Aerobic oxidation of 1,3,5-triisopropylbenzene using N-hydroxyphthalimide (NHPI) as key catalyst

Article abstract of DOI:10.1016/j.tet.2005.08.087

The first systematic study on the aerobic oxidation of 1,3,5- triisopropylbenzene was examined by the use of N-hydroxyphthalimide (NHPI) as a key catalyst. It was found that 1,3,5-triisopropylbenzene was efficiently oxidized with O₂ in the presence of a catalytic amount of NHPI and azobisisobutyronitrile (AIBN) at 75°C. Upon treatment of the resulting products with sulfuric acid followed by acetic anhydride led to 5-acetoxy-1,3-diisopropylbenzene and 3,5-diacetoxy-1-isopropylbenzene as major products and a small amount of 1,3,5-triacetoxybenzene. When t-butylperoxypivalate (BPP) was employed as a radical initiator, the oxidation could be achieved in good yield even at 50°C. This oxidation provides a facile method for preparing phenol derivatives bearing an isopropyl moiety, which can be used as pharmaceutical starting materials.

Full text of DOI:10.1016/j.tet.2005.08.087

Tetrahedron 61 (2005) 10995–10999
Aerobic oxidation of 1,3,5-triisopropylbenzene using
N-hydroxyphthalimide (NHPI) as key catalyst
*
Yasuhiro Aoki, Naruhisa Hirai, Satoshi Sakaguchi and Yasutaka Ishii
Department of Applied Chemistry and High Technology Research Center, Faculty of Engineering, Kansai University, Suita,
Osaka 564-8680, Japan
Received 20 July 2005; revised 20 August 2005; accepted 22 August 2005
Available online 16 September 2005
Abstract—The first systematic study on the aerobic oxidation of 1,3,5-triisopropylbenzene was examined by the use of
N-hydroxyphthalimide (NHPI) as a key catalyst. It was found that 1,3,5-triisopropylbenzene was efficiently oxidized with O2 in the
presence of a catalytic amount of NHPI and azobisisobutyronitrile (AIBN) at 75 8C. Upon treatment of the resulting products with sulfuric
acid followed by acetic anhydride led to 5-acetoxy-1,3-diisopropylbenzene and 3,5-diacetoxy-1-isopropylbenzene as major products and a
small amount of 1,3,5-triacetoxybenzene. When t-butylperoxypivalate (BPP) was employed as a radical initiator, the oxidation could be
achieved in good yield even at 50 8C. This oxidation provides a facile method for preparing phenol derivatives bearing an isopropyl moiety,
which can be used as pharmaceutical starting materials.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
as a key catalyst in the presence or absence of a radical
initiator (Eq. 1).
Aerobic oxidation of alkylbenzenes is a very important
industrial process for the production of primary chemicals
and monomer materials. For instance, the aerobic oxidation
of p-xylene to terephthalic acid is practiced in large scale in
the chemical industry worldwide.1 Another important
aerobic oxidation is the conversion of isopropylbenzene to
cumene hydroperoxide which on subsequent treatment with
sulfuric acid affords phenol and acetone.2 The aerobic
oxidation of m- and p-diisopropylbenzenes leading to
resorcinol and hydroquinone is also an important autoxida-
tion process.3 In recent years, we have developed a new
catalytic method for the aerobic oxidation of alkylbenzenes
using N-hydroxyphthalimide (NHPI) as a key catalyst,4 and
applied to the aerobic oxidation of m- and p-diisopropyl-
benzenes to develop an alternative route to resorcinol and
hydroquinone.5
(1)
2. Results and discussion
The oxidation of 1 under atmospheric dioxygen in the
presence of NHPI and AIBN under various conditions is
shown in Table 1.
However, there has been little study so far of the aerobic
oxidation of 1,3,5-triisopropylbenzene (1) except for several
patent works.6 Therefore, the aerobic oxidation of 1 to
obtain the corresponding phenol derivatives is thought to be
interesting. In this paper, we would like to report the first
systematic study on the aerobic oxidation of 1 using NHPI
Compound 1 (3 mmol) was reacted with atmospheric
dioxygen (1 atm) under the influence of NHPI (0.3 mmol)
and AIBN (0.09 mmol) in acetonitrile (5 mL) at 75 8C for
2 h, followed by treatment with 0.3 M sulfuric acid in
acetonitrile (1 mL) at room temperature. The reaction
solution was evaporated and then treated with acetic
anhydride (10 mmol) containing pyridine (50 mg) under
reflux for 2 h to convert the resulting hydroxyl benzenes into
Keywords: Aerobic oxidation; 1,3,5-Triisopropylbenzene; Hydroperoxide;
N-hydroxyphthalimide.
*
Corresponding author. Tel.: C81 6 6368 0793; fax: C81 6 6339 4026;
e-mail: ishii@ipcku.kansai-u.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.087

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Y. Aoki et al. / Tetrahedron 61 (2005) 10995–10999
Table 1. Aerobic oxidation of 1,3,5-triisopropylbenzene (1) by NHPI under various conditionsa
Entry
Temperature/8C
Time/h
Conversion/%
Yield/%b
2
3
4
1
75
75
75
75
65
65
75
75
2
5
7
5
3
5
2
2
78
85
96
63
71
84
30
nr
52 (67)
45 (53)
30 (31)
51 (81)
51 (73)
47 (56)
25 (83)
15 (19)
30 (35)
52 (55)
11 (17)
17 (24)
29 (35)
3 (10)
1 (1.3)
1 (1.1)
2 (2.1)
nd
nd
2 (2.4)
nd
2c
3
4d
5
6
7e
8f
a Compound 1 (3 mmol) was reacted in the presence of NHPI (10 mol%) and AIBN (3 mol%) under O2 (1 atm) in CH3CN (5 mL). See text.
b Numbers in parenthesis show selectivity based on 1 reacted.
c CH3CN (10 mL).
d O2/N2 (0.5 atm/0.5 atm).
e Without AIBN.
f
Without NHPI.
acetoxybenzene derivatives whose quantities are deter-
mined by GC measurement. As an example, the reaction
step of this transformation of 1 to 1,3,5-triacetoxybenzene
derivative is shown in Scheme 1. Thus, the amount of
phenol derivatives obtained by the oxidation of 1 was
estimated as the amount of acetoxybenzene derivatives.
Elongation of the reaction time for 7 h under these
conditions resulted in the preferential formation of diacetate
3 (52%) over monoacetate 2 (30%) (entry 3). When oxygen
concentration was halved under these conditions, 2 was
formed in 51% at higher selectivity (81%) (entry 4). The
reaction took place smoothly even at 65 8C, affording 2
(51%) and 3 (17%) for 3 h and 2 (47%) and 3 (29%) for 5 h
(entries 5 and 6). The reaction in the absence of AIBN led to
2 and 3 in lower yields, and no reaction took place at all in
the absence of NHPI (entries 7 and 8).
To inspect suitable solvents to convert 1 into 2, 3, and 4, the
effect of several solvents was studied under O2 (1 atm) at
75 8C for 2 and 5 h (Table 2).
The solvent effect was clearly observed in shorter-time
reactions. For example, the oxidation of 1 for 2 h gave rise
to 2 (52%) and 3 (15%) at higher conversion (78%) in
CH3CN, but the oxidation in AcOEt afforded 2 (36%) and 3
(6%) at low conversion (42%), although the selectivity of 2
was high (86%) (entries 1 and 2). In the oxidation for 5 h,
however, the conversion of 1 was attained up to over 90% in
both solvents. On the contrary, the conversions of the
oxidations in PhCN and PhCF3 for 2 h were low compared
with that in CH3CN, but the total selectivities of 2 and 3 of
the reaction in both solvents were very high (entries 3 and
4). Acetic acid, which is a good solvent in the NHPI-
catalyzed oxidation of toluene to benzoic acid,7 was not
suited for the present oxidation, since a part of the resulting
hydroperoxides was subject to decomposition by acetic acid
to form phenols, which serve as radical inhibitors. In fact,
Scheme 1. Sequential transformation of 1 to 4.
The oxidation of 1 followed by above treatment led to 3,5-
diisopropyl-1-acetoxybenzene (2) (52%), 3-isopropyl-1,5-
diacetoxybenzene (3) (15%), and 1,3,5-triacetoxybenzene
(4) (1%) along with small amounts of decomposed
oxidation products like 1-isopropenyl-3,5-diisopropyl-
benzene (5) and 1-acetoxy-3,5- diisopropylbenzene (6) at
78% conversion (entry 1).The reaction in acetonitrile
(10 mL) for 5 h gave 2 and 3 in 45 and 30% yields,
respectively, along with 4 (1%) at 85% conversion (entry 2).
Table 2. Aerobic oxidation of 1,3,5-triisopropylbenzene (1) by NHPI under several solventsa
Entry
Solvent
Time/h
Conversion/%
Yield/%b
2
3
4
1
2
3
4
5
CH3CN
AcOEt
PhCN
2
5
2
5
2
5
2
5
2
5
78
96
42
92
66
76
55
81
25
30
52 (67)
29 (30)
36 (86)
31 (34)
42 (64)
46 (61)
36 (65)
33 (41)
24 (96)
25 (83)
15 (19)
51 (53)
6 (14)
44 (48)
22 (33)
28 (37)
16 (29)
36 (44)
1 (4.0)
3 (10)
1 (1.2)
2 (2.1)
nd
1 (1.1)
nd
nd
1 (1.8)
1 (1.2)
nd
PhCF3
AcOH
nd
a Compound 1 (3 mmol) was reacted in the presence of NHPI (10 mol%) and AIBN (3 mol%) under O2 (1 atm) in solvent (5 mL) for 2 or 5 h at 75 8C.
b Numbers in parenthesis show selectivity based on 1 reacted.

Y. Aoki et al. / Tetrahedron 61 (2005) 10995–10999
10997
the conversion in the oxidation of 1 for 2 h was almost the
same as that for 5 h (entry 5). This fact indicates that the
oxidation in acetic acid is inhibited at an early stage of
the reaction owing to the formation phenols. On the basis of
these results, acetonitrile is thought to be a good solvent for
the oxidation of 1 from viewpoints of the reaction rate and
selectivity among the solvents examined.
reasonable to assume the formation of phenol derivatives,
which inhibit the radical chain transfer. It is well known that
hydroperoxides undergo the rapid self-decomposition when
their concentration increases over the boundary concen-
tration. In fact, we confirmed the formation of 5-isopropyl
resorcinol (2%) in the oxidation of 1 with O2 (1 atm) in the
presence of NHPI (10 mol%) and AIBN (3 mol%) in
acetonitrile at 75 8C for 6 h. These phenol derivatives
generated during the reaction is increased with time and
inhibited the further oxidation of 1 to 3 and 4. As a result,
the yield of 1,3,5-triacetoxybenzene 4 was not increased
with time.
In order to obtain further insight into the reaction course, the
time-dependence of the oxidation of 1 by the NHPI/AIBN
system under O2 (1 atm) in acetonitrile at 75 8C was
followed by GC at an appropriate time interval (Figure 1).
To achieve the reaction at lower temperature, the reaction
was carried out under several conditions (Table 3).
The oxidation of 1 was examined using t-butylperoxy-
pivarate (BPP), which decomposes at lower temperature
(t ⁄
1
Z10 h at 55 8C in benzene) than AIBN (t ⁄ Z10 h at
1
2
2
65 8C in toluene), in CH3CN at 50 8C for 6 h.8 It was found
that 1 is selectively converted into 2 (48%) and 3 (27%) at
81% conversion (entry 1). In the oxidation at lower
temperature, 4 was not formed at all. By the oxidation
using AIBN at 50 8C, the conversion was only 38%, but 2
was selectively produced (entry 2). In a previous paper, we
showed that Co(II) reacts with dioxygen to generate a
Co(III)-dioxygen complex, which can initiate the NHPI-
catalyzed oxidation.7 Thus, the oxidation of 1 by NHPI
combined with Co(OAc)2 in place of radical initiators like
AIBN and BPP was examined at 50 8C for 1 h. The
oxidation was also induced by the NHPI/Co(OAc)2 to give 2
in high selectivity (91%) in moderate conversion (44%)
(entry 3), but the formation of 3, and 4 was very low. When
the reaction time was prolonged to 6 h, the conversion was
increased to 95% to lead to 3 (52%) in preference to 2
(34%). High total selectivity of 2, and 3 indicates that the
resulting hydroperoxides are relatively stable and do not
undergo rapid decomposition by Co ions under these
conditions. In contrast, since Cu ions promote the redox
decomposition of hydroperoxides, the oxidation of 1 using
the NHPI/Cu(OAc)2 system resulted in a complex mixture
compared with that of the NHPI/Co(OAc)2 system probably
because of side reactions caused by decomposition of the
resulting hydroperoxides by Cu ions (entry 6).
Figure 1. Time-dependence curves for the oxidation of 1 (3 mmol) under
O2 (1 atm) by NHPI (10 mol%) and AIBN (3 mol%) in CH3CN (5 mL) at
75 8C.
Compound 1 was almost linearly oxidized in 2 h under these
conditions to give 2, and 3 with higher selectivity, and the
yield of 2 attained maximum (50%) after 2 h. A slightly
rapid increase of 3 was observed with the elapse of 1.5 h, but
the yield of 3 was not increased beyond 50% and the
reaction was stopped at around 6 h. From the consideration
of the time-dependence curves of 1, 2, and 3, the reactivity
of 2 is thought to be slightly decreased by introduction of
OOH group to 1 than that of the stating 1. However, the
difficulty of the formation of 4 is believed to be other
reasons rather than decrease of the reactivity of 3 by two
OOH groups as discussed later.
In order to clarify the reason why the oxidation is stopped at
around 6 h, the recovery of NHPI catalyst after the oxidation
was examined. Most of the NHPI was found to be recovered
without decomposition after 6 h. This fact indicates that the
termination of the reaction is not due to the decomposition
of NHPI in the course of the oxidation. Consequently, it is
Figure 2 shows the time-dependence curves for the
oxidation of 1 by NHPI combined with BPP or AIBN at
50 8C. The reaction by the NHPI/AIBN system proceeded
more slowly than that by the NHPI/BPP system owing to the
difficulty of the decomposition of AIBN at 50 8C. After
Table 3. Aerobic oxidation of 1,3,5-triisopropylbenzene (1) by NHPI at 50 8C in the presence of various initiatorsa
Entry
Initiator (mol%)
Time/h
Conversion/%
Yield/%b
2
3
4
1
2
3
4
5
6
BPP (3)
AIBN (3)
Co(OAc)2 (0.1)
Co(OAc)2 (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
6
6
1
6
1
6
81
38
44
95
48 (59)
37 (97)
40 (91)
34 (36)
41 (81)
27 (33)
1 (2.6)
1 (2.6)
52 (55)
7 (13)
nd
nd
1 (1.2)
2 (2.1)
nd
55
Complex mixture
a Compound 1 (3 mmol) was reacted in the presence of NHPI (10 mol%) and radical initiator under O2 (1 atm) in CH3CN (5 mL) at 50 8C for 1 or 6 h.
b Numbers in parenthesis show selectivity based on 1 reacted.

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Y. Aoki et al. / Tetrahedron 61 (2005) 10995–10999
fact that the yield of 4 by the oxidation of 1 with air was
increased compared with that with pure oxygen is believed
to be due to the slower formation of phenol derivatives,
which serve as radical inhibitor, with air than that with O2.
In conclusion, we have first examined the aerobic oxidation
of 1 to obtain polyphenols by the use of combined catalytic
system of NHPI with a radical initiator like AIBN or BPP.
The NHPI/AIBN system was found to be a good system for
the oxidation of 1 to 2, and 3, and the NHPI/BPP system
showed high performance for the oxidation of 1 at lower
temperature. The oxidation of 1 by NHPI in the presence of
AIBN under pressurized air (30 atm) followed by above
treatment led to 1,3,5-triacetoxybenzene 4 in fair yield
(21%).
3. Experimental
3.1. General procedure
1H NMR and 13C NMR were measured at 270 and
67.5 MHz, respectively, in CDCl3 with TMS as the internal
standard. Infrared (IR) spectra were measured as thin films
on NaCl plate or KBr press disk. A GLC analysis was
performed with a flame ionization detector using a
0.2 mm!25 m capillary column (OV-17). Mass spectra
were determined at an ionizing voltage of 70 eV. All
starting materials, catalysts, and initiators were purchased
from commercial sources and used without further
treatment. The yields of products were estimated from the
peak areas based on the internal standard technique.
Figure 2. Time-dependence curves for aerobic oxidation of 1 (3 mmol)
under O2 (1 atm) by NHPI (10 mol%)/AIBN (3 mol%) or NHPI (10 mol%)/
BPP (3 mol%) in CH3CN (5 mL) at 50 8C.
3.2. General procedure for the oxidation of 1,3,5-
triisopropylbezene (1) to acetoxylbenzene derivatives,
2, 3, and 4
15 h, the yields of 2, 3, and 4 in the oxidation of 1 by the
NHPI/BPP system attained 40, 58, and 1% yields,
respectively, while in the oxidation by the NHPI/AIBN
system the starting 1 was remained even after 15 h. These
observations suggest that the NHPI/BPP system is more
efficient than the NHPI/AIBN one in the oxidation of 1 to 2,
and 3 at 50 8C.
An acetonitrile (5 mL) solution of 1,3,5-triisopropylbenzene
(1) (3 mmol), AIBN (3 mol%), and NHPI (10 mol%) was
placed in a two-necked flask equipped with a balloon filled
with O2, and the solution was stirred at 75 8C for 2–7 h. The
reactant was treated with 0.3 M H2SO4 in CH3CN (1 mL) at
25 8C for 2 h. In this reaction, the resulting hydroperoxides
are conformed to be converted into phenol derivatives and
acetone by GC–MS measurement. After removal of solvent
under reduced pressure, the mixture was treated with acetic
anhydride (10 mmol) containing pyridine (50 mg) under
reflux for 1 h to covert into acetoxybenzene derivatives
whose quantities are determined by GC measurement. The
resulting products were purified by column chromatography
on silica gel using n-hexane to give 5-acetoxy-1,3-
diisopropylbenzene (2), 3,5-diacetoxy-1-isopropylbenzene
(3), 1,3,5-triacetoxybenzene (4). These products were
characterized by 1H and 13C NMR, IR, and HRMS,
respectively.
Since it was difficult to obtain 1,3,5-triacetoxybenzene 4 by
the oxidation of 1 under O2 (1 atm), the oxidation of 1 under
pressurized air (30 atm) was carried out by use of the NHPI/
AIBN system at 75 8C for 24 h (Eq. 2).
1
3.2.1. 5-Acetoxy-1,3-diisopropylbenzene (2). H NMR d
6.94 ppm (s, 1H), 6.75 ppm (d, JZ1.4 Hz, 2H), 2.91–
2.83 ppm (m, 2H), 2.28 ppm (s, 3H), 1.23 ppm (d, JZ
6.9 Hz, 12H); 13C NMR 169.4, 150.6, 150.1, 122.3, 116.7,
34.1, 24.0, 21.2; IR(NaCl) 2961, 2871, 1768, 1458, 1207,
872, 704 cmK1; HRMS (EI): calcd for C14H20O2 [MKH]C:
220.1436; found: 220.1463.
(2)
The reaction afforded 4 in 21% yield along with 3 (54%) and
2 (10%), although 4 was difficult to obtain selectively. The

Y. Aoki et al. / Tetrahedron 61 (2005) 10995–10999
10999
1
1996. (b) Partenheimer, W. Catal. Today 1995, 23, 69. (c)
Parshall, G. W.; Ittel, S. D. Heterogeneous Catalysis, 2nd ed.;
Wiley: New York, 1992.
3.2.2. 3,5-Diacetoxy-1-isopropylbenzene (3). H NMR d,
6.78 ppm (q, JZ2.4 Hz, 2H), 6.74 ppm (s, 1H) 2.91–
2.88 ppm (m, 1H), 2.28 ppm (s, 3H), 1.23 ppm (d, JZ
6.9 Hz, 6H); 13C NMR 169.1, 151.3, 150.8, 117.0, 112.7,
33.9, 23.6, 21.1; IR(NaCl) 2956, 2871, 1771, 1455, 1198,
891, 707 cmK1; HRMS (EI): calcd for C13H16O4 [MKH]C:
236.1051; found: 236.1049.
2. (a) Hock, H.; Lang, S. Ber. Dtsch. Chem. Ges. 1944, B77, 257.
(b) Jordan, W.; Van Barneveld, H.; Gerlich, O.; Boymann,
M. K.; Ullrich, J.; Ullmann’s Encyclopedia of Industrial
Organic Chemicals; Wiley-VCH: Weinheim, 1985; Vol. A9;
pp 299–312.
1
3.2.3. 1,3,5-Triacetoxybenzene (4). H NMR d 6.83 ppm
3. (a) Wessermel, K.; Arpe, H.-J. Industrial Organic Chemistry.;
Wiley-VCH: Weinheim, 2003; pp 364–366.(b) Ching Y. W.
Eur. Patent 322245, 1989.
(s, 3H), 2.27 ppm (2, 9H); 13C NMR 168.4, 151.0, 21.2;
IR(NaCl) 3091, 1772, 1457, 1189, 918, 670 cmK1; HRMS
(EI): calcd for C12H12O6 [MKH]C: 252.0658; found:
252.0634.
4. Fukuda, O.; Sakaguchi, S.; Ishii, Y. Adv. Synth. Catal. 2001,
343, 809.
5. (a) Aoki, Y.; Sakaguchi, S.; Ishii, Y. Tetrahedron 2005, 61,
5219. (b) Aoki, Y.; Sakaguchi, S.; Ishii, Y. Adv. Synth. Catal.
2001, 346, 199. (c) Arends, I. W. C. E.; Sasiidharan, M.;
Kuhnle, A.; Duda, M.; Jost, C.; Sheldon, R. A. Tetrahedron
2002, 58, 9055.
Acknowledgements
This work was partially supported by a Grant-in-Aid for
Scientific Research on Priority Areas (17065019) from the
Ministry of Education, Science and Culture, Culture, Japan,
and Daicel Chemical Industries Ltd.
6. (a) Ogino, T. JP 03044344, 1991. (b) Mizuno, K. JP 61152635,
1986.(c) Reichle, W. T.; Konrad, F. M.; Brooks, J. R. Benzene
and its Industrial Derivatives; Benn: London, 1975.
7. Yoshino, Y.; Hayashi, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem.
1997, 62, 6810.
8. It has been reported that the self-accelerating decomposition
temperatures of AIBN and BPP were 50.0 and 27.0 8C,
respectively; Bosch, C. M.; Velo, E.; Recasens, F. Chem.
Eng. Sci. 2001, 56, 1451.
References and notes
1. (a) Park, C.; Sheehan, J. R. In Kirk-Othmer Encyclopedia of
Chemical Technology, 4th ed.; Wiley: New York, Vol. 18W,