New applications of the imine-ketenimine intramolecular [2+2] cycloaddition reaction: Highly stereocontrolled synthesis of azeto[1,2-a]pyrimidines

Article abstract of DOI:10.1002/1099-0690(200212)2002:24<4222::AID-EJOC4222>3.0.CO;2-M

Imino-ketenimines 7, in which the reactive functionalities are linked by an allylic tether connecting the imino and ketenimino nitrogen atoms, undergo a formal intramolecular [2+2] cycloaddition to yield azeto[1,2-a]pyrimidines 8. When enantiotopic ketenimine and imine fragments are combined, the resulting azeto[1,2-a]pyrimidines 8e-i contain two stereogenic carbon atoms C-6 and C-7, and the cycloaddition takes place with complete diastereoselectivity in favor of the cis diastereoisomers. This methodology has also been applied to the preparation of some azeto[1,2-a][1,3]thiazolo[4,5-d]pyrimidines 16, representative examples of a new fused heterocyclic system. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200212)2002:24<4222::AID-EJOC4222>3.0.CO;2-M

FULL PAPER
New Applications of the Imine-Ketenimine Intramolecular [2؉2] Cycloaddition
Reaction: Highly Stereocontrolled Synthesis of Azeto[1,2-a]pyrimidines
[a]
[a]
[a]
´
´
Mateo Alajarın,* Angel Vidal, and Raul-Angel Orenes
Keywords: Cycloaddition / Diastereoselectivity / Imines / Ketenimines / Nitrogen heterocycles
Imino-ketenimines 7, in which the reactive functionalities are
takes place with complete diastereoselectivity in favor of the
linked by an allylic tether connecting the imino and ketenim- cis diastereoisomers. This methodology has also been ap-
ino nitrogen atoms, undergo a formal intramolecular [2+2]
cycloaddition to yield azeto[1,2-a]pyrimidines 8. When en-
antiotopic ketenimine and imine fragments are combined,
the resulting azeto[1,2-a]pyrimidines 8e−i contain two ste-
reogenic carbon atoms C-6 and C-7, and the cycloaddition
plied to the preparation of some azeto[1,2-a][1,3]thiazolo[4,5-
d]pyrimidines 16, representative examples of a new fused
heterocyclic system.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2002)
Introduction
quinazolines
2 in a highly stereocontrolled manner
(Figure 1).[6Ϫ10]
Ketenimines are able to participate in [2ϩ2] cycloaddi-
tion reactions through either their CϭN or their CϭC
bonds.[1,2] Usually these heterocumulenes undergo [2ϩ2]
cycloaddition reactions through their cumulated CϭC
bond, thus contributing two carbon atoms to the new four-
membered ring, which should also contain an exocyclic im-
ino group. This chemical behavior of ketenimines has al-
ready been successfully exploited in the synthesis of four-
membered heterocycles,[3] based on the reaction between ke-
tenimines and compounds containing carbonϪheteroatom
(CϭX) or heteroatomϪheteroatom (XϭY) double bonds,
such as heterocumulenes, azo and nitroso compounds, alde-
hydes and (thio)ketones, and imines.
Reactions between ketenimines and imines to furnish az-
etidin-2-imines were first reported by Regitz in 1979, who
showed that N-cyano-C-(diphenylamino)ketenimine cyclo-
added to benzylideneaniline in an intermolecular fashion.[4]
A year later, Ghosez studied the reactions of N-alkyl- and
N-arylketenimines with imines, proving that enhancement
of the electrophilic character of the ketenimine by the intro-
duction of an electron-withdrawing substituent (such as to-
syl) on its nitrogen atom was mandatory for the occurrence
of the cycloaddition.[5] Since then, these reactions remained
unexplored until recently, when we undertook the study of
the intramolecular [2ϩ2] cycloaddition reaction between
ketenimine and imine functions supported on an ortho-
benzylic scaffold (e.g., 1), which afforded the azeto[2,1-b]-
Figure 1. Intramolecular [2ϩ2] cycloaddition of imino-ketenimines
on an ortho-benzylic scaffold
As result of a study aimed towards exploration of the
efficiency of these [2ϩ2] cycloaddition reactions in other
imino-ketenimines related to 1, bearing different tethers be-
tween their reactive functionalities, we present here a new
synthetic approach to azeto[1,2-a]pyrimidines and
a
method for the preparation of the previously unknown az-
eto[1,2-a][1,3]thiazolo[4,5-d]pyrimidine ring system. In
these cases, the CϭC double bond of the allylic system con-
necting the nitrogen atoms of the ketenimine and imine
functions is part of an acyclic alkene or a thiazole ring, re-
spectively.
Results and Discussion
The starting compound for the synthesis of azeto[1,2-a]p-
yrimidines was the previously unreported (Z)-3-azido-3-
phenyl-2-propen-1-amine (4). A Mitsunobu reaction be-
tween the 2-propen-1-ol 3[11] and triphenylphosphane, di-
ethyl azodicarboxylate and phthalimide followed by hydra-
zinolysis afforded the amine 4. Treatment of 4 with aro-
matic, heteroaromatic and α,β-unsaturated aldehydes under
mild conditions, in diethyl ether solution and in the pres-
ence of anhydrous magnesium sulfate,[12] provided the cor-
responding aldimines 5 in almost quantitative yields. Azido-
[a]
´
´
´
Departamento de Quımica Organica, Facultad de Quımica,
Universidad de Murcia, Campus de Espinardo,
Espinardo, 30100 Murcia, Spain
Fax: (internat.) ϩ 34-968/364149
E-mail: alajarin@um.es
4222
 2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1224Ϫ4222 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 4222Ϫ4227

Highly Stereocontrolled Synthesis of Azeto[1,2-a]pyrimidines
FULL PAPER
imines 5 were used in the next reaction step as crude prod- decomposition of compounds 8 during the purification
ucts, due to the hydrolytic sensitivity of the imine function. step. We have observed that heterocycles 8 are not stable in
In fact, all attempts to purify compounds 5 either by crys- solution at room temperature, slowly decomposing to yield
tallization or column chromatography failed, yielding mix- complex mixtures that we were not able to resolve.
tures of the amine 4 and the corresponding aldehyde.
Staudinger treatment[13] of azidoimines 5 with trimethyl- based on their H and 13C NMR spectroscopic data. Their
phosphane, in toluene solution at room temperature, 1H NMR spectra show 3-H as
triplet at
The structural characterization of compounds 8 is mainly
1
a
δ ϭ
yielded the P,P,P-trimethyl-λ5-phosphazenes 6. The conver- 5.36Ϫ5.53 ppm (3J ϭ 2.9Ϫ3.3 Hz) and 6-H as a singlet [ex-
sion 5 Ǟ 6 was complete in less than 30 min, as monitored cept for 8d and 8i, in which R1 ϭ (E)-2-O2NC6H4CHϭCH]
by IR (disappearance of the azide vibration near 2100 at δ ϭ 4.59Ϫ5.55 ppm. The two methylene protons at C-4
cmϪ1). In the same reaction flask, the trimethylphosphaz- appear as diastereotopic (each one as a doublet of doublets,
enes 6 were treated with 1 equiv. of diphenyl ketene or with a geminal coupling constant of 12.0Ϫ12.8 Hz) in com-
methyl phenyl ketene, giving the intermediate ketenimines pounds 8aϪd, whereas for the remaining compounds 8eϪi
7, which could be detected in the reaction medium by IR these protons just appear as doublets. The protons of the
spectroscopy (2000 cmϪ1, NϭCϭC) shortly after the addi- 7-CH3 methyl group in compounds 8eϪi appear as singlets
tion of the ketene. Compounds 7 underwent a straightfor- at δ ϭ 1.82Ϫ1.94 ppm. In their 13C NMR spectra the sig-
ward transformation within minutes in toluene solution at nals at δ ϭ 67.0Ϫ75.3 ppm and δ ϭ 61.6Ϫ71.3 ppm are
room temperature, yielding 6,7-dihydro-4H-azeto[1,2-a]pyr- attributable to the methine and quaternary carbon atoms
imidines (8) (Scheme 1). The separation of the reaction C-6 and C-7, respectively. The IR, MS and analytical data
products from the trimethylphosphane oxide was carried of compounds 8 are in perfect agreement with the pro-
out by column chromatography. Azetopyrimidines 8 were posed structures.
obtained in low to acceptable overall yields (20Ϫ60%) for
Imino-ketenimines 7eϪi, in which R2 ϭ CH3, combine
the conversion 5 Ǟ 8, three reaction steps in a one-pot pro- imine and ketenimine fragments with enantiotopic faces.
cess (Table 1). The low yields may be the result of partial Consequently, the intramolecular cyclization of these com-
pounds could provide mixtures of cis- and trans-azeto[1,2-
a]pyrimidines 8eϪi (Figure 2). However, the intramolecular
cyclization of 7eϪi in each case provided a single diastereo-
1
isomer, cis-8, as corroborated by H NMR analysis of the
crude reaction mixtures before chromatography.
Figure 2. Azeto[1,2-a]pyrimidines cis-8 and trans-8
The relative configurations of the two stereogenic centers
Scheme 1. Reagents and conditions: (a) (i) PPh3, EtO2CNϭ
(C-6 and C-7) in compounds 8eϪi were assigned on the
NCO2Et, phthalimide, THF, 0 °C 1 h, room temp. 36 h; (ii)
basis of the values of the chemical shifts of the 7-CH3 pro-
N2H4·H2O, THF/EtOH, room temp. 16 h, 50 °C 2 h; (b) R1CHO,
tons, and on analysis of their gate-decoupled 13C NMR
MgSO4, room temp., 16 h; (c) PMe3, toluene, room temp., 30 min
(d) R2PhCϭCϭO, toluene, room temp., 30 min
spectra. Figure 3 presents the chemical shifts of the 7-CH3
protons of the azeto[1,2-a]pyrimidines 8eϪi, and those of
the 2-CH3 protons of the structurally related azeto[2,1-
Table 1. 2-Phenyl-6,7-dihydro-4H-azeto[1,2-a]pyrimidines 8 and
2,5,5-triphenyl-5,8-dihydro-6H-azeto[1,2-a][1,3]thiazolo[4,5-d]-
pyrimidines 16
Compound
R1
R2
Yield [%]
8a
8b
8c
8d
8e
8f
8g
8h
8i
16a
16b
4-BrC6H4
4-O2NC6H4
3-furyl
(E)-2-O2NC6H4CHϭCH
4-BrC6H4
4-ClC6H4
4-O2NC6H4
3-furyl
(E)-2-O2NC6H4CHϭCH
4-BrC6H4
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
42
39
20
34
60
48
52
41
30
51
64
Figure 3. Selected 1H NMR (δ, ppm) data for compounds cis-8eϪi,
cis-2, cis-9 and trans-9
4-ClC6H4
Eur. J. Org. Chem. 2002, 4222Ϫ4227
4223

M. Alajarin, A. Vidal, R.-A. Orenes
FULL PAPER
b]quinazolines cis-2 and azeto[2,1-b][1,3]benzodiazepines
Some methods have been reported in the literature for
cis-9 and trans-9, for which the relative cis/trans configura- the synthesis of azeto[1,2-a]pyrimidines (also known as aza
tions have been determined unequivocally.[8] By analysis of analogues of cephams). The one most generally applicable
these data, relative cis configurations could be reliably as- involves the formation of the azetidine ring on a preformed
signed to the compounds 8eϪi prepared in this work.
pyrimidine system, by means of a [2ϩ2] cycloaddition reac-
Moreover, the gate-decoupled 13C NMR spectra of com- tion between ketenes and dihydro- or tetra-
pounds 8eϪi allowed observation of the coupling between hydropyrimidines.[15Ϫ20] Other less versatile procedures for
the CH3 carbon atom linked to C-7 and the proton 6-H. the synthesis of azeto[1,2-a]pyrimidines have also been de-
From the values of these coupling constants (3JC,H
ϭ
veloped.[21,22]
3.5Ϫ4.2 Hz) a dihedral angle close to 35° between the men-
The synthetic sequence resulting in azeto[1,2-a][1,3]thi-
tioned nuclei can be calculated,[14] which is also in agree- azolo[4,5-d]pyrimidines 16 started with the new 5-(amino-
ment with a cis geometry (Figure 4). Nearly no coupling methyl)thiazole 13, which could be obtained in four steps
would be expected for the trans isomers.
by standard procedures in 35% overall yield starting from
the known azido aldehyde 10.[23] This involved: i) sodium
borohydride reduction to alcohol 11, ii) conversion into
bromide 12 with Ph3PBr2 and iii) Gabriel-style synthesis of
amine 13. Treatment of 13 with 4-bromo- or 4-chloroben-
zaldehyde in diethyl ether solution in the presence of anhyd-
rous magnesium sulfate yielded the expected aldimines 14.
Sequential treatment of toluene solutions of aldimines 14
with trimethylphosphane and diphenyl ketene provided im-
ino-ketenimines 15. Compounds 15 were found to be fairly
stable in toluene solution at room temperature, and no
cycloaddition was observed at this temperature after 24 h.
Indeed, the formal intramolecular [2ϩ2] cycloaddition of
imino-ketenimines 15 only took place after heating of the
reaction mixture at reflux for 1 h. Azeto[1,2-a][1,3]thi-
azolo[4,5-d]pyrimidines 16 were obtained in moderate
yields after column chromatography (Scheme 2, Table 1).
Compounds 16 were fully characterized by their analytical
and spectroscopic data.
Figure 4. Newman projection of cis-8 (R2 ϭ CH3) and trans-8
(R2 ϭ CH3) along the C-6ϪC-7 bond
From a mechanistic point of view, the formation of the
bicyclic compounds 8 from imino-ketenimines 7 can be ex-
plained by a two-step sequence: initial nucleophilic addition
of the nitrogen atom of the imine function to the sp-hybrid-
ized carbon atom of the ketenimine, and subsequent conro-
tatory 4π-electrocyclization of the resulting zwitterionic
intermediate.[8Ϫ10] On the basis of this mechanistic se-
quence, the conversion of imino-ketenimines 7eϪi, which
bear two different substituents (CH3 and Ph) on the sp2
carbon terminus of the ketenimine fragment, into the [2ϩ2]
cycloadducts cis-8 should occur through the zwitterionic in-
termediate (E)-INT (Figure 5), resulting from the nucleo-
philic ring-closure of compounds 7eϪi through a Ph-exo[8]
transition state. Conrotation of (E)-INT should produce
cis-8. The experimental results show that [2ϩ2] cycloaddi-
tions of compounds 7eϪi to produce 8 occur with high di-
astereoselectivity, as the trans-8 adducts were never isolated
nor detected. This fact can be explained by considering that
the cyclization of compounds 7 giving rise to the zwitter-
ionic intermediates occurs exclusively by the sterically less
congested Ph-exo mode of addition.
Scheme 2. Reagents and conditions: (a) NaBH4, THF/Et2O, 0 °C
Ǟ room temp., 12 h; (b) PPh3Br2, Et3N, benzene, room temp., 12 h;
(c) (i) potassium phthalimide, DMF, 80 °C, 12 h; (ii) N2H4·H2O,
THF/EtOH, room temp. 16 h, 60 °C 1.5 h; (d) R1CHO, MgSO4,
Et2O, room temp., 16 h; (e) (i) PMe3, toluene, room temp., 30 min;
(ii) Ph2CϭCϭO, toluene, room temp., 15 min; (f) toluene, reflux,
1 h
Conclusion
In summary, we have presented new synthetic applica-
tions proving the wide applicability of the formal intramole-
Figure 5. Mechanism for the conversion 7 Ǟ 8
4224
Eur. J. Org. Chem. 2002, 4222Ϫ4227

Highly Stereocontrolled Synthesis of Azeto[1,2-a]pyrimidines
FULL PAPER
Compound 8a: 0.29 g, 42%. IR (nujol): ν˜ ϭ 1663 (CϭN) cmϪ1. H
1
cular [2ϩ2] cycloaddition between ketenimine and imine
functions to yield 2-iminoazetidines. This methodology has
now allowed us to prepare different types of azeto[1,2-a]-
pyrimidines, either isolated or fused to a thiazole ring, with
excellent diastereoselectivity in the newly formed CϪC
bond, when applicable.
NMR (300 MHz, CDCl3, 25 °C): δ ϭ 3.98 (dd, J ϭ 12.8, 3.1 Hz,
1 H), 4.04 (dd, J ϭ 12.8, 3.1 Hz, 1 H), 5.30 (s, 1 H), 5.38 (t, J ϭ
3.1 Hz, 1 H), 6.92Ϫ6.95 (m, 6 H), 7.05Ϫ7.08 (m, 2 H), 7.18Ϫ7.32
(m, 7 H), 7.67 (d, J ϭ 7.6 Hz, 2 H), 7.74 (d, J ϭ 7.6 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ ϭ 42.6, 70.6 (s), 73.8, 100.4,
125.6, 126.9, 127.3, 127.8, 128.0, 128.2, 128.7, 129.4, 131.5, 132.5
(s), 134.5 (s), 138.0 (s), 139.4 (s), 141.7 (s), 144.3 (s), 165.4 (s) ppm.
MS (70 eV, EI): m/z (%) ϭ 492 (24) [Mϩ, for 81Br], 490 (26) [Mϩ,
for 79Br], 165 (100). C30H23BrN2 (491.42): calcd. C 73.32, H 4.72,
N 5.70; found C 73.19, H 4.79, N 5.59.
Experimental Section
General Remarks: All melting points were determined with a Kofler
hot-plate melting-point apparatus and are uncorrected. IR spectra
were obtained as Nujol emulsions or films with a Nicolet Impact
400 spectrophotometer. 1H and 13C NMR spectra were recorded
with a Bruker AC 200 or a Varian Unity 300 spectrometer and are
reported in ppm on the δ scale. The signal of the solvent was used
as reference. Mass spectra were recorded with a HewlettϪPackard
5993C spectrometer. Microanalyses were performed with a Carlo
Erba EA-1108 instrument. (Z)-3-Azido-3-phenyl-2-propen-1-ol,[11]
4-azido-5-formyl-2-phenylthiazole,[23] diphenyl ketene[24] and
methyl phenyl ketene[25] were prepared by literature procedures. Al-
dimines 5 and 14 were obtained by standard procedures.[12]
Compound 8b: 0.25 g, 39%. IR (nujol): ν˜ ϭ 1673 (CϭN), 1521
(NO2), 1349 (NO2) cmϪ1. 1H NMR (300 MHz, CDCl3, 25 °C): δ ϭ
4.16Ϫ4.17 (m, 2 H), 5.53 (t, J ϭ 3.3 Hz, 1 H), 5.55 (s, 1 H),
6.99Ϫ7.03 (m, 3 H), 7.10Ϫ7.13 (m, 2 H), 7.31Ϫ7.45 (m, 8 H), 7.78
(d, J ϭ 7.2 Hz, 2 H), 7.83 (d, J ϭ 7.2 Hz, 2 H), 8.04 (d, J ϭ 8.7 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ ϭ 42.8, 71.3 (s),
73.1, 100.5, 123.4, 125.5, 127.2, 127.6, 127.8, 127.9, 128.0, 128.1,
128.2, 128.4, 128.7, 137.4 (s), 139.0 (s), 141.0 (s), 143.1 (s), 144.1
(s), 147.6 (s), 164.9 (s) ppm. MS (70 eV, EI): m/z (%) ϭ 457 (59)
[Mϩ], 321 (100). C30H23N3O2 (457.52): calcd. C 78.75, H 5.07, N
9.18; found C 78.69, H 5.15, N 9.10.
1
Compound 8c: 0.11 g, 20%. IR (nujol): ν˜ ϭ 1670 (CϭN) cmϪ1. H
Amine 4: Diethyl azodicarboxylate (1.5 g, 8.57 mmol) was added at
0 °C to a solution of triphenylphosphane (2.25 g, 8.57 mmol) in
dry THF (15 mL) and the reaction mixture was stirred for 30 min.
A solution of 3 (1 g, 5.71 mmol) in dry THF (10 mL) and phthali-
mide (1.26 g, 8.57 mmol) were then added. The mixture was stirred
for 1 h at 0 °C and for 36 h at room temperature. The solvent was
removed under reduced pressure and the residue was chromato-
graphed [silica gel, hexanes/EtOAc (4:1, v/v)] to give N-[(Z)-3-az-
ido-3-phenyl-2-propen-1-yl]phthalimide as a colorless oil (1.15 g,
68%). Hydrazine hydrate (7.5 equiv.) was then added to a solution
of the N-[(Z)-3-azido-3-phenyl-2-propen-1-yl]phthalimide (1 g,
3.29 mmol) in a mixture of THF (40 mL) and EtOH (6 mL), and
the reaction mixture was stirred for 16 h at room temperature and
for 2 h at 50 °C. After cooling, the mixture was filtered, the solid
was washed with THF (10 mL), and the solvent was removed from
the filtrate. The resulting material was purified by column chroma-
tography [silica gel, Et2O/EtOH (1:1, v/v)] to yield amine 4 as a
yellow oil (0.27 g, 48%). IR (neat): ν˜ ϭ 3376 (NH2), 3314 (NH2),
2112 (N3) cmϪ1. 1H NMR (200 MHz, CDCl3, 25 °C): δ ϭ 1.48 (br.
s, 2 H), 3.50 (d, J ϭ 6.8 Hz, 2 H), 5.27 (t, J ϭ 6.8 Hz, 1 H), 7.39
(s, 5 H) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ ϭ 38.6, 120.9,
127.0, 128.7, 128.9, 134.6 (s), 137.5 (s) ppm. MS (70 eV, EI): m/z
(%) ϭ 174 (30) [Mϩ], 146 (100) [Mϩ Ϫ N2]. C9H10N4 (174.20):
calcd. C 62.05, H 5.79, N 32.16; found C 62.25, H 5.71, N 32.04.
NMR (300 MHz, CDCl3, 25 °C): δ ϭ 4.01 (dd, J ϭ 12.0, 3.1 Hz,
1 H), 4.05 (dd, J ϭ 12.0, 3.1 Hz, 1 H), 5.29 (s, 1 H), 5.38 (t, J ϭ
3.1 Hz, 1 H), 5.83Ϫ5.84 (m, 1 H), 7.03Ϫ7.34 (m, 13 H), 7.62Ϫ7.66
(m, 2 H), 7.72Ϫ7.77 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ ϭ 42.4, 67.0, 100.5, 109.6, 121.4 (s), 125.6, 127.0, 127.3,
127.7, 128.1, 128.2, 128.3, 128.6, 138.7 (s), 139.5 (s), 141.3, 141.8
(s), 143.4, 144.4 (s), 165.4 (s) ppm. MS (70 eV, EI): m/z (%) ϭ 402
(65) [Mϩ], 114 (100). C28H22N2O (402.49): calcd. C 83.56, H 5.51,
N 6.96; found C 83.48, H 5.42, N 6.85.
Compound 8d: 0.23 g, 34%. IR (nujol): ν˜ ϭ 1665 (CϭN), 1521
(NO2), 1345 (NO2) cmϪ1. 1H NMR (300 MHz, CDCl3, 25 °C): δ ϭ
4.18 (dd, J ϭ 12.8, 2.9 Hz, 1 H), 4.28 (dd, J ϭ 12.8, 2.9 Hz, 1 H),
5.03 (d, J ϭ 8.0 Hz, 1 H), 5.47 (t, J ϭ 2.9 Hz, 1 H), 5.74 (dd, J ϭ
15.7, 8.0 Hz, 1 H), 7.00 (dd, J ϭ 7.5, 1.3 Hz, 1 H), 7.18Ϫ7.50 (m,
14 H), 7.71 (d, J ϭ 7.3 Hz, 2 H), 7.80 (d, J ϭ 6.8 Hz, 2 H), 7.95
(dd, J ϭ 8.1, 1.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3, 25
°C): δ ϭ 42.7, 69.0 (s), 72.3, 100.6, 124.7, 125.6, 127.3, 127.5, 127.7,
127.8, 128.2, 128.4, 128.5, 128.7, 129.2, 130.2, 131.7, 132.3 (s),
133.4, 138.6 (s), 139.5 (s), 141.2 (s), 144.4 (s), 147.6 (s), 165.0 (s)
ppm. MS (70 eV, EI): m/z (%) ϭ 483 (8) [Mϩ], 164 (100).
C32H25N3O2 (483.56): calcd. C 79.48, H 5.21, N 8.69; found C
79.33, H 5.10, N 8.83.
1
Compound 8e: 0.36 g, 60%. IR (nujol): ν˜ ϭ 1668 (CϭN) cmϪ1. H
General Procedure for the Preparation of the 7-Methyl(phenyl)-2,7-
diphenyl-6,7-dihydro-4H-azeto[1,2-a]pyrimidines (8): Trimethylpho-
sphane (1.4 mmol, 1.4 mL of a 1  toluene solution) was added to a
solution of the corresponding aldimine 5 (1.4 mmol) in dry toluene
(10 mL) and the reaction mixture was stirred at room temperature
until the evolution of nitrogen ceased (30 min). A solution of di-
phenyl ketene or methyl phenyl ketene (1.4 mmol) in the same solv-
ent (2 mL) was then added. After the mixture had been stirred at
room temperature for 30 min, the solvent was removed under re-
duced pressure and the resulting material was chromatographed on
a silica gel column, with hexanes/EtOAc as eluent. After removal
of the solvent from the relevant column chromatography fractions
under reduced pressure, the resulting solid material was triturated,
dried at room temperature under high vacuum for 12 h, and used
as such for characterization. Compounds 8 were stored in the dark
at 0 °C.
NMR (300 MHz, CDCl3, 25 °C): δ ϭ 1.87 (s, 3 H), 4.02 (d, J ϭ
3.3 Hz, 2 H), 4.59 (s, 1 H), 5.39 (t, J ϭ 3.3 Hz, 1 H), 6.80 (d, J ϭ
8.3 Hz, 2 H), 6.95Ϫ7.00 (m, 5 H), 7.17 (d, J ϭ 8.3 Hz, 2 H), 7.21
(d, J ϭ 6.8 Hz, 1 H), 7.28 (t, J ϭ 7.1 Hz, 2 H), 7.69 (d, J ϭ 7.3 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ ϭ 24.6, 42.4, 63.1
(s), 75.3, 100.5, 121.9 (s), 125.5, 126.7, 127.2, 127.7, 128.0, 128.1,
128.9, 131.2, 134.7 (s), 138.2 (s), 139.3 (s), 144.3 (s), 167.0 (s) ppm.
MS (70 eV, EI): m/z (%) ϭ 430 (40) [Mϩ, for 81Br], 429 (27), 428
(43) [Mϩ, for 79Br], 105 (100). C25H21BrN2 (429.35): calcd. C 69.94,
H 4.93, N 6.52; found C 69.75, H 4.99, N 6.64.
1
Compound 8f: 0.26 g, 48%. IR (nujol): ν˜ ϭ 1659 (CϭN) cmϪ1. H
NMR (300 MHz, CDCl3, 25 °C): δ ϭ 1.85 (s, 3 H), 4.00 (d, J ϭ
3.3 Hz, 2 H), 4.59 (s, 1 H), 5.38 (t, J ϭ 3.3 Hz, 1 H), 6.84 (d, J ϭ
8.7 Hz, 2 H), 6.93Ϫ7.03 (m, 6 H), 7.20Ϫ7.29 (m, 4 H), 7.67Ϫ7.70
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ ϭ 24.6, 42.5,
Eur. J. Org. Chem. 2002, 4222Ϫ4227
4225

M. Alajarin, A. Vidal, R.-A. Orenes
FULL PAPER
63.2 (s), 75.3, 100.6, 125.6, 126.8, 127.2, 127.7, 128.0, 128.2, 128.3,
for 45 min. A solution of alcohol 11 (0.48 g, 2.08 mmol) and trie-
128.7, 133.8 (s), 134.3 (s), 138.3 (s), 139.4 (s), 144.4 (s), 167.1 (s) thylamine (0.2 g, 2.08 mmol) in dry benzene (10 mL) was then ad-
ppm. MS (70 eV, EI): m/z (%) ϭ 386 (27) [Mϩ, for 37Cl], 385 (26),
ded in one portion. After the mixture had been stirred at room
384 (57) [Mϩ, for 35Cl], 117 (100). C25H21ClN2 (384.90): calcd. C temperature for 12 h, the white suspension was filtered off. The
78.01, H 5.50, N 7.28; found C 77.87, H 5.60, N 7.41.
solvent was removed from the filtrate under reduced pressure and
the residue was purified by column chromatography [silica gel, hex-
anes/EtOAc (2:1, v/v)] to give bromide 12 (0.45 g, 74%) as pale
yellow prisms. M.p. 80Ϫ81 °C (Et2O). IR (nujol): ν˜ ϭ 2143 (N3)
Compound 8g: 0.29 g, 52%. IR (nujol): ν˜ ϭ 1665 (CϭN), 1519
(NO2), 1345 (NO2) cmϪ1. 1H NMR (300 MHz, CDCl3, 25 °C): δ ϭ
1.94 (s, 3 H), 4.08 (d, J ϭ 3.3 Hz, 2 H), 4.74 (s, 1 H), 5.46 (t, J ϭ
3.3 Hz, 1 H), 6.93Ϫ7.03 (m, 4 H), 7.13 (d, J ϭ 8.7 Hz, 2 H),
7.18Ϫ7.33 (m, 4 H), 7.68Ϫ7.71 (m, 2 H), 7.91 (d, J ϭ 8.7 Hz, 2 H)
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ ϭ 24.3, 42.8, 64.0 (s),
75.1, 100.8, 123.4, 125.6, 127.1, 127.2, 127.9, 128.0, 128.2, 128.3,
137.6 (s), 139.2 (s), 143.4 (s), 144.3 (s), 147.5 (s), 166.8 (s) ppm.
MS (70 eV, EI): m/z (%) ϭ 395 (42) [Mϩ], 259 (100). C25H21N3O2
(395.45): calcd. C 75.93, H 5.35, N 10.63; found C 76.04, H 5.25,
N 10.78.
cmϪ1 1H NMR (200 MHz, CDCl3, 25 °C): δ ϭ 4.59 (s, 2 H),
.
7.39Ϫ7.46 (m, 3 H), 7.85Ϫ7.90 (m, 2 H) ppm. 13C NMR (50 MHz,
CDCl3, 25 °C): δ ϭ 22.1, 116.4 (s), 126.2, 129.1, 131.0, 132.7 (s),
147.0 (s), 166.9 (s) ppm. MS (70 eV, EI): m/z (%) ϭ 296 (2) [Mϩ,
for 81Br], 294 (2) [Mϩ, for 79Br], 215 (25) [Mϩ Ϫ Br], 129 (100).
C10H7BrN4S (295.16): calcd. C 40.69, H 2.39, N 18.98; found C
40.82, H 2.33, N 18.87.
Preparation of Amine 13: A mixture of bromide 12 (2 g, 6.78 mmol)
and potassium phthalimide (1.47 g, 8.13 mmol) in dry DMF
(10 mL) was heated at 80 °C for 12 h, with vigorous stirring. The
cooled mixture was poured into ice/water (100 mL) and extracted
with CH2Cl2 (3 ϫ 50 mL). The combined organic phases were
washed with H2O (3 ϫ 100 mL), dried (MgSO4) and concentrated
in vacuo. The resulting residue was purified by column chromato-
graphy [silica gel, hexanes/EtOAc (7:3, v/v)] to yield 4-azido-2-
phenyl-5-(phthalimidomethyl)thiazole (1.59 g, 65%). Hydrazine hy-
drate (7.5 equiv.) was added to a solution of the 4-azido-2-phenyl-
5-(phthalimidomethyl)thiazole (1.6 g, 4.43 mmol) in a mixture of
THF (40 mL) and EtOH (6 mL), and the reaction mixture was
stirred for 16 h at room temperature and 1.5 h at 50 °C. After cool-
ing, the mixture was filtered, the solid was washed with THF
(10 mL), and the solvent was removed from the filtrate. The re-
sulting material was purified by column chromatography [silica gel,
Et2O/MeOH (1:1, v/v)] to yield amine 13 (0.81 g, 79%) as yellow
prisms. M.p. 95Ϫ97 °C (Et2O). IR (neat): ν˜ ϭ 3373 (NH2), 3310
1
Compound 8h: 0.20 g, 41%. IR (nujol): ν˜ ϭ 1669 (CϭN) cmϪ1. H
NMR (300 MHz, CDCl3, 25 °C): δ ϭ 1.82 (s, 3 H), 4.01 (d, J ϭ
3.3 Hz, 2 H), 4.60 (s, 1 H), 5.36 (t, J ϭ 3.3 Hz, 1 H), 5.69 (d, J ϭ
1.1 Hz, 1 H), 7.03Ϫ7.28 (m, 10 H), 7.66Ϫ7.71 (m, 2 H) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ ϭ 24.6, 42.2, 61.9 (s), 67.9,
100.6, 109.3, 125.6, 126.9, 127.2, 127.7, 128.1, 128.2, 139.1 (s),
139.6 (s), 141.0, 143.2, 144.2 (s), 144.5 (s), 167.1 (s) ppm. MS
(70 eV, EI): m/z (%) ϭ 340 (49) [Mϩ], 105 (100). C23H20N2O
(340.42): calcd. C 81.15, H 5.92, N 8.23; found C 81.28, H 5.78,
N 8.36.
Compound 8i: 0.18 g, 30%. IR (nujol): ν˜ ϭ 1670 (CϭN), 1526
(NO2), 1346 (NO2) cmϪ1. 1H NMR (300 MHz, CDCl3, 25 °C): δ ϭ
1.85 (s, 3 H), 4.13 (d, J ϭ 3.2 Hz, 2 H), 4.27 (d, J ϭ 8.0 Hz, 1 H),
5.36 (t, J ϭ 3.2 Hz, 1 H), 5.47 (dd, J ϭ 15.7, 8.0 Hz, 1 H), 6.83
(dd, J ϭ 7.5, 1.7 Hz, 1 H), 6.98 (d, J ϭ 15.7 Hz, 1 H), 7.12Ϫ7.45
(m, 10 H), 7.60Ϫ7.68 (m, 2 H), 7.83 (dd, J ϭ 7.7, 1.6 Hz, 1 H)
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ ϭ 24.1, 42.5, 61.6 (s),
73.4, 100.7, 124.5, 125.6, 127.2, 127.3, 127.7, 128.2, 128.4, 128.5,
129.0, 129.6, 131.9, 133.3, 138.8 (s), 139.5 (s), 144.4 (s), 147.3 (s),
147.5 (s), 166.7 (s) ppm. MS (70 eV, EI): m/z (%) ϭ 421 (73) [Mϩ],
259 (100). C27H23N3O2 (421.49): calcd. C 76.94, H 5.50, N 9.97;
found C 76.89, H 5.42, N 10.06.
1
(NH2), 2144 (N3) cmϪ1. H NMR (200 MHz, CDCl3, 25 °C): δ ϭ
1.72 (br. s, 2 H), 3.87 (s, 2 H), 7.39Ϫ7.43 (m, 3 H), 7.86Ϫ7.89 (m,
2 H) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ ϭ 36.8, 122.5 (s),
125.9, 129.0, 130.3, 133.2 (s), 143.8 (s), 164.6 (s) ppm. MS (70 eV,
EI): m/z (%) ϭ 231 (21) [Mϩ], 203 (20) [Mϩ Ϫ N2], 121 (100).
C10H9N5S (231.28): calcd. C 51.93, H 3.92, N 30.28; found C 51.79,
H 3.98, N 30.14.
Preparation of Alcohol 11: A solution of the aldehyde 10 (3 g,
13 mmol) in a mixture of THF (25 mL) and Et2O (25 mL) was
treated at 0 °C with a solution of sodium borohydride (0.61 g,
16.3 mmol) in H2O (4 mL). The reaction mixture was stirred for
30 min at 0 °C and then allowed to warm to room temperature
over 2 h. The organic solvents were then removed under reduced
pressure, brine (50 mL) was added, and the mixture was extracted
with CH2Cl2 (3 ϫ 50 mL). The combined organic phases were
washed with brine (50 mL), dried (MgSO4) and concentrated under
reduced pressure. The resulting crude material was chromato-
graphed [silica gel, hexanes/EtOAc (7:3, v/v)] to yield alcohol 11
(2.75 g, 91%) as yellow prisms. M.p. 107Ϫ109 °C (Et2O). IR (nu-
jol): ν˜ ϭ 3304 (OH), 2161 (N3) cmϪ1. 1H NMR (200 MHz, CDCl3,
25 °C): δ ϭ 2.36 (br. s, 1 H), 4.67 (s, 2 H), 7.38Ϫ7.45 (m, 3 H),
7.83Ϫ7.90 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ ϭ
55.2, 119.1 (s), 126.0, 129.0, 130.5, 132.8 (s), 145.1 (s), 166.1 (s)
General Procedure for the Preparation of the 2,5,5-Triphenyl-5,8-
dihydro-6H-azeto[1,2-a][1,3]thiazolo[4,5-d]pyrimidines 16: Trime-
thylphosphane (1 mmol, 1 mL of a 1  toluene solution) was added
to a solution of the corresponding aldimine 14 (1 mmol) in dry
toluene (10 mL) and the reaction mixture was stirred at room tem-
perature until the evolution of nitrogen ceased (30 min). A solution
of diphenyl ketene (0.19 g, 1 mmol) in the same solvent (5 mL) was
then added. The reaction mixture was stirred at room temperature
for 15 min and was then heated at reflux temperature for 1 h. The
solvent was removed under reduced pressure and the resulting mat-
erial was chromatographed on a silica gel column, with hexanes/
EtOAc as eluent.
Compound 16a: 0.28 g, 51%. M.p. 161Ϫ163 °C (CH2Cl2/Et2O). IR
(nujol): ν˜ ϭ 1653 (CϭN) cmϪ1 1H NMR (300 MHz, CDCl3, 25
.
ppm. MS (70 eV, EI): m/z (%) ϭ 232 (27) [Mϩ], 204 (33) [Mϩ
Ϫ
°C): δ ϭ 4.69 (d, J ϭ 11.2 Hz, 1 H), 4.78 (d, J ϭ 11.2 Hz, 1 H),
5.57 (s, 1 H), 7.01Ϫ7.06 (m, 5 H), 7.19Ϫ7.42 (m, 10 H), 7.78Ϫ7.81
(m, 2 H), 7.99Ϫ8.02 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ ϭ 43.0, 69.4 (s), 72.9, 106.1 (s), 122.7 (s), 126.2, 127.0,
127.5, 127.6, 128.1, 128.8, 128.9, 129.5, 130.0, 131.7, 133.5 (s),
133.6 (s), 137.6 (s), 141.4 (s), 155.2 (s), 164.6 (s), 165.2 (s) ppm.
MS (70 eV, EI): m/z (%) ϭ 549 (45) [Mϩ, for 81Br], 548 (28), 547
N2], 104 (100). C10H8N4OS (232.26): calcd. C 51.71, H 3.47, N
24.12; found C 51.63, H 3.41, N 24.01.
Preparation of Bromide 12:
A solution of bromine (0.33 g,
2.08 mmol) in dry benzene (10 mL) was added dropwise at 0 °C to
a solution of triphenylphosphane (0.52 g, 2.08 mmol) in the same
solvent (15 mL), and the mixture was stirred at that temperature
4226
Eur. J. Org. Chem. 2002, 4222Ϫ4227

Highly Stereocontrolled Synthesis of Azeto[1,2-a]pyrimidines
FULL PAPER
M. Alajarın, P. Molina, A. Vidal, F. Tovar, Tetrahedron 1997,
[7]
[8]
(57) [Mϩ, for 79Br], 167 (100). C31H22BrN3S (548.50): calcd. C
67.88, H 4.04, N 7.66; found C 68.03, H 3.92, N 7.80.
´
53, 13449Ϫ13472.
´
M. Alajarın, A. Vidal, F. Tovar, A. Arrieta, B. Lecea, F. P.
´
Cossıo, Chem. Eur. J. 1999, 5, 1106Ϫ1117.
Compound 16b: 0.32 g, 64%. M.p. 153Ϫ155 °C (CH2Cl2/Et2O). IR
[9]
´
´
F. P. Cossıo, A. Arrieta, B. Lecea, M. Alajarın, A. Vidal, F.
(nujol): ν˜ ϭ 1655 (CϭN) cmϪ1 1H NMR (300 MHz, CDCl3, 25
.
Tovar, J. Org. Chem. 2000, 65, 3633Ϫ3643.
°C): δ ϭ 4.68 (d, J ϭ 11.4 Hz, 1 H), 4.79 (d, J ϭ 11.4 Hz, 1 H),
5.59 (s, 1 H), 7.00Ϫ7.43 (m, 15 H), 7.78Ϫ7.82 (m, 2 H), 7.98Ϫ8.03
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ ϭ 42.9, 69.3
(s), 72.7, 106.0 (s), 126.1, 127.0, 127.5, 127.6, 128.0, 128.1, 128.7,
128.8, 128.9, 129.1, 130.0, 133.0 (s), 133.5 (s), 134.5 (s), 137.6 (s),
141.3 (s), 155.1 (s), 164.6 (s), 165.2 (s) ppm. MS (70 eV, EI): m/z
(%) ϭ 505 (65) [Mϩ, for 37Cl], 504 (66), 503 (100) [Mϩ, for 35Cl].
C31H22ClN3S (504.05): calcd. C 73.87, H 4.40, N 8.34; found C
73.71, H 4.51, N 8.22.
[10]
´
´
´
M. Alajarın, A. Vidal, F. Tovar, M. C. Ramırez de Arellano,
F. P. Cossıo, A. Arrieta, B. Lecea, J. Org. Chem. 2000, 65,
7512Ϫ7515.
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Acknowledgments
This work was supported by the MCYT and FEDER (Project
´
´
BQU2001-0010), Fundacion Seneca-CARM (Project PI-1/00749/
´
FS/01), and Acedesa (a division of Takasago). R.-A. O. thanks the
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Spanish Ministerio de Educacion, Cultura y Deporte for a fellow-
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[O02442]
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4227