Divergent Pathways in the Reaction of Hexamethylbenzene with Dimethyldioxirane

Article abstract of DOI:10.1021/jo971339f

Hexamethylbenzene (1) reacts with dimethyldioxirane (2) via three separate reaction pathways. In the major pathway the reaction proceeds through an arene oxide which is rapidly transformed to the oxepin valence tautomer. In the first example of the reaction of an oxepin with 2 the oxepin is oxidized to first the cis-dioxide and then to the trioxide with the third oxide trans to the other two oxide rings. In a second competing pathway a methyl group migrates in the first produced arene oxide to give a hexamethyl-cyclohexadienone. This material then reacts rapidly with 2 to give a trans-diepoxide. The third reaction pathway involves the C-H insertion reaction of 2. This process gives first the derived benzyl alcohol and then the corresponding benzoic acid. Two other minor products are also formed, one is rationalized as arising from reaction of the arene oxide with water. The other is a tricyclic compound of unknown origin.

Full text of DOI:10.1021/jo971339f

8794
J . Org. Chem. 1997, 62, 8794-8799
Diver gen t P a th w a ys in th e Rea ction of Hexa m eth ylben zen e w ith
Dim eth yld ioxir a n e1,2
Robert W. Murray,* Megh Singh, and Nigam Rath
Department of Chemistry, University of MissourisSt. Louis, St. Louis, Missouri 63121
Received J uly 22, 1997X
Hexamethylbenzene (1) reacts with dimethyldioxirane (2) via three separate reaction pathways.
In the major pathway the reaction proceeds through an arene oxide which is rapidly transformed
to the oxepin valence tautomer. In the first example of the reaction of an oxepin with 2 the oxepin
is oxidized to first the cis-dioxide and then to the trioxide with the third oxide trans to the other
two oxide rings. In a second competing pathway a methyl group migrates in the first produced
arene oxide to give a hexamethyl-cyclohexadienone. This material then reacts rapidly with 2 to
give a trans-diepoxide. The third reaction pathway involves the C-H insertion reaction of 2. This
process gives first the derived benzyl alcohol and then the corresponding benzoic acid. Two other
minor products are also formed, one is rationalized as arising from reaction of the arene oxide
with water. The other is a tricyclic compound of unknown origin.
In tr od u ction
ported on silica gel or fluorosil, with O(3P) atoms gave
hexamethyl-2,4-cyclohexadienone and its keto epoxide.12
Oxyfunctionalization of aromatic hydrocarbons, including
1, as well as methoxybenzenes, with the hydrogen
peroxide/methyltrioxorhenium system or with hydrogen
peroxide/hexafluoroacetone hydrate, gave the p-quino-
nes.13,14 Acid-catalyzed oxidation of methoxybenzenes by
dimethyldioxirane (2) afforded the corresponding p-
quinones in good yields.15
Dioxiranes are now recognized as versatile oxygen
transfer reagents that can be used under extremely mild
conditions.16 Dioxiranes also show electrophilic character
in their chemistry and might be expected to react with
1. We describe here a study of the reaction of 1 with
dioxirane 2. The resulting chemistry is rich and includes
the first example of the reaction of 2 with an oxepin.
Electron rich hexamethylbenzene (1) has been oxidized
by a variety of reagents, most notably peracids. Oxida-
tion of 1 with perbenzoic acid gives the ring-opened
products, biacetyl and sym-dimethyldiacetyl ethylene.3
Whereas the oxidation of 1 with trifluoroperacetic acid
afforded acetic acid only.4 However, when the trifluo-
roperacetic acid is used with boron trifluoride, then the
product is hexamethyl-2,4-cyclohexadienone.5 Many natu-
ral or nonnatural aromatic compounds including perm-
ethylated benzenes have been oxidized by m-chloroper-
benzoic acid to give quinones or hydroxylated products.6
Oxidation of 1 with HOF‚CH3CN also gave hexamethyl-
2,4-cyclohexadienone as an intermediate which then was
further oxidized to two keto epoxides.7 When 1 was
photooxidized in methanol a mixture of permethylated
benzyl ethers and tetramethylphthalide was obtained.8
Whereas dye-sensitized photooxidation of 1 in acetoni-
trile, involving singlet oxygen, afforded epidioxy hydro-
peroxide via a [4 + 2]-cycloaddition, followed by an ene
reaction.9 Several polyalkylbenzenes, including 1, have
been ozonized in carbon tetrachloride and acetic acid. In
the case of 1 the reaction yielded the ring cleaved
products, biacetyl and acetic acid.10 When 1 is oxidized
with the Cu(II)-peroxy disulfate system the product is
pentamethylbenzyl alcohol.11 The oxidation of 1, sup-
Resu lts a n d Discu ssion
The reaction of 1 with 2 was studied under a variety
of experimental conditions. When the reaction is carried
out at room temperature for 24 h using solutions of 1
and 2 in acetone with a ratio of 4:1 (compound 2:1) the
1H NMR spectrum indicated that a number of products
are formed, with the major product being 2,3:4,5:6,7-
triepoxy-2,3,4,5,6,7-hexamethyloxepane (3). It is ac-
companied by 2,3:6,7-diepoxy-2,3,4,5,6,7-hexamethylox-
epin, 4, and several minor products. The structures of 3
X Abstract published in Advance ACS Abstracts, December 1, 1997.
(1) Chemistry of Dioxiranes. 35. Part 34: Murray, R. W.; Singh,
M.; Rath, N. Tetrahedron Lett. 1996, 37, 8671.
(2) Portions of this work were published in preliminary form:
Murray, R. W.; Singh, M., Rath, N. J . Org. Chem. 1996, 61, 7660.
(3) Andrews, L. J .; Keefer, R. M. J . Am. Chem. Soc. 1955, 77, 2545.
(4) Liotta, R.; Hoff, W. S. J . Org. Chem. 1980, 45, 2887.
(5) Hart, H.; Collins, P. M.; Wearing, A. J . J . Am. Chem. Soc. 1966,
88, 1005.
(12) Zadok, E.; Rubinraut, S.; Frolow, F.; Mazur, Y. J . Am. Chem.
Soc. 1985, 107, 2489.
(13) Adam, W.; Herrmann, W. A.; Saha-Moller, C. R.; Shimizu, M.
J . Mol. Catal. 1995, 97, 15.
(14) (a) Adam, W.; Ganeshpure, P. A. Synthesis 1993, 280. (b)
Ganeshpure, P. A.; Adam, W. Synthesis 1996, 179.
(15) Adam, W.; Shimizu, M. Synthesis 1994, 560.
(6) Asakawa, Y.; Matsuda, R.; Tori, M.; Sono, M. J . Org. Chem. 1988,
53, 5453.
(7) Kol, M; Rozen, S. J . Org. Chem. 1993, 58, 1593.
(8) Wasserman, H. H.; Mariano, P. S.; Keehn, P. M. J . Org. Chem.
1971, 36, 1765.
(9) (a) Van den Heuvel, C. J . M.; Steinberg, H; De Boer, T. J . Recl.
Trav. Chim. Pays-Bas 1977, 96, 157. (b) Van den Heuvel, C. J . M.;
Hofland, H; Steinberg, H.; De Boer, T. J . Recl. Trav. Chim. Pays-Bas
1980, 99, 275.
(10) Nakagawa, T. W.; Andrews, L. J .; Keefer, R. M. J . Am. Chem.
Soc. 1960, 82, 269.
(16) For reviews of dioxirane chemistry see: (a) Murray, R. W.
Chem. Rev. (Washington, D.C.) 1989, 89, 1187. (b) Curci, R. In
Advances in Oxygenated Processes; Baumstark, A. L., Ed.; J AI Press:
Greenwich, CT, 1990; Vol. 2, Chapter 1. (c) Adam, W.; Hadjiarapoglou,
L. P.; Curci, R.; Mello, R. In Organic Peroxides; Ando, W., Ed.; J . Wiley
and Sons: New York, 1992; Chapter 4. (d) Adam, W.; Curci, R.;
Edwards, J . O. Acc. Chem. Res. 1989, 22, 205. (e) Adam, W.;
Hadjiarapoglou, L. P. Top. Curr. Chem. 1993, 49, 2227. (f) Curci, R.;
Dinoi, A.; Rubino, M. F. Pure and Appl. Chem. 1995, 67, 811. (g)
Murray, R. W.; Singh, M. In Comprehensive Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon
Press: Oxford, 1996, Chapter 1.14, p 429. (h) Clennan, E. L. Trends
Org. Chem. 1995, 5, 231.
(11) Cort, A. D.; Mandolini, L.; Panaioli, S. Synth. Commun. 1988,
18, 613.
S0022-3263(97)01339-X CCC: $14.00 © 1997 American Chemical Society

Reaction of Hexamethylbenzene with Dimethyldioxirane
J . Org. Chem., Vol. 62, No. 25, 1997 8795
F igu r e 1. ORTEP drawing of diepoxide 4.
F igu r e 3. ORTEP drawing of tricyclic compound 6.
Sch em e 1. Oxid a tion of Hexa m eth ylben zen e by
Dim eth yld ioxir a n e
Sch em e 2. Com p etin g P a th w a y in th e Oxid a tion
of 1 by 2
F igu r e 2. ORTEP drawing of triepoxide 3.
and 4 were confirmed by X-ray crystallographic analysis.
These structures show that the epoxide groups in 4
(Figure 1) are cis to each other and that the third epoxide
group in 3 (Figure 2) is installed trans to the other two
epoxide groups. An additional quantity of 2 (10 mL, 0.74
mmol) was added and stirring continued for an additional
24 h. Removal of the solvent on the rotovap and
chromatography on the Chromatotron gave samples of
the pure products. Oxepane 3 was formed in 51% yield.
Oxepin 4, the presumed precursor to 3, was no longer in
the product mixture. When the reaction is repeated with
a lower amount of 2 then 4 becomes the major product,
confirming its precursor status. The next most abundant
product (19%) was identified as trans-3,4:5,6-diepoxy-
2,2,3,4,5,6-hexamethylcyclohexanone, 5. The minor prod-
ucts included the interesting tricyclic compound, trans-
4,8-dihydroxy-2,6,9-trioxatricyclo[3.3.1.01]nonane, 6. The
structure of this unusual product was confirmed by an
X-ray structure determination (Figure 3). Other minor
products were identified as trans-diepoxy-1,2,3,4,5,6-
hexamethylcyclohexane-trans-1,4-diol, 7, 2,3,4,5,6-pen-
tamethylbenzyl alcohol, 8 (6.4%), and 2,3,4,5,6-pentam-
ethylbenzoic acid, 9. Performing the reaction at -20 °C
gave almost the same distribution of products. The
exceptions being that none of acid 9 or the tricyclic
compound 6 were present. This is presumably because
the reaction proceeds at a slower rate. When the reaction
at room temperature is repeated with a small amount of
solid sodium bicarbonate added, then the products are
3-5 only. No traces of 6-9 were evident. This effect of
added bicarbonate turns out to be an important observa-
tion. We now routinely use this modification in preparing
arene oxides and dioxides and find that formation of side
products is suppressed and oxides yields are optimized.
We believe that the primary reaction proceeds as
shown in Scheme 1. The high electron ring density in 1
permits direct oxidation by 2 to give arene oxide 10.
Many arene oxides rearrange to phenols under appropri-
ate conditions. Other arene oxides are in dynamic
equilibrium with their valence tautomers. A small
number of arene oxides rearrange to stable oxepins.17
Methyl groups are known17 to stabilize oxepins leading
to the facile conversion of 10 to oxepin 11. The oxepin is
rapidly oxidized by 2 to give the cis-diepoxide 4 which is
further oxidized to the oxepane 3. We believe that this
is the first example of the oxidation of an oxepin by 2.
The primary reaction shown in Scheme 1 competes
with two other processes. In the first of these a methyl
group migrates in arene oxide 10 to give dienone 12
(Scheme 2). This material is then epoxidized by 2 to give
the observed trans diepoxide 5, presumably via the mono
(17) For reviews and monographs on oxepin chemistry see: (a)
Vogel, E.; Gunther, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 385. (b)
Boyd, D. R.; J erina, D. M. Small Ring Heterocycles, Part III. In The
Chemistry of Heterocyclic Compounds; Hassner, A., Ed.; J . Wiley and
Sons: New York, 1985; Vol. 42, p 197. (c) Shirwaiker, G. S.; Bhatt,
M. V. in Advances in Heterocylic Chemistry; Katritzky, A. R., Ed.;
Academic Press: Orlando, FL; 1984; Vol. 37, p 67. (d) Boyd, D. R. In
Comprehensive Heterocylic Chemistry; Katritzky, A. R., Rees, C. W.,
Lwowski, W., Eds.; Pergamon Press: Oxford, 1984; Vol. 7, Chapter
5.17, p 547. (e) Harvey, R. G. In Polycyclic Aromatic Hydrocarbons:
Chemistry and Carcinogenicity; Cambridge University Press: Cam-
bridge, 1991, p 276. (f) Boyd, D. R.; Sharma, N. D. Chem. Soc. Rev.
1996, 289.

8796 J . Org. Chem., Vol. 62, No. 25, 1997
Murray et al.
Sch em e 3. Com p etin g In ser tion Rea ction in th e
Oxid a tion of 1 by 2
epoxide 13. This sequence has been verified by synthe-
sizing authentic 12 and oxidizing it with 2 to give first
13 which is then further oxidized to 5. It is interesting
that only trans-5 is formed either in the basic reaction
of 1 or in the direct oxidation of 12. To gain more
information on the factors which contribute to the opera-
tion of the basic reaction versus the methyl migration
route, we have studied several variations of the basic
procedure. We speculated that the process shown in
Scheme 2 might be acid catalyzed. In the first of the
reaction variations we have carried out the basic reaction
procedure with a crystal of p-toluenesulfonic acid added.
Under these conditions only two major products are
formed, namely, diepoxide 5 and oxepane 3. They are
formed in the ratio of 85:15 (5:3). This result is to be
compared to the ratio of 25:75 (5:3) obtained in the basic
reaction procedure of 1 with 2. The reaction sequence
given in Scheme 2 is clearly acid catalyzed. This result
raised the question of whether the operation of this
competing process is also catalyzed by some acid in the
basic reaction. Some time ago Baumstark and Vasquez18
had shown that adding water to the reaction medium
increases the rate of some epoxidation reactions of 2.
Suspecting that water could act as an acid catalyst in
our current work, we prepared a solution of 2 which was
dried with molecular sieves in order to remove traces of
water. When the reaction of 1 is performed with this
extra dry solution of 2, then the products 5 and 3 are
formed in a ratio of 20:80 (5:3). In this case the benzoic
acid 9 is actually formed in larger yield than is 5. This
result suggests that water provides some acid catalysis.
The formation of alcohol 8 and acid 9 is due to the
operation of a second competing process. These products
arise from the C-H insertion reaction of 2 (Scheme 3).
This most unusual process was first reported by us19 for
2 in 1986 and was followed by a report20 by Curci et al.
of a similar reaction for trifluoromethylmethyldioxirane.
To support this interpretation we have oxidized the
benzyl alcohol 8 with 2 and found acid 9 to be the major
product. When the oxidation of 1 was performed with
an extra dry solution of 2 as described above, the second
most abundant product was acid 9. This is presumably
because the removal of water from the reaction medium
has slowed the rate of the competing epoxidation reac-
tions and allowed the C-H insertion reaction to assume
a more prominent role in the overall reaction.
F igu r e 4. ORTEP drawing of diol 7.
expected to be formed in approximately equal amounts
in a nonconcerted reaction. The stereochemistry in the
trans diol has been confirmed by X-ray diffraction (Figure
4).21 We are uncertain as to the origin of tricyclic
compound 6. Its structure has been confirmed by X-ray
crystallographic analysis (Figure 3).21 On the basis of
atom composition, we considered the possibility that 6
could arise from 3 by reaction with water. When heated
with acetone-water for several days, 3 was recovered
unchanged, however. We have also speculated that a
small amount of the all cis isomer of 3 could have been
formed in the basic reaction and that it was converted
to 6 by water. We have attempted to synthesize all cis-3
by reacting 4 with a variety of oxidants. When MCPBA,
2, or trifluoroacetic anhydride/urea hydrogen peroxide
adduct (UHP) were reacted with 4, only 3 was formed.
When methyltrioxorhenium/UHP was used as the oxi-
dant, neither 3 nor its all cis isomer was produced. Thus
to date we have not been able to determine whether the
all cis isomer of 3 serves as a precursor to 6.
Exp er im en ta l Section
Ma ter ia ls a n d Rea gen ts. Hexamethylbenzene was ob-
tained from Aldrich Chemical and was recrystallized from
ethanol prior to use. Silica gel (Merck, 35-70 mesh, 40 Å)
was obtained from Aldrich. Oxone (DuPont), 2KHSO5‚
KHSO4‚K2SO4, was obtained from Aldrich and used as re-
ceived. Trifluoroacetic anhydride, urea hydrogen peroxide
complex (UHP), and methyltrioxorhenium (MTO) were all
purchased from Aldrich. m-Chloroperbenzoic acid (70-78%)
was obtained from J anssen Chimica and used as received.
Acetone (Fisher reagent grade) was fractionally distilled over
anhydrous potassium carbonate. Methylene chloride and
hexane were obtained from Fisher and were distilled from
calcium hydride before use. The dimethyldioxirane solution
in acetone was prepared according to the literature proce-
dure22,23 and was assayed for dioxirane content using phenyl
methyl sulfide and the GLC method,23 or concentration was
determined using a calibration curve of dioxirane concentra-
tion versus UV absorbance at 335 nm.
In str u m en ta tion . 1H and 13C NMR spectra were recorded
on a 300 MHz NMR spectrometer with CDCl3 as solvent. All
NMR data are reported in ppm or δ values downfield from
TMS. The multiplicities of 13C NMR signals were determined
by the attached proton test (APT) pulse sequence. Electron
impact and chemical ionization mass spectra were recorded
Some comment is due on the formation of the minor
products, diol 7 and the tricyclic compound 6. We believe
that 7 is formed in a concerted opening of arene oxide
10 by water, followed by epoxidation by 2. Consistent
with this suggestion is the absence of this product in the
reaction of 1 with extra dry 2. We suggest that the
reaction is concerted since the trans diol is accompanied
by only a trace of the cis isomer. The isomers might be
(21) A complete list of atomic coordinates, geometric parameters,
anisotropic thermal parameters, hydrogen atom coordinates, and
structure factors are deposited with the Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge, CB2 1EZ, UK and can be
obtained on request fron the Director of CCDC.
(22) (a) Murray, R. W.; J eyaraman, R. J . Org. Chem. 1985, 50, 2847.
(b) Singh, M.; Murray, R. W. J . Org. Chem. 1992, 57, 4263. (c) Adam,
W.; Hadjiarapoglou, L.; Bialas, J . Chem. Ber. 1991, 124, 2377.
(23) Murray, R. W.; Singh, M. Org. Synth. 1996, 74, 91.
(18) Baumstark, A. L.; Vasquez, P. C. J . Org. Chem. 1988, 53, 3437.
(19) Murray, R. W.; J eyaraman, R.; Mohan, L. J . Am. Chem. Soc.
1986, 108, 2470.
(20) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J . Am. Chem. Soc.
1989, 111, 6749.

Reaction of Hexamethylbenzene with Dimethyldioxirane
J . Org. Chem., Vol. 62, No. 25, 1997 8797
at 70 eV ionizing voltage on a twin EI and CI quadrupole mass
spectrometer connected to a gas chromatograph fitted with a
12 m × 0.2 mm × 0.33 µm Ultra-1 (cross-linked methyl
silicone) column. Infrared spectra were recorded in KBr pellets
on an FT-IR spectrometer. UV-vis spectra were obtained on
a UV-vis spectrophotometer. Melting points were determined
on a hot stage apparatus and are uncorrected. Chromato-
graphic separations on the Chromatotron were accomplished
using 2 mm Kieselgel 60 PF254 gypsum coated plates. Gas
chromatography was performed on a gas chromatograph using
a flame ionization detector, a fused silica capillary column
(methyl 5% phenyl silicone liquid phase, 30 mm × 0.25 mm;
film thickness 0.5 µm), and He as the carrier gas. The
chromatograph was interfaced with an integrator. Elemental
analyses were performed by Atlantic Microlab, Inc. (Norcross,
GA).
8.01. The first minor product was isolated as a colorless
viscous liquid (0.278 g, 19%) and was identified as the trans-
1
diepoxyketone, 5, by comparing its H and 13C NMR and mass
spectral data with those of an authentic sample.7,9 The second
minor product was identified as the tricyclic diol 6 (0.0045 g,
3%) on the basis of its X-ray crystallographic structure and
the following data: mp 120-122 °C; 1H NMR (CDCl3, 300
MHz): δ 1.32 (s, 6H), 1.33 (s, 12H), 1.81 (br s, 2H); 13C NMR
(75 MHz, CDCl3): δ 13.76, 14.84, 15.23, 78.98, 88.26, 107.60;
MS (EI, 70 eV): m/z (relative intensity) 201(0.1), 183(3), 157(3),
141(21), 115(100), 99(12), 88(19), 43(20); Calcd for C12H20O5:
244.28. The third minor product was isolated as a colorless
crystalline solid (0.012 g, 7.5%) and was identified as trans-
2,3:5,6-diepoxy-1,2,3,4,5,6-hexamethylcyclohexane-trans-1,4-
diol, 7, on the basis of the following data: mp 130-135 °C
(dec); 1H NMR (300 MHz, CDCl3): δ 1.34 (s, 6H), 1.37 (s, 6H),
1.41 (s, 6H), 2.10 (br s, 2H); 13C NMR (75 MHz, CDCl3): δ
14.80, 16.11, 20.75, 67.11, 68.84, 72.08; MS (EI, 70 eV): m/z
(relative intensity) 167(1), 153(9), 141(62), 125(97), 115(15),
99(29), 83(27), 81(9), 55(15), 43(100); Calcd for C12H20O4:
228.28. Another minor product was isolated as a colorless
crystalline solid (0.008 g, 6.4%) and was identified as 2,3,4,5,6-
pentamethylbenzyl alcohol, 8; mp 160-162 °C, lit.8,24 mp 160-
161 °C; 1H NMR (300 MHz, CDCl3): δ 1.31 (br s, 1H), 2.22 (s,
6H), 2.24 (s, 3H), 2.35 (s, 6H), 4.76 (s, 2H); 13C NMR (75 MHz,
CDCl3): δ 16.26, 16.74, 17.06, 60.18, 132.78, 132.83, 133.93,
135.04; MS (EI, 70 EV): m/z (relative intensity) 179(M + 1,
7), 178 (M+, 58), 161(22), 160(100), 145(57), 135(17), 119(24),
105(15),91(19), 77(11); Calcd for C12H18O: 178.28. The final
minor product was isolated as a colorless crystalline solid
(0.007 g, 5%) and was identified as 2,3,4,5,6-pentamethylben-
Gen er a l P r oced u r e for th e Rea ction of Hexa m eth yl-
ben zen e w ith Dim eth yld ioxir a n e. The reactions of 1 mol
equiv of hexamethylbenzene with 1-7 mol equiv of an acetone
solution of dimethyldioxirane were carried out by adding the
dioxirane solution to a magnetically stirred solution of hex-
amethylbenzene in acetone at room temperature (20-22 °C)
unless otherwise stated. The progress of the reaction was
monitored periodically by GLC and GC-MS. Additional
amounts of the dioxirane solution were added in several hour
intervals until complete consumption of the starting material
and/or intermediate products was observed. The relative ratio
of the products was determined by GLC and GC-MS analysis
of the reaction mixture or by 1H NMR analysis of the crude
reaction mixture residue obtained by removal of solvent. The
ratios determined by NMR analysis were comparable to those
determined by GLC or GC-MS analysis. Solvent was removed
on the rotary evaporator and the residue was dissolved in
methylene chloride and the solution dried with anhydrous
sodium sulfate. The residue obtained by evaporation of the
solvent was dried in vacuo. The residue was subjected to
radial chromatography on the Chromatotron. The separated
products were reanalyzed to ensure purity. The products were
1
zoic acid, 9, mp 210-211 °C, lit.25 mp 211 °C; H NMR (300
MHz, CDCl3): δ 2.20 (s, 6H), 2.23 (s, 3H), 2.27 (s, 6H), 11.2
(br s, 1H); 13C NMR (75 MHz, CDCl3): δ 16.13, 16.76, 17.68,
128.94, 132.01, 132.88, 136.49, 177.13; MS (EI, 70 eV): m/z
(relative intensity) 193 (M + 1, 13), 192 (M+, 100), 177(33),
174(57), 147(70), 131(52), 115(16), 105(14), 91(25), 77(12);
Calcd for C12H16O2: 192.26.
1
characterized using H and 13C NMR, X-ray crystallography,
When the same procedure was performed with a reduced
amount of 2, the intermediate diepoxyoxepin 4 could be
isolated as the major product. To a magnetically stirred
solution of 1 (0.110 g, 0.678 mmol) in 2 mL of acetone was
added 20 mL (1.36 mmol) of 0.069 M 2 in acetone. The
reaction mixture was stirred at room temperature for 5 h to
give an orange solution. No trace of 2 was observed (KI/
starch). The solvent was removed on the rotovap to give a
colorless residue (0.1206 g). 1H NMR and GLC analysis of the
residue indicated the presence of unreacted 1 (62%), diepoxide
4 (29%), triepoxide 3 (5%), epoxy ketone 13 (5%), and traces
of diepoxy ketone 5. Purification of the residue on the
Chromatotron using acetone (5-10%) in hexane afforded
diepoxide 4 as a colorless solid (0.036 g, 25%); mp 115-117
°C; IR (KBr): 2938, 1477, 1379, 1252, 1188, 1139, 1112, 991,
902, 884, 806, 722, 632 cm-1; 1H NMR (CDCl3): δ 1.37 (s, 6H),
1.75 (s, 6H), 1.79 (s, 6H); 13C NMR (CDCl3), 75 MHz): δ 14.68,
17.36, 20.57, 66.10, 90.71, 127.89; MS (EI, 70 eV): m/z (relative
intensity) 194(1), 167(M+ - CH3CO,2), 153(40), 151(66),
125(58), 111(18), 91(12), 55(8), 43(100); MS (CI, methane) did
not show the M + H or M peak; Calcd for C12H18O3: 210.28.
Anal. Calcd for C12H18O3: C, 68.55; H, 8.63. Found: C, 68.64;
H, 8.69.
and mass spectrometry and by comparison of their spectral
and chromatographic properties with those of authentic samples
or with literature values.
Rea ction of Hexa m eth ylben zen e w ith Dim eth yld iox-
ir a n e. 1. At Room Tem p er a tu r e. To a magnetically stirred
solution of hexamethylbenzene, 1 (0.1135 g, 0.7 mmol), in 3
mL of acetone was added 38 mL (2.8 mmol) of an 0.074 M
solution of dimethyldioxirane, 2, in acetone. The reaction
mixture was stirred at room temperature for 24 h to give an
orange-yellow solution. The solvent was removed and an 1H
NMR spectrum of the residue recorded. The spectrum indi-
cated the presence of 2,3:4,5:6,7-triepoxy-2,3,4,5,6,7-hexam-
ethyloxepane, 3, 2,3:6,7-diepoxy-2,3,4,5,6,7-hexamethyloxepin,
4, 3,4:5,6-diepoxy-2,2,3,4,5,6-hexamethylcyclohexanone, 5, 4,5-
epoxy-2,3,4,5,6,6-hexamethyl-2-cyclohexen-1-one, 13, and sev-
eral other products, but no starting material. An additional
quantity of 2 (10 mL) was added and the reaction mixture was
stirred for an additional 24 h. Solvent was removed on the
rotovap to give a colorless residue (0.1484 g). GLC and 1H
NMR analysis of the residue indicated the presence of the
triepoxide, 3, as the major product and the diepoxy ketone, 5,
as the minor product, in the ratio 75:25. Other minor products
present were identified as trans-4,8-dihydroxy-2,6,9-
trioxatricyclo[3.3.1.01]nonane, 6, trans-2,3:5,6-diepoxy-1,2,3,4,5,6-
hexamethylcyclohexane-trans-1,4-diol, 7, 2,3,4,5,6-pentameth-
ylbenzyl alcohol, 8, and 2,3,4,5,6-pentamethylbenzoic acid, 9.
Purification of the residue on the Chromatotron using
acetone (5-10%) in hexane as eluent gave the triepoxide, 3,
as a colorless crystalline solid (0.081 g, 51%); mp 137-138 °C;
IR (KBr) 3009, 2945, 1459, 1387, 1195, 1135, 1090, 996, 891,
2. At -25 °C. The general procedure was followed using
0.082 g (0.5052 mmol) of 1 in 3 mL of acetone and 46 mL (3.03
mmol) of an 0.066 M solution of 2 in acetone. The reaction
mixture was stirred at -25 °C (CCl4/dry ice bath) and
monitored periodically by GLC and GC/MS. The reaction
mixture was stirred for 72 h to give a pale yellow solution.
Solvent was removed on the rotovap to give a colorless residue
1
1
872, 802, 738, 679 cm-1; H NMR (300 MHz, CDCl3): δ 1.39
(0.1082 g). GLC, GC/MS, and H NMR analysis of the residue
(s, 6H), 1.44 (s, 6H), 1.66 (s, 6H); 13C NMR (75 MHz, CDCl3):
δ 14.80, 15.71, 19, 74, 65.78, 66.54, 88.38; MS (EI, 70 eV): m/z
(relative intensity) 183 (M+-CH3CO,1), 169 (4), 141 (45), 123
(10), 113 (8), 99 (20), 88 (83), 83 (20), 55 (12), 43 (100); MS
(CI, methane) 227 (M + 1, 5); Calcd for C12H18O4: 226.28. Anal.
Calcd for C12H18O4: C, 63.70; H, 8.02. Found: C, 63.70; H,
indicated the presence of the triepoxide 3, diepoxide 4 (major
(24) Masnovi, J . M.; Sankaraman, S.; Kochi, J . K. J . Am. Chem. Soc.
1989, 111, 2263.
(25) Rodd’s Chemistry of Carbon Compounds; Coffey, S., Ed.,
Elsevier: Amsterdam, 1978; Vol III, Part G, p 11.

8798 J . Org. Chem., Vol. 62, No. 25, 1997
Murray et al.
Ta ble 1. Cr ysta l Da ta a n d Str u ctu r e Refin em en t for
Com p ou n d 3
Ta ble 3. Cr ysta l Da ta a n d Str u ctu r e Refin em en t for
Com p ou n d 6
empirical formula
formula weight
temperature
C12H18O4
226.26
193(2) K
empirical formula
formula weight
temperature
C12H20O5
244.28
298(2) K
crystal system
space group
monoclinic
P21/c
crystal system
space group
orthorhombic
C2221
unit cell dimensions
a ) 14.6110(7) Å, R ) 90°
b ) 8.3409(5) Å, â ) 99.188(2)°
c ) 9.8061(4) Å, γ ) 90°
1179.73(10) Å3, 4
1.274 mg/m3
unit cell dimensions
a ) 10.8553(2) Å, R ) 90°
b ) 13.4006(2) Å, â ) 90°
c ) 8.5790(2) Å, γ ) 90°
1247.97(4) Å3, 4
1.300 mg/m3
volume, z
volume, z
density (calculated)
absorption coefficient
crystal size
density (calculated)
absorption coefficient
crystal size
0.095 mm-1
0.100 mm-1
0.10 × 0.20 × 0.33 mm
0.33 × 0.33 × 0.09 mm
θ range for data collection
reflections collected
independent reflections
data/restraints/parameters
goodness-of-fit on F2
final R indices [I > 2σ(I)]
R indices (all data)
largest diff peak and hole
1.41 to 22.50°
θ range for data collection
reflections collected
independent reflections
data/restraints/parameters
goodness-of-fit on F2
final R indices [I > 2σ(I)]
R indices (all data)
largest diff peak and hole
2.41 to 28.00°
5337
6580
1537 (Rint ) 0.0860)
1519/0/145
1.080
R1 ) 0.0926, wR2 ) 0.2622
R1 ) 0.1113, wR2 ) 0.2917
0.346 and -0.687 e Å-3
1516 (Rint ) 0.0578)
1507/0/78
1.093
R1 ) 0.0502, wR2 ) 0.1258
R1 ) 0.0615, wR2 ) 0.1359
0.298 and -0.230 e Å-3
Ta ble 2. Cr ysta l Da ta a n d Str u ctu r e Refin em en t for
Com p ou n d 4
Ta ble 4. Cr ysta l Da ta a n d Str u ctu r e Refin em en t for
Com p ou n d 7
empirical formula
formula weight
temperature
C12H18O3
210.26
298(2) K
empirical formula
formula weight
temperature
C12H22O4
230.30
298(2) K
crystal system
space group
unit cell dimensions
monoclinic
P21/c
wavelength
crystal system
space group
0.71073 Å
triclinic
P1h
a ) 14.6871(9) Å, R ) 90°
b ) 8.3848(5) Å, â ) 99.289(2)°
c ) 9.9452(6) Å, γ ) 90°
1208.68(13) Å3, 4
1.155 mg/m3
unit cell dimensions
a ) 7.6039(3) Å, R ) 73.117(2)°
b ) 8.3499(2) Å, â ) 80.608(2)°
c ) 12.1530(4) Å, γ ) 66.424(2)°
675.76(4) Å3, 2
volume, z
density (calculated)
absorption coefficient
crystal size
volume, z
0.082 mm-1
density (calculated)
absorption coefficient
F (000)
crystal size
θ range for data collection 3.51 to 24.78°
limiting indices
reflections collected
independent reflections
adsorption correction
refinement method
1.201 mg/m3
0.55 × 1.15 × 0.10 mm
0.093 mm-1
θ range for data collection
reflections collected
independent reflections
data/restraints/parameters
goodness-of-fit on F2
final R indices [I > 2σ(I)]
R indices (all data)
largest diff peak and hole
1.40 to 22.50°
268
5512
0.15 × 0.10 × 0.10 mm
1567 (Rint ) 0.0862)
1542/0/137
1.082
R1 ) 0.0714, wR2 ) 0.1985
R1 ) 0.0952, wR2 ) 0.2278
0.333 and -0.199 e Å-3
-8 e h e 8, -9 e k e 9, 0 e 1 e 14
6051
2257 (Rint ) 0.078)
none
full-matrix least-squares on F2
data/restraints/parameters 2213/0/154
goodness-of-fit on F2
1.025
final R indices [I > 2σ(I)] R1 ) 0.0697, wR2 ) 0.1675
product), epoxy ketone 13, and diepoxy diol 7. Unreacted 1
was also present as were traces of diepoxy ketone 5 and benzyl
alcohol 8.
R indices (all data)
R1 ) 0.1637, wR2 ) 0.2195
3. With Ad d ed Sod iu m Bica r bon a te. The general
procedure was followed using 0.122 g (0.752 mmol) of 1 in 2
mL of acetone, sodium bicarbonate (0.50 g), and 75 mL (4.5
mmol) of an 0.064 M solution of 2 in acetone. The reaction
mixture was stirred at room temperature in the dark. The
progress of the reaction was monitored periodically by GLC
and GC/MS. Analysis of the reaction mixture after 64 h
indicated the presence of oxepane 3, oxepin 4, and diepoxy
ketone 5 in the ratio of 58:27:15. No starting material was
present. An additional quantity of 2 was added, and the
reaction mixture was stirred overnight. GLC and 1H NMR
analysis of the reaction mixture showed only the presence of
oxepane 3 and diepoxy ketone 5 in the ratio 90:10. None of
the other previously observed minor products were present.
4. Usin g An Extr a Dr y Solu tion of 2. To a magnetically
stirred solution of 1 (0.044 g, 0.272 mmol) in 3 mL of acetone
was added 21 mL (1.64 mmol) of an 0.0785 M solution of 2
which had been dried with molecular sieves. The reaction
mixture was stirred at room temperature, and the progress of
the reaction was monitored by GLC and GC/MS. After 96 h
the solvent was removed on the rotovap to give a colorless
largest diff peak and hole 0.256 and -0.253 e Å-3
a small crystal of p-toluenesulfonic acid in 3 mL of acetone
was added 11 mL (0.813 mmol) of an 0.074 M solution of 2 in
acetone. the reaction mixture was stirred at room temperature,
and the progress of the reaction was monitored periodically
by GLC and GC/MS. After 96 h the solvent was removed on
the rotovap to give a colorless viscous liquid (0.032 g). GLC
1
and H NMR analysis of the residue indicated the presence of
the diepoxy ketone 5 and oxepane 3 in the ratio of 85:15. The
residue also contained traces of the diol 7 and acid 9.
Rea ction of 2,3,4,5,6,6-Hexa m eth yl-2,4-cycloh exa d i-
en e-1-on e, 12, w ith 2. A sample of 12 was synthesized
following the literature procedure.5,26 To a magnetically
stirred solution of 12 (0.0446 g, 0.25 mmol) in acetone (2 mL)
was added 11 mL (0.75 mmol) of 0.07 M 2 in acetone. The
reaction mixture was stirred at room temperature and was
monitored periodically by 1H NMR, GLC, and GC/MS. 1H
NMR analysis of the reaction mixture after 27 h showed the
presence of monoepoxide 13 and diepoxide 5 in a 20:80 ratio.
The reaction mixture was treated with a fresh solution of 2 in
acetone and stirring continued at room temperature for
another 20 h. Solvent was removed on the rotary evaporator
to give diepoxide 5 as a colorless viscous liquid (0.0472 g, 90%).
1
residue (0.0575 g). GLC and H NMR analysis of the residue
indicated the presence of oxepane 3 as the major product
accompanied by diepoxy ketone 5 and acid 9 as minor products
in the ratio 58:16:27. The oxepane-to-diepoxy ketone ratio (3:
5) was found to be 80:20. None of the other minor products
were found to be present.
1
The product was identified by comparing its H and 13C NMR
data with those in the literature.
5. With a Tr a ce of P -tolu en esu lfon ic Acid Ad d ed . To
a magnetically stirred solution of 1 (0.022 g, 0.135 mmol) and
(26) Hart, H.; Lange, R. M.; Collins, P. M. Organic Syntheses;
Wiley: New York, 1973; Coll. Vol. 5, p 598.

Reaction of Hexamethylbenzene with Dimethyldioxirane
J . Org. Chem., Vol. 62, No. 25, 1997 8799
Rea ction of 2,3,4,5,6-P en ta m eth ylben zyl Alcoh ol, 8,
w ith 2. To a magnetically stirred solution of 8 (0.051 g, 0.286
mmol) in acetone (2 mL) was added a solution of 0.066 M 2 in
acetone (13 mL, 0.858 mmol) at room temperature. The
reaction mixture was stirred at room temperature and moni-
tored periodically by GLC and GC/MS. After 3 days reaction
was complete. The solvent was removed on the rotary
evaporator to afford a colorless crystalline solid (0.0628 g).
Purification of the residue by neutralization with sodium
bicarbonate solution, extraction with methylene chloride, and
acidification of the aqueous solution with dilute HCl afforded
a colorless crystalline solid which was identified as 2,3,4,5,6-
pentamethylbenzoic acid. The 1H and 13C NMR and mass
spectral data of this compound were identical with those of
an authentic sample of 9.
Intensity data were collected with frame width of 0.3° in ω
and counting time of 10 s/frame at a crystal to detector
distance of 4.930 cm. The double pass method of scanning was
used to exclude any noise. A SMART software package
(Siemen’s Analytical X-ray, Madison, WI, 1995) was used for
data collection and SAINT was used for frame integration
(Siemen’s Analytical X-ray, Madison, WI, 1995). Structure
solution and refinement were carried out using the SHELXTL-
PLUS (5.03) software package (Sheldrick, G. M., Siemen’s
Analytical X-ray, Madison, WI, 1995). The structures were
solved by direct methods and full matrix least-squares refine-
2
ment was carried out by minimizing Σw(Fo - Fc2)2 to conver-
gence. A summary of crystal data and structure refinement
parameters is given in Tables 1-4.
Attem p ted Rea ction of Oxep a n e 3 w ith Wa ter .
A
Ack n ow led gm en t. The project described was sup-
ported by grant number ES01984 from the National
Institute of Environmental Health Sciences, NIH. Its
contents are solely the responsibility of the authors and
do not necessarily represent the official views of the
NIEHS, NIH. The Varian XL-300 NMR spectrometer
was purchased with partial support from the National
Science Foundation.
solution of 3 (5 mg) in 2 mL of acetone containing a drop of
water was stirred at room temperature and then at acetone
reflux. After 10 days the oxepane was unchanged, and no
other products were formed.
X-r a y Diffr a ction Stu d ies. Single-crystal X-ray diffrac-
tion analyses of the compounds 3, 4, 6, and 7 were undertaken
to elucidate their solid-state structures unambiguously. Crys-
tals of appropriate dimensions were mounted on glass fibers
in random orientations. Data were collected using a Siemens
SMART CCD area detector system (Mo KR, λ ) 0.71073 Å).
J O971339F