Reactions of alkylidenepyrrolidines with α-chlorooximes and α-chlorohydrazones

Article abstract of DOI:10.1016/j.tetlet.2009.10.086

The reactions of alkylidenepyrrolidines with α-chlorooximes give isoxazoles via an acylation reaction followed by ring isomerisation. In contrast, and in line with a previous report, the corresponding α-chlorohydrazones give the simple acylation products,

Full text of DOI:10.1016/j.tetlet.2009.10.086

Tetrahedron Letters 50 (2009) 7392–7394
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Reactions of alkylidenepyrrolidines with
-chlorohydrazones
a-chlorooximes and
a
Cevher Altug˘ a,b, Yasar Dürüst b, Mark C. Elliott a,
*
a School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK
b
_
Department of Chemistry, Abant Izzet Baysal University, TR-14280 Bolu, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactions of alkylidenepyrrolidines with
lowed by ring isomerisation. In contrast, and in line with a previous report, the corresponding
hydrazones give the simple acylation products, although in one instance a cycloadduct was also obtained.
a
-chlorooximes give isoxazoles via an acylation reaction fol-
-chloro-
Received 17 September 2009
Revised 8 October 2009
Accepted 19 October 2009
Available online 22 October 2009
a
Ó 2009 Elsevier Ltd. All rights reserved.
a
-Chlorooximes and
a
-chlorohydrazones are widely used in or-
lene groups adjacent to nitrogen and to the isoxazole ring are
slightly higher in compounds 7.
ganic synthesis, mainly as precursors of nitrile oxide and nitrili-
mine dipoles for use in cycloaddition chemistry.1 However, they
can also be considered as highly functionalised electrophiles.2
We have recently reported the reaction of alkylidenepyrrolidine
1 with nitrolic acids 2, in which the HNO2 that is eliminated from
the nitrolic acid nitrosates the alkylidenepyrrolidine double-bond.
Two cycloaddition reactions then take place to give the observed
products 3 (Scheme 1).3
Isoxazoles possess a range of useful biological activity.8 In par-
ticular, a variety of compounds (e.g., 10, Fig. 1) closely related to 7
are ghrelin receptor modulators, having potential for the treatment
of various eating disorders.9 Therefore a new method for the for-
mation of such compounds from readily available starting materi-
als is noteworthy. The reverse of the ring transformation depicted
in Scheme 3 is known, leading to the formation of aromatic pyrrole
compounds from suitably substituted isoxazoles.10
The reaction of alkylidenepyrrolidines such as 1 with a-chloro-
hydrazones 4 has been reported to give products 5, by simple acyl-
ation of the alkylidenepyrrolidine double-bond (Scheme 2).4
This preference for C-acylation is unsurprising.5 The possibility
that the products 5 could isomerise to give the corresponding pyr-
azoles was mentioned by the authors, although it was not observed
in this instance. However, the formation of isoxazoles has been re-
ported following the reaction of alkylidenepyrrolidine ketones
with hydroxylamine.6 The reaction of alkylidenepyrrolidine 1 with
Surprisingly, when the 3-nitrophenyl chlorooxime 6e was used,
compound 11 was obtained as the sole product (Scheme 4).11 This
result is entirely reproducible, although it is not clear why the
oxime cyclises onto the ester in this case, but onto the alkylidene-
pyrrolidine ring in other cases.
Reactions of alkylidenepyrrolidine 1 with
do proceed with simple acylation as previously reported.4 How-
ever, in one instance (with -chlorohydrazone 12), in addition to
a-chlorohydrazones
a
a
-chlorooximes 6 has not been reported, and would appear to have
the expected compound 13, we were also able to obtain compound
14, this being formed by 1,3-dipolar cycloaddition onto the imine
tautomer of the alkylidenepyrrolidine (Scheme 5). The failure of
compound 13 to undergo conversion into the pyrazole, in a manner
analogous to the corresponding oximes, can most likely be attrib-
more in common with the former case. We therefore reacted alky-
lidenepyrrolidine 1 with a range of
a-chlorooximes 6. Products 7
were obtained in good yields (Scheme 3; Table 1),7 presumably
by initial acylation to give compound 8 followed by isomerisation
to give 9 and a rapid second acylation to give the observed prod-
ucts. Use of a single equivalent of the a-chlorooxime gave the same
products, but in lower yield and with some alkylidenepyrrolidine
left unreacted. Mass spectrometry confirmed that compounds 7
are 1:2 adducts with loss of two equivalents of HCl. NMR data
for these compounds are similar to those reported by Dannhardt
et al.6 for analogues lacking the ester and side-chain acylation,
although as would be expected, the chemical shifts of the methy-
2
N
OH
2
R
N
R
CO Et
2
N
NO
O
N
O
thermal or microwave
heating
NH
R
N
1
3, 58-76%
* Corresponding author. Tel.: +44 29 20874686; fax: +44 29 20874030.
E-mail address: elliottmc@cardiff.ac.uk (M.C. Elliott).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.086

C. Altug˘ et al. / Tetrahedron Letters 50 (2009) 7392–7394
7393
4
Cl
N
NHAr
Ph
CO Et
2
Ph
CO Et
2
ArHN
CO Et
2
Cl
N
+
NH
Cl
EtOH, 15 h or
CHCl , 8 h
NH
NH
N
NH
5, 35-52%
3
1
1
O N
2
12
Scheme 2.
Et N, CH Cl
2
3
2
25 ºC, 18 h
6
Cl
OH
Cl
Cl
N
Ar
CO Et
2
CO Et
2
Ar
N
O
H
NH
+
N
Ar
N
N
N
N
NH
Et N, CH Cl
2
3
2
EtO C
CO Et
2
2
25 ºC, 18 h
N
OH
1
7
NO
2
O N
2
NH
13, 59%
14, 10%
Ar
Ar
CO Et
2
N
CO Et
2
Scheme 5.
N
O
OH
NH
NH
2
uted to steric hindrance and to the lower nucleophilicity of the
arylated nitrogen.
8
9
Scheme 3.
Acknowledgements
_
Table 1
Formation of adducts 7
We are extremely grateful to the Abant Izzet Baysal University,
Directorate of Research Projects Commission (BAP Grant
2007.03.03.260) and TUBITAK (The Scientific and Technological Re-
search Council of Turkey, Grant 106T645) for financial support and
to Mr. Robin Hicks for technical assistance.
6a-d
OH
N
Ar
CO Et
2
CO Et
2
Ar
Cl
References and notes
N
O
H
N
Ar
NH
Et N, CH Cl
2
3
2
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1973, 95, 7287–7301; (e) Wagner, G.; Danks, T. N.; Vullo, V. Tetrahedron 2007,
63, 5251–5260; (f) Vullo, V.; Danks, T. N.; Wagner, G. Eur. J. Org. Chem. 2004,
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25 ºC, 18 h
N
OH
1
7
Product
Ar
Yield (%)
7a
7b
7c
7d
2,6-Dichlorophenyl
2,4-Dichlorophenyl
Phenyl
69
67
68
56
2-Nitrophenyl
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Cl
O
NMe
2
Cl
N
N
H
O
Me
10
Figure 1.
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7. Ethyl 5-(3-(2,6-dichloro-N’-hydroxybenzimidamido)propyl)-3-(2,6-dichlorophenyl)
isoxazole-4-carboxylate (7a): The alkylidenepyrrolidine 1 (155 mg, 1 mmol) in
6e
OH
N
O N
2
Cl
N
O
CO Et
2
O
CH2Cl2 (5 mL)wasaddedtoasolutionofa-chloroaldoxime6a(448 mg, 2 mmol)in
NH
Et N, CH Cl
2
3
2
NH
11, 34-41%
CH2Cl2 (5 mL). Triethylamine (250 mg, 2.5 mmol) was added dropwise over 2 min
and the reaction mixture was stirred at ambient temperature for 18 h. The crude
reaction mixture was filtered through a short plug of silica gel to remove
triethylamine hydrochloride, then concentrated in vacuo and purified by flash
column chromatography (eluent 2:1 petroleum ether/EtOAc) to give the title
O N
2
25 ºC, 18 h
1
Scheme 4.

7394
C. Altug˘ et al. / Tetrahedron Letters 50 (2009) 7392–7394
compound (366 mg, 69%) as a colourless solid, mp 122–123 °C (Found: MH+,
530.0182. C22H20N3O435Cl4 requires M, 530.0208); mmax (KBr disc) 3372, 2922,
10. Roy, A. K.; Pathak, R.; Yadav, G. P.; Maulik, P. R.; Batra, S. Synthesis 2006, 1021–
1027.
1721, 1644, 1457, 1377, 1297, 910, 784 and 732 cmÀ1; dH (400 MHz; CDCl3) 7.39–
7.11 (6H, m, aromatic CH), 5.57 (1H, br s, NH), 4.01 (2H, q, J 7.1, OCH2), 3.13 (2H, t, J
7.4, CH2CH2CH2N), 2.88 (2H, poorly resolved app. q, J 5.1, CH2CH2CH2N), 1.88 (2H,
app. quintet, J 7.0, CH2CH2CH2N) and 0.90 (3H, t, J 7.1, CH2CH3); dC (100 MHz;
CDCl3) 178.1 (C), 170.0 (C), 158.6 (C), 150.4 (C), 136.0 (2ÂC–Cl), 135.4 (2ÂC–Cl),
131.3 (CH), 131.0 (CH), 129.5 (C), 128.3 (C), 128.1 (2ÂCH), 127.7 (2ÂCH), 109.3 (C),
60.8 (CH2), 42.0 (CH2), 28.0 (CH2), 24.6 (CH2) and 13.6 (CH3); m/z (TOF ES+) 532
(MH+, 100%) (isotopic distribution consistent with 4ÂCl).
11. 3-(3-Nitrophenyl)-4-(pyrrolidin-2-ylidene)isoxazol-5(4H)-one
(10):
The
alkylidenepyrrolidine 1 (155 mg, 1 mmol) in CH2Cl2 (5 mL) was added to a
solution of N-hydroxy-3-nitrobenzimidoyl chloride 6e (400 mg, 2 mmol) in
CH2Cl2 (5 mL). Triethylamine (250 mg, 2.5 mmol) was added dropwise over
2 min and the reaction mixture was stirred at ambient temperature for 18 h. The
crude reaction mixture was filtered through a short plug of silica gel to remove
triethylamine hydrochloride, then concentrated in vacuo and purified by flash
column chromatography (eluent 1:1 petroleum ether/EtOAc) to give the title
compound (193 mg, 41%) as a yellow solid, mp 144–146 °C (Found: M+, 273.0750;
C13H11N3O4 requires M, 273.0750); mmax (KBr disc) 3284, 2926, 1691, 1599 and
1351 cmÀ1; dH (400 MHz; CDCl3) 10.11 (1H, br s, NH), 8.38 (1H, dd, J 8.2, 2.3), 8.31
(1H,app. brs), 8.00(1H,d,J7.6),7.80(1H,app. t,J8.0),3.62(2H,t,J7.0,CH2N),2.53–
2.47(2H, m,CH2C)and1.89(2H,app.quintet, J7.2,CH2CH2N);dC (100 MHz;CDCl3)
173.9(C),170.0(C),161.2(C),148.1(C),135.8(CH), 132.6(C), 130.7(CH),125.0(C),
123.9 (CH), 85.2 (C), 49.6 (CH2), 33.8 (CH2) and 20.8 (CH2); m/z (TOF EI+) 273 (M+,
58%), 230 (100), 200 (93) and 184 (73).
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M.; Rondanin, R.; Piccagli, L.; Baruchello, R.; Rossi, M.; Romagnoli, R.; Invidiata, F.
P.; Grimaudo, S.; Jung, M. K.; Hamel, E.; Gebbia, N.; Crosta, L.; Abbadessa, V.; Di
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