Unusual facial selectivity in the cycloaddition of singlet oxygen to a simple cyclic diene

Article abstract of DOI:10.1021/jo9604292

Syntheses of 5-isopropyl-1,3-cyclohexadiene and syn-5-isopropyl-2,3-dioxabicyclo[2.2.2]octane, by routes that would allow completely diastereoselective introduction of deuterium labels, are described. The reaction of the isopropyl cyclohexadiene with singlet oxygen is shown to give an endoperoxide that is derived by preferential attack on the more sterically hindered face of the diene. A possible mechanistic explanation of this result is that the attack from the less hindered face leads to "ene" reaction rather than endoperoxide formation. However, this mechanism would require that the "ene" reaction and cycloaddition proceed via a common intermediate-presumably a perepoxide.

Full text of DOI:10.1021/jo9604292

J . Org. Chem. 1996, 61, 4617-4622
4617
Un u su a l F a cia l Selectivity in th e Cycloa d d ition of Sin glet Oxygen
to a Sim p le Cyclic Dien e1
Kelly M. Davis and Barry K. Carpenter*
Department of Chemistry, Baker Laboratory, Cornell University, Ithaca, New York 14853-1301
Received March 1, 1996X
Syntheses of 5-isopropyl-1,3-cyclohexadiene and syn-5-isopropyl-2,3-dioxabicyclo[2.2.2]octane, by
routes that would allow completely diastereoselective introduction of deuterium labels, are described.
The reaction of the isopropyl cyclohexadiene with singlet oxygen is shown to give an endoperoxide
that is derived by preferential attack on the more sterically hindered face of the diene. A possible
mechanistic explanation of this result is that the attack from the less hindered face leads to “ene”
reaction rather than endoperoxide formation. However, this mechanism would require that the
“ene” reaction and cycloaddition proceed via a common intermediatespresumably a perepoxide.
Sch em e 1
In tr od u ction
As part of an ongoing project designed to investigate
the role of intramolecular dynamics in the thermal
transformations of reactive intermediates,2 we sought to
prepare the deuterium-labeled derivatives of syn-5-iso-
propyl-2,3-dioxabicyclo[2.2.2]octane, 1h and 1d , with
defined relative stereochemistry at the four stereogenic
centers.
It seemed clear from the outset that the normally most
efficient means of constructing the 2,3-dioxabicyclo[2.2.2]-
octane skeletonscycloaddition of O2 (1∆g) to a 1,3-cyclo-
hexadiene, followed by diimide reductionswould be
unlikely to be fruitful in the present case, because attack
of the singlet oxygen on the diene would be expected to
occur preferentially from the less-hindered face, giving
an adduct in which the labeled isopropyl substituent
would be anti to the peroxide bridge.
In this paper we report a synthetic scheme that allows
introduction of the isotopic labels with the desired
stereochemistry and reveals that the preferred mode of
cycloaddition in fact is not the one expected from the
above analysis. Mechanistic implications of this observa-
tion are discussed.
Resu lts
of the CD3 could be accomplished by use of CD3I in place
of CH3I in the alkylation step, and introduction of the
tertiary deuterium of 1d could be accomplished by base-
catalyzed H/D exchange on the lactone 6.
Our expectation of an unfavorable stereochemistry in
the cycloaddition of singlet oxygen to 5-isopropyl-1,3-
cyclohexadiene led us first to investigate preparation of
1 by oxidative coupling of cis,cis-2-isopropylcyclohexane-
1,4-diol, 2. Compound 2 was prepared by a sequence
(Scheme 1) that would allow introduction of the isotopic
labels with defined stereochemistry. Thus, introduction
Unfortunately, none of the techniques investigated for
the oxidative closure of 2 to 1 was successful. We chose,
1
therefore, to investigate the O2 + 5-isopropyl-1,3-cyclo-
hexadiene reaction in the hope that even a small amount
of cycloaddition from the more hindered face of the diene
would provide enough of the desired endoperoxide to
conduct the subsequent investigations.
X Abstract published in Advance ACS Abstracts, J une 15, 1996.
(1) Dedicated to Clayton H. Heathcock on the occasion of his 60th
birthday.
(2) (a) Carpenter, B. K. J . Am. Chem. Soc. 1995, 117, 6336. (b) Lyons,
B. A.; Pfeifer, J .; Peterson, T. H.; Carpenter, B. K. J . Am. Chem. Soc.
1993, 115, 2427. (c) Peterson, T. H.; Carpenter, B. K. J . Am. Chem.
Soc. 1992, 114, 1496. (d) Carpenter, B. K. Acc. Chem. Res. 1992, 25,
520. (e) Lyons, B. A.; Pfeifer, J .; Carpenter, B. K. J . Am. Chem. Soc.
1991, 113, 9006.
In the event that the 1O2 cycloaddition afforded enough
of the syn stereoisomer to make this route to 1 viable, it
would be necessary to prepare 5-isopropyl-1,3-cyclohexa-
diene (3) in a manner that permitted stereoselective
introduction of the isotopic labels. A synthesis that
S0022-3263(96)00429-X CCC: $12.00 © 1996 American Chemical Society

4618 J . Org. Chem., Vol. 61, No. 14, 1996
Davis and Carpenter
Sch em e 2
stereoisomers would be easily distinguishable by this
technique. Further evidence for there being only a single
stereoisomer of the endoperoxide was obtained by direct
reduction of the crude reaction mixture with H2 and a
Pd catalyst, followed by GC-MS analysis. Unambiguous
stereochemical assignment could be made by comparison
of the diol from H2/Pd treatment of the endoperoxide with
1
diol 2. The compounds were identical, as judged by H
and 13C NMR and IR spectroscopy.
Discu ssion
The identity of the diol prepared by reductive cleavage
of the 5-isopropyl-2,3-dioxabicyclo[2.2.2]octane, and com-
pound 2 prepared by independent synthesis, implies that
the endoperoxide had the desired syn stereochemistry,
and that it was therefore formed by approach of the
singlet oxygen to the more hindered face of the diene.
Inspection of neither physical nor computational (molec-
ular mechanics) models of the diene reveals any way in
which the syn approach could be sterically preferred, and
so the observation of this as the favored mode of cycload-
dition presumably carries mechanistic information.
It is known that polar substituents can influence the
facial selectivity of singlet-oxygen 4 + 2 cycloadditions,3
but, to our knowledge, there is no evidence showing that
a simple alkyl substituent has a significant effect of this
kind.
Sch em e 3
One possible explanation is that approach of the
oxygen from the anti face leads not to cycloaddition but
rather to “ene” reactionsyielding the observed hydrop-
eroxide after diimide reduction of the disubstituted
double bond. Approach from the syn face could not give
this product, although an “ene” product derived by
hydrogen abstraction from the secondary carbon could
have been formed in principle. No such product was
detected.
This explanation for the preferred mode of cycloaddi-
tion carries with it further implications that become
apparent when one takes into account the large amount
of work showing that the “ene” reaction of singlet oxygen
involves rate-limiting formation of a perepoxide inter-
mediate.4 Since the hydrogen abstraction is not rate-
determining, the presence or absence of a syn tertiary
hydrogen would have no influence on the ratio of stere-
oisomeric 4 + 2 cycloadducts, if these adducts were
formed in a single-step Diels-Alder reaction. However,
if the 4 + 2 adducts and “ene” products came from
perepoxides as common intermediates (Scheme 4), then
the observed facial selectivity for the cycloaddition might
well be the expected outcome. Such an explanation
would require that tertiary C-H abstraction by the
perepoxide have a smaller activation free energy than
would rearrangement to the endoperoxide. There is no
easy way to assess whether this is reasonable.
accomplished this goal is shown in Scheme 2. As before,
the CD3 could be introduced stereoselectively by use of
CD3I in place of CH3I in the alkylation, and the tertiary
deuterium could be introduced by H/D exchange on the
lactone prior to alkylation (or by use of AcOD in the
reduction of the dichloroketene cycloadduct).
Tetraphenylporphyrin-photosensitized addition of oxy-
gen to diene 3, followed by immediate reduction of the
double bond with diimide (Scheme 3), yielded a mixture
of 5-isopropyl-2,3-dioxabicyclo[2.2.2]octane and 3-hydro-
peroxy-1-isopropylcyclohexene in a combined isolated
yield of approximately 60% and a ratio of approximately
3:2, respectively. Exact yields of these peroxides are
difficult to determine because they suffer decomposition
during purification.
It could be that the formation of a perepoxide inter-
mediate is the first step in all of the common reaction
modes of 1O2 with dienes, i.e. “ene” reaction,3 2 + 2
(3) (a) Adam, W.; Peters, E. M.; Peters, K.; Prein, M.; von Schnering,
H. G. J . Am. Chem. Soc. 1995, 117, 6686. (b) Mehta, G.; Uma, R.
Tetrahedron Lett. 1995, 36, 4873.
(4) (a) Grdina, B. Orfanopoulos, M.; Stephenson, L. M. J . Am. Chem.
Soc. 1973, 95, 7888. (b) Grdina, B. Orfanopoulos, M.; Stephenson, L.
M. J . Am. Chem. Soc. 1973, 95, 7888. (c) Orfanopoulos, M.; Foote, C.
S. J . Am. Chem. Soc. 1988, 110, 6583. (d) Orfanopoulos, M.; Stratakis,
M.; Elemes, Y. J . Am. Chem. Soc. 1990, 112, 6417. (e) Song, Z.; Beak.
P. J . Am. Chem. Soc. 1990, 112, 8126. (f) Orfanopoulos, M.; Stratakis,
M.; Elemes, Y.; J ensen, F. J . Am. Chem. Soc. 1991, 113, 3180. (g) Poon,
T. H. W.; Pringle, K.; Foote, C. S. J . Am. Chem. Soc. 1995, 117, 7611.
NMR analysis of the crude reaction mixture suggested
that the endoperoxide was a single stereoisomer, al-
though it was not clear which one, or even that the two

Cycloaddition of Singlet Oxygen to a Simple Cyclic Diene
J . Org. Chem., Vol. 61, No. 14, 1996 4619
from a mixture of 0.87 g of ferrous ammonium sulfate, 0.65 g
of ammonium thiocyanate, 12.5 mL of H2O, and 0.23 g of
sulfuric acid). Column chromatography was gravity fed and
carried out with silica gel 60 (0.04-0.063 mm, 230-240 mesh).
1H NMR spectra were recorded at 200 or 400 MHz and 13C
NMR spectra were recorded at 100 MHz. Melting points were
uncorrected.
Sch em e 4
P r ep a r a tion of En a m in e 4. A 250 mL round-bottom flask
equipped with a Dean-Stark trap and reflux condenser was
charged with 1,4-cyclohexanedione mono-ethylene ketal (5.2
g, 33.3 mmol) and pyrolidine (2.4 mL, 33.3 mmol) in anhydrous
benzene (200 mL). The solution was refluxed for 8 h, until no
more H2O was collected in the Dean-Stark trap. The Dean-
Stark trap was removed and replaced with a distillation head,
and the benzene was removed by distillation. The product was
distilled (0.2 torr, 105 °C) to give the known9 enamine 4 (4.78
g, 23.0 mmol, 69%) as a yellow viscous oil, which was used
immediately to avoid decomposition: 1H NMR (200 MHz,
CDCl3) δ 1.82 (m, 4 H, 2.00-2.51 (m, 6 H), 3.02 (m, 4 H), 4.01
(br s, 4 H), 4.10 (m, 1 H).
P r ep a r a tion of Keton e 5 fr om En a m in e 4. A 250 mL
round-bottom flask was equipped with a reflux condenser and
charged with anhydrous benzene (150 mL) and freshly distilled
enamine 4 (4.78 g, 0.023 mol). Ethyl bromoacetate (3.03 mL,
0.072 mol) was added via syringe. The solution was refluxed
for 12 h, and the reflux condenser was replaced with a
distillation head. The benzene was removed by distillation
almost to dryness to give the enamine salt as a solid. H2O
(150 mL) was added, and the solution was stirred at room
temperature for 24 h. The aqueous solution was extracted
with diethyl ether (4 × 100 mL), and the combined organic
extracts were washed with H2O (2 × 100 mL) and saturated
aqueous NaCl (2 × 100 mL). After being dried over MgSO4,
the ether was removed on a rotary evaporator to give the crude
ketone 5 (3.05 g, 18.3 mmol, 55%) as a light-brown solid which
was used without further purification: mp 49-52 °C; IR (neat)
1716, 1733 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.20 (t, J ) 7.2
Hz, 3 H), 1.75 (m, 1 H), 1.90-2.20 (m, 3 H), 2.40 (m, 1 H),
2.60-2.80 (m, 2 H), 3.15 (m, 1 H), 4.01 (br s, 4 H), 4.10 (q, J )
7.2 Hz, 2 H); 13C NMR (CDCl3): δ 14.36, 34.05, 34.16, 34.76,
38.02, 38.56, 43.27, 60.69, 64.82, 107.28, 172.23, 209.76.
P r ep a r a tion of La cton e 6. A dry 200 mL round-bottom
flask was charged with anhydrous THF (150 mL) and was
purged with dry N2. Ketone 5 (3.0 g, 12.39 mmol) was added,
and the solution was cooled to -78 °C using a dry-ice/acetone
bath. K-Selectride (1 M in THF) (12.4 mL , 12.4 mmol) was
added via syringe. The reaction was stirred at -78 °C for 2
h. The reaction was quenched by the addition of 3 M aqueous
NaOH (3 mL), followed by warming to room temperature. A
20 mL amount of 30% aqueous H2O2 was added carefully,
dropwise. Following the initial exothermic reaction, the
solution was stirred for an additional 30 min. Aqueous HCl
(5%) (3 mL) was added via syringe, and the solution stirred
for 15 min, followed by transfer to a separatory funnel. The
aqueous solution was extracted with diethyl ether (3 × 50 mL).
The combined organic extracts were washed successively with
H2O (2 × 50 mL), saturated aqueous NaHCO3 (3 × 50 mL),
and saturated aqueous NaCl (2 × 50 mL). The ether was
removed on a rotary evaporator to give the crude lactone as a
clear yellow oily solid. Purification by chromatography utiliz-
ing 10% CH3CN in CH2Cl2 as the eluent gave the lactone 6
(0.87 g, 4.33 mmol, 35%) as a white crystalline solid. Typical
yields ranged from 20-40%: mp 55-59 °C; IR (neat) 1774
cycloaddition,5 and 4 + 2 cycloaddition. The involvement
of a perepoxide in the 4 + 2 reaction was apparently first
proposed by Dewar and Thiel6 on the basis of MINDO/3
calculations. Experimentally, Paquette and co-workers7
have shown that the facial selectivity for 4 + 2 reactions
1
of O2 with some tricyclic cyclopentadiene derivatives is
unlike that seen for all other 4 + 2 cycloadditions
examined, indicating that the mechanism might be
different from that of most Diels-Alder reactions. And
most recently, De Lucchi et al. have shown that cycload-
dition of 1O2 to 3,3′,4,4′-tetrahydro-1,1′-binaphthalene
occurs with a preference for antarafacial addition, which
could also be consistent with the intermediacy of a
perepoxide.8
1
If the 4 + 2 cycloaddition of O2 to dienes generally
occurs via a perepoxide, the regio- and stereochemistry
of the reaction might be quite different from that of the
Diels-Alder addition. Such information would be im-
portant in the design of syntheses involving the 1O2
reaction.
Exp er im en ta l Section
Gen er a l. Reagents were purchased from Aldrich and used
without purification unless specified otherwise. Reaction
solvents were purified according to standard procedures. All
reactions were carried out under dry nitrogen in oven-dried
glassware. Chromatographic solvents were used without
purification. Thin layer chromotography was carried out on
1
cm-1; H NMR (200 MHz, CDCl3) δ 1.50-2.39 (m, 7 H), 2.73
glass plates coated with 0.25 mm of silica gel 60 F254
.
(m, 2 H), 4.01 (br s, 4 H), 4.50 (m, 1 H); 13C NMR (CDCl3) δ
25.83, 28.83, 35.21, 35.70, 37.84, 64.82, 64.82, 78.14, 107.80,
177.33.
P r ep a r a tion of Meth yla ted La cton e 7. A 100 mL round-
bottom flask was equipped with a stir bar and a pressure
equalizing funnel and charged with anhydrous THF (50 mL).
Approximately 10 mg 1,10-phenanthrolein was added, and the
solution was blanketed with argon. Diisopropylamine (0.80
mL, 6.0 mmol) was added via syringe. The solution was cooled
Visualization was achieved with anisaldehyde stain (prepared
from a mixture of 9 mL of anisaldehyde, 340 mL of EtOH, 12.5
mL of sulfuric acid, and 4 mL of glacial acetic acid), and
peroxides were visualized with thiocyanate stain (prepared
(5) (a) Clennan, E. L.; Lewis, K. K. J . Am. Chem. Soc. 1987, 109,
2475. (b) Clennan, E. L.; Nagraba, K. J . Am. Chem. Soc. 1988, 110,
4312.
(6) Dewar, M. J . S.; Thiel, W. J . Am. Chem. Soc. 1977, 99, 2338.
(7) Paquette, L. A.; Carr, R. V. C.; Arnold, E.; Clardy, J . J . Org.
Chem. 1980, 45, 4907.
(8) Delogu, G.; Fabbri, D.; Fabris, F.; Sbrogio`, F.; Valle, G.; De
Lucchi, O. J . Chem. Soc., Chem. Commun. 1995, 1887.
(9) Haga, K.; Oohashi, M.; Kaneko, R.Bull. Chem. Soc. J apan 1984,
57, 1586.

4620 J . Org. Chem., Vol. 61, No. 14, 1996
Davis and Carpenter
to 0 °C, and n-BuLi (1.6 M in THF) was added dropwise via
syringe until the red color of the LDA/1,10-phenanthrolein
charge transfer complex persisted. Additional n-BuLi (3.60
mL, 6.0 mmol) was then introduced via syringe. After stirring
for 30 min at 0 °C, the solution was cooled to -78 °C in a dry
ice-acetone slush bath. A solution of lactone 6 (0.87 g, 5.40
mmol) in THF (10 mL) was added dropwise from the addition
funnel over a period of 10 min and at a rate which maintained
the reaction flask temperature at -78 °C. The solution was
stirred an additional 30 min at -78 °C, and methyl iodide (0.4
mL, 6.47 mmol) was added via syringe. The solution was
allowed to warm to room temperature over a period of 2 h,
and then the reaction was quenched by the addition of H2O (3
mL). The reaction mixture was transferred to a separatory
funnel containing an equivalent volume of saturated aqueous
NaCl. The mixture was extracted with three 50 mL portions
of ether, and the combined extracts were washed successively
with H2O (5 × 50 mL), 10% aqueous HCl (2 × 50 mL),
saturated aqueous NaHCO3 (2 × 50 mL), and saturated
aqueous NaCl (50 mL). After drying over MgSO4, the solvent
was removed under reduced pressure, and the crude product
was purified by chromatography utilizing 10% acetonitrile in
CH2Cl2 as the eluent. Pure methylated lactone 7 (0.63 g, 2.97
in THF, 2.2 mmol) was added via syringe over a period of 5
min. The solution was stirred for 1 h at -78 °C and then
allowed to warm to 0 °C and quenched by addition of methanol,
dropwise, over a period of 10 min until no further reaction
occurred (about 0.5 mL). The reaction was warmed to room
temperature, excess MeOH was added, and the reaction was
stirred until precipitation of white borane salts was completed.
The solution was filtered through a pad of Celite to remove
the borane salts and washed with hot MeOH (50 mL) and
diethyl ether (50 mL). The solvent was removed on a rotary
evaporator to provide the crude reduction product. Purifica-
tion was achieved by elution down a silica gel column with a
gradient of 10% to 50% of CH3CN in CH2Cl2. This provided
the lactol (0.14 g, 0.83 mmol, 75%) as a mixture of epimers:
IR (neat) 3200-3300 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.03-
1.12 (m, 3 H), 1.50-2.30 (m, 8 H), 3.45-3.95 (m, 1 H), 4.01-
4.32 (m, 1 H), 5.02,5.60 (m, m, 1 H).
Into a 10 mL round-bottom flask was placed the lactol (0.030
g, 0.174 mmol), 1,2-ethanedithiol (0.032 mL, 0.34 mmol), and
CH2Cl2 (5 mL) under a N2 blanket. BF3‚OEt2 (0.022 mL, 0.174
mmol) was added via syringe. The reaction was stirred at
room temperature for 2 h, followed by the addition of H2O (3
mL). The solution was transferred to a separatory funnel
containing an equal volume of saturated aqueous NaCl. The
solution was extracted with three 20 mL portions of CH2Cl2.
The combined organic extracts were washed successively with
H2O (2 × 20 mL), saturated aqueous NaHCO3 (20 mL), and
saturated aqueous NaCl (20 mL). After drying over MgSO4,
the solvent was removed on a rotary evaporator. This gave
the product as a mixture of stereoisomeric thioketals 9 and
10. The mixture was separated by column chromatography
utilizing a solvent gradient of 1% to 20% CH3CN in CH2Cl2.
Purification gave the first thioketal (0.015 g, 0.061 mmol, 35%)
as a viscous oil (Rf ) 0.5, 10% CH3CN in CH2Cl2). Further
elution afforded the second thioketal (0.014 g, 0.061, 35%) as
a white semisolid (Rf ) 0.4, 10% CH3CN in CH2Cl2). The
stereochemistry of the cis and trans diols was determined by
mass spectroscopy, and the first product was determined to
be the cis isomer 10 and the second product the trans isomer
9.
mmol, 55%) was obtained as a semisolid: IR (neat) 1773 cm-1
;
1H NMR (200 MHz, CDCl3) δ 1.21 (d, J ) 7.2 Hz, 3 H), 1.50-
2.02 (m, 6 H), 2.34 (q, J ) 6.7 Hz, 1 H), 2.71 (q, J ) 7.3 Hz, 1
H), 3.90 (br s, 4 H), 4.52 (q, J ) 6.1 Hz, 1 H); 13C NMR (CDCl3)
δ 15.92, 25.81, 28.54, 35.61, 36.08, 37.90, 64,33, 66.35, 78.20,
108.16, 176.97.
P r ep a r a tion of Alcoh ols 8 fr om La cton e 7. Into a 50
mL round-bottom flask was placed methylated lactone 7 (0.60
g, 2.82 mmol) in 25 mL of CH2Cl2 at room temperature. BF3‚-
OEt2 (3.47 mL, 28.2 mol) was added via syringe and the
solution stirred for 12 h at room temperature. When the
reaction was complete by TLC (10% CH3CN in CH2Cl2), it was
quenched by the addition of H2O (5 mL) and transferred to a
separatory funnel containing an equal volume of saturated
aqueous NaCl. The solution was extracted with three 10 mL
portions of CH2Cl2. The combined extracts were washed
successively with H2O (2 × 10 mL), saturated aqueous
NaHCO3 (10 mL), and saturated aqueous NaCl (10 mL). After
drying over MgSO4, the solvent was removed on a rotary
evaporator and the product was purified by column chroma-
tography utilizing a gradient of 2% to 10% CH3CN in CH2Cl2
to give the ketone (0.39 g, 2.26 mmol, 80%) as a white
crystaline solid: mp 43-45 °C; IR (neat) 1712, 1762 cm-1; 1H
NMR (200 MHz, CDCl3) δ 1.29 (d, J ) 7.2 Hz, 3 H), 2.10-2.70
m, 8 H), 4.91 (m, 1 H); 13C NMR (CDCl3) δ15.04, 26.74, 34.78,
40.74, 40.96, 41.14, 74.67, 178.23, 208.66.
1
10: IR (CDCl3) 3300 cm-1; H NMR (200 MHz, CDCl3): δ
1.10 (d, J ) 7.0 Hz, 3 H), 1.47-2.01 (m, 7 H), 3.20 (m, 4 H),
4.15 (br s, 2 H), 5.02 (d, J ) 3.0 Hz, 1 H); 13C NMR (CDCl3):
δ 12.93, 26.90, 28.69, 31.88, 39.58, 40.01, 40.86, 41.19, 5.03,
66.99, 67.84.
9: IR (CDCl3) 3300 cm-1 1H NMR (200 MHz, CDCl3): δ
;
0.9 (d, J ) 7.0, 3 H), 1.10-2.10 (m, H), 3.22 (m, 4 H), 3.61 (br
s, 1 H), 4.09 (br s, 1 H), 4.91 (d, J ) 4.0 Hz, 1 H); 13C NMR
(CDCl3): δ 13.30, 29.76, 32.75, 34.25, 39.59, 39.96, 41.28, 46.46,
58.39, 66.87, 71.36.
A 50 mL round-bottom flask equipped with a magnetic stirer
was charged with MeOH (50 mL), CeCl3‚7H2O (0.10 g, 0.37
mmol), and ketone prepared as above (0.31 g, 1.83 mmol). The
stirred solution was cooled to 0 °C, and NaBH4 (0.35 g, 9.1
mmol) was added in portions over a 5 min period. The
suspension was stirred for 30 min upon completion of the
addition, and excess reducing agent was destroyed by pouring
the suspension into a mixture of ice and 10% HCl. After
stirring to dissolve completely, the solution was transferred
to a separatory funnel containing an equal volume of saturated
aqueous NaCl and was extracted with three 50 mL portions
of ether. The combined extracts were washed successively
with H2O (2 × 50 mL), saturated aqueous NaHCO3 (50 mL),
and saturated aqueous NaCl (50 mL) and were dried over
MgSO4. The solvent was removed under reduced pressure,
and the crude products were purified by chromatography
utilizing 50% ethyl acetate in hexanes as the eluent. This gave
the alcohols 8 (0.25 g, 1.46 mmol, 80%) (approximately a 1:1
mixture of epimers by 1H NMR) which were not separated:
IR (neat) 1767, 3200 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.31
(2d, J ) 7.2 Hz, 3 H total), 1.50-2.05 (m, 4 H), 2.11 (m, 2 H),
2.45 (m, 1 H), 2.60 (m, 1 H), 3.81,3.94 (m, m, 1 H), 4.52 (m, 1
H).
P r ep a r a tion of cis,cis-2-Isop r op ylcycloh exa n e-1,4-d iol
(2). A 50 mL round-bottom flask was equipped with a reflux
condenser and was charged with the thioketal 10 (10 mg, 0.040
mmol) in 20 mL of anhydrous ethanol. Raney nickel in EtOH
was added in small portions over a period of 4 h while the
reaction was monitored by TLC, utilizing 25% EtOAc in
hexanes as the eluent and visualizing with anisaldehyde stain.
When none of the dithiane remained, the suspension was
filtered through a bed of Celite and washed with acetone. The
solvent was removed on a rotary evaporator to give the cis,-
cis-2-isopropylcyclohexane-1,4-diol (2) (6.5 mg, 0.039 mmol,
98%) as a white solid: mp 102-103 °C; IR (neat) 3300 cm-1
;
1H NMR (200 MHz, acetone-d6) δ 1.89 (d, J ) 7.0 Hz, 3 H),
1.91 (d, J ) 7.0 Hz, 3 H), 1.20-2.03 m, 8 H), 3.51 (br s, 2 H);
13C NMR (acetone-d6) δ 21.198, 21.273, 29.322, 34.685, 48.264,
65.408, 70.984 (2 resonances obscured by the solvent). Anal.
Calcd for C9H18O2: C, 68.31; H, 11.46. Found: C, 67.95; H,
11.41.
P r ep a r a tion of Dich lor ocyclobu ta n on e 11. A 500 mL
three-neck round bottom flask equipped with a pressure-
equalizing addition funnel was placed under a blanket of N2
and placed into the middle of an ultrasound bath. A 300 mL
amount of anhydrous ether was placed in the flask; Zn powder
(6.92 g, 110.0 mmol) and 1,4-cyclohexadiene (10.3 mL, 110.0
mmol) were added, and the ultrasound was started. The water
bath was cooled to 15 °C by adding pieces of ice periodically.
P r ep a r a tion of Th iok eta ls 9 a n d 10. A 100 mL round-
bottom flask equipped with a magnetic stirer was charged with
with alcohols 8 (181 mg, 1.1 mmol) in THF and cooled to -78
°C. Di-isobutylaluminum hydride (DIBAL) (2.1 mL of 1.0 M

Cycloaddition of Singlet Oxygen to a Simple Cyclic Diene
J . Org. Chem., Vol. 61, No. 14, 1996 4621
A solution of trichloroacetyl chloride (8.96 mL, 110.0 mmol)
in 100 mL of anhydrous ether was added over a period of 1.5
h, followed by ultrasound for 1 h, while maintaining the water
bath temperature at 15 °C. When the reaction was complete,
the solids were removed by vacuum filtration and the ether
was washed with H2O (3 × 100 mL), saturated aqueous
NaHCO3 (3 × 100 mL), and saturated aqueous NaCl (200 mL).
The ether was dried with MgSO4 and removed using a rotary
evaporator. The resulting brown oil was purified by bulb-to-
bulb distillation (80 °C, 0.2 torr) to give the known10 dichlo-
rocyclobutanone 11 as a clear oil (7.8 g, 44.0 mmol, 40%): 1H
NMR (200 MHz, CDCl3) δ 2.00-2.68 (m, 4 H), 2.31 (ddd, J )
10.8, 7.8, 2.3 Hz, 1 H), 4.11 (ddd, J ) 10.8, 7.2, 2.5 Hz, 1 H),
5.85 (m, 2 H).
P r ep a r a tion of Cyclobu ta n on e 12. A 250 mL round-
bottom flask was charged with Zn (15 g, 0.23 mol) in HOAc
(75 mL). The dichloroketone 11 (7.5 g, 0.039 mol) dissolved
in 25 mL of HOAc was added, dropwise to the solution, while
stirring with a mechanical stirrer. The solution became warm
but required no external cooling if the dichloride was added
slowly. The reaction was then warmed to 70 °C for 1 h and
then allowed to cool to room temperature and stirred for 8 h.
The mixture was diluted with diethyl ether (100 mL), and the
solids were filtered off, washing with diethyl ether. The
solution was transferred to a separatory funnel and washed
with H2O (5 × 50 mL), with saturated aqueous NaHCO3 until
no HOAc remained and then with saturated aqueous NaCl (2
× 50 mL). After drying with MgSO4, the solvent was removed
using a rotary evporator and the product was purified by bulb-
to-bulb distillation under reduced pressure (80 °C, 35 torr) to
give the known10 ketone 12 (4.05 g, 0.19 mol, 84%) as a clear
oil: 1H NMR (200 MHz, CDCl3) δ 2.02-2.60 (m, 5 H), 2.81
(m, 1 H), 3.20 (ddd, J ) 18.0, 9.0, 4.1 Hz, 1 H), 3.41 (m, 1 H),
5.92 (m, 2 H).
saturated aqueous NaCl (50 mL). After drying over MgSO4,
the solvent was removed under reduced pressure and the crude
product was purified by chromatography utilizing 10% CH3-
CN in CH2Cl2 as the eluent. Pure methylated lactone 14 (0.65
g, 4.22 mmol, 55%) was obtained as an oil: IR (neat) 1776
1
cm-1; H NMR (200 MHz, CDCl3) δ 1.35 (d, J ) 6.4 Hz, 3 H),
2.10-2.72 (m, 6 H), 4.71 (m, 1 H), 5.7 (m, 2 H); 13C NMR
(CDCl3) δ 13.60, 25.19, 27.97, 39.34, 39.99, 74.85, 123.76,
124.89.
P r ep a r a tion of La ctol 15. A 100 mL round-bottom flask
equipped with a magnetic stirrer was charged with with
methylated lactone 14 (0.68 g, 4.44 mmol) in anhydrous
toluene and cooled to -78 °C. DIBAL (8.9 mL 2.0 M in
toluene, 8.9 mmol) was added via syringe over a period of 5
min. The solution was stirred for 2 h at -78 °C and then
quenched by addition of 1 mL of methanol (added until gas
evolution ceased) dropwise over a period of 10 min. The
reaction was allowed to warm to room temperature, and excess
MeOH (1 mL) was added. The solution was transferred to a
separatory funnel with an equal volume of saturated aqueous
NaCl. HCl 5% was added to break up the resulting emulsion.
The organic layer was washed with saturated aqueous NaH-
CO3 (3 × 50 mL), H2O (50 mL), and saturated aqueous NaCl
(100 mL). The solvent was removed on a rotary evaporator
to provide the crude reduction product. Purification was
achieved by bulb-to-bulb distillation (110 °C, 0.5 torr). This
provided the lactol 15 (0.55 g, 3.60 mmol, 81%) as a mixture
1
of epimers: IR (neat) 3200-3300 cm-1; H NMR (200 MHz,
CDCl3) δ 0.97-1.22 (m, 3 H), 1.80-2.51 (m, 5 H), 2.90, 3.41
(br s, br s, 1 H), 4.21, 4.52 (m, m, 1 H), 5.01, 5.30 (m, m, 1 H),
5.70,5.80 (m, m, 1 H).
P r ep a r a tion of Th iok eta l 16. Into a 100 mL round-
bottom flask was placed lactol 15 (1.98 g, 12.86 mmol), dithiol
(2.0 mL, 23.8 mmol), and CH2Cl2 (80 mL) under a N2 blanket.
BF3‚OEt2 (2.0 mL, 16.2 mmol) was added via syringe. The
reaction was stirred at room temperature for 2 h, followed by
the addition of H2O (20 mL). The solution was transferred to
a separatory funnel. The layers were separated, and the
aqueous solution was extracted with two 50 mL portions of
CH2Cl2. The organic extracts were combined and washed
successively with H2O (2 × 50 mL), saturated aqueous
NaHCO3 (2 × 50 mL mL), and saturated aqueous NaCl (50
mL). After drying over MgSO4, the solvent was removed on a
rotary evaporator. This gave the crude thioketal 16 (2.68 g,
11.70 mmol, 91%) as an oil which was used without further
purification: IR (CDCl3) 3200 cm-1; 1H NMR (200 MHz, CDCl3)
δ 1.09 (d, J ) 7.0 Hz, 3 H), 1.80-2.52 (m, 6 H), 3.21 (m, 4 H),
4.19 (br s, 1 H), 5.02 (d, J ) 7.0 Hz, 1 H), 5.50 (m, 1 H), 5.72
(m, 1 H); 13C NMR (CDCl3) δ 24.32, 28.14, 34.23, 38.30, 38.51,
39.87, 41.88, 57.13, 65.33, 122.35, 126.36.
P r ep a r a tion of La cton e 13. A 250 mL round-bottom flask
was equiped with a stir-bar and charged with ketone 12 (4.0
g, 32.8 mmol) in 60 mL of 90% aqueous HOAc. The solution
was cooled to 0 °C and 30% H2O2 (10.0 g) was added in 40 mL
of 90% HOAc. The reaction was stirred at 0 °C for 24 h and
then diethyl ether (200 mL) was added and the solution
transferred to a separatory funnel. The ether was washed
with H2O (3 × 100 mL) and then with aqueous NaHCO3 until
no acid remained. After drying with MgSO4, the ether was
removed using a rotary evporator, giving the lactone 13 (3.98
g, 28.9 mmol, 88%) as a clear oil. No further purification was
1
required: IR (neat) 1775 cm-1; H NMR (200 MHz, CDCl3) δ
1.89-2.82 (m, 7 H), 4. (m, 1 H), 5.85 (m, 2 H); 13C NMR
(CDCl3) δ 26.07, 27.30, 32.03, 36.64, 77.72, 123.91, 125.61,
177.08.
P r ep a r a tion of Meth yla ted La cton e 14. A 200 mL
round-bottom flask was charged with THF (50 mL). Ap-
proximately 10 mg of 1,10-phenanthrolein was added, and the
solution was blanketed with argon. Diisopropylamine (1.40
mL, 9.9 mmol) was added via syringe. The solution was colled
to 0 °C, and 1.6 M n-BuLi was added dropwise via syringe
until the red color of the LDA/1,10-phenanthrolein charge
transfer complex persisted. Additional 1.6 M n-BuLi (6.24 mL,
9.99 mmol) was then introduced via syringe. After stirring
for 30 min at 0 °C, the solution was cooled to -78 °C in a dry
ice-acetone slush bath. A solution of lactone 13 (1.06 g, 7.68
mmol) in THF (50 mL) was added dropwise from the addition
funnel over a period of 10 min and at a rate which maintained
the reaction flask temperature at approximately -78 °C. The
solution was stirred an additional 30 min at -78 °C, and
methyl iodide (0.53 mL, 9.99 mmol) was added via syringe.
The solution was allowed to warm to room temperature over
a period of 2 h, and then the reaction was quenched by the
addition of H2O (3 mL). The reaction mixture was transferred
to a separatory funnel containing an equivalent volume of
saturated aqueous NaCl. The mixture was extracted with
three 50 mL portions of ether, and the combined extracts were
washed successively with H2O (5 × 50 mL), 10% aqueous HCl
(2 × 50 mL), saturated aqueous NaHCO3 (2 × 50 mL), and
P r ep a r a tion of 6-Isop r op ylcycloh ex-3-en -1-ol (17). A
250 mL round-bottom flask was equipped with
a reflux
condenser and was charged with thioketal 16 (1.6 g, 7.77
mmol) in 100 mL anhydrous ethanol. Acetone (0.5 mL) was
added, to deactivate the Raney nickel and avoid reduction of
the olefin. The solution was heated to reflux, and Raney nickel
in EtOH was added in small portions over a period of 12 h
while the reaction was monitored closely by TLC (eluting with
25% EtOAc in hexanes and visualizing with anisaldehyde
stain). When none of the thioketal remained, the suspension
was filtered through a bed of Celite and washed with acetone.
The solvent was removed on a rotary evaporator to give the
crude product, which was purified by bulb-to-bulb distillation
(0.50 g, 3.57 mmol, 46%) to give 17 as a clear oil: IR (neat)
1
3200-3300 cm-1; H NMR (200 MHz, CDCl3) δ 0.92 (d, J )
6.1 Hz, 3 H), 0.98 (d, J ) 6.1 Hz, 3 H), 1.50-2.50 (m, 6 H),
3.70 (m, 1 H), 5.6 (m, 1 H), 5.8 (m, 1 H); 13C NMR (CDCl3) δ
19.68, 20.61, 25.01, 29.47, 34.63, 44.25, 65.43, 122.65, 127.14.
P r ep a r a t ion of 5-Isop r op yl-1,3-cycloh exa d ien e (3).
Alcohol 17 (1.2 g, 8.57 mmol) was dissolved in 100 mL of
anhydrous ether in a round-bottom flask and cooled to 0 °C
under an N2 blanket. n-BuLi (1.6 M in THF) (6.43 mL, 1.03
× 10-2 mol) was added via syringe, and the solution was
stirred at 0 °C for 1 h. Phenyl chlorothionoformate (1.31 mL,
9.43 mmol) was added via syringe, and the solution was
allowed to warm up to room temperature and then stirred for
(10) Liotta, F. J .; Van Duyne, G.; Carpenter, B. K. Organometallics
1987, 6, 1010.

4622 J . Org. Chem., Vol. 61, No. 14, 1996
Davis and Carpenter
12 h. The LiCl salts which had formed were dissolved by the
adition of H2O, the mixture was transferred to a separatory
funnel, and the layers were separated. The aqueous layer was
extracted with ether (2 × 20 mL), and the organic layers were
combined and washed with H2O (20 mL), saturated aqueous
NaHCO3 (2 × 20 mL), and saturated aqueous NaCl (20 mL).
After drying with MgSO4, the ether was removed using a
rotary evaporator and the product was dried further under
reduced pressure, to remove any remaining traces of phenyl
chlorothionoformate. The product was purified by column
chromotography utilizing 20% EtOAc in hexanes to give the
thioester (1.55 g, 5.3 mmol, 62%) as a yellow solid: mp 81-85
solution was then allowed to warm up to room temperature
slowly, over 2-3 h, and stirred overnight. The yellow solid
was then filtered through a glass fritted filter, washing with
CH2Cl2. The CH2Cl2 was removed at 0 °C using a rotary
evaporator. The residue was purified by silica gel chroma-
tography (utilizing CH2Cl2 as the eluent and visualizing with
thiocyanate stain for peroxides) to give 3-hydroperoxy-1-
isopropylcyclohexene (0.10 g, 0.62 mmol, 24%). Further elu-
tion afforded 5-isopropyl-2,3-dioxabicyclo[2.2.2]octane (1) (0.15
g, 0.94 mmol, 36%) as an oily solid.
5-Isop r op yl-2,3-d ioxa bicyclo[2.2.2]octa n e (1): 1H NMR
(200 MHz, CDCl3) δ 0.91 (d, J ) 8.1 Hz, 3 H), 0.95 (d, J ) 8.1
Hz, 3 H), 1.20-1.40 (m, 2 H), 1.50-1.90 (m, 4 H), 2.00-2.40
(m, 2 H), 4.00-4.10 (br s, 2 H); 13C NMR (CDCl3) δ 20.47(2),
24.53, 30.37, 31.17, 31.78, 42.12, 71.60, 73.54. Anal. Calcd
for C9H16O2: C, 69.20; H, 10.32. Found: C, 69.72; H, 10.32.
3-Hyd r op er oxy-1-isop r op ylcycloh exen e: 1H NMR (200
MHz, CDCl3) δ 0.89 (d, J ) 7.2, 3 H), 0.97 (d, J ) 7.1, 3 H),
1.50-2.40 (m, 7 H), 4.61 (m, 1 H), 6.62 (m, 1 H); 13C NMR
(CDCl3) δ 19.42, 19.81, 20.47, 28.69, 32.49, 40.72, 73.86, 130.19,
132.64. Anal. Calcd for C9H16O2: C, 69.20; H, 10.32. Found:
C, 69.85; H, 10.38.
Red u ction of 5-Isop r op yl-2,3-d ioxa bicyclo[2.2.2]octa n e
to 2-Isop r op yl-1,4-cycloh exa n ed iol w ith H2/P d . A solution
of 5-isopropyl-2,3-dioxabicyclo[2.2.2]octane (1) (20 mg, 0.13
mmol) in ethanol (10 mL) was placed in a high pressure bottle.
Approximately 15 mg of 5% palladium on carbon was added,
and the suspension was shaken for 2 h at room temperature
under 50 psi of H2. After removal of the catalyst by filtration
through a Celite pad, the solvent was removed on a rotary
evaporator to give 2-isopropyl-1,4-cyclohexanediol (15 mg,
0.098 mmol, 75%) as a white solid, exactly identical to diol 2,
prepared as described above: mp 101-104 °C; IR (neat) 3300
cm-1; 1H NMR (200 MHz, acetone-d6): δ 1.9 (d, J ) 7.0 Hz, 3
H), 1.9 (d, J ) 7.0 Hz, 3 H), 1.2-2.0 m, 8 H), 3.5 (br s, 2 H);
13C NMR (acetone-d6): δ 21.19, 21.27, 32.88, 34.66, 48.26,
65.39, 70.98 (2 resonances obscured by the solvent).
1
°C; IR (CDCl3) 1224 (w) cm-1; H NMR (200 MHz, CDCl3) δ
0.95 (d, J ) 6.1 Hz, 3 H), 1.00 (d, J ) 6.1 Hz, 3 H), 1.30-1.61
(m, 2 H), 2.00-2.70 (m, 4 H), 5.60 (m, 1 H), 5.80 (m, 2 H),
7.10-7.60 (m, 5 H); 13C NMR (CDCl3) δ 20.78, 25.82, 29.51,
30.32, 43.39, 4742, 80.22, 121.79, 126.35, 126.79, 127.09,
129.35, 153.22, 194.51.
The thioester (1.55 g, 5.3 mmol) was heated to 105 °C in a
bulb-to-bulb distillation flask. As the ester was pyrolyzed the
resulting diene was distilled and trapped in the collection flask
at -78 °C in a dry ice/acetone slush bath. The hydrocarbon
product was purified by column chromatography utilizing
pentane as the eluent, to remove traces of phenol biproduct.
The pentane was removed using a rotary evaporator at 0 °C.
5-Isopropyl-1,3-cyclohexadiene (3) (0.32 g, 2.65 mmol, 50%)
was obtained as a clear oil: IR (neat) 1605 cm-1; 1H NMR (200
MHz, CDCl3) δ 0.90 (d, J ) 6.0 Hz, 3 H), 0.94 (d, J ) 6.0 Hz,
3 H), 1.50-2.33 (m, 4 H), 5.65-5.80 (m, 2 H), 5.80-6.01 (m, 5
H); 13C NMR (CDCl3) δ 19.67, 25.36, 31.24, 39.30, 123.85,
123.96, 126.31, 129.91.
Sin glet Oxygen Ad d ition to 5-Isop r op yl-1,3-cycloh exa -
d ien e (3). A 100 mL three-neck round-bottom flask was
equipped with a thermometer and placed under a N2 blanket.
5-Isopropyl-1,3-cyclohexadiene (3) (320 mg, 2.6 mmol) and
approximately 10 mg of tetraphenylporphyrin (TPP) in 50 mL
of CH2Cl2 were placed in the flask and then cooled to -78 °C.
O2 was bubbled continuously through the solution, and a
sunlamp was shone on it for 5 h, while maintaining the
temperature constant at -78 °C. A second 250 mL three-neck
round-bottom flask was prepared: it was equipped with a stir
bar, pressure-equalizing funnel, and placed under a N2 blanket
while being cooled to -78 °C. Into this flask were placed
potassium azodicarboxylate (PADC) (2.7 g, 14.6 mmol) in 50
mL of CH2Cl2. HOAc (1.59 g, 26.5 mmol) in 50 mL of CH2Cl2
was placed in the addition funnel. The diene solution was
transferred into the PADC solution via cannula, while the
HOAc solution was added dropwise at aproximately the same
rate. The additions were made over a period of 30 min, while
the temperature was maintained at -78 °C . The PADC
Ack n ow led gm en t. We thank the National Science
Foundation (CHE-9528843) for financial support of this
work.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of new
compounds (15 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9604292