Stereochemistry of the singlet oxygenation of simple alkenes: A stereospecific transformation

Article abstract of DOI:10.1021/ol801488w

(Chemical Equation Presented) The stereochemistry of the allylic oxidation (ene reaction) mediated by singlet oxygen (¹O₂), using the optically active alkene (S,S)-cis-1,4-diphenyl-2-butene-1,4-d₂, In MeOH and aprotic solv

Full text of DOI:10.1021/ol801488w

ORGANIC
LETTERS
2008
Vol. 10, No. 18
3997-4000
Stereochemistry of the Singlet
Oxygenation of Simple Alkenes: A
Stereospecific Transformation†
Mariza N. Alberti, Georgios Vassilikogiannakis, and Michael Orfanopoulos*
Department of Chemistry, UniVersity of Crete, 71003, Voutes-Heraklion, Crete, Greece
orfanop@chemistry.uoc.gr
Received July 1, 2008
ABSTRACT
The stereochemistry of the allylic oxidation (ene reaction) mediated by singlet oxygen (1O2), using the optically active alkene (S,S)-cis-1,4-
diphenyl-2-butene-1,4-d2, in MeOH and aprotic solvents was investigated. Our findings indicate that the title reaction is a highly stereospecific
suprafacial process, independent of solvent polarity. The observation of an isotope effect, which matches the stereogenic ratio exactly, rules
out biradical or open dipolar intermediates.
Recent years have seen a burgeoning in research interest
directed toward unraveling the chemistry of singlet oxygen
tance as well as its powerful synthetic potential.5 Among
the reactions of 1O2 with unsaturated substrates,6 the ene or
Schenk reaction7 has received the most extensive experi-
mental and theoretical attention. Several mechanisms have
been postulated for this reaction. Although recent theoretical
1,2
1
(1O2, ∆g). This increased attention has been motivated
by singlet oxygen’s environmental3 and biological4 impor-
† This paper was presented in part at the 23rd International Conference
on Photochemistry (ICP2007), Cologne, Germany, 29 July-3 August, 2007;
Abstract No. IL-13, p 169.
Goddard, W. A., III; Janda, K. D.; Eschenmoser, A.; Lerner, R. A. Science
2001, 293, 1806–1809. (c) Wentworth, P. J.; McDunn, J.; Wentworth, A. D.;
Takeuchi, C.; Nieva, J.; Janda, K. D.; Eschenmoser, A.; Lerner, R. A.
Science 2002, 298, 2195–2199. (d) Davies, M. J. Biochem. Biophys. Res.
Commun. 2003, 305, 761–770. (e) Chin, K. K.; Trevithick-Sutton, C. C.;
McCallum, J.; Jockusch, S.; Turro, N. J.; Scaiano, J. C.; Foote, C. S.; Garcia-
Garibay, M. A. J. Am. Chem. Soc. 2008, 130, 6912–6913.
(1) (a) Wasserman, H. H.; Murray, R. W. Singlet Oxygen; Academic
Press: New York, 1979. (b) Frimer, A. A.; Stephenson, L. M. In Singlet
Oxygen. Reactions, Modes and Products; Frimer, A. A., Ed.; CRC Press,
Boca Raton, FL, 1985. (c) Foote, C. S.; Clennan, E. L. In ActiVe Oxygen
in Chemistry; Foote, C. S., Valentine, J. S., Greenberg, A., Liebman, J. F.,
Eds.; Chapman and Hall: London, 1995; pp 105-140.
(5) (a) Hoffmann, N. Chem. ReV 2008, 108, 1052–1103, and references
cited therein. (b) Griesbeck, A. G.; Blunk, D.; El-Idreesy, T. T.; Raabe, A.
Angew. Chem., Int. Ed. 2007, 46, 8883–8886. (c) Griesbeck, A. G.; El-
Idreesy, T. T. Tetrahedron 2006, 62, 10615–10622. (d) Montagnon, T.;
Tofi, M.; Vassilikogiannakis, G. Acc. Chem. Res. 2008, 41, 1001–1011.
(e) Margaros, I.; Montagnon, T.; Tofi, M.; Pavlakos, E.; Vassilikogiannakis,
G. Tetrahedron 2006, 62, 5308–5317. (f) Georgiou, T.; Tofi, M.; Montag-
non, T.; Vassilikogiannakis, G. Org. Lett. 2006, 8, 1945–1948. (g)
Vassilikogiannakis, G.; Margaros, I.; Montagnon, T.; Stratakis, M. Chem.
Eur. J. 2005, 11, 5899–5907.
(2) For the effect of strain on 1O2 reactions, see: (a) Frimer, A. A.; Weiss,
J. J. Org. Chem. 1993, 58, 3660–3667. (b) Frimer, A. A.; Weiss, J.; Gottlieb,
H. E.; Wolk, J. L. J. Org. Chem. 1994, 59, 780–792. (c) Frimer, A. A.;
Afri, M.; Baumel, S. D.; Gilinsky-Sharon, P.; Rosenthal, Z.; Gottlieb, H. E.
J. Org. Chem. 2000, 65, 1807–1817. (d) Sharon, O.; Frimer, A. A.
Tetrahedron 2003, 59, 8153–8162
.
(3) (a) Ranby, B.; Rabek, J. F. Photodegradation, Photooxidation and
Photostabilization of Polymers; Wiley: London, 1975. (b) Abdou, M. S. A.;
Holdcroft, S. Macromolecules 1993, 26, 2954–2962. (c) Scurlock, R. D.;
Wang, B.; Ogilby, P. R.; Sheats, J. R.; Clough, R. L. J. Am. Chem. Soc.
1995, 117, 10194–10202.
(6) For singlet oxygen [2 + 2] and [4 + 2] cycloadditions, see: (a) Adam,
W.; Prein, M. Acc. Chem. Res. 1996, 29, 275–283. (b) Iesce, M. R.
Photooxygenation of the [4 + 2] and [2 + 2] Type In Synthetic Organic
Photochemistry; Griesbeck, A. G., Mattay, J., Ed.; Marcel Dekker: New
York, 2005; pp 299-363.
(4) (a) Gollnick, K.; Hartmann, H. Oxygen and Oxy Radicals in Biology;
Academic Press, New York, 1981; pp. 379-395. (b) Wentworth, P. J.; Jones,
L. H.; Wentworth, A. D.; Zhu, X.; Larsen, N. A.; Wilson, I. A.; Xu, X.;
10.1021/ol801488w CCC: $40.75
Published on Web 08/16/2008
2008 American Chemical Society

calculations support a two-step no-intermediate mechanism,8
it is generally accepted that the ene reaction proceeds through
an intermediate. In particular, previous isotopic studies of
teramethylethylenes-d6 (TME-d6)9a and trapping experi-
ments9b,c have already excluded the possibility of a concerted
mechanism. Additionally, biradicals,10 open dipolar inter-
mediates,10 perepoxides,9,11 and gradations between all of
these possibilities have found both experimental and theoreti-
cal support.
The photooxygenation of (S,S)-cis-1,4-diphenyl-2-butene-
1,4-d2 (1) was examined. This olefin has three distinctive
characteristics: (a) chirality at the two reactive allylic carbons
C1 and C4, by virtue of stereospecific deuteration, (b)
different groups at both ends of the double bond such that
the ene adducts will contain a new stereogenic center, and
(c) a C2 symmetry axis such that the two faces of the double
bond are equal.
Studies on the stereoselectivity12 and regioselectivity13 of
1
the O2 ene reaction with nonfunctionalized alkenes have
also attracted considerable attention. It is generally recog-
nized that 1O2 adds to trisubstituted alkenes with syn
selectivity (cis effect)14 and to nonsymmetrical cis-1,2-
dialkylsubstituted alkenes with regioselective double-bond
formation next to the large group (nonbonding large group
effect).15 Moreover, the addition of O2 to alkylsubstituted
1
alkenes shows a general preference for hydrogen abstraction
from the group that is geminal to the larger substituent of
the double bond.16
The key intermediate for the synthesis of (S,S)-cis-1,4-
diphenyl-2-butene-1,4-d2 (1) is the optically active (by virtue
deuterium labeling) alcohol 7, whose chiro-optical properties
are known17 (Scheme 1). Esterification of (S)-(+)-mandelic
In this paper, we report details regarding the stereochem-
1
istry of the O2 ene reaction with simple nonfunctionalized
alkenes. To the best of our knowledge, this is the first
example for the photooxygenation of a symmetrical and
optically active alkene bearing equivalent double bond faces.
The results presented may have important implications
regarding the precise mechanism of this classical ene
reaction.
Scheme 1
.
Synthesis of (S,S)-cis-1,4-Diphenyl-2-butene-1,4-d2
from (S)-(+)-Mandelic Acid (2)
(7) Griesbeck, A. G.; El-Idreesy, T. T.; Adam, W. ; Krebs, O. Ene
Reactions with Singlet Oxygen In CRC Handbook of Organic Photochem-
istry and Photobiology; Horspool, W. M., Lenci, F., Eds.; CRC Press: Boca
Raton, 2004; Chapter 8.
(8) (a) Leach, A. G.; Houk, K. N. Chem. Commun. 2002, 1243–1255.
(b) Singleton, D. A.; Hang, C.; Szymanski, M. J.; Meyer, M. P.; Leach,
A. G.; Kuwata, K. T.; Chen, J. S.; Greer, A.; Foote, C. S.; Houk, K. N.
J. Am. Chem. Soc. 2003, 125, 1319–1328.
(9) (a) Stephenson, L.; Grdina, S. B.; Orfanopoulos, M. Acc. Chem. Res.
1980, 13, 419–425. (b) Schaap, A. P.; Recher, S. G.; Faler, G. R.; Villasenor,
S. R. J. Am. Chem. Soc. 1983, 105, 1691–1693. (c) Poon, T. H. W.; Pringle,
K.; Foote, C. S. J. Am. Chem. Soc. 1995, 117, 7611–7618.
(10) (a) Harding, L. B.; Goddard, W. A. J. Am. Chem. Soc. 1980, 102,
439–449. (b) Jefford, C. W.; Kohmoto, S.; Boukouvalas, J.; Burger, U.
J. Am. Chem. Soc. 1983, 105, 6498–6499. (c) Maranzana, A.; Ghigo, G.;
Tonachini, G. Chem. Eur. J. 2003, 9, 2616–2626.
(11) For selected experimental work, see: (a) Orfanopoulos, M.; Foote,
C. S. J. Am. Chem. Soc. 1988, 110, 6583–6584. (b) Orfanopoulos, M.;
Smonou, I.; Foote, C. S. J. Am. Chem. Soc. 1990, 112, 3607–3614. (c)
Alberti, M. N.; Orfanopoulos, M. Org. Lett. 2008, 10, 2465–2468. For
theoretical work, see: (d) Dewar, M. J. S.; Thiel, W. J. Am. Chem. Soc.
1975, 97, 3978–3986. (e) Yamaguchi, K.; Yabushita, S.; Fueno, T.; Houk,
K. N. J. Am. Chem. Soc. 1981, 103, 5043–5046. (f) Yoshioka, Y.; Yamada,
S.; Kawakami, T.; Nishino, M.; Yamaguchi, K.; Saito, I. Bull. Chem. Soc.
acid (2) afforded (S)-(+)-methyl mandelate (3) which was
reduced with LiAlH4 to (S)-(+)-phenylethylene glycol (4).
Reaction of 4 with trimethyl orthoacetate by the method of
Newman18 afforded a mixture of two diastereomers (2S,4S)-
and (2R,4S)-2-methoxy-2-methyl-4-phenyl-1,3-dioxolane (5).
Subsequent treatment with trimethylsilyl chloride afforded
(R)-2-chloro-2-phenylethyl acetate (6).17 Reduction of 6 with
LiAlD4 to the corresponding alcohol (7), followed by
mesylation and subsequent reaction with PPh3 of the resultant
mesylate 8, afforded the phosphonium salt 9. Finally, the
Jpn. 1996, 69, 2683–2699
.
(12) (a) Stephenson, L. M.; McClure, D. E.; Sysak, P. K. J. Am. Chem.
Soc. 1973, 95, 7888–7889. (b) Orfanopoulos, M.; Stephenson, L. M. J. Am.
Chem. Soc. 1980, 102, 1417–1418. (c) Prein, M.; Adam, W. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 477–494.
(13) (a) Stratakis, M.; Orfanopoulos, M. Tetrahedron 2000, 56, 1595–
1615. (b) Clennan, E. D. Tetrahedron 2000, 56, 9151–9179. (c) Alberti,
M. N.; Orfanopoulos, M. Tetrahedron 2006, 62, 10660–10675.
(14) (a) Schulte-Elte, K. H.; Muller, B. L.; Rautenstrauch, V. HelV. Chim.
Acta 1978, 61, 2777–2783. (b) Orfanopoulos, M.; Grdina, M. B.; Stephen-
son, L. M. J. Am. Chem. Soc. 1979, 101, 275–276.
(15) (a) Orfanopoulos, M.; Stratakis, M.; Elemes, Y. J. Am. Chem. Soc.
1990, 112, 6417–6419. (b) Orfanopoulos, M.; Stratakis, M.; Elemes, Y.;
Jensen, F. J. Am. Chem. Soc. 1991, 113, 3180–3181.
(17) Elsenbaumer, R. L.; Mosher, H. S. J. Org. Chem. 1979, 44, 600–
604, and references cited therein.
(16) (a) Clennan, E. L.; Chen, X.; Koola, J. J. J. Am. Chem. Soc. 1990,
112, 5193–5199. (b) Orfanopoulos, M.; Stratakis, M.; Elemes, Y. J. Am.
Chem. Soc. 1990, 112, 6417–6418. (c) Stratakis, M.; Orfanopoulos, M.
Synth. Commun. 1993, 23, 425–430.
(18) (a) Newman, M. S.; Chen, C. H. J. Am. Chem. Soc. 1973, 95, 278–
279. (b) Newman, M. S.; Olsen, D. O. J. Org. Chem. 1973, 38, 4203–
4204.
3998
Org. Lett., Vol. 10, No. 18, 2008

preparation of the optically active olefin 1 was accomplished
through a Wittig reaction with ylide 9 in the presence of
molecular oxygen. Olefin 1 was synthesized in 96% geo-
metrical purity.
Olefin 1 reacted smoothly with singlet oxygen that had
been generated in situ using irradiation of a TPP containing
solution (10-4 M in CHCl3) at 0 °C, with oxygen being
bubbled through by a 300 W xenon lamp. A catalytic amount
of galvinoxyl radical (2 × 10-4 M) was also added to the
reaction mixture as a free radical scavenger in order to avoid
the formation of any products unrelated to singlet oxygen’s
action. The photooxygenation reactions of 1 were also run
in (CH3)2CO, CH3CN, and MeOH. In all cases, products of
type 10 were obtained in high yield (Scheme 2). As expected,
Scheme 2. Allylic Oxidation of Olefin 1
Figure 1.
Portions of the 1H NMR spectra of allylic hydroperoxides
(SH,R)-10 and (RD,R)-10.
In order to determine the chirality of the new stereogenic
centers S/R of 10 and to correlate the S/R and kH/kD ratios of
1
the ene products of 1, a detailed H NMR analysis was
conducted. Fortunately, examination of the diastereotopic
benzylic protons, H3 and H6, of 10 by NMR reveals that
both are measurably separated, even in the absence of any
chiral shift reagent. Thus, the benzylic proton H3 resonates
as a doublet at a higher magnetic field than the diastereomeric
benzylic proton H6 (Figure 1B). It is worth mentioning here
that the coupling constant of H3 is slightly different than
that of H6, because of the syn and anti relationship with the
neighboring H2 and H5 respectively. In addition, it is simple
to demonstrate that one isomer of product 10 has only H at
the crucial vinylic position, while the other has only D.
Integration of H3 and H6 signals determines the ratio of the
newly formed stereogenic centers SH/RD ) 1.23 ( 0.05. The
unequal formation of these stereogenic centers (10% ee of
the S enantiomer) is due to the competition for abstraction
at the chiral allylic centers of the olefin 1. It is important to
emphasize here the correspondence of the diastereomeric
ratio (SH,R)-10:(RD,R)-10 of 1.23 with the isotopic kH/kD ratio
of 1.20.
only the trans allylic hydroperoxides were found in the
reaction mixture.11a For convenience, we have presented the
mechanistic possibilities here considering the approach of
1O2 from only one of the two equivalent faces of the double
bond. Approach of 1O2 from the top face will form the new
S-stereogenic center and produce the trans allylic hydrop-
eroxide on abstraction of H, whereas formation of the
R-stereogenic center will occur following D abstraction
(Scheme 2). We define the new stereogenic centers as SH or
RD indicating H or D abstraction from the allylic position of
alkene 1, and these two diastereomeric products are labeled
(SH,R)-10 and (RD,R)-10. With this mechanistic possibility
(via perepoxide formation), one could obtain crossover
products (RH,R)-10 and (SD,R)-10 only to the extent that the
opposite enantiomer (R,R)-cis-1,4-diphenyl-2-butene-1,4-d2
is present in the starting material.
The ratio of products (SH,R)-10:(RD,R)-10, which is the
result of competition for abstraction at the two allylic centers
of the olefin, is proportional to the primary kinetic isotope
effect kH/kD. In the photooxygenations of 1 (in CHCl3),
integration of the vinylic signal at 6.64 ppm (H7) of (RD,R)-
10 and the overlapping vinylic signals at 6.17 ppm (H1 and
H4) of (SH,R)-10 and (RD,R)-10 isomers was used to
determine the primary isotope effect kH/kD ) 1.20 ( 0.05
(Figure 1A). The same isotopic ratio was found when
(CH3)2CO, CH3CN, or MeOH was used as the reaction
solvent.
Identical diastereomeric ratios are found when (CH3)2CO,
CH3CN, or MeOH is used as the solvent in the photooxy-
genation of 1, under similar reaction conditions. In all cases,
the ratio of the two diastereomeric allylic hydroperoxides is
equal to the primary isotope effect.
These results are best rationalized by involving the
formation of a perepoxide (PE) as intermediate. An exciplex19
between the olefin and oxygen with similar stereochemical
requirements to that of a PE might also accommodate the
results. In Scheme 3, a PE intermediate is used for illustrative
purposes. From this intermediate, abstraction of deuterium
Org. Lett., Vol. 10, No. 18, 2008
3999

be formed in equal amounts. This implies that neither (RH,R)-
10 nor (SD,R)-10 products would be preferentially formed,
andbecauseoffreerotationaroundthepreviouscarbon-carbon
double bond, a nonstereospecific reaction would occur
leading to racemic products.
Scheme 3
.
Proposed Mechanism of the Sensitized
Photooxygenation of Olefin 1
In conclusion, our results provide strong evidence of a
stereospecific suprafacial mechanism for the 1O2 ene reaction
of simple olefins. Taking also into consideration that the
majority of previously reported studies9-11 precluded the
possibility of a concerted mechanism, we strongly suggest
1
that the O2 ene reaction with simple alkenes proceeds via
the irreversible formation of a perepoxide or an exciplex
intermediate.
(D), and subsequent C-O bond formation, leads to the RD
stereogenic center with hydrogen (H) remaining in the
product double bond, while abstraction of H leads to the
formation of the SH stereogenic center. These results clearly
indicate that the 1O2 allylic oxidation is a highly stereospecific
suprafacial process. Had the crossover products (RH,R-10 and
SD,R-10) been formed, the 1H NMR would have been more
complicated. The observation of an isotope effect, which
matches exactly the stereogenic ratio, makes it difficult to
argue that the reaction proceeds through a biradical or an
open dipolar intermediate. For a stepwise biradical or open
dipolar mechanism, intermediates I1 and I2 are expected to
Acknowledgment. We thank Dr. T. Montagnon for
valuable comments and discussions. The project was co-
funded by the European Social Fund and National Resources
(PENED 2001, Pythagoras II 2005).
Supporting Information Available: Detailed experimen-
1
tal procedures and spectral data. H NMR, 13C NMR, and
1
HMQC spectra for compound 1. H and 13C NMR spectra
1
1
of compounds 3-8. H NMR spectra of compound 9. H
NMR spectra for the measurement of primary isotope effect
and diastereomeric ratio of (SH,R)-10 and (RD,R)-10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) (a) Clennan, E. L.; Nagraba, K. J. Am. Chem. Soc. 1983, 105, 5932–
5933. (b) Gorman, A. A.; Hamblett, I.; Lambert, C.; Spencer, B.; Standen,
M. C. J. Am. Chem. Soc. 1988, 110, 8053–8059. (c) Aubry, J-M.; Mandard-
Cazin, B.; Rougee, M.; Bensasson, R. V. J. Am. Chem. Soc. 1995, 117,
9159–9164.
OL801488W
4000
Org. Lett., Vol. 10, No. 18, 2008