Quantitative analyses of the seven isomeric 3,4- and 3,6-dimethylcyclohexenes by gas chromatography

Article abstract of DOI:10.1021/jo000956s

Quantitative analyses of mixtures of the seven isomeric 3,4- and 3,6-dimethylcyclohexenes have been achieved by gas chromatography. Correlations of structure and absolute stereochemistry with elution order have been made rigorously with the aid of authentic optically active samples all derived from (3R)-methylcyclohexanone.

Full text of DOI:10.1021/jo000956s

J . Org. Chem. 2000, 65, 7145-7150
7145
Qu a n tita tive An a lyses of th e Seven Isom er ic 3,4- a n d
3,6-Dim eth ylcycloh exen es by Ga s Ch r om a togr a p h y
J ohn E. Baldwin* and Richard C. Burrell
Department of Chemistry, Syracuse University,Syracuse, New York 13244
jbaldwin@syr.edu
Received J une 23, 2000
Quantitative analyses of mixtures of the seven isomeric 3,4- and 3,6-dimethylcyclohexenes have
been achieved by gas chromatography. Correlations of structure and absolute stereochemistry with
elution order have been made rigorously with the aid of authentic optically active samples all derived
from (3R)-methylcyclohexanone.
In tr od u ction
chemical assignments for the four isomers of 1-(E)-
propenyl-2-methylcyclobutane now ascertained with the
aid of X-ray crystallography,2 one may address the
complex kinetic situation posed by the simultaneous
stereomutations, fragmentations, and conversions of
these cyclobutanes to mixtures of seven isomeric di-
methylcyclohexenes with confidence that the stereochem-
ical characteristics of the vinylcyclobutane-to-cyclohexene
isomerizations may be deciphered.
Accurate determinations of relative concentrations of
the seven 3,4- and 3,6-dimethylcyclohexenes on a sub-
milligram scale, an analytical capability required for a
projected stereochemical investigation, might be achieved
using enantioselective capillary columns based on modi-
fied cyclodextrins as chiral stationary phases.1 To realize
this objective would require the successful completion of
several tasks: preparations of authentic samples of cis-
3,4-dimethylcyclohexene ((()-1), trans-3,4-dimethylcyclo-
hexene ((()-2), trans-3,6-dimethylcyclohexene ((()-3),
and the meso isomer cis-3,6-dimethylcyclohexene (4);
demonstrations that they can be distinguished by capil-
lary gas chromatography on achiral columns and that the
pairs of enantiomers can be separated well on chiral
columns; and conclusive correlations between absolute
stereochemistry and elution order on chiral columns for
each of the three pairs of enantiomers.
Resu lts
Ra cem ic a n d Meso Sa m p les. The literature recounts
various preparations and characterizations of (()-1, (()-
2, (()-3, and 4.3-9 The synthetic routes adopted here
utilized conveniently available starting materials and the
stereochemical control one may achieve through the
formation and deprotonation of 2,4,6-triisopropylben-
zenesulfonyl hydrazones (trisylhydrazones).10
The 3,4-dimethylcyclohexenes (()-1 and (()-2 were
prepared as outlined in Scheme 1. A mixture of isomeric
2,3-dimethyl-cyclohexanols (6) was oxidized to a mixture
of cis- and trans-2,3-dimethylcyclohexanones11,12 (7) with
pyridinium chlorochromate (PCC) in CH2Cl2.13 Conden-
sation of these ketones with 2,4,6-triisopropylbenzene-
sulfonyl hydrazine (TrisylNHNH2),10,14 followed by a
These tasks have all been accomplished. Two of the
three pairs of enantiomers proved to be baseline resolv-
able on a CycloSil-B column, and the third pair of
enantiomers could be resolved on a Cyclodex-B fused
silica capillary column. The correlations of relative elu-
tion order with absolute stereochemistry were made
using samples of (3R,4R)-1, (3S,4R)-2, and (3R,6R)-3
prepared from (3R)-(+)-methylcyclohexanone, (3R)-5.
(2) (a) Alexander, J . S.; Baldwin, J . E.; Burrell, R. C.; Ruhlandt-
Senge, K. Chem. Commun., submitted. (b) Baldwin, J . E.; Burrell, R.
C. J . Org. Chem. 2000, 65, 7139-7144.
(3) Hu¨ckel, W.; Feltkamp, H.Chem. Ber. 1959, 92, 2851-2855.
(4) Shuikin, N. I.; Tulupova, E. D.; Ostapenko, E. G. Neftekhimiya
1964, 4, 876-879; Chem. Abstr. 1965, 63, 6874c.
(5) Kugatova-Shemyakina, G. P.; Lutsenko, V. V. Izv. Akad. Nauk
SSSR, Ser. Khim. 1964, 1429-1436; Chem. Abstr. 1966, 64, 19436c.
(6) Bartlett, P. D.; Schueller, K. E. J . Am. Chem. Soc. 1968, 90,
6071-6077.
(7) Pehk, T. I.; Kooskora, H. E.; Lippmaa, E. T.; Lysenkov, V. I.;
Bardyshev, I. I. Vestsi Akad. Navuk BSSR, Ser. Khim. Navuk 1976,
27-32; Chem. Abstr. 1976, 85, 76985a.
(8) Bazyl′chik, V. V.; Bardyshev, I. I. Vestsi Akad. Navuk BSSR,
Ser. Khim. Navuk 1980, 93-95; Chem. Abstr. 1980, 93, 185819k.
(9) Ba¨ckvall, J . E.; J untunen, S. K. J . Am. Chem. Soc. 1987, 109,
6396-6403.
(10) Chamberlin, A. R.; Sheppeck, J . E. In Encyclopedia of Reagents
for Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995;
Vol. 7; pp 5177-5180.
With these synthetic, stereochemical, and analytical
results in hand, and with equally secure absolute stereo-
(11) Pfeffer, P. E.; Osman, S. F. J . Org. Chem. 1972, 37, 2425-2428.
(12) Van Den Berg, T.; Abou-Mandour, A. A.; Czygan, F. C. Angew.
Bot. 1995, 69, 140-144.
(1) (a) Ko¨nig, W. A. Gas Chromatographic Enantiomer Separations
with Modified Cyclodextrins; Hu¨thig Buch Verlag: Heidelberg, 1992.
(b) Asuncion, L. A.; Baldwin, J . E. J . Org. Chem. 1995, 60, 5778-5784.
(13) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 11, 2647-
2650.
10.1021/jo000956s CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/19/2000

7146 J . Org. Chem., Vol. 65, No. 21, 2000
Baldwin and Burrell
Sch em e 1
three pairs of enantiomers and to establish correlations
between elution order and absolute stereochemistry.
Ch ir a l GC Sep a r a tion s. Initial attempts to separate
samples of (()-1, (()-2, and (()-3 with chiral capillary
GC columns were not encouraging. Trials with the chiral
columns on hand (Cyclodex-B (10.5% heptakis(2,3,6-tri-
O-methyl)-â-cyclodextrin in DB-1701), 30 m, purchased
in 1991 from J &W; Chiraldex G-BP (octakis(3-O-butyryl-
2,6-di-O-methyl)-γ-cyclodextrin), 20 m, from Advanced
Separation Technologies; Lipodex C (heptakis(2,3,6-tri-
O-pentyl)-â-cyclodextrin), 50 m glass, Macherey-Nagel)
failed to give any resolutions, or gave slightly broadened
peaks, or, at best, partial resolutions. Three new columns
were secured. The first (Hydrodex â-3P (heptakis(2,6-di-
O-methyl-3-O-pentyl)-â-cyclodextrin in OV-1701), 25 m,
Macherey-Nagel) did not solve the impasse, but the
second and third, under carefully defined temperature,
pressure, and flow-rate conditions, proved to give satis-
factory resolutions (Figure 1). A CycloSil B column
resolved the enantiomers of (()-2 and of (()-3, and a new
Cyclodex B column separated the enantiomers of (()-1.
The baseline character of these separations may be
judged from the chromatograms visually or, more clearly,
from the relative integrated intensities of the pairs of
peaks. For the three separations shown in Figure 1, the
(first enantiomer):(second enantiomer) proportions were
measured to be 49.7:50.3, 50.1:49.9, and 49.8:50.2, close
to the theoretically expected 50:50 balance.
Ch ir a l Sa m p les fr om (3R)-(+)-Meth ylcycloh ex-
a n on e. Authentic samples of either enantiomer of 1-3
were needed to correlate absolute stereochemistry with
elution order for these dimethylcyclohexenes. All three
reference samples required for these correlations were
derived from (3R)-methylcyclohexanone, (3R)-5, as shown
in Schemes 3 and 4.
Condensation of (3R)-5 with ethyl formate gave mostly
2-formyl-5-methylcyclohexanones (11), along with much
smaller amounts of 2-formyl-3-methyl isomers.18-21 This
mixture of isomers, without separation, was converted
into the corresponding n-butylthiomethylene deriva-
tives22 and then on to the R-methyl ketones with W-2
Raney nickel.23 The desired chiral trans-3,6-dimethyl-
cyclohexene (3R,6R)-3 was then readily obtained by way
of the trisylhydrazone and a methyllithium-promoted
elimination.24
Sch em e 2
Shapiro reaction,15,16 gave as expected a mixture of the
3,4-dimethylcyclohexenes (()-1 and (()-2 as well as some
2,3-dimethylcyclohexene as a minor side product.
A 40:60 mixture of (()-1 and (()-2 was reduced with
hydrogen over a palladium catalyst to form, respectively,
meso-cis-1,2-dimethylcyclohexane (8) and the racemic
trans isomer ((()-9). The stereochemical assignments for
the 1,2-dimethylcyclohexanes, and thus of the 3,4-di-
methylcyclohexenes, were confirmed by spectroscopy,
chromatographic comparisons with authentic samples,
and chiral gas chromatography. trans-1,2-Dimethyl-
cyclohexane ((()-9) was resolved on a CycloSil B column
to two equal-area peaks corresponding to its distinct
enantiomeric forms.
The 3,6-dimethylcyclohexenes (()-3 and 4 were made
through a similar route from a commercially available
mixture of 2,5-dimethylcyclohexanols (10) as summarized
in Scheme 2. Again, the reaction sequence from ketones
to arylsulfonylhydrazones to cyclohexenes gave olefinic
products with high regioselectivity; little 1,4-dimethyl-
cyclohexene was formed.
Pure samples of (()-3 and 4 were collected by prepara-
tive GC and the structural assignments were made
through NMR spectroscopy. The assignments were con-
firmed by chiral GC on a CycloSil B column: (()-3 gave
two equal-intensity peaks while cis isomer 4 showed but
a single peak.
Ach ir a l GC Sep a r a tion s. The four samples (()-1,
(()-2, (()-3, and 4 were well separated on an achiral
phenylmethyl silicone capillary GC column. The relative
concentrations of [(+)-1 + (-)-1], [(+)-2 + (-)-2], [(+)-3
+ (-)-3], and 4 in samples containing the seven isomers
in any proportions may thus be determined conve-
niently.17
The crude mixture of R-formyl ketones 11 (Scheme 3)
served just as well as a precursor for (3R,4R)-1 and
(3S,4R)-2 (Scheme 4). Conversion of 11 to a mixture of
dianions, using two equivalents of LDA in THF, followed
by methylation with methyl iodide and hydrolytic re-
moval of the formyl functions,25 gave (2,3R) isomers of
2,3-dimethylcyclohexanone ((3R)-7). It was converted into
a mixture of (3R,4R)-1 and (3S,4R)-2 (Scheme 4) without
difficulty, and the two optically active hydrocarbon
products were separated and purified by preparative GC.
Using a â,â′-oxydipropionitrile (ODPN) column, mix-
tures of [(+)-1 + (-)-1], [(+)-2 + (-)-2], [(+)-3 + (-)-3],
and 4 could be readily separated on a small preparative
scale into the four distinct structural and diastereomeric
components. Thus, for a complete analysis of a mixture
of the seven dimethylcyclohexene isomers under consid-
eration, it remained only to separate quantitatively the
(18) Ainsworth C. Org. Synth. 1963, Coll. Vol. 4, 536-539.
(19) Gorthey, L. A.; Vairamari, M.; Djerassi, C. J . Org. Chem. 1985,
50, 4173-4182.
(20) Elguero, J .; Shimizu, G. An. Quim. Ser. C 1988, 84, 176-182.
(21) Chelucci, G.; Cossu, S.; Scano, G.; Soccolini, F. Heterocycles
1990, 31, 1397-1403.
(22) Ireland, R. E.; Marshall, J . A. J . Org. Chem. 1962, 27, 1615-
1619.
(14) Bertz, S. H.; Dabbagh, G. J . Org. Chem. 1983, 48, 116-119.
(15) Shapiro, R. H. Org. React. 1976, 23, 405-507.
(16) Chamberlin, A. R.; Bond, F. T. Synthesis 1979, 44-45.
(17) Compare Cupalov, A. A.; Zenkevich, I. G. Zh. Org. Khim. 1996,
32, 675-684.
(23) Mozingo, R. Organic Syntheses; Wiley: New York, 1955; Collect.
Vol. III, pp 181-183.
(24) Compare Kuroki, T.; Katsuki, T. Chem. Lett. 1995, 337-338.
(25) Harris, T. M.; Hauser C. R. Organic Syntheses; Wiley: New
York, 1973; Collect. Vol. V, p 187-190.

Quantitative Analyses of Isomeric and Dimethylcyclohexenes
J . Org. Chem., Vol. 65, No. 21, 2000 7147
F igu r e 1. Chiral chromatographic separations of enantiomers of (()-1, (()-2, and (()-3 on modified cyclodextrin columns.
reactions at the original C3 sp3 center as (3R)-5 was
Sch em e 3
converted into (3R,4R)-1, (3S,4R)-2, and (3R,6R)-3. Mix-
tures of (()-1 with (3R,4R)-1, (()-2 with (3S,4R)-2, and
(()-3 with (3R,6R)-3 were prepared and analyzed by
chiral GC to secure the assignments: (3S,4S)-1 elutes
on the new Cyclodex B column before (3R,4R)-1; (3R,4S)-2
elutes on the CycloSil B column before (3S,4R)-2; and
(3S,6S)-3 elutes on the CycloSil B column before (3R,6R)-3
(Figure 2). Thus the associations of specific chromato-
graphic peaks in these chiral GC chromatograms with
specific stereoisomers of the chiral 3,4- and 3,6-dimeth-
ylcyclohexenes were demonstrated.
With the relative concentrations of any pair of enan-
tiomers of 1, 2, and 3 in whatever proportions and of the
Sch em e 4
meso isomer 4 known from achiral capillary GC analyses,
and the relative concentrations of each enantiomer of 1,
2, and 3 available from chiral GC separations on one or
another modified cyclodextrin capillary column, the rela-
tive concentrations of each of the seven isomers of 3,4-
and 3,6-dimethylcyclohexene in a sample may be calcu-
lated.
Con clu sion s
Specific rotations for very small samples of GC-purified
(3R,4R)-1, (3S,4R)-2, and (3R,6R)-3 were measured, in
duplicate, using a 2-mL volumetric flask and a 1-mL 10-
cm length micro polarimeter cell. The values obtained
were none too precise: for (3R,4R)-1, [R]D +200 and +240;
for (3S,4R)-2, [R]D -46 and -57; and for (3R,6R)-3, [R]D
+180 and +240 (in reagent-grade hexanes, with 0.2- to
7-mg samples). Such uncertainties in specific rotations,
given the balances employed and the limited qualities of
hydrocarbons invested, seem unsurprising. The observed
lack of high precision in measuring specific rotations for
these very small samples underscores the advantages of
the alternative chiral GC methodology for determinations
of enantiomeric excess!
Absolu te Ster eoch em ica l Assign m en ts for Ch ir a l
GC P ea k s. The GC-purified (3R,4R)-1, (3S,4R)-2, and
(3R,6R)-3 samples gave single peaks on chiral GC colums
under conditions known to separate (()-1, (()-2, and
(()-3 into pairs of peaks representing the two enanti-
omers, a conformation of the essentially 100% ee char-
acter of the (3R)-5 used in the preparations of Schemes
3 and 4, and of the lack of stereochemically compromising
The results attained demonstrate that one may analyze
an unknown mixture of the seven dimethylcyclohexenes
under consideration on the scale and with the precision
and accuracy associated with capillary GC. The various
isomers may be separated using standard analytical and
preparative GC and chiral GC methods, and the struc-
tural and absolute stereochemical assignments with
chromatographic peak elution order have been made in
a rigorous fashion. The power of chiral GC, in conjunction
with other chromatographic methods and with efficient
synthetic routes to reference compounds of known struc-
ture and absolute stereochemistry, have been combined
in this instance to pave the way for detailed stereochem-
ical investigations2 that, in the recent past, would have
seemed too daunting for serious engagement.
Exp er im en ta l Section
The two 30-m × 0.25 id fused silica chiral GC columns which
gave satisfactory resolutions (CycloSil-B (30% heptakis(2,3-
di-O-methyl-6-O-tert-butyldimethylsilyl)-â-cyclodextrin in DB-
1701) and Cyclodex-B (10.5% heptakis(2,3,6-tri-O-methyl)-â-

7148 J . Org. Chem., Vol. 65, No. 21, 2000
Baldwin and Burrell
F igu r e 2. Mixtures of (()-1 with (3R,4R)-1, (()-2 with (3S,4R)-2, and (()-3 with (3R,6R)-3 analyzed on modified cyclodextrin
capillary GC columns.
cyclodextrin in DB-1701) were obtained from J &W Scientific,
Folsom, CA 95630. The instrumentation and standard proce-
dures used in this work have been detailed elsewhere.1b,26-27
2,3-Dim eth ylcycloh exa n on es (7). Oxidation of a mixture
of cis- and trans-2,3-dimethylcyclohexanols (6; Aldrich, 2.02
g, 15.8 mmol) with PCC13 (5.04 g, 23.4 mmol) in dry CH2Cl2
(30 mL), followed by a conventional workup and column
chromatography (silica gel, hexanes/ethyl acetate, 9:1), gave
1.96 g (99%) of 7 as a clear oil, a 1:2.1 mixture (analytical GC
on a phenylmethyl silicone column) of the known trans and
cis isomers For trans-2,3-dimethylcyclohexanone: MS m/z (rel
intensity) 126 (40, M+), 111 (11), 98 (28), 83 (47), 82 (58), 69
(70), 55 (100), 41 (70); for the cis isomer: MS m/z (rel intensity)
126 (26, M+), 111 (12), 98 (23), 83 (50), 82 (50), 69 (38), 55
(100), 41 (61).
3,4-Dim eth ylcycloh exen es ((()-1, (()-2). To a 50-mL
round-bottomed flask were added dry ether (30 mL), 2,4,6-
triisopropylbenzenesulfonyl hydrazide28 (2.61 g, 8.73 mmol),
and the mixture of 2,3-dimethylcyclohexanones (1.05 g, 7.93
mmol). The reaction mixture was stirred under argon for 7 h
at room temperature, then concentrated and dried under
vacuum for 1 h to give 3.17 g of off-white solid. This crude
triisopropylbenzenesulfonyl hydrazone, TMEDA (18 mL, freshly
distilled from KOH), and 1.4 M MeLi (11.7 mL, 16.4 mmol)
were added to a 50-mL three-necked flask at -78 °C;16 the
reaction mixture was allowed to warm to room temperature
and was stirred for 24 h under argon. The resultant orange
solution was cooled to 0 °C and was quenched carefully with
water (40 mL). The aqueous layer was extracted with pentane
(3 × 25 mL), and the combined organic layers were then
washed with HCl (2 M, 3 × 20 mL), NaOH (3 M, 20 mL), and
water (20 mL). The organic material was dried (MgSO4),
filtered, and concentrated by distillation to give 0.62 g (71%
for the two steps) of the 3,4-dimethylcyclohexenes, a 1.1:1
mixture (analytical GC) of the trans (7.7 min) and cis (9.2 min)
isomers. Preparative GC afforded pure samples of the two
isomers; these separations, and all other preparative GC work
with dimethylcyclohexenes, employed a 2.3-m × 6.4-mm 20%
â,â′-oxydipropionitrile (ODPN) on Chromasorb P-NAW column
at 45 °C.
For cis-3,4-dimethylcyclohexene ((()-1): 1H NMR δ 5.52-
5.64 (m, 2 H), 2.12-2.23 (m, 1 H), 1.95-2.04 (m, 2 H), 1.74-
1.88 (m, 1 H), 1.33-1.53 (m, 2 H), 0.87 (d, J ) 6.86 Hz, 3 H),
0.86 (d, J ) 7.41 Hz, 3 H); 13C NMR δ 133.2, 125.6, 33.6, 31.4,
26.6, 24.5, 16.9, 15.8 (lit.7 δ 133.0, 125.5, 34.2, 32.1, 27.2, 24.9,
17.0, 16.0); MS m/z (rel intensity) 110 (47, M+), 95 (90), 81
(71), 67 (100), 53 (26), 41 (54). Analytical GC on a new chiral
Cyclodex B column at 30 °C and 15 psi (Figure 1) gave two
peaks with retention times (relative peak areas) of 35.0 min
(49.8%) and 35.6 min (50.2%).
For trans-3,4-dimethylcyclohexene ((()-2): 1H NMR δ 5.58-
5.67 (m, 1 H), 5.41-5.49 (m, 1 H), 1.96-2.05 (m, 2 H), 1.61-
1.82 (m, 2 H), 1.14-1.36 (m, 2 H), 0.98 (d, J ) 7.13 Hz, 3 H),
0.97 (d, J ) 6.04 Hz, 3 H); 13C NMR δ 133.4, 129.5, 37.7, 35.9,
30.6, 25.2, 20.3, 20.1 (lit.7 δ 133.5, 125.7, 38.1, 36.4, 31.0, 25.6,
20.3 (both Me); MS m/z (rel intensity) 110 (48, M+), 95 (92),
81 (76), 67 (100), 53 (28), 41 (56). Analytical gas chromatog-
raphy on a chiral CycloSil B column at 50 °C and 15 psi (Figure
1) gave two peaks with retention times (relative peak areas)
of 12.4 min (50.1%) and 13.0 min (49.9%).
1,2-Dim eth ylcycloh exa n es (8 and (()-9) were obtained
by reducing a small sample of a 40:60 mixture of (()-1 and
(()-2 with hydrogen over palladium on carbon. Analytical GC
on a capillary phenylmethyl silicone column at 40 °C showed
a 60:40 mixture of trans ((()-9, 7.1 min) and cis (8, 9.1 min)
isomers of 3,4-dimethylcyclohexane. Authentic samples (Phil-
ips 66) of the 3,4-dimethylcyclohexanes had analytical GC
retention times of 7.1 min for the trans and 9.1 min for the
cis isomers. Analytical GC on a new CycloSil B column at 50
°C and 15 psi gave two peaks with retention times (relative
peak areas) of 11.1 min (50.0%) and 12.0 min (50.0%) for (()-9
and one peak (16.9 min) for 8.
(26) Baldwin, J . E.; Bonacorsi, S. J . J . Org. Chem. 1994, 59, 7401-
7409.
(27) Baldwin, J . E.; Bonacorsi, S. J . J . Am. Chem. Soc. 1996, 118,
8258-8265.
(28) Cusack, N. J .; Reese C. B.; Roozpeikar B. Tetrahedron 1976,
32, 2157-2162.

Quantitative Analyses of Isomeric and Dimethylcyclohexenes
J . Org. Chem., Vol. 65, No. 21, 2000 7149
3,6-Dim eth ylcycloh exen es ((()-3, 4). A mixture of 2,5-
dimethylcyclohexanones29 was prepared by oxidizing 2,5-
dimethyl-cyclohexanols (10; TCI America, 2.05 g, 16.0 mmol)
with PCC in dry CH2Cl2. A conventional workup and column
chromatography (silica gel, hexanes:ethyl acetate, 9:1) gave
1.91 g (95%) of the ketones as a clear oil. The two isomers had
essentially identical mass spectra: MS m/z (rel intensity) 126
(33, M+), 111 (7), 98 (18), 82 (48), 69 (100), 56 (55), 41 (58-
64).
A portion of this mixture of isomeric ketones (1.06 g, 7.94
mmol), dry ether (30 mL), and 2,4,6-triisopropylbenzenesul-
fonyl hydrazide (2.63 g, 8.74 mmol) were combined in a 50-
mL round-bottomed flask, and the reaction mixture was stirred
under argon for 7 h at room temperature. Concentration and
drying under vacuum gave 3.58 g of a white solid, which was
subjected to the Shapiro reaction protocol detailed above to
give 0.56 g (64% for the two steps) of a mixture of the cis and
trans isomers of 3,6-dimethylcyclohexenes, along with a small
amount of 1,4-dimethylcyclohexene. Analytical GC showed a
1:1.7 mixture of the trans (6.9 min) and cis (7.3 min) 3,6-
dimethylcyclohexenes. Small samples of each were collected
by preparative GC.
For trans-3,6-dimethylcyclohexene ((()-3): 1H NMR δ 5.46
(s, 2 H), 2.05-2.21 (m, 2 H), 1.74-1.87 (m, 2 H), 1.09-1.21
(m, 2 H), 0.96 (d, J ) 6.59 Hz, 6 H); 13C NMR δ 132.7, 31.5,
30.5, 21.9 (lit.7 δ 133.6, 31.9, 30.9, 22.1); MS m/z (rel intensity)
110 (32, M+), 95 (81), 81 (29), 68 (100), 67 (88), 55 (40), 39
(41). Analytical GC on a CycloSil B column at 50 °C and 15
psi gave two peaks with retention times (relative peak areas)
of 9.6 min (49.7%) and 9.8 min (50.3%).
For cis-3,6-dimethylcyclohexene (4): 1H NMR δ 5.51 (d, J
) 1.1 Hz, 2 H), 2.08-2.21 (m, 2 H), 1.59-1.72 (m, 2 H), 1.26-
1.39 (m, 2 H), 0.97 (d, J ) 7.14 Hz, 6 H); 13C NMR δ 132.5,
29.6, 28.2, 21.5 (lit.7 δ 132.7, 30.0, 28.6, 21.7); MS m/z (rel
intensity) 110 (30, M+), 95 (86), 81 (25), 68 (100), 67 (95), 55
(39), 39 (41). Analytical GC on the CycloSil B column at 50 °C
and 15 psi gave one peak with a retention time of 12.2 min.
Ach ir a l a n a lytica l ga s ch r om a togr a p h ic sep a r a tion s
of 1, 2, 3, and 4 on the capillary phenylmethyl silicone column
at 40 °C gave the elution sequence 3 (6.9 min), 4 (7.3 min), 2
(7.7 min) and 1 (9.2 min).17 Preparative separations on the
ODPN column gave the dimethylcyclohexenes at 7.29 min (3),
8.18 min (4), 9.11 min (2) and 11.34 min (1).
2-F or m yl-(5R)-m eth ylcycloh exa n on e (11) was prepared
by condensing (3R)-methylcyclohexanone ((3R)-5; Aldrich; 2.9
g) with ethyl formate.18-21 A conventional workup led to 4.2 g
of a yellow oil. Analytical GC indicated an 8.8:1 preponderance
of 11 (16.0 min) over the 2-formyl-3-methyl isomer (16.1 min).
A small sample of both isomers was purified by preparative
GC (10% SE-30, 100 °C): 1H NMR δ 9.94 (d, J ) 2.19 Hz),
9.71 (s), 8.74 (d, J ) 3.02 Hz), 8.68 (d, J ) 2.74 Hz), 2.60-
2.70 (m), 2.27-2.49 (m), 1.94-2.06 (m), 1.71-1.68 (m), 1.41-
1.49 (m), 1.17-1.33 (m), 1.14 (d, J ) 6.86 Hz), 1.02 (d, J )
6.59 Hz); MS m/z (rel intensity) 140 (100, M+), 125 (30), 111
(43), 97 (36), 79 (28), 70 (84), 55 (64), 39 (60).
2,(5R)-Dim eth ylcycloh exa n on es (12). Crude intermedi-
ate 11 (2.10 g, 14.9 mmol), dry benzene (70 mL), butanethiol
(2.08 mL, 1.75 g, 19.4 mmol), and p-TsOH (40 mg) were
combined and heated to reflux for 20 h as 1.7 mL of water
was removed by azeotropic distillation.19,22 The prescribed
workup led to a red oil, which was distilled (bp 100-120 °C
(1-2 mm)) to give 1.76 g of the butylthiomethylene intermedi-
ate19 as a yellow oil: m/z (rel intensity) 212 (16, M+), 179 (6),
155 (100), 113 (7), 93 (10), 85 (11), 69 (7), 55 (10), 41 (20). This
intermediate was reduced in ethanol at 55 °C under argon with
W-2 Raney Ni; 12 g of Raney Ni were added in 3 g portions
over a 50-min period.23 The reaction mixture was stirred for
16 h at 55 °C under argon and then cooled and filtered through
Florisil. The Florisil was washed with 200 mL of ethanol and
the combined ethanolic material was concentrated by distil-
lation to give a yellow oil. Column chromatography (silica gel,
hexanes:ethyl acetate, 9:1) gave 0.48 g (29% from (3R)-5) of
12 as a clear oil. Analytical GC showed there was a 4.4:1 trans
(12.5 min):cis (13.0 min) mixture of 2,(5R)-dimethylcyclo-
hexanones and some 10% of the 2,(3R)-dimethylcyclo-
hexanones.
(3R,6R)-tr a n s- a n d cis-3,6-Dim eth ylcycloh exen es ((3R,
6R)-3 a n d 4). The mixture of ketones prepared immediately
above was combined with 2,4,6-triisopropylbenzenesulfonyl
hydrazide (1.25 g, 4.19 mmol) and dry ether (15 mL); the
formation of the trisylhydrazone and its decomposition through
a Shapiro reaction was conducted as detailed above to give
0.14 g (33% for the two steps) of (3R,6R)-3 and 4, and a small
amount of the 3,(4R)-dimethylcyclohexenes. Analytical GC
showed a 4:1 mixture of (3R,6R)-3 (6.7 min) and 4 (7.2 min)
isomers. Preparative GC afforded pure samples of each.
For (3R,6R)-tr a n s-d im eth ylcycloh exen e ((3R,6R)-3), GC
on the CycloSil B column at 50 °C and 15 psi gave one peak
with a retention time of 9.9 min. Samples of (()-3 and
(3R,6R)-3 were combined and analyzed under same conditions;
the two peaks observed (Figure 2) had retention times (relative
peak areas) of 9.6 min (30.8%) and 9.8 min (69.2%). Two
specific rotation determinations (2-mL volumetric flask, 10-
cm path length 1-mL polarimeter cell, reagent-grade hexanes
as solvent) gave [R]D values of +180 (c 0.36) and +240 (c 0.20).
The cis isomer 4 on the CycloSil B column gave one peak
with a retention time of 12.2 min.
2,(3R)-Dim eth ylcycloh exa n on es ((3R)-7). To a 100-mL
three-necked flask were added diisopropylamine (2.94 g, 29.0
mmol), dry THF (20 mL), and 1.4 M MeLi (20.7 mL, 29.0
mmol) at -78 °C. The mixture was warmed to 0 °C, stirred
for 15 min under argon, and cooled again cooled to -78 °C.
Intermediate 11 (2.10 g, 14.9 mmol), prepared as described
above and used without purification, was added dropwise in
THF (10 mL).25 After the addition was complete, the reaction
mixture was warmed to 0 °C and stirred for 1 h. It was then
cooled to -78 °C and MeI (2.68 g, 18.9 mmol, 1.17 mL) was
added; the reaction mixture was allowed to warm to room
temperature and was stirred for 9 h. It was quenched with
water (30 mL) and acidified with 2 M HCl; the organic layer
was removed and the aqueous layer was extracted with ether
(4 × 25 mL). The combined organic material was dried
(MgSO4), filtered, and concentrated. The oily concentrate and
32 mL of 0.4 M NaOH were then heated to reflux for 6 h.25
The hydrolysis reaction mixture was cooled to room temper-
ature, acidified with 2 M HCl, and extracted with ether (4 ×
25 mL). The combined organic material was washed with 1 M
HCL (4 × 15 mL), dried (MgSO4), filtered, and concentrated.
Column chromatography (silica gel, hexanes:ethyl acetate, 9:1)
gave 0.54 g (33% from (3R)-methylcyclohexanone) of 2,3-
dimethylcyclohexanones as a slightly yellow oil. Analytical GC
showed there was a 4.1:1 mixture of the trans (13.1 min) and
cis (13.6 min) 2,(3R)-dimethylcyclohexanone isomers, and 13%
of the 2,(5R)-dimethylcyclohexanones.
This mixture of ketones was converted into cyclohexenes by
way of the trisylhydrazones, following the protocols described
above. The product mixture (0.28 g, 33% for the two steps)
contained the 3,(4R)-dimethylcyclohexenes, a 4.2:1 mixture of
the trans (7.6 min) and cis (9.1 min) isomers according to
analytical GC, and small amounts of two 3,6-dimethylcyclo-
hexenes. Preparative GC provided pure samples of the cis and
trans isomers (3R,4R)-1 and (3S,4R)-2.
(3R,4R)-cis-Dim eth ylcycloh exen e ((3R,4R)-1) had meas-
ured [R]D values of +200 (c 0.01) and +240 (c 0.03). Analytical
GC on a new chiral Cyclodex B column at 30 °C and 15 psi
gave one peak with a retention time of 35.4 min. Samples of
(()-1 and (3R,4R)-1 were then mixed together and analyzed
under the same conditions; the two peaks observed had
retention times (relative peak areas) of 35.1 min (3.1%) and
35.7 min (96.9%) (Figure 2).
(3S,4R)-tr a n s-Dim eth ylcycloh exen e ((3S,4R)-2) had meas-
ured [R]D values of -46 (c 0.20) and -57 (c 0.27). Analytical
GC on the CycloSil B column at 50 °C and 15 psi gave one
peak with a retention time of 12.9 min. Samples of (()-2 and
(3S,4R)-2 were mixed and analyzed under the same conditions;
(29) Bartlett, P. D.; Schueller, K. E. J . Am. Chem. Soc. 1968, 90,
6077-6082.

7150 J . Org. Chem., Vol. 65, No. 21, 2000
Baldwin and Burrell
the two GC peaks seen (Figure 2) had retention times (relative
peak areas) of 12.4 min (9.7%) and 12.9 min (90.3%).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for (()-1, (()-2, (()-3, and 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank the National Science
Foundation for supporting this work through Grant
CHE 95-32016.
J O000956S