Multicomponent synthesis of dihydropyrimidines and thiazines

Article abstract of DOI:10.1002/chem.200600168

A broad range of differently substituted dihydropyrimidines and thiazines can be efficiently prepared by using a four-component reaction between phosphonates, nitriles, aldehydes, and iso(thio)cyanates. The scope and limitations of this multicomponent reaction are fully described. Variation of all four components has been investigated. The nitrile and aldehyde inputs can be varied extensively, but variation of the phosphonate input remains limited. An interesting rearrangement leading to phosphoramidates has been observed, Furthermore, the multicomponent reaction seems to be restricted to the use of isocyanates with strongly electron-withdrawing substituents, but an interesting additional exchange reaction under microwave conditions leads to dihydropyrimidines with less electron-withdrawing substituents at N3. In addition, a diastereoselective formation of dihydropyrimidines has been observed when using a chiral aldehyde as the input. Finally, by changing the isocyanate component to an isothiocyanate, thiazines are efficiently formed instead of the corresponding thio-dihydropyrimidines.

Full text of DOI:10.1002/chem.200600168

DOI: 10.1002/chem.200600168
Multicomponent Synthesis of Dihydropyrimidines and Thiazines
Danielle J. Vugts, Manoe M. Koningstein, Rob F. Schmitz, Frans J. J. de Kanter,
Marinus B. Groen, and Romano V. A. Orru*[a]
Abstract: A broad range of differently
substituted dihydropyrimidines and
thiazines can be efficiently prepared by
using a four-component reaction be-
tween phosphonates, nitriles, alde-
leading to phosphoramidates has been
observed. Furthermore, the multicom-
ponent reaction seems to be restricted
to the use of isocyanates with strongly
electron-withdrawing substituents, but
an interesting additional exchange re-
action under microwave conditions
leads to dihydropyrimidines with less
electron-withdrawing substituents at
N3. In addition, a diastereoselective
formation of dihydropyrimidines has
been observed when using a chiral al-
dehyde as the input. Finally, by chang-
ing the isocyanate component to an
isothiocyanate, thiazines are efficiently
formed instead of the corresponding
thio-dihydropyrimidines.
hydes, and iso(thio)cyanates. The scope
G
and limitations of this multicomponent
reaction are fully described. Variation
of all four components has been inves-
tigated. The nitrile and aldehyde inputs
can be varied extensively, but variation
of the phosphonate input remains lim-
ited. An interesting rearrangement
Keywords: heterocycles
·
hetero-
Diels–Alder reaction
·
Horner–
Wadsworth–Emmons reaction
microwave-assisted synthesis
multicomponent reactions
·
·
Introduction
useful tools for parallel syntheses of arrays of structurally di-
verse products of considerable complexity.[3–5]
Structurally diverse libraries of small molecules are conven-
iently generated by combinatorial assembly of different
types of building blocks onto a common scaffold. Most ap-
proaches rely on a stepwise protocol, but for more compli-
cated skeletons such sequential re-iteration of individual re-
actions becomes a limiting factor. A more convergent ap-
proach is desired that ideally provides the suitably decorated
scaffold in a single synthetic operation. Procedures that
yield complex molecules by performing multiple reaction
steps in which several bonds are formed without isolation of
intermediates are commonly referred to as tandem reac-
tions.[1] An important subclass of tandem reactions are the
multicomponent reactions (MCRs), which are defined as
one-pot processes in which at least three easily accessible
components are combined to form a single product.[2] In this
regard, MCRs are receiving ever-increasing attention as
Many small synthetic organic molecules with high medici-
nal potential contain heterocyclic rings. Also, the most
potent ligand systems in (transition) metal-mediated (asym-
metric) catalysis are often based on heterocyclic cores. The
range of easily accessible and suitably functionalised hetero-
cyclic building blocks is, however, surprisingly limited and
the construction of even a small array of, for example, 500
relevant heterocyclic compounds is far from trivial. Hetero-
cyclic chemistry therefore continues to attract the attention
of medicinal and synthetic chemists,[6] and the development
of novel methodologies allowing efficient access to heterocy-
cles is still highly appreciated. Traditionally, methods based
on MCRs have proved quite efficient for the construction of
many different types of heterocycles.[5] For example, the
Hantzsch four-component pyridine synthesis, the Bucherer–
Bergs three-component thiazole synthesis, and the Biginelli
three-component reaction for the preparation of dihydropyr-
imidinones are all well-known MCRs for the construction of
heterocyclic species.[5] Recently, we have also contributed
with several examples in this area.[7,8a]
[a] D. J. Vugts, M. M. Koningstein, R. F. Schmitz, F. J. J. de Kanter,
Prof. Dr. M. B. Groen, Dr. R. V. A. Orru
Department of Chemistry and Pharmaceutical Sciences
Vrije Universiteit
Most relevant to the present work is a multicomponent
approach for generating dihydropyrimidines (DHPMs).[8a] In
this four-component reaction, phosphonates 1, nitriles 2, and
aldehydes 3 are combined to produce 1-azadienes 4 by a
De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands)
Fax : (+31)20-598-7488
E-mail: orru@few.vu.nl
7178
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7178 – 7189
Please note: Minor changes have been made to this manuscript since its publication in Chemistry - A European Journal Early View. The Editor.

FULL PAPER
Horner–Wadsworth–Emmons (HWE) reaction.[8b] Subse-
quent in situ aza-Diels–Alder (aza-DA) cycloaddition with
isocyanates 5 gives DHPMs of type 6 (Scheme 1).
work on the synthesis of batzelladine A,[16a,b] for which they
developed an aza-DA reaction between a dihydro-oxazole
and isocyanates that led to oxazolopyrimidines.[16c,d] Other
well-known approaches to DHPMs use the classical Biginelli
three-component reaction.[9a] In the past decade, a series of
procedures has been developed to overcome the relatively
harsh conditions (EtOH, HCl, D) of the original reaction.[17]
A serious drawback of these protocols is that only the phar-
macologically less important N1-substituted and N3-unsub-
stituted DHPM derivatives can be obtained. Additional syn-
thetic manipulations are needed to obtain the biologically
active N3-substituted DHPMs.[9a,18]
The four-component reaction (4CR) depicted in Scheme 1
offers an alternative, which largely overcomes these prob-
lems and produces the desired N3-substituted DHPMs 6 in
a single step. The reaction seems quite flexible with respect
to the nitriles 2 and aldehydes 3 that may be used, but only
a limited number of combinations have been tested to
date.[8a] Further studies employing more functionalised ni-
trile and aldehyde inputs are presented herein. In addition,
an extensive scope study is reported that addresses the influ-
ence of the phosphonate (1) and the isocyanate (5) compo-
nents on the HWE/aza-DA four-component assembly of
DHPMs 6. Steric and electronic factors that direct this
MCR are discussed in detail to fully define its exploratory
power, EN. Also, the use of optically active inputs has been
explored with a view to obtaining the desired DHPMs 6 dia-
stereoselectively.
Scheme 1. Inputs in Horner–Wadsworth–Emmons/aza-Diels–Alder four-
component reaction (HWE/aza-DA 4CR).
DHPMs are versatile heterocyclic six-membered-ring scaf-
folds with remarkable pharmacological activities.[9] They are
widely used in medicinal chemistry. For example, antiviral,
antitumour, antibacterial, and anti-inflammatory activities
have been reported, and DHPMs are also used as calcium
channel modulators, a1a-adrenoceptor-selective antagonists,
and anti-hypertensive agents.[10,11] The methods hitherto
used for the preparation of biologically active DHPMs have
all involved multistep processes.[12–15] An interesting ap-
proach was reported by Elliott and co-workers during their
Results and Discussion
The HWE/aza-DA 4CR for the synthesis of 6 proceeds via
1-azadiene intermediates 4. These species are conveniently
generated by mixing a phosphonate (1) with a base (e.g.,
nBuLi) at ꢀ788C, followed by addition of a nitrile (2) and
an aldehyde (3).[8] The mixture is then allowed to warm to
room temperature, whereupon addition of an isocyanate (5)
Abstract in Dutch: Een breed spectrum van verschillend ge-
substitueerde dihydropyrimidines en thiazines kan gesyntheti-
seerd worden via een vier-componenten reactie van fosfona-
induces
a formal Diels–Alder cycloaddition to give 6
(Scheme 1). Thus, reaction of diethyl methylphosphonate
(1a) and tosyl isocyanate (5a) with aromatic nitriles 2 and
aromatic aldehydes 3 proceeds smoothly and efficiently af-
fords the corresponding DHPMs 6a–f (entries 1–6; Table 1).
Aliphatic nitriles 2 in combination with aromatic alde-
hydes 3, 1a, and 5a gave modest to good yields of the corre-
sponding DHPMs 6g–o (entries 7–15; Table 1). When secon-
dary nitriles 2b and 2d were used (entries 7–13; Table 1) the
yields of the corresponding DHPMs 6g–m were still satisfy-
ing. However, when the sterically more demanding pivaloni-
trile (2e) was used as input (entry 14; Table 1) the yield of
6n was rather poor. Also, use of the primary nitrile 2 f re-
sulted in only a trace amount of the desired DHPM 6o
(entry 15; Table 1). In a related study directed towards the
synthesis of a,b-unsaturated ketones via in situ generated 1-
azadienes, it was reported that primary nitriles are quite
prone to dimerisation and polymerisation,[19] which may ac-
count for the diminished yield of DHPM 6o.
ten,nitrillen,aldehydes en iso
A
worden de mogelijkheden en de beperkingen van deze multi-
component reactie uitgebreid beschreven,waarbij variatie van
alle vier de componenten onderzocht is. De variatiemogelijk-
heid in nitril en aldehyde is zeer uitgebreid,terwijl variatie in
fosfonaat beperkt is. Hierbij is een interessante omlegging
waargenomen die leidt tot fosforamidaten. Verder leidt alleen
het gebruik van isocyanaten met sterk electronen-zuigende
groepen tot de efficiente vorming van dihydropyrimidines.
Dihydropyrimidines met zwak electronen-zuigende groepen
kunnen echter gesynthetiseerd worden door uitwisseling van
het isocyanaat onder magnetron condities. In dit artikel wordt
ook de diastereoselectieve vorming van dihydropyrimidines
beschreven waarbij een chiraal aldehyde gebruikt wordt. Ten-
slotte,als het isocyanaat vervangen wordt door een isothio-
cyanaat,wordt een thiazine in plaats van het thio-dihydropy-
rimidine gevormd.
Chem. Eur. J. 2006, 12, 7178 – 7189
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7179

R. V. A. Orru et al.
Table 1. HWE/aza-DA 4CR of phosphonate 1a and isocyanate 5a with
nitriles 2 and aromatic aldehydes 3.
bocationic species II, which is reflected in a less dramatic
effect on the final cyclocondensation step.
Entry Nitrile
R2
Alde-
hyde
R3
Yield [%] DHPM
Another point of diversity in the DHPM scaffold (6) is
R1, which is introduced through the phosphonate input 1.
Therefore, we decided to investigate the application of dif-
ferent phosphonates in the HWE/aza-DA 4CR. Phospho-
nates 1 were prepared by way of the Michaelis–Arbuzov re-
action.[20] Thus, reaction of triethyl phosphite with appropri-
ate halides under controlled microwave heating in a mono-
mode reactor afforded phosphonates 1a–d in very good
yields.[21]
Phosphonates 1a–d were used in combination with a
small set of nitriles (2a–c), anisaldehyde (3a), and tosyl iso-
cyanate (5a). The results are summarised in Table 3 and
Table 4. The use of phosphonate 1b instead of 1a in combi-
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2c
2b
2b
2b
2b
2b
2b
2d
2e
2 f
Ph
Ph
Ph
Ph
Ph
2-furyl
iPr
iPr
iPr
iPr
3a
3b
3c
3d
3e
3a
3a
3b
3c
3d
3e
3 f
3a
3a
3b
4-MeOC6H4
4-ClC6H4
65
80
71
54
38
61
73
65
55
49
60
55
49
15
< 5
6a
6b
6c
6d
6e
6 f
6g
6h
6i
6j
6k
6l
6m
6n
6o
Ph
4-Me2NC6H4
3-NO2C6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
9
Ph
10
11
12
13
14
15
4-Me2NC6H4
3-NO2C6H4
4-NO2C6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
iPr
iPr
CH(Me)Et
tBu
nPr
Table 3. HWE/aza-DA 4CR of phosphonates 1a and 1b, nitriles 2a–c, al-
dehyde 3a, and isocyanate 5a.
Entry
Phosphonate
R1
Nitrile
R2
Yield [%]
DHPM
Besides aromatic aldehydes, aliphatic aldehydes were also
1
2
3
4
5
6
1a
1a
1a
1b
1b
1b
H
H
H
Me
Me
Me
2a
2c
2b
2a
2c
2b
Ph
2-furyl
iPr
Ph
2-furyl
iPr
65
61
73
35
90
–
6a
6 f
6h
6u
6v
–
used as inputs in the MCR. When these aliphatic aldehydes
(3g, 3h, and 3i) were allowed to react with nitriles 2a–c, 1a,
and 5a, only moderate yields of the corresponding DHPMs
6p–t could be isolated (Table 2).
Table 2. HWE/aza-DA 4CR of phosphonate 1a and isocyanate 5a with
nitriles 2 and aliphatic aldehydes 3.
nation with aromatic nitriles 2a/2c, 3a, and 5a was found to
result in moderate to good yields of the corresponding
DHPMs 6u and 6v (entries 4 and 5, Table 3), although the
yield of 6u was considerably lower than that of 6v. More-
over, when the aliphatic nitrile 2b was reacted with 1b, 3a,
and 5a, no DHPM could be detected (entry 6; Table 3). The
other two synthesised phosphonates, 1c and 1d, also failed
to give DHPMs in the HWE/aza-DA 4CR.
Entry Nitrile
R2
Aldehyde
R3
Yield (%) DHPM
1
2
3
4
5
2a
2a
2c
2b
2b
Ph
Ph
2-furyl
iPr
3g
3i
3g
3g
3h
iPr
Me
iPr
35
15
36
40
21
6p
6q
6r
6s
6t
iPr
iPr
PhCH2OCH2
To clarify the course of the reaction, the consumption of
phosphonates 1b, 1c, and 1d by either 2a or 2b was studied
in more detail by 31P NMR spectroscopy. For the reaction
involving 1b, this revealed that although initial deprotona-
tion with nBuLi proceeds smoothly, the resulting anion
reacts rather slowly with 2b. Even after stirring the reaction
mixture at room temperature overnight, considerable
amounts of unreacted 1b were still detected. Nevertheless,
formation of the corresponding intermediate of type I
(Scheme 2) most likely took place. When the reaction mix-
ture was quenched with MeI (no products could be identi-
fied with H2O), the intermediate was indeed trapped. A
mixture of products was formed; the main products were
identified as the phosphoramidates (E)- and (Z)-7a (37%,
entry 1; Table 4). Also, when phosphonate 1c was used in
combination with 2a, 3a, and 5a in the 4CR, no correspond-
ing DHPM was formed at all. However, if after initial de-
protonation and addition of 2a the reaction was quenched
using MeI, the sole identifiable product was phosphorami-
date (Z)-7b (quant., entry 2; Table 4). On the other hand,
when the same reaction mixture was quenched with water
instead of MeI (entry 3; Table 4), the phosphoramidates
(E)- and (Z)-8a (58%) together with the imine 9 (42%)
As became clear in the course of our earlier studies, gen-
eration of the initial intermediate I (Scheme 2) is crucial.
Therefore, the use of aromatic nitriles or nitriles with poorly
accessible a-H atoms is favourable (R2). Furthermore,
HWE reaction of the aldehyde component (R3) with I pro-
duces 1-azadiene intermediates 4, which undergo final cyclo-
condensation with the isocyanate (R4) to form the corre-
sponding DHPMs 6. This most likely proceeds through sta-
bilised dipolar intermediates II (Scheme 2). Compared to
aliphatic R3 substituents, aromatic R3 substituents (Table 1
versus Table 2) are more efficient at stabilising the inter-
mediate carbocation in II, which ultimately results in more
efficient cyclocondensation. The electronic nature of R2 is
less important than that of R3 for the stabilisation of the car-
Scheme 2. Intermediates I and II.
7180
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7178 – 7189

Four-Component Heterocycle Synthesis
FULL PAPER
Table 4. Reaction of phosphonates 1b–d with nitriles 2a and 2b.[a]
tion of imine 9. After initial deprotonation of the phospho-
nates 1b–d, the resulting anions A react with nitriles 2a or
2b to form the corresponding stabilised intermediates B.
Then, B rearranges to D, which is also resonance-stabilised.
Ultimately, the observed rearranged products are formed by
reaction of D with MeI (7) or water (8 and 9). The rear-
rangement B ! D may proceed via C, which is a four-mem-
bered N,P-containing ring analogous to the oxaphosphetane
intermediates that play a role in the usual HWE reac-
tions.[24]
Intermediates B are similar to the previously postulated I
(Scheme 2). Efficient formation of B depends on the stabili-
ty of the initial anion A in combination with the accessibility
of the a-proton of the nitrile input.[8] Furthermore, the inter-
mediate B derived from 1b is less stable than the corre-
sponding anion derived from 1c or 1d.[25] Consequently,
DHPMs 6 can still be formed upon reaction of the anion A
of 1b with aromatic nitriles 2 followed by a quick HWE/
aza-DA process with 3a and 5a (entries 4 and 5; Table 3).
On the other hand, after deprotonation of the phosphonates
1c and 1d, the anion reacts smoothly with the nitrile input
to form B, but then fast rearrangement to D is preferred,
which ultimately leads to products 7, 8, and 9. Only one
precedent for a similar rearrangement exists in the litera-
ture.[26]
Entry Phosphonate Nitrile Quench
method
Products
Recovery
of 1 [%]
7a (37%) E:Z
= 1:6
1
2
3
1b
1c
1c
2b
2a
2a
MeI
MeI
H2O
56[b]
(Z)-7b (100%)
–
8a (58%) E:Z
= 1:1.5
9 (42%)
–
4
5
1c
1c
2b
2b
MeI
H2O
(Z)-7c (20%)
7[c]
(Z)-8b (25%)[d] 7[c]
Two commercially available phosphonates 1e and 1 f were
treated with nBuLi and a nitrile in a similar manner as de-
scribed above. Deprotonation was successful in both cases,
but resulted in a very stable anion that did not react with
benzonitrile (2a) at all and no rearranged products were ob-
served. Also, one-pot reaction of either 1e or 1 f with 2a,
3a, and 5a did not give the corresponding DHPM as a prod-
uct. Addition of crown ethers or the use of HMPA as a co-
solvent did not result in reaction of the anion. Also, the use
of alternative bases, such as KOtBu or LDA, did not result
in any reaction of the anion of 1e or 1 f with 2a.
In order to further explore the scope of the HWE/aza-DA
4CR for the synthesis of DHPMs 6, the isocyanate input 5
was also varied (Scheme 4). Isocyanates are versatile start-
ing materials, which are also used in other MCRs.[27] Earlier,
we showed that reaction of 5b (instead of 5a) with 1a, 2a,
and 3a in the presence of nBuLi afforded DHPM 6w in a
modest yield of 26%.[8a]
6
1d
2a
MeI
(E)-7d (37%)
(E)-10 (63%)
–
[a] After reaction with nitrile was complete (entries 2, 3, and 6) or after stirring
at room temperature overnight (entries 1, 4, and 5), the reactions were quenched
with either MeI or H2O and the product composition was analysed by H and 31P
1
NMR; see Experimental Section for more details. [b] A third phosphoramidate
(6%) was identified as well, see ref. [22]. [c] Another phosphonate (10–20%)
was identified besides residual 1c; see ref. [23]. [d] Phosphoramidate (Z)-8b rap-
idly decomposes.
were found, as concluded on the basis of the NMR data.
Next, the reaction of 1c with isobutyronitrile (2b) was in-
vestigated (entries 4 and 5; Table 4). Although initial depro-
tonation seemed to proceed smoothly, the resulting anion
reacted only relatively slowly with 2b. After stirring at room
temperature overnight, 7% of unreacted 1c remained. Ad-
ditionally, some 20–25% of the corresponding phosphorami-
dates (Z)-7c and (Z)-8b were identified when MeI and
water, respectively, were used to quench the reaction. Final-
ly, when diethylallyl phosphonate (1d) was deprotonated in
a similar fashion as above with nBuLi, the resulting anion
was indeed found to react with benzonitrile (2a). After
quenching with MeI, two main products, (E)-7d and 10,
were identified in a 1:2 ratio (entry 6; Table 4).
Strongly electron-withdrawing R4 groups on the isocya-
nate favour aza-DA of the initially formed 1-azadiene 4 to
form the corresponding DHPM 6. Several pharmacological
studies have shown that an ester or amide function at N3 or
C5 in DHPMs such as 6 is required for biological activity.[9c]
Therefore, the isocyanate 5e was also considered as an
input. In this way, pharmaceutically more relevant DHPMs
6x and 6y were prepared in 70% and 29% isolated yield,
respectively. In addition, the use of benzoyl isocyanate (5d)
in combination with 1a, 2a, and 3a afforded DHPM 6z in
70% yield.
However, application of isocyanates 5 with less electron-
withdrawing R4 substituents did not give the desired
DHPMs. For example, when 5c (R4 = Ph) was used in com-
The process depicted in Scheme 3 can rationalise the for-
mation of phosphoramidates 7 and 8 as well as the forma-
Chem. Eur. J. 2006, 12, 7178 – 7189
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7181

R. V. A. Orru et al.
tively strongly electron-with-
drawing substituents R4. How-
ever, the application of 5 with
less electron-withdrawing R4
can
DHPMs
successfully
under
lead
microwave
to
(MW) conditions. To our satis-
faction, 11a could be cyclised
under MW conditions at 1208C
in THF as the solvent and the
desired DHPM 12 could be iso-
lated in 38% yield (Scheme 5).
Moreover, we also observed an
interesting exchange reaction
under MW-irradiation. When
DHPM 6a (R4
65%) was heated together with
isocyanate 5c (R4
Ph) at
= Ts, yield
=
1908C in dioxane for 1 h in a
monomode MW oven, the
DHPM 12 was formed in 58%
yield (Scheme 5).
The biological activity of
DHPMs depends on the abso-
lute configuration at the C4
centre, whereby the orientation
of the substituent acts as a mo-
Scheme 3. Mechanism for the formation of phosphoramidates 7–9.
Scheme 5. Synthesis of DHPMs 12 with less electron-withdrawing R4 sub-
stituents.
Scheme 4. DHPMs 6 formed with various isocyanates 5.
bination with 1a, 2a, and 3a, the non-cyclised 11a was
formed, rather than the corresponding DHPM (Scheme 5).
The isolation of the non-cyclised linear precursor 11a
strongly supports a stepwise cycloaddition of the corre-
sponding 1-azadiene intermediate 4 with 5c.[28] Thus, the
HWE/aza-DA approach for the direct formation of DHPMs
6 seems to be confined to the use of isocyanates with rela-
lecular switch between agonist and antagonist activities.[10]
A
stereoselective synthesis of optically pure DHPMs is there-
fore of great relevance for medicinal applications of these
compounds. Although not comparable to the HWE/aza-DA
4CR, stereoselective formation of DHPMs by way of the
classical Biginelli 3CR has been reported. Dondoni and co-
workers achieved good de values by using C-glycosylated
7182
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7178 – 7189

Four-Component Heterocycle Synthesis
FULL PAPER
inputs,[29] and very recently an enantioselective Biginelli
3CR has been reported using a chiral ytterbium catalyst.[30]
In order to induce chirality in our HWE/aza-DA 4CR, three
reactions were performed with different optically pure
inputs (Scheme 6). First, a reaction was performed with the
commercially available optically pure nitrile (S)-(+)-2d in
combination with 1a, 3a, and 5a. This gave a 1:1 diastereo-
meric mixture of 13a in 60% yield. When optically pure iso-
cyanate (R)-5 f was combined with 1a, 2a, and 3a, the cor-
responding DHPM was not formed. Instead, triazinanedione
11b was isolated in 42% yield as a 1:1.5 mixture of diaster-
eomers. Formation of triazinanediones has been observed
previously for less reactive isocyanate inputs.[8a] This inter-
esting reaction will be the subject of a forthcoming paper.
However, when the commercial (ꢀ)-myrtenal 3j was used
as the aldehyde input (with 1a, 2a, and 5a), the correspond-
ing DHPM 13b was formed in 80% yield as an 11:1 diaster-
eomeric mixture.
Scheme 7. Use of ketones 14 in the HWE/aza-DA 4CR.
forded the thiazine derivative
18a in good yield (74%,
entry 1; Table 5). This proce-
dure proved to be quite general
and a number of differently
substituted thiazines 18 could
be synthesised in reasonable to
good yields by combining the
appropriate inputs (Table 5).
By simply changing the nature
of the fourth component in our
MCR from isocyanate to iso-
thiocyanate, the course of the
final cyclocondensation is al-
tered. Thiazines are scarcely
described in the literature and
little is known about their bio-
logical activities.[12a,32] Our syn-
thetic approach provides access
Scheme 6. Use of chiral inputs in the HWE/aza-DA 4CR.
to 18 and may facilitate further
studies aimed at elucidating the
To further explore the scope of the four-component
HWE/aza-DA reaction, some ketones were also used as
inputs instead of aldehydes. When cyclohexanone 14a or
benzophenone 14b was combined with 1a, 5a, and either 2a
or 2b, the corresponding DHPM was not formed
(Scheme 7). However, when the reactions were quenched
with sulfuric acid prior to addition of 5a, the a,b-unsaturat-
ed ketones 15 and 16 were detected.[31] This indicates that
the HWE process took place and that the corresponding 1-
azadiene intermediate was indeed formed. Apparently,
these are not reactive enough to undergo subsequent cyclo-
addition upon in situ treatment with 5a to give the desired
DHPM analogues.
biological relevance of these systems. In general, the thia-
zines 18 are rather stable compounds; they can be easily pu-
rified by column chromatography on silica gel, although in
the case of 18b (entry 2; Table 5) a rearrangement to the
corresponding thio-DHPM was observed when a solution in
CDCl3 was left to stand at room temperature for a couple of
hours. A more detailed study on this so-called Dimroth rear-
rangement[33,34] will be reported elsewhere.[35] Interestingly,
not only electron-withdrawing but also alkyl R4-substituents
Finally, application of isothiocyanates 17 instead of isocya-
nates 5 in the HWE/aza-DA 4CR was also explored
(Scheme 8). Thus, in situ combination of 1a, 2a, and 3c in
the presence of nBuLi and subsequent addition of 17a af-
Scheme 8. Synthesis of thiazines 18.
Chem. Eur. J. 2006, 12, 7178 – 7189
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7183

R. V. A. Orru et al.
Table 5. Four-component reaction of phosphonate 1a with nitriles 2, al-
dehydes 3, and isothiocyanates 17.
resolution mass spectra (HRMS, EI) were recorded on a Finnigan
MAT 900 spectrometer at 70 eV. IR spectra were recorded on a Mattson
6030 Galaxy spectrophotometer and are reported in cmꢀ1. Melting points
were measured on a Stuart Scientific SMP3 melting point apparatus and
are uncorrected. Diastereomeric excess (de) was determined on a Shi-
madzu Prominence, equipped with a DAD detector and a Shimadzu SIL-
20A auto-injector. Optical rotation was determined with an AA-10 auto-
matic polarimeter from Optical Activity Ltd. Microwave reactions were
performed in a monomode microwave (MW) reactor equipped with an
autosampler (CEM Explorer). The temperature was controlled through-
out the reaction and was assessed by measuring the surface temperature
at the bottom of the reaction vessel by means of an infrared sensor. In all
cases, capped vessels were used, allowing a pressure to build-up. The
pressure was assessed by measuring the bulging of the septum, but never
exceeded 20 bar. Tetrahydrofuran (THF) was dried and distilled from
sodium benzophenone prior to use. PE was distilled prior to use. Benzo-
nitrile (2a), isobutyronitrile (2d), and benzaldehyde (3c) were dried, dis-
tilled, and stored under a dry nitrogen atmosphere. Other commercially
available chemicals were used as purchased.
Entry
Nitrile
Aldehyde
Isothiocyanate
Thiazine
Yield [%]
1
2
3
4
5
2a
2a
2b
2a
2a
3c
3a
3c
3a
3a
17a
17a
17a
17b
17c
18a
18b
18c
18d
18e
74
58
61
56
64
are tolerated in the formation of thiazines 18, which is in
contrast to the 4CR leading to DHPMs 6.
Conclusion
A four-component HWE/aza-DA approach for the synthesis
of a variety of DHPMs has been extensively explored. A
broad range of different R2 (nitrile) and R3 (aldehyde) sub-
stituents can be introduced on the DHPM scaffold by way
of this procedure. However, variation of R1 (phosphonate)
remains limited. Besides R1 = H, R1 = Me is tolerated de-
pending on the type of nitrile applied, but with other R1
groups in the phosphonate input a rearrangement reaction is
observed that results in a phosphoramidate as the main
product. The R4 substituent can be varied, although direct
formation of DHPMs is restricted to the use of isocyanates
that bear a strongly electron-withdrawing R4 substituent.
However, less electron-withdrawing R4 substituents can be
easily introduced by heating the initially formed DHPM
with appropriate isocyanates under microwave conditions.
Furthermore, we have demonstrated that, in particular, the
use of optically pure aldehydes as inputs results in diastereo-
selective formation of the corresponding DHPMs. Finally,
when the fourth component in our MCR was changed from
an isocyanate to an isothiocyanate, the final cyclocondensa-
tion could be directed towards the formation of thiazines in-
stead of DHPMs. In summary, the HWE/aza-DA 4CR is a
versatile reaction that can, in principle, be applied for the
synthesis of a broad variety of N1-unsubstituted DHPMs.
As such, this reaction represents a useful alternative to the
Biginelli three-component approach.
Diethyl methylphosphonate (1a): Triethyl phosphite (3.0 mL, 17.5 mmol)
and methyl iodide (1.95 mL, 31.3 mmol) were heated in a microwave
oven (maximum power 50 W, ramp time 10 min, hold time 5 min at
1308C). The ethyl iodide formed as a side product was distilled off at
408C and 10 mbar. Yield: 97%; 1H NMR (250.13 MHz, CDCl3): d =
1.34 (t, J = 7.0 Hz, 6H; CH3CH2), 1.48 (d, J = 17.5 Hz, 3H; CH3), 4.04–
4.10 ppm (m, 4H; CH2); 13C NMR (50.32 MHz, CDCl3): d = 10.4 (d, J
= 144.2 Hz), 15.7 (d, J = 6.2 Hz), 60.6 ppm (d, J = 6.2 Hz); 31P NMR
(101.25 MHz, CDCl3): d = 29.7 ppm.[21]
Diethyl ethylphosphonate (1b): Triethyl phosphite (1.0 mL, 5.83 mmol)
and ethyl bromide (0.44 mL, 5.83 mmol) were heated in a microwave
oven (maximum power 50 W, ramp time 10 min, hold time 15 min at
2008C and 10 min at 1808C). Ethyl bromide was distilled off from the re-
sulting solution at 408C and 100 mbar. Yield: 100%; 1H NMR
(200.13 MHz, CDCl3): d
CH3CH2P), 1.00 (t, J
= 0.83 (dt, J = 19.9 Hz, J = 7.7 Hz, 3H;
=
7.1 Hz, 6H; CH3CH2O), 1.32–1.49 (m, 2H;
CH2P), 3.70–3.83 ppm (m, 4H; CH2O); 13C NMR (50.32 MHz, CDCl3): d
= 6.3 (d, J = 6.8 Hz), 16.2 (d, J = 6.0 Hz), 18.5 (d, J = 142.6 Hz),
61.1 ppm (d,
J = d =
6.5 Hz); 31P NMR (101.25 MHz, CDCl3):
34.4 ppm.[21]
Diethyl benzylphosphonate (1c): Triethyl phosphite (3.0 mL, 17.5 mmol)
and benzyl bromide (2.71 mL, 22.75 mmol) were heated in a microwave
oven (maximum power 200 W, ramp time 10 min, hold time 15 min at
1408C). Ethyl bromide (408C/100 mbar) and diethyl ethylphosphonate
(908C/20 mbar) were distilled off to leave the pure product. Yield: 98%;
1H NMR (250.13 MHz, CDCl3): d = 1.26 (t, J = 7.0 Hz, 6H; CH3), 3.18
(d, J = 21.7 Hz, 2H; CH2Ph), 3.97–4.10 (m, 4H; CH2), 7.25–7.34 ppm
(m, 5H; Ph-H); 13C NMR (50.32 MHz, CDCl3): d
6.0 Hz), 33.5 (d, J = 138.0 Hz), 61.9 (d, J 6.8 Hz), 126.6 (d, J
=
16.1 (d, J
=
=
=
3.6 Hz), 128.3 (d, J = 3.1 Hz; 2C), 129.6 (d, J = 6.5 Hz, 2C), 131.4 ppm
(d, J = 9.1 Hz); 31P NMR (101.25 MHz, CDCl3): d = 27.6 ppm.[21]
Diethyl allylphosphonate (1d): Triethyl phosphite (1.0 mL, 5.83 mmol)
and allyl bromide (0.6 mL, 6.93 mmol) were heated in a microwave oven
(maximum power 250 W, ramp time 10 min, hold time 5 min at 1808C).
Ethyl bromide was distilled off from the resulting solution at 408C and
100 mbar. Yield: 94%; 1H NMR (250.13 MHz, CDCl3): d = 1.35 (t, J =
7.1 Hz, 6H; CH3), 2.64 (dd, J = 7.4 Hz, J = 21.9 Hz, 2H; PCH2), 4.08–
4.20 (m, 4H; CH2CH3), 5.22–5.29 (m, 2H; CH2=CH), 5.77–5.88 ppm (m,
1H; CH); 13C NMR (50.32 MHz, CDCl3): d = 16.0 (d, J = 6.0 Hz), 31.4
Experimental Section
General: All reactions were carried out under dry nitrogen or argon. 1H
and 13C nuclear magnetic resonance (NMR) spectra were recorded on a
Bruker AC 200 (200.13 and 50.32 MHz, respectively), a Bruker Avance
250 MHz (250.13 and 62.90 MHz, respectively), or
a Bruker MSL
(d,
J
=
139.3 Hz), 61.5 (d,
J
=
6.6 Hz), 119.5 (d,
J = 14.4 Hz),
400 MHz spectrometer (400.13 and 100.61 MHz, respectively); chemical
shifts (d) are given in ppm, internally referenced to residual solvent reso-
nances (1H: d = 7.29 ppm, 13C: d = 77.0 ppm). 31P NMR spectra were
recorded on the Bruker Avance 250 MHz instrument at 101.25 MHz.
Column chromatography was performed on Baker 7024–02 silica gel
(40 mm, 60 Š) with petroleum ether (PE, boiling range 40–608C) and
ethyl acetate (EA) as eluents. Thin-layer chromatography (TLC) was per-
formed using silica plates from Merck (Kieselgel 60 F254 on aluminium
with fluorescence indicator). Compounds on the TLC plates were visual-
ised under UV light or by treatment with an anisaldehyde solution. High-
127.2 ppm (d,
27.9 ppm.[21]
J
=
11.2 Hz); 31P NMR (101.25 MHz, CDCl3):
d =
General procedure for the synthesis of 6, 11, 13, 15, and 16 by the HWE/
aza-DA reaction: nBuLi (1.6m in hexane; 1.2 equiv) was added dropwise
to a stirred solution of phosphonate 1 (0.2m in dry THF) at ꢀ788C. The
resulting solution was stirred for 1.5 h and then nitrile 2 (1.1 equiv) was
added. The reaction mixture was allowed to warm to ꢀ58C over 1.5 h
and then aldehyde 3 (1.1 equiv) was added. The mixture was stirred for a
further 0.5 h at ꢀ58C and thereafter for 1.5 h at room temperature. Iso-
7184
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7178 – 7189

Four-Component Heterocycle Synthesis
FULL PAPER
cyanate 5 (1.1 equiv) was then added dropwise over 10 min and the re-
sulting solution was stirred overnight. The solvent was removed under re-
duced pressure and the crude product was purified by crystallisation,
column chromatography (PE/EA, 4:1 ! 1:1) or column chromatography
and recrystallisation.
(100.61 MHz, CDCl3): d
=
21.9, 55.8, 59.5, 100.0, 107.7, 112.1, 114.7
(2C), 126.1, 129.2 (2C), 129.3 (4C), 133.3, 136.7, 143.4, 144.6, 146.5,
150.8, 160.2 ppm; IR (KBr): n˜ = 3243 (w), 3121 (w), 1697 (s), 1684 (s),
1510 (m), 1169 cmꢀ1 (s); HRMS: m/z: 424.1118 [M]+; calcd for
C22H20N2O5S: 424.1093.
4-(4-Methoxyphenyl)-6-phenyl-3-tosyl-3,4-dihydropyrimidin-2
(6a): The product was crystallised from THF. Yield: 65%; m.p. 179–
1828C [THF]; 1H NMR (250.13 MHz, CDCl3):
2.32 (s, 3H;
A
6-Isopropyl-4-(4-methoxyphenyl)-3-tosyl-3,4-dihydropyrimidin-2(1H)-one
G
(6g): The product was crystallised from THF. Yield: 73%; m.p. 178–
d
=
1798C [THF]; 1H NMR (200.13 MHz, CDCl3): d = 1.01 (d, J = 6.9 Hz,
CH3C6H4), 3.83 (s, 3H; CH3O), 5.51 (d, J = 6.1 Hz, 1H; CHC), 6.15 (d,
J = 6.1 Hz, 1H; CHN), 6.88 (d, J = 8.6 Hz, 2H; Ph-H), 6.99 (d, J =
8.3 Hz, 2H; Ph-H), 7.34–7.53 (m, 9H; Ph-H), 7.93 ppm (s, 1H; NH); 13C
NMR (50.32 MHz, CDCl3): d = 21.4, 55.3, 59.1, 101.7, 114.2 (2C), 125.2
(2C), 125.3 (2C), 128.5 (2C), 128.7 (2C), 128.9 (2C), 129.3, 132.9 (2C),
134.0, 136.0, 143.9, 150.5, 159.6 ppm; IR (KBr): n˜ = 3243 (m), 3125 (m),
2932 (m), 1691 (s), 1356 (s), 1248 (s), 1168 cmꢀ1 (s); HRMS (EI): m/z:
434.1285 [M]+; calcd for C24H22N2O4S: 434.1300.
6H; (CH3)2CH), 2.15–2.26 (m, 1H; CH(CH3)2), 2.26 (s, 3H; CH3C6H4),
G
3.76 (s, 3H; CH3O), 4.84 (d, J = 5.7 Hz, 1H; CHC), 5.83 (d, J = 5.7 Hz,
1H; CHN), 6.82 (d, J = 8.7 Hz, 2H; Ph-H), 7.01 (d, J = 8.4 Hz, 2H; Ph-
H), 7.22–7.30 (m, 4H; Ph-H), 7.61 ppm (s, 1H; NH); 13C NMR
(100.61 MHz, CDCl3): d = 19.1, 19.2, 20.5, 29.9, 54.4, 58.1, 97.7, 113.1
(2C), 127.6 (2C), 127.8 (2C), 127.9 (2C), 132.8, 135.6, 138.9, 142.9, 149.8,
158.7 ppm; IR (KBr): n˜ = 3223 (m), 3111 (m), 2969 (m), 1676 (s), 1510
(s), 1343 (s), 1169 cmꢀ1 (s); HRMS (EI): m/z: 400.1444 [M]+; calcd for
C21H24N2O4S: 400.1457.
4-(4-Chlorophenyl)-6-phenyl-3-tosyl-3,4-dihydropyrimidin-2
(6b): The product was crystallised from THF. Yield: 80%; m.p. 186–
1898C [THF]; 1H NMR (200.13 MHz, CDCl3):
2.35 (s, 3H;
A
4-(4-Chlorophenyl)-6-isopropyl-3-tosyl-3,4-dihydropyrimidin-2(1H)-one
G
d
=
(6h): The product was crystallised from THF. Yield: 65%; m.p. 186–
CH3C6H4), 5.39 (d, J = 6.1 Hz, 1H; CHC), 6.05 (d, J = 6.1 Hz, 1H;
CHN), 7.00 (d, J = 8.5 Hz, 2H; Ph-H), 7.24–7.45 (m, 12H; Ph-H and
NH); 13C NMR (50.32 MHz, CDCl3): d = 21.4, 58.8, 100.8, 125.2, 128.5
(2C), 128.7 (2C), 128.9 (6 C), 129.5 (2C), 132.6, 134.2, 134.6, 135.7, 139.2,
144.4, 150.3; IR (KBr): n˜ = 3239 (m), 3122 (m), 1693 (s), 1681 (s), 1360
(s), 1171 cmꢀ1 (s); HRMS (EI): m/z: 438.0809 [M]+; calcd for
C23H19ClN2O3S: 438.0805.
1878C [THF]; 1H NMR (400.13 MHz, CDCl3): d = 1.08 (d, J = 6.8 Hz,
6H; (CH3)2CH), 2.20–2.30 (m, 1H; CH(CH3)2), 2.33 (s, 3H; CH3C6H4),
U
4.87 (d, J = 5.3 Hz, 1H; CHC), 5.9 (d, J = 5.3 Hz, 1H; CHN), 7.03–7.35
(m, 8H; Ph-H), 7.90 ppm (s, 1H; NH); 13C NMR (100.61 MHz, CDCl3):
d = 20.1 (2C), 21.5, 30.6, 58.8, 97.9, 128.7 (4C), 128.9 (2C), 129.0 (2C),
134.1, 136.3, 140.2, 140.7, 144.3, 155.0 ppm; IR (KBr): n˜ = 3225 (m),
3117 (m), 2962 (m), 1705 (s), 1676 (s), 1344 (s), 1169 cmꢀ1 (s); HRMS
(EI): m/z: 404.0961 [M]+; calcd for C20H21ClN2O3S: 404.0961.
4,6-Diphenyl-3-tosyl-3,4-dihydropyrimidin-2(1H)-one (6c): The product
A
was purified by column chromatography and recrystallised from THF/
pentane. Yield: 71%; m.p. 183–1858C [THF]; 1H NMR (250 MHz,
CDCl3): d = 2.33 (s, 3H; CH3C6H4), 5.52 (d, J = 6.1 Hz, 1H; CHC),
6.17 (d, J = 6.1 Hz, 1H; CHN), 7.00 (d, J = 8.2 Hz, 2H; Ph-H), 7.29–
7.48 (m, 12H; Ph-H), 7.65 ppm (s, 1H; NH); 13C NMR (50.32 MHz,
CDCl3): d = 21.4, 59.6, 101.4, 125.2 (2C), 127.2 (2C), 128.4, 128.5 (2C),
128.8 (2C), 128.9 (4C), 129.4, 132.8, 134.3, 135.8, 140.7, 144.0, 150.5 ppm;
IR (KBr): n˜ = 3242 (m), 2986 (m), 1696 (s), 1683 (s), 1395 (s), 1361 (s),
1169 (s), 1086 cmꢀ1 (s); HRMS (EI): m/z: 404.1193 [M]+; calcd for
C23H20N2O3S: 404.1195.
6-Isopropyl-4-phenyl-3-tosyl-3,4-dihydropyrimidin-2(1H)-one (6i): The
A
product was purified by column chromatography. Yield: 55%; m.p. 178–
1808C [EA]; 1H NMR (200.13 MHz, CDCl3): d = 1.05 (d, J = 6.8 Hz,
6H; (CH3)2CH), 2.15–2.30 (m, 1H; CH(CH3)2), 2.29 (s, 3H; CH3C6H4),
G
4.91 (d, J = 5.7 Hz, 1H; CHC), 5.91 (d, J = 5.7 Hz, 1H; CHN), 6.98 (d,
J = 8.3 Hz, 2H; Ph-H), 7.21–7.30 (m, 8H; Ph-H), 7.97 ppm (s, 1H; NH);
13C NMR (50.32 MHz, CDCl3): d = 19.9, 20.0, 21.4, 30.8, 59.5, 98.2, 127.2
(2C), 128.2, 128.4 (2C), 128.7 (2C), 128.8 (2C), 136.2, 140.1, 141.5, 143.8,
151.1 ppm; IR (KBr): n˜ = 3219 (m), 3107 (m), 2962 (m), 1705 (s), 1678
(s), 1356 (s), 1169 cmꢀ1 (s); HRMS (EI): m/z: 370.1358 [M]+; calcd for
C20H22N2O3S: 370.1351.
4-(4-(Dimethylamino)phenyl)-6-phenyl-3-tosyl-3,4-dihydropyrimidin-2-
A
4-(4-(Dimethylamino)phenyl)-6-isopropyl-3-tosyl-3,4-dihydropyrimidin-2-
Yield: 54%; m.p. 187–1898C [EA]; 1H NMR (250.13 MHz, CDCl3): d =
2.28 (s, 3H; CH3C6H4), 2.94 (s, 6H; (CH3)2N), 5.45 (d, J = 6.1 Hz, 1H;
CHC), 6.03 (d, J = 6.1 Hz, 1H; CHN), 6.68 (d, J = 8.8 Hz, 2H; Ph-H),
7.00 (d, J = 8.2 Hz, 2H; Ph-H), 7.28–7.40 (m, 10H; Ph-H and NH); 13C
NMR (100.61 MHz, CDCl3): d = 21.4, 40.6 (2C), 59.5, 102.3, 112.5 (2C),
125.3 (2C), 128.4, 128.6 (4C), 129.0 (2C), 129.1 (2C), 129.3, 133.3, 133.8,
136.5, 143.7, 150.6, 150.8; IR (KBr): n˜ = 3208 (m), 3108 (m), 2926 (m),
1674 (s), 1522 (s), 1350 (s), 1169 cmꢀ1 (s); HRMS (EI): m/z: 447.1621
[M]+; calcd for C25H25N3O3S: 447.1617.
ACHTREUNG
AHCTREUNG
CH3C6H4), 2.94 (s, 6H; (CH3)2N), 4.88 (d, J = 5.7 Hz, 1H; CHC), 5.83
(d, J = 5.7 Hz, 1H; CHN), 6.62 (d, J = 8.8 Hz, 2H; Ph-H), 6.99 (d, J =
8.2 Hz, 2H; Ph-H), 7.15–7.29 (m, 4H; Ph-H), 7.40 ppm (s, 1H; NH); 13C
NMR (100.61 MHz, CDCl3): d = 20.6 (2C), 21.9, 31.02, 41.0 (2C), 59.8,
99.3, 112.9 (2C), 128.9 (2C), 129.0 (2C), 129.3 (2C), 129.6, 137.2, 139.9,
143.9, 151.1, 151.3 ppm; IR (KBr): n˜ = 3230 (m), 2971 (m), 1676 (s),
1350 (s), 1169 cmꢀ1 (s); HRMS (EI): m/z: 413.1755 [M]+; calcd for
C22H27N3O3S: 413.1773.
4-(3-Nitrophenyl)-6-phenyl-3-tosyl-3,4-dihydropyrimidin-2
The product was purified by column chromatography. Yield: 38%; m.p.
195–1978C [EA]; 1H NMR (200.13 MHz, CDCl3): d
2.30 (s, 3H;
A
=
6-Isopropyl-4-(3-nitrophenyl)-3-tosyl-3,4-dihydropyrimidin-2(1H)-one
N
CH3C6H4), 5.47 (d, J = 6.1 Hz, 1H; CHC), 6.27 (d, J = 6.1 Hz, 1H;
CHN), 7.07 (d, J = 8.4 Hz, 2H; m-CH (Ts)), 7.42–7.54 (m, 7H; Ph-H),
7.73 (d, J = 7.8 Hz, 1H; Ph-H), 8.00 (s, 1H, NH), 8.14–8.17 ppm (m, 2H;
Ph-H); 13C NMR (100.61 MHz, CDCl3): d = 21.6, 59.7, 99.9, 121.9, 123.3,
125.3 (2C), 129.0 (4C), 129.2 (2C), 130.0, 130.1, 132.5, 133.0, 135.7, 135.8,
142.9, 145.0, 148.6, 149.8 ppm; IR (KBr): n˜ = 3217 (m), 3106 (m), 1694
(s), 1676 (s), 1528 (s), 1348 (s), 1169 cmꢀ1 (s); HRMS (EI): m/z: 449.1064
[M]+; calcd for C23H19N3O5S: 449.1045.
(6k): The product was purified by column chromatography. Yield: 60%;
m.p. 155–1578C [EA]; 1H NMR (250.13 MHz, CDCl3): d = 1.14 (d, J =
6.1 Hz, 6H; (CH3)2CH), 2.25–2.35 (m, 1H; CH(CH3)2), 2.33 (s, 3H;
G
CH3C6H4), 4.97 (d, J = 5.3 Hz, 1H; CHC), 6.11 (d, J = 5.3 Hz, 1H;
CHN), 7.07 (d, J = 8.0 Hz, 2H; m-CH (Ts)), 7.49–7.57 (m, 4H; Ph-H),
7.67 (d, J = 7.7 Hz, 1H; CH (3-NO2C6H4)), 8.14–8.18 ppm (m, 2H; Ph-H
and NH); 13C NMR (100.61 MHz, CDCl3): d = 20.1 (2C), 21.5, 30.7,
58.5, 96.9, 122.0, 123.1, 128.8 (2C), 128.9 (2C), 130.0, 133.1, 136.0, 141.9,
143.6, 144.7, 148.5, 150.7 ppm; IR (KBr): n˜ = 3243 (m), 2967 (m), 1676
(s), 1535 (s), 1356 (s), 1169 (s), 689 (m), 573 cmꢀ1 (m); HRMS (EI): m/z:
415.1223 [M]+; calcd for C20H21N3O5S: 415.1202.
6-(Furan-2-yl)-4-(4-methoxyphenyl)-3-tosyl-3,4-dihydropyrimidin-2(1H)-
A
one (6 f): The product was crystallised from Et2O. Yield: 61%; m.p.
1148C (decomp) [Et2O]; 1H NMR (400.13 MHz, CDCl3): d = 2.26 (s,
3H; CH3C6H4), 3.74 (s, 3H; CH3O), 5.56 (dd, J = 1.2 Hz, J = 6.1 Hz,
1H; CHC), 6.04 (d, J = 6.1 Hz, 1H; CHN), 6.38 (dd, J = 1.6 Hz, J =
3.2 Hz, 1H; CH (furan)), 6.58 (d, J = 3.2 Hz, 1H; CH (furan)), 6.77 (d,
J = 8.6 Hz, 2H; m-CH (C6H4OMe)), 6.99 (d, J = 8.1 Hz, 2H; m-CH
(Ts)), 7.25 (d, J = 8.6 Hz, 2H; o-CH (C6H4OMe)), 7.32–7.34 (m, 3H;
CH (furan) and o-CH (Ts)), 7.71 ppm (s, 1H; NH); 13C NMR
6-Isopropyl-4-(4-nitrophenyl)-3-tosyl-3,4-dihydropyrimidin-2(1H)-one
R
(6l): The product was purified by column chromatography and recrystal-
lised from THF/pentane. Yield: 55%; m.p. 170–1718C [THF]; 1H NMR
(400.13 MHz, CDCl3): d = 1.07 (d, J = 6.5 Hz, 6H; (CH3)2CH), 2.11–
2.28 (m, 1H; CH
A
1H; CHC), 6.05 (d, J = 5.4 Hz, 1H; CHN), 6.91 (s, 1H; NH), 7.10 (d, J
Chem. Eur. J. 2006, 12, 7178 – 7189
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7185

= 8.2 Hz, 2H; m-CH (Ts)), 7.44–7.47 (m, 4H; o-CH (Ts) and o-CH (4-
NO2C6H4)), 8.16 ppm (d, J
8.2 Hz, 2H; m-CH (4-NO2C6H4)); 13C
6-(Furan-2-yl)-4-isopropyl-3-tosyl-3,4-dihydropyrimidin-2(1H)-one (6r):
G
R. V. A. Orru et al.
=
The product was purified by column chromatography. Yield: 36%; m.p.
908C (decomp) [EA]; 1H NMR (400 MHz, CDCl3): d = 0.92 (d, J =
6.8 Hz, 3H; CH3CH), 1.01 (d, J = 6.9 Hz, 3H; CH3CH), 2.24–2.29 (m,
NMR (100.61 MHz, CDCl3): d = 20.0, 20.1, 21.6, 30.7, 58.7, 97.0, 124.2
(2C), 127.7 (2C), 128.9 (4C), 135.9, 141.4, 144.9, 147.7, 148.4, 150.2 ppm;
IR (KBr): n˜ = 3211 (w), 3113 (w), 2963 (w), 1709 (m), 1680 (s), 1522 (s),
1346 (s), 1171 cmꢀ1 (s); HRMS (EI): m/z: 415.1218 [M]+; calcd for
C20H21N3O5S: 415.1202.
1H; CH(CH3)2), 2.39 (s, 3H; CH3C6H4), 5.05–5.09 (m, 1H; CHN), 5.47
G
(dd, J = 6.2 Hz, J = 1.9 Hz, 1H; CHC), 6.44 (dd, J = 1.6 Hz, J =
3.5 Hz, 1H; CHCHO (furan)), 6.51 (d, J = 3.5 Hz, 1H; CHC (furan)),
7.08 (s, 1H; NH), 7.26 (d, J = 8.1 Hz, 2H; m-CH (Ts)), 7.40 (d, J =
1.6 Hz, 1H; CHO (furan)), 7.88 ppm (d, J = 8.1 Hz, 2H; o-CH (Ts));
13C NMR (100.61 MHz, CDCl3): d = 15.7, 18.2, 21.5, 35.3, 61.4, 95.6,
106.6, 111.6, 127.6, 128.7 (2C), 129.2 (2C), 136.5, 142.8, 144.4, 146.1,
150.5 ppm; IR: n˜ = 3243 (w), 2967 (w), 1696 (s), 1684 (s), 1177 cmꢀ1 (s);
HRMS: m/z: 360.1184 [M]+; calcd for C18H20N2O4S: 360.1143.
6-sec-Butyl-4-(4-methoxyphenyl)-3-tosyl-3,4-dihydropyrimidin-2(1H)-one
R
(6m): The product was crystallised from THF and was thereby obtained
as a 1:1 mixture of diastereomers. Yield: 49%; m.p. 170–1718C [THF];
1H NMR (250.13 MHz, CDCl3): d = 0.78 (t, J = 8.0 Hz, 6H; CH3CH),
1.09 (d, J = 8.2 Hz, 6H; CH3CH), 1.18–1.49 (m, 4H; CH2CH), 2.01–2.17
(m, 2H; CHCH3), 2.36 (s, 6H; CH3C6H4), 3.73 (s, 6H; CH3O), 4.90 (d, J
= 5.8 Hz, 2H; CHC), 5.87 (dd, J = 5.8 Hz, J = 3.2 Hz, 2H; CHN), 6.53
(s, 2H; NH), 6.82 (d, J = 8.7 Hz, 4H; o-CH (C6H4OMe)), 7.09 (d, J =
8.4 Hz, 4H; m-CH (Ts)), 7.28–7.41 ppm (m, 8H; NH); 13C NMR
(100.61 MHz, CDCl3): d = 10.8 (2C), 17.1, 17.4, 20.8 (2C), 26.1, 26.3,
36.8, 36.9, 54.7 (2C), 58.3, 58.4, 98.3, 98.6, 113.3 (4C), 127.9 (4C), 128.0
(4C), 128.2 (4C), 133.3, 133.4, 136.0 (2C), 138.6 (2C), 143.1 (2C), 149.6
(2C), 158.8 ppm (2C); IR (KBr): n˜ = 3239 (m), 2962 (m), 1681 (s), 1509
(m), 1345 (s), 1167 cmꢀ1 (s); HRMS (EI): m/z: 414.1603 [M]+; calcd for
C22H26N2O4S: 414.1613.
4,6-Diisopropyl-3-tosyl-3,4-dihydropyrimidin-2(1H)-one (6s): The prod-
U
uct was crystallised from THF. Yield: 40%; m.p. 177–1818C [THF]; 1H
NMR (400.13 MHz, CDCl3): d = 0.82 (d, J = 6.9 Hz, 3H; CH3CH), 0.91
(d, J = 6.9 Hz, 3H; CH3CH), 1.04 (d, J = 6.8 Hz, 6H; CH3CH), 2.08–
2.25 (m, 2H; CH(CH3)2), 4.70 (d, J = 5.7 Hz, 1H; CHC), 4.87 (t, J =
E
5.7 Hz, 1H; CHN), 6.87 (s, 1H; NH), 7.24 (d, J = 8.1 Hz, 2H; m-CH
(Ts)), 7.85 ppm (d, J = 8.1 Hz, 2H; o-CH (Ts)); 13C NMR (100.61 MHz,
CDCl3): d = 15.7, 18.5, 20.7, 20.9, 22.0, 31.1, 35.3, 61.5, 94.0, 129.1 (2C),
129.5 (2C), 137.4, 142.8, 144.6, 151.8 ppm; IR (KBr): n˜ = 3455 (w), 2961
(w), 1676 (s), 1350 (m), 1163 cmꢀ1 (m); HRMS (EI): m/z: 336.1516 [M]+;
calcd for C17H24N2O3S: 336.1508.
6-tert-Butyl-4-(4-methoxyphenyl)-3-tosyl-3,4-dihydropyrimidin-2(1H)-
N
one (6n): The product was purified by column chromatography. Yield:
1
16%; m.p. 197–2028C [EA]; H NMR (200.13 MHz, CDCl3): d = 1.10 (s,
4-(Benzyloxymethyl)-6-isopropyl-3-tosyl-3,4-dihydropyrimidin-2(1H)-one
C
9H; (CH3)3C), 2.31 (s, 3H; CH3C6H4), 3.81 (s, 3H; CH3O), 4.95 (d, J =
5.9 Hz, 1H; CHC), 5.89 (d, J = 5.9 Hz, 1H; CHN), 6.82 (d, J = 8.7 Hz,
2H; o-CH (C6H4OMe)), 7.03 (d, J = 8.2 Hz, 2H; m-CH (Ts)), 7.15–
7.26 ppm (m, 5H; Ph-H and NH); 13C NMR (100.61 MHz, CDCl3): d =
21.5, 27.7 (3C), 33.2, 55.4, 58.9, 98.4, 114.1 (2C), 128.6 (2C), 128.8 (4C),
133.7, 136.5, 142.0, 143.8, 150.8, 159.7 ppm; IR (KBr): n˜ = 3435 (m),
3237 (w), 2961 (m), 1676 (s), 1350 (s), 1260 (s), 1163 cmꢀ1 (s); HRMS
(EI): m/z: 414.1613 [M]+; calcd for C22H26N2O4S: 414.1613.
(6t): The product was purified by column chromatography. Yield: 21%;
m.p. 148–1498C [EA]; 1H NMR (400.13 MHz, CDCl3): d = 1.09 (d, J =
6.9 Hz, 6H; (CH3)2CH), 2.14–2.29 (m, 1H; CH(CH3)2), 2.42 (s, 3H;
A
CH3C6H4), 3.42–3.53 (m, 2H; CH2CH), 4.51 (s, 2H; CH2Ph), 4.87 (d, J =
5.2 Hz, 1H; CHC), 5.11–5.19 (m, 1H; CHN), 6.45 (s, 1H; NH), 7.22–
7.98 ppm (m, 9H; Ph-H); 13C NMR (62.90 MHz, CDCl3): d = 20.2 (2C),
21.6, 30.6, 55.1, 72.0, 73.1, 95.1, 127.4 (2C), 127.6, 128.0 (2C), 128.9 (2C),
129.0 (2C), 136.9, 138.0, 143.1, 144.2, 150.8 ppm; IR (KBr): n˜ = 3221
(w), 3115 (w), 2963 (w), 1699 (s), 1670 (s), 1348 (s), 1167 cmꢀ1 (s);
HRMS (EI): m/z: 414.1612 [M]+; calcd for C22H26N2O4S: 414.1613.
4-(4-Chlorophenyl)-6-propyl-3-tosyl-3,4-dihydropyrimidin-2(1H)-one
A
(6o): The product was purified by column chromatography. Yield:
< 5%; m.p. 144–1478C [EA]; 1H NMR (200.13 MHz, CDCl3): d = 0.90
(t, J = 7.3 Hz, 3H; CH3CH2), 1.43–1.57 (m, 2H; CH2CH3), 2.03 (t, J =
7.4 Hz, 2H; CH2C), 2.34 (s, 3H; CH3C6H4), 4.90 (d, J = 5.8 Hz, 1H;
CHC), 5.90 (d, J = 5.8 Hz, 1H; CHN), 7.05–7.39 ppm (m, 9H; Ph-H and
NH); 13C NMR (62.9 MHz, CDCl3): d = 13.3, 19.7, 21.5, 33.8, 59.0, 100.2,
127.8 (2C), 128.5 (2C), 128.7 (2C), 128.9 (2C), 134.1, 134.8, 136.2, 140.1,
144.4, 150.4 ppm; IR (KBr): n˜ = 3223 (m), 3113 (m), 2961 (m), 1709 (s),
1680 (s), 1356 (s), 1167 (s), 1088 cmꢀ1 (s); HRMS (EI): m/z: 404.0940
[M]+; calcd for C20H21ClN2O3S: 404.0961.
4-(4-Methoxyphenyl)-5-methyl-6-phenyl-3-tosyl-3,4-dihydropyrimidin-2-
A
1
35%; m.p. 194–1958C [EA]; H NMR (400.13 MHz, CDCl3): d = 1.65 (s,
3H; CH3C), 2.32 (s, 3H; CH3C6H4), 3.83 (s, 3H; CH3O), 5.75 (s, 1H;
CHN), 6.28 (s, 1H; NH), 6.85 (dd, J = 6.7 Hz, J = 2.0 Hz, 2H; m-CH
(Ph)), 7.04 (d, J = 8.3 Hz, 2H; m-CH (Ts)), 7.28–7.40 ppm (m, 9H; Ph-
H); 13C NMR (100.61 MHz, CDCl3): d = 15.7, 21.5, 55.4, 63.9, 109.8,
114.2 (2C), 128.5 (2C), 128.7 (2C), 128.8, 128.9 (2C), 129.0 (2C), 129.1
(3C), 132.2, 133.8, 136.4, 144.0, 149.6, 159.9 ppm; IR (KBr): n˜ = 3208
(m), 3102 (m), 2932 (m), 1680 (s), 1511 (m), 1351 (m), 1167 cmꢀ1 (s);
HRMS (EI): m/z: 448.1465 [M]+; calcd for C25H24N2O4S: 448.1457.
4-Isopropyl-6-phenyl-3-tosyl-3,4-dihydropyrimidin-2(1H)-one (6p): The
G
product was purified by column chromatography. Yield: 35%; m.p. 170–
1718C [THF]; 1H NMR (400.13 MHz, CDCl3): d = 0.88 (d, J = 6.8 Hz,
3H; CH3CH), 0.96 (d, J = 6.8 Hz, 3H; CH3CH), 2.18–2.31 (m, 1H; CH-
6-(Furan-2-yl)-4-(4-methoxyphenyl)-5-methyl-3-tosyl-3,4-dihydropyrimi-
din-2(1H)-one (6v): The product was crystallised from ethyl acetate.
R
A
Yield: 90%; m.p. 202–2048C (decomp) [EA]; 1H NMR (200.13 MHz,
CDCl3): d = 1.89 (s, 3H; CH3C), 2.32 (s, 3H; CH3C6H4), 3.81 (s, 3H;
CH3O), 5.77 (s, 1H; CHN), 6.45–6.48 (m, 2H; CH (furan)), 6.78 (s, 1H;
NH), 6.82 (d, J = 8.8 Hz, 2H; m-CH (C6H4OMe)), 7.06 (d, J = 8.2 Hz,
2H; m-CH (Ts)), 7.31 (d, J = 8.8 Hz, 2H; o-CH (C6H4OMe)), 7.39 (d, J
= 8.2 Hz, 2H; o-CH (Ts)), 7.41–7.45 ppm (m, 1H; CHO (furan)); 13C
NMR (50.32 MHz, CDCl3): d = 16.1, 21.4, 55.2, 64.0, 109.9, 110.0, 111.6,
114.0 (2C), 120.5, 128.6 (2C), 128.8 (2C), 129.0 (2C), 131.5, 136.1, 142.0,
144.0, 145.8, 149.5, 159.7 ppm; IR (KBr): n˜ = 3225 (m), 3116 (m), 2925
(w), 1688 (s), 1674 (s), 1510 (s), 1258 cmꢀ1 (s); HRMS (EI): m/z:
438.1261 [M]+; calcd for C23H22N2O5S: 438.1249.
6.1 Hz, J = 1.4 Hz, 1H; CHN), 6.68 (s, 1H; NH), 7.32 (s, 3H; Ph-H),
7.82–7.84 (m, 4H; Ph-H), 7.83 ppm (d, J = 8.2 Hz, 2H; Ph-H); 13C NMR
(100.61 MHz, CDCl3): d = 16.1, 18.7, 22.0, 35.7, 61.9, 98.2, 125.6 (2C),
129.3 (2C), 129.5 (2C), 129.6 (2C), 129.9, 133.7, 136.9, 137.0, 144.8,
151.2 ppm; IR (KBr): n˜ = 3238 (m), 2965 (m), 1693 (s), 1674 (s), 1344
(s), 1171 cmꢀ1 (s); HRMS (EI): m/z: 369.1280 [M]+; calcd for
C20H22N2O3S: 369.1273.
4-Methyl-6-phenyl-3-tosyl-3,4-dihydropyrimidin-2(1H)-one (6q): The
A
product was purified by column chromatography and recrystallised from
THF/pentane. Yield: 15%; m.p. 177–1798C [THF]; 1H NMR
(200.13 MHz, CDCl3): d = 1.45 (d, J = 6.5 Hz, 3H; CH3CHN), 2.40 (s,
3H; CH3C6H4), 5.21–5.35 (m, 1H; CHCH3), 5.40 (dd, J = 6.2 Hz, J =
1.9 Hz, 1H; CHC), 6.89 (s, 1H; NH), 7.26 (d, J = 8.2 Hz, 2H; o-CH
(Ts)), 7.38 (s, 5H; Ph-H), 7.93 ppm (d, J = 8.2 Hz, 2H; m-CH (Ts)); 13C
NMR (250.13 MHz, CDCl3): d = 22.0, 22.7, 52.6, 102.9, 125.5 (2C), 129.3
(2C), 129.4 (2C), 129.6 (2C), 129.9, 133.5, 135.7, 137.1, 144.9, 150.6 ppm;
IR (KBr): n˜ = 3236 (m), 3116 (m), 1693 (s), 1678 (s), 1409 (s), 1345 (s),
1162 cmꢀ1 (s); HRMS (EI): m/z: 342.1062 [M]+; calcd for C18H18N2O3S:
342.1038.
4-(4-Methoxyphenyl)-3-(4-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2-
A
26%; m.p. 211–2148C [THF]; 1H NMR (250.13 MHz, CDCl3): d = 3.77
(s, 3H; CH3O), 5.34 (d, J = 5.1 Hz, 1H; CHC), 5.45 (d, J = 5.1 Hz, 1H;
CHN), 6.79–8.14 ppm (m, 14H; Ph-H and NH); 13C NMR (100.61 MHz,
CDCl3): d = 55.3, 63.8, 100.1, 114.5 (2C), 124.2 (2C), 125.1 (2C), 127.4
(2C), 127.8 (2C), 129.0 (2C), 129.5, 133.1, 133.6, 134.7, 145.4, 147.1,
152.4, 159.6 ppm; IR (KBr): n˜ = 3225 (w), 3109 (w), 1667 (s), 1510 (s),
7186
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7178 – 7189

Four-Component Heterocycle Synthesis
FULL PAPER
1345 cmꢀ1 (s); HRMS (EI): m/z: 401.1387 [M]+; calcd for C23H19N3O4:
401.1376.
136.0 (d, J = 1.2 Hz), 141.0 ppm (d, J = 3.3 Hz); 31P NMR (101.25 MHz,
CDCl3): d = 6.0 ppm.
Methyl
6-(4-methoxyphenyl)-2-oxo-4-phenyl-2,3-dihydropyrimidine-1-
(Z)-Diethyl
methyl(3-methyl-1-phenylbut-1-en-2-yl)phosphoramidate
A
(7c): Application of the general procedure (see above) using 1c and 2b
with overnight stirring gave 7c. Yield: 20%; 1H NMR (400.13 MHz,
CDCl3): d = 1.18 (d, J = 6.8 Hz, 6H; (CH3)2CH), 1.28 (td, J = 7.1 Hz,
J = 0.7 Hz, 6H; CH3CH2O), 2.72 (d, J = 8.8 Hz, 3H; NCH3), 2.73–2.81
raphy. Yield: 70%; m.p. 147–1508C [EA]; 1H NMR (400.13 MHz,
CDCl3): d = 3.68 (s, 3H; CH3), 3.80 (s, 3H; CH3), 5.49 (dd, J = 6.4 Hz,
J = 1.5 Hz, 1H; CHC), 5.87 (d, J = 6.4 Hz, 1H; CHN), 6.80 (d, J =
8.6 Hz, 2H; Ph-H), 7.00 (s, 1H; NH), 7.29–7.41 ppm (m, 7H; Ph-H); 13C
NMR (100.61 MHz, CDCl3): d = 54.6, 55.7, 57.2, 102.2, 114.6 (2C), 125.6
(2C), 128.6 (2C), 129.5 (2C), 129.9, 132.6, 133.6, 135.6, 150.7, 155.0,
159.9 ppm; IR (KBr): n˜ = 3259 (m), 2910 (m), 1734 (s), 1694 (s), 1408
(s), 1268 cmꢀ1 (s); HRMS: m/z: 338.1251 [M]+; calcd for C19H18N2O4:
338.1267.
(m, 1H; CH
C
4.0 ppm. Besides 1c and 7c, 10–20% of another phosphonate was identi-
fied.[23]
(E)-Diethyl
N-(methyl)-N-(1-phenylbuta-1,3-dienyl)phosphoramidate
(7d): Application of the general procedure (see above) using 1d and 2a
with overnight stirring gave 7d and 10.
Methyl 4-isopropyl-6-(4-methoxyphenyl)-2-oxo-2,3-dihydropyrimidine-1-
7d: Yield: 37%; 1H NMR (400.13 MHz, CDCl3): d = 1.16–1.20 (m, 6H;
CH3CH2O), 2.62 (d, J = 8.9 Hz, 3H; NCH3), 3.94–4.04 (m, 4H; OCH2),
4.86 (d, J = 9.4 Hz, 1H; =CH2), 5.11 (d, J = 16.0 Hz, 1H; =CH2), 6.10–
6.38 ppm (m, 2H; =CHCH=), 7.16–7.53 ppm (m, 5H; Ph-H); 31P NMR
(101.25 MHz, THF): d = 6.2 ppm.
ACHTREUNG
a
ACHTREUNG
J
=
(E)-Diethyl
1-(methylamino)-1-phenylbuta-1,3-dien-2-ylphosphonate
1
(C6H4OMe)), 7.58 ppm (s, 1H; NH); 13C NMR (100.61 MHz, CDCl3): d
= 20.4, 20.8, 20.9, 54.3, 55.6, 57.0, 99.0, 114.5 (2C), 128.5 (2C), 133.4,
141.7, 151.7, 155.1, 159.7 ppm; IR (KBr): n˜ = 3240 (w), 2962 (w), 1770
(s), 1714 (s), 1512 (m), 1255 cmꢀ1 (s); HRMS: m/z: 304.1433 [M]+; calcd
for C16H20N2O4: 304.1423.
(10): Yield: 63%; H NMR (400.13 MHz, CDCl3): d = 1.16–1.20 (m, 6H;
CH3CH2O), 2.89 (d, J = 6.5 Hz, 3H; NCH3), 3.73–4.04 (m, 4H; OCH2),
5.35 (d, J = 6.8 Hz, 1H; =CH2), 5.62–5.69 (m, 1H; =CH2), 6.98–7.14 (m,
1H; CH=CH2), 7.17–7.53 ppm (m, 5H; Ph-H); 31P NMR (101.25 MHz,
THF): d = 22.1 ppm.
3-Benzoyl-4-(4-methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-
A
Trapping experiment with H2O
one (6z): The product was crystallised from THF. Yield: 70%; m.p. 186–
1878C (decomp) [THF]; 1H NMR (400.13 MHz, CDCl3): d = 3.78 (s,
3H; CH3), 5.74 (d, J = 6.3 Hz, 1H; CHC), 6.01 (d, J = 6.3 Hz, 1H;
CHN), 6.87 (d, J = 8.8 Hz, 2H; o-CH (C6H4OMe)), 7.35–7.46 (m, 10H;
Ph-H), 7.57–7.59 ppm (m, 2H; o-CH (COPh)); 13C NMR (100.61 MHz,
CDCl3): d = 55.3, 55.9, 102.9, 114.1 (2C), 125.1 (2C), 127.8 (2C), 128.0
(2C), 128.4 (2C), 129.1 (2C), 129.5, 131.2, 132.0, 133.0, 135.4, 136.3,
152.3, 159.4, 171.7 ppm; IR (KBr): n˜ = 3282 (s), 2968 (w), 2839 (w), 1702
(s), 1688 (s), 1509 (s), 1396 cmꢀ1 (s); HRMS (EI): m/z: 384.1485 [M]+;
calcd for C24H20N2O3: 384.1474.
Application of the general procedure (see above) using 1c and 2a with
overnight stirring gave 8a and 9. Three products were identified, (E)-
and (Z)-8a (yield: 58%; E:Z = 1:1.5) and 9 (yield: 42%).
(Z)-Diethyl N-(1,2-diphenylvinyl)phosphoramidate (8a): 1H NMR
(400.13 MHz, CDCl3): d = 1.10 (dt, J = 0.9 Hz, J = 7.1 Hz, 6H; CH3),
3.86–3.96 (m, 4H; CH2), 5.91 (s, 1H; CHPh), 7.16–7.57 ppm (m, 10H;
Ph-H); 31P NMR (101.25 MHz, CDCl3): d = 3.7 ppm.
(E)-Diethyl N-(1,2-diphenylvinyl)phosphoramidate (8a): 1H NMR
(400.13 MHz, CDCl3): d = 1.32 (dt, J = 0.7 Hz, J = 7.1 Hz, 6H; CH3),
4.11–4.16 (m, 4H; CH2), 6.32 (s, 1H; CHPh), 6.82–7.01 (m, 5H; Ph-H),
General procedure for the trapping experiments with MeI and H2O:
nBuLi (1.6m in hexane; 1.2 equiv) was added dropwise to a stirred solu-
tion of phosphonate 1 (0.2m in dry THF) at ꢀ788C. The resulting solu-
tion was stirred for 1.5 h and then nitrile 2 (1.1 equiv) was added. The re-
action mixture was allowed to warm to ꢀ58C over 1.5 h. After comple-
tion or overnight stirring at room temperature, MeI or H2O (1.1 equiv)
was added. The solvent was then removed from the reaction mixture
under reduced pressure at room temperature. The crude product was pu-
rified by column chromatography. The composition of the product was
analysed by applying various NMR techniques (see below).
7.16–7.57 ppm (m, 5H; Ph-H); 31P NMR (101.25 MHz, CDCl3): d
=
10.4 ppm.
Diethyl N-(1,2-diphenylethylidene)phosphoramidate (9): 1H NMR
(400.13 MHz, CDCl3): d = 1.24 (dt, J = 0.7 Hz, J = 7.1 Hz, 6H; CH3),
3.98–4.04 (m, 4H; CH2O), 4.20 (s, 2H; CH2Ph), 7.16–7.57 (m, 8H; Ph-
H), 7.93–7.95 ppm (m, 2H; Ph-H); 31P NMR (101.25 MHz, CDCl3): d =
2.2 ppm.
1-(3-(4-Methoxyphenyl)-1-phenylallylidene)-3-phenylurea (11a): The
general HWE/aza-DA procedure was followed using 1a, 2a, 3a, and 5c.
After purification by column chromatography, 11a was isolated as a
sticky oil. Yield: 40%; 1H NMR (250.13 MHz, CDCl3): d = 3.82 (s, 3H;
CH3O), 5.19 (s, 1H; NH), 6.81–7.72 ppm (m, 16H; Ph-H and CH); 13C
NMR (100.61 MHz, CDCl3): d = 55.4, 114.1 (2C), 118.9, 119.0 (2C),
123.8, 127.2, 128.4 (2C), 129.0 (2C), 129.3 (2C), 129.9 (2C), 130.7, 137.3,
137.9, 145.5, 161.1 (2C), 172.3 ppm; IR (KBr): n˜ = 3380 (w), 3017 (w),
1580 (s), 1254 (m), 1173 cmꢀ1 (m); HRMS (EI): m/z: 356.1523 [M]+;
calcd for C23H20N2O2: 356.1525.
Trapping experiments with MeI
(E,Z)-Diethyl N-methyl-N-((Z)-(2-methylpent-3-en-3-yl)) phosphorami-
date (7a): Application of the general procedure (see above) using 1b
and 2b with overnight stirring gave 7a. Yield: 37%; E:Z = 1:6; (Z)-7a:
1H NMR (400.13 MHz, CDCl3):
d
=
1.02 (d,
(CH3)2CH), 1.25–1.29 (m, 6H; CH3CH2), 1.60–1.64 (m, 3H; =CHCH3),
2.43–2.50 (m, 1H; CH(CH3)2), 2.76 (d, J = 9.0 Hz, 3H; NCH3), 3.97–4.13
(m, 4H; OCH2CH3), 5.5 ppm (q, J
6.8 Hz, 1H; =CH); 31P NMR
J = 6.8 Hz, 6H;
ACHTREUNG
=
(161.98 MHz, CDCl3): d = 7.2; (E)-7a: 1H NMR (400.13 MHz, CDCl3):
d = 1.07 (d, J = 7.0 Hz, 6H; (CH3)2CH), 1.25–1.29 (m, 6H; CH3CH2),
1.60–1.64 (m, 3H; =CHCH3), 2.74 (d, J = 9.9 Hz, 3H; NCH3), 2.78–2.87
6-(4-Methoxystyryl)-6-phenyl-1,3-bis((S)-1-phenylethyl)-1,3,5-triazinane-
2,4-dione (11b): The general HWE/aza-DA procedure was followed
using 1a, 2a, 3a, and (S)-5 f. The product was purified by column chro-
matography to afford 11b in 42% yield with 20% de. Diastereomeric
excess was determined by HPLC analysis (Pathfinder 100PS, 5.0 mm,
methanol/0.02m ammonium acetate buffer pH 4.5 70/30, 1 mLminꢀ1); tr
= 70.88 min (minor), tr = 63.73 min (major); R = 2.22, a = 1.12; m.p.
(m, 1H; CH(CH3)2), 3.97–4.13 (m, 4H; OCH2CH3), 5.46 ppm (dq, J =
A
2.7 Hz, J = 7.1 Hz, 1H; =CH); 31P NMR (161.98 MHz, CDCl3): d =
7.8 ppm. Besides 7a, 6% of another phosphoramidate was identified.[22]
(Z)-Diethyl-1,2-diphenylvinyl-(methyl)phosphoramidate (7b): Applica-
tion of the general procedure (see above) using 1c and 2a with overnight
stirring gave 7b. Yield: 100%; 1H NMR (400.13 MHz, CDCl3): d = 1.24
(t, J = 7.1 Hz, 6H; CH3CH2), 2.62 (d, J = 9.1 Hz, 3H; NCH3), 4.06–4.18
(m, 4H; CH2), 6.49 (s, 1H; =CHPh), 6.82–7.25 ppm (m, 10H; Ph-H); 13C
NMR (100.61 MHz, CDCl3): d = 16.1 (d, J = 7.2 Hz), 35.5 (d, J =
5.7 Hz), 64.0 (d, J = 6.2 Hz), 123.0 (d, J = 3.2 Hz), 126.5 (s), 127.9 (s,
2C), 128.5 (s, 3C), 129.0 (s, 2C), 129.8 (s, 2C), 135.3 (d, J = 5.1 Hz),
66–698C [EA]; [a]D20
(400.13 MHz, CDCl3): d = 1.72 (d, J = 7.0 Hz, 3H; CH3CH), 1.73 (d, J
= 7.0 Hz, 3H; CH3CH), 1.75 (d, J = 7.0 Hz, 3H; CH3CH), 1.78 (d, J =
7.0 Hz, 3H; CH3CH), 3.81 (s, 3H; CH3O), 3.85 (s, 3H; CH3O), 4.44 (q, J
=
ꢀ72.0 (c
=
1.0 in CHCl3); 1H NMR
=
7.0 Hz, 1H; CH3CH), 4.61 (brs, 1H; CH3CH), 5.61–5.66 (m, 2H;
CH3CH), 6.15 (d, J = 15.9 Hz, 1H; CHCH), 6.29 (d, J = 15.6 Hz, 1H;
CHCH), 6.30 (d, J = 15.9 Hz, 1H; CHCH), 6.63 (d, J = 15.6 Hz, 1H;
Chem. Eur. J. 2006, 12, 7178 – 7189
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7187

R. V. A. Orru et al.
CHCH), 6.81 (d, J = 8.7 Hz, 2H; Ph-H), 6.91 (d, J = 8.7 Hz, 2H; Ph-
H), 7.00–8.01 ppm (m, 34H; Ph-H); 13C NMR (100.61 MHz, CDCl3): d =
16.5, 16.6, 19.9, 20.2, 51.1 (2C), 55.3, 55.4, 56.4, 57.5, 76.1, 76.6, 114.0
(2C), 114.2 (2C), 125.3, 125.5, 126.2, 126.3, 126.7, 126.9 (4C), 127.0 (2C),
127.1, 127.7 (6 C), 127.8 (6 C), 128.0 (2C), 128.2 (2C), 128.4 (4C), 128.6
(2C), 129.0 (2C), 129.4, 129.7, 132.3, 132.5, 140.3, 140.5, 141.2 (2C),
142.0, 142.3, 152.2, 152.5, 152.6, 153.1, 160.0, 160.2 ppm; IR (KBr): n˜ =
3027 (w), 1711 (s), 1698 (s), 1512 (s), 1446 (s), 1250 (s), 1028 cmꢀ1 (s);
HRMS (EI): m/z: 531.2522 [M]+; calcd for C34H33N3O3: 531.2522.
1089 cmꢀ1 (m); HRMS (EI): m/z: 448.1813 [M]+; calcd for C26H28N2O3S:
448.1821.
a,b-Unsaturated ketones (15a,b and 16a,b): The general HWE/aza-DA
procedure was followed, but instead of isocyanate 5, 5n sulfuric acid
(1 mL) was added and the reaction mixture was stirred for 1 h. The mix-
ture was then extracted with diethyl ether (3”20 mL). The combined or-
ganic layers were washed with water (20 mL) and dried over Na2SO4. 1H
NMR analysis of the crude reaction mixture revealed that the a,b-unsa-
turated ketones 15 or 16 had been formed. The analytical data were in
agreement with those reported previously.[30]
4-(4-Methoxyphenyl)-3,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one (12):
A
DHPM 12 was prepared under MW conditions from 6a (procedure A)
or from 11a (procedure B).
General procedure for the synthesis of thiazines 18a–f: nBuLi (1.6m in
hexane; 1.2 equiv.) was added dropwise to a stirred solution of phospho-
nate 1 (0.2m in dry THF) at ꢀ788C. The resulting solution was stirred for
1.5 h and then nitrile 2 (1.1 equiv.) was added. The reaction mixture was
allowed to warm to ꢀ58C over 1.5 h and then aldehyde 3 (1.1 equiv.) was
added. The resulting mixture was stirred for a further 0.5 h at ꢀ58C and
thereafter for 1.5 h at room temperature. Isothiocyanate 17 (1.1 equiv.)
was then added dropwise over 10 min and the resulting solution was stir-
red overnight. The solvent was removed under reduced pressure and the
crude product was isolated by column chromatography (PE/EA, 10:1 !
3:1).
Procedure A: DHPM 6a (0.053 mmol, 23 mg) and phenyl isocyanate
(1.2 equiv.) were dissolved in dry dioxane (1 mL) and heated in a micro-
wave oven (maximum power 300 W, ramp time 30 min, hold time 60 min
at 1908C). The solvent was then evaporated and the crude product was
purified by column chromatography using PE/EA (4:1) ! EA. DHPM
12 was isolated in 58% yield.
Procedure B: Urea 11a (0.13 mmol, 47 mg) was dissolved in toluene
(2.5 mL) and heated in a microwave oven (maximum power 300 W, ramp
time 20 min, hold time 75 min at 1208C). The solvent was then evaporat-
ed and the crude product was purified by column chromatography using
PE/EA (3:1) ! EA. DHPM 12 was isolated in 38% yield.
N,4,6-Triphenyl-6H-1,3-thiazin-2-amine (18a): Yield: 74%; m.p. 128–
1298C [EA]; 1H NMR (200.13 MHz, CDCl3): d = 5.03 (d, J = 5.6 Hz,
1H; CHC), 5.76 (d, J = 5.6 Hz, 1H; CHS), 7.11 (t, J = 7.3 Hz, 1H; Ph-
H), 7.29–7.57 (m, 12H; Ph-H), 7.79 ppm (d, J = 6.9 Hz, 2H; Ph-H); 13C
NMR (100.61 MHz, CDCl3): d = 44.5, 101.1, 120.9 (2C), 123.7, 125.9
(2C), 127.9 (2C), 128.1, 128.4, 128.5 (2C), 128.9 (4C), 138.2, 140.7, 141.5,
145.6, 150.0 ppm; IR (KBr): n˜ = 1574 (s), 1493 (w), 1292 (w), 1205 (w),
756 (m), 692 cmꢀ1 (m); HRMS (EI): m/z: 342.1187 [M]+; calcd for
C22H18N2S 342.1191.
m.p. 139–1428C [EA]; 1H NMR (400.13 MHz, CDCl3): d = 3.81 (s, 3H;
CH3O), 5.28 (dd, J
= 2.1 Hz, J = 4.9 Hz, 1H; CHC), 5.34 (d, J =
4.9 Hz, 1H; CHN), 6.80 (d, J = 8.7 Hz, 2H; m-CH (C6H4OMe)), 6.93 (s,
1H; NH), 7.07–7.51 ppm (m, 12H; Ph-H); 13C NMR (100.61 MHz,
CDCl3): d = 55.2, 64.6, 99.9, 114.0 (2C), 125.0 (2C), 127.0, 128.0 (2C),
128.5 (2C), 128.9 (4C), 129.1, 134.1, 134.2, 134.9, 141.0, 153.0, 159.4 ppm;
IR (NaCl): n˜
= 2902 (w), 2839 (w), 1652 (s), 1507 (s), 1249 (m),
1174 cmꢀ1 (m); HRMS (EI): m/z: 356.1516 [M]+; calcd for C23H20N2O2
6-(4-Methoxyphenyl)-N,4-diphenyl-6H-1,3-thiazin-2-amine (18b): The
product was isolated as a yellow-brown oil. Yield: 58%; 1H NMR
(400.13 MHz, DMSO): d = 3.70 (s, 3H; CH3), 5.11 (d, J = 6.5 Hz, 1H;
CHC), 5.91 (d, J = 6.5 Hz, 1H; CHS), 6.88 (d, J = 8.6 Hz, 2H; m-CH
(C6H4OMe)), 6.96–6.99 (m, 1H; p-CH (NHPh)), 7.25–7.40 (m, 7H; Ph-
H), 7.78–7.81 (m, 4H; o-CH (NHPh and Ph)), 9.32 ppm (s, 1H; NH); 13C
NMR (100.61 MHz, DMSO): d = 42.0, 55.1, 101.1, 114.0 (2C), 119.5
(2C), 122.3, 125.3 (2C), 127.7, 128.3 (2C), 128.5 (2C), 128.6 (2C), 133.6,
139.1, 140.5, 146.2, 148.4, 158.7 ppm; IR (NaCl): n˜ = 2961 (w), 1577 (s),
1509 (s), 1253 (s), 1030 cmꢀ1 (s); HRMS (EI): m/z: 372.1230 [M]+; calcd
for C23H20N2OS: 372.1296.
356.1525.
(4R/S,6R)-6-sec-Butyl-4-(4-methoxyphenyl)-3-tosyl-3,4-dihydropyrimi-
din-2(1H)-one (13a): The general HWE/aza-DA procedure was followed
R
using 1a, (S)-2d, 3a, and 5a. The product was purified by column chro-
matography to afford 13a as a 1:1.01 mixture of diastereomers. Yield:
60%. Diastereomeric ratio was determined by HPLC analysis (LiChro-
CART 250–4 Whelk-O 1, n-hexane/2-propanol, 90:10, 1 mLminꢀ1); tr
=
9.33 min (minor), tr = 10.88 min (major); R = 2.19, a = 1.26; m.p. 149–
1538C [EA]; 1H NMR (400.13 MHz, CDCl3): d = 0.88 (t, J = 7.3 Hz,
6H; CH3CH2), 1.10 (dd, J = 1.1 Hz, J = 5.8 Hz, 6H; CH3CH), 1.41–1.52
(m, 4H; CH2CH3), 2.02–2.08 (m, 2H; CHCH3), 2.35 (s, 6H; CH3C6H4),
3.85 (s, 6H; CH3O), 4.90 (d, J = 4.5 Hz, 2H; CHC), 5.82–5.90 (m, 2H;
CHN), 6.86 (d, J = 8.2 Hz, 4H; o-CH (C6H4OMe)), 7.06 (d, J = 8.1 Hz,
4H; m-CH (Ts)), 7.24–7.29 ppm (m, 10H; Ph-H); 13C NMR
(100.61 MHz, CDCl3): d = 11.5, 11.6, 17.9, 18.0, 21.5, 21.5, 26.8, 26.9,
37.9, 38.1, 55.4, 55.4, 59.1, 59.2, 100.0, 100.1, 114.0 (2C), 114.1 (2C), 128.6
(4C), 128.8 (8C), 133.8, 133.9, 136.4 (2C), 138.2, 138.3, 143.9 (2C), 151.0
(2C), 159.6 ppm (2C); IR: (KBr): n˜ = 3239 (m), 2962 (m), 1681 (s), 1509
(m), 1345 (s), 1167 cmꢀ1 (s); HRMS (EI): m/z: 414.1603 [M]+; calcd for
C22H26N2O4S: 414.1613.
4-Isopropyl-N,6-diphenyl-6H-1,3-thiazin-2-amine (18c): Yield: 61%; m.p.
124–1288C [EA]; 1H NMR (200.13 MHz, CDCl3): d
=
1.20 (d, J
(CH3)2), 4.77 (d, J = 4.9 Hz,
1H; CHC), 4.99 (d, J = 4.9 Hz, 1H; CHS), 7.01–7.29 ppm (m, 10H; Ph-
H); 13C NMR (100.61 MHz, CDCl3): d
21.5, 21.6, 34.3, 44.3, 97.7,
=
6.9 Hz, 6H; CH3), 2.40–2.61 (m, 1H; CH
ACHTREUNG
=
121.6, 123.8, 128.2 (2C), 128.3 (2C), 129.1 (2C), 129.2 (2C), 139.3, 141.2,
149.9, 150.3 ppm; IR (KBr): n˜ = 3201 (w), 2962 (w), 1603 (s), 1581 (s),
1489 (m), 1309 (m), 1194 cmꢀ1 (m); HRMS (EI): m/z: 308.1354 [M]+;
calcd for C19H20N2S: 308.1347.
N-Ethyl-6-(4-methoxyphenyl)-4-phenyl-6H-1,3-thiazin-2-amine
(18d):
The product was isolated as
a
yellow oil. Yield: 56%; 1H NMR
(1S,4R/S,5R)-4-(6,6-Dimethylbicyclo
A
(400.13 MHz, CDCl3): d = 1.23 (t, J = 7.3 Hz, 3H; CH3CH2), 3.57–3.60
(m, 2H; CH2), 3.78 (s, 3H; CH3O), 4.88 (d, J = 5.8 Hz, 1H; CHS), 5.71
(d, J = 5.8 Hz, 1H; CHCHS), 6.84 (d, J = 8.7 Hz, 2H; Ph-H), 7.25–7.36
tosyl-3,4-dihydropyrimidin-2(1H)-one (13b): The general HWE/aza-DA
AHCTREUNG
procedure was followed using 1a, 2a, (ꢀ)-myrtenal (3j), and 5a. The
product was purified by column chromatography to afford 13b as a
10.8:1 mixture of diastereomers (de = 83%). Yield: 80%. Diastereomer-
ic excess was determined by HPLC analysis (LiChroCART 250–4 Whelk-
O 1, n-hexane/2-propanol, 95:5, 1 mLminꢀ1); tr = 13.39 min (minor), tr
= 16.12 min (major); R = 2.92, a = 1.25; m.p. 76–798C; [a]2D0 = +118
(c = 1.0 in CHCl3); 1H NMR (400.13 MHz, CDCl3): peaks of the major
isomer are reported: d = 0.76 (s, 3H; CH3 myrtenal), 1.13 (s, 3H; CH3
myrtenal), 1.96–2.27 (m, 6H; 2 ” CH2, 2 ” CH (myrtenal)), 2.34 (s, 3H;
CH3C6H4), 5.15 (d, J = 6.2 Hz, 1H; CHC), 5.50–5.53 (m, 2H; CHN and
CHCH2), 6.69 (s, 1H; NH), 7.17–7.34 (m, 7H; Ph-H), 7.89 ppm (d, J =
8.1 Hz, 2H; Ph-H); 13C NMR (100.61 MHz, CDCl3: d = 21.6, 22.0, 26.5,
31.2, 31.6, 38.6, 40.9, 42.5, 60.1, 99.6, 121.3, 125.6 (2C), 129.4 (2C), 129.5
(2C), 129.7 (2C), 129.9, 133.8, 136.1, 137.0, 144.8, 145.4, 150.9 ppm; IR
(KBr): n˜ = 3259 (m), 2912 (m), 1689 (s), 1669 (s), 1357 (s), 1171 (s),
(m, 5H; Ph-H), 7.80 ppm (d,
J =
7.4 Hz, 2H; Ph-H); 13C NMR
(100.61 MHz, CDCl3): d = 14.9, 37.3, 43.9, 55.3, 99.9, 114.2 (2C), 125.6
(2C), 127.8, 128.1 (2C), 128.9 (2C), 133.5, 139.4, 147.4, 152.4, 159.2 ppm;
IR (NaCl): n˜ = 3400 (w), 2969 (w), 1567 (s), 1510 (s), 1249 cmꢀ1 (s);
HRMS (EI): m/z: 324.1310 [M]+; calcd for C19H20N2OS: 324.1296.
6-(4-Methoxyphenyl)-4-phenyl-N-(1-phenylethyl)-6H-1,3-thiazin-2-amine
(18e): The product was isolated as a yellow oil as a 1:1 mixture of dia-
stereomers. Yield: 64%; 1H NMR (250.13 MHz, CDCl3): d = 1.54 (d, J
= 7.2 Hz, 3H; CH
(s, 3H; OCH3), 3.80 (s, 3H; OCH3), 4.85 (d, J = 6.0 Hz, 1H; CHS), 4.88
(d, J = 5.6 Hz, 1H; CHS), 5.38–5.41 (m, 2 ” 1H; CH(CH3)Ph), 5.68 (d,
A
N
AHCTREUNG
J = 5.6 Hz, 1H; CHCHS), 5.71 (d, J = 6.0 Hz, 1H; CHCHS), 6.81–
7.60 ppm (m, 28H; Ph-H); 13C NMR (400.13 MHz, CDCl3): d = 22.7,
7188
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7178 – 7189

Four-Component Heterocycle Synthesis
FULL PAPER
22.8, 43.8, 44.1, 51.9 (2C), 55.3, 55.4, 99.8, 100.3, 114.1 (2C), 114.2 (2C),
125.7 (4C), 126.0 (2C), 126.1 (2C), 127.0, 127.1, 127.8 (2C), 128.0 (4C),
128.5 (2C), 128.6 (2C), 128.9 (4C), 133.3, 133.4, 139.1 (2C), 144.0, 144.1,
150.3, 150.7, 159.2 (2C), 188.7 ppm (2C); IR (NaCl): n˜ = 3399 (w), 2929
(w), 1567 (s), 1509 (s), 1250 cmꢀ1 (s); HRMS (EI): m/z: 400.1612 [M]+;
calcd for C25H24N2OS: 400.1609.
[19] a) K. Lee, D. Y. Oh, Synthesis 1991, 213–214; b) W. S. Shin, K. Lee,
D. Y. Oh, Tetrahedron Lett. 1995, 36, 281; c) G. Sumrell, J. Org.
Chem. 1954, 19, 817–819.
[20] A. K. Bhattacharya, G. Thyagarajan, Chem. Rev. 1981, 81, 415–430.
[21] For examples, see: a) J. J. Kiddle, Synth. Commun. 2001, 31, 3377–
3382; b) B. Boutevin, Y. Hervaud, T. Jeanmaire, A. Boulahna, M.
Elasri, Phosphorus Sulfur Silicon Relat. Elem. 2001, 174, 1–14;
c) R. G. Gillis, J. F. Horwood, G. L. White, J. Am. Chem. Soc. 1958,
80, 2999–3002; d) F. Kagan, R. D. Birkenmeyer, R. E. Strube, J.
Am. Chem. Soc. 1959, 81, 3026–3031; e) J. J. Kiddle, A. F. Gurley,
Phosphorus Sulfur Silicon Relat. Elem. 2000, 160, 195–205; f) D.
Villemin, F. Simeon, H. Decreus, P. A. Jaffres, Phosphorus Sulfur
Silicon Relat. Elem. 1998, 133, 209–213; g) J. Y. Winum, M. Kamal,
H. Agnaniet, A. Leydet, J. L. Montero, Phosphorus Sulfur Silicon
Relat. Elem. 1997, 129, 83–88.
Acknowledgements
This work was financially supported by NWO-CW Jonge Chemici and
NWO Vernieuwingsimpuls VICI. We thank Dr. Marek Smoluch for
measuring the high-resolution mass spectra of the samples.
[22] Phosphoramidate a, bearing an additional Me group, was also iden-
tified.
[1] L. F. Tietze, Chem. Rev. 1996, 96, 115–136.
[2] a) A. Domling, I. Ugi, Angew. Chem. 2000, 112, 3300–3344; Angew.
Chem. Int. Ed. 2000, 39, 3169–3210; b) A. Domling, Chem. Rev.
2006, 106, 17–89.
[3] L. Banfi, R. Riva, in Organic Reactions,Vol. 65 (Ed.: L. E. Over-
man), Wiley, Hoboken, New Jersey (USA), 2005, pp. 1–140.
[4] a) J. P. Zhu, Eur. J. Org. Chem. 2003, 7, 1133–1144; b) H. Bienayme,
C. Hulme, G. Oddon, P. Schmitt, Chem. Eur. J. 2000, 6, 3321–3329.
[5] R. V. A. Orru, M. de Greef, Synthesis 2003, 1471–1499.
[6] a) A recent issue of Chem. Rev. 2004, 104, 2125–2812, Guest editor
A. Katritzky, was completely devoted to heterocycles; b) C. Simon,
T. Constantieux, J. Rodriguez, Eur. J. Org. Chem. 2004, 24, 4957–
4980.
[23] Besides the phosphoramidates, considerable amounts of the phos-
phonate b were also observed.
[7] a) R. S. Bon, C. G. Hong, M. J. Bouma, R. F. Schmitz, F. J. J. de Ka-
nter, M. Lutz, A. L. Spek, R. V. A. Orru, Org. Lett. 2003, 5, 3759–
3762; b) R. S. Bon, B. van Vliet, N. E. Sprenkels, R. F. Schmitz,
F. J. J. de Kanter, C. V. Stevens, M. Swart, F. M. Bickelhaupt,
R. V. A. Orru, J. Org. Chem. 2005, 70, 3542–3553; c) E. Gelens,
F. J. J. de Kanter, R. F. Schmitz, L. A. J. M. Sliedregt, B. J. van Steen,
C. G. Kruse, R. Leurs, M. B. Groen, R. V. A. Orru, Mol. Diversity
2006, 10, 17–22.
[8] a) D. J. Vugts, H. Jansen, R. F. Schmitz, F. J. J. de Kanter, R. V. A.
Orru, Chem. Commun. 2003, 2594–2595. b) For related work on the
preparation of azadienes, see also refs. [19a] and [19b].
[9] a) C. O. Kappe, Acc. Chem. Res. 2000, 33, 879–888, and references
therein; b) C. O. Kappe, QSAR Comb. Sci. 2003, 22, 630–645.
[10] G. C. Rovnyak, S. D. Kimball, B. Beyer, G. Cucinotta, J. D. Dimarco,
J. Gougoutas, A. Hedberg, M. Malley, J. P. McCarthy, R. A. Zhang,
S. Moreland, J. Med. Chem. 1995, 38, 119–129.
[11] K. S. Atwal, B. N. Swanson, S. E. Unger, D. M. Floyd, S. Moreland,
A. Hedberg, B. C. Oreilly, J. Med. Chem. 1991, 34, 806–811.
[12] a) K. S. Atwal, B. C. Oreilly, J. Z. Gougoutas, M. F. Malley, Hetero-
cycles 1987, 26, 1189–1192; b) B. C. Oreilly, K. S. Atwal, Heterocy-
cles 1987, 26, 1185–1188; c) K. S. Atwal, G. C. Rovnyak, B. C. Oreil-
ly, J. Schwartz, J. Org. Chem. 1989, 54, 5898–5907.
[13] E. Gossnitzer, G. Feierl, U. Wagner, Eur. J. Pharm. Sci. 2002, 15,
49–61.
[14] B. B. Snider, Z. P. Shi, J. Org. Chem. 1993, 58, 3828–3839.
[15] A. D. Shutalev, E. A. Kishko, N. V. Sivova, A. Y. Kuznetsov, Mole-
cules 1998, 3, 100–106.
[16] a) M. C. Elliott, M. S. Long, Org. Biomol. Chem. 2004, 2, 2003–
2011; b) M. C. Elliott, M. S. Long, Tetrahedron Lett. 2002, 43, 9191–
9194; c) M. C. Elliott, E. Kruiswijk, D. J. Willock, Tetrahedron 2001,
57, 10139–10146; d) M. C. Elliott, E. Kruiswijk, M. S. Long, Tetra-
hedron 2001, 57, 6651–6677.
[17] C. O. Kappe, Eur. J. Med. Chem. 2000, 35, 1043–1052.
[18] a) R. Perez, T. Beryozkina, O. I. Zbruyev, W. Haas, C. O. Kappe, J.
Comb. Chem. 2002, 4, 501–510; b) A. S. Paraskar, G. K. Dewkar, A.
Sudalai, Tetrahedron Lett. 2003, 44, 3305–3308; c) S. Martinez, M.
Meseguer, L. Casas, E. Rodriguez, E. Molins, M. Moreno-Manas, A.
Roig, R. M. Sebastian, A. Vallribera, Tetrahedron 2003, 59, 1553–
1556.
[24] B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89, 863–927.
[25] a) M. P. Teulade, P. Savignac, E. E. Aboujaoude, N. Collignon, J. Or-
ganomet. Chem. 1986, 312, 283–295; b) M. N. Mattson, H. Rapo-
port, J. Org. Chem. 1996, 61, 6071–6074.
[26] W. B. Jang, K. Lee, C. W. Lee, D. Y. Oh, Chem. Commun. 1998,
609–610.
[27] D. Strubing, H. Neumann, S. Hubner, S. Klaus, M. Beller, Org. Lett.
2005, 7, 4321–4324.
[28] a) L. F. Tietze, J. Fennen, H. Geissler, G. Schulz, E. Anders, Liebigs
Ann. 1995, 1681–1687; b) M. Behforouz, M. Ahmadian, Tetrahedron
2000, 56, 5259–5288; c) M. C. Elliott, E. Kruiswijk, J. Chem. Soc.
Perkin Trans. 1 1999, 3157–3166.
[29] A. Dondoni, A. Massi, S. Sabbatini, V. Bertolasi, J. Org. Chem.
2002, 67, 6979–6994.
[30] Y. Huang, F. Yang, C. Zhu, J. Am. Chem. Soc. 2005, 127, 16386–
16387.
[31] a) M. S. Newman, W. C. Liang, J. Org. Chem. 1973, 38, 2438–2441;
b) L. J. Zhang, Y. Z. Huang, J. Organomet. Chem. 1993, 454, 101–
103; c) T. R. Barbee, K. F. Albizati, J. Org. Chem. 1991, 56, 6764–
6773; d) I. Shimizu, T. Sugiura, J. Tsuji, J. Org. Chem. 1985, 50, 537–
539.
[32] a) G. A. Strohmeier, W. Haas, C. O. Kappe, Chem. Eur. J. 2004, 10,
2919–2926; b) G. A. Strohmeier, C. O. Kappe, Angew. Chem. 2004,
116, 631–634; Angew. Chem. Int. Ed. 2004, 43, 621–624.
[33] For reviews on the Dimroth rearrangement, see: a) E. S. H. El
Ashry, Y. El Kilany, N. Rashed, H. Assafir, Adv. Heterocycl. Chem.
1999, 75, 79–167; b) M. Wahren, Z. Chem. 1969, 9, 241–252; c) D. J.
Brown in Mechanisms of Molecular Migrations, Vol. 1 (Ed.: B. S.
Thyagarajan), Wiley-Interscience, New York, 1968, 1, 209–245.
[34] a) D. J. Brown, J. S. Harper, J. Chem. Soc. 1963, 1276–1284; b) D. J.
Brown, B. T. England, J. Chem. Soc. C 1971, 14, 2507–2512.
[35] T. N. Glasnov, D. J. Vugts, M. M. Koningstein, B. Desai, W. M. F.
Fabian, R. V. A. Orru, C. O. Kappe, QSAR Comb. Chem. 2006, in
press.
Received: February 7, 2006
Revised: April 10, 2006
Published online: July 18, 2006
Chem. Eur. J. 2006, 12, 7178 – 7189
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7189