Reactions of Singlet Oxygen and N-Methyltriazolinediones with β,β-Dimethylstyrene. Exceptional Syn Selectivity in the Ene Products

Full text of DOI:10.1021/jo9715332

J . Org. Chem. 1998, 63, 1315-1318
1315
gen abstraction next to the bulkiest group.7 Also, gemi-
nal selectivity8 with respect to a bulky alkyl substituent
at allylic or vinylic position is observed. These selectivi-
ties were rationalized in terms of nonbonded interactions
in the product-forming transition states.9 Furthermore,
coordination of 1O2 to hydroxyl10 and amino11 groups, or
electronic repulsions with several other functionalities12
in the allylic positions, can lead not only to highly threo
or erythro diastereoselective ene reactions but also can
control the regioselectivity.13
Rea ction s of Sin glet Oxygen a n d
N-Meth yltr ia zolin ed ion es w ith
â,â-Dim eth ylstyr en e. Excep tion a l Syn
Selectivity in th e En e P r od u cts
Manolis Stratakis,*,†,‡ Michael Orfanopoulos,† and
Christopher S. Foote*,‡
Department of Chemistry, University of Crete,
71409 Iraklion, Greece, and Department of Chemistry and
Biochemistry, University of California,
In this paper, we report an unprecedentedly high “cis
effect” selectivity in the ene products from singlet oxygen
and MTAD addition to â,â-dimethylstyrene (1). It was
reported12 several years ago that sensitized photooxy-
genation of 1 in several solvents affords a variable
mixture of ene product (1b), benzaldehyde, and two
diastereomeric diendoperoxides 1d and 1e in 68/32 ratio;
diendoperoxides arise from initial [4 + 2] addition of 1O2
Los Angeles, California 90095-1569
Received August 14, 1997
The ene reactions of singlet oxygen (1O2) and triazo-
linediones (RTAD, R ) methyl or phenyl, usually) with
alkenes are closely related mechanistically and exhibit
a fascinating variety of regio- and stereoselectivities. Both
reactions appear to proceed via intermediates; the singlet
oxygen reaction via a “perepoxide” 1 and the RTAD
reaction via an aziridinium imide (AI).2 In the reaction
of 1O2 with trisubstituted alkenes3 and enol ethers,4 the
more reactive side of the olefin is the more substituted
one (“cis effect”), but there is very little Markovnikov
selectivity. These results have been rationalized5 by
postulating an attractive interaction of singlet oxygen
with allylic hydrogens on the more substituted side of
the double bond. On the other hand, phenyl- and
methyltriazolinedione (PTAD and MTAD) exhibit strong
Markovnikov selectivity, giving products with the nitro-
gen exclusively on the less substituted carbon.6
1
to 1, followed by a second addition of O2 to the newly
formed diene endoperoxide 1c, (Scheme 1).
To distinguish the syn/anti stereosectivity of the ene
products produced from the two geminal methyls, the
anti-methyl group was specifically labeled (>99% geo-
metrical purity) by a literature procedure.15 The ene
adducts can be separated from the reaction mixture by
column chromatography using benzene as eluent. Ex-
amination of the syn/anti stereoselectivity of the ene
products of 2 in different solvents revealed that there is
a strong selectivity for attack on the methyl syn to the
phenyl group. The magnitude of this selectivity depends
on solvent polarity. On increasing the dielectric constant
of the solvent, a substantial increase in the amount of
hydrogen abstraction in the syn-methyl group occurs. For
instance, the ratio of syn/anti ene products increases by
a factor of 3.4 on going from CCl4 to methanol (Table 1).
The intermolecular isotope effect upon competition of
1 with the deuterated olefin 3 in chloroform is negligible
(kH/kD)total ) 1.00 ( 0.02), which means that formation
of perepoxide is irreversible, as in other trisubstituted
In the reaction of 1O2 and RTAD with cis-disubstituted
alkenes, the major ene products arise from allylic hydro-
(7) (a) Orfanopoulos, M.; Stratakis, M.; Elemes, Y. Tetrahedron Lett.
1989, 30, 4875-4878. (b) Elemes, Y.; Stratakis, M.; Orfanopoulos, M.
Tetrahedron Lett. 1989, 30, 6903-6906.
(8) (a) Orfanopoulos, M.; Stratakis, M.; Elemes, Y. J . Am. Chem.
Soc. 1990, 112, 6417-6419. (b) Orfanopoulos, M.; Elemes, Y.; Stratakis,
M. Tetrahedron Lett. 1990, 31, 5775-5778. (c) Clennan, E. L.; Chen,
X.; Koola, J . J . J . Am. Chem. Soc. 1990, 112, 5193-5199. (d) Clennan,
E. L.; Koola, J . J .; Oolman, K. A. Tetrahedron Lett. 1990, 31, 6759-
6762.
(9) Orfanopoulos, M.; Stratakis, M.; Elemes, Y.; J ensen, F. J . Am.
Chem. Soc. 1991, 113, 3180-3181.
(10) (a) Adam, W.; Nestler, B. J . Am. Chem. Soc. 1992, 114, 6549-
6550. (b) Adam, W.; Nestler, B. J . Am. Chem. Soc. 1993, 115, 5041-
5049.
† University of Crete.
‡ University of California.
(1) Stephenson, L. M.; Grdina, M. B.; Orfanopoulos, M. Acc. Chem.
Res. 1980, 13, 419-425.
(2) (a) Seymour, C. A.; Greene, F. D. J . Am. Chem. Soc. 1980, 102,
6384-6385. (b) Orfanopoulos, M.; Smonou, I.; Foote, C. S. J . Am. Chem.
Soc. 1990, 112, 3607-3614. (c) Squillacote, M.; Mooney, M.; De
Felippis, J . J . Am. Chem. Soc. 1990, 112, 5364-5365. (d) Poon, T. H.
W.; Park, S. H.; Elemes, Y.; Foote, C. S. J . Am. Chem. Soc. 1995, 117,
10468-10473.
(3) (a) Orfanopoulos, M.; Grdina, M. B.; Stephenson, L. M. J . Am.
Chem. Soc. 1979, 101, 275-276. (b) Schulte-Elte, K. H.; Rautenstrauch,
V. J . Am. Chem. Soc. 1980, 102, 1738-1740.
(4) (a) Rousseau, G.; Le Perchec, P.; Conia, J . M. Tetrahedron Lett.
1977, 2517-20. (b) Lerdal, D.; Foote, C. S. Tetrahedron Lett. 1978,
3227-3230.
(5) (a) Stephenson, L. M. Tetrahedron Lett. 1980, 21, 1005-08. (b)
Hurst, J . R.; Schuster, G. B. J . Am. Chem. Soc. 1982, 104, 6854-6856.
(c) Hurst, J . R.; Wilson, S. L.; Schuster, G. B. Tetrahedron 1985, 41,
2191-2197. (d) Stratakis, M.; Orfanopoulos, M. Tetrahedron Lett. 1995,
36, 4291-4294.
(6) Cheng, C. C.; Seymour, C. A.; Petti, M. A.; Greene, F. D.; Blount,
J . F. J . J . Org. Chem. 1984, 49, 2910-2916.
(11) (a) Adam, W.; Bru¨nker, H.-G. J . Am. Chem. Soc. 1993, 115,
3008-3009. (b) Bru¨nker, H.-G.; Adam, W. J . Am. Chem. Soc. 1995,
117, 3976-3982.
(12) Adam, W.; Bru¨nker, H.-G.; Kumar, A. S.; Peters, E.-M.; Peters,
K.; Schneider, U.; von Schnering, H. G. J . Am. Chem. Soc. 1996, 118,
1899-1905.
(13) Stratakis, M.; Orfanopoulos, M.; Foote, C. S. Tetrahedron Lett.
1996, 37, 7159-7162.
(14) (a) Matsumoto, M.; Dobashi, S.; Kuroda, K. Tetrahedron Lett.
1977, 3361-3364. (b) Matsumoto, M.; Kuroda, K. Synth. Commun.
1981, 11, 987-992.
(15) Grdina, M. B.; Orfanopoulos, M.; Stephenson, L. M. J . Org.
Chem. 1979, 44, 2936-2938.
S0022-3263(97)01533-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

1316 J . Org. Chem., Vol. 63, No. 4, 1998
Notes
Sch em e 1
Sch em e 2
solvent, this stabilization becomes more significant be-
cause the transition state becomes more polar.
We propose that an analogous interaction between the
negatively charged oxygen of the perepoxide and the
methoxy group (made electron deficient by its electron
donation to the adjacent perepoxidic carbon) can also
explain the “cis effect” behavior observed previously in
the photooxygenation of trisubstituted enol ethers.4
Ta ble 1. Ster eoselectivity of th e P h otooxygen a tion of 2
in a Va r iety of Solven ts
Addition of N-methyl-1,2,4-triazoline-3,5-dione (MTAD)
to 2 in CH2Cl2 at -78 °C or in CDCl3 at rt affords the
ene product exclusively, and with greater than 99% syn
selectivity. No [2 + 2] or [4 + 2] adducts were observed,
which would be expected to derive from a zwitterionic
intermediate where the positive charge is stabilized by
the phenyl. Zwitterionic intermediates have been pro-
posed in the addition of PTAD to conjugated dienes17 and
substituted indenes.18 Also, when the addition was
carried out in 1/1 MeOH/CH2Cl2 at -78 °C, or in
methanol-d4 at rt, no methanol adducts (which are
formed in many ene reactions with RTAD)19 could be
solvent
sensitizera
syn/anti selectivity
CCl4
C6H6
CHCl3
CH3CN
CH3OH
TPP
TPP
MB
MB
MB
56/44
57/43
63/37
71/29
82/18
a
TPP, tetraphenylporphine; MB, methylene blue.
alkenes.16 It also requires a very early transition state,
where rehybridization is negligible.
1
identified by H NMR. Again, only the ene product was
observed, with >99% syn selectivity.
In contrast to the singlet oxygen reaction, kinetic
competition of 1 versus 3 gave a significant inverse
intermolecular isotope effect (kH/kD)total ) 0.76 ( 0.02 in
CHCl3, and 0.72 ( 0.02 in methanol (kH/kD ) 0.96 per H
atom), clearly revealing that formation of the AI is
irreversible and that the transition state is much later
than in the singlet oxygen reaction. The inverse isotope
effect is caused by the change in hybridization of the
olefinic carbons from sp2 to sp3 during the rate-determin-
ing step for formation of the intermediate, which favors
deuterium over hydrogen; the transition state in AI
formation is rather loose.20
A possible mechanism that accounts for the observed
results is depicted in Scheme 2. The incoming oxygen
oriented toward the more substituted side of the olefin
in TSI interacts only with one allylic hydrogen, but this
transition state affords the major product. In TSII, which
leads to the anti ene product (D-abstraction), oxygen also
interacts only with one allylic hydrogen. Thus the extra
stabilization for the preferential formation of the more
hindered TSI must arise from interaction of singlet
oxygen with the phenyl group. In TSI, the benzylic
carbon is slightly electron-deficient and is stabilized by
electron donation from the phenyl. Interaction of the
negatively charged oxygen of the perepoxide with the
partially positive phenyl results in stabilization of the
syn transition state. On increasing the polarity of the
These results are consistent with the formation of a
syn AI intermediate between MTAD and 2 in the rate-
determining step, with interaction of the incoming elec-
trophile with the phenyl ring. Subsequent decomposition
of the intermediate produces the ene products with the
(17) J ensen, F.; Foote, C. S. J . Am. Chem. Soc. 1987, 109, 6376-
6385.
(18) Smonou, I.; Orfanopoulos, M.; Foote, C. S. Tetrahedron Lett.
1988, 29, 2769-2772.
(19) Smonou, I.; Khan, S.; Foote, C. S.; Elemes, Y.; Mavridis, I. M.;
Pantidou, A.; Orfanopoulos, M. J . Am. Chem. Soc. 1995, 117, 7081-
7087.
(16) Stratakis, M.; Orfanopoulos, M.; Chen, J . S.; Foote, C. S.
Tetrahedron Lett. 1996, 37, 4105-4108.

Notes
J . Org. Chem., Vol. 63, No. 4, 1998 1317
A vigorous evolution of hydrogen gas was observed. After 1 h,
4.6 mL of benzaldehyde (45 mmol) was added and the mixture
was stirred at rt for 5 h more and then quenched with saturated
NaHCO3 until alkaline pH was reached. The aqueous layer was
acidified and extracted with ether. The crude unsaturated acid
(1H NMR: 7.87 (d, J ) 1.6 Hz, 1H), 7.3-7.5 (m, 5H), 2.15 (d,
J ) 1.6 Hz, 3H)) was dissolved in 100 mL of methanol, and ∼100
mg of p-TsOH was added. The solution was refluxed for one
night and then extracted with ether. The ether layer was
washed with saturated NaHCO3 and brine. The ether was
removed to afford 3.2 g of ester (40% overall yield). GC and
NMR analysis indicated the existence of only one isomer. 1H
NMR: 7.70 (d, J ) 1.4 Hz, 1H), 7.30-7.41 (m, 5H), 3.82 (s, 3H),
2.13 (d, J ) 1.4 Hz, 3H).
(E)-3-P h en yl-2-m eth ylp r op -2-en -1-ol-1,1-d 2. The R,â-un-
saturated ester (3.1 g, 17 mmol) was added dropwise at 0 °C to
a solution containing 0.76 g of LiAlD4 (18 mmol) and 0.80 g of
anhydrous AlCl3. The AlCl3 had been added in portions to the
LiAlD4 at 0 °C over a 15 min period. After 30 min, GC showed
the disappearance of the starting material. The solution was
quenched with HCl (1 N) and then extracted with ether to afford
2.2 g of allylic alcohol-d2. 1H NMR: 7.17-7.38 (m, 5H), 6.52 (s,
1H), 1.91 (d, J ) 1.3 Hz, 3H), 1.62 (br s, 1H).
(E)-1-P h en yl-2-m eth ylp r op -1-en e-3,3,3-d 3 (2). The allylic
alcohol was transformed to the allylic choride according to a
literature procedure.15 To a slurry of N-chlorosuccinimide (2.66
g, 20 mmol) in dry CH2Cl2 was added at 0 °C 1.75 mL of dimethyl
sulfide. The reaction mixture became cloudy. After 30 min, the
solution was cooled to -40 °C, and the allylic alcohol was added
dropwise. The solution was stirred at low temperature for 3 h
and then warmed at rt for 1 h. The allylic choride-d2 was
isolated by extraction with CH2Cl2 (∼2.2 g) and used directly in
the next step without further purification. 1H NMR: 7.21-7.38
(M, 5H), 6.59 (s, 1H), 1.99 (d, J ) 1.4 Hz, 3H).
observed stereochemistry. The positive charge developed
on the benzylic carbon during AI formation is much more
substantial than that developed during perepoxide for-
mation because of the later transition state, thus the
phenyl-AI interaction is much more important. This
interaction probably stabilizes the ene pathway, making
it more energetically favorable21 compared to the zwit-
terionic pathway.
In conclusion, we have shown for the first time that
the phenyl ring of styrene substrates can dictate the syn/
anti stereochemistry in their ene reactions with singlet
oxygen and triazolinediones. We propose that a favorable
interaction of the enophiles with the phenyl directs the
orientation of perepoxide or the AI.
In a flame-dried flask were added 0.3 g of LiAlD4 and 50 mL
dry of THF. A solution of the allylic chloride-d2 in THF was
added dropwise at rt. The reaction mixture was left overnight.
At that time, the allylic chloride had completely disappeared.
The crude alkene was isolated by flash column chromatography
over silica gel using hexane as eluant and finally distilled under
vacuum. The geometric purity was > 97% by NMR. 1H NMR:
7.17-7.33 (m, 5H), 6.27 (s, 1H), 1.86 (d, J ) 1.3 Hz, 3H). 13C
NMR: 138.62, 135.16, 128.68, 127.94, 125.71, 125.23, 19.19.
HRMS: calcd for C10D3H9 135.1127, found 135.1128.
Exp er im en ta l Section
All NMR spectra were taken in CDCl3.
â,â-Dim eth ylstyr en e (1). This compound was synthesized
by Wittig coupling of isopropylidene-triphenylphosphorane (from
the phosphonium salt of 2-iodopropane) with benzaldehyde in
40% yield. Purification was accomplished by flash column
chromatography (hexane/ether ) 5/1). 1H NMR: 7.12-7.36 (m,
5H), 6.27 (s, 1H), 1.90 (d, J ) 1.3 Hz, 3H), 1.86 (d, J ) 1.3 Hz,
3H).
P h otooxygen a tion of 1. A solution of 100 mg of 1 in 10
mL of CCl4 containing 10 mg of 2,6-di-tert-butylphenol as free
radical scavenger was irradiated (TPP, 1 × 10-4 M as sensitizer)
for 1.5 h at 0 °C. A filter was used to cut off wavelengths below
588 nm. The same procedure was followed in several other
solvents (see Table 1). The products were fractionated on silica
gel (benzene as eluent) and identified by NMR, according to their
published spectroscopic data.14a
P r ep a r a tion of 3. Isop r op yl-d 7-tr ip h en ylp h osp h on iu m
Mesyla te. The mesylate of 2-propanol-d8 (SIC, 99.5% D) was
prepared in 65% yield, by adding 1 equiv of MeSO2Cl to 1 equiv
of 2-propanol-d8 in dry CH2Cl2 containing 3 equiv of triethy-
lamine at -10 °C. After 2 h of stirring at 0 °C, the mesylate
was isolated by extraction with CH2Cl2. The organic layer was
washed first with cold 1 N HCl then with saturated NaHCO3
and finally with brine. 1H NMR: 3.01 (s, 3H).
N-Meth yl-1,2,4-tr ia zolin e-3,5-d ion e (MTAD) Ad d ition to
1. Solid MTAD was added to a solution of 1 in several solvents
affording the ene product as the only product. 1H NMR: 7.28-
7.67 (m, 5H), 5.72 (s, 1H), 5.17 (s, 1H), 4.91 (s, 1H), 1.75 (s, 3H).
Syn th esis of 2. (E)-Meth yl r-Meth ylcin n a m a te. The
corresponding acid was prepared according to a literature
procedure.22 In a flame-dried flask were placed 4.23 g of NaH
(80% in oil, 150 mmol) and 120 mL of dry DME. The flask was
cooled to 0 °C, and then 6 mL of triethyl phosphite (47 mmol)
was added slowly dropwise. The solution was stirred for 30 min;
then 3.9 mL of 2-chloropropionic acid was added slowly at 0 °C.
The neat mesylate was placed in a sealed tube and was heated
with 1.2 equiv of Ph3P at 120 °C for one night, until the mixture
solidified. The solid was washed with hot toluene and then dried
under vaccum. 1H NMR: 7.70-7.88 (m, 15H), 3.94 (s, 3H).
1-P h en yl-2-m eth ylp r op -1-en e-3,3,3,2′,2′,2′-d 6 (3). Alkene
2 was prepared by Wittig coupling of the ylide produced by
n-BuLi addition to the above salt, with benzaldehyde (30% yield).
Purification was accomplished by flash column chromatography
and then by vacuum distillation. 1H NMR: 7.17-7.33 (m, 5H),
6.27 (s, 1H). No proton absorptions were detected in the region
of the allylic methyl absorption (1.85-1.90 ppm). GC-MS: M+
) 138. In the preparation of 3, the ylide derived from benzyl-
triphenylphosphonium chloride was used instead via coupling
with acetone-d6, significant scrambling at the allylic methyls and
the olefinic hydrogen was observed.
(20) Similar inverse intramolecular isotope effect have been mea-
sured in the reaction of PTAD with trimethylethylene. Elemes Y.;
Orfanopoulos, M., unpublished results.
(21) Preliminary studies have shown that MTAD addition to the
p-methyl derivative of 1 affords the ene product exclusively. Even with
the p-methoxy derivative, where the p-methoxybenzyl cation is far
more stable than the tertiary alkyl, there is a significant amount of
ene product (∼20%), along with several other adducts, including [2 +
2] and [4 + 2] products. Stratakis, M.; Hadjimarinaki, M.; Orfanopo-
ulos, M., unpublished results.
In ter m olecu la r Kin etic Isotop e Effects. Perprotio olefin
1 and deuterated olefin 3 are sufficiently separated on a capillary
GC column (HP-5 cross-linked, 5% phenyl methyl silicone) for
direct analysis, and the change in the ratio of 1 to 3 was easily
monitored at several percentages of reaction progress with 1O2
or MTAD. For the estimation of the kinetic isotope effect, the
(22) Brittelli, D. R. J . Org. Chem. 1981, 46, 2514-2520.

1318 J . Org. Chem., Vol. 63, No. 4, 1998
Notes
following expression23 was used:
Ack n ow led gm en t. NATO Grant CRG 931419 for
travel expenses is acknowledged; supported by NSF
Grant CHE 94-23027.
kH log[1 - Hr/Ht]
)
kD
log[1 - Dr/Dt]
J O9715332
where Hr and Dr are the amounts of 1 and 3 that reacted, or the
amounts of adducts formed by 1 and 3, and Ht and Dt are the
initial amounts of 1 and 3, respectively.
(23) Higgins, R.; Foote, C. S.; Cheng, H. ACS Adv. Chem. Ser. 1968,
77, 102.