Multicomponent Synthesis of Uracil Analogues Promoted by Pd-Catalyzed Carbonylation of α-Chloroketones in the Presence of Isocyanates and Amines

Article abstract of DOI:10.1021/acs.joc.5b01270

A short and efficient one-pot synthesis of uracil derivatives with a high structural variability is described. The process is a multicomponent reaction based on a palladium-catalyzed carbonylation of α-chloroketones in the presence of primary amines and i

Full text of DOI:10.1021/acs.joc.5b01270

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Multicomponent Synthesis of Uracil Analogues Promoted by Pd-Catalyzed Carbonylation of α-
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Chloroketones in the Presence of Isocyanates and Amines
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Serena Perrone,a Martina Capua,a Antonio Salomone,b,* and Luigino Troisia,*
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aDipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Prov.le LecceꢀMonteroni, Lecce
73100, Italy
bDipartimento di FarmaciaꢀScienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S., Via
E. Orabona 4, Bari 70125, Italy
Abstract:
A short and efficient oneꢀpot synthesis of uracil derivatives with a high structural variability is described.
The process is a multicomponent reaction based on a palladiumꢀcatalyzed carbonylation of αꢀchloroketones in the
presence of primary amines and isocyanates. In most cases, when the formation of unsymmetrical N,N'ꢀ
disubstituted uracil derivatives can occur, the methodology demonstrates to be highly regioselective. A mechanistic
hypothesis involving
discussed.
βꢀdicarbonyl palladium intermediates and urea derivatives, generated in situ, has been
Introduction
The increasing attention paid by modern organic chemists to economic and ecological issues has oriented
their investigations towards the discovery of new sustainable processes.1 In this context, the multicomponent
reactions (MCRs), can be considered as a very powerful synthetic tool that takes into account efficiency,
selectivity, molecular diversity and, in particular, atomꢀeconomy.2 Simply by combining at least three starting
materials, the MCR produces selectively and in a oneꢀpot process a new product. The latter incorporates, if not all,
at least the most part of the atoms of the reagents. All these features probably make the MCR the ideal alternative
to sequential multistep synthesis.
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In the recent past, our research group was interested in the reactivity of acylꢀpalladium intermediates (A,
Scheme 1) generated in situ by means of Pdꢀcatalyzed carbonylation of allyl and benzyl halides; such key
intermediates were successfully coupled to amines, alcohols and acetylenes to obtain amides (path a),3 esters (path
b)4 and acetylenic ketones (path c),5 respectively. Moreover, an interesting reactivity was observed in the coupling
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reactions of A with imines (path d) and heterocycles containing a C−N double bond (path e) to give
Nꢀ(2ꢀchloroethyl)imides,7 respectively (Scheme 1).
β
ꢀlactams6 and
Scheme 1. Synthetic utility of acylꢀpalladium species A in the
synthesis of acyclic and cyclic carbonyl compound.
More recently we have also verified that the Pdꢀcatalyzed carbonylation of other unsaturated halides such
ꢀchloroketones constitutes an efficient method to generate valuable ꢀdicarbonyl palladium chloride
as
α
β
intermediates (B, Scheme 2).8 We supposed that these palladium species, when generated in the presence of
triethylamine, can convert to ketenes (C) that are very useful reagents in cycloaddition reactions. In fact, the
postulated intermediate C was successfully employed for the synthesis of 3ꢀacylꢀ4ꢀhydroxyꢀ2ꢀpyranones (path a)8a
via a dimerizative [4+2] cycloaddition and also coupled with aromatic imines, to yield, in a [2+2] cycloaddition,
(Z)ꢀconfigured
α
ꢀalkylideneꢀ
β
ꢀoxoamides (path b)8b with a high stereoselectivity (Scheme 2).
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Scheme 2. Synthesis of 3ꢀacylꢀ4ꢀhydroxyꢀ2ꢀpyranones (path a) or
catalyzed carbonylation of αꢀchloroketones (path b).
αꢀalkylideneꢀβꢀoxoamides via Pdꢀ
Results and Discussion
In line with our research work we then investigated the reactivity of βꢀdicarbonyl palladium species B
towards isocyanates as a potential partner for the cycloaddition reaction with inꢀsitu generated ketenes C (Scheme
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2).
The first reaction was performed according to the following experimental details: phenylisocyanate (1
mmol), chloroacetone (1 mmol), NEt3 (3 mmol), Pd(OAc)2 (0.04 mmol) and PPh3 (0.16 mmol) were dissolved in
THF (15 mL); the resulting mixture was placed in an autoclave, under CO pressure (27 atm), and heated at 110 °C
for 15 hours. After this time, the TLC analysis of the reaction mixture showed almost complete disappearance of
the phenylisocyanate, while a new major product with m/z = 278 appeared, as indicated by GC/MS analysis, beside
a minor one with a m/z = 243. After column chromatography on silicaꢀgel, both products were isolated and the
resulting spectroscopic investigation agreed with the heteroaromatic structures 3a9 and 4a10 showed in Table 1
(entry 1).
It is noteworthy that the product 3a is an uracil derivative; uracil analogues are known to exhibit
remarkable biological activities such as cytostatic, antiviral, antagonists of GnRH (GonadotrophinꢀReleasing
Hormone) just to cite few of their most relevant pharmacological roles.11
Encouraged by the significant synthetic value of the process and by its complete novelty as a three
component reaction (isocyanate, chloroketone, CO), we started a survey of the experimental conditions to clarify
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the reaction mechanism and find out the most critical parameters influencing the chemoselectivity of the reaction in
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favour of the uracil analogues 3a. For this end a series of experiments were carried out and reported in Table 1.
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At first glance it might seem possible to improve the yield of 3a just by increasing the amount of
phenylisocyanate respect to the chloroacetone because of the presence of two phenyl rings in the 3a structure, but,
unfortunately, the experiments described in entries 2ꢀ3 (Table 1) clearly demonstrated that the two and threeꢀfold
excess of phenylisocyanate scarcely influenced the chemoselectivity of the reaction (ratio 3a/4a = 62/38 and 65/35
respectively); however, we noticed a slight improvement of the total yield (46 and 55% respectively).
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Table 1. Examination of the experimental conditions for the carbonylative
coupling between chloroacetone and phenylisocyanate.a
Entry
Isocyanate
1a (equiv.)
Chloroacetone
2a (equiv.)
Total Yieldb
(%)
Ratio
3a/4a
1
2
3
4
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8
1
1
37
46
60/40
62/38
65/35
55/45
47/53
−
2
1
3
1
55
1
2
25
1
3
34
1
1
N.R.c
N.R.
N.R.
1
Acetone (1)d
−
PhNH2 (1)e
1
−
aReagents and conditions on 1 mmole scale: phenylisocyanate (1.0 to 3.0
mmol), chloroacetone (1.0 to 3.0 mmol), NEt3 (3.0 mmol), Pd(OAc)2 (0.04
mol%), PPh3 (0.0 to 0.16 mol%), CO (27 atm), THF (15 mL), 110 °C, 15
b
hours. All reactions were run in duplicate. Calculated by GC analysis of the
crude reaction mixture.bymeans of internal standard (decane) technique.
d
cReaction performed under N2 atmoshpere, without CO. Acetone (1 mmol)
e
was used instead of chloroacetone. Aniline (1 mmol) was used instead of
phenylisocyanate.
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Alternatively, we tried to direct the reaction towards the formation of 4a by increasing the amount of
carbonyl compound (entries 4 and 5, Table 1), since a simple analysis of 4a structure seems to indicate that two
equivalents of chloroketone and only one of phenylisocyanate are necessary to its formation. Also in this case, we
found a poor variation of the chemoselectivity of the process being the ratio 3a/4a nearly equimolar (entry 4, Table
1). However, an inversion of the trend was observed by using a three fold excess of chloroacetone (entry 5, Table 1,
ratio 3a/4a = 47/53). In both cases, an erosion of the total yield was also observed (25 and 34% respectively).
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Subsequently, we examined the hypothesis that the compound 3a could be formed from 2 equiv. of
phenylisocyanate and 1 equiv. of chloroacetone without the participation of carbon monoxide; to this goal, we
performed the reaction under a nitrogen atmosphere, as indicated in entry 6 (Table 1). No new product could be
detected, suggesting that a Pdꢀcatalyzed carbonylation is essential for the formation of both heterocycles 3a and 4a.
Supposing that acetone instead of chloroacetone could participate in the reaction, and having previously
found that palladium(0) can promote the dehalogenation of α
ꢀchloroketones,8a,12 in a further experiment acetone
was used in place of chloroacetone (entry 7, Table 1). Also in this case no new product was formed. Moreover, it is
known that hydrolysis of isocyanates can easily occur13 leading to carbamic acid derivatives that can smoothly
decarboxylate to produce the corresponding amines; for this reason we performed an experiment starting from
aniline instead of phenylisocyanate, but no uracil derivative was detected by 1H NMR analysis of the crude reaction
mixture (entry 8, Table 1).
Looking at the molecular structure of 3a it is possible to recognize an urea motif. For this reason we
performed a carbonylation experiment by replacing the phenylisocyanate with the N,N'ꢀdiphenylurea 5a, in the
presence of 1 equivalent of chloroacetone (Scheme 3). To our delight, the product 3a formed in 65% yield as sole
product beside a not negligible amount of unreacted N,N'ꢀdiphenylurea (30%).
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Scheme 3. Synthesis of 3a starting from urea 5a and
chloroacetone 2a.
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On the basis of the collected data (Table 1 and Scheme 3), we hypothesized that the in situ formation of the
N,N'ꢀdiphenylurea 5a from phenylisocyanate is a key step in our multicomponent process; particularly, the partial
hydrolysis of the isocyanates 1a (Scheme 4, path a),13 caused by traces of water in the reaction medium, could form
aniline 6a that performs a nucleophilic attack to the remaining phenylisocyanate affording the urea 5a.
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Scheme 4. Synthesis of 3a starting from either isocyanates 1a (path a) or a
mixture of 1a and 6a (path b). Reaction conditions and reagents (i):
Pd(OAc)2, Ph3P, Et3N, CO (27 atm), THF, 110 °C, 15 hours (path a) or 10
hours (path b).
A confirmation of our hypothesis occurred by introducing one equivalent of a primary amine (aniline) in
the reaction mixture. Specially, converting the process from three to four components (isocyanate, amine,
chloroketone, CO) we found the best experimental conditions. Indeed, a sensible improvement of the reaction yield
(95%) and chemoselectivity in favor of 3a (Scheme 4, path b) was achieved in a shorter time (10 hours). The
addition of the primary amine as a further reaction component, increased the synthetic potential of our MCR
process because a wider molecular diversity can be reached.
With the aim to investigate the scope and limitations of our Pdꢀcatalyzed MCR, a number of aliphatic and
aromatic isocyanates 1a-e, amines 6a-e and αꢀchloroketones 2a-e were employed (Table 2). The best experimental
conditions settled for the synthesis of 3a (see Scheme 4, path b) were applied for the preparation of a large number
of variously Nꢀ and Cꢀsubstituted uracil analogues (3b-o and 7l-n, Table 2).
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Our initial goal was to investigate the efficiency of the methodology starting from equally substituted
isocyanates and amines to yield symmetrical ureas and then avoiding any problems of regioselectivity. The
employment of benzyl isocyanate 1b and benzyl amine 6b, in the reactions with the ketones 2a-c, gave the
corresponding desired products 3b-d in good to excellent yield (70ꢀ95%, entries 1ꢀ3, Table 2). It is noteworthy that
the carbonylative coupling occurred smoothly also in the presence of both a bulky aliphatic group (i.e. R3 = tꢀBu,
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entry 2, Table 2) and an aromatic ring (i.e. R3 = Ph, entry 3, Table 2) on the
αꢀchloroketone 2.
Table 2. Multicomponent synthesis of uracil analogues 3b-o, 7l-n.a
Entry
1
Isocyanate
Amine
Chloroketone
Product 3
Product 7
(Yield%)b
(Yield%)b
1
6
2
−
−
−
1b
1b
6b
6b
2a
3b (95)
2
3
2b
2c
3c (70)
3d (70)
1b
6b
4
5
−
−
1a
1a
6a
6b
2d
2a
3e (90)
O
N
N
Ph
Ph
O
3f (85)
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7
1a
6b
2b
3g (60)
9
2a
−
−
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6c
6c
1c
1c
3h (91)
8
2e
3i (60)
9
6a
6a
2a
−
−
1d
1e
1b
3j (85)
10
2c
3k (46)
11
12
6c
6c
2a
3l (38)c
7l (57)c
7m (43)
1b
2b
3m (43)
13
14
1b
1a
2a
6e
3n (38)
7n (38)
2a
−
(S)ꢀ6d
3o (95), ee (98%)d
aReagents and conditions: isocyanate 1 (1.0 mmol), chloroketone 2 (3.0 mmol), amine 6 (1.5 mmol), Pd(OAc)2 (0.04
b
mmol), PPh3 (0.32 mmol), Et3N (2 mmol), CO (27 atm), dry THF (15 mL), 110 °C, 10 hours. After isolation by column
chromatography on silica gel. cInseparable mixture of isomers. Yield determined by 1H NMR after column chromatography
d
1
on silica gel. The optical purity of (−)ꢀ3o was determined via H NMR by means of shift reagent technique (see
Experimental Section).
The use of 2ꢀchlorocyclohexanone 2d, as a model cyclic chloroketone, proved to be equally viable
providing the bicyclic uracil analogue 3e in a very good yield (90%, entry 4, Table 2).
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Our attention was then turned towards the investigation of the carbonylative coupling in the presence of
differently substituted isocyanates and amines to produce, in situ, unsymmetrical ureas. These last ones, reacting
with chloroketones and CO, under Pdꢀcatalysis, could provide two isomeric uracils. Conversely, we were pleased
to find that the Pd(0)ꢀcatalyzed MCR of chloroacetone 2a with phenylisocyanate 1a, benzylamine 6b and CO led to
the product 3f in 85% yield (entry 5, Table 2) as a sole isomer.14 Its structure was established both by 1H, 13C, GCꢀ
MS and 1Hꢀ1H 2D NOESY experiments.
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On the basis of the last experiment (entry 5, Table 2), we hypothesize that the unsymmetrical urea 8,
formed in situ from 1a and 6b (Scheme 5), was acylated only at the alkylꢀsubstituted nitrogen because of its better
nucleophilicity, to produce the intermediate 9 in a selective manner. The subsequent intramolecular nucleophilic
attack of the arylꢀsubstituted nitrogen produces, after elimination of the water, the product 3f (Scheme 5).
Scheme 5. Mechanistic hypothesis for the observed regioselective formation of
1ꢀaryl 3ꢀalkyl substituted uracil 3f.
In order to assay our hypothesis, a number of experiments was performed by using aromatic isocyanates
and aliphatic amines (entries 6ꢀ8) or, complementarily, aliphatic isocyanates with aniline (entries 9ꢀ10, Table 2). In
all cases, the formation of the predicted 1ꢀaryl 3ꢀalkyl uracil derivative 3g-k, as the only regioisomer, in moderate
to good yields (46ꢀ91%) was observed.
Encouraged by the above mentioned results, we probed the scope of the reaction with regard to the
presence of a nonꢀsymmetrical N,N'ꢀdialkyl substituted urea generated in situ. Two experiments were performed by
employing the aliphatic isocyanate 1b and the alkylamine 6c, in the presence of the ketones 2a-b (entries 11ꢀ12,
Table 2). Although these reactions provided the uracil analogues in good overall yields (86ꢀ95%), no
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regioselectivity was observed. Indeed, a nearly equimolar mixture of the regioisomers 3l-m and 7l-m was isolated
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after column chromatography.
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We then wondered if our methodology would be effective in the preparation of uracil analogues bearing an
hydroxyl group; this could be an important aspect for the synthesis of uracil nucleoside derivatives. We were
pleased to find that a couple of Nꢀ(2ꢀhydroxyethyl) substituted uracil analogues 3n (yield: 38%) and 7n (yield:
38%), were formed by our Pdꢀcarbonylation reaction, starting from ethanolamine 6e, benzylisocyanate 1b and
chloroacetone 2a (entry 13, Table 2).
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Finally, a simple experiment was carried out to check if an enantiopure uracil derivative could be also
synthesized. As shown in entry 14 (Table 2), the carbonylative coupling of chloroacetone 2a with enantiomerically
pure (S)ꢀ1ꢀphenylethylamine 6d and benzyl isocyanate 1b, gave straightforwardly the product (−)ꢀ3o as the sole
regioisomer in very good yield (95%) and with the same optical purity of the starting amine (S)ꢀ6d.
On the basis of our previous results and the experiments presented herein, some considerations about the
reactivity of the βꢀoxoacylꢀpalladium intermediate B (Scheme 6) can be carried out. In a recent study, we have
found that the Pdꢀcatalyzed carbonylation of
oxoamides,8b whereas the simple carbonylation of
hydroxyꢀ2ꢀpyranones8a (Scheme 6). We hypothesize that, in the absence of a nucleophile, the dicarbonyl palladium
αꢀcloroketones in the presence of imines gave αꢀalkylidene βꢀ
αꢀchloroketones with CO and a Pd(0) source gave 3ꢀacylꢀ4ꢀ
intermediate B is involved in a βꢀelimination reaction promoted by NEt3 to afford the ketene C, a key intermediate
for the subsequent [2+2] and [4+2] cycloaddition reactions (path a, Scheme 6).
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Scheme 6. Reactivity of the dicarbonyl palladium species B in the absence of nucleophiles (path a) or in
the presence of N,N'ꢀdisubstituted urea derivatives as nucleophilic reagents (path b).
On the contrary, the acylpalladium B behaves differently when it is formed in the presence of
nucleophiles,3a,b such as the in situ generated ureas derived from amines and isocyanates (path b, Scheme 6).
Specifically, the strong electrophilic character of the carbonyl group bound to palladium, in structure B, should
promote the acylation of the nucleophile providing, after a condensation reaction, the uracil analogues described in
the present work (Scheme 6).15
In a further expansion of the applicability of our MCR, we employed functionalized chlorinated carbonyl
compounds as substrates for the carbonylation process or isothiocyanates as precursors of thiourea derivatives
(Table 3).
Table 3. Pdꢀcatalyzed carbonylation attempts on functionalized carbonyl
compounds 2f,g or isothiocyanate 1f: synthesis of thiazolꢀ2ꢀimine derivatives
10.a
Iso(thio)cyanate1
1a (X = O)
Amine 6
Carbonyl compound 2
Product10
Entry
1
R1
R2
(Yield %)b
Ph (6a)
−
(2f)
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1a (X = O)
1f (X = S)
PhCH2(6b)
(2g)
−
Ph
N
S
N
Ph (6a)
CH3(2a)
Ph
10a(95)
9
Ph
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N
N
4
1f (X = S)
PhCH2(6b)
CH3(2a)
Ph
S
10b(97)
aReagents and conditions: iso(thio)cyanate 1 (1.0 mmol), chloroketone 2 (3.0 mmol),
amine 6 (1.5 mmol), Pd(OAc)2 (0.04 mmol), PPh3 (0.32 mmol), Et3N (2.0 mmol), CO
(27 atm), dry THF (15 mL), 110 °C, 10 hours. bAfter isolation by column
chromatography on silica gel.
Unfortunately, in both cases no uracil analogues were detected. Particularly, in the reactions performed
with ethyl 4ꢀchloroꢀ3ꢀoxobutanoate 2f (entry 1) or 2ꢀchloroꢀ1ꢀmorpholinoethanone 2g (entry 2), as chlorinated
carbonyl compounds, the starting reagents were quantitatively recovered (Table 3).
In the experiments with the isothiocyanate 1f, chloroacetone 2a, and amines 6a or 6b, two sulfur containing
heterocyclic products 10a or 10b were formed in a very high yield (95ꢀ97%, entries 3ꢀ4, Table 3). Such thiazolꢀ2ꢀ
imine derivatives are obtained, presumably, by a simple nucleophilic attack of the in situ generated thiourea to the
chloroacetone, without any participation of palladium and carbon monoxide (Scheme 7). This hypothesis has been
formulated in analogy to the work reported by Patel et al. in which the thiazolꢀ2ꢀimine derivatives 10a,b were
formed starting from thiourea derivatives and
α
ꢀbromoketones (Scheme 7).16
Present work
O
R2
N
Cl
R3
H
H
R3
NEt3
N
N
R2
R1
R2 NH2
N
R1 NCS
+
R1
S
S
10
generated
in situ
NEt3
-H2O
H
H
R2
N
N
R2
R1
Br
R2
N
HN
N
R1
R3
R3
O
S
S
HO
N
O
R1
S
R3
Patel work
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Scheme 7. Synthesis of thiazolꢀ2ꢀimine derivatives 10.
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Conclusions
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In conclusion, this paper reports a new method for the synthesis of uracil analogues, which are valuable
products showing a wide range of biological activities. The reaction is based on the Pdꢀcatalyzed carbonylation of
ꢀchloroketones in the presence of primary amines and isocyanates; in some cases, when Nꢀaryl, N'ꢀalkyl
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α
disubstituted ureas could be formed, the reaction showed a complete regioselectivity leading to only one uracil
isomer.
Moreover, enantiopure amines can also be employed for this reaction to provide the desired optically active
uracil analogue without the loss of any chiral purity from the starting amines.
We believe that the methodology described herein represents a good example of modern organic synthesis
being a catalytic multicomponent reaction that allows the preparation of uracil derivatives with high structure
variability, in a single synthetic step, starting from easily available substrates and with high atom economy.
Experimental Section
General methods
Isocyanates 1a-e,
αꢀchloroketones 2a-e, primary amines 6a-e, triethylamine (NEt3), Pd(AcO)2, PPh3, were
of commercial grade and used without further purification. THF was purified by distillation from sodium before
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use. Petroleum ether refers to the 40−60 °C boiling fraction. The H and the C NMR spectra were recorded at
400.13 MHz for 1H and 100.62 MHz for 13C, with CDCl3 as the solvent and TMS as an internal standard (δ = 7.26
ppm for 1H spectra; δ = 77.0 ppm for 13C spectra). The IR spectra were recorded with an FTꢀIR spectrophotometer.
Gas chromatography (GC) was conducted on an Rtxꢀ5 30ꢀm fused silica capillary column (split ratio 100:1). The
following program was used: method A = initial temperature of 100 °C for 0.0 min, ramp 10 °C/min to 280 °C, and
hold for 15 min; the standard operating conditions were 300 °C injector temperature and 290 °C detector
temperature. GCꢀMS analyses, conducted using method A, were performed with a gas chromatograph equipped
with a 5% phenylpolymethylsiloxane capillary column, 30 m, 0.25 mm i.d., and a massꢀselective detector
operating at 70 eV. The electrospray ionization [HRMS (ESI)] experiments were carried out in a hybrid QꢀTOF
mass spectrometer equipped with an ionꢀspray ionization source. MS (+) spectra were acquired by direct infusion
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(5 mL minꢀ1) of a solution containing the appropriate sample (10 pmol mLꢀ1) dissolved in a solution 0.1% acetic
acid, methanol/water (50:50) at the optimum ion voltage of 4800 V. The nitrogen gas flow was set at 30 psi
(pounds per square inch) and the potentials of the orifice, the focusing ring and the skimmer were kept at 30, 50
and 25 V relative to ground, respectively. TLC was performed on silica gel plates with Fꢀ254 indicator; viewing
was by UV light (254 nm) or pꢀanisaldehyde and phosphomolybdic acid staining solution. Chromatographic
separations were performed on silica gel (63−200 mesh) using petroleum ether/ethyl acetate (AcOEt) mixture as
eluent. All reactions involving airꢀsensitive reagents were performed under an atmosphere of nitrogen in ovenꢀdried
glassware by using syringe/septum cap techniques.
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The structure of unsymmetrical uracils 3f-o and 7l-n was established both by H, C, GCꢀMS and Hꢀ1H
2D NOESY experiments.
Enantiomeric purity assay for compound (−)ꢀ3o was carried out with both racemic and optically active
1
substrates using H NMR (400 MHz) in the presence of the chiral shift reagent Europium(III) tris[3ꢀ
(heptafluoropropylhydroxymethylene)ꢀdꢀcamphorate], Eu(hfc)3. The chromatographed product (10 mg) was
dissolved in CDCl3 (0.5 mL) and a solution of the shift reagent Eu(hfc)3 (50 mg in 1 mL of CDCl3) was sequentially
added in small portions (50 ꢀL) until the singlet at 5.70 ppm was split on two separated singlets. The enantiomeric
excess was calculated from the integral values of two separated singlets.
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General Procedure for the multicomponent synthesis of the uracil analogues 3a-o and 7l-n
A solution containing the isocyanate 1 (1.0 mmol),
αꢀchloroketone 2 (3.0 mmol), primary amine 6 (1.5
mmol), Pd(AcO)2 (9 mg, 0.04 mmol), PPh3 (85 mg, 0.32 mmol) and NEt3 (0.28 mL, 2.0 mmol) in anhydrous THF
(15 mL) was placed in a 45 mL autoclave. The autoclave was purged, pressurized with CO (27 atm) and then
heated at 110 °C under magnetic stirring, for 10 hours. After this time, the solution was cooled to room temperature
and the solvent was removed under reduced pressure to give a crude material. The crude mixture was then purified
by chromatography on silica gel [petroleum ether/AcOEt (90:10 to 50:50)] to obtain the corresponding uracil
derivatives 3a-o and 7l-n as pure compounds.
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1,3ꢀDibenzylꢀ6ꢀphenylpyrimidineꢀ2,4(1H,3H)ꢀdione 3d is known and its characterization data resulted in
agreement with those reported in the literature.17
Spectroscopic data for the uracil analogues 3a-c,e-o and 7l-n are reported below.
6ꢀMethylꢀ1,3ꢀdiphenylpyrimidineꢀ2,4(1H,3H)ꢀdione (3a). Purification was carried out by column
chromatography (petroleum ether/AcOEt 90:10 ꢀ 50:50) to afford the uracil analogue 3a as a pure white solid
(264 mg, 95%); mp 182−183 °C; Rf = 0.47 (petroleum ether/AcOEt 70:30); 1H NMR (CDCl3, 400.13 MHz): δ 1.91
(s, 3H), 5.84 (s, 1H), 7.27−7.50 (m, 10H) ppm; 13C NMR (CDCl3, 100.62 MHz): δ 20.9,101,6, 128.2, 128.3, 128.4,
128.5, 129.1, 129.6, 132.7, 136.6, 152.0, 152.3, 162.3 ppm; FTꢀIR (CHCl3): ν 3012, 2966, 2927, 2857, 1712, 1669,
1488, 1411, 1376 cmꢀ1; GC/MS (70 eV): m/z (%) = 278 (80) [M]+, 159 (100), 144 (50), 131 (45), 130 (60), 118
(40); 77 (75); HRMS (ESI): calcd. for C17H15N2O2 [M+H]+ 279.1134; found 279.1132.
1,3ꢀDibenzylꢀ6ꢀmethylpyrimidineꢀ2,4(1H,3H)ꢀdione (3b). Purification was carried out by column
chromatography (petroleum ether/AcOEt 80:20ꢀ60:40). This gave the uracil analogue 3b as a pale yellow solid
1
(291 mg, 95%); mp 72−73 °C; Rf = 0.55 (petroleum ether/AcOEt 80:20); H NMR (CDCl3, 400.13 MHz): δ 2.30
(s, 3H), 5.07 (s, 2H), 5.16 (s, 2H), 5.64 (s, 1H); 7.11−7.48 (m, 10H) ppm; 13C NMR (CDCl3, 100.62 MHz): δ 19.3,
44.7, 48.0, 102.0, 126.4, 127.5, 127.8, 128.4, 128.9, 129.0, 136.1, 137.0, 151.9, 152.6, 162.1 ppm; FTꢀIR (CHCl3):
ν 3011, 2959, 2929, 2870, 1705, 1663, 1465, 1432 cmꢀ1; GC/MS (70 eV): m/z (%) = 306 (95) [M]+, 215 (16), 172
(75), 132 (18), 91 (100); HRMS (ESI): calcd. for C19H19N2O2 [M+H]+ 307.1447; found 307.1449.
1,3ꢀDibenzylꢀ6ꢀtertꢀbutylpyrimidineꢀ2,4(1H,3H)ꢀdione (3c). Purification was carried out by column
chromatography (petroleum ether/AcOEt 70:30ꢀ80:20). This gave the uracil analogue 3c as a pale yellow oil (244
mg, 70%); Rf = 0.65 (petroleum ether/AcOEt 70:30);1H NMR (CDCl3, 400.13 MHz): δ 1.34 (s, 9H), 5.09 (s, 2H),
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5.31 (s, 2H), 5.92 (s, 1H), 7.21−7.36 (m, 10H) ppm; C NMR (CDCl3, 100.62 MHz): δ 30.2, 36.1, 44.6, 50.0,
100.2, 127.2, 127.3, 128.3, 128.6, 128.7, 129.0, 138.1, 156.5, 161.9, 162.7 ppm; FTꢀIR (CHCl3): ν 3030, 2971,
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2936, 2876, 1698, 1654, 1440 cmꢀ1; GC/MS (70 eV): m/z (%) = 348 (72) [M]+, 257 (33), 214 (34), 152 (40), 91
(100); HRMS (ESI): calcd. for C22H25N2O2 [M+H]+ 349.1917; found 349.1916.
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1,3ꢀDiphenylꢀ5,6,7,8ꢀtetrahydroquinazolineꢀ2,4(1H,3H)ꢀdione (3e). Purification was carried out by column
chromatography (petroleumether/AcOEt90:10 ꢀ 70:30) to give the uracil analogue 3e as a yellow solid (286 mg,
90%); mp 190−171 °C; Rf = 0.52 (petroleum ether/AcOEt 70:30); 1H NMR (CDCl3, 400.13 MHz): δ 1.68−1.72 (m,
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4H), 2.03−2.11 (m, 2H), 2.48−2.56 (m, 2H), 7.26−7.52 (m, 10H) ppm; C NMR (CDCl3, 100.62 MHz): δ 21.1,
22.0, 22.1, 28.1, 109.6, 128.3∗, 128.8, 129.1, 129.4, 129.5, 135.2, 136.5, 148.7, 151.6, 163.1 ppm, two carbon
∗
atoms with identical chemical shift; FTꢀIR (CHCl3): ν3012, 2946, 2934, 2863, 1704, 1652, 1490, 1438 cmꢀ1;
GC/MS (70 eV): m/z (%) = 318 (100) [M]+, 240 (17), 199 (27), 198 (30), 143 (50), 77 (30); HRMS (ESI): calcd.
for C20H19N2O2 [M+H]+ 319.1447; found319.1448.
3ꢀBenzylꢀ6ꢀmethylꢀ1ꢀphenylpyrimidineꢀ2,4(1H,3H)ꢀdione (3f). Purification was performed by column
chromatography (petroleum ether/AcOEt 80:20 ꢀ 60:40) to give the uracil analogue 3f as a pale yellow solid (248
1
mg, 85%); mp 227−228 °C; Rf = 0.44 (petroleum ether/AcOEt 80:20); H NMR (CDCl3, 400.13 MHz): δ 1.84 (s,
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3H), 5.12 (s, 2H), 5.74 (s, 1H), 7.20−7.32 (m, 5H), 7.44−7.53 (m, 5H) ppm; C NMR (CDCl3, 100.62 MHz): δ
20.8, 44.4, 101.5, 127.6, 128.3, 128.5, 129.4, 129.5, 129.8, 136.9∗, 151.6, 152.2, 162.3 ppm, two carbon atoms
with identical chemical shift; FTꢀIR (CHCl3): ν 3009, 2956, 2930, 2855, 1707, 1663, 1447, 1416 cmꢀ1; GC/MS (70
eV): m/z (%) = 292 (100) [M]+, 160 (38), 159 (51), 130 (28), 77 (32); HRMS (ESI): calcd. for C18H17N2O2 [M+H]+
293.1291; found 293.1293.
∗
3ꢀBenzylꢀ6ꢀtertꢀbutylꢀ1ꢀphenylpyrimidineꢀ2,4(1H,3H)ꢀdione (3g). Purification was carried out by column
chromatography (petroleum ether/AcOEt80:20ꢀ70:30). This gave the uracil analogue 3g as a yellow oil (200 mg,
60%);Rf = 0.62 (petroleum ether/AcOEt 80:20);1H NMR (CDCl3, 400.13 MHz): δ 1.34 (s, 9H), 5.10 (s, 2H), 5.99
13
(s, 1H), 6.96−7.56 (m, 10H) ppm; C NMR (CDCl3, 100.62 MHz): δ 30.2, 36.1, 44.7, 100.7, 127.5, 128.3, 128.6,
129.5, 129.7, 130.3, 136.7, 136.8, 153.2, 153.5, 162.7 ppm; FTꢀIR (CHCl3): ν3030, 2966, 2936, 2875, 1701, 1654,
1447, 1444 cmꢀ1;GC/MS (70 eV): m/z (%) = 334 (100) [M]+, 186 (48), 167 (40), 144 (91), 77 (38);HRMS (ESI):
calcd. for C21H23N2O2 [M+H]+ 335.1760; found 335.1759.
3ꢀButylꢀ6ꢀmethylꢀ1ꢀpꢀtolylpyrimidineꢀ2,4(1H,3H)ꢀdione(3h). Purification was performed by column
chromatography (petroleum ether/AcOEt70:30ꢀ60:40) to give the uracil analogue 3h as a pale yellow solid (247
mg, 91%); mp 95−96 °C; Rf = 0.43 (petroleum ether/AcOEt 70:30);1H NMR (CDCl3, 400.13 MHz): δ 0.92 (t, J =
7.4 Hz, 3H), 1.37 (sextet, J = 7.4 Hz, 2H), 1.60−1.68 (m, 2H), 1.85 (s, 3H), 2.40 (s, 3H), 3.94 (dd, J = 7.5 Hz, J =
7.5 Hz, 2H), 5.70 (s, 1H), 7.09 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H) ppm; 13C NMR (CDCl3, 100.62 MHz):
δ 13.6, 20.1, 20.5, 21.0, 29.5, 41.1, 101.2, 127.9, 130.3, 134.1, 139.3, 151.8, 152.2, 162.5 ppm; FTꢀIR (CHCl3):
ν3010, 2962, 2932, 2874, 1701, 1623, 1513, 1450, 1433, 1420 cmꢀ1; GC/MS (70 eV): m/z (%) = 272 (9) [M]+, 255
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(80), 216 (51), 173 (100), 144 (39), 91 (35);HRMS (ESI): calcd. for C16H21N2O2 [M+H]+ 273.1604; found
273.1605.
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3ꢀButylꢀ6ꢀ(4ꢀchlorophenyl)ꢀ1ꢀpꢀtolylpyrimidineꢀ2,4(1H,3H)ꢀdione (3i). Purification was performed by
column chromatography (petroleum ether/AcOEt 85:15ꢀ70:30) to give the uracil analogue 3i as a pale yellow
solid (221 mg, 60%); mp 110−111 °C; Rf = 0.47 (petroleum ether/AcOEt 85:15);1H NMR (CDCl3, 400.13 MHz): δ
0.93 (t, J = 7.4 Hz, 3H), 1.39 (sextet, J = 7.4 Hz, 2H), 1.66−1.71 (m, 2H), 2.29 (s, 3H), 3.98−4.02 (m, 2H), 5.83 (s,
1H), 6.94 (d, J = 8.3 Hz, 2H), 7.04−7.08 (m, 4H), 7.17 (d, J = 8.5 Hz, 2H) ppm;13C NMR (CDCl3, 100.62 MHz): δ
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13.7, 20.3, 21.1, 29.6, 41.5, 103.3, 128.5, 128.8, 129.7∗ 131.9, 134.5, 135.6, 138.6, 152.0, 152.8, 162.2 ppm,∗two
,
carbon atoms with identical chemical shift; FTꢀIR (CHCl3): ν3002, 2962, 2933, 2874, 1706, 1666, 1492, 1438 cmꢀ1;
GC/MS (70 eV): m/z (%) = 368 (12) [M]+, 351 (100), 312 (75), 369 (81), 241 (96), 91 (51);HRMS (ESI): calcd. for
C21H22ClN2O2 [M+H]+ 369.1371; found 369.1373.
3ꢀCyclohexylꢀ6ꢀmethylꢀ1ꢀphenylpyrimidineꢀ2,4(1H,3H)ꢀdione (3j). Purification was performed by column
chromatography (petroleum ether/AcOEt 70:30ꢀ50:50) to give the uracil derivative 3j as a white solid (241 mg,
85%); mp 122−123 °C; Rf = 0.45 (petroleum ether/AcOEt 70:30);1H NMR (CDCl3, 400.13 MHz): δ 1.21−1.40 (m,
4H), 1.60−1.78 (m, 4H), 1,82 (s, 3H), 2.35−2.45 (m, 2H), 4.78−4.84 (m, 1H), 5.67 (s, 1H), 7.18−7.27 (m, 2H),
7.45−7.55 (m, 3H) ppm;13C NMR (CDCl3, 100.62 MHz): δ 20.6, 25.2, 26.3, 28.4, 53.8, 101.7, 128.1, 128.5, 129.1,
129.7, 137.1, 151.1, 162.8 ppm; FTꢀIR (CHCl3): ν3010, 2934, 2857, 1701, 1664, 1447, 1419 cmꢀ1; GC/MS (70 eV):
m/z (%) = 284 (3) [M]+, 203 (100), 160 (13), 130 (13), 77 (15);HRMS (ESI): calcd. for C17H21N2O2 [M+H]+
285.1604; found 285.1602.
3ꢀButylꢀ1,6ꢀdiphenylpyrimidineꢀ2,4(1H,3H)ꢀdione (3k). Purification was carried by column
chromatography (petroleum ether/AcOEt 80:20 ꢀ 70:30) to give the uracil derivative 3k as a yellow oil (147 mg,
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46%); Rf = 0.58 (petroleum ether/AcOEt 80:20); H NMR (CDCl3, 400.13 MHz): δ 0.82 (t, J = 7.4 Hz, 3H),
1.23−1.29 (m, 2H), 1.55−1.63 (m, 2H), 3.90−3.95 (m, 2H), 5.74 (s, 1H), 6.93−7.45 (m, 10H) ppm; 13C NMR
(CDCl3, 100.62 MHz): δ 13.6, 20.1, 29.5, 41.4, 89.5, 128.0, 128.2, 128.4, 128.7, 129.0, 135.8, 137.1, 151.9, 154.0,
162.4 ppm; FTꢀIR (CHCl3): ν 3013, 2962, 2930, 1687, 1661, 1598, 1446, 1416 cmꢀ1; GC/MS (70 eV): m/z (%) =
320 (8) [M]+, 264 (38), 221 (36), 193 (100), 77 (48); HRMS (ESI): calcd. for C20H21N2O2 [M+H]+ 321.1604; found
321.1606.
1ꢀBenzylꢀ3ꢀbutylꢀ6ꢀmethylpyrimidineꢀ2,4(1H,3H)ꢀdione (3l) and 3ꢀbenzylꢀ1ꢀbutylꢀ6ꢀmethylpyrimidineꢀ
2,4(1H,3H)ꢀdione (7l). Purification was carried by column chromatography (petroleum ether/AcOEt 70:30
ꢀ50:50) to give the uracil derivatives 3l and 7l as an inseparable mixture of isomers, yellow oil (258 mg, 95%);
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ratio 3l/7l = 40/60 calculated by H NMR; Rf = 0.41 (petroleum ether/AcOEt 70:30); H NMR (CDCl3, 400.13
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MHz): δ 0.93‒0.97 (m, 6H), 1.32‒1.43 (m, 4H), 1.57‒1.68 (m, 4H), 2.15 (s, 3H), 2.22 (s, 3H), 3.75‒3.79 (m, 2H),
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3.95‒3.99 (m, 2H), 5.10 (s, 4H), 5.60 (s, 1H), 5.61 (s, 1H), 7.15‒7.46 (m, 10H) ppm; C NMR (CDCl3, 100.62
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MHz): δ 13.6, 13.7, 19.6, 19.8, 19.9, 20.1, 29.5, 30.8, 41.2, 44.2, 45.0, 47.7, 101.5, 101.9, 126.0, 127.3, 127.6,
128.2, 128.7, 128.9, 136.1, 136.9, 151.2, 151.4, 151.9, 152.4, 162.1 ppm; FTꢀIR (CHCl3): ν 3010, 2964, 2935,
2876, 1699, 1659, 1466, 1445, 1430 cmꢀ1; Minor isomer, GC/MS (70 eV): m/z (%) = 272 (9) [M]+, 255 (43), 216
(38), 215 (35), 91 (100); Major isomer, GC/MS (70 eV): m/z (%) = 272 (100) [M]+, 257 (23), 216 (49), 199 (15),
91 (63); HRMS (ESI): calcd. for C16H21N2O2 [M+H]+ 273.1604; found 273.1607.
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1ꢀBenzylꢀ6ꢀtertꢀbutylꢀ3ꢀbutylpyrimidineꢀ2,4(1H,3H)ꢀdione
(3m)
and
3ꢀbenzylꢀ6ꢀtertꢀbutylꢀ1ꢀ
butylpyrimidineꢀ2,4(1H,3H)ꢀdione (7m). Purification was carried out by column chromatography (petroleum
ether/AcOEt 80:20 ꢀ 70:30) to afford the uracil analogue 3m and 7m as a pure compound. 3m: pale yellow oil
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(135 mg, 43%); Rf = 0.52 (petroleum ether/AcOEt 80:20); H NMR (CDCl3, 400.13 MHz): δ 0.93 (t, J = 7.4 Hz,
3H), 1.33‒1.37 (m, 11H), 1.52‒1.58 (m, 2H), 3.87‒3.91 (m, 2H), 5.32 (s, 2H), 5.89 (s, 1H), 7.01‒7.02 (m, 2H)
7.29‒7.34 (m, 3H) ppm;13C NMR (CDCl3, 100.62 MHz): δ 13.7,20.1, 30.3, 31.2, 36.0, 41.2, 50.0, 100.2, 124.9,
127.1, 128.7, 137.3, 152.7, 161.7, 162.8 ppm; FTꢀIR (CHCl3): ν 3026, 2963, 2933, 2874, 1698, 1652, 1446cmꢀ1;
GC/MS (70 eV): m/z (%) = 314 (20) [M]+, 297 (33), 243 (25), 91 (100); HRMS (ESI): calcd. for C19H27N2O2
[M+H]+ 315.2073; found 315.2072. 7m: pale yellow oil (135 mg, 43%); Rf = 0.59 (petroleum ether/AcOEt 80:20);
1H NMR (CDCl3, 400.13 MHz): δ 0.95 (t, J = 7.5 Hz, 3H), 1.35‒1.39 (m, 11H), 1.59‒1.68 (m, 2H), 3.92‒3.97 (m,
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2H), 5.12 (s, 2H), 5.82 (s, 1H), 7.23‒7.32 (m, 3H), 7.47‒7.49 (m, 2H) ppm; C NMR (CDCl3, 100.62 MHz): δ
13.6,19.9, 30.0, 30.4, 36.1, 44.3, 47.1, 104.1, 127.4, 128.3, 129.0, 136.8, 152.8, 161.6, 162.9 ppm; FTꢀIR (CHCl3):
ν 3026, 2964, 2934, 2875, 1695, 1649, 1442 cmꢀ1; GC/MS (70 eV): m/z (%) = 314 (100) [M]+, 258 (65), 257 (55),
138 (67), 91 (90); HRMS (ESI): calcd. for C19H27N2O2 [M+H]+ 315.2073; found 315.2071.
1ꢀBenzylꢀ3ꢀ(2ꢀhydroxyethyl)ꢀ6ꢀmethylpyrimidineꢀ2,4(1H,3H)ꢀdione (3n) and 3ꢀbenzylꢀ1ꢀ(2ꢀhydroxyethyl)ꢀ
6ꢀmethylpyrimidineꢀ2,4(1H,3H)ꢀdione (7n). Purification was carried out by column chromatography (petroleum
ether/AcOEt 20:80) to afford the uracil analogue 3n and 7n as a pure compound. 3n: yellow oil (99 mg, 38%); Rf =
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0.50 (petroleum ether/AcOEt 20:80); H NMR (CDCl3, 400.13 MHz): δ 2.16 (s, 3H), 2.85 (broad s, 1H, OH,
exchange with D2O), 3.85 (t, J = 5.1 Hz, 2H), 4.23 (t, J = 5.1 Hz, 2H), 5.10 (s, 2H), 5.64 (s, 1H), 7.20‒7.38 (m, 5H)
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ppm; C NMR (CDCl3, 100.62 MHz): δ 19.9, 44.0, 48.1, 61.6, 102.0, 126.1, 127.5, 129.0, 135.7, 152.6, 153.3,
163.0 ppm; FTꢀIR (CHCl3): ν 3015, 2963, 2927, 2856, 1697, 1657, 1465, 1431, 1355 cmꢀ1; GC/MS (70 eV): m/z
(%) = 260 (8) [M]+, 217 (65), 91 (100); HRMS (ESI): calcd. for C14H17N2O3 [M+H]+ 261.1240; found 261.1243.
7n: yellow oil (99 mg, 38%); Rf = 0.58 (petroleum ether/AcOEt 20:80); 1H NMR (CDCl3, 400.13 MHz): δ 2.26 (s,
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3H), 2.82 (broad s, 1H, OH, exchange with D2O), 3.83 (t, J = 5.1 Hz, 2H), 3.95 (t, J = 5.1 Hz, 2H), 5.07 (s, 2H),
5.59 (s, 1H), 7.14‒7.41 (m, 5H) ppm; 13C NMR (CDCl3, 100.62 MHz): δ 20.4, 44.3, 47.3, 60.6, 101.7, 127.8,
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128.3, 128.8, 136.8, 152.3, 152.4, 162.2 ppm; FTꢀIR (CHCl3): ν 3012, 2960, 2927, 2855, 1699, 1659, 1465, 1430,
1350 cmꢀ1; GC/MS (70 eV): m/z (%) = 260 (100) [M]+, 216 (38), 132 (15), 96 (81); HRMS (ESI): calcd. for
C14H17N2O3 [M+H]+ 261.1240; found 261.1242.
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(−)ꢀ(S)ꢀ6ꢀMethylꢀ1ꢀphenylꢀ3ꢀ(1ꢀphenylethyl)pyrimidineꢀ2,4(1H,3H)ꢀdione (3o). Purification was carried by
column chromatography (petroleum ether/AcOEt70:30 ꢀ 50:50) to give the uracil derivative (−)ꢀ3o as a yellow
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solid (291 mg, 95%); Rf = 0.43 (petroleum ether/AcOEt 70:30); [α]D24 = −125.5 (c = 0.1, CHCl3), ee = 98%; H
NMR (CDCl3, 400.13 MHz): δ 1.80 (s, 3H), 1.87 (d, J = 7.2Hz, 3H), 5.70 (s, 1H), 6.31 (q, J = 7.2Hz, 1H),
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7.08−7.11 (m, 1H), 7.19−7.25 (m, 2H), 7.26−7.30 (m, 2H), 7.40−7.49 (m, 5H) ppm; C NMR (CDCl3, 100.62
MHz): δ 15.8,20.6, 50.4, 101.4, 126.9, 127.4, 127.9, 128.3, 128.5, 129.1, 129.6, 136.8, 140.2, 151.5, 162.6 ppm;
FTꢀIR (CHCl3): ν 3013, 1706, 1665, 1490, 1418 cmꢀ1; GC/MS (70 eV): m/z (%) = 306 (100) [M]+, 202 (41), 160
(55), 159 (60), 105 (85), 77 (70); HRMS (ESI): calcd. for C19H19N2O2 [M+H]+ 307.1447; found 307.1445.
Supporting Information
Copies of NMR spectra for compounds 3a-o and 7l-n are reported. This material is available free of charge
via the Internet at http://pubs.acs.org.
Author information
Corresponding authors:
Eꢀmail: antonio.salomone@uniba.it
Eꢀmail: luigino.troisi@unisalento.it
Acknowledgment
The authors thank the University of Salento and the Consorzio Interuniversitario Nazionale Metodologie e
Processi Innovativi di Sintesi (C.I.N.M.P.I.S.).
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(14) No trace of the isomeric product 3f was detected by 1HꢀNMR analysis on the crude reaction mixture.
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(15) In principle, also the ketene C can act as an acylating agent to produce the Nꢀacylated urea and then the corresponding
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formation of the highly reactive ketene C is not favored. In fact, we have never found the product of ketene dimerization (2ꢀ
pyranones derivatives) previously described (see reference 8a) probably because the intermediate B reacts very rapidly with
the urea derivative.
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