Metalation of 2-chloromethyl-2-oxazolines: Synthesis of 1,2,3-tris(oxazolinyl)cyclopropanes and derivatives

Article abstract of DOI:10.1021/jo015962i

2-Chloromethyl-2-oxazoline converts cleanly into trans-1,2,3-tris(oxazolinyl)cyclopropane upon treatment with strong bases such as LDA or KN(SiMe₃)₂. Deprotonation of the above cyclopropane followed by the addition of electrophiles allows the preparation of more functionalized tris-(oxazolinyl)cyclopropanes.

Full text of DOI:10.1021/jo015962i

J . Org. Chem. 2002, 67, 759-763
759
Meta la tion of 2-Ch lor om eth yl-2-oxa zolin es: Syn th esis of
1
,2,3-Tr is(oxa zolin yl)cyclop r op a n es a n d Der iva tives
Vito Capriati, Saverio Florio,* Renzo Luisi, and Maria Teresa Rocchetti
Centro C.N.R. “M.I.S.O.”, Dipartimento Farmaco-Chimico, Universit a` di Bari, Via E. Orabona 4,
I-70125 Bari, Italy
florio@farmchim.uniba.it
Received J uly 24, 2001
2
-Chloromethyl-2-oxazoline converts cleanly into trans-1,2,3-tris(oxazolinyl)cyclopropane upon
treatment with strong bases such as LDA or KN(SiMe
3 2
) . Deprotonation of the above cyclopropane
followed by the addition of electrophiles allows the preparation of more functionalized tris-
(oxazolinyl)cyclopropanes.
In tr od u ction
Sch em e 1
Metalated 2-chloroalkyl-2-oxazolines, which are syn-
thetically useful intermediates, have received some at-
1
tention in recent years: a few papers from our laboratory
have proved that lithiated chloroalkyloxazolines behave
as Darzens reagents and add to carbonyl compounds and
imines to produce functionalized epoxides and aziridines.2
It was observed that stability and reactivity of such
lithiated heterocycles depend markedly on the R substi-
tution so that, while the unsubstituted ones are unstable
and very reactive, the substituted ones are quite stable
at low temperature and allow a detailed spectroscopic
examination.3
Resu lts a n d Discu ssion
We report herein on the fate of certain metalated
chloroalkyloxazolines in the absence of an external
electrophile. When treated with 2 equiv of LDA in THF
at -98 °C, 2-chloromethyl-2-oxazoline 1a is quickly (few
seconds) and almost quantitatively converted into a
compound that has been assigned the structure of trans-
1
,2,3-tris(oxazolinyl)cyclopropane 6 on the basis of el-
1
13
emental analysis, GC-MS, and H and C NMR data.
In particular, the H NMR spectrum clearly indicated
1
that the three oxazolinyl groups on the cyclopropane ring
are in a trans arrangement. Indeed, the three cyclopro-
pane ring hydrogens constitute two sets of nuclei within
an A X-type spin system; H and HA′ (see Scheme 1),
2 A
which can be interchanged by reflection at a plane of
X
Hz) while the third cyclopropane ring hydrogen (H ) gives
a triplet (J ) 5.9 Hz), the coupling constant value being
4
also in agreement with a typical trans arrangement.
symmetry, are enantiotopic, and give a doublet (J ) 5.9
1
3
This consideration is also supported by the C NMR
spectrum, which shows only two ring carbons appearing
at 20.5 and 22.6 ppm, confirming the stereochemistry
shown. A possible explanation for the formation of 6 is
illustrated in Scheme 1.
*
To whom correspondence should be addressed. Phone:
39.080.5442749. Fax: +39.080.5442231.
1) (a) Meyers, A. I.; Knaus, G.; Kendall, P. M. Tetrahedron Lett.
974, 3495. (b) Kamata, K.; Sato, H.; Takagi, E.; Agata, I.; Meyers, A.
+
(
1
I. Heterocycles, 1999, 51, 373. (c) Liddell, R.; Whiteley, C. G. J . Chem.
Soc., Chem. Commun. 1983, 1535. (d) English, R. B.; Liddell, J . R.;
Whiteley, C. G. S.-Afr. J . Chem. 1987, 40, 39. (e) Liddell, J . R.;
Whiteley, C. G. S.-Afr. J . Chem. 1991, 44, 35. (f) Florio, S.; Capriati,
V.; Luisi, R.; Abbotto, A. Tetrahedron Lett. 1999, 40, 7421. (g) Florio,
S.; Capriati, V.; Luisi, R. Tetrahedron Lett. 2000, 41, 5295.
(4) Vicinal coupling constants between protons of cyclopropanes
exhibit a strong dependence on the stereochemistry of the two protons
and depend also on the electronegativities of the substituents, decreas-
ing as the latter increase. The relationship J cis (8-12 Hz) > J trans (4-7
Hz) is always observed, and there are no known exceptions (see:
Gaudemar, A. In Stereochemistry: fundamentals and methods; Kagan,
H. B., Ed.; Georg Thieme Publishers: Stuttgart, 1977; Vol. 1. Deter-
mination of configurations by spectrometric methods, pp 77-83). In
(
2) (a) Florio, S.; Capriati, V.; Luisi, R. Tetrahedron Lett. 1996, 37,
4
1
781. (b) Florio, S.; Troisi, L.; Capriati, V.; Coletta, G. Tetrahedron
999, 35, 9859. (c) Florio, S.; Troisi, L.; Capriati, V.; Ingrosso, G.
Tetrahedron Lett. 1999, 40, 6101. (d) Florio, S.; Capriati, V.; Luisi, R.;
Abbotto, A.; Pippel, D. J . Tetrahedron 2001, 57, 6775.
our case, all-trans-tris(oxazolinyl)cyclopropanes (6, 18-21, 23-24)
3
(
3) Abbotto, A.; Bradamante, S.; Florio, S.; Capriati, V. J . Org. Chem.
exhibit a
J
H-H in the range of 6.6-7.1, while only in the case of a
3
1
997, 62, 8937.
presumed cis derivative (22) the J H-H observed has been of 10.1 Hz.
1
0.1021/jo015962i CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/08/2002

7
60 J . Org. Chem., Vol. 67, No. 3, 2002
Capriati et al.
Sch em e 2
is not an intermediate in the 1a f 6 conversion. Indeed,
when in another experiment 7 was subjected to depro-
tonation with LDA, the resulting stabilized propenyl
anion did not cyclize to 6, and 7 was recovered unchanged
4
after quenching with NH Cl. This confirms that cyclo-
propane 6 arises from the 1,4-addition of 2a to 4a
followed by the intramolecular cyclization of the resulting
organolithium 5. Instead, compound 7 likely results from
the ring opening of 6. Indeed, treatment of 6 with 2 equiv
of LDA at 0 °C afforded an almost quantitative yield of
7
, while the use of only 1 equiv of LDA led to a mixture
of 6 (83%) and 7 (17%) (by GC analysis). In another
experiment, carried out in order to confirm that alkene
4
4
a is actually an intermediate, a mixture of 1 equiv of
a and 1 equiv of 1a was treated at -98 °C with 0.5 equiv
of LDA: an almost 1:1 mixture of 1a and 4a was obtained
together with cyclopropane 6 (40% yield, 0.4 equiv). The
7
lack of increase of 4a in such experiment would support
the above mechanism, while there are no evidences that
Sch em e 3
6
could form via a second nucleophilic substitution of 2a
on 3 to give 5 (path b, Scheme 1). An even cleaner and
faster reaction occurred when oxazoline 1a was treated
with KN(SiMe ) : cyclopropane 6 formed quantitatively.
3 2
The bias of metalated 2-chloromethyl-2-oxazoline 1a
to undergo cyclopropanation seems to be peculiar of this
five-membered ring heterocycle. Indeed, we have found
that six-membered ring heterocycles such as 2-(chloro-
methyl)pyridine 8 and 2-(chloromethyl)-4,4,6-trimethyl-
5
(
,6-dihydro-4H-[1,3]oxazine 10 when treated with KN-
SiMe under the same conditions used for 1a gave
quantitative yields of (E)-1,2-bis(2-pyridyl)ethene 9 and
E)-1,2-bis(4,4,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-
3 2
)
(
5
yl)ethene 11. 4-(Chloromethyl)pyridine 12 has been
reported to give trans-1,2,3-tris(4-pyridyl)cyclopropane 13
(
°
22% yield) upon treatment with NaH (DMF, 2 days, 0
C) (Scheme 2).8
3 2
The different behavior toward KN(SiMe ) shown by
chloromethyl derivatives 1a and 10 could be explained
in terms of a different electrophilicity of the correspond-
ing alkenes 4a and 11. By using the electrophilicity index
proposed by Parr,9 we have found that, at the B3LYP/
a
6
-31G* level, bis(oxazolinyl)alkene 4a (ωgs ) 1.05 eV) has
a larger electrophilic character than the bis(dihydro-
oxazinyl)alkene 11 (ωgs ) 0.91 eV),9b and this could
explain the fact that 11 does not undergo the Michael-
type addition by lithiated 2-chloromethyloxazine 10 to
give the corresponding cyclopropane derivative. The
diverse electrophilicities could be explained by the dif-
a
The acidity of the R hydrogens of 1a (pK likely lower
than 20) is such that treatment of 1a with 2 equiv of LDA
should convert it almost quantitatively into 2a . The
homocoupling reaction5a of carbenoid 2a might take place
to give compound 3 and then the E-bis(oxazolinyl)ethene
5
b
4
a
(path a, Scheme 1). Then, a Michael-type addition
(6) The E stereochemistry of the double bond of compound 7 as well
of 2a to 4a would occur leading to the formation of 6.
Such a hypothesis was supported by the experimental
evidence that the deprotonation reaction of 1a , carried
out by using only 0.55 equiv of LDA, led to the formation
of the ethene 4a (3.3%), cyclopropane 6 (27%), starting
as the relative configuration of compounds 20-24 have been also
supported by their phase-sensitive NOESY spectra.
(7) The minor quantity of 6 found instead of the expected 0.5 equiv
could be ascribed to a competitive consumption of base by the
1
cyclopropane 6 formed. 1a /4a /6 ratio based on the H NMR spectra on
the crude reaction mixture.
6
(8) (a) Breslow, R.; Crispino, G. A. Tetrahedron Lett. 1991, 32, 601.
b) Breslow, R.; Crispino, G. A. J . Org. Chem. 1992, 57, 1849.
oxazoline 1a (66%), and compound 7 (3%). Compound 7
(
(
9) (a) Parr, R. G.; Szentp a´ ly, L a´ szl o´ , v.; Liu, S. J . Am. Chem. Soc.
(
5) (a) Reaction of carbenoids to give alkenes have been extensively
studied; see: Boche, G.; Lohrenz, J . C. W. Chem. Rev. 2001, 101, 697.
b) The E configuration of 4a and 11 was established by considering
1999, 121, 1922. (b) Ab initio calculations (Density functional theory
(DFT) and B3LYP/6-31G*) have been performed on optimized geom-
etries with a point group symmetry C2h and C for alkenes 4a and 11,
i
(
1
3
the doublet of doublets arising from C satellites for the peaks at δ
respectively; ωgs has been calculated for both in terms of the ionization
potential I and electron affinity A according to the Parr equation, I
and A being the energy differences between the radical cation and the
neutral and between the neutral and the radical anion, respectively.
It might be useful pointing out that different values of electrophilicity
indexes could be obtained by using different methods of calculation of
I (HOMO Energy) and A (LUMO Energy). (c) One of the referees
provided us with the electrophilicity index of 4b (1.37 eV) calculated
(DFT and B3LYP/6-31G*) for the HOMO and LUMO energies for the
full optimized molecule at the ground state.
1
6
.66 and 6.56 in their H NMR spectra, respectively. The larger
1
splittings due to a
J 13C-H are 168.4 and 166.5 Hz, while the smaller
H-H splittings are 16.5 and 16.6 Hz. The magnitude of
ones due to a 3
J
the latter gives evidence for a trans arrangement of the vinylic
hydrogens. Spectroscopic data for 4a and 11 have been reported in:
Abbotto, A.; Capriati, V.; Degennaro, L.; Florio, S.; Luisi, R.; Pierrot,
M.; Salomone, A. J . Org. Chem. 2001, 66, 3049. Malone, G. R.; Meyers,
A. I. J . Org. Chem. 1974, 39, 618. Compound 9 shows spectroscopic
data identical to that of the commercially available one.

Metalation of 2-Chloromethyl-2-oxazolines
J . Org. Chem., Vol. 67, No. 3, 2002 761
Ch a r t 1
MS analysis). The reaction of 1e with KN(SiMe
equiv, -98 °C f r.t., 4 h) furnished mainly 2-butene 4b
E + Z) (80% combined yield, E/Z ) 1.6:1). No trace of
3 2
) (1.3
(
compound 16 could be detected in this case. The reluc-
tancy of metalated a-chloroethyl oxazoline 1e could be
similarly explained by assuming that alkene 4b is not
sufficiently electrophilic because of the electron-releasing
methyl groups on the C-C double bond.9
c
Lit h ia t ion of tr a n s-1,2,3-Tr is(oxa zolin yl)cyclo-
p r op a n e 6. There are two sets of nuclei having chemical
shift equivalence (H /HA′ and H ) on the cyclopropane
A X
ring of 6 which are susceptible of removal by a base to
generate metalated species 17a (path a) and 17b (path
b), both of them being stabilized by intramolecular
chelation. In practice, lithiation of 6 with s-BuLi/TMEDA
occurred in a highly regioselective and stereoselective
manner furnishing organolithium 17a (Scheme 3).
Its trapping with methallylbromide afforded cyclopro-
ferent endocyclic nature of the C-N double bond in the
oxazolinyl alkene and in the dihydrooxazinyl alkene (five
atoms versus six atoms, respectively). The larger strain
of the unsaturated five membered ring could polarize
more effectively the C-N double bond along the nucleo-
philic attack of 2a thus increasing the electrophilicity of
the alkene 4a .
1
pane derivative 18 (95% yield, by H NMR analysis on
the crude reaction mixture), with the oxazolinyl groups
in a trans arrangement as suggested by the vicinal
coupling between the two cyclopropane ring hydrogens
In an effort to tune the reactivity of metalated oxazo-
line 1a toward the preferential formation of cyclopropane
3
4
(
J
H-H ) 6.8 Hz) and confirmed by a phase-sensitive
NOESY experiment showing a cross-peak to be ascribed
to the interaction between H and the methylene hydro-
6
or ethene 4a , we addressed our attention to some other
metalated derivatives. Addition of LDA to a 1:4.2 mixture
of 1a and MgBr at -98 °C produced the putative
A
2
gens belonging to the methallyl chain. Comparable
magnesium derivative 1b (Chart 1) that rapidly trans-
formed into (E)-1,2-bis(oxazolinyl)ethene 4a (53% isolated
yield) and cyclopropane 6 (10% isolated yield). In con-
trast, zinc derivative 1c, prepared by addition of LDA to
a 1:2 mixture of 1a and ZnBr , did not undergo any
2
transformation in the absence of electrophiles, even at
room temperature. However, the addition of isobutyr-
results were obtained when 17a was treated with allyl-
3
4
bromide to give 19 ( J H-H(trans) ) 6.6 Hz) (90% yield, by
1
H NMR analysis on the crude reaction mixture) (Scheme
3
).
Equally stereoselective was the reaction of 17a with
aldehydes. Indeed, the addition of benzaldehyde to 17a
1
furnished a very good yield (> 90%, by H NMR analysis
aldehyde or benzophenone furnished chlorohydrins 14a ,b
on the crude reaction mixture) of substituted hydroxy-
and epoxides 15a ,b2
a,10
upon treatment with NaOH.
3
4,6
benzylcyclopropanes 20 ( J H-H(trans) ) 7.1 Hz) and 21
Titanium derivative 1d , prepared by addition of LDA to
a 1:1.3 mixture of oxazoline 1a and Ti(i-PrO) , was found
3
4,6
3
(
J
H-H(trans) ) 6.8 Hz) in a 4:1 ratio, traces of 22 ( J H-H(cis)
4
10.1 Hz),4 and about 5% of the starting cyclopropane
,6
)
6
to be rather reluctant to undergo the homocoupling
reaction at least at low temperature. Indeed, a GC
analysis of the reaction mixture after 2 h at low temper-
ature indicated the presence of just small amounts (about
. The structure of 20 was also unambiguously confirmed
by X-ray analysis (Scheme 3).
1
2
Moreover, addition of isobutyraldehyde resulted in the
stereoselective formation of substituted hydroxyalkyl
1
0%) of the alkene 4a . Warming of the reaction mixture
3
cyclopropanes 23 and 24 ( J H-H(trans) ) 6.6 Hz for 23;
to room temperature afforded a mixture of 4a and 6 (in
3
4,6
J
H-H(trans) ) 7.1 Hz for 24) (in a 7/3 ratio; > 80%
1
a 2:3 ratio; 98% combined yield by H NMR ).
1
combined yield by H NMR analysis on the crude reaction
mixture) (Scheme 3).
The homocoupling reaction and consequently the cyclo-
propanation of metalated chloroalkyloxazolines is mark-
edly sensitive to the R substitution. Indeed, lithiation of
Con clu sion s
2
-(1-chloroethyl)oxazoline 1e, under the same conditions
used for the lithiation of 1a , generated derivative 1f,
which was found to be much more stable than 2a and
could be kept at low temperature even for days without
In conclusion, in this paper we have shown for the first
time that 2-chloroalkyloxazolines, when metalated, be-
have like chlorocarbenes and tend to “dimerize” to give
bis(oxazolinyl)alkenes or to “trimerize” to give tris-
(oxazolinyl)cyclopropanes depending upon the R substitu-
tion and the metal used. Moreover, it is worth pointing
out that the above so far undescribed oxazolinylcyclo-
propanes are potential intermediates for the synthesis
of functionalized cyclopropanes, among which oligopep-
tides, by elaboration of the oxazolinyl groups on the
cyclopropane ring.
3
undergoing any transformation. However, warming of
1
2
f to room temperature afforded mainly substituted
-butene 4b as a mixture of two separable E- and
1
1
Z-stereoisomers (17% combined yield, E/Z ) 3/1) and
very small amounts of cyclopropane 16 (detected by GC-
(
10) Capriati, V.; Florio, S.; Luisi, R.; Russo, V.; Salomone, A.
Tetrahedron Lett. 2000, 41, 8835.
11) The configuration of the two E- and Z-butenes has been
(
1
13
assigned either on the basis of H or C chemical shifts of the “allylic”
proton/carbon atoms. As regards C NMR spectra, it has been reported
see: Gaudemar, A. In Stereochemistry: fundamentals and methods;
1
3
(12) Crystallographic data for compound 20 have been deposited at
the Cambridge Crystallographic Data Centre (deposition no. CCDC-
163504). Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. [fax:
(int.) + 44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk]. ORTEP
view and crystallographic data for compound 20 have been also
reported as Supporting Information; all diagrams and calculations were
performed using maXus (Nonius, Delft & MacScience, J apan).
(
Kagan, H. B., Ed.; Georg Thieme Publishers: Stuttgart, 1977; Vol. 1.
Determination of configurations by spectrometric methods, pp 55-56)
that these carbon atoms resonate at higher field in Z-isomers than in
1
E-ones (17.51 vs 18.58 δ, in our case). Finally, in H NMR spectra,
allylic protons in the E-isomer should get a double oxazolinyl deshield-
ing effect and so resonate at lower field (2.07 vs 1.94 δ).

7
62 J . Org. Chem., Vol. 67, No. 3, 2002
Capriati et al.
Exp er im en ta l Section
(CH
2
O), 79.1 (CH
2
O), 123.4 (CH)), 133.2 (C)), 160.4 (CdN),
-
1
1
1
2
61.9 (CdN), 163.2 (CdN); FT-IR (film, cm ) 1670 (s, CdN),
632 (s, CdN); GC-MS (70 eV) m/z 333 (M , 72.4), 318 (65.6),
78 (33.8), 277 (30.4), 246 (47.3), 235 (100.0), 219 (40.1), 174
Gen er a l Meth od s. Tetrahydrofuran (THF) and diethyl
ether (Et O) were freshly distilled under a nitrogen atmo-
2
sphere over sodium/benzophenone ketyl. N,N,N′,N′-Tetra-
methylethylenediamine (TMEDA) was distilled over finely
powdered calcium hydride. 2-Chloromethyl-4,4-dimethylox-
+
27 3 3
(55.9). Anal. Calcd for C18H N O : C, 64.84; H, 8.16; N, 12.60.
Found: C, 64.46; H, 7.84; N, 12.57.
Rea ction of 2-Ch lor om eth yl-4,4-d im eth yl-2-oxa zolin e
2
a
azoline (1a ) and 2-(1-chloroethyl)-4,4-dimethyl-2-oxazoline
1e) were prepared as reported. All other chemicals were of
(
1a ) w ith LDA a n d MgBr
C) THF (50 mL) solution of compound 1a (3.38 mmol) and
(14.20 mmol) was added dropwise a
solution of LDA [from n-BuLi (6.08 mmol) and i-Pr NH (6.08
mmol in dry THF (10 mL), under N ]. The reaction mixture
was stirred at -98 °C for 30 min, quenched with saturated
aqueous NH
2
. To a stirred and precooled (-98
3
(
°
commercial grade (Aldrich) and used without further purifica-
tion. Petroleum ether refers to the 40-60 °C boiling fraction.
Commercial solutions of n-BuLi (2.5 M solution in hexanes)
and s-BuLi (1.3 M solution in cyclohexane) were titrated by
perfectly dry MgBr
2
2
2
1
3
1
13
using N-pivaloyl-o-toluidine prior to use. For the H and
C
4
Cl, extracted with AcOEt (3 × 20 mL), and
1
13
NMR spectra ( H NMR 300, 500 MHz; C NMR 50.3, 125
MHz) CDCl was used as solvent. GC-MS spectrometry
analyses were performed on a gas chromatograph HP 5890 II
dimethylsilicon capillary column, 30 m, 0.25 mm i.d.) equipped
evaporated in vacuo to give a mixture of 4a and 6 which was
column chromatographed on silica gel using first AcOEt to
elute 4a (200 mg, 53% yield) and then AcOEt /MeOH 95/5 to
elute 6 (38 mg, 10% yield).
3
(
with a mass selective detector operating at 70 eV (EI). Melting
points were uncorrected. TLC was performed on Merck silica
gel plates with F-254 indicator; visualization was accomplished
Reaction of 2-Ch lor om eth yl-4,4-dim eth yloxazolin e (1a)
w ith LDA a n d Zn Br
Et O solution (50 mL) of 1a (3.38 mmol) and ZnBr
was added dropwise a solution of LDA [from n-BuLi (6.76
mmol) and i-Pr NH (6.76 mmol in dry Et O (10 mL), under
]. The reaction mixture was slowly allowed to warm to room
2
. To a stirred and precooled (-98 °C)
2
2
(6.76 mmol)
2
by UV light (254 nm) and by exposing to I vapor. All reactions
involving air-sensitive reagents were performed under nitrogen
in oven-dried glassware using syringe-septum cap technique.
P r ep a r a tion of tr a n s-1,2,3-Tr is(4,4-d im eth yl-2-oxa zo-
lin -2-yl)cyclop r op a n e (6). To a stirred solution of 0.5 g (3.38
mmol) of 2-chloromethyl-4,4-dimethyl-2-oxazoline (1a ) in 20
mL of dry THF was added 9 mL (6.76 mmol) of potassium bis-
2
2
N
2
temperature, and after 2.5 h, isobutyraldehyde (3.71 mmol)
was added. The mixture was stirred overnight, quenched with
saturated aqueous NH
and evaporated in vacuo to give the crude chlorohydrin 14a
syn/anti: 1/1), which was quantitatively converted into the
4
Cl, extracted with AcOEt (3 × 20 mL),
(
trimethylsilyl)amide (0.15 M solution in toluene) at - 98 °C,
under N . After 5 min, the reaction mixture was quenched with
saturated aqueous NH Cl solution (20 mL), the cooling bath
(
2
epoxide 15a upon treatment with NaOH 5% w/w (10 mL) in
i-PrOH (5 mL) and purified by column chromatography (silica
gel, petroleum ether/AcOEt 7/3, 65% combined yield, cis/trans
10
4
removed, and the mixture allowed to warm to room temper-
ature. AcOEt was then added, the organic layer was separated,
and the aqueous layer was extracted with AcOEt (2 × 20 mL).
1
:1). When 1 equiv of benzophenone was added after 2.5 h to
the reaction mixture instead of isobutyraldehyde, chlorohydrin
The combined organic extracts were dried (MgSO
4
) and
2a
1
4b and then epoxide 15b were obtained; the latter being
evaporated in vacuo to give 370 mg of 6 as a dark-yellow
purified by column chromatography (silica gel, AcOEt/petro-
leum ether 3/7, 53% yield).
Rea ction of 2-Ch lor om eth yl-4,4-d im eth yl-2-oxa zolin e
1
viscose oil (98% yield, by H NMR). Compound 6 could be used
straightforwardly in the next chemical transformations. Fur-
ther purification of the crude oil could be performed either by
flash chromatography (silica gel, acetone/CH
(
1a ) w ith LDA a n d Ti(i-P r O)
-98 °C) solution of LDA [from n-BuLi (2.64 mmol) and i-Pr
O (10 mL), under N ] was added
dropwise a solution of Ti(i-PrO) (2.64 mmol) in Et O (10 mL);
after a few seconds, 1a (2.03 mmol) was added all at once. After
.45 h, the reaction mixture was quenched with saturated
aqueous NH
Cl, extracted with AcOEt (3 × 20 mL), and
evaporated in vacuo to give a mixture of 4a and 1a (4a /1a )
4
. To a stirred and precooled
2
Cl
2
) 9/1, R )
f
(
2
-
0
.37) or by high vacuum distillation by means of a kugelrohr
NH (2.64 mmol) in dry Et
2
2
-
2
apparatus (165 °C, 10 mmHg). Crystallization of the light
yellow oil so obtained by Et O gave a white solid: mp 72 °C;
H NMR (500 MHz) δ 1.18 (s, 6 H, 2 × CH ), 1.19 (s, 6 H, 2 ×
CH ), 2.42 (d, J ) 5.9 Hz, 2 H, 2 ×
), 1.20 (s, 6 H, 2 × CH
CH), 2.69 (t, J ) 5.9 Hz, 1 H, CH), 3.78-3.84 (m, 6 H, 3 ×
4
2
2
1
3
1
3
3
4
1
3
CH
8.1 (2 × CH
C(CH ], 67.2 [C(CH
2
O); C NMR (125 MHz, DEPT) δ 20.5 (CH), 22.6 (2 × CH),
), 28.2 (2 × CH ), 28.3 (2 × CH ), 67.1 [2 ×
O), 79.2 (CH O), 160.8
1
1
(
/9 by H NMR ). In another experiment, a solution of LDA
2.64 mmol in 10 mL of Et O) was added to a well-stirred and
precooled (-98 °C) solution of 1a (2.03 mmol) and Ti(i-PrO)
2.64 mmol) in 10 mL of Et O. The reaction mixture was
2
3
3
3
2
3
)
2
3
)
2
], 79.1 (2 × CH
2
2
4
-
1
(
CdN), 162.6 (2 × CdN); FT-IR (film, cm ) 1662 (s, CdN);
(
2
+
GC-MS (70 eV) m/z (%) 333 (M , 2.8), 319 (25.9), 318 (100.0),
monitored by GC analysis with the following results: only
compound 1a was detected after 30 min (at -98 °C); a mixture
of 1a , 4a and 6 (in a 58/24/18 ratio) after 1.5 h; a mixture of
3
02 (7.6), 246 (47.1), 205 (39.0), 174 (41.4), 55 (9.0). Anal. Calcd
for C18 : C, 64.84; H, 8.16; N, 12.60. Found: C, 64.72;
H, 7.93; N, 12.57.
Reaction of 2-Ch lor om eth yl-4,4-dim eth yloxazolin e (1a)
w ith LDA to Give 4a , 6, a n d 7. To a precooled (-98 °C, with
a methanol liquid nitrogen bath) solution of LDA [prepared
27 3 3
H N O
1
4
a and 6 (in a 2/3 ratio; 98% combined yield by H NMR )
after 4 h. It is possible to isolate 4a and 6 as reported in the
procedure with MgBr
Rea ction of 2-(1-Ch lor oeth yl)-4,4-d im eth yl-2-oxa zolin e
2
1b) w ith P ota ssiu m Bis(tr im eth ylsilyl)a m id e [(Me Si) -
2
.
from n-BuLi (7.05 mmol) and i-Pr
or dry THF), under N at 0 °C] was added dropwise a solution
of 1a (3.38 mmol) in 20 mL of Et O (or THF). The reaction
mixture was stirred for 5 min, quenched with saturated
aqueous NH
2 2
NH (7.05 mmol) in dry Et O
(
3
(
2
NK]. To a stirred and precooled (-98 °C) solution of 2-(1-
chloroethyl)-4,4-dimethyl-2-oxazoline (1b) (0.5 g, 3.1 mmol) in
THF (20 mL) was added potassium bis(trimethylsilyl)amide
2
4
Cl, extracted with AcOEt (3 × 10 mL), and
(
4.0 mmol, 5.4 mL) under N
allowed to warm to room temperature and after 4 h was
quenched with saturated aqueous NH Cl (20 mL). The aqueous
layer was extracted with AcOEt (3 × 20 mL), and the combined
organic extracts were dried (MgSO ) and concentrated in vacuo
2
. The reaction mixture was slowly
evaporated under reduced pressure to give a mixture of 6, 4a ,
and 7, which were separated by column chromatography on
4
1
silica gel (95% combined yield; 6/4a /7 ) 85:5:10 by H NMR
analysis on the crude; AcOEt/petroleum ether 9/1 to elute 4a 5
4
(
(
R
R
f
) 0.2), then AcOEt/MeOH 95/5 to elute 7 (R
f
) 0.2) and 6
to give 4b as a mixture of E and Z isomers (Z/E ) 1/1.6; 80%
combined yield by H NMR on the crude), which were
separated and purified by flash chromatography (silica gel,
AcOEt, Rf(Z) ) 0.20, Rf(E) ) 0.11) and showed the following
spectral data:
1
f
) 0.1)]. (E)-1,2,3-Tr is(4,4-d im eth yl-2-oxa zolin -2-yl)-
1
p r op en e (7): waxy solid; H NMR (500 MHz) δ 1.16 (s, 6 H,
× CH ), 1.23 (s, 12 H, 4 × CH ), 3.82-3.92 (m, 8 H, 3 ×
CH O + CH Cd), 6.79 (s, 1 H, CHd); C NMR (125 MHz,
DEPT) δ 28.0 (2 × CH ), 28.1 (2 × CH ), 28.1 (2 × CH ), 66.9
C(CH ], 67.9 (CH Cd), 78.6 (CH O), 79.0
], 67.0 [2 × C(CH
2
3
3
1
3
2
2
3
3
3
(
2E)-Bis(4,4-d im et h yl-2-oxa zolin -2-yl)-2-b u t en e (4b ):
[
3
)
2
3
)
2
2
2
1
light yellow oil; H NMR (500 MHz) δ 1.22 (s, 12 H, 4 × CH
3
1
3
oxazoline), 1.94 (s, 6 H, 2 × CH
3
), 3.86 (s, 4 H, 2 × CH
2
O).
C
(
13) Suffert, J . J . Org. Chem. 1989, 54, 509-512.
NMR (125 MHz, DEPT) δ 17.5 (2 × CH
3
), 27.9 (4 × CH
3

Metalation of 2-Chloromethyl-2-oxazolines
J . Org. Chem., Vol. 67, No. 3, 2002 763
oxazoline), 67.2 [2 × C(CH
3
)
2
], 78.8 (2 × CH
2
O), 128.6 (2 ×
raphy on silica gel [AcOEt/MeOH 95/5 in the case of 18 (R
0.15), AcOEt in the case of 19 (R ) 0.1), 20 (R ) 0.20), 21 (R
) 0.21), 22 (R ) 0.26) and acetone/petroleum ether 3/7 in the
case of 23 (R ) 0.20), 24 (R ) 0.19)].
f
)
f
-1
Cd), 163.3 (2 × CdN); FT-IR (KBr, cm ) 1662 (s, CdN), 1642
f
f
+
(
s, CdN); GC-MS (70 eV) m/z 250 (M , 0.5), 236 (4.4), 205
f
(9.2), 194 (96.2), 179 (21.3), 163 (100.0), 149 (4.7), 136 (5.8),
f
f
1
C
9
25 (7.2), 108 (10.3), 53 (9.1), 41 (6.3). Anal. Calcd for
: C, 67.17; H, 8.86; N, 11.19. Found: C, 67.46; H,
.12; N, 11.37. (2Z)-Bis(4,4-d im eth yl-2-oxa zolin -2-yl)-2-
H
22
N
2
O
2
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 Ministero dell’Universit a` e della Ricerca
Scientifica e Tecnologica (MURST, Rome) and by the
University of Bari and CNR (Rome). We are also
indebted to Prof. Marcel Pierrot of the Centre Scienti-
fique Saint-J e´ r oˆ me, Marseille, France, for performing
the X-ray analysis on compound 20 and to Prof. A.
Abbotto of the University of Milano-Bicocca for ab initio
calculations concerning the electrophilicities of oxazoli-
nyl and oxazinyl ethenes 4a and 11. We are also grateful
to one of the reviewers of this paper for suggesting that
we calculate and use the electrophilicity indexes to
explain the different behavior toward cyclopropanation
of compounds 4a , 4b, and 11.
14
1
bu ten e (4b). Light yellow oil. H NMR (500 MHz) δ 1.28 (s,
1
2
2 H, 4 × CH
3
oxazoline), 2.07 (s, 6 H, 2 × CH
3
), 3.93 (s, 4 H,
O). C NMR (125 MHz, DEPT) δ 18.5 (2 × CH ), 28.1
O), 129.2
1
3
× CH
2
3
(
4 × CH
3
oxazoline), 67.1 [2 × C(CH
3
)
2
], 78.4 (2 × CH
2
-
1
(2 × C)), 163.3 (2 × C)N). FT-IR (KBr, cm ) 1655 (s, CdN).
+
GC-MS (70 eV) m/z (%) 250 (M , 38.0), 235 (11.3), 205 (12.3),
1
(
94 (17.6), 178 (27.3), 165 (100.0), 152 (29.2), 138 (57.8), 124
13.7), 107 (16.2), 80 (13.0), 53 (20.8), 41 (16.1). Anal. Calcd
for C14 : C, 67.17; H, 8.86; N, 11.19. Found: C, 67.55;
22 2 2
H N O
H, 9.19; N, 11.15.
P r ep a r a tion of Tr is(oxa zolin yl)cyclop r op a n e Der iva -
tives: Gen er a l P r oced u r e. To a well-stirred and precooled
(
-98 °C) solution of 6 (1.35 mmol) and TMEDA (1.48 mmol)
in 20 mL of THF, under N , was added dropwise s-BuLi (1.75
2
mmol). After 1 h, the electrophile (allyl bromide, methallyl
bromide, benzaldehyde or isobutyraldehyde) (1.48 mmol) was
added, and the resulting mixture was slowly allowed to warm
to room temperature and stirred overnight. After this time,
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
for compounds 18-24, ORTEP view, and crystallographic data
for compound 20. This material is available free of charge via
the Internet at http://pubs.acs.org.
the mixture was quenched with saturated aqueous NH
extracted with AcOEt (3 × 20 mL), and the combined organic
extracts were dried (MgSO ) and concentrated in vacuo. The
crude product so obtained was purified by flash chromatog-
4
Cl and
4
J O015962I