Cycloaddition reactions of 1,3-diazabuta-1,3-dienes with alkynyl ketenes

Article abstract of DOI:10.1016/j.tet.2009.04.041

The cycloaddition reactions of 'all-carbon' 1,3-diazabuta-1,3-dienes with a few conjugated and unconjugated alkynyl ketenes are described. The reactions provide some interesting azetidinones and dihydropyrimidinones bearing an alkynyl moiety. The regiochemistry of cycloadduct is related with the degree of conjugation of the alkynyl ketene. Moreover, two alternative approaches to 'all-carbon' 1,3-diazabuta-1,3-dienes are reported.

Full text of DOI:10.1016/j.tet.2009.04.041

Tetrahedron 65 (2009) 4664–4670
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cycloaddition reactions of 1,3-diazabuta-1,3-dienes with alkynyl ketenes
*
Giorgio Abbiati , Alessandro Contini, Donatella Nava, Elisabetta Rossi
`
DISMABdSezione Chimica Organica ‘Alessandro Marchesini’, Universita degli Studi di Milano, Via Venezian 21, I-20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The cycloaddition reactions of ‘all-carbon’ 1,3-diazabuta-1,3-dienes with a few conjugated and un-
conjugated alkynyl ketenes are described. The reactions provide some interesting azetidinones and di-
hydropyrimidinones bearing an alkynyl moiety. The regiochemistry of cycloadduct is related with the
degree of conjugation of the alkynyl ketene. Moreover, two alternative approaches to ‘all-carbon’ 1,3-
diazabuta-1,3-dienes are reported.
Received 23 December 2008
Received in revised form 23 March 2009
Accepted 9 April 2009
Available online 17 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Diazabuta-1,3-dienes
Alkynyl ketenes
[2þ2] Cycloaddition
[4þ2] Cycloaddition
Azetidin-2-ones
Dihydropyrimidinones
1. Introduction
investigated the cycloaddition reactions with isocyanates and iso-
thiocyanates to give triazin-2-ones and triazin-2-thiones.18
Cycloaddition reactions involving 1,3-diazabuta-1,3-dienes re-
present a useful strategy for the preparation of a number of four-,
five- and six-member nitrogen-containing heterocycles.1 A wide
variety of different reaction partners were tested and a lot of ex-
ample of cycloaddition reactions with different partners, such as
isocyanides,2 phosphoric compounds,3 the Simmons–Smith re-
agent,4 acetylenes,5 enamines,6 sulfenes,7 oxazolinones,8 acry-
The aim of this work is to conclude our investigation on the
cycloaddition between 1,3-diazabuta-1,3-dienes and ketenes test-
ing the reactivity of some unusual alkynyl ketenes. To our knowl-
edge, this feature of the chemistry of 1,3-diazabuta-1,3-dienes was
never previously investigated and only a few researchers have ex-
plored the reactivity of some alkynyl ketenes with imines.19–22 For
example, in a more extensive study on the reactivity of cyanoke-
tenes with imines,19 Moore and Nguyen investigated the cycload-
dition of cinnamylideneamines and benzylideneamines with the
strongly activate hexynylcyanoketene, generated in situ by the
thermolysis of 2,5-diazido-3,6-dihexynyl-1,4-benzoquinone.20 Al-
caide and co-workers reported the first example of a cycloaddition
of a diimine with an unconjugated alkynyl ketene generated in situ
from the corresponding acyl chloride.21 More recently, Rosenblum
and co-workers prepared some 3-alkynyl azetidinones in low to
moderate yields, through the cycloaddition of aryl alkynyl ketenes
and (4-methoxy-benzylidene)-phenyl-amine.22 In this paper we
report two new favourable strategies to prepare ‘all-carbon’ 1,3-
diazabuta-1,3-dienes and the results of our experimental studies on
their cycloaddition reactions with simple acetylenic ketenes.
lates,9 the Reformatsky reagent,10 nitriles11 and -nitrostyrenes,12
a
have been reported. However, cycloaddition reactions between
differently substituted 1,3-diazabuta-1,3-dienes and ketenes rep-
resent the most studied application of these compounds in het-
erocyclic synthesis, leading up to several different azetidinones and
pyrimidinones.5,13 In connection with our ongoing interest in the
synthesis of heterocyclic compounds starting from amidines and
their derivatives,14 we widely investigated the cycloaddition re-
actions of a few 2,4-diphenyl-1,3-diazabuta-1,3-dienes charac-
terised by (1) the mono-substitution on C-4 and (2) the ‘all-carbon’
substitution on the diazadiene scaffold. We explored the reactivity
of these substrates with mono and di-substituted ketenes15 and the
thermal and photochemical cycloreversion of the [2þ2] cyclo-
adduct into the corresponding [4þ2] adduct.16 We extended our
study to the cycloaddition reactions with some chiral ketenes
leading up to optically active azetidinones.17 Furthermore, we
2. Results and discussion
Some years ago, we described a new useful synthetic approach
to the 1,3-diazabuta-1,3-diene framework starting from dibutyl-
phosphoramidates and aryl aldehydes.14b Despite the method
working well for the preparation of N-aryl diazadienes, the overall
* Corresponding author. Tel.: þ39 02 50314474; fax: þ39 02 50314476.
E-mail address: giorgio.abbiati@unimi.it (G. Abbiati).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.041

G. Abbiati et al. / Tetrahedron 65 (2009) 4664–4670
4665
Cl
Ph
N
Ph
TiCl4
1) Ph CH2 NH2
EtOH
Ph
NH2
Ph
Ph-CHO
Ph
C
N
Ph
NH2
Ph
NH2
N
HCl
Toluene, TEA
74%
N
EtOH
100%
2) NaOH
66%
N
Ph
OEt
Ph
1a
CCl4
TEA
Overall yield: 48%
H-PO(O-C4H9)2
89%
Overall yield: 33%
Scheme 3.
O-C4H9
Ph
N
Ph
O
N
P
O-C4H9
starting from p-tolyl-benzaldehyde (Scheme 2). Clearly, the draw-
back of this approach is to allow only the synthesis of homo-
substituted 2,4-diaza-1,3-pentadienes.
Ph-CHO
NaH / toluene
57%
Ph
NH
N
1a
Ph
Ph
An alternative synthesis was developed on the basis of
Wu¨rthwein’s findings.25 It is well known that titanium tetrachlo-
ride can promote imine intermediate formation through its vigor-
ous water scavenger and useful Lewis acid double activity.26 Thus,
1a was prepared by direct condensation of N-benzyl benzamidine
with benzaldehyde in the presence of half equivalent of TiCl4 in
toluene and an excess of triethylamine (Scheme 3). The greatest
strength of this approach is the ease of product isolation. With
respect to the standard method the overall process yield was in-
creased to 48%.
Regarding the dienophile reaction partner, alkynyl ketenes were
generated in situ by dehydrohalogenation of the corresponding
acyl chlorides 3a–d. The latter were easily prepared in good yields
according to the standard methods by reacting the corresponding
acids 2a–d with thionyl chloride or oxalyl chloride. Alkynoic acids
2a–d were synthesised in good yields starting from the corre-
sponding alkynols by an ‘inverse addition’ Jones oxidation.27 Fi-
nally, 5-aryl-4-pentyn-1-ols 2c,d were obtained by means of
Sonogashira coupling28 of 4-pentynol with the appropriate aryl
iodide29 (Scheme 4).
Scheme 1.
yield for the synthesis of the 1-benzyl-2,4-diphenyl-1,3-diazabuta-
1,3-diene 1a15 was improvable (Scheme 1).
An alternative approach was developed through the optimisa-
tion of a method previously reported by Hunter and Sim.23 The
synthesis of diazadiene 1a was achieved in 51% yield by a base-
promoted prototropic rearrangement of the corresponding hydro-
benzamide (Scheme 2).24 The latter was easily obtained in almost
quantitative yield through the condensation of benzaldehyde with
concentrated aqueous ammonia. Although a significant amount of
the by-product amarine 6 was obtained besides the desired product
1a, the number of steps, the cheapness of reagents, the easy
product isolation and the overall process yields (50%) made this
synthetic strategy useful (Scheme 2). Moreover, this method was
successfully used to prepare the new diazadiene 1b in 43% yield
H2O
Ar
N
H
N
3
Ar CHO +
NH3
Ar
Ar
Cycloaddition reactions of diazadienes 1a,b and alkynyl ketenes
were initially performed following the standard procedure repor-
ted in our previous works15 (method A), by slow addition of a so-
lution of the appropriate acyl chloride (1.1 mmol) in dry toluene to
an ice cooled diluted solution (about 0.085 M) of 1,3-diaza-1,3-di-
ene (1 mmol) and triethylamine (2.3 mmol) in dry toluene. Un-
expectedly, under these conditions the reactions failed or gave very
poor yields (Scheme 5). It has been reported that reaction between
an acid halide and an imine in the presence of triethylamine to give
the azetidinone nuclei only works well if the acid halide have an
Ar = Ph (98%)
Ar = p-Tol (96%)
Overall yield 1a: 50%
MeONa
Ar
MeOH
Ar
N
Ar
N
NH
Ar
N
Ar
Ar
electron-withdrawing substituent in the
a
-position.30a On the
6
Ar = Ph, 1a (51%)
Ar = p-Tol, 1b (43%)
other hand, it has been demonstrated that a suitable choice of the
reaction conditions (solvent, base, temperature, concentration) can
affect both the yields and the stereoselectivity of the cycloaddition
Ar = Ph, p-Tol
Scheme 2.
O
(COCl)2
(73%)
O
CrO3/H2SO4
OH
OH
Cl
(69%)
3a
2a
OH
Cl
OH
CrO3/H2SO4
(79%)
SOCl2
(95%)
O
O
2b
3b
PdCl2(PPh3)2
CuI, Et2NH
R
R
I
OH
OH
Cl
O
(COCl)2
CrO3
R
O
R
H2SO4
R= H (52%)
R= Cl (83%)
2c: R= H (91%)
2d: R= Cl (89%)
3c: R= H (88%)
3d: R = Cl (98%)
Scheme 4.

4666
G. Abbiati et al. / Tetrahedron 65 (2009) 4664–4670
reactions involving base-generated ketenes.30b Thus, better results
were obtained by optimising the reaction conditions suggested by
Vaccaro30b for inactivated ketenes (method B), i.e., by slow addition
of a solution of the acyl chloride (1.5 mmol) in dry toluene to a well
stirred solution of 1,3-diaza-1,3-butadiene (1 mmol) and tributyl-
amine (2.5 mmol) in dry toluene at rt under a nitrogen atmosphere,
as reported in Scheme 5.
Ar
Ar
Ar
H
1
1
Ar
O
N
N
Ar
N
N
C2-attack
C4-attack
2
N
O
3
R
1
4
R
Ar
O
C
4
Ar
N
Ar
Ar
2
3
N
4
H
R
Ar
The reaction of the conjugated alkynyl ketene, obtained in situ
by slow addition of 3a to a toluene solution of 1a in the presence of
2.5 equiv of tributylamine at rt (method B), gave the desired aze-
tidinone 4a in moderate yields. The regiochemical preference of
reactions performed in the presence of conjugated alkynyl ketenes
was confirmed by the results of the cycloaddition reactions with
diazadiene 1b. As previously reported,16 the diastereoselectivity of
this [2þ2] cycloaddition was demonstrated by 1H NMR spectro-
scopic analysis and NOE experiments showing the presence of a
single diastereoisomer with a cis relationship between the benzy-
lideneimino group at C-4 and the hydrogen on C-3. Unexpectedly,
unconjugated ketenes derived from acyl chlorides 3b–d showed
different behaviour. Under standard conditions (method A), the
reaction of 1a with the ketene derived from 3b failed, giving rise to
a complex mixture of unidentified products besides traces of 1-
benzyl-2,4,6-triphenyl-1,2-dihydro-[1,3,5]triazine.31 On the con-
trary, the reaction performed under the new conditions (method B)
resulted in a diastereoisomeric mixture of dihydropyrimidinones
5b(trans) and 50b(cis) in 3:2 ratio. Despite the unsatisfactory re-
action yield, no trace of azetidinone 4b was detected by TLC in the
reaction crude. Moreover, an identical regio- and stereochemical
outcome, but in better yield, was observed by reacting 1a with
ketenes arising from acyl chloride 3c,d.
Ar
Ar
Ar
N
O
O
1
3
2
N
N
3
R
R
4
Ar
5
Ar
Scheme 6.
upon the carbonyl group of ketene, thus leading to the formation of
a zwitterionic intermediate. Subsequent intramolecular attack of
the nucleophilic a-C of carbonyl group on C-2 or C-4 of the diene
system can lead to the formation of
pyrimidinones, respectively (Scheme 6).
b-lactams or dihydro-
Mahajan and co-workers32 have also recently published the
results of ab initio calculations performed on the [2þ2] cycload-
dition reaction between the unsubstituted 1,3-diazabuta-1,3-diene
and ketene that confirm the intermediacy of a zwitterionic com-
pound. Moreover, these results are in concordance with the ab
initio study on the mechanism of imine–ketene cycloaddition
(Staudinger reaction) reported by Sordo,33 which confirmed the
experimental data obtained by Moore and co-workers.19 Finally,
Chemouri and Mekelleche recently reported a theoretical study
dealing with the mechanism and the regiochemistry of the cyclo-
addition of 1,3-diazabuta-1,3-dienes with ketenes using DFT-based
reactivity indexes.34
As reported in the literature,5,13c,e the most widely accepted
mechanism for the cycloaddition reactions of 1,3-diaza-1,3-dienes
and ketenes involves the nucleophilic attack of N-1 of the diene
method A
Ph
Ph
Ph
N
Ph
(5%)
N
N
O
O
+
N
Cl
Cl
Ph
H
method B
(47%)
Ph
4a
3a
1a
p-Tol
p-Tol
p-Tol
N
p-Tol
N
N
O
method B
O
+
N
p-Tol
H
p-Tol
4e (41%)
1b
3a
method A
(0%)
Ph
Ph
Ph
N
Ph
Ph
Cl
Ph
N
O
N
N
+
N
H
O
Ph
method B
H
Ph
1a
3b
5b (trans) (18%)
5'b (cis) (12%)
Ph
N
Ph
N
O
Cl
O
method B
+
N
H
Ar
H
Ph
Ph
Ar
Ar = Ph:
3c,d
1a
5c (trans) (39%), 5'c (cis) (25%)
Ar = p-Cl-Ph:
5d (trans) (42%), 5'd (cis) (26%)
Method A: 1/3/TEA = 1:1.1:2.3, toluene, from 0 °C to rt
Method B: 1/3/TBA = 1:1.5:2.5, toluene, rt.
Scheme 5.

G. Abbiati et al. / Tetrahedron 65 (2009) 4664–4670
4667
With the aim to clarify the different outcome observed by
reacting conjugated versus unconjugated ketenes, the problem was
tentatively approached from a theoretical point of view. The in-
vestigation was restricted to all potential products arising from the
[2þ2] and [4þ2] cycloaddition reaction of diazadiene 1a with
alkynyl ketenes derived from 3a and 3b. We calculated the minima
energies of geometric isomers of azetidinones 4a,b/40a,b and
dihydropyrimidinones 5a,b/50a,b at ground state. The mini-
misations were performed at the DFT level using the B3LYP func-
tional and the 6-31þG(d,p) basis-set.35 Calculations were performed
on isolated molecules in the gas phase and the character of minima was
delocalising the negative charge. As already reported,15 this would
theoretically increase the tendency to give the thermodynamically
controlled cycloadduct. On contrary, we observed an opposite ex-
perimental behaviour. These evidences suggest that the regio-
chemical outcome is not controlled by simple and intuitive
electronic factors. Probably the mode of cyclisation is determined
by steric reasons and/or some kind of specific
p-interaction be-
tween the different alkynyl moieties and the benzylidene frame-
work in the zwitterionic intermediates.
3. Conclusions
confirmed by the absence of imaginary frequencies. Selected
isolated and hypothetical isomers are reported in Table 1.
DE among
In conclusion, two alternative approaches to ‘all-carbon’ 1,3-
diazabuta-1,3-dienes have been reported. Some examples of
regiospecific cycloaddition reactions of these substrates with con-
jugated and unconjugated alkynyl ketenes have been presented.
These reactions gave rise in modest to good yields to some in-
teresting azetidinones and dihydropyrimidinones bearing an
alkynyl moiety susceptible to further modification.
The energetic difference between trans and cis form of both
azetidinones 4a/40a and 4b/40b was very low (0.1 and 0.4 kcal/mol,
respectively, in favour of product cis), according to the statement
thatconfigurational preferencesin such cycloaddition are controlled
by orbital symmetry and torquoselectivity considerations36 rather
than relative stability of isomeric products (entries 1 and 2). The not
isolated cis isomer 50a was slightly favoured over the trans isomer 5a
(
D
Ecis–trans¼ꢀ0.7 kcal/mol), while an opposite relationship was ob-
4. Experimental
served for the couple 5b/50b (derived from the reaction with the
unconjugated ketenes) where the trans isomer 5b was 1 kcal/mol
more stable than 50b, in concordance with the ratio trans/cis¼3:2
experimentally observed (see Scheme 5). Finally, no substantial
4.1. General details
All chemicals and solvents are commercially available and were
used after distillation or treatment with drying agents. Fluka silica
gel F254 thin-layer plates were employed for thin-layer chromato-
graphy (TLC). Davisil silica gel LC 60Awas employed for flash column
chromatography. Melting points, measured with a Stuart Scientific
SMP3 apparatus, are uncorrected. Infrared spectra were recorded on
an FT-IR Perkin Elmer Spectrum One spectrophotometer using KBr
tablets. Proton NMR spectra were recorded at rt in CDCl3, on Varian-
Gemini 200 at 200 MHz, with residual chloroform as the internal
reference (dH¼7.27 ppm). 13C NMR spectra were recorded at rt in
CDCl3, on the same spectrometer, at 50.3 MHz, with the central peak
of chloroform as the internal reference (dC¼77.3 ppm). The APT or
DEPT sequences were used to distinguish the methine and methyl
carbon signals fromthose due to methylene and quaternarycarbons.
Two-dimensional NMR experiments (NOESY) were used, where
appropriate, to aid in the assignment of signals in the proton spectra.
‘PE’ refers tothe fraction of petroleum ether with boiling pointof 40–
60 ꢁC. ‘EtOAc’ means ethyl acetate. TEA means triethylamine. 1,3,5-
Triaryl-2,4-diaza-1,4-pentadienes23,24 (hydrobenzamides), diazadiene
1a,15,23 3-pentynoic acid,35 4-pentynoic acid,27 3-pentynoic acyl
chloride,37 4-pentynoic acyl chloride,38 5-phenyl-4-pentyn-1-ol,29
5-phenyl-4-pentynoic acid22 and 5-phenyl-4-pentynoic acyl chlo-
ride22 are known compounds.
differences were observed among the
isomeric forms of the couples azetidinone/dihydropyrimidinone
40a/5a and 40b/5b: in both cases, the calculated
E were high, con-
DE between the more stable
D
firming that azetidinones can only arise under kinetic control
whereas dihydropyrimidinones are the thermodynamic products.
Despite these computational results providing insights into the
reaction thermodynamics, they were unable to explain the regio-
chemical behaviour observed and probably only an in-depth the-
oretical investigation on the transition states involved could clarify
the relationship between specificity observed and the degree of
conjugation of the ketene, but this is beyond the scope of this paper.
A simple comparison between the structures of the two possible
zwitterions shows that the intermediate derived from the reaction
of azadiene 1a with the ketene 3a could be stabilised by the pres-
ence of a conjugated
p-system on the ketene moiety capable of
Table 1
Selected
D
E (kcal/mol) among isolated and hypothetical isomers
Ph
Ph
Ph
Ph
Ph
N
Ph
Ph
Ph
N
O
Ph
N
O
N
N
N
O
O
N
H
N
H
Ph
Ph
H
H
H
H
Ph
5a (trans)
Ph
4'a (cis)
4.2. Synthesis of hydrobenzamides
4a (trans)
5'a (cis)
Ph
Ph
Ph
Ph
A mixture of benzaldehyde or 4-methyl-benzaldehyde (83.0 mmol)
and aqueous ammonia 30% (60.0 mL) was stirred for 3 days at rt.
The white solid is filtered over a Buchner funnel and dried under vac-
uum over CaCl2.
Ph
Ph
N
O
Ph
N
O
N
N
N
N
O
O
N
H
N
H
Ph
Ph
H
H
H
H
Ph
Ph
4b (trans)
4'b (cis)
5b (trans)
5'b (cis)
4.2.1. 1,3,5-Triphenyl-2,4-diaza-1,4-pentadiene
experimentally isolated products
experimentally unobserved products
Yield 8.09 g, 98%. White solid.
4.2.2. 1,3,5-Tri-(4-methyl-phenyl)-2,4-diaza-1,4-pentadiene
Entry
Compounds
D
Ea
Yield 9.04 g, 96%. White solid.
1
2
3
4
5
6
40a(cis)–4a(trans)
40b(cis)–4b(trans)
50a(cis)–5a(trans)
50b(cis)–5b(trans)
40a(cis)–5a(trans)
40b(cis)–5b(trans)
ꢀ0.1
ꢀ0.4
ꢀ0.7
1.0
13.7
20.0
4.3. Base-promoted prototropic rearrangement of the
hydrobenzamides
The appropriate hydrobenzamide (7 mmol) was stirred for 3
days at 40 ꢁC in 0.5 M sodium methoxide/methanol (20 mL). The
a
ZPE corrected energy differences.

4668
G. Abbiati et al. / Tetrahedron 65 (2009) 4664–4670
solvent was quickly removed under reduced pressure. The residue
was dissolved in EtOAc (20 mL) and washed with NaH2PO4
(2ꢂ20 mL). The organic layer was dried over anhydrous sodium
sulfate and the solvent removed at reduced pressure. To completely
remove the by-product (amarine), the residue was purified through
a rapid flash chromatography over a short silica gel column (eluent:
PE/TEA¼8:2).
was dissolved in water (100 mL) and extracted with diethyl ether
(4ꢂ50 mL). The combined organic layers were washed with water
(50 mL) and the volume was reduced by half under reduced
pressure. Then, the ether solution was extracted with 3 M NaOH
(2ꢂ50 mL). The combined basic solution was cooled and acidified
by dropping 37% HCl. The acidic solution was finally extracted
with diethyl ether (3ꢂ50 mL). The organic layer, dried over so-
dium sulfate, was evaporated to dryness to give yellowish oil. The
acids were sufficiently pure to be transformed into the corre-
sponding acyl chlorides by standard methods without further
purification.
4.3.1. N-Benzyl-N0-benzylidene-benzamidine 1a
Yield 1.06 g, 51%. White-yellowish solid. Mp: 87–90 ꢁC (lit.15 89–
90 ꢁC).
4.3.2. 4-Methyl-N-(4-methyl-benzyl)-N0-(4-methyl-benzylidene)-
4.6.1. 5-(4-Chlorophenyl)-4-pentynoic acid 2d
benzamidine 1b
Yield 89%. Yellow oil. IR (NaCl)
(C–Cl) cmꢀ1. 1H NMR:
¼2.73 (m, 4H, CH2–CH2), 7.31 (m, 4H, arom),
10.50 (br s, 1H, COOH, exchange with D2O) ppm. 13C NMR:
33.6 (CH2), 80.6, 88.8 (C^C),122.1,134.1 (C quat. arom.),128.8,133.1
(CH arom.), 178.6 (C]O) ppm. ESI-MS m/z (%): 209 [Mþþ1] (100).
n
¼3435 (O–H), 1694 (C]O), 1093
Yield 1.02 g, 43%. White solid. Mp: 67–68 ꢁC. IR (KBr)
n
¼1637,
¼2.35 (s, 3H, CH3), 2.39 (s, 3H,
CH3), 2.47 (s, 3H, CH3), 4.59 (s, 2H, CH2), 7.12–7.38 (m, 8H, arom.),
7.76–7.83 (m, 4H, arom.), 8.15 (s, 1H, CH]N) ppm. 13C NMR:
d
1605 (C]C/C]N) cmꢀ1. 1H NMR:
d
d
¼15.3,
d
¼21.4,
21.6, 21.9 (CH3), 53.1 (CH2), 127.9, 128.0, 129.1, 129.2, 129.9 (CH
arom., one signal obscured),132.7,133.5,136.0, 138.6, 140.6,143.3 (C
quat. arom.), 161.9 (CH]N), 164.2 (N–C]N) ppm. C24H24N2
(340.46): calcd C 84.67, H 7.11, N 8.23; found: C 84.58, H 7.05, N 8.28.
4.6.2. 5-(4-Chlorophenyl)-4-pentynoyl chloride 3d
Yield 98%. Light-brown solid. 1H NMR:
d
¼2.80 (t, 2H, CH2,
J¼7.2 Hz), 3.22 (t, 2H, CH2, J¼7.2 Hz), 7.28, 7.34 (AA0BB0 system, 4H,
arom. J¼9.2 Hz) ppm.
4.4. TiCl4 promoted synthesis of 1a
4.7. Reactions of 1,3-diaza-1,3-butadienes 1a,b
with ketenes 3a–d
To a stirred solution of N-benzyl benzamidine (2.0 g, 9.5 mmol),
benzaldehyde (1.1 g, 10.4 mmol) and triethylamine (2.4 g,
23.8 mmol) in dry toluene (56 mL) at 0 ꢁC, a solution of TiCl4
(0.90 g, 4.8 mmol) in dry toluene (18 mL) was slowly added
(90 min) dropwise under a nitrogen atmosphere. After that the
mixture was stirred for additional 5 h at rt. The resulting white-
yellow suspension was rapidly filtered under vacuum over a Celite
pad and the clear liquid was stored in a sealed flask overnight at
4–6 ꢁC. The cold cloudy solution was re-filtered under vacuum over
a well-pressed Celite pad and freed from solvent under reduced
pressure without heating to give 1a. Yield: 2.1 g, 74%. White solid,
mp 88–90 ꢁC.
4.7.1. Method A
A solution of the appropriate acyl chloride (1.1 mmol) in dry
toluene (8 mL) was slowly added (1 h) to a nitrogen flushed, well
stirred and ice-water cooled solution of 1,3-diaza-1,3-butadiene
1a or 1b (1.0 mmol) and triethylamine (2.3 mmol) in dry toluene
(14 mL). After complete addition of the acyl chloride, the reaction
mixture was stirred at 25 ꢁC until no starting material was
detected by TLC analysis. It was then washed with a cold satu-
rated solution of NaHCO3 (1ꢂ70 mL) and cold water (1ꢂ70 mL).
The organic layer was dried over anhydrous sodium sulfate and
freed from solvent under reduced pressure at 40 ꢁC. The crude
product was purified by flash chromatography over silica gel
column.
4.5. Synthesis of 5-aryl-4-pentyn-1-ols
Under a nitrogen atmosphere, a solution of 4-pentyn-1-ol (2.0 g,
23.8 mmol), the appropriate aryl-halide (23.8 mmol), CuI (23 mg,
0.12 mmol) and PdCl2(PPh3)2 (170 mg, 0.24 mmol) in dry diethyl-
amine (40 mL) was stirred overnight at rt, until no more starting
product was detectable by TLC analysis. The excess diethylamine
was removed under reduced pressure, the residue diluted with
brine (150 mL) and extracted with EtOAc (3ꢂ40 mL). The organic
layer, dried over anhydrous sodium sulfate, was evaporated to
dryness and the crude purified by flash chromatography over
a silica gel column (eluent: PE/EtOAc¼8:2).
4.7.2. Method B
A solution of the appropriate acyl chloride (1.5 mmol) in dry
toluene (8 mL) was slowly added (1 h) to a nitrogen flushed, well
stirred solution of 1,3-diaza-1,3-butadiene 1a or 1b (1.0 mmol) and
tributylamine (2.5 mmol) in dry toluene (20 mL) at rt. After com-
plete addition of the acyl chloride, the reaction mixture was stirred
until no starting material was detected by TLC analysis. The reaction
mixture was washed with 1 M HCl (1ꢂ70 mL) and 2 N NH4Cl
(1ꢂ70 mL). The organic layer was dried over anhydrous sodium
sulfate and freed from solvent under reduced pressure at 40 ꢁC. The
crude product was purified by flash chromatography over silica gel
column.
4.5.1. 5-(4-Chlorophenyl)-4-pentyn-1-ol
Yield 3.71 g, 83%. Yellowoil. IR (NaCl)
n
¼3339 (O–H), 2234 (C^C),
1489 (C]C), 1060 (CꢀOH) cmꢀ1. 1H NMR:
¼1.61 (br s, 1H, OH), 1.88
d
(quin., 2H, CH2–CH2 CH2–OH, J¼6.6 Hz), 2.55 (t, 2H, CH2–CH2CH2–
OH, J¼6.6 Hz), 3.84 (t, 2H, CH2–CH2CH2–OH, J¼6.5 Hz), 7.30 (m, 4H,
4.7.3. 1-Benzyl-4-(benzylidene-amino)-4-phenyl-3-prop-1-
ynyl-azetidin-2-one 4a
arom.) ppm. 13C NMR:
128.7, 133.0 (CH arom.), 122.5, 133.8 (C quat. arom.) ppm.
d
¼16.2, 31.5, 61.7 (CH2), 80.3, 90.7 (C^C),
Eluent for chromatography: PE/EtOAc (95:5). Orange oil. IR (KBr)
n
¼1765 (C]O), 1647 (C]C/C]N) cmꢀ1
.
1H NMR:
d
¼1.62 (d, 3H,
CH3, 5J¼2.7 Hz), 3.83 (d, 1H, CH2, 2J¼15.0 Hz), 3.96 (q, 1H, C3H,
5J¼2.7 Hz), 4.84 (d, 1H, CH2, 2J¼15.0 Hz), 7.26–7.64 (m, 15H, arom.),
4.6. General method for the oxidation of alcohols
7.95 (s, 1H, CH]N) ppm. 13C NMR:
d
¼3.9 (CH3), 45.5 (CH2), 58.5
A solution of the appropriate alcohol (15 mmol) in acetone
(50 mL) was added dropwise (2 h) to a cooled solution of Cr2O3
(3.0 g, 30 mmol) in 10 M H2SO4 (37.5 mL), maintaining a temper-
ature of 5–10 ꢁC. The reaction mixture was stirred for additional
2 h at rt. After concentration under reduced pressure, the residue
(C3–H), 70.4 (C4), 86.3, 86.4 (C^C), 128.0, 128.2, 128.5, 128.6, 128.8,
128.9, 129.0, 129.5, 131.8 (CH arom.), 135.4, 136.5, 137.0 (C quat.
arom.), 159.3 (CH]N), 165.6 (C]O) ppm. ESI-MS m/z (%): 379
[Mþþ1] (100). C26H22N2O (378.47): calcd C 82.51, H 5.86, N 7.40;
found: C 82.42, H 5.84, N 7.38.

G. Abbiati et al. / Tetrahedron 65 (2009) 4664–4670
4669
4.7.4. 1-(4-Methyl-benzyl)-4-[(4-methyl-benzylidene)-amino]-3-
prop-1-ynyl-4-(4-methyl-phenyl)-azetidin-2-one 4e
7.54 (m, 18H, arom) ppm. 13C NMR:
d
¼16.5 (CH2–C^C), 44.9 (C5–
H), 47.7 (Ph–CH2), 60.3 (C6–H), 83.2, 86.9 (C^C), 127.9, 128.1, 128.5,
128.6, 128.7, 128.8, 130.4, 131.9 (CH arom., four signals obscured),
123.7, 135.1, 136.5, 136.8 (C quat. arom.), 157.1 (CH]N), 171.2
(C]O) ppm. EIMS m/z (%): 454 [Mþ] (33). C32H26N2O (454.56):
calcd. C 84.55, H 5.77, N 6.16; found: C 84.50, H 5.74, N 6.18.
Eluent for chromatography: PE/TEA (98:2).Yellow oil. IR (KBr)
n
¼1766 (C]O), 1645 (C]C/C]N) cmꢀ1
.
1H NMR:
d
¼1.63 (d, 3H,
C^C–CH3, 5J¼2.7 Hz), 2.32 (s, 3H, CH3), 2.38(s, 3H, CH3), 2.39(s, 3H,
CH3), 3.77 (d, 1H, CH2, 2J¼14.6 Hz), 3.92 (q,1H, C3H, 5J¼2.7 Hz), 4.77
(d, 1H, CH2, 2J¼14.6 Hz), 7.06–7.27 (m, 8H, arom.), 7.42 (m, 4H,
arom.), 7.85 (s, 1H, CH]N) ppm. 13C NMR:
d¼4.0 (C^C–CH3), 21.3,
4.7.9. (trans)-3-Benzyl-5-[3-(4-chlorophenyl)-prop-2-ynyl]-2,6-
diphenyl-5,6-dihydro-3H-pyrimidin-4-one 5d(trans)
21.4, 21.7 (CH3), 45.1 (CH2), 58.3 (C3–H), 70.7 (C4), 80.0, 80.2 (C^C),
128.5,128.9,129.2,129.4,129.5,129.6 (CH arom.),132.9,133.6,133.7,
137.6, 138.4, 142.1 (C quat. arom.) 159.0 (CH]N), 165.6 (C]O) ppm.
C29H28N2O (420.55): calcd C 82.82, H 6.71, N 6.66; found C 82.59, H
6.74, N 6.61.
Eluent for chromatography: PE/TEA (8:2).Yellow oil. IR (KBr)
n
¼
1698 (C]O),1638 (C]C/C]N) cmꢀ1. 1H NMR:
d¼2.32 (dd,1H, CH2–
C^C, 2J¼16.6 Hz, 3J¼4.4 Hz), 2.88 (dt, 1H, C5–H, 3J¼4.4, 12.3 Hz),
3.10 (dd, 1H, CH2–C^C, 2J¼16.6 Hz, 3J¼4.4 Hz), 4.49 (d, 1H, Ph–CH2,
2J¼15.0 Hz), 4.93 (d, 1H, C6–H, 3J¼12.3 Hz), 5.33 (d, 1H, Ph–CH2,
2J¼15.0 Hz), 6.90 (d, 2H, arom., 3J¼6.6 Hz), 7.13 (m, 3H, arom.), 7.26–
4.7.5. (trans)-3-Benzyl-2,6-diphenyl-5-prop-2-ynyl-5,6-dihydro-
3H-pyrimidin-4-one 5b(trans)
7.44 (m, 14H, arom) ppm. 13C NMR:
d
¼18.3 (CH2–C^C), 45.7 (C5–
Eluent for chromatography: PE/TEA (95:5).Yellow oil. IR (KBr)
H), 47.5 (Ph–CH2), 61.5 (C6–H), 81.8, 87.7 (C^C), 127.6, 127.7, 127.9,
128.0, 128.5, 128.7, 128.9, 130.3, 133.2 (CH arom., two signals ob-
scured), 122.2, 134.0, 134.8, 137.4, 140.9 (C quat. arom.), 156.5
(CH]N), 170.9 (C]O) ppm. ESI-MS m/z (%): 489 [Mþþ1] (100).
C32H25ClN2O (489.01): calcd C 78.60, H 5.15, N 5.73; found: C 78.48,
H 5.17, N 5.70.
n
¼1698 (C]O), 1647 (C]C/C]N) cmꢀ1. 1H NMR:
¼2.04–2.20 (m,
d
2H, C^C–H and CH2–C^C), 2.79–2.94 (m, 2H, C5–H and CH2–
C^C), 4.52 (d, 1H, Ph–CH2, 2J¼15.4 Hz), 4.89 (d, 1H, C6–H,
3J¼11.7 Hz), 5.29 (d, 1H, Ph–CH2, 2J¼15.4 Hz), 6.89 (m, 2H, arom.),
7.17–7.49 (m, 13H, arom) ppm. 13C NMR:
d¼17.4 (CH2–C^C), 45.5
(C5–H), 47.4 (Ph–CH2), 61.2 (C6–H), 70.7 (C^C–H), 80.9 (C^C–H),
127.6, 127.7, 127.8, 127.9, 128.4, 128.6, 128.7, 128.9, 130.3 (CH arom.),
134.9, 137.2, 140.8 (C quat. arom.), 156.4 (CH]N), 170.8 (C]O) ppm.
C26H22N2O (378.47): calcd C 82.51, H 5.86, N 7.40; found C 82.65, H
5.89, N 7.37.
4.7.10. (cis)-3-Benzyl-5-[3-(4-chlorophenyl)-prop-2-ynyl]-2,6-
diphenyl-5,6-dihydro-3H-pyrimidin-4-one 50d(cis)
Eluent for chromatography: PE/TEA (8:2).Yellow oil. IR (KBr)
n
¼1699 (C]O), 1639 (C]C/C]N) cmꢀ1
.
1H NMR:
d¼2.32 (dd, 1H,
CH2–C^C, 2J¼17.4 Hz, 3J¼8.4 Hz), 2.86 (dd, 1H, CH2–C^C,
2J¼17.4 Hz, 3J¼6.0 Hz), 3.28 (dt, 1H, C5–H, 3J¼6.0, 8.4 Hz), 4.86 (d,
1H, Ph–CH2, 2J¼15.0 Hz), 4.96 (d, 1H, Ph–CH2, 2J¼15.0 Hz), 5.28 (d,
1H, C6–H, 3J¼6.0 Hz), 6.96 (m, 2H, arom.), 7.21–7.47 (m, 17H,
4.7.6. (cis)-3-Benzyl-2,6-diphenyl-5-prop-2-ynyl-5,6-dihydro-
3H-pyrimidin-4-one 50b(cis)
Eluent for chromatography: PE/TEA (95:5). Yellow oil. IR (KBr)
n
¼1698 (C]O), 1639 (C]C/C]N) cmꢀ1. 1H NMR:
d
¼2.05–2.18 (m,
arom) ppm. 13C NMR:
d¼16.4 (CH2–C^C), 44.9 (C5–H), 47.6 (Ph–
2H, C^C–H and CH2–C^C), 2.62–2.84 (m, 1H, CH2–C^C), 3.20 (dt,
1H, C5–H, 3J¼8.4, 6.2 Hz), 4.86 (d, 1H, Ph–CH2, 2J¼15.0 Hz), 4.96 (d,
1H, Ph–CH2, 2J¼15.0 Hz), 5.24 (1H, C6–H, 3J¼6.2 Hz), 6.92 (m, 2H,
CH2), 60.3 (C6–H), 82.0, 88.0 (C^C), 127.8, 127.9, 128.0, 128.2, 128.5,
128.6, 128.7, 128.8, 128.9, 130.4, 133.1 (CH arom.), 122.2, 134.1, 135.0,
136.6, 136.8 (C quat. arom.), 157.1 (CH]N), 171.1 (C]O) ppm. ESI-
MS m/z (%): 489 [Mþþ1] (100). C32H25ClN2O (489.01): calcd C
78.60, H 5.15, N 5.73; found: C 78.69, H 5.12, N 5.73.
arom.), 7.15–7.66 (m, 13H, arom) ppm. 13C NMR:
d¼15.4 (CH2–
C^C), 44.7 (C5–H), 47.6 (Ph–CH2), 60.1 (C6–H), 70.9 (C^C–H), 81.4
(C^C–H), 127.8, 127.9, 128.4, 128.6, 128.7, 128.8, 128.9, 129.0, 130.4
(CH arom.), 135.1, 136.3, 136.8 (C quat. arom.), 156.9 (CH]N), 170.9
(C]O) ppm. C26H22N2O (378.47): calcd C 82.51, H 5.86, N 7.40;
found C 82.49, H 5.84, N 7.41.
References and notes
1. For some reviews see: (a) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetra-
hedron 2002, 58, 379–471; (b) Barluenga, J.; Tomas, M. Synthesis of Heterocy-
cles from Azadienes. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.;
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2869–2939.
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3. Burger, K.; Penninger, S. Synthesis 1978, 526–528.
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5. Ibnusaud, I.; Padma Malar, E. J.; Sundaram, N. Tetrahedron Lett. 1990, 31, 7357–
7358.
6. (a) Barluenga, J.; Toma`s, M.; Ballestreros, A.; Lopez, L. A. Tetrahedron Lett. 1989,
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4.7.7. (trans)-3-Benzyl-2,6-diphenyl-5-(3-phenyl-prop-2-ynyl)-
5,6-dihydro-3H-pyrimidin-4-one 5c(trans)
Eluent for chromatography: PE/TEA (9:1).Yellow solid. Pf 141–
143 ꢁC. IR (KBr)
d
n
¼1690 (C]O), 1635 (C]C/C]N) cmꢀ1
.
1H NMR:
¼2.39 (dd, 1H, CH2–C^C, 2J¼16.5 Hz, 3J¼4.4 Hz), 2.93 (dt, 1H, C5–
H, 3J¼4.4, 12.1 Hz), 3.18 (dd, 1H, CH2–C^C, 2J¼16.5 Hz, 3J¼4.4 Hz),
4.52 (d, 1H, Ph–CH2, 2J¼15.4 Hz), 5.04 (d, 1H, C6–H, 3J¼12.1 Hz),
5.39 (d, 1H, Ph–CH2, 2J¼15.4 Hz), 6.94 (d, 2H, arom., 3J¼7.0 Hz), 7.13
(m, 3H, arom.), 7.25–7.51 (m, 15H, arom) ppm. 13C NMR:
d¼18.4
(CH2–C^C), 45.8 (C5–H), 47.4 (Ph–CH2), 61.5 (C6–H), 83.1, 86.6
(C^C), 127.6, 127.7, 127.9, 128.1, 128.4, 128.5, 128.7, 128.9, 130.3
132.0 (CH arom., two signals obscured), 123.8, 134.9, 137.4, 141.0 (C
quat. arom.), 156.5 (CH]N), 171.0 (C]O) ppm. ESI-MS m/z (%): 455
[Mþþ1] (35). C32H26N2O (454.56): calcd C 84.55, H 5.77, N 6.16;
found: C 84.68, H 5.79, N 6.19.
4.7.8. (cis)-3-Benzyl-2,6-diphenyl-5-(3-phenyl-prop-2-ynyl)-5,6-
dihydro-3H-pyrimidin-4-one 50c(cis)
Eluent for chromatography: PE/TEA (9:1).Yellow solid. Pf 105–
107 ꢁC. IR (KBr)
d
n
¼1701 (C]O), 1638 (C]C/C]N) cmꢀ1
.
1H NMR:
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}
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