Reaction of heterocyclic enamines with nitrile oxide and nitrilimine precursors

Article abstract of DOI:10.1039/c0ob00286k

Alkylidenepyrrolidines 1, 21, 24 and 26 undergo reactions with nitrile oxides and nitrilimines or their precursors to give a range of novel heterocyclic compounds. With alkylidenepyrrolidine ester 1, nitrolic acids give products in which the liberated nitrous acid reacts with the alkylidenepyrrolidine, followed by two cycloadditions to give adducts 3. In contrast, hydroximoyl chlorides give isoxazoles 10, presumably by cycloaddition/elimination. With hydrazonyl chlorides, simple acylation of the alkylidenepyrrolidine occurs to give compounds 17. With sulfonyl alkylidenepyrrolidines 24 and 26, cycloaddition onto the imine tautomer is the preferred pathway, with a stereoselective reaction taking place in the latter case.

Full text of DOI:10.1039/c0ob00286k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Reaction of heterocyclic enamines with nitrile oxide and nitrilimine
precursors†
Cevher Altug˘,a,b Yasar Du¨ru¨st,b Mark C. Elliott,*a Benson M. Kariuki,a Tillique Rorstada and Mark Zaala
Received 18th June 2010, Accepted 3rd August 2010
DOI: 10.1039/c0ob00286k
Alkylidenepyrrolidines 1, 21, 24 and 26 undergo reactions with nitrile oxides and nitrilimines or their
precursors to give a range of novel heterocyclic compounds. With alkylidenepyrrolidine ester 1, nitrolic
acids give products in which the liberated nitrous acid reacts with the alkylidenepyrrolidine, followed by
two cycloadditions to give adducts 3. In contrast, hydroximoyl chlorides give isoxazoles 10, presumably
by cycloaddition/elimination. With hydrazonyl chlorides, simple acylation of the alkylidenepyrrolidine
occurs to give compounds 17. With sulfonyl alkylidenepyrrolidines 24 and 26, cycloaddition onto the
imine tautomer is the preferred pathway, with a stereoselective reaction taking place in the latter case.
Table 1 Formation of adducts 3
Introduction
Nitrile oxides1 and nitrilimines2 are versatile 1,3-dipoles,3 un-
dergoing cycloaddition reactions with a wide range of alkenes
and alkynes. Nitrile oxides are generally prepared by treatment
of hydroxamic acid chlorides with base, or by oxidation of
aldoximes, although their formation by elimination of HNO2 from
nitrolic acids has also been reported.4 This latter method has not
yet seen widespread application. There are a small number of
reports of reactions of nitrilimines and their hydrazonyl chloride
precursors with heterocyclic enamines, with both acylation5 and
cycloaddition products6 being reported. Alkylidenepyrrolidines
are versatile synthetic intermediates, and have been converted
into a broad range of compounds of biological interest.7 As part
of our continued interest in this class of compound,8 we have
investigated the reactions of alkylidenepyrrolidines with nitrile
oxide and nitrilimine precursors, and now report the results of
this investigation in full.9
Compound
R
Conditions
Yield (%)
76
3a
3b
3c
6-Chloro-3-pyridyl
4-Pyridyl
Me
Benzene, reflux, 2 h
110 ◦C, 100 W, 10 mina 58
Toluene, reflux, 2 h
65
a CEM Discover microwave reactor
Results and discussion
The reactions of nitrolic acids 2 with alkylidenepyrrolidine 1 give
compounds 3 in good yield (Table 1). The structural assignment
of compound 3a was confirmed by single-crystal X-ray diffraction
(Fig. 1), with other compounds being assigned by analogy.
For the formation of compound 3a, simply heating the pre-
cursors in benzene is sufficient, while the reaction to produce
compound 3c requires a slightly higher temperature. Reaction of
nitrolic acid 2b was considerably slower, but was accelerated by mi-
crowave irradiation (Table 1). In all cases, complete consumption
of the alkylidenepyrrolidine reagent 1 was observed.
Fig. 1 Structure of compound 3a from single crystal X-ray data.
compound 2a is trapped by the alkylidenepyrrolidine, giving
nitrosoalkene 4 or its oxime tautomer 5. The presence of the oxime
will presumably render the ester more susceptible to hydrolysis,
and there is precedent for the decarboxylation of oximinocar-
boxylic acids, albeit on the corresponding O-acyl compounds,10
so that ester hydrolysis and decarboxylation to give the nitrile 6
is not unreasonable (ester hydrolysis/decarboxylation to give the
aldoxime, followed by nitrile oxide cycloaddition/dehydration is
also a possibility11). From this point, cycloaddition of the nitrile
oxide 7 onto the nitrile12 and imine13 bonds will give the observed
product 3.
The formation of these products was rationalised by the mecha-
nism shown in Scheme 1. The nitrous acid liberated upon heating
aSchool of Chemistry, Cardiff University, Park Place, Cardiff, UK, CF10
3AT. E-mail: elliottmc@cardiff.ac.uk; Fax: +44 29 20874030; Tel: +44 29
20874686
b
˙
Department of Chemistry, Abant Izzet Baysal University, TR-14280 Bolu,
Turkey
† Electronic supplementary information (ESI) available: Full experimental
procedures and copies of NMR spectra of new compounds. CCDC
reference numbers 731459 and 776572. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c0ob00286k
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Table 2 Formation of adducts 10
Compound
Ar
Yield (%)
10a
10b
10c
10d
Phenyl
68
69
67
56
2,6-Dichlorophenyl
2,4-Dichlorophenyl
2-Nitrophenyl
These reactions give interesting products with a considerable
increase in molecular complexity. However, the reactions do
not involve direct reaction of the nitrile oxide with the alkyli-
denepyrrolidine, and so we elected to investigate reactions of the
corresponding a-chlorooximes 9 under basic conditions to form
the nitrile oxides without this added complexity. In this case,
isoxazoles 10 were formed (Table 2). Use of a single equivalent of
the a-chlorooxime gave the same products, but in lower yield and
with some alkylidenepyrrolidine left unreacted. However, when
the 3-nitrophenyl chlorooxime 9e was used, compound 11 was
obtained as the sole product (Scheme 3).
Scheme 1
Upon examination of crude reaction mixtures, particularly
for the slower reactions, a by-product was observed in which
the alkylidenepyrrolidine was clearly present, but lacking its
alkene hydrogen. This therefore appeared to be consistent with
either structure 4 or 5. Upon chromatography, compound 5 was
obtained (Scheme 2), this being similar, but not identical to, the
compound observed in the crude reaction mixtures. We therefore
assign the product observed in the crude reaction mixtures to
be compound 4, which undergoes tautomerisation to give the
more stable compound 5 upon purification. The modest yield of
this compound is due to its isolation from the crude reaction
mixture under milder conditions which led to lower conversion.
The oxime carbon in compound 5 resonates at 143.1 ppm, whereas
the corresponding carbon in alkylidenepyrrolidine 1 resonates
at 76.5 ppm. Nitrosation of the alkene, as in compound 4, is
unlikely to lead to such a dramatic increase, whereas related a-
oximinoesters show very similar chemical shifts.10,14 Reaction of
phenylnitrolic acid only gave compound 4, with compound 3 not
observed even under forcing conditions.
Scheme 3
There are two possible distinct mechanisms for the formation
of compounds 10. Initial C-acylation of compound 115 could lead
to the formation of compound 12. This would then undergo
isomerisation to compound 13 followed by a second rapid
acylation. Alternatively, cycloaddition of nitrile oxide 14 onto
the alkylidenepyrrolidine 1 would give spirocyclic compound 15
which could undergo elimination to give the same compound
13. There is some precedent for the isomerisation of compounds
12 to give the isoxazoles in the work of Dannhardt on the
reaction of alkylidenepyrrolidine ketones with hydroxylamine.16
The reverse of the ring transformation in Scheme 4 is known,
leading to the formation of aromatic pyrrole compounds from
suitably substituted isoxazoles.17 However, Dadiboyena and co-
workers have recently reported6 the cycloaddition/elimination
pathway for the corresponding nitrilimines. Since cyclisation of
intermediate 12 would require the oxime geometry shown, and
would be a disfavoured 5-endo-trig cyclisation, we would also tend
to favour the cycloaddition/elimination pathway for the formation
of compounds 10. It is not clear why compound 11 is formed
from a-chlorooxime 9e. It is conceivable that the nitrile oxide
Scheme 2
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Scheme 5
Scheme 4
14 would be formed more rapidly from compounds 9b–d due
to steric acceleration. However, rapid formation of cycloadducts
from compound 9e has been reported,18 and if this was the
explanation, we would also expect to observe a similar product
from a-chlorooxime 9a.
The reaction of alkylidenepyrrolidines, including compound 1,
with a-chlorohydrazones 16 has been reported to give products 17
by simple acylation of the alkylidenepyrrolidine double bond.5
The possibility that the products 17 could isomerise to give
the corresponding pyrazoles was mentioned by the authors, but
only to exclude these compounds as possible reaction products.
We were intrigued by the difference between the behaviour of
a-chlorooximes and a-chlorohydrazones, and therefore reacted
alkylidenepyrrolidine 1 with several a-chlorohydrazones (Scheme
5).
Fig. 2
22, prepared from the alkylidenepyrrolidine methyl ester 21 in
the same manner (Scheme 6, Fig. 3). It is clear from this
structure that the hydrazone group is almost perpendicular to the
alkylidenepyrrolidine double bond, which explains the apparent
diastereotopicity as well as the relatively minor effect of the
hydrazone on the alkene carbon chemical shift. The low yield in
this case is more likely attributable to losses on purification rather
than any fundamental problem with the reaction.
In each case, the major product (17) obtained has NMR data
broadly in line with that reported by Miao et al.5 In one case we
obtained an additional product 18b, formed by 1,3-dipolar cy-
cloaddition onto the imine tautomer of the alkylidenepyrrolidine.
We were initially surprised by some aspects of the NMR data for
compounds 17. In particular, the two hydrogen atoms at position
4 of the pyrrolidine ring are clearly in different environments, and
we were also rather surprised that the 13C chemical shift of C-a in
compound 17c is 79.8 ppm, compared to 76.6 ppm in compound 1.
Acylation will typically increase the chemical shift of this carbon
further, for example to 97.7 ppm in compound 1919 and 86.6 ppm
in compound 2020 (Fig. 2).
Scheme 6
The isolation of compounds 17 and 22 rather than the pyrazole
23 (analogous to compounds 10) is surprising. If these reactions
proceeded by nitrilimine cycloaddition followed by fragmentation
(Scheme 7) it seems unlikely that compounds 17/22 would be
formed exclusively, at the expense of the aromatic pyrazole. We
We therefore sought unambiguous proof of these structural
assignments, and obtained an X-ray structure of compound
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Table 3 Formation of adducts 25
Product
Method
Ar
Yield (%)
25a
25b
25c
25e
25f
25g
25h
25i
a
a
a
a
a
a
a
b
b
Phenyl
69
75
44
76
73
66
78
68
58
2,6-Dichlorophenyl
2,4-Dichlorophenyl
3-Nitrophenyl
4-Fluorophenyl
4-Bromophenyl
Thien-2-yl
4-Pyridyl
3-Pyridyl
25j
Table 4 Formation of adducts 27
Fig. 3 Structure of compound 22 from single crystal X-ray data.
Product
Ar
Yield (%)
27a
27b
27c
27f
27g
Phenyl
46
51
65
56
29a
2,6-Dichlorophenyl
2,4-Dichlorophenyl
4-Fluorophenyl
Scheme 7
4-Bromophenyl
a
= 47% based on recovered 26.
would therefore favour a simple acylation mechanism in this
instance.
Conclusion
The formation of compound 18b presents an interesting oppor-
tunity. We considered the possibility that with alkylidenepyrro-
lidines with substituents that are less able to stabilise the enamine
tautomer, this type of reaction could become the predominant
pathway. With the sulfone 24, this is indeed the case, with the
reaction being high-yielding and general for the formation of
compounds 25 (Table 3) using either nitrolic acids or hydroximoyl
chlorides as nitrile oxide precursors.
A range of interesting heterocyclic systems has been obtained
by the reaction of alkylidenepyrrolidines with 1,3-dipoles and/or
their precursors. The differing products obtained with quite similar
systems would have made it difficult to predict the outcome of these
reactions.
Experimental section
These results then presented a further opportunity; the use
of chiral alkylidenepyrrolidines to deliver diastereoselective cy-
cloaddition chemistry. Alkylidenepyrrolidine 26 was prepared by
a method previously developed in the Elliott group.21 Reaction
of this compound with a representative range of hydroximoyl
chlorides gave the corresponding cycloadducts 27, all as single
diastereoisomers. Although we were unable to obtain diagnostic
nOe enhancements that would confirm the stereochemistry, the
stereochemistry shown in Table 4 seems most likely as a result of
approach of the nitrile oxide to the least hindered face of the imine
tautomer. Compound 27b shows evidence of hindered rotation of
the 2,6-dichlorophenyl ring (broadening of peaks in the 13C NMR
spectrum) which was not observed for compound 25b. Molecular
modelling22 shows that the 2,6-dichlorophenyl ring is close to the
ester in both possible diastereoisomers, and therefore we are unable
to assign stereochemistry based on this observation.
General experimental points
Melting points were determined on a Gallenkamp melting point
apparatus and are uncorrected. Infrared spectra were recorded
on a Perkin Elmer 1600 FTIR spectrophotometer. Mass spectra
were recorded on a Fisons VG Platform II spectrometer and
on a Micromass Q-TOF Micro spectrometer. NMR spectra
were recorded on a Bruker DPX 400 spectrometer operating at
◦
1
400 MHz for H and at 100 MHz for 13C at 25 C. All chemical
shifts are reported in ppm downfield from TMS. Coupling
constants (J) are reported in Hz. Crystallographic data were
recorded on a Nonius KappaCCD diffractometer equipped with
an Oxford Cryosystem cryostat. The structures were solved by
direct methods with additional light atoms found by Fourier
methods. Hydrogen atoms were added at calculated positions and
refined using a riding model. Anisotropic displacement parameters
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were used for all non-H atoms; H-atoms were given isotropic
displacement parameters equal to 1.2 or 1.5 times the equivalent
isotropic displacement parameter of the atom to which the H-
atom is attached. Alkylidenepyrrolidines 1 and 24 were prepared
according to a literature procedure;21 compound 21 was prepared
by a similar method. The nitrolic acids,23 a-chlorooximes24 and
a-chlorohydrazones25 used in this study were all prepared by
standard methods.
and 2.05–1.99 (1H, m, one of CH2CH2N); dC (100 MHz; CDCl3)
177.8 (C), 167.0 (C), 157.6 (C), 150.5 (4 ¥ CH), 133.8 (C), 132.8
(C), 121.7 (2 ¥ CH), 121.4 (2 ¥ CH), 104.3 (C), 53.7 (CH2), 37.2
(CH2) and 25.0 (CH2); m/z (TOF AP+) 376 (MH+ + CH3CN,
100%) and 335 (MH+, 45).
3-Methyl-7a-(3-methyl-1,2,4-oxadiazol-5-yl)-5,6,7,7a-
tetrahydropyrrolo[1,2-d][1,2,4]oxadiazole (3c)
Acetonitrolic acid (2c) (208 mg, 2 mmol) was added to ethyl 2-
pyrrolidin-2-ylidene acetate (1) (155 mg, 1 mmol) in dry toluene
(10 mL) and the mixture was heated under reflux for 2 h. The
reaction mixture was concentrated in vacuo and the crude residue
purified by flash column chromatography (eluent 1 : 1 petroleum
ether–ethyl acetate) to give the title compound (135 mg, 65%) as
a yellow oil; nmax. (neat) 2982, 1622, 1561, 1436, 1396, 1302, 1105
and 853 cm-1; dH (400 MHz; CDCl3) 3.45 (1 H, ddd, J 11.3, 6.9,
3.5, one of CH2N), 3.18 (1 H, ddd, J 11.3, 9.5, 6.1, one of CH2N),
2.62 (1 H, ddd, J 14.0, 9.4, 7.1, one of CH2C), 2.46 (1 H, ddd, J
14.0, 7.5, 4.4, one of CH2C), 2.36 (3 H, s, CH3), 2.08–1.84 (2 H, m,
CH2CH2N) and 1.96 (3 H, s, CH3); dC (100 MHz; CDCl3) 177.4
(C), 167.3 (C), 155.7 (C), 102.4 (C), 50.9 (CH2), 37.3 (CH2), 24.8
(CH2), 11.6 (CH3) and 10.2 (CH3); m/z (TOF EI+) 208 (M+, 22%),
178 (100), 111 (38) and 85 (95).
3-(6-Chloropyridin-3-yl)-7a-[3-(6-chloropyridin-3-yl)-1,2,4-
oxadiazol-5-yl]-5,6,7,7a-tetrahydropyrrolo[1,2-d][1,2,4]oxadiazole
(3a)
6-Chloropyridin-3-nitrolic acid (2a) (2.0 eq., 201 mg, 1.0 mmol)
was added to ethyl 2-pyrrolidin-2-ylidene acetate (1) (77.5 mg,
0.5 mmol) in dry benzene (10 mL) and the mixture was heated
to reflux for 2 h. The reaction was concentrated in vacuo, and the
crude residue was purified by flash column chromatography (elu-
ent 1 : 1 petroleum ether–ethyl acetate) to give the title compound
◦
(154 mg, 76%) as a yellow solid, m.p. 162–163 C (CDCl3); nmax.
(KBr) 3060, 2980, 1597, 1584, 1382, 1134, 1113, 840 and 740 cm-1;
dH (400 MHz; CDCl3) 9.03 (1 H, dd, J 2.4, 0.6, pyridine 2-H),
8.71 (1 H, d, J 2.4, 0.6, pyridine 2-H), 8.27 (1 H, dd, J 8.4, 2.4,
pyridine 4-H), 8.02 (1 H, dd, J 8.4, 2.4, pyridine 4-H), 7.40 (1 H,
dd, J 8.4, 0.6, pyridine 5-H), 7.38 (1 H, dd, J 8.4, 0.6, pyridine
5-H), 3.43–3.40 (2 H, m, CH2N), 2.88 (1 H, ddd, J 14.2, 10.7, 6.9,
one of CH2C), 2.72 (1 H, ddd, J 14.2, 7.1, 3.3, one of CH2C), 2.15–
2.07 (1 H, m, one of CH2CH2N) and 2.05–1.98 (1 H, m, one of
CH2CH2N); dC (100 MHz; CDCl3) 178.2 (C), 166.3 (C), 156.8 (C),
154.7 (C), 154.5 (C), 149.3 (CH), 149.2 (CH), 138.3 (CH), 137.9
(CH), 125.2 (CH), 125.1 (CH), 122.0 (C), 121.1 (C), 104.4 (C), 54.1
(CH2), 37.7 (CH2) and 25.6 (CH2); m/z (TOF ES+) 446 (MH+ +
CH3CN, 67%), 444 (MH+ + CH3CN, 100), 405 (M+, 16) and 403.0
(M+, 25). Selected crystallographic data: C17H12Cl2N6O2, FW =
Ethyl 2-(3,4-dihydro-2H-pyrrol-5-yl)-2-(hydroxyimino)acetate (5)
Pyridine-4-nitrolic acid (2b) (334 mg, 2 mmol) was added to
ethyl (2-pyrrolidin-2-ylidene acetate (1) (155 mg, 1 mmol) in dry
benzene (10 mL) and the mixture was heated under reflux for 2 h.
The reaction was concentrated in vacuo, and the crude residue
(expansion of proton NMR spectrum provided in ESI†) was
purified by flash column chromatography (2 : 1 petroleum ether–
ethyl acetate) to give the title compound (65 mg, 35%) as a yellow
oil; nmax. (neat) 3546, 2988, 1739, 1608, 1291, 1205, 1029 and 946
cm-1; dH (400 MHz; CDCl3) 4.33 (2 H, q, J 7.1, OCH2), 3.89 (2 H,
t, J 7.7, NCH2), 3.14 (2 H, t, J 8.1, CH2), 1.97 (2 H, app. quintet, J
7.9, CH2) and 1.33 (3 H, t, J 7.1, CH3); dC (100 MHz; CDCl3) 167.8
(C), 164.5 (C), 143.1 (C), 61.3 (CH2), 54.5 (CH2), 36.0 (CH2), 19.6
(CH2) and 14.2 (CH3); m/z (TOF AP+) 248 (MNa+ + CH3CN,
61%), 185 (MH+, 100) and 152 (38).
˚
403.23, T = 150(2) K, l = 0.71073 A, Monoclinic, P21/c, a ◦=
˚
˚
6.8900(3) A, b = 13.7810(5) A, c = 18.1120(9), b = 94.5030(10) ,
3
-3
˚
V = 1714.45(13) A , Z = 4, r(calc) = 1.562 Mg m , crystal size =
0.50 ¥ 0.12 ¥ 0.12 mm3, reflections collected = 6624, independent
reflections = 3885, R(int) = 0.0569, parameters = 244, R1 [I >
2s(I)] = 0.0848, wR2 [I > 2s(I)] = 0.188, R1 (all data) = 0.117, wR2
(all data) = 0.205. Full crystallographic data for this compound
have been deposited with the CCDC, reference number 731459.†
General experimental procedure for the formation of isoxazoles
(10)
3-(Pyridin-4-yl)-7a-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)-
The alkylidenepyrrolidine 1 (155 mg, 1 mmol) in CH2Cl2 (5 mL)
was added to a solution of a-chlorooxime 9 (2 mmol) in CH2Cl2
(5 mL). Triethylamine (250 mg, 2.5 mmol) was added dropwise
and reaction mixture 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 as described below.
5,6,7,7a-tetrahydropyrrolo[1,2-d][1,2,4]oxadiazole (3b)
Pyridine-4-nitrolic acid (2b) (334 mg, 2 mmol) was added to ethyl
2-pyrrolidin-2-ylidene acetate (1) (155 mg, 1 mmol) in dry toluene
(4 mL) and the mixture was heated in a CEM Discover microwave
reactor for 10 min (100 W, 110 ◦C, 240 Psi). The reaction mixture
was concentrated in vacuo, and the crude residue was purified by
flash column chromatography (eluent 20 : 20 : 1 petroleum ether–
ethyl acetate–methanol) to give the title compound (193 mg, 58%)
as a pale oil (Found: M+, 334.1183; C17H14N6O2 requires M,
334.1178); nmax. (neat) 2924, 1679, 1599, 1375, 1257, 835 and 799
cm-1; dH (400 MHz; CDCl3) 8.73–8.67 (4 H, m), 7.92 (2 H, app.
broad d, J 6.1), 7.63–7.59 (2 H, m), 3.53–3.29 (2 H, m, CH2N),
2.89 (1 H, ddd, J 14.2, 10.8, 6.9, one of CH2C), 2.73 (1 H, ddd, J
14.2 7.1, 3.1, one of CH2C), 2.15–2.06 (1 H, m, one of CH2CH2N)
Ethyl 5-(3-(N¢-hydroxybenzimidamido)propyl)-3-phenylisoxa-
zole-4-carboxylate (10a). The crude product was purified by
flash column chromatography (eluent 2 : 1 petroleum ether–ethyl
acetate) to give the title compound (267 mg, 68%) as a yellow oil
(Found: M+, 393.1690. C22H23N3O4 requires M, 393.1689); nmax.
(neat) 3372, 3063, 2980, 1722, 1627, 1447, 1306, 767 and 698
cm-1; dH (400 MHz; CDCl3) 7.49 (2 H, dd, J 7.8, 1.7), 7.38–7.25
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(8 H, m), 5.45 (1 H, broad s, NH), 4.09 (2 H, q, J 7.1, OCH2),
3.09–2.94 (4 H, m, CH2CH2CH2N), 1.79 (2 H, app. quintet, J
7.2, CH2CH2CH2N) and 1.05 (3 H, t, J 7.1, OCH2CH3); dC (100
MHz; CDCl3) 178.0 (C), 162.5 (C), 161.7 (C), 156.2 (C), 131.1
(C), 129.7 (CH), 129.6 (CH), 129.3 (2 ¥ CH), 128.4 (2 ¥ CH),
128.4 (2 ¥ CH), 128.3 (C), 127.9 (2 ¥ CH), 108.2 (C), 60.8 (CH2),
42.7 (CH2), 28.8 (CH2), 24.5 (CH2) and 13.8 (CH3); m/z (TOF
ES+) 393 (M+, 3%), 245 (12), 144 (26) and 104 (100).
(C), 161.0 (C), 160.7 (C), 152.6 (C), 148.7 (C), 148.2 (C), 133.4
(CH), 133.2 (CH), 132.1 (CH), 131.8 (CH), 130.7 (CH), 130.5
(CH), 126.3 (C), 124.7 (C), 124.5 (CH), 124.4 (CH), 108.6 (C),
60.9 (CH2), 42.5 (CH2), 28.0 (CH2), 24.2 (CH2) and 13.5 (CH3);
m/z (TOF ES+) 506 (MNa+, 46%) and 484 (MH+, 100).
3-(3-Nitrophenyl)-4-(pyrrolidin-2-ylidene)isoxazol-5(4H)-one (11)
The alkylidenepyrrolidine 1 (155 mg, 1 mmol) in CH2Cl2 (5 mL)
was added to a solution of N-hydroxy-3-nitrobenzimidoyl chloride
(9e) (400 mg, 2 mmol) in CH2Cl2 (5 mL). Triethylamine (250 mg,
2.5 mmol) was added dropwise and the reaction mixture 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–ethyl ac-
etate) to give the title compound (193 mg, 41%) as a yellow solid,
m.p. 144–146 ◦C (Found: M+, 273.0750; C13H11N3O4 requires M,
273.0750); nmax. (KBr disk) 3284, 2926, 1691, 1599 and 1351 cm-1;
dH (400 MHz; d6-DMSO) 10.11 (1 H, broad s, NH), 8.38 (1 H,
dd, J 8.2, 2.3), 8.31 (1 H, app. broad s), 8.00 (1 H, d, J 7.6), 7.80
(1 H, app. t, J 8.0), 3.62 (2 H, t, J 7.0, CH2N), 2.53–2.47 (2 H,
m, CH2C) and 1.89 (2 H, app. quintet, J 7.2, CH2CH2N); dC (100
MHz; d6-DMSO) 173.4 (C), 169.5 (C), 160.7 (C), 147.7 (C), 135.3
(CH), 132.1 (C), 130.2 (CH), 124.5 (CH), 123.4 (CH), 84.6 (C),
49.1 (CH2), 33.3 (CH2) and 20.3 (CH2); m/z (TOF EI+) 273 (M+,
58%), 230 (100), 200 (93) and 184 (73).
Ethyl 5-(3-(2,6-dichloro-N¢-hydroxybenzimidamido)propyl)-3-
(2,6-dichlorophenyl)isoxazole-4-carboxylate (10b). The crude
product was purified by flash column chromatography (eluent
2 : 1 petroleum ether–ethyl acetate) to give the title compound
(366 mg, 69%) as a colourless solid, m.p. 122–123 ◦C (Found:
MH+, 530.0182. C22H20N3O435Cl4 requires M, 530.0208); nmax.
(neat) 3372, 2922, 1721, 1644, 1457, 1377, 1297, 910, 784 and 732
cm-1; dH (400 MHz; CDCl3) 7.39–7.11 (6 H, m, aromatic CH),
5.57 (1 H, broad s, NH), 4.01 (2 H, q, J 7.1, OCH2), 3.13 (2 H, t,
J 7.4, CH2CH2CH2N), 2.88 (2 H, poorly resolved app. q, J 5.1,
CH2CH2CH2N), 1.88 (2 H, app. quintet, J 7.0, CH2CH2CH2N)
and 0.90 (3 H, t, J 7.1, CH2CH3); dC (100 MHz; CDCl3) 177.9
(C), 160.7 (C), 158.3 (C), 150.2 (C), 135.7 (2 ¥ C–Cl), 135.0 (2 ¥
C–Cl), 131.0 (CH), 130.8 (CH), 129.4 (C), 127.9 (C), 127.8 (2
¥ CH), 127.4 (2 ¥ CH), 109.0 (C), 60.5 (CH2), 41.7 (CH2), 27.8
(CH2), 24.1 (CH2) and 13.4 (CH3); m/z (TOF ES+) 532 (MH+,
100%) (isotopic distribution consistent with 4 ¥ Cl).
Ethyl 5-(3-(2,4-dichloro-N¢-hydroxybenzimidamido)propyl)-3-
(2,4-dichlorophenyl)isoxazole-4-carboxylate (10c). The crude
residue was purified by flash column chromatography (eluent
2 : 1 petroleum ether–ethyl acetate) to give the title compound
(179 mg, 67% using 0.5 mmol of compound 1) as an orange oil
(Found: MH+, 530.0205. C22H20N3O435Cl4 requires M, 530.0208);
nmax. (neat) 3383, 3090, 2980, 1723, 1634, 1594, 1433, 1372, 1308,
1246, 1102 and 825 cm-1; dH (400 MHz; CDCl3) 7.43 (1 H, d,
J 1.3), 7.39 (1 H, d, J 1.8), 7.31–7.21 (4 H, m), 5.52 (1 H, app.
broad t, J 5.7, NH), 4.07 (2 H, q, J 7.1, OCH2), 3.09 (2 H, t, J
7.4, CH2CH2CH2N), 2.93 (2 H, app. q, J 6.5, CH2N), 1.87 (2
H, app. quintet, J 7.2, CH2CH2CH2N) and 1.01 (3 H, t, J 7.1,
CH2CH3); dC (100 MHz; CDCl3) 177.7 (C), 161.3 (C), 160.0 (C),
152.5 (C), 136.3 (C), 136.3 (C), 134.9 (C), 134.8 (C), 132.4 (CH),
131.8 (CH), 129.6 (CH), 129.3 (CH), 129.0 (C), 127.4 (CH), 127.2
(C), 127.0 (CH), 109.6 (C), 61.0 (CH2), 42.1 (CH2), 28.5 (CH2),
24.3 (CH2) and 13.7 (CH3); m/z (TOF ES+) 532 (MH+, 100%)
(isotopic distribution consistent with 4 ¥ Cl).
General experimental procedure for the formation of compounds
17a, 17b, 18b, 17c and 22
The alkylidenepyrrolidine 1 (39 mg, 0.25 mmol) in CH2Cl2 (5 mL)
was added to a solution of a-chlorohydrazone 16 (0.5 mmol) in
CH2Cl2 (5 mL). Triethylamine (75 mg, 0.75 mmol) was added
dropwise and reaction mixture 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 as described below.
Ethyl 3-phenyl-3-(2-phenylhydrazono)-2-(pyrrolidin-2-ylidene)-
propanoate (17a). The crude product was purified by flash col-
umn chromatography (eluent 2 : 1 petroleum ether–ethyl acetate)
to give the title compound (32 mg, 37%) as a pale yellow solid,
◦
◦
m.p. 122–124 C (lit.5 127–129 C) (Found: MH+, 350.1854;
C21H24N3O2 requires M, 350.1869); nmax. (KBr) 3362, 3273, 1649,
1601, 1501, 1234, 1057 and 748 cm-1; dH (400 MHz; CDCl3) 8.67
(1 H, broad s, NH), 7.84 (1 H, broad s, NH), 7.73 (2 H, app. broad
d, J 7.1, aromatic CH), 7.32 (2 H app. broad t, J 7.4, aromatic
CH), 7.29–7.24 (3 H, m, aromatic CH), 7.17 (2 H, app. broad d,
J 7.5, aromatic CH), 6.84 (1 H, app. tt, J 7.4, 1.1, aromatic CH),
4.10–4.01 (2 H, m, OCH2), 3.64 (2 H, app. td, J 7.2, 3.6, CH2N),
2.42 (1 H, app. dt, J 17.2, 7.8, one of CH2), 2.31 (1 H, app. dt, J
17.2, 7.9, one of CH2), 1.93 (2 H, app. quintet, J 7.4, CH2) and
1.03 (3 H, t, J 7.1, CH3); m/z (TOF ES+) 350 (MH+, 100%).
Ethyl
5-(3-(N¢-hydroxy-2-nitrobenzimidamido)propyl)-3-(2-
nitrophenyl)isoxazole-4-carboxylate (10d). The crude product
was purified by flash column chromatography (eluent 2 : 1
petroleum ether–ethyl acetate) to give the title compound (135 mg,
56% using 0.5 mmol of compound 1) as a yellow oil (Found:
MH+, 484.1479. C22H22N5O8 requires M, 484.1468); nmax. (neat)
3382, 2980, 1718, 1637, 1529, 1348, 1315, 912 and 855 cm-1; dH
(400 MHz; CDCl3) 8.16 (1 H, dd, J 8.0, 1.3), 7.96 (1 H, dd, J 8.1,
1.0), 7.66 (1 H, app. td, J 7.5, 1.5), 7.62–7.57 (2 H, m), 7.52 (1
H, app. td, J 7.7, 1.5), 7.47 (1 H, dd, J 7.5, 1.4), 7.44 (1 H, dd,
J 7.5, 1.4), 5.53 (1 H, broad s, NH), 4.04 (2 H, q, J 7.1, OCH2),
3.10 (2 H, t, J 7.4, CH2CH2CH2N), 2.95 (2 H, app. q, J 6.4,
CH2CH2CH2N), 1.89 (2 H, app. quintet, J 7.1, CH2CH2CH2N)
and 0.95 (3 H, t, J 7.1, OCH2CH3); dC (100 MHz; CDCl3) 177.6
Ethyl 3-(2-(4-chlorophenyl)hydrazono)-3-(4-nitrophenyl)-2-(pyr-
rolidin-2-ylidene)propanoate (17b) and ethyl [2-{1-(4-chloro-
phenyl)-3-(4-nitrophenyl)-5,6,7,7a-tetrahydropyrrolo[1,2-d][1,2,4]-
triazol-7a-yl}acetate (18b). The crude product was purified by
flash column chromatography (eluent 2 : 1 petroleum ether–ethyl
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 4978–4986 | 4983
©

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acetate) to give compound 17b (63 mg, 59%) as an orange solid
and compound 18b (10 mg, 10%) as a pale oil.
(3 H, m, aromatic CH), 7.17 (2 H, d, J 7.6, aromatic CH), 6.84 (1
H, app. t, J 7.2, aromatic CH), 3.69–3.60 (2 H, m, CH2N), 3.56 (3
H, s, OCH3), 2.47–2.26 (2 H, m, CH2), and 1.93 (2 H, app. quintet,
J 7.6, CH2); dC (100 MHz; CDCl3) 169.7 (C), 168.1 (C), 145.3 (C),
141.5 (C), 139.5 (C), 129.6 (2 ¥ CH), 128.7 (2 ¥ CH), 128.0 (CH),
126.2 (2 ¥ CH), 120.1 (CH), 113.5 (2 ¥ CH), 80.4 (C), 51.4 (CH3),
48.2 (CH2), 31.9 (CH2) and 22.0 (CH2); m/z (TOF ES+) 336 (MH+,
100%) and 304 (20). Selected crystallographic data: C20H21N3O2,
Data for compound 17b. Orange solid (63 mg, 59%), m.p. 151–
◦
153 C (Found: MH+, 429.1337. C21H22N4O435Cl requires M,
429.1300); nmax. (KBr) 3368, 3248, 1649, 1572, 1336, 1238, 852
and 821 cm-1; dH (400 MHz; CDCl3) 8.69 (1 H, broad s, NH), 8.11
(2 H, d, J 8.9, aromatic CH), 7.97 (1 H, broad s, NH), 7.77 (2 H,
d, J 8.9, aromatic CH), 7.18 (2 H, d, J 9.1, aromatic CH), 7.06 (2
H, d, J 9.1, aromatic CH), 4.04–3.92 (2 H, m, OCH2), 3.61 (2 H,
app. broad t, J 6.6, CH2N), 2.32 (1 H, app. dt, J 17.2, 7.8, one of
CH2C), 2.20 (1 H, app. dt, J 17.2, 7.8, one of CH2C), 1.91 (2 H,
app. quintet, J 7.5, CH2) and 0.96 (3 H, t, J 7.1, CH3); m/z (TOF
ES+) 470 (MH+ + CH3CN, 68%) and 429 (MH+, 100).
Data for compound 18b. Pale oil (10 mg, 10%) (Found: MH+,
429.1346. C21H22N4O435Cl requires M, 429.1300); nmax. (KBr) 2924,
1726, 1591, 1489, 1340, 1091, and 856 cm-1; dH (400 MHz; CDCl3)
8.24 (2 H, d, J 9.0, aromatic CH), 7.93 (2 H, d, J 9.0, aromatic
CH), 7.23 (2 H, d, J 9.1, aromatic CH), 7.12 (2 H, d, J 9.0, aromatic
CH), 4.09–3.96 (2 H, m, CH2O), 3.44 (1 H, ddd, J 10.2, 7.5, 6.4,
one of CH2N), 3.26 (1 H, ddd, J 10.2, 6.8, 5.5, one of CH2N),
3.06 (1 H, d, J 14.5, one of CH2), 2.91 (1 H, d, J 14.5, one of
CH2), 2.65–2.52 (2 H, m, CH2), 2.09–1.99 (1 H, m, one of CH2),
1.93–1.82 (1 H, m, one of CH2) and 1.18 (3 H, t, J 7.1, CH3);
dC (100 MHz; CDCl3) 169.3 (C), 150.5 (C), 147.7 (C), 140.5 (C),
135.0 (C), 129.1 (CH), 127.3 (CH), 124.9 (C), 123.9 (CH), 115.6
(CH), 92.2 (C), 60.7 (CH2), 53.2 (CH2), 42.9 (CH2), 37.2 (CH2),
26.0 (CH2) and 14.1 (CH3); m/z (TOF ES+) 429 (MH+, 95%), 391
(100) and 341 (94).
˚
FW = 335.40, T = 150(2) K, l = 0.71073 A, Monoclinic, P21/n, a◦=
˚
˚
˚
10.4390(7) A, b = 8.2177(7) A, c = 20.2299(13) A, b = 102.142(4) ,
3
-3
˚
V = 1696.6(2) A , Z = 4, r(calc) = 1.313 Mg m , crystal size =
0.35 ¥ 0.15 ¥ 0.04 mm3, reflections collected = 3780, independent
reflections = 2266, R(int) = 0.0557, parameters = 227, R1 [I >
2s(I)] = 0.059, wR2 [I > 2s(I)] = 0.124, R1 (all data) = 0.092,
wR2 (all data) = 0.139. The low data to parameter ratio for this
compound is due to the weakness of the data from the crystals
which could only be obtained as thin plates. Full crystallographic
data for this compound have been deposited with the CCDC,
reference number 776572.†
3-Phenyl-7a-(phenylsulfonylmethyl)-5,6,7,7a-
tetrahydropyrrolo[1,2-d][1,2,4]oxadiazole (25a)
Triethylamine (30 mg, 0.3 mmol) was added to a solution of (Z)-2-
(phenylsulfonylmethylene)pyrrolidine (24) (56 mg, 0.25 mmol) and
a-chlorooxime 9a (39 mg, 0.25 mmol) in dry CH2Cl2 (5 mL). The
reaction mixture was heated under reflux for 18 h. The solution
was then washed with water (3 ¥ 15 mL), dried over magnesium
sulfate and the solvent removed under reduced pressure. The crude
product was purified by flash column chromatography on silica
gel (eluent 3 : 1 petroleum ether–ethyl acetate) to give the title
compound (59 mg, 69%) as a yellow oil (Found: MH+, 343.1121.
C18H19N2SO3 requires M, 343.1116); nmax.(neat) 2974, 1593, 1562,
1447, 1371, 1308, 1143, 1082, 751 and 690 cm-1; dH (400 MHz;
CDCl3) 7.87 (2 H, d, J 7.1, aromatic CH), 7.56 (1 H, app. tt, J
7.4, 2.1, aromatic CH), 7.47 (2 H, app. t, J 7.6, aromatic CH),
7.36–7.30 (3 H, m, aromatic CH), 7.24 (2 H, app. broad tt, J 7.4,
1.3, aromatic CH), 3.69 (1 H, d, J 14.8, one of CH2SO2), 3.67 (1
H, d, J 14.8, one of CH2SO2), 3.21–3.01 (2 H, m, CH2N), 2.73 (1
H, ddd, J 14.1, 11.7, 7.0, one of CH2C), 2.38 (1 H, ddd, J 14.1,
7.1, 1.0, one of CH2C), 1.89–1.79 (1 H, m, one of CH2CH2N) and
1.78–1.67 (1 H, m, one of CH2CH2N); dC (100 MHz; CDCl3) 159.4
(C), 140.8 (C), 133.5 (CH), 130.9 (CH), 129.1 (2 ¥ CH), 128.5 (2
¥ CH), 127.7 (2 ¥ CH), 127.6 (2 ¥ CH), 125.5 (C), 105.5 (C), 60.9
(CH2), 52.8 (CH2), 36.5 (CH2) and 24.8 (CH2); m/z (TOF ES+)
343 (MH+, 100%) and 224 (7).
Ethyl
3-(4-bromophenyl)-3-(2-(4-chlorophenyl)hydrazono)-2-
(pyrrolidin-2-ylidene)propanoate 17c). The crude product was
purified by flash column chromatography (eluent 2 : 1 petroleum
ether–ethyl acetate) to give the title compound (59 mg, 51%) as
◦
a pale yellow solid, m.p. 134–136 C (Found: MH+, 462.0561.
C21H22N3O335Cl79Br requires M, 462.0584); nmax. (KBr) 3356,
3267, 1657, 1595, 1497, 1483, 1244, 1086, 824 and 783 cm-1; dH
(400 MHz; CDCl3) 8.68 (1 H, broad s, NH), 7.83 (1 H, broad
s, NH), 7.58 (2 H, d, J 8.7, aromatic CH), 7.44 (2 H, d, J 8.7,
aromatic CH), 7.21 (2 H, d, J 8.9, aromatic CH), 7.08 (2 H, d,
J 8.9, aromatic CH), 4.11–4.00 (2 H, m, OCH2), 3.65 (2 H, app.
td, J 7.3, 2.4, CH2N), 2.41–2.21 (2 H, m, CH2), 1.94 (2 H, app.
quintet, J 7.3, CH2) and 1.03 (3 H, t, J 7.1, CH3); dC (100 MHz;
CDCl3) 168.5 (C), 167.6 (C), 143.2 (C), 141.0 (C), 138.0 (C),
131.2 (CH), 129.0 (CH), 127.4 (CH), 124.3 (C), 121.6 (C), 114.1
(CH), 79.8 (C), 59.3 (CH2), 47.7 (CH2), 31.5 (CH2), 21.5 (CH2)
and 14.5 (CH3); m/z (TOF ES+) 505 (MH+ + CH3CN, 41%) and
464 (MH+, 100) (isotopic distribution consistent with 1 ¥ Br and
1 ¥ Cl).
Compounds 25b–25h were prepared by a similar procedure, as
detailed in the ESI.†
Methyl 3-phenyl-3-(2-phenylhydrazono)-2-(pyrrolidin-2-
ylidene)propanoate (22)
7a-(Phenylsulfonylmethyl)-3-(pyridin-4-yl)-5,6,7,7a-
tetrahydropyrrolo[1,2-d][1,2,4]oxadiazole (25i)
The crude product was purified by flash column chromatography
(eluent 2 : 1 petroleum ether–ethyl acetate) to give the title
compound (20 mg, 21% from 0.28 mmol of alkylidenepyrrolidine
21) as a pale yellow solid, m.p. 165–170 ◦C (hexane–Et2O) (Found:
MH+, 336.1718; C20H22N3O2 requires M, 336.1712); nmax. (Nujol)
3389, 3273, 1653, 1601, 1575 and 1505 cm-1; dH (400 MHz; CDCl3)
8.66 (1 H, broad s, NH), 7.86 (1 H, broad s, NH), 7.74 (2 H, d, J
7.3, aromatic CH), 7.33 (2 H app. t, J 7.5, aromatic CH), 7.29–7.23
A solution of the nitrolic acid 2b (42 mg, 0.25 mmol) and (Z)-2-
(phenylsulfonylmethylene) pyrrolidine (24) (56 mg, 0.25 mmol) in
dry toluene (5 mL) was heated under reflux for 2 h. The solvent
was removed in vacuo and the crude product purified by flash
column chromatography on silica gel (eluent 2 : 1 petroleum ether–
ethyl acetate) to give the title compound (58 mg, 68%) as a pale oil
(Found: MH+, 343.1074. C17H18N3SO3 requires M, 344.1069); nmax.
4984 | Org. Biomol. Chem., 2010, 8, 4978–4986
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©

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(neat) 3059, 1590, 1447, 1374, 1307 and 1143 cm-1; dH (400 MHz;
CDCl3) 8.56 (2 H, d, J 6.0, pyridine 2-H and 6-H), 7.87 (2 H,
broad app. d, J 7.3, aromatic CH), 7.59 (1 H, app. tt, J 7.4, 1.9,
aromatic CH), 7.50 (2 H, app. t, J 7.6, aromatic CH), 7.26 (2 H, d,
J 6.0, pyridine 3-H and 5-H), 3.69 (1 H, d, J 14.8, one of CH2SO2),
3.64 (1 H, d, J 14.8, one of CH2SO2), 3.20–3.10 (2 H, m, CH2N),
2.75 (1 H, ddd, J 14.2, 11.7, 6.9, one of CH2C), 2.42 (1 H, ddd, J
14.2, 7.3, 1.7, one of CH2C), 1.95–1.86 (1 H, m, one of CH2CH2N)
and 1.82–1.68 (1 H, m, one of CH2CH2N); dC (100 MHz; CDCl3)
157.8 (C), 150.3 (2 ¥ CH), 140.8 (C), 133.8 (CH), 133.4 (C), 129.3
(2 ¥ CH), 127.7 (2 ¥ CH), 121.5 (2 ¥ CH), 106.9 (C), 61.0 (CH2),
53.1 (CH2), 36.7 (CH2) and 25.0 (CH2); m/z (TOF ES+) 385 (MH+
+ CH3CN, 41%) and 344 (MH+, 100%).
under reduced pressure. The crude product was purified by flash
column chromatography on silica gel (eluent 3 : 1 petroleum ether–
ethyl acetate) to give the title compound (48 mg, 46%) as a yellow
oil (Found: MH+, 415.1338. C21H23N2SO5 requires M, 415.1328);
nmax. (neat) 2980, 1732, 1608, 1447, 1370, 1309, 1084, 750 and 688
cm-1; dH (400 MHz; CDCl3) 7.91 (2 H, app. broad d, J 7.1), 7.60–
7.54 (3 H, m), 7.48 (2 H, app. broad t, J 7.5), 7.38 (1 H, app. tt,
J 7.4, 1.4), 7.31 (2 H, app. broad t, J 7.3), 4.18 (2 H, q, J 7.1,
OCH2), 3.98 (1 H, dd, J 7.2, 2.2, CHN), 3.88 (1 H, d, J 14.7, one
of CH2SO2), 3.62 (1 H, d, J 14.7, one of CH2SO2), 2.65–2.60 (2 H,
m, CH2C), 2.15–2.04 (2 H, m, CH2CHN) and 1.25 (3 H, t, J 7.1,
CH3CH2); dC (100 MHz; CDCl3) 171.2 (C), 158.2 (C), 140.4 (C),
133.8 (CH), 131.5 (CH), 129.1 (2 ¥ CH), 129.0 (2 ¥ CH), 128.3
(2 ¥ CH), 128.0 (2 ¥ CH), 125.1 (C), 106.2 (C), 64.5 (CH), 63.2
(CH2), 61.8 (CH2), 35.7 (CH2), 29.1 (CH2) and 14.2 (CH3); m/z
(TOF MS ES+) 415 (MH+, 64%) and 296 (100).
Compound 25j was prepared by a similar procedure, as detailed
in the ESI.†
Compounds 27b,c,f,g were prepared by a similar procedure, as
detailed in the ESI.†
(S,Z)-Ethyl 5-(phenylsulfonylmethylene)pyrrolidine-2-carboxylate
(26)
A solution of n-BuLi (1.6M in hexanes, 3.8 mL, 6.1 mmol was
added to a solution of diisopropylamine (0.84 mL, 6 mmol) in
THF (40 mL) at 0 ◦C. A solution of phenyl methyl sulfone (925 mg,
6 mmol) in THF (5 mL) was added dropwise over 30 min and the
solution allowed to stir for a further 30 min. (2S)-1-tert-butyl 2-
ethyl 5-oxopyrrolidine-1,2-dicarboxylate (1.54 g, 6 mmol) in THF
(5 mL) was added over 30 min and the solution allowed to warm
to 25 ◦C and stirred for 18 h. Saturated aqueous NH4Cl solution
(25 mL) was added and the organic layer extracted with CH2Cl2 (3
¥ 25 mL). The combined organic extracts were washed with brine
(2 ¥ 50 mL), dried (MgSO4) and the solvent removed in vacuo. The
resulting oil was dissolved in CH2Cl2 (5 mL) and trifluoroacetic
acid (1.37 g, 12 mmol) added. The resulting solution was stirred
for 18 h at 25 ◦C before being concentrated in vacuo. Saturated
aqueous sodium bicarbonate solution (20 mL) was added and
the organic materials extracted into CH2Cl2 (3 ¥ 25 mL). The
combined organic extracts were washed with brine (2 ¥ 50 mL),
dried over MgSO4 and the solvent removed in vacuo. Purification
by flash column chromatography (eluent 2 : 1 petroleum ether–
ethyl acetate) gave the title compound (885 mg, 51%) as a pale oil
(Found: MH+, 296.0945. C14H18NO4S requires M, 296.0957); nmax.
(neat) 3395, 2981, 1735, 1607, 1446, 1279, 1199, 1078, 847 and 717
cm-1; dH (400 MHz; CDCl3) 7.83 (2 H, broad d, J 7.0), 7.53–7.37
(3 H, m), 4.68 (1 H, s, alkene CH), 4.30 (1 H, dd, J 8.4, 4.8, CHN),
4.14 (2 H, q, J 7.1, OCH2), 2.64–2.49 (2 H, m, CH2C), 2.27–2.16
(1 H, m, one of CH2CHN), 2.06–1.96 (1 H, m, one of CH2CHN)
and 1.22 (3 H, t, J 7.1, CH3CH2); dC (100 MHz; CDCl3) 171.6
(C), 160.4 (C), 144.8 (C), 131.9 (CH), 128.8 (2 ¥ CH), 125.7 (2 ¥
CH), 85.3 (CH), 61.6 (CH2), 60.5 (CH), 31.7 (CH2), 25.7 (CH2)
and 14.1 (CH3); m/z (TOF MS AP+) 296 (MH+, 100%).
Acknowledgements
˙
We are extremely grateful to the Abant Izzet Baysal Univer-
sity, Directorate of Research Projects Commission (BAP grant
2007.03.03.260) and TUBITAK (The Scientific and Technological
Research Council of Turkey, grant 106T645) for financial support
and to Mr Robin Hicks for technical assistance. We would also
like to thank Dr Robert Richardson (School of Chemistry, Cardiff
University) for helpful discussions.
Notes and references
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2 D. J. P. Pinto, M. J. Orwat, S. Koch, K. A. Rossi, R. S. Alexander, A.
Smallwood, P. C. Wong, A. R. Rendina, J. M. Luettgen, R. M. Knabb,
K. He, B. Xin, R. R. Wexler and P. Y. S. Lam, J. Med. Chem., 2007, 50,
5339; M. Esseffar, M. El Messaoudi, S. Azzouzi, R. Jalal, J. A. Saez,
L. R. Domingo, J. Latorre and M. Liu-Gonzalez, J. Phys. Org. Chem.,
2009, 22, 31.
3 A. Padwa, 1,3-Dipolar Cycloaddition Chemistry, John Wiley & Sons,
New York, 1984.
4 C. Matt, A. Gissot, A. Wagner and C. Mioskowski, Tetrahedron Lett.,
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©