Synthesis of 4-nitromethylene-1,4-dihydropyrimidine derivatives as pyrimidine nucleoside analogues

Article abstract of DOI:10.1016/j.tet.2008.09.079

The synthesis of 4-nitromethylene-1,4-dihydropyrimidine derivatives as pyrimidine nucleoside analogues was developed, starting from 3-nitropyran-2-one N-functionalized amidines. Primary amines were reacted with amidines yielding 4-nitromethylene-1,4-dihydropyrimidine derivatives. In an initial survey, several 4-nitromethylene-1,4-dihydropyrimidines turned into 4-nitromethylene-1,2,3,4-tetrahydropyrimidine derivatives under different reduction conditions. The reduction reaction also induced a change in the exocyclic double bond configuration from (E) to (Z), due to an intramolecular hydrogen bond.

Full text of DOI:10.1016/j.tet.2008.09.079

Tetrahedron 64 (2008) 11067–11073
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 4-nitromethylene-1,4-dihydropyrimidine derivatives as pyrimidine
nucleoside analogues
*
Alessandro Contini, Emanuela Erba, Pasqualina Trimarco
`
Istituto di Chimica Organica ‘A. Marchesini’, Facolta di Farmacia e Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di Sistemi Etero e Carbociclici,
`
Universita degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2008
Received in revised form 8 September 2008
Accepted 25 September 2008
Available online 7 October 2008
The synthesis of 4-nitromethylene-1,4-dihydropyrimidine derivatives as pyrimidine nucleoside ana-
logues was developed, starting from 3-nitropyran-2-one N-functionalized amidines. Primary amines
were reacted with amidines yielding 4-nitromethylene-1,4-dihydropyrimidine derivatives. In an initial
survey, several 4-nitromethylene-1,4-dihydropyrimidines turned into 4-nitromethylene-1,2,3,4-tetrahy-
dropyrimidine derivatives under different reduction conditions. The reduction reaction also induced
a change in the exocyclic double bond configuration from (E) to (Z), due to an intramolecular hydrogen
bond.
Keywords:
3-Nitro-2H-pyran-2-one amidines
4-Nitromethylene-1,4-dihydropyrimidines
Nucleoside analogues
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
triazol-1-yl group displacement of the C-4 activated pyrimidines
with malonate-type C-nucleophiles.2b,4
Nucleosides, fundamental building blocks of biological systems,
are sequentially phosphorylated by kinases into nucleotides, and
the resultant nucleotides are processed by polymerases and
transformed into nucleic acids, the biopolymers carrying the cell
genetic information.
We are interested in pyrimidine nucleoside mimetics modified
at the N-1 and C-2 positions, bearing an extended conjugation
system on C-4, and possessing a set of groups able to act both as
hydrogen bond donors and acceptors towards proteins and nucleic
acids.
It is plain that the search for nucleoside analogues, which act as
selective inhibitors of kinases and polymerases has been the sub-
ject of intense study.
In recent years, several biological activities have been claimed
for pyrimidine and purine analogues of natural bases. For instance,
unnatural nucleoside analogues containing a modified pyrimidine
nucleus have become prime candidates in the search for new an-
tiviral and anticancer agents.1
A survey of the literature revealed that few reports deal with the
synthesis of pyrimidine nucleosides having an extended conjuga-
tion system linked to C-4 in place of the amino or oxo substituents
of naturally occurring nucleosides. These pyrimidine nucleoside
analogues have been studied as potential cytidine deaminase (CDA)
inhibitors to understand the CDA role in antitumour activity.2
Synthetic routes to substituted 4-methylene-dihydropyrimidine
involve approaches based on either (i) the sulfur extrusion reaction
of the corresponding C-4 alkylthio derivatives3 or (ii) the 1,2,4-
At the same time, the present study is included in a research
program related to triacetic acid lactone amidines. Within this
context, we recently developed5 a new method for the synthesis of
4-dialkyaminopyridine derivatives by reacting secondary amines
with acetamidines bearing the 3-nitro-2H-pyran-2-one group
on N-1.
These acetamidines are characterized by three electrophilic
centers: the amidine iminic carbon,6 C-2 and C-6 of the pyran-
2-one ring7 in which the latter is highly susceptible to nucleophilic
attack due to the extended conjugation, and the presence of an
electron-withdrawing substituent at the C-3 position.8
Both open-chain intermediates, directly arising from the open-
ing of 2H-pyran-2-one by nucleophiles, and the combined
reactivity of the amidine iminic carbon exhibit a strong tendency to
cyclize into a new heterocyclic system.9
Thus, the above observations and the described success in
synthesizing 4-dialkyaminopyridine derivatives prompted us to
exploit the behaviour of 3-nitro-2H-pyran-2-one acetamidines and
primary amines with the purpose of building pyrimidine nucleo-
side mimetics bearing a NO2 conjugated system on C-4.
We now wish to report an approach for the synthesis of C-4
substituted 4-nitromethylene-1,4-dihydropyrimidine derivatives
* Corresponding author. Tel.: þ39 02 50314475; fax: þ39 02 50314476.
E-mail address: pasqualina.trimarco@unimi.it (P. Trimarco).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.079

11068
A. Contini et al. / Tetrahedron 64 (2008) 11067–11073
Table 1
based on the combined nucleophilic feature of both the 3-nitro-2H-
pyran-2-one moiety and the amidine imino group.
In order to study the polyfunctional character of the 4-nitro-
methylene-1,4-dihydropyrimidine derivatives we focused on a re-
duction reaction to explore the effects of the substituents.
Synthesis of 4-nitromethylene-1,4-dihydropyrimidine 4 and 4-morpholinopyridine
5 from amidines 3
O
H
N
NO2
H
O
N
O2N
O
H2NR2
EtOH
+
N
N
CH3
N
CH3
N
2. Results and discussion
R1
R1
O
R2
NO2
R1
4-Chloro-3-nitro-2H-pyran-2-one 1 was reacted with sodium
azide and suitable enamines 2a–c in a chilled DMF solution yielding
amidines 3a–c. The low inner temperature (ꢀ50 ꢁC) avoided the
known azide transformation into the 6-methyl-4H-pyrano[3,4-c]
[1,2,5]oxadiazol-4-one 3-oxide5 and allowed the isolation of the
amidines 3a–c, as already described. The unsuccessful isolation of
the 4,5-dihydro-triazole B is due to the electron-withdrawing effect
of the N-1 substituent,10 which facilitates the cleavage of the N1–N2
bond and promotes the amidine rearrangement (Scheme 1).
3a-c
4a-j
5a-b
R1
Ph
Et
5
a
b
R1
Ph
Et
4
R1
R2
3
a
b
c
a
b
c
d
Ph
Ph
Ph
Ph
Ph
CH2Ph
Et
Et
Et
CH2Ph
Pr
4-CH3OPh
CH2CH2OH
C6H10OH
CH2Ph
CH2Ph
CH2CH2OH
C6H10OH
CH2Ph
e
f
g
h
i
Cl
N3
O
R1
H
H
NO2
O
NO2
NaN3/DMF
- 40 °C
j
+
Ph
CH2COOCH3
NR2
O
1
H3C
2a-c
O
H3C
Amidines 3
NH2R2
t (h)
Yields of isolated
products (%)
A
- 50 °C
3a
3a
3a
3a
3a
3c
3b
3b
3b
3a
R2¼CH2Ph
2
3
20
2
8
4
2
2
4
6
4a (72)
4b (60)
4c (65)
4d (85)
4e (65), 5a (5)
4f (56)
4g (71)
R1
2, 3
NR2
R2¼CH2CH2CH3
R2¼4-CH3OPh
R2¼CH2CH2OH
R2¼C6H10OH
R2¼CH2Ph
morpholine
morpholine
morpholine
a
b
c
Ph
Et
CH2Ph
R1
N
O
R2¼CH2Ph
R2¼CH2CH2OH
R2¼C6H10OH
R2¼CH2COOCH3
4h (72)
N
O2N
R2N
4ia (40), 5b (35)
4jb (78)
N
O
O2N
CH3
3a-c
N
a
After 48 h at room temperature the yield is 83%: see Section 2.
CH2Cl2, 35 ꢁC: see Section 4.
b
O
O
CH3
R2N
R1
B
Scheme 1. Synthesis of the amidines 3a–c.
experiment only displayed a correlation between the singlets at
2.82 (CH3 linked to C-6) and 8.02, thus validating both the CH-5
attribution and the exocyclic double bond (E) configuration.
The formation of the substituted 1,4-dihydropyrimidine 4a is
rationalized as shown in Scheme 3.
With the aim to synthesize 4-nitromethylene-1,4-dihydropyr-
imidine derivatives we performed a preliminary experiment by
heating amidine 3a in an ethanol solution at 50 ꢁC with an equi-
molar amount of benzylamine (Scheme 2). In about 2 h the starting
materials turned into the expected 1,4-dihydropyrimidine de-
rivative 4a in good yield (Table 1).
d
Amidine 3a, by reacting with a primary amine, underwent
a nucleophilic attack at C-6 of the pyran-2-one ring, followed by
ring opening to give the labile intermediate D. Subsequent nucle-
ophilic addition to the amidine imino group provided 4-nitro-
methylene-1,4-dihydropyrimidine 4a, due to secondary amine
elimination. This result matches with previously reported data.5
Indeed, the strong electron-withdrawing group at the C-3 position
of the pyran-2-one moiety enhances the reactivity towards nucle-
ophiles at the C-6 site.8
Continuing our research we attempted to extend the above
protocol to variously substituted amidines. For this purpose ami-
dines 3b, 3c were reacted with several amines and the results are
summarized in Table 1.
In most cases the expected 1,4-dihydropyrimidine derivatives
were obtained in satisfactory yield and in a short reaction time.
Standard reaction conditions did not enable us to reach the 1,4-
dihydropyrimidine derivative 4j. When glycine methyl ester hy-
drochloride, previously deprotected by TEA in CH2Cl2 solution, was
reacted with amidine 3a in ethanol solution, at 50 ꢁC or at room
temperature, intractable mixtures were only recovered. However,
the 1,4-dihydropyrimidine derivative 4j was easily achieved by
performing the reaction of the amidine 3a with the deprotected
glycine ester in CH2Cl2 solution at 35 ꢁC (see Section 4).
O
H
N
NO2
O2N
O
3
5
H
H2NCH2Ph
EtOH, 50 °C
72%
4
CH3
N
N
2
1
6
N
CH3
Ph
O
CH2Ph
Ph
3a
(E) 4a
Scheme 2. Synthesis of 4-nitromethylene-1,4-dihydropyrimidine 4a.
The structure of compound 4a was initially deduced from
spectroscopic data. The protons and carbons in the 1H and 13C NMR
spectra were assigned using two-dimensional experiments per-
formed in CDCl3 solution. An HSQC experiment validated the at-
tribution of CH2–N (
on C-6 ( 2.28, 20.7), and allowed the attribution of the signals
related to the vinylic CH ( 7.16, 118.4) and H-5 of the 1,4-dihy-
dropyrimidine ring (
8.02, 109.7).11 Quaternary carbons were
assigned from the results of the HMBC experiments.
The high frequency signal related to H-5 ( 8.02) shows that the
CH-5 is cis-oriented to the nitro group.12 Moreover, a NOESY
d 5.08, 51.1), CH2 on C-2 (d 3.99, 42.1) and CH3
d
d
d
d

A. Contini et al. / Tetrahedron 64 (2008) 11067–11073
11069
NO2
O
NHR2
H
O2N
H2C
R1
O
R2NH2
–CO2
N
R2HN
N
N
N
CH3
O
CH3
N
N
NO2
R1
O
O
R1
3
D
E
R2NH2
HN
O
+
NO2
NO2
H
O
N
O
O
N
N
HN
N
N
CH3
N
CH3
N
R2
R1
H
R2
R1
R1
NO2
F
5
4
Scheme 3. Suggested mechanism for the formation of 4 and 5.
The amidines 3a, 3b reacted with trans-2-aminocyclohexanol
Under different reaction conditions 4a and 4d always turned
into 1,2,3,4-tetrahydropyrimidine derivatives 6a and 6b, re-
spectively. Results are reported in Table 2 and yields are related to
purified products.
under standard conditions (50 ꢁC) also showed
behaviour.
a different
After 8 h, the reaction mixture of the amidine 3a and trans-
2-aminocyclohexanol provided the substituted 1,4-dihydropyr-
imidine 4e and the 4-morpholinopyridine derivative 5a in 65%
and 5% yield, respectively. On the other hand, the reaction
mixture, arising from the amidine 3b (R1¼ethyl group) and trans-
2-aminocyclohexanol, gave the expected 1,4-dihydropyrimidine
derivative 4i in 4 h in about 40% yield, in addition to a consid-
erable amount of the substituted 4-morpholinopyridine 5b (35%)
as by-product. The structures of 5a, 5b were validated by com-
paring 1H NMR (C6D6) spectra of authentic samples previously
achieved.5
As it can be seen in Table 2, the best results were achieved by
reacting 1,4-dihydropyrimidine derivatives 4a, 4d with a large
amount of NaBH4, while the palladium on charcoal did not in-
fluence the reaction. Smaller amounts of NaBH4 left some of the
starting 1,4-dihydropyrimidine compound 4a in an incomplete
reaction. No better results were obtained by using LiAlH4 for de-
rivative 4a, while the catalytic hydrogenation reaction carried out
on 4d allowed to isolate 6b in low yield (about 20%), while no other
identifiable compounds were isolated from the crude reaction
product.
It can be reasonably assumed that the formation of 4 and 5
(Scheme 3) depends on the same transient intermediate D, through
cyclization and morpholine loss. Morpholine elimination in the
intermediate F gives rise to 1,4-dihydropyrimidine derivative 4i
and promotes the amine exchange in intermediate E. The amine
competition, favoured by temperature, could explain the un-
satisfactory yield of the 1,4-dihydropyrimidine 4i.
Indeed, the expected 1,4-dihydropyrimidine 4i was obtained as
the only product in 48 h and with about 80% yield by conducting
the reaction of 3b and trans-2-aminocyclohexanol at room
temperature.
The structures of the new compounds 4b–j were validated by
spectroscopic analysis and are in accordance with data previously
reported for the 1,4-dihydropyrimidine derivative 4a. All the ana-
lytical and spectroscopic data of compounds 4b–j also supported
the (E) steric arrangement previously observed for derivative 4a.
4-Nitromethylene-1,4-dihydropyrimidine derivatives 4 share
with substituted amidines two nitrogen atoms at the 1,3-position of
an allylic system. This atom set confers a strong basic character,
thus allowing N-protonation to give amidinium cations stabilized
by resonance.13 This feature could reasonably provide derivatives 4
with additional binding properties towards proteins and nucleic
acids.14 Such imino conjugated nitromethylene substituted com-
pounds can be thus considered a convenient starting material for
further synthetic modifications, prompting us to explore further
structural changes.
Table 2
Reaction of 1,4-dihydropyrimidines 4a and 4d with reducing agents: effect of the
experimental condition on 6a, 6b yields
H
H
NO2
H
O2N
H
red
HN
N
R1
R1
N
CH3
N
CH3
H
R2
R2
(E) 4a, 4d
(Z) 6a-b
4
R1 R2
Ph CH2Ph
Ph CH2CH2OH
6
R1 R2
Ph CH2Ph
Ph CH2CH2OH
a
d
a
b
1,4-Dihydropyrimidine 4
Experimental conditions
Yields of
isolated
products(%)
4a
4a
NaBH4 4 equiv, MeOH
NaBH4 4 equiv, 0.1 equiv Pd10%C,
MeOH
NaBH4 6 equiv, MeOH
NaBH4 6 equiv, 0.1 equiv Pd10%C,
MeOH
6a (30), 4a (10)
6a (30), 4a (10)
4a
4a
6a (60)
6a (55)
4a
4d
4d
LiAlH4 4 equiv, THF
H2/10%Pd/C, EtOH
NaBH4 6 equiv, MeOH
6a (50)
6b (20)
6b (55)
Therefore we carried out a preliminary study by undertaking
reduction reactions of the 4-nitromethylene-1,4-dihydropyr-
imidines 4a and 4d.

11070
A. Contini et al. / Tetrahedron 64 (2008) 11067–11073
Generally, the different adopted experimental conditions never
3. Conclusions
affected the nature of the major product. In all the selected cases,
the reduction occurred on the amidinic C-2]C-3 double bond,
affording 4-nitromethylene-1,2,3,4-tetrahydropyrimidines 6a, 6b
as the only detected products.
Although the exocyclic double bond of the 4-nitromethylene-
1,4-dihydropyrimidines 4a, 4d had the (E) configuration, the
4-nitromethylene-1,2,3,4-tetrahydropyrimidines 6a, 6b were ex-
clusively detected as the (Z) isomers.
We have described the preparation of 4-nitromethylene-1,4-
dihydropyrimidine derivatives 4 as pyrimidine nucleoside ana-
logues through a one-pot reaction between amidines 3 and primary
amines, adding further proof of the utility of substituted 2H-pyran-
2-one acetamidines as building blocks in organic synthesis.
We have reported the preparation of several 4-nitromethylene-
1,2,3,4-tetrahydropyrimidine derivatives 6 through reduction re-
actions of the derivatives 4.
The structure assignment for compounds 6a, 6b is based on the
literature data available for similar substitution patterns,15 and on
the spectroscopic data collected for the 1,2,3,4-tetrahydropyr-
imidine derivative 6a.
4. Experimental
4.1. General
The 1H NMR spectrum of 1,2-dibenzyl-6-methyl-4-(nitro-
methylene)-1,2,3,4-tetrahydropyrimidine 6a (CDCl3 at 300 MHz)
showed two doublets at
d
3.77 and 4.54 (J¼16.5 Hz), two sets of
3.03 and 3.16 (J¼13.1, 7.1, 6.5 Hz)16 and a complex
Melting points were determined using a Buchi 510 (capillary) or
an Electrothermal 9100 apparatus and are uncorrected. IR spectra
were measured using Perkin–Elmer FT-IR 16 P.C. (Nujol) and Per-
kin–Elmer FT-IR ‘Spectrum One’ (KBr, CHCl3 spectroscopic grade)
spectrometers. 1H and 13C NMR spectra were recorded on a Varian
Mercury 200 MHz or on a Bruker Avance 300 or on Bruker Avance
500 spectrometer in CDCl3 solution, unless otherwise stated.
Chemical shifts are expressed in parts per million from internal
signals at
d
multiplet at
d
4.86. Three singlets at d 2.09, 4.96, 6.58 and an ex-
changeable proton signal at
observed. The latter signal was also validated by the IR (CHCl3)
stretching at 3254 cmꢀ1
d 9.91, related to the NH, were also
.
The protons, carbons and the exocyclic double bond stereo-
chemistry assignments were made by two-dimensional NMR
experiments. An HSQC experiment allowed the attribution of the
standard tetramethylsilane (d) and coupling constants (J) are given
CH-2 (
d
4.86, 69.8), the CH-5 (
d 4.96, 92.5) and the nitromethylene
in hertz. Mass spectroscopy data (MS) were obtained by electron
impact ionization (EI) (70 eV) on ThermoQuest MD 800 or by
electrospray ionization (ESI) on ThermoFinnigan ‘LCQ Advantage’.
Column chromatography was performed on Kieselgel 60 (Merck)
0.063–0.200 mm with eluants and ratios indicated below.
Materials. Enamines 2a,20 2b,21 2c22 are known compounds. 4-
Chloro-3-nitro-2H-pyran-2-one 1 and amidines 3a–c have already
been described.5
proton (C]CH–NO2,
The quaternary carbon was assigned from the results of an
HMBC experiment.
The NOESY experiment displayed spatial proximity between the
H-2 (d 4.86) and both the CH2 linked to C-2 (d 3.03 and 3.16) and
benzyl CH2 on N-1 (
changeable proton at
spatial proximity of the CH-5 (
d
6.58, 106.6).
d
3.77 and 4.54) as well as with the NH ex-
9.91. A positive Overhauser effect proved the
d
d
4.96) to the methyl group (
d
2.09)
on C-6 as well as to the exocyclic H signal (
d 6.58), thus validating
the double bond (Z) configuration.
4.2. Deprotection procedure for trans-2-aminocyclohexanol
hydrochloride
1H and 13C NMR data recorded in C6D6 (see Section 4) and
related 1,2,3,4-tetrahydropyrimidine derivative 6a supported in all
cases the reported structure.
To a vigorously stirred solution of NaOMe in MeOH (0.070 g,
3 mmol of Na in 6 mL of MeOH) was added trans-2-amino-
cyclohexanol hydrochloride (0.365 g, 2.4 mmol).The mixture was
stirred for 1 h at room temperature. The precipitated NaCl was
removed by filtration through Celite and the filter cake was rinsed
with MeOH (5 mL). The solvent was removed under reduced
pressure to provide trans-2-aminocyclohexanol, which was suffi-
ciently pure for the next step.
The experimental results can be rationalized as depicted in
Scheme 4.
Both catalytic hydrogenation and chemical reduction by NaBH4
gave rise to the labile intermediate G as the (E) isomer. Ethanol or
methanol, polar solvents, favouring the tautomeric equilibrium17
between species G and H, promoted the achievement of the (Z)
isomer.
Imino amidine bond reduction is uncommon up to date,18 and
hitherto available reactions involve reductive cleavage of amidi-
nes.18a The reported results highlight the weight of the NO2 group
over both the reduction site of the 1,4-dihydropyrimidine com-
pounds 4 and the stereochemistry of the resulting 1,2,3,4-tetrahy-
dropyrimidine derivatives 6. The conjugated nitromethylene group
enhances the reactivity at the imino bond, favouring the reduction
reaction. The exclusive formation of the (Z) isomer is due to a strong
stabilization by an intramolecular hydrogen bond, and it is known
4.3. General procedure for the synthesis of 4-
(nitromethylene)-1,4-dihydropyrimidine 4a–i
Amidines 3a–c (2 mmol) suspended in ethanol (20 mL) with an
equimolar amount of the suitable amine were put in a preheated oil
bath at 50 ꢁC. The reaction mixture was heated for the reaction
times indicated in Table 1 until disappearance (TLC monitoring) of
the starting amidine.
to occur with other b
-amino derivatives of nitroolefins.4,19,15b
H
H
O2N
H
NO2
H
NO2
H
H
H
O2N
H
H
red
HN
H
HN
N
N
CH3
N
R2
N
R2
CH3
R1
R1
H
N
R2
CH3
H
N
R2
R1
CH3
4(E)
H
R1
6(Z)
G
Scheme 4. Suggested mechanism for the formation of 6.

A. Contini et al. / Tetrahedron 64 (2008) 11067–11073
11071
The workup of the reaction mixture was strongly dependent on
amine and amidine used. Therefore we describe separately the
workup of the reaction mixtures obtained.
(2H, m, CH2N), 4.27 (s, 2H, CH2C6H5), 5.25 (1H, t, J¼5.5 Hz, OH ex-
changeable), 6.76 (1H, s, HC]), 7.19–7.39 (5H, m, ArH), 7.86 (1H, s,
H-5); 13C NMR (50 MHz, DMSO-d6)
d 21.2 (CH3), 41.1 (CH2C6H5),
Method A. The mixture was cooled to room temperature to give
a solid product, which was recrystallized from ethanol to afford
pure the 1,4-dihydropyrimidine derivatives 4a or 4d, respectively.
Method B. The solvent was removed in vacuo and the crude
residue was purified through a short silica gel column (eluant in-
dicated later) affording 1,4-dihydropyrimidine derivatives 4b as
a thick orange oil and 4c, 4f, 4g, 4h afterwards recrystallized from
iPr2O. The crude reaction mixtures arising from amidines 3a and 3b
reacting with trans-2-aminocyclohexanol were instead separated
by silica gel column (eluant indicated later) giving a first fraction
containing the compounds 4e and 4i, and a second fraction
containing the pyriridine derivatives 5a and 5b,5 respectively, as
a minor product. Both derivatives 4e and 4i were crystallized as
indicated. 1H NMR (C6D6) for 5a and 5b were in accordance with the
corresponding data of authentical samples previously obtained.5
50.8 (NCH2), 60.2 (HOCH2), 109.2 (CH-5), 115.3 (HC]), 127.7, 129.3,
129.4 (ArCH), 136.0 (ArCqu), 155.5 (C-6), 157.2 (C-4), 161.0 (C-2);
ESI-MS: m/z (% relative intensity): 310 [MþNa] (18), 288 [Mþ1]
(100), 242 [Mþ1ꢀ46, NO2] (45). Anal. Calcd for C15H17N3O3: C,
62.71; H, 5.96; N, 14.63. Found: C, 62.56; H, 5.92; N, 14.52.
4.3.5. (E)-2-(2-Benzyl-6-methyl-4-(nitromethylene)pyrimidin-
1(4H)-yl)cyclohexanol 4e
EtOAc/methanol, 95:5; deep yellow powder from ethanol, mp
238 ꢁC; IR nmax (KBr) 3399 (OH), 1627 (C]N), 1551 (NO2) cmꢀ1; 1H
NMR (200 MHz, DMSO-d6)
d 0.60–2.20 (8H, m, CH2 CH2 CH2 CH2),
2.55 (3H, s, CH3), 3.86–4.00 (1H, m, CHOH), 4.06–4.38 (1H, m, CHN-
1), 4.17 and 4.54 (2H, 2ꢂd, J¼15.4 Hz, CH2C6H5), 5.45 (1H, d,
J¼5.5 Hz, OH exchangeable), 6.81 (1H, s, HC]), 7.16–7.40 (5H, m,
ArH), 7.81 (1H, s, H-5); 13C NMR (50 MHz, DMSO-d6)
d 22.7 (CH3),
24.2, 25.8, 30.2, 36.4 (4ꢂCH2), 43.7 (CH2C6H5), 69.3 (CHN-1), 69.5
(CHOH), 111.1 (CH-5), 115.2 (HC]), 129.0, 129.6, 129.7 (Ar–CH),
136.2 (ArCqu), 155.2 (C-6), 156.7 (C-4), 162.0 (C-2); ESI-MS: m/z (%
relative intensity): 364 [MþNa] (28), 342 [Mþ1] (100), 296
[Mþ1ꢀ46, NO2] (30). Anal. Calcd for C19H23N3O3: C, 66.84; H, 6.79;
N, 12.31. Found: C, 66.89; H, 6.68; N, 12.20.
4.3.1. (E)-1,2-Dibenzyl-6-methyl-4-(nitromethylene)-1,4-
dihydropyrimidine 4a
Yellow powder from ethanol, mp 150 ꢁC; IR nmax (KBr) 1629
(C]N), 1546 (NO2) cmꢀ1
;
1H NMR (300 MHz)
d
2.28 (3H, s, CH3),
3.99 (2H, s, CH2C6H5), 5.08 (2H, s, NCH2C6H5), 6.98–7.44 (10H, m,
ArH), 7.16 (1H, s, HC]), 8.02 (1H, s, H-5); 13C NMR (75 MHz)
20.7
d
(CH3), 42.1 (CH2C6H5), 51.1 (NCH2C6H5), 109.7 (CH-5), 118.4 (HC]),
125.2, 128.2, 128.5, 129.0, 129.7, 130.1 (ArCH), 134.1, 134.5 (ArCqu),
151.9 (C-6), 156.1 (C-4), 159.6 (C-2); (EI): m/z (% relative intensity)
333 [Mþ] (15), 287 [MþꢀNO2] (12), 197 (13), 91 (100). Anal. Calcd
for C20H19N3O2: C, 72.05; H, 5.74; N, 12.60. Found: C, 71.85; H, 5.74;
N, 12.44.
4.3.6. (E)-1-Benzyl-6-methyl-4-(nitromethylene)-2-phenethyl-1,4-
dihydropyrimidine 4f
CH2Cl2/Et2O,1:1; pale nut crystals from iPr2O, mp 125 ꢁC; IR nmax
(Nujol) 1625 (C]N), 1552 (NO2) cmꢀ1 1H NMR (200 MHz)
; d 2.27
(3H, s, CH3), 2.89–2.97 and 3.03–3.11 (4H, 2ꢂm, CH2CH2C6H5), 5.07
(s, 2H, NCH2C6H5), 6.90–7.42 (11H, m, ArHþHC]), 7.95 (1H, s, H-5);
13C NMR (50 MHz)
d 20.6 (CH3), 32.7 (CH2CH2C6H5), 35.8
4.3.2. (E)-2-Benzyl-6-methyl-4-(nitromethylene)-1-propyl-1,4-
dihydropyrimidine 4b
(CH2CH2C6H5), 50.8 (NCH2C6H5), 109.5 (CH-5), 117.5 (HC]), 125.1,
126.7, 128.7, 128.8, 129.9 (10ꢂArCH), 133.9, 140.2 (ArCqu), 152.0
(C-6), 156.4 (C-4), 160.3 (C-2); ESI-MS: m/z (% relative intensity):
348 [Mþ1] (100), 302 [Mþ1ꢀ46, NO2] (100). Anal. Calcd for
C21H21N3O2: C, 72.60; H, 6.09; N, 12.10. Found: C, 72.43; H, 6.16; N,
12.07.
AcOEt/cyclohexane, 8:2; thick orange oil; IR nmax (KBr) 1630
(C]N), 1553 (NO2) cmꢀ1
and 7.7 Hz, CH3CH2), 1.48 (2H, sex, J¼7.3 and 7.7 Hz, CH3CH2), 2.31
(3H, s, CH3), 3.68–3.80 (2H, m, CH2N), 4.08 (2H, s, CH2C6H5), 6.93
(1H, s, HC]), 7.15–7.31 (5H, m, ArH), 7.84 (1H, s, H-5); 13C NMR
;
1H NMR (200 MHz)
d
0.86 (3H, t, J¼7.3
(50 MHz)
d
11.2 (CH3CH2CH2), 20.3 (CH3), 23.6 (CH3CH2CH2), 42.0
4.3.7. (E)-1-Benzyl-6-methyl-4-(nitromethylene)-2-propyl-1,4-
dihydropyrimidine 4g
(CH2C6H5), 50.0 (CH3CH2CH2N), 110.0 (CH-5), 117.3 (HC]), 128.0,
128.5, 129.0, 129.4 (ArCH), 134.7 (ArCqu), 151.7 (C-6), 156.5 (C-4),
159.0 (C-2); ESI-MS: m/z (% relative intensity): 308 [MþNa] (100),
286 [Mþ1] (92), 242 [Mþ1ꢀ46, NO2] (39). Anal. Calcd for
C16H19N3O2: C, 67.35; H, 6.71; N, 14.73. Found: C, 67.17; H, 6.61; N,
14.62.
CH2Cl2/Et2O,1:1; pale nut powder from iPr2O, mp 148 ꢁC; IR nmax
(Nujol) 1620 (C]N), 1540 (NO2) cmꢀ1 1H NMR (200 MHz)
; d 0.94
(3H, t, J¼7.0 Hz, CH3CH2), 1.62–1.82 (2H, m, CH3CH2), 2.29 (3H, s,
CH3), 2.56–2.64 (2H, m, CH2 on C-2), 5.19 (2H, s, NCH2C6H5), 7.04
(1H, s, HC]), 6.97–7.07 and 7.34–7.42 (5H, 2ꢂm, ArH), 7.94 (1H, s,
H-5); 13C NMR (50 MHz)
d 13.8 (CH3), 20.3 (CH3CH2CH2), 20.6 (CH3),
4.3.3. (E)-2-Benzyl-1-(4-methoxyphenyl)-6-methyl-4-
(nitromethylene)-1,4-dihydropyrimidine 4c
36.3 (CH2 on C-2), 50.9 (NCH2C6H5), 109.5 (CH-5), 117.3 (HC]),
125.1, 128.7, 129.8 (ArCH), 134.1 (ArCqu), 152.2 (C-6), 156.7 (C-4),
161.2 (C-2); ESI-MS: m/z (% relative intensity): 308 [MþNa] (100),
286 [Mþ1] (12), 240 [Mþ1ꢀ46, NO2] (100). Anal. Calcd for
C16H19N3O2: C, 67.35; H, 6.71; N, 14.73. Found: C, 67.45; H, 6.62; N,
14.60.
i
AcOEt/cyclohexane, 7:3; beige amorphous powder from Pr2O,
mp 118 ꢁC; IR nmax (KBr) 1639 (C]N), 1553 (NO2) cmꢀ1 1H NMR
;
(200 MHz, C6D6)
CH2C6H5), 6.40 and 6.54 (4H, J¼8.8 Hz, ArH), 6.80–7.02 (5H, m,
ArH), 7.63 (1H, s, HC]), 8.08 (1H, s, H-5); 13C NMR (50 MHz)
21.4
d 1.31 (3H, s, CH3), 3.13 (s, 3H, OCH3), 3.55 (2H, s,
d
(CH3), 42.1 (CH2C6H5), 55.9 (OCH3), 108.0 (CH-5), 118.3 (HC]),
115.3, 127.4, 128.7, 128.8, 129.2 (ArCH), 129.8, 134.9 (ArCqu), 152.3
(C-6), 156.3 (C-4), 159.5 (ArCOCH3), 160.8 (C-2); ESI-MS: m/z (%
relative intensity): 350 [Mþ1] (100), 304[Mþ1ꢀ46, NO2] (4). Anal.
Calcd for C20H19N3O3: C, 68.75; H, 5.48; N,12.03. Found: C, 68.64; H,
5.33; N, 12.12.
4.3.8. (E)-2-(6-Methyl-4-(nitromethylene)-2-propylpyrimidin-
1(4H)-yl)ethanol 4h
CH3CN/CH3OH, 95:5; pale orange powder from iPr2O, mp
143 ꢁC; IR nmax (Nujol) 1620 (C]N), 1540 (NO2) cmꢀ1 1H NMR
;
(200 MHz, DMSO-d6)
d
0.94 (3H, t, J¼7.3 Hz, CH3CH2CH2), 1.66 (2H,
sex, J¼7.3 and 7.7 Hz, CH3CH2CH2), 2.47 (3H, s, CH3), 2.83 (2H, t,
J¼7.7 Hz, CH2 on C-2), 3.64–3.72 (2H, m, CH2OH), 4.11–4.17 (2H, m,
CH2N), 5.16 (1H, t, J¼5.5 Hz, OH exchangeable), 6.75 (1H, s, HC]),
4.3.4. (E)-2-(2-Benzyl-6-methyl-4-(nitromethylene)pyrimidin-
1(4H)-yl)ethanol 4d
7.84 (1H, s, H-5); 13C NMR (50 MHz, DMSO-d6)
d 14.1 (CH3CH2CH2),
Deep yellow powder from ethanol, mp 205 ꢁC; IR nmax (KBr)
20.4 (CH3CH2CH2), 21.3 (CH3), 36.1 (CH2 on C-2), 50.3 (NCH2), 60.1
(HOCH2), 108.8 (CH-5), 115.1 (HC]), 155.1 (C-6), 157.3 (C-4), 162.3
(C-2); ESI-MS: m/z (% relative intensity): 262 [MþNa] (32), 240
3308 (OH), 1624 (C]N), 1547 (NO2) cmꢀ1 1H NMR (200 MHz,
;
DMSO-d6)
d 2.47 (3H, s, CH3), 3.62–3.72 (2H, m, CH2OH), 4.05–4.12

11072
A. Contini et al. / Tetrahedron 64 (2008) 11067–11073
[Mþ1] (100), 194 [Mþ1ꢀ46, NO2] (23). Anal. Calcd for C11H17N3O3:
(300 MHz)
d
2.09 (3H, s, CH3), 3.03 and 3.16 (2H, 2ꢂdd, J¼13.1, 7.1,
C, 55.22; H, 7.16; N, 17.56. Found: C, 55.18; H, 7.27; N, 17.42.
6.5 Hz, CH2C6H5), 3.77 and 4.54 (2H, 2ꢂd, J¼16.5 Hz, NCH2C6H5),
4.86 (1H, m, H-2), 4.96 (1H, s, H-5), 6.58 (1H, s, HC]), 7.08–7.40
(10H, m, ArH), 9.91 (1H, br s exchangeable, NH); 1H NMR (500 MHz,
4.3.9. (E)-2-(6-Methyl-4-(nitromethylene)-2-propylpyrimidin-
1(4H)-yl)cyclohexanol 4i
C6D6)
d
1.36 (3H, s, CH3), 2.69 and 2.87 (2H, 2ꢂdd, J¼12.9, 7.7,
Yellow powder from ethanol, mp 178 ꢁC; IR nmax (Nujol) 3330
5.8 Hz, CH2C6H5), 3.25 and 3.86 (2H, 2ꢂd, J¼16.6 Hz, NCH2C6H5),
4.36–4.40 (1H, m, H-2), 4.44 (1H, s, H-5), 6.80 (1H, s, HC]), 6.85–
7.26 (10H, m, ArH), 10.05 (1H, br s exchangeable, NH); 13C NMR
(OH),1620 (C]N),1550 (NO2) cmꢀ1; 1H (300 MHz, DMSO-d6)
d 0.94
(3H, t, J¼7.3 Hz, CH3CH2CH2), 1.25–1.42 (2H, m, CH2 ring), 1.71–1.81
and 1.99–2.07 (8H, 2ꢂm, CH2 CH2 CH2 ringþCH3CH2), 2.58 (3H, s,
CH3 on C-6), 2.87 (2H, t, J¼7.3 Hz, CH2 on C-2), 4.06 (1H, s, CHOH),
4.17 (1H, m, CH-N1), 5.12 (1H, s, OH exchangeable), 6.76 (1H, s,
(75 MHz)
d 20.2 (CH3), 37.6 (CH2C6H5), 54.0 (NCH2C6H5), 69.8 (CH-
2), 92.5 (CH-5), 106.6 (HC]), 126.9, 127.8, 128.6, 129.2, 129.6, 129.9
(10ꢂArCH), 135.3, 136.0 (ArCqu), 151.9 (C-6), 154.5 (C-4); 13C NMR
HC]), 7.73 (1H, s, H-5); 13C NMR (75.5 MHz, DMSO-d6)
d
14.2 (CH3),
(125.7 MHz, C6D6) d 18.7 (CH3), 37.3 (CH2C6H5), 53.5 (NCH2C6H5),
21.4 (CH2), 22.9 (CH3 on C-6), 24.3, 26.1, 30.6, 36.5 (4ꢂCH2 ring),
37.8 (CH2 on C-2), 68.3 (CHN-1), 69.6 (CHOH), 110.0 (CH-5), 114.7
(HC]), 155.8 (C-6), 156.9 (C-4), 162.9 (C-2); ESI-MS: m/z (% relative
intensity): 316 [MþNa] (100), 294 [Mþ1] (29), 248[Mþ1ꢀ46, NO2]
(15). Anal. Calcd for C15H23N3O3: C, 61.41; H, 7.90; N, 14.32. Found:
C, 61.45; H, 8.03; N, 14.21.
69.5 (CH-2), 92.1 (CH-5), 106.8 (HC]), 126.3, 126.9, 127.7, 128.9,
129.7 (10ꢂArCH), 135.8, 136.7 (ArCqu), 150.5 (C-6), 151.7 (C-4); ESI-
MS: m/z (% relative intensity): 358 [MþNa] (100), 336 [Mþ1] (92),
289 [Mþ1ꢀ46, NO2] (100). Anal. Calcd for C20H21N3O2: C, 71.62; H,
6.31; N, 12.53. Found: C, 71.75; H, 6.44; N, 12.35.
4.5.2. (Z)-2-(2-Benzyl-6-methyl-4-(nitromethylene)-3,4-
dihydropyrimidin-1(2H)-yl) ethanol 6b
4.4. Reaction of amidine 4a with glycine methyl ester
hydrochloride: synthesis of (E)-methyl 2-(2-benzyl-6-methyl-
4-(nitromethylene)pyrimidin-1(4H)-yl)acetate 4j
CH3CN/MeOH, 95:5; orange thick oil; IR nmax (CHCl3) 3271 (NH),
3018 (OH), 1593 (C]C), 1547 (NO2) cmꢀ1 1H NMR (300 MHz,
;
DMSO-d6)
d 2.06 (3H, s, CH3), 2.73–2.88 (1H, m, CH2N), 2.88–3.04
TEA (5.6 mL, 4 mmol) was added to a stirred suspension of
glycine methyl ester hydrochloride (0.502 g, 4 mmol) in CH2Cl2
(15 mL). After an additional 30 min stirring, amidine 3a (0.715 g,
2 mmol) was then added in CH2Cl2 (15 mL) solution. The reaction
mixture was heated at 35 ꢁC for 6 h until disappearance (TLC
monitoring) of the starting compound 3a, then quenched with
water and extracted with CH2Cl2 (3ꢂ30 mL). The combined organic
layers were washed with H2O (60 mL), dried with Na2SO4 and then
evaporated in vacuo. The crude residue was purified through
a short silica gel column (CH2Cl2/acetone/Et2O, 7:2:1) affording 4j.
Yield 78%, yellow crystals, mp 145 ꢁC; IR nmax (KBr) 1736 (C]O),
(2H, m, CH2C6H5), 3.06–3.43 (2Hþ1H, m, CH2OH and CH2N), 4.89
(1H, br s exchangeable, OH), 4.95 (1H, s, H-5), 5.19 (1H, s, H-2), 6.42
(1H, s, HC]), 7.15–7.35 (5H, m, ArH), 9.63 (1H, br s exchangeable,
NH); 13C NMR (75 MHz, DMSO-d6)
d 20.1 (CH3), 36.6 (CH2C6H5),
52.6 (CH2N), 60.5 (CH2OH), 69.2 (CH-2), 91.5 (CH-5), 105.2 (HC]),
127.5, 129.2, 130.5 (ArCH), 136.7 (ArCqu), 152.0 (C-6), 156.3 (C-4);
ESI-MS: m/z (% relative intensity): 290 [Mþ1] (100), 243 [Mþ1ꢀ46,
NO2] (35). Anal. Calcd for C15H19N3O3: C, 62.27; H, 6.62; N, 14.52.
Found: C, 62.37; H, 6.53; N, 14.43.
1638 (C]N), 1560 (NO2) cmꢀ1 1H NMR (200 MHz)
; d 2.23 (3H, s,
Acknowledgements
CH3), 3.66 (3H, s, OCH3), 4.03 (2H, s, CH2C6H5), 4.55 (2H, s,
NCH2COOCH3), 7.11 (1H, s, HC]), 7.18–7.40 (5H, m, ArH), 7.90 (1H, s,
`
Financial support by Ministero dell’Universita e della Ricerca
H-5); 13C NMR (50 MHz)
d 20.3 (CH3), 42.4 (CH2C6H5), 49.0
(MUR-PRIN 2005) is gratefully acknowledged. Thanks are due to
Mrs. D. Nava for providing the NMR two-dimensional experiments.
(NCH2COOCH3), 53.4 (OCH3), 108.9 (CH-5), 118.6 (HC]), 128.0,
128.7, 129.4 (ArCH), 133.6 (ArCqu), 151.2 (C-6), 155.4 (C-4), 158.7 (C-
2), 166.7 (C]O); ESI-MS: m/z (% relative intensity): 338 [MþNa]
(100), 316 [Mþ1] (10), 270 [Mþ1ꢀ46, NO2] (26). Anal. Calcd for
C16H17N3O4: C, 60.94; H, 5.43; N, 13.33. Found: C, 60.88; H, 5.45; N,
13.15.
References and notes
1. (a) Hsu, L.-Y.; Wise, D. S.; Shannon, W. M.; Drach, J. C.; Townsend, L. B. Nucle-
osides Nucleotides 1994, 13, 563–584; (b) Mansour, T. S.; Evans, C. A.; Charron,
M.; Korba, B. Bioorg. Med. Chem. Lett. 1997, 7, 303–308; (c) Wallis, M. P.; Mah-
mood, N.; Fraser, W. Farmaco 1999, 54, 83–89; (d) Kifli, N.; De Clercq, E.; Bal-
zarini, J.; Simons, C. Bioorg. Med. Chem. 2004, 12, 4245–4252; (e) Coutouli-
Argyropoulou, E.; Lianis, P.; Mitakou, M.; Giannoulis, A.; Nowak, J. Tetrahedron
2006, 62, 1494–1501.
2. (a) Kim, C.-H.; Marquez, V. E.; Mao, D. T.; Haines, D. R.; McKormack, J. J. J. Med.
Chem. 1986, 29, 1374–1380; (b) Blanalt-Feidt, S.; Doronina, S. O.; Behr, J. P.
Tetrahedron Lett. 1999, 6229–6232.
3. Yamane, A.; Inoue, H.; Uerda, T. Chem. Pharm. Bull. 1980, 28, 157–162.
4. Timoshchuk, V. Nucleosides, Nucleotides Nucleic Acids 2005, 24, 1043–1046.
5. Bertacche, V.; Contini, A.; Erba, E.; Nava, D.; Trimarco, P. Tetrahedron 2007, 63,
9652–9662.
6. Boyd, G. V. In The Chemistry of Amidines and Imidates; Patai, S., Rappoport, Z.,
Eds.; Interscience: London, 1991; Vol. 2, pp 375–378 and references cited
therein.
4.5. Reaction of the 4-(nitromethylene)-1,4-
dihydropyrimidines 4a, 4d with NaBH4: synthesis of
compounds 6a, 6b
To a stirred suspension of 4a (0.333 g, 1 mmol) or 4d (0.287 g,
1 mmol) in MeOH (25 mL) at 0 ꢁC was added, in portions, NaBH4
(0.227 g, 6 mmol). The reaction mixture was stirred at room tem-
perature until disappearance (about 2 h, TLC monitoring) of start-
ing compounds 4a or 4d. The mixture was quenched with water
and extracted with CH2Cl2 (4ꢂ30 mL). The combined organic layers
were washed with H2O (80 mL), dried with Na2SO4 and then
evaporated in vacuo. The crude residue was purified through
a short silica gel column (eluant indicated later) affording the cor-
responding 4-(nitromethylene)-1,4-dihydropyrimidine derivatives
6a or 6b, respectively, in pure form. Isolated yields of the products
6a and 6b are listed in Table 2.
7. Ellis, G. P. In Comprehensive Heterocyclic Chemistry; Boulton, A. J., Mc Killop, A.,
Eds.; Pergamon: Oxford, 1984; Vol. 3; p 681 and references cited therein.
8. Ram, V. J.; Srivastava, P.; Saxena, A. S. J. Org. Chem. 2001, 66, 5333–5337.
9. Moreno-Man˜as, M.; Pleixats, R. Adv. Heterocycl. Chem. 1992, 53, 56–65 and
references cited therein.
ˇ
10. Kadaba, P. K.; Stanovnik, B.; Tisler, M. Adv. Heterocycl. Chem. 1984, 37, 339–342
and references cited therein.
11. (a) Coustard, J. M. Eur. J. Org. Chem. 2001, 1525–1531; (b) Beit-Yannai, M.; Chen,
X.; Rappoport, Z. J. Chem. Soc., Perkin Trans. 2 2001, 1534–1545.
12. Buurman, D. J.; van Veldhuizen, A.; van der Plas, H. C. J. Org. Chem. 1990, 55,
778–780.
13. Ha¨felinger, G.; Kuske, F. K. H. In The Chemistry of Amidines and Imidates; Patai, S.,
Rappoport, Z., Eds.; Interscience: London, 1991; Vol. 2, pp 1–93 and references
cited therein.
4.5.1. (Z)-1,2-Dibenzyl-6-methyl-4-(nitromethylene)-1,2,3,4-
tetrahydropyrimidine 6a
CH2Cl2/acetone, 8:2; yellow crystals, mp 153–154 ꢁC; IR nmax
(CHCl3) 3254 (NH), 1593 (C]C), 1542 (NO2) cmꢀ1
;
1H NMR

A. Contini et al. / Tetrahedron 64 (2008) 11067–11073
11073
14. Wendt, M. D.; Rockway, T. W.; Geyer, A.; McClellan, W.; Weitzberg, M.; Zhao, X.;
Klinghofer, V.; Giranda, V. L. J. Med. Chem. 2004, 47, 303–324.
15. (a) Kearney, T.; Harris, P. A.; Jakson, A.; Joule, J. A. Synthesis 1992, 769–772; (b)
Chiara, J. L.; Gomez-Sanchez, A.; Bellanato, J. J. Chem. Soc., Perkin Trans. 2 1992,
787–798; (c) Reddy, T. I.; Bhawal, B. M.; Rajappa, S. Tetrahedron 1993, 49,
2101–2108; (d) Hutchinson, I. S.; Matlin, S. A.; Mete, A. Tetrahedron Lett. 2001,
1773–1776.
16. (a) Gu¨nter, H. NMR Spectroscopy; John Wiley & Sons: Chichester, UK, 1995, pp
170–181; (b) Bertacche, V.; Milanese, A.; Nava, D.; Pini, E.; Stradi, R. J. Pharm.
Biomed. Anal. 2007, 45, 642–647.
17. (a) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrel, R. J. Am.
Chem. Soc. 1963, 85, 207–222; (b) Gurowitz, W. D.; Joseph, M. A. Tetrahedron Lett.
1965, 4433–4439; (c) Reichardt, C. Angew. Chem., Int. Ed. Engl. 1979, 18, 98–110.
18. (a) Yamamoto, H.; Maruoka, K. J. Am. Chem. Soc. 1981, 103, 4186–4194; (b) Re-
naud, T.; Hurvois, J.-P.; Uriac, P. Eur. J. Org. Chem. 2001, 987–996.
19. Rajappa, S.; Nagarajan, K. J. Chem. Soc., Perkin Trans. 2 1978, 912–914.
20. Broekhof, N. L. J. M.; Jonkers, F. L.; van der Gen, A. Tetrahedron Lett. 1979,
2433–2436.
21. May, G.; Pinhey, L. J. Aust. J. Chem. 1982, 35, 1859–1871.
22. Fisher, G. B.; Lee, L.; Klettke, F. W. Synth. Commun. 1994, 24, 1541–1546.