Synthesis and isomerization of N-α-aza-heteroaryl-β-lactams

Article abstract of DOI:10.1016/j.tet.2006.09.075

The [2+2] carbonylative cycloaddition of N-α-aza-heteroaryl substituted imines with allyl bromide led partially to β-lactams, which underwent isomerization to the more stable α,β-unsaturated carbonyl compound. Pyrimidinone derivatives together with doubly

Full text of DOI:10.1016/j.tet.2006.09.075

Tetrahedron 62 (2006) 12064–12070
Synthesis and isomerization of N-a-aza-heteroaryl-b-lactams
a
a
a
Luigino Troisi,a, Ludovico Ronzini, Catia Granito, Emanuela Pindinelli,
*
Alessandro Troisib and Tullio Pilatic
aDipartimento di Scienze e Tecnologie Biologiche ed Ambientali, University of Lecce, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy
bDepartment of Chemistry, Gibbet Hill Rd, CV4 7AL Coventry, Warwick, UK
cC.N.R ‘Institute of Molecular Science and Technology’, Via C. Golgi 19, I-20133 Milan, Italy
Received 19 May 2006; revised 6 September 2006; accepted 21 September 2006
Available online 25 October 2006
Abstract—The [2+2] carbonylative cycloaddition of N-a-aza-heteroaryl substituted imines with allyl bromide led partially to b-lactams,
which underwent isomerization to the more stable a,b-unsaturated carbonyl compound. Pyrimidinone derivatives together with doubly
unsaturated amides represent the remaining isolated products. The strong electron-withdrawing effect of the two a-aza-heterocycles linked
to the nitrogen atom and to the C4 of the 2-azetidinone structure could give a ring expansion, through a 2-azetinone intermediate that affords
the pyrimidinone compounds. The substituted amides, instead, should result from a ring-opening reaction of the b-lactam.
Ó 2006 Elsevier Ltd. All rights reserved.
X
Ar
'
Ar
'
O
Ar
'
O
1. Introduction
R3
R2
N
N
CO(400psi)
, 100 °C
N
+
Et3N, Pd(OAc)2, PPh3
R3
R2
b-Lactams show a wide range of pharmacological activities
and synthetic routes to such compounds continue to be
developed.1–4 The use of 2-azetidinones as starting materials
in organic synthesis is based on the impressive variety of
transformations that can be derived from this system. For
instance, Alcaide and Almendros described the selective
bond cleavage and rearrangement of the b-lactam nucleus
with applications in the stereocontrolled synthesis.5 Thus,
compounds such as alkaloids,6,7 carbohydrates8,9 and differ-
ent kinds of heterocycles10–14 have been produced from
b-lactams. Recently, we reported the stereoselective syn-
thesis of b-lactams by an improved Pd-catalyzed [2+2]
carbonylative cycloaddition of allyl halides with various
imines,15 where the catalytic species involved was Pd(0)16
(Scheme 1). Moreover, we found that the presence of an
a-aza-heterocycle attached to the iminic carbon, for exam-
ple, where Ar¼2-benzothiazole or 2-thiazole or 2-pyridine,
led partially to b-lactams having a vinylic moiety conjugated
to the carbonyl group.16 The high electron-withdrawing
effect of the a-aza-heterocycle should increase the acidity
of the proton linked to C3, favouring isomerization in the
presence of Et3N.
R1
Ar
Ar
Ar
H
R3
R2
R1
R1
Scheme 1.
The deprotonation and the stereoselective functionalization
of the C3 carbon atom of b-lactams have been also reported
by us.17 It has been shown that the deprotonation of the C4
carbon could be achieved only with a structure showing no
protons at C3 and having an a-aza-heterocycle linked at
C4, which increased the acidity of the directly attached
hydrogen (Scheme 2).
Ph
Ph
O
O
N
N
+
R'
R=H
Ph
O
Ar
Ar
N
1) n-BuLi
2) R'X
R'
R
Ar
Ph
O
R = CH3
Ar = Het
N
R
R'
Ar
Scheme 2.
In order to thoroughly investigate the electron-withdrawing
effect of various heterocycles linked at the different
positions of the b-lactam nucleus, we thought to perform,
under the same conditions, the [2+2] carbonylative cyclo-
addition of N-a-aza-heteroaryl substituted imines with allyl
bromide.
Keywords: b-Lactams; Pyrimidinones; Carbonylative cycloaddition; Iso-
merization.
* Corresponding author. Tel./fax: +39 0832 298 701; e-mail: luigino.
troisi@unile.it
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.075

L. Troisi et al. / Tetrahedron 62 (2006) 12064–12070
12065
2. Results and discussion
According to previous results,15 the [2+2] carbonylative
cycloaddition of the imines 1–7 with allyl bromide under
CO pressure, in the presence of Et3N and Pd(OAc)2/Ph3P,
should afford b-lactams A (Scheme 4).
The reacting N-a-aza-heteroaryl imines 1–7 were prepared
by coupling reactions of the appropriate amines with the
corresponding aldehydes according to the Taguchi’s meth-
odology (Scheme 3).18
Ar'
H
Ar'
Ar
O
CO(400psi), 100 °C
N
N
Br
+
8-21
Et3N, Pd(OAc)2, PPh3
Ar'
Ar
Molecular
sieves
O
N
1-7
A
Ar' NH2
+
Ar
H
Ar
H
Scheme 4.
1-7
S
N
Ar' =
Ar' =
Ar' =
1 : Ar = Ph;
2 : Ar = Ph;
Surprisingly, such structures were not obtained but, from the
reaction mixtures compounds 8–21 listed in Table 1 were
isolated.
S
N
S
N
S
N
S
;
3 : Ar =
4 : Ar =
5 : Ar =
S
N
The relative configuration of the a,b-unsaturated b-lactams
was assigned from their H NMR spectra: the Z isomers
;
;
Ar' =
Ar' =
1
N
S
N
;
displayed vinylic protons with an upfield chemical shift,
whereas the E compounds showed a downfield chemical
shift as these protons are in the deshielding region of the
neighbouring carbonyl group.19–21 The structures of com-
N
S
6 : Ar =
7 : Ar =
Ar' =
N
S
N
; Ar' =
1
pounds 10 and 11 have been assigned by H NMR spectra
on the basis of spectroscopic data reported in literature for
N
N
analogous structures.22 The structures of compounds 14
Scheme 3.
Table 1. [2+2] Carbonylative cycloaddition of imines 1–7 with allyl bromide
H
N
H
N
Ar'
Ar'
Ar
Ar'
O
Ar'
Ar
O
O
O
N
N
Ar
8,12,16,20
Ar
Ar'
H
11
9,13,17,21
10
CO(400psi), 100 °C
Et3N, Pd(OAc)2, PPh3
N
Br
+
Ar
+
O
O
1-7
N
N
S
Ar
N
Ar
N
14,15
18,19
Entry
Ar
Ar0
Total yield
(%)a
Product distributions (%)b
S
N
1
2
3
Ph
Ph
80
85
97
8 (traces)
9 (54)
13 (68)
—
—
10 (24)
—
11 (21)
—
S
12 (32)
—
N
S
N
S
N
—
14 (100)
—
—
S
S
N
4
5
6
50
98
—
—
15 (100)
18 (99)
—
—
—
—
N
S
16 (traces)
17 (traces)
N
N
S
40
30
—
—
19 (100)
—
—
—
—
N
N
S
N
7
20 (80)
21 (20)
—
N
a
Isolated yields.
Diasteromeric ratios evaluated by GC and 1H NMR spectroscopy.
b

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L. Troisi et al. / Tetrahedron 62 (2006) 12064–12070
N
O
N
N
H
Ar
H
Et3N
O
N
H
Ar
Ar = Ph
Ar = Het
N
N
N
N
O
N
O
O
N
N
+
Ph
8,9,12,13,16
Ph
Het
Et3N
O
17,20,21
N
H
N
N
O
Ph
Het
B
10,11
N
N
O
N
O
N
Het
Het
Figure 1. Molecular structure of compound 14 at 90 K, ellipsoids at 50%
probability level, H atoms not to scale. Molecular structure of compound
18 at room temperature, ellipsoids at 50% probability level, H atoms not
to scale.
D
C
14,15,18,19
Scheme 5.
and 18 have been assigned by X-ray23 measurements and
their molecular structures are reported in Figure 1.
ketenic form initially, and then finally to the pyrimidinonic
product. The proposed relative stability of the three forms
is confirmed by free energy quantum chemical calculations
of the structures B, C and D, respectively. Calculations
were performed at the 6-311G*/B3LYP level (in the gas
phase).31 According to the calculations, the ketenic structure
C is only 5.3 kcal/mol more stable than B, which is strongly
antiaromatic, while the stable structure D has a free energy
36.1 kcal/mol lower than C.
The remaining structures 15 and 19 were assigned compar-
ing the spectroscopic data with those obtained for com-
pounds 14 and 18.
Scheme 5 shows a possible rearrangement of the b-lactam A,
obtained by the [2+2] carbonylative cycloaddition reaction,
and leading to the compounds listed in Table 1.
The transformation of B to the ketene C first, and then to
the pyrimidinone D, could be related to the presence of two
a-aza-heterocycles linked to the nitrogen atom and to the
C4 of the 2-azetidinone structure, respectively. A similar
rearrangement has been recently described by Alajarin and
co-workers on 4-acyloxy-b-lactams resulting in a final cycle
broadening, through a 2-azetinone intermediate formation
and C2–N1 bond cleavage.32 Moreover, when C4 does
not link a heterocycle (Ar¼Ph), the deprotonation at C3,
described above, led to a ring-opening reaction of the
b-lactamic systems, the cleavage of the C4–N1 bond afford-
ing the doubly unsaturated amides 10 and 11.
Products 8, 9, 12, 13, 16, 17, 20 and 21 should derive from
a first deprotonation of A at the C3, and a subsequent iso-
merization of the carbanion to the more stable a,b-unsatu-
rated carbonyl compound. The generation of products 10
and 11 could be explained by a C4–N1 bond breakage in
the same intermediate carbanion, which occurs under basic
conditions. This latter behaviour is reported in the literature
as one of the possible bond cleavages of the b-lactam
nucleus.24 The 2-azetinone B should result from a double
isomerization: a first deprotonation at the C3 should lead
to the a,b-unsaturated b-lactam, while a subsequent deproto-
nation at the C4 should shift the double bond inside the
b-lactamic ring, affording the 2-azetinone. This behaviour
could be due to the strong electron-withdrawing effect by
both heterocycles directly linked to the ring. The 2-azetinone
is often proposed as a short-lived intermediate,25–28 which
evolves to a ketene, for which only in few cases has it
been isolated and characterized.29,30 The high antiaromatic
character of this small ring, in fact, does not confer enough
thermal stability to the molecule, which rapidly leads to the
3. Conclusion
In summary, we have prepared N-a-aza-heteroaryl b-lactams,
which underwent isomerization. Novel a,b-unsaturated
2-azetidinones were prepared together with new pyrimidi-
none derivatives and doubly unsaturated amides. The pyrimi-
dinone compounds seem to be produced from ring expansion

L. Troisi et al. / Tetrahedron 62 (2006) 12064–12070
12067
of the rearranged b-lactams through a 2-azetinone inter-
mediate. Thisbehaviour hasbeenobserved onlyforstructures
showing two heterocyclic moieties linked to the nitrogen
atom and to the C4 carbon, respectively. The unsaturated am-
ides are the result of a ring-opening reaction of the b-lactam
systems having the heterocycle linked only to the nitrogen
atom. The electron-withdrawing effect of the various hetero-
cycleslinked at the different positionsof the b-lactam nucleus
has been thoroughly exploited. A mechanism has been pro-
posed through structures of different relative stabilities,
confirmed by free energy quantum chemical calculations.
The selective bond cleavage and the rearrangement of the
b-lactam nucleus afforded novel structures of potential use
in the organic synthesis of biologically and pharmacologi-
cally interesting compounds.
corresponding aldehyde (1 mmol) in anhydrous Et2O, in
˚
the presence of 7 g of molecular sieves (Aldrich, 4 A,
1.6 mm pellets) for 24 h, according to Taguchi’s method.18
4.2.1. Benzylidene-thiazol-2-yl-amine 1. Yield 150 mg
(80%), yellow solid, mp 116–117 ꢀC (petroleum ether).
1H NMR (400.13 MHz): d 7.23 (d, J¼3.5 Hz, 1H), 7.46–
7.56 (m, 3H), 7.68 (d, J¼3.5 Hz, 1H), 7.97–7.99 (m, 2H),
9.04 (s, 1H). 13C NMR (100.62 MHz): d 118.3, 128.9,
129.8, 132.6, 135.0, 141.4, 163.3, 173.1, 192.0. GC–MS
(70 eV) m/z (rel int.): 188 (96) M+, 187 (100), 161 (10),
104 (14), 85 (24), 58 (42). IR (CHCl3): 3060, 3020, 2997,
1607, 1577, 1484, 1451, 1365, 1312, 1194, 1135 cmꢁ1
.
Anal. Calcd for C10H8N2S: C, 63.80; H, 4.28; N, 14.88.
Found: C, 63.86; H, 4.26; N, 14.86.
4.2.2. Benzothiazol-2-yl-benzylidene-amine 2. Yield
202 mg (85%), yellow solid, mp 82–84 ꢀC (petroleum
4. Experimental
4.1. General
1
ether). H NMR (400.13 MHz): d 7.35 (t, J¼8.2 Hz, 1H),
7.46–7.63 (m, 4H), 7.84 (d, J¼8.0 Hz, 1H), 7.99 (d,
J¼7.9 Hz, 1H), 8.03 (d, J¼7.0 Hz, 2H), 9.10 (s, 1H).
13C NMR (100.62 MHz): d 121.7, 123.1, 125.1, 126.4,
129.0, 130.2, 133.2, 135.0, 137.5, 153.1, 166.1, 172.0.
GC–MS (70 eV) m/z (rel int.): 238 (47) M+, 237 (100),
211 (11), 210 (12), 135 (16), 108 (13). IR (CHCl3): 3060,
3001, 2980, 1605, 1315, 1150 cmꢁ1. Anal. Calcd for
C14H10N2S: C, 70.56; H, 4.23; N, 11.75. Found: C, 70.50;
H, 4.25; N, 11.80.
THF, triethylamine, palladium(II)acetate, triphenyl-phos-
phine, allyl bromide, 4-formylmorpholine, 2-pyridinecarb-
oxaldehyde, 2-aminothiazole, 2-aminopyridine, 3-amino-
pyridine, 4-methyl-thiazole, 2-aminothiophenol, glycolic
acid and all other chemicals were of commercial grade
(Aldrich) and were used without further purification. Benz-
aldehyde and allyl bromide of commercial grade (Aldrich),
were purified by distillation prior to use. Petroleum ether
refers to the 40–60 ꢀC boiling fraction. The 1H and the 13C
NMR spectra were recorded on a Bruker Avance 400 appara-
tus (400.13 MHz and 100.62 MHz, for 1H and 13C, respec-
tively) with CDCl3 as solvent and TMS as internal standard
(d¼7.24 for 1H spectra; d¼77.0 for 13C spectra). The IR spec-
tra were recorded with an FT-IR spectrophotometer Digilab
Scimitar Series FTS 2000. GC–MS analyses were performed
with an Agilent Technologies 6850 series II gas chromato-
graph (5% phenyl-polymethylsiloxane capillary column,
30 m, 0.25 mm i.d.), equipped with a 5973 Network mass-
selective detector operating at 70 eV (EI). The electrospray
ionization (HR-ESI-MS) experiments were carried out in
a hybrid QqTOF mass spectrometer (PE SCIEX-QSTAR)
equipped with an ion spray ionization source. MS (+) spectra
were acquired by direct infusion (5 mL/min) of a solution
containing the appropriate sample (10 pmol/mL), dissolved
in a 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
30, 50 and 25 V relative to ground, respectively. Elemental
analyses were performed on a Carlo Erba C, H, N analyzer.
Melting points were determined using an Electrothermal
melting point apparatus and are uncorrected. TLC was per-
formed on Merck silica gel plates with F-254 indicator; view-
ing 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.
4.2.3. (4-Methyl-thiazol-2-yl-methylene)-thiazol-2-yl-
amine 3. Yield 203 mg (97%), yellow solid, mp 80–82 ꢀC
(petroleum ether). H NMR (400.13 MHz): d 2.56 (s, 3H),
1
7.18 (s, 1H), 7.31 (d, J¼3.4 Hz, 1H), 7.73 (d, J¼3.4 Hz,
1H), 9.16 (s, 1H). 13C NMR (100.62 MHz): d 17.1, 119.2,
119.6, 142.0, 155.2, 155.8, 166.7, 171.2. GC–MS (70 eV)
m/z (rel int.): 209 (100) M+, 182 (52), 125 (73), 111 (55),
99 (20), 72 (60). IR (CHCl3): 3019, 2977, 2825, 1522,
1423 cmꢁ1. Anal. Calcd for C8H7N3S2: C, 45.91; H, 3.37;
N, 20.08. Found: C, 45.98; H, 3.36; N, 20.15.
4.2.4. Benzothiazol-2-yl-methylene-thiazol-2-yl-amine 4.
Yield 196 mg (80%), yellow solid, mp 172–174 ꢀC (petrol-
1
eum ether). H NMR (400.13 MHz): d 7.39 (d, J¼3.4 Hz,
1H), 7.51–7.58 (m, 2H), 7.78 (d, J¼3.4 Hz, 1H), 7.97 (d,
J¼7.5 Hz, 1H), 8.16 (d, J¼7.6 Hz, 1H), 9.34 (s, 1H).
13C NMR (CDCl3): d 120.6, 122.2, 124.7, 126.8, 127.8,
135.9, 142.3, 154.2, 155.9, 165.8, 170.7. GC–MS (70 eV)
m/z (rel int.): 245 (100) M+, 218 (41), 161 (24), 135 (19),
108 (19). IR (CHCl3): 3067, 2999, 2928, 2857, 1698,
1586, 1477, 1262 cmꢁ1. Anal. Calcd for C11H7N3S2: C,
53.85; H, 2.88; N, 17.13. Found: C, 53.76; H, 2.85; N, 17.10.
4.2.5. (4-Methyl-thiazol-2-yl-methylene)-pyridin-2-yl-
amine 5. Yield 199 mg (98%), yellow solid, mp 66–67 ꢀC
(petroleum ether). H NMR (CDCl3): d 2.55 (s, 3H), 7.11
1
(s, 1H), 7.21 (dd, J¼5.0, 7.0 Hz, 1H), 7.37 (d, J¼7.9 Hz,
1H), 7.76 (t, J¼7.9 Hz, 1H), 8.51 (d, J¼5 Hz, 1H), 9.3 (s,
1H). 13C NMR (CDCl3): d 17.1, 118.0, 120.3, 122.7,
138.2, 149.0, 155.3, 155.5, 159.5, 165.9. GC–MS (70 eV)
m/z (rel int.): 203 (77) M+, 175 (8), 158 (19), 125 (24), 79
(100), 78 (71). IR (CHCl3): 3057, 2992, 2927, 1689, 1589,
1510, 1428, 1241 cmꢁ1. Anal. Calcd for C10H9N3S: C,
59.09; H, 4.46; N, 20.67. Found: C, 59.15; H, 4.48; N, 20.62.
4.2. General procedure for the preparation of
N-a-aza-heteroaryl imines 1–7
The N-a-aza-heteroaryl imines were prepared by coupling
reactions of 1 mmol of the appropriate amine with the

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L. Troisi et al. / Tetrahedron 62 (2006) 12064–12070
4.2.6. Benzothiazol-2-yl-methylene-pyridin-2-yl-amine 6.
Yield 232 mg (97%), yellow solid, mp 140–141 ꢀC (petro-
leum ether). 1H NMR (CDCl3): d 7.24–7.27 (m, 1H),
7.42–7.60 (m, 3H), 7.80 (td, J¼1.8, 7.7 Hz, 1H), 7.95 (d,
J¼7.8 Hz, 1H), 8.15 (d, J¼7.9 Hz, 1H), 8.55 (d, J¼3.5 Hz,
1H), 9.50 (s, 1H). 13C NMR (CDCl3): d 120.9, 122.1,
123.3, 124.5, 126.5, 127.0, 135.6, 138.2, 149.1, 154.1,
156.3, 159.0, 167.0. GC–MS (70 eV) m/z (rel int.): 239
(88) M+, 238 (25), 211 (22), 186 (4), 135 (20), 79 (100),
78 (50). IR (CHCl3): 3063, 2998, 2860, 1698, 1615, 1587,
1485, 1460, 1436, 1320, 1237 cmꢁ1. Anal. Calcd for
C13H9N3S: C, 65.25; H, 3.79; N, 17.56. Found: C, 65.30;
H, 3.80; N, 17.58.
(petroleum ether). 1H NMR (400.13 MHz): d 5.61 (d,
J¼11.3 Hz, 1H), 5.74 (d, J¼17.9 Hz, 1H), 6.83 (ddd,
J¼1.2, 11.3, 17.9 Hz, 1H), 6.95 (d, J¼3.6 Hz, 1H), 7.34–
7.45 (m, 8H). 13C NMR (100.62 MHz): d 113.7, 122.1,
128.5, 129.1, 130.1, 130.5, 132.8, 134.7, 136.7, 137.3,
159.2, 165.9. GC–MS (70 eV) m/z (rel int.): 256 (44) M+,
157 (68), 129 (85), 128 (100). IR (CHCl3): 3399, 3020,
2967, 1676, 1530, 1212 cmꢁ1
.
Anal. Calcd for
C14H12N2OS: C, 65.60; H, 4.72; N, 10.93. Found: C,
65.53; H, 4.70; N, 10.96.
4.3.4. (Z)-N-Thiazol-2-yl-2-benzylidene-but-3-enamide
11. Yield 43 mg (17%), yellow solid, mp 104–108 ꢀC (petro-
leum ether). 1H NMR (400.13 MHz): d 5.27 (d, J¼10.7 Hz,
1H), 5.29 (d, J¼17.4 Hz, 1H), 6.54 (ddd, J¼0.8, 10.7,
17.4 Hz, 1H), 6.70 (s, 1H), 6.96 (d, J¼3.6 Hz, 1H), 7.15–
7.22 (m, 6H), 7.28 (d, J¼3.6 Hz, 1H). 13C NMR
(100.62 MHz): d 113.3, 117.5, 128.3, 128.5, 129.0, 133.0,
134.4, 135.3, 135.9, 136.8, 159.3, 166.4. GC–MS (70 eV)
m/z (rel int.): 256 (38) M+, 157 (65), 129 (85), 128 (100).
4.2.7. Benzothiazol-2-yl-methylene-pyridin-3-yl-amine 7.
Yield 225 mg (94%), yellow solid, mp 165–167 ꢀC (petro-
1
leum ether). H NMR (CDCl3): d 7.37 (dd, J¼4.7, 8.0 Hz,
1H), 7.47–7.56 (m, 2H), 7.63 (d, J¼8.0 Hz, 1H), 7.95 (d,
J¼8.0 Hz, 1H), 8.13 (d, J¼8.0 Hz, 1H), 8.56 (d, J¼4.7 Hz,
1H), 8.63 (d, J¼2.2 Hz, 1H), 8.82 (s, 1H). 13C NMR
(CDCl3): d 122.1, 123.8, 124.4, 126.7, 127.1, 127.7, 135.5,
143.2, 145.4, 148.7, 153.7, 155.2, 166.4. GC–MS (70 eV)
m/z (rel int.): 239 (41) M+, 238 (100), 212 (27), 186 (7),
135 (12), 78 (22). IR (CHCl3): 3065, 2994, 2860, 1699,
1622, 1498, 1475, 1420, 1319, 1240 cmꢁ1. Anal. Calcd for
C13H9N3S: C, 65.25; H, 3.79; N, 17.56. Found: C, 65.18;
H, 3.76; N, 17.50.
IR (CHCl3): 3399, 3020, 2967, 1676, 1530, 1212 cmꢁ1
.
Anal. Calcd for C14H12N2OS: C, 65.60; H, 4.72; N, 10.93.
Found: C, 65.69; H, 4.74; N, 10.87.
4.3.5. (Z)-1-Benzothiazol-2-yl-3-ethylidene-4-phenyl-
azetidin-2-one 12. Yield 83 mg (27%), yellow solid, mp
155–156 ꢀC (petroleum ether). 1H NMR (400.13 MHz):
d 2.19 (d, J¼7.2 Hz, 3H), 5.41 (s, 1H), 6.21 (q, J¼7.2 Hz,
1H), 7.23–7.70 (m, 8H), 8.32 (d, J¼7.9 Hz, 1H). 13C NMR
(100.62 MHz): d 16.6, 66.3, 117.8, 121.7, 121.8, 125.6,
126.3, 126.9, 127.0, 127.7, 128.3, 128.4, 128.7, 140.1,
154.0, 161.9. GC–MS (70 eV) m/z (rel int.): 306 M+ (100),
291 (15), 277 (25), 229 (72). IR (CHCl3): 3060, 2990,
1650, 1500, 1450, 1340, 1180 cmꢁ1. Anal. Calcd for
C18H14N2OS: C, 70.56; H, 4.60; N, 9.14. Found: C, 70.62;
H, 4.59; N, 9.19.
4.3. General procedure for the preparation of
compounds 8–21
A mixture of 1.0 mmol of 1–7, 1.5 mmol of allyl bromide,
0.08 mmol of PPh3, 0.02 mmol of Pd(OAc)2 and 2 mmol
of Et3N were dissolved in 10 mL of solvent (THF) and
placed in a 45 mL autoclave. The autoclave was purged,
pressurized (400 psi of CO), and then heated to 100 ꢀC for
18–65 h. The reaction was then cooled to room temperature,
worked up by addition of water (15 mL) and extracted with
Et2O (3ꢂ5 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The crude products
were purified by column chromatography (silica gel, petro-
leum ether/Et2O¼7/3) to afford the pure products (8–21);
yields: 30–98%.
4.3.6. (E)-1-Benzothiazol-2-yl-3-ethylidene-4-phenyl-
azetidin-2-one 13. Yield 177 mg (58%), yellow solid, mp
142–144 ꢀC (petroleum ether). 1H NMR (400.13 MHz):
d 1.87 (d, J¼7.1 Hz, 3H), 5.82 (s, 1H), 7.18 (q, J¼7.1 Hz,
1H), 7.29–7.59 (m, 8H), 8.33 (d, J¼7.9 Hz, 1H). 13C NMR
(100.62 MHz): d 14.6, 60.3, 117.9, 121.5, 123.4, 125.5,
126.3, 126.6, 127.7, 128.8, 129.1, 135.9, 140.4, 141.2,
154.8, 161.7. GC–MS (70 eV) m/z (rel int.): 306 M+ (100),
291 (15), 277 (23), 229 (70). IR (CHCl3): 3060, 2990,
1650, 1500, 1450, 1340, 1180 cmꢁ1. Anal. Calcd for
C18H14N2OS: C, 70.56; H, 4.60; N, 9.14. Found: C, 70.45;
H, 4.58; N, 9.11.
4.3.1. (Z)-3-Ethylidene-4-phenyl-1-thiazol-2-yl-azetidin-
2-one 8. Traces measured by GC–MS (70 eV) m/z (rel
int.): 256 (100) M+, 241 (14), 227 (24), 179 (95), 129 (36),
115 (25).
4.3.2. (E)-3-Ethylidene-4-phenyl-1-thiazol-2-yl-azetidin-
2-one 9. Yield 110 mg (43%), white solid, mp 158–159 ꢀC
(petroleum ether). 1H NMR (400.13 MHz): d 1.83 (d,
J¼7.4 Hz, 3H), 5.78 (s, 1H), 6.08 (d, J¼5.3 Hz, 1H), 7.13
(d, J¼5.3 Hz, 1H), 7.27–7.35 (m, 7H). 13C NMR
(100.62 MHz): d 14.7, 61.1, 105.6, 120.6, 126.6, 126.7,
127.9, 128.8, 140.8, 142.1, 155.9, 160.0. GC–MS (70 eV)
m/z (rel int.): 256 (100) M+, 241 (15), 227 (26), 179 (93),
129 (34), 115 (31). IR (CHCl3): 3019, 1670, 1540,
1205 cmꢁ1. Anal. Calcd for C14H12N2OS: C, 65.60; H,
4.72; N, 10.93; S, 12.51. Found: C, 65.65; H, 4.76; N, 10.89.
4.3.7. 3-Ethyl-2-(4-methyl-thiazol-2-yl)-thiazolo[3,2-a]-
pyrimidin-4-one 14. Yield 269 mg (97%), yellow solid, mp
169–171 ꢀC (petroleum ether). 1H NMR (400.13 MHz):
d 1.23 (t, J¼7.3 Hz, 3H), 2.54 (s, 3H), 3.32 (q, J¼7.3 Hz,
2H), 6.96 (d, J¼4.5 Hz, 1H), 7.08 (s, 1H), 7.95 (d,
J¼4.5 Hz, 1H). 13C NMR (100.62 MHz): d 12.8, 17.5,
18.8, 111.3, 117.6, 118.8, 121.8, 148.8, 155.0, 158.4,
160.0, 166.5. GC–MS (70 eV) m/z (rel int.): 277 M+ (100),
262 (18), 248 (41), 234 (59). IR (CHCl3): 3123,
3007, 2970, 2931, 2873, 1661, 1561, 1520, 1341, 1194,
1062, 980, 918 cmꢁ1. Anal. Calcd for C12H11N3OS2:
C, 51.96; H, 4.00; N, 15.15. Found: C, 51.99; H, 3.98; N,
15.20.
4.3.3. (E)-N-Thiazol-2-yl-2-benzylidene-but-3-enamide
10. Yield 49 mg (19%), yellow solid, mp 96–98 ꢀC

L. Troisi et al. / Tetrahedron 62 (2006) 12064–12070
12069
4.3.8. 2-Benzothiazol-2-yl-3-ethyl-thiazolo[3,2-a]pyrimi-
din-4-one 15. Yield 156 mg (50%), yellow solid, mp 236–
4.3.13. (E)-4-Benzothiazol-2-yl-3-ethylidene-1-pyridin-3-
yl-azetidin-2-one 21. Compound characterized only by
1H NMR as it was isolated in low quantity containing an
inseparable mixture of the two Z and E isomers (20+21).
Yield 6% (evaluated by GC analysis of the crude product).
1H NMR (400.13 MHz): d 1.91 (d, J¼7.0 Hz, 3H), 7.55 (q,
J¼7.0 Hz, 1H), 7.10–7.24 (m, 1H), 7.43 (t, J¼7.2 Hz, 1H),
7.52 (t, J¼8.0 Hz, 1H), 7.83–787 (m, 2H), 8.06 (d,
J¼8.2 Hz, 1H), 8.31–8.34 (m, 1H), 8.68 (d, J¼2.0 Hz,
1H). GC–MS (70 eV) m/z (rel int.): 307 M+ (100), 278
(53), 186 (72), 78 (14).
1
238 ꢀC (petroleum ether). H NMR (400.13 MHz): d 1.30
(t, J¼7.3 Hz, 3H), 3.43 (q, J¼7.3 Hz, 2H), 7.01 (d,
J¼4.8 Hz, 1H), 7.45 (t, J¼7.5 Hz, 1H), 7.53 (t, J¼7.5 Hz,
1H), 7.96–8.00 (m, 2H), 8.13 (d, J¼8.9 Hz, 1H). 13C NMR
(100.62 MHz): d 13.0, 19.0, 111.9, 120.9, 121.6, 121.9,
124.4, 126.0, 126.2, 136.4, 148.8, 154.7, 158.5, 159.9,
167.6. GC–MS (70 eV) m/z (rel int.): 313 M+ (100), 298
(37), 284 (51), 270 (56), 186 (15). IR (CHCl3): 3030,
3000, 2928, 2855, 1664, 1560, 1496, 1458 cmꢁ1. Anal.
Calcd for C15H11N3OS2: C, 57.49; H, 3.54; N, 13.41. Found:
C, 57.40; H, 3.52; N, 13.37.
Acknowledgements
4.3.9. 3-Ethylidene-4-(4-methyl-thiazol-2-yl)-1-pyridin-
2-yl-azetidin-2-one 16 and 17. Traces measured by GC–
MS (70 eV) m/z (rel int.): 271 M+ (47), 256 (24), 242 (88),
228 (100), 78 (51).
We like to thank the MIUR, Rome, and the University of
Lecce (Italy) for financial support.
References and notes
4.3.10. 3-Ethyl-2-(4-methyl-thiazol-2-yl)-pyrido[1,2-a]-
pyrimidin-4-one 18. Yield 265 mg (98%), yellow solid, mp
149–150 ꢀC (petroleum ether). 1H NMR (400.13 MHz):
d 1.27 (t, J¼7.3 Hz, 3H), 2.54 (d, J¼0.8 Hz, 3H), 3.41 (q,
J¼7.3 Hz, 2H), 7.01–7.05 (m, 1H), 7.08 (q, J¼0.8 Hz,
1H), 7.57–7.60 (m, 2H), 8.95–8.97 (m, 1H). 13C NMR
(100.62 MHz): d 12.8, 17.5, 19.5, 114.7, 117.6, 118.1,
126.1, 126.9, 134.6, 148.0, 149.7, 154.8, 159.3, 167.3.
GC–MS (70 eV) m/z (rel int.): 271 M+ (89), 256 (29), 242
(76), 228 (100), 78 (81). IR (CHCl3): 3009, 2971, 2930,
2873, 1666, 1637, 1538, 1489, 1243 cmꢁ1. Anal. Calcd for
C14H13N3OS: C, 61.97; H, 4.83; N, 15.48. Found: C,
61.85; H, 4.80; N, 15.53.
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4.3.11. 2-Benzothiazol-2-yl-3-ethyl-pyrido[1,2-a]pyrimi-
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1
218 ꢀC (petroleum ether). H NMR (400.13 MHz): d 1.34
(t, J¼7.3 Hz, 3H), 3.52 (q, J¼7.3 Hz, 2H), 7.01–7.11 (m,
1H), 7.44 (t, J¼7.3 Hz, 1H), 7.52 (t, J¼7.0 Hz, 1H), 7.66
(d, J¼3.5 Hz, 2H), 7.98 (d, J¼8.0 Hz, 1H), 8.14 (d,
J¼8.0 Hz, 1H), 9.01 (d, J¼7.3 Hz, 1H). 13C NMR
(100.62 MHz): d 13.1, 19.7, 115.2, 120.0, 121.5, 124.4,
125.9, 126.1, 126.4, 127.1, 134.9, 136.5, 148.1, 149.8,
154.8, 159.4, 168.6. GC–MS (70 eV) m/z (rel int.): 307 M+
(100), 292 (78), 278 (83), 264 (86), 78 (60). IR (KBr):
3100, 3060, 2973, 2924, 2874, 1662, 1632, 1536, 1483,
1210, 922, 771, 753, 729, 701 cmꢁ1. Anal. Calcd for
C17H13N3OS: C, 66.43; H, 4.26; N, 13.67. Found: C,
66.35; H, 4.25; N, 13.70.
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4.3.12. (Z)-4-Benzothiazol-2-yl-3-ethylidene-1-pyridin-3-
yl-azetidin-2-one 20. Yield 24% (evaluated by GC analysis
of the crude product), brown oil. H NMR (400.13 MHz):
1
d 2.16 (d, J¼7.2 Hz, 3H), 5.87 (s, 1H), 6.03 (q, J¼7.2 Hz,
1H), 7.10–7.24 (m, 1H), 7.43 (t, J¼7.2 Hz, 1H), 7.52 (t,
J¼8.0 Hz, 1H), 7.83–7.87 (m, 2H), 8.06 (d, J¼8.2 Hz,
1H), 8.31–8.34 (m, 1H), 8.68 (d, J¼2.0 Hz, 1H). 13C NMR
(100.62 MHz): d 29.7, 60.4, 122.0, 123.5, 123.80, 123.83,
126.0, 126.5, 131.1, 134.2, 135.1, 138.27, 139.3, 145.4,
153.0, 161.0, 168.2. GC–MS (70 eV) m/z (rel int.): 307 M+
(100), 278 (48), 186 (67), 78 (18). IR (CHCl3): 3064,
2992, 2927, 2855, 1757, 1486, 1435, 1366 cmꢁ1. HR-ESI-
MS: m/z calcd for C17H13N3OS: 307.0781, [M+H]+; found:
307.0790.
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12070
L. Troisi et al. / Tetrahedron 62 (2006) 12064–12070
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publication numbers CCDC 607028 and CCDC 607027.
Copies of the data can be obtained, free of charge, on applica-
tion to CCDC, 12 Union Road, Cambridge CB2 IEZ, UK [fax:
+44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
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31. Full optimization and frequency analysis was performed on all
structures. Free energy was computed at T¼298.15 K and
P¼1.0 atm including the zero point energy and the contribution
from translation, rotations and vibrations. Total free energies in
hartree are (in parenthesis the purely electronic energy):
GB¼ꢁ1139.634309 (ꢁ1139.804609), GC¼ꢁ1139.642790
(ꢁ1139.812132), GD¼ꢁ1139.700231 (ꢁ1139.877497).
`
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`
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`
ꢀ
26. Alajarın, M.; Sanchez-Andrada, S. J. Org. Chem. 2001, 66,
`
ꢁ
32. Alajarın, M.; Vidal, A.; Sanchez-Andrada, P.; Tovar, F.; Ochoa,
8470–8477.
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