1,2,4-Oxadiazoles from cycloreversions of oxadiazabicyclo[3.2.0]heptenes: 1-Azetines as thiocyanate equivalents

Article abstract of DOI:10.1016/j.tet.2012.12.007

1,3-Dipolar cycloaddition of nitrile oxides to 4-aryl-2-alkylthio-1- azetines gave a series of oxadiazabicyclo[3.2.0]heptenes as single diastereoisomers. Heating these cycloadducts in toluene resulted in an overall [2+2]-cycloreversion to give 5-alkylthio-3-aryl-1,2,4-oxadiazoles. In this process, the 1-azetine behaves as a thiocyanate equivalent. When the nitrile oxide substituent was 2-azidobenzene, the azide could be converted into a 1,2,3-triazole giving a (1,2,4-oxadiazolo)-(1,2,3-triazolo)-1,2-disubstituted benzene. 1,2,4-Oxadiazoles are sought after in medicinal chemistry and materials sciences.

Full text of DOI:10.1016/j.tet.2012.12.007

Tetrahedron 69 (2013) 1279e1284
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
1,2,4-Oxadiazoles from cycloreversions of oxadiazabicyclo[3.2.0]
heptenes: 1-azetines as thiocyanate equivalents
*
Karl Hemming , Musharraf N. Khan, Paul A. O’Gorman, Arnaud Pitard
Institute for Materials, Medicines and Molecular Sciences, Division of Chemistry, School of Applied Sciences, University of Huddersfield, West Yorkshire, HD1 3DH, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
1,3-Dipolar cycloaddition of nitrile oxides to 4-aryl-2-alkylthio-1-azetines gave
a series of ox-
Received 15 September 2012
Received in revised form 15 November 2012
Accepted 3 December 2012
Available online 7 December 2012
adiazabicyclo[3.2.0]heptenes as single diastereoisomers. Heating these cycloadducts in toluene resulted
in an overall [2þ2]-cycloreversion to give 5-alkylthio-3-aryl-1,2,4-oxadiazoles. In this process, the 1-
azetine behaves as a thiocyanate equivalent. When the nitrile oxide substituent was 2-azidobenzene,
the azide could be converted into
a 1,2,3-triazole giving a (1,2,4-oxadiazolo)-(1,2,3-triazolo)-1,2-
disubstituted benzene. 1,2,4-Oxadiazoles are sought after in medicinal chemistry and materials sciences.
Keywords:
Azetine
Ó 2012 Elsevier Ltd. All rights reserved.
Nitrile oxide
1,2,4-Oxadiazole
Cycloreversion
Azide
1,2,3-Triazole
1. Introduction
1,2,4-Oxadiazoles have attracted attention due to their bi-
ological activity, often related to their bioisosteric nature and use in
medicinal chemistry.1 This area has been extensively reviewed1 and
a selection of recent compounds of interest is shown in Fig. 1.
Compound 1 is one of a series of 1,2,4-oxadiazoles that are potent
EthR inhibitors that boost ethionamide activity in the treatment of
multi-drug resistant tuberculosis.2 Compound 2 is of interest as
a combretastatin A-4 analogue with higher efficacy as an antimi-
totic agent.3 Thiol linked 1,2,4-oxadiazoles 3 that have electron
withdrawing aryl substituents show great potency towards an-
drogen independent prostrate cancer cell-lines.4 Compound 4 is an
excellent in vivo sphingosine phosphate receptor-1 (S1P1) selective
modulator that suppresses the development of autoimmune dis-
eases including multiple sclerosis and adjuvant-induced arthritis
models.5 Compound 5 is representative of a potent class of tank-
yrase (TNKS1/2) dual inhibitors that show no activity at poly(ADP-
ribose) polymerase (PARP1 and 2) domains, and are inhibitors of
the Wnt pathway whose dysregulation is a key priority in multiple
diseases including several cancers.6 In 2011 the first 1,2,4-
oxadiazole natural products, phidianidines A (6, X¼Br) and B (6,
X¼H), were isolated7adfrom a marine opisthobranch sourcedand
their synthesis reported shortly thereafter.7b 1,2,4-Oxadiazoles are
also of interest in materials research1 with recent examples
Fig. 1. A selection of 1,2,4-oxadiazoles of recent interest.
including bent-core8 and bent-rod liquid crystals9 with stable liq-
uid phases over broad temperature ranges. 3-Nitro-5-substituted-
1,2,4-oxadiazoles, such as compound 7 are reported as ‘exploso-
phoric’ energetic, insensitive high explosives.10 Finally, the use of
* Corresponding author. E-mail address: k.hemming@hud.ac.uk (K. Hemming).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.007

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K. Hemming et al. / Tetrahedron 69 (2013) 1279e1284
pyridyl-1,2,4-oxadiazoles11 and bis-1,2,4-oxadiazole12 as ligands
that chelate NiII, CuII, ZnII and PdII has been reported, together with
a report that bis(pyridyl)-1,2,4-oxadiazole CuII complexes display
promising activity as DNA groove binders.13
thio-
-lactams were obtained from the reaction of the
either Lawesson’sreagent,19 orthemuchmoreconvenientand odour-
free P4S10-pyridine complex developed by Bergman.20 The
-lactams
b
-lactams 18 withMeerwein’s salts ordimethyl sulfate. The thio-
b
b-lactam 17 with
b
1,2,4-Oxadiazoles are most commonly constructed using 1,3-
dipolar cycloadditions between nitrile oxides and nitriles1,14 or
from the reactions of a nitrile-derived amidoxime with a carboxylic
acid derivative.1,15 In this report, we show that 5-alkylthio-1,2,4-
17 were easilyavailable fromthereactionof chlorosulfonyl isocyanate
(CSI)with therelevant styrene.21 The nitrile oxides were generated by
the standard route22 of dehydrochlorination of the chloro-oximes 19.
This approach produced seven examples, 9aec and 9eeh, of the de-
sired oxadiazabicycles 9 as summarised in Table 1. As seen in Table 1,
the oxadiaza[3.2.0]bicycles 9 were produced in yields of 43e72%. It is
worth noting that each of the adducts 9 was a single diastereoisomer
with (NOESY) cis stereochemistry between the Ar1 and SR1 groups,
presumably a result of the incoming 1,3-dipole approaching trans to
the existing Ar1 group, thus forcing the SR1 group cis to the Ar1 sub-
stituent. The treatment of the azido compound 9a (Ar2¼2-N3eC6H4)
with triphenylphosphine followed by hydrolysis gave the corre-
sponding amino species 9d (Ar2¼2-NH2eC6H4) in 70% overall yield,
giving us access to an eighth example of an oxadiaza[3.2.0]bicycle.
oxadiazoles 10 can be obtained from
a
formal [2þ2]-
cycloreversion of the oxadiazabicyclo[3.2.0]heptenes 9 [Scheme 1],
which in turn are readily constructed from the 1,3-dipolar cycload-
dition of a nitrile oxide to a 4-aryl-1-azetine 8. In this process, the 1-
azetine acts as an equivalent for the nitrile species R1SeCN, known
as either an alkyl thiocyanate or an alkyl thiocyanic ester.16
Scheme 1. Synthesis of 1,2,4-oxadiazoles from 1-azetines.
2. Results and discussion
This work has its origins in our studies [Scheme 2] that focused
upon the synthesis of azabicycles 13 from the reaction of cyclic
imines 11 with cyclopropenones 12, where the latter function as
all-carbon 1,3-dipole equivalents 14.17 When the imine 11 was a 4-
aryl-1-azetine the intermediate bicycles 13a (n¼1) gave the tetra-
substituted pyridines 16.18 We postulated that this transformation
proceeded through a [2þ2] cycloreversion to give a non-isolable,
high-energy azacyclopentadienone 15 and a styrene. The styrene
and intermediate 15 then recombine by DielseAlder reaction, fol-
lowed by chelotropic extrusion of carbon monoxide and aromati-
sation to yield the pyridine, parallelling the synthesis of benzenes
from cyclopentadienones. The ease with which this process pro-
duced the proposed intermediate 15 led us look at this as a route for
the formation of 1,2,4-oxadiazoles, which we anticipated would be
isolable and not undergo further reaction.
Scheme 3. The synthesis of 5-alkylthio-1,2,4-oxadiazoles 10.
When heated to reflux in toluene, all but one of the oxadiaza-
bicycles 9aeh formed the 5-alkylthio-1,2,4-oxadiazole 10 (Scheme
3), in good to excellent yields (see Table 1). The one exception was
compound 9d, which proved to be stable, possibly as a result of
increased stability resulting from intramolecular hydrogen bonding
between the amino group and N-2 or N-4 of the oxadiazolidine ring
(as shown for N-2 in Scheme 3). The products of these reactions, 5-
alkylthio-1,2,4-oxadiazoles 10, are a class of 1,2,4-oxadiazole that
have attracted no other synthetic approaches to our knowledge.1
We are currently exploring the synthetic utility of the 5-
alkylthio-1,2,4-oxadiazoles 10.
A further example of a 5-alkylthio-1,2,4-oxadiazole, the aryl-
triazole compound 10i (Scheme 4), was obtained by reacting the
azido compound 9a with dimethylacetylene dicarboxylate (DMAD)
in toluene for 20 h at reflux. The product presumably forms through
consecutive [2þ2]-cycloreversion and azide 1,3-dipolar cycloaddi-
tion. The presumed intermediate of the cycloaddition-first pathway
(pathway A, Scheme 4), compound 9i, could not be detected,
whereas TLC indicated that the 1,2,4-oxadiazole 10a was present in
small amounts, implying that the cycloreversion-first pathway
(pathway B, Scheme 4) represents the correct sequence of events.
Compound 10i could be obtained in 65% yield by treating 1,2,4-
oxadiazole 10a with DMAD in toluene for 4 h at reflux confirming
that it can act as a credible precursor for the formation of 1,2,4-
oxadiazole 10i.
Scheme 2. Pyridines from azacyclopentadienones.19
As shown in Scheme 3 and Table 1, the 1-azetines 8 required for
this study were synthesised from the alkylation of the corresponding

K. Hemming et al. / Tetrahedron 69 (2013) 1279e1284
1281
Table 1
1-Azetines 8, oxadiaza[3.2.0]bicycles 9 and 1,2,4-oxadiazoles 10 produced as per Scheme 3
Entry
Ar1
Yield of 17 (%)
Yield of 18 (%)
Yield of 8 (%)
R1
Ar2
Yield of 9 (%)
Yield of 10 (%)
a
b
c
d
e
f
g
h
i
Ph
2-Naphth
Ph
Ph
Ph
4-MeeC6H4
4-MeeC6H4
2-Naphth
dd
75e77a
64
63e86a
73
46e61a
40
Et
Me
Et
2-N3eC6H4
2-N3eC6H4
Ph
2-NH2eC6H4
4-MeOeC6H4
4-MeOeC6H4
4-MeOeC6H4
4-MeOeC6H4
See Scheme 4
63
44
51
68
83
dc
88
82
81
87
41d
75e77a
63e86a
46e61a
db
60
db
75e77a
83
db
63e86a
82
Et
70b
43
41
39
Me
Me
Et
Me
Et
43
72
48
44
83
82
64
73
40
dd
dd
dd
Not formedd
a
The sequence of reactions leading to 1-azetine 8a (R1¼Et, Ar1¼Ph) was performed more than once, hence giving a range of yields.
Produced by Staudinger reaction and subsequent hydrolysis of compound 9a.
The adduct 9d was stable.
b
c
d
Compound 10i was formed directly from compound 9adsee Scheme 4.
molecular sieves (10% w/v), and then distilled over freshly activated
ꢀ
ꢀ
3 A molecular sieves over 3e4 h. Chloroform was dried over 4 A
molecular sieves or distilled over phosphorus pentoxide (3% w/v).
Dichloromethane, ethyl acetate and toluene were distilled over cal-
cium hydride (5% w/v) over 4e6 h. Diethyl ether and THF were pre-
dried over sodium wire, and then distilled over sodium wire (1e2%
w/v) with benzophenone (0.2e0.3% w/v) as an indicator. Any other
anhydrous solvents were purchased fromAcros or SigmaeAldrich. All
reactions were monitored by TLC, which was carried out on 0.20 mm
MachereyeNagel AlugramÒ Sil G/UV254 silica gel-60 F254 precoated
aluminium plates and visualisation was achieved using UV light and/
or vanillin stain. Column chromatography was performed on Merck
ꢀ
silica gel (0.063e0.200 mm, 60 A). NMR spectra were recorded on
a Bruker DPX-400 instrument or on a Bruker Avance 500. IR spectra
were recorded on a Nicolet 380 FT-IR instrument as a thin film for oils,
a drop for liquids or neat for solids. Mass spectra were recorded on
a Bruker Daltonics micrOTOF mass spectrometer operating at a posi-
tive ion mode under an electrospray ionisation (ESIþ) method. High
resolution mass spectra were recorded on a Finnegan MAT 900 XTL
instrument operated by the EPSRC National Mass Spectrometry ser-
vice at the University of Swansea. Melting points were recorded on
a Gallenkamp apparatus. 1-Azetines 8aeh were synthesised as re-
ported previously,18 and gave consistent spectroscopic data.
Scheme 4. Routes to the 3-(triazoloaryl)-1,2,4-oxadiazole 10i.
3. Conclusions
1,3-Dipolar cycloadditions of nitrile oxides to 4-aryl-2-alkylthio-
1-azetines gave oxadiazabicyclo[3.2.0]heptenes that underwent
a formal [2þ2]-cycloreversion and loss of a styrene to furnish 5-
alkylthio-3-aryl-1,2,4-oxadiazoles. The use of 2-azido-benzonitrile
oxide allowed subsequent 1,3-dipolar cycloaddition of DMAD to the
azide (‘click’ reaction) in order to furnish the 1-(1,2,4-oxadiazolo)-
2-(1,2,3-triazolo)-substituted benzene 10i. In these processes, a 2-
alkylthio-1-azetine functions as an equivalent of the alkyl thiocy-
anate or alkyl thiocyanic ester functional group. We are currently
exploring the properties and synthetic utility of the 5-alkylthio-
1,2,4-oxadiazoles 10, and are also extending our studies to look at
other nitrilium betaines and other 1-azetines. As part of a recently
initiated programme of study23 focused upon 1,2,4-oxadiazoles as
ligands in supramolecular coordination chemistry, we are also ex-
ploring the ligand properties of compound 10i.
4.2. 2-(2-Azidophenyl)-5-ethylthio-7-phenyl-4,1,3-
oxadiazabicyclo[3.2.0]hept-2-ene 9a
To 2-ethylthio-4-phenyl-1-azetine (8a)18 (176 mg, 0.920 mmol)
and 2-azidobenzohydroximoyl chloride24 (19a) (181 mg,
0.921 mmol) was added triethylamine (0.153 mL, 112 mg,
1.10 mmol) diluted in diethyl ether (5 mL) dropwise over 5 h at
room temperature. The mixture was stirred overnight under an
inert atmosphere. The solution was filtered and the solvent was
removed in vacuo to give the crude product as an orange oil, which
was purified by gravity silica chromatography (Rf¼0.3; PE
40e60 ꢀC/EtOAc: 9/1) to give the product as
a single di-
astereoisomer as a yellow oil (206 mg, 63%).
IR nmax (cmꢁ1) 2928 (w), 2114 (s), 1683 (m), 1592 (m), 1577 (m),
1498 (m), 1455 (m), 1293 (m), 1164 (m), 1090 (m), 1054 (m), 749 (s),
698 (s).
4. Experimental section
4.1. General
1H NMR:
d
(400 MHz, CDCl3) 7.57 (2H, d, J¼7.1 Hz, Ph), 7.43e7.33
(5H, m, Ph), 7.24 (1H, d, J¼7.4 Hz, Ph), 6.87 (1H, t, J¼7.6 Hz, Ph), 4.81
(1H, dd, J¼9.3 and 5.4 Hz, PhCHN), 3.69 (1H, dd, J¼13.1 and 9.3 Hz,
PhCHCH2), 2.86 (1H, dq, J¼12.6 and 7.5 Hz, SCH2CH3), 2.75 (1H, dq,
J¼12.6 and 7.5 Hz, SCH2CH3), 2.72 (1H, dd, J¼13.1 and 5.4 Hz,
PhCHCH2), 1.36 (3H, t, J¼7.5 Hz, SCH2CH3).
All reactions were conducted using oven-dried glassware under
ꢀ
nitrogen dried through 4 A molecular sieves and delivered through
a gas manifold. Work-up procedures were carried out in air. All sol-
vents were purchased from Fisher Chemicals and were of analytical
grade. Anhydrous grade solvents were freshly distilled using a con-
13C NMR
d (100 MHz, CDCl3) 158.6 (NeC]N), 140.5 (C, Ar), 138.8
ꢀ
tinuous still under nitrogen. Acetone was dried overnight over 3 A
(C, Ar), 131.7 (CH, Ar), 131.6 (C, Ar), 130.8 (CH, Ar), 128.6 (CH, Ar),

1282
K. Hemming et al. / Tetrahedron 69 (2013) 1279e1284
128.0 (CH, Ar), 126.1 (CH, Ar), 124.6 (CH, Ar), 119.4 (CH, Ar), 110.9
(CeSEt), 66.8 (CH), 45.2 (SCH2CH3), 22.5 (CH2), 14.6 (SCH2CH3).
MS (m/z) 352.1 [MþH]þ, 374.1 [MþNa]þ, 725.2 [M2þNa]þ.
HRMS (m/z) [M]þ for C18H17N5OS calculated 351.1148 measured
351.1145.
1H NMR
d (500 MHz, CDCl3) 7.50e7.60 (2H, m, AreH), 7.38e7.32
(2H, m, AreH), 7.31e7.28 (1H, m, AreH), 7.01e7.13 (1H, m, AreH),
6.89 (1H, dd, J¼5.0, 1.0 Hz, AreH), 6.63 (1H, dd, J¼8.1, 1.0 Hz, AreH),
6.31e6.42 (1H, m, AreH), 5.39 (2H, s, NH2), 4.75 (1H, dd, J¼10.0,
5.0 Hz, PhCH), 3.55e3.59 (1H, m, PhCHCH2), 2.74e2.78 (1H, m,
PhCHCH2), 2.71e2.63 (2H, m, CH3CH2), 1.27 (3H, t, J¼7.5 Hz, CH3).
13C NMR
d (125 MHz, CDCl3) 161.9 (C]N), 147.1 (Ar, C), 140.7 (Ar,
4.3. 2-(2-Azidophenyl)-5-methylthio-7-(20-naphthyl)-4,1,3-
oxadiazabicyclo[3.2.0]hept-2-ene 9b
C), 131.6 (Ar, CH), 129.7 (Ar, CH), 128.8 (Ar, CH), 128.4 (Ar, CH), 126.7
(Ar, CH), 116.6 (Ar, CH), 115.7 (Ar, CH), 110.0 (Ar, C), 106.9 (CSEt), 67.4
(CH), 45.2 (CH2), 29.7 (CH2), 14.8 (CH3).
Obtained as per the method for compound 9a as a clear yellow
oil (74 mg, 44%) from 2-methylthio-4-(20-naphthyl)-1-azetine
(8b)18 (100 mg, 0.440 mmol) and 2-azidobenzohydroximoyl chlo-
ride (19a) (100 mg, 0.509 mmol); Rf¼0.3 (PE 40e60 ꢀC/EtOAc: 10/
1).
HRMS (m/z) [M]þ for C18H19N3OS calculated¼325.1243,
measured¼325.1245.
4.6. 2-(40-Methoxyphenyl)-5-methylthio-7-phenyl-4,1,3-
oxadiazabicyclo[3.2.0]hept-2-ene 9e
IR nmax (cmꢁ1) 2968 (m), 2918 (m), 2128 (s), 1597 (m), 1581 (m),
1447 (m), 1300 (m), 751 (m).
1H NMR:
d (500 MHz, CDCl3) 7.95e7.85 (2H, m, Ar), 7.82 (1H, dd,
Obtained as per the method for compound 9a as a clear yellow
oil (140 mg, 43%) from 2-methylthio-4-phenyl-1-azetine (8e)18
(180 mg, 0.984 mmol) and 4-methoxybenzohydroximoyl chloride
(19e) (182 mg, 0.981 mmol); Rf¼0.3 (PE 40e60 ꢀC/EtOAc: 10/1).
IR nmax (cmꢁ1) 2905 (w), 1606 (s) 1510 (s), 1421 (m), 1347 (m),
1305 (m), 1256 (s), 1172 (m), 1026 (m), 836 (m), 753 (m).
J¼7.0 and 1.5 Hz, Ar), 7.58e7.50 (2H, m, Ar), 7.44e7.38 (2H, m, Ar),
7.28e7.23 (2H, m, Ar), 7.18 (1H, d, J¼8.0 Hz, Ar), 6.96 (1H, td, J¼1.0
and 7.0 Hz, Ar), 5.01 (1H, dd, J¼9.3 and 5.5 Hz, ArCHN), 3.74 (1H, dd,
J¼13.0 and 9.3 Hz, ArCHCH2), 2.82 (1H, dd, J¼13.0 and 5.5 Hz,
ArCHCH2) 2.3 (3H, s, SCH3).
1H NMR:
d (500 MHz, CDCl3) 7.64e7.38 (5H, m, Ph), 6.97 (2H, d,
13C NMR
d (125 MHz, CDCl3) 158.8 (N]CeN), 139.1 (C, Ar), 137.9
J¼7.0 Hz, Ar), 6.82 (2H, d, J¼7.0 Hz, Ar), 4.83 (1H, dd, J¼5.5, 9.3 Hz,
PhCH), 3.82 (3H, s, OCH3), 3.67 (1H, dd, J¼13.0 and 9.3 Hz,
PhCHCH2), 2.72 (1H, dd, J¼13.0 and 5.5 Hz, PhCHCH2), 2.17 (3H, s,
SCH3).
(C, Ar),133.2 (C, Ar),132.2 (C, Ar),132.0 (CH, Ar),131.0 (CH, Ar),130.2
(CH, Ar),128.9 (CH, Ar), 128.4 (CH, Ar),128.0 (CH, Ar),126.4 (CH, Ar),
126.3 (CH, Ar), 124.8 (CH, Ar), 124.0 (CH, Ar), 119.6 (CH, Ar), 118.8 (C,
Ar), 116.1 (CeSMe), 66.8 (CH), 22.7 (CH2), 10.8 (CH3).
HRMS (m/z) [MþNa]þ for C21H17N5NaOS calculated 410.1046,
measured 410.1046.
13C NMR
d (125 MHz, CDCl3) 161.7 (N]CeN), 160.6 (C, Ar), 140.6
(C, Ar), 137.5 (C, Ar), 133.9 (CH, Ar), 128.7 (CH, Ar), 128.6 (CH, Ar),
126.9 (CH, Ar),114.6 (CH, Ar),114.4 (CeSMe), 66.5 (CH), 55.3 (OCH3),
44.6 (CH2), 10.3 (SCH3).
MS (m/z) 349.1 [MþNa]þ, 675.2 [M2þNa]þ.
HRMS (m/z) [MþNa]þ for C18H18N2NaO2S calculated¼349.0164,
measured¼349.0159.
4.4. 2,7-Diphenyl-5-ethylthio-4,1,3-oxadiazabicyclo[3.2.0]
hept-2-ene 9c
Obtained as per the method for compound 9a as a clear yellow
oil (197 mg, 60%) from 2-ethylthio-4-phenyl-1-azetine (8a)18
(200 mg, 1.05 mmol) and benzohydroximoyl chloride (19c)
(160 mg, 1.05 mmol); Rf¼0.3 (PE 40e60 ꢀC/EtOAc: 10/1).
IR nmax (cmꢁ1) 3054 (w), 1592 (m), 1421.9 (m), 1265.3 (s), 1167
(m), 1092 (m), 1060 (m), 750 (s), 701 (s).
4.7. 2-(40-Methoxyphenyl)-5-methylthio-7-(40-tolyl)-4,1,3-
oxadiazabicyclo[3.2.0]hept-2-ene 9f
Obtained as per the method for compound 9a as a clear yellow
oil (140 mg, 72%) from 2-methylthio-4-(40-tolyl)-1-azetine (8f)18
(110 mg, 0.571 mmol) and 4-methoxybenzohydroximoyl chloride
(19e) (107 mg, 0.574 mmol); Rf¼0.3 (PE 40e60 ꢀC/EtOAc: 10/1).
IR nmax (cmꢁ1) 2893 (w), 1608 (s) 1512 (s), 1346 (s), 1306 (m),
1255 (s), 1172 (s), 1051 (m), 1031 (m), 838 (m), 753 (m).
1H NMR:
d (400 MHz, CDCl3) 7.50e7.46 (6H, m, AreH), 7.44e7.40
(4H, m, AreH), 4.85 (1H, dd, J¼9.2, 5.4 Hz, CHPh), 3.72e3.68 (1H, m,
PhCHCH2), 2.89 (1H, dq, J¼12.6, 7.8 Hz, SCH2), 2.78e2.76 (2H, m, 1ꢂ
SCH2þ1ꢂ PhCHCH2), 1.37 (3H, t, J¼7.8 Hz, CH3).
13C NMR
d (100 MHz, CDCl3) 192.2 (C]N), 160.7 (C, Ar), 156.1 (C,
1H NMR:
d
(500 MHz, CDCl3) 7.42e7.39 (4H, m, 2ꢂ Ar1, 2ꢂ Ar2),
7.14 (2H, d, J¼8.0 Hz, Ar1), 6.71 (2H, d, J¼7.2 Hz, Ar2), 4.68 (1H, dd,
J¼5.4 and 9.4 Hz, Ar1CH), 3.68 (3H, s, OCH3), 3.54 (1H, dd, J¼13.3
and 9.4 Hz, Ar1CHCH2), 2.61 (1H, dd, J¼5.4 and 13.5 Hz, Ar1CHCH2),
2.30 (3H, s, SCH3), 2.13 (3H, s, CH3).
Ar), 140.5 (Ar, CH), 130.9 (Ar, CH), 128.9 (Ar, CH), 128.8 (Ar, CH),
128.7 (Ar, CH), 128.1 (Ar, CH), 117.2 (CeSEt), 66.7 (CH), 45.4 (CH2),
22.5 (CH2), 14.7 (CH3).
HRMS (m/z) [MþH]þ calculated for C18H19N2OS 311.1213,
measured¼311.1214.
13C NMR
d (125 MHz, CDCl3) 161.8 (N]CeN), 160.7 (C, Ar), 138.1
(C, Ar), 137.9 (C, Ar), 129.1 (CH, Ar), 128.7 (CH, Ar), 126.4 (CH, Ar),
116.9 (C, Ar), 114.7 (CH, Ar), 111.2 (CeSMe), 66.5 (CH), 55.4 (OCH3),
44.7 (CH2), 21.1 (ArCH3), 10.4 (SCH3).
4.5. 2-(20-Aminophenyl)-5-ethylthio-7-phenyl-4,1,3-
oxadiazabicyclo[3.2.0]hept-2-ene 9d
MS (m/z) 341.1 [MþHþ], 363.1 [MþNa]þ.
2-(20-Azidophenyl)-5-(ethylthio)-7-phenyl-4-oxa-1,3-
diazabicyclo3.2.0]-hept-2-ene 9a (0.0468 g, 0.133 mmol) and triphe-
nylphosphine (0.039 g, 0.149 mmol), were dissolved in tetrahydrofu-
ran (5 mL) and stirred for 24 h at room temperature under an
atmosphere of nitrogen. Water (0.250 mL) was then added in one
portion and the reaction was heated at reflux for a further 24 h. The
sample was concentrated under vacuum purified by silica column
chromatography (eluent: petroleum ether:ethyl acetate, 6:1) to yield
the amine (9d; 0.030 g, 70% yield) as a yellowoil;Rf¼0.3 (PE 40e60 ꢀC/
EtOAc: 10/1).
HRMS (m/z) [MþH]þ for C19H21N2O2S calculated¼341.0501,
measured¼341.0503.
4.8. 2-(40-Methoxyphenyl)-5-ethylthio-7-(40-tolyl)-4,1,3-
oxadiazabicyclo[3.2.0]hept-2-ene 9g
Obtained as per the method for compound 9a as a clear yellow
oil (83 mg, 48%) from 2-ethylthio-4-(40-tolyl)-1-azetine (8g)18
(100 mg, 0.485 mmol) and 4-methoxybenzohydroximoyl chloride
(19e) (100 mg, 0.539 mmol); Rf¼0.3 (PE 40e60 ꢀC/EtOAc: 10/1).
IR nmax (cmꢁ1) 2915 (w), 1608 (s), 1590 (m), 1512 (s), 1345 (m),
1256 (s), 1173 (m), 1030 (m), 838 (m).
IR nmax (cmꢁ1) 3448 (m, broad), 2977 (m), 2847 (m), 1593 (s),
1412 (m), 1390 (m), 1302 (m), 1178 (m).

K. Hemming et al. / Tetrahedron 69 (2013) 1279e1284
1283
1H NMR:
d
(500 MHz, CDCl3) 7.54e7.49 (2H, m, ArH), 7.29e7.24
IR nmax (cmꢁ1) 2966 (w), 2128 (s), 1597 (m), 1578 (m), 1501 (m),
1300 (m), 750 (m).
(2H, m, ArH), 6.95 (2H, dd, J¼2.4 and 8.1 Hz, ArH), 6.83 (2H, d,
J¼7.2 Hz, ArH), 4.80 (1H, dd, J¼9.3 and 5.3 Hz, ArCH), 3.8 (3H, s,
OCH3), 3.62 (1H, dd, J¼13.0 and 9.3 Hz, ArCHCH2), 2.92e2.75 (2H,
m, SCH2CH3), 2.71 (1H, dd, J¼5.3 and 13.0 Hz, ArCHCH2), 2.42 (3H, s,
AreCH3), 1.36 (3H, t, J¼7.0, SCH2CH3).
1H NMR: dH (500 MHz, CDCl3) 7.97 (1H, dd, J¼2.0 and 8.0 Hz,
ArH), 7.55-7.45 (1H, m, ArH), 7.37 (1H, dd, J¼2.0 and 8.0 Hz, ArH),
7.27e7.22 (1H, m, ArH), 2.73 (3H, s, SCH3).
13C NMR
d (125 MHz, CDCl3) 178.0 (C, oxadiazole), 166.7 (C,
13C NMR:
d
(125 MHz, CDCl3) 161.8 (N]CeN),160.7 (C, Ar),138.0
oxadiazole), 138.8 (C, Ar), 132.1 (CH, Ar), 131.0 (CH, Ar), 124.9 (CH,
Ar), 119.3 (CH, Ar), 118.9 (C, Ar), 15.3 (SCH3).
(C, Ar),137.8 (C, Ar),129.4 (CH, Ar),129.0 (CH, Ar),126.4 (C, Ar),114.4
(CH, Ar), 114.2 (CH, Ar), 111.5 (C, CSEt), 66.77 (CH), 55.3 (OCH3), 45.4
(ArCHCH2), 22.7 (SCH2), 21.1 (ArCH3), 14.8 (SCH2CH3).
MS (m/z) 377.1 [MþNa]þ, 731.2 [M2þNa]þ.
HRMS (m/z) [MþNa]þ for C9H7N5NaOS calculated 256.0264
measured 256.0273.
HRMS (m/z) [MþH]þ for C20H23N2O2S calculated¼355.0657,
measured¼355.0657.
4.12. 3-(Phenyl)-5-ethylthio-1,2,4-oxadiazole 10c
Obtained as a clear, yellow oil (72 mg, 83% yield) as per the
method for compound 10a from 2,7-diphenyl-5-ethylthio-4-oxa-
1,3-diazabicyclo[3.2.0]-hept-2-ene (9c, 130 mg) after silica chro-
matography (Rf¼0.2; eluent: petroleum ether:ethyl acetate, 16:1).
IR nmax (cmꢁ1) 2935 (m), 1544 (m), 1522 (s), 1474 (m), 1359 (m),
1266 (s), 1195 (m).
4.9. 2-(20-Methoxyphenyl)-5-methylthio-7-(20-naphthyl)-
4,1,3-oxadiazabicyclo[3.2.0]hept-2-ene 9h
Obtained as per the method for compound 9a as a clear yellow
oil (72 mg, 44%) from 2-methylthio-4-(20-naphthyl)-1-azetine
(8b)18 (100 mg, 0.440 mmol) and 4-methoxybenzohydroximoyl
chloride (19e) (100 mg, 0.539 mmol); Rf¼0.3 (PE 40e60 ꢀC/
EtOAc: 10/1).
1H NMR
d (400 MHz, CDCl3) 7.27e7.33 (3H, m, AreH), 7.23e7.13
(2H, m, AreH), 3.38 (2H, q, J¼7.5 Hz, SCH2), 1.56 (3H, t, J¼7.5 Hz,
CH3).
IR nmax (cmꢁ1) 2928 (w), 1608 (s), 1511 (s), 1404 (m), 1349 (m),
1256 (s), 1172 (m), 1028 (m), 836 (m).
13C NMR
d (100 MHz, CDCl3) 176.9 (C), 137.8 (C), 130.9 (CH, Ar),
128.9 (CH, Ar), 126.1 (C), 125.3 (CH, Ar), 28.9 (CH2), 21.4 (CH3).
HRMS (m/z) [MþH]þ for C10H10N2OS calculated¼207.1404,
measured¼207.1407.
1H NMR:
d
(500 MHz, CDCl3) 7.98 (2H, d, J¼8.8 Hz, 4-MeOAr),
7.94e7.85 (2H, m, naphth), 7.57e7.47 (3H, m, naphth), 7.0e6.95
(2H, m, naphth), 6.80 (2H, d, J¼8.8 Hz, 4-MeOAr), 5.0 (1H, dd, J¼9.5
and 5.5 Hz, naphthCH), 3.77 (3H, s, OCH3), 3.74 (1H, dd, J¼9.5 and
13.5 Hz, naphthCHCH2), 2.82 (1H, dd, J¼13.5 and 5.5 Hz,
naphthCHCH2), 2.30 (3H, s, SCH3).
4.13. 3-(4-Methoxyphenyl)-5-methylthio-1,2,4-oxadiazole
10e/f/h
13C NMR
d
(125 MHz, CDCl3) 161.8 (N]CeN), 138.1 (C, Ar), 133.3
Obtained as a clear, yellow oil (45 mg, 88% yield), (52 mg, 82%
(C, Ar), 133.2 (C, Ar), 130.2 (C, Ar), 130.0 (CH, Ar), 129.0 (CH, Ar),
128.4 (CH, Ar), 128.1 (CH, Ar), 126.8 (CH, Ar), 126.4 (CH, Ar), 125.2
(CH, Ar), 123.9 (CH, Ar), 116. 8 (CH, Ar), 114.4 (C, Ar), 111.3 (CeSMe),
66.6 (CH), 55.3 (OCH3), 44.7 (CH2), 10.4 (SCH3).
yield) and (34 mg, 87% yield), as per the method for compound 10a,
from
2-(40-methoxyphenyl)-5-methylthio-7-phenyl-4,1,3-
oxadiazabicyclo[3.2.0]hept-2-ene (9e, 80 mg) or 2-(40-methox-
yphenyl)-5-methylthio-7-(40-tolyl)-4,1,3-oxadiazabicyclo[3.2.0]
hept-2-ene (9f, 100 mg), or 2-(40-methoxyphenyl)-5-methylthio-7-
(20-naphthyl)-4,1,3-oxadiazabicyclo[3.2.0]hept-2-ene (9h, 70 mg),
respectively, after silica chromatography (eluent: petroleum
ether:ethyl acetate, 16:1); Rf¼0.5 (PE 40e60 ꢀC/EtOAc: 10/1).
IR nmax (cmꢁ1) 2919 (m), 1611 (s), 1509 (s), 1466 (m), 1422 (m),
1346 (m), 1297 (m), 1250 (s), 1198 (m), 1117 (m), 1027 (m), 833 (s),
758 (s).
HRMS (m/z) [MþNa]þ for C22H20N2NaO2S calculated 399.1138
measured 399.1142.
4.10. 3-(2-Azidophenyl)-5-ethylthio-1,2,4-oxadiazole 10a
2-(2-Azidophenyl)-5-ethylthio-7-phenyl-4,1,3-oxadiazabicyclo
[3.2.0]hept-2-ene (9a) (100 mg, 0.284 mmol) was dissolved in
toluene (5 mL) and heated at reflux for 47 h. The solvent was re-
moved in vacuo and the crude product was purified by gravity silica
chromatography (Rf¼0.4; PE 40e60 ꢀC/EtOAc: 7/1) to yield the title
product as an orange oil (36 mg, 51%).
1H NMR: dH (500 MHz, CDCl3) 7.99 (2H, d, J¼8.0, ArH), 6.98 (2H,
d, J¼8.0, ArH), 3.85 (3H, s, OMe), 2.78 (3H, s, SMe).
13C NMR: dC (125 MHz, CDCl3) 178.1 (C, oxadiazole), 168.3 (C,
oxadiazole), 162.0 (C, Ar), 129.1 (CH, Ar), 119.0 (C, Ar), 114.2 (CH, Ar),
55.4 (OeCH3), 14.2 (SeCH3).
IR nmax (cmꢁ1) 2930 (w), 2130e2100 (s), 1582 (m), 1520 (m),
1505 (m), 1470 (m), 1339 (s), 1304 (m), 1271 (m), 1187 (m), 750 (m).
HRMS (m/z) [MþNa]þ for C10H10N2NaO2S calculated¼245.0355,
measured¼245.0350.
1H NMR
d
(400 MHz, CDCl3) 7.99 (1H, dd, J¼7.7 and 1.6 Hz, ArH),
7.55 (1H, ddd, J¼8.1, 7.4 and 1.6 Hz, ArH), 7.27 (1H, dd, J¼8.1 and
0.8 Hz, ArH), 7.19 (1H, td, J¼7.7 and 0.8 Hz, ArH), 3.34 (2H, q,
J¼7.4 Hz, SCH2CH3), 1.54 (3H, t, J¼7.4 Hz, SCH2CH3).
4.14. 3-(4-Methoxyphenyl)-5-ethylthio-1,2,4-oxadiazole 10g
13C NMR
d
(100 MHz, CDCl3) 177.6 (SeC]N), 166.7 (NeC]N),
Obtained as a clear, yellow oil (40 mg, 81% yield) as per the
method for compound 10a from 2-(40-methoxyphenyl)-5-
ethylthio-7-(40-tolyl)-4,1,3-oxadiazabicyclo[3.2.0]hept-2-ene (9g,
80 mg) after silica chromatography (eluent: petroleum ether:ethyl
acetate, 16:1); Rf¼0.5 (PE 40e60 ꢀC/EtOAc: 10/1).
138.9 (C, Ar), 132.1 (CH, Ar), 131.6 (CH, Ar), 124.9 (CH, Ar), 119.3 (CH,
Ar), 118.2 (C, Ar), 27.3 (SCH2CH3), 14.8 (SCH2CH3).
MS (m/z) 248.1 [MþH]þ, 270.0 [MþNa]þ, 517.1 [M2þNa]þ.
HRMS (m/z) [MþH]þ for C10H10N5OS calculated 248.0601 mea-
sured 248.0603.
IR nmax (cmꢁ1) 2920 (w), 1611 (s), 1505 (s), 1420 (m), 1348 (s),
1299 (m), 1250 (s), 1171 (m), 1028 (m), 838 (m), 753 (m).
1H NMR: dH (500 MHz, CDCl3): 7.98 (2H, d, J¼8.1 Hz, ArH), 6.96
(2H, d, J¼8.1 Hz, ArH), 3.86 (3H, s, OMe), 3.32 (2H, q, J¼7.9 Hz,
CH2CH3), 1.52 (3H, t, J¼7.9 Hz, CH2CH3).
4.11. 3-(2-Azidophenyl)-5-methylthio-1,2,4-oxadiazole 10b
Obtained as a clear, yellow oil (41 mg, 68% yield) as per the
method for compound 10a from 2-(2-azidophenyl)-7-(20-naph-
thyl)-5-methylthio-4-oxa-1,3-diazabicyclo[3.2.0]-hept-2-ene (9b,
100 mg) after silica chromatography (Rf¼0.2; eluent: petroleum
ether:ethyl acetate, 16:1).
13C NMR
d (125 MHz, CDCl3): 177.6 (C, oxadiazole), 168.3 (C,
oxadiazole), 162.0 (C, Ar), 129.0 (CH, Ar), 119.0 (C, Ar), 114.2 (CH, Ar),
55.4 (OeCH3), 27.3 (SeCH2), 14.8 (SeCH2CH3).
MS (m/z) 259.0 [MþNa]þ, 731.2 [M2þNa]þ.

1284
K. Hemming et al. / Tetrahedron 69 (2013) 1279e1284
HRMS (m/z) [MþNa]þ for C11H12N2NaO2S calculated¼259.0511,
2012, 55, 1817; (e) Goldberg, K.; Groombridge, S.; Hudson, J.; Leach, A. G.;
MacFaul, P. A.; Pickup, A.; Poultney, R.; Scott, J. S.; Svensson, P. H.; Sweeney,
J. Med. Chem. Commun. 2012, 3, 600.
measured¼259.0518.
2. Flipo, M.; Desroses, M.; Lecat-Guillet, N.; Villemagne, B.; Blondiaux, N.; Leroux,
€
F.; Piveteau, C.; Mathys, V.; Flament, M.-P.; Siepmann, J.; Villeret, V.; Wohlkonig,
4.15. Synthesis of 1,2,3-triazole 10i: reaction of 2-(2-
azidophenyl)-5-ethylthio-7-phenyl-4,1,3-oxadiazabicyclo
[3.2.0]-hept-2-ene with DMAD
A.; Wintjens, R.; Soror, S. H.; Christophe, T.; Jeon, H. K.; Locht, C.; Brodin, P.;
ꢂ
Deprez, B.; Baulard, A. R.; Willand, N. J. Med. Chem. 2012, 55, 68.
3. Das, B. C.; Tang, X.-Y.; Rogler, P.; Evans, T. Tetrahedron Lett. 2012, 53, 3947.
4. Khatik, G. L.; Kaur, J.; Kumar, V.; Tikoo, K.; Nair, V. A. Bioorg. Med. Chem. Lett.
2012, 22, 1912.
5. Nakamura, T.; Asano, M.; Sekiguchi, Y.; Mizuna, Y.; Tamaki, K.; Nara, F.; Kawase,
Y.; Yabe, Y.; Nakai, D.; Kamiyama, E.; Urasaki-Kaneno, Y.; Shimozato, T.; Doi-
Komuro, H.; Kagari, T.; Tomisato, W.; Inoue, R.; Nagasaki, M.; Yuita, H.; Oguchi-
Oshima, K.; Kaneko, R.; Nishi, T. Eur. J. Med. Chem. 2012, 51, 92.
6. Shultz, M. D.; Kirby, C. A.; Stams, T.; Chin, D. N.; Blank, J.; Charlat, O.; Cheng, H.;
Cheung, A.; Cong, F.; Feng, Y.; Fortin, P. D.; Hood, T.; Tyagi, V.; Xu, M.; Zhang, B.;
Shao, W. J. Med. Chem. 2012, 55, 1127.
7. (a) Carbone, M.; Li, Y.; Irace, C.; Mollo, E.; Castelluccio, F.; Di Pascale, A.; Cimino,
G.; Santamaria, R.; Guo, Y.-W.; Gavagnin, M. Org. Lett. 2011, 13, 2516; (b) Lin, H.-
Y.; Snider, B. B. J. Org. Chem. 2012, 77, 4832.
8. Shanker, G.; Tschierske, C. Tetrahedron 2011, 67, 8635.
9. Gallardo, H.; Ferreira, M.; Vieira, A. A.; Westphal, E.; Molin, F.; Eccher, J.;
Bechtold, I. H. Tetrahedron 2011, 67, 9491.
10. Fu, Z.; Su, R.; Yang, W.; Wang, Y.-F.; Zeng, W.; Xiao, N.; Wu, Y.; Zhou, Z.; Chen, J.;
Chen, F.-X. Chem.dEur. J. 2012, 18, 1886.
11. Terenzi, A.; Barone, G.; Palumbo Piccionello, A.; Giorgi, G.; Guarcello, A.; Pace, A.
Inorg. Chim. Acta 2011, 373, 62.
12. Richardson, C.; Steel, P. J. Inorg. Chem. Commun. 2007, 10, 884.
13. Terenzi, A.; Barone, G.; Palumbo Piccionello, A.; Giorgi, G.; Guarcello, A.; Por-
tanova, P.; Calvaruso, G.; Buscemi, S.; Vivona, N.; Pace, A. Dalton Trans. 2010, 39,
9140.
2-(2-Azidophenyl)-5-ethylthio-7-phenyl-4,1,3-oxadiaza bicyclo
[3.2.0]hept-2-ene (9a) (110 mg, 0.313 mmol) and dimethylacety-
lene dicarboxylate (DMAD) (42 mL, 49 mg, 0.34 mmol,1 equiv) were
dissolved in toluene (5 mL) and the solution was heated at reflux
under nitrogen overnight. The solvent was removed in vacuo to
give the crude product as an orange oil, which was purified by
gravity silica chromatography (Rf¼0.3; PE 40e60 ꢀC/EtOAc: 10/1) to
give the triazole derivative 10i as a yellow oil (50 mg, 41%).
IR nmax (cmꢁ1) 2954 (w), 1735 (s, C]O), 1557 (w), 1507 (m), 1474
(m),1448 (m),1358 (s), 1290 (m),1232 (m),1181 (m),1105 (m),1078
(m), 1004 (w), 963 (w), 826 (w), 809 (w), 777 (w), 758 (m), 669 (w).
1H NMR
d
(500 MHz, CDCl3) 8.25 (1H, dd, J¼7.1 and 2.2 Hz, ArH),
7.68e7.74 (2H, m, ArH), 7.54 (1H, dd, J¼7.4 and 1.6 Hz, ArH), 4.02
(3H, s, CO2Me), 3.76 (3H, s, CO2Me), 3.09 (2H, q, J¼7.4 Hz, SCH2CH3),
1.36 (3H, t, J¼7.4 Hz, SCH2CH3).
13C NMR
d (125 MHz, CDCl3) 178.9 (EtSeC]N), 165.5 (NeC]N),
160.4 (C]O), 158.1 (C]O), 139.1 (C, Ar), 133.8 (C]C), 133.1 (C]C),
131.6 (CH, Ar), 131.4 (CH, Ar), 130.1 (CH, Ar), 128.7 (CH, Ar), 124.2 (C,
Ar), 53.3 (CO2CH3), 52.7 (CO2CH3), 27.4 (SCH2CH3), 14.5 (SCH2CH3).
MS (m/z) 390.1 [MþH]þ, 412.1 [MþNa]þ, 779.2 [M2þH]þ, 801.1
[M2þNa]þ.
14. Recent examples: (a) Nishiwaki, N.; Kobiro, K.; Hirao, S.; Sawayama, J.; Saigo, K.;
Ise, Y.; Okajima, Y.; Ariga, M. Org. Biomol. Chem. 2011, 9, 6750; (b) Kumar, R. R.;
ꢂ
Perumal, S.; Menendez, J. C.; Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem. 2011,
19, 3444.
15. Recent examples: (a) Kaboudin, B.; Malekzadeh, L. Tetrahedron Lett. 2011, 52,
6424; (b) Palumbo Piccionello, A.; Musumeci, R.; Cocuzza, C.; Fortuna, C. G.;
Guarcello, A.; Pierro, P.; Pace, A. Eur. J. Med. Chem. 2012, 50, 441.
16. For a review of this functional group, see: Erian, A. W.; Sherif, S. M. Tetrahedron
1999, 55, 7957.
HRMS (m/z) [MþH]þ for C16H16N5O5S calculated 390.0867
measured 390.0867.
17. (a) Kondakal, V. V. R.; Qamar, M. I.; Hemming, K. Tetrahedron Lett. 2012, 53,
4100; (b) O’Gorman, P. A.; Chen, T.; Cross, H. E.; Naeem, S.; Pitard, A.; Qamar, M.
I.; Hemming, K. Tetrahedron Lett. 2008, 49, 6316; (c) Hemming, K.; O’Gorman, P.
A.; Page, M. I. Tetrahedron Lett. 2006, 47, 425.
18. Hemming, K.; Khan, M. N.; Kondakal, V. V. R.; Pitard, A.; Qamar, M. I.; Rice, C. R.
Org. Lett. 2012, 14, 126.
Acknowledgements
We thank the University of Huddersfield for studentships and
fee-waiver bursaries (to M.N.K., P.O’G. and A.P.), and Dr. Neil McLay,
University of Huddersfield, for NMR and mass spectroscopic sup-
port. We are grateful to the EPSRC National Mass Spectrometry
Service, University of Wales, Swansea for HRMS.
19. Reviews: (a) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061; (b) Ozturk,
T.; Ertas, E.; Mert, O. Chem. Rev. 2007, 107, 5210.
20. Bergman, J.; Pettersson, B.; Hasimbegovic, V.; Svensson, P. H. J. Org. Chem. 2011,
76, 1546.
ꢂ
ꢂ
ꢂ
€ €
21. (a) Forro, E.; Paal, T.; Tasnadi, G.; Fulop, F. Adv. Synth. Catal. 2006, 348, 917; (b)
Hollywood, F.; Suschitzky, H.; Hull, R. Synthesis 1982, 662.
References and notes
€
22. Caramella, P.; Grunanger, P. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed. 1,3-Dipolar Cycloaddition Chemistry; Wiley: New York, NY, 1984; Vol. 1,
p 291.
23. Blackburn, J.; Cooke D. J.; Harding, L. P.; Hemming, K.; Rice, C. R.; Riis-
Johannessen, T., submitted for publication.
1. Reviews: (a) Hemming, K. In Comprehensive Heterocyclic Chemistry III; Ka-
tritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier:
London, 2008; Vol. 5, pp 243e314; (b) Hemming, K. J. Chem. Res., Synop.
2001, 209; (c) Pace, A.; Pierro, P. Org. Biomol. Chem. 2009, 7, 4337; (d)
24. Hemming, K.; Loukou, C.; Elkatip, S.; Smalley, R. K. Synlett 2004, 101.
€
ꢁ
Bostrom, J.; Hogner, A.; Llinas, A.; Wellner, E.; Plowright, A. T. J. Med. Chem.