Preparation of 1,4-hydrobenzoquinones by the PCC/SiO2-promoted double oxidation of 3-cyclohexene-1,2-diols

Article abstract of DOI:10.1039/b511067j

The PCC/SiO₂-promoted double oxidation of 3-cyclohexene-1,2- diols, which were easily prepared by the two-step sequence of α-hydroxylation of various conjugated cyclohexenones and the subsequent nucleophilic carbonyl addition of alkyl anions, produced diversely substituted 1,4-hydrobenzoquinones. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b511067j

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C O M M U N I C A T I O N
Preparation of 1,4-hydrobenzoquinones by the PCC/SiO2-promoted
double oxidation of 3-cyclohexene-1,2-diols
Hee Jin Kim and Sangho Koo*
Department of Chemistry, Myong Ji University, Yongin, Kyunggi-Do, 449-728, Korea.
E-mail: sangkoo@mju.ac.kr; Fax: 82 31 335 7248; Tel: 82 31 330 6185
Received 3rd August 2005, Accepted 26th August 2005
First published as an Advance Article on the web 2nd September 2005
The PCC/SiO2-promoted double oxidation of 3-cyclo-
hexene-1,2-diols, which were easily prepared by the two-
ꢀ
step sequence of a -hydroxylation of various conjugated
cyclohexenones and the subsequent nucleophilic carbonyl
addition of alkyl anions, produced diversely substituted 1,4-
hydrobenzoquinones.
Quinones or hydroquinones are useful building blocks for
constructing polycyclic compounds in organic synthesis.1
Quinoids containing polyprenyl side chains such as ubiquinones,
menaquinones, and plastoquinones are biologically impor-
tant natural products, which show physiological and clinical
activities.2 Most of the synthetic methods for these chemi-
cally and biologically important quinones or hydroquinones
are based on the oxidation of phenol or methoxybenzene
derivatives,3 which generally require strongly acidic or basic
Scheme 1 A synthetic plan for 1,4-hydrobenzoquinones 2 by the double
oxidation of 3-cyclohexene-1,2-diols 1 (R = alkyl).
conditions.
We devised a totally different synthetic approach to 1,4-hydro-
benzoquinones 2 by the double oxidation of 3-cyclohexene-1,2-
diols 1 (Scheme 1). While the secondary homoallylic alcohol
of 1 is oxidized to the ketone of A, the chromate ester of
the sterically congested tertiary allylic alcohol of B (R = H)
undergoes allylic migration to give the ester of the secondary
allylic alcohol of C, which can be oxidized to the ketone
of D. Enolization of the 1,4-diketone D gives rise to 1,4-
hydrobenzoquinone 2. This scenario has proven to be successful
for 2-methyl-3-cyclohexene-1,2-diol (1) (R = Me in Scheme 1),
where 2-methyl-1,4-hydrobenzoquinone (2) was obtained after
the double oxidation with the mild Cr(VI)-based reagents in
CH2Cl2 at RT (Table 1). An excess of oxidant (4 equiv.) was
required to give the optimum yield, even though two equiv.
was theoretically necessary. Silica gel supported pyridinium
chlorochromate4 (PCC) provided the best result (entry 4), which
was prepared by mixing and pulverizing equal weight amounts
of each material.
t-BuOK–t-BuOH conditions.5 We prepared 2-cyclohexen-1-
ones 3 with methyl or ethyl substituents at the 2-, 4-, and 5-
positions, which would constitute the three substituents (R1,
R2, and R3, respectively) of the 1,4-hydrobenzoquinones 2.
ꢀ
Pb(OAc)4-mediated direct a -acetoxylation6 of the conjugated
cyclohexenones 3 in refluxing toluene (conditions: A) produced
6-acetoxy-2-cyclohexen-1-ones 4 in reasonable yields except
ꢀ
for R-(−)-carvone (3f), where no reaction was observed. a -
Hydroxylation of the sterically demanding R-(−)-carvone (3f)
should be carried out by the peroxycarboxylic acid oxidation of
the corresponding trimethylsilyl (TMS) enol ether,7 which was
prepared by the reaction with TMSCl in the presence of sodium
hexamethyldisilazide (NaHMDS, conditions: B). Desilylated 6-
hydroxy-2-cyclohexen-1-one 4f was obtained in 90% yield in this
case (entry 16). The fourth substituent R4 was introduced by
the nucleophilic addition of alkyl metal species to the carbonyl
group of 4. MeLi, EtMgBr, and n-BuLi were used to add Me, Et,
and n-Bu groups, respectively to the six different cyclohexenones
4a–f to produce eighteen different 3-cyclohexene-1,2-diols 1a–r
in reasonable yields.8
The scope of this synthetic method for 1,4-hydrobenzo-
quinones 2 depends on the availability of diversely substituted
3-cyclohexene-1,2-diols 1. The preparation and the double
oxidation of 1 was delineated in Scheme 2, and summarized in
Table 2. We have reported a highly efficient synthetic method of
methyl-substituted conjugated cyclohexenones by the reaction
of b-ketoesters and a,b-unsaturated carbonyl compounds under
The key double oxidation of the 3-cyclohexene-1,2-diols
1a–r proceeded well under the standard conditions of 4
equiv. of silica supported PCC in CH2Cl2 at RT for 1 h to
give rise to the diversely substituted 1,4-hydrobenzoquinones
2a–r in decent yields.9 1,4-Hydrobenzoquinones 2 were formed
exclusively under an argon atmosphere even with an excess
(4 equiv.) of PCC oxidant. However, it was not possible to
avoid obtaining the oxidized 1,4-benzoquinones during the
purification process of SiO2 column chromatography. The actual
yield of 1,4-hydrobenzoquinones 2 must be higher by ca. 10%
than the reported yields in Table 2.
We then studied the possibility of synthesizing 1,2-
hydrobenzoquinones 5 by the PCC/SiO2 oxidation of the 3-
cyclohexene-1,2-diols 1s, 1t, and 1u, which were easily prepared
by hydride addition to the carbonyl groups of 4a, 4b, and
4f, respectively (Scheme 3 and Table 3). We expected that
the double oxidation of the secondary allylic and homoallylic
Table 1 The optimization of the double oxidation of 2-methyl-3-
cyclohexene-1,2-diol (1) (R = Me in Scheme 1)
Entry
Oxidant/equiv.
Reaction condition
Yield 2 (%)a
1
2
3
4
PCC (2)
PDC (4)
PCC (4)
PCC (4)–SiO2
RT for 3 h in CH2Cl2
RT for 1 h in CH2Cl2
RT for 2 h in CH2Cl2
RT for 1 h in CH2Cl2
30
33
56
78
a Isolated yield of 2-methyl-1,4-hydrobenzoquinone (2) after SiO2 chro-
matographic separation. 1,4-Benzoquinone was also obtained during
the purification process, the yield of which was about 10% of the
yield 2.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 7 9 – 3 4 8 1
3 4 7 9
©

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Table 2 The yields of each reaction in Scheme 2 for diverse substrates
c
Entry
3
R1
H
R2
H
R3
Conditionsa
A
4
R
Yield 4 (%)b
1
R4
Yield 1 (%)b
2
Yield 2 (%)b,d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
3a
Me
4a
Ac
81
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
Me
Et
Bu
Me
Et
Bu
Me
Et
Bu
Me
Et
Bu
Me
Et
Bu
Me
Et
76
55
52
80
69
54
71
67
66
75
64
59
91
72
81
77
56
70
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
71
59
62
70
66
78
67
57
52
64
55
69
81
63
69
77
67
60
3b
3c
3d
3e
3f
H
Me
H
H
A
A
A
A
B
4b
4c
4d
4e
4f
Ac
Ac
Ac
Ac
H
65
68
70
77
90
Me
Me
H
H
H
Me
Et
Me
H
Me
Bu
a Reaction conditions for 4, A: 3 and Pb(OAc)4 (2 equiv.) in toluene at reflux for 4 h; B: (i) 3, TMSCl, and NaHMDS in THF at 0 ◦C, (ii) urea–H2O2
(UHP) and phthalic anhydride in MeCN at RT for 5 h. b Isolated yields after SiO2 chromatographic separation. c An excess amount (3 equiv.) of MeLi,
EtMgBr, or n-BuLi was used to produce 3-cyclohexene-1,2-diols 1. d A small amount of 1,4-benzoquinone was also obtained during the purification
process, which was about 10% of the yield of 2.
Scheme 2 Synthesis of 1,4-hydrobenzoquinones 2 from 2-cyclohexen-1-ones 3.
Table 3 The yield 4 of the reaction in Scheme 3
subsequent oxidations. The 1,4-hydrobenzoquinones can be
efficiently utilized in the total synthesis of various polycyclic
natural products.
Entry
1
R1
R2
R3
4
Yield of 4 (%)a
This work was supported by the Korea Research Foundation
Grant (KRF-2003-015-C00342).
1
2
3
1s
1t
1u
H
H
Me
H
Me
H
Me
H
4s
4t
4f
78
69
83
References
1 (a) M. A. Ott and J. H. Noordik, J. Chem. Inf. Comput. Sci., 1997, 37,
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de Arias, H. Nakayama, S. Torres, J. Miret and M. E. Ferreira,
Tetrahedron, 2001, 57, 8653.
a Isolated yields after SiO2 chromatographic separation.
2 (a) R. H. Thomson, Naturally Occurring Quinones, Academic Press,
New York, 1971; (b) P. Mitchell and J. Moyle, Coenzyme Q, ed.
G. Lenaz, Wiley, Chichester, UK, 1985; (c) G. Lenaz, Coenzyme Q,
Biochemistry, Bioenergetics and Clinical Applications of Ubiquinone,
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Fischer and J. D. G. Correia, Angew. Chem., Int. Ed., 1994, 33, 2475;
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Tohma, H. Morioka, Y. Harayama, M. Hashizume and Y. Kita,
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Chandrasekharam, R. Srinivasan and A. K. Singh, Synth. Commun.,
2001, 31, 657; (f) O. Cherkaoui, P. Nebois and H. Fillion, Tetrahedron,
1996, 52, 9499; (g) S.-I. Murahashi, T. Naota, N. Miyaguchi and S.
Noda, J. Am. Chem. Soc., 1996, 118, 2509; (h) R. Salsdino, V. Neri, E.
Mincione and P. Filippone, Tetrahedron, 2002, 58, 8493.
Scheme 3 The oxidation of 3-cyclohexene-1,2-diols 1s–u using the
standard silica supported PCC (4 equiv.) conditions at RT (see Table 3).
alcohols of 1s–u would directly produce the corresponding 1,2-
hydrobenzoquinones 5. However, only the mono oxidation of the
allylic alcohol of 1s–u was observed to produce the 6-hydroxy-
2-cyclohexen-1-ones 4s, 4t and 4f in 69–83% yields. No 1,2-
hydrobenzoquinone 5 was obtained under the above PCC/SiO2
oxidation conditions.
4 (a) F. A. Luzzio, R. W. Fitch, W. J. Moore and K. J. Mudd, J. Chem.
Educ., 1999, 76, 974; (b) G. Piancatelli, A. Scettri and M. D’Auria,
Synthesis, 1982, 245.
In conclusion, we have developed a novel and efficient syn-
thetic method for diversely alkyl-substituted 1,4-hydrobenzo-
quinones 2 by the mild PCC/SiO2-promoted double oxidation
of 3-cyclohexene-1,2-diols 1, which were readily prepared from
the corresponding 2-cyclohexen-1-ones 3. This double oxidation
requires the secondary allylic alcohol and a tertiary allylic
alcohol in the 1,2-position to produce 1,4-hydrobenzoquinones
2 after allylic migration of the tertiary allylic alcohol and the
5 B.-D. Chong, Y.-I. Ji, S.-S. Oh, J.-D. Yang, W. Baik and S. Koo, J. Org.
Chem., 1997, 62, 9323.
6 J. E. Yeo, X. Yang, H. J. Kim and S. Koo, Chem. Commun., 2004, 236.
7 (a) G. M. Rubottom and J. M. Gruber, J. Org. Chem., 1978, 43, 1599;
(b) S. Choi and S. Koo, J. Org. Chem., 2005, 70, 3328.
8 The representative experimental procedure for 1a: To a stirred solution
of 4a (0.26 g, 1.5 mmol) in THF at −78 ◦C under an argon atmosphere
was added a 1.6 M solution of MeLi in ether (2.9 mL, 4.6 mmol).
The mixture was stirred at that temperature for 1 h and then at
3 4 8 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 7 9 – 3 4 8 1

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RT for 2 h. The reaction was quenched with 10% aqueous NH4Cl
solution, and extracted with ethyl acetate. The organic mixture was
washed with saturated aqueous NaCl solution, dried over anhydrous
K2CO3, filtered, and concentrated under reduced pressure. The crude
product was purified by SiO2 flash column chromatography to give
9 The representative experimental procedure for 2a: A mixture of PCC
(1.20 g, 5.6 mmol) and silica gel (1.20 g, 70–230 mesh) was pulverized
to give a light orange fine powder, which was added to a stirred solution
of 1a (0.17 g, 1.4 mmol) in CH2Cl2 at RT under an argon atmosphere.
The mixture was stirred for 1 h, and the resulting mixture was filtered
through a short pad of silica gel. The filtrate was concentrated under
reduced pressure. The crude product was purified by SiO2 flash column
chromatography to give 2a (0.13 g, 0.98 mmol) in 71% yield. The
corresponding 1,4-benzoquinone (0.01, 0.08 mmol) was also obtained
1
1a (0.17 g, 1.2 mmol) in 76% yield. Data for 1a (major isomer): H
NMR d 1,09 (d, J = 6.2 Hz, 3H), 1.29 (s, 3H), 1.71 (s, 1H), 1.76–
2.08 (m, 3H), 2.72 (s, 1H), 3.51 (d, J = 5.0 Hz, 1H), 5.49 (dt of A of
ABq, JAB = 9.8, Jd = 1.8, Jt = 0.9 Hz, 1H), 5.69 (dt of B of ABq,
JAB = 9.8, Jd = 1.4, Jt = 0.9 Hz, 1H) ppm; 13C NMR d 18.3, 28.4,
30.9, 31.9, 71.4, 76.9, 126.8, 131.7 ppm; IR (KBr) 3419, 1450, 1373,
1
in 6% yield. Data for 2a: H NMR d 2.18 (d, J = 2.2 Hz, 6H), 5.44
(br s, 1H),5.47 (br s, 1H), 5.93 (br s, 2H) ppm; 13C NMR d 17.8, 128.2,
1240 cm−1
.
128.5, 144.1, 158.7 ppm; IR (KBr) 3450, 1377, 1235 cm−1
.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 7 9 – 3 4 8 1
3 4 8 1