2-groups were used.
Blank reactions were run with only CoII or only NHPI
(1a) as catalysts. The former reaction yielded 2% of ketone
and 1% of alcohol, the latter 5% and 2% of these products,
respectively.
Discussion
A mechanism for the catalytic oxidation of toluene with
NHPI, CoII and O2 has been proposed by the group of
Ishii.5,6 It involves the formation of the phthalimide-N-
oxyl radical 2, and the subsequent abstraction by this radical
of a hydrogen atom from the substrate as the initiating steps.
After this, the substrate radical Rz reacts rapidly with O2,
forming an alkylperoxy radical. Two molecules of the latter
rearrange to the ketone (K) and alcohol (A); the well-known
Russell termination (Scheme 1).1,12 It is expected from this
mechanism that the K/A ratio is 1.0. During the ®rst 20 min
of the reaction, ketone and alcohol formation takes place
only via Russell termination (see Fig. 2), but at higher
conversions it is clear that other mechanisms play an
important role. Also, it is not immediately clear from the
Russell termination mechanism what the in¯uence of aryl
substituents in NHPI and the substrate is on the reaction rate
and selectivity. We would like to further specify the
proposed mechanism so that it explains these issues.
Since the differences in catalyst activity do not stand out
very well at high conversions, we decided to investigate the
product distribution at low conversions, to study possible
effects of the substituents in the NHPI co-catalysts. The
formation of 1-phenylethanol and acetophenone during the
®rst 50 min of the reaction is plotted in Fig. 2 and during the
®rst ®ve hours of the reaction in Fig. 3. Several NHPI co-
catalysts were used. A number of interesting observations
can be made from these plots. First, it can be seen that both
A relatively simple explanation for the substituent effect is
possible using the polar transition state model which has
been proposed for related reactions (Fig. 4).13,14 It is obvious
Figure 3. Oxidation of ethylbenzene using different substituted NHPI catalysts. Left: formation of 1-phenylethanol; right: formation of acetophenone. For
reaction conditions see Table 3. a: NHPI, b: 3-Me-NHPI, c: 4-Me-NHPI, d: 3-F-NHPI, e: 3-OMe-NHPI.

B. B. Wentzel et al. / Tetrahedron 56 (2000) 7797±7803
7801
Haber±Weiss mechanism. More alkoxy radical is formed
when more CoII, generated through reduction of CoIII by
NHPI, is present. This process is enhanced when NHPI is
more negatively charged, i.e. when its reduction potential is
higher. Thus, more alcohol is produced when NHPI has a
more electron donating substituent. The E1/2 values of a
series of 4-substituted NHPI's were measured by Gorgy
et al.15 and were found to correlate linearly with the
Hammett parameter s of the substituent, a more positive
s-value (a more electron withdrawing substituent) corre-
sponding to a higher E1/2. The NHPI's with a more electron
donating ligand have a higher reduction potential (E1/2).
Thus, the reducing power of the NHPI co-catalyst may
indeed play an important role in the distribution of products
formed with the NHPI/cobalt(II) system described here. For
the electrooxidation of borneol with only NHPI as the
catalyst, Gorgy and co-workers also found that a higher
oxidizing character of the catalyst (which is the driving
Scheme 1.
Figure 4. Transition state for the abstraction of a hydrogen atom from
ethylbenzene by the PINO radical.
Scheme 2.
Scheme 3.
that an electron donating substituent on the aromatic ring of
the substrate (R1) will stabilize the partial positive charge on
the benzylic carbon atom, just as an electron withdrawing
ring substituent on NHPI (R2) will stabilize a partially
negatively charged hydroxyl oxygen atom. Thus, 3-F-
NHPI (1d) will oxidize ethylbenzene at a higher rate than
3-OMe-NHPI (1e) as is observed (see Fig. 3). A comparison
may be made with the benzylic oxidation of substituted
toluenes for which the same observations have been
reported in the literature. Thus, p-chlorotoluene is more
dif®cult to oxidize than p-methoxytoluene.5 Furthermore,
the polar transition state model explains the high reactivity
of 1-phenylethanol compared to ethylbenzene (see entries
9 and 10, Table 1). The benzylic OH-group of 1-phenyl-
ethanol stabilizes the partial positive charge on the benzylic
carbon atom by resonance, and thus favors further oxidation
to ketone, as is observed.
force in their reaction) gave a more ef®cient catalytic
process in agreement with our observations (Scheme 3).
In conclusion, we have found that the catalytic system
presented here provides a very active, selective and mild
method for benzylic oxidations with molecular oxygen as
the ®nal oxidant. While such oxidations usually take place
at temperatures over 1008C, the CoII/NHPI system is active
at almost ambient temperatures, making it much more
feasible for application in industrial processes. It has been
possible to tune the NHPI co-catalyst with respect to the
reaction rate and the ketone±alcohol ratio (K/A) by using
different substituents on its aromatic ring. An electron with-
drawing substituent increases the rate and the K/A ratio,
whereas an electron donating substituent on NHPI induces
a slower reaction and leads to a lower K/A ratio, especially
at low conversions.
Although the in¯uence of the NHPI aryl substituents on the
reaction rate can be understood with the polar transition
state model, it does not clarify the favored formation of
the alcohol product (lower K/A ratio) when the NHPI sub-
stituent is electron donating (e.g. methoxy). An explanation
may be given on the basis of the reduction potential of
NHPI. As shown in Scheme 2, the dissociation of the alkyl-
peroxide into an alkoxy radical may be aided by a reductant
if we regard this dissociation as a one-electron reduction
process. The reductant may be CoII, analogous to the
Experimental
General
All chemicals were purchased from Acros Chimica or
Aldrich and were used as received. NMR spectra were
taken on a Bruker AM-300 (300 MHz) or Bruker ACF-
200 (200 MHz) spectrometer, chemical shifts are given in
ppm with TMS as internal standard. FT-IR measurements in

7802
B. B. Wentzel et al. / Tetrahedron 56 (2000) 7797±7803
KBr tablets were performed on a Perkin±Elmer 298 spectro-
meter. Elemental analyses were measured on a Carlo Erba
Instruments CHNSO 1108. Mass spectra (EI) were taken on
a Fisons VG7070E instrument.
119.6 (d, JC±Fˆ3.2 Hz, Ar), 114.7 (d, JC±Fˆ12.5 Hz, Ar),
max (KBr): 1789, 1744, 1707 cm21; m/z (EI) 181 (100 M1);
165 (10), 151 (33), 122 (41), 108 (6), 94 (41).
n
3- and 4-Methoxy-N-hydroxyphthalimide, 1e and 1f. 2,3-
Dimethylanisole or 3,4-dimethylanisole (3.4 g, 25 mmol)
and a large excess of KMnO4 (25 g, 0.16 mol) were
dissolved in 140 mL of a water/t-BuOH mixture (70/30%
v/v). The reaction mixture was re¯uxed overnight, 50 mL of
EtOH was added to destroy unreacted KMnO4 and the
alcohols were distilled off. The resulting brown suspension
was ®ltered over Celite. The colorless solution was con-
centrated to 100 mL, acidi®ed with conc. HCl after which
the phthalic acid crystallized as a white solid. The obtained
phthalic acid (10 mmol, and 12.3 mmol resp. of 3- and
4-methoxyphthalic acid) was placed in a sublimation
apparatus with a cold ®nger, which could be heated with a
high temperature silicon oil bath under 1 mbar pressure.
3 equiv. of powdered NH2OH´HCl (2.1 g, 30 mmol and
2.6 g, 36.9 mmol, resp.) were added. The mixture was
heated to 1708C under reduced pressure, with occasional
stirring. The evaporation of water could be observed, after
which a light yellow solid started to form. After 5 h no
further reaction could be observed, and the reaction was
stopped. The resulting yellow-brown solids were recrystal-
lized from boiling water (75 mL) or toluene±EtOH (20:1
v/v, 50 mL). 3-OMe-NHPI, 1e: Yellow powder, yield:
21% (0.41 g, 2.1 mmol); mp 2328C; [Found: C, 51.03; H,
4.23; N, 6.61. C9H7NO4´H2O requires C, 51.04; H, 4.32; N,
6.61%]; dH (300 MHz DMSO-d6): 10.65 (1H, bs, N±OH),
7.76 (1H, dd, Jˆ8.4 Hz, Jˆ7.2 Hz, ArH), 7.45 (1H, d,
Jˆ8.4 Hz, ArH), 7.35 (1H, d, Jˆ7.2 Hz, ArH), 3.97 (3H,
s, OCH3); dC (75.5 MHz DMSO-d6): 167.7 (CvO), 166.9
(CvO), 160.0 (Ar), 140.7 (Ar), 134.6 (Ar), 122.9 (Ar),
119.0 (Ar), 117.3 (Ar), 60.3 (OCH3); nmax (KBr): 1788,
1766, 1718, m/z (EI) 193 (100 M1), 176 (71), 158 (41),
145 (65), 133 (39), 117 (20), 104 (53), 92 (29). 4-OMe-
NHPI, 1f: Light yellow powder, yield: 29% (0.69 g,
3.6 mmol); mp 2138C; [Found: C, 55.65; H, 3.64; N, 7.17.
C9H7NO4 requires C, 55.96; H, 3.65; N, 7.25%]; dH
(300 MHz DMSO-d6): 10.74 (1H, bs, N±OH), 7.78 (1H,
d, Jˆ8.2 Hz, ArH), 7.38 (1H, d, Jˆ2.3 Hz, ArH), 7.28±
7.24 (1H, dd, Jˆ8.2 Hz, Jˆ2.3 Hz, ArH), 3.93 (3H, s,
OCH3); dC (75.5 MHz DMSO-d6): 168.4 (CvO), 147.4
(Ar), 135.3 (Ar), 129.0 (Ar), 124.0 (Ar) 123.3 (Ar), 112.7
(Ar), 60.3 (OCH3); nmax (KBr): 1787, 1731 cm21; m/z (EI)
193 (100 M1), 177 (4), 163 (30), 134 (56), 120 (5), 106 (23),
92 (9).
Syntheses
The substituted N-hydroxyphthalimides 1a±d, 1g and 1h
were synthesized by reacting the corresponding phthalic
anhydrides with hydroxylamine in solution, according to
modi®ed literature procedures.16±18 Due to solubility
problems, the methoxy substituted compounds 1e and 1f
could not be obtained in this way. These were synthesized
by heating methoxy substituted phthalic acid in vacuo
at 1708C in a sublimation apparatus, with an excess
(2±3 equiv.) of hydroxylamine HCl salt, until elimination
of water and HCl could no longer be observed. The light
yellow sublimate was recrystallized together with the
residue, which also contained phthalimide product, to obtain
3-methoxy-NHPI or 4-methoxy-NHPI (.99% pure).
Detailed procedures and analyses are described below.
3- and 4-Methyl-N-hydroxyphthalimide, 1b and 1c.
NH2OH´HCl (0.67 g, 9.6 mmol) and N(Et)3 (1.3 mL,
9.5 mmol) were dissolved in ethanol (60 mL). After stirring
for 10 min 3- or 4-methyl phthalic anhydride (1.59 g,
9.8 mmol) was added. The mixture was re¯uxed overnight.
The clear solution was concentrated to 10 mL. The resulting
yellow oil was poured into 100 mL of water. The product
precipitated as a white powder, which was ®ltered and dried
under vacuum. 3-Me-NHPI, 1b: White powder; yield: 49%
(0.84 g, 4.7 mmol); mp 2218C; [Found: C, 60.91; H, 3.97;
N, 7.77. C9H7NO3 requires C, 61.02; H, 3.98; N, 7.91%]; dH
(300 MHz DMSO-d6): 10.74 (1H, bs, N±OH), 7.68 (3H, m,
ArH), 2.62 (3H, s, CH3); dC (75.4 MHz DMSO-d6): 164.9
(CvO), 164.0 (CvO), 137.2 (Ar), 136.7 (Ar), 134.1 (Ar),
129.2 (Ar), 125.4 (Ar), 120.8 (Ar); nmax (KBr): 1791, 1725;
1704 cm21. m/z (EI) 177 (100 M1), 161 (31), 147 (7), 132
(10), 118 (23), 103 (20), 89 (40). 4-Me-NHPI, 1c: White
powder; yield: 47% (0.81 g, 4.6 mmol); mp 2028C; [Found:
C, 60.74; H, 4.23; N, 7.71. C9H7NO3 requires C, 61.02; H,
3.98; N, 7.91%]; dH (300 MHz CDCl3): 7.71 (1H, d,
Jˆ7.6 Hz, ArH), 7.63 (1H, s, ArH), 7.53 (1H, d, Jˆ
7.6 Hz, ArH), 2.50 (3H, s, CH3); dC (75.5 MHz DMSO-
d6): 168.2 (CvO), 149.4 (Ar), 138.7 (Ar), 133.0 (Ar),
130.0 (Ar), 127.5 (Ar), 126.9 (Ar), 25.4 (CH3); nmax
(KBr): 1788, 1741, 1704 cm21; m/z (EI) 177 (65 M1), 161
(27), 147 (70), 133 (42), 118 (99), 104 (38), 89 (100).
3- and 4-Nitro-N-hydroxyphthalimide, 1g and 1h. To
toluene (80 mL) were added 3- or 4-nitrophthalic anhydride
(3.81 g, 19.7 mmol), NH2OH´HCl (1.34 g, 19.2 mmol) and
triethylamine (2.66 mL, 19 mmol). The mixture was
re¯uxed overnight. Water was removed during the reaction
by azeotropic distillation. The yellow solution was then
concentrated and the resulting yellow oil was puri®ed by
column chromatography on silica gel (eluent: hexane±
ethylacetateˆ4:1). 3-NO2-NHPI, 1g: Yellow powder;
yield: 9% (0.37 g, 1.8 mmol); mp 209±2138C; [Found: C,
42.76; H, 2.55; N 12.34. C8H4N2O5´H2O requires C, 42.49;
H, 2.67; N, 12.39%]; dH (200 MHz DMSO-d6): 11.81 (1H,
bs, N±OH), 8.18 (3H, m, ArH); dC (75.5 MHz DMSO-d6):
171.2 (CvO), 168.6 (CvO), 148.3 (Ar), 140.0 (Ar), 138.6
3-Fluoro-N-hydroxyphthalimide, 1d. NH2OH´HCl (0.84 g,
12.1 mmol) and K2CO3 (0.84 g, 6.1 mmol) were dissolved
in water (20 mL). The solution was stirred for 20 min and
3-¯uorophthalic anhydride (2.0 g, 12.0 mmol) was added.
The solution was stirred overnight at room temperature.
The resulting white suspension was ®ltered and the residue
dried under vacuum to give 1d (1.12 g, 6.2 mmol, 51%) as a
white powder, mp 2168C; [Found: C, 49.21; H, 2.76; N,
7.12. C8H4NO3F´0.8H2O requires C, 49.14; H, 2.89; N,
7.16%]; dH (200 MHz DMSO-d6): 10.93 (1H, bs, N±OH),
7.88 (1H, m, ArH), 7.68 (2H, m, ArH); dC (50.3 MHz
DMSO-d6): 163.3 (d, JC±Fˆ3.2 Hz, CvO), 161.2 (s,
CvO), 156.4 (d, JC±Fˆ261.3 Hz, Ar), 137.5 (d, JC±
ˆ8.0 Hz, Ar), 131.4 (s, Ar), 122.9 (d, JC±Fˆ19.9 Hz, Ar),
F

B. B. Wentzel et al. / Tetrahedron 56 (2000) 7797±7803
7803
with Organometallic Compounds, Cornils, B., Herrmann, W. A.
Eds.; VCH: Weinheim, 1996; Vol. 1.
(Ar), 132.1 (Ar), 130.8 (Ar), 127.8 (Ar); nmax (KBr): 1773,
1734, 1709, 1540 cm21; m/z (EI) 208 (M1); 192, 178.
4-NO2-NHPI, 1h: This compound has been described in
the literature,16 Registry No. 105969-98-0
2. Ishii, Y.; Nakayama, K.; Takeno, M.; Sakaguchi, S.; Iwahama,
T.; Nishiyama, Y. J. Org. Chem. 1995, 60, 3934±3935.
3. Ishii, Y.; Iwahama, T.; Sakaguchi, S.; Nakayama, K.;
Nishiyama, Y. J. Org. Chem. 1996, 61, 4520±4526.
4. Iwahama, T.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 1998,
39, 9059±9062.
Arylacetic esters and mandelic esters
General procedure for ethylbenzene oxidations. A solu-
tion of 10 mmol of ethylbenzene in 10 mL of acetic acid
containing 0.5 mmol (5%) of NHPI catalyst 1 and
0.05 mmol (0.5%) of Co(OAc)2´4H2O was placed in a
three-necked ¯ask equipped with a rubber balloon ®lled
with 100% O2 (Hoek Loos, 99.9%) and heated to 808C
with vigorous stirring. 1,2,4-Trichlorobenzene was added
to the reaction mixture as an internal standard for GC analy-
sis. Regularly taken aliquots were analyzed with a Chrom-
pack Packard 438A chromatograph (FFAP CB column,
15 m, 0.32 mm internal diameter, dfˆ1.0 mm or a CPSIL
5. Yoshino, Y.; Hayashi, Y.; Iwahama, T.; Sakaguchi, S.; Ishii, Y.
J. Org. Chem. 1997, 62, 6810±6813.
6. Ishii, Y. J. Mol. Catal. A: Chemical 1997, 117, 123±137.
7. Sergeev, P. G.; Sladkov, A. M. Zhur. Obshchei. Khim. 1957, 27,
819±821; Chem. Abstr. 1958, 51, 16348g.
8. Matsunaka, K.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. Tetrahedron
Lett. 1999, 40, 2165±2168.
9. Ishibashi, H.; Takagaki, K.; Imada, N.; Ikeda, M. Tetrahedron
1994, 50, 10215±10224.
10. Choudary, B. M.; Reddy, G. V. S.; Rao, K. K. J. Chem. Soc.,
Chem. Commun. 1993, 323±324.
5
CB column, 25 m, 0.32 mm internal diameter,
11. Tanko, J. M.; Kamrudin, N.; Blackert, J. F. J. Org. Chem.
1991, 56, 6395±6399.
dfˆ1.2 mm), or a Hewlett Packard 5890 Series II chromato-
graph (CP-SIL 5 CB column, 25 m, 0.32 mm internal
diameter, dfˆ1.2 mm). The commercially available phenyl-
acetic acids or mandelic acids were esteri®ed by standard
procedures in 80±91% yield.
12. Howard, J. A. ACS Symposium Series 1978, 69, 413±432.
13. Huyser, E. S. Free-Radical Chain Reactions; Wiley
Interscience: New York, 1970.
Â
14. Vasvari, G.; Gal, D. Ber. Bunsenges. Phys. Chem. 1993, 97,
Â
22±28.
General procedure for the oxidation of arylacetic esters
and mandelic esters. The reaction was performed in a simi-
lar way as described for the oxidation of ethylbenzene, with
the exception that 1 mmol (10%) of NHPI catalyst was used.
The mixture was stirred at 408C. The reaction was followed
by GC analysis as described above. The crude products were
isolated by evaporating the solvent and washing with hot
heptane, and were analyzed by NMR. Puri®cation was
performed by crystallization from hot pentane or by
column chromatography (silica gel, eluent: chloroform or
petroleumether±ethylacetate 7:3 v/v). The analyses of the
products were identical to the following literature refer-
ences: 4-Methoxyphenylglyoxylate methyl ester (4b)
and ethyl ester (6c)19 Ethyl phenylglyoxylate (6a)20,21
Ethyl p-tolylglyoxylate (6d)22,23 Ethyl 3-thiopheneglyoxyl-
ate (12)24 Ethyl 2-(formylamino)-4-thiazoleglyoxylate
(14).25,26 Registry No. 4b 32766-61-3; 6a 1603-79-8; 6c
40140-16-7; 6d 5524-56-1; 12 53091-09-1; 14 64987-03-7.
15. Gorgy, K.; Lepretre, J.-C.; Saint-Aman, E.; Einhorn, C.;
Einhorn, J.; Marcadal, C.; Pierre, J.-L. Electrochim. Acta 1998,
44, 385±393.
16. Chan, C. L.; Lien, E. J.; Tokes, Z. A. J. Med. Chem. 1987, 30,
509±514.
17. Coe, P. L.; Croll, B. T.; Patrick, C. R. Tetrahedron 1967, 23,
505±508.
18. Bauer, L.; Miarka, S. V. J. Am. Chem. Soc. 1957, 79, 1983±
1985, and references therein.
19. Hu, S.; Neckers, D. C. J. Org. Chem. 1996, 61, 6407.
20. Sakakura, T.; Yamjashita, H.; Kobayashi, T.-A.; Hayashi, T.;
Tanaka, M. J. Org. Chem. 1987, 52, 5733.
21. Kolasa, T.; Miller, M. J. J. Org. Chem. 1987, 52, 4978.
22. Kindler, K.; Metzendorf, W.; Kwok, D.-Y. Ber. 1943, 76, 308.
23. Smith, H. A.; Buehler, C. A.; Magee, T. A.; Nayak, K. V.;
Glenn, D. M. J. Org. Chem. 1959, 24, 1301.
24. Jeffries, A. T.; Moore, K. C.; Ondeyka, D. M.; Springsteen,
A. W.; MacDowell, D. W. H. J. Org. Chem. 1981, 46, 2885.
25. Kamiya, T.; Tanaka, K.; Nakai, Y.; Sakane, K. (Fujisawa
Pharmaceutical Co. Ltd.) Ger. Offen. 2,710,282, 1977. Chem.
Abstr. 1978, 88, 22954h.
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