1,3-Dipolar cycloadditions of diazomethane to chiral electron-deficient olefins: The origin of the π-facial diastereoselection

Article abstract of DOI:10.1021/jo991227j

The stereochemical outcome of diazomethane cycloadditions to several chiral electron-deficient olefins has been investigated in order to establish the origin of the π-facial diastereoselection. Nitro olefins, vinyl sulfones, enoates, and 2-amino enoates h

Full text of DOI:10.1021/jo991227j

388
J . Org. Chem. 2000, 65, 388-396
1,3-Dip ola r Cycloa d d ition s of Dia zom eth a n e to Ch ir a l
Electr on -Deficien t Olefin s: Th e Or igin of th e π-F a cia l
Dia ster eoselection
Elena Muray,† Angel Alvarez-Larena,‡ J oan F. Piniella,‡ Vicenc¸ Branchadell,*,† and
Rosa M. Ortun˜o*,†
Departament de Quı´mica, and Unitat de Cristal.lografia, Universitat Auto`noma de Barcelona,
08193 Bellaterra, Barcelona, Spain
Received August 2, 1999
The stereochemical outcome of diazomethane cycloadditions to several chiral electron-deficient
olefins has been investigated in order to establish the origin of the π-facial diastereoselection. Nitro
olefins, vinyl sulfones, enoates, and 2-amino enoates have been used for such a purpose. These
substrates have been prepared from D-glyceraldehyde acetonide through Wittig-type condensations
and present an alkoxy substituent, provided by the bulky dioxolane ring, attached to the stereogenic
allylic carbon. Syn-adducts have been obtained in all cases as the major isomers, independently of
the Z/ E stereochemistry of the double bond and the number and the nature of the substituents,
the chirality of the asymmetric allylic carbon being the only thing responsible for the diastereo-
selection. Theoretical calculations show that steric hindrance due to the bulky dioxolane group is
the main factor governing the preference for the syn-attack of diazomethane to the olefinic double
bond.
Ch a r t 1
In tr od u ction
Cyclopropanation of electron-deficient olefins by means
of 1,3-dipolar cycloadditions of diazomethane, affording
pyrazolines that under photolysis give cyclopropanes, is
a method widely employed in organic synthesis. The use
of chiral olefins to induce the absolute configuration of
the cyclopropane stereogenic centers confers on this
protocol a great versatility in the synthesis of natural or
unnatural enantiopure cyclopropane derivatives.1 The
control of the π-facial diastereoselection in the cycload-
dition is, therefore, crucial to obtain the target molecules
with high stereoselectivity.
Several theoretical models and empiric relationships
have been suggested to rationalize the origin of the
diastereoselection in the cycloadditions of several dipoles
to chiral olefins. Thus, for instance, the principle of 1,3-
allylic strain2 or the inside alkoxy theory3 has been
successfully invoked to rationalize the selectivity of many
1,3-dipolar cycloadditions. Nevertheless, these models do
not apply to all kind of dipoles and dipolarophiles. Esters
Z/ E-2 (Chart 1) and related γ-alkoxy-R,â-unsaturated
esters have been extensively used in the investigation of
π-facial diastereoselectivity in 1,3-dipolar cycloadditions.
Anti isomers predominate when these compounds add to
azomethyne ylides,4a,b nitrones,4a,c and nitrile oxides,4a,d
whereas syn isomers result from the addition to nitril-
imines,4e silyl nitronates,4f diazomethane,4g,h and other
diazo compounds.4h
The model stated by Houk and based on the inside
alkoxy effect has been applied to predict the stereochem-
ical outcome of several concerted processes, including
Diels-Alder reactions5 and 1,3-dipolar cycloadditions. A
good agreement between theoretical predictions and
experimental results was found for the reactions between
nitrile oxide and chiral allylic alcohols and ethers3a and
for the cycloadditions of nitrones to γ-alkoxy-R,â-unsatur-
ated esters.4c In contrast, for the addition of diazo-
* Corresponding authors. E-mail: (V.B.) vicenc@klingon.uab.es.
(R.M.O.) rosa.ortuno@uab.es.
(4) (a) Annunziata, R.; Benaglia, M.; Cinquini, M.; Raimondi, L.
Tetrahedron 1993, 49, 8629. (b) Galley, G.; Liebscher, J .; Pa¨tzel, M. J .
Org. Chem. 1995, 60, 5005. (c) Busque´, F.; de March, P.; Figueredo,
M., Font, J .; Monsalvatje, M.; Virgili, A.; AÄ lvarez-Larena, A.; Piniella,
J . F. J . Org. Chem. 1996, 61, 8578. (d) J a¨ger, V.; Mu¨ller, I.; Schohe,
R.; Frey, M.; Ehrler, R.; Ha¨fele, B.; Schro¨ter, D. Lect. Heterocycl. Chem.
1985, 8, 79. (e) Grubert, L.; Galley, G.; Pa¨tzel, M. Tetrahedron:
Asymmetry 1996, 7, 1137. (f) Galley, G.; J ones, P. G.; Pa¨tzel, M.
Tetrahedron: Asymmetry 1996, 7, 2073. (g) Annunziata, R.; Benaglia,
M.; Cinquini, M.; Cozzi, F.; Raimondi, L. Electronic Conference on
Heterocyclic Chemistry (ECHET96). CD-ROM included in J . Chem.
Soc., Chem. Commun. 1997, no 6. (h) Galley, G.; Pa¨tzel, M.; J ones, P.
G. Tetrahedron 1995, 51, 1631.
† Departament de Qu´ımica.
‡ Unitat de Cristal.lografia.
(1) (a) J ime´nez, J . M.; Rife´, J .; Ortun˜o, R. M. Tetrahedron: Asym-
metry 1996, 7, 537. (b) J ime´nez, J . M.; Ortun˜o, R. M. Tetrahedron:
Asymmetry 1996, 7, 3203. (c) Mart´ın-Vila`, M.; Hanafi, N.; J ime´nez, J .
M.; Alvarez-Larena, A.; Piniella, J . F.; Branchadell, V.; Oliva, A.;
Ortun˜o, R. M. J . Org. Chem. 1998, 63, 3581.
(2) (a) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841. (b) Broeker, J .
L.; Hoffmann, R. W.; Houk, K. N. J . Am. Chem. Soc. 1991, 113, 5006.
(3) (a) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; J a¨ger,
V.; Schohe, R.; Fronczek, F. R. J . Am. Chem. Soc. 1984, 106, 3880. (b)
Houk, K. N.; Duh, H.-Y.; Wu, Y.-D.; Moses, S. R. J . Am. Chem. Soc.
1986, 108, 2754. (c) Raimondi, L.; Wu, Y.-D.; Brown, F. K.; Houk, K.
N. Tetrahedron Lett. 1992, 33, 4409.
(5) Haller, J .; Niwayama, S.; Duh, H.-Y.; Houk, K, N. J . Org. Chem.
1997, 62, 5728.
10.1021/jo991227j CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/31/1999

1,3-Dipolar Cycloadditions of Diazomethane
J . Org. Chem., Vol. 65, No. 2, 2000 389
Ch a r t 2
Ta ble 1. Syn /An ti Dia ster eom er ic Excess (% d e) in th e
methane to similar dipolarophiles, the sense of diaste-
reoselectivity is opposite to that predicted by Houk’s
model.1c,4g,h A similar result was found in the cycloaddi-
tions of nitrones to chiral allyl ethers, the stereoselec-
tivity being rationalized in these cases by means of the
so-called outside alkoxy model suggested by Raimondi.6
On the other hand, the predominant stereochemistry
observed in the cycloaddition of diazomethane to chiral
γ-amino-R,â-dehydro amino acid esters is not explained
by the 1,3-allylic strain, being necessary to consider the
transition states to rationalize the factors controlling the
diastereoselectivity.7
In this paper we present the results of our studies on
the 1,3-dipolar cycloaddition of diazomethane to several
Z/ E chiral olefins conjugated to a nitro, sulfone, ester,
or R-amino ester group, the double bond being di- or
trisubstituted and owning in all cases an alkoxy sub-
stituent at the allylic position. All these olefins have been
synthesized from D-glyceraldehyde as a source of chiral-
ity. In this work, we rationalize the influence on the
diastereoselection of factors such as the chirality of the
stereogenic center in the substrates, the Z/ E geometry
of the double bond, the nature of the conjugated substit-
uents, and the mono or di-substitution at the olefinic C1.
The experimental results have been rationalized by
theoretical calculations, allowing us to state the origin
of stereoselectivity involved in this kind of cycloadditions.
Ad d ition of Dia zom eth a n e to Olefin s 2-7
Z-olefin pyrazolines % dea E-olefin pyrazolines % dea
2
3
4
5
6
7
13
14
9
84
>95
96
86
100
2
3
4
5
6
8
13
14
10
12
82
>95
96
84
100
11
a
Determined by 250-MHz 1H NMR.
olefins Z- and E-2,8 and Wittig or Wittig-Horner con-
densations for the preparation of sulfones Z-9 and E-3,10
esters Z- and E-4,11 Z-12 and E-5,13 and amino esters Z-
and E-61a (Chart 1).
Cycloadditions of diazomethane to these substrates
were achieved in nearly quantitative yield, affording
∆1-pyrazolines 7-12 from 1,1-disubstituted olefins 2, 5,
and 6, and ∆2-pyrazolines 13 and 14 from 1-substituted
olefins 3 and 4, respectively (Chart 2. See therein the
structures for syn/anti isomers). It is noteworthy that syn
adducts were the major products in all cases indepedent
of Z/ E geometry, anti-adducts not being detected for
amino esters 6.1a Diastereomeric excesses were deter-
mined by NMR and are shown in Table 1. Sulfone 3, in
both Z and E isomeric forms, afforded the same syn-∆2-
pyrazoline 13. Similarly, Z- and E-esters 4 gave 14.1c
In earlier works, we assigned unambiguously syn
configuration to the major pyrazoline 14 obtained from
esters 41c and to the only pyrazoline syn-11 obtained from
amino ester Z-6,1a by means of X-ray analysis.14 Com-
pound 11 was an oily material which was derivatized to
solid thiocarbonate 27 according to the procedure shown
Resu lts a n d Discu ssion
1. Cycloa d d ition Rea ction s a n d Ster eoch em ica l
Assign m en ts. Olefins 2-6, as pure Z or E diastereo-
mers, were prepared according to methods described in
the bibliography. In all cases, D-glyceraldehyde 1 was the
chiral precursor bearing the chiral center (S configura-
tion) which must induce π-facial diastereoselection in the
addition of diazomethane. The methods used involve
nitroaldol reaction between 1 and nitroethane to give
(8) Galley, G.; Hu¨bner, J .; Anklam, S.; J ones, P. G.; Pa¨tzel, M.
Tetrahedron Lett. 1996, 37, 6307.
(9) Shahak, I.; Almog, J . Synthesis 1970, 145.
(10) Craig, D.; Ley, S. V.; Simptkins, N. S. J . Chem. Soc., Perkin
Trans. 1 1985, 1949.
(11) Mann, J .; Partlett, N. K.; Thomas, A. J . Chem. Res. (S) 1987,
369.
(12) Trost, B. M.; Reiffen, M.; Crimmin, M. J . Am. Chem. Soc. 1979,
101, 259.
(6) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi,
L. Eur. J . Org. Chem. 1998, 1823.
(7) Reetz, M. T.; Kayser, F.; Harms, K. Tetrahedron Lett. 1992, 33,
3453.
(13) Ibuka, T.; Akimoto, N.; Tanaka, M.; Nishii, S.; Yamamoto, Y.
J . Org. Chem. 1989, 54, 4055.
(14) J ime´nez, J . M.; Casas, R.; Ortun˜o, R. M. Tetrahedron Lett. 1994,
32, 5945.

390 J . Org. Chem., Vol. 65, No. 2, 2000
Muray et al.
Sch em e 1
F igu r e 1. Structures of cyclopropanes 21 and 22 and of
pyrazoline syn-9 as determined by X-ray structural analysis.
-8, -10, and -12 was carried out by irradiation with a
125-W medium-pressure mercury lamp of solutions con-
tained in Pyrex reactors and by using acetone or ben-
zophenone as sensitizers (Table 2). In the former cases,
acetone was also the solvent (entries 1 and 2). Yields were
rather low for the photolysis of syn-7 and syn-8 since
other unidentified photoproducts resulted, probably due
to the lability of the nitro group under the reaction
conditions. On the contrary, cyclopropanes syn-18-20
were obtained in good yields.
Hydrolysis of the acetonide in compounds syn-15, -16,
and -18 afforded diols which were nice solids for 21 and
22 (Scheme 1), so configurational assignment was fea-
sible by X-ray diffraction (Figure 1). It is noteworthy that
in the solid state, compound 21 adopts two conformations,
I and II, mainly resulting from different relative ar-
rangements of the two hydroxyl groups. The conformation
of diol 22 is similar to 21-I and 21-II but differs from
them in the disposition of the two hydroxyls. Unfortu-
nately, neither diol 23 nor thiocarbonyl derivative 26
were solids. Moreover, the carboxylic acid resulting from
saponification of 23 was a pasty solid with low melting
point. The stereochemistry was, therefore, assigned to
pyrazoline syn-10 and its derivatives by comparison with
the other compounds considered in this work or descibed
in the literature for similar substrates.4g
The stereochemistry of the only pyrazoline obtained
from ester E-6 had previously been assigned by us as
anti-12 through conversion into the corresponding cyclo-
propane followed by acid hydrolysis of the acetonide
(some drops of 5% HCl, rt, 9.5 h), to afford a diol which
cyclized to lactone 28a , [R]D +33 (Scheme 1). Careful
NMR analysis and NOE experiments conducted on this
rigid compound led us to assign anti-configuration to 28a
and, by extension, to pyrazoline 12 and cyclopropane 20.15
Once the present experimental work was concluded and
also considering the results of the theoretical calculations,
that predicted syn-configuration as the most favorable
one (vide infra), we decided to examine the procedure to
transform cyclopropane 20 into a lactone derivative.
Actually, compound 28 was obtained after 1.5 h of
stirring cyclopropane acetonide 20 with some drops of 5%
HCl in a methanolic solution at room temperature. The
diol intermediate was not detected in the reaction
in Scheme 1 through photolysis of the pyrazoline to afford
cyclopropane syn-19 (Chart 2). Hydrolysis of the ace-
tonide provided diol 24, which was easily converted into
27 by reaction with thiocarbonyldiimidazole (TCDI).14 We
have verified that the chirality of the pyrazoline stereo-
genic centers remains unaltered through the photolysis
process to afford cyclopropanes.15 Moreover, configuration
of the cyclopropane chiral centers was also confirmed by
correlation of the specific rotations and spectral data for
several products synthesized from syn-19 with those
previously described for known compounds. Syn-stereo-
chemistry was also predominant when the cycloaddition
was achieved on similar aminopentenoates in which the
amino group was protected as an acetamide or tert-butyl
carbamate.1a
In this work, pyrazoline syn-9 afforded nice crystals
whose stereochemical assignment could be fairly ac-
complished (Figure 1). In contrast, ∆2-pyrazoline 13 was
obtained as a solid unsuitable for single-crystal X-ray
analysis and was assigned to be the syn isomer by
analogy with ∆2-pyrazoline 14. In all other cases, syn-
stereochemistry was assigned through photochemical
decomposition of the ∆1-pyrazolines to give the corre-
sponding cyclopropanes. Photolysis of pyrazolines syn-7,
(15) J ime´nez, J . M.; Bourdelande, J . L.; Ortun˜o, J . M. Tetrahedron,
1997, 53, 3777.

1,3-Dipolar Cycloadditions of Diazomethane
J . Org. Chem., Vol. 65, No. 2, 2000 391
Ta ble 2. P h otolysis of ∆1-P yr a zolin es To Affor d Cyclop r op a n esa
entry
pyrazoline
solventb
acetone
photosensitizer (equiv)
time
4 h
6.5 h
1.5 h
cyclopropane
% yieldc
ref
1
2
3
4
5
6
7
syn-7
syn-8
syn-8
syn-10
syn-11
syn-11a
syn-12
syn-15
syn-16
syn-16
syn-18
syn-19
syn-19a
syn-20
52
46
37
this work
acetone
dichloromethane
dichloromethane
dichloromethane
dichloromethane
dichloromethane
benzophenone (0.1)
benzophenone (0.1)
benzophenone (0.1)
benzophenone (0.1)
benzophenone (0.1)
0.5 h
88
13 min
15 min
14 min
100
100
100
1a
1a
15
a
Irradiations were performed with a 125-W medium-pressure mercury lamp refrigerated by circulating methanol cooled at -35 °C.
The whole system was refrigerated by immersion into a dry ice-acetone bath. 0.02 M solutions were used in all cases. c Isolated yield.
b
mixture. Lactone 28 shows specific rotation [R]D -40 and
spectral data different from those obtained for 28a .
Moreover, selective proton irradiation of 28 gave NOE
enhancements consistent with the syn-configuration, as
depicted in Figure 2. Therefore, we must conclude that,
F igu r e 2. Relevant % NOE values for the stereochemical
assignment of lactone 28.
F igu r e 3. Optimized structures of olefins 2 and 6a . Selected
bond lengths in Å.
in our previous work, isomerization occurred when 20
adopts an orientation in which the C3-H bond is nearly
eclipsed with the C1-C2 double bond, in good agreement
with the results obtained by Gung et al.16 for several allyl
ethers. The values of the dihedral angles corresponding
to rotation around C2-C3 are shown in Figure 4.
was submitted to acid hydrolytic conditions for a long
period of time. Probably, isomerization takes place on the
diol intermediate since such a process had been observed
on closely related substrates.1a Furthermore, some epimer-
ization resulted when acetonide syn-19 was exposed to
acid for 5 days. A diastereomerically pure diol was
obtained, however, when syn-19 was treated with acid
for 4-4.5 h.1a
Syn-stereoselectivity is, therefore, predominant in all
cases independent of the substitution and the geometry
of the olefins considered. These results are in good
agreement with those described by Raimondi on the
cycloadditions of diazomethane to several γ-alkoxy-R,â-
unsaturated esters and diesters4g and allow us to extend
her earlier conclusions to other kinds of olefins.
2. Th eor etica l Ca lcu la tion s. Density functional cal-
culations were done to rationalize the π-facial diastereo-
selection in the attack of diazomethane to such chiral
olefins. Nitro compounds 2 and acetyl amino pentenoates
6a were chosen as representative systems to be studied.
Figure 3 presents the optimized geometries of Z and
E isomers of olefins 2 and 6a . In all cases we have
examined the different conformations arising from the
rotation around the C2-C3 bond, and for 6a we have also
considered different conformations of the ester and acetyl
amino groups. The structures presented in Figure 3
correspond to the most stable ones for each molecule.
Figure 3 shows that there are slight differences in the
value of the C1-C2 bond length. This bond is longer in
6a than in 2. There are also differences between steroi-
somers: for 2, the C1-C2 bond is longer in the Z isomer,
whereas for 6a the E isomer presents a larger bond
length. These results seem to indicate that the dioxolane
group has a larger repulsion with the nitro and ester
groups than with the methyl and acetyl amino groups.
We can also observe that in all cases the dioxolane group
F igu r e 4. Values of the dihedral angles (in degrees) corre-
sponding to the rotation around the C2-C3 bond for the
equilibrium geometries of olefins 2 and 6a .
We have studied the attack of diazomethane on both
isomers of olefins 2 and 6a . In all cases, we have located
transition states leading to each one of the two possible
diastereoisomers, syn and anti. The corresponding tran-
sition state structures are represented in Figures 5 and
6. Table 3 presents the values of selected geometry
parameters for these transition states, and the computed
energy barriers are presented in Table 4.
Table 4 shows that in all cases the attack at the syn-
face is kinetically the most favorable, in excellent agree-
ment with the observed diastereoselectivity. The values
(16) Gung, B. J .; Melnick, J . P.; Wolf, M. A.; King, A J . Org. Chem.
1995, 60, 1947.

392 J . Org. Chem., Vol. 65, No. 2, 2000
Muray et al.
When diazomethane attacks the syn-face of a substi-
tuted olefin, there are two different ways to minimize
steric repulsion with the substituents: an counterclock-
wise rotation around the C2-C3 bond (see Figure 4) and
torsion around the C2-C5 axis. When the attack is
produced on the anti-face, the same kinds of rearrange-
ments are observed. For the transition states of Z-2,
torsion around C2-C5 moves the methylene group of
diazomethane away from dioxolane and brings the N3
atom of diazomethane closer to the nitro group. The
displacement from planarity is larger for the anti transi-
tion state, while the distortion corresponding to rotation
around C2-C3 is smaller. On the other hand, for the
transition states of E-2, torsion around C2-C5 brings the
N3 atom of diazomethane closer to the methyl group. The
torsion angles are smaller, indicating that the repulsion
with the methyl group is larger than with the nitro group.
Since the deviation from planarity is smaller, the distor-
tion corresponding to C2-C3 rotation is larger both for
syn and anti transition states (see Table 3 and Figure
5).
F igu r e 5. Structures of the transition states of the reactions
between 2 and diazomethane. The hydrogen atoms of dioxolane
methyl groups have been omitted for clarity.
For the reactions of 6a (Figure 6), torsion around C2-
C5 moves the N3 atom of diazomethane away from the
acetyl amino group. For Z-syn, this torsion brings the
CH2 group of diazomethane closer to the dioxolane ring,
so an important torsion around C2-C3 is produced to
minimize repulsion. For Z-anti, repulsion with dioxolane
is so large that torsion around C2-C5 is very small and
rotation around C3-C2 is very important. Both for E-syn
and E-anti, torsion around C2-C5 moves N3 away from
the acetyl amino group and the CH2 group of diazo-
methane away from dioxolane, so that rotation around
C2-C3 is less important.
The values of energy barriers presented in Table 4
show that in all cases the syn transition state is the
energetically most favorable one, in excellent agreement
with the experimental results. The energy barriers
obtained with the TZP basis set are slightly larger than
the ones corresponding to the 6-31G(d) basis set, due to
a decrease in the basis set superposition error.
To discuss the origin of the facial selectivity, we will
perform an energy partition for the potential energy
barriers. According to the method developed by Ziegler
and Rauk,18 the interaction energy between two frag-
ments, ∆E, can be decomposed into the following terms:
F igu r e 6. Structures of the transition states of the reactions
between 6a and diazomethane. The hydrogen atoms of diox-
olane methyl groups have been omitted for clarity.
of the âC dihedral angle at the syn transition states show
that the orientation of the dioxolane group in the olefin
moiety is very similar to the one corresponding to the
isolated molecules (see Figure 4). In this way, the syn-
face is less sterically hindered. On the other hand, anti
transition states can be related to the same conformation
of the isolated olefins.
∆E ) ∆Eprep + ∆Est + ∆Eorb
where ∆Eprep, the preparation energy term, is the energy
necessary to distort the fragments from their equilibrium
geometries to the ones they have at the transition state.
The second term, ∆Est, is called the steric energy term
and represents the interaction energy between both
fragments with the geometries corresponding to the
transition state, but with the densities they would have
in the absence of the other fragment. Finally, ∆Eorb is
the orbital interaction term and represents the energy
stabilization produced when the densities of both frag-
ments are allowed to relax. The results of this analysis
are shown in Table 5.
The values of the distances corresponding to the two
forming bonds (C2-C5 and C1-N3) at the transition
states of the studied reactions can be compared with the
values obtained for the reaction between diazomethane
and ethylene (2.301 and 2.406 Å, respectively).17 We can
observe that the presence of the substituents in the olefin
leads to a larger asynchrony at the transition states. For
the transition state of the reaction between diazomethane
and ethylene it was observed that the five atoms directly
involved in the cycloaddition process were coplanar. This
is no longer the case for olefins 2 and 6a , for which
different degrees of deviation from planarity are observed
from the values of the âN dihedral angle (see Table 3).
The preparation and steric energy terms are always
larger for anti transition states than for the syn ones.
(18) (a) Ziegler, T.; Rauk, A. Theor. Chim. Acta 1977, 46, 1. (b)
Ziegler, T.; Rauk, A. Inorg. Chem. 1979, 18, 1558. (c) Ziegler, T.; Rauk,
A. Inorg. Chem. 1979, 18, 1755.
(17) Branchadell, V.; Muray, E.; Oliva, A.; Ortun˜o, R. M.; Rodr´ıguez-
Garc´ıa, C. J . Phys. Chem. A 1998, 102, 10106.

1,3-Dipolar Cycloadditions of Diazomethane
J . Org. Chem., Vol. 65, No. 2, 2000 393
Ta ble 3. Selected Geom etr y P a r a m eter sa for th e Tr a n sition Sta tes of th e Rea ction s of Olefin s 2 a n d 6a w ith
Dia zom eth a n e
c
d
olefin
isomer
TSb
C2-C5
C1-N3
C1-C2
C5-N2
N2-N3
C5-N2-N3
âC
âN
2
Z
syn
anti
syn
anti
syn
anti
syn
2.171
2.155
2.173
2.176
2.180
2.120
2.147
2.154
2.629
2.679
2.636
2.691
2.778
2.730
2.837
2.849
1.400
1.401
1.395
1.394
1.397
1.406
1.402
1.401
1.344
1.343
1.341
1.339
1.336
1.346
1.339
1.338
1.159
1.159
1.158
1.158
1.158
1.162
1.162
1.162
150.7
151.4
151.4
152.8
154.0
150.0
153.0
153.8
70.3
78.0
80.9
68.3
75.9
62.0
75.4
79.5
8.4
-15.9
3.3
-7.2
-19.0
2.4
E
Z
E
6a
25.1
-23.4
anti
a
b
d
Bond distances in Å and angles in degrees. See Figures 5 and 6. c C4-C3-C2-C1 dihedral angle. N2-C5-C2-C1 dihedral angle.
Ta ble 4. P oten tia l En er gy Ba r r ier sa for th e Rea ction s of
Olefin s 2 a n d 6a w ith Dia zom eth a n e Com p u ted w ith
inside. On the other hand, according to Raimondi and to
the inside alkoxy model formulated by Houk,3 the pres-
Differ en t Ba sis Sets
ence of the oxygen in the anti-position would not be
olefin
isomer
TSb
6-31G(d)
TZP
favored since electron density from the C-C π orbital
would be transferred to the C-O σ* bond. The examina-
tion of the frontier orbitals of diazomethane and of olefins
2 and 6a shows that the most favorable interaction is
the one involving the HOMO of diazomethane and the
LUMO of the olefin (see Chart 3). Thus, there is a charge
2
Z
syn
anti
syn
anti
syn
anti
syn
10.2
10.9
8.7
11.6
7.9
13.3
8.1
10.3
13.0
14.4
11.6
14.3
11.1
17.4
11.5
14.1
E
Z
E
6a
Ch a r t 3
anti
a
b
In kcal mol-1
.
See Figures 5 and 6.
Steric hindrance is larger when diazomethane ap-
proaches the anti-face. This repulsion can be relieved
through geometry distortion of both fragments. The
orbital interaction term is very similar for both transition
states in E-2 and E-6a . For Z-2, it is more stabilizing for
the anti transition state. In this case, the value of the
C2-C5 distance is shorter than for the syn transition
state (see Table 3). The same kind of behavior is observed
for Z-6a , where syn-anti differences in all contributions
to the barrier are notably large. In this system, the anti
transition state is clearly closer to the products in the
reaction coordinate (see the values of C2-C5 and C1-
N3 in Table 3) and both fragments are more distorted.
As we have already said, torsion around C2-C5 is very
unfavorable in this case, so the relief of steric repulsion
can only be achieved through larger distortion of the
fragments and by a transition state in which the degree
of bond formation is higher.
Steric repulsion due to the dioxolane group plays a
major role in the facial selectivity of the studied reactions.
The most favorable transition states always involve
attack to the less sterically hindered syn-face of the olefin.
It may seem surprising that anti transition states can
be also related to the same conformation of the olefin.
Rotation around the C2-C3 bond would lead to a
conformation in which the oxygen atom linked to C3 is
antiperiplanar with respect to the incoming diazomethane
molecule, and then the anti-face would be less sterically
hindered. In fact, for the anti attack to E-2, we have
located a stationary point on the potential energy surface
with such an orientation of dioxolane, but this structure
is 0.5 kcal mol-1 higher in energy than the E-anti
transition state presented in Figure 5.
transfer from diazomethane to the olefin. The values of
charge transfer at the transition states determined from
Mulliken population analysis range from 0.17 to 0.22 au,
being slightly larger for the reactions of 2 than for the
reactions of 6a . A conformation in which electrons are
withdrawn from the C-C π region would favor interac-
tion with diazomethane, but this do not seem to be the
case.
We have done model calculations on two different
conformations of E-2 that differ from each other in the
orientation of the dioxolane group. For these structures,
we have calculated the interaction energy with an
ammonia molecule placed at 2 Å from C2 in the same
direction in which the carbon atom of diazomethane
approaches at the anti transition state. The interaction
is more favorable when the olefin has the same confor-
mation as in the E-anti transition state shown in Figure
5. We have also done a similar calculation substituting
ammonia by a pyramidally distorted BH3 molecule. In
this case, the preferred conformation is the one in which
O is in the anti-position. These results seem to show that
the interaction of an electron donor is not favorable when
there is an oxygen atom in the anti-position.
The HOMO of olefins 2 and 6b is an orbital with a
large contribution from the p orbitals of dioxolane oxygen
atoms perpendicular to the ring. When oxygen is in the
anti-position, some kind of interaction with the C-C π*
orbital seems possible, thus interfering with the charge
transfer from diazomethane (see Chart 4).
According to the outside alkoxy model defined by
Raimondi,4g the presence of oxygen in the outside position
(see Figure 7) at the transition state is favored due to
the electrostatic interaction with the positively charged
carbon atom of diazomethane. This interpretation would
be consistent with our results, which show that in the
formation of the preferred diastereoisomer, the oxygen
is always in the outside position and the hydrogen is
Con clu d in g Rem a r k s
As a conclusion of our investigations, the stereochem-
ical outcome of the diazomethane cycloadditions to chiral

394 J . Org. Chem., Vol. 65, No. 2, 2000
Muray et al.
Ta ble 5. P a r tition of th e En er gy Ba r r ier sa for th e Rea ction s of Olefin s 2 a n d 6a w ith Dia zom eth a n e
olefin
isomer
TSb
∆Eprep
∆Est
∆Eorb
∆E
2
Z
syn
anti
syn
anti
syn
anti
syn
18.5 (0.0)
19.4 (+0.9)
17.4 (0.0)
19.3 (+1.9)
15.3 (0.0)
21.9 (+6.6)
15.1 (0.0)
16.9 (+1.8)
36.1 (0.0)
38.9 (+2.8)
35.6 (0.0)
36.2 (+0.6)
35.0 (0.0)
42.0 (+7.0)
38.0 (0.0)
39.0 (+1.0)
-41.6 (0.0)
-43.9 (-2.3)
-41.4 (0.0)
-41.2 (+0.2)
-39.2 (0.0)
-46.5 (-7.3)
-41.6 (0.0)
-41.8 (-0.2)
13.0 (0.0)
14.4 (+1.4)
11.6 (0.0)
14.3 (+2.7)
11.1 (0.0)
17.4 (+6.3)
11.5 (0.0)
14.1 (+2.6)
E
Z
E
6a
anti
a
Energies computed with the TZP basis set in kcal mol-1. See the text for definitions. In parentheses are values relative to the syn
b
transition state. See Figures 5 and 6.
prepared according to protocols described in the literature,
their sectroscopic data and physical constants being in good
agreement with those previously reported for such products.
Com p u ta tion a l Deta ils. All calculations have been done
using density functional (DFT) methods within the generalized
gradient approximation (GGA). Molecular geometries have
been fully optimized using Becke’s19 functional for exchange
and the correlation functional due to Perdew and Wang20
(BPW91). This functional has been shown to yield excellent
results for the addition of diazomethane to ethylene.17 Molec-
ular geometries have been fully optimized at this level of
calculation using the standard 6-31G(d) basis set.21 Stationary
points have been characterized as energy minima or transition
states through the calculations of the energy second deriva-
tives. These calculations have been done with the Gaussian
94 program.22 Single point calculation have been done for the
previously optimized geometries using an uncontracted Slater
type orbital (STO) triple-ú basis set supplemented with a set
of d polarization functions for C, N, and O, and with a set of
p functions for H (TZP).23 These calculations have been done
using the ADF program.24
F igu r e 7. Possible conformations of olefins 2 and 6a arising
from the rotation around the C2-C3 bond.
Ch a r t 4
Gen er a l P r oced u r e for th e Cycloa d d ition s of Dia zo-
m eth a n e to Olefin s 2, 3, 5, a n d 6. A typical experiment is
described for the synthesis of pyrazoline syn-7. An ethereal
solution of excess diazomethane was distilled onto Z-1 (307
mg, 1.6 mmol) in 10 mL of ether, at 0 °C. The light-protected
resultant solution was stirred at 0 °C for 1 h, then excess
diazomethane was destroyed by addition of CaCl2, and solvent
was removed. The residue was chromatographed on silica gel
(1:3 EtOAc-hexane) to afford pure syn-7, which was crystal-
lized from EtOAc-pentane. The new pyrazolines syn-8, anti-
8, syn-9, syn-10, and 13 and known syn-1215 were prepared in
a similar manner.
(3R,4R,4′S)-4-(2′,2′-Dim eth yl-1′,3′-d ioxol-4′-yl)-3-m eth -
yl-3-n itr o-1,2-p yr a zolin e, syn -7: yield, 280 mg (75%); crys-
tals, mp 93-95 °C (from EtOAc-pentane); [R]D +192.5 (c 0.8,
CHCl3); IR (KBr) 1557, 1382 cm-1; 250-MHz 1H NMR (CDCl3)
1.24 (s, 3H), 1.35 (s, 3H), 2.00 (s, 3H), 2.14 (ddd, J ) J ′ ) J ′′
) 8.0 Hz, 1H), 3.60 (dd, J ) 8.0 Hz, J ′ ) 5.1 Hz, 1H), 3.77 (m,
1H), 3.98 (dd, J ) 8.0 Hz, J ′ ) 5.8 Hz, 1H), 4.66 (dd, J )18.0
Hz, J ′ ) 8.0 Hz, 1H), 4.97 (dd, J ) 18.0 Hz, J ′ ) 8.0 Hz, 1H);
62.5-MHz 13C NMR (CDCl3) 22.63, 24.92, 26.57, 46.06, 67.83,
γ-alkoxy olefins, bearing different electron-withdrawing
substituents conjugated to the double bond, has been
established and rationalized.
Single-crystal X-ray structural analysis and NMR
experiments confirm syn diastereoselection to be pre-
ferred, independently of the Z/ E stereochemistry of the
substrate, the mono- or disubstitution at the olefinic C1
position, and the nature of the conjugated functional
groups.
Theoretical calculations allow us to state the main role
played by the dioxolane ring in the diastereoselection.
Thus, steric factors account mainly for the diazomethane
prefferential syn-attack to all studied olefins.
Therefore, as a general conclusion, the origin of the
π-facial diastereoselection in these cycloadditions is found
in the chirality of the dioxolane stereogenic center, as
the most relevant feature determining the stereochem-
istry of the resulting adducts.
(19) Becke, A. D. Phys. Rev. A 1988, 38, 3098.
(20) (a) Wang, Y.; Perdew, J . P. Phys. Rev. B 1991, 44, 13298. (b)
Perdew, J . P. Chevary, J . A.; Vosko, S. H., J ackson, K. A.; Pederson
M. R.; Singh, D. J .; Fiolhais, C. Phys. Rev. B 1992, 46, 6671.
(21) Hehre, W. J .; Radom, L.; Schleyer, P. v. R.; Pople, J . A. Ab Initio
Molecular Orbital Theory; Wiley: New York: 1986.
(22) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T. A.; 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.; Andre´s, J . L.; Replogle, E. S.; Gomperts,
R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.; Defrees, D. J .; Baker, J .;
Stewart, J . J . P.; Head-Gordon, M.; Gonzalez, C.; Pople, J . A. Gaussian
94, Revision B.3; Gaussian Inc.: Pittsburgh, PA, 1995.
(23) Vernooijs, P.; Snijders, G. J .; Baerends, E. J . Slater Type Basis
Functions for the whole Periodic System; Internal Report, Freie
Universiteit Amsterdam, The Netherlands, 1981.
(24) (a) ADF 2.3, Theoretical Chemistry, Vrije Universiteit, Am-
sterdam. (b) Baerends, E. J .; Ellis, D. E.; Ros, P. Chem. Phys. 1973, 2,
41. (c) Velde, G.; Baerends, E. J . J . Comput. Phys. 1992, 99, 84.
Exp er im en ta l Section
Flash column chromatography was carried out on silica gel
(240-400 mesh). Melting points were determined on a hot
stage and are uncorrected. Distillation of small amounts of
material was effected in a bulb-to-bulb distillation apparatus,
with oven temperatures (ot) being reported. Electron impact
mass spectra were recorded at 70 eV. Chemical shifts in NMR
spectra are given on the δ scale.
Olefins Z- and E-2,8 Z-9 and E-3,10 Z- and E-4,11 Z-12 and
E-5,13 and E-6,1a and compounds syn-12, and syn-2015 were

1,3-Dipolar Cycloadditions of Diazomethane
J . Org. Chem., Vol. 65, No. 2, 2000 395
74.00, 80.79, 109.41, 119.52. Anal. Calcd for C9H15N3O4: C,
47.16; H, 6.59; N, 18.33. Found C, 47.49; H, 6.68; N, 18.89.
(3S,4R,4′S)-4-(2′,2′-Dim eth yl-1′,3′-d ioxol-4′-yl)-3-m eh yl-
3-n itr o-1,2-p yr a zolin e, syn -8: yield, 600 mg (76%); crystals,
mp 50-53 °C (from EtOAc-pentane); [R]D -448.0 (c 0.86,
CHCl3); IR (KBr) 1539, 1380 cm-1; 250-MHz 1H NMR (CDCl3)
1.27 (s, 3H), 1.35 (s, 3H), 2.01 (s, 3H), 2.64 (ddd, J ) 6.8 Hz,
J ′ ) 3.5 Hz, 1H), 3.52 (dd, J ) 8.4 Hz, J ′ ) 6.6 Hz, 1H), 4.10
(dd, J ) 8.4 Hz, J ′ ) 6.6 Hz, 1H), 4.22 (ddd, J ) J ′ ) 6.6 Hz,
J ′′ ) 3.5 Hz, 1H), 4.83 (d, J ) 6.8 Hz, 2H); 62.5-MHz 13C NMR
(CDCl3) 17.39, 24.80, 26.02, 42.82, 68.10, 72.18, 78.66, 110.13,
123.30. Anal. Calcd for C9H15N3O4: C, 47.16; H, 6.59; N, 18.33.
Found C, 46.83; H, 6.72; N, 18.18.
68.82, 74.59, 109.24; HRMS (EI) m/z calcd for C8H12NO4
186.0766 (M - 15), found 186.0768 (M - 15).
(1R,2R,4′S)-2-(2′,2′-Dim eth yl-1′,3′-d ioxol-4′-yl)-1-m eth -
yl-1-n itr ocyclop r op a n e, syn -16: yield, 97 mg (46%); oil, ot
60 °C (0.1 Torr); [R]D -87.7 (c 1.75, CHCl3); IR (film) 1539,
1
1356 cm-1; 250 MHz H NMR (CDCl3) 1.22 (dd, J ) 7.7 Hz, J ′
) 5.5 Hz, 1H), 1.31 (s, 3H), 1.38 (s, 3H), 1.73 (s, 3H), 2.00 (dd,
J ) 7.7 Hz, J ′ ) 5.5 Hz, 1H), 2.17 (m, 1H), 3.70 (dd, J ) 8.4
Hz, J ′ ) 6.5 Hz, 1H), 3.92 (ddd, J ) J ′ ) J ′′ )6.5 Hz, 1H),
4.12 (dd, J ) 8.4 Hz, J ′ ) 6.5 Hz, 1H); 62.5-MHz 13C NMR
(CDCl3) 14.93, 21.28, 25.68, 26.35, 31.76, 63.05, 69.29, 73.47,
109.74. Anal. Calcd for C9H15NO4: C, 53.72; H, 7.51; N, 6.96.
Found C, 53.57; H, 7.44; N, 6.97.
(3R,4S,4′S)-4-(2′,2′-Dim eth yl-1′,3′-d ioxol-4′-yl)-3-m eth yl-
3-n itr o-1,2-p yr a zolin e, a n ti 8: yield, 40 mg (5%); crystals,
mp 94-95 °C (from EtOAc-pentane); [R]D +363.1 (c 1.26,
CHCl3); IR (KBr) 1558, 1378 cm-1; 250-MHz 1H NMR (CDCl3)
1.29 (s, 3H), 1.31 (s, 3H), 1.85 (s, 3H), 2.92 (ddd, J ) J ′ ) J ′′
) 8.8 Hz, 1H), 3.56 (dd, J ) 8.0 Hz, J ′ ) 5.1 Hz, 1H), 3.03 (m,
3H), 4.92 (dd, J ) 17.6, J ′ ) 8.8 Hz, 1H); 62.5-MHz 13C NMR
(CDCl3) 15.97, 25.24, 26.42, 45.12, 68.15, 73.74, 77.97, 110.26,
124.03. Anal. Calcd for C9H15N3O4: C, 47.16; H, 6.59; N, 18.33.
Found C, 47.04; H, 6.64; N, 18.25.
Eth yl (1R,2R,4′S)-1-m eth yl-2-(2′,2′-d im eth yl-1′,3′-d iox-
ola n -4′-yl)cyclop r op a n e ca r boxyla te, syn -18: yield, 200 mg
(88%); oil, ot 60 °C (0.01 Torr); [R]D -41.5 (c 2.14, CHCl3); IR
1
(film) 1722 cm-1; 250-MHz H NMR (CDCl3) 0.78 (dd, J ) 6.6
Hz, J ) 4.4 Hz, 1H), 1.19 (t, J ) 6.6, 3H), 1.26 (s, 3H), 1.32 (s,
3H), 1.40 (s, 3H), 1.44 (m, 1H), 1.57 (m, 1H), 3.64 (t, J ) 7.3
Hz, 1H), 3.75 (q, J ) 7.3 Hz, 1H), 4.05 (m, 3H); 62.5-MHz 13C
NMR (CDCl3) 14.09, 14.54, 20.80, 21.97, 25.77, 26.63, 28.37,
60.73, 69.43, 76.25, 109.02, 174.95. Anal. Calcd for C12H20O4:
C, 63.14; H, 8.83. Found C, 62.98; H, 8.93.
(3R,4R,4′S)-4-(2′,2′-Dim eth yl-1′,3′-d ioxol-4′-yl)-3-eth oxy-
ca r bon yl-3-m eth yl-1,2-p yr a zolin e, syn -9: yield, 266 mg
(90%); crystals, mp 49-51 °C (from EtOAc-pentane); [R]D
+132.3 (c 0.94, CHCl3); IR (KBr) 1722 cm-1; 250-MHz 1H NMR
(CDCl3) 1.23 (t, J ) 7.3 Hz, 3H), 1.24 (s, 3H), 1.32, (s, 3H),
1.61 (s, 3H), 1.90 (q, J ) 8.4 Hz, 1H), 3.52 (m, 1H), 3.93 (m,
2H), 4.15 (m, 2H), 4.44 (dd, J ) 18.0 Hz, J ′ ) 8.4 Hz, 1H),
4.81 (dd, 2H, J ) 18.0 Hz, J ′ ) 0.4 Hz, 1H); 62.5-MHz 13C
NMR (CDCl3) 13.94, 22.53, 25.18, 26.53, 47.03, 61.79, 68.27,
74.50, 79.18, 92.53, 109.03, 169.00. Anal. Calcd for
Hyd r olysis of Aceton id es syn -15, syn -16, syn -18, a n d
syn -20. A methanolic solution of acetonide containing some
drops of aqueous 5% HCl was stirred at room temperature for
4-5 h in the case of syn-15, syn-16, syn-18 and 1.5 h in the
case of syn-20, until consumption of the starting material (TLC
monitoring). Solvent was removed at reduced pressure and the
crude product was purified by column chromatography on
silica gel (EtOAc-hexane mixtures). Diols 21, 22, and 23 and
hydroxy lactone 28 were thus obtained.
(1S,2R,1′S)-1-Meth yl-1-n itr o-2-(1′,2′-d ih yd r oxyeth yl)cy-
clop r op a n e, 21: yield, 70 mg (95%); crystals, mp 43-45 °C
(from EtOAc-pentane); [R]D +19.1 (c 0.31, CHCl3); IR (KBr)
3700-3050 (broad), 1533, 1391 cm-1; 250-MHz 1H NMR
(CDCl3) 1.29 (dd, J ) 9.5 Hz, J ′ ) 6.3 Hz, 1H), 1.49 (ddt, J )
J ′ ) 9.5 Hz, J ′′) 1.5 Hz, 1H), 1.75 (s, 3H), 2.16 (t, J ) 6.3 Hz,
1H), 3.55 (m, 3H), 2.3 and 2.7 (broad, OH); 62.5-MHz 13C NMR
(CDCl3) 20.31, 21.03, 32.09, 65.74, 65.86, 69.79. Anal. Calcd
for C6H11NO4: C, 44.72; H, 6.83; N, 8.70. Found C, 44.73; H,
7.00; N, 8.65.
(1R,2R,1′S)-1-Met h yl-1-n it r o-2-(1′,2′-d ih yd r oxyet h yl)-
cyclop r op a n e, 22: yield, 67 mg (84%); crystals, mp 64-66
°C (from EtOAc-pentane); [R]D -52.9 (c 1.16, MeOH); IR (KBr)
3332, 1532, 1363 cm-1; 250-MHz 1H NMR (MeOH-d4) 1.22 (dd,
J ) 10.0 Hz, J ′ ) 5.9 Hz, 1H), 1.77 (s, 3H), 1.93 (dd, J ) 10.0
Hz, J ′ ) 5.1 Hz, 1H), 2.18 (m, 1H), 3.45 (m, 1H), 3.57 (d, J )
5.1 Hz, 2H); 62.5-MHz 13C NMR (MeOH-d4) 16.33, 23.04, 34.32,
65.79, 67.86, 72.11. Anal. Calcd for C6H11NO4: C, 44.72; H,
6.83; N, 8.70. Found C, 44.60; H, 6.66; N, 8.47.
(1R,2R,1′S)-1-E t h oxyca r b on yl-1-m et h yl-2-(1′,2′-d ih y-
d r oxyeth yl)cyclop r op a n e, 23: yield, 160 mg (94%); oil
unsuitable for [R]D determination and for micronalysis; IR
(film) 3395 (broad), 1715 cm-1; 250-MHz 1H NMR (CDCl3) 0.72
(dd, J ) 6.6 Hz, J ′ ) 3.7 Hz, 1H),1.19 (t, J ) 7.0 Hz, 3H), 1.26
(s, 3H), 1.35 (dd, J ) 9.5 Hz, J ′ ) 3.7 Hz, 1H), 1.49 (m, 1H),
3.33-3.64 (complex absorption, 5H), 4.04 (q, J ) 7.0 Hz, 2H);
62.6-MHz 13C NMR (CDCl3) 14.03, 14.30, 20.06, 22.53, 27.94,
60.85, 66.56, 71.94, 175.35; MS, m/z (%) 189 (M + 1, 1), 157
(16), 143 (22), 111 (100), 83 (96), 55 (47).
C
12H20N2O4: C, 56.23; H, 7.87; N, 10.93. Found C, 56.36; H,
7.67; N, 11.06.
(3S,R,4′S)-4-(2′,2′-Dim eth yl-1′,3′-d ioxol-4′-yl)-3-eth oxy-
ca r bon yl-3-m eth yl-1,2-p yr a zolin e, syn -10: yield, 340 mg
(71%); oil; IR (film) 1736 cm-1; 250-MHz 1H NMR (CDCl3) 1.27
(t, J ) 7.3 Hz, 3H), 1.29 (s, 3H), 1.36 (s, 3H), 1.56 (s, 3H), 2.41
(m, 1H), 3.52 (m, 1H), 4.06 (m, 2H), 4.21 (q, J ) 7.3), 4.65 (m,
2H); 62.5-MHz 13C NMR (CDCl3) 13.96, 16.12, 25.15, 26.33,
41.24, 62.00, 68.44, 73.74, 78.47, 93.94, 109.35, 170.88. Anal.
Calcd for C12H20N2O4: C, 56.23; H, 7.87; N, 10.93. Found C,
56.18; H, 7.93; N, 11.25.
(4R,4′S)-4-(2′,2′-Dim et h yl-1′,3′-d ioxola n -4′-yl)-3-(p h e-
n ylsu lfon yl)-4,5-d ih yd r o-1H-p yr a zole, 13: yield, (a) from
Z-3, 486 mg (70%); (b) from E-3, 564 mg (75%); solid, mp 150-
152 °C (dec); [R]D +22.9 (c 0.88, CHCl3); IR (KBr) 3360, 1532,
1145 cm-1; 250-MHz 1H NMR (CDCl3) 1.23 (s, 3H), 1.34 (s,
3H), 3.55 (m, 1H), 3.77 (m, 3H), 4.14 (dd, J ) 8.8 Hz, J ′ ) 6.5
Hz, 1H), 4.46 (dt, J ) 12.0 Hz, J ′ ) 6.5 Hz, 1H), 7.57 (m, 3H),
7.95 (m, 2H); 62.5-MHz 13C NMR 24.94, 26.39, 48.18, 51.77,
68.41, 73.47, 109.32, 128.29, 129.03, 133.70, 139.61, 150.11.
Anal. Calcd for C14H18N2O4S: C, 54.18; H, 5.84; N, 9.03; S,
10.33. Found C, 54.33; H, 5.71; N, 8.89; S, 10.20.
Gen er a l P r oced u r e for th e P h otolysis of P yr a zolin es
syn -7, syn -8, syn -10, syn -12, a n d 13. In a typical experiment,
a 0.02 M solution of pyrazoline contained in a Pyrex reactor
under nitrogen atmosphere was irradiated with a 125 W
medium-pressure mercury lamp refrigerated by circulating
methanol cooled at -35 °C. The whole system was cooled by
immersion into a dry ice-acetone bath. Solvent, photosensi-
tizer, and reaction time for each case is shown in Table 1. The
reaction progress was monitored by UV (λmax ) 323-328 nm
for syn-7, syn-8, and syn-10, and 410 nm for syn-12). When
total conversion was accomplished, solvent was removed and
the residue was chromatographed (EtOAc-hexane mixtures)
to afford the new cyclopropanes syn-15, syn-16, and syn-18 and
the already known syn-20.15
(1R ,4S ,5R )-1-(N -B e n z y lo x y c a r b o n y la m in o )-4-h y -
d r oxym eth yl-3-oxa bicyclo[3.1.0]h exa n -2-on e, 28: yield, 87
mg (80%); oil; [R]D -40.1 (c 0.76, CHCl3); IR (film) 3100-3690
1
(broad), 1778, 1715 cm-1; 400-MHz H NMR (DMSO-d6) 1.31
(dd, J ) 8.0, J ′ ) 5.2, 1H); 1.37 (dd, J ) 5.9, J ′ ) 5.9, 1H);
2.27 (m, 1H), 3.14 (broad s, 1H), 3.47 (m, 1H), 4.57 (m, 1H),
4.92 (m, 1H), 5.02 (s, 2H), 7.33 (m, 5H); 13C NMR (acetone-d6)
15.10, 26.09, 39.30, 62.44, 67.06, 78.77, 128.68, 129.15, 137.56,
157.32, 174.41.
Eth yl (1R,2R,4′S)-1-Meth yl-2-(1′,3′-d ioxola n -2′-th ioxo-
4′-yl)cyclop r op a n e ca r boxyla te, 26. A mixture of diol 23
(160 mg, 0.8 mmol) and N′,N′-thiocarbonyldiimidazole (336 mg,
1.7 mmol) in anhydrous THF was heated at 60 °C for 7.5 h,
under nitrogen atmosphere. Solvent was removed at reduced
(1S,2R,4′S)-2-(2′,2′-Dim eth yl-1′,3′-d ioxol-4′-yl)-1-m eth yl-
1-n itr ocyclop r op a n e, syn -15: yield, 106 mg (52%); oil [R]D
1
+20.1 (c 0.82, CHCl3); IR (film) 1536, 1362 cm-1; 250-MHz H
NMR (CDCl3) 1.35 (m, 2H), 1.30 (s, 3H), 1.42 (s, 3H), 1.73 (s,
3H), 2.12 (t, J ) 7.3 Hz, 1H), 3.61 (m, 1H), 3.95 (m, 2H); 62.5-
MHz 13C NMR (CDCl3) 21.14, 21.19, 25.33, 26.79, 32.61, 65.00,

396 J . Org. Chem., Vol. 65, No. 2, 2000
Muray et al.
pressure and the residue was chromatographed on silica gel
(2:1 EtOAc-hexane as eluent) to give pure 26 (106 mg, 55%
yield) as a pale-yellow oil (ot 190 °C, 0.01 Torr): [R]D -70.6 (c
Ack n ow led gm en t. E.M. thanks the Ministerio de
Educacio´n for a predoctoral fellowship. Financial sup-
port from DGESIC through the project PB97-0214 is
gratefully acknowledged.
1
1.18, CHCl3); IR (film) 1715 cm-1; 250-MHz H NMR (CDCl3)
0.94 (dd, J ) 6.0 Hz, 1H),1.22 (t, J ) 7.3 Hz, 3H), 1.32 (s, 3H),
1.58 (dd, J ) 8.8 Hz, J ′ ) 6.0 Hz, 1H), 1.82 (m, 1H), 4.10 (q,
J ) 7.3 Hz, 2H),4.41 (t, J ) 8.0 Hz, 1H) 4.64 (q, J ) 8.0 Hz,
1H), 4.75 (t, J ) 8.0 Hz, 1H); 62.5-MHz 13C NMR (CDCl3)
14.06, 14.51, 20.62, 22.83, 27.15, 61.32, 73.56, 82.38, 173.55,
191.31. Anal. Calcd for C10H14O4S: C, 52.16; H, 6.13; S, 13.92.
Found C, 52.27; H, 6.11; S, 14.17.
Su p p or tin g In for m a tion Ava ila ble: Crystal data, refine-
ment details, atomic coordinates, thermal parameters, dis-
tances, and angles for structures syn-9, 21, and 22. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O991227J