Heteroatom influence on the π-facial selectivity of Diels-Alder cycloadditions to 1-oxa-4-thia-6-vinylspiro[4.5]dec-6-ene, 3-Methoxy-3-methyl-2-vinylcyclohexene, and 3-methoxy-2-vinylcyclohexene

Article abstract of DOI:10.1021/jo0106400

The facial selectivities of the Diels-Alder cycloadditions of several dienophiles to the title substrates were studied. The observed selectivities are interpreted as a consequence of the relative steric interactions offered by the substituents. The addition of dimethylacetylene dicarboxylate (DMAD) is influenced by the electrostatic repulsion arising from the interaction of an electron pair orbital on the acetal oxygen and the orthogonal π-orbital of the acetylene unit in DMAD in the syn-to-oxygen addition of the latter. This repulsion is offset on coordination of Li⁺ to the said oxygen electron pair orbital, and the addition thus proceeds syn to oxygen. The enhanced and accelerated syn-to-oxygen addition in lithium perchlorate in nitromethane is interpreted as a consequence of the coordination of Li⁺ to both the acetal oxygen and a heteroatom in the dienophile that brings them in close proximity to facilitate a reaction. The Li⁺-oxygen combination, however, also exerts some steric effect that results in reduced syn-to-oxygen addition of dienophiles having large substituents such as N-phenylmaleimide.

Full text of DOI:10.1021/jo0106400

J . Org. Chem. 2002, 67, 1109-1117
1109
Heter oa tom In flu en ce on th e π-F a cia l Selectivity of Diels-Ald er
Cycloa d d ition s to 1-Oxa -4-th ia -6-vin ylsp ir o[4.5]d ec-6-en e,
3-Meth oxy-3-m eth yl-2-vin ylcycloh exen e, a n d
3-Meth oxy-2-vin ylcycloh exen e†,‡
Veejendra K. Yadav,*,§ Govindaraji Senthil,§ K. Ganesh Babu,§ Masood Parvez,|, and
J ennifer Lee Reid|
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India,
and Department of Chemistry, University of Calgary, Calgary, Alberta, Canada T2N 1N4
vijendra@iitk.ac.in
Received J une 22, 2001
The facial selectivities of the Diels-Alder cycloadditions of several dienophiles to the title substrates
were studied. The observed selectivities are interpreted as a consequence of the relative steric
interactions offered by the substituents. The addition of dimethylacetylene dicarboxylate (DMAD)
is influenced by the electrostatic repulsion arising from the interaction of an electron pair orbital
on the acetal oxygen and the orthogonal π-orbital of the acetylene unit in DMAD in the syn-to-
oxygen addition of the latter. This repulsion is offset on coordination of Li+ to the said oxygen
electron pair orbital, and the addition thus proceeds syn to oxygen. The enhanced and accelerated
syn-to-oxygen addition in lithium perchlorate in nitromethane is interpreted as a consequence of
the coordination of Li+ to both the acetal oxygen and a heteroatom in the dienophile that brings
them in close proximity to facilitate a reaction. The Li+-oxygen combination, however, also exerts
some steric effect that results in reduced syn-to-oxygen addition of dienophiles having large
substituents such as N-phenylmaleimide.
In tr od u ction
π-orbital distortion,3 hyperconjugative interactions,4 sec-
ondary orbital interactions,5 torsional effects,6 electro-
static interactions,7 van der Waals-London attractions,8
polarizability effects,9 and product stability10 may also
induce π-selectivity.
The Diels-Alder (DA) cycloaddition is one of the
standard methods for forming six-membered carbocycles
as well as heterocycles.1 The most recent stereochemical
issue is that of π-facial control2 that arises when a
dienophile adds to the two faces of a diene at different
rates. To enhance the required facial discrimination, a
suitable understanding of the factors responsible for this
differential reactivity becomes a genuine necessity. The
factors known to influence the π-facial selectivity are (a)
the presence of a chiral center in the diene or dienophile
or both and (b) the presence of a chiral Lewis acid
catalyst. The facial discrimination is achieved by ef-
fectively blocking one prochiral face of the substrate so
that the addition takes place on the less hindered face
to avoid steric destabilization. Other factors such as
The directing effect of a heteroatom in DA cycloaddi-
tions has been extensively studied. From the work of
Woodward on cycloadditions to 5-acetoxycyclopentadi-
ene11 and that of Fallis on the cycloadditions to 5-oxygen-
and 5-sulfur-substituted pentamethylcyclopentadienes,12
the addition is understood to occur syn to oxygen and anti
to sulfur. When these syn- and anti-directing effects of
oxygen and sulfur are coupled together, one is led to
expect a highly enhanced syn-to-oxygen addition in
reactions of dienes that have both O and S at the same
carbon. These results, however, could not be extrapolated
to 1 (Figure 1). There was no evidence for the syn-
directing effect of the allylic oxygen on the additions of
NPM and TCNE.13 Franck and co-workers14 have studied
* To whom correpondence should be addressed. FAX: 91-512-
597436.
† This paper is dedicated to Professor H. J unjappa on the occasion
of his 65th birthday.
‡ Abbreviations: NMM ) N-methylmaleimide, NPM ) N-phenyl-
maleimide, MTAD ) N-methyl-1,3,4-triazoline-2,5-dione, PTAD )
N-phenyl-1,3,4-triazoline-2,5-dione, NQ ) 1,4-naphthoquinone, DMAD
) dimethylacetylene dicarboxylate, MVK ) methyl vinyl ketone, PDC
) pyridinium dichromate, EA ) ethyl acrylate, TCNE ) tetracyano-
ethylene, LPDE ) lithium perchlorate in diethyl ether, LPNM )
lithium perchlorate in nitromethane, TS ) transition state, PPTS )
pyridinium p-toluenesulfonate.
(3) Paquette, L. A.; Gugelchuk, M. J . Org. Chem. 1988, 53, 1835.
Gleiter, R.; Paquette, L. A. Acc. Chem. Res. 1983, 16, 328.
(4) Coxon, J . M.; McDonald, D. Q. Tetrahedron Lett. 1992, 33, 651.
(5) Gleiter, R.; Ginsburg, D. Pure Appl. Chem. 1979, 51, 1301.
(6) Brown, F. K.; Houk, K. N. J . Am. Chem. Soc. 1985, 107, 1971.
Brown, F. K.; Houk, K. N.; Burnell, D. J .; Valenta, Z. J . Org. Chem.
1987, 52, 3050. Coxon, J . M.; Froese, R. D. J .; Ganguly, B.; Marchand,
A. P.; Morokuma, K. Synlett 1999, 1681.
(7) Kahn, S. D.; Hehre, W. J . J . Am. Chem. Soc. 1987, 109, 663.
(8) Williamson, K. L.; Hsu, Y.-F.; Lacko, R.; Youn, C. H. J . Am.
Chem. Soc. 1969, 91, 6129. Williamson, K. L.; Hsu, Y.-F. J . Am. Chem.
Soc. 1970, 92, 7385.
(9) Assteld, X.; Ruiz-Lopez, M. F.; Garcia, J . I.; Mayoral, J . A.;
Salvatella, L. Chem. Commun. 1995, 1371.
(10) Hagenbuch, J .-P.; Vogel, P.; Pinkerton, A. A.; Schwarzenbach,
D. Helv. Chim. Acta 1981, 64, 1818.
(11) Winstein, S.; Shatavsky, M.; Norton, C.; Woodward, R. B. J .
Am. Chem. Soc. 1955, 77, 4183.
(12) Macaulay, J . B.; Fallis, A. G. J . Am. Chem. Soc. 1988, 110, 4074.
(13) Fisher, M. J .; Hehre, W. J .; Kahn, S. D.; Overman, L. E. J . Am.
Chem. Soc. 1988, 110, 4625.
§ Indian Institute of Technology.
| University of Calgary.
E-mail: parvez@acs.ucalgary.ca.
(1) Carruthers, W. Some Modern Methods of Organic Synthesis, 3rd
ed.; Cambridge University Press: Cambridge, 1986; p 184. Oppolzer,
W. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Paquette, L. A., Eds.; Pergamon Press: New York, 1991; Vol. 5, p 315.
(2) Letourneau, J . E.; Wellman, M. A.; Burnell, J . D. J . Org. Chem.
1997, 62, 7272. Wellman, M. A.; Burry, L. C.; Letourneau, J . E.;
Bridson, J . N.; Miller, D. O.; Burnell, D. J . J . Org. Chem. 1997, 62,
939. Crisp, G. T.; Gebauer, M. G. J . Org. Chem. 1996, 61, 8425.
Gandolfi, R.; Amade, M. S.; Rastelli, A.; Bagatti, M.; Montanari, D.
Tetrahedron Lett. 1996, 37, 517.
10.1021/jo0106400 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/23/2002

1110 J . Org. Chem., Vol. 67, No. 4, 2002
Yadav et al.
Sch em e 1. Syn th esis of 7a
a
Reagents: (a) aqueous HCHO, DMAP, THF; (b) HSCH2CH2OH,
PPTS, C6H6, reflux; (c) PDC, CH2Cl2; (d) Ph3P+CH3I-, n-BuLi,
THF, 0 °C.
F igu r e 1. Structures of the dienes 1-9.
AlCl3-catalyzed DA cycloadditions of 1,3-butadiene to 6
(n ) 1, 2). It is clear from these contradicting reports that
the facial control elements are not yet properly under-
stood and, therefore, more studies are desirable.
In continuation of our studies on the facial effect of the
1-oxa-4-thiolan function,20 we have studied the selectivi-
ties of 1-oxa-4-thia-6-vinylspiro[4.5]dec-6-ene (7), 3-meth-
oxy-3-methyl-2-vinylcyclohexene (8), and 3-methoxy-2-
vinylcyclohexene (9). The σ bonds formed from a DA
cycloaddition are 1,3/1,4 from the stereogenic center. In
the examples studied earlier by others, the bonds formed
are either 1,2/1,2 or 1,2/1,5 from the stereogenic center.
the facial selectivities of the dienes 2 and proposed the
existence of a balance of electronic and steric forces that
controlled the selectivity. The steric effects, however,
dominated.
Paquette15 has explained the cycloaddition of several
dienophiles to the dispiro-1,3-cyclohexadienes 3 from a
consideration of the partial Mulliken charges on the
hydrogen, carbon, and nitrogen atoms. Whereas the
hydrogen and carbon atoms of the carbon-carbon double
bond in NMM had positive charge, MTAD had a slightly
positive charge on the doubly bonded nitrogen atoms and
a negative charge in the region of the nitrogen lone pairs.
Also, the partial charges on the atoms of interest in the
diene were calculated to be (O) -0.25, (S) +0.14, and
(CH2, bonded to the cyclohexadiene ring carbon bearing
the heteroatom), +0.10. It is evident from these charges
that the oxygen in 3 will have a stabilizing effect with
NPM in the syn approach. Hence, the syn cycloadducts
were the major or single product. A similar argument
favors anti addition of MTAD as was indeed observed.
Two important points had emerged: (a) proximity to
oxygen results in the onset of electrostatic factors, and
(b) in a competition between S and CH2, the larger steric
factor of S dominates.
The above electrostatic model, however, failed to
explain the preferred syn-to-O addition of MTAD to 3b
(X ) O, Y ) S); the model predicted addition syn to S.
This anomaly was attributed to the large steric bulk of
S that guided the reaction anti to it. This had also
explained the exclusively syn-to-O addition of MTAD to
the tricyclic diene 4.16 In contrast, the propelladiene 5
underwent cycloaddition exclusively syn to S, which was
attributed to secondary orbital effects by Ginsburg.17
In brief, the origin of π-selectivity has been rationalized
sometimes as a consequence of purely electronic ef-
fects,11,12 sometimes purely steric effects,13,14 and some-
times a combination of both.15,16 Rokach has even con-
cluded that there is no such effect of heteroatom
substituent(s) on the dienophile and that only such
substituents on the diene contribute to the facial selectiv-
ity.18 These results contradict the findings of Danishef-
sky,19 who achieved very good syn selection from the
Sta r tin g Ma ter ia ls a n d Dia ster eom er An a lysis
The diene 7 was synthesized as shown in Scheme 1.
Baylis-Hillman reaction of 2-cyclohexenone with forma-
lin using a literature protocol21 furnished 10. The con-
densation of 10 with 2-mercaptoethanol was effected in
benzene at reflux under a Dean-Stark setup to obtain
the monothioacetal 11. This, on oxidation with PDC in
CH2Cl2,22 furnished the aldehyde 12. Wittig olefination
with the lithium salt of methyltriphenylphosphonium
iodide in THF at 0 °C gave the diene 7 that was stored
at -10 °C for a week with very little decomposition.
The dienes 8 and 9 were synthesized from 17, which,
in turn, was prepared as shown in Scheme 2. The ketone
17 was reacted with MeMgI in Et2O, and the resultant
alcohol was O-methylated to 8. Further, the reduction
of 17 with LiAlH4 in Et2O and O-methylation of the
resultant alcohol furnished 9.
All the dienophiles used in the present study were used
as received from Aldrich Chemical Co. The distribution
of the diastereomers formed from DA cycloadditions was
calculated from the integrals of the vinylic hydrogen
atoms and also OMe. The relative stereochemical char-
acterizations were made from the chemical shifts of the
vinylic hydrogen atoms and the X-ray structural data of
several DA cycloadducts and their derivatives.
(18) Pudukulathan, Z.; Manna, S.; Hwang, S. W.; Khanapure, S.
P.; Lawson, J . A.; FitzGerald, G. A.; Rokach, J . J . Am. Chem. Soc. 1998,
120, 11953.
(19) Danishefsky, S. J .; Paz Cabal, M.; Chow, K. J . Am. Chem. Soc.
1989, 111, 3456.
(20) J eyaraj, D. A.; Yadav, V. K.; Parvez, M.; Gauniyal, H. M. J .
Org. Chem. 1998, 63, 3831. Yadav, V. K.; J eyaraj, D. A.; Parvez, M.;
Yamdagni, R. J . Org. Chem. 1999, 64, 2928. Yadav, V. K.; J eyaraj, D.
A.; Parvez, M. J . Chem. Soc., Perkin Trans. 1 2000, 1423.
(21) Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39, 5965.
(22) Furniss, B. S.; Hannaford, A. J .; Smith, P. W. G.; Tatchell, A.
R. Vogel’s Textbook of Practical Organic Chemistry; Longman Group:
Harlow, U.K., 1989.
(14) Datta, S. C.; Franck, R. W.; Tripathy, R.; Quigley, G. J ; Huang,
L.; Chen, S.; Sihaed, A. J . Am. Chem. Soc. 1990, 112, 8472.
(15) Paquette, L. A.; Branan, B. M.; Rogers, R. D.; Bond, A. H.;
Lange, H.; Gleiter, R. J . Am. Chem. Soc. 1995, 117, 5992.
(16) Branan, B. M.; Paquette, L. A. J . Am. Chem. Soc. 1994, 116,
7658.
(17) Ginsburg, D. Tetrahedron 1983, 39, 2025.

π-Facial Selectivity of Diels-Alder Cycloadditions
J . Org. Chem., Vol. 67, No. 4, 2002 1111
Ta ble 1. Ster eoch em ica l Resu lts a n d th e P r od u ct
Distr ibu tion fr om th e Diels-Ald er Ad d ition s of 7 to
Selected Dien op h iles u n d er Th er m a l a n d Lew is Acid
Con d ition s
Sch em e 2. Syn th esis of th e Keton e 17, th e
P r ecu r sor of th e Dien es 8 a n d 9a
yield
(%)
r atio
18:19
entry dienophile
reaction conditions
time
1
2
3
NPM
NPM
MTAD
40 °C, toluene
rt, 4 M LPNM
70 °C to rt,
11 h
6 h
4 h
99
99
99
8.0:1.0
2.2:1.0
10.0:1.0
DCM:THF ) 1:1
rt, 4 M LPNM
40 °C, toluene
reflux, toluene
rt, 4 M LPNM
rt, nitromethane
rt, 4 M LPDE
rt, toluene
rt, 4 M LPNM
rt, toluene
110 °C, toluene
rt, 4 M LPNM
0 °C, 4 M LPNM
rt, 1 M LiClO4/CH3CN 12h
rt, 1 M LiBF4/CH3CN 4 h
rt, 4 M LPDE
rt, toluene
110 °C, toluene
rt, 4 M LPNM
rt, 4 M LPDE
4
5
6
7
8
MTAD
DMAD
DMAD
DMAD
DMAD
DMAD
NQ
decomposition of MTAD
42 h
6 h
3 h
6 h
12 h
24 h
5 h
7 d
12 h
4 h
93
76
99
99
1.0:1.7
1.0:1.4
2.5:1.0
0.5:1.0
1.5:1.0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
no reaction
a
Reagents: (a) Br2, Et3N, CCl4, 0 °C to rt; (b) HOCH2CH2OH,
NQ
50
99
60
99
99
99
95
90
3.6:1.0
1.0:1.0
2.0:1.0
6.0:1.0
7.2:1.0
3.6:1.0
5.6:1.0
8.8:1.0
p-TSA, C6H6, reflux; (c) n-BuLi, HCONMe2, -80 °C; (d) CH2dPPh3,
0 °C to rt; (e) p-TSA, acetone, rt.
MVK
MVK
MVK
MVK
MVK
MVK
MVK
EA
Sch em e 3. Diels-Ald er Cycloa d d u cts of 7 w ith
6h
Selected Dien op h iles
6 h
24 h
24 h
12 h
16
no reaction
EA
EA
EA
63
99
92
1.6:1.0
1.0:0.0
9.5:1.0
at δ 6.16 (t, J ) 4.2 Hz) and that of the major adduct at
δ 5.82 (t, J ) 3.9 Hz). These adducts were separated by
radial chromatography. The stereochemical assignment
of the major adduct was secured as in 18a , a product of
endo-addition syn to O, from its X-ray crystal data.
Likewise, the stereostructure of the minor adduct was
confirmed as in 19a , a product of endo-addition syn to S,
from its X-ray crystal data.
The cycloaddition of MTAD at -70 °C in a 1:1 mixture
of THF and CH2Cl2 gave a mixture of two adducts in a
10:1 ratio (entry 3). The vinylic hydrogens appeared at δ
6.39 (t, J ) 2.4 Hz, minor) and δ 5.81 (t, J ) 1.8 Hz,
major). Our all attempts to separate the two adducts by
chromatography failed. However, a recrystallization from
MeOH-CH2Cl2 furnished crystals of the major adduct
that had, from its X-ray crystal data, the stereostructure
shown in 18b. The cycloaddition, therefore, had pro-
ceeded predominantly syn to O via an endo-TS. The minor
adduct must, therefore, be the product of endo-addition
syn to S and possess the stereostructure 19b in ac-
cordance with the results obtained from the cycloaddition
of NPM above.
DMAD reacted with the diene at 40 °C in toluene to
provide a mixture of two separable adducts in a 1:1.7
ratio (entry 5). The vinylic H appeared at δ 5.66 (t, J )
3.4 Hz) in the minor adduct and at δ 6.25 (t, J ) 3.0 Hz)
in the major adduct. The major adduct that was recrys-
tallized from EtOAc-hexanes had the stereostructure
19c from its X-ray structural data. The major adduct,
therefore, is derived from addition syn to S. It is signifi-
cant to note the S in 19c is disposed equatorially. The
minor adduct, therefore, must have the stereostructure
18c. When compared to the reactions with NPM and
MTAD above, the reversal in selectivity in the cycload-
dition of DMAD is obvious. The syn-to-O cycloaddition
was somewhat enhanced to 18c:19c ) 1:1.4 on carrying
out the reaction in toluene at reflux (entry 6).
Resu lts a n d Discu ssion
The DA cycloadditions of various dienophiles to 7 were
carried out both thermally and in the presence of selected
Lewis acids. The reactions and their products are col-
lected in Scheme 3 and the stereochemical results in
Table 1. We present below a detailed account of these
reactions.
Diels-Ald er Ad d ition s u n d er Th er m a l Con d i-
tion s. The diene 7 reacted with NPM in toluene at 40
°C to furnish a mixture of two adducts in an 8:1 ratio
(entry 1).23 The vinylic H of the minor adduct appeared
(23) We observe only kinetic products. This conclusion was made
from separate experiments that involved heating a solution of each
adduct of NPM with 7 in toluene for 5 h. There was no change in either
instance.

1112 J . Org. Chem., Vol. 67, No. 4, 2002
Yadav et al.
The cycloaddition of NQ in toluene at 25 °C failed, and
neither 18d nor 19d was formed (entry 10). At higher
temperatures there was extensive decomposition.
The DA cycloadditions of unsymmetrical dienophiles
were also attempted. MVK reacted very slowly (toluene,
7 days, 25 °C) and furnished a mixture of four adducts.
Clearly, the cycloaddition had proceeded syn to both
oxygen and sulfur through regioisomeric TSs. The chemi-
cal shift of the vinylic H of each adduct was different from
those of the others, and these appeared in two sets. Two
adducts had the vinylic H atoms at δ 6.36 and 6.26, a
region where the syn-to-S adducts 19e and 19e′ will be
expected. The other set had the vinylic H atoms at δ 5.74
and 5.69, a region where the syn-to-O adducts 18e and
18e′ will be expected. The ratio of the two sets of adducts
was 1:1 (entry 12), and their separation was difficult. A
moderate enhancement in syn-to-O selectivity to 2:1 was,
however, observed when the cycloaddition was carried
out in a sealed tube at 110 °C (entry 13).
NQ reacted smoothly in LPNM to furnish a mixture
of two adducts in a 3.6:1 ratio (entry 11). H chemical
1
shift data of the vinylic H atoms (major adduct, δ 5.75;
minor adduct, δ 6.34) indicated the dominance of syn-
to-O addition. It is significant to recall that NQ had not
reacted with 7 in toluene at 25 °C. Our attempts to
separate the isomers by chromatography over silica gel
resulted in extensive decomposition. Fractional recrys-
tallization also failed to furnish a pure sample of either
adduct.
The reaction with MVK proceeded readily with high
stereocontrol, regiocontrol, and facial control. From the
three adducts that were formed, one was present in large
excess of the other two. The ratio 6:1 calculated as before
from the 1H chemical shifts favored addition syn to O
(entry 14). A recrystallization from EtOAc-hexanes
furnished the most major adduct, which, from its X-ray
structural data, was 18e (R ) Me). This isomer had the
vinylic H at δ 5.69. The other syn-to-O adduct displayed
the vinylic H at δ 5.74, probably having the structure
18e′ (R ) Me). Both 18e and 18e′ are the products of
the corresponding endo-TSs.
The cycloaddition of EA was even more selective than
the addition of MVK as it gave only one of the total four
adducts possible (entry 21). This adduct displayed the
vinylic H at δ 5.66 that corresponded very well with that
of 18e (R ) Me, δ 5.69). This product must, therefore, be
18e (R ) OEt). This material and the corresponding
alcohol were liquids. We did not succeed in making a
suitable crystalline derivative of the alcohol either.
We have compared the catalytic activity of LPNM to
those of LPDE and LiBF4.30 The syn-to-O addition was
favored in all the cases. The selectivity of MVK addition
in LPDE (8.8:1.0, entry 18) was better than that in LPNM
(6:1, entry 14). DMAD and EA, however, showed some-
what poor selectivity in LPDE compared to LPNM (cf.
entries 7 and 21 with entries 9 and 22, respectively). The
selectivity of MVK addition catalyzed by 1 M LiBF4 in
CH3CN (5.6:1.0, entry 17) was comparable to that of the
4 M LPNM-catalyzed addition (6.0:1.0, entry 14).
Ab In itio MO In vestiga tion s. We have computed the
ground-state geometry of 7 using DFT ab initio MO
methods at the Becke3LYP/6-31+G* level.31 It could be
an equilibrium mixture of the two conformers 7a and 7b
(Figure 2). Conformer 7a is 0.18 kcal mol-1 more stable
than conformer 7b. This energy difference translates into
a 1.4:1 distribution of 7a and 7b at 25 °C, respectively.
The diene moiety is not planar in either conformer. The
plane of the external olefin is 32.6° toward S from the
plane of the ring olefin in 7a and 42° toward oxygen in
7b.
EA did not add to 7 at 25 °C (entry 19). However, four
adducts had formed when the reaction mixture was
heated to 110 °C in a sealed tube. The trend for the
chemical shifts of the vinylic H atoms was similar to
those of the MVK cycloadducts. A similar calculation of
the ratio (1.6:1, entry 20) showed a marginal selectivity
in favor of syn-to-O addition.
Diels-Ald er Cycloa d d ition s u n d er Ca ta lysis by
LP NM. We turned our attention next to Lewis acid-
catalyzed DA cycloadditions that are reported to proceed
at low temperatures with high regio-, stereo-, and enan-
tiocontrol.24 Recently, the use of LiClO4 in carbon-carbon
bond formation reactions has gained much significance.
A solution of LiClO4 in Et2O or CH3NO2 is very effective
in catalyzing Claisen,25 Michael,26 and DA cycloaddi-
tions.27a The rationale for the catalytic activity of LiClO4
has been disputed. Grieco et al.27a,b have suggested the
large internal pressure caused by the change in solvent
structure that induces a compression of the reactants as
the rationale for the observed rate acceleration. Braun
and Sauer28 have attributed the rate acceleration to polar
solvent effects. Forman and Dailey29 have presented
evidence in favor of the catalytic effect of Li+. It is now
generally accepted that both the medium effect and Li+
are responsible for the said catalytic activity.
We chose to explore DA cycloadditions to 7 in 4 M
LPNM mostly as it is essentially a neutral medium.26 An
increase in the rate of cycloaddition of DMAD to 7 at 25
1
°C was evident from its completion in <3 h (entry 7). H
NMR analysis of the product mixture showed it to favor
syn-to-O addition (18c:19c ) 2.5:1). This selectivity is
opposite that of the normal reaction that favored addition
syn to S (entries 5-8). To assess the contribution of the
solvent to the facial control, the reaction was carried out
in CH3NO2 at 25 °C without any LiClO4. The reaction
furnished a diastereomeric ratio of 0.5:1 (entry 8) that
compared favorably with the 0.6:1 selectivity observed
from the reaction in toluene at 40 °C (entry 5). Thus, the
syn-to-O addition in LPNM was due primarily to LiClO4.
The syn-to-O addition to 7a requires an axial carbon-
carbon bond formation on C7. However, the syn-to-S
addition to 7a requires the formation of an equatorial
carbon-carbon bond. Since the formation of an axial bond
(30) Smith, D. A.; Houk, K. N. Tetrahedron Lett. 1991, 32, 1549.
Babu, B. S.; Balasubramanian, K. K. Synlett 1999, 1261.
(31) All the geometry optimizations and the calculations of anti-
periplanar effects were performed at the Becke3LYP/6-31G* level using
the program GAUSSIAN 94, Revision C.2: Frish, M. J .; Trucks, G. W.;
Schlegel, H. B.; J ones, P. M. W.; J ohnson, B. G.; Robb, M. A.;
Cheeseman, J . R.; Keith, T.; Petersson, G. A.; Montgomery, J . A.;
Raghavachari, K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J . V.;
Foresman, J . B.; Cioslowski, J .; Stefanov, B. B.; Nanayakkara, A.;
Challacombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.;
Andres, J . L.; Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J .;
Binkley, J . S.; Defrees, D. J .; Baker, J .; Stewart, J . P.; Head-Gordon,
M.; Gonzalez, C.; Pople, J . A., Gaussian, Inc., Pittsburgh, PA, 1995.
(24) Yates, P.; Eaton, P. E. J . Am. Chem. Soc. 1960, 82, 4436.
(25) Grieco, P. A.; Clark, J . D.; J agoe, C. T. J . Am. Chem. Soc. 1991,
113, 5488.
(26) Saraswathy, V. G.; Sankararaman, S. J . Org. Chem. 1995, 60,
5024.
(27) (a) Grieco, P. A.; Nunes, J . J .; Gaul, M. D. J . Am. Chem. Soc.
1990, 112, 4595. (b) Kumar, A. J . Org. Chem. 1994, 59, 4612.
(28) Braun, S.; Sauer, J . Chem. Ber. 1986, 119, 1269.
(29) Forman, M. A.; Dailey, W. P. J . Am. Chem. Soc. 1991, 113, 2761.

π-Facial Selectivity of Diels-Alder Cycloadditions
J . Org. Chem., Vol. 67, No. 4, 2002 1113
as well. This, however, does not conform to the stereo-
electronic effects.
The preferential syn-to-S addition of DMAD appears
to be a consequence of electrostatic repulsion of an
electron pair of acetal oxygen with the orthogonal π-or-
bital of the acetylene unit. The magnitude of this interac-
tion, however, is expected to be low because the inter-
acting orbitals are somewhat away from each other in
the TS for addition. As a result, the preference for syn-
to-S addition is likely not very high. Similar interactions
involving an electron pair of sulfur in 7b and the
acetylene unit will not be possible because of an energy
mismatch. The energy of the π-orbital of acetylene is
closer to that of the 2p electron pairs of oxygen than those
of S.33 An explanation based on such n-π interactions
has been invoked previously.21,34
The cycloaddition of DMAD is predominantly syn to O
in LPNM. This suggests a possible coordination of Li+ to
an electron pair of the acetal oxygen that eliminates the
above electrostatic repulsion and, thus, allows the addi-
tion to proceed syn to O. An extended coordination of Li+
with an ester function of DMAD will accelerate the
addition. In practice, the syn-to-O addition was favored
only by a factor of 2.5 over the syn-to-S addition. The low
selectivity is likely due to the increased steric encum-
brance caused by Li+-oxygen combination on the face
syn to O. Such a rationale receives good support from
the observation that the syn-to-O addition of NPM was
reduced from 8.0:1.0 in toluene to 2.2:1.0 in LPNM. The
large size of the phenyl ring comes close to the Li+-
oxygen combination in the syn-to-O addition and results
in unfavorable steric interactions. Such steric interactions
will, however, be less important for small dienophiles
such as EA and MVK, and thus, predominantly syn-to-O
addition will be expected. This is observed indeed from
the present experiments (vide supra).
F igu r e 2. Ab initio MO conformers of 7: (a) 7a ; (b) 7b; (c)
7a -Li+; (d) 7b-Li+.
F igu r e 3. Preferred transition states for DA addition to 7a
and 7b.
We have computed the effect of coordination of Li+ with
the acetal oxygen on the geometry of 7. The oxygen
electron pair that was closer to the diene function was
allowed for the said coordination. The geometrical changes
are very significant and interesting. In 7a -Li+ (Figure
2c), the external olefin has moved 40.3° upward and close
to O/Li+. Likewise, the external olefin has moved 46.1°
downward, close to O/Li+, in 7b-Li+ (Figure 2d). Con-
former 7a -Li+ is 0.05 kcal mol-1 more stable than
conformer 7b-Li+. This small energy difference allows
for an almost equal equilibrium concentration of the two
species. The extended coordination of Li+ with a dieno-
phile will allow the addition syn to O in both the species.
For the fact that an axial carbon-carbon bond formation
on C7 is favored over that of an equatorial bond, we
believe that most of the syn-to-O product is formed from
7a -Li+. Though the addition syn to S in 7b-Li+ involves
an axial carbon-carbon bond formation on C7, it suffers
from (a) 1,3-diaxial interactions arising from the sulfur
and (b) the absence of proximity of the two addends
arising from the coordination of Li+ with both the diene
and the dienophile.
is favored over an equatorial bond from stereoelectronic
considerations,32 7a undergoes addition syn to O. Simi-
larly, 7b undergoes addition syn to S. If we presume that
the activation energies for the reactions of both 7a and
7b are equal, the ratio of the two adducts must reflect
the above 7a :7b ratio. This, however, is not so. The syn-
to-O addition takes place in far excess of the calculated
value.
The TSs for additions to 7a and 7b are given in Figure
3. These transition states (and the resultant adducts),
however, suffer from 1,3-diaxial interactions of the axial
acetal heteroatom with the axial carbon-carbon bond
formed on C7. The larger steric interactions with S in
the TS for addition to 7b is likely to favor addition to 7a
wherein such steric interactions are relatively less.
Further, these 1,3-diaxial interactions may also induce
a ring flip in the product. As a consequence, a syn-to-O
adduct from 7a will have the C-O and C-S bonds,
respectively, equatorial and axial. The reverse applies to
a syn-to-S adduct formed from 7b. This is indeed observed
from the X-ray structures of 18a , 19a , 18b, 18e, and 19c
(see the Supporting Information). It is interesting to note
that one may arrive at these conclusions by invoking the
formation of an equatorial carbon-carbon bond on C7
Mor e Diels-Ald er Ad d ition s. We have studied DA
cycloadditions to the dienes 8 and 9 as well (Scheme 4).
(33) Coxon, J . M.; Maclagan, R. G. A. R.; McDonald, D. Q.; Steel, P.
J . J . Org. Chem. 1991, 56, 2542.
(32) Deslongchamps, P. In Stereoelectronic Effects in Organic Chem-
istry; Baldwin, J . E., Ed.; Pergamon: New York, 1983; Vol. 1, Chapters
2 and 3. Newitt, L. A.; Steel, P. G. J . Chem. Soc., Perkin Trans. 1 1997,
2033. Adcock, W.; Cotton, J .; N. R.; Trout, N. A. J . Org. Chem. 1994,
59, 1867.
(34) Fessner, W. D.; Scheumann, K.; Prinzbach, H. Tetrahedron Lett.
1991, 32, 5939. Coxon, J . M.; O’ Connell, M. J .; Steel, P. J . J . Org.
Chem. 1987, 52, 4726. Coxon, J . M.; Fong, S. T.; McDonald, D. Q.; Steel,
P. J . Tetrahedron Lett. 1993, 34, 163. Mehta, G.; Uma, R. Tetrahedron
Lett. 1995, 36, 4873. Mehta, G.; Uma, R. J . Org. Chem. 2000, 65, 1685.

1114 J . Org. Chem., Vol. 67, No. 4, 2002
Yadav et al.
Sch em e 4. Diels-Ald er Cycloa d d u cts of 8 a n d 9
w ith Selected Dien op h iles
F igu r e 4. Ab initio MO conformers: (a) 8a ; (b) 8b; (c) 9a ; (d)
9b.
Ta ble 2. Ster eoch em ica l Resu lts a n d P r od u ct
Distr ibu tion fr om th e Diels-Ald er Ad d ition s of th e
Dien es 8 a n d 9 to Selected Dien op h iles u n d er Th er m a l
a n d Lew is Acid Con d ition s
reaction
conditions
yield
(%)
ratio
syn:anti O
entry
reaction
time
1
2
3
4
5
6
8 + NPM
40 °C, toluene
33 h
6 h
24 h
6 h
6 h
4 h
90+
90+
90+
90+
90+
90+
1.0:1.1
1.0:1.6
1.0:4.3
1.0:1.8
2.1:1.0
>10:1.0
8 + DMAD reflux, toluene
9 + NPM
40 °C, toluene
These dienes differ from Franck’s diene 2 with respect
to the location of the external olefinic bond. The steric
factor being the lone factor for facial discrimination, one
would expect the anti-to-OMe addition to prevail but only
to the extent that the difference of the substituents’ n
values35 would permit. With a dienophile such as DMAD
that is less susceptible to steric interactions, repulsive
interactions are likely to control the addition and allow
it to proceed preferably anti to OMe. Both 8 and 9 may,
therefore, exhibit very similar selectivities in their DA
cycloadditions to DMAD. Further, the anti-to-OMe ad-
dition of a sterically susceptible dienophile such as NPM
must increase from 8 to 9.
The substrates 8 and 9, however, could exist as an
equilibrium mixture of the equivalents of 7a and 7b.
Conformers 8a and 9a are 2.98 and 0.98 kcal mol-1 more
stable than conformers 8b and 9b, respectively (Figure
4). Thus, 8a /9a prevailing over 8b/9b, the preference for
DA cycloadditions anti to OMe must indeed be a conse-
quence of steric effects. The experimental selectivities of
the substrates 8 and 9 are collected in Table 2.
Both 8 and 9 showed similar anti-to-OMe addition of
DMAD. The anti-to-OMe addition of NPM is larger with
9 than with 8. This is in accordance with the above
analysis, and it follows the steric control model of facial
selection. The cycloadditions of DMAD and MVK to 9 in
LPNM at room temperature proceeded largely syn to O
to furnish 2.1:1 and >10:1 product distributions. In
contrast, MVK did not react with 9 in toluene at room
temperature, and it furnished a mixture of several
adducts when refluxed in a sealed tube. The enhanced
9 + DMAD reflux, toluene
9 + DMAD rt, 4 M LPNM
9 + MVK
rt, 4 M LPNM
Ta ble 3. Ster eoch em ica l Ch a r a cter iza tion of th e
P r od u cts fr om th e 1H Ch em ica l Sh ifts (δ) of th e Vin ylic
Hyd r ogen s a n d OMe
δvinylic H
δOMe
anti to O
reaction
syn to O
anti to O
syn to O
7 + NPM
7 + MTAD
7 + DMAD
7 + NQ
7 + MVK
7 + EA
8 + NPM
8 + DMAD
9 + NPM
9 + DMAD
9 + MVK
5.82
5.81
5.66
5.75
5.69/5.74
5.66/5.74
5.93
5.73
5.72
6.16
6.39
6.25
6.34
6.26/6.36
6.25/6.37
5.66
5.59
5.70
3.07
3.32
3.31
3.42
3.42
3.02
3.06
3.21
3.19
3.23
5.64
5.62
5.59
5.62
syn-to-O addition to 9 in LPNM can be easily explained
by invoking coordination of Li+ to the oxygen and its
extended coordination with DMAD and MVK. It is
important to note that this extended coordination will
also improve the regioselectivities of monofunctional
dienophiles. The crystal structure of the anti-to-O adduct
of NPM with 9 shows that it is a product of endo-addition
wherein the OMe is disposed axially.
1H Ch em ica l Sh ifts of th e Vin ylic Hyd r ogen a n d
OMe a s P r obes to Ster eoch em ica l Ch a r a cter iza tion .
The chemical shifts of the vinylic H and OMe in the
DA cycloadducts prepared in the present study are
collected in Table 3. The vinylic H in the syn-to-O adduct
of 7 appeared at a lower δ value than the vinylic H in
the syn-to-S adduct. While the vinylic H is close to the
(35) Forster, H.; Vogtle, F. Angew. Chem., Int. Ed. Engl. 1977, 16,
429.

π-Facial Selectivity of Diels-Alder Cycloadditions
J . Org. Chem., Vol. 67, No. 4, 2002 1115
TMS used as an internal standard and the central line for
CDCl3. IR spectra were recorded on a Perkin-Elmer 1320
infrared spectrophotometer. Melting points are uncorrected.
Column chromatography was performed over silica gel (100-
200 mesh) using petroleum ether (bp 60-80 °C) and EtOAc
mixtures as the eluent. The separation of the isomers and their
further rigorous purification were achieved by radial chroma-
tography using 1-2 mm thick plates coated with silica gel
PF254 (E. Merck). Solvents were removed under reduced
pressure on a rotovap. The visualization of the spots on TLC
was effected by UV illumination, exposure to iodine vapor,
DNP solution in ethanol containing 10% H2SO4, and heating
of the plates dipped in 10% aqueous H2SO4 in EtOH.
acetal oxygen in the former, it is close to the acetal S in
the latter. The larger δ value of the vinylic H in the syn-
to-O adducts of 8 and 9 is likely due to its proximity to
OMe. Further, the OMe in the syn-to-O adduct is some-
what deshielded compared to the OMe in the anti-to-O
adduct. This is likely due to the anisotropic effect of the
olefin to which the OMe has better proximity in the syn-
to-O adduct than the OMe in the corresponding anti
adduct.
Con clu sion s
The preferred syn-to-O selectivity in the DA cycload-
ditions to 7 is due largely to the steric encumbrance
caused by the large sulfur atom. The reversal in selectiv-
ity in the addition of DMAD to 7 has its origin in the
electrostatic repulsion between an electron pair orbital
of the acetal oxygen and the orthogonal π-orbital of the
acetylene unit in DMAD.36 LPNM helps the additions of
sterically less sensitive dienophiles to 7 to proceed syn
to O by promoting coordination of Li+ to the acetal oxygen
and the dienophile. Additionally, the coordination of Li+
with the dienophile improves the regioselectivity of
addition of monofunctional dienophiles as well. The
dienes 8 and 9 exhibited a preference for anti-to-O
addition that is a consequence of the relative steric effects
of the substituents. This selectivity, however, reversed
as expected when the addition was carried out in LPNM.
The Cieplak model37 favors bond construction anti to
the more electron-donating of the C-O and C-S bonds.
Since a C-S bond is more electron-donating than a C-O
bond, a dominant anti-to-S selectivity of 7 with dieno-
philes such as NPM, MTAD, and EA would appear to
follow. However, the preferred syn-to-S addition of DMAD
(Table 1, entry 5) and lack of facial discrimination by
MVK at room temperature (Table 1, entry 12) are not
explained. The preferred anti-to-OMe additions to 8 and
9 also do not obey the Cieplak model. Both a C-C bond
and a C-H bond on the stereogenic centers in 8 and 9,
respectively, are more electron-donating than the C-O
bond on the same center.
6-Hyd r oxym eth yl-1-oxa -4-th ia sp ir o[4.5]d ec-6-en e (11).
A solution of the keto alcohol 10 (630 mg, 5 mmol), 2-mercap-
toethanol (365 mg, 5 mmol), and PPTS (25 mg, 0.1 mmol) in
benzene (100 mL) was refluxed under N2 under azeotropic
removal of water using a Dean-Stark setup. After 10 h, the
reaction mixture was cooled to rt and the solvent removed.
The residue was purified by chromatography to furnish 11 (250
mg) and 10 (460 mg). 1H NMR (400 MHz): δ 1.62-1.77 (m,
1H), 1.83-1.89 (m, 1H), 1.97-2.04 (td, J ) 12, 3 Hz, 1H), 2.05-
2.16 (m, 4H), 2.40-2.80 (br s, 1H), 3.08-3.13 (m, 1H), 3.17-
3.24 (m, 1H), 4.04 (d, J ) 12 Hz, 1H), 4.04-4.11 (dt, J ) 9.5,
5.6 Hz, 1H), 4.33 (d, J ) 12.2 Hz, 1H), 4.40-4.45 (m, 1H), 5.92
(t, J ) 3.7 Hz, 1H). 13C NMR (100 MHz): δ 20.6, 24.7, 34.5,
38.4, 64.1, 70.5, 95.2, 130.7, 138.1. IR (film): 3380, 2900, 1250,
1140, 1080, 890 cm-1. Anal. Calcd for C9H14O2S: C, 58.04; H,
7.58. Found: C, 57.90; H, 7.48.
1-Oxa -4-t h ia sp ir o[4.5]d ec-6-en e-6-ca r b a ld eh yd e (12).
To a stirred solution of pyridine (948 mg, 12 mmol) in dry CH2-
Cl2 (15 mL) was added chromium trioxide (600 mg, 6 mmol)
in one portion, and the stirring was continued for 15 min. To
the dark red solution was added the alcohol 11 (1 mmol, 186
mg) in CH2Cl2 (2 mL). An immediate black precipitation was
observed. The stirring was continued for 15 min. The solvent
was removed, and the residue was extracted into Et2O. This
was filtered through a short column of silica gel, and the
solvent was removed. The crude residue was purified by
chromatography to furnish 12 (127 mg, 71%). 1H NMR (400
MHz): δ 1.70-1.76 (m, 1H), 1.83-1.88 (m, 1H), 2.00-2.13 (m,
2H), 2.27-2.32 (m, 2H), 3.12-3.16 (m, 1H), 3.34-3.38 (m, 1H),
4.07-4.12 (m, 1H), 4.48-4.52 (m, 1H), 6.90 (t, J ) 4.0 Hz, 1H),
9.52 (s, 1H). 13C NMR (100 MHz): δ 20.4, 25.8, 35.1, 38.9, 71.6,
90.4, 140.3, 146.9, 191.5. Anal. Calcd for C9H12O2S: C, 58.67;
H, 6.57. Found: C, 58.52; H, 6.48.
Exp er im en ta l Section
1H and 13C NMR spectra were recorded using solutions in
1-Oxa -4-th ia -6-vin ylsp ir o[4.5]d ec-6-en e (7). To a mag-
netically stirred suspension of methyltriphenylphosphonium
iodide (139 mg, 0.342 mmol) in THF (2 mL) was added n-BuLi
(0.342 mmol) dropwise at 0 °C, which resulted in a yellow
coloration. Now, the aldehyde 12 (42 mg, 0.23 mmol), dissolved
in THF (2 mL), was added and the resultant mixture stirred
for 2 h before it was quenched with saturated aqueous NH4-
Cl. The reaction mixture was diluted with Et2O (5 mL), and
the layers were separated. The solvents were removed and the
crude product purified by chromatography to give 7 (38 mg,
CDCl3. The 1H and 13C spectra are referred, respectively, to
(36) In the view of one reviewer, an alternate explanation to the
reversal in selectivity of DMAD addition to 7 is as follows. Sulfur no
longer imposes a significant steric difference between the two faces.
Instead, the energy difference between A and C given below is likely
to be in the same order as the difference between 7a and 7b because
the steric bias of sulfur is rendered negligible by the linearity of DMAD.
The small difference in selectivity in this case is due to a preference
for addition to the face away from the C9 methylene (A vs B and C vs
D) residue and the small difference in energy between A and C. The
ratios of products (1:1.7 at 40 °C and 1:1.4 at 110 °C) are close to the
calculated ratio for 7a and 7b (1:1.4 for a 0.18 kcal mol-1 difference).
1
74% yield). H NMR (400 MHz): δ 1.66-1.76 (m, 1H), 1.79-
1.88 (m, 1H), 1.99-2.06 (m, 1H), 2.09-2.15 (m, 3H), 3.09-
3.21 (m, 2H), 4.05-4.11 (m, 1H), 4.38-4.43 (m, 1H), 5.02-
5.05 (dd, J ) 11.0, 1.2 Hz, 1H), 5.40-5.45 (ddd, J ) 17.6, 2,
0.7 Hz, 1H), 6.05 (t, J ) 3.9 Hz, 1H), 6.37-6.44 (dd, J ) 17.6,
11.0 Hz, 1H). 13C NMR (50 MHz): δ 20.7, 25.2, 34.6, 38.6, 70.7,
94.0, 113.3, 127.4, 134.6, 138.2. IR (film): 2920, 1610, 1420,
1340, 1260, 1150, 1070, 1050, 900 cm-1. Anal. Calcd for C10H14
OS: C, 65.90; H, 7.76. Found: C, 65.78; H, 7.63.
-
Gen er al P r ocedu r es for Diels-Alder Addition . Meth od
A. A mixture of one of the dienes 7-9 (0.1 mmol) and a
dienophile (0.1 mmol) in dry toluene (5 mL) was either stirred
at rt or heated to 110 °C in a sealed tube under N2. After a
given time or completion of the reaction, the solvent was
removed, and the crude product was filtered through a short
silica gel column. The separation of the isomers was achieved
by radial chromatography.
(37) Cieplak, A. S. J . Am. Chem. Soc. 1981, 103, 4540. Cieplak, A.
S.; Tait, B. D.; J ohnson, C. R. J . Am. Chem. Soc. 1989, 111, 8447.

1116 J . Org. Chem., Vol. 67, No. 4, 2002
Yadav et al.
Meth od B. To a mixture of one of the dienes 7-9 (0.1 mmol)
and a dienophile (0.1 mmol) was added 4 M LPNM/1 M
LiClO4/1 M LiBF4 in acetonitrile (125 µL). The reaction
mixture was stirred under a nitrogen atmosphere at rt or at 0
°C till the completion of the reaction (TLC).
(2.03 g, 32.8 mmol), and p-toluenesulfonic acid (p-TSA) (156
mg, 5 mol %) in benzene (200 mL) was refluxed for 12 h under
a Dean-Stark setup. The solvent was removed under reduced
pressure, and the crude material was chromatographed to
furnish 14 (3.10 g, 80%). 1H NMR (400 MHz): δ 1.77-1.83
(m, 2H), 1.92-1.95 (m, 2H), 2.09-2.13 (m, 2H), 3.98-4.01 (m,
2H), 4.19-4.22 (m, 2H), 6.35 (t, J ) 4.2 Hz, 1H). 13C NMR
(100 MHz): δ 20.3, 27.5, 35.6, 65.8, 105.8, 124.5, 136.1.
1,4-Dioxa -6-for m ylsp ir o[4.5]d ec-6-en e (15). n-BuLi (20
mmol) was added to a THF solution of 14 (4 g, 18.2 mmol) in
THF (80 mL) at -80 °C. After 5 min, DMF (1.46 g, 20 mmol)
was introduced. The reaction mixture was stirred for 10 min
at this temperature, and the cooling bath was removed. The
reaction mixture was immediately washed with saturated
aqueous NH4Cl, and the solvent was removed. The residue was
purified as quickly as possible by chromatography to obtain
1
Da ta for 18a . Mp: 124 °C. H NMR (300 MHz): δ 1.10-
1.25 (dq, J ) 12.3, 4.0 Hz, 1H), 1.50-1.68 (tq, J ) 12.9, 3.6
Hz, 1H), 1.77-1.87 (dt, J ) 12.6, 4.2 Hz, 1H), 1.89-2.00 (m,
2H), 2.08 (d, J ) 10.8 Hz, 1H), 2.48-2.52 (m, 1H), 2.75-2.88
(m, 2H), 3.00-3.08 (m, 2H), 3.16-3.24 (dt, J ) 9.6, 2.4 Hz,
1H), 3.38 (t, J ) 8.7 Hz, 1H), 4.06-4.14 (m, 1H), 4.28-4.37
(m, 1H), 5.82 (t, J ) 3.9 Hz, 1H), 7.26-7.49 (m, 5H). 13C NMR
(75 MHz): δ 20.0, 24.7, 29.7, 33.0, 35.4, 37.2, 41.5, 42.5, 70.6,
97.7, 113.0, 126.2, 128.4, 129.1, 131.8, 140.8, 177.4, 178.5. IR
(CHCl3): 3000, 1700, 1200 cm-1. Anal. Calcd for C20H21NO3S:
C, 67.58; H, 5.96. Found: C, 67.45; H, 5.85.
1
1
Da ta for 19a . H NMR (400 MHz): δ 1.50-1.61 (m, 2H),
15 (2.75 g, 90%). H NMR (400 MHz): δ 1.80-1.81 (m, 4H),
1.79-1.85 (m, 2H), 1.87-1.95 (m, 2H), 2.18-2.24 (td, J ) 12.8,
5.2 Hz, 1H), 2.39-2.46 (m, 1H), 2.84-2.90 (ddd, J ) 18.0, 4.8,
2.8 Hz, 1H), 2.95-3.00 (td, J ) 10.0, 5.6 Hz, 1H), 3.06-3.12
(td, J ) 10.0, 6.0 Hz, 1H), 3.21-3.26 (dt, J ) 8.8, 2.8 Hz, 1H),
3.28 (t, J ) 8.4 Hz, 1H), 3.89-3.94 (td, J ) 9.6, 6.0 Hz, 1H),
4.17 (td, J ) 8.8, 5.6 Hz, 1H), 6.16 (t, J ) 4 Hz, 1H), 7.28-
7.47 (m, 5H). 13C NMR (100 MHz): δ 21.6, 22.1, 27.3, 33.0,
34.5, 38.3, 39.6, 42.7, 69.7, 96.5, 120.4, 126.3, 128.4, 129.1,
142.1, 177.2, 178.7. Anal. Calcd for C20H21NO3S: C, 67.58; H,
5.96. Found: C, 67.44; H, 5.84.
2.33-2.37 (m, 2H), 3.98-4.07 (m, 2H), 4.20-4.28 (m, 2H), 7.0
(t, J ) 3.7 Hz, 1H ), 9.46 (s, 1H). 13C NMR (100 MHz): δ 19.8,
26.1, 34.4, 65.6, 105.0, 139.9, 153.3, 191.3. Anal. Calcd for
C9H12O3: C, 64.25; H, 7.20. Found: C, 64.12; H, 7.10.
1,4-Dioxa -6-vin ylsp ir o[4,5]d ec-6-en e (16). n-BuLi (9.2
mmol) was added dropwise to a magnetically stirred suspen-
sion of methyltriphenylphosphonium iodide (3.70 g, 9.15 mmol)
in THF (50 mL) at 0 °C. This resulted in a yellow coloration.
Now, a solution of the aldehyde 15 (1.28 g, 7.65 mmol) in THF
(4 mL) was added dropwise and the reaction mixture stirred
for 1 h. The reaction was quenched with saturated aqueous
NH4Cl. The layers were separated, and the organic layer was
dried and concentrated. The crude product was purified to 16
(1.12 g, 75%). 1H NMR (400 MHz): δ 1.70-1.79 (m, 4H), 2.10-
2.15 (q, J ) 4.9 Hz, 2H), 4.00-4.04 (m, 4H), 5.00-5.03 (dd, J
) 11.3, 1.7 Hz, 1H), 5.35-5.41 (dd, J ) 17.6, 2.0 Hz, 1H), 6.16
(t, J ) 4.2 Hz, 1H), 6.25-6.33 (ddd, J ) 18.6, 11.0, 1.0 Hz,
1H). 13C NMR (100 MHz): δ 20.2, 25.3, 33.4, 64.7, 106.8, 113.6,
130.4, 133.4, 136.7. Anal. Calcd for C10H14O2: C, 72.25; H, 8.49.
Found: C, 72.13; H, 8.36.
1
Da ta for 18b. Mp: 158 °C. H NMR (400 MHz): δ 1.28-
1.38 (dq, J ) 12.0, 4.0 Hz, 1H), 1.59-1.71 (tq, J ) 13.6, 3.7
Hz, 1H), 1.79-1.87 (dt, J ) 13.6, 4.12 Hz, 1H), 1.93-1.99 (m,
1H), 2.10-2.13 (d, J ) 12.2 Hz, 1H), 2.42-2.45 (m, 1H), 3.09
(s, 3H), 3.04-3.14 (m, 2H), 3.92-3.97 (td, J ) 16.1, 2.7 Hz,
1H), 4.17-4.45 (m, 4H), 5.81-5.83 (m, 1H). 13C NMR (75
MHz): δ 21.8, 25.0, 30.2, 33.0, 41.7, 42.7, 55.0, 71.5, 95.8,
108.6, 139.7, 152.6, 154.1. IR (CHCl3): 3000, 1750, 1698, 1640,
1200 cm-1. Anal. Calcd for C13H17N3O3S: C, 52.86; H, 5.81;
N, 14.24. Found: C, 52.72; H, 5.69.
1
Da ta for 19b. Characteristic signals from the H NMR (300
2-Vin yl-2-cycloh exen on e (17). A solution of 16 (168 mg,
1 mmol) and p-TSA (10 mg, 5 mol %) in acetone (10 mL) was
stirred for 1 h at rt. The solvent was removed and the residue
MHz) of a mixture of 18b and 19b: δ 2.25-2.37 (m, 1H), 4.60-
4.70 (br d, 1H), 6.40 (t, J ) 2.4 Hz, 1H).
1
1
Da ta for 18c (Liqu id ). H NMR (400 MHz): δ 1.17-1.24
purified by chromatography to obtain 100 mg (80%) of 17. H
(m, 1H), 1.58-1.68 (m, 1H), 1.80-1.87 (dt, J ) 12.9, 3.9 Hz,
1H), 1.90-1.96 (m, 2H), 2.10 (d, J ) 11.5 Hz, 1H), 2.90-3.18
(m, 4H), 3.19-3.25 (m, 1H), 3.76 (s, 3H), 3.80 (s, 3H), 4.20-
4.35 (m, 2H), 5.66 (t, J ) 3.4 Hz, 1H). 13C NMR (100 MHz): δ
24.7, 27.4, 32.5, 32.7, 39.2, 41.8, 52.2, 71.4, 96.9, 110.7, 129.4,
138.3, 138.8, 167.7, 168.9. Anal. Calcd for C16H20O5S: C, 59.24;
H, 6.22. Found: C, 59.18; H, 6.15.
NMR (400 MHz): δ 1.97-2.04 (quintet, J ) 6.8 Hz, 2H), 2.43-
2.49 (m, 4H), 5.16 (d, J ) 11.2 Hz, 1H), 5.65 (d, J ) 17.8 Hz,
1H), 6.50-6.58 (dd, J ) 17.6, 11.2 Hz, 1H), 7.04 (t, J ) 4.4
Hz, 1H). 13C NMR (100 MHz): δ 22.5, 26.1, 38.6, 115.6, 131.1,
136.4, 145.3, 198.4.
3-Meth oxy-3-m eth yl-2-vin ylcycloh exen e (8). A solution
of 17 (124 mg, 1 mmol) in Et2O (2 mL) was added dropwise to
a freshly prepared solution of MeMgI (1.5 mmol) in Et2O (2
mL) at 0 °C. The reaction mixture was stirred for 30 min and
then quenched with saturated aqueous NH4Cl. The layers were
separated, and the solvent was removed. Purification of the
crude product afforded 1-methyl-2-vinylcyclex-2-en-1-ol (126
Da ta for 19c. Mp: 84 °C. 1H NMR (400 MHz): δ 1.22-
1.30 (dq, J ) 12.2, 3.6 Hz, 1H), 1.71-1.76 (m, 1H), 1.80-1.92
(dq, J ) 17.1, 4.1 Hz, 2H), 1.92-2.02 (m, 2H), 2.27-2.32 (br
d, J ) 12.2 Hz, 1H), 2.94-3.20 (m, 4H), 3.44-3.46 (m, 1H),
3.76 (s, 3H), 3.80 (s, 3H), 4.18-4.25 (m, 1H), 6.25 (t, J ) 3 Hz,
1H). 13C NMR (100 MHz): δ 23.5, 27.7, 32.7, 32.9, 37.7, 41.0,
52.2, 68.7, 97.5, 120.6, 128.7, 137.2, 139.4, 167.6, 169.1. IR
(CHCl3): 2940, 1710, 1420, 1260, 1060 cm-1. Anal. Calcd for
1
mg, 90%). H NMR (400 MHz, CDCl3): δ 1.38 (s, 3H), 1.54-
1.80 (m, 4H), 1.83 (br s, 1H), 2.02-2.18 (m, 2H), 5.02-5.05
(dd, J ) 11.0, 1.7 Hz, 1H), 5.42-5.47 (dd, J ) 17.6, 1.5 Hz,
1H), 5.87 (t, J ) 4.2 Hz, 1H), 6.33-6.40 (dd, J ) 17.6, 11.2
Hz, 1H). 13C NMR (100 MHz): 19.7, 25.9, 27.4, 40.0, 70.2,
114.1, 127.0, 135.5, 141.4.
C
16H20O5S: C, 59.24; H, 6.22. Found: C, 59.15; H, 6.14.
Da ta for 18e (R ) Me). Mp: 124 °C. H NMR (400 MHz):
1
δ 1.13-1.27 (tq, J ) 12.7, 3.6 Hz, 1H), 1.25-1.32 (tt, J ) 12.5,
3.6 Hz, 1H), 1.53-1.82 (m, 5H), 1.85-2.08 (m, 2H), 2.10-2.22
(m, 1H), 2.18 (s, 3H), 2.59-2.65 (m, 1H), 2.74-2.81 (m, 1H),
3.01-3.10 (m, 2H), 4.13-4.20 (m, 1H), 4.32-4.38 (m, 1H), 5.69
(d, J ) 5.64 Hz, 1H). 13C NMR (100 MHz): δ 19.2, 24.1, 25.0,
28.7, 28.8, 32.9, 38.4, 42.7, 51.3, 70.9, 98.0, 115.2, 142.0, 210.7.
IR (CHCl3): 3000, 2940, 1690, 1210 cm-1. Anal. Calcd for
A solution of the above alcohol (70 mg, 0.5 mmol) in THF (1
mL) was added to a suspension of NaH (29 mg, 0.6 mmol) in
THF (2 mL) at 0 °C, and the reaction mixture was stirred for
1 h. MeI (142 mg, 1 mmol) was administered now, and the
contents were stirred for 4 h at rt. The reaction mixture was
diluted with Et2O (10 mL), washed with saturated NH4Cl, and
dried, in that order. The solvent was removed and the residue
filtered through a short column of silica gel to furnish 8 (65
C
14H20O2S: C, 66.64; H, 7.99. Found: C, 66.52; H, 7.85.
Da ta for 18e (R ) OEt, Liqu id ). H NMR (300 MHz): δ
1
1
1.20-1.32 (m, 1H), 1.28 (t, J ) 7.3 Hz, 3H), 1.39-1.44 (m, 1H),
1.50-2.13 (m, 8H), 2.50-2.60 (m, 1H), 2.68-2.73 (m, 1H), 3.06
(t, J ) 5.4 Hz, 2H), 4.09-4.21 (m, 3H), 4.42-4.37 (td, J ) 8.7,
5.4 Hz, 1H), 5.67 (br d, J ) 5.1 Hz, 1H). IR (film): 2920, 1710,
1440, 1990 cm-1. Anal. Calcd for C15H22O3S: C, 63.80; H, 7.86.
Found: C, 63.65; H, 7.72.
mg, 85%). H NMR (400 MHz, CDCl3): δ 1.37 (s, 3H), 1.49-
1.54 (m, 1H), 1.55-1.66 (m, 1H), 1.73-1.80 (m, 1H), 1.97-
2.03 (dt, J ) 12.4, 3.2 Hz, 1H), 2.06-2.12 (m, 2H), 3.13 (s, 3
H), 4.97-5.00 (dd, J ) 11.0, 1.7 Hz, 1H), 5.50 (dd, J ) 17.6,
1.4 Hz, 1H), 6.00 (t, J ) 4.2 Hz, 1H), 6.21-6.28 (ddd, J ) 17.6,
11.2, 0.8 Hz, 1H). 13C NMR (100 MHz): δ 20.5, 25.8, 26.4,
32.7, 49.9, 76.1, 113.5, 129.9, 135.9, 139.6. Anal. Calcd for
1,4-Dioxa -6-br om osp ir o[4.5]d ec-6-en e (14). A mixture of
2-bromocyclohexenone (2.88 g, 16.4 mmol), ethylene glycol
C
10H16O2: C, 78.89; H, 10.60. Found: C, 78.75; H, 10.45.

π-Facial Selectivity of Diels-Alder Cycloadditions
J . Org. Chem., Vol. 67, No. 4, 2002 1117
3-Meth oxy-2-vin ylcycloh exen e (9). NaBH4 (38 mg, 1
mmol) was added to a stirred solution of 17 (124 mg, 1 mmol)
and CeCl3‚7H2O (373 mg, 1 mmol) in methanol (2.5 mL) at 0
°C. The reaction mixture was stirred for 20 min, diluted with
Et2O (10 mL), and washed with cold 5% aqueous HCl (3 mL).
The aqueous layer was extracted with Et2O (5 mL), and the
combined organic solution was washed with brine (5 mL) and
dried. The residue obtained after solvent removal was filtered
through a small column of silica gel to obtain 2-vinylcyclohex-
2-en-1-ol (100 mg, 80%). 1H NMR (400 MHz): δ 1.57-1.67 (m,
2H), 1.69-1.80 (m, 1H), 1.88-1.95 (m, 1H), 2.02-2.11 (m, 2H),
2.16-2.22 (m, 1H), 4.47 (s, 1H), 5.02 (dd, J ) 11.0, 1.0 Hz,
1H), 5.36 (d, J ) 17.8 Hz, 1H), 5.86 (t, J ) 3.72 Hz, 1H), 6.26
(dd, J ) 17.8, 11.0 Hz, 1H). 13C NMR(100 MHz): δ 16.8, 25.8,
30.8, 62.6, 111.4, 132.4, 137.3, 137.8.
Da ta for 22a . Characteristic signals from the 1H NMR (400
MHz) spectrum of a mixture of isomers (1:4.3): δ 2.00-2.08
(m 1H), 3.31 (s, 3H), δ 3.53 (m, 1H), 5.72 (t, J ) 4.6 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 20.8, 22.8, 28.4, 33.2, 35.7, 38.1,
41.8, 56.5, 81.4, 116.2, 128.4, 129.1, 131.8, 139.0, 177.4, 178.7.
1
Da ta for 23a . Mp: 119 °C. H NMR (400 MHz): δ 1.15-
1.25 (dq, J ) 12.2, 3.9 Hz, 1H), 1.44-1.53 (tt, J ) 12.4, 3.7
Hz, 1H), 1.55-1.65 (m, 2H), 1.75-1.85 (tq, J ) 13.2, 1.0 Hz,
1H), 1.94-2.00 (m, 2H), 2.42-2.52 (tdd, J ) 18.3, 10.0, 2.4
Hz, 1H), 2.81 (d, J ) 18.6 Hz, 1H), 2.90 (t, J ) 9.3 Hz, 1H),
3.21 (s, 3H), 3.17-3.35 (m, 2H), 3.79 (t, J ) 2.9 Hz, 1H), 5.70
(t, J ) 3.0 Hz, 1H), 7.27-7.49 (m, 5H). 13C NMR (100 MHz,
CDCl3): δ 20.1, 21.6, 30.5, 31.6, 33.0, 37.7, 41.6, 55.6, 81.8,
119.4, 126.2, 128.5, 129.2, 131.8, 139.0, 177.7, 178.6. Anal.
Calcd for C19H21O3N: C, 73.28; H, 6.80. Found: C, 73.15; H,
6.67.
The procedure adopted above for the O-methylation of
1-methyl-2-vinylcyclohex-2-en-1-ol was followed to obtain 9
1
Da ta for 22b. Characteristic signals from the H NMR (400
1
(94%). H NMR (400 MHz): δ 1.43 (tt, J ) 13.7, 3.4 Hz, 1H),
MHz) spectrum of a mixture of isomers: δ 3.42 (s, 3H), 3.77
1.55-1.60 (m, 1H), 1.67-1.77 (m, 1H), 2.04-2.22 (m, 3H), 3.39
(s, 3H), 3.94 (t, J ) 2.9 Hz, 1H), 4.98 (dd, J ) 11.0, 0.5 Hz,
1H), 5.21 (d, J ) 17.6 Hz, 1H), 5.91 (t, J ) 4.16 Hz, 1H), 6.28
(dd, J ) 17.6, 10.8 Hz, 1H). 13C NMR (100 MHz) δ 17.0, 25.5,
25.9, 56.1, 71.8, 110.9, 133.0, 136.0, 138.2. Anal. Calcd for
C9H14O: C, 78.20; H, 10.22. Found: C, 78.06; H, 10.10.
Da ta for 20a a n d 21a (1:1.07). 1H NMR (400 MHz): δ 1.27
(s, 3H), 1.30 (s, 3H), 1.15-1.60 (m, 4H), 1.76-1.92 (m, 6H),
2.12-2.34 (m, 2H), 2.50-2.55 (m, 2H), 2.79-3.00 (m, 2H), 3.02
(s, 3H), 3.07 (s, 3H), 3.10-3.30 (m, 4H), 5.66 (t, J ) 3.7 Hz,
1H), 5.93 (quintet, J ) 2 Hz, 1H). 13C NMR (100 MHz): δ 20.4,
20.5, 21.6, 21.9, 23.4, 23.7, 25.0, 30.5, 32.4, 34.8, 35.4, 36.9,
39.4, 41.1, 41.9, 43.4, 49.5, 49.9, 76.3, 77.3, 118.4, 120.5, 126.1,
126.2, 128.3, 128.4, 129.0, 129.1, 131.8, 132.0, 142.1, 142.5,
177.1, 178.0, 178.8, 178.9. Anal. Calcd for C20H23NO3: C, 73.81;
H, 7.13. Found: C, 73.66; H, 6.97.
(s, 3H), 3.79 (s, 3H), 5.62-5.65 (m, 1H).
1
Da ta for 23b. Characteristic signals from the H NMR (400
MHz) spectrum of a mixture of isomers: δ 3.19 (s, 3H), 3.76
(s, 3H), 3.80 (s, 3H), 5.58-5.61 (dt, J ) 3.2, 1.2 Hz, 1H).
Da ta for 22c. 1H NMR (400 MHz): δ 1.12-1.25 (m, 2H),
1.25-1.31 (m, 2H), 1.44 (tq, J ) 13.4, 4.3 Hz, 1H), 1.64 (dq, J
) 12.4, 5.8 Hz, 1H), 1.73-1.76 (m, 1H), 1.86 (md, J ) 13.4
Hz, 1H), 1.97-2.08 (m, 1H), 2.11-2.19 (m, 1H), 2.16 (s, 3H),
2.30-2.35 (m, 1H), 2.74 (ddd, J ) 12.6, 5.6, 2.7 Hz, 1H), 3.42
(s, 3H), 3.49-3.52 (m, 1H), 5.62 (br d, J ) 5.6 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 19.5, 24.2, 24.3, 28.7, 29.3, 35.2,
38.7, 51.3, 57.2, 82.3, 115.6, 140.1, 210.9. Anal. Calcd for
C
13H20O2: C, 74.95; H, 9.68. Found: C, 74.76; H, 9.54.
Ack n ow led gm en t. We thank the CSIR, Govern-
ment of India, for financial support and the staff of
the Computer Center, Indian Institute of Technology,
Kanpur, for generous allocation of computer time on the
Silicon Graphics series of minisupercomputers.
Da ta for 20b. Characteristic signals of 20b from the 1H
NMR (400 MHz) spectrum of a mixture of isomers: δ 1.31 (s,
1H), 3.32 (s, 3H), 3.75 (s, 3H), 3.80 (s, 3H), 5.73 (t, J ) 3.2 Hz,
1H).
Da ta for 21b. Characteristic signals of 21b from the 1H
NMR (400 MHz) spectrum of a mixture of isomers: δ 1.27, (s,
3H), 3.06 (s, 3H), 3.76 (s, 3H), 3.81 (s, 3H), 5.59 (t, J ) 2.9 Hz,
1H).
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C spectra of several of the compounds, Cartesian coordinates
of the optimized structures of 7a and 7b and their Li+
complexes, and ORTEP plots of the X-ray crystal structures
of 18a , 19a , 18b, 18e, 19c, and 23a . This material is available
free of charge via the Internet at http://pubs.acs.org.
Da ta for 20b a n d 21b. 13C NMR (100 MHz): δ 21.1, 21.2,
21.8, 22.9, 27.4, 27.5,33.0, 33.2. 36.3, 37.0, 37.8, 40.5, 49.5, 49.6,
52.2, 75.6, 112.8, 117.1, 128.0, 128.8, 138.5, 138.9, 139.2, 140.0,
167.5, 167.6, 169.4, 169.5.
J O0106400