On the addition of lithiated 2-alkyl- and 2-(chloroalkyl)-4,5-dihydro-1,3-oxazoles to nitrones - A mechanistic investigation

Article abstract of DOI:10.1002/1099-0690(200209)2002:17<2961::AID-EJOC2961>3.0.CO;2-F

The addition of 2-(lithioalkyl)-4,5-dihydro-1,3-oxazoles 2a-c and 2-[chloro(lithio)alkyl]-4,5-dihydro-1,3-oxazoles 2d,e to nitrones 3 has been studied. While lithiated 2-methyl-4,5-dihydro-1,3-oxazole 2a adds stereoselectively to nitrones 3, resulting after long reaction times (3 h) in the formation of 2-[(E)-alkenyl]-4,5-dihydro-1,3-oxazoles 8a-h, lithiated 2-(chloromethyl)-4,5-dihydro-1,3-oxazole 2e affords 2-[(Z)-alkenyl]-4,5-dihydro-1,3-oxazoles 26a-d and 26f-h. α-Lithiated 2-ethyl-4,5-dihydro-1,3-oxazole 2b adds to 3a to give the 1,6-dioxa-2,9-diazaspiro[4.4]nonane 9 and 2-alkenyl-4,5-dihydro-1,3-oxazole 14 after treatment with oxalic acid. Quenching after short reaction times shows that the conversions of 2a to 8 and of 2b to 14 go through spirocyclic compounds 7 and 9, while the reaction between 2e and 3a, quenched even at short reaction times, gives a mixture of the 1,6-dioxa-2,9-diazaspiro[4.4]nonanes 21-H and 22-H and the 2-(1,2-oxazetidin-4-yl)-4,5-dihydro-1,3-oxazoles 25a and 27a. The addition of 2c to 3a furnishes the 1,6-dioxa-2,9-diazaspiro-[4.4]nonane 15 and then isoxazolidin-5-one 16 upon hydrolysis with oxalic acid. The addition of 2d to 3a gives the 1,6- dioxa-2,9-diazaspiro[4.4]nonanes 17b and 18b after short reaction times and the 2-(1,2-oxazetidin-4-yl)-4,5-dihydro-1,3-oxazole 19 after long reaction times. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200209)2002:17<2961::AID-EJOC2961>3.0.CO;2-F

FULL PAPER
On the Addition of Lithiated 2-Alkyl- and 2-(Chloroalkyl)-4,5-dihydro-1,3-
oxazoles to Nitrones ؊ A Mechanistic Investigation
Vito Capriati,[a] Leonardo Degennaro,[a] Saverio Florio,*[a] and Renzo Luisi[a]
Keywords: Lithiation / Nucleophilic addition / Oxygen and nitrogen heterocycles / Spiro compounds
The addition of 2-(lithioalkyl)-4,5-dihydro-1,3-oxazoles 2a−c
and 2-[chloro(lithio)alkyl]-4,5-dihydro-1,3-oxazoles 2d,e to
nitrones 3 has been studied. While lithiated 2-methyl-4,5-di-
and 9, while the reaction between 2e and 3a, quenched even
at short reaction times, gives a mixture of the 1,6-dioxa-2,9-
diazaspiro[4.4]nonanes 21-H and 22-H and the 2-(1,2-oxazet-
hydro-1,3-oxazole 2a adds stereoselectively to nitrones 3, idin-4-yl)-4,5-dihydro-1,3-oxazoles 25a and 27a. The addi-
resulting after long reaction times (3 h) in the formation of
2-[(E)-alkenyl]-4,5-dihydro-1,3-oxazoles 8a−h, lithiated 2-
(chloromethyl)-4,5-dihydro-1,3-oxazole 2e affords 2-[(Z)-alk-
enyl]-4,5-dihydro-1,3-oxazoles 26a−d and 26f−h. α-Lithiated
2-ethyl-4,5-dihydro-1,3-oxazole 2b adds to 3a to give the 1,6-
dioxa-2,9-diazaspiro[4.4]nonane 9 and 2-alkenyl-4,5-dihy-
dro-1,3-oxazole 14 after treatment with oxalic acid. Quench-
ing after short reaction times shows that the conversions of
2a to 8 and of 2b to 14 go through spirocyclic compounds 7
tion of 2c to 3a furnishes the 1,6-dioxa-2,9-diazaspi-
ro[4.4]nonane 15 and then isoxazolidin-5-one 16 upon hydro-
lysis with oxalic acid. The addition of 2d to 3a gives the 1,6-
dioxa-2,9-diazaspiro[4.4]nonanes 17b and 18b after short re-
action times and the 2-(1,2-oxazetidin-4-yl)-4,5-dihydro-1,3-
oxazole 19 after long reaction times.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
selectively with a number of nitrones to give 2-[(Z)- and
(E)-alkenyl]-4,5-dihydro-1,3-oxazoles. In order to explain
the stereoselectivity of the above reactions and to obtain
mechanistic information we decided to study the addition
of such lithiated species to nitrones in some detail, and we
report the relevant results here.
Nucleophilic addition of carbon nucleophiles, including
enolates, to nitrones has been extensively investigated in re-
cent years.[1] Nucleophilic addition of azaenolates to nitro-
nes, which would be expected to produce N-(3-iminoalk-
yl)hydroxylamines or, in the case of cyclic azaenolates, spiro-
cyclic isoxazolidines, has not been studied so far
(Scheme 1).[2]
Results and Discussion
2-(Lithiomethyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole
(2a), generated by deprotonation of 2,4,4-trimethyl-4,5-di-
hydro-1,3-oxazole (1a) (LDA, THF, Ϫ98 °C) (Scheme 2),
probably exists in equilibrium between an imine and an en-
amine form, as suggested by certain spectroscopic evidence
obtained for lithiated 2-alkyl-4,5-dihydro-1,3-oxazoles.[5]
We found that the addition of the commercially available
nitrone 3a to the lithiated species 2a, followed by immediate
(a few seconds) quenching with sat. aq. NH4Cl, afforded a
high yield (78%) of the crystalline hydroxylamino derivative
6.[6] Compound 6, the structure of which has been estab-
lished spectroscopically (1H and 13C NMR, MS-ESI, IR,
and elemental analysis), is probably the result of the nucleo-
philic addition of 2a to 3a, yielding the lithiated hy-
droxylamine 4, which then cyclizes on the CϭN bond of
the 4,5-dihydro-1,3-oxazole moiety to give the spirocyclic
form 5. Acidic quenching would produce the hydroxylamine
derivative 6, which, when in CDCl3 solution, equilibrates
with the spirocyclic compound 7 (two diastereomers) [7/6 ϭ
7.1:1; dr(7) ϭ 7:3] (Scheme 2).
Scheme 1
In our research work concerning the chemistry of
metallated 2-alkyl-4,5-dihydro-1,3-oxazoles with elec-
trophiles,[3] we have recently discovered[4] that lithiated 2-
(chloromethyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole and
2,4,4-trimethyl-4,5-dihydro-1,3-oxazole react highly stereo-
[a]
Istituto di Chimica dei Composti OrganoMetallici-ICCOM,
`
Dipartimento Farmaco-Chimico, Universita di Bari,
Via E. Orabona 4, 70125 Bari, Italy
Fax: (internat.) ϩ 39-080/544-2231
E-mail: florio@farmchim.uniba.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2002, 2961Ϫ2969  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0917Ϫ2961 $ 20.00ϩ.50/0
2961

V. Capriati, L. Degennaro, S. Florio, R. Luisi
FULL PAPER
cies 13. Treatment with nitrone 3a, cyclization, and acidic
quenching would furnish 10. In comparison with 4, com-
pound 12, which probably equilibrates with its spirocyclic
form 11 in solution, is much less prone to eliminate tert-
butylhydroxylamine, under the basic conditions of the reac-
tion mixture, for steric reasons due to the methyl substitu-
tion and for having only one hydrogen atom β to the
lithiated hydroxylamine group.
Scheme 2
Quenching of the reaction mixture obtained by addition
of nitrone 3a to 2a with satd. aq. NH4Cl after 18 h gave the
2-[(E)-styryl]-4,5-dihydro-1,3-oxazole 8a (Table 1) in excel-
lent yield (95%) and diastereomeric ratio [(E)/(Z) Ͼ 99:1;
3JH,H(E) ϭ 15.8 Hz]. A high (E) stereoselectivity was also
observed in the reaction with other aryl or alkyl nitrones
3bϪh, providing the corresponding 2-[(E)-alkenyl]-4,5-dihy-
dro-1,3-oxazoles 8bϪh in good yields (Table 1). The anti-β
elimination of tert-butylhydroxylamine occurring in com-
pound 6 could be the stereoselective determining step, as
previously reported.[4]
Lithiation of commercially available 2-ethyl-4,4-dimethyl-
4,5-dihydro-1,3-oxazole (1b) to give 2-(1-lithioethyl)-4,4-di-
methyl-4,5-dihydro-1,3-oxazole (2b), followed by the addi-
tion of nitrone 3a, gave rise (after 3 h) to the formation of
the 1,6-dioxa-2,9-diazaspiro[4.4]nonane 9 (70% yield) as a
mixture of three diastereoisomers (dr ϭ 87:9:4) (structures
ascertained by NOESY phase-sensitive experiments) and a
very small amount of 10 (ca. 2% yield) (Scheme 3). A pos-
sible explanation for the formation of 10 is also shown in
Scheme 3. Lithiated spirocyclic compound 11, present in
the reaction mixture, opens to give 12, which would un-
Scheme 3
However, treatment of the isolated spirocyclic compound
9 with 1 equiv. of oxalic acid gave a quantitative yield of
the
4,4-dimethyl-2-(1-methyl-2-phenylvinyl)-4,5-dihydro-
1,3-oxazole (14) [diastereomeric mixture: (E)/(Z) ϭ 9:1].
Diastereomers could be separated by column chromato-
graphy[7] (Scheme 4).
dergo further deprotonation to generate the dilithiated spe- Scheme 4
Table 1. Synthesis of 2-[(E)-alkenyl]-4,5-dihydro-1,3-oxazoles 8
Nitrone
R
Compound
Conversion (%)
(E)/(Z)[c]
(yield %)[a][b]
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
p-MeC6H4
p-ClC6H4
p-CH3OC6H4
2,4,6-(CH3O)3C6H2
3,4-(methylenedioxy)C6H3
cyclohexyl
CH3[CH2]6
p-O2NC6H4
8a (95)
8b (95)
8c (70)
8d (85)
8e (95)
8f (70)
8g (60)
8h (52)
8i[d]
Ͼ 95
Ͼ 95
Ͼ 95
90
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
Ϫ
70
Ͼ 95
Ͼ 95
Ͼ 95
Ϫ
[a]
[b]
[c]
1
[d]
Based on the converted nitrone. Yields were not optimized. Determined by H NMR analysis. No reaction.
2962
Eur. J. Org. Chem. 2002, 2961Ϫ2969

Addition of Lithiated 2-Alkyl- and 2-(Chloroalkyl)-4,5-dihydro-1,3-oxazoles to Nitrones
FULL PAPER
2-(1-Lithio-1-methylethyl)-4,4-dimethyl-4,5-dihydro-1,3- takes place. As the Cl leaving group departs, electrons in
oxazole (2c), readily available from 1c,[8] added to nitrone the σ bond to the migrating group (oxygen atom) have to
3a to furnish the 1,6-dioxa-2,9-diazaspiro[4.4]nonane 15 flow into the CϪCl σ* orbital. The best overlap between
1
(dr ϭ 95:5 by H NMR, 69% yield). Compound 15 could these two orbitals (σ and σ*) occurs when they are oriented
be hydrolyzed into the corresponding isoxazolidin-5-one 16 anti-periplanar to one another (Scheme 6). Such an anti-
(73% yield, conv. 73%) with oxalic acid (Scheme 5). Com- periplanar requirement is not permitted for 18a, which does
pound 15, of course, having no β-hydrogen atom, could not not convert into the 2-(1,2-oxazetidin-4-yl)-4,5-dihydro-1,3-
eliminate tert-butylhydroxylamine. The conversion of spiro- oxazole 20. In an experiment designed to test the above
cyclic compound 15 into the isoxazolidin-5-one 16 occurs considerations, the 2-(1,2-oxazetidin-4-yl)-4,5-dihydro-1,3-
very easily. In comparison, compound 9 does not undergo oxazole 19 was formed quantitatively when a sample of 17b
this kind of reaction, the β-elimination of hydroxylamine to was treated with 1 equiv. of LDA in THF (Ϫ98 °C, THF).
give the alkene 14 evidently being faster.
Under the same conditions, the spirocyclic compound 18b
Treatment of 2-(1-chloro-1-lithioethyl)-4,4-dimethyl-4,5- did not transform into the oxazetidine 20 and was quantit-
dihydro-1,3-oxazole (2d)[9] with 3a (Scheme 6) furnished the atively recovered unchanged. The relative configurations of
spirocyclic compounds 17b and 18b and the 2-(1,2-oxazeti- compounds 17b and 18b were assigned by means of
din-4-yl)-4,5-dihydro-1,3-oxazole 19 in relative amounts NOESY phase-sensitive experiments[11] and confirmed by
that depended upon the reaction times. Quenching of the an X-ray analysis (see Supporting Information), while the
reaction mixture after a very short reaction time (5 s) relative configuration of the 2-(1,2-oxazetidin-4-yl)-4,5-di-
yielded 80% of 17b and 18b (17b/18b ϭ 13:1) and 20% of hydro-1,3-oxazole 19 was determined by the NOESY phase-
1
19, while quenching after 10 min afforded 57% of 17b and sensitive spectrum and confirmed by H NMR correlation
18b (17b/18b ϭ 5:1) and 39% of 19. Finally, quenching per- with spectroscopic data of the 2-(1,2-oxazetidin-4-yl)-4,5-
formed after 1 h gave 85% of 19 and a small amount (Ͻ dihydro-1,3-oxazoles 25a and 27a (see below).[12]
5%) of 17b and 18b (Scheme 6).[10] All these data seem to
The reaction between lithiated 2-(chloromethyl)-4,4-di-
suggest that lithiated spirocyclic compound 17a tends to methyl-4,5-dihydro-1,3-oxazole 2e and nitrone 3a was care-
convert into the 2-(1,2-oxazetidin-4-yl)-4,5-dihydro-1,3-ox- fully investigated. We found that addition of 2e to 3a and
azole 19, through a stereoelectronically allowed ring-con- acidic quenching after 3 h gave alkenes 26a and 8a (46%
traction process. Here the NLi group would provide the yield; 26a/8a ϭ 97:3), together with the 2-(1,2-oxazetidin-4-
electronic ‘‘push’’ to form the dihydrooxazolyl ring, and the yl)-4,5-dihydro-1,3-oxazoles 25a (22% yield) and 27a (7%
isoxazolidine ring would contract by oxygen migration and yield) (Scheme 7, Figure 1). In order to explain the forma-
chloride replacement. If we look at the orbitals involved in tion of the above alkenes and oxazetidines, a careful exam-
the reaction, we can understand why this ring-contraction ination of the reaction mixture at shorter reaction times,
1
supported by H NMR investigation, was performed. The
reaction mixture obtained by addition of 3a to 2e[3a,13]
(Scheme 7, Figure 1) with quenching after 1 min was chro-
matographed to give the trans-spirocyclic compound 21-H
(7%), a mixture of the threo/erythro (4.1:1 ratio) compounds
23-H and 24-H and the cis-spirocyclic compound 22-H
(44% combined yield; (23-H ϩ 24-H)/21-H ϭ 9:1), trans-2-
(1,2-oxazetidin-4-yl)-4,5-dihydro-1,3-oxazole 25a (2%), cis-
2-(1,2-oxazetidin-4-yl)-4,5-dihydro-1,3-oxazole 27a (1%),
Scheme 5
and a mixture of the two 2-[(Z)- and (E)-alkenyl]-4,5-dihy-
dro-1,3-oxazoles 26a and 8a [13% combined yield; (Z)/
(E) ϭ 3:1]. All these compounds were isolated and spectro-
1
scopically characterized. H NMR inspection of the above
reaction mixture after 1 min (Figure 1) showed the presence
of a diastereomeric mixture of two trans-1,6-dioxa-2,9-di-
azaspiro[4.4]nonanes 21-H,[14] together with the cis-spiro-
cyclic form 22-H [22-H/21-H ϭ 7:3; dr(21-H) ϭ 6:1], a dia-
stereomeric mixture of the corresponding hydroxylamine
forms 23-H and 24-H (threo/erythro ϭ 4.1:1),[15] a mixture
of cis- and trans-2-(1,2-oxazetidin-4-yl)-4,5-dihydro-1,3-ox-
azole 27a and 25a[13] (cis/trans ϭ 1:2), and a mixture of
(Z)- and (E)-4,4-dimethyl-2-styryl-4,5-dihydro-1,3-oxazoles
26a and 8a [(Z)/(E) ϭ 3:1]. 1H NMR inspection after longer
reaction times (Figure 1) revealed that signals correspond-
ing to the 4,5-dihydro-1,3-oxazole 25a, as well as to (Z)-
alkene derivative 26a, tended to increase while signals of
Scheme 6
spirocyclic compounds 21-H and 22-H and the correspond-
Eur. J. Org. Chem. 2002, 2961Ϫ2969
2963

V. Capriati, L. Degennaro, S. Florio, R. Luisi
FULL PAPER
ing opened forms 24-H and 23-H tended to decrease. Ac-
We have also established that the alkenes do not originate
cording to these results it is reasonable that the stereoselec- from oxazetidines. Indeed, subjection of a mixture of the
tive determining step in the reaction between 2e and nitrone threo/erythro forms of 23-H and 24-H (threo/erythro ϭ
3a is the addition of the litiated species 2e to the CϭN bond 87:13) to deprotonation with 1 equiv. of LDA resulted after
of 3a. Now, the point is: why are (Z)-alkene 26a and trans- 2 h in the formation of a mixture of alkenes 26a and 8a
4,5-dihydro-1,3-oxazole 25a the main reaction products at [(Z)/(E) ϭ 90:10] and oxazetidines 25a/27a (trans/cis ϭ
long reaction times? In view of the fact that oxazetidines 53:47). In contrast, starting from a mixture of the two trans-
could derive primarily from a ring-contraction process of spirocyclic compounds 21-H, only the trans-oxazetidine 25a
the spirocyclic compounds (as just seen for 17b and 18b) (87%) and traces of alkene 8a formed upon treatment with
and that the molar ratio between the opened forms 23-H 1 equiv. of LDA. Moreover, upon warming to high temper-
and 24-H and the corresponding spirocyclic compounds 21- atures (300 °C) or treatment with NaH/DMSO, the trans-
H and 22-H is approximately constant during the reaction oxazetidine 25a cycloreverted to a mixture of 4,5-dihydro-
(4:1 and 3:1, respectively), it is possible that the conversion 1,3-oxazole-2-carbaldehyde and N-tert-butylbenzylidenim-
of 21-Li into 25a could be more favored than that of 22-Li ine. Therefore, alkenes 26a and 8a cannot have been formed
to 27a for the same reason as why 17b affords 19 but 18b from oxazetidines 27a and 25a, respectively.
does not give 20. It follows that the propensity of 21-Li and
Treatment of 2e with nitrones 3bϪd and 3fϪh with
23-Li to give 25a and 26a could be higher than that of 24- quenching after 3 h afforded the 2-[(Z)-alkenyl]-4,5-dihy-
Li and 22-Li to give 8a and 27a, respectively, which would dro-1,3-oxazoles 26 (see Table 2) highly stereoselectively,
explain the increasing amounts of 25a and 26a with time.
with the (Z)/(E) ratios ranging from 90:10 to 97:3. In all
cases, small amounts of the corresponding cis- and trans-
1
oxazetidines were observed in the H NMR spectra of the
crude reaction mixtures. In the case of the reaction between
2e and 3c, oxazetidines 25c and 27c (Scheme 7) were also
isolated and characterized.
Conclusion
In conclusion, we report in this paper that lithiated 2-
alkyl-4,5-dihydro-1,3-oxazoles 2a,b add highly stereoselec-
tively to nitrones 3 to produce isolable 1,6-dioxa-2,9-diaza-
spiro[4.4]nonanes initially, and then 2-[(E)-alkenyl]-4,5-dihy-
dro-1,3-oxazoles 8 and 14 at longer reaction times (3 h),
with elimination of tert-butylhydroxylamine. The reaction
between 2c and 3a ends with the formation of spirocyclic
compound 15 (the hydroxylamine elimination not being
possible).
The lithiated 2-(chloromethyl)- and 2-(1-chloroethyl)-4,5-
dihydro-1,3-oxazoles 2e and 2d behave differently. Com-
pound 2d reacts with nitrone 3a to furnish 1,6-dioxa-2,9-
diazaspiro[4.4]nonanes 17b and 18b after short reaction
times, while 17b converts over time into oxazetidine 19. The
reactions between α-lithiated 2-(chloromethyl)-4,5-dihydro-
1,3-oxazole 2e and nitrones 3 stereoselectively provides 2-
[(Z)-alkenyl]-4,5-dihydro-1,3-oxazoles 26. A detailed 1H
NMR examination of the reaction mixture at short reaction
times allowed us to isolate and identify the precursors of 2-
alkenyl-4,5-dihydro-1,3-oxazoles 26. In any case, this work
has allowed the development of a stereoselective method
of preparation of 2-[(Z)- and (E)-alkenyl]-4,5-dihydro-1,3-
oxazoles, which are potentially useful Michael acceptors
and activated dienophiles. Moreover, the elucidation of the
reaction paths should be useful in the future for selection
of appropriate experimental conditions for the preparation
of 1,6-dioxa-2,9-diazaspiro[4.4]nonanes, 2-(1,2-oxazetidin-
4-yl)-4,5-dihydro-1,3-oxazoles, and isoxazolidin-5-ones.
Scheme 7
Figure 1. Time-resolved 1H NMR (500 MHz) spectra for the reac-
tion between 2e and 3a in CDCl3 at room temperature; the reaction
time is marked on each spectrum
2964
Eur. J. Org. Chem. 2002, 2961Ϫ2969

Addition of Lithiated 2-Alkyl- and 2-(Chloroalkyl)-4,5-dihydro-1,3-oxazoles to Nitrones
FULL PAPER
Table 2. Synthesis of 2-[(Z)-alkenyl]-4,5-dihydro-1,3-oxazoles 26
Nitrone
R
Compound
(yield%)[a][b]
Conversion (%)
(Z)/(E)[c]
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
p-MeC6H4
p-ClC6H4
p-CH3OC6H4
2,4,6-(CH3O)3C6H2
3,4-(methylenedioxy)C6H3
cyclohexyl
CH3(CH2)6
p-O2NC6H4
26a (46)
26b (67)
26c (66)
26d (57)
26e[d]
26f (38)
26g (55)
26h (49)
26i[d]
75
57
77
50
Ϫ
86
Ͼ 95
45
97:3
97:3
97:3
97:3
Ϫ
94:6
90:10
90:10
Ϫ
Ϫ
[a]
[b]
[c]
1
[d]
Based on the converted nitrone. Yields were not optimized. Determined by H NMR analysis. No reaction.
vided (E)-alkenes 8aϪh. All these compounds could be purified by
flash chromatography on silica gel (petroleum ether/EtOAc,
Experimental Section
9Ϫ8:1Ϫ2).
General Remarks: Tetrahydrofuran (THF) was freshly distilled from
sodium benzophenone ketyl under nitrogen. Diisopropylamine and
TMEDA were distilled from finely powdered calcium hydride. All the
other chemicals were of commercial grade (Aldrich) and were used
without further purification. ‘‘Petroleum ether’’ refers to the fraction
boiling at 40Ϫ60 °C. Commercial solutions of nBuLi (in hexanes)
and sBuLi (in cyclohexane) from Aldrich were titrated with N-piva-
loyl-o-toluidine prior to use.[16] NMR: Bruker (300 or 500 MHz and
75.4 or 125 MHz, for 1H and 13C, respectively). For 1H NMR, CDCl3
2-{2-[tert-Butyl(hydroxy)amino]-2-phenylethyl}-4,4-dimethyl-4,5-
dihydro-1,3-oxazole (6): Yield: 136 mg (78%), m.p. 114Ϫ115 °C (n-
hexane). MS (ESI): m/z ϭ 313 (6) [M ϩ Na]ϩ, 290 (10) [M]ϩ, 289
(10), 233 (19) [Mϩ Ϫ tBu], 202 (100) [Mϩ Ϫ tBuNOH]. FT-IR (KBr):
ν˜ ϭ 3251 (br., OH) cmϪ1, 1652 (CϭN), 1363, 701. C17H26N2O2
(290.40): calcd. C 70.31, H 9.02, N 9.65; found C 69.91, H 9.27, N
9.35. In CDCl3 solution, it equilibrates to a mixture of the two dia-
stereomeric 2-tert-butyl-8,8-dimethyl-3-phenyl-1,6-dioxa-2,9-diaza-
spiro[4.4]nonanes 7 [7/6 ϭ 7.1:1; dr(7) ϭ 7:3]: 1H NMR (500 MHz):
δ ϭ 0.91 (s, 9 H, N-tBu-H, compd. 7 major), 0.97 (s, 9 H, N-tBu-H,
compd. 6), 0.98 (s, 9 H, N-tBu-H, compd. 7 minor), 1.17 and 1.33
(2 ϫ s, 2 ϫ 3 H, 2 ϫ CH3 dihydrooxazolyl, compd. 6), 1.18 and 1.32
(2 ϫ s, 2 ϫ 3 H, 2 ϫ CH3 dihydrooxazolyl, compd. 7 minor), 1.19 and
1.23 (2 ϫ s, 2 ϫ 3 H, 2 ϫ CH3 dihydrooxazolyl, compd. 7 major),
2.42Ϫ2.54 [m, 1 H (4-H, compd. 7 major) ϩ 2 H (4-H ϩ 4-HЈ,
compd. 7 minor)], 2.54 and 2.71 (2 ϫ dd, J ϭ 9.0, 13.0 Hz, 2 ϫ 2 H,
4-H ϩ 4-HЈ, compd. 6), 3.09 (dd, J ϭ 10.7, 13.5 Hz, 1 H, 4-HЈ,
compd. 7 major), 3.65 and 3.71 (2 ϫ d, AB system, J ϭ 7.0 Hz, CH2
dihydrooxazolyl, compd. 7 minor), 3.67 and 3.68 (2 ϫ d, AB system,
J ϭ 7.3 Hz, CH2 dihydrooxazolyl, compd. 6), 3.87 and 3.88 (2 ϫ d,
AB system, J ϭ 7.7 Hz, CH2 dihydrooxazolyl, compd. 7 major), 4.17
(like t, J ϭ 8.6 Hz, 1 H, 2-H, compd. 6), 4.37 (dd, J ϭ 6.0, 10.2 Hz, 1
H, 2-H, compd. 7 major), 4.46 (dd, J ϭ 6.8, 12.0 Hz, 1 H, 2-H,
compd. 7 minor), 7.18Ϫ7.38 (m, 3 ϫ 3 H, Ar-H, compd. 6 ϩ 7 major
ϩ7 minor), 7.41Ϫ7.52 (m, 3 ϫ 2 H, Ar-H, compd. 6 ϩ 7 major ϩ 7
minor) ppm. 13C NMR (125 MHz) (selected data for compd. 6 ϩ 7
major ϩ 7 minor): δ ϭ 25.9, 26.1, 26.6, 28.0, 28.1, 34.8, 50.2, 50.9,
57.3, 58.9, 62.0, 63.2, 63.5, 66.5, 72.4, 76.6, 76.9, 79.0, 117.5, 126.8,
126.9, 127.2, 127.8, 128.1, 129.0, 141.6, 142.7, 164.9 ppm.
as solvent, δH ϭ 7.26 ppm; for 13C NMR, CDCl3 as solvent, δC
ϭ
77.0 ppm. FT-IR: PerkinϪElmer Spectrum One. GC-MS spectro-
metry analyses were performed with an HP 6890 gas chromatograph
(HP-5MS capillary column, 30 m, 0.25 mm i.d.) equipped with a
mass-selective detector operating at 70 eV (EI). Electron Spray Ion-
ization (ESI) mass spectrometry was carried out with a LCQ-Finni-
gan Mat single quadrupole ion trap mass spectrometer, coupled with
an Excalibur data system. Melting points were uncorrected. TLC was
performed on Merck silica gel plates with F-254 indicator; viewing
was accomplished by UV light (254 nm). Column chromatography
was performed on silica gel (70Ϫ230 mesh), with petroleum ether (or
hexane)/Et2O (or EtOAc) mixture as eluent. All reactions involving
air-sensitive reagents were performed under nitrogen in oven-dried
glassware by syringe/septum cap techniques. Spectroscopic data for
compounds 8b and 26b have been reported in ref.[4]
Typical Procedure for the Synthesis of Compounds 6, 8a؊h, 9, 10, 15,
17b, 18b, and 19: A solution of 4,5-dihydro-1,3-oxazole 1a (or 1b, 1c,
or 1d, 0.66 mmol) in 1.3 mL of THF was added dropwise under N2
to a precooled (Ϫ98 °C with a methanol/liquid nitrogen bath) solu-
tion of LDA (0.66 mmol) in dry THF (5 mL), and the resulting mix-
ture was stirred at this temperature for 20 min. In the case of 15, to a
precooled (Ϫ78 °C) solution of 1c (0.66 mmol) and TMEDA (0.92
mmol) in dry THF (5 mL), sBuLi (0.92 mmol) was added dropwise
(E)-4,4-Dimethyl-2-styryl-4,5-dihydro-1,3-oxazole
(8a):
Yield:
1
and the resulting mixture was stirred at this temperature for 1 h. After 114 mg (95%), yellow oil, dr (E)/(Z) Ͼ 99:1. H NMR (500 MHz):
this time, a solution of nitrone 3 (0.60 mmol) in 1.3 mL of THF was
added dropwise at Ϫ98 °C. When the reaction mixture was stirred for
δ ϭ 1.31 (s, 6 H), 4.00 (s, 2 H), 6.58 (d, J ϭ 15.8 Hz, 1 H), 7.31 (d, J ϭ
15.8 Hz, 1 H), 7.32Ϫ7.38 (m, 3 H), 7.41Ϫ7.45 (m, 2 H) ppm. 13C
only 10 min, quenched with sat. aq. NH4Cl, extracted with Et2O (3 NMR (75.4 MHz): δ ϭ 28.5, 67.4, 78.9, 115.6, 127.5, 129.0, 129.5,
ϫ 10 mL), and concentrated in vacuo, compounds 6, 9, 17b, 18b, and
19 could be obtained. When the reaction mixture was stirred over-
night and then quenched with sat. aq. NH4Cl, a similar workup pro-
135.4, 139.8, 162.0 ppm. GC-MS (70 eV): m/z (%) ϭ 201 (17) [Mϩ],
186 (100), 130 (25), 115 (26). FT-IR (film): ν˜ ϭ 2967 cmϪ1, 1655 (Cϭ
N), 1608 (CϭC), 1355, 1004, 973, 758, 697.
Eur. J. Org. Chem. 2002, 2961Ϫ2969
2965

V. Capriati, L. Degennaro, S. Florio, R. Luisi
FULL PAPER
(E)-2-[2-(4-Chlorophenyl)vinyl]-4,4-dimethyl-4,5-dihydro-1,3-oxa- (selected data for the trans major isomer): δ ϭ 9.0, 26.1, 26.8, 28.3,
zole (8c): Yield: 98 mg (70%), yellow oil, dr (E)/(Z) Ͼ 99:1. 1H NMR 52.3, 55.9, 59.2, 69.1, 76.7, 119.2 (C spiro), 126.8, 127.0, 128.0, 142.5
(300 MHz): δ ϭ 1.31 (s, 6 H), 4.00 (s, 2 H), 6.53 (d, J ϭ 16.2 Hz, 1
ppm. GC-MS (70 eV): m/z (%) ϭ 304 (1) [Mϩ], 214 (100), 200 (28),
H), 7.25 (d, J ϭ 16.2 Hz, 1 H), 7.27Ϫ7.48 (m, 4 H) ppm. 13C NMR 127 (23), 115 (28), 91 (15), 57 (14), 41 (12). FT-IR (film): ν˜ ϭ 3353
(75.4 MHz): δ ϭ 28.5, 67.5, 79.0, 116.3, 128.7, 129.3, 134.0, 135.4,
(NϪH) cmϪ1, 2972, 1464, 1381, 1362, 1049, 994, 844, 691, 600.
C18H28N2O2 (304.43): calcd. C 71.01, H 9.27, N 9.20; found C 69.93,
138.4, 161.7 ppm. GC-MS (70 eV): m/z (%) ϭ 236 (13) [Mϩ ϩ 2], 234
(30), 220 (100), 164 (24). FT-IR (film): ν˜ ϭ 2965 cmϪ1, 1653 (CϭN), H 9.48, N 8.91.
1604 (CϭN), 1491, 1088.
N-tert-Butyl-N-[(2-tert-butyl-4,8,8-trimethyl-3-phenyl-1,6-dioxa-
2,9-diazaspiro[4.4]non-4-yl)phenylmethyl]hydroxylamine (10): Yield:
14 mg (5% yield, dr ϭ 95:5 by 1H NMR), m.p. 122Ϫ124 °C (n-hex-
ane). 1H NMR (300 MHz) (selected data for the major isomer): δ ϭ
0.71 (s, 3 H), 0.99 (s, 9 H), 1.00 (s, 9 H), 1.19 (s, 3 H), 1.23 (s, 3 H),
1.8Ϫ1.9 (br. s, exchanges with D2O, 2 H), 3.74 (s, 1 H), 3.75 (d, J ϭ
10.8 Hz, 1 H), 4.38 (s, 1 H), 5.04 (d, J ϭ 7.8 Hz, 1 Ar-H), 6.74Ϫ7.50
(8 m, 8 Ar-H), 7.92 (d, J ϭ 7.7 Hz, 1 Ar-H) ppm. 13C NMR
(125 MHz) (selected data for the major isomer): δ ϭ 21.8, 25.8, 26.7,
26.9, 28.8, 53.9, 58.6, 59.9, 66.1, 67.8, 69.5, 75.8, 117.3, 126.5, 127.0,
127.4, 127.8, 128.0, 128.3, 129.8, 130.5, 138.6, 140.0 ppm. MS (ESI):
m/z ϭ 504 (20) [M ϩ Na]ϩ 482 (100) [M ϩ H]ϩ. FT-IR (KBr): ν˜ ϭ
3483 cmϪ1, 3401, 2973, 1362, 1215, 1056, 709. C29H43N3O3 (481.67):
calcd. C 72.31, H 9.00, N 8.72; found C 71.93, H 8.78, N 8.53.
(E)-2-[2-(4-Methoxyphenyl)vinyl]-4,4-dimethyl-4,5-dihydro-1,3-oxa-
zole (8d): Yield: 105 mg (85%, based on 90% conversion), yellow oil,
dr (E)/(Z) Ͼ 99:1. 1H NMR (300 MHz): δ ϭ 1.34 (s, 6 H), 3.83 (s, 3
H), 4.02 (s, 2 H), 6.47 (d, J ϭ 16.2 Hz, 1 H), 6.89 (d, J ϭ 8.7 Hz, 2 H),
7.29 (d, J ϭ 16.2 Hz, 1 H), 7.42 (d, J ϭ 8.4 Hz, 2 H) ppm. 13C NMR
(75.4 MHz): δ ϭ 28.6, 55.6, 67.3, 79.0, 113.3, 114.5, 128.2, 129.1,
139.4, 160.8, 162.3 ppm. GC-MS (70 eV): m/z (%) ϭ 230 (100) [Mϩ
Ϫ 1], 216 (33), 145 (20). FT-IR (film): ν˜ ϭ 2967 cmϪ1, 1655 (CϭN),
1603 (CϭC), 1512, 1294.
(E)-4,4-Dimethyl-2-[2-(2,4,6-trimethoxyphenyl)vinyl]-4,5-dihydro-
1,3-oxazole (8e): Yield: 116 mg (95%, based on 70% conversion),
m.p. 140Ϫ142 °C (n-hexane), dr (E)/(Z) Ͼ 99:1. 1H NMR
(300 MHz): δ ϭ 1.30 (s, 6 H), 3.80 (s, 3 H), 3.82 (s, 6 H), 3.98 (s, 2 H),
6.08 (s, 2 H), 6.99 (d, J ϭ 16. 2 Hz, 1 H), 7.64 (d, J ϭ 16.2 Hz, 1 H)
ppm. 13C NMR (75.4 MHz): δ ϭ 28.4, 55.3, 55.6, 66.8, 78.5, 90.3,
106.3, 115.6, 130.2, 160.5, 161.8, 163.5 ppm. GC-MS (70 eV): m/z
2-tert-Butyl-4,4,8,8-tetramethyl-3-phenyl-1,6-dioxa-2,9-diazaspiro-
[4.4]nonane (15): Yield: 131 mg (69% yield, dr ϭ 95:5 by 1H NMR),
1
m.p. 67Ϫ69 °C (n-hexane). H NMR (300 MHz) (selected data for
(%) ϭ 291 (3) [Mϩ], 260 (100), 205 (15). FT-IR (KBr): ν˜ ϭ 2970 cmϪ1
,
the major isomer): δ ϭ 0.80 (s, 3 H), 0.88 (s, 3 H), 0.99 (s, 9 H), 1.18
(s, 3 H), 1.35 (s, 3 H), 1.8Ϫ1.9 (br. s, exchanges with D2O, 1 H), 3.64
and 3.78 (2 ϫ d, AB system, J ϭ 7.5 Hz, 2 H), 4.24 (s, 1 H), 7.04Ϫ7.07
(m, 1 H), 7.19Ϫ7.32 (m, 3 H), 7.73Ϫ7.75 (m, 1 H) ppm. 13C NMR
(125 MHz) (selected data for the major isomer): δ ϭ 19.2, 20.0, 26.9,
27.4, 28.9, 48.9, 55.9, 59.5, 70.9, 77.3, 121.9 (C spiro), 126.9, 127.3,
127.5, 129.2, 140.5 ppm. GC-MS (70 eV): m/z (%) ϭ 318 (1) [Mϩ],
232 (39), 192 (4), 175 (12), 148 (15), 105 (100), 77 (25), 58 (8). FT-IR
(KBr): ν˜ ϭ 3378 (NϪH) cmϪ1, 2973, 1454, 1362, 1258, 1217, 1084,
1032, 971, 707. C19H30N2O2 (318.45): calcd. C 71.66, H 9.49, N 8.80;
found C 71.65, H 9.60, N 8.61.
1639 (CϭN), 1606 (CϭC), 1573, 1197, 1118, 800. C16H21NO4
(291.34): C 65.96, H 7.27, N 4.81; found C 65.78, H 7.28, N 4.79.
2-[(E)-2-(1,3-Benzodioxol-5-yl)vinyl]-4,4-dimethyl-4,5-dihydro-1,3-
oxazole (8f): Yield: 102 mg (70%), yellow oil, dr (E)/(Z) Ͼ 99:1. 1H
NMR (300 MHz): δ ϭ 1.34 (s, 6 H), 4.02 (s, 2 H), 6.00 (s, 2 H), 6.43
(d, J ϭ 16.2 Hz, 1 H), 6.79Ϫ6.85 (m, 2 H), 6.88Ϫ6.95 (m, 2 H), 6.99
(s, 1 H), 7.25 (d, J ϭ 16.2 Hz, 1 H) ppm. 13C NMR (75.4 MHz): δ ϭ
26.4, 65.2, 76.9, 99.8, 104.1, 106.6, 111.6, 121.3, 127.8, 137.3, 146.3,
146.8, 159.9 ppm. GC-MS (70 eV): m/z (%) ϭ 244 (100) [Mϩ], 230
(40), 159 (23). FT-IR (film): ν˜ ϭ 2968, 1658 (CϭN), 1608 (CϭC),
1489, 1253, 1039, 808 cmϪ1
.
(3R*,4S*,5R*)-2-tert-Butyl-4-chloro-4,8,8-trimethyl-3-phenyl-1,6-
dioxa-2,9-diazaspiro[4.4]nonane (17b): Overall yield: 116 mg (57%),
17b/18b ϭ 5:1, m.p. 81Ϫ82 °C (n-hexane). 1H NMR (500 MHz): δ ϭ
0.99 (s, 9 H), 1.25 (s, 3 H), 1.33 (s, 3 H), 1.36 (s, 3 H), 2.0Ϫ2.2 (br. s,
1 H, exchanges with D2O), 3.78 (d, J ϭ 7.6 Hz, 1 H), 3.83 (d, J ϭ
7.6 Hz, 1 H), 4.62 (s, 1 H), 7.23Ϫ7.31 (m, 4 H), 7.68Ϫ7.70 (m, 1 H)
ppm. 13C NMR (125 MHz): δ ϭ 22.7, 26.7, 27.1, 27.8, 60.2, 70.7,
73.5, 77.9, 107.5, 127.3, 127.9, 128.8, 129.0, 137.6 ppm. GC-MS
(70 eV): m/z (%) ϭ 340 (1) [Mϩ ϩ 2], 338 (2) [Mϩ], 216 (42), 178 (29),
161 (100), 122 (60), 57 (14), 41 (7). FT-IR (KBr): ν˜ ϭ 3374 (sharp,
NϪH) cmϪ1, 1455, 1255, 1077, 704. C18H27ClN2O2 (338.18): calcd.
C 63.80, H 8.03, N 8.27, found C 64.12, H 8.31, N 8.56.
(E)-2-(2-Cyclohexylvinyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (8g):
Yield: 74 mg (60%), colorless oil, dr (E)/(Z) Ͼ 99:1. 1H NMR
(300 MHz): δ ϭ 1.02Ϫ1.25 (m, 10 H), 1.61Ϫ1.72 (m, 6 H), 2.05Ϫ2.07
(m, 1 H), 3.91 (s, 2 H), 5.85 (dd, J ϭ 1.3, 15.9 Hz, 1 H), 6.47 (dd, J ϭ
6.8, 15.9 Hz, 1 H) ppm. 13C NMR (75.4 MHz): δ ϭ 25.4, 25.9, 28.3,
31.8, 40.6, 66.8, 78.6, 115.5, 148.8, 161.7 ppm. GC-MS (70 eV): m/z
(%) ϭ 207 (53) [Mϩ], 192 (100), 110 (90). FT-IR (film): ν˜ ϭ 2926
cmϪ1, 1672 (CϭN), 1610 (CϭC), 1449, 976.
(E)-4,4-Dimethyl-2-(non-1-enyl)-4,5-dihydro-1,3-oxazole (8h): Yield:
70 mg (52%), colorless oil, dr (E)/(Z) Ͼ 99:1. 1H NMR (300 MHz):
δ ϭ 0.84Ϫ1.00 (m, 6 H), 1.05Ϫ1.72 (m, 13 H), 2.12Ϫ2.25 (m, 2 H),
3.92 (s, 2 H), 5.90 (d, J ϭ 15.9 Hz, 1 H), 6.54 (dt, J ϭ 6.8, 15.9 Hz, 1
H) ppm. 13C NMR (75.4 MHz): δ ϭ 14.2, 22.8, 28.5, 29.3, 31.9, 32.7,
67.1, 79.3, 118.0, 144.1, 161.7 ppm. GC-MS (70 eV): m/z (%) ϭ 223
(7) [Mϩ], 208 (100), 110 (33). FT-IR (film): ν˜ ϭ 2927 cmϪ1, 1674 (Cϭ
N), 1612 (CϭC), 1002, 974.
(3R*,4R*,5R*)-2-tert-Butyl-4-chloro-4,8,8-trimethyl-3-phenyl-1,6-
dioxa-2,9-diazaspiro[4.4]nonane (18b): M.p. 101Ϫ102 °C (n-hexane).
1H NMR (500 MHz): δ ϭ 1.00 (s, 9 H), 1.23 (s, 3 H), 1.38 (s, 3 H), 1.43
(s, 3 H), 2.42 (br. s, 1 H, exchanges with D2O), 3.71 (d, J ϭ 7.2 Hz, 1
H), 3.89 (d, J ϭ 7.2 Hz, 1 H), 4.41 (s, 2 H), 7.06Ϫ7.07 (m, 1 H),
7.23Ϫ7.29 (m, 2 H), 7.31Ϫ7.34 (m, 1 H), 7.90Ϫ7.92 (m, 1 H) ppm.
13C NMR (125 MHz): δ ϭ 21.2, 26.9, 27.6, 28.3, 56.3, 59.8, 70.8,
78.6, 79.2, 120.4, 127.4, 127.9, 130.7, 138.0 ppm. GC-MS (70 eV):
m/z (%) ϭ 340 (1) [Mϩ ϩ 2], 338 (3) [Mϩ], 216 (44), 178 (30), 161
(100), 122 (54). FT-IR (KBr): ν˜ ϭ 3393 (sharp, NϪH) cmϪ1, 1455,
1379, 1057, 971. C18H27ClN2O2 (338.18): calcd. C 63.80, H 8.03, N
8.27; found C 64.19, H 8.41, N 8.28.
trans-2-tert-Butyl-4,8,8-trimethyl-3-phenyl-1,6-dioxa-2,9-diaza-
1
spiro[4.4]nonane (9): Yield: 127 mg (70% yield, dr ϭ 87:9/4 by H
1
NMR), m.p. 75Ϫ77 °C (n-hexane). H NMR (300 MHz) (selected
data for the trans major isomer): δ ϭ 0.86 (d, J ϭ 7.0 Hz, 3 H), 0.97
(s, 9 H), 1.17 (s, 3 H), 1.34 (s, 3 H), 2.04Ϫ2.26 (br. s, exchanges with
D2O, 1 H), 2.28Ϫ2.40 (m, 1 H), 3.58 and 3.73 (2 ϫ d, AB system, J ϭ
7.3 Hz, 2 H), 3.90 (d, J ϭ 11.3 Hz, 1 H), 7.16Ϫ7.20 (m, 1 H),
(3R*,4S*)-2-(2-tert-Butyl-4-methyl-3-phenyl-1,2-oxazetidin-4-yl)-
7.22Ϫ7.28 (m, 2 H), 7.33Ϫ7.45 (m, 2 H) ppm. 13C NMR (125 MHz) 4,4-dimethyl-4,5-dihydro-1,3-oxazole (19): Yield: 70 mg (39%), m.p.
2966
Eur. J. Org. Chem. 2002, 2961Ϫ2969

Addition of Lithiated 2-Alkyl- and 2-(Chloroalkyl)-4,5-dihydro-1,3-oxazoles to Nitrones
79Ϫ80 °C (n-hexane). 1H NMR (500 MHz): δ ϭ 1.09 (s, 9 H), 1.28 and 3.94 (2 ϫ d, AB system, J ϭ 7.8 Hz, 2 H, CH2O dihydrooxazolyl,
FULL PAPER
(s, 3 H), 1.32 (s, 3 H), 1.34 (s, 3 H), 4.03 (s, 2 H), 5.47 (s, 1 H),
cis), 4.22 (d, J ϭ 4.3 Hz, 1 H, CHCl, threo), 4.32 (d, J ϭ 10.3 Hz, 1
7.26Ϫ7.55 (2 m, 5 H) ppm. 13C NMR (75.4 MHz, DEPT): δ ϭ 21.2 H, CHCl, erythro), 4.42 and 4.46 (2 ϫ d, AB system, J ϭ 10.4 Hz, 2
(CH3), 23.7 (CH3), 28.2 (CH3), 59.2, 65.5 (CH), 67.4, 78.1, 79.7 H, isoxazolidinyl, cis), 4.60Ϫ4.80 (br.s, exchanges with D2O, 2 ϫ 1
(CH2), 127.5 (ArCH), 128.1 (ArCH), 137.4 (C ipso), 165.4 (CϭN).
Two complementary fragments corresponding to 4,4-dimethyl-4,5-
dihydro-1,3-oxazol-2-yl methyl ketone (M. W. 141) and to N-tert-bu-
tylbenzylideneamine (M. W. 161) were observed in the GC-MS of 19
at 70 eV, with the following fragmentations (respectively): m/z (%) ϭ
141 (6) [Mϩ], 126 (2), 84 (68), 69 (89), 56 (100), 41 (76); m/z (%) ϭ
161 (10) [Mϩ], 160 (5), 146 (100), 106 (24), 104 (25), 89 (10), 77 (11),
57 (20), 41 (10). FT-IR (KBr): ν˜ ϭ 1663 (CϭN), cmϪ1, 1451, 1365,
1244, 1088. C18H26N2O2 (302.20): C 71.49, H 8.67, N 9.26; found C
71.87, H 8.98, N 9.06.
H, OH), 4.87 (d, J ϭ 4.3 Hz, 1 H, CHPh, threo), 5.12 (d, J ϭ 10.3 Hz,
1 H, CHPh, erythro), 7.18Ϫ7.36 (m, 4 ϫ 3 H, Ar-H, threo ϩ erythro
ϩ cis ϩ trans), 7.42Ϫ7.52 (m, 4 ϫ 2 H, Ar-H, threo ϩ erythro ϩ cis
ϩ trans).
trans-2-(2-tert-Butyl-3-phenyl-1,2-oxazetidin-4-yl)-4,4-dimethyl-4,5-
dihydro-1,3-oxazole (25a): Yield: 38 mg (22%), yellow oil. 1H NMR
(500 MHz): δ ϭ 1.07 (s, 9 H), 1.28 (s, 2 ϫ 3 H), 3.99 and 4.01 (2 ϫ d,
AB system, J ϭ 7.6 Hz, 2 H, CH2O dihydrooxazolyl hydrogen
atoms), 5.16 and 5.22 (2 ϫ d, AB system, J ϭ 8.1 Hz, 2 H, oxazetidine
vicinal hydrogen atoms), 7.24Ϫ7.40 (2 m, 3 H), 7.50Ϫ7.65 (m, 2 H)
ppm. 13C NMR (125 MHz): δ ϭ 23.2, 27.8, 27.9, 59.5, 62.8, 67.0,
75.5, 79.0, 127.8, 136.8, 162.2 ppm. MS (ESI): m/z ϭ 289 (100) [M ϩ
H]ϩ, 202 (10). FT-IR (film): ν˜ ϭ 2970 cmϪ1, 1681 (CϭN), 1455, 1364,
1070, 699.
Typical Procedure for the Synthesis of Compounds 21-H, 23-H, 24-H,
25a, 25c, 26a؊d, 26f؊h, 27a, and 27c: A solution of 2-(chlorome-
thyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (1e) (97 mg, 0.66 mmol)
and nitrone 3 (0.60 mmol) in 3 mL of THF was added dropwise un-
der N2 to a precooled (Ϫ98 °C with a methanol/liquid nitrogen bath)
solution of LDA (0.66 mmol) in dry THF (5 mL), and the resulting
mixture was stirred overnight, quenched with sat. aq. NH4Cl, ex-
tracted with Et2O (3 ϫ 10 mL), and concentrated in vacuo. Com-
pounds 25a, 25c, 26aϪd, 26fϪh, 27a, and 27c could be isolated by
flash chromatography on silica gel (petroleum ether/Et2O, 3:2). On
the other hand, compounds 21-H, 23-H, and 24-H could be isolated
by quenching the reaction mixture after 1 min and usual workup as
described above.
trans-2-[2-tert-Butyl-3-(4-chlorophenyl)-1,2-oxazetidin-4-yl]-4,4-
dimethyl-4,5-dihydro-1,3-oxazole (25c): Yield: 23 mg (12%, based on
77% conversion), yellow oil. 1H NMR (500 MHz): δ ϭ 1.07 (s, 9 H),
1.29 (s, 3 H), 1.30 (s, 3 H), 4.01 and 4.03 (2 ϫ d, AB system, J ϭ
8.0 Hz, 2 H), 5.11 and 5.19 (2 ϫ d, AB system, J ϭ 8.1 Hz, 2 H),
7.30Ϫ7.36 (m, 2 H), 7.52Ϫ7.56 (m, 2 H) ppm. 13C NMR (125 MHz):
δ ϭ 23.4, 28.0, 28.2, 59.6, 64.3, 67.5, 76.0, 79.6, 128.6, 128.7, 134.0,
137.4, 161.5. Two complementary fragments corresponding to 4,4-
dimethyl-4,5-dihydro-1,3-oxazol-2-carbaldehyde (M. W. 127) and to
N-tert-butyl(p-chlorobenzylidene)amine (M. W. 195) were observed
in the GC-MS of 25c at 70 eV, with the following fragmentations
(respectively): m/z (%) ϭ 127 (47) [Mϩ], 112 (19), 97 (100), 69 (32), 57
(37), 42 (95): m/z (%) ϭ 195 (12) [Mϩ], 182 (38), 180 (100), 138 (20),
82 (24), 57 (90). FT-IR (film): ν˜ ϭ 2970 cmϪ1, 1664 (CϭN), 1491,
1364, 1089, 1014, 990.
trans-2-tert-Butyl-4-chloro-8,8-dimethyl-3-phenyl-1,6-dioxa-2,9-
diazaspiro[4.4]nonane (21-H): Yield: 14 mg (7% yield, dr ϭ 86:14 by
1H NMR), m.p. 89Ϫ91 °C (n-hexane). 1H NMR (500 MHz) (selected
data): δ ϭ 0.99 (s, 2 ϫ 9 H, major ϩ minor), 1.21 (s, 3 H, minor), 1.24
(s, 3 H, major), 1.33 (s, 3 H, minor), 1.35 (s, 3 H, major), 2.2Ϫ2.5 (br.
s, exchanges with D2O, 2 ϫ 1 H), 3.71 and 3.82 (2 ϫ d, AB system,
J ϭ 7.7 Hz, 2 H, minor), 3.74 and 3.82 (2 ϫ d, AB system, J ϭ 7.3 Hz,
2 H, major), 4.09 (d, J ϭ 6.4 Hz, 1 H, minor),4.10 (d, J ϭ 10.7 Hz, 1
H, major), 4.29 (d, J ϭ 10.7 Hz, 1 H, major),4.36 (d, J ϭ 6.4 Hz, 1
H, minor), 7.24Ϫ7.40 (m, 2 ϫ 3 H, major ϩ minor), 7.45Ϫ7.58 (m,
2 ϫ 2 H, major ϩ minor) ppm. 13C NMR (125 MHz) (selected data):
δ ϭ 26.1 (minor), 26.2 (major), 26.6 (minor), 27.0 (major), 27.2 (mi-
nor), 27.6 (major), 56.9, 57.7, 58.8, 60.3, 67.3, 67.5, 68.8, 73.0, 73.4,
77.9 (minor), 78.0 (major), 116.7 (C spiro minor),116.8 (C spiro ma-
jor), 127.5, 127.8, 128.0, 128.4, 128.5, 139.6, 139.7 ppm. MS (ESI):
m/z ϭ 327 (33) [M ϩ 2 ϩ H]ϩ, 325 (100) [M ϩ H]ϩ, 236 (5), 178 (25),
122 (7). FT-IR (KBr): ν˜ ϭ 3354 (NϪH) cmϪ1, 2973, 2878, 1466,
1383, 1359, 1210, 1040, 972, 766. C17H25ClN2O2 (324.85): calcd. C
62.85, H 7.75, N 8.62; found C 62.65, H 7.52, N 8.41.
(Z)-4,4-Dimethyl-2-styryl-4,5-dihydro-1,3-oxazole (26a): Yield:
42 mg (46%, based on 75% conversion), yellow oil, dr (Z)/(E) ϭ 97:3.
1H NMR (300 MHz) (selected data): δ ϭ 1.27 (s, 6 H), 3.88 (s, 2 H),
6.01 (d, J ϭ 12.6 Hz, 1 H), 6.83 (d, J ϭ 12.6 Hz, 1 H), 7.32Ϫ7.45 (m,
5 H) ppm. 13C NMR (75.4 MHz) (selected data): δ ϭ 28.3, 67.1, 79.0,
116.8, 128.0, 128.5, 129.7, 135.8, 139.4, 161.3 ppm. GC-MS (70 eV):
m/z (%) ϭ 200 (100) [Mϩ Ϫ 1], 186 (24), 130 (20), 115 (22). FT-IR
(film): ν˜ ϭ 2967 cmϪ1, 1655 (CϭN), 1607 (CϭC), 1355, 1001, 974,
759, 696.
(Z)-2-[2-(4-Chlorophenyl)vinyl]-4,4-dimethyl-4,5-dihydro-1,3-oxa-
zole (26c): Yield: 69 mg (66%, based on 77% conversion), yellow oil,
dr (Z)/(E) ϭ 97:3. 1H NMR (300 MHz) (selected data): δ ϭ 1.30 (s, 6
H), 3.91 (s, 2 H), 6.04 (d, J ϭ 12.6 Hz, 1 H), 6.80 (d, J ϭ 12.6 Hz, 1
H), 7.28 (d, J ϭ 7.0 Hz, 2 H), 7.43 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C
NMR (75.4 MHz) (selected data): δ ϭ 28.3, 67.3, 79.0, 117.5, 128.2,
131.1, 134.3, 134.4, 138.1, 161.0 ppm. GC-MS (70 eV): m/z (%) ϭ
236 (38) [Mϩ ϩ 2], 234 (100), 220 (22), 164 (17). FT-IR (film): ν˜ ϭ
2967 cmϪ1, 1657 (CϭN), 1588 (CϭC), 1491, 1091.
threo- and erythro-N-tert-Butyl-N-[2-chloro-2-(4,4-dimethyl-4,5-di-
hydro-1,3-oxazol-2-yl)-1-phenylethyl]hydroxylamine (23-H ؉ 24-H):
Yield: 86 mg (44%), m.p. 122Ϫ124 °C (n-hexane). MS (ESI): m/z ϭ
327 (33) [M ϩ 2 ϩ H]ϩ, 325 (100) [M ϩ H]ϩ, 267 (1), 236 (14), 178
(29), 122 (8). FT-IR (KBr): ν˜ ϭ 3290 cmϪ1, 2970, 1669 (CϭN), 699,
657. C17H25ClN2O2 (324.85): calcd. C 62.86, H 7.76, N 8.62; found
C 62.47, H 8.60, N 7.53. In CDCl3 solution, they equilibrate to a mix-
ture of the corresponding diastereomeric trans- and (Z)-2-[2-(4-Methoxyphenyl)vinyl]-4,4-dimethyl-4,5-dihydro-1,3-
cis-2-tert-butyl-4-chloro-8,8-dimethyl-3-phenyl-1,6-dioxa-2,9-
diazaspiro[4.4]nonanes (21-H ϩ 22-H) [(23-H ϩ 24-H)/(21-H ϩ 22-
H) ϭ 9:1; 23-H/24-H ϭ 85:15; 22-H/21-H ϭ 4:1]. 1H NMR
oxazole (26d): Yield: 40 mg (57%, based on 50% conversion), yellow
oil, dr (Z)/(E) ϭ 97:3. 1H NMR (300 MHz) (selected data): δ ϭ 1.31
(s, 6 H), 3.80 (s, 3 H), 3.93 (s, 2 H), 5.90 (d, J ϭ 12.2 Hz, 1 H), 6.76
(500 MHz) (selected data): δ ϭ 1.02 (s, 9 H, N-tBu-H, threo), 1.04 (s, (d, J ϭ 12.2 Hz, 1 H), 6.83 (d, J ϭ 8.4 Hz, 2 H), 7.50 (d, J ϭ 8.4 Hz,
9 H, N-tBu-H, erythro), 1.22 (s, 3 H, CH3, threo), 1.35 (s, 3 H, CH3, 2 H) ppm. 13C NMR (75.4 MHz) (selected data): δ ϭ 28.4, 55.4, 67.1,
threo), 2.20Ϫ2.70 (br.s, exchanges with D2O, 2 ϫ 1 H, NH), 3.59 (d,
78.9, 113.4, 114.6, 128.4, 131.6, 139.0, 159.9, 161.5 ppm. GC-MS
(film): ν˜ ϭ 2967 cmϪ1, 1655 (CϭN), 1604 (CϭC), 1511, 1252.
J ϭ 10.7 Hz, 1 H, CHO dihydrooxazolyl, erythro), 3.75 and 3.88 (2 (70 eV): m/z (%) ϭ 230 (100) [Mϩ Ϫ 1], 216 (21), 145 (18). FT-IR
ϫ d, AB system, J ϭ 7.7 Hz, 2 H, CH2O dihydrooxazolyl, threo), 3.77
Eur. J. Org. Chem. 2002, 2961Ϫ2969
2967

V. Capriati, L. Degennaro, S. Florio, R. Luisi
FULL PAPER
2-[(Z)-2-(1,3-Benzodioxol-5-yl)vinyl]-4,4-dimethyl-4,5-dihydro-1,3- (Z)-4,4-Dimethyl-2-(1-methyl-2-phenylvinyl)-4,5-dihydro-1,3-oxa-
oxazole (26f): Yield: 48 mg (38%, based on 86% conversion), yellow zole (14): Yield: 13 mg [quantitative yield of (Z) and (E) isomers, (E)/
oil, dr (Z)/(E) ϭ 94:6. 1H NMR (300 MHz) (selected data): δ ϭ 1.30 (Z) ϭ 9:1], oil. 1H NMR (300 MHz): δ ϭ 1.29 (s, 2 ϫ 3 H, 2 ϫ CH3
(s, 6 H), 3.93 (s, 2 H), 5.89 (d, J ϭ 12.8 Hz, 1 H), 5.94 (s, 2 H), 6.71
(d, J ϭ 12.8 Hz, 1 H), 6.74 (d, J ϭ 8.0 Hz, 1 H), 6.93 (dd, J ϭ 8.0,
1.3 Hz, 1 H), 7.25 (d, J ϭ 1.3 Hz, 1 H) ppm. 13C NMR (75.4 MHz)
(selected data): δ ϭ 28.1, 64.0, 78.7, 101.1, 107.7, 109.6, 111.4, 111.6,
oxazoline), 2.16 (d, J ϭ 0.8 Hz, 3 H, CH3 Cϭ), 3.85 (s, 2 H, CH2
oxazoline), 6.71 (m, 1 H, vinylic H), 7.18Ϫ7.42 (2 m, 5 H, Ar-H)
ppm. 13C NMR (125 MHz): δ ϭ 22.9, 28.0, 67.1, 78.7, 127.3, 127.7,
128.4, 134.3, 136.7, 163.2 ppm. GC-MS (70 eV): m/z (%) ϭ 214 (100)
114.7, 123.1, 124.7, 138.7, 170.8 ppm. GC-MS (70 eV): m/z (%) ϭ [Mϩ Ϫ 1], 115 (23), 55 (40). FT-IR (KBr): ν˜ ϭ 2925 cmϪ1, 1644 (Cϭ
244 (100) [Mϩ], 230 (20), 159 (26). FT-IR (film): ν˜ ϭ 2967cmϪ1, 1654
(CϭN), 1606 (CϭC), 1490, 1446, 1241, 1039.
N), 1614, 1094, 696.
(E)-4,4-Dimethyl-2-(1-methyl-2-phenylvinyl)-4,5-dihydro-1,3-oxa-
zole (14): Yield: 114 mg [quantitative yield of (Z) and (E) isomers,
(E)/(Z) ϭ 9:1], oil. 1H NMR (300 MHz): δ ϭ 1.34 (s, 2 ϫ 3 H, 2 ϫ
CH3 dihydrooxazolyl), 2.18 (d, J ϭ 1.4 Hz, 3 H, CH3 Cϭ), 4.02 (s, 2
H, CH2 dihydrooxazolyl), 7.15Ϫ7.45 (2 m, 6 H, Ar-H ϩ 1 vinylic H)
ppm. 13C NMR (125 MHz): δ ϭ 15.1, 28.3, 67.4, 78.8, 127.6, 128.2,
129.4, 134.8, 136.3, 164.1 ppm. GC-MS (70 eV): m/z (%) ϭ 214 (100)
[Mϩ Ϫ 1], 200 (30), 115 (30). FT-IR (KBr): ν˜ ϭ 2966 cmϪ1, 1643 (Cϭ
N), 1614, 1090, 759, 707, 693.
(Z)-2-(2-Cyclohexylvinyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole
(26g): Yield: 68 mg (55%), colorless oil, dr (Z)/(E) ϭ 90:10. 1H NMR
(300 MHz) (selected data): δ ϭ 0.98Ϫ1.44 (m, 10 H), 1.58Ϫ1.84 (m,
6 H), 2.96Ϫ3.06 (m, 1 H), 3.97 (s, 2 H), 5.71 (d, J ϭ 12.0 Hz, 1 H),
5.78 (dd, J ϭ 9.4, 12.0 Hz, 1 H) ppm. 13C NMR (75.4 MHz) (selected
data): δ ϭ 25.7, 26.1, 28.5, 32.9, 37.9, 66.3, 79.1, 114.7, 149.7, 162.2
ppm. GC-MS (70 eV): m/z (%) ϭ 207 (40) [Mϩ], 110 (38), 55 (39),
41 (100). FT-IR (film): ν˜ ϭ 2926 cmϪ1, 1664 (CϭN), 1638 (CϭC),
1448, 999.
2-tert-Butyl-4,4-dimethyl-3-phenylisoxazolidin-5-one (16): Yield:
77 mg (73% based on 65% conversion), m.p. 100Ϫ102 °C (n-hexane).
1H NMR (500 MHz): δ ϭ 0.92 (s, 3 H), 1.03 (s, 9 H), 1.18 (s, 3 H),
4.20 (s, 1 H), 7.01Ϫ7.68 (3 m, 5 H) ppm. 13C NMR (125 MHz): δ ϭ
21.2, 22.0, 25.9, 46.7, 60.9, 72.9, 127.1, 127.9, 128.0, 128.2, 128.9,
137.0, 178.4 ppm. GC-MS (70 eV): m/z (%) ϭ 247 (8) [Mϩ], 232 (11),
146 (22), 104 (70), 57 (100). FT-IR (KBr): ν˜ ϭ 2977 cmϪ1, 1770 (Cϭ
O), 1456, 1142, 705. C15H21NO2 (247.16): calcd. C 72.84, H 8.56, N
5.66; found C 72.95, H 8.74, N 5.66.
(Z)-4,4-Dimethyl-2-(non-1-enyl)-4,5-dihydro-1,3-oxazole
(26h):
Yield: 29 mg (49%, based on 45% conversion), colorless oil, dr (Z)/
(E) ϭ 90:10. 1H NMR (300 MHz) (selected data): δ ϭ 0.84Ϫ0.88 (m,
6 H), 1.14Ϫ1.61 (m, 13 H), 2.36Ϫ2.62 (m, 2 H), 3.94 (s, 2 H), 5.81 (d,
J ϭ 11.8 Hz, 1 H), 6.80 (dt, J ϭ 11.8, 7.5 Hz, 1 H) ppm. 13C NMR
(75.4 MHz) (selected data): δ ϭ 14.3, 22.8, 28.5, 29.3, 29.4, 32.0, 32.7,
66.6, 78.8, 116.5, 144.7, 162.2 ppm. GC-MS (70 eV): m/z (%) ϭ 223
(8) [Mϩ], 208 (21), 152 (100). FT-IR (film): ν˜ ϭ 2926 cmϪ1, 1666 (Cϭ
N), 1643 (CϭC), 1000.
X-ray Crystallographic Study: Crystallographic data and the most sa-
lient experimental parameters relating to the X-ray measurements
and the crystal structure analysis for compounds 17b and 18b are re-
ported in the Supporting Information. All diagrams and calculations
were produced with maXus (Nonius, Delft & MacScience, Japan),[17]
SIR92[18] and ORTEP.[19] CCDC-163503 and -163502 contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge at www.ccdc.cam.ac.uk/conts/retriev-
ing.html or from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; Fax: (internat.) ϩ44-1223/
336-033; E-mail: deposit@ccdc.cam.ac.uk].
cis-2-(2-tert-Butyl-3-phenyl-1,2-oxazetidin-4-yl)-4,4-dimethyl-4,5-
dihydro-1,3-oxazole (27a): Yield: 12 mg (7%), yellow oil. H NMR
1
(300 MHz): δ ϭ 0.82 (s, 3 H), 1.04 (s, 3 H), 1.14 (s, 9 H), 3.53 and 3.56
(2 ϫ d, AB system, J ϭ 8.1 Hz, 2 H), 5.27 and 5.56 (2 ϫ d, AB system,
J ϭ 10.0 Hz, 2 H, oxazetidine vicinal hydrogens), 7.27Ϫ7.36 (m, 3
H), 7.56Ϫ7.58 (m, 2 H) ppm. 13C NMR (125 MHz): δ ϭ 22.5, 27.0,
27.2, 58.6, 64.0, 66.4, 75.1, 78.5, 126.2, 127.1, 127.5, 137.8,
160.6 ppm. MS (ESI): m/z ϭ 289 (100) [M ϩ H]ϩ, 202 (2). FT-IR
(film): ν˜ ϭ 2970 cmϪ1, 1667 (CϭN), 1364, 990, 733, 700.
cis-2-[2-tert-Butyl-3-(4-chlorophenyl)-1,2-oxazetidin-4-yl]-4,4-
dimethyl-4,5-dihydro-1,3-oxazole (27c): Yield: 33 mg (17%, based on
77% conversion), yellow waxy solid. 1H NMR (300 MHz): δ ϭ 0.82
(s, 3 H), 1.00 (s, 3 H), 1.07 (s, 9 H), 3.50 and 3.55 (2 ϫ d, AB system,
J ϭ 7.9 Hz, 2 H), 5.17 (d, J ϭ 10.0 Hz, 1 H), 5.48 (d, J ϭ 10.0 Hz, 1
H), 7.10Ϫ7.13 (m, 2 H), 7.40Ϫ7.50 (m, 2 H) ppm. 13C NMR
(125 MHz): δ ϭ 23.1, 27.8, 27.9, 59.5, 62.0, 67.1, 75.3, 79.1, 127.9,
129.3, 133.6, 161.9. Two complementary fragments corresponding to
4,4-dimethyl-4,5-dihydro-1,3-oxazole-2-carbaldehyde (M. W. 127)
and to N-tert-butyl(p-chlorobenzylidene)amine (M. W. 195) were ob-
served in the GC-MS of 27c at 70 eV, with the following fragmenta-
tions (respectively): m/z (%) ϭ 127 (47) [Mϩ], 112 (19), 97 (100), 69
(32), 57 (37), 42 (95): m/z (%) ϭ 195 (12) [Mϩ], 182 (38), 180 (100),
138 (20), 82 (24), 57 (90). FT-IR (film): ν˜ ϭ 2965 cmϪ1, 1661 (CϭN),
1490, 1259, 1089, 1016, 803.
Acknowledgments
This work was carried out under the auspices of the National Project
‘‘Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni’’
supported by the Ministero dell’Istruzione, dell’Universita e della
Ricerca (MIUR, Rome) and by the University of Bari and the CNR
(Rome). The authors are also grateful to Prof. Marcel Pierrot of the
Centre Scientifique Saint-Jerome, Marseille, France, for performing
`
´ ˆ
X-ray analyses on spirocyclic compounds 17b and 18b.
[1] [1a]
D. Enders, U. Reinhold, Tetrahedron: Asymmetry 1997, 8,
1895Ϫ1946. [1b] R. Bloch, Chem. Rev. 1998, 98, 1407Ϫ1438. [1c]
M. Lombardo, C. Trombini, Synthesis 2000, 759Ϫ774. [1d] P. M e -
rino, S. Franco, F. L. Merchan, T. Tejero, Synlett 2000, 440Ϫ454.
[1e]
P. Merino, T. Tejero, Tetrahedron 2001, 57, 8125Ϫ8128 and
Hydrolysis of Spirocyclic Compounds 9 and 15: An aq. solution of
(COOH)2 (2% w/w, 1.32 mmol) was added to a solution of the spiro-
cyclic compound 9 or 15 in THF (0.66 mmol in 3 mL), and the re-
sulting mixture was stirred at room temp. for 24 h. After this time,
the mixture was poured into brine, extracted with EtOAc (3 ϫ
10 mL), and concentrated in vacuo. Flash chromatography on silica
gel (petroleum ether/EtOAc, 4:1) afforded the following com-
pounds, respectively.
ref. therein.
[2]
One example of addition of a lithiated azaenolate was reported
a few years ago: A. Kaiser, W. Wiegrebe, Monatsh. Chem. 1996,
127, 397.
[3]
[3a] S. Florio, V. Capriati, S. Di Martino, A. Abbotto, Eur. J. Org.
[3b]
Chem. 1999, 409Ϫ417.
V. Capriati, S. Florio, R. Luisi, V.
Russo, A. Salomone, Tetrahedron Lett. 2000, 41, 8835Ϫ8838. [3c]
S. Florio, V. Capriati, R. Luisi, A. Abbotto, D. J. Pippel, Tetra-
2968
Eur. J. Org. Chem. 2002, 2961Ϫ2969

Addition of Lithiated 2-Alkyl- and 2-(Chloroalkyl)-4,5-dihydro-1,3-oxazoles to Nitrones
FULL PAPER
hedron 2001, 57, 6775Ϫ6786. [3d] V. Capriati, S. Florio, R. Luisi,
Eur. J. Org. Chem. 2001, 2035Ϫ2039 and refs. therein.
V. Capriati, L. Degennaro, S. Florio, R. Luisi, Tetrahedron Lett.
2001, 42, 9183Ϫ9186.
NOESY phase-sensitive spectra), a phenyl ring on the same side
of an dihydrooxazolyl ring induced a shielding effect on both its
geminal methylenic protons and on the two methyl groups; the
latter, in particular, were shifted to high field with respect to the
tert-butyl protons. Analogously, in the case of oxazetidine 19, a
downfield shift (ca. 0.3 ppm) observed for the two dihydrooxazo-
lyl methyl protons with respect to the tert-butyl protons confirms
the (3R*,4S*) geometry as that depicted in Scheme 6 for this
compound.
Lithiated 2-chloromethyl derivative 2e tends to convert into (E)-
1,2-bis(dihydrooxazolyl)ethene and trans-1,2,3-tris(dihydroox-
azolyl)cyclopropane, as reported in: V. Capriati, S. Florio, R. Lu-
isi, M. T. Rocchetti, J. Org. Chem. 2002, 67, 759Ϫ763. The addi-
tion to nitrone was therefore performed under Barbier’s condi-
tions, the mixture of 2-(chloromethyl)-4,5-dihydro-1,3-oxazole
1e and nitrone 3a being added to the LDA solution.
[4]
[5] [5a]
M. A. Hobbler, D. E. Bergbreiter, M. Newcomb, J. Am.
Chem. Soc. 1978, 100, 8182Ϫ8185. [5b] A. I. Meyers, E. S. Snyder,
J. J. H. Ackerman, J. Am. Chem. Soc. 1978, 100, 8186Ϫ8189. [5c]
M. Le Bail, D. J. Aitken, F. Vergne, H. P. Husson, J. Chem. Soc.,
[5d]
Perkin Trans. 1 1997, 1681Ϫ1689.
A. Abbotto, S. Bradam-
[13]
ante, S. Florio, V. Capriati, J. Org. Chem. 1997, 62, 8937Ϫ8940.
About a 20% yield of (E)-4,4-dimethyl-2-styryl-4,5-dihydro-1,3-
oxazole (8a) was also formed. We presume it forms from 4 by
elimination of N-tert-butylhydroxylamine. The (Z) and (E) con-
figurations of the styrene derivatives obtained in the reactions of
[6]
2a and 2d were assigned on the basis of the coupling constants
3
of the vinylic hydrogen atoms (3JH,H(E) ϭ 15.8 Hz; JH,H(Z)
ϭ
[14]
12.6 Hz).
The relative configurations were assigned to compounds 21-H,
22-H, 25a, and 27a on the basis of their NOESY phase-sensitive
spectra. In the cases of 22-H and 27a (cis isomers) cross peaks
[7]
[8]
The (E) isomer should be the one with the more deshielded vi-
nylic proton (see Exp. Sect.) with respect to the (Z) one, as re-
ported (ref.[3d]) for other similar β-dihydrooxazolylstyrenes.
2-Isopropyl-4,4-dimethyl-4,5-dihydro-1,3-oxazole (1c) was pre-
pared by lithiation (LDA 2.5 equiv., THF, Ϫ98 °C, 3 h) of the
commercially available 2-ethyl-4,4-dimethyl-4,5-dihydro-1,3-ox-
azole (quantitative yield); spectroscopic data have been reported
in: H. Feuer, H. S. Bevinakatti, Xuan-Gan Luo, J. Heterocycl.
Chem. 1986, 23, 825Ϫ832.
were seen between the two vicinal isoxazolidine (3JH,H
ϭ
10.7 Hz) and oxazetidine (3JH,H ϭ 10.0 Hz) ring hydrogen
atoms, and also, for 22-H, two additional cross peaks between
Ha and the two geminal oxazolidinyl ring hydrogen atoms. In the
cases of 21-H (trans isomer; 3JH,H ϭ 7.0 Hz) and 25a (trans iso-
mer; 3JH,H ϭ 8.2 Hz), none of these cross-peaks were observed.
The small (3JH,H ϭ 4.3 Hz) and the large (3JH,H ϭ 10.3 Hz) coup-
ling constants found for 23-H and 24-H, respectively, as well as
the absence of NOEs for the latter, are indicative of a gauche and
a anti arrangement of the two vicinal protons in the two stag-
gered rotamers (see: N. Matsumori, D. Kaneno, M. Murata, H.
Nakamura, K. Tachibana, J. Org. Chem. 1999, 64, 866Ϫ876),
also favoured by possible intramolecular hydrogen bonding be-
tween the OH group and the dihydrooxazolyl nitrogen atom.
J. Suffert, J. Org. Chem. 1989, 509Ϫ512.
[15]
[9]
2-(1-Chloroethyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole
(1d)
was prepared by chlorination of 2-ethyl-4,4-dimethyl-4,5-dihy-
dro-1,3-oxazole (1b) with tert-butyl hypochlorite as reported in
ref.[5d] Unlike lithiated 2-(chloromethyl)-4,4-dimethyl-4,5-dihy-
dro-1,3-oxazole (see ref.[13]), lithiated 2-(1-chloroethyl)-4,4-di-
methyl-4,5-dihydro-1,3-oxazole is quite stable at low temper-
atures.
[10]
[11]
[12]
[16]
[17]
Under Barbier’s conditions, the only two products formed were
spirocyclic compounds 18b (15% yield) and oxazetidine 19 (60%
yield), easily separable by column chromatography (silica gel;
petroleum ether/Et2O, 3:2).
In the case of compound 17b, a significant cross-peak between
the methyl and the hydrogen atom lying in a 1,3-relationship on
the isoxazolidine ring was observed, testifying to a cis relation-
ship.
In the NOESY phase-sensitive spectrum of oxazetidine 19, no
cross peak was observed between the oxazetidine methyl protons
and the vicinal benzylic-type proton. Moreover, as seen for dias-
tereomeric oxazetidines 25a and 27a (and confirmed by their
S. Mackay, C. J. Gilmore, C. Edwards, N. Stewart, K. Shankland,
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