Stereochemistry of the triazollinedione - Alkene ene reaction: A stereospecific suprafacial transformation [2]

Full text of DOI:10.1021/ja001190g

9540
J. Am. Chem. Soc. 2000, 122, 9540-9541
Scheme 1. Preparation of (R,R)-cis-3-hexene-2,5-d2 from
(S)-(-)-Ethyl Lactate
Stereochemistry of the Triazollinedione-Alkene Ene
Reaction: A Stereospecific Suprafacial
Transformation
Georgios Vassilikogiannakis, Yiannis Elemes,† and
Michael Orfanopoulos*
Department of Chemistry, UniVersity of Crete
71409 Iraklion, Crete, Greece
ReceiVed April 5, 2000
ReVised Manuscript ReceiVed June 29, 2000
Triazolinedione (RTAD, R ) methyl or phenyl), one of the
most reactive electrophiles,1 reacts with conjugated dienes to give
Diels-Alder products2-4 and with olefins to produce ene or [2+2]
adducts.4-6 The ene reaction has attracted considerable mechanis-
tic5-12 and theoretical attention.13,14 Most of the experimental
studies5-12 and to a lesser extent computational work13 support a
stepwise mechanism with formation of an aziridinium imide, AI,
intermediate in the rate determinig step. AI intermediates also
have been observed spectroscopically and reported independently
by a number of investigators.15-17
Scheme 2. PTAD Ene Addition to Olefin 1
The stereoselectivity of this synthetically useful transforma-
tion18-21 has received conciderable attention. For example, RTAD
adds to various alkenes and shows a number of regioselectivi-
ties5,7,22,23 depending on the double bond substitution. It also adds
to allylic alcohols showing a remarkable diastereoselectivity,12,24,25
and to allyl silanes affording cis ene products.26
In this paper we report the stereochemistry of this reaction with
simple alkenes and discuss mechanistic possibilities in the light
of the present results. This stereochemistry has not been previously
† Permanent address: Department of Chemistry, University of Ioannina,
45110 Ioannina, Greece.
(1) Moody, C. J. AdV. Heterocycl. Chem. 1982, 30, 1 and references therein.
(2) Jensen, F.; Foote, C. S. J. Am. Chem. Soc. 1987, 109, 6376-6385.
(3) Chen, S. C.; Houk, K. N.; Foote, C. S. J. Am. Chem. Soc. 1998, 120,
12303-12309.
recognized and may hold important implications for the mech-
anism of this reaction.
(4) Clennan, E. L.; Earlywine, A. D. J. Am. Chem. Soc. 1987, 109, 7104-
7110.
The optically active, by virtue of deuterium substitution, and
isomerically pure olefin, (R,R)-cis-3-hexene-2,5-d2 (1), is well
suited to test the stereochemical requirements of this classical
ene reaction. This olefin has three distinctive characteristics: (a)
asymmetry at the two reactive allylic carbons C2 and C2′, by virtue
of stereospecific deuteration, (b) distinguishable 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 equally accessible.
(5) Cheng, C. C.; Seymour, C. A.; Petti, M. A.; Greene, F. D.; Blount, J.
F. J. J. Org. Chem. 1984, 49, 2910-2916.
(6) Orfanopoulos, M.; Smonou, I.; Foote, C. S. J. Am. Chem. Soc. 1990,
112, 3607-3614.
(7) Orfanopoulos, M.; Stratakis, M.; Elemes, Y.; Jensen, F. J. Am. Chem.
Soc. 1991, 113, 3180-3181
(8) Elemes, Y.; Foote, C. S. J. Am. Chem. Soc. 1992, 114, 6044-6050.
(9) Clennan, E. L.; Koola, J. J. J. Am. Chem. Soc. 1993, 115, 3802-3803.
(10) Smonou, I.; Khan, S.; Foote, C. S.; Elemes, Y.; Mavridis, I. M.;
Pantidou, A.; Orfanopoulos, M. J. Am. Chem. Soc. 1995, 117, 7081-7087.
(11) Stratakis, M.; Orfanopoulos, M.; Foote, C. S. J. Org. Chem. 1998,
63, 1315-1318.
(12) Vassilikogiannakis, G.; Stratakis, M.; Orfanopoulos, M.; Foote C. S.
J. Org. Chem. 1999, 64, 4130-4139.
(13) Chen, J. S.; Houk, K. N.; Foote, C. S. J. Am. Chem. Soc. 1997, 119,
9852-9855.
(14) Singleton, D. A.; Hang, C. J. Am. Chem. Soc. 1999, 121, 11885-
11893.
(15) . Poon, T. H. W.; Park, S.; Elemes, Y.; Foote, C. S. J. Am. Chem.
Soc. 1995, 117, 10468-10473.
(16) Squillacote, M.; Mooney, M.; De Felipis, J. J. Am. Chem. Soc. 1990,
112, 5364-5365.
The preparation27 of (R,R)-cis-3-hexene-2,5-d2 (1) from (S)-
(-)-ethyl lactate is shown in Scheme 1. The reaction of this olefin
with PTAD at -40 °C in dicloromethane quantitatively gave
product 2 with only the trans stereochemistry. For convenience,
we present here mechanistic possibilities considering only one
of the two equivalent faces of the double bond. Approach of
PTAD from the top face would abstract H and form an S
stereogenic center, whereas abstraction of D would form the R
stereogenic center (Scheme 2). We define the new stereogenic
(17) Nelsen, S. F.; Kapp, D. L. J. Am. Chem. Soc. 1985, 107, 5548-5549.
(18) Gau, A. H.; Lin, G. L.; Uang, B. J.; Liao, F. L.; Wang, S. L. J. Org.
Chem. 1999, 64, 2194-2201 and references therein.
(19) Corey, E. J.; Snider, B. B. Tetrahedron Lett. 1973, 3091-3094
(20) Breslow, R.; Corcoran, R. J.; Snider, B. B.; Doll, R. J.; Khanna, P.
L.; Kaleya, R. J. Am. Chem. Soc. 1977, 99, 905-915.
(21) Adam, W.; Pastor, A.; Wirth, T. Org. Lett. 2000, 2, 1295-1297.
(22) Elemes, Y.; Stratakis, M.; Orfanopoulos, M. Tetrahedron Lett. 1997,
38, 6437-6440.
(23) Orfanopoulos, M.; Elemes, Y.; Stratakis, M. Tetrahedron Lett. 1990,
31, 5775-5778.
(24) Prein, M.; Adam, W. Angew. Chem., Int. Ed. Engl. 1996, 35, 477-
494 and references therein.
(27) The synthesis proceeds through the key intermediate 1-propanol-2-
d1, a compound whose chirooptical properties have been well documented:
Green, M. M.; Moldowan, J. M.; McGrew, J. G., II J. Org. Chem. 1974, 39,
2166-2171
(25) Stratakis. M.; Vassilikogiannakis, G.; Orfanopoulos. M. Tetrahedron
Lett. 1998, 39, 2393-2396.
(26) Adam, W.; Schwarm, M. J. Org. Chem. 1988, 53, 3129-3130.
10.1021/ja001190g CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/16/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 39, 2000 9541
Scheme 3. Mechanistic Possibility of Ene Product Formation
centers as SH or RD indicating H or D abstraction from the allylic
position of alkene 1, and these two diastereomeric products are
labeled 2-SH,R and 2-RD,R. With this mechanistic possibility, one
could obtain crossover products (RH,R and SD,R) only to the extent
that the trans olefin isomer or the opposite enantiomer (S,S)-cis-
3-hexene-2,5-d2 is present in the starting material. The ratio of
these products 2-SH,R:2-RD,R, which is the result of intramo-
lecular isotopic competition between the cis-chiral allylic centers
of the olefin, is proportional to the primary product isotope effect
kH/kD. Integration of the vinylic signals H3 of 2-RD,R as well as
the hydrogen next to the nitrogen for both ene adducts of 2
determines the primary isotope effect kH/kD ) 3.66 ( 0.05. When
the reaction was run at -30 °C, a smaller isotope effect was found,
kH/kD ) 2.02 ( 0.05, as expected.28 This result is in agreement
with previous reported isotope effects in this reaction.5,6
To probe the stereochemistry further and obtain information
on the chirality of the newly formed stereogenic centers S/R as
well as to correlate the S/R and kH/kD ratios in the ene products
2, a detailed 1H NMR analysis was performed. Although the ene
products 2 are diastereomers, 1H NMR resolution of their
diastereomeric groups was only achieved in the presence of a
chiral shift reagent. Thus, examination of both the allylic methyls
and the methylene hydrogens of 2 by 1H NMR revealed that both
are measurably separated in the presence of Eu(hfc)3. An
impressive chiral shift separation of diastereotopic groups was
achieved. The allylic methyl group, Me1, of 2-SH,R resonates as
a singlet at a higher magnetic field than its diastereomeric allylic
methyl group Me2 (doublet) of 2-RD,R. From 1H NMR integration
of the two diastereomeric methyl signals (Me1 and Me2) the ratio
of the newly formed stereogenic centers SH:RD was determined
to be 3.62 ( 0.05, which represents a 56% ee of the S enantiomer
(Scheme 3). Identical results were obtained by 1H NMR integra-
tion of the resolved H1 and H2 methylene hydrogens of 2. It is
important to emphasize here the correspondence of the diaster-
eomeric ratio 2-SH,R:2-RD,R of 3.62 to the isotopic kH/kD ratio
Figure 1. 1H NMR spectra of the ene adducts 2-RD,R and 2-SH,R in the
absence (A) and in the presence (B) of Eu(hfc)3 chiral shift reagent.
mediate. For a stepwise biradical or dipolar mechanism, interme-
diates IR and IS are expected to be formed in equal amounts. This
implies that neither 2-R,R nor 2-S,R products would be prefer-
entially formed, and because of free rotation around the previous
carbon-carbon double bond, a nonstereospecific reaction would
have been expected and the product would have been racemic.
In a recent theoretical study, a biradical intermediate was
proposed.14 However, in that mechanism, the following restrictions
were postulated: (a) the biradical (key intermediate) equilibrates
rapidly with the AI intermediate; (b) it retains the stereochemical
orientation of the AI; and (c) rotation in the biradical intermediate
is not allowed. If all of these conditions apply, then these results
also may be rationalized by a “biradical-like aziridinium imide
intermediate”.
1
of 3.66. When the reaction was run at -30 °C, an identical H
NMR analysis showed similar correspondence of the diastereo-
meric ratio of 2.01 to the isotopic ratio of 2.02.
These results can be best rationalized via the formation of the
established aziridinium-like intermediate. In AI, abstraction of
deuterium D, and subsequent carbon-nitrogen bond formation,
leads to the RD stereogenic center with H remaining in the product
double bond, while abstraction of hydrogen H leads to the
formation of the SH stereogenic center with D remaining in the
product double bond (Scheme 3). They furher indicate that the
RTAD-ene reaction is a highly stereospecific suprafacial process.
Had the crossover products (2-RH,R, 2-SD,R) been formed, the
1H NMR would have been more complicated. The presence of
an isotopic ratio, which matches exactly the stereogenic ratio,
makes it difficult to argue for a biradical or zwitterionic inter-
In conclusion, our results provide strong evidence for the
stereospecific suprafacial mechanism of TAD-ene reactions with
simple alkenes.
Acknowledgment. G.V. is grateful to the Greek Secretariat of
Research and Technology (ΥΠΕΡ-1995) for research fellowships. M.O.
thanks professor K. C. Nicolaou for his generous hospitality during his
sabbatical stay at The Scripps Research Institute (2000).
Supporting Information Available: 1H NMR analysis of protio and
deuterio ene adducts in the absence and in the presence of Eu(hfc)3 chiral
shift reagent (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(28) Because of hydrogen tunneling, the kH/kD isotope effect of the ene
reaction of PTAD depends strongly on temperature: Elemes, Y.; Orfan-
opoufos, M. J. Am. Chem. Soc. 1992, 114, 11007-11009.
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