An efficient synthesis of uracil derivatives from 2-alkyl-Δ2-oxazolines and nitriles

Article abstract of DOI:10.1016/j.jfluchem.2008.04.004

An efficient and convenient synthesis of new fluorinated and non-fluorinated uracils is described herein. The condensation of nitriles with enolates generated from 2-alkyl-Δ²-oxazolines (I) affords fluorinated β-enamino acid derivatives, which

Full text of DOI:10.1016/j.jfluchem.2008.04.004

Journal of Fluorine Chemistry 129 (2008) 836–847
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
An efficient synthesis of uracil derivatives from 2-alkyl-D2-oxazolines and nitriles
a,b
a
a
Santos Fustero a,b, , Juan F. Sanz-Cervera , Salvador Merida , Raquel Roman ,
*
´
´
a
a,1
´
Salvador Villanova , Carmen Ramırez de Arellano
a
´
´
Departamento de Quımica Organica, Universidad de Valencia, E-46100 Burjassot, Spain
b
´
´
Centro de Investigacion Prıncipe Felipe, E-46013 Valencia, Spain
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient and convenient synthesis of new fluorinated and non-fluorinated uracils is described herein.
The condensation of nitriles with enolates generated from 2-alkyl-D2-oxazolines (I) affords fluorinated
Received 11 March 2008
Received in revised form 8 April 2008
Accepted 10 April 2008
Available online 25 April 2008
b
-enamino acid derivatives, which react with triphosgene to give an isomeric mixture of
oxazolopyrimidinones. These can then be easily transformed into a single C-6 pyrimidindione derivative
through reaction with a suitable nucleophile.
ß 2008 Elsevier B.V. All rights reserved.
Keywords:
Uracils
Fluorinated compounds
2
ꢀ -Oxazolines
Fluorinated
b-enamino acid derivatives
1. Introduction
2. Results and discussion
The disruption of the biological mechanisms associated with
nucleic acids is a major field in drug discovery research, especially
that focussed on the development of effective antitumoral and/or
antiviral agents. In this context, the preparation of molecules that
mimic the structures of nucleic acids or their building blocks has
led to many examples of therapeutically useful compounds [1].
Moreover, it has been shown that the introduction of fluorine
atoms into organic molecules usually promotes dramatic changes
in their biological properties and, as a result, this strategy has been
successfully applied to the synthesis of biologically active
fluorinated nucleotides and nucleosides [2,3]. Emblematic exam-
ples include 5-fluorouracil and trifluridine (Fig. 1), both potent
inhibitors of thymidylate synthase. While the former is widely
used in the treatment of several types of cancer, the latter has
proven to be an effective antiviral agent against Herpes simplex
infections. In other drugs, such as the antitumoral compound
gemcitabine, the fluorine atoms are positioned in the sugar moiety.
The potential of this class of compounds, however, is not limited to
the field of medicine. C-6 Fluorinated uracils, for example, have
found important applications as agrochemicals [4].
In previous articles we described several synthetic routes for
the efficient preparation of C-6 fluoroalkylated uracils 1 starting
from fluorinated nitriles (RFCN) 2 (Scheme 1). In our strategy, the
target uracils (X = O) or thiouracils (X = S) 1 are obtained in two
steps from nitriles 2 and esters 3 via the corresponding b-enamino
esters 4 with the aid of both solution (R3 = Et) and solid-phase
(R3 = Wang’s resin) techniques [5], as well as through fluorous
synthesis [6]. In addition, when suitable olefin substituents are
introduced into the
b-enamino esters, a ring closing metathesis
reaction can be performed to afford bicyclic fluorinated uracils 6
and 7 [7]. Our second methodology, which was initially published
as a communication [8], allows for the preparation of uracils 1 from
2-alkyl-D2-oxazolines 8 and fluorinated nitriles 2. This paper will
give a full account of the development of this latter strategy, which
we have also applied to the preparation of non-fluorinated uracils
with various substitution patterns at R2.
Our first synthetic approach (via compounds 4, Scheme 1) did
not allow for the preparation of uracils with a –CH2CH2Cl
substituent on the
isocyanate (NCO–CH2CH2Cl) was used in the condensation
reaction with the -enamino ester 4, only ill-defined mixtures
N atom [5,8]. When the corresponding
b
were formed, perhaps because the highly basic reaction conditions
promote elimination in either the isocyanate or in the uracil after
its formation. Still, these types of compounds seemed to constitute
an interesting synthetic target, as the functionalized side chain
would permit the introduction of further functionality. We thus
devised a second strategy for the preparation of these compounds.
´
´
* Corresponding author at: Departamento de Quımica Organica Facultad de
´
´
Farmacia, Universidad de Valencia Avda, Vicente Andres Estelles, s/n, 46100
Burjassot (Valencia), Spain. Tel.: +34 963544279; fax: +34 963544939.
E-mail address: santos.fustero@uv.es (S. Fustero).
1
X-ray analysis.
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.04.004

S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 836–847
837
Fig. 1. Some biologically active fluorinated uracil-based compounds.
Scheme 2. The condensation of oxazolines 8 and nitriles 2 affords oxazoline-
The starting materials used in this new approach were two
protected
b-enamino acids 9.
commercial oxazolines, namely 2-methyl-D2-oxazoline (8a) and
2-ethyl-D2-oxazoline (8b), as well as (R)-2-methyl-4-phenyl-D2
-
Table 1
oxazoline (8c). This last compound, although not yet commercially
available, can be easily prepared by following methods described
in the literature [9]. Additional starting materials included both
aromatic and aliphatic, fluorinated and non-fluorinated nitriles 2.
While all the aromatic fluorinated nitriles were commercially
available, only one of the aliphatic fluorinated nitriles (2c,
perfluorooctanenitrile) could be purchased. For that reason, 2e
[10], 2b [10,11], and 2a [11,12] were prepared in accordance with
procedures previously described in the literature.
In the first step of the synthesis, 2-alkyl-D2-oxazolines 8 were
treated with 1 equiv. of LDA at ꢁ78 8C to afford their lithium
enolates. These were then condensed with different fluorinated
and non-fluorinated nitriles 2, which, after hydrolysis, gave the
Results for the reaction between oxazolines 8 and nitriles 2
Entry
8
R1
R2
2
R3a
Product (9)
Yield (%)b
1
2
8a
8a
8a
8a
8b
8c
8c
8a
8a
8a
8c
8a
8a
8a
8a
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
2e
2b
2a
2c
2e
2e
2b
2f
CF2(
b
a
-C10H7)
-C10H7)
9a
9b
9c
9d
9e
9f
84
80
70
60
76
74
65
70
93
70
72
81
78
85
80
H
CF2(
3
H
CF2C6H5
4
H
(CF2)6CF3
5
H
CF2(
CF2(
CF2(
b
b
a
-C10H7)
-C10H7)
-C10H7)
6
C6H5
C6H5
H
7
9g
9h
9i
8
2,4-F2C6H3
p-CF3C6H4
p-FC6H4
9
H
2g
2h
2h
2i
10
11
12
13
14
15
H
9j
C6H5
H
p-FC6H4
9k
9l
p-CH3C6H4
C6H5
oxazoline-protected
b-enamino acids 9 in yields ranging from 60
H
2j
9m
9n
9o
to 93% (Scheme 2). Both fluorinated and non-fluorinated com-
pounds 9 appeared exclusively in the enamino form [13]. In this
fashion, then, a variety of chiral and achiral compounds 9 were
prepared (see Table 1). The yields of this condensation reaction are
good to excellent and seem to be independent of whether the
nitrile is fluorinated (entries 1–11, Table 1) or not (entries 12–15,
Table 1).
The second step consisted of a condensation with either
phosgene or triphosgene [14]. These reagents have previously been
used in reactions with N,N0-binucleophiles such as diamines or
aminocarboxyamides to afford cyclic ureas (imidazol-2-ones) or
related heterocycles with 5 or 6-membered rings [14]. Triphosgene
has also been used with 1-azadiene derivatives to give 2-(1H)-
pyrimidones in good yields [15]. In our synthesis, triphosgene
H
2k
2l
p-CH3OC6H4
Thiophenyl
H
a
b
-C10H7
=
b
-naphtyl;
a
-C10H7
=
a-naphtyl.
b
Yields for purified products.
use one molar equivalent of triphosgene in each reaction. We were
also able to determine that an excess of triphosgene influenced
neither the yields nor the proportion of the final products.
In most cases, pyrimidinone derivatives 15 were the pre-
dominant products of the condensation reaction. In many cases,
both oxazolopyrimidinones 14 and 15 were isolated and purified,
but in some instances only 15 was isolated (entries 2, 3, 5, 6, and
9). The results for the reactions with non-fluorinated compounds
(entries 11–14, Table 2) indicate that the outcome of this reaction
reacted with the protected, fluorinated
b-enamino acids 9 to give a
is not dependent on whether the starting oxazoline-protected b-
mixture of isomeric oxazolopyrimidinones 14 and 15 in yields
ranging from 70 to 95% (Scheme 3; Table 2) after quenching of the
crude reaction with 5 M aqueous KOH solution.
Because substituting phosgene for triphosgene did not affect
the yields and since triphosgene is easier to work with, we chose to
enamino acid is fluorinated or not. However, while isomer 15 is
the main product in the reaction of fluorinated compounds 9 with
triphosgene (Table 2, entries 1–10), in the same reaction with
non-fluorinated compounds 9, isomer 14 is the major product
obtained.
Scheme 1. Previous strategies for the preparation of uracil derivatives developed by our group.

838
S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 836–847
Scheme 3. The reaction of compounds 9 with triphosgene affords a mixture of
compounds 14 and 15 after aqueous basic work-up.
Table 2
Preparation of compounds 14 and 15
Entrya
9
R1
R2
R3
Yield (%)b 14/15c Isolated
productsd
1
2
9a
9b
9c
9d
9e
9f
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CF2(
CF2(
b
a
-C10H7) 80
-C10H7) 82
30/70
10/90
5/95
14a, 15a
15b
3
CF2C6H5
72
70
15c
4
(CF2)6CF3
10/90
20/80
10/90
35/65
30/70
35/65
30/70
60/40
50/50
65/35
75/25
14d + 15de
15e
5
CF2(
b
b
-C10H7) 85
-C10H7) 90
6
(R)-Ph CF2(
15f
7
9h
9i
H
H
H
2,4-F2C6H3
p-CF3C6H4
p-FC6H4
95
89
82
87
85
80
78
84
14g, 15g
14h, 15h
15i
Fig. 3. Ellipsoid plot of compound 15k (50% probability level).
8
9
9j
10
11
12
13
14
9k
9l
(R)-Ph p-FC6H4
14j, 15j
14k, 15k
14l, 15l
14m, 15m
14n, 15n
member fused system determines an eclipsed conformation for the
C(2)–C(3) bond. The p-CF3–C6H4 moiety is coplanar respect to the
molecular main plane (dihedral angle 1.108).
H
H
H
H
p-CH3C6H4
9m
9n
9o
C6H5
p-CH3OC6H4
Thiophenyl
The molecular structure of 15k (Fig. 3) displays a non planar
oxazolo[3,2-a]pyrimidinone conformation. The five-membered
C1–C2–C3–N3(A)–C7(A) ring is slightly folded in an envelope
a
b
-C10H7
= b-naphthyl; a-C10H7 = a-naphthyl.
b
c
Yield of 14 + 15 crude mixture.
Proportion 14/15 in the crude reaction mixture, as determined through 1H and/
˚
conformation with the C(2) atom 0.179(3) A out of the plane. The
or 19F NMR analysis.
d
p-tolyl group forms
a dihedral angle of 11.138 with the
Isolated and purified products; see Experimental Section for individual isolated
oxazolo[3,2-a]pyrimidinone main plane.
yields.
e
In these reactions, we were able to determine which type of
aqueous reaction work-up conditions led to specific compounds
being isolated as the final products. Thus, when the crude reaction
mixture was treated with water or aqueous bicarbonate solution, a
mixture of compounds 14, 15, and 16 was obtained (see Tables 2
and 3). However, as discussed above, when the reaction mixture
was quenched with 5 M aqueous KOH solution, only compounds
14 and 15 were isolated. Finally, when the crude reaction mixture
was treated with 1 M aqueous HCl solution, only compounds 16
were isolated in good to excellent yields (85–91%) (Scheme 4).
Table 3 shows several examples of the direct preparation of
compounds 16 from enaminooxazolines 9.
It was not possible to separate this mixture.
The structures for isomeric compounds 14 and 15 were
unambiguously confirmed by means of X-ray diffraction techni-
ques. Single crystals suitable for X-ray analysis for compounds 14h
(entry 8, Table 2) and 15k (entry 11, Table 2) were obtained by slow
ethyl acetate/n-hexane and chloroform/n-hexane liquid diffusion,
respectively. The corresponding crystal structures indicate that,
whereas compound 14h displays
c]pyrimidinone structure (Fig. 2), 15k is an oxazolo[3,2-a]pyr-
imidinone (Fig. 3).
a fluorinated oxazolo[3,2-
The X-ray molecular structure of 14h (Fig. 2) shows an
essentially planar conformation for the oxazolo[3,2-c]pyrimidi-
Taking all these facts into account, the formation of compounds
14, 15, and 16 can be rationalized as depicted in Scheme 5. The
nucleophilic attack of the enamine moiety to triphosgene would
give rise to an intermediate, which, after loss of HCl, would evolve
to the corresponding non-isolated carbamyl chloride. This
compound, in turn, would cyclize to compound 14 (Scheme 5).
Protonation of the carbonyl oxygen of 14 would favor the
˚
none system (mean deviation 0.017 A). The planarity of the nine
nucleophilic attack of chloride anion on the
a carbon relative to
the oxazoline ring oxygen atom, thus generating a halogenated
intermediate 16. The heterocyclization of this compound with
concomitant HCl elimination would then afford the oxazolopyr-
imidone 15 [16].
Table 3
Preparation of compounds 16
Entry
9
R3
Yield (%)
Isolated product
1
11
12
13
14
9c
C6H5CF2
88
88
85
83
91
16a
16b
16c
16d
16e
9l
p-CH3C6H4
C6H5
9m
9n
9o
p-CH3OC6H4
Thiophenyl
Fig. 2. Ellipsoid plot of compound 14h (50% probability level).

S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 836–847
839
Scheme 4. The reaction of compounds 9 with triphosgene affords compounds 16
after aqueous acidic work-up.
The last step in the synthesis consisted of an oxazoline ring-
opening reaction by a nucleophile. Although this type of process is
infrequent, there are precedents for such reactions in the literature
[17–19]. We thus decided to study the reactivity of pyrimidinones
14 and 15 with nucleophiles such as MeOH, EtOH, H2O, AcOH, and
HCl – under basic or acidic conditions – to determine what
combination of factors would give rise to compounds 16 most
efficiently (Scheme 6).
The oxazoline ring-opening reaction of 14 and 15 under basic
conditions took place in refluxing THF and was followed by
hydrolysis with an aqueous solution of NH4Cl to give uracils 16
(method A, Scheme 6 and Table 4).
Scheme 6. Compounds 14 and 15 are efficient precursors of derivatives 16.
Alternatively, when compounds 14 and/or 15 were dissolved in
THF and treated with 1.2 equiv. of 4 M HCl in dioxane at room
temperature, subsequent hydrolysis with NH4Cl aqueous solution
also afforded uracils 16 (Nu = Cl; method B, Scheme 6 and Table 4)
[20].
Scheme 5. A possible mechanism for the formation of compounds 14–16.
Table 4
Results for the ring-opening reaction of pyrimidinones 14 and/or 15 with nucleophiles
Entrya
Substrate
R1
R2
R3
Nu
Methodb
Yield (%)c
Product
1
2
15c
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
CF2C6H5
Cl
B
96
80
98
72
95
92
75
91
78
72
78
92
75
80
79
70
70
16a
16f
15b
H
CF2(
CF2(
a
b
-C10H7)
-C10H7)
OMe
Cl
A
B
3
14a, 15a
14d + 15d
15e
H
16g
16h
16i
4
H
(CF2)6CF3
OH
Cl
A
B
Bd
A
B
5
H
CF2(
CF2(
b
b
-C10H7)
-C10H7)
6
15f
(R)-Ph
Cl
16j
7
14g, 15g
14g, 15g
14h, 15h
14h, 15h
15i
H
2,4-F2C6H3
2,4-F2C6H3
p-CF3C6H4
p-CF3C6H4
p-FC6H4
OH
Cl
16k
16l
8
H
9
H
OMe
OH
OEt
Cl
A
A
A
Bd
A
B
16m
16n
16o
16p
16q
16b
16r
16s
16t
10
11
12
13
14
15
16
17
H
H
14j, 15j
14k, 15k
14k, 15k
14k, 15k
14k, 15k
14k, 15k
(R)-Ph
p-FC6H4
H
H
H
H
H
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
OAc
Cl
OH
OMe
Fe
A
A
A
Synthesis of uracils 16.
a
b
-C10H7
=
b
-naphthyl;
a
-C10H7
=
a
-naphthyl.
b
c
Method A: RONa/ROH, THF, reflux. Method B: HCl/dioxane, THF, rt.
Yield of purified product.
d
e
At 50 8C.
0.5 M solution of TBAF in THF under reflux was used as reagent.

840
S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 836–847
3. Conclusions
In summary, we have described a convenient procedure for the
preparation of both fluorinated and non-fluorinated uracil
derivatives 14, 15, and 16 from oxazolines 8 and nitriles 2 in
only three steps and with good chemical yields. The ring-opening
reaction of intermediate oxazolopyrimidinones 14 and 15 by a
number of different nucleophiles allows for the preparation of a
variety of potentially bioactive uracils. Compounds 16 are also
suitable substrates for nucleophilic substitution reactions, thus
increasing the versatility of this family of compounds.
4. Experimental
4.1. General experimental procedures
Scheme 7. An example of the use of compounds 14 and 15 as substrates for
All reactions were performed with magnetic stirring in flame-
dried glassware under an argon atmosphere with dry, distilled
solvents. Tetrahydrofuran (THF) was distilled over Na–K alloy.
Dichloromethane (CH2Cl2) was distilled over CaH2. Acetonitrile
(CH3CN) was distilled over P2O5 and collected under inert
nucleophilic ring-opening.
It is worth noting that the same uracil 16 was obtained
regardless of whether compound 14, 15, or a mixture thereof was
used, thus making this method quite useful from a synthetic point
of view. In all cases, the ring-opening reaction in acidic medium
was faster (0.5–2 h) and produced better yields (80–98%) than the
corresponding reactions under basic conditions (5–7 h; 72–80%).
In cases in which the oxazoline ring had a substituent (R2 ¼ H,
entries 6 and 12, Table 4), the ring-opening reaction under acidic
conditions occurred more slowly and the temperature had to be
raised to 50 8C to obtain the corresponding uracils 16j and 16p,
respectively.
To confirm the validity of our approach as a general method of
introducing a nucleophile into these systems, we attempted to do
so with the cyclic amine t-butyl 1-piperazinecarboxylate
(Scheme 7). We chose this compound not only because it would
allow for the introduction of other groups after N-BOC
deprotection, but also because analogous systems form part of
several pharmaceutically significant compounds, including
˚
atmosphere over molecular sieves (4 A). All other commercially
obtained solvents or reagents were used as received. All reactions
were monitored with thin layer chromatography (TLC) in which
precoated 250
mm softlayer silica gel GF uniplates (Merck) were
used. TLC plates were visualized with UV light (254 nm), vanillin,
or cerium molybdate stains. Flash chromatography was performed
with the indicated solvent system on 60 (230–400 mesh, particle
size 0.040–0.063 mm) normal phase silica gel. In several cases, all
of which are clearly identified in the text, the silica gel for column
chromatography was deactivated prior to the actual separation
through overnight treatment with a 2% solution of triethylamine in
hexane, followed by equilibration with the solvent mixture finally
employed. ‘Concentrated’ refers to the removal of solvent with a
rotary evaporator at normal water aspirator pressure followed by
further evacuation with a two-stage mechanical pump. Yields refer
to chromatographically and spectroscopically pure compounds. All
new compounds were determined to be at least 95% pure by means
of NMR. All melting points were determined with an open
Ketanserine [19],
a 5-HT2 serotonin antagonist drug, and
Zopiclone [21], an ansiolytic drug that acts as a benzodiazepine
receptor agonist.
capillary. Chemical shifts were reported in
d values relative to
We found that when a solution of a mixture of 14g and
15g in 1,4-dioxane was slowly added to a solution of N-BOC-
piperazine in a 1:1 mixture of aqueous K2CO3 and 1,4-dioxane
and stirred at 100 8C for 24 h, the desired compound 17 was
obtained in 80% yield, thus proving the validity of our approach
(Scheme 7).
Compounds 16 also constitute suitable substrates for further
derivatization through obvious nucleophilic attack. As an
example of this, compound 16b was treated with sodium
methoxide in methanol and with TBAF in THF to afford the
corresponding derivatives 16s and 16t, in 65 and 67% yields,
respectively (Scheme 8).
tetramethylsilane in 1H NMR standard, fluorotrichloromethane in
19F NMR, and the solvent peak in 13C NMR. 1H NMR was measured
at 300 MHz, 19F NMR at 282.4 MHz, and 13C NMR at 75.5 MHz. The
units for coupling constants are Hertz (Hz). Peak splitting patterns
in NMR are reported as follows: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad. Crystallographic data (excluding
structure factors) for the structures in this paper have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 684059 and 684060. Copies
of the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk).
4.2. Preparation of compounds 9
4.2.1. General procedure
To a solution of diisopropylamine (14 mmol) in THF (10 mL) at
ꢁ20 8C, n-butyllithium (17.5 mmol, 2.5 M in hexane) was slowly
added. The mixture was stirred for 30 min at that temperature,
after which the temperature was lowered to ꢁ78 8C. Then, a
solution of the oxazoline (8a, 8b, or (R)-8c; 15.0 mmol) in THF
(15 mL) was added dropwise and the reaction mixture was stirred
1 h at that temperature to allow azaenolate formation. A solution
of the nitrile 7 (14 mmol) in THF (10 mL) was added slowly. The
reaction progress was monitored by means of TLC, and after ca. 2 h
Scheme 8. Transformation of compound 16b into derivatives 16s and 16t through
nucleophilic substitution.

S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 836–847
841
it was quenched with satd. aq. NH4Cl solution and extracted with
CH2Cl2 (3 ꢂ 25 mL). The organic layers were pooled together,
washed with brine, dried over anh. Na2SO4, and concentrated to
give crude product 8, which was purified in each case as described
below.
yellowish oil (76% yield). 1H NMR (300 MHz, CDCl3)
J = 2.3 Hz, 3H), 3.97 (t, J = 8.9 Hz, 2H), 4.10–4.16 (m, 2H), 7.00 (br
d
1.53 (t,
s, 2H), 7.43–7.51 (m, 2H), 7.60–7.64 (m, 1H), 7.78–7.84 (m, 3H),
8.02 (s, 1H); 13C NMR (75.5 MHz, CDCl3)
d 12.6 (c), 54.5 (t), 65.6
3
1
(t), 90.0 (t, JCF = 3.4 Hz), 118.9 (t, JCF = 243.4 Hz), 122.3 (t,
3
3JCF = 4.3 Hz), 125.7 (t, JCF = 6.0 Hz), 126.7 (d), 127.4 (d), 127.7
2
4.2.2. (Z)-1-Difluoro(2-naphthyl)methyl-2-(4,5-dihydro-1,3-oxazol-
2-yl)-1-ethenylamine (9a)
(d), 128.7 (d), 128.8 (d), 132.4 (s), 132.5 (t, JCF = 27.0 Hz), 134.1
(s), 146.0 (t, 2JCF = 25.3 Hz), 168.3 (s); 19F NMR (282 MHz, CDCl3)
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (3:1)] on deactivated silica gel (Et3N 2%) gave a
d
ꢁ90.57 (s, 2F). HRMS calcd for C17H16F2N2O 302.1230, found
302.1220.
brownish solid (84%): mp 79–81 8C. 1H NMR (300 MHz, CDCl3)
d
3.82 (t, J = 9.4 Hz, 2H), 4.03 (t, J = 9.8 Hz, 2H), 4.85 (s, 1H), 6.36 (br s,
4.2.7. (Z)-1-[Difluoro(2-naphthyl)methyl]-2-[(4R)-4-phenyl-(4,5-
dihydro-1,3-oxazol-2-yl)]-1-ethenylamine (9f)
2H), 7.41–7.51 (m, 3H), 7.76–7.78 (m, 3H), 7.98 (s, 1H); 13C NMR
(75.5 MHz, CDCl3)
d
54.3 (t), 65.7 (t), 82.9 (t, 3JCF = 6.0 Hz), 118.2 (t,
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (5:1)] on deactivated silica gel (Et3N 2%) gave a
3
3
1JCF = 243.9 Hz), 122.3 (t, JCF = 5.1 Hz), 125.5 (t, JCF = 6.9 Hz),
126.7 (d), 127.4 (d), 127.6 (d), 128.5 (d), 128.6 (d), 131.8 (t,
yellow oil (74% yield). ½a D25
ꢃ
ꢁ 76:6 (c 1.35, CHCl3). 1H NMR
2
2JCF = 31.6 Hz), 132.2 (s), 133.9 (s), 150.3 (t, JCF = 28.7 Hz), 165.6
(300 MHz, CDCl3) d 4.02–4.09 (m, 1H), 4.56–4.63 (m, 1H), 5.16 (s,
(s); 19F NMR (282 MHz, CDCl3)
d
ꢁ98.34 (s, 2F). HRMS calcd for
1H), 5.38 (t, J = 9.1 Hz, 1H), 6.71 (br s, 2H), 7.37–7.46 (m, 5H), 7.62–
C16H14F2N2O 288.1074, found 288.1069.
7.75 (m, 3H), 7.90–7.99 (m, 3H), 8.23 (s, 1H); 13C NMR (75.5 MHz,
3
CDCl3)
d
69.5 (d), 72.9 (t), 82.3 (t, JCF = 5.7 Hz), 118.2 (t,
3
3
4.2.3. (Z)-1-Difluoro(1-naphthyl)methyl-2-(4,5-dihydro-1,3-oxazol-
2-yl)-1-ethenylamine (9b)
1JCF = 244.9 Hz), 122.3 (t, JCF = 5.1 Hz), 125.5 (t, JCF = 8.2 Hz),
126.5 (d), 126.7 (d), 127.3 (d), 127.4 (d), 127.6 (d), 128.5 (d), 128.6
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (4:1)] on deactivated silica gel (Et3N 2%) gave a
(d), 128.6 (d), 132.0 (t, 2JCF = 24.7 Hz), 132.2 (s), 133.9 (s), 143.0 (s),
2
151.0 (t, JCF = 27.5 Hz), 165.9 (s); 19F NMR (282 MHz, CDCl3)
d
yellow solid (80% yield): mp 67–68 8C. 1H NMR (300 MHz, CDCl3)
d
ꢁ97.78 (d, J = 258.8 Hz, 1F), ꢁ98.80 (d, J = 256.7 Hz, 1F); HRMS
3.86 (t, J = 9.2 Hz, 2H), 4.05 (t, J = 9.9 Hz, 2H), 4.72 (s, 1H), 6.46 (br s,
2H), 7.41–7.46 (m, 3H), 7.76–8.04 (m,4H); 13C NMR (75.5 MHz,
calcd for C22H18F2N2O 364.1387, found 364.1387.
3
CDCl3)
d
54.2 (t), 65.6 (t), 83.3 (t, JCF = 6.1 Hz), 119.2 (t,
4.2.8. (Z)-[1-Difluoro(1-naphthyl)methyl]-2-[(4R)-4-phenyl-(4,5-
dihydro-1,3-oxazol-2-yl)-1-ethenylamine (9g)
1JCF = 243.7 Hz), 124.2 (d), 124.8 (d), 125.5 (t, JCF = 8.6 Hz),
3
2
126.1 (d), 127.0 (d), 128.6 (d), 129.4 (t, JCF = 24.7 Hz), 129.7 (s),
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (4:1)] on deactivated silica gel (Et3N 2%) gave an
131.7 (d), 133.8 (s), 150.4 (t, JCF = 27.5 Hz), 165.6 (s); 19F NMR
2
(282 MHz, CDCl3)
288.1074, found 288.1073.
d
ꢁ94.19 (s, 2F). HRMS calcd for C16H14F2N2O
orange oil (65% yield). ½a D25
ꢃ
ꢁ 106:0 (c 1.05, CHCl3). 1H NMR
(300 MHz, CDCl3) d 3.85 (t, J = 8.2 Hz, 2H), 4.42 (dd, J = 9.8 Hz,
J = 8.5 Hz, 2H), 4.78 (s, 1H), 5.20 (t, J = 9.0 Hz, 2H), 6.60 (br s, 2H),
7.17–7.46 (m, 8H), 7.78–8.09 (m, 4H); 13C NMR (75.5 MHz, CDCl3)
4.2.4. (Z)-1-Difluoro(phenyl)methyl-2-(4,5-dihydro-1,3-oxazol-2-
yl)-1-ethenylamine (9c)
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (4:1)] on deactivated silica gel (Et3N 2%) gave a
yellowish solid (70% yield): mp 33–5 8C. 1H NMR (300 MHz, CDCl3)
d
3
1
69.5 (d), 73.0 (t), 82.7 (t, JCF = 6.0 Hz), 119.2 (t, JCF = 243.7 Hz),
3
124.2 (d), 124.9 (d), 125.5 (t, JCF = 8.2 Hz), 126.1 (d), 126.5 (d),
2
127.0 (d), 127.3 (d), 128.5 (d), 128.6 (d), 129.4 (t, JCF = 24.7 Hz),
2
129.8 (s), 131.8 (d), 133.9 (s), 143.0 (s), 151.0 (t, JCF = 27.5 Hz),
d
3.83 (t, J = 9.3 Hz, 2H), 4.04 (t, J = 9.4 Hz, 2H), 4.79 (s, 1H), 6.32 (br
165.9 (s); 19F NMR (282 MHz, CDCl3)
d
ꢁ93.38 (d, J = 268.7 Hz, 1F),
s, 2H), 7.31–7.48 (m, 5H); 13C NMR (75.5 MHz, CDCl3)
d
54.2 (t),
ꢁ94.35 (d, J = 268.6 Hz, 1F); HRMS calcd for
C22H18F2N2O
3
1
65.7 (t), 82.6 (t, JCF = 5.7 Hz), 118.0 (t, JCF = 244.3 Hz), 125.4 (d),
128.4 (d), 130.4 (d), 134.6 (t, JCF = 27.0 Hz), 150.3 (t,
2JCF = 28.7 Hz), 165.5 (s); 19F NMR (282 MHz, CDCl3)
364.1387, found 364.1374.
2
d
ꢁ98.85 (s,
4.2.9. (Z)-1-(2,4-Difluorophenyl)-2-(4,5-dihydro-1,3-oxazol-2-yl)-1-
ethenylamine (9h)
2F). HRMS calcd for C12H12F2N2O. 238.0917, found 238.0936.
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (4:1)] on deactivated silica gel (Et3N 2%) gave a
yellowish solid (70% yield): mp 83–85 8C. 1H NMR (300 MHz,
4.2.5. (Z)-2-(4,5-dihydro-1,3-oxazol-2-yl)-1-
(1,1,2,2,3,3,4,4,7,7,8,8,7,7-pentadecafluoro heptyl)-1-ethenylamine
(9d)
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (4:1] on deactivated silica gel (Et3N 2%) gave a
yellow solid (60% yield): mp 64–6 8C. 1H NMR (300 MHz, CDCl3)
CDCl3)
d 3.92 (t, J = 9.3 Hz, 2H), 4.12 (t, J = 9.8 Hz, 2H), 4.75 (s, 1H),
6.55 (br s, 2H), 6.75–6.86 (m, 2H), 7.35–7.45 (m, 1H); 13C NMR
4
(75.5 MHz, CDCl3)
d
54.3 (t), 65.5 (t), 83.6 (d, JCF = 2.3 Hz), 104.6
d
(dd, 2JCF = 26.4 Hz, 2JCF = 26.4 Hz), 111.6 (d, 2JCF = 21.2 Hz), 121.9 (d,
3
3
3.91 (t, J = 9.3 Hz, 2H), 4.15 (t, J = 9.1 Hz, 2H), 5.01 (s, 1H), 6.38 (br s,
2JCF = 16.0 Hz), 130.4 (dd, JCF = 9.1 Hz, JCF = 9.1 Hz), 149.9 (s),
2H); 13C NMR (75.5 MHz, CDCl3)
d 54.3 (t), 66.0 (t), 85.3 (t,
159.7 (dd, 1JCF = 252.9 Hz, 3JCF = 12.0 Hz), 163.2 (dd, 1JCF = 252.9 Hz,
3JCF = 7.2 Hz), 108–119 (signals from the group C7F15 were
3JCF = 12.0 Hz), 166.3 (s); 19F NMR (282 MHz, CDCl3)
d
ꢁ108.58 (m,
2
obscured because of their low intensity), 142.3 (t, JCF = 25.0 Hz),
1F), ꢁ111.19 (m, 1F). HRMS calcd for C11H10F2N2O 224.0761, found
165.0 (s); 19F NMR (282 MHz, CDCl3)
ꢁ122.1 (s, 2F), ꢁ122.5 (s, 2F), ꢁ123.0 (s, 2F), ꢁ123.2 (s, 2F), ꢁ126.6
(s, 2F).CI HRMS calcd for C12H8F15N2O (M++1) 481.0397, found
481.0406.
d
ꢁ81.3 (s, 3F), ꢁ118.5 (s, 2F),
224.0754.
4.2.10. (Z)-2-(4,5-Dihydro-1,3-oxazol-2-yl)-1-(4-
trifluoromethylphenyl)-1-ethenylamine (9i)
Recrystallization of the crude reaction product from n-hexane-
4.2.6. (Z)-[1-Difluoro(2-naphthyl)methyl]-2-(4,5-dihydro-1,3-
oxazol-2-yl)-1-propenylamine (9e)
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (4:1)] on deactivated silica gel (Et3N 2%) gave a
EtOH (9:1) gave a yellowish solid (93% yield): mp 119–121 8C. 1
H
NMR (300 MHz, CDCl3)
2H), 4.90 (s, 1H), 6.55 (br s, 2H), 7.59 (s, 4H); 13C NMR (75.5 MHz,
CDCl3)
54.3 (t), 65.7 (t), 82.8 (d), 124.3 (q, 1JCF = 290.0 Hz), 125.7
d 3.94 (t, J = 9.0 Hz, 2H), 4.15 (t, J = 9.0 Hz,
d

842
S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 836–847
(d), 131.2 (d), 132.6 (q, 2JCF = 33.0 Hz), 141.4 (s), 153.9 (s), 166.5 (s);
19F NMR (282 MHz, CDCl3)
ꢁ63.29 (s, 3F). HRMS calcd for
12H11F3N2O 256.0823, found 256.0782.
4.2.16. (Z)-2-(4,5-Dihydro-1,3-oxazol-2-yl)-1-(2-thiophenyl)-1-
ethenylamine (9o)
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (4:1)] on deactivated silica gel (Et3N 2%) gave a
yellow solid (80% yield): mp 89–91 8C. 1H NMR (250 MHz, CDCl3)
d
d
C
4.2.11. (Z)-2-(4,5-Dihydro-1,3-oxazol-2-yl)-1-(4-fluorophenyl)-1-
ethenylamine (9j)
Recrystallization of the crude reaction mixture from n-hexane-
EtOH (9:1) gave a yellow solid (70% yield): mp 89–90 8C. 1H NMR
3.87 (t, J = 6.8 Hz, 2H), 4.08 (t, J = 6.7 Hz, 2H), 4.98 (s, 1H), 6.96 (m,
1H), 7.19 (m, 2H); 13C NMR (62.8 MHz, CDCl3)
54.6 (t), 65.8 (t),
d
81.8 (d), 125.0 (d), 126.5 (d), 127.8 (d), 141.0 (s), 148.8 (s), 166.6 (s).
HRMS calcd for C9H10N2SO 194.0513, found 193.9971.
(300 MHz, CDCl3)
d 3.92 (t, J = 9.2 Hz, 2H), 4.13 (t, J = 9.1 Hz, 2H),
4.81 (s, 1H), 6.44–6.56 (br s, 2H), 6.89–7.04 (m, 2H), 7.44–7.46 (m,
2H); 13C NMR (75.5 MHz, CDCl3)
(d, JCF = 21.6 Hz), 127.8 (d), 134.1 (s), 154.6 (s), 163.4 (d,
1JCF = 249.3 Hz), 166.6 (s); 19F NMR (282 MHz, CDCl3)
d
54.3 (t), 65.5 (t), 81.5 (d), 115.6
4.3. Preparation of compounds 14 and 15
2
d
ꢁ111.70
4.3.1. General procedure
(m, 1F). HRMS calcd for C11H10FN2O 205.0777, found 205.0777.
To a solution of triphosgene (1.0 mmol) in toluene (1 mL) and
THF (5 mL), a solution of compound 9 (1.0 mmol) in THF (5 mL)
was slowly added, followed by triethylamine (2.0 mmol). The
mixture was stirred at room temperature. When TLC showed that
the reaction was complete (between 3 and 7 h) it was quenched
with 5 M aq. KOH soln. at 0 8C and extracted with CH2Cl2
(3 ꢂ 25 mL). The organic layers were pooled together, dried on
anh. MgSO4, and the solvent removed under vacuum. The resulting
crude reaction mixture consisted of a mixture of compounds 14
and 15, which was purified and separated as indicated in each case.
4.2.12. (Z)-1-(4-Fluorophenyl)-2[(4R)-4-phenyl-4,5-dihydro-1,3-
oxazol-2-yl-(4-fluoromethylphenyl)-1-ethenylamine (9k)
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (4:1)] on deactivated silica gel (Et3N 2%) gave a
yellow solid (72% yield): mp 106–8 8C. ½a D25
ꢁ 205:3 (c 1.00, CHCl3).
ꢃ
1H NMR (300 MHz, CDCl3)
d 3.92 (t, J = 8.2 Hz, 2H), 4.48 (dd,
J = 9.8 Hz, J = 8.1 Hz, 2H), 4.86 (s, 1H), 5.25 (dd, J = 9.8 Hz, J = 8.0 Hz,
2H), 6.45–6.66 (br s, 2H), 6.99–7.05 (m, 2H), 7.18–7.33 (m, 5H),
7.46–7.51 (m, 2H); 13C NMR (75.5 MHz, CDCl3)
d 69.6 (d), 72.9 (t),
2
81.0 (d), 115.7 (d, JCF = 21.3 Hz), 126.6 (d), 127.3 (d), 127.9 (d,
4.3.2. 7-Difluoro(2-naphthyl)methyl-2,3-dihydro-5H-
3JCF = 8.0 Hz), 128.6 (d), 134.1 (d, 4JCF = 3.4 Hz), 143.6 (s), 155.2 (d),
[1,3]oxazolo[3,2-c]pyrimidin-5-one (14a)
1
163.5 (d, JCF = 249.4 Hz), 166.9 (s); 19F NMR (282 MHz, CDCl3)
d
The crude yield of the mixture 14a + 15a was 80%. Flash
chromatography [n-hexane:EtOAc (1:1)] on deactivated silica gel
(Et3N 2%) gave 14a as a yellow solid (20% isolated yield): mp 149–
ꢁ111.70 (m, 1F). HRMS calcd for C17H15FN2O 282.1168, found
282.1127.
150 8C. 1H NMR (300 MHz, CDCl3)
d 4.20 (t, J = 8.9 Hz, 2H), 4.75 (t,
4.2.13. (Z)-2-(4,5-Dihydro-1,3-oxazol-2-yl)-1-(4-methylphenyl)-1-
ethenylamine (9l)
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (4:1)] on deactivated silica gel (Et3N 2%) gave a
yellow solid (81% yield): mp 85–87 8C. 1H NMR (250 MHz, CDCl3)
J = 8.7 Hz, 2H), 6.24 (s, 1H), 7.44–7.63 (m, 3H), 7.78–7.83 (m, 3H),
8.08 (s, 1H); 13C NMR (75.5 MHz, CDCl3)
d
43.7 (t), 69.6 (t), 81.9 (d),
1
3
117.1 (t, JCF = 245.5 Hz), 122.3 (t, JCF = 5.1 Hz), 125.7 (t,
3JCF = 6.9 Hz), 126.6 (d), 127.3 (d), 127.6 (d), 128.4 (d), 128.6 (d),
131.9 (t, JCF = 27.0 Hz), 132.3 (s), 133.9 (s), 154.1 (s), 165.9 (s),
172.3 (t, JCF = 30.7 Hz); 19F NMR (282 MHz, CDCl3)
2
d
2
2.37 (s, 3H), 4.00 (t, J = 6.7 Hz, 2H), 4.22 (t, J = 6.7 Hz, 2H), 4.95 (s,
1H), 7.20 (d, J = 6.3, 2H), 7.49 (d, J = 6.3, 2H); 13C NMR (62.8 MHz,
d
ꢁ100.68 (s,
2F). HRMS calcd for C17H12F2N2O2 314.0866, found 314.0863.
CDCl3)
d 54.2 (q), 55.1 (t), 65.3 (t), 80.2 (d), 113.8 (d), 127.1 (d),
130.1 (s), 155.2 (s), 160.5 (s), 166.7 (s). MS (m/z): 202 (M+), 201
(100%); Elemental analysis calcd for C12H14N2O: C, 71.26; H, 6.93;
N, 13.86. Found: C, 71.25; H, 6.96; N, 13.90.
4.3.3. 7-Difluoro(2-naphthyl)methyl-2,3-dihydro-5H-
[1,3]oxazolo[3,2-a]pyrimidin-5-one (15a)
Flash chromatography [n-hexane:EtOAc (1:1)] of the mixture of
14a + 15a on silica gel gave 15a as a yellow solid (50% isolated
4.2.14. (Z)-2-(4,5-Dihydro-1,3-oxazol-2-yl)-1-phenyl-1-
ethenylamine (9m)
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (4:1)] on deactivated silica gel (Et3N 2%) gave a
yellow solid (78% yield): mp 56–58; 1H NMR (250 MHz, CDCl3)
yield): mp 182–4 8C. 1H NMR (300 MHz, CDCl3)
d
4.18 (t, J = 8.7 Hz,
2H), 4.63 (t, J = 8.5 Hz, 2H), 6.52 (s, 1H), 7.44–7.55 (m, 3H), 7.77–
7.85 (m, 3H), 8.04 (s, 1H); 13C NMR (75.5 MHz, CDCl3)
42.1 (t),
d
3
1
66.4 (t), 104.7 (t, JCF = 4.9 Hz), 117.4 (t, JCF = 245.5 Hz), 122.3 (t,
3JCF = 5.1 Hz), 125.7 (t, 3JCF = 6.9 Hz), 126.7 (d), 127.3 (d), 127.6 (d),
d
2
3.97 (t, J = 6.7 Hz, 2H), 4.16 (t, J = 6.7 Hz, 2H), 4.94 (s, 1H), 6.50
(NH2, 2H), 7.36–7.52 (m, 5H); 13C NMR (62.8 MHz, CDCl3)
54.2 (t),
128.4 (d), 128.6 (d), 131.9 (t, JCF = 27.0 Hz), 132.2 (s), 133.9 (s),
2
d
160.2 (s), 160.7 (s), 161.3 (t, JCF = 31.6 Hz); 19F NMR (282 MHz,
65.4 (t), 81.2 (d), 128.6 (d), 128.9 (d), 129.4 (d), 137.9 (s), 155.5 (s),
164.0 (s). MS (m/z): 188 (M+), 187 (100%); Elemental analysis calcd
for C11H12N2O: C, 70.21; H, 6.66; N, 14.89. Found: C, 70.18; H, 6.70;
N, 14.92.
CDCl3)
found 314.0863.
d
ꢁ100.87 (s, 2F). HRMS calcd for C17H12F2N2O2 314.0866,
4.3.4. 7-Difluoro(1-naphthyl)methyl-2,3-dihydro-5H-
[1,3]oxazolo[3,2-a]pyrimidin-5-one (15b)
4.2.15. (Z)-2-(4,5-Dihydro-1,3-oxazol-2-yl)-1-(4-methoxyphenyl)-
1-ethenylamine (9n)
Flash chromatography of the crude reaction product [n-
hexane:EtOAc (4:1)] on deactivated silica gel (Et3N 2%) gave a
yellow solid (85% yield): mp 66–68 8C. 1H NMR (250 MHz, CDCl3)
Flash chromatography [n-hexane:EtOAc (1:1)] on silica gel of
the crude reaction mixture 14b + 15b gave 10b as a colorless oil
(70% isolated yield). Compound 14b could not be isolated. 1H NMR
(300 MHz, CDCl3)
d 4.16 (t, J = 8.7 Hz, 2H), 4.59 (t, J = 8.5 Hz, 2H),
d
6.52 (s, 1H), 7.39–7.48 (m, 3H), 4.78–8.00 (m, 4H); 13C NMR
3.82 (s, 3H), 3.98 (t, J = 6.8 Hz, 2H), 4.19 (t, J = 6.7 Hz, 2H), 4.90 (s,
1H), 6.91 (d, J = 6.3, 2H), 7.49 (d, J = 6.3, 2H); 13C NMR (62.8 MHz,
(75.5 MHz, CDCl3) d 42.1 (t), 66.3 (t), 105.6 (d), 118.4 (t,
3
1JCF = 245.5 Hz), 124.4 (d), 124.5 (d), 125.6 (t, JCF = 9.1 Hz),
2
CDCl3)
d
54.2 (q), 55.1 (t), 65.3 (t), 80.2 (d), 113.8 (d), 127.1 (d),
125.9 (d), 126.8 (d), 128.8 (d), 129.1 (s), 129.6 (t, JCF = 24.1 Hz),
130.1 (s), 155.2 (s), 160.5 (s), 166.7 (s). MS (m/z): 218 (M+), 217
(100%); Elemental analysis calcd for C12H14N2O2: C, 66.05; H, 6.42;
N, 12.84. Found: C, 66.07; H, 6.44; N, 12.85.
131.5 (d), 133.8 (s), 160.1 (s), 160.7 (s), 161.4 (t, 2JCF = 30.4 Hz); 19
F
NMR (282 MHz, CDCl3)
d
ꢁ95.65 (s, 2F). HRMS calcd for
C17H12F2N2O2 314.0866, found 314.0863.

S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 836–847
843
4.3.5. 7-Difluoro(1-phenyl)methyl-2,3-dihydro-5H-[1,3]oxazolo[3,2-
a]pyrimidin-5-one (15c)
a white solid (28%): mp 172–4 8C. 1H NMR (300 MHz, CDCl3)
d
4.31
(t, J = 8.8 Hz, 2H), 4.80 (t, J = 8.7 Hz, 2H), 6.41 (s, 1H), 6.77–6.94 (m,
2H), 8.16–8.24 (m, 1H); 13C NMR (75.5 MHz, CDCl3)
43.7 (t), 69.2
Flash chromatography [n-hexane:EtOAc (1:1)] on silica gel of
the crude reaction mixture 14c + 15c gave compound 15c as a
colorless oil in 60% isolated yield. Compound 14c could not be
d
2
2
(t), 85.7 (d), 104.4 (dd, JCF = 27.0 Hz, JCF = 25.3 Hz), 112.0 (dd,
2JCF = 21.3 Hz, JCF = 3.4 Hz), 121.1 (d, JCF = 13.8 Hz), 133.1 (d,
4
2
isolated. 1H NMR (300 MHz, CDCl3)
d 4.22 (t, J = 8.6 Hz, 2H), 4.68 (t,
3JCF = 10.3 Hz), 154.4 (s), 161.3 (dd, 1JCF = 253.0 Hz, 3JCF = 12.7 Hz),
J = 8.6 Hz, 2H), 6.46 (s, 1H), 7.35–7.57 (m, 5H); 13C NMR (75.5 MHz,
165.1 (dd, JCF = 252.9 Hz, JCF = 12.7 Hz), 166.3 (s), 168.3 (s); 19F
1
3
3
CDCl3)
d
42.2 (t), 66.4 (t), 104.6 (t, JCF = 4.9 Hz), 117.2 (t,
NMR (282 MHz, CDCl3)
calcd for C12H8F2N2O2 250.0553, found 250.0554.
d
ꢁ105.18 (m, 1F), ꢁ109.15 (m, 1F). HRMS
1JCF = 245.1 Hz), 125.6 (t, JCF = 6.3 Hz), 128.4 (d), 129.3 (d),
134.6 (t, 2JCF = 20.0 Hz), 160.2 (s), 160.7 (s), 161.3 (t, 2JCF = 31.6 Hz);
3
19F NMR (282 MHz, CDCl3)
13H10F2N2O2 264.0710, found 264.0709.
d
ꢁ101.09 (s, 2F). HRMS calcd for
4.3.10. 7-(2,4-Difluorophenyl)-2,3-dihydro-5H-[1,3]oxazolo[3,2-
a]pyrimidin-5-one (15g)
C
Flash chromatography [n-hexane:EtOAc (1:1)] on silica gel of
the crude reaction mixture 14g + 15g (crude yield 95%) gave 15g as
a white solid (55% isolated yield): mp 142–4 8C. 1H NMR (300 MHz,
4.3.6. 7-(1,1,2,2,3,3,4,4,5,5,6,6,7,7,7-Pentadecafluoroheptyl)-2,3-
dihydro-5H-[1,3] oxazolo[3,2-a]- and [3,2-c]pyrimidin-5-one
(14d + 15d)
CDCl3)
d 4.28 (t, J = 8.6 Hz, 2H), 4.72 (t, J = 8.6 Hz, 2H), 6.59 (s,
Flash chromatography [n-hexane:EtOAc (1:1)] on silica gel gave
a mixture of 14d and 15d as a colorless oil (80% yield) in proportion
10:90 as deduced from the 19F NMR spectrum. This mixture could
1H),6.78–6.92 (m, 2H), 7.93–8.01 (m, 1H); 13C NMR (75.5 MHz,
2
2
CDCl3)
d 42.7 (t), 66.5 (t), 104.6 (dd, JCF = 27.0 Hz, JCF = 25.3 Hz),
3
2
4
107.5 (d, JCF = 13.7 Hz), 112.1 (dd, JCF = 20.7 Hz, JCF = 3.4 Hz),
121.1 (d, 2JCF = 13.8 Hz), 132.3 (d, 3JCF = 9.7 Hz), 157.7 (s), 159.7 (s),
161.7 (dd, JCF = 253.0 Hz, JCF = 12.7 Hz), 162.6 (s), 164.4 (dd,
1JCF = 252.9 Hz, JCF = 12.7 Hz); 19F NMR (282 MHz, CDCl3)
d
not be separated. 14d: 1H NMR (300 MHz, CDCl3)
d
4.30 (t,
1
3
J = 8.6 Hz, 2H), 4.78 (t, J = 8.6 Hz, 2H), 6.44 (s, 1H); 19F NMR
3
(282 MHz, CDCl3)
d
ꢁ81.2 (s, 3F), ꢁ116.6 (s, 2F), ꢁ121.8 (s, 2F),
ꢁ122.0 (s, 2F), ꢁ122.4 (s, 2F), ꢁ123.2 (s, 2F), ꢁ126.5 (s, 2F). 15d: 1H
ꢁ106.80 (m, 1F), ꢁ108.25 (m, 1F). HRMS calcd for C12H8F2N2O2
NMR (300 MHz, CDCl3)
2H), 6.15 (s, 1H); 19F NMR (282 MHz, CDCl3)
d
4.34 (t, J = 8.9 Hz, 2H), 4.88 (t, J = 8.6 Hz,
250.0553, found 250.0551.
d
ꢁ81.1 (s, 3F), ꢁ116.4
(s, 2F), ꢁ121.7 (s, 2F), ꢁ121.8 (s, 2F), ꢁ122.3 (s, 2F), ꢁ123.1 (s, 2F),
4.3.11. 7-(4-Trifluoromethylphenyl)-2,3-dihydro-5H-
ꢁ126.5 (s, 2F). HRMS calcd for
C
13H5F15N2O2 (14d + 15d)
[1,3]oxazolo[3,2-c]pyrimidin-5-one (14h)
506.0111, found 506.0093.
Flash chromatography [n-hexane:EtOAc (1:1)] on silica gel of
the crude reaction mixture 14h + 15h (89% crude yield) gave 14h
as a white solid (59% isolated yield): mp 164–6 8C. 1H NMR
4.3.7. 7-Difluoro(2-naphthyl)methyl-6-methyl-2,3-dihydro-5H-
[1,3]oxazolo[3,2-a] pyrimidin-5-one (15e)
(300 MHz, CDCl3)
6.2 (s, 1H), 7.64 (d, J = 8.3 Hz, 2H), 8.0 (d, J = 8.1 Hz, 2H); 13C NMR
(75.5 MHz, CDCl3) 43.7 (t), 69.3 (t), 82.3 (d), 127.4 (q,
1JCF = 275.3 Hz), 125.6 (d), 128.1 (d), 133.1 (q, JCF = 32.7 Hz),
139.8 (s), 154.6 (s), 165.3 (s), 171.7 (s); 19F NMR (282 MHz, CDCl3)
d 4.32 (t, J = 8.8 Hz, 2H), 4.82 (t, J = 8.7 Hz, 2H),
Flash chromatography [n-hexane:EtOAc (1:1)] on silica gel of
the crude reaction mixture 14e + 15e gave compound 15e as a
yellow solid in 62% yield. Compound 14e could not be isolated. Mp
d
2
125–7 8C. 1H NMR (300 MHz, CDCl3)
d
2.08 (t, J = 3.1Hz, 3H), 4.22 (t,
d
J = 8.5 Hz, 2H), 4.66 (t, J = 8.5 Hz, 2H), 7.44–7.59 (m, 3H), 7.77–7.88
ꢁ63.32 (s, 3F). HRMS calcd for C13H9F3N2O2 263.0632, found
(m, 3H), 7.99 (s, 1H); 13C NMR (75.5 MHz, CDCl3)
d
10.5 (c), 42.7 (t),
263.0682.
66.3 (t), 116.1 (s), 118.8 (t, 1JCF = 245.6 Hz), 122.4 (t, 3JCF = 5.1 Hz),
Crystal data for 14h: C13H9F3N2O2, M = 282.22, monoclinic,
3
˚
125.3 (t, JCF = 6.3 Hz), 126.7 (d), 127.3 (d), 127.7 (d), 128.5 (d),
a = 17.0270(20), b = 8.1299(12), c = 8.7201(14) A,
b
= 101.934(6)8,
(Mo
7133 reflections measured, 2407 unique
2
3
˚
128.7 (d), 132.4 (s), 132.9 (t, JCF = 27.0 Hz), 133.9 (s), 154.7 (t,
V = 1181.0(3) A , T = 133(2) K, space group P21/c, Z = 4,
m
2JCF = 29.3 Hz), 156.9 (s), 162.2 (s); 19F NMR (282 MHz, CDCl3)
d
Ka
) = 0.140 mmꢁ1
,
ꢁ93.3 (s, 2F). HRMS calcd for C18H14F2N2O2 328.1023, found
(Rint = 0.039), direct primary solution and refinement on F2
(SHELXL-97, G.M. Sheldrick, University of Go¨ttingen, 1997), 209
parameters, the CF3 group is disordered over two sites, hydrogen
328.1011.
4.3.8. (3R)-7-Difluoro(2-naphthyl)methyl-3-phenyl-2,3-dihydro-5H-
[1,3]oxazolo[3,2-a] pyrimidin-5-one (15f)
atoms refined as riding, R1[I > 2
0:1061.
s
(I)] = 0.0383, wR2ðall dataÞ ¼
Flash chromatography [n-hexane:EtOAc (1:1)] on silica gel of
the crude reaction mixture 14f + 15f gave 15f as a yellowish solid
(78% yield). Compound 14f could not be isolated. Mp 160–2 8C.
4.3.12. 7-(4-Trifluoromethylphenyl)-2,3-dihydro-5H-
[1,3]oxazolo[3,2-a]pyrimidin-5-one (15h)
½
a 2D5
ꢃ
ꢁ 44:48 (c 1.03, CHCl3). 1H NMR (300 MHz, CDCl3)
d
4.50 (dd,
Flash chromatography [n-hexane:EtOAc (1:1)] on silica gel of
the crude reaction mixture 14h + 15h (89% crude yield) gave 15h
as a white solid (22% isolated yield): mp 262–4 8C. 1H NMR
J = 9.2 Hz, J = 4.3 Hz, 1H), 4.82 (t, J = 9.1 Hz, 1H), 5.53 (dd, J = 9.0 Hz,
J = 4.3 Hz, 1H), 6.46 (s, 1H), 7.16–7.29 (m, 5H), 7.45–7.60 (m, 3H),
7.73–7.83 (m, 3H), 8.06 (s, 1H); 13C NMR (75.5 MHz, CDCl3)
(d), 74.2 (t), 105.6 (d), 117.5 (t, JCF = 245.5 Hz), 122.4 (t,
3JCF = 5.4 Hz), 125.8 (t, JCF = 6.3 Hz), 126.3 (d), 126.7 (d), 127.3
d
58.3
(300 MHz, CDCl3)
d 4.30 (t, J = 8.6 Hz, 2H), 4.76 (t, J = 8.6 Hz, 2H),
1
6.51 (s, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H); 13C NMR
3
(75.5 MHz, CDCl3) d 42.3 (t), 66.3 (t), 103.9 (d), 124.6 (q,
(d), 127.3 (d), 127.6 (d), 128.4 (d), 128.7 (d), 129.3 (d), 131.9 (t,
2JCF = 27.1 Hz), 132.4 (s), 133.9 (s), 136.2 (s), 160.0 (s), 160.1 (s),
3JCF = 3.6 Hz), 126.3 (d), 159.7 (s), 161.3 (s), 161.7 (s), the rest of
the signals were obscured because of their low intensity; 19F NMR
2
161.2 (t, JCF = 31.9 Hz); 19F NMR (282 MHz, CDCl3)
d
ꢁ100.03 (d,
(282 MHz, CDCl3)
263.0632, found 263.0759.
d
ꢁ63.25 (s, 3F). HRMS calcd for C13H9F3N2O2
J = 250.5 Hz, 1F), ꢁ101.25 (d, J = 250.5 Hz, 1F). HRMS calcd for
C
23H16F2N2O2 390.1179, found 390.1186.
4.3.13. 7-(4-Fluorophenyl)-2,3-dihydro-5H-[1,3]oxazolo[3,2-
a]pyrimidin-5-one (15i)
Flash chromatography [n-hexane:EtOAc (1:1)] on silica gel of
the crude reaction mixture 14i + 15i (82% crude yield) gave 10i as a
white solid (50% isolated yield). Compound 14i could not be
4.3.9. 7-(2,4-Difluorophenyl)-2,3-dihydro-5H-[1,3]oxazolo[3,2-
c]pyrimidin-5-one (14g)
Flash chromatography [n-hexane:EtOAc (1:1)] on silica gel of
the crude reaction mixture 14g + 15g (crude yield 95%) gave 14g as

844
S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 836–847
isolated. Mp 91–3 8C. 1H NMR (300 MHz, CDCl3)
2H), 4.73 (t, J = 8.4 Hz, 2H), 6.41 (s, 1H), 7.02–7.09 (m, 3H), 7.83–
7.88 (m, 2H); 13C NMR (75.5 MHz, CDCl3)
42.6 (t), 66.6 (t), 102.7
(d), 116.1 (d, 2JCF = 21.8 Hz), 129.5 (d, 3JCF = 8.6 Hz), 132.0 (s), 159.9
(s), 161.9 (d, 4JCF = 3.4 Hz), 162.6 (s), 164.8 (d, 1JCF = 251.1 Hz); 19
NMR (282 MHz, CDCl3)
ꢁ110.09 (s, 1F). HRMS calcd for
12H9FN2O2 232.0648, found 232.0646.
d
4.28 (t, J = 8.4 Hz,
(SHELXL-97), 156 parameters, methyl hydrogen atoms refined
as rigid, others riding, R1[I > 2
0:1526.
s(I)] = 0.0512, wR2ðall dataÞ ¼
d
F
4.3.18. 7-Phenyl-2,3-dihydro-5H-[1,3]oxazolo[3,2-c]pyrimidin-5-
one (14l)
The crude yield of the mixture 14l + 15l was 80%. Flash
chromatography [EtOAc/MeOH (4:1)] on silica gel afforded 14l as a
white solid (40% isolated yield): mp 168–170 8C. 1H NMR
d
C
4.3.14. (3R)-7-(Fluorophenyl)-3-phenyl-2,3-dihydro-5H-
[1,3]oxazolo[3,2-c]pyrimidin-5-one (14j)
(300 MHz, CDCl3)
2H), 6.35 (s, 1H), 7.42–7.51 (m, 3H), 8.04 (m, 2H); 13C NMR
(75.5 MHz, CDCl3) 173.6 (s), 165.3 (s), 155.3 (s), 137.0 (s), 132.0
(d), 129.0 (d), 128.2 (d), 82.3 (d), 69.5 (t), 44.1 (t). HRMS calcd for
12H10N2O2 214.0742, found 214.0709.
d 4.36 (t, J = 8.6 Hz, 2H), 4.84 (t, J = 8.6 Hz,
Flash chromatography [n-hexane:EtOAc (9:1)] on silica gel of
the crude reaction mixture 14j + 15j (87% crude yield) gave 14j as a
d
yellow solid (20% isolated yield): mp 170–3 8C. ½a D25
ꢁ 224:1 (c
ꢃ
1.16, CHCl3). 1H NMR (300 MHz, CDCl3)
d
4.66 (dd, J = 9.0 Hz,
C
J = 3.7 Hz, 1H), 5.00 (t, J = 8.9 Hz, 1H), 5.68 (dd, J = 8.8 Hz, J = 3.7 Hz,
1H), 6.29 (s, 1H), 7.03–7.09 (m, 2H), 7.19–7.31 (m, 5H), 7.99–8.03
4.3.19. 7-Phenyl-2,3-dihydro-5H-[1,3]oxazolo[3,2-a]pyrimidin-5-
one (15l)
(m, 2H); 13C NMR (75.5 MHz, CDCl3)
d 59.3 (d), 77.3 (t), 81.3 (d),
2
115.6 (d, JCF = 21.8 Hz), 126.2 (d), 129.1 (d), 129.3 (d), 130.1 (d,
Flash chromatography of the crude mixture of 14l + 15l on silica
gel [EtOAc/MeOH (7:1)] afforded 15l as a white solid (40% isolated
3JCF = 8.6 Hz), 132.7 (d, 4JCF = 3.4 Hz), 136.7 (s), 153.8 (s), 164.9 (s),
165.0 (d, JCF = 252.4 Hz), 172.0 (s); 19F NMR (282 MHz, CDCl3)
d
yield): mp 163–165 8C. 1H NMR (300 MHz, CDCl3)
d
4.36 (t,
J = 8.8 Hz, 2H), 4.91 (t, J = 8.8 Hz, 2H), 6.51 (s, 1H), 7.49–7.52 (m,
3H), 8.04–8.07 (m, 2H); 13C NMR (75.5 MHz, CDCl3)
162.5 (s),
1
ꢁ108.55 (m, 1F). HRMS calcd for C18H13FN2O2 308.0961, found
308.0957.
d
161.3 (s), 160.8 (s), 137.1 (s), 130.7 (d), 128.9 (d), 127.2 (d), 102.2
(d), 67.1 (t), 42.7 (t). HRMS calcd for C12H10N2O2 214.0742, found
214.0742.
4.3.15. (3R)-7-(Fluorophenyl)-3-phenyl-2,3-dihydro-5H-
[1,3]oxazolo[3,2-a]pyrimidin-5-one (15j)
Flash chromatography [n-hexane:EtOAc (9:1)] on silica gel of
the crude reaction mixture 14j + 15j (87% crude yield) gave 15j as a
4.3.20. 7-(4-Methoxyphenyl)-2,3-dihydro-5H-[1,3]oxazolo[3,2-
c]pyrimidin-5-one (14m)
The crude yield of the mixture 14m + 15m was 78%. Flash
chromatography [EtOAc/MeOH (4:1)] on silica gel afforded 14m as
a yellow solid (50% isolated yield): mp 154–156 8C. 1H NMR
yellow solid (58% isolated yield): mp 165–7 8C. ½a D25
: ꢁ33:0 (c
ꢃ
1.02, CHCl3). 1H NMR (300 MHz, CDCl3)
d
4.56 (dd, J = 9.0 Hz,
J = 3.9 Hz, 1H), 4.92 (t, J = 9.0 Hz, 1H), 5.64 (dd, J = 8.8 Hz, J = 3.9 Hz,
1H), 6.36 (s, 1H), 7.00–7.07 (m, 2H), 7.24–7.40 (m, 5H), 7.83–7.88
(m, 2H); 13C NMR (75.5 MHz, CDCl3)
115.6 (d, JCF = 21.9 Hz), 126.1 (d), 129.0 (d), 129.2 (d), 129.3 (d,
3JCF = 9.8 Hz), 132.1 (s), 136.9 (s), 159.4 (s), 160.7 (s), 161.9 (s),
164.4 (d, 1JCF = 251.8 Hz); 19F NMR (282 MHz, CDCl3)
d
58.2 (d), 74.0 (t), 103.0 (d),
(300 MHz, CDCl3)
J = 8.7 Hz, 2H), 6.26 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 8.01 (d,
J = 8.8 Hz, 2H); 13C NMR (75.5 MHz, CDCl3)
171.3 (s), 163.7 (s),
d 3.84 (s, 3H), 4.31 (t, J = 8.7 Hz, 2H), 4.80 (t,
2
d
d
ꢁ110.05 (m,
161.6 (s), 154.0 (s), 128.7 (s), 127.9 (s), 112.9 (d), 80.1 (d), 68.1 (t),
54.4 (q), 42.6 (t). HRMS calcd for C13H12N2O3 244.0848, found
244.0844.
1F). HRMS calcd for C18H13FN2O2 308.0961, found 308.0960.
4.3.16. 7-(4-Methylphenyl)-2,3-dihydro-5H-[1,3]oxazolo[3,2-
c]pyrimidin-5-one (14k)
Flash chromatography [EtOAc:MeOH (7:3)] on silica gel of the
crude reaction mixture 14k + 15k (79% crude yield) gave 14k as a
white solid (20% isolated yield): mp 189–191 8C. 1H NMR
4.3.21. 7-(4-Methoxyphenyl)-2,3-dihydro-5H-[1,3]oxazolo[3,2-
a]pyrimidin-5-one (15m)
Flash chromatography of the crude mixture 14m + 15m [EtOAc/
MeOH (7:1)] on silica gel afforded 15m as a yellow solid (28%
isolated yield): mp 182–184 8C. 1H NMR (300 MHz, CDCl3)
d3.85 (s,
(300 MHz, CDCl3)
J = 8.5 Hz, 2H), 6.42 (s, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.74 (d,
J = 8.3 Hz, 2H); 13C NMR (75.5 MHz, CDCl3)
20.4 (q), 41.3 (t), 65.1
d
2.32 (s, 3H), 4.25 (t, J = 8.5 Hz, 2H), 4.69 (t,
3H), 4.33 (t, J = 8.7 Hz, 2H), 4.77 (t, J = 8.7 Hz, 2H), 6.45 (s, 1H), 6.93
(d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H); 13C NMR (75.5 MHz,
d
(t), 101.0 (d), 125.9 (d), 128.4 (d), 132.2 (d), 140.2 (s), 158.5 (s),
160.7 (s), 162.2 (s). HRMS calcd for C13H12N2O2 228.0899, found
228.0894.
CDCl3)
(s), 114.4 (d), 101.5 (d), 66.5 (t), 55.8 (q), 42.7 (t). HRMS calcd for
13H12N2O3 244.0848, found 244.0838.
d 163.3 (s), 162.24 (s), 162.16 (s), 159.8 (s), 129.1 (d), 128.8
C
4.3.17. 7-(4-Methylphenyl)-2,3-dihydro-5H-[1,3]oxazolo[3,2-
a]pyrimidin-5-one (15k)
4.3.22. 7-(2-Thiophenyl)-2,3-dihydro-5H-[1,3]oxazolo[3,2-
c]pyrimidin-5-one (14n)
Flash chromatography [EtOAc] on silica gel of the crude
reaction mixture 14k + 15k (79% crude yield) gave 15k as a
white solid (49% isolated yield): mp 209–211 8C. 1H NMR
The crude yield of the mixture 14n + 15n was 84%. Flash
chromatography [EtOAc/MeOH (4:1)] on silica gel afforded 14n as
a yellow solid (62% isolated yield, method A): mp 185–187 8C. 1
H
(300 MHz, CDCl3)
J = 6.8 Hz, 2H), 5.95 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H),
7.50 (d, J = 8.3 Hz, 2H); 13C NMR (75.5 MHz, CDCl3)
21.9 (q),
d
2.37 (s, 3H), 3.70 (t, J = 6.8 Hz, 2H), 4.26 (t,
NMR (300 MHz, CDCl3)
2H), 6.24 (s, 1H), 7.13 (dd, J = 5.1 Hz, J = 4.4 Hz, 1H), 7.56 (d,
J = 5.1 Hz, 1H), 7.71 (d, J = 3.4 Hz, 1H); 13C NMR (75.5 MHz, CDCl3)
d 4.33 (t, J = 8.7 Hz, 2H), 4.83 (t, J = 8.7 Hz,
d
d
40.4 (t), 41.9 (t), 98.3 (d), 126.6 (d), 128.5 (d), 130.5 (d), 143.0
(s), 151.0 (s), 153.5 (s), 163.5 (s). HRMS calcd for C13H12N2O2
228.0899, found 228.0889.
167.0 (s), 164.5 (s), 154.5 (s), 142.2 (s), 132.0 (d), 129.1 (d), 128.1
(d), 80.5 (d), 69.1 (t), 43.6 (t). HRMS calcd for C10H8N2O2S
220.0306, found 220.0271.
Crystal data for 15k: C13H12N2O2, M = 228.25, monoclinic,
˚
a = 7.0142(2), b = 13.3603(4), c = 11.3277(4) A,
b
= 90.982(4)8,
(Cu
5284 reflections measured, 1701 unique
(Rint = 0.043), direct primary solution and refinement on F2
4.3.23. 7-(2-Thiophenyl)-2,3-dihydro-5H-[1,3]oxazolo[3,2-
a]pyrimidin-5-one (15n)
Flash chromatography of the crude mixture 14n + 15n on silica
gel [EtOAc/MeOH (7:1)] afforded 15n as a yellow solid (22%
3
˚
V = 1061.38(6) A , T = 110(2) K, space group P21/c, Z = 4,
m
K
a
) = 0.098 mmꢁ1
,

S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 836–847
845
isolated yield): mp 189–193 8C. 1H NMR (300 MHz, CDCl3)
d
4.33 (t,
4.4.6. 3-(2-Chloroethyl)-6-phenyl-1,2,3,4-tetrahydro-2,4-
J = 8.7 Hz, 2H), 4.78 (t, J = 8.7 Hz, 2H), 6.42 (s, 1H), 7.11 (dd,
J = 5.1 Hz, J = 3.8 Hz, 1H), 7.48 (dd, J = 0.9 Hz, J = 4.9 Hz, 1H), 7.64
pyrimidindione (16c)
Flash chromatography on silica gel (EtOAc) afforded 16c as a
white solid in 85% yield. Mp 205–207 8C. 1H NMR (300 MHz, CDCl3)
(dd, J = 1.1 Hz, J = 3.8 Hz, 1H); 13C NMR (75.5 MHz, CDCl3)
d 165.7
(s), 159.4 (s), 157.8 (s), 141.2 (s), 129.8 (d), 128.3 (d), 127.6 (d),
100.2 (d), 66.2 (t), 42.3 (t). HRMS calcd for C10H8N2O2S 220.0306,
found 220.0303.
d
3.76 (t, J = 6.8 Hz, 2H), 4.32 (t, J = 6.8 Hz, 2H), 6.04 (d, J = 2.3, 1H),
7.54 (m, 3H), 7.68 (dd, J = 7.9, J = 1.5, 2H), 10.33 (s, 1H); 13C NMR
(75.5 MHz, CDCl3) 162.0 (s), 152.1 (s), 149.6 (s), 130.9 (d), 130.0
(s), 128.4 (d), 125.3 (d), 97.6 (d), 40.6 (t), 39.0 (t). HRMS calcd for
12H11N2O2Cl 250.0509, found 250.0498.
d
4.4. Preparation of compounds 16
C
4.4.1. Method A: Basic conditions
4.4.7. 3-(2-Chloroethyl)-6-(4-methoxyphenyl)-1,2,3,4-tetrahydro-
2,4-pyrimidindione (16d)
Flash chromatography on silica gel (EtOAc) afforded 16d as a
white solid in 83% yield. Mp 190–193 8C. 1H NMR (300 MHz,
To a solution of compounds 14 and/or 15 (1.5 mmol) in THF
(10 mL), a solution of ROꢁ/ROH (7.5 mmol) diluted in THF (10 mL)
was added and then the reaction mixture was refluxed for 5–7 h,
until TLC showed completion. The reaction was quenched with
satd. aq. NH4Cl soln. and extracted with CH2Cl2 (3 ꢂ 25 mL). The
organic layers were pooled together, dried over anh. Na2SO4, and
the solvent removed under vacuum to afford crude 16, which was
then purified as shown below.
DMSO)
5.98 (s, 1H), 7.02 (d, J = 8.8, 2H), 7.62 (d, J = 8.8, 2H), 9.90 (s, 1H); 13
NMR (75.5 MHz, DMSO) 163.5 (s), 162.9 (s), 153.2 (s), 150.6 (s),
d 3.77 (t, J = 6.8 Hz, 2H), 3.88 (s, 3H), 4.33 (t, J = 6.8 Hz, 2H),
C
d
128.2 (d), 123.4 (s), 115.2 (d), 97.6 (d), 55.9 (q), 41.9 (t), 40.4 (t).
HRMS calcd for C13H13N2O3Cl 280.0615, found 280.0609.
4.4.2. Method B: Acidic conditions
4.4.8. 3-(2-Chloroethyl)-6-(4-methylphenyl)-1,2,3,4-tetrahydro-2,4-
pyrimidindione (16e)
Flash chromatography on silica gel (EtOAc) afforded 16e as a
white solid in 87% yield. Mp 202–205 8C. 1H NMR (300 MHz, CDCl3)
To a solution of compounds 14 and/or 15 (1.5 mmol) in THF
(10 mL), was added 4N HCl (1.2 eq.) in 1,4-dioxane; the reaction
was stirred at room temperature for 0.5–2 h, until TLC showed that
it was complete. The reaction was quenched with satd. aq. NH4Cl
soln. and extracted with CH2Cl2 (3 ꢂ 25 mL). The organic layers
were pooled together, dried over anh. Na2SO4, and the solvent
removed under vacuum to afford crude 16, which was then
purified as shown below.
d
2.44 (s, 3H), 3.77 (t, J = 6.8 Hz, 2H), 4.33 (t, J = 6.8 Hz, 2H), 6.00 (d,
J = 2.1, 1H), 7.32 (d, J = 8.2, 2H), 7.53 (d, J = 8.2, 2H), 9.51 (s, 1H); 13
NMR (75.5 MHz, CDCl3) 164.5 (s), 154.5 (s), 152.1 (s), 143.9 (s),
C
d
131.4 (d), 129.4 (s), 127.6 (d), 99.3 (d), 42.9 (t), 41.4 (t), 22.9 (q).
HRMS calcd for C13H13N2O2Cl 264.0666, found 264.0655.
4.4.3. Directly from compounds 9
4.4.9. 6-[Difluoro(1-naphthyl)methyl]-3-(2-methoxyethyl)-1,2,3,4-
tetrahydro-2,4-pyrimidindione (16f)
To a solution of triphosgene (1.0 mmol) in toluene (1 mL) and
THF (5 mL), a solution of compound 9 (1.0 mmol) in THF (5 mL)
was slowly added, followed by triethylamine (2.0 mmol). The
mixture was stirred at room temperature. When TLC showed
that the reaction was complete (between 3 and 7 h) it was
quenched with 1 M aq. HCl soln. at 0 8C and extracted with
CH2Cl2 (3 ꢂ 25 mL). The organic layers were pooled together,
dried on anh. MgSO4, and the solvent removed under vacuum.
The resulting crude reaction mixture consisted of crude
compound 16, which was purified and separated as indicated
in each case.
Recrystallization from n-hexane:EtOAc (9:1) gave a white solid
(80% yield): mp 131–3 8C. 1H NMR (300 MHz, CDCl3)
d
3.25 (s, 3H),
3.52 (t, J = 5.7 Hz, 2H), 4.04 (t, J = 5.6 Hz, 2H), 5.71 (s, 1H), 7.47–7.50
(m, 3H), 7.77–7.98 (m, 4H); 13C NMR (75.5 MHz, CDCl3)
39.7 (c),
d
3
1
58.6 (t), 68.8 (t), 101.6 (t, JCF = 4.6 Hz), 117.8 (t, JCF = 246.6 Hz),
3
124.0 (d), 124.3 (d), 125.9 (t, JCF = 8.9 Hz), 126.6 (d), 126.7 (t,
2JCF = 29.3 Hz), 127.7 (d), 129.1 (d), 129.2 (s), 132.9 (s), 134.0 (s),
2
146.1 (t, JCF = 31.6 Hz), 151.7 (s), 162.5 (s); 19F NMR (282 MHz,
CDCl3)
found 346.1124.
d
ꢁ94.79 (s, 2F). HRMS calcd for C18H16F2N2O3 346.1128,
4.4.4. 3-(2-Chloroethyl)-6-[difluoro(phenyl)methyl]-1,2,3,4-
tetrahydro-2,4-pyrimidindione (16a)
4.4.10. 3-(2-Chloroethyl)-6-[difluoro(2-naphthyl)methyl]-1,2,3,4-
tetrahydro-2,4-pyrimidindione (16g)
Recrystallization from n-hexane:EtOH (9:1) gave a yellowish
Recrystallization from n-hexane:EtOAc (10:1) gave a yellow
solid (96% yield): mp 167–9 8C. 1H NMR (300 MHz, CDCl3)
d
3.65 (t,
J = 6.7 Hz, 2H), 4.20 (t, J = 6.7 Hz, 2H), 5.80 (s, 1H), 7.44–7.50 (m,
5H), 8.81 (br s, 1H); 13C NMR (75.5 MHz, CDCl3)
40.0 (t), 42.1 (t),
solid (98% yield): mp 182–4 8C. 1H NMR (300 MHz, CDCl3)
d 3.63 (t,
J = 6.7 Hz, 2H), 4.17 (t, J = 6.8 Hz, 2H), 5.90 (s, 1H), 7.49–7.56 (m,
d
3H), 7.84–8.02 (m, 4H), 9.46 (br s, 1H); 13C NMR (75.5 MHz, CDCl3)
3
1
101.1 (t, JCF = 4.9 Hz), 117.4 (t, JCF = 247.5 Hz), 125.5 (t,
d
39.6 (t), 41.7 (t), 100.6 (t, 3JCF = 5.2 Hz), 116.3 (t, 1JCF = 247.7 Hz),
2JCF = 32.2 Hz), 125.9 (t, JCF = 5.7 Hz), 129.5 (d), 132.2 (d), 142.0
121.5 (t, JCF = 5.1 Hz), 126.0 (t, JCF = 6.9 Hz), 127.4 (d), 127.9 (d),
3
3
3
(t, 2JCF = 29.8 Hz), 151.5 (s), 162.5 (s); 19F NMR (282 MHz, CDCl3)
d
128.2 (d), 128.7 (d), 129.0 (t, JCF = 32.0 Hz), 129.3 (d), 132.2 (s),
134.3 (s), 146.6 (t, JCF = 33.3 Hz), 151.6 (s), 162.0 (s); 19F NMR
2
2
ꢁ100.06 (s, 2F). HRMS calcd for C13H11F2ClN2O2 300.0477, found
300.0464.
(282 MHz, CDCl3)
350.0633, found 350.0620.
d
ꢁ99.57 (s, 2F). HRMS calcd for C17H13F2ClN2O2
4.4.5. 3-(2-Chloroethyl)-6-(4-methylphenyl)-1,2,3,4-tetrahydro-2,4-
pyrimidindione (16b)
4.4.11. 3-(2-Hidroxyethyl)-6-(1,1,2,2,3,3,4,4,5,5,6,6,7,7,7-
Flash chromatography [n-hexane:EtOAc (1:1)] on silica gel
afforded 16b as a white solid (82% yield): mp 236–8 8C. 1H NMR
pentadecafluoroheptyl)-1,2,3,4-tetrahydro-2,4-pyrimidindione (16h)
Recrystallization from n-hexane:EtOAc (9:1) gave a white solid
(300 MHz, CDCl3)
J = 6.8 Hz, 1H), 5.95 (d, J = 2.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 7.50
(d, J = 8.3 Hz, 2H), 9.91 (br s, 1H); 13C NMR (75.5 MHz, CDCl3)
21,9
d
2.73 (s, 3H), 3.70 (t, J = 6.8 Hz, 2H), 4.26 (t,
(72% yield): mp 160–2 8C. 1H NMR (300 MHz, CD3OD)
d
3.64 (t,
J = 6.0 Hz, 2H), 3.97 (t, J = 5.9 Hz, 2H), 6.01 (s, 1H); 13C NMR
(75.5 MHz, CD3OD) 44.0 (t), 59.9 (t), 104.1 (d). The signals for the
C7F15 group were obscured because of their low intensity, 141.4 (s),
152.8 (s), 164.4 (s); 19F NMR (282 MHz, CD3OD)
ꢁ82.0 (s, 3F),
ꢁ118.36 (s, 2F), ꢁ122.80 (s, 2F), ꢁ123.39 (s, 2F), ꢁ123.40 (s, 2F),
d
d
(q), 40.4 (t), 41.9 (t), 98.3 (d), 126.6 (d), 128.4 (s), 130.5 (d), 142.9
(s), 151.0 (s), 153.5 (s), 163.5 (s). HRMS calcd for C13H13N2O2Cl
264.4421, found 264.4413.
d

846
S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 836–847
ꢁ124.15 (s, 2F), ꢁ127.74 (s, 2F). HRMS calcd for C13H5F15N2O2 (M-
(282 MHz, CDCl3)
314.0878, found 314.0867.
d
ꢁ63.47 (s, 3F). HRMS calcd for C14H13F3N2O3
H2O+) 506.0111, found 506.0087.
4.4.12. 3-(2-Chloroethyl)-6-[difluoro(2-naphthyl)methyl]-5-methyl-
1,2,3,4-tetrahydro-2,4-pyrimidindione (16i)
4.4.17. 3-(2-Hidroxyethyl)-6-(4-trifluoromethylphenyl)-1,2,3,4-
tetrahydro-2,4-pyrimidindione (16n)
Recrystallization from n-hexane:EtOAc (9:1) gave a yellowish
Recrystallization from n-hexane:EtOAc (9:1) gave a white solid
(72% yield): mp 207–9 8C. 1H NMR (300 MHz, CD3OD)
d 3.66 (t,
solid (95% yield): mp 135–7 8C. 1H NMR (300 MHz, CDCl3)
d
1.79 (t,
J = 2.2 Hz, 3H), 3.70 (t, J = 6.7 Hz, 2H), 4.27 (t, J = 6.6 Hz, 2H), 7.49–
J = 6.1 Hz, 2H), 4.01 (t, J = 6.1 Hz, 2H), 5.90 (s, 1H), 7.72 (d,
7.56 (m, 3H), 7.83–7.96 (m, 4H), 8.56 (br s, 1H); 13C NMR (75.5 MHz,
J = 8.6 Hz, 2H), 7.77 (d, J = 8.6 Hz, 2H); 13C NMR (75.5 MHz, CD3OD)
3
1
CDCl3)
d
10.6 (q), 39.8 (t), 42.2 (t), 109.7 (t, JCF = 2.3 Hz), 117.2 (t,
d
43.7 (t), 60.2 (t), 100.5 (d), 125.6 (q, JCF = 274.1 Hz), 127.5 (q,
1JCF = 246.0 Hz), 121.3 (t, 3JCF = 4.0 Hz), 125.7 (t, 3JCF = 6.3 Hz), 127.4
3JCF = 3.8 Hz), 129.2 (d), 134.2 (q, 2JCF = 32.6 Hz), 137.4 (s), 152.5 (s),
(d), 127.8 (d), 128.2 (d), 128.7 (d), 129.5 (d), 130.0 (t,
154.0 (s), 166.2 (s); 19F NMR (282 MHz, CD3OD)
d
ꢁ64.94 (s, 3F). CI
2
2JCF = 30.2 Hz),132.4 (s), 134.9 (s), 140.4 (t, JCF = 29.3 Hz), 150.1
HRMS calcd for C13H12F3N2O3 (M+ + H) 301.0800, found 301.0834.
(s), 163.8 (s); 19F NMR (282 MHz, CDCl3)
d
ꢁ92.23 (s, 2F).
4.4.18. 3-(2-Ethoxyethyl)-6-(4-fluorophenyl)-1,2,3,4-tetrahydro-
2,4-pyrimidindione (16o)
4.4.13. 3-[(1R)-2-Chloro-1-phenylethyl)-6-difluoro(1-
naphthyl)methyl-1,2,3,4-tetrahydro-2,4-pyrimidindione (16j)
Recrystallization from n-hexane:EtOAc (9:1) gave a yellowish
Recrystallization from n-hexane:EtOAc (9:1) gave a white solid
(78% yield): mp 168–170 8C. 1H NMR (300 MHz, CDCl3)
d 1.06 (t,
solid (92% yield): mp 180–2 8C. ½a D25
ꢃ
ꢁ 50:2 (c 1.00, CHCl3).1H NMR
J = 7.0 Hz, 3H), 3.44 (c, J = 7.0 Hz, 2H), 3.61 (t, J = 5.9 Hz, 2H), 4.11 (t,
J = 5.8 Hz, 2H), 5.91 (s, 1H), 7.09–7.19 (m, 2H), 7.60–7.63 (m, 2H);
(300 MHz, CDCl3)
d 4.00 (dd, J = 10.9 Hz, J = 5.6 Hz, 1 H), 4.61 (t,
J = 10.6 Hz, 1H), 5.61 (s, 1 H), 6.13 (dd, J = 10.2 Hz, J = 5.6 Hz, 1 H),
7.18–7.51 (m, 8 H), 7.63–8.01 (m, 4 H), 9.69 (br s, 1 H); 13C NMR
13C NMR (75.5 MHz, CDCl3)
(d), 116.4 (d, JCF = 22.4 Hz), 127.4 (d, JCF = 2.9 Hz), 128.6 (d,
3JCF = 8.6 Hz), 149.4 (s), 153.4 (s), 163.2 (s), 164.6 (d,
1JCF = 253.5 Hz); 19F NMR (282 MHz, CDCl3)
d
15.0 (q), 39.6 (t), 66.1 (t), 66.7 (t), 98.6
2
4
(75.5 MHz, CDCl3)
(t, JCF = 245.1 Hz), 124.2 (t, JCF = 3.2 Hz), 124.4 (d), 126.0 (t,
3JCF = 8.9 Hz), 126.7 (d), 126.8 (t, JCF = 23.6 Hz), 127.8 (d), 128.4
d
42.2 (t), 56.9 (d), 102.1 (t, 3JCF = 4.9 Hz), 117.6
1
3
d
ꢁ107.96 (m, 1F).
2
HRMS calcd for C14H15FN2O3 278.1066, found 278.1057.
(d), 128.5 (d), 128.5 (d), 129.1 (d), 129.3 (s), 132.9 (d), 134.0 (d),
2
135.6 (s), 146.3 (t, JCF = 31.0 Hz), 151.9 (s), 162.6 (s); 19F NMR
4.4.19. 3-[(1R)-2-Chloro-1-phenylethyl]-6-(4-fluorophenyl)-1,2,3,4-
tetrahydro-2,4-pyrimidindione (16p)
(282 MHz, CDCl3)
d
ꢁ94.13 (d, JFF = 4.1 Hz, 2F). HRMS calcd for
C23H17FClN2O2 426.0946, found 426.0922.
Recrystallization from n-hexane:EtOAc (9:1) gave a yellowish
solid (92% yield): mp 39–41 8C. ½a D25
ꢃ
þ 25:26 (c 0.95, CHCl3). 1H
4.4.14. 3-(2-Hidroxyethyl)-6-(2,4-difluorophenyl)-1,2,3,4-
tetrahydro-2,4-pyrimidindione (16k)
NMR (300 MHz, CDCl3) d 4.11 (dd, J = 10.9 Hz, J = 5.6 Hz, 1H), 4.69
(t, J = 10.6 Hz, 1H), 5.91 (s, 1H), 6.23 (m, 1H), 7.05–7.31 (m, 7H),
Recrystallization from n-hexane:EtOAc (9:1) gave a yellowish
7.57–7.60 (m, 2H), 10.86 (br s, 1H); 13C NMR (75.5 MHz, CDCl3)
d
solid (75% yield): mp 185–6 8C. 1H NMR (300 MHz, CD3OD)
d
3.66
(t, J = 6.2 Hz, 2H), 4.00 (t, J = 6.2 Hz, 2H), 5.73 (s, 1H), 7.02–7.11 (m,
2H), 7.51–7.57 (m, 1H); 13C NMR (75.5 MHz, CD3OD)
43.7 (t), 60.2
(t), 102.2 (d, 4JCF = 2.9 Hz), 106.3 (dd, 2JCF = 26.1 Hz, 2JCF = 26.1 Hz),
42.8 (t), 56.8 (d), 99.0 (d), 116.4 (d, JCF = 21.8 Hz), 127.2 (d,
4JCF = 2.9 Hz), 127.9 (d), 128.3 (d), 128.4 (d), 128.7 (d, 3JCF = 8.6 Hz),
2
1
d
136.3 (s), 149.8 (s), 153.5 (s), 163.3 (s), 164.6 (d, JCF = 253.5 Hz);
19F NMR (282 MHz, CDCl3)
C18H14FClN2O2 344.0727, found 344.0722.
d
ꢁ107.42 (m, 1F). HRMS calcd for
2
4
3
113.7 (dd, JCF = 22.4 Hz, JCF = 4.0 Hz), 132.9 (d, JCF = 13.2 Hz),
148.5 (s), 153.8 (s), 166.2 (s), the rest of the signals were obscured
because of their low intensity; 19F NMR (282 MHz, CD3OD)
ꢁ107.53 (m, 1F), ꢁ111.43 (m, 1F).
d
4.4.20. 2-[6-(4-Methylphenyl)-1,2,3,4-tetrahydro-3-
pyrimidinyl]ethyl acetate (16q)
Recrystallization from n-hexane:EtOAc (7:1) gave a white solid
(75% yield): mp 171–3 8C. 1H NMR (250 MHz, CDCl3)
d 1.98 (s, 3H),
2.42 (s, 3H), 4.22 (t, J = 4.6 Hz, 2H), 4.38 (t, J = 4.6 Hz, 2H), 6.13 (s,
1H), 7.25 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 10.21 (br s, 1H);
13C NMR (62.8 MHz, CDCl3)
d 20.8 (q), 21.5 (q), 39.4 (t), 61.3 (t),
4.4.15. 3-(2-Chloroethyl)-6-(2,4-difluorophenyl)-1,2,3,4-tetrahydro-
2,4-pyrimidindione (16l)
Recrystallization from n-hexane:EtOAc (9:1) gave a yellowish
solid (91% yield): mp 169–171 8C. 1H NMR (300 MHz, CDCl3)
d
3.67
(t, J = 6.7 Hz, 2H), 4.21 (t, J = 6.7 Hz, 2H), 5.95 (s, 1H), 6.90–7.05 (m,
98.0 (d), 126.1 (d), 126.1 (s), 130.1 (d), 142.5 (s), 150.4 (s), 153.2 (s),
163.4 (s), 171.0 (s). CI HRMS calcd for C15H17N2O4 (M+ + 1)
289.1189, found 289.1190.
2H), 7.50–7.56 (m, 1H), 10.07 (br s, 1H); 13C NMR (75.5 MHz,
4
CDCl3)
d
39.8 (t), 41.5 (t), 101.6 (d, JCF = 5.1 Hz), 105.4 (dd,
2
4
2JCF = 25.6 Hz), 112.6 (d, JCF = 21.8 Hz, JCF = 4.0 Hz), 115.6 (dd,
2JCF = 12.0 Hz, 4JCF = 4.0 Hz), 130.4 (dd, 3JCF = 10.3 Hz, 5JCF = 3.4 Hz),
145.1 (s), 152.7 (s), 160.2 (dd, 1JCF = 256.4, Hz, 3JCF = 12.6 Hz), 162.6
4.4.21. 3-(2-Hidroxyethyl)-6-(4-methylphenyl)-1,2,3,4-tetrahydro-
2,4-pyrimidindione (16r)
The compound was purified by flash chromatography [EtOAc/
MeOH (5:1)] on silica gel, which afforded 9a as a white solid in 79%
yield (method A). Mp 212–214 8C. 1H NMR (300 MHz, DMSO)
d
(s), 164.7 (dd, 1JCF = 256.4, Hz, JCF = 12.1 Hz); 19F NMR (282 MHz,
3
CDCl3)
d
ꢁ108.64 (m, 1F), ꢁ103.38 (m, 1F). HRMS calcd for
C
12H9F2ClN2O2 286.0321, found 286.0320.
2.40 (s, 3H), 3.56 (c, J = 6.2 Hz, 2H), 3.93 (t, J = 6.6 Hz, 2H), 4.82 (t,
OH), 5.96 (s, 1H), 7.34 (d, J = 8.1, 2H), 7.68 (d, J = 8.3, 2H) 11.34 (s,
4.4.16. 3-(2-Methoxyethyl)-6-(4-trifluoromethylphenyl)-1,2,3,4-
tetrahydro-2,4-pyrimidindione (16m)
1H); 13C NMR (75.5 MHz, DMSO)
d 163.9 (s), 152.8 (s), 151.6 (s),
Recrystallization from n-hexane:EtOAc (9:1) gave a white solid
(78% yield): mp 248–9 8C. 1H NMR (300 MHz, CDCl3)
d 3.24 (s, 3H),
142.1 (s), 130.4 (d), 129.4 (s), 127.7 (d), 97.8 (d), 58.5 (t), 42.5 (t),
21.8 (q). HRMS calcd for C13H14N2O3 246.1004, found 246.1012.
3.58 (t, J = 5.6 Hz, 2H), 4.13 (t, J = 5.6 Hz, 2H), 6.00 (s, 1H), 7.70 (d,
J = 8.5 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 10.65 (br s, 1H); 13C NMR
4.4.22. 3-(2-Methoxyethyl)-6-(4-methylphenyl)-1,2,3,4-tetrahydro-
2,4-pyrimidindione (16s)
The compound was purified by flash chromatography [EtOAc/
MeOH (5:1)] on silica gel and afforded 9a as a white solid in 70%
(75.5 MHz, CDCl3)
d 39.7 (t), 58.6 (c), 69.0 (t), 100.0 (d), 123.4 (q,
3
1JCF = 273.0 Hz), 126.2 (q, JCF = 3.8 Hz), 126.9 (d), 133.3 (q,
2JCF = 32.9 Hz), 134.6 (s), 148.9 (s), 153.3 (s), 162.9 (s); 19F NMR

S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 836–847
847
yield from 14k + 15k in basic medium (method A, see Scheme 6),
68% yield from 14k + 15k in acidic medium (method B, see Scheme
6), and 65% from 16b. The preparation of 16s from 16b was
performed as follows: to a solution of 16b (0.4 mmol) in THF
(3 mL), a solution of NaOH (2.8 mmol) in 3 mL of methanol diluted
in THF (1 mL) was added and then the reaction mixture was
refluxed for 5–7 h, until TLC showed completion. The reaction was
quenched with satd. aq. NH4Cl soln. and extracted with CH2Cl2
(3 ꢂ 25 mL). The organic layers were pooled together, dried over
anh. Na2SO4, and the solvent removed under vacuum to afford
crude 9, which was then purified as indicated above. Mp 204–
CDCl3)
d
ꢁ103.6 (d, J = 10.3 Hz, 1F), ꢁ108.9 (d, J = 10.3 Hz, 1F).
HRMS calcd for C21H26F2N4O4 436.1922, found 436.1909.
Acknowledgements
The authors wish to thank the IMPIVA and Industrias Afrasa
(IMIDTD/2007/230), the Ministerio de Educacion
´
y Ciencia
(CTQ2007-61462 and CTQ2006-01317), and the Generalitat
Valenciana of Spain (GR03/193) for financial support. We thank
Professor Peter G. Jones of the Institut fu¨r Anorganische und
Analytische Chemie, Technische Universita¨t Braunschweig, Ger-
many for the use of his X-ray diffraction facilities.
206 8C. 1H NMR (300 MHz, CDCl3)
J = 5.6 Hz, 2H), 4.20 (t, J = 5.6 Hz, 2H), 5.99 (s, 1H), 7.29 (d, J = 8.1,
2H), 7.55 (d, J = 8.1, 2H) 9.83 (s, 1H); 13C NMR (75.5 MHz, CDCl3)
d 2.42 (s, 3H), 3.35 (s, 3H), 3.66 (t,
d
163.5 (s), 153.0 (s), 150.1 (s), 142.2 (s), 130.0 (d), 128.4 (s), 126.1
(d), 98.2 (d), 69.2 (t), 58.6 (q), 39.5 (t), 21.4 (q). HRMS calcd for
Appendix A. Supplementary data
C14H16N2O3 260.1161, found 260.1174.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2008.04.004.
4.4.23. 3-(2-Fluoroethyl)-6-(4-methylphenyl)-1,2,3,4-tetrahydro-
2,4-pyrimidindione (16t)
The compound was purified by flash chromatography [EtOAc/
MeOH (4:1)] on silica gel and gave 9d as a white solid in 69% yield
from 14k + 15k in basic medium (method A, see Scheme 6), and
67% from 16b. The preparation of 16s from 16b was performed as
follows: to a solution of 16b (0.56 mmol) in THF (2 mL), a solution
of 1 M TBAF in THF (1.7 mmol, 3 equiv.) was added and then the
reaction mixture was refluxed for 3–4 h, until TLC showed
completion. The reaction was quenched with satd. aq. NH4Cl soln.
and extracted with CH2Cl2 (3 ꢂ 25 mL). The organic layers were
pooled together, dried over anh. Na2SO4, and the solvent removed
under vacuum to afford crude 9, which was then purified as
References
[1] C.K. Chu, D.C. Baker (Eds.), Nucleosides and Nucleotides as Antitumor and Anti-
viral Agents, Plenum Press, New York, 1993.
[2] S. Ozaki, Med. Res. Rev. 16 (1996) 51–86.
[3] (a) I. Ojima, J.R. McCarthy, J.T. Welch, Biomedical Frontiers of Fluorine Chemistry,
ACS. Symp. Series, vol. 639, American Chemical Society, Washington, DC, 1996;
(b) R. Filler, Y. Kobayashi, Biomedicinal Aspects of Fluorine Chemistry, Elsevier
Biomedical Press, New York and Kodansha Ltd., Tokyo, 1982;
(c) K.W. Pankiewicz, Carbohydr. Res. 327 (2000) 87–105.
[4] As examples, see:;
(a) Y. Tohyama, Y. Sanemitsu, Eur. Pat. Appl. EP 1,122,244 A1 (2001).;
(b) G. Theodoridis, S.D. Crawford, (FMC Corporation, USA) US 6,277,847 B1 (2001).;
(c) M.-W. Drewes, R. Andree, M. Dollinger, (Bayer A.-G., Germany) Ger. Offen. DE
19,632,005 A1 (1998).;
indicated above. Mp 160–163 8C. 1H NMR (300 MHz, CDCl3)
d 2.43
(d) T. Koiso, S. Ono, H. Kondo, T. Asada, (Dainippon Ink and Chemicals, Inc., Japan)
Jpn. Kokai Tokkyo Koho JP 09,241,245 (1997).;
(e) V. Kameswaran, (American Cyanamid Co. USA) US 6,191,275 B1 (2001).
(f) K. Yagi, K. Akimoto, N. Mimori, T. Miyake, M. Kudo, K. Arai, S. Ishii, Pest Manag.
Sci. 56 (2000) 65–73.
(s, 3H), 4.33 (dt, J1 = 23.3 Hz, J2 = 5.2 Hz, 2H), 4.69 (dt, J1 = 47.1 Hz,
J2 = 5.2 Hz, 2H), 6.01 (s, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.54 (d,
d 163.9 (s), 153.4 (s),
151.2 (s), 142.8 (s), 130.5 (d), 128.8 (s), 126.5 (d), 98.3 (d), 81.1 (t,
J = 8.3 Hz, 2H); 13C NMR (75.5 MHz, CDCl3)
´
´
[5] S. Fustero, J. Piera, J.F. Sanz-Cervera, S. Catalan, C. Ramırez de Arellano, Org. Lett. 6
JC-F = 170.2 Hz), 40.8 (t, JC-F = 22.4 Hz), 21.9 (q). HRMS calcd for
(2004) 1417–1420.
C13H13N2O2F 248.0961, found 248.0958.
[6] S. Fustero, S. Catalan, S. Flores, D. Jimenez, C. del Pozo, J.L. Acena, J.F. Sanz-Cervera,
´
´
˜
´
S. Merida, QSAR Comb. Sci. 25 (2006) 753–760.
[7] S. Fustero, S. Catala´n, J. Piera, J.F. Sanz-Cervera, B. Ferna´ndez, J.L. Acen˜a, J. Org.
Chem. 71 (2006) 4010–4013.
4.5. Preparation of compound 17
[8] Preliminary results were published as a communication; see: S. Fustero, E.
Salavert, J.F. Sanz-Cervera, J. Piera, A. Asensio, Chem. Commun. (2003) 844–845.
[9] K. Kamata, I. Agata, A.I. Meyers, J. Org. Chem. 63 (1998) 3113–3116.
[10] C.C. Kotoris, M.-J. Chen, S. Taylor, J. Org. Chem. 63 (1998) 8052–8057.
[11] W.J. Middleton, E.M. Bingham, J. Org. Chem. 45 (1980) 2883–2887.
[12] We obtained improved chemical yields (91% vs. 61%) when 2.2 equiv. of Deoxo-
fluor1 (dimethoxyethylaminotrifluorosulfurane) were used at room temperature
for 24 h instead of DAST. See: G.S. Lal, G.P. Pez, R.J. Pesaresi, F.M. Prozonic, H.
Cheng, J. Org. Chem. 64 (1999) 7048–7054.
4.5.1. tert-Butyl 4-{2-[6-(2,4-Difluorophenyl)-2,4-dioxo-1,2,3,4-
tetrahydro-2,4-pyrimidinyl] ethyl}-1-piperazinecarboxylate (17)
To a solution of tert-butyl 1-piperazinecarboxylate (1.0 mmol)
in 2.5 mL of a 10% aq. soln. of K2CO3 and 2.5 mL of 1,4-dioxane at
100 8C, a solution of 14g + 15g (1.0 mmol) in 1,4-dioxane (4 mL)
was slowly added. The reaction mixture was stirred at 100 8C for
24 h, cooled and the volatiles were removed under vacuum. The
residue was taken up in 25 mL ethyl acetate. The suspension was
dried over anh. Na2SO4, filtered, and the solvent removed under
vacuum to give crude product 17. Flash chromatography [n-
hexane:EtOAc (1:1)] on silica gel gave pure 17 as a yellow oil (80%
´
[13] S. Fustero, D. Dıaz, A. Asensio, A. Navarro, J.S. Kong, E. Aguilar, Tetrahedron 55
(1999) 2695–2712.
[14] For a review see: L. Cotarca, P. Delogu, A. Nardelli, V. Sunji, Synthesis, (1996) 553–
576.
[15] J. Barluenga, J.F. Lo´pez-Ortiz, V.J. Gotor, Chem. Soc., Perkin Trans. I (1983) 2273–
2276.
[16] A similar behavior has been observed in related systems. See for example: G.R.
Brown, J. Chem. Soc. Perkin Trans, 1 (1973) 2022–2024.
[17] R. Lis, T.K. Morgan, A.J. Marisca, R.P. Go´mez, J.M. Lind, D.D. Davey, G.B. Philips, M.E.
Sullivan, J. Med. Chem. 33 (1990) 2883–2891.
[18] C. Agami, L. Dechoux, L. Hamon, M. Melaimi, J. Org. Chem. 65 (2000) 6666–6669,
and references cited therein.
[19] J.L. Herndon, A. Ismaiel, P. Ingher, M. Teitler, R.A. Glennon, J. Med. Chem. 35 (1992)
4903–4910.
[20] It is noteworthy that compounds 16 in which Nu = Cl revert to a mixture 14 + 15
in proportions similar to those observed when they were obtained from 9 upon
treatment with a base (i.e. aq. K2CO3/dioxane).
yield). 1H NMR (300 MHz, CDCl3)
d 1.38 (s, 9H), 2.38 (t, J = 4.6 Hz,
4H), 2.54 (t, J = 6.8 Hz, 2H), 3.30 (t, J = 4.6 Hz, 4H), 3.98 (t, J = 6.8 Hz,
2H), 5.88 (s, 1H), 6.89–6.97 (m, 2H), 7.46–7.52 (m, 1H), 9.58 (br s,
1H); 13C NMR (75.5 MHz, CDCl3)
d
28.3 (c), 37.6 (t), 52.9 (t), 52.9 (t),
4
2
55.1 (t), 79.5 (s), 101.5 (d, JCF = 4.0 Hz), 105.4 (dd, JCF = 25.9 Hz,
2
4
2JCF = 25.9 Hz), 112.7 (dd, JCF = 21.8 Hz, JCF = 4.0 Hz), 115.9 (dd,
4
3
2JCF = 12.1 Hz, JCF = 4.0 Hz), 130.5 (dd, JCF = 10.2 Hz), 144.6 (s),
152.3 (s), 154.7 (s), 160.2 (dd, 1JCF = 257.0, Hz, 3JCF = 12.6 Hz), 162.9
1
3
(s), 164.6 (dd, JCF = 260.9, Hz, JCF = 12.0 Hz); 19F NMR (282 MHz,
[21] S. Noble, H. Langtry, H.M. Lamb, Drugs 55 (1998) 277–302.