Efficient synthesis of 4-cyano 2,3-dihydrooxazoles by direct amination of 2-alkylidene 3-oxo nitriles

Article abstract of DOI:10.1055/s-2005-917097

The addition of N-protected O-sulfonyl hydroxylamine derivatives on 2-alkylidene 3-oxo nitrites gives 2,5-disubstituted 4-cyano 2,3-dihydrooxazoles (4-oxazolines) by a practical and efficient synthetic procedure under very mild conditions in high yields. Likely, the formation of N,O-heterocycles proceeds through a domino reaction involving a fast rearrangement of unstable 2-acyl 2-cyano aziridines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-917097

LETTER
2673
Efficient Synthesis of 4-Cyano 2,3-Dihydrooxazoles by Direct Amination of
2-Alkylidene 3-Oxo Nitriles
S
ynthesis of 4-C
d
yano 2,3-Di
o
hydrooxazol
a
es rdo Burini, Stefania Fioravanti,* Alberto Morreale, Lucio Pellacani,* Paolo A. Tardella*
Dipartimento di Chimica, Università degli Studi di Roma ‘La Sapienza’, P.le Aldo Moro 2, 00185 Roma, Italy
Fax +3906490631; E-mail: lucio.pellacani@uniroma1.it
Received 18 July 2005
Abstract: The addition of N-protected O-sulfonyl hydroxylamine
derivatives on 2-alkylidene 3-oxo nitriles gives 2,5-disubstituted 4-
cyano 2,3-dihydrooxazoles (4-oxazolines) by a practical and effi-
cient synthetic procedure under very mild conditions in high yields.
Likely, the formation of N,O-heterocycles proceeds through a dom-
ino reaction involving a fast rearrangement of unstable 2-acyl 2-cy-
ano aziridines.
Scheme 1 Amination of 2-alkylidene 3-oxo nitriles
Key words: Michael additions, cyclizations, domino reactions, 2-
acyl aziridines, heterocycles
10–25 (Scheme 1) with high purity, as shown by NMR
spectra.6
General synthetic approaches to N- and/or O-heterocyclic
Reaction conditions and yields are reported in Table 1.
structures involve often cycloaddition reactions, ring ex-
The presence of bulky groups like neopentyl (entries 6–8)
pansion or contraction, and intramolecular cyclization re-
or tert-butyl (entry 14) as well as the presence of a phenyl
group (entries 15–16) on the double bond of starting al-
kenes did not influence the reaction outcomes, even by
changing the residue of the acyl moiety.
actions.1
We reported the formation of functionalized aziridines by
an aza-MIRC (Michael-initiated ring-closure) reaction
given by N-protected O-sulfonyl hydroxylamine deriva-
tives in the presence of bases on variously substituted ole-
fins.2 Recently, we applied this aziridination reaction to
prepare a large number of 2-cyano aziridines, obtained in
high yields and purities from different 2-cyano acrylates
or a,b-unsaturated 1,1-dinitriles.3
Although the Z group of the sulfonyloxycarbamates was
found to strongly characterize the pathway of these reac-
tion leading often to different results,7 functionalized 2,3-
dihydrooxazoles were always obtained as the only prod-
ucts by using different nosyloxycarbamates.
N,O-Heterocycles could be formed by a domino reaction
involving a fast rearrangement of the unstable 2-acyl 2-
cyano aziridines I.8 The last ones led to the substituted
2,3-dihydrooxazoles under mild conditions, reasonably
through the enolate mesomeric forms III of the intermedi-
ate azomethine ylides II (Scheme 2).9
Continuing our studies, we addressed our attention to the
reactivity of 2-alkylidene 3-oxo nitriles in order to consid-
er the influence of the oxo group on these amination reac-
tions and on the stability of the corresponding 2-acyl
aziridines. In fact, these compounds can show interesting
chemical behaviors like thermal rearrangement leading to
important synthetic intermediates.4
Alkenes 1–9 were synthesized through Knoevenagel con-
densation reactions3,5 catalyzed by alumina from different
aldehydes and 3-oxo nitriles. After filtration, compounds
1–6 (purities up to 95%, determined by NMR and HPLC
analyses) were used without further purification, while
compounds 7–9 required chromatographic purification
due to the presence of unreacted excesses of aldehydes in
the crude reaction mixtures.
Amination reactions were performed using different
nosyloxycarbamates3 (NsONH–Z, Ns = 4-nitrophenyl-
sulfonyl; Z = CO2Et, Boc, Cbz) in the presence of calcium
oxide at room temperature and led to the unexpected for-
mation of 2,5-disubstituted 4-cyano 2,3-dihydrooxazoles
Scheme 2 Possible pathway for the synthesis of substituted 2,3-di-
hydrooxazoles
SYNLETT 2005, No. 17, pp 2673–2675
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7
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0
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0
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5
Advanced online publication: 05.10.2005
DOI: 10.1055/s-2005-917097; Art ID: G23005ST
© Georg Thieme Verlag Stuttgart · New York

2674
E. Burini et al.
LETTER
Table 1 Synthesis of 2,5-Disubstituted 4-Cyano 2,3-Dihydrooxazoles
Entry
1
Substratea
R
R1
Z
Product
10
Molar ratiosb Time (h)
Yield (%)c
1
1
2
2
2
3
4
4
5
6
6
7
7
8
9
9
Ph
Et
CO2Et
Cbz
1:2:2
1:2:2
1:3:3
1:2:1
1:8:4
1:3:2
1:2:1
1:2:1
1:2:2
1:2:2
1:2:2
1:3:2
1:3:2
1:2:2
1:3:2
1:3:2
2
2
80
62
75
81
77
61
86
91
88
72
93
70
77
55
90
92
2
Ph
Et
11
3
t-Bu
t-Bu
t-Bu
Ph
Et
CO2Et
Cbz
12
2
4
Et
13
2
5
Et
Boc
14
24
3
6
Neopentyl
Neopentyl
Neopentyl
i-Bu
i-Bu
i-Bu
Pentyl
Pentyl
t-Bu
Ph
CO2Et
CO2Et
Cbz
15
7
t-Bu
t-Bu
Ph
16
4
8
17
4
9
CO2Et
CO2Et
Boc
18
20
6
10
11
12
13
14
15
16
t-Bu
t-Bu
Ph
19
20
2
CO2Et
Boc
21
2
Ph
22
2
t-Bu
Ph
CO2Et
CO2Et
Boc
23
24
8
24
Ph
Ph
25
8
a All alkenes were obtained as pure E isomers, but 3 (entry 6) as an E/Z = 2:1 mixture (NMR).
b Substrate:CaO:NsONH–Z.
c Isolated yield. The structure of all compounds was confirmed by 1H NMR, 13C NMR and HRMS analyses.
It has been reported that 2,3-dihydrooxazoles can be ob-
tained by thermal or photochemical C–C bond cleavage of
2-acyl aziridines through the corresponding azomethine
ylides.10 These last 1,3-dipolar reactive intermediates are
commonly employed to synthesize heterocyclic com-
pounds,11 but their isolation is often difficult and second-
ary reactions can afford different products like pyrroles,
Scheme 3 Synthesis of bicyclic aziridines
piperazines or exactly 2,3-dihydrooxazoles.9
According to Scheme 2, the presence of the intermediate
aziridine I was detected by 1H NMR spectra performed on
the crude amination mixture of alkene 2 with NsONHCbz
(Table 1, entry 4).12 While standing at room temperature,
the aziridine disappeared spontaneously and quantitative-
ly gave the corresponding 2,3-dihydrooxazole 13.
applications in different fields.15 Therefore, the develop-
ment of new methods for preparation of functionalized
2,3-dihydrooxazoles (4-oxazolines) is a continuous at-
tracting feature for the synthetic organic chemists.16
Acknowledgment
Finally, cyclic 2-alkylidene 3-oxo nitrile 26 yielded stable
bicyclic aziridines 27 (yield 75%) and 28 (yield 62%), as
expected (Scheme 3), supporting the proposed pathway.
We thank the Italian Ministero dell’Istruzione, dell’Università e
della Ricerca (MIUR) and the Università degli Studi di Roma La
Sapienza (National Project ‘Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni’) for financial support.
In the reactions reported herein, a different and important
role could be played from the geminal position of the cy-
ano and the oxo groups,13 allowing a practical and effi-
cient synthetic approach to diverse N,O-heterocycles
under mild conditions. These compounds are reported to
have synthetic relevance as a route to stabilized azo-
methine ylides14 and more recently they have also found
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Synlett 2005, No. 17, 2673–2675 © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Cyano 2,3-Dihydrooxazoles
2675
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Figure 1
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1.28 (s, 9 H), 1.67–1.78 (m, 2 H), 5.23 (s, 2 H), 5.97 (t,
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Synlett 2005, No. 17, 2673–2675 © Thieme Stuttgart · New York