Diastereoselective synthesis of 2-oxiranyl and 2-aziridinyl thiazoles

Article abstract of DOI:10.1016/S0040-4020(03)00105-4

2-Chloroalkylthiazolyllithiums, prepared by deprotonating the 2-chloroalkylthiazoles with n-BuLi at -78°C in THF, add to ketones or imines affording in 'one-pot' oxiranes and aziridines in a Z stereoselective manner.

Full text of DOI:10.1016/S0040-4020(03)00105-4

Tetrahedron 59 (2003) 1381–1387
Diastereoselective synthesis of 2-oxiranyl
and 2-aziridinyl thiazoles
Fabio Bona,a Luisella De Vitis,a Saverio Florio,b Ludovico Ronzinia and Luigino Troisia
,
*
aDipartimento di Scienze e Tecnologie Biologiche ed Ambientali, University of Lecce, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy
bDipartimento Farmaco-Chimico, CNR ‘Istituto di Chimica dei Composti Organometallici—I.C.C.O.M.’,
University of Bari, Via E. Orabona 4, 70125 Bari, Italy
Received 7 November 2002; revised 19 December 2002; accepted 16 January 2003
Abstract—2-Chloroalkylthiazolyllithiums, prepared by deprotonating the 2-chloroalkylthiazoles with n-BuLi at 2788C in THF, add to
ketones or imines affording in ‘one-pot’ oxiranes and aziridines in a Z stereoselective manner. q 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
We now describe a rather general method of preparation of
various thiazolyl oxiranes and aziridines based on the
lithiation of 2-chloroalkylthiazoles and subsequent coupling
with carbonyl compounds and imines.
2-Oxiranyl and aziridinyl thiazoles represent a versatile
class of intermediates in synthetic organic chemistry. The
high degree of ring strain of the oxiranyl and aziridinyl
rings,1 which gives them the propensity to undergo ring
opening reactions, jointly with the susceptibility of the
thiazole moiety to be elaborated (thiazole is a masked
carbonyl function)2 makes them particularly appealing in
synthetic organic chemistry for the preparation of a variety
of organic compounds, such as a-hydroxy-b-amino and
a-amino-b-hydroxyaldehydes.3
2. Results and discussion
The precursors 2-chloroalkylthiazoles 1a–c were first
synthesized. 2-(Chloromethyl)-4-methylthiazole 1a was
prepared by formylation8 of 4-methylthiazole, reduction9
of the obtained 2-thiazolylaldehyde and halogenation10 of
the corresponding 2-thiazolylcarbinol. 2-(1-Chloroethyl)-
4-methylthiazole 1b and 2-(chloro-phenyl-methyl)-4-
methylthiazole 1c were prepared by the coupling reaction
of 2-(4-methyl)thiazolyllithium with acetaldehyde and
benzaldehyde respectively,11 and successive halogenation10
of the resulting 2-thiazolylcarbinols. Lithiation of 1a with
n-BuLi at 2788C in THF produced a dark brown solution of
2-(4-methyl)thiazolylchloromethyllithium 1a0 (Scheme 1).
The synthesis of 2-benzothiazolyl,4 2-oxazolinyl,5 2 (3 and
4)-pyridinyl4b,6 oxiranes and aziridines, based on the
coupling reaction of a-heteroarylchloromethyllithium
which acts as a Darzens reagent, with carbonyl compounds
or imines has been reported. These reactions were almost
always characterized by a high E diastereoselectivity.
Despite their synthetic potential, few papers have been
reported on the synthesis of oxiranyl and aziridinyl
thiazoles. Recently, thiazolyl epoxides and aziridines have
been stereoselectively obtained by the coupling of thiazo-
lyllithium, generated by deprotonation of the 2-unsubsti-
tuted thiazole with n-BuLi, with a-chloroketones and
a-chloroimines.7 The number, however, of thiazolyl
epoxides and aziridines that could be synthesized by this
procedure is limited by the commercial availability of
a-chloroketones and a-chloroimines.
The addition of cyclohexanone 2a to the solution of 1a0,
gave the 2-thiazolyloxirane 3a in high yield (Table 1:
entry 1).
Lithiation of 1b and 1c followed by the coupling with
ketones 2a–c produced oxiranes 3c–e, 3h, respectively
(entries 3–5, 8). The coupling reaction of lithiated
chloroalkyllithiums 1a0 –c0 with asymmetrically substituted
carbonyl compounds proceeded with a stereochemistry
which was different with respect to that of the reported
heteroarylmethyllithiums,4a,5a,6 which afforded oxiranyl
derivatives of E configuration exclusively. Indeed, using
acetaldehyde 2d and benzaldehyde 2e, the coupling
reactions of 1a0 –c0 afforded a mixture of isomeric epoxides
Keywords: thiazolylalkyloxiranes; thiazolylalkylaziridines; carbanion;
nucleophilic addition.
*
Corresponding author. Tel./fax: þ39-832-320-701;
e-mail: luigino.troisi@unile.it
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00105-4

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F. Bona et al. / Tetrahedron 59 (2003) 1381–1387
Scheme 1.
(entry 2, Z/E,1:3; entry 6, Z/E,1:2; entry 9, Z/E,4:1;
entry 10, Z/E 2:1). The reaction of 1b0 with benzaldehyde
2e led almost exclusively to the epoxide 3g showing Z
configuration (entry 7, Z/E,95:5).
Table 1. The coupling reactions between lithiated thiazolylalkylchlorides
and carbonyl and imine compounds affording thiazolyl oxiranes and
aziridines
Entry
Reagents
Products
Yield (%)a
drb (Z/E)
2-Aziridinyl thiazoles could be prepared by the coupling
reaction of 2-chloroalkylthiazoles 1a0 –c0 with imines. We
found that 2-chloroethylthiazolyllithium 1b0 at 2788C in
THF reacts with imine 2g giving aziridine 3p (entry 14) and
with imine 2f to give stereoselectively aziridine 3n showing
Z configuration (entry 12). The coupling reactions of 1a0
and 1c0 with 2f produced an isomeric mixture of aziridines:
Z/E¼65:35 (entry 11) and 40:60 (entry 13) respectively,
while the reactions of heteroarylmethyllithiums, as repor-
ted,4b,5a gave aziridines of E configuration exclusively.
1
2
3
4
5
6
7
8
1a0þ2a
1a0þ2e
1b0þ2a
1b0þ2b
1b0þ2c
1b0þ2d
1b0þ2e
1c0þ2a
1c0þ2d
1c0þ2e
1a0þ2f
1b0þ2f
1c0þ2f
1b0þ2g
3a
3b
3c
3d
3e
3f
3g
3h
3i
90
80
80
63
70
70
76
73
90
78
40
84
50
50
–
25:75
–
–
–
32:68
95:5
–
80:20
70:30
65:35
100:0
40:60
–
9
10
11
12
13
14
3l
3m
3n
3o
3p
The stereochemistry of epoxide 3b and aziridine 3m was
1
assigned on the basis of the H NMR coupling constants
between the two oxiranyl or aziridinyl hydrogens12 (Jcis.
Jtrans); the configurations of oxiranes 3f and g, 3i–l, and
a
Isolated yields.
Diastereomeric ratio.
b

F. Bona et al. / Tetrahedron 59 (2003) 1381–1387
1383
Scheme 2.
aziridines 3n and o were established on the basis of an
upfield shift for a CH3 group and H in the case of a cis
relationship with a Ph group or with a CH3 group. Indeed, it
has been reported that a high field displacement occurs
when a CH3 group is on the same side of a Ph group, while a
smaller upfield shift is observed when two Me groups are
on the same side.13 The configuration assignment was
confirmed, for oxirane 3g and aziridine 3n, by 13C NMR
spectroscopy.14 Indeed, in the 13C–H coupled spectrum the
spectroscopic evidence15 that in heterocyclic azines and
azoles, as in compounds 1a0 –c0, a substantial proportion of
the negative charge is delocalized on the aza-heterocyclic
system. Such propensity of heterocyclic groups to deloca-
lize negative charge is responsible for the double bond
fixation of the exocyclic CvC bond in anions 1a0 –c0.
Chloroalkyllithiums 1a0 –c0, therefore, should exist as an
equilibrium of the isomeric forms B and C (which resonate
with A; Scheme 2). Considering the experimental con-
ditions of the Darzens reaction of 1a0 –c0, the B/C ratio
should be substantially shifted toward the stereomeric form
C.16 We presume that the reacting carbanionic species C
may discriminate between the two enantiotopic faces of the
electrophile leading to transition states TS1 and TS2. These
are both stabilized by the intramolecular chelation of
lithium, but one of the0two should be energetically favoured
in view of the R and R groups steric interaction (Scheme 2).
3JCH3
–H (1.76 Hz) of the Z isomer (having the CH3 and the
ring hydrogen on the same side) was found to be larger than
that of the E isomer (3JCH3–H,0 Hz).
A possible explanation of the results reported here might be
given by considering the structure of the heteroarylchloro-
alkyllithiums 1a0 –c0 and the rate-determining step in
the reactions leading to oxiranes and aziridines. There is

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F. Bona et al. / Tetrahedron 59 (2003) 1381–1387
In particular, when R¼H, TS1, which would evolve to the E
oxirane or aziridine, is evidently for steric reasons of lower
energy than transition state TS2, which would lead to the Z
form (entry 2). Instead, when R¼CH3, TS2 could become
energetically favoured providing, therefore,0the Z diastereo-
mer exclusively (entry 12). Moreover, the R structure could
sterically influence the transition state formation, and conse-
quently the Z/E ratio, as showed by the remaining results.
30, 50, and 25 V relative to ground, respectively. Melting
points were determined using an electrothermal melting
point apparatus and were uncorrected. TLC were performed
on Merck silica gel plates with F-254 indicator; viewing
was by UV light (254 nm). Column chromatographies were
performed on silica gel (63–200 mm) using petroleum
ether/diethyl ether (Et2O) mixtures as eluents. All reactions
involving air-sensitive reagents were performed under
nitrogen, in oven-dried glassware using syringe/septum
cap techniques. Microanalyses were performed on a Carlo
Erba C, H, N, analyzer.
The E epoxide 3i and Z aziridine 3n were unmasked upon
thiazole ring opening according to a known protocol.2c
While the oxirane 3i gave the expected oxiranyl adehyde
4a, as reported,7 the aziridine 3n gave the hydroxyamino-
aldehyde 4b through the opening of both the thiazole and
the aziridine ring.
4.1. General procedure for the preparation of 2-thiazolyl
oxiranes (3a–l)
A stirred solution of 2 mmol of 1a–c in THF (30 mL), at
2788C was treated with n-BuLi in hexanes (2.5 M, 1 mL,
2.5 mmol), and then a solution of the electrophile 2a–h
(2 mmol) in THF (5 mL) was added dropwise, under N2.
The reaction mixtures were kept at 2788C for 30 min, and
then warmed and kept to room temperature for 10–12 h,
quenched with water (10 mL), and extracted with Et2O
(3£20 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated in vacuo. The crude
products were purified by column chromatography (silica
gel, petroleum ether/Et2O, 8:2) to afford the pure thiazolyl
oxiranes (colourless oils), yields: 63–90%.
3. Conclusion
In conclusion, thiazolyl chloroalkyllithiums 1a0 –c0, easily
available by lithiation of chloroalkanes 1a–c, react as
Darzens-type reagents with ketones and imines, sometimes
in a stereoselective way, to form substituted thiazolyl
oxiranes and aziridines, which are potentially useful
intermediates for the synthesis of pharmacologically and
biologically interesting compounds.
4.1.1. 4-Methyl-2-(1-oxa-spiro[2.5]oct-2-yl)-thiazole (3a).
Yield: 376.2 mg, (90%), oil. IR (film): 3100, 3060, 2920,
1
2845, 1515, 1440, 1300, 1225, 910, 730 cm21. H NMR
(200 MHz, CDCl3): d 1.52–1.86 (m, 10H), 2.46 (d, 3H, J¼
0.9 Hz), 4.08 (s, 1H), 6.85 (q, 1H, J¼0.9 Hz). 13C NMR
(50.3 MHz, CDCl3): d 15.2, 24.5, 24.9, 25.3, 28.6, 35.0,
62.4, 65.8, 113.3, 153.0, 171.0. GC-MS (70 eV) m/z (rel.
int.): 209 (33, Mþ), 192 (62), 180 (42), 164 (45), 152 (13),
128 (100), 112 (24), 100 (44). HR-ESI-MS: m/z calcd for
C11H16NOS: 210.0953, [MþH]þ; found 210.0980.
4. Experimental
n-Butyllithium (n-BuLi) was bought as a commercial
solution in hexanes (Aldrich) and titrated with N-pivaloyl-
o-toluidine prior to use.17 THF, 4-methylthiazole, cyclo-
hexanone, acetone, adamantanone, dichloromethane,
triethylamine, lithium diisopropylamine were of commer-
cial grade (Aldrich), and they were used without further
purification. Acetaldehyde and benzaldehyde of commercial
grade (Aldrich), were purified by distillation prior to use.
Petroleum ether refers to the 40–608C boiling fraction. The
1H and the 13C NMR spectra were recorded on a Bruker
AC200 apparatus (200 and 50.3 MHz, for 1H and 13C,
respectively); with CDCl3 as solvent and TMS as internal
standard (dH¼7.24 for 1H spectra; dH¼77.0 for 13C spectra).
The IR spectra were recorded on a Perkin–Elmer
spectrometer Model 283. GC-MS analyses were performed
with Hewlett–Packard HP-5890 series II gas chromato-
graph (5% phenyl-methylsiloxane capillary column, 30 m,
0.25 mm i.d.), equipped with an HP 5971 mass-selective
detector operating at 70 eV (EI). The electrospray ionisation
(HR-ESI-MS) experiments were carried out in a hybrid
QqTOF mass spectrometer (PE SCIEX-QSTAR) equipped
with an ion spray ionisation source. MS (þ) spectra were
acquired by direct infusion (5 mL/min) of a solution
containing the appropriate sample (10 pmol/mL), dissolved
in solution 0.1% acetic acid, methanol/water 50:50 at the
optimum ion voltage of 4800 V. The nitrogen gas flow was
set at 30 psi (pounds per square inch) and the potentials of
the orifice, the focusing ring and the skimmer were kept at
4.1.2. 4-Methyl-2-(3-phenyl-oxiranyl)-thiazole (3b).
Overall yield: 347.2 mg (80%), oil. Z. Yield: 86.8 mg
(25%), oil. IR (CHCl3): 3030, 2930, 2860, 1610, 1450,
.
1300, 1035, 860, 760, 700 cm21 1H NMR (200 MHz,
CDCl3): d 2.34 (d, 3H, J¼0.8 Hz), 4.49 (d, 1H, J¼4.1 Hz),
4.60 (d, 1H, J¼4.1 Hz), 6.65 (q, 1H, J¼0.8 Hz), 7.25–7.36
(m, 5H). 13C NMR (50.3 MHz, CDCl3): d 16.8, 57.8, 60.4,
114.2, 127.1, 128.0, 128.2, 133.0, 152.6, 167.0. GC-MS
(70 eV) m/z (rel. int.): 217 (7, Mþ), 200 (95), 188 (100), 167
(3), 147 (3), 126 (8), 105 (9), 91 (24). HR-ESI-MS: m/z
calcd for C12H12NOS: 218.0640, [MþH]þ; found 218.0612.
E. Yield: 260.4 mg (75%), oil. IR (CHCl3): 3030, 2930,
1
2860, 1610, 1450, 1300, 1035, 860, 760, 700 cm21. H
NMR (200 MHz, CDCl3): d 2.42, (d, 3H, J¼0.8 Hz), 4.08
(d, 1H, J¼1.8 Hz), 4.18 (d, 1H, J¼1.8 Hz), 6.84 (q, 1H, J¼
0.8 Hz), 7.2–7.3 (m, 5H). 13C NMR (50.3 MHz, CDCl3): d
22.6, 59.9, 63.3, 113.7, 125.6, 128.7, 128.8, 135.5, 153.4,
167.0. GC-MS (70 eV) m/z (rel. int.): 217 (11, Mþ), 200
(90), 188 (100), 167 (4), 147 (3), 126 (10), 105 (10), 91 (26).
HR-ESI-MS: m/z calcd for C12H12NOS: 218.0640,
[MþH]þ; found 218.0620.
4.1.3. 4-Methyl-2-(2-methyl-1-oxa-spiro[2.5]oct-2-yl)-
thiazole (3c). Yield: 356.8 mg (80%), oil. IR (CHCl3):

F. Bona et al. / Tetrahedron 59 (2003) 1381–1387
1385
3100, 3060, 3000, 2920, 2850, 1500, 1420, 1200,
1030 cm21 1H NMR (200 MHz, CDCl3): d 1.2–1.8
[MþH]þ; found 232.0780. E: traces identified in reaction
mixture with Z form. 1H NMR (200 MHz, CDCl3): d 1.62 (s,
3H), 2.46 (s, 3H), 5.25 (s, 1H), 6.87 (s, 1H), 7.25–7.28 (m,
5H). GC-MS (70 eV) m/z (rel. int.): 231 (100, Mþ), 213
(25), 202 (38), 154 (58), 125 (73), 124 (67). HR-ESI-MS:
m/z calcd for C13H14NOS: 232.0797, [MþH]þ; found
232.0765.
.
(m, 10H), 2.0 (s, 3H), 2.4 (d, 3H, J¼0.85 Hz), 6.81 (q,
1H, J¼0.85 Hz). 13C NMR (50.3 MHz, CDCl3): d 17.1,
21.7, 21.8, 25.5, 27.3, 31.2, 31.9, 72.0, 76.4, 114.0,
152.8, 170.2. GC-MS (70 eV) m/z (rel. int.): 223 (26,
Mþ), 204 (7), 180 (100), 152 (23), 126 (45), 124 (44).
HR-ESI-MS: m/z calcd for C12H18NOS: 224.1110,
[MþH]þ; found 224.1136.
4.1.8. 4-Methyl-2-(2-phenyl-1-oxa-spiro[2.5]oct-2-yl)-
thiazole (3h). Yield: 416 mg (73%), oil. IR (CHCl3):
3060, 3030, 2940, 2850, 1600, 1520, 1490, 1450, 1300,
4.1.4. 4-Methyl-2-(2,3,3,trimethyl-oxiranyl)-thiazole
(3d). Yield: 230.6 mg (63%), oil. IR (CHCl3): 3020, 2960,
2920, 2880, 1530, 1440, 1370, 1300, 1200, 1140,
1
1130 cm21. H NMR (200 MHz, CDCl3): d 1.3–1.7 (m,
10H), 2.42 (d, 3H, J¼0.8 Hz), 6.75 (q, 1H, J¼0.8 Hz),
7.25–7.40 (m, 3H), 7.68–7.70 (m, 2H). 13C NMR
(50.3 MHz, CDCl3): d 17.2, 24.4, 24.5, 25.2, 30.8, 30.9,
69.5, 71.8, 113.2, 127.2, 127.6, 127.9, 137.0, 153.0, 169.4.
GC-MS (70 eV) m/z (rel. int.): 285 (66, Mþ), 268 (12), 205
(100), 187 (41), 186 (36), 147 (42), 105 (34). HR-ESI-MS:
m/z calcd for C17H20NOS: 286.1267, [MþH]þ; found
286.1292.
1
1050 cm21. H NMR (200 MHz, CDCl3): d 1.18 (s, 3H),
1.45 (s, 3H), 1.73 (s, 3H), 2.42 (d, 3H, J¼0.8 Hz), 6.77 (q,
1H, J¼0.8 Hz). 13C NMR (50.3 MHz, CDCl3): d 17.1, 19.4,
20.7, 21.0, 65.4, 65.8, 113.0, 153.0, 172.0. GC-MS (70 eV)
m/z (rel. int.): 183 (34, Mþ), 168 (54), 142 (100), 100 (36),
72 (67). HR-ESI-MS: m/z calcd for C9H14NOS: 184.0793,
[MþH]þ; found 184.0815.
4.1.5. 30-Methyl-30-[2-(methylthiazolyl)]-20spiroadaman-
tan-oxirane (3e). Yield: 385 mg (70%), oil. IR (CHCl3):
2910, 2850, 1530, 1450, 1375, 1300, 1070, 1050 cm21. 1H
NMR (200 MHz, CDCl3): d 1.26–2.1 (m, 14H), 1.75 (s,
3H), 2.45 (d, 3H, J¼0.8 Hz), 6.78 (q, 1H, J¼0.8 Hz). 13C
NMR (50.3 MHz, CDCl3): d 17.7, 18.7, 27.1, 27.3, 32.5,
33.3, 35.3, 35.5, 36.1, 36.6, 36.8, 67.2, 75.3, 113.4, 153.3,
172.0. GC-MS (70 eV) m/z (rel. int.): 275 (38, Mþ), 233
(40), 232 (100), 142 (10), 125 (15), 91 (16), 72 (16).
HR-ESI-MS: m/z calcd for C16H22NOS: 276.1423,
[MþH]þ; found 276.1462.
4.1.9. 4-Methyl-2-(3-methyl-2-phenyl-oxiranyl)-thiazole
(3i). Overall yield: 415.8 mg (90%), oil. Z. Yield: 332.6 mg
(80%), oil. IR (CHCl3): 3050, 2960, 2920, 2850, 1600,
1
1530, 1445, 1370, 1290, 1010, 750, 700 cm21. H NMR
(200 MHz, CDCl3): d 1.33 (d, 3H, J¼5.3 Hz), 2.50 (s, 3H),
3.46 (q, 1H, J¼5.3 Hz), 6.86 (s, 1H), 7.28–7.41 (m, 3H),
7.58–7.64 (m, 2H). 13C NMR (50.3 MHz, CDCl3): d 14.6,
17.2, 64.0, 64.7, 114.4, 126.3, 128.0, 128.1, 138.1, 153.2,
167.0. GC-MS (70 eV) m/z (rel. int.): 231 (68, Mþ), 202
(100), 186 (70), 147 (94), 105 (79). HR-ESI-MS: m/z calcd
for C13H14NOS: 232.0797, [MþH]þ; found 232.0840. E.
Yield: 83.2 mg (20%), oil. IR (CHCl3): 3100, 3060, 2960,
2920, 2850, 1600, 1530, 1445, 1370, 1290, 1010, 750,
700 cm21. 1H NMR (200 MHz, CDCl3): d 1.15 (d, 3H, J¼
5.3 Hz), 2.43 (s, 3H), 3.88 (q, 1H, J¼5.3 Hz), 6.80 (s, 1H),
7.28–7.41 (m, 3H), 7.58–7.64 (m, 2H). 13C NMR
(50.3 MHz, CDCl3): d 14.6, 17.2, 63.4, 64.7, 113.7, 126.3,
128.1, 128.2, 138.1, 153.2, 167.0. GC-MS (70 eV) m/z (rel.
int.): 231 (60, Mþ), 202 (90), 186 (65), 147 (100), 105 (70).
HR-ESI-MS: m/z calcd for C13H14NOS: 232.0797,
[MþH]þ; found 232.0820.
4.1.6. 2-(2,3-Dimethyl-oxiranyl)-4-methyl-thiazole (3f).
Overall yield: 236.6 mg (70%), oil. Z. Yield: 75.7 mg
(32%), oil. IR (film): 3100, 2960, 2925, 2880, 1530, 1450,
1
1385, 1300, 1270, 1070, 810 cm21. H NMR (200 MHz,
CDCl3): d 1.15 (d, 3H, J¼5.5 Hz), 1.7 (s, 3H), 2.38 (d, 3H,
J¼0.8 Hz), 3.20 (q, 1H, J¼5.5 Hz), 6.7 (q, 1H, J¼0.8 Hz).
13C NMR (50.3 MHz, CDCl3): d 13.6, 17.2, 22.6, 59.5, 63.0,
113.4, 153.3, 174.1. GC-MS (70 eV) m/z (rel. int.): 169 (50,
Mþ), 154 (100), 142 (20), 126 (70), 72 (90). HR-ESI-MS:
m/z calcd for C8H12NOS: 170.0640, [MþH]þ; found
170.0630. E. Yield: 161.0 mg (68%), oil. IR (film): 3100,
2960, 2925, 2880, 1530, 1450, 1385, 1300, 1270, 1070, 810,
4.1.10. 2-(2,3-Diphenyl-oxiranyl)-4-methyl-thiazole (3l).
Overall yield: 457.1 mg (78%), oil. Z. Yield: 320 mg (70%),
oil. IR (CHCl3): 3060, 3030, 2940, 2850, 1600, 1520, 1490,
1
750 cm21. H NMR (200 MHz, CDCl3): d 1.35 (d, 3H,
1
J¼5.4 Hz), 1.7 (s, 3H), 2.35 (d, 3H, J¼0.8 Hz), 3.13 (q, 1H,
J¼5.4 Hz), 6.7 (q, 1H, J¼0.8 Hz). 13C NMR (50.3 MHz,
CDCl3): d 14.0, 15.7, 17.1, 60.1, 64.0, 113.2, 152.9, 173.0.
GC-MS (70 eV) m/z (rel. int.): 169 (55, Mþ), 154 (100), 142
(22), 126 (70), 72 (92). HR-ESI-MS: m/z calcd for
C8H12NOS: 170.0640, [MþH]þ; found 170.0675.
1450 cm21. H NMR (200 MHz, CDCl3): d 2.23, (d, 3H,
J¼0.8 Hz), 4.4 (s, 1H), 6.74 (q, 1H, J¼0.8 Hz), 7.10–7.71
(m, 10H). 13C NMR (50.3 MHz, CDCl3): d 17.1, 66.1, 68.7,
113.6, 126.6, 127.7, 127.8, 128.3, 128.4, 128.8, 140.0,
152.8, 170.1. GC-MS (70 eV) m/z (rel. int.): 293 (20, Mþ),
264 (27), 186 (25), 167 (100), 147 (36), 105 (30). HR-ESI-
MS: m/z calcd for C18H16NOS: 294.0954, [MþH]þ; found
294.0967. E. Yield: 137 mg (30%), oil. IR (CHCl3):
4.1.7. 4-Methyl-2-(2-methyl-3-phenyl-oxiranyl)-thiazole
(3g). Overall yield: mg 351.1 (76%), oil. Z. Yield: 333.6 mg
(95%), oil. IR (CHCl3): 3060, 2920, 2850, 1600, 1490,
3060, 3030, 2940, 2850, 1600, 1520, 1490, 1450 cm21
.
1H NMR (200 MHz, CDCl3): d 2.49, (d, 3H, J¼0.8 Hz),
4.91 (s, 1H), 6.87 (q, 1H, J¼0.8 Hz), 7.10–7.71 (m, 10H).
13C NMR (50.3 MHz, CDCl3): d 17.2, 66.5, 67.5, 114.8,
126.2, 126.7, 127.8, 128.0, 128.3, 128.6, 128.9, 134.0,
153.7, 170.1. GC-MS (70 eV) m/z (rel. int.): 293 (22, Mþ),
264 (24), 186 (25), 167 (100), 147 (39), 105 (30). HR-ESI-
MS: m/z calcd for C18H16NOS: 294.0954, [MþH]þ; found
294.0980.
1
1450, 1100, 1070 cm21. H NMR (200 MHz, CDCl3): d
1.89 (s, 3H), 2.46 (d, 3H, J¼0.8 Hz), 5.23 (s, 1H), 6.86 (q,
1H, J¼0.8 Hz), 7.25–7.28 (m, 5H). 13C NMR (50.3 MHz,
CDCl3): d 17.1, 28.6, 72.8, 80.3, 114.6, 127.6, 128.1, 128.2,
138.1, 152.8, 173.1. GC-MS (70 eV) m/z (rel. int.): 231
(100, Mþ), 230 (51), 213 (26), 202 (36), 154 (60), 125 (73),
124 (64). HR-ESI-MS: m/z calcd for C13H14NOS: 232.0797,

1386
F. Bona et al. / Tetrahedron 59 (2003) 1381–1387
4.2. General procedure for the preparation of 2-thiazolyl
aziridines (3m–3p)
MS: m/z calcd for C24H21N2S: 369.9939, [MþH]þ; found
369.9914. Anal. calcd for C24H20N2S (368.490): C, 78.23;
H, 5.47; N, 7.60; S, 8.70; found: C, 78.30; H, 5.39; N,
7.49; S, 8.69. E. Yield: 220.2 mg (60%), oil. IR (CHCl3):
3060, 3030, 2940, 2840, 1600, 1495, 1450, 1375, 1210,
A solution of n-BuLi in hexane (2.5 M, 1 mL, 2.5 mmol)
was added to 10 mL of THF, at 2788C, under N2, and then a
solution of 2-thiazolyl derivatives 1a–c (2 mmol) and the
electrophiles 2f and g (2 mmol) in THF (5 mL) were added
dropwise. The reaction mixtures were kept at 2788C for
30 min, and then warmed and kept to room temperature
for 5–6 h, quenched with 50 mL of a saturated aqueous
NH4Cl solution, and extracted with Et2O (3£20 mL). The
combined organic layers were dried over anhydrous Na2SO4
and concentrated in vacuo. The crude products were purified
by column chromatography (silica gel, petroleum ether/
Et2O, 7:3) to afford the pure thiazolyl aziridines (oils),
yields: 40–84%. GC-MS data are not available because of
the on column cleavage of the aziridinic ring. However, the
empirical formulae were confirmed by microanalyses.
1
1050 cm21. H NMR (200 MHz, CDCl3): d 2.38 (d, 3H,
J¼0.8 Hz), 4.80 (s, 1H), 6.74–7.50 (m, 16H). 13C NMR
(50.3 MHz, CDCl3): d 17.2, 60.1, 63.8, 113.8, 114.3, 118.5,
124.1, 127.0, 127.4, 127.5, 128.2, 128.7, 128.9, 129.0,
129.2, 141.1, 153.0, 173.4. HR-ESI-MS: m/z calcd for
C24H21N2S: 369.1421, [MþH]þ; found 369.1430. Anal.
calcd for C24H20N2S (368.501): C, 78.22; H, 5.47; N, 7.60;
S, 8.70; found: C, 78.20; H, 5.49; N, 7.45; S, 8.59.
4.2.4. 2-Methyl-2-(4-methyl-thiazol-2-yl)-1-phenyl-1-
aza-spiro[2.5]octane (3p). Yield: 298 mg (50%), oil. IR
(CHCl3): 3030, 2920, 2860, 1600, 1490, 1450, 1370, 1220,
1050 cm21. 1H NMR (200 MH, CDCl3): d 1.58 (s, 3H), 2.47
(d, 3H, J¼0.8 Hz), 1.40–1.86 (m, 10H), 6.76 (q, 1H, J¼
0.8 Hz), 6.95–6.99 (m, 3H), 7.26–7.29 (m, 2H). 13C NMR
(50.3 MHz, CDCl3): d 17.1, 21.7, 21.8, 25.6, 27.3, 31.0,
31.9, 52.6, 77.3, 113.3, 120.8, 121.7, 129.3, 146.4, 153.4,
171.1. HR-ESI-MS: m/z calcd for C18H23N2S: 299.1582,
[MþH]þ; found 299.1600. Anal. calcd for C18H22N2S
(298.450): C, 72.44; H, 7.43; N, 9.39; S, 10.74; found: C,
72.50; H, 7.35; N, 9.30; S, 10.80.
4.2.1. 2-(1,3-Diphenyl-aziridin-2-yl)-4-methyl-thiazole
(3m). Overall yield: 160 mg (40%), oil. Z. Yield: 104 mg
(65%), oil. IR (CHCl3): 3060, 3030, 2960, 2920, 2840,
1495, 1450, 1350, 1270 cm21. 1H NMR (200 MH, CDCl3):
d 2.44, (d, 3H, J¼0.8 Hz), 3.26 (d, 1H, J¼15.1 Hz), 3.96 (d,
1H, J¼15.1 Hz), 6.71 (q, 1H, J¼0.8 Hz), 6.9–7.4 (m, 10H).
13C NMR (50.3 MHz, CDCl3): d 17.0, 46.9, 49.8, 113.4,
113.8, 119.7, 123.4, 127.6, 128.0, 128.2, 129.3, 147.6,
152.3, 166.5. HR-ESI-MS: m/z calcd for C18H17N2S:
293.1114, [MþH]þ; found 293.1080. Anal. calcd for
C18H16N2S (292.325): C, 73.96; H, 5.52; N, 9.58; S,
10.97; found: C, 73.69; H, 5.48; N, 9.47; S, 10.88. E. Yield:
56 mg (35%)104, oil. IR (CHCl3): 3060, 3030, 2960, 2920,
4.3. Thiazolyl ring opening reaction
The ring-opening reaction was carried out according to
Dondoni’s method2c on 1 mmol of 3i and 3n.
1
2840, 1495, 1450, 1350, 1270 cm21. H NMR (200 MHz,
4.3.1. 3-Methyl-2-phenyl-oxirane-2-carboxyaldehyde
(4a). Yield: 145 mg (90%), oil. IR (CHCl3): 3060, 3040,
2990, 2820, 1730, 1500, 1450, 1420, 1375, 1240,
CDCl3): d 2.35 (d, 3H, J¼0.8 Hz), 3.80 (d, 1H, J¼6.3 Hz),
3.97 (d, 1H, J¼6.3 Hz,), 6.67 (q, 1H, J¼0.8 Hz), 6.85–7.45
(m, 10H). 13C NMR (50.3 MHz, CDCl3): d 17.0, 52.6, 52.8,
113.8, 114.3, 120.3, 123.3, 127.5, 127.8, 128.1, 129.1,
147.6, 152.2, 166.2. HR-ESI-MS: m/z calcd for C18H17N2S:
293.1112, [MþH]þ; found 293.1127. Anal. calcd for
C18H16N2S (292.403): C, 73.94; H, 5.52; N, 9.58; S,
10.96; found: C, 73.72; H, 5.58; N, 9.49; S, 10.85.
1
1100 cm21. H NMR (200 MH, CDCl3): d 1.12 (d, 3H,
J¼5.0 Hz), 3.56 (q, 1H, J¼5.0 Hz), 7.33–7.45 (m, 5H), 9.2
(s, 1H). 13C NMR (50.3 MHz, CDCl3): d 13.6, 58.1, 64.2,
127.7, 127.8, 128.1, 128.4, 197.6. GC-MS (70 eV) m/z (rel.
int.): 162 (26, Mþ), 147 (27), 105 (100), 90 (35), 89 (35), 77
(42). HR-ESI-MS: m/z calcd for C10H11O2: 163.0759,
[MþH]þ; found 163.0765. Anal. calcd for C10H10O2
(162.188): C, 74.06; H, 6.21; found: C, 74.15; H, 5.35.
4.2.2. 4-Methyl-2-(2-methyl-1,3-diphenyl-aziridin-2-yl)-
thiazole (3n). Yield: 514.1 mg (84%), oil. Z. Yield:
514.1 mg (100%), oil. IR (CHCl3): 3060, 3030, 2940,
2920, 2860, 1600, 1490, 1450, 1380, 1240, 1070, 1030,
760 cm21. 1H NMR (200 MHz, CDCl3): d 1.65 (s, 3H), 2.24
(d, 3H, J¼0.8 Hz), 3.60 (s, 1H), 6.45 (q, 1H, J¼0.8 Hz),
6.96–7.40 (m, 10H). 13C NMR (50.3 MHz, CDCl3): d 17.0,
18.8, 50.2, 54.6, 113.5, 120.0, 122.8, 127.2, 127.8, 128.9,
135.0, 148.2, 152.6, 170.8. HR-ESI-MS: m/z calcd for
C19H19N2S: 307.1270, [MþH]þ; found 307.1250. Anal.
calcd for C19H18N2S (306.430): C, 74.47; H, 5.92; N, 9.14;
S, 10.46; found: C, 74.55; H, 5.80; N, 8.99; S, 10.28.
4.3.2. 2-Hydroxy-2-methyl-3-(methyl-phenyl-amino)-3-
phenyl-proprionaldehyde (4b). Yield: 107 mg (40%),
oil. IR (film): 3350 (broad), 3060, 2920, 2850, 1695,
.
1590, 1485, 1375, 1365, 1200, 1100 cm21 1H NMR
(200 MH, CDCl3): d 1.57 (s, 3H), 2.92 (s, 3H), 3.3 (s,
broad, 1H), 5.27 (s, 1H), 6.6–7.5 (m, 10H), 10.0 (s, 1H). 13C
NMR (50.3 MHz, CDCl3): d 17.0, 29.7, 52.5, 61.1, 120.8,
125.9, 128.7, 128.8, 128.9, 129.1, 129.7, 131.3, 192.1.
HR-ESI-MS: m/z calcd for C17H20NO2: 270.1495,
[MþH]þ; found 270.1480. Anal. calcd for C17H19NO2
(269.344): C, 75.81; H, 7.11; N, 5.20; found: C, 75.70; H,
7.05; N, 5.15.
4.2.3. 4-Methyl-2-(1,2,3-triphenyl-aziridin-2-yl)-thiazole
(3o). Overall yield: 368 mg (50%), oil. Z. Yield: 147.2 mg
(40%), oil. IR (CHCl3): 3060, 3030, 2940, 2840, 1600,
1
1495, 1450, 1375, 1210, 1050 cm21. H NMR (200 MHz,
Acknowledgements
CDCl3): d 2.40 (d, 3H, J¼0.8 Hz), 4.20 (s, 1H), 6.75–7.47
(m, 16H). 13C NMR (50.3 MHz, CDCl3): d 17.3, 61.4, 68.2,
113.9, 115.4, 118.5, 124.1, 127.1, 127.2, 127.6, 128.1,
128.7, 128.8, 129.0, 129.5, 138.1, 152.9, 173.1. HR-ESI-
For the electrospray ionization (ESI) experiments, the
authors are grateful to Dr Anna Napoli and Dr Leonardo
Di Donna from the Laboratorio di Spettrometria di Massa

F. Bona et al. / Tetrahedron 59 (2003) 1381–1387
1387
Tetrahedron 2001, 57, 6775–6786. (b) Florio, S.; Troisi, L.;
Capriati, V.; Ingrosso, G. Tetrahedron Lett. 1999, 40,
6101–6104.
`
del Dipartimento di Chimica, Universita degli Studi della
Calabria, Via Pietro Bucci, Cubo 15/C, Arcavacata di Rende
(CS), Italy. This work was carried out within the framework
of the National Project ‘Stereoselezione in Sintesi Organica:
Metodologie ed Applicazioni’ supported by the Ministero
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7. Florio, S.; Troisi, L.; Capriati, V. Tetrahedron Lett. 1994, 39,
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dell’Istruzione, dell’Universita e della Ricerca, Rome.
We also thank the Italian Consorzio Interuniversitario
Nazionale ‘Metodologie e Processi Innovativi di Sintesi’
(CINMPIS), Bari and the University of Lecce for financial
support.
8. Olah, G. A.; Ohonnesian, L.; Arvanaghi, M. J. Org. Chem.
1984, 49, 3856–3857.
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