Michael addition of chloroalkyloxazolines to electron-poor alkenes: Synthesis of heterosubstituted cyclopropanes

Article abstract of DOI:10.1021/jo026661r

Lithiated 2-(1-chloroethyl)-4,4-dimethyl-2-oxazoline 7 adds to electron-poor alkenyl heterocycles to afford substituted cyclopropanes in excellent yields. A route to chiral nonracemic heterosubstituted cyclopropanes, starting from optically active 2-chloromethyl-2-oxazolines, is highlighted as well.

Full text of DOI:10.1021/jo026661r

Mich a el Ad d ition of Ch lor oa lk yloxa zolin es to Electr on -P oor
Alk en es: Syn th esis of Heter osu bstitu ted Cyclop r op a n es†
Maria Teresa Rocchetti, Vincenzo Fino, Vito Capriati, Saverio Florio,* and Renzo Luisi
Dipartimento Farmaco-Chimico, Universita` di Bari, Via E. Orabona 4, I-70125 Bari, Italy,
CNR, Istituto di Chimica dei Composti Organo Metallici “ICCOM”, Sezione di Bari
florio@farmchim.uniba.it
Received November 5, 2002
Lithiated 2-(1-chloroethyl)-4,4-dimethyl-2-oxazoline 7 adds to electron-poor alkenyl heterocycles
to afford substituted cyclopropanes in excellent yields. A route to chiral nonracemic heterosubstituted
cyclopropanes, starting from optically active 2-chloromethyl-2-oxazolines, is highlighted as well.
In tr od u ction
Recent papers from our1 and other research labs2,3 have
disclosed that certain metalated haloalkyl heterocycles,
which proved to be good Darzens reagents and add to
carbonyl compounds and imines to produce substituted
oxiranes and aziridines4 and to nitrones to give alkenyl
heterocycles,5 in the absence of external electrophiles
tend to undergo a sort of “trimerization”, giving cyclo-
propane derivatives. Such a remarkable propensity turned
out to be very much dependent upon the R-substitution
and the size and the nature of the heterocyclic sys-
tem, so that metalated 2-(chloromethyl)-2-oxazolines do
undergo cyclopropanation, while 2-(1-chloroethyl)-2-
oxazoline,1 2-(chloromethyl)-5,6-dihydro-4H-[1,3]oxazine,1
2-(chloromethyl)pyridine,2 and 2-(chloromethyl)triazine3
do not or do in small percentages, undergoing mostly
the “dimerization” reaction to give diheterosubsti-
tuted alkenes (Scheme 1). This has been rationalized in
terms of a diverse electrophilicity of the corresponding
alkenes that could be ascribed to the different endocyclic
nature of the C-N double bond of the involved hetero-
cyclic ring.1
F IGURE 1.
poor alkenyl heterocycles. Our concern for heterosubsti-
tuted cyclopropanes is justified by the occurrence that
chiral bisoxazolines and trisoxazolines have been suc-
cessfully used in several catalytic asymmetric processes
as bidentate and tridentate chiral ligands.6 Moreover, it
is well-known that the cyclopropyl moiety plays an
important role in many natural and nonnatural prod-
ucts.7 Despite this, while a number of methods exist for
stereoselective preparation of disubstituted cyclo-
propanes, synthetic procedures to trisubstituted cyclo-
propane derivatives are rather limited.8,9
(6) Zhou, J .; Tang, Y. J . Am. Chem. Soc. 2002, 31, 9030-9031.
(7) For examples of well-known cyclopropyl derivatives, see: Lin,
H. W.; Walsh, C. T. In The Chemistry of the Cyclopropyl Group; Patai,
S., Rappoport, Z., Eds.; Wiley: New York, 1987; Vol. 16. Martel, J . In
Chirality in Industry; Collins, A. N., Sheldrake, N. G., Crosby, J ., Eds.;
Wiley: Chichester, U.K., 1992; Chapter 4 and references therein.
Barrett, A. G. M.; Kasdorf, J . J . Am. Chem. Soc. 1996, 118, 11030-
11037 and references therein. Charette, A. B.; Lebel, H. J . Am. Chem.
Soc. 1996, 118, 10327-10328 and references therein.
(8) For examples of direct carbene insertion into olefins from diazo
precursors utilizing transition metals (stoichiometric and catalytic),
see: Pfaltz, A. In Comprehensive Asymmetric Catalysis I-III; Chapter
16.1, Lydon, K. M., McKervey, M. A., Eds.; Chapter 16.2, Charette, A.
B., Lebel, H., Eds.; Chapter 16.3, J acobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer-Verlag: Berlin, Heildelberg, New York, 2000.
(9) For examples of Michael addition of nucleophiles to R,â-unsatu-
rated ketones and esters followed by intramolecular cyclization, see:
Salaun, J . Chem. Rev. 1989, 89, 1247-1270. Li, A.-H.; Dai, L.-X.;
Aggarwal, V. K. Chem. Rev. 1997, 97, 2341-2372 and references
therein. Krief, A.; Provins, L.; Froidbise, A. Tetrahedron Lett. 1998,
39, 1437-1440. For synthesis via cationic intermediates, see: Taylor,
R. E.; Engelhardt, F. C.; Schmitt, M. J .; Yuan, H. J . Am. Chem. Soc.
2001, 123, 2964-2969. Avery, T. D.; Taylor, D. K.; Tiekink, E. R. T. J .
Org. Chem. 2000, 65, 5531-5546. Avery, T. D.; Fallon, G.; Greatrex,
B. W.; Pyke, S. M.; Taylor, D. K.; Tiekink, E. R. T. J . Org. Chem. 2001,
66, 7955-7966. Kimber, M. C.; Taylor, D. K. J . Org. Chem. 2002, 67,
3142-3144 and references therein.
Resu lts a n d Discu ssion
In this paper we report the preparation of a number
of substituted cyclopropanes based on the Michael addi-
tion of lithiated 2-(1-chloroalkyl)oxazolines to electron-
* To whom correspondence should be addressed. Phone:
+39.080.5442749. Fax: +39.080.5442231.
† Dedicated to Prof. A. I. Meyers on the occasion of his 70th birthday.
(1) Capriati, V.; Florio, S.; Luisi, R.; Rocchetti, M. T. J . Org. Chem.
2002, 67, 759-763.
(2) (a) Breslow, R.; Crispino, G. A. Tetrahedron Lett. 1991, 32, 601-
604. (b) Crispino, G. A.; Breslow, R. J . Org. Chem. 1992, 57, 1849-
1855.
(3) Stephens, C. L.; Nyquist, H. L.; Hardcastle, K. I. J . Org. Chem.
2002, 67, 3051-3056.
(4) (a) Florio, S.; Capriati, V.; Luisi, R. Tetrahedron Lett. 1996, 37,
4781-4784. (b) Florio, S.; Troisi, L.; Capriati, V.; Coletta, G. Tetra-
hedron 1999, 35, 9859-9866. (c) Florio, S.; Troisi, L.; Capriati, V.;
Ingrosso, G. Tetrahedron Lett. 1999, 40, 6101-6104. (d) Florio, S.;
Capriati, V.; Luisi, R.; Abbotto, A.; Pippel, D. J . Tetrahedron 2001,
57, 6775-6786.
(5) (a) Capriati, V.; Degennaro, L.; Florio, S.; Luisi, R. Tetrahedron
Lett. 2001, 42, 9183-9186. (b) Capriati, V.; Degennaro, L.; Florio, S.;
Luisi, R. Eur. J . Org. Chem. 2002, 2961-2969.
10.1021/jo026661r CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/23/2003
1394
J . Org. Chem. 2003, 68, 1394-1400

Michael Addition of Chloroalkyloxazolines to Alkenes
SCHEME 1
SCHEME 2
TABLE 1. Syn th esis of Heter osu bstitu ted
Cyclop r op a n es 12a ,b a n d 13a ,b fr om Oxa zolin ylstyr en es
5a -d
The needed alkenes for the cyclopropanation reaction
under investigation were prepared as follows: trans-bis-
(2-pyridyl)ethene 1 and trans-bis(dihydrooxazinyl)ethene
2 (Figure 1) were prepared in almost quantitative yields
by treating 2-(chloromethyl)pyridine and 2-(chlorometh-
yl)dihydrooxazine with potassium bis(trimethylsilyl)-
amide, respectively; trans-bis(4-pyridyl)ethene 3 was
commercially available, while bis(2-oxazolinyl)ethene 41
and oxazolinylstyrenes 5a -d were prepared as reported.5
We first investigated the reaction of lithiated 2-(1-
chloroethyl)-4,4-dimethyl-2-oxazoline 7, which was gen-
erated by lithiation of 2-(1-chloroethyl)-4,4-dimethyl-2-
oxazoline (6) (LDA, THF, -98 °C), turned out to be quite
stable at least at low temperature, and could be examined
by NMR.10,11 The addition of 7 to the trans-bis(2-pyridyl)-
ethene 1 produced the trans-1-methyl-1-oxazolinyl-2,3-
bis(2-pyridyl)cyclopropane 8 in an excellent yield (Scheme
2).
entry
base
solvent
styrene yielda (%)
dr
1
2
3
4
5
6
7
8
9
LDA
LDA
LDA
LDA
KN(SiMe3)2
LDA
KN(SiMe3)2
KN(SiMe3)2
LDA
THF
THF
THF
THF
THF
Et2O
Et2O
THF/HMPA
toluene
5a
5b
5c
5d
5d
5d
5d
5d
5c
5c
12a /13a , 95 1:1b
12b/13b, 56 1:1b
12a /13a , 86 1:2b
12b/13b, 90 1:2b
12b/13b, 85 1:3b
12b/13b, 80 1:2b
12b/13b, 85 1:3c
12b/13b, 62 1:1.6c
10 LDA/Ti(O-i-Pr)4 THF
a
b
Isolated yields. Diastereomeric ratio calculated on isolated
products after column cromatography on silica gel. c Diastereo-
meric ratio calculated on the basis of 1H NMR spectra of the crude
reaction mixture.
The addition reaction was stereospecific: only the
stereoisomer setting the two pyridyl rings trans on the
cyclopropane ring was obtained. Equally stereospecific
was the addition of 7 to the trans-bis(4-pyridyl)ethene
3, affording the cyclopropane 9 in an almost quantitative
yield. Moreover, the addition of 7 to the trans-bis(di-
hydrooxazinyl)ethene 2 and to the trans-bis(2-oxazolinyl)-
ethene 4 afforded the cyclopropane 10 and tris(oxa-
zolinyl)cyclopropane 11, respectively, yet in a stereo-
specific way (Scheme 2).
The addition reaction of 7 to nonsymmetrical electron-
poor alkenes was then considered worth investigation,
and therefore, we decided to study the cyclopropanation
F IGURE 2.
reaction with cis- and trans-oxazolinylstyrenes 5a -d
(Figure 1). The reaction of lithiated 2-(1-chloroethyl)-
oxazoline 7 with cis-oxazolinylstyrene 5a in THF at -98
°C followed by warming to room temperature and quench-
ing with saturated aq NH4Cl furnished a 1:1 diastereo-
meric mixture of cyclopropanes 12a and 13a (Figure 2,
Table 1, entry 1). It is worth noting that the reaction is
stereospecific with reference to the geometry of the
starting alkene but there is no stereoselection as far as
the newly created stereogenic center. Comparable results
were obtained when 7 was added to the cis-oxazolinyl-
p-chlorostyrene 5b, affording cyclopropanes 12b and 13b
(10) Abbotto, A.; Bradamante, S.; Florio, S.; Capriati, V. J . Org.
Chem. 1997, 62, 8937-8940.
(11) That lithiated 2-(1-chloroethyl)-2-oxazoline 7 is stable, at least
at low temperature, so that it can be spectroscopically studied is well
established. It was found (see ref 10) that the effect of H/Li exchange
upon the 13C chemical shift of the 2-(1-chloroethyl)-2-oxazoline CR
carbon atom was that of a low 13C-deshielding (∆δ ) 12.73 ppm). This
result could be accounted for in terms of a low carbenoid character
(Boche, G.; Lohrenz, J . C. W. Chem. Rev. 2001, 101, 697-756)
associated with the above-mentioned Li/Cl carbenoid species (in
contrast to a higher one found in the case of the 2-chloromethyl-2-
oxazoline; see ref 1) that would justify its greater thermodynamic
stability and a less pronounced tendency toward an “eliminative
dimerization” process so typical of carbenoid species.
J . Org. Chem, Vol. 68, No. 4, 2003 1395

Rocchetti et al.
SCHEME 3
SCHEME 4
(Figure 2, Table 1, entry 2). An appreciable stereoselec-
tion could be observed in the reaction of 7 with trans-
oxazolinylstyrenes 5c and 5d : diastereomeric cyclo-
propanes 12a /13a and 12b/13b were smoothly obtained
in a 1:2 stereoisomeric ratio (Table 1, entries 3 and 4).
Diastereomers 12a and 13a (as well as 12b and 13b )
could be easily separated by column chromatography on
silica gel. Relative configurations to all cyclopropanes
p-chlorostyrene 5d under different experimental condi-
tions in terms of solvent, cosolvent, reaction time, and
temperature (Table 1, entries 5-10). The best results in
stereoselection were obtained by using KN(SiMe3)2 as the
metalating agent (Table 1, entries 5 and 7).
The stereospecific outcome of the reaction of 7 with the
Michael-type acceptors 1-4 to give cyclopropane deriva-
tives 8-11 might reasonably be accounted for with a
nucleophilic 1,4-addition reaction leading to the lithium
derivatives 14 and 15 (Scheme 3). The cyclopropanation
that follows results from the intramolecular nucleophilic
SN2 displacement of chlorine, as proposed for the reported
cyclopropanation reaction of metalated 2-chloromethyl-
oxazoline.1 It might be useful to point out that with
symmetrical Michael acceptors such as 1-4 it does not
matter which face (si or re) the reagent 7, which is known
to equilibrate between the iminic and the enaminic forms,
shows to the reaction partner as the same product will
result.
The lack of stereoselection or the modest diastereo-
selection of the reactions of 7 with both unsymmetrical
cis- and trans-styrenes 5a -d , affording cyclopropanes
12a ,b and 13a ,b, as well as the relevant regioselectivity
deserves some remarks. First of all, we observed that the
addition of 7 to alkenes 5 in all cases occurs in a
completely regioselective fashion at the aryl-bearing
carbon atom, thus leading to the carbanionic intermedi-
ate R to the heterocyclic ring (Schemes 4 and 5). This
can reasonably be explained with the stronger electron-
withdrawing ability of the oxazolinyl group with respect
to that of the aryl group. Support for this comes from
1
8-13 could be assigned by H and 13C NMR. The vicinal
coupling constant values between the cyclopropane ring
hydrogens HA and HX (3J
) 6.8-7.2 Hz) (Scheme 2
HA-HX
and Figure 2) were diagnostic of a trans configuration
as previously reported for similarly substituted cyclo-
propanes.1,12 Furthemore, the two different small long-
3
range J CH coupling constants13 (3J
) 5.2 Hz,
CH3-HX
3
J
) 1.9 Hz) between the methyl group and the
CH3-HA
above-mentioned hydrogens definitively proved a trans-
trans arrangement.14
With the aim of increasing the diastereomeric ratio of
the addition reaction, we studied the addition of meta-
lated 2-(1-chloroethyl)oxazoline 7 to the trans-oxazolinyl-
(12) Gaudemar, A. In Stereochemistry: fundamentals and methods;
Kagan, H. B., Ed.; George Thieme Publishers: Stuttgart, 1977; Vol.
1, Determination of configurations by spectrometric methods, pp 77-
83.
(13) Kingsbury, C. A.; Durham, D. L.; Hutton, R. J . Org. Chem.
1978, 43, 4696-4700.
(14) NOESY phase-sensitive experiments performed on compounds
8, 12a , and 13a also showed that, as a general pattern, the most
deshielded cyclopropane ring hydrogen was always the one between
the two heterocyclic rings, and that an oxazoline ring had, on the other
hydrogen,
a greater shielding effect with respect to a phenyl-
substituted ring.
1396 J . Org. Chem., Vol. 68, No. 4, 2003

Michael Addition of Chloroalkyloxazolines to Alkenes
SCHEME 5
SCHEME 6
the reported higher acidity of hydrogens R to the oxazo-
line ring15 with respect to those R to the aryl group.16
In a recent work from our laboratory we reported that
the base-promoted deprotonation of cis- and trans-
oxazolinylaryloxiranes takes place R to the oxazolinyl
group.17 Moreover, the negative charge demand, a quan-
titative measure of the electron-withdrawing capability,
reported for pyridyl and other heterocyclic groups,10,18
provides a reasonable explanation for the observed re-
gioselectivity.
Concerning the reaction of 7 with trans-alkenes 5c and
5d , leading to cyclopropanes 12a , 13a and 12b , 13b
(Scheme 4), respectively, all setting the oxazolinyl group
belonging to the starting alkene and the aryl group trans
to each other, the observed diastereoselectivity could be
explained considering that 7 approaches the alkene
showing its re or si face to give carbanionic diastereomeric
intermediates 16 and 17 and, then, after the intra-
molecular nucleophilic SN2 displacement of chlorine, the
cyclopropanes 12a ,b and 13a ,b (Scheme 4).
Diastereomeric intermediate 17, leading to the pre-
dominant cyclopropanes 13a ,b, seems to be more favored
with respect to 16, leading to cyclopropanes 12a ,b, for
steric reasons (Scheme 4). Indeed, looking at the inter-
mediate 16, the appropriate orbital alignment allowing
the overlap of the carbanion lone pair with the antibond-
ing orbital of the C-Cl bond is somehow hindered by the
steric interactions between the two oxazolinyl groups.
Such a steric repulsion is absent in the intermediate 17.
The absence of stereoselection of the reaction of 7 with
cis-alkenes 5a and 5b, affording cyclopropanes 12a , 13a
and 12b, 13b (Scheme 5), respectively, could be ascribed
to the fact that carbanionic intermediates 18 and 19,
generated by the syn 1,4-addition of 7 to 5a and 5b,
before undergoing cyclization rotate around the newly
formed σ bond to put the oxazolinyl and the aryl group
in a more stable trans arrangement as that found in the
final product. It could be that the rotation transforming
18 into 16 is faster than that converting 19 into 17
(having the suitable stereoelectronic arrangement for the
SN2 chlorine displacement) for steric reasons. The ob-
served lack of steroselection might result from a balance
between the higher reactivity of 17 with respect to 16
and the slower transformation of 19 into 17 with respect
to that of 18 into 16.
(15) Facchetti, A.; Streitwieser, A. J . Org. Chem. 1999, 64, 2281-
2286.
(16) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
(17) Capriati, V.; Degennaro, L.; Favia, R.; Florio, S.; Luisi, R. Org.
Lett. 2002, 4 (9), 1551-1554.
(18) (a) Abbotto, A.; Bradamante, S.; Pagani, G. A. J . Org. Chem.
1996, 61, 1761-1769. (b) Abbotto, A.; Bradamante, S.; Pagani, G. A.
J . Org. Chem. 1993, 58, 449-455.
The treatment of (4S)-2-chloromethyl-4-isopropyl-2-
oxazoline (20a ) with KN(SiMe3)2 in THF at low temper-
J . Org. Chem, Vol. 68, No. 4, 2003 1397

Rocchetti et al.
ethene5 (5a ), (Z)-1-(4,4-dimethyl-2-oxazolin-2-yl)-2-(4-chloro-
phenyl)ethene5 (5b ), (E)-1-(4,4-dimethyl-2-oxazolin-2-yl)-2-
phenylethene5 (5c), (E)-1-(4,4-dimethyl-2-oxazolin-2-yl)-2-(4-
chlorophenyl)ethene5 (5d ), 2-(1-chloroethyl)-4,4-dimethyl-2-
oxazoline10 (6), (4S)-2-chloromethyl-4-isopropyl-2-oxazoline4d
(20a ), and (4R)-2-chloromethyl-4-isopropyl-2-oxazoline19 (20b)
were prepared as reported. All other chemicals were of
commercial grade and were used without further purification.
Petroleum ether refers to the 40-60 °C boiling fraction. A
commercial solution of n-BuLi (2.5 M solution in hexanes) was
titrated by using N-pivaloyl-o-toluidine prior to use.20 For 1H
and 13C NMR spectra (1H NMR, 300 and 500 MHz; 13C NMR,
75.4 and 125 MHz) CDCl3 was used as solvent. GC-MS
spectrometry analyses were performed on a gas chromatograph
(MS capillary column, 30 m, 0.25 mm i.d. × 0.25 µm) equipped
with a 5973 mass selective detector operating at 70 eV (EI).
TLC was performed on Merck silica gel plates with F-254
indicator; visualization was accomplished by UV light (254 nm)
and by exposure to I2 vapor. All reactions involving air-
sensitive reagents were performed under nitrogen in oven-
dried glassware using the syringe-septum cap technique.
P r ep a r a tion of (E)-1,2-Bis(2-p yr id yl)eth en e (1) a n d
(E)-1,2-Bis(4,4,6-tr im eth yl-5,6-d ih yd r o-4H-[1,3]oxa zin -2-
yl)eth en e (2). To a precooled (-98 °C, with a methanol-liquid
nitrogen bath) solution of potassium bis(trimethylsilyl)amide
(1.1 g, 5.72 mmol) in 10 mL of dry THF was added dropwise
a solution of 2-(chloromethyl)pyridine (0.47 g, 2.86 mmol)
[or 2-(chloromethyl)-4,4,6-trimethyl-5,6-dihydro-4H-[1,3]ox-
azine] in 10 mL of dry THF, under N2 and magnetic stirring.
The reaction mixture was slowly allowed to warm to room
temperature and after 7 h was quenched with saturated aq
NH4Cl. The aqueous layer was extracted with AcOEt (3 × 20
mL), and the combined organic extracts were dried (MgSO4)
and concentrated in vacuo to give the crude 1 (or 2). Com-
pounds 1 and 2 were purified by crystallization (Et2O) (221
mg, 85% yield, and 234 mg, 90% yield, respectively). Com-
pound 1 is commercially available; the spectroscopic data of 2
matched very well those reported in the literature.21
P r epar ation of Heter osu bstitu ted Cyclopr opan es 8-13.
Gen er a l P r oced u r e. To a precooled (-98 °C) solution of LDA
[prepared from n-BuLi (0.81 mmol) and i-Pr2NH (0.81 mmol)
in 3 mL of dry THF (or dry Et2O), under N2 at 0 °C] was added
dropwise a solution of 6 (0.12 g, 0.74 mmol) in 2 mL of dry
THF. After 30 min at this temperature, a solution of 1 (0.13
g, 0.74 mmol) in 3 mL of dry THF was added dropwise, and
the resulting mixture was slowly allowed to warm to room
temperature under magnetic stirring and quenched with
saturated aq NH4Cl. The resulting mixture was extracted with
AcOEt (3 × 15 mL) and the combined organic extracts dried
(Na2SO4) and concentrated in vacuo. The crude product so
obtained was purified by column chromatography [silica gel;
petroleum ether/acetone, 1/1, in the case of 8 (95% yield);
petroleum ether/acetone, 6/4, in the case of 10 (mixture of four
diasteroisomers, 62% overall yield)]. No further purification
was needed in the case of 11 (95% yield). Compound 9 was
purified by crystallization (AcOEt) (white solid, 93% yield).
Compounds 12a and 13a were separated by column chro-
matography on silica gel (petroleum ether/acetone, 1/1): 95%
overall yield, dr(12a /13a ) ) 1/1, from 5a ; 86% overall yield,
dr(12a /13a ) ) 1/2, from 5c.
SCHEME 7
ature produced the trans-tris(oxazolinyl)cyclopropane 21a
(one predominant stereoisomer) (Scheme 6) in a good
yield. Similarly, the reaction of (4R)-2-chloromethyl-4-
isopropyl-2-oxazoline (20b) with KN(SiMe3)2 gave rise to
the trans-tris(oxazolinyl)cyclopropane 21b (one predomi-
nant stereoisomer). Moreover, it is interesting to point
out that 21a and 21b are enantiomers (same H and 13C
1
NMR, opposite optical activity). Compounds 21a and 21b
are likely the result of a sort of “trimerization” reaction
of metalated 20a and 20b passing, most probably,
through the corresponding trans-bis(oxazolinyl)alkenes
22a and 22b, as demonstrated for 2-chloromethyl-4,4-
dimethyl-2-oxazoline.1
Taking into consideration that the cyclopropanation
reaction occurs via a 1,4-addition of the metalated
2-chloromethyl-2-oxazoline 20a (or 20b) to the corre-
sponding alkene intermediate (22a or 22b, respectively),1
we evaluated the possibility of preparing cyclopropanes
bearing a different chiral oxazolinyl appendage, by choos-
ing the appropriate reaction conditions to avoid the self-
trimerization. We were pleased to find that treatment of
a mixture of 20a and trans-bis(oxazolinyl)ethene 4 with
LDA in Et2O at -98 °C (Barbier’s technique) afforded
trans-tris(oxazolinyl)cyclopropane 23 (40% yield) as an
equimolar mixture of two diastereoisomers, as deter-
mined by 1H and 13C NMR, and the unreacted (40%)
starting ethene 4 (Scheme 7). We presumed that 20a was
partially consumed in the self-trimerization to give 21a .
Con clu sion s
In conclusion, in this paper we report a simple syn-
thesis of heterosubstituted cyclopropanes and demon-
strate the synthetic potential of alkenyloxazolines as
electron-poor alkenes for the cyclopropanation reaction.
Work is at present in progress exploring the synthetic
utility of the above triheterosubstituted cyclopropanes as
ligands and as potential precursors of functionalized
cyclopropanes. Results will be reported in due course.
Compounds 12b and 13b were also easily separated by
column chromatography on silica gel (petroleum ether/acetone,
7/3): 56% overall yield, dr(12b/13b) ) 1/1, from 5b; 90%
overall yield, dr(12b/13b) ) 1/2, from 5d .
Da ta for (2R*,3R*)-1-m eth yl-1-(4,4-d im eth yl-2-oxa zo-
lin -2-yl)-tr a n s-2,3-bis(2-p yr id yl)cyclop r op a n e (8): yield
1
216 mg (95%); yellow oil; H NMR (500 MHz) δ 0.93 (s, 3 H,
CH3), 1.07 (s, 3 H, CH3), 1.35 (s, 3 H, CH3), 3.32 (d, J ) 6.8
Exp er im en ta l Section
Gen er a l In for m a tion . Tetrahydrofuran (THF) and diethyl
ether (Et2O) were freshly distilled under a nitrogen atmo-
sphere over sodium/benzophenone ketyl. (E)-1,2-Bis(oxa-
zolinyl)ethene1 (4), (Z)-1-(4,4-dimethyl-2-oxazolin-2-yl)-2-phenyl-
(19) 20b {[R]25 ) +97.8 (c 5, CHCl3)} was prepared as reported in
D
the case of 20a (see ref 4d).
(20) Suffert, J . J . Org. Chem. 1989, 54, 509-512.
(21) Malone, G. R.; Meyers, A. I. J . Org. Chem. 1974, 39, 618-628.
1398 J . Org. Chem., Vol. 68, No. 4, 2003

Michael Addition of Chloroalkyloxazolines to Alkenes
Hz, 1 H, CH cyclopropyl), 3.52 (d, J ) 8.0 Hz, 1 H, CH2O),
3.62 (d, J ) 8.0 Hz, 1 H, CH2O), 3.77 (d, J ) 6.8 Hz, 1 H, CH
cyclopropyl), 7.03-7.06 (m, 1 H, CH pyridyl), 7.08-7.11 (m, 1
H, CH pyridyl), 7.31 (d, J ) 7.9 Hz, 1 H, CH pyridyl), 7.45 (d,
J ) 7.9 Hz, 1 H, CH pyridyl), 7.51-7.54 (m, 1 H, CH pyridyl),
7.57-7.60 (m, 1 H, CH pyridyl), 8.46-8.47 (m, 1 H, CH
pyridyl), 8.51-8.52 (m, 1 H, CH pyridyl); 13C NMR (125 MHz)
δ 16.1 (CH3), 28.0 (CH3), 28.2 (CH3), 31.3 (C cyclopropyl), 33.9
(CH cyclopropyl), 36.8 (CH cyclopropyl), 66.7 (C-4 oxazolinyl),
78.9 (CH2O), 121.2 (CH pyridyl), 121.4 (CH pyridyl), 123.9 (CH
pyridyl), 125.0 (CH pyridyl), 135.7 (CH pyridyl), 135.9 (CH
pyridyl), 148.7 (CH pyridyl), 148.8 (CH pyridyl), 156.8 (CdN
pyridyl), 157.3 (CdN pyridyl), 165.3 (CdN oxazolinyl); GC-
MS (70 eV) m/z (rel intens) 307 (M+, 3), 292 (24), 209 (44),
208 (100), 161 (49); FT-IR (film, cm-1) 2967, 1655 (CdN), 1590,
1474, 1434.
Data for (1R*,2S*,3R*)-1-m eth yl-cis-1,2-bis(4,4-dim eth yl-
2-oxa zolin -2-yl)-tr a n s-3-p h en ylcyclop r op a n e (12a ): yield
69.5 mg (29%); yellow oil; H NMR (300 MHz) δ 0.87 (s, 3 H,
1
CH3), 1.02 (s, 3 H, CH3), 1.26 (s, 3 H, CH3), 1.30 (s, 3 H, CH3),
1.56 (s, 3 H, CH3), 2.84 (d, J ) 7.0 Hz, 1 H, CH cyclopropyl),
3.01 (d, J ) 7.0 Hz, 1 H, CH cyclopropyl), 3.35 (d, J ) 7.9 Hz,
1 H, CH2O), 3.53 (d, J ) 7.9 Hz, 1 H, CH2O), 3.93 and 3.99 (2
d, AB system, J ) 8.0 Hz, 2 H, CH2O), 7.10-7.21 (m, 5 H, 5
CH phenyl); 13C NMR (125 MHz) δ 16.7 (CH3), 24.5 (CH
cyclopropyl), 27.9 (CH3), 28.2 (CH3), 28.3 (CH3), 28.6 (CH3),
29.4 (C cyclopropyl), 35.9 (CH cyclopropyl), 66.8 (C-4 oxa-
zolinyl), 67.2 (C-4 oxazolinyl), 78.8 (CH2O), 79.1 (CH2O), 126.5
(CH phenyl), 127.6 (2 CH phenyl), 128.7 (2 CH phenyl), 135.7
(C ipso), 163.1 (CdN), 164.2 (CdN); GC-MS (70 eV) m/z (rel
intens) 326 (M+, 53), 311 (23), 227 (100), 166 (75), 160 (67),
138 (27), 112 (29), 77 (81), 55 (18); FT-IR (film, cm-1) 2968,
1657 (CdN), 1462, 1365, 1120, 993, 733.
Data for (1R*,2S*,3R*)-1-m eth yl-cis-1,2-bis(4,4-dim eth yl-
2-oxazolin-2-yl)-tra ns-3-(4-chlorophenyl)cyclopropane (12b):
yield 74 mg (28%); yellow oil; 1H NMR (300 MHz) δ 0.92 (s, 3
H, CH3), 1.05 (s, 3 H, CH3), 1.27 (s, 3 H, CH3), 1.32 (s, 3 H,
CH3), 1.56 (s, 3 H, CH3), 2.80 (d, J ) 7.0 Hz, 1 H, CH
cyclopropyl), 2.98 (d, J ) 7.0 Hz, 1 H, CH cyclopropyl), 3.40
(d, J ) 8.0 Hz, 1 H, CH2O), 3.58 (d, J ) 8.0 Hz, 1 H, CH2O),
3.94 and 4.00 (2 d, AB system, J ) 8.1 Hz, 2 H, CH2O), 7.14-
7.21 (m, 4 H, 4 CH phenyl); 13C NMR (75.4 MHz) δ 16.1 (CH3),
24.8 (CH cyclopropyl), 28.0, 28.3, 28.7, 29.5 (CH cyclopropyl),
35.3 (CH cyclopropyl), 67.0 (C-4 oxazolinyl), 67.3 (C-4 oxa-
zolinyl), 78.9 (CH2O), 79.1 (CH2O), 127.8 (2 CH phenyl), 130.1
(2 CH phenyl), 132.4 (C ipso), 134.5 (C ipso), 162.7 (CdN),
164.0 (CdN); GC-MS (70 eV) m/z (rel intens) 362 (M+ + 2,
17), 360 (M+, 48), 261 (100), 194 (65), 166 (77); FT-IR (film,
cm-1) 2968, 1658 (CdN), 1495, 1364, 1190, 1121, 1089, 992,
736.
Da ta for (2R*,3R*)-1-m eth yl-1-(4,4-d im eth yl-2-oxa zo-
lin -2-yl)-tr a n s-2,3-bis(4-p yr id yl)cyclop r op a n e (9): yield
1
211 mg (93%); mp 137-138 °C (AcOEt); H NMR (500 MHz)
δ 0.83 (s, 3 H, CH3), 1.06 (s, 3 H, CH3), 1.18 (s, 3 H, CH3), 2.59
(d, J ) 7.2 Hz, 1 H, CH cyclopropyl), 3.49 (d, J ) 8.0 Hz, 1 H,
CH2O), 3.50 (d, J ) 7.2 Hz, 1 H, CH cyclopropyl), 3.56 (d, J )
8.0 Hz, 1 H, CH2O), 7.16-7.19 (m, 4 H, 4 CH pyridyl), 8.43-
8.50 (m, 4 H, 4 CH pyridyl);13C NMR (125 MHz) δ 17.0 (CH3),
28.0 (CH3), 28.2 (CH3), 29.9 (C cyclopropyl), 31.1 (CH cyclo-
propyl), 34.4 (CH cyclopropyl), 66.9 (C-4 oxazolinyl), 78.9
(CH2O), 123.9 (CH pyridyl), 124.0 (CH pyridyl), 124.2 (CH
pyridyl), 124.3 (CH pyridyl), 145.4 (2 C pyridyl), 149.2 (2 CH
pyridyl), 149.6 (2 CH pyridyl), 163.9 (CdN oxazolinyl); GC-
MS (70 eV) m/z (rel intens) 307 (M+, 100), 292 (26), 252 (32),
229 (24), 215 (22); FT-IR (KBr, cm-1) 2971, 1646 (CdN), 1597,
1414, 1365, 1121, 992, 804. Anal. Calcd for C19H21N3O: C,
74.24; H, 6.89; N, 13.67. Found: C, 74.22; H, 7.15; N, 13.45.
Da ta for (2R*,3R*)-1-m eth yl-1-(4,4-d im eth yl-2-oxa zo-
lin -2-yl)-tr a n s-2,3-bis(4,4,6-tr im eth yl-5,6-d ih yd r o-4H-[1,3]-
oxa zin -2-yl)cyclop r op a n e (10): yield 185 mg (62%); yellow
oil, mixture of four inseparable diastereoisomers; 1H NMR (500
MHz) (selected signals) δ 1.11-1.22 (two groups of singlets,
24 H, 8 CH3), 1.32-1.38 [m, 5 H, CH3 + (2 CHaHb oxazinyl)],
1.58-1.68 (m, 2 H, CHaHb oxazinyl), 2.21, 2.25, and 2.28 (3 d,
J ) 6.7 Hz, 1 H, CH’s cyclopropyl of three main diastereo-
isomers), 2.61, 2.65, and 2.66 (3 dd, J ) 6.7, 0.6 Hz, 1 H, CH’s
cyclopropyl of three main diastereoisomers), 3.71-4.12 [m, 4
H, CH2O oxazolinyl + (2 CHO) oxazinyl]; 13C NMR (125 MHz)
(selected signals) δ 16.3, 16.4, 16.5, 16.6 (4 s, CH3’s cyclo-
propyl), 21.20, 21.24, 21.30, 21.35 (4 s overlapping, CH3CH’s
oxazinyl), 27.9-33.0 (29 s overlapping, CH3’s oxazolinyl +
CH3’s oxazinyl + CH’s cyclopropyl + C’s cyclopropyl), 41.6,
41.7, 41.8, 41.9, 42.0, 42.1 (6 s overlapping, CH2’s oxazinyl),
49.7, 49.8, 50.1 (3 s overlapping, C’s oxazinyl), 66.90, 66.96,
67.4, 67.6, 67.7, 68.0 (6 s overlapping, CHO’s oxazinyl + C’s
oxazolinyl), 78.5, 78.7 (2 s overlapping, CH2O’s oxazolinyl),
153.5, 153.8, 153.94, 153.99, 154.02, 154.05 (6 s overlapping,
CdN’s oxazinyl), 165.5, 165.61, 165.67, 165.7 (4 s, CdN’s
oxazolinyl); GC-MS (four diastereoisomers) (70 eV) m/z (rel
intens) 403 (M+, 32), 388 (27), 304 (32), 277 (39), 205 (23), 178
(19), 124 (17), 98 (9), 83 (47), 55 (100), 41 (87); FT-IR (four
diastereoisomers) (film, cm-1) 2970, 1660 (CdN), 1543, 1453,
1363, 1262, 1188, 998.
Da t a for (2R*,3R*)-1-m et h yl-tr a n s-1,2,3-t r is(4,4-d i-
m eth yl-2-oxa zolin -2-yl)cyclop r op a n e (11): yield 243 mg
(95%); yellow oil; 1H NMR (500 MHz) δ 1.12 (s, 3 H, CH3),
1.13 (s, 3 H, CH3), 1.15 (s, 6 H, 2 CH3), 1.16 (s, 3 H, CH3), 1.19
(s, 3 H, CH3), 1.39 (s, 3 H, CH3), 2.27 (d, J ) 6.7 Hz, 1 H, CH
cyclopropyl), 2.77 (d, J ) 6.7 Hz, 1 H, CH cyclopropyl), 3.73-
3.88 (m, 6 H, 3 CH2O); 13C NMR (125 MHz) δ 16.2 (CH3), 25.1
(C cyclopropyl), 27.5, 27.8, 27.9, 28.06, 28.10, 28.2, 28.3, 28.4,
67.0 (C-4 oxazolinyl), 67.2 (C-4 oxazolinyl), 67.3 (C-4 oxa-
zolinyl), 78.9 (CH2O), 79.0 (CH2O), 79.1 (CH2O), 161.1 (CdN),
161.4 (CdN), 164.0 (CdN); GC-MS (70 eV) m/z (rel intens)
347 (M+, 8), 332 (100), 260 (34), 219 (44), 188 (37); FT-IR (film,
cm-1) 2970, 1661 (CdN), 1462, 1365, 1190, 1120, 999, 733.
Da t a for (1R*,2R*,3S*)-1-m et h yl-tr a n s-1,2-b is(4,4-d i-
m e t h y l-2-o x a z o li n -2-y l)-c i s -3-p h e n y lc y c lo p r o p a n e
(13a ): yield 137.5 mg (57%); yellow oil; H NMR (300 MHz)
1
δ 1.07 (s, 3 H, CH3), 1.20 (s, 3 H, CH3), 1.21 (s, 3 H, CH3), 1.22
(s, 6 H, 2 CH3), 2.14 (d, J ) 7.0 Hz, 1 H, CH cyclopropyl), 3.32
(d, J ) 7.0 Hz, 1 H, CH cyclopropyl), 3.80-3.84 (m, 4 H, 2
CH2O), 7.17-7.22 (m, 5 H, 5 CH phenyl);13C NMR (75.4 MHz)
δ 17.5 (CH3), 27.2 (CH cyclopropyl), 28.1, 28.2, 28.4, 32.9 (CH
cyclopropyl), 67.0 (C-4 oxazolinyl), 67.1 (C-4 oxazolinyl), 78.9
(CH2O), 79.0 (CH2O), 126.7 (CH phenyl), 128.0 (2 CH phenyl),
129.4 (2 CH phenyl), 135.3 (C ipso), 162.7 (CdN), 165.4 (CdN);
GC-MS (70 eV) m/z (rel intens) 326 (M+, 44), 311 (14), 227
(100), 166 (53), 160 (49), 138 (26), 128 (19), 112 (22), 77 (67),
55 (15); FT-IR (film, cm-1) 2969, 1664 (CdN), 1462, 1364, 1118,
994, 733.
Da t a for (1R*,2R*,3S*)-1-m et h yl-tr a n s-1,2-b is(4,4-d i-
methyl-2-oxazolin-2-yl)-cis-3-(4-chlorophenyl)cyclopropane
1
(13b): yield 165 mg (62%); yellow oil; H NMR (300 MHz) δ
1.11 (s, 3 H, CH3), 1.23 (s, 3 H, CH3), 1.24 (s, 9 H, 3 CH3), 2.14
(d, J ) 6.9 Hz, 1 H, CH cyclopropyl), 3.30 (d, J ) 6.9 Hz, 1 H,
CH cyclopropyl), 3.85-3.93 (m, 4 H, 2 CH2O), 7.18-7.27 (m,
4 H, 4 CH phenyl);13C NMR (75.4 MHz) δ 17.7 (CH3), 27.6 (CH
cyclopropyl), 28.1, 28.2, 28.3, 28.5, 32.4 (CH cyclopropyl), 67.2
(C-4 oxazolinyl), 67.3 (C-4 oxazolinyl), 79.1 (CH2O), 79.2
(CH2O), 128.3 (2 CH phenyl), 130.5 (2 CH phenyl), 132.7 (C
ipso), 134.1 (C ipso), 162.5 (s, CdN), 165.2 (CdN); GC-MS
(70 eV) m/z (rel intens) 362 (M+ + 2, 12), 360 (M+, 33), 261
(100), 194 (56), 166 (64); FT-IR (film, cm-1) 2968, 1663 (CdN),
1495, 1364, 1191, 1118, 1089, 995, 736.
Rea ction of 2-(1-Ch lor oeth yl)-4,4-d im eth yl-2-oxa zolin e
(6) w ith KN(SiMe3)2 a n d (E)-1-(4,4-Dim eth yl-2-oxa zolin -
2-yl)-2-(p-ch lor op h en yl)eth en e (5d ). To a precooled (-98
°C) solution of potassium bis(trimethylsilyl)amide (75 mg, 0.37
mmol) in 5 mL of dry THF was added dropwise (Barbier’s
tecnique) under N2 a solution of 6 (34 mg, 0.21 mmol) and 5d
(50 mg, 0.21 mmol) in 2 mL of dry THF. The reaction mixture
was slowly allowed to warm to room temperature, quenched
with saturated aq NH4Cl (10 mL), and extracted with AcOEt
J . Org. Chem, Vol. 68, No. 4, 2003 1399

Rocchetti et al.
(3 × 15 mL). The combined organic extracts were dried
(Na2SO4) and evaporated in vacuo. The slurry was then
purified by chromatography on silica gel (petroleum ether/
acetone, 7/3), affording diastereomeric compounds 12b (15 mg,
20%) and 13b (50 mg, 65%) in an overall yield of 85%.
P r ep a r a tion of (4′S)-tr a n s-1,2,3-Tr is(4-isop r op yl-2-ox-
a zolin -2-yl)cyclop r op a n e (21a ) a n d (4′R)-tr a n s-1,2,3-Tr is-
(4-isop r op yl-2-oxa zolin -2-yl)cyclop r op a n e (21b ). To a
stirred solution of potassium bis(trimethylsilyl)amide (0.55 g,
2.78 mmol) in 10 mL of dry THF (-98 °C) was added dropwise
under N2 a solution of 20a (0.3 g, 1.86 mmol) in 10 mL of dry
THF. After 5 min, the reaction mixture was quenched with
saturated aq NH4Cl (20 mL), the cooling bath was removed,
and the reaction mixture was allowed to warm to room
temperature. The aqueous layer was extracted with AcOEt (3
× 20 mL), and the combined organic extracts were dried
(Na2SO4) and evaporated in vacuo to give 21a as a dark-yellow
oil which was purified by flash chromatography (silica gel;
acetone/petroleum ether, 1/9; Rf ) 0.52), affording 21a (130
mg, 56% yield). The same procedure, starting from 20b, was
followed for the synthesis of 21b obtained in similar yield
(56%).
solution of 20a (87 mg, 0.54 mmol) and 4 (120 mg, 0.54 mmol)
in 2 mL of dry Et2O (Barbier’s technique). After 30 min at this
temperature, the mixture was quenched with saturated aq
NH4Cl (5 mL), the cooling bath was removed, and the reaction
mixture was allowed to warm to room temperature. The
aqueous layer was extracted with AcOEt (3 × 10 mL), and
the combined organic extracts were dried (Na2SO4) and
evaporated in vacuo to give a slurry which was purified by
column chromatography (silica gel; petroleum ether/acetone,
7/3) to give cyclopropane 23 as an equimolar mixture of the
two inseparable diasteroisomers (75 mg, 40% overall yield) and
42% (50 mg) of the starting unreacted alkene 4.
Da ta for 23: yellow oil; 1H NMR (300 MHz) δ 0.80 [(d, J )
6.7 Hz, 6 H, (CH3)2CH), diastereomer A], 0.90 (d, J ) 6.7 Hz,
3 H, CH3CH, diastereomer B), 0.92 (d, J ) 6.7 Hz, 3 H, CH3CH,
diastereomer B), 1.18, 1.19, and 1.20 (3 s, 24 H, 8 CH3,
diastereomers A + B), 1.55-1.72 (m, 2 H, 2 CH3CH, diaster-
eomers A + B), 2.43-2.46 (m, 4 H, 4 CH cyclopropyl, diaster-
eomers A + B), 2.69-2.73 (m, 2 H, 2 CH cyclopropyl,
diastereomers A + B), 3.76-3.87 (m, 12 H, 6 CH2O, diaster-
eomers A + B), 4.10-4.16 (m, 2 H, 2 CHN, diastereomers A +
B); 13C NMR (75.4 MHz) (diastereomers A + B) δ 18.0, 18.2,
18.8, 18.9, 20.5, 22.1, 22.4, 22.5, 27.8, 28.0, 28.1, 32.3, 32.5,
67.1, 70.1, 70.3, 72.2, 72.4, 79.1, 79.1, 79.2, 160.8, 160.9, 162.3,
162.6; GC-MS (70 eV) (diastereomers A + B) m/z (rel intens)
347 (M+, 1), 332 (7), 304 (100), 260 (9), 233 (12), 160 (48), 133
(5), 108 (2), 73 (4), 55 (9), 43 (4); FT-IR (film, cm-1) (diaster-
eomers A + B) 2970, 1664 (CdN), 1463, 1363, 1170, 1000, 943,
755.
Da ta for 21a : light yellow oil; [R]25 ) -112 (c 1, CHCl3);
D
1H NMR (500 MHz) δ 0.78-0.81 (m, 9 H, 3 CH3), 0.89-0.91
(m, 9 H, 3 CH3), 1.58-1.68 [m, 3 H, 3 CH(CH3)2], 2.44 (dd, J
) 10.0, 6.0 Hz, 1 H, CH cyclopropyl), 2.48 (ddd, J ) 10.0, 6.0,
0.5 Hz, 1 H, CH cyclopropyl), 2.78 (t, J ) 6.0 Hz, 1 H, CH
cyclopropyl), 3.75-3.86 (m, 6 H, 3 CH2O), 4.11-4.17 (m, 3 H,
3 CHN); 13C NMR (125 MHz) δ 18.0 (CH3), 18.2 (CH3), 18.3
(CH3), 18.8 (2 CH3), 18.9 (CH3), 20.7 (CH cyclopropyl), 22.4
(CH cyclopropyl), 22.7 (CH cyclopropyl), 32.4 [CH(CH3)2], 32.6
[CH(CH3)2], 32.7 [CH(CH3)2], 70.2 (CH2O), 70.4 (CH2O), 70.5
(CH2O), 72.3 (2 CHN), 72.4 (CHN), 162.2 (2 CdN), 163.9
(CdN); GC-MS (70 eV) m/z (rel intens) 375 (M+, 1), 350 (11),
332 (100), 291 (41), 246 (16), 263 (5), 160 (14), 135 (5), 69 (13),
43 (8); FT-IR (film, cm-1) 2960, 1651 (CdN), 1557, 1469, 1367,
1073, 733.
Ack n ow led gm en t. This work was carried out under
the framework of the National Project “Stereoselezione
in Sintesi Organica. Metodologie ed Applicazioni” sup-
ported by the University of Bari and CNR (Rome) and
by CINMPIS (Consorzio Interuniversitario Nazionale
Metodologie e Processi Innovativi di Sintesi).
Da ta for 21b: [R]25 ) +116 (c 1, CHCl3).
D
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
(1H or 13C NMR) for compounds 8, 10, 11, 12a , 12b, 13a , 13b,
21a , 21b, and 23. This material is available free of charge via
the Internet at http://pubs.acs.org.
P r ep a r a tion of (4′S,2S*,3R*)-1-[4-Isop r op yl-2-oxa zolin -
2-yl]-tr a n s-2,3-bis(4,4-d im eth yl-2-oxa zolin -2-yl)cyclop r o-
p a n e (23). To a precooled (-98 °C) solution of LDA [prepared
from n-BuLi (2.2 M, 0.65 mmol) and i-Pr2NH (0.65 mmol) in 2
mL of dry Et2O, under N2 at 0 °C] was added dropwise a
J O026661R
1400 J . Org. Chem., Vol. 68, No. 4, 2003