Studies on the synthesis of 2-alkyl-5-aryl-1,3,4-oxadiazolines from N-acylhydrazones

Article abstract of DOI:10.1055/s-0031-1290609

Reaction of N-acylhydrazones with benzyloxyacetyl chloride in the presence of i-Pr₂EtN affords new 1,3,4-oxadiazolines in excellent yields (72-95%), under mild reaction conditions and in short reaction times. The structures of the products were confirmed by single-crystal X-ray diffractometry. A plausible reaction mechanism is proposed. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290609

LETTER
885
Studies on the Synthesis of 2-Alkyl-5-aryl-1,3,4-oxadiazolines from
N-Acylhydrazones
S
ynthesis of 2-A
u
lkyl-5-aryl-
g
1, 3,4-oxadia
e
zoline
s
nia Marqués-López,a,1, Elena Díez,a Eloísa Martín-Zamora,a Eleuterio Álvarez,b Rosario Fernández,*a
José M. Lassaletta*b
a
Departamento de Química Orgánica, Universidad de Sevilla, Apdo. de Correos N° 1203, 41071 Seville, Spain
E-mail: ffernan@us.es
b
Instituto de Investigaciones Químicas (CSIC-US), Américo Vespucio 49, 41092 Seville, Spain
Fax +34(95)4460565; E-mail: jmlassa@iiq.csic.es
Received 24 November 2011
chloride.7 Other methods include oxidative cyclization of
aldazines using Pb(OAc)4.8 On the other hand, the forma-
tion of similar structures is described for reactions involv-
ing ketenes (generated in situ) and N-acylhydrazones or
Abstract: Reaction of N-acylhydrazones with benzyloxyacetyl
chloride in the presence of i-Pr2EtN affords new 1,3,4-oxadiazo-
lines in excellent yields (72–95%), under mild reaction conditions
and in short reaction times. The structures of the products were con-
firmed by single-crystal X-ray diffractometry. A plausible reaction 2,3-diaza-1,3-dienes (azines) either with moderate to
good yields or as by-products.9 The absence of reports for
mechanism is proposed.
the synthesis of simple 2-alkyl-5-arylderivatives is note-
worthy.
Key words: N-acylhydrazones, oxadiazolines, benzyloxyacetyl
chloride, acylation, heterocycles
During the last few years, our research group has been in-
terested in the asymmetric synthesis of b-lactams by a
Staudinger-like reaction between aldehyde N,N-dialkyl-
hydrazones and functionalized benzyloxyketene10 (gener-
ated in situ from benzyloxyacetyl chloride 4 with a base)
or amino ketenes.11 Recently, we decided to explore the
behavior of more reactive N-acylhydrazones 5 as the imi-
ne component in the [2+2] cycloaddition. Taking advan-
tage of the high relative stability of hydrazones toward
enolization, we decided to focus on aliphatic derivatives.
Thus, the reaction of isovaleraldehyde benzoyl hydrazone
(5a) as a model substrate and benzyloxyacetyl chloride (4)
as the reagent, was chosen for preliminary experiments.
However, under our previously optimized conditions (2
equiv of 4, 4 equiv of Et3N in anhydrous toluene),10 the re-
action afforded no trace of the corresponding b-lactam 6,
instead, formation of oxadiazoline 7a in 80% yield was
observed after 24 hours at room temperature (Scheme 1).
Among five-membered heterocycles, 1,3,4-oxadiazolines
and derivatives have been the subject of chemical and bi-
ological studies on account of their interesting pharmaco-
logical properties, including antimicrobial,2 anti-
inflammatory,3 antiviral,4 and antitumor activities.5 Se-
lected structures 1–3, are outlined in Figure 1. As a conse-
quence of the significant biological activity, the synthesis
of new and easily accessible 1,3,4-oxadiazolines seems an
aim of great interest.
Previous synthetic methods reported for these compounds
involve cyclization of anionic N-acylhydrazones under
acylation conditions using acetic anhydride6 or acetyl
N
O
N
O
O
N
O
N
F
H
O
Ph
O
O
O2N
HO
O
NH
N
1
2
O
N
Ph
BnO
O
NH
H
6
N
N
Et3N
MeO
Cl
+
BnO
toluene
r.t.
O
O
X
MeO
O
BnO
4
MeO
5a
N
N
3a: X = NMe2
3b: X = OMe
80%
Ph
O
Figure 1 Selected bioactive 1,3,4-oxadiazolines: 1 (antifungal),2 2
(anti-inflammatory),3 and 3a and 3b (antitumor)5a,c
7a
Scheme 1 Formation of oxadiazoline 7a
SYNLETT 2012, 23, 885–888
x
x.
x
x.
2
0
1
2
Advanced online publication: 15.03.2012
DOI: 10.1055/s-0031-1290609; Art ID: D71011ST
© Georg Thieme Verlag Stuttgart · New York

886
E. Marquéz-López et al.
LETTER
Using the same model reaction, further experiments were
performed to investigate the influence of the base and/or
the reaction temperature on the product distribution. To
this end, reactions performed at room temperature using
diisopropylethylamine and tribenzylamine were analyzed
after 24 hours and compared with the triethylamine-pro-
moted reaction. The results, collected in Table 1 (entries
1–3), indicate a slight improvement with diisopropylethy-
lamine and a significant drop of yield in the case of the
less basic tribenzylamine.12 Finally, performing the reac-
tions at 80 °C not only provided a slightly better yield, but
also led to a significant rate acceleration, leading to virtu-
ally complete reactions in only five hours (entries 4 and
5).
Table 2 Synthesis of Oxadiazolines 7a–g from N-Acylhydrazones
5a–g
O
BnO
H
N
Ar
i-Pr2EtN
Cl
N
+
N
N
BnO
toluene
80 °C
O
O
Ar
R
H
R
O
4
5a–g
7a–g
Entry
5
Ar
R
Time
(h)
7
Yield
(%)a
1
2
3
4b
5
6
7
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
i-Bu
i-Pr
5
5
7a
7b
7c
7d
7e
7f
88
86
89
72
93
95
89
CH2CH2Ph
t-Bu
5
Table 1 Screening of Reaction Conditionsa
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
16
5
Cl
O
BnO
BnO
i-Pr
O
H
N
Ph
N
N
4
i-Bu
4
N
Ph
O
R3N (4 equiv), toluene
O
5g
4-MeOC6H4
i-Bu
4
7g
H
5a
a Isolated yields after column chromatography.
b Reaction performed at 100 °C.
7a
Entry
Base
Et3N
Temp (°C)
Time (h)
Yield (%)b
tion. Ensuing nucleophilic addition of the sp2 imine nitro-
gen of 5 to the electron-deficient ketene central carbon
and spontaneous cyclization of the resulting zwitterionic
intermediate 10 would render the product 7 (Scheme 2,
blue path). A second possible path starts with the acyla-
tion of the imino nitrogen of the substrate by 4 to form
acyl immonium intermediate 9 from which deprotonation
by the base renders the final product 7 through the same
zwitterionic intermediate 10.
1
2
3
4
5
r.t.
r.t.
r.t.
80
80
24
24
24
5
80
84
51
88
64
i-Pr2EtN
Bn3N
i-Pr2EtN
Bn3N
5
a Reactions performed at 0.5 mmol scale using 4 (2 equiv) and base (4
equiv).
b Isolated yield after column chromatography.
Several pieces of evidence suggest that the mechanism in-
volving ketene 8 can be disregarded. First, previous
studies11b indicate that the rate of ketene formation de-
creases in the order Et3N > i-Pr2EtN >> Bn3N, with the lat-
ter being much slower than the observed reaction rate.
Such a dependence on the base is not consistent with the
observed trend. Further evidence for 9 as a reaction inter-
mediate was obtained from the reaction of 5g with 4 in the
These optimized conditions [hydrazone (2 equiv), i-
Pr2EtN (4 equiv), anhydrous toluene, 80 °C] were then ap-
plied to the reaction of different N-acylhydrazones 5a–g
with benzyloxyacetyl chloride (4) for the synthesis of ad-
ducts 7a–g. The results, collected in Table 2, indicate the
efficiency of the reaction for primary (entries 1, 3, 6, and
7), secondary (entries 2 and 5), and even tertiary (entry 4)
aliphatic derivatives, although higher reaction tempera-
tures and longer reaction times were required in the latter
case. Examples that illustrate the compatibility with elec-
tron-withdrawing (entries 4–6) or electron-donating (en-
try 7) groups are included.
In addition to the usual spectroscopic characterization
(see the Supporting Information), single-crystal X-ray dif-
fraction analysis of adduct 7e (Figure 2)13 unequivocally
confirmed the proposed structure.
Two plausible reaction paths can be a priori proposed for
this reaction. As is the case in reactions with N,N-dialkyl-
hydrazones, benzyloxyacetyl chloride 4 could possibly re-
act first with the base to form the corresponding
benzyloxy ketene 8 after hydrogen chloride b-elimina-
Figure 2 X-ray crystal structure of oxadiazoline 7e. Hydrogen
atoms omitted for clarity. Thermal ellipsoids drawn at the 50% proba-
bility level.
Synlett 2012, 23, 885–888
© Thieme Stuttgart · New York

LETTER
Synthesis of 2-Alkyl-5-aryl-1,3,4-oxadiazolines
887
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
H
Cl–
H
H
Ar
BnO
N
Ar
H
N
N
O
+
+
O
N
O
O
Cl
R
BnO
Acknowledgment
5
R
4
We thank the Spanish Ministerio de Ciencia e Innovación (grant
numbers CTQ2010-15297 and CTQ2010-14974), the European
FEDER funds, and the Junta de Andalucía (grant numbers 2008/
FQM-3833 and 2009/FQM-4537) for financial support.
9
R3N
– R3NH+Cl–
R3N
– R3NH+Cl–
BnO
H
N
Ar
References and Notes
N
+
O
(1) Present address: Laboratorio de Síntesis Asimétrica,
Departamento de Química Orgánica, Instituto de Síntesis
Química y Catálisis Homogénea, Universidad de Zaragoza-
CSIC, 50009 Zaragoza, Spain
O
R
5
8
(2) Rollas, S.; Gulerman, N.; Erdeniz, H. Il Farmaco 2002, 57,
171.
(3) Rajak, H.; Kharya, M. D.; Mishra, P. Yakugazu Zasshi 2007,
127, 1757.
H
Ar
Ar
N
–
O
N
O
+
+
N
-
O
N
O
(4) Ali, O. M.; Amer, H. H.; Abdel-Rahman, A. A.-H. Synthesis
2007, 2823.
BnO
BnO
R
R
(5) (a) Tahir, S. K.; Han, E. K.-H.; Credo, B.; Jae, H.-S.;
Pietenpol, J. A.; Scatena, C. D.; Wu-Wong, J. R.; Frost, D.;
Sham, H.; Rosenberg, S. H.; Ng, S.-C. Cancer Res. 2001, 61,
5480. (b) Hans, J.; Wallace, E. M.; Zhao, Q.; Lyssikatos, J.
P.; Aicher, T. D.; Robinson, J.; Allen, S. PCT Int. Appl. WO
2006044825, 2006. (c) Lee, L.; Robb, L. M.; Lee, M.; Davis,
R.; Mackay, H.; Chavda, S.; Babu, B.; O’Brien, E. L.;
Risinger, A. L.; Mooberry, S. L.; Lee, M. J. Med. Chem.
2010, 53, 325.
(6) For selected examples, see: (a) Somogyi, L. Liebigs Ann.
Chem. 1994, 623. (b) Somogyi, L. Bull. Chem. Soc. Jpn.
2001, 74, 873. (c) El Ashry, E. S. H.; Rashed, N.; Awad, L.
F.; Abdel-Rahman, A. A. H.; Rasheed, H. A. J. Chem. Res.,
Miniprint 2001, 440.
10
7
Scheme 2 Plausible reaction mechanisms
presence of a large excess of tribenzylamine (8 equiv) as
the base. Under these conditions, a moderate (50% yield)
amount of product 7g was obtained, along with a small
amount (22%) of enhydrazine by-product 11 (Scheme 3),
which is presumed to form by competitive deprotonation
of the acidic a-methylene from the same intermediate 9.
(7) (a) Armesto, D.; Gallego, M. G.; Horspool, W. M.; Ramos,
A. Tetrahedron Lett. 1988, 29, 3581. (b) Somogyi, L.
Tetrahedron 1985, 41, 5187.
O
O
H
N
H
Ar
Ar
N
N
O
(8) Gillis, B. T.; Lamontagne, M. P. J. Org. Chem. 1967, 32,
N
N
N
4
Ar
3318.
+
BnO
O
BnO
O
Bn3N
H
(9) (a) Alcaide, B.; Miranda, M.; Pérez-Castells, J.; Polanco, C.;
Sierra, M. A. J. Org. Chem. 1994, 59, 8003. (b) Singh, G.
S.; Shang, M.; Ibata, T. Indian J. Chem., Sect. B: Org. Chem.
Incl. Med. Chem. 2000, 39, 554. (c) Singh, G. S.
J. Heterocycl. Chem. 2006, 43, 1653. (d) Kaspentakis, G.
C.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J.
J. Heterocycl. Chem. 2007, 44, 425.
(10) (a) Fernández, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.;
Monge, A. Angew. Chem. Int. Ed. 2000, 39, 2893.
(b) Fernández, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.;
Martín-Zamora, E. Angew. Chem. Int. Ed. 2002, 41, 831.
(c) Martín-Zamora, E.; Ferrete, A.; Llera, J. M.; Muñoz, J.
M.; Pappalardo, R. R.; Fernández, R.; Lassaletta, J. M.
Chem. Eur. J. 2004, 10, 6111.
PhMe
r.t.
5g
11
(22%)
7g
(50%)
Ar = p-anisyl
Ar
H
O
N
Bn3N
+N
O
BnO
H
9
(11) (a) Díez, E.; Fernández, R.; Marqués-López, E.; Martín-
Zamora, E.; Lassaletta, J. M. Org. Lett. 2004, 6, 2749.
(b) Marqués-López, E.; Martín-Zamora, E.; Díez, E.;
Fernández, R.; Lassaletta, J. M. Eur. J. Org. Chem. 2008,
2960.
(12) (a) Graton, J.; Besseau, F.; Berthelot, M.; Raczynska, E. D.;
Laurence, C. Can. J. Chem. 2002, 80, 1375. (b) Canle, L.
M.; Demirtas, I.; Freire, A.; Maskill, H.; Mishima, M. Eur.
J. Org. Chem. 2004, 5031.
Scheme 3
In summary, use of diisopropylethylamine as the base en-
ables a mild and efficient synthesis of 5-alkyl-1,3,4-oxa-
diazolines 7a–g from N-acylhydrazones 5a–g and
benzyloxyacetyl chloride 4. Experimental evidence sug-
gests that the reaction proceeds through N-acyliminium
intermediates resulting from direct acylation of the hydra-
zone N(sp2) atom by acyl chloride 4.
(13) Crystal data for 7e (CCDC 850772): C20H21N3O5;
M = 383.40; monoclinic; a = 33.9831 (8) Å, b = 6.14820
© Thieme Stuttgart · New York
Synlett 2012, 23, 885–888

888
E. Marquéz-López et al.
LETTER
final R1 values were 0.0474 (I > 2s(I)). The final wR(F2)
values were 0.1106 (I > 2s(I)). The final R1 values were
0.0941 (all data). The final wR(F2) values were 0.1314 (all
data); goodness-of-fit: 1.030.
(10) Å, c = 20.2932 (5) Å, a = 90.00°, b = 118.3420 (10)°,
g = 90.00°; V = 3731.71 (14) Å3; T = 100 (2) K; space group
C2/c; Z = 8; m(MoKa) = 0.100 mm–1; 34754 reflections
measured, 5690 independent reflections (Rint = 0.0436). The
Synlett 2012, 23, 885–888
© Thieme Stuttgart · New York

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