A new diversity oriented and metal-free approach to highly functionalized 3H-pyrimidin-4-ones

Article abstract of DOI:10.1039/c0ob00978d

A new synthesis of 3H-pyrimidin-4-ones, characterized by four different sets of decorations, is presented. The strategy is based on the synthetic elaboration of readily available α-substituted β-ketoesters that, upon transformation into the corresponding acyl enamines, have been cyclized to give 6H-1,3-oxazin-6-ones. These reactive intermediates have been in turn cleanly converted into highly functionalized pyirimidinones, by treatment with an appropriate primary amine. The whole sequence does not need the use of any metal mediator or catalyst.

Full text of DOI:10.1039/c0ob00978d

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PAPER
A new diversity oriented and metal-free approach to highly functionalized
3H-pyrimidin-4-ones
Renata Riva,* Luca Banfi, Andrea Basso and Paola Zito
Received 3rd November 2010, Accepted 13th December 2010
DOI: 10.1039/c0ob00978d
A new synthesis of 3H-pyrimidin-4-ones, characterized by four different sets of decorations, is
presented. The strategy is based on the synthetic elaboration of readily available a-substituted
b-ketoesters that, upon transformation into the corresponding acyl enamines, have been cyclized to give
6H-1,3-oxazin-6-ones. These reactive intermediates have been in turn cleanly converted into highly
functionalized pyirimidinones, by treatment with an appropriate primary amine. The whole sequence
does not need the use of any metal mediator or catalyst.
Introduction
The pyrimidin-4-one moiety is the core structure of many bi-
ologically active compounds. Some examples of compounds in
clinical use are reported in Scheme 1: they include atypical
antipsychotics risperidone 1 and its follow-up paliperidone 2,1,2
the phosphodiesterase type 5 inhibitor sildenafil 3 (best known as
ViagraTM),3 the anxiolytic and antidepressant (also endowed with
antiobesity activity) GW-803430 4,4 the angiotensin II receptor
antagonist LR-B/081 5,5 and the indolequinazoline alkaloid
rutaecarpine 6, characterized by several interesting properties,
including antiinflammatory activity.6 Moreover, 3H-pyrimidin-4-
ones, are also used as agrochemicals, owing to their activity as
herbicides.7,8 Finally, 3H-pyrimidin-4-ones are synthetic interme-
diates for the preparation of 4-aminopyrimidines, an essential
fragment in very important molecules such as the antitumor
antibiotics bleomycins.9 Thus the pyrimidin-4-one ring is definitely
a privileged structure, and the availability of efficient routes
that allow a combinatorial entry to this scaffold, varying the
substituents at all free positions (2, 3, 5, and 6), will be particularly
useful.
Several methods have been reported for preparing both pyrim-
idinones and quinazolinones. In this paper however we will focus
our attention only on the synthesis of 2,3,5,6-tetrasubstituted 3H-
pyrimidin-4-ones.
In the literature, a series of different approaches can be found.
They mostly differ for the nature of the acyclic reagents that
provide the necessary nitrogen atoms, whereas in most cases
the three carbon atom fragment (C4-C5-C6 in the pyrimidinone)
is introduced employing an appropriate b-dicarbonyl derivative.
Scheme 1 Examples of biological relevant 3H-pyrimidin-4-ones.
reported only with commercially available amidines (R4 = H,
Me). The fourth diversity point (R5) is then introduced by N-
alkylation.5 This latter reaction is however critical because of
Scheme 2 summarizes some of these strategies: b-ketoester 7 can
be condensed with amidine 9 (R5 = H) to give 3-unsubstituted
the competitive O-alkylation, a typical behaviour of heterocyclic
ambident anions.10 To avoid the alkylation of the pyrimidinone,
3H-pyrimidinones 10 (route A). However, this reaction was
a N-substituted amidine (R5 π H) can be employed as well. The
reaction was initially limited to a-unsubstitued 7,11 but recently,
Department of Chemistry and Industrial Chemistry, University of Genova,
via Dodecaneso 31, 16146 Genova, Italy. E-mail: riva@chimica.unige.it;
Fax: +39 010 3536118; Tel: +39 010 3536106
working under pressure, the protocol showed a more general
scope.7
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Scheme 2 Literature survey on the synthesis of 2,3,5,6-tetrasubstituted 3H-pyrimidin-4-ones.
Compounds 9 (R5 π H) react smoothly also with malonyl
dichlorides 11 to give 12 (route B), which can be converted into
10, after cross-coupling of the corresponding triflate with a higher
order cuprate.12 This strategy is however hampered by the high
reactivity and scarce availability of compounds 11.
The two nitrogen atoms can also derive from two different
acyclic substrates: b-ketoesters 7 are converted into the acyle-
namino esters 13, which can be easily cyclized in the presence of
trimethylaluminium and of the hydrochloride of a primary amine
(route C).13
On the other hand, in route D the intramolecular dehydration
is performed directly on the acylenamino amide 14.14 Protocols
C and D are efficient, but both have some drawbacks: the first
one represents a fast entry to pyrimidinones (only three steps), but
the entire process is poorly sustainable. Because of the mechanism
proposed by the authors, at least 3 equivalents of Me3Al (a well
known pyrophoric organometallic derivative) and of the primary
amine are required, thus producing a lot of waste, a condition in
contrast with atom economy. Moreover, in the final pyrimidinone
(route C) only simple alkyl or aryl groups can be introduced on
carbon 2. In the latter strategy (route D) eight steps from the b-
ketoester are necessary and substituent R5 is introduced early in
the synthesis (fourth step). This means that, for each R5 group,
five synthetic steps have to be performed independently. Recently,
a method for preparing isomers of 12 (with the OH group in
position 5 instead of 6), through the thermal rearrangement of O-
substituted amidoximes under microwave heating, was reported.15
Finally, a very recent microwave assisted methodology allowed
the transformation of Meldrum’s acid 15 into 10 going through
N-acyl-b-ketoamides 8 (route E). This strategy has however been
reported only to prepare compounds with R5 = H.16
Scheme 3 Retrosynthetic plan.
gradual increase of the diversity of the system. This is clearly
more advantageous, in combinatorial chemistry, than performing
several synthetic steps after the introduction of all diversity inputs,
as it happens for route C and, especially, for route D. Moreover, it
is also possible to add further diversity, by modifying the final
compounds 16, through reactions involving the CO2R4 group.
Finally, we wanted to develop a method that could be easily scaled
up for the kilogram synthesis of these compounds, thus avoiding
dangerous or expensive reagents, very low temperatures or metals
that could contaminate the final products.
Results and Discussion
When this project started, we were interested in particular in
synthesizing 2-carbalkoxy pyrimidinones like 16. We initially
followed more closely the previously reported routes C and D,
studying an alternative synthesis of N-acylenaminoamides such as
23 that avoids the use of Me3Al (Scheme 4). Our preliminary efforts
started therefore from b-ketoester 7a, prepared in 82% yield by
alkylation of ethyl acetoacetate.17 The transformation into amide
20 was accomplished by ester hydrolysis followed by coupling
with nBuNH2 to give the desired product in acceptable yield,
notwithstanding the propensity of the intermediate b-ketoacid to
undergo decarboxylation if inappropriate reaction and work-up
conditions are employed. Nevertheless every effort to convert 20
In this paper we propose a third possibility in which a stepwise
introduction of the two N atoms is performed, with the last one
entering after the cyclization. This approach is illustrated in the
retrosynthetic Scheme 3. A great advantage of our synthetic plan
is that the various diversity inputs are introduced sequentially
(one for each synthetic step). This means the possibility to use
common intermediates for preparing several products with a
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other acids, obtaining acceptable results with camphorsulfonic
acid working at 60 ◦C in diethyl ether under MW heating
in a closed vessel. Although a very clean reaction occurred,
the conversion was always around 50% and addition of more
catalyst was not beneficial, also because of poor solubility of
ammonium camphorsulfonate. After a careful optimization we
found ammonium acetate to be the ideal catalyst. In this case no
need of an additional solvent was necessary and the conversion
into 21b resulted almost complete after heating a solution of
7b in the presence of 9 equivalents of ethanolic ammonia and
4 equivalents of NH4OAc in a sealed tube at 60 ◦C. With this
procedure 18b was isolated with a high purity and an overall 81%
yield after acylation.
The following step was the hydrolysis of the t-butyl ester 18b
with CF3CO2H and the transformation of the resulting acid 24 into
amide 23, by treatment with N,N¢-carbonyl diimidazole (CDI)
and nBuNH2. We were surprised to obtain a complex mixture
containing pyrimidinone 16aa (48%), oxazinone 17a (11%), acid
24 (21%), 2-undecanone (from decarboxylation of 24, 2%) and a
small amount (about 10%) of a mixture of products (among them
only traces of the expected amide 23 were identified). Moreover,
it is fundamental to stir the solution of the acid in the presence
of CDI for at least 20 min before adding the amine; otherwise no
reaction takes place.
Interestingly, treatment of 24 with CDI without adding the
amine, promoted a smooth transformation into 17a (71% from
18b). This allowed us to establish that oxazinone 17a, rather than
the amide 23, is the intermediate of this cyclization reaction. This
result was not completely unexpected since these heterocycles have
been demonstrated to be intermediates in the Me3Al mediated
synthesis of 10.13 The isolated oxazinone 17a is however quite
reactive, being smoothly converted into 16aa upon treatment with
nBuNH2 at room temperature without the need of any catalyst.
This behaviour supports the scarce available literature data on
these heterocyclic systems: actually, in only two other cases,
oxazinones have been used as intermediates for the synthesis of
very specific pyrimidinones,22,23 thanks to their propensity to react
with N-nucleophiles.
The synthesis of 17a by treatment of 24 with CDI has however
some drawbacks: even in the presence of an excess of condensing
agent the reaction never reached completion and variable amounts
of decarboxylation product were always identified. In order to
overcome this undesired outcome, we examined the possibility to
transform directly 18b or 18a into 17a, avoiding the involvement of
24 as intermediate. Treatment of 18b with a base such as EtONa,
however, did not promote the O-cyclization, probably due to the
weak nucleophilic power of the reacting species. Only cleavage of
the amide bond to give a mixture of 21b and 7b occurred.
So we turned our attention on a completely different approach.
Wamhoff et al. reported the serendipitous synthesis of hetero-
condensed 6H-1,3-oxazin-6-ones arising from treatment of a very
peculiar family of N-acylenamine esters, quite different from ours,
with PPh3 in hexachloroethane in the presence of Et3N.24,25 The
authors, relying on the previous reports by Appel,26 envisaged
dichlorotriphenylphosphorane, generated by the combination of
PPh3 with C2Cl6, as the promoter of the whole sequence. We
reasoned that a similar protocol could have been applied to
our compounds, simply using carbon tetrachloride instead of
hexachloroethane and working initially in 1,2-dichloroethane as
Scheme 4 Reagents and conditions: a) i. KOH, EtOH; ii. CDI, nBuNH2,
THF, r.t.; b) NH4OAc, toluene, reflux; c) NH3 (2.8 M in EtOH), NH4OAc,
60 ◦C, sealed tube; d) ClCOCO2Et, Py, CH2Cl2/Et2O 2 : 1, r.t.; e)
CF3CO2H, CH2Cl2, r.t.; f) i. CDI, THF, 20 min, r.t.; ii. nBuNH2, r.t.;
g) CDI, THF, r.t.; h) nBuNH2, THF, r.t.
into 22 (and then into 23) failed, either using NH4OAc13,18 or
ammonia in the presence of a Lewis acid, such as, for example,
AlCl3.14
So we chose to work on the corresponding ester 18a, planning
to transform the ester into an amide later. The method proposed
by Jeong et al. (ammonium acetate in refluxing toluene)13 worked
this time well, affording the enamine 18a in a good 72% yield from
21a after acylation with ethyl 2-chloro-2-oxoacetate,19 although
we were never able to drive the reaction to completion (conversion
was always £90%). The formation of the enamine was highly
stereoselective, giving almost exclusively the more hindered Z
stereoisomer (>97%), whose formation is most likely favoured
by the stabilization through an intramolecular H bond. The
presence, in 18a, of two ethyl ester groups could make selective
hydrolysis troublesome, although the oxalic ester was expected to
be more reactive according to literature data.20 Thus we repeated
the sequence starting from tert-butyl b-ketoester 7b, prepared in
72% yield by alkylation of t-butyl acetoacetate.21 To our surprise
the formation of enamine 21a under Jeong conditions13 was this
time rather sluggish. Conversions never went over 70–80% and
long reaction times were detrimental because of decomposition of
starting material. As a result, the yield was always £ 41%.
We therefore tried to optimize this reaction, inspired by the
methods that employ gaseous ammonia and an appropriate
acid.14,20 For practical reasons we decided to avoid bubbling
a stream of ammonia into the reaction, preferring instead a
freshly prepared 2.8 M solution of ammonia in ethanol, that was
added to a solution of the substrate in an appropriate solvent
(diethyl ether, dioxane, hexane). Working in the presence of AlCl3
we did not, however, obtain the expected results. We explored
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solvent. The choice of the solvent was made on the basis of
two considerations: a) the possibility to explore a wider range of
temperatures, compared to dichloromethane; b) a higher dielectric
constant and dipole moment, which was expected to favour the
formation of dichlorotriphenylphosphorane.26
A possible condensed mechanism, which ensues from previous
findings and from our results,24 is depicted in Scheme 5. It’s
important to notice that at least 2 equivalents of phosphine are
required, because only 0.5 mole of dichlorodiphenylphosporane
is produced from 1 mole of PPh3. The reactive precursor of 17a
is most likely acyl chloride 26. The faster reaction of the t-butyl
ester 18b is probably due to a faster conversion into 25, facilitated
by the exit of a t-butyl cation, which is then trapped by a chloride
ion.
An important feature of oxazinone 17a is its limited stability:
this means that it can be isolated and purified by chromatography,
but it is not stable enough to be stored for a long time, even
at -25 ◦C. We therefore preferred to submit it immediately to
the following reaction, just after a very rapid purification by
chromatography, which is necessary to remove Ph3PO. On the
other side, this chromatography can not be avoided, because direct
treatment of crude oxazinone with the amine gave an overall lower
yield.
We performed therefore two experiments under the same
conditions on 18a and 18b respectively. Both were converted into
the same oxazinone 17a working at reflux, but with quite different
rate: after 30 min the reaction resulted complete only for 18b, while
no complete conversion of 18a was reached even after heating for
several hours. The isolated yields were different too: 60% from 18a
and 78% from 18b. Since the transformation from 18b appeared to
be more promising, the optimization was performed only on this
compound. At the end of the tuning process we found that 1,2-
dichloroethane can be conveniently substituted by the less toxic
dichloromethane, since the temperature can be lowered to about
40 ◦C, with only an acceptable increase in the reaction time (2.5 h)
and a comparable yield (78%) (Scheme 5).
Having previously demonstrated that oxazinones 17 can be
easily transformed into pyrimidinones 16, the following step was to
expand the scope of this method, introducing different decorations
on the final 3H-pyrimidin-4-ones.
The starting materials were commercially available b-ketoesters,
with the exception of 27, which was synthesized in good overall
yield (75% isolated, 94% considering recovered unreacted starting
material) by treatment of (p-methoxyphenoxy)acetic acid, pre-
viously activated as the imidazolide, with Meldrum acid 15,27
followed by monodecarboxylation and esterification (Scheme 6).
Scheme 6 Reagents and conditions: a) i. CDI, CH2Cl2, r.t.; ii. 15, DMAP,
CH2Cl2/Py, r.t.; iii. 2 M HCl, r.t.; iv. tBuOH, toluene, 85 ◦C.
Alkylation of the b-ketoesters was performed following different
procedures, in order to achieve the highest yields (Table 1). A
careful monitoring of the experimental conditions was necessary
in order to suppress as much as possible the double alkylation.
The most critical example is represented by 7d (entry 4). Bases
that are usually employed for this kind of reaction gave only
Scheme 5 Reagents and conditions: a) PPh3/CCl4, Et3N, CH2Cl2, reflux.
Table 1 Synthesis of a small library of oxazinones 17
Entry
R1
R2
R3
Conditions of alkylation of b-ketoester
EtONa, nC8H17Br, KI, EtOH, reflux
Yield % (7)
Yield % (18)a
Yield % (17)b
1
2
3
4
5
Me
Me
Me
nC8H17
nC8H17
iBu
CH2CH2OBn
Et
Et
82 (7a)
72 (7b)
69 (7c)
70 (7d)
70 (7e)
72 (18a)
81 (18b)
82 (18c)
60 (18d)
43 (18e)c
60 (17a)
78 (17a)
74 (17c)
57 (17d)
55 (17e)
tBu
tBu
tBu
tBu
NaH, nC8H17Br, toluene-DMF, 100 ◦
C
NaH, iBuBr, toluene-DMF, 100 ◦C
Me
Cs2CO3, BnOCH2CH2Br, tBuOH, reflux
NaH, EtBr, toluene-DMF, 100 ◦
p-AnOc
C
a i. NH4OAc, toluene, reflux (21a), NH3 (2.8 M in EtOH), NH4OAc, 60 ◦C, sealed tube (21b–d); ii. ClCOCO2Et, Py, CH2Cl2/Et2O 2 : 1, r.t. (18);
b PPh3/CCl4, Et3N, CH2Cl2, reflux; c p-AnO = p-anisyloxy; d the isolated yield refers only to the Z isomer (see also text).
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Table 2 Transformation of oxazinones 17 into pyrimidinones 16
Entry R1
R2
R3
Yield % (16)a
1
2
3
4
5
6
7
8
Me
nC8H17
nC8H17
nC8H17
nC8H17
iBu
nBu
80 (16aa)
89 (16ab)
81 (16ac)
66 (16ad)
68 (16ca)
62 (16cb)
72 (16cc)
Scheme 7 Reagents and conditions: a) BnOCOCl, NaOH/H2O, r.t.; b)
tBuOH, DCC, DMAP, CH2Cl2, r.t.; c) H2, Pd/C, MeOH, r.t.
Me
Me
Me
Me
Me
Me
Me
Me
(CH2)3CO2tBu
(CH2)3CO2Et
iBu
Moreover, the possibility to tune the nature of the R groups,
together with the presence of an ester function on C2 disclosed
also the opportunity to submit 16 to following transformations in
order to increase the accessible diversity around the pyrimidinone
scaffold.
In particular bi-functionalized amines gave very good yields
(entries 2, 3, 9) and this prompted us to investigate the Dieckmann
reaction involving the two ester functionalities on 16ab and 16ac,
as depicted in Scheme 8. To the best of our knowledge this
approach was used on similar compounds only in a recently
reported total synthesis of rutaecarpine 6.6 It is however important
to notice that the reported precursor is characterized by a benzene
ring condensed with the pyrimidinone instead of having two R1
and R2 groups.
iBu
iBu
(2-furyl)methyl
(2-thienyl)methyl
iBu
iBu
(4-methoxy)benzyl 75 (16cd)
9
10
11
CH2CH2OBn (CH2)3CO2tBu
75 (16d)
77 (16ea)
77 (16eb)
p-AnOCH2 Et
p-AnOCH2 Et
nBu
Bn
a amine, THF, r.t.
moderate yields (for example 51% under conditions employed for
preparing 7b, 7c or 7e). So we turned our attention on alkaline
carbonates and we noticed a strict dependence upon the nature of
the counterion: while with Na2CO3 the reaction did not start, with
K2CO3 the yield was again around 50%. The best results (70%)
were however obtained with Cs2CO3 under conventional reflux
in tBuOH, while the same reaction, performed under microwave
heating in DMF, gave only 52% yield. The formation of N-acyl
enamines 18 gave good results in most cases, the only exception
being represented by 18e. The poorer yield is most likely to ascribe
to a less stereoselective enamine formation. The higher steric
hindrance of the p-anisyloxy group compared with the methyl
can explain this different behaviour. It is worth noting that Z-
18e is the only stereoisomer able to be transformed into 17e, and
therefore the isomeric E-18e, chromatographically separated from
Z-18e, had to be discared.
The following cyclization mediated by the PPh3/CCl4 system,
allowed to prepare a series of representative oxazinones 17.
As experienced before for the parent compound 17a, all these
heterocycles are quite unstable and must be isolated and purified
as soon as possible and immediately submitted to the following
reaction for avoiding an extended decomposition, which heavily
affects the overall yield.
For the synthesis of 16 we chose a series of amines having
different structures (Table 2). We employed either simple, com-
mercially available, linear (entries 1, 10) or branched (entries
4, 5) primary amines, but we used also amines with aromatic
(entries 8, 11) or heteroaromatic (entries 6, 7) groups. Moreover
bi-functional amines have been tested too (entries 2, 3, 9). Ethyl 4-
aminobutyrate is commercially available as the hydrochloride and,
for this reason, the addition of one equivalent of triethylamine was
necessary. On the contrary, the corresponding tBu ester 30 had to
be synthesized from g-aminobutyric acid as depicted in Scheme 7.
After protecting the amino group as Cbz (28),28 the ester function
was introduced.29 Amine 30 could not be stored because it is not
very stable. For this reason the protecting group was removed by
hydrogenolysis just before the reaction with oxazinone 17a or 17b.
The protocol leading to pyrimidinones 16, showed to be very
efficient in most cases, as summarized in Table 2.
Scheme 8 Reagents and conditions: a) from 16ab: i. tBuOK, THF, r.t.; ii.
0.5 M HCl, dioxane, reflux; from 16ac: i. tBuONa, THF, r.t.; ii. 6 M HCl,
reflux; b) NaH, DMF; c) MeONa, MeOH, r.t.
When we submitted 16ab to the same condi◦tions (NaH, 1.2
equivalents, DMF with heating overnight at 70 C) we obtained
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a complex reaction mixture of at least four compounds in the
following ratio (GC-MS): 14% of unreacted starting material,
79% of decarboxylated 36 (60% isolated yield), about 3% of
desired 31 and about 4% of 37 in which, in addition to the
decarboxylation, a transesterification occurred too. We were quite
surprised by these results and, in particular by the formation of
36 and 37, and therefore we decided to further investigate the
reaction. Changing the conditions and working in the presence of
EtONa (1.5 equivalents) in toluene at 70 ◦C only a mixture of 31
and 37 was obtained. Switching to lithium bis(trimethylsilyl)amide
(1.1 equivalents) in THF at room temp. the reaction was slow,
affording again 36 as major product, 31, and traces of 37. By
warming at reflux, the starting material and 36 disappeared and
the major product was again 37.
We demonstrated also that this decarboxylation is not peculiar
of 16ab only: actually, 16aa, which is not a substrate for the Dieck-
mann reaction, underwent exactly the same fast decarboxylation
to give exclusively 40 in excellent yield.
While decarboxylation of pyrimidinones bearing a COOH
group on C2 is known to be a spontaneous transformation,9 the
same reaction under basic conditions is however unlikely and is
hard to justify.
Initially, we hypothesized the formation of a carbanion on C2
through an E2 process promoted by the attack of the base at
the terminal carbon of the ethyl group as depicted in Scheme
8 on compound 16aa. Such a reactive intermediate should
however react easily with an electrophile, an example being an
alkyl halide or an aldehyde, but all attempts to trap it failed.
Moreover, we were able to exclude a mechanism proceeding
through E2 elimination, because methyl ester 39 (prepared through
an unusually fast transesterification under very mild basic con-
ditions) was converted into 40 too, even faster than 16aa. The
involvement of a radical mechanism during the decarboxylation
was excluded too, because basic treatment in the presence of a
radical inhibitor, such as 2-tert-butyl-4-((3-(2-hydroxypropan-2-
yl)-4,5-dimethylphenyl)sulfanyl)-6-methylphenol, led again to 40.
Finally, we treated compound 16ab with tBuOK (2 equivalents)
in THF at room temp.: after addition of the base we noticed a
sudden colour change from pale yellow to brick red and, after 10
min, the initial colour was established again. The reaction resulted
complete after half an our and the only product we found was 31.
The same result was obtained working at 0 ◦C, even if the reaction
mixture resulted less clean. On the contrary, working at 0 ◦C, but
in the presence of only 1.2 equivalents of base, the crude resulted
a 62 : 38 mixture of 31 and 36 respectively. Similar results were
obtained substituting tBuOK with NaH (always 2 equivalents),
including colour changes, which occurred this time only after
refluxing the mixture. Comparing the precursor of rutaecarpine
6 with 16ab the most significant difference is the presence, in
our compound, of a CH2 group bonded to C5. At this point we
were able to hypothesize a mechanism which agrees with all the
experimental data reported above (Scheme 9).
Compound 16ab has 3 acidic sites. Deprotonation on carbon
a leads to the Dieckmann product (31), through enolate 41.
Deprotonation on carbon b gives carbanion 42, which is stabilized
by resonance but which is not able to give any new product. On
the contrary, deprotonation on carbon c gives a highly delocalized
carbanion (43 ↔ 44, the most likely candidate responsible for the
brick red colour we observed), which, upon loss of ethylate through
a E1cb mechanism, is transformed into ketene 45. During work-up,
if no Dieckmann reaction occurred, a molecule of water adds to
45, giving acid 47, which soon decarboxylate to give 36, whereas
ethylate, produced during the formation of 45, is responsible for the
observed transesterification, following one of the paths displayed
Scheme 9 A possible mechanism for explaining the behaviour in bases of compound 16ab.
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in the Scheme 9. The exclusive formation of 31, when 2 equivalents
of base are employed, can be explained by the irreversible attack
of the enolate of 45 to the highly electrophilic ketene moiety.
Of course, when less than 2 equivalents of base are used, the
conversion into 31 cannot be complete.
Compound 31 was shown to exist almost exclusively in the
1
enolic form 33, as proved at H NMR by the chemical shift of
the enol proton resonating at 12.06 ppm,6,30 and at 13C NMR by
the absence of the ketone and of CHCO2tBu and by the presence
of a quaternary carbon at 104.8 ppm for = CCO2tBu. This result
is perfectly in accord with literature data on similar compounds.
b-Ketoester 31, moreover, is not very stable and decomposed quite
rapidly even during chromatography. For this reason its structure
was demonstrated on the crude and then it was directly submitted
to a hydrolysis-decarboxylation protocol, leading to 35 in 65%
overall yields. It is worth noting that 35 possesses the same bicyclic
skeleton present in important drugs such as risperidone 1 and
paliperidone 2.
Encouraged by our findings we tried to extend the same protocol
on 16ac. Under exactly the same conditions used for 16ab, we
obtained a 6 : 4 mixture of 32 and 38 (in which, in addition to
the decarboxylation, the hydrolysis of the ethyl ester occurred
too). Harsher conditions for the hydrolysis of the ethyl ester were
required and finally 35 was isolated in only 22% overall yield. The
yield was however improved up to 43% switching to tBuONa.
The clean decarboxylation reaction, achieved on compounds
16 by treatment with 1 equivalent of base, allows the access to 2-
unsubstituted pyrimidinones, as exemplified by the synthesis of 40
from 16aa in 86% yield. These unsubstituted compounds are not
easily prepared using the strategies depicted in Scheme 2. Apart
from this useful reaction, the high reactivity of the ester function
bonded to C2 prompted us to study other types of transformations,
that are summarized in Scheme 10 starting from compound 16cd.
For example, exploiting trimethylaluminium mediated reac-
tions, the ester group was directly converted into an amide (49)
or into an O-protected hydroxamate (50), in the presence of the
hydrochlorides of a primary amine or of an O-alkyl hydroxylamine
respectively. These functional groups are not directly accessible
from the beginning, since only few mono-oxalyl chlorides are
available. Nevertheless, every transformation of the ester function,
passing through the carboxylic group has to be avoided, to prevent
the very fast decarboxylation. Also the transesterification reaction
was shown to be possible on 16cd to give 51 under basic conditions.
Generally speaking this procedure allows a fast entry to different
carboxylates attached to C2.
Scheme 10 Reagents and conditions: a) Me3Al, CH2Cl2, MeNH2·HCl
(for 49) or BnONH2·HCl (for 50), r.t.; b) BnOH, NaH, benzene, reflux; a)
NaBH4, MeOH, r.t.
diversity can be realized step by step under an efficient procedure
carried out under mild conditions, tolerated by most func-
tional groups. Moreover, with some limitations, these compounds
showed to be pluripotent substrates31 as demonstrated by the
possibility to elaborate them after the formation of the heterocyclic
scaffold. Apparently, our method seems to be suited only for
the preparation of 3H-pyrimidin-4-one-2-carboxylic esters. We
demonstrated however that the carbalkoxy group can be efficiently
removed, leading to 2-unsubstituted compounds, or transformed
into different carboxylic derivatives. Moreover, if a potential C-
nucleophile is placed in the substituent at position 3, a cyclization
onto the electrophilic 2-CO2R group is possible, allowing the
preparation of bicyclic systems. For the simplicity and the mildness
of our conditions we think therefore that our methodology should
find possible applications as a fast entry in the development of
possible drug-like structures.
Treatment of these pyrimidin-3H-ones with mild reducing
agents, such as NaBH4, showed, on the contrary, not be consistent
with the heterocyclic system. For example the ester function of
16cd was rapidly reduced to give alcohol 52 even with a mild
reagent as NaBH4, but in very modest yield. This is most likely
due to not complete stability of the heterocyclic moiety under
reducing conditions.
Experimental Section
NMR spectra were measured at room temp. in CDCl3 at 300 MHz
(1H), and 75 MHz (13C), with TMS as internal standard for
1H NMR and the central peak of CDCl3 (at 77.02 ppm) for
13C NMR spectroscopy. Chemical shifts are reported in ppm (d
scale); coupling constants are reported in hertz. Peak assignments
were made with the aid of DEPT and gHSQC experiments. Peak
Conclusions
In this paper we described a new, convergent and combinatorial
four step synthesis of a family of differently substituted 3H-
pyrimidin-4-ones from readily available b-ketoesters. Starting
from few common intermediates a sequential increase of chemical
1
assignment in H NMR spectra was also made with the aid of
gCOSY experiments. In AB systems the proton A is considered
upfield and B downfield. GC-MS were carried out using an
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HP-1 column (11.85 m long, 0.2 mm wide), electron impact at
70 eV, and a mass temperature of about 170 ◦C. Only m/z >
33 were detected. All analyses were performed (unless otherwise
stated) with a constant He flow of 0.9 mL min-1 with initial temp.
dropped over a period of 30 min (so that the reaction mixture
resulted just lukewarm), while the reaction was vigorously stirred.
After 15 min 1-bromooctane (6.76 mL, 39.1 mmol) was added
and the resulting yellow solution was heated at 100 ◦C for 3
h. The orange suspension was partitioned between saturated aq
NH4Cl and PE/Et2O 1 : 1 and the pH of the aqueous layer was
adjusted to 7–8 by addition of a small amount of concentrated
HCl. After complete extraction the organic layers were washed
with water and brine. After solvent evaporation, the crude was
purified by chromatography with PE/Et2O 9 : 1 to give pure 7b
(7.60 g, 72%) as a colourless oil. Rf 0.40 (PE/Et2O 85 : 15, b).
◦
100 ◦C, init. time 2 min, rate 20 C min-1, final temp. 290 ◦C,
inj. temp. 250 ◦C, det. temp. 280 ◦C. HR-MS were recorded
employing ESI ionization method. IR spectra were recorded as
CHCl3 solutions and absorptions are reported in cm-1. Melting
points are uncorrected. TLC analyses were carried out on silica gel
plates and viewed under a) UV (254 nm) or developed by dipping
into a solution of b) (NH4)4MoO4·4 H2O (21 g) and Ce(SO4)2·4
H2O (1 g) in H2SO4 (31 mL) and H2O (469 mL) or into a solution
of c) ninhydrin (900 mg dissolved in 300 mL of nBuOH and
9 mL of acetic acid) and warming. Rf were measured after an
elution of 7–9 cm. Column chromatographies were done with the
“flash” ◦methodology using 220–400 mesh silica. Petroleum ether
(40–60 C) is abbreviated as PE. In extractive work-up, aqueous
solutions were always reextracted three times with the appropriate
organic solvent. Organic extracts were always dried over Na2SO4
and filtered, before evaporation of the solvent under reduced
pressure. All reactions employing dry solvents were carried out
under a nitrogen atmosphere.
n
max(CHCl3)/cm-1 3675, 3610, 3015, 2974, 2931, 1700, 1506, 1474,
1418, 1368, 1230, 1042, 924. dH(300 MHz; CDCl3) 0.88 (3 H, t,
J 6.9, CH3(CH2)7), 1.22–1.32 (12 H, m, CH3(CH2)6), 1.46 (9 H,
s, (CH3)3C), 1.74–1.84 (2 H, m, CHCH2), 2.21 (3 H, s, CH3CO),
3.29 (1 H, t, J 7.4, CHCH2). dC(75 MHz; CDCl3; Me4Si) 14.0
(CH3(CH2)7), 22.6 (CH3CH2CH2), 27.2 (CHCH2CH2), 27.8 (3 C,
(CH3)3C), 28.0 (CHCH2CH2), 28.5 (CH3CO), 29.1, 29.2 and 29.3
(3 C, CH3CH2CH2(CH2)3), 31.8 (CH3CH2CH2), 60.9 (CHCH2),
81.6 (OC(CH3)3), 169.1 (CO2tBu), 203.6 (COCH3). GC-MS: Rt
6.13 min; m/z (EI) 214 (M+ – 56, 1.3%), 197 (7.7), 158 (7.6), 115
(6.8), 112 (11), 103 (43), 102 (42), 98 (48), 97 (5.6), 84 (8.2), 73
(6.9), 71 (14), 58 (8.8), 57 (100), 56 (8.0), 55 (15), 43 (69), 41 (27).
m/z (ESI-) 269.2124 (M – H+. C16H29O3 requires 269.2117).
Ethyl 2-octyl-3-oxobutanoate 7a
Sodium ethoxide (5.64 g, 82.9 mmol) was suspended in absolute
ethanol (65 mL). After cooling to 0 ◦C ethyl acetoacetate (10 mL,
79.1 mmol) was dropped through an addition funnel over a period
of 10 min using 5 mL of EtOH for a complete addition of the
reagent. After 5 min the reaction was allowed to stir at room temp.
for 15 min. Then solid KI (1.25 g, 7.53 mmol) was rapidly added
followed by dropping, over a period of 5 min, of 1-bromooctane
(15.6 mL, 90.3 mmol). The reaction was refluxed for 24 h. The
reaction mixture was partitioned between water and Et2O and
extracted three times. After solvent removal the crude was purified
by distillation under reduced pressure to give 7a (15.76 g, 82%)
as a pale yellow oil. This compound, such as other esters 7, is
sometimes contaminated by small amounts of dialkylated product,
tert-Butyl 2-isobutyl-3-oxobutanoate 7c
It was prepared by the same methodology employed for 7b, using
this time isobutyl bromide, to give 7c as a colourless oil in 69%
◦
yield after distillation. B.p. 96–97 C, 7 mbar. Rf 0.48 (PE/Et2O
8 : 2, b). nmax(CHCl3)/cm-1 3545, 2926, 1727, 1631, 1267, 1116.
dH(300 MHz; CDCl3; Me4Si) 0.90 and 0.92 (6 H, 2 d, J 1.8
and 1.5, (CH3)2CH), 1.46 (9 H, s, (CH3)3C), 1.51–1.80 (3 H,
m, (CH3)2CHCH2), 2.21 (3 H, s, CH3CO), 3.39 (1 H, dd, J
8.4, 6.6, CHCH2CH(CH3)2). dC(75 MHz; CDCl3) 22.1 and 22.5
(2 C, (CH3)2CH), 26.1 ((CH3)2CH), 27.8 (3 C, (CH3)3C), 28.4
(CH3CO), 36.8 (CH2CH(CH3)2), 59.2 (CHCH2CH(CH3)2), 81.6
(OC(CH3)3), 169.2 (CO2tBu), 203.6 (COCH3). GC-MS: Rt 2.95
min; m/z (EI) 214 (M+, 0.023%), 158 (11), 141 (19), 116 (5.6), 115
(6.3), 103 (29), 102 (20), 99 (9.3), 98 (26), 73 (16), 71 (14), 70 (8.0),
69 (17), 58 (5.7), 57 (100), 56 (9.5), 55 (25), 43 (76), 41 (31), 39
(8.2). m/z (ESI-) 213.1486 (M – H+. C12H21O3 requires 213.1491).
◦
which can however be separated by chromatography. B.p. 60 C,
0.35 mbar. Rf 0.36 (PE/Et2O 9 : 1, a or b). nmax(CHCl3)/cm-1 3675,
3612, 3017, 2973, 2924, 1706, 1509, 1469, 1418, 1212, 1042, 925.
dH(300 MHz; CDCl3; Me4Si) 0.87 (3 H, t, J 6.6, CH3(CH2)7),
1.25–1.32 (12 H, m, CH3(CH2)6), 1.27 (3 H, t, J 7.1, CH3CH2O),
1.79–1.90 (2 H, m, CHCH2), 2.22 (3 H, s, CH3CO), 3.40 (1 H, t, J
7.5, CHCH2), 4.20 (2 H, q, J 7.1, CH3CH2O). dC(75 MHz; CDCl3)
14.1 (2 C, CH3CH2), 22.6 (CH3CH2CH2), 27.4 (CHCH2CH2),
28.2 (CHCH2CH2), 28.7 (CH3CO), 29.1, 29.2 and 29.3 (3 C,
CH3CH2CH2(CH2)3), 31.8 (CH3CH2CH2), 59.9 (CHCH2), 61.2
(OCH2), 169.9 (CO2Et), 203.4 (COCH3). GC-MS: Rt 5.75 min;
m/z (EI) 242 (M+, 0.61%), 200 (18), 157 (23), 143 (19), 131 (12),
130 (78), 115 (13), 102 (18), 101 (60), 98 (6.8), 97 (9.0), 88 (11), 85
(7.2), 84 (9.6), 83 (5.4), 73 (39), 71 (6.5), 69 (9.8), 55 (25), 43 (100),
42 (5.5), 41 (23), 39 (6.3). m/z (ESI-) 241.1803 (M – H+. C14H25O3
requires 241.1804).
tert-Butyl 2-(2-benzyloxyethyl)-3-oxobutanoate 7d
A solution of t-butyl acetoacetate (2.34 g, 14.8 mmol) in dry
tBuOH (30 mL) was treated with benzyl 2-bromoethyl ether
(2.58 mL, 16.3 mmol). Then solid Cs2CO3 (7.25 g, 22.2 mmol)
was added and the mixture was refluxed for 18 h. Cs2CO3 was
filtered over a celite pad and washed with Et2O. The resulting
yellow solution was poured into a separatory funnel together with
a 1 : 1 mixture of H2O:sat. aq NH4Cl. After extraction, washing
of the organic layers with brine and solvent removal, the crude
was chromatographed with PE/Me2CO 98 : 2 → 9 : 1 to give 7d
(3.06 g, 70%) as a colourless oil. Rf 0.37 (PE/Me2CO 9 : 1, a or b).
n
max(CHCl3)/cm-1 3008, 2868, 1709, 1218, 1140, 920. dH(300 MHz;
tert-Butyl 2-octyl-3-oxobutanoate 7b
CDCl3; Me4Si) 1.44 (9 H, s, (CH3)3C), 2.12 (2 H, quintet, J
6.5,CHCH2), 2.22 (3 H, s, CH3CO), 3.48 (2 H, t, J 5.9, CH2OBn)
3.61 (1 H, t, J 7.2, CHCH2), 4.46 (2 H, s, CH2Ph), 7.25–7.38 (5 H,
m, Ph). dC(75 MHz; CDCl3) 27.8 (3 C, (CH3)3C), 28.0 (CHCH2),
In a two necked flask NaH (60% in mineral oil, 1.74 g, 43.5 mmol)
was suspended in a mixture of dry toluene (25 mL) and DMF
(20 mL). Then t-butyl acetoacetate (6.49 mL, 39.1 mmol) was
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29.2 (CH3CO), 57.5 (CHCH2), 67.5 (CH2OBn), 72.9 (CH2Ph),
81.8 (OC(CH3)3), 127.57 (CH para of Ph), 127.64 (2 C, CH ortho
of Ph), 128.3 (2 C, CH meta of Ph), 138.1 (C ipso of Ph), 168.7
(CO2tBu), 203.4 (COCH3). GC-MS: Rt 7.32 min; m/z (EI) 236
(M+ – 56, 0.26%), 129 (46), 107 (8.7), 102 (8.2), 92 (10), 91 (100),
87 (5.9), 69 (11), 65 (7.0), 57 (28), 43 (19), 41 (9.5). m/z (ESI-)
291.1605 (M – H+. C17H23O4 requires 291.1596).
(Z)-Ethyl 3-(2-ethoxy-2-oxoacetamido)-2-octylbut-2-enoate 18a
a) GC-MS (21a): Rt 6.63 min; m/z (EI) 241 (M+, 6.7%), 196
(5.3), 143 (8.7), 142 (100), 129 (5.7), 96 (33), 70 (5.7), 55
(9.9), 42 (8.4). b) Chromatography of crude 18a with PE/Et2O
9 : 1 → 7 : 3 gave a pale yellow oil (72% from 7a). Rf 0.28
(PE/AcOEt/CH2Cl2 90 : 5 : 5, a or b). nmax(CHCl3)/cm-1 2920,
2852, 1709, 1662, 1612, 1247, 1122. dH(300 MHz; CDCl3;
Me4Si) 0.88 (3 H, t, J 6.7, CH3(CH2)7), 1.24–1.36 (12 H, m,
CH3(CH2)6), 1.32 (3 H, t, J 7.1, CH3CH2OCO), 1.40 (3 H, t,
J 7.1, CH3CH2OCOCO), 2.31 (2 H, br t, J 7.5, CH2(CH2)7CH3),
2.46 (3 H, s, CH3CNH), 4.26 (2 H, q, J 7.2, CH3CH2OCO), 4.39 (2
H, q, J 7.2, CH3CH2OCOCO). dC(75 MHz; CDCl3) 13.8 and 14.0
(2 C, CH3(CH2)7 and CH3CH2OCOCO), 14.1 (CH3CH2OCO),
16.5 (CH3CNH), 22.6 (CH3CH2CH2), 26.9 (CH2(CH2)6CH3),
29.1, 29.2 and 29.3 (x 2) (4 C, CH2(CH2)4(CH2)2CH3), 31.7
(CH3CH2CH2), 60.6 (CH3CH2OCO), 63.3 (CH3CH2OCOCO),
112.5 (CC8H17), 147.2 (CNHCO), 154.6 (COCO2Et), 160.6
(COCO2Et), 169.4 (CO2Et). GC-MS: Rt 9.34 min; m/z (EI) 341
(M+, 5.7%), 296 (8.3), 242 (28), 269 (18), 268 (100), 240 (23), 225
(8.4), 224 (13), 223 (5.5), 222 (31), 197 (10), 196 (79), 194 (16), 182
(5.7), 178 (6.8), 169 (12), 168 (14), 156 (14), 152 (5.1), 151 (22), 150
(16), 142 (9.8), 140 (6.2), 124 (12), 123 (6.5), 122 (21), 110 (8.2),
109 (9.1), 108 (5.3), 98 (6.9), 97 (14), 96 (49), 95 (12), 94 (9.2), 83
(6.9), 82 (6.6), 81 (17), 80 (5.4), 79 (6.2), 70 (19), 69 (16), 68 (10), 67
(12), 57 (10), 56 (5.0), 55 (39), 54 (7.2), 53 (10), 44 (7.3), 43 (35), 42
(44), 41 (40), 39 (8.0). m/z (ESI-) 340.2133 (M – H+. C18H30NO5
requires 340.2124).
tert-Butyl 2-ethyl-4-(4-methoxyphenoxy)-3-oxobutanoate 7e
It was prepared by the same methodology employed for 7b, using
this time ethyl iodide, to give 7e as a colourless oil in 70% yield
after chromatography (PE/Et2O 9 : 1). Rf 0.42 (PE/Et2O 7 : 3, a
or b). nmax(CHCl3)/cm-1 2969, 2930, 2877, 1721, 1499, 1455, 1239,
1153, 1064, 1034. dH(300 MHz; CDCl3; Me4Si) 0.96 (3 H, t, J
7.5, CH3CH2), 1.43 (9 H, s, (CH3)3C), 1.90 (2 H, centre of m,
CH3CH2), 3.55 (1 H, t, J 7.1, CHCH2), 3.77 (3 H, s, OCH3),
4.59 and 4.61 (2 H, AB system, J 16.6, OCH2CO), 6.83 (4 H, s,
aromatics). dC(75 MHz; CDCl3) 11.8 (CH3CH2), 20.9 (CH3CH2),
27.9 (3 C, (CH3)3C), 55.7 (OCH3), 57.6 (CHCH2), 73.0 (ArOCH2),
82.0 (OC(CH3)3), 114.7 and 115.5 (2 ¥ 2C, aromatic CH), 151.7
and 154.5 (2 C, aromatic C), 168.5 (CO2tBu), 203.0 (COCH2O).
GC-MS (based on the usual method but with final temp. 280 ◦C):
Rt 7.88 min; m/z (EI) 308 (M+, 18%), 308 (18), 235 (18), 137 (21),
129 (7.2), 125 (8.5), 124 (100), 109 (11), 107 (8.7), 92 (7.7), 77 (12),
57 (41), 55 (5.2), 41 (15). m/z (ESI-) 307.1543 (M – H+. C17H23O5
requires 307.1545).
(Z)-tert-Butyl 3-(2-ethoxy-2-oxoacetamido)-2-octylbut-2-enoate
18b
General procedure for the preparation of acylenamines 18
a) GC-MS (21b): Rt 6.84 min; m/z (EI) 269 (M+, 1.4%), 115 (7.0),
114 (100), 101 (10), 96 (14), 70 (5.8), 57 (8.5), 55 (7.2), 42 (7.6),
41 (8.3). b) Chromatography of crude 18b with PE/Et2O 8 : 2 →
75 : 25 gave a pale yellow oil (81% from 7b). Rf 0.64 (PE/Et2O 7 : 3,
a). b) Chromatography of crude 18b with PE/Et2O 9 : 1 → 7 : 3
gave a pale yellow oil (72% from 7b). Rf 0.28 (PE/AcOEt/CH2Cl2
90 : 5 : 5, a or b). nmax(CHCl3)/cm-1 2917, 2852, 1704, 1609, 1451,
1367, 1194, 1010. dH(300 MHz; CDCl3; Me4Si) 0.88 (3 H, t,
J 6.8, CH3(CH2)7), 1.24–1.42 (12 H, m, CH3(CH2)6), 1.40 (3
H, t, J 7.1, CH3CH2O), 1.52 (9 H, s, (CH3)3C), 2.26 (2 H, br
t, J 7.5, CH2(CH2)7CH3), 2.42 (3 H, s, CH3CNH), 4.38 (2 H,
q, J 7.2, CH3CH2O). dC(75 MHz; CDCl3) 13.8 and 14.0 (2 C,
CH3(CH2)7 and CH3CH2), 16.5 (CH3CNH), 22.6 (CH3CH2CH2),
27.4 (CH2(CH2)6CH3), 28.0 (3 C, (CH3)3C), 29.2, 29.3, 29.4
and 29.5 (4 C, CH2(CH2)4(CH2)2CH3), 31.7 (CH3CH2CH2), 63.2
(CH3CH2O), 81.2 (OC(CH3)3), 114.1 (CC8H17), 146.0 (CNHCO),
154.5 (COCO2Et), 160.6 (COCO2Et), 168.8 (CO2tBu). GC-MS:
Rt 9.44 min; m/z (EI) 313 (M+ –56, 0.81%), 214 (19), 212 (8.8),
197 (11), 196 (30), 151 (12), 140 (8.1), 128 (10), 124 (6.6), 122 (15),
118 (30), 114 (15), 110 (7.2), 109 (6.2), 97 (8.9), 96 (40), 95 (10), 94
(7.2), 83 (6.0), 81 (12), 70 (18), 69 (14), 68 (8.0), 67 (9.0), 58 (5.5),
57 (100), 56 (7.5), 55 (36), 53 (7.4), 44 (7.2), 43 (28), 42 (33), 41
(60). m/z (ESI-) 368.2439 (M – H+. C20H34NO5 requires 368.2437).
a) Formation of enamine 21a: a solution of 7a (2.50 mmol) in
dry toluene (15 mL) was treated with NH4OAc (14.5 mmol) and
AcOH (9.68 mmol) and stirred with a Dean Stark apparatus. The
solid slowly dissolved. After 2.3 h an additional amount of both
NH4OAc (10.48 mmol) and AcOH (6.99 mmol) was added and
the reaction was refluxed for 0.7 h. The solution was diluted with
CH2Cl2 and washed with 5% NaHCO3. After solvent removal the
crude was directly used in the next reaction.
b) Formation of enamines 21b–d: for this reaction a saturated
solution of NH3, prepared by bubbling ammonia into absolute
ethanol, was employed. The concentration of ammonia was
established to be 2.8 M after titration. A solution of 7b–d (3.14
mmol) in 2.8 M ammonia (10.1 mL, 28.3 mmol) was prepared in
a pressure tube. After addition of NH4OAc (968 mg, 12.6 mmol)
the tube was sealed and stirred at 60 ◦C overnight. Disappearance
of starting material and formation of 21b–d was demonstrated
by GC-MS. The crude was poured into brine (100 mL) and 1 M
NaOH (10 mL) and an extraction with Et2O was performed. After
solvent evaporation the oily residue was dried at 0.2 mbar for 1.5
h and then directly submitted to the following reaction.
c) Formation of acylenamine 18: crude 21 was dissolved in dry
CH2Cl2 (10 mL) and treated with dry pyridine (762 ml, 9.42 mmol).
After cooling to 0 ◦C ethyl 2-chloro-2-oxoacetate (4.56 ml, 4.08
mmol) was added. After 5 min the solution was allowed to stir
at room temp. for 4 h. The crude was poured into a mixture of
5% aq (NH4)H2PO4, brine (50 mL) and 1 M HCl (10 mL). After
extraction with Et2O the product was purified by chromatography.
(Z)-tert-Butyl 3-(2-ethoxy-2-oxoacetamido)-2-
isobutylbut-2-enoate 18c
a) GC-MS (based on the usual method but with final temp. 280 ◦C)
(21c): Rt 4.19 min; m/z (EI) 213 (M+, 3.5%), 140 (6.6), 115
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(6.7), 114 (100), 96 (22), 57 (7.0), 55 (8.5), 42 (16), 41 (9.0). b)
Chromatography of crude 18c with PE/Et2O 95 : 5 → 8 : 2 gave
a pale yellow oil (82% from 7c). Rf 0.35 (PE/Et2O 85 : 15, a).
82.3 (OC(CH3)3), 114.6 and 116.5 (2 ¥ 2 C, aromatic CH), 121.2
(CCH2CH3), 141.7 (CNHCO), 152.5, 154.2 and 154.4 (3 C, 2 C
ipso of Ar and COCO2Et), 160.4 (COCO2Et), 168.1 (CO2tBu).
GC-MS (based on the usual method but with final temp. 280 ◦C):
Rt 10.39 min (not completely stable under the analysis conditions);
m/z (EI) 334 (M+ – 73, 1.2%), 229 (5.5), 228 (48), 189 (7.6), 184
(8.9), 182 (26), 125 (9.0), 124 (100), 123 (38), 110 (5.7), 109 (9.5),
57 (27), 56 (5.1), 41 (16), 39 (5.6). m/z (ESI-) 406.1869 (M – H+.
C21H28NO7 requires 406.1866).
n
max(CHCl3)/cm-1 3012, 2953, 2865, 1706, 1607, 1463, 1251, 1151,
1125. dH(300 MHz; CDCl3; Me4Si) 0.90 (6 H, d, J 6.6, (CH3)2CH),
1.41 (3 H, t, J 7.2, CH3CH2O), 1.52 (9 H, s, (CH3)3C), 1.71 (1
H, centre of m, (CH3)2CH), 2.20 (2 H, d, J 7.2, CH2CH), 2.43
(3 H, s, CH3CNH), 4.39 (2 H, q, J 7.1, CH3CH2O). dC(75 MHz;
CDCl3) 13.8 (CH3CH2O), 17.0 (CH3CNH), 22.3 (2 C, (CH3)2CH),
27.8 (3 C, (CH3)3C), 29.2 ((CH3)2CH), 35.9 (CH2CH), 63.2
(CH3CH2O), 81.2 (OC(CH3)3), 113.2 (CC8H17), 146.6 (CNHCO),
154.5 (COCO2Et), 160.6 (COCO2Et), 168.9 (CO2tBu). GC-MS:
Rt 7.54 min; m/z (EI) 313 (M+, 2.0%), 257 (9.0), 240 (7.9), 215
(11), 214 (100), 212 (14), 197 (6.3), 196 (16), 184 (19), 166 (10), 156
(5.7), 140 (8.8), 122 (9.9), 114 (6.1), 97 (7.5), 96 (33), 95 (7.7), 70
(8.9), 57 (48), 55 (17), 53 (5.3), 43 (13), 42 (20), 41 (34), 39 (7.0).
m/z (ESI-) 312.1809 (M – H+. C16H26NO5 requires 312.1811).
General procedure for the preparation of oxazinones 17
A solution of acylenamine 18 (2.80 mmol) in dry CH2Cl2 (15 mL)
was treated sequentially with triphenyl phosphine (1.54 g, 5.87
mmol), tetrachloromethane (377 ml, 3.91 mmol) and triethylamine
(817 ml, 5.86 mmol) and then refluxed until complete reaction was
observed (typically 4–5 h). After dilution with CH2Cl2 the organic
layer was washed with 5% aq Na2S2O5. After solvent evaporation
a very fast chromatography was performed and the corresponding
oxazinone was immediately submitted to the following reaction,
due to its limited stability. Only compound 17a was characterized,
(Z)-tert-Butyl 2-(2-benzyloxyethyl)-3-(2-ethoxy-2-
oxoacetamido)-2-butenoate 18d
a) GC-MS (21d): Rt 8.04 min; m/z (EI) 291 (M+, 6.9%), 170 (6.8),
157 (15), 115 (7.6), 114 (100), 101 (41), 96 (23), 91 (16), 65 (5.7), 57
(7.6), 55 (7.9), 42 (9.5), 41 (8.5). b) Chromatography of crude 18d
with PE/Et2O 6 : 4 → 1 : 1 gave a pale yellow oil (60% from 7d). Rf
0.49 (PE/Et2O 1 : 1, a or b). nmax(CHCl3)/cm-1 3002, 1711, 1614,
1229, 1154, 1135, 1100. dH(300 MHz; CDCl3; Me4Si) 1.40 (3 H, t,
J 7.1, CH3CH2O), 1.47 (9 H, s, (CH3)3C), 2.47 (3 H, s, CH3CNH),
2.63 (2 H, t, J 7.2, CH2CH2O), 3.48 (2 H, t, J 7.2, CH2CH2O), 4.38
(2 H, q, J 7.1, CH3CH2O), 4.51 (2 H, s, CH2Ph), 7.25–7.37 (5 H,
m, Ph). dC(75 MHz; CDCl3) 13.9 (CH3CH2O), 16.8 (CH3CNH),
28.0 (3 C, (CH3)3C), 28.1 (CH2CH2O), 63.3 (CH3CH2O), 69.0
(CH2CH2O), 72.8 (CH2Ph), 81.6 (OC(CH3)3), 109.8 (C(CH2)2),
127.4 (2 C, CH ortho of Ph), 127.5 (CH para of Ph), 128.3 (2 C,
CH meta of Ph), 138.3 (C ipso of Ph), 148.2 (CNHCO), 154.6
(COCO2Et), 160.5 (COCO2Et), 168.5 (CO2tBu). GC-MS: Rt 7.54
min (not completely stable under the analysis conditions); m/z
(EI) 318 (M+ – 73, 0.070%), 274 (112), 229 (7.9), 218 (5.6), 214
(20), 196 (21), 173 (9.2), 156 (16), 128 (19), 122 (5.2), 96 (15), 92
(8.9), 91 (100), 70 (5.2), 65 (7.2), 57 (23), 55 (6.9), 42 (7.2), 41 (12).
m/z (ESI-) 390.1906 (M – H+. C21H28NO6 requires 390.1917).
while for all other derivatives only H NMR and, when feasible,
1
GC-MS have been recorded.
Ethyl 4-methyl-5-octyl-6-oxo-6H-1,3-oxazine-2-carboxylate 17a
The reaction on 18a was performed in 1,2-dichloroethane at
reflux (2.5 h). The isolated yield, after chromatography with
PE/Et2O 100 : 0 → 6 : 4, gave a pale yellow oil in 60% (67%
on unrecovered starting material) yield. Starting from 18b the
reaction in 1,2-dichloroethane was complete after 30 min. The
solvent was however successfully substituted by CH2Cl2, with
no appreciably affecting the yield. Oxazinone 17a was isolated
in 78% yield. Rf 0.24 (PE/Et2O 7 : 3, a or b). nmax(CHCl3)/cm-1
3002, 2868, 1744, 1630, 1390, 1300, 1185. dH(300 MHz; CDCl3;
Me4Si) 0.88 (3 H, t, J 6.8, CH3(CH2)7), 1.21–1.56 (12 H, m,
CH3(CH2)6), 1.42 (3 H, t, J 7.2, CH3CH2O), 2.35 (3 H, s,
CH3C-N), 2.51 (2 H, t, J 7.6, CH2(CH2)6CH3), 4.64 (2 H, q,
J 7.1, CH3CH2O). dC(75 MHz; CDCl3) 14.0 and 14.1 (2 C,
CH3(CH2)7 and CH3CH2O), 20.8 (CH3C-N), 22.6 (CH3CH2CH2),
26.6 (CH2(CH2)6CH3), 27.8 (CH2CH2(CH2)5CH3), 29.2, 29.3 and
29.6 (3 C, (CH2)2(CH2)3(CH2)2CH3), 31.8 (CH3CH2CH2), 63.7
(CH3CH2O), 124.7 (C(C O)N), 149.8 (C N), 157.4, 158.4,
158.5 (3 C, 2 CO and CH3C-N). GC-MS: Rt 8.51 min; m/z (EI)
295 (M+, 0.11%), 223 (16), 222 (100), 197 (6.8), 196 (16), 169 (6.2),
151 (11), 126 (23), 125 (17), 124 (19), 97 (6.5), 96 (33), 95 (12), 94
(5.3), 93 (5.8), 82 (5.6), 81 (20), 79 (6.8), 70 (7.8), 69 (13), 68 (8.7),
67 (15), 57 (7.5), 56 (5.7), 55 (23), 54 (9.8), 53 (12), 43 (21), 42 (19),
41 (32), 39 (7.9).
(Z)-tert-Butyl 3-(2-ethoxy-2-oxoacetamido)-2-ethyl-4-(4-
methoxyphenoxy)but-2-enoate 18e
a) GC-MS (based on the usual method but with final temp. 280 ◦C)
(21e): Rt 8.67 min; m/z (EI) 303 (M+, 3.3%), 234 (5.7), 137 (9.6),
128 (69), 125 (8.6), 124 (100), 123 (16), 109 (16), 57 (15), 42 (6.4),
41 (13). b) Chromatography of crude 18e with PE/Et2O 8 : 2 →
75 : 25 gave a white solid (43% of Z isomer from 7e; Z+E overall
◦
yield 65%). Mp 65.8-67.8 C (PE/Et2O). Rf 0.27 (PE/Et2O 7 : 3,
Ethyl 5-isobutyl-4-methyl-6-oxo-6H-1,3-oxazine-2-carboxylate
17c
a or b). nmax(CHCl3)/cm-1 3001, 1708, 1618, 1259, 1191, 1152,
1127. dH(300 MHz; CDCl3; Me4Si) 1.07 (3 H, t, J 7.5, CH3CH2),
1.38 (3 H, t, J 7.2, CH3CH2O), 1.54 (9 H, s, (CH3)3C), 2.40
(2 H, q, J 7.4, CH3CH2), 3.77 (3 H, s, OCH3), 4.37 (2 H, q,
J 7.2, CH3CH2O), 5.16 (2 H, s, OCH2CO), 6.87 (4 H, centre
of m, aromatics), 12.44 (1 H, br s, NH). dC(75 MHz; CDCl3)
14.0 (CH3CH2O), 14.8 (CH3CH2), 21.3 (CH3CH2), 28.1 (3 C,
(CH3)3C), 55.7 (OCH3), 63.3 and 63.4 (2 C, CH2OAr, CH3CH2O),
Chromatography with PE/Et2O 8 : 2 gave a pale yellow oil (74%).
Rf 0.23 (PE/Et2O 7 : 3, a or b). dH(300 MHz; CDCl3; Me4Si) 0.95
(6 H, d, J 6.6, (CH3)2CH), 1.42 (3 H, t, J 7.1, CH3CH2O), 1.99
(1 H, nonuplet, J 6.8, (CH3)2CH), 2.34 (3 H, s, CH3C-N), 2.42 (2
H, d, J 7.5, CH2CH), 4.47 (2 H, q, J 7.2, CH3CH2O). GC-MS: Rt
6.25 min; m/z (EI) 239 (M+, 9.0%), 167 (11), 166 (100), 140 (5.7),
2116 | Org. Biomol. Chem., 2011, 9, 2107–2122
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138 (5.1), 124 (7.6), 123 (12), 97 (6.1), 96 (9.6), 95 (16), 81 (8.1), 67
(10), 55 (9.5), 54 (9.8), 53 (7.3), 43 (18), 42 (19), 41 (18), 39 (8.5).
(11), 135 (9.8), 124 (43), 123 (35), 122 (14), 121 (10), 96 (27), 95
(7.8), 94 (6.6), 93 (5.4), 81 (7.6), 80 (5.2), 79 (7.4), 69 (9.6), 67 (17),
57 (13), 56 (8.9), 55 (41), 53 (22), 43 (32), 42 (26), 41 (56), 39 (10).
m/z (ESI-) 349.2507 (M – H+. C20H33N2O3 requires 349.2491).
Ethyl 5-(2-(benzyloxy)ethyl)-4-methyl-6-oxo-6H-1,3-oxazine-2-
carboxylate 17d
Ethyl 3-(3-(tert-butoxycarbonyl)propyl)-6-methyl-5-octyl-3H-
pyrimidin-4-one-2-carboxylate 16ab
Chromatography with PE/Et2O 6 : 4 → 1 : 1 gave a yellow–orange
oil (57%). Rf 0.33 (PE/Et2O 1 : 1, a or b). dH(300 MHz; CDCl3;
Me4Si) 1.42 (3 H, t, J 7.1, CH3CH2O), 2.39 (3 H, s, CH3C-N),
2.84 (2 H, t, J 6.2, CH2CH2O), 3.69 (2 H, t, J 6.3, CH2CH2O),
4.70 (2 H, q, J 7.1, CH3CH2O), 4.74 (2 H, s, CH2Ph), 7.24–7.35 (5
H, m, Ph). GC-MS: Rt 9.42 min; m/z (EI) 317 (M+, 0.15%), 214
(5.1), 211 (20), 183 (9.1), 138 (10), 96 (4.4), 92 (10), 91 (100), 65
(11), 42 (6.2).
Starting oxazinone: 17a. Amine: freshly prepared 30, obtained by
deprotection of 29 (see below), was employed. Chromatography
with PE/Et2O 9 : 1 → 6 : 4 gave a yellow–brown oil (89%).
Rf 0.45 (PE/Et2O 6 : 4, a or b). nmax(CHCl3)/cm-1 3675, 3611,
3018, 2971, 2925, 2893, 1724, 1653, 1506, 1473, 1424, 1195,
1044, 924. dH(300 MHz; CDCl3; Me4Si) 0.88 (3 H, t, J 6.9,
CH3(CH2)7), 1.19–1.52 (12 H, m, CH3(CH2)6), 1.44 (9 H, s,
(CH3)3C), 1.44 (3 H, t, J 6.9, CH3CH2O), 2.00 (2 H, centre of
m, CH2CH2CH2N), 2.29 (2 H, t, J 7.2, CH2CH2CH2N), 2.32 (3
H, s, CH3C-N), 2.52 (2 H, t, J 7.5, CH2(CH2)6CH3), 4.03 (2 H,
centre of m, CH2N), 4.48 (2 H, q, J 7.1, CH3CH2O). dC(75 MHz;
CDCl3) 13.8 (CH3CH2O), 14.0 (CH3(CH2)7), 21.0 (CH3C-N), 22.5
(CH3CH2(CH2)6), 24.2 (CH2CH2CH2N), 26.4 (CH2(CH2)6CH3),
27.8 (CH2CH2(CH2)5CH3), 27.9 (3 C, (CH3)3C), 29.2, 29.3 and
29.7 (3 C, (CH2)2(CH2)3(CH2)2CH3), 31.7 (CH3CH2CH2(CH2)5),
32.4 (CH2CH2CH2N), 44.8 (CH2N), 63.2 (CH3CH2O), 80.4
((CH3)3C), 126.8 (C(C O)N), 147.5 (C N), 157.2 (CH3C-N),
160.9 (C(C O)N), 161.1 (CO2Et), 171.6 (CO2tBu). GC-MS: Rt
11.25 min; m/z (EI) 436 (M+, 2.3%), 380 (12), 365 (10), 363 (21),
338 (6.4), 295 (6.5), 293 (12), 283 (15), 282 (100), 196 (17), 191 (6.0),
163 (8.1), 123 (7.9), 96 (5.4), 69 (8.7), 57 (14), 43 (5.1), 41 (12). m/z
(ESI-) 435.2849 (M – H+. C24H39N2O5 requires 435.2859).
Ethyl 4-((4-methoxyphenoxy)methyl)-5-ethyl-6-oxo-6H-1,3-
oxazine-2-carboxylate 17e
Chromatography with PE/AcOEt 7 : 3 gave a yellow oil (55%). Rf
0.35 (PE/AcOEt 7 : 3, a or b). dH(300 MHz; CDCl3; Me4Si) 1.17
(3 H, t, J 7.5, CH3CH2), 1.43 (3 H, t, J 7.2, CH3CH2O), 2.67
(2 H, q, J 7.5, CH3CH2), 3.78 (3 H, s, OCH3), 4.47 (2 H, q, J
7.1, CH3CH2O), 4.92 (2 H, s, OCH2C-N), 6.87 (4 H, centre of m,
aromatics). GC-MS: unsuitable for this analysis.
General procedure for the preparation of 3H-pyrimidin-4-ones 16
A solution of oxazinone 17 (2.00 mmol) in dry THF (5 mL) was
treated at room temp. with 1.3 equivalents of the desired primary
amine. The solution was allowed to stir until complete. Usually
4 h are enough but, since in most cases 16 and 17 are not well
separated in tlc, the reaction was allowed to stir overnight. The
resulting solution was partitioned between H2O and Et2O and
extracted. The excess of amine can be removed by washing the
organic layers with slightly acid (HCl) brine. Chromatography
with the appropriate solvent (see below) furnished 16.
Ethyl 3-(3-(ethoxycarbonyl)propyl)-6-methyl-5-octyl-3H-
pyrimidin-4-one-2-carboxylate 16ac
Starting oxazinone: 17a. Amine: commercially available
ethyl 4-aminobutyrate hydrochloride was used. This time an
addition of triethylamine (1.15 equiv. with respect to the
hydrochloride) was necessary. Chromatography with PE/Et2O
6 : 4 → 1 : 1 gave a yellow oil (81%). Rf 0.30 (PE/Et2O 6 : 4, a).
Ethyl 3-butyl-6-methyl-5-octyl-3H-pyrimidin-4-one-2-carboxylate
16aa
Starting oxazinone: 17a. Amine: nbutylamine. Chromatography
with PE/Et2O 8 : 2 gave a pale yellow oil (80%). Rf 0.34 (PE/Et2O
7 : 3, a). nmax(CHCl3)/cm-1 2957, 2923, 2852, 1736, 1655, 1598,
1442, 1381, 1210, 1108. dH(300 MHz; CDCl3; Me4Si) 0.88 (3 H,
t, J 6.8, CH3(CH2)7), 0.94 (3 H, t, J 7.2, CH3(CH2)3N), 1.22–1.49
(14 H, m, CH3(CH2)6 and CH3CH2(CH2)2N), 1.43 (3 H, t, J 7.2,
CH3CH2O), 1.71 (2 H, centre of m, CH3CH2CH2CH2N), 2.31 (3
H, s, CH3C-N), 2.52 (2 H, t, J 7.8, CH2(CH2)6CH3), 3.97 (2 H,
centre of m, CH2N), 4.46 (2 H, q, J 7.2, CH3CH2O). dC(75 MHz;
CDCl3) 13.6 (CH3CH2O), 14.0 (CH3(CH2)7), 14.1 (CH3(CH2)3N),
20.1 (CH3CH2(CH2)2N), 21.1 (CH3C-N), 22.6 (CH3CH2(CH2)6),
26.6 (CH2(CH2)6CH3), 28.0 (CH2CH2(CH2)5CH3), 29.3, 29.4 and
29.8 (3 C, (CH2)2(CH2)3(CH2)2CH3), 30.9 (CH3CH2CH2CH2N),
31.8 (CH3CH2CH2(CH2)5), 45.5 (CH2N), 63.1 (CH3CH2O), 126.9
(C(C O)N), 147.7 (C N), 157.2 (CH3C-N), 161.1 (C(C O)N),
161.3 (CO2Et). GC-MS: Rt 9.48 min; m/z (EI) 350 (M+, 8.4%),
335 (14), 321 (5.3), 295 (9.9), 279 (9.1), 278 (20), 277 (100), 265
(11), 253 (15), 252 (100), 251 (7.4), 223 (6.1), 221 (5.2), 209 (5.9),
207 (6.3), 197 (10), 196 (13), 195 (8.9), 193 (5.6), 180 (5.6), 179
(40), 177 (6.4), 163 (6.1), 151 (11), 150 (26), 149 (11), 138 (6.9), 137
n
max(CHCl3)/cm-1 2919, 2851, 1730, 1649, 1597, 1445, 1370, 1205,
1084, 1016. dH(300 MHz; CDCl3; Me4Si) 0.88 (3 H, t, J 6.8,
CH3(CH2)7), 1.24–1.50 (12 H, m, CH3(CH2)6), 1.26 (3 H, t, J 6.9,
CH3CH2OCOCH2), 1.44 (3 H, t, J 6.9, CH3CH2OCOC N),
2.05 (2 H, centre of m, CH2CH2CH2N), 2.32 (3 H, s, CH3C-
N), 2.38 (2 H, t, J 7.2, CH2CH2CH2N), 2.52 (2 H, t, J 7.6,
CH2(CH2)6CH3), 4.05 (2 H, centre of m, CH2N), 4.13 (2 H, q, J
7.2, CH3CH2OCOCH2), 4.48 (2 H, q, J 7.2, CH3CH2OCOC N).
dC(75 MHz; CDCl3) 13.9 (CH3CH2OCOC N), 14.1
(CH3(CH2)7), 14.2 (CH3CH2OCOCH2), 21.1 (CH3C-N), 22.6
(CH3CH2(CH2)6), 24.1 (CH2CH2CH2N), 26.6 (CH2(CH2)6CH3),
28.0 (CH2CH2(CH2)5CH3), 29.3, 29.4 and 29.8 (3 C,
(CH2)2(CH2)3(CH2)2CH3), 31.3 (CH3CH2CH2(CH2)5), 32.4
(CH2CH2CH2N), 44.9 (CH2N), 60.6 (CH3CH2OCOCH2), 63.4
(CH3CH2OCOC N), 127.0 (C(C O)N), 147.6 (C N), 157.3
(CH3C-N), 161.1 (C(C O)N), 161.2 (N CCO2Et), 172.5
(CH2CO2Et). GC-MS: Rt 10.88 min; m/z (EI) 408 (M+, 2.3%),
408 (6.5), 363 (15), 335 (6.8), 311 (10), 310 (59), 293 (15), 264
(6.6), 207 (5.1), 196 (14), 191 (12), 165 (7.6), 164 (6.5), 163 (13),
150 (6.7), 124 (7.6), 123 (13), 122 (5.1), 116 (7.0), 115 (100), 96
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(8.0), 87 (60), 69 (20), 55 (12), 53 (7.8), 45 (9.4), 43 (27), 42 (9.8),
41 (25). m/z (ESI+) 409.2720 (M + H+. C22H37N2O5 requires
409.2702).
d, J 6.6, (CH3)2CH), 1.40 (3 H, t, J 7.0, CH3CH2O), 1.97 (1 H,
nonuplet, J 6.8, (CH3)2CH), 2.32 (3 H, s, CH3C-N), 2.45 (2 H,
d, J 7.5, CH2CH), 4.45 (2 H, q, J 7.2, CH3CH2O), 5.47 (2 H, s,
CH2(furan-2-yl)), 6.29 (1 H, dd, J 3.3, 1.8, CH(CH)2-O), 6.32 (1
H, d, J 3.0, CHCHCH-O), 7.30 (1 H, dd, J 1.8, 0.6, (CH)2CH-O).
dC(75 MHz; CDCl3) 13.9 (CH3CH2O), 21.6 (CH3C-N), 22.6 (2 C,
(CH3)2CH), 27.9 ((CH3)2CH), 35.5 (CH2CH), 39.6 (CH2(furan-2-
yl)), 63.2 (CH3CH2O), 109.7 (CH(CH)2-O), 110.5 (CHCHCH-O),
126.4 (C(C O)N), 142.7 ((CH)2CH-O), 146.8 (C N), 148.9 (C
of furyl), 157.7 (CH3C-N), 161.0 (C(C O)N), 161.3 (CO2Et).
GC-MS (based on the usual method but with final temp. 280 ◦C):
Rt 8.33 min; m/z (EI) 319 (7.9), 318 (M+, 38%), 245 (6.4), 237 (11),
195 (11), 165 (5.6), 163 (9.4), 82 (12), 81 (100), 53 (22), 43 (5.9),
41 (6.3). m/z (ESI + Na+) 341.1465 (M + Na+. C17H22N2NaO4
requires 341.1477).
Ethyl 3-isobutyl-6-methyl-5-octyl-3H-pyrimidin-4-one-
2-carboxylate 16ad
Starting oxazinone: 17a. Amine: isobutylamine. Chromatography
with PE/Et2O 9 : 1 → 6 : 4 gave a pale yellow oil (66%). Rf 0.28
(PE/Et2O 7 : 3, a). nmax(CHCl3)/cm-1 2920, 2851, 1735, 1649, 1597,
1422, 1369, 1183, 1136, 1113, 1023. dH(300 MHz; CDCl3; Me4Si)
0.87 (3 H, t, J 6.9, CH3(CH2)7), 0.89 (6 H, d, J 6.9, (CH3)2CH),
1.21–1.50 (12 H, m, CH3(CH2)6), 1.42 (3 H, t, J 7.2, CH3CH2O),
2.05 (1 H, nonuplet, J 6.9, (CH3)2CH), 2.32 (3 H, s, CH3C-
N), 2.52 (2 H, t, J 7.6, CH2(CH2)6CH3), 3.96 (2 H, d, J 7.5,
NCH2CH), 4.45 (2 H, q, J 7.2, CH3CH2O). dC(75 MHz; CDCl3)
14.0 (CH3CH2O), 14.1 (CH3(CH2)7), 19.9 (2 C, (CH3)2CH),
21.1 (CH3C-N), 22.7 (CH3CH2(CH2)6), 26.6 (CH2(CH2)6CH3),
28.0 (CH2CH2(CH2)5CH3), 28.3 ((CH3)2CH), 29.3, 29.4 and 29.8
(3 C, (CH2)2(CH2)3(CH2)2CH3), 31.8 (CH3CH2CH2(CH2)5), 51.4
(CH2N), 63.1 (CH3CH2O), 126.9 (C(C O)N), 147.7 (C N),
156.9 (CH3C-N), 161.38 and 161.41 (2 C, C(C O)N and CO2Et).
GC-MS: Rt 9.25 min; m/z (EI) 350 (M+, 6.2%), 335 (5.3), 296 (19),
295 (100), 277 (16), 253 (6.7), 252 (40), 223 (6.4), 221 (6.8), 209
(7.2), 197 (16), 196 (24), 195 (8.4), 151 (6.4), 150 (22), 149 (6.4), 137
(7.8), 135 (6.2), 124 (17), 123 (31), 122 (9.2), 121 (6.9), 96 (17), 95
(5.3), 67 (11), 57 (12), 56 (8.8), 55 (24), 53 (12), 43 (24), 42 (15), 41
(41), 39 (7.7). m/z (ESI+) 351.2654 (M + H+. C20H35N2O3 requires
351.2648).
Ethyl 5-isobutyl-6-methyl-3-((thien-2-yl)methyl)-3H-pyrimidin-4-
one-2-carboxylate 16cc
Starting oxazinone: 17c. Amine: 2-thiophenemethylamine. Chro-
matography with PE/Et2O 6 : 4 gave a yellow oil (72%). Rf 0.29
(PE/Et2O 6 : 4, a). nmax(CHCl3)/cm-1 3010, 2950, 2864, 1727, 1645,
1594, 1415, 1366, 1330, 1290, 1247, 1143. dH(300 MHz; CDCl3;
Me4Si) 0.94 (6 H, d, J 6.6, (CH3)2CH), 1.36 (3 H, t, J 7.2,
CH3CH2O), 1.97 (1 H, nonuplet, J 6.8, (CH3)2CH), 2.31 (3 H,
s, CH3C-N), 2.46 (2 H, d, J 7.2, CH2CH), 4.43 (2 H, q, J 7.2,
CH3CH2O), 5.56 (2 H, s, CH2(thien-2-yl)), 6.91 (1 H, dd, J 5.1, 3.6,
CHCHCH-S), 7.03 (1 H, dd, J 3.6, 1.2, CH(CH)2-S), 7.22 (1 H,
dd, J 5.1, 1.2, (CH)2CH-S). dC(75 MHz; CDCl3) 13.8 (CH3CH2O),
21.5 (CH3C-N), 22.5 (2 C, (CH3)2CH), 27.9 ((CH3)2CH), 35.3
(CH2CH), 42.0 (CH2(thien-2-yl)), 63.2 (CH3CH2O), 126.37 and
126.40 (2 C, CH(CH)2-S), 126.5 (C(C O)N), 127.9 (CH(CH)2-
S), 137.6 (C of thienyl), 146.4 (C N), 157.7 (CH3C-N), 161.0
(C(C O)N), 161.1 (CO2Et), GC-MS: Rt 9.12 min; m/z (EI) 335
(5.9), 334 (M+, 27%), 261 (6.0), 237 (13), 195 (9.6), 165 (5.6), 163
(7.7), 99 (5.2), 98 (12), 97 (100), 53 (9.5), 45 (7.5), 43 (5.0), 41 (5.1).
m/z (ESI+) 335.1426 (M + H+. C17H23N2O3S requires 335.1429).
Ethyl 3,5-diisobutyl-6-methyl-3H-pyrimidin-4-one-2-carboxylate
16ca
Starting oxazinone: 17c. Amine: isobutylamine. Chromatography
with PE/Et2O 9 : 1 → 85 : 15 gave a yellow oil (68%). Rf 0.56
(PE/Et2O 8 : 2, a or b). nmax(CHCl3)/cm-1 3675, 3610, 3021, 2973,
1732, 1650, 1596, 1511, 1471, 1418, 1191, 1043. dH(300 MHz;
CDCl3; Me4Si) 0.86 (6 H, d, J 6.9, (CH3)2CHCH2N) 0.90 (6 H,
d, J 6.6, (CH3)2CHCH2C), 1.40 (3 H, t, J 7.2, CH3CH2O), 1.93
(1 H, nonuplet, J 6.8, (CH3)2CHCH2C), 2.02 (1 H, nonuplet, J
7.0, (CH3)2CHCH2N), 2.30 (3 H, s, CH3C-N), 2.41 (2 H, d, J
7.2, CCH2CH), 3.93 (2 H, d, J 7.5, NCH2CH), 4.43 (2 H, q, J
7.1, CH3CH2O). dC(75 MHz; CDCl3) 13.9 (CH3CH2O), 19.9 (2 C,
(CH3)2CHCH2N), 21.5 (CH3C-N), 22.6 (2 C, (CH3)2CHCH2C),
27.9 ((CH3)2CHCH2C), 28.2 ((CH3)2CHCH2N), 35.4 (CCH2CH),
51.3 (NCH2CH), 63.1 (CH3CH2O), 126.0 (C(C O)N), 147.7
(C N), 157.6 (CH3C-N), 161.4 (C(C O)N), 161.6 (CO2Et). GC-
MS: Rt 7.25 min; m/z (EI) 294 (M+, 6.3%), 251 (7.7), 240 (15), 239
(100), 221 (16), 197 (5.2), 196 (12), 195 (31), 167 (7.1), 166 (18),
165 (21), 150 (15), 123 (15), 122 (9.4), 121 (8.4), 96 (24), 67 (11),
57 (6.5), 56 (7.1), 55 (25), 53 (20), 43 (19), 42 (18), 41 (34), 39 (11).
m/z (ESI-) 293.1864 (M – H+. C16H25N2O3 requires 293.1865).
Ethyl 5-isobutyl-3-(4-methoxybenzyl)-6-methyl-3H-pyrimidin-
4-one-2-carboxylate 16cd
Starting oxazinone: 17c. Amine: (4-methoxybenzyl)amine. Chro-
matography with PE/Et2O 8 : 2 gave a yellow oil (75%). Rf 0.18
(PE/Et2O 7 : 3, a). nmax(CHCl3)/cm-1 3005, 1732, 1655, 1498, 1415,
1192, 1029, 922. dH(300 MHz; CDCl3; Me4Si) 0.93 (6 H, d, J 6.6,
(CH3)2CH), 1.22 (3 H, t, J 7.0, CH3CH2O), 1.97 (1 H, nonuplet,
J 6.8, (CH3)2CH), 2.31 (3 H, s, CH3C-N), 2.45 (2 H, d, J 7.2,
CH2CH), 3.75 (3 H, s, OCH3), 4.28 (2 H, q, J 7.2, CH3CH2O),
5.30 (2 H, s, CH2Ar), 6.80 (2 H, dt J 8.7, 2.1, H ortho to OCH3),
7.13 (2 H, dt J 8.7, 2.4, H meta to OCH3). dC(75 MHz; CDCl3)
13.7 (CH3CH2O), 21.6 (CH3C-N), 22.6 (2 C, (CH3)2CH), 27.9
((CH3)2CH), 35.5 (CH2CH), 46.6 (CH2Ar), 55.2 (OCH3), 63.1
(CH3CH2O), 114.0 (2 C, CH ortho to OCH3), 126.3 (C(C O)N),
128.0 (C para to OCH3), 129.2 (2 C, CH meta to OCH3), 147.5
(C N), 157.8 (CH3C-N), 159.2 (C-OCH3), 161.4 (C(C O)N),
161.5 (CO2Et). GC-MS: Rt 10.02 min; m/z (EI) 358 (M+, 6.9%),
122 (16), 121 (100), 77 (5.9). m/z (ESI-) 357.1801 (M – H+.
C20H25N2O4 requires 357.1814).
Ethyl 3-((furan-2-yl)methyl)-5-isobutyl-6-methyl-3H-pyrimidin-4-
one-2-carboxylate 16cb
Starting oxazinone: 17c. Amine: furfurylamine. Chromatography
with PE/Et2O 9 : 1 → 85 : 15 gave a yellow oil (62%). Rf 0.38
(PE/Et2O 1 : 1, a). nmax(CHCl3)/cm-1 3010, 2956, 1731, 1658, 1595,
1415, 1292, 1174, 1037. dH(300 MHz; CDCl3; Me4Si) 0.93 (6 H,
2118 | Org. Biomol. Chem., 2011, 9, 2107–2122
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Ethyl 5-(2-(benzyloxy)ethyl)-3-(3-(tert-butoxycarbonyl)propyl)-6-
methyl-3H-pyrimidin-4-one-2-carboxylate 16d
2.69 (2 H, q, J 7.4, CH3CH2CC O), 3.77 (3 H, s, OCH3), 4.25
(2 H, q, J 7.2, CH3CH2O) 4.90 (2 H, s, OCH2C-N), 5.43 (2 H, s,
CH2N), 6.88 (4 H, centre of m, aromatics (C6H4OMe)), 7.18–7.39
(5 H, m, aromatics (Ph)). dC(75 MHz; CDCl3) 13.0 and 13.6 (2
C, CH3CH2CC O and CH3CH2O), 20.0 (CH3CH2CC O), 47.2
(CH2N), 55.7 (OCH3), 63.1 (CH3CH2O), 69.2 (CH2OAr), 114.6
and 115.7 (2 ¥ 2 C, aromatic CH (C6H4OMe)), 127.8 (2 C, CH
ortho of Ph), 128.0 (CH para of Ph), 128.7 (2 C, CH meta of Ph),
131.7 (C(C O)N), 135.5 (C ipso of Ph), 148.1 (C N), 152.5,
153.9 and 154.2 (3 C, 2 C ipso of C6H4OMe and OCH2C-N),
161.0 (C(C O)N), 161.5 (CO2Et). GC-MS (based on the usual
method but with init. temp. 200 ◦C, rate 35 ◦C min-1, final temp.
280 ◦C). Rt 6.36 min; m/z (EI) 422 (M+, 32%), 124 (18), 123 (100),
95 (12), 92 (8.9), 91 (97), 65 (12), 41 (7.8). m/z (ESI+) 423.1902
(M + H+. C24H27N2O5 requires 423.1920).
Starting oxazinone: 17d. Amine: freshly prepared 30 (see be-
low). Chromatography with PE/Et2O 6 : 4 → 4 : 6 gave an
amber-coloured oil (75%). Rf 0.68 (PE/AcOEt 1 : 1, a or b).
n
max(CHCl3)/cm-1 2969, 2863, 1721, 1657, 1599, 1443, 1367, 1190,
1077. dH(300 MHz; CDCl3; Me4Si) 1.44 (3 H, t, J 7.1, CH3CH2O),
1.44 (9 H, s, (CH3)3C), 1.98 (2 H, centre of m, CH2CH2CH2N),
2.28 (2 H, t, J 7.4, CH2CH2CH2N), 2.36 (3 H, s, CH3C-N), 2.88
(2 H, t, J 6.8, CH2CH2O), 3.65 (2 H, t, J 6.6, CH2CH2O), 4.01
(2 H, centre of m, CH2N), 4.49 (2 H, q, J 7.2, CH3CH2O), 4.50
(2 H, s, CH2Ph), 7.23–7.35 (5 H, m, Ph). dC(75 MHz; CDCl3)
13.8 (CH3CH2O), 21.5 (CH3C-N), 24.2 (CH2CH2CH2N), 27.3
(CH2CH2O), 28.0 (3 C, (CH3)3C), 32.5 (CH2CH2CH2N), 44.9
(CH2N), 63.3 (CH3CH2O), 67.9 (CH2CH2O), 72.8 (CH2Ph), 80.4
((CH3)3C), 123.2 (C(C O)N), 127.4 (3 C, CH ortho and para of
Ph), 128.2 (2 C, CH meta of Ph), 138.3 (C ipso of Ph), 148.0
(C N), 159.1 (CH3C-N), 160.9 (C(C O)N), 161.0 (CO2Et),
171.6 (CO2tBu). GC-MS: Rt 13.07 min; m/z (EI) 385 (M+ – 73,
9.1%), 312 (5.5), 311 (34), 296 (16), 295 (7.6), 293 (7.5), 281 (9.1),
225 (24), 223 (9.4), 210 (13), 209 (14), 196 (5.7), 195 (17), 163 (9.0),
138 (6.9), 135 (6.0), 123 (6.9), 96 (14), 92 (9.1), 91 (100), 87 (5.8),
69 (12), 65 (8.7), 57 (28), 56 (7.4), 55 (9.7), 53 (7.1), 43 (6.3), 42
(7.1), 41 (27.6), 40 (5.5), 39 (7.4). m/z (ESI-) 457.2339 (M – H+.
C25H33N2O6 requires 457.2339).
tert-Butyl 4-(4-methoxyphenoxy)-3-oxobutanoate 27
A solution of Meldrum’s acid 15 (2.07 g, 14.3 mmol) in dry
CH2Cl2 was cooled to 0 ◦C; then dry pyridine (2.5 mL) was added.
A suspension of (p-methoxyphenoxy)acetic acid (2.37 g, 13.0
mmol) in dry CH2Cl2 (5 mL) was treated portionwise with N,N¢-
carbonyldiimidazole (2.33 g, 14.3 mmol). After gas evolution
stopped the colourless solution wad added to the solution of
Meldrum’s acid at 0 ◦C, with the help of additional 10 mL of
CH2Cl2. Finally, 4-dimethylaminopyridine (80 mg, 652 mmol) was
added and, after 1 h, the mixture was allowed to stir at room
temp. overnight. The solution was poured into a separatory funnel
containing 2 M HCl and extracted with CH2Cl2. After treatment
with brine the organic layers were concentrated to give a pale
yellow solid that was suspended in dry toluene (15 mL). Then
tBuOH (1.87 mL, 19.6 mmol) was added and the suspension
was refluxed for 1 h, becoming a pale yellow solution soon after
heating started. After solvent evaporation the crude was purified
by chromatography to give 27 (2.26 g, 75%) as a pale yellow oil
and starting acid (474 mg, 20%), with a 94% overall yield based
on unrecovered starting material. Rf 0.42 (PE/Et2O 7 : 3, a or b).
Ethyl 3-butyl-5-ethyl-6-((4-methoxyphenoxy)methyl)-3H-
pyrimidin-4-one-2-carboxylate 16ea
Starting oxazinone: 17e. Amine: nbutylamine. Chromatography
with PE/AcOEt 9 : 1 → 85 : 15 gave a yellow oil (77%). Rf
0.56 (PE/AcOEt 7 : 3, a or b). nmax(CHCl3)/cm-1 2962, 2867,
1734, 1658, 1462, 1245, 1195, 1016. dH(300 MHz; CDCl3;
Me4Si) 0.95 (3 H, t, J 7.4, CH3(CH2)3N), 1.16 (3 H, t, J 7.5,
CH3CH2CC O), 1.38 (2 H, centre of m, CH3CH2(CH2)2N), 1.43
(3 H, t, J 7.1, CH3CH2O), 1.66–1.78 (2 H, m, CH3CH2CH2CH2N),
2.65 (2 H, q, J 7.4, CH3CH2CC O), 3.77 (3 H, s, OCH3),
4.00 (2 H, centre of m, CH2N), 4.47 (2 H, q, J 7.1,
CH3CH2O) 4.89 (2 H, s, OCH2C-N), 6.88 (4 H, centre of m,
aromatics). dC(75 MHz; CDCl3) 13.0 (CH3CH2CC O), 13.6
(CH3CH2O), 14.0 (CH3(CH2)3N), 19.8 (CH3CH2CC O), 20.1
(CH3CH2(CH2)2N), 30.8 (CH3CH2CH2CH2N), 45.7 (CH2N), 55.7
(OCH3), 63.2 (CH3CH2O), 69.3 (CH2OAr), 114.6 and 115.8 (2 ¥ 2
C, aromatic CH), 131.4 (C(C O)N), 148.4 (C N), 152.5, 153.9
and 154.2 (3 C, 2 C ipso of Ar and OCH2C-N), 161.0 (C(C O)N),
161.3 (CO2Et). GC-MS (based on the usual method but with init.
temp. 70 ◦C and final temp. 260 ◦C): Rt 12.55 min; m/z (EI) 388
(M+, 2.2%), 135 (6.1), 124 (17), 123 (100), 121 (6.4), 109 (5.4),
95 (12), 67 (16), 65 (6.7), 57 (5.8), 55 (6.1), 41 (22). m/z (ESI-)
387.1912 (M – H+. C21H27N2O5 requires 387.1920).
n
max(CHCl3)/cm-1 2971, 2891, 1717, 1496, 1368, 1322, 1205, 1148.
dH(300 MHz; CDCl3; Me4Si) 1.45 (9 H, s, (CH3)3C), 3.54 (2 H,
s, COCH2CO), 3.77 (3 H, s, OCH3), 4.58 (2 H, s, ArOCH2CO),
6.83 (4 H, s, aromatics). dC(75 MHz; CDCl3; Me4Si) 28.0 (3 C,
(CH3)3C), 47.4 (COCH2CO), 55.7 (OCH3), 73.2 (ArOCH2), 82.3
(OC(CH3)3), 114.8 and 115.5 (2 ¥ 2 C, aromatic CH), 151.7 and
154.6 (2 C, aromatic C), 165.9 (CO2tBu), 201.3 (COCH2O) ppm.
GC-MS: unsuitable for this analysis. m/z (ESI-): 279.1245 (M –
H+. C15H19O5 requires 279.1232.
tert-Butyl 4-(benzyloxycarbonylamino)butanoate 29
a) Formation of 28: a solution of g-aminobutyric acid (5.22 g,
50.6 mmol) in 2 M NaOH (25 mL) was cooled to 0 ◦C and treated
with benzyl chloroformate (8.23 mL, 55.6 mmol), while pH is
maintained around 10 by continuous addition of 3 M NaOH.
After 15 min the reaction was allowed to stir at room temp for
4.5 h. After two extractions with Et2O, the pH of the aqueous
solution was adjusted to 1.5 by addition of 6 M HCl. After
having saturated with solid NaCl compound 28 was extracted
with AcOEt (28 is not soluble enough in Et2O). The combined
organic layers were washed with brine, dried and concentrated.
Ethyl 3-benzyl-5-ethyl-6-((4-methoxyphenoxy)methyl)-3H-
pyrimidin-4-one-2-carboxylate 16eb
Starting oxazinone: 17e. Amine: benzylamine. Chromatography
with PE/Et2O 8 : 2 gave a pale yellow oil (77%). Rf 0.15 (PE/Et2O
7 : 3, a or b). nmax(CHCl3)/cm-1 2976, 2934, 1735, 1657, 1499, 1439,
1420, 1286, 1221, 1176, 1033. dH(300 MHz; CDCl3; Me4Si) 1.16
(3 H, t, J 6.9, CH3CH2O), 1.18 (3 H, t, J 7.2, CH3CH2CC O),
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The oily residue was taken up with Et2O and the solvent removed
again to give a white solid (10.01 g) which was directly submitted
to the esterification. Rf 0.48 (PE/AcOEt 4 : 6 + 1% AcOH, a or
b). b) Formation of 29: compound 28 from the above reaction
was dissolved in dry CH2Cl2 (100 mL). After addition of tBuOH
(14.5 mL, 151.7 mmol) and 4-dimethylaminopyridine (618 mg,
5.06 mmol), the solution was cooled to 0 ◦C before adding
dicyclohexylcarbodiimide (12.52 g, 60.7 mmol). A white solid
suddenly precipitate. After 1 h the reaction was allowed to stir
vigorously at room temp. for 8 h. Dicyclohexylurea was filtered
and washed with AcOEt. The filtrate was washed with 1 M HCl,
brine, 5% aqueous NaHCO3 and again with brine. After solvent
removal the crude was purified by chromatography (PE/AcOEt
85 : 15 → 75 : 25) to give a colourless oil that becomes a solid when
stored at -25 ◦C (12.61 g, 85% from 27). Rf 0.47 (PE/AcOEt 8 : 2,
a or b). nmax(CHCl3)/cm-1 3668, 3446, 2968, 1709, 1499, 1366,
1248, 1148. dH(300 MHz; CDCl3; Me4Si) 1.44 (9 H, s, (CH3)3C),
1.80 (2 H, quintet, J 7.1, ZNHCH2CH2CH2), 2.27 (2 H, t, J 7.2,
ZNHCH2CH2CH2), 3.24 (2 H, q, J 6.5, ZNHCH2CH2CH2), 4.89
(1 H, br s, NH), 5.09 (2 H, s, CH2O), 7.31–7.37 (5 H, m, aromatics).
dC(75 MHz; CDCl3; Me4Si) 25.1 (ZNHCH2CH2CH2), 28.0 (3 C,
(CH3)3C), 32.7 (ZNHCH2CH2CH2), 40.4 (ZNHCH2CH2CH2),
66.5 (CH2O), 80.4 (OC(CH3)3), 127.9 (2 C, CH ortho of Ph),
128.4 (3 C, CH meta and para of Ph), 136.5 (C ipso of Ph), 156.4
(CO2Bn), 172.5 (CO2tBu) ppm. GC-MS: Rt 8.24 min; m/z (EI)
237 (M+ - 56, 5.0%), 146 (5.1), 112 (6.1), 108 (42), 107 (30), 102
(9.7), 92 (8.7), 91 (100), 84 (12), 79 (7.1), 65 (9.1), 57 (30), 56
(6.1), 41 (13). m/z (ESI-): 292.1556 (M – H+. C16H22NO4 requires
292.1549).
1.56 (9 H, s, (CH3)3C), 2.40 (3 H, s, CH3C-N), 2.55 (2 H, t, J
7.8, CH2(CH2)6CH3), 2.64 (2 H, t, J 7.0, CH2CH2N), 4.13 (2 H,
t, J 7.0, CH2CH2N), 12.06 (1 H, s, OH). dC(75 MHz; CDCl3)
14.1 (CH3(CH2)7), 22.6 (2 C, CH3C-N and CH3CH2(CH2)6), 26.8,
28.2, 28.3, 29.3, 29.5, 29.8 and 31.9 (7 C, 6 CH2 of octyl and
CH2CH2N), 28.1 (3 C, (CH3)3C), 38.5 (CH2N), 83.6 ((CH3)3C),
104.8 ( CCO2tBu) 126.5 (C(C O)N), 145.7 (C N), 155.9
(CH3C-N), 157.8 (C(C O)N), 161.0 ( COH), 170.3 (CO2tBu).
GC-MS: under the analysis conditions compound 31 underwent
a clean decarboxylation. Retention time (9.75 min) and mass
spectrum (290 (M+)) resulted superimposable with the ones of
ketone 35.
Ethyl 2-methyl-3-octyl-4,9-dioxo-6,7,8,9-tetrahydro-4H-
pyrido[1,2-a]pyrimidine-8-carboxylate 32
Exactly the same procedure described above for the preparation
of 31 was followed, starting from 16ac (102 mg, 250 mmol) and
using tBuONa (60 mg, 624 mmol) instead of tBuOK. Due to the
instability of 32 under chromatographic conditions, it was directly
submitted to the decarboxylation procedure. Rf 0.11 (PE/Me2CO
8 : 2, a or c). GC-MS: under the analysis conditions compound
32 underwent a clean decarboxylation. Retention time (9.75 min)
and mass spectrum (290 (M+, 17)) resulted superimposable with
the ones of ketone 35 and compound 31.
2-Methyl-3-octyl-7,8-dihydro-6H-pyrido[1,2-a]pyrimidine-4,9-
dione 35
a) From 31: a solution of crude 31 in a 0.5 M solution of HCl
in dioxane was stirred 2.5 h at 60 ◦C and then refluxed for
additional 2 h. The solution was poured into 5% aq (NH4)H2PO4
and extracted with Et2O. After washing with brine and solvent
removal chromatography with PE/Et2O 8 : 2 → 1 : 1 furnished 35
(49 mg) as a pale yellow oil in 65% overall yield from 16ab. b)
From 32: crude 32 was treated with 6 M HCl and refluxed for
5 h. The pH was adjusted to 7 by addition of 3 M NaOH and
K2HPO4. Extraction with AcOEt and chromatography as above
furnished 35 (31 mg) as a pale yellow oil in 43% overall yield from
16ac. Rf 0.24 (PE/Me2CO 8 : 2, c). nmax(CHCl3)/cm-1 2921, 2851,
1648, 1594, 1390, 1177. Note that NMR spectra show a 82 : 18
mixture of ketone (k) and enol (e). dH(300 MHz; CDCl3; Me4Si)
0.86 (3 H (k + e), t, J 6.8, CH3(CH2)7), 1.20–1.53 (12 H (k + e),
m, CH3(CH2)6), 2.27–2.35 (2 H (k), m, CH2CH2CH2N), 2.28 (3 H
(e), s, CH3C-N), 2.40 (3 H (k), s, CH3C-N), 2.47–2.58 (2 H (k + e)
and 2 H (e), m, CH2(CH2)6CH3 and C(OH) CH-CH2), 2.84 (2 H
(k), t, J 6.6, CH2CH2CH2N), 4.10 (2 H (e), t, J 7.4, CH2CH2N),
4.18 (2 H (k), centre of m, CH2CH2CH2N), 5.66 (1 H (e), t, J 4.6,
CH COH), 12.06 (1 H (e), s, OH). dC(75 MHz; CDCl3) 14.1 (k +
e) (CH3(CH2)7), 20.2 (e) and 20.5 (k) (CH2CH2N), 21.0 (e) and
21.5 (k) (CH3C-N), 22.6 (k + e) (CH3CH2CH2), 26.6 (e) and 26.9
(k) (CH2(CH2)6CH3), 27.9 (k) and 28.2 (e) (CH2CH2(CH2)5CH3),
29.2, 29.4, 29.5 and 29.8 (k + e) (3 C, (CH2)2(CH2)3(CH2)2CH3),
31.83 (k) and 31.85 (e) (CH3CH2CH2), 37.1 (k) and 39.0 (e)
(CH2N), 42.3 (k) (CH2CO), 103.7 (e) (CH CCO) 124.6 (e) and
129.0 (k) (C(C O)N), 145.1 (k) and 146.8 (e) (C N), 156.2 (e),
157.9 (k) and 161.1 (k + e) (CH3C-N and C(C O)N), 161.4 (e)
tert-Butyl 4-aminobutanoate 30
A solution of 30 (580 mg, 1.22 mmol) in methanol (5 mL)
was treated with Pd/C (10%; 59 mg) and hydrogenated. After
1 h the catalyst was filtered over a celite pad and washed with
CH2Cl2/MeOH 8 : 2. The solvent was carefully evaporated. Due
to the volatility of the product, crude 30 was not dried under
vacuum. It was actually transferred into a volumetric flask and
diluted with THF to give a 0.33 M solution (concentration based
on a supposed 100% yield in the hydrogenolysis), that was used as
such for the formation of 16ab and 16d. Rf 0.04 (AcOEt/MeOH
8 : 2, c). GC-MS: Rt 1.57 min; m/z (EI) 159 (M+, 0.065), 103 (46),
102 (36), 87 (5.9), 86 (100), 85 (7.6), 84 (60), 69 (43), 59 (6.4), 58
(6.8), 57 (95), 56 (26), 44 (17), 43 (39), 42 (11), 41 (69), 39 (16).
t-Butyl 6,7,8,9-tetrahydro-2-methyl-3-octyl-4,9-dioxo-4H-
pyrido[1,2-a]pyrimidine-8-carboxylate 31
A solution of 16ab (113 mg, 259 mmol) in dry THF (3 mL) was
treated with tBuOK (58 mg, 518 mmol) at room temp. The initial
pale yellow solution suddenly became brick red and went back
to yellow after 10 min. After 0.5 h the reaction was complete.
The solution was diluted with saturated aq NH4Cl, extracted
with Et2O, washed with brine and concentrated to give a gold
yellow oil. Due to the instability of 31 under chromatographic
conditions, it was partially characterized only as crude derivative
and then directly submitted to the decarboxylation procedure. Rf
0.44 (PE/Me2CO 8 : 2, a, b or c). dH(300 MHz; CDCl3; Me4Si)
0.88 (3 H, t, J 6.8, CH3(CH2)7), 1.18–1.52 (12 H, m, CH3(CH2)6),
(
COH), 189.6 (k) (CH2CO). GC-MS: Rt 8.24 min; m/z (EI) 290
(M+ - 56, 10), 219 (7.6), 205 (19), 193 (12), 192 (100), 191 (38), 164
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(9.8), 163 (40), 135 (6.0), 96 (14), 69 (13), 68 (9.3), 67 (9.8), 55 (18),
53 (12), 43 (7.6), 42 (13), 41 (29), 39 (7.9). m/z (ESI-): 289.1921
(M – H+. C17H25N2O2 requires 289.1916.
475 mmol). After 5 min the resulting red solution was stirred at
room temp. for 1 h. The reaction was partitioned between 5% aq
(NH4)H2PO4 and Et2O and extracted as usual. The organic layers
were washed with H2O and then with brine. After solvent removal
chromatography with Et2O gave 40 (56 mg, 87%) as a pale yellow
oil. Rf 0.41 (Et2O, a or b). nmax(CHCl3)/cm-1 2920, 2851, 1647,
1603, 1438, 1234. dH(300 MHz; CDCl3; Me4Si) 0.88 (3 H, t, J
6.8, CH3(CH2)7), 0.96 (3 H, t, J 7.2, CH3(CH2)3N), 1.20–1.52 (14
H, m, CH3(CH2)6 and CH3CH2(CH2)2N), 1.72 (2 H, centre of m,
CH3CH2CH2CH2N), 2.30 (3 H, s, CH3C-N), 2.51 (2 H, t, J 8.1,
CH2(CH2)6CH3), 3.87 (2 H, t, J 7.5 CH2N), 7.89 (1 H, s, CH N).
dC(75 MHz; CDCl3) 13.6 (CH3(CH2)3N), 14.1 (CH3(CH2)7), 19.9
(CH3CH2(CH2)2N), 21.2 (CH3C-N), 22.6 (CH3CH2(CH2)6), 26.2
(CH2(CH2)6CH3), 28.1 (CH2CH2(CH2)5CH3), 29.3, 29.4 and 29.8
(3 C, (CH2)2(CH2)3(CH2)2CH3), 31.2 (CH3CH2CH2CH2N), 31.8
(CH3CH2CH2(CH2)5), 47.1 (CH2N), 125.6 (C(C O)N), 146.8
(CH N), 158.4 (CH3C-N), 161.4 (C(C O)N). GC-MS: Rt 8.37
min; m/z (EI) 278 (M+, 5.8%), 263 (6.7), 207 (9.2), 193 (17), 181
(12), 180 (100), 179 (32), 163 (6.5), 151 (9.7), 138 (40), 137 (15),
125 (15), 124 (41), 123 (51), 96 (11), 68 (5.5), 67 (7.6), 57 (12), 55
(23), 54 (5.2), 53 (13), 43 (13), 42 (22), 41 (40), 39 (8.3). m/z (ESI+)
279.2428 (M + H+. C17H31N2O requires 279.2436).
3-(3-(tert-Butoxycarbonyl)propyl)-6-methyl-5-octyl-3H-
pyrimidin-4-one 36
A solution of 16ab (82 mg, 188 mmol) in dry DMF (1 ml) was
treated with NaH (60% in mineral oil, 9.0 mg, 225 mmol) and
heated at 70 ◦C overnight. The mixture was diluted with 5%
aq (NH4)H2PO4 and extracted with Et2O, washed with brine
and concentrated. Chromatography with PE/Et2O 6 : 4 → Et2O
gave 36 (41 mg) as a pale yellow oil (60%). Rf 0.56 (Et2O, a).
n
max(CHCl3)/cm-1 2922, 2850, 1720, 1649, 1602, 1415, 1367, 1145.
dH(300 MHz; CDCl3; Me4Si) 0.86 (3 H, t, J 6.6, CH3(CH2)7), 1.17–
1.49 (12 H, m, CH3(CH2)6), 1.42 (9 H, s, (CH3)3C), 2.00 (2 H, quin-
tet, J 7.1, CH2CH2CH2N), 2.26 (2 H, t, J 6.6, CH2CH2CH2N),
2.28 (3 H, s, CH3C-N), 2.48 (2 H, t, J 7.6, CH2(CH2)6CH3),
3.91 (2 H, centre of m, CH2N), 7.89 (1 H, s, CHC N).
dC(75 MHz; CDCl3) 14.1 (CH3(CH2)7), 21.2 (CH3C-N), 22.6
(CH3CH2(CH2)6), 24.3 (CH2CH2CH2N), 26.2 (CH2(CH2)6CH3),
28.06 (3 C, (CH3)3C), 28.09 (CH2CH2(CH2)5CH3), 29.3, 29.4
and 29.8 (3 C, (CH2)2(CH2)3(CH2)2CH3), 31.8 and 32.0 (2 C,
CH3CH2CH2(CH2)5 and CH2CH2CH2N), 46.3 (CH2N), 80.8
((CH3)3C), 125.6 (C(C O)N), 146.9 (CH N), 158.6 (CH3C-N),
161.4 (C(C O)N), 171.8 (CO2tBu). GC-MS: Rt 10.12 min; m/z
(EI) 364 (M+, 1.5%), 308 (11), 293 (15), 292 (5.5), 291 (28), 223
(7.8), 211 (12), 210 (100), 192 (34), 164 (8.4), 124 (7.6), 123 (11),
69 (6.2), 41 (9.0). m/z (ESI+): 365.2792 (M + H+. C21H37N2O3
requires 365.2804).
General procedure for the conversion of ethyl ester into amide or
hydroxamate
The nitrogen reagent, as the corresponding hydrochloride (1.20
mmol), was put in a flask with 2 mL of dry CH2Cl2. After
cooling to 0 ◦C a solution of Me3Al (2 M in toluene, 600 ml)
was added dropwise. At the end a colorless solution was obtained
which was stirred ar room temp. for 15 min. Half of this solution
was transferred into another flask and a solution of 16cd (300
mmol) in CH2Cl2 (1 mL) was added dropwise. The mixture was
stirred at room temp. for 4 h and then poured into a separatory
funnel containing 1 M HCl and extracted with CH2Cl2. After
washing with brine and solvent removal the crude was purified by
chromatography.
Methyl 3-butyl-6-methyl-5-octyl-3H-pyrimidin-4-one-2-
carboxylate 39
MeONa (25 mg, 463 mmol) was added to a solution of 16aa (107
mg, 305 mmol) in dry methanol (4.5 mL) and the suspension was
stirred for 1.25 h at room temp. The reaction was partitioned
between 5% aq (NH4)H2PO4 and Et2O and extracted as usual.
After washing with brine and solvent removal, chromatography
with PE/Et2O 6 : 4 gave 39 (84 mg, 82%) as a pale yellow oil. Rf
0.24 (PE/Et2O 7 : 3, a or b). nmax(CHCl3)/cm-1 2960, 2920, 2855,
1737, 1650, 1600, 1440, 1381, 1105. dH(300 MHz; CDCl3; Me4Si)
0.88 (3 H, t, J 6.8, CH3(CH2)7), 0.94 (3 H, t, J 7.4, CH3(CH2)3N),
1.21–1.52 (14 H, m, CH3(CH2)6 and CH3CH2(CH2)2N), 1.65–1.75
(2 H, m, CH3CH2CH2CH2N), 2.32 (3 H, s, CH3C-N), 2.53 (2 H, t,
J 7.5, CH2(CH2)6CH3), 4.00 (3 H, s, OCH3), 4.00 (2 H, t, CH2N).
GC-MS: Rt 9.24 min; m/z (EI) 336 (M+, 3.7%), 321 (7.5), 281
(8.5), 278 (13), 277 (64), 265 (5.1), 251 (9.9), 239 (15), 238 (100),
237 (7.1), 209 (5.5), 195 (12), 193 (5.1), 183 (16), 182 (23), 181 (18),
179 (36), 177 (7.2), 163 (8.4), 151 (9.0), 150 (35), 149 (14), 138 (6.7),
137 (8.9), 135 (14), 124 (41), 123 (25), 122 (18), 121 (16), 108 (5.3),
96 (41), 95 (7.2), 94 (7.1), 93 (6.8), 81 (8.2), 80 (5.8), 79 (8.9), 69
(11), 68 (5.7), 67 (21), 59 (6.9), 57 (15), 56 (9.9), 55 (48), 54 (8.1),
53 (25), 43 (27), 42 (34), 41 (57), 39 (3.4). m/z (ESI-) 335.2342 (M
– H+. C19H31N2O3 requires 335.2335).
5-Isobutyl-3-(4-methoxybenzyl)-N,6-dimethyl-3H-pyrimidin-
4-one-2-carboxamide 49
Nitrogen nucleophile: methylamine hydrochloride. Chromatogra-
phy: PE/AcOEt 8 : 2 → 75 : 25 gave 49 as a white solid (82%).
Mp 91.8–93.9 ◦C (PE/AcOEt). Rf 0.15 (PE/AcOEt 7 : 3, a or b).
n
max(CHCl3)/cm-1 3431, 2996, 2949, 1654, 1505, 1225, 1168, 1024.
dH(300 MHz; CDCl3; Me4Si) 0.92 (6 H, d, J 6.9, (CH3)2CH), 1.97
(1 H, nonuplet, J 6.8, (CH3)2CH), 2.26 (3 H, s, CH3C-N), 2.44 (2
H, d, J 7.2, CH2CH), 2.91 (3 H, d, J 5.1, CH3NH), 3.76 (3 H, s,
OCH3), 5.77 (2 H, s, CH2Ar), 6.79 (2 H, dt, J 8.7, 2.5, H ortho
to OCH3), 7.27 (2 H, dt, J 8.7, 2.6, H meta to OCH3), 7.39 (1 H,
br d, J 3.9, NH). dC(75 MHz; CDCl3) 21.4 (CH3C-N), 22.6 (2
C, (CH3)2CH), 26.4 (CH3NH), 27.9 ((CH3)2CH), 35.6 (CH2CH),
45.7 (CH2N), 55.2 (OCH3), 113.7 (2 C, CH ortho to OCH3), 126.3
(C(C O)N), 129.5 (C para to OCH3), 129.8 (2 C, CH meta to
OCH3), 147.3 (C N), 156.4 (CH3C-N), 158.9 (C-OCH3), 161.7
(C(C O)N), 162.4 (CONHCH3). GC-MS: Rt 10.78 min; m/z
(EI) 343 (M+, 18%), 286 (14), 285 (12), 192 (5.5), 150 (10), 122
(12), 121 (100), 91 (5.2), 78 (5.5), 77 (8.0). m/z (ESI-) 342.1816 (M
– H+. C19H24N3O3 requires 342.1818).
3-Butyl-6-methyl-5-octyl-3H-pyrimidin-4-one 40
A solution of 16aa (81 mg, 231 mmol) in dry DMF (1 mL)
was treated at 0 ◦C with NaH (60% in mineral oil, 19 mg,
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Org. Biomol. Chem., 2011, 9, 2107–2122 | 2121
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N-(Benzyloxy)-5-isobutyl-3-(4-methoxybenzyl)-6-methyl-3H-
pyrimidin-4-one-2-carboxamide 50
tia Srl, Novara (Italy) for financial assistance and Fon-
dazione S. Paolo for a contribution to the purchase of NMR
instrument.
Nitrogen nucleophile: O-benzylhydroxylamine hydrochloride.
Chromatography: PE/AcOEt 8 : 2 → 75 : 25 gave 50 as a pale yel-
low oil (80%). Rf 0.30 (PE/AcOEt 7 : 3, a or b). nmax(CHCl3)/cm-1
3030, 2995, 2952, 1703, 1652, 1503, 1222. dH(300 MHz; CDCl3;
Me4Si) 0.91 (6 H, d, J 6.6, (CH3)2CH), 1.95 (1 H, nonuplet, J 6.8,
(CH3)2CH), 2.16 (3 H, s, CH3C-N), 2.40 (2 H, d, J 7.8, CH2CH),
3.77 (3 H, s, OCH3), 4.88 (2 H, s, CH2ONHCO), 5.71 (2 H, s,
CH2Ar), 6.81 (2 H, dt, J 8.7, 2.6, H ortho to OCH3), 7.25 (2 H,
dt, J 8.4, 2.6, H meta to OCH3), 7.30–7.37 (5 H, m, Ph) 9.54 (1
H, br s, NH). dC(75 MHz; CDCl3) 21.2 (CH3C-N), 22.6 (2 C,
(CH3)2CH), 27.9 ((CH3)2CH), 35.6 (CH2CH), 45.3 (CH2N), 55.2
(OCH3), 78.4 (CH2ONHCO), 113.8 (2 C, CH ortho to OCH3),
127.1 (C(C O)N), 128.6, 129.3, 129.9 (3 ¥ 2 C, CH ortho to OMe
and CH ortho and meta of Ph), 128.9 (CH para of Ph), 129.1 (C
para to OCH3), 134.8 (C ipso of Ph), 145.9 (C N), 156.4 (CH3C-
N), 159.0 (C-OCH3), 159.6 (C(C O)N), 162.1 (CONHCH3).
GC-MS: unsuitable for this analysis. m/z (ESI-) 434.2065 (M –
H+. C25H28N3O4 requires 434.2080).
Notes and references
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3-Butyl-6-methyl-5-octyl-3H-pyrimidin-4-one 51
A solution of benzyl alcohol (116 ml, 1.12 mmol) in dry benzene
(1 mL) was treated at 0 ◦C with NaH (60% in minera oil,
13.4 mg 335 mmol). A solution of 16cd (100 mg, 279 mmol) in
benzene (0.5 mL) was dropped into the benzylate solution, using
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removal of ethanol was performed, adding additional benzene to
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Et2O and extracted. Final washing with brine and solvent removal
was followed by a double chromatography: PE/AcOEt 85 : 15 →
8 : 2 and CH2Cl2/Et2O 97 : 3 to give 51 as a pale yellow oil (88 mg,
75%). Rf 0.58 (PE/Et2O 7 : 3, a or b). nmax(CHCl3)/cm-1 2957, 2866,
1735, 1650, 1597, 1510, 1274, 1248, 1172. dH(300 MHz; CDCl3;
Me4Si) 0.94 (6 H, d, J 6.6, (CH3)2CH), 1.97 (1 H, nonuplet, J
6.8, (CH3)2CH), 2.31 (3 H, s, CH3C-N), 2.45 (2 H, d, J 7.2,
CH2CH), 3.74 (3 H, s, OCH3), 5.26 (2 H, s, CH2OCO), 5.27
(2 H, s, NCH2Ph), 6.71 (2 H, dt, J 8.7, 3.0, H ortho to OCH3),
7.29 (2 H, dt, J 9.0, 3.0, H meta to OCH3), 7.23–7.37 (5 H, m,
Ph). dC(75 MHz; CDCl3) 21.6 (CH3C-N), 22.6 (2 C, (CH3)2CH),
28.0 ((CH3)2CH), 35.5 (CH2CH), 46.5 (CH2N), 55.2 (OCH3), 68.6
(CH2OCO), 114.0 (2 C, CH ortho to OCH3), 126.4 and 127.9 (2
C, C(C O)N and C para to OCH3), 128.6, 128.9, 129.3 (7 C,
CH ortho to OMe and CH of Ph), 133.9 (C ipso of Ph), 147.2
(C N), 157.9 (CH3C-N), 159.2 (C-OCH3), 161.2 (C(C O)N),
161.5 (CONHCH3). GC-MS (based on the usual method but with
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◦
◦
◦
init. temp. 200 C, rate 35 C min-1, final temp. 280 C): Rt 6.25
min; m/z (EI) 420 (M+, 1.2), 329 (16), 193 (13), 165 (14), 122 (14),
121 (100), 91 (17). m/z (ESI-) 419.1978 (M – H+. C25H27N2O4
requires 419.1971).
Acknowledgements
The authors thank Dr Francesca Musumeci and Ms Feder-
ica Gastaldo for their contribution to this work, Chemessen-
2122 | Org. Biomol. Chem., 2011, 9, 2107–2122
This journal is
The Royal Society of Chemistry 2011
©