A new strategy for the synthesis of fluorinated 3,4-dihydropyrimidinones

Article abstract of DOI:10.1016/j.jfluchem.2009.06.001

A new family of 3,4-dihydropyrimidinones (DHPMs) bearing fluorinated substituents at C6 have been prepared from gem-difluorinated nitriles, alkyl 3-butenoates and iso(thio)cyanates. This novel Biginelli-type process relies on the γ-addition of the ester-derived enolate to fluorinated nitriles. A tandem nucleophilic addition aza-Michael reaction sequence completes the synthetic process.

Full text of DOI:10.1016/j.jfluchem.2009.06.001

Journal of Fluorine Chemistry 130 (2009) 1145–1150
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
A new strategy for the synthesis of fluorinated 3,4-dihydropyrimidinones
a
b
a
Santos Fustero a,b, , Silvia Catalan , Jose Luis Acena , Carlos del Pozo
˜
*
´
´
a
´
Departamento de Quı´mica Organica, Universidad de Valencia, E-46100 Burjassot, Spain
b
´
´
´
Laboratorio de Mole´culas Organicas, Centro de Investigacion Prıncipe Felipe, E-46012 Valencia, Spain
A R T I C L E I N F O
A B S T R A C T
Article history:
A new family of 3,4-dihydropyrimidinones (DHPMs) bearing fluorinated substituents at C6 have been
Received 14 May 2009
Received in revised form 29 May 2009
Accepted 2 June 2009
prepared from gem-difluorinated nitriles, alkyl 3-butenoates and iso(thio)cyanates. This novel Biginelli-
type process relies on the
nucleophilic addition aza-Michael reaction sequence completes the synthetic process.
ß 2009 Elsevier B.V. All rights reserved.
g-addition of the ester-derived enolate to fluorinated nitriles. A tandem
Available online 7 June 2009
Keywords:
Fluorinated nitriles
Fluorinated dihydropyrimidinones
Multicomponent reactions
Intramolecular aza-Michael reaction
4-Aryl-3,4-dihydropyrimidin-2(1H)-ones
1
(DHPMs) were
as substituents in the aromatic ring on C4 or as a trifluoromethyl
reported for the first time more than a century ago. In 1893 the
Italian chemist Pietro Biginelli discovered an acid-catalyzed
multicomponent reaction between aromatic aldehydes, urea and
ethyl acetoacetate that produced multifunctionalized DHPMs 1 [1],
in a simple one-pot process (Scheme 1).
However, the real interest in DHPMs 1 arose several decades
later, having experienced a remarkable rebirth in the early 1980s
[2]. This was mainly due to their structural relationship with the
clinically important dihydropyridine calcium channel blockers (e.g.
nifedipine 2, Fig. 1), used in the treatment of high blood pressure
[3]. Additionally, the multicomponent approach is considered a
powerful tool for preparing biologically relevant compounds in an
efficient manner, the Biginelli reaction being an emblematic
example [4]. Many DHPMs have been synthesized using this
methodology and many of them have shown important pharma-
ceutical properties, including calcium channel modulation (3, 4)
[5,6], antiviral (e.g. nitractin 5) [7], antitumoral (e.g. monastrol 6)
group in C6. In this context, we have developed a new variant of the
Biginelli reaction that allows the preparation of a new family of C6-
fluoroalkyl substituted DHPMs 10. The synthetic strategy is
depicted below (Scheme 2).
In an ongoing project from our laboratory aiming at the
synthesis of fluorinated heterocycles [12], we found that the
reaction of ester enolates with fluorinated nitriles and subsequent
treatment with iso(thio)cyanates led to the formation of uracils.
The reaction took place efficiently, and it was adapted both to solid
phase [13] and fluorous synthesis [14]. As an extension of this
methodology, we planned to prepare bicyclic uracils. To this end,
the ester of choice was ethyl 3-butenoate 8, since it would allow us
to create the second ring unit by means of a ring closing metathesis
reaction over uracils 13 (RF = CF2allyl) (Scheme 2) [15]. The
ambident nature of the enolate of 8 explains the formation of two
products in its reaction with fluorinated nitriles 7, one coming
from the attack at the
the second one from the attack at the a
g
-position (thermodynamic product, 11) and
-position (kinetic product,
[8], anti-inflammatory [2,9] and
ism activities (Fig. 1) [5b–c,10].
a
1a-adrenergic receptor antagon-
12). While the reaction of 12 with iso(thio)cyanates 9 led to the
formation of uracils 13 [15], the same protocol applied to enamino
esters 11 would lead to the formation of DHPMs 10. Herein we
describe our efforts to direct the reaction of the lithium enolate of
ester 8 with fluorinated nitriles 7 towards the formation of
products 11, which in turn would react with heterocumulenes 9 to
render DHMPs 10 (Scheme 3).
Moreover, the introduction of fluorine atoms into organic
molecules usually promotes dramatic changes in their biological
properties [11]. Although fluorinated entities are important in
medicinal chemistry, their appearance in DHPMs is limited either
The first step of our study involved the search for suitable
conditions to obtain the thermodynamic regioisomers 11. When
nitrile 7a [16] was treated at À78 8C with the lithium enolate
derived from 8, a 50:50 mixture of regioisomeric enamino esters
´
´
* Corresponding author at: Departamento de Quımica Organica, Facultad de
Farmacia, Universidad de Valencia, Avda. Vicente Andre´s Estelle´s, s/n, 46100
Burjassot (Valencia), Spain. Tel.: +34 963544279; fax: +34 963544939.
E-mail address: santos.fustero@uv.es (S. Fustero).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.06.001

1146
S. Fustero et al. / Journal of Fluorine Chemistry 130 (2009) 1145–1150
Scheme 1. Biginelli synthesis of 3,4-dihydropyrimidin-2(1H)-ones 1 (DHPMs).
Scheme 2. Synthetic strategy.
11a and 12a was obtained (Table 1, entry 1) [15]. However, a very
slow addition of a THF solution of nitrile 7a over the enolate with a
syringe pump (2 mL/h) led to the selective formation of 11a
(Table 1, entry 3). When those conditions were applied to nitrile
7b, it was possible to obtain both regioisomers selectively: the fast
addition of nitrile 7b led to the exclusive formation of 12b, whereas
the slow addition led to the preferred formation of 11b (Table 1,
entries 2, 4). Although other parameters of the reaction were also
tested (temperature, solvent and reaction time), no significant
improvements were observed, indicating that the addition rate of
nitrile 7 was crucial in the process. It is worth mentioning that the
regioisomeric mixtures were separated by flash chromatography.
However, the final products were partially unstable under the
purification conditions, which explains the moderated isolated
yields obtained.
Enamino esters 11, isolated exclusively in their enamino
tautomeric form, were condensed with either isocyanates or
isothiocyanates 9 to furnish the corresponding DHPMs 10, through
a tandem nucleophilic addition-intramolecular aza-Michael reac-
tion sequence (Scheme 4). Hence, the treatment of compounds 11
with NaH in DMF at 0 8C, and further addition of different
iso(thio)cyanates gave DHPMs 10 in moderate isolated yields
(Table 2). Different substituents could be introduced at the N À 3
position (from different iso- or isothiocyanates), including
aliphatic (Table 2, entries 2, 4–8), aromatic (Table 2, entries 1, 3,
9), and chiral groups (Table 2, entries 6, 7). Although the reaction
with chiral isocyanates was not very selective, it was possible to
separate both diastereoisomers by flash chromatography, which
allowed us to access compounds 10f and 10g in enantiomerically
pure form [17]. It is also noteworthy that the reaction with
isothiocyanates was more efficient, giving rise to the final products
in good yields (Table 2, entries 2, 5).
In summary, we have prepared a small library of a new family
of fluorinated 3,4-dihydropyrimidinones starting from fluori-
nated nitriles, using a tandem nucleophilic addition-intramole-
cular aza-Michael sequence. The overall process constitutes a
variant of the Biginelli multicomponent reaction and allows for
the preparation of DHPMs bearing fluorinated substituents at C6
other than CF3.
1. Experimental
1.1. General experimental procedures
Reactions were carried out under nitrogen atmosphere unless
otherwise indicated. The solvents were purified prior to use:
CH2Cl2 was distilled from calcium hydride; hexanes, toluene and
THF from sodium. All reagents were used as received. The reactions
were monitored with the aid of thin-layer chromatography (TLC)
on 0.25 mm E. Merck precoated silica gel plates. Visualization was
carried out with UV light and aqueous ceric ammonium molybdate
solution or potassium permanganate stain. Flash column chro-
matography was performed with the indicated solvents on silica
gel 60 (particle size 0.040–0.063 mm). Optical rotations were
measured on a Jasco P-1020 polarimeter. 1H, 13C, and 19F NMR
spectra were recorded on a 300 MHz Bruker AC300 spectrometer
and 400 MHz Bruker Avance. Chemical shifts are given in ppm (d),
and are referenced to the residual proton resonances of the
solvents or to fluorotrichloromethane in the 19F NMR experiments.
Coupling constants (J) are given in Hertz (Hz). High-resolution
mass spectra were carried out by the Universidad de Valencia Mass
Spectrometry Service using
Micromass Instruments).
a VGmAutospec (VG Analytical,
Fig. 1. Medicinally relevant DHPMs.

S. Fustero et al. / Journal of Fluorine Chemistry 130 (2009) 1145–1150
1147
Scheme 3. Reaction pathways in the treatment of 8-derived enolate with fluorinated nitriles 7.
Table 1
Reaction conditions for the preparation of enamino esters 11 and 12.
.
Entry
7
RF
Reaction conditionsa
11:12 ratio
Yield (%)b
1
2
3
4
7a
7b
7a
7b
CF2CH2CH5CH2
CF2Ph
A
A
B
B
50:50
0:100
94:6
30 (12a)c
42 (12b)
40 (11a)
50 (11b)
CF2CH2CH5CH2
CF2Ph
95:5
a
Reaction conditions: (A) LDA/THF, À78 8C, fast addition of a solution of nitrile 7 in THF; (B) LDA/THF, À78 8C, addition of a solution of nitrile 7 in THF with a syringe pump at
2 mL/h rate.
b
Isolated yields of 11 and 12.
30% yield of -alkylation product 11a was also obtained.
c
g
Scheme 4. Mechanism of formation of DHPMs 10.
1.1.1. 2,2-Difluoro-4-pentenenitrile (7a)
solvents were removed under reduced pressure and the crude was
used in the next step without further purification. The ester was
redissolved in THF (40 mL) and was treated with and aqueous
NH4OH solution (40 mL, 25% solution in water) at 0 8C. The mixture
was stirred for 24 h at this temperature, and then, extracted with
EtOAc (3 Â 30 mL). The combined organic layers were dried over
It was prepared from 2,2-difluoro-4-pentenoic acid [18]. To a
solution of this acid (3.0 g, 22 mmol) and EtOH (2.5 mL) in CHCl3
(100 mL) was added DOWEX-H+ 50XB (2.0 g) and the mixture
stirred 24 h under reflux. The suspension was then cooled to room
temperature, filtered and washed with CH2Cl2 (3 Â 30 mL). The

1148
S. Fustero et al. / Journal of Fluorine Chemistry 130 (2009) 1145–1150
Table 2
1.2.2. (2E,4Z)-Ethyl 5-amino-6,6-difluoro-6-phenyl-2,4-
hexadienoate (11b)
Reaction of enamino esters 11 with iso(thio)cyanates 9.
Entry
RF (11)
R
X
10
Yield (%)a
By means of the general procedure previously described, 11b
was obtained from 7b as a yellow oil (150 mg) in 50% yield after
flash chromatography with hexanes:ethyl acetate (4:1) as eluent.
1
2
3
4
5
6
7
8
9
CF2CH2CH5CH2 (11a)
CF2CH2CH5CH2 (11a)
CF2Ph (11b)
Ph
O
S
10a
10b
10c
10d
10e
10f
40
61
Et
1H NMR (300 MHz, CDCl3)
d 1.28 (t, J = 7.1 Hz, 3H), 4.19 (q,
Ph
O
O
S
46
CF2Ph (11b)
Et
48
J = 7.1 Hz, 2H), 5.36 (d, J = 12.1 Hz, 1H), 5.77 (d, J = 15.0 Hz, 1H),
7.40–7.48 (m, 1H), 7.44–7.49 (m, 3H), 7.54–7.57 (m, 2H). 13C NMR
CF2Ph (11b)
Et
68
CF2Ph (11b)
(R)-Ph(Me)CH
(R)-(C10H7)(Me)CH
CH2CO2Et
Cl3C6H2
O
O
O
O
52b
50c
35
(75.5 MHz, CDCl3) d
14.3, 60.1, 99.2 (t, 3JCF = 6.4 Hz), 117.8, 118.6 (t,
CF2Ph (11b)
10g
10h
10i
1JCF = 243.5 Hz), 125.6 (t, 3JCF = 5.6 Hz), 128.5, 130.6 (t,
5JCF = 1.6 Hz), 134.8 (t, 2JCF = 27.3 Hz), 137.0, 144.5 (t,
CF2Ph (11b)
CF2Ph (11b)
40
2JCF = 27.7 Hz), 167.5. 19F NMR (282.4 MHz, CDCl3)
d
À98.6 (s,
a
Isolated yields.
Mixture of diastereoisomers (34:66), determined by 19F NMR.
Mixture of diastereoisomers (25:75), determined by means of 19F NMR.
2F). HRMS (EI+): m/z calc. for C14H15F2NO2 (M+): 267.1071, found:
b
c
231.1087.
1.2.3. (Z)-Ethyl 3-amino-4,4-difluoro-2-vinyl-2,6-heptadienoate
(12a)
Na2SO4, filtered and evaporated in vacuo. The white solid formed
(2,2-difluoro-4-pentenamide) was introduced in a distillation flask
and treated with P2O5 (4.68 g, 33 mmol). The mixture was heated
at atmospheric pressure until 7a (1.0 g) distilled as a colorless
liquid (b.p. 43–45 8C, 39% overall yield). 1H NMR (300 MHz, CDCl3)
By means of the general procedure previously described, 12a
was obtained with a fast addition of 7a (Table 1, entry 1) as a
yellow oil (90 mg) in 30% yield after flash chromatography with
hexanes:ethyl acetate (4:1) as eluent. This compound was
previously described [15].
d
2.63–2.76 (m, 2H), 5.17–5.25 (m, 2H), 5.48–5.62 (m, 1H). 13C
2
NMR (75.5 MHz, CDCl3)
d
42.4 (t, JCF = 23.8 Hz), 110.8 (t,
1JCF = 244.8 Hz), 112.4 (t, 2JCF = 45.9 Hz), 124.5, 125.2 (t,
1.2.4. (Z)-Ethyl 3-amino-4,4-difluoro-4-phenyl-2-vinyl-2-butenoate
(12b)
3JCF = 4.9 Hz). 19F NMR (282.4 MHz, CDCl3)
d
À90.8 (t, JFH = 14.9,
2F). HRMS (EI+): m/z calc. for C5H5F2N (M+): 117.0967, found:
By means of the general procedure previously described, 12b
was obtained with a fast addition of 7b (Table 1, entry 2) as a
yellow oil (126 mg) in 42% yield after flash chromatography with
117.0962.
1.1.2. 2,2-Difluoro-2-phenylacetonitrile (7b)
This nitrile was commercially available in SynQuest Labs.
Fluorochemical. See, also Ref. [16b].
hexanes:ethyl acetate (4:1) as eluent. 1H NMR (300 MHz, CDCl3)
d
1.31 (t, J = 7.1 Hz, 3H), 4.23 (q, J = 7.1 Hz, 2H), 4.83 (dd, 1J = 2.2 Hz,
2J = 11.7 Hz, 1H), 5.22 (dd, 1J = 2.1 Hz, 2J = 17.4 Hz, 1H), 6.00 (tdd,
1J = 2.6 Hz, 2J = 11.7 Hz 3J = 17.4 Hz, 1H), 7.26 (br s, 2H), 7.41–7.47
1.2. General procedure for the preparation of fluorinated enamino
(m, 3H), 7.55–7.58 (m, 2H). 13C NMR (75.5 MHz, CDCl3)
d 14.2, 60.1,
3
1
esters (11 and 12)
97.3 (t, JCF = 3.0 Hz), 115.2, 118.2 (t, JCF = 245.0 Hz), 125.6 (t,
3JCF = 5.0 Hz), 128.6, 128.9, 130.7 (t, JCF = 1.8 Hz), 134.8 (t,
2JCF = 26.0 Hz), 152.3 (t, 2JCF = 24.8 Hz), 170.3. 19F NMR
5
To a solution of freshly prepared LDA (2.1 mmol) in THF
(4 mL) at À50 8C, another solution of ester 8 (1.5 mmol) in THF
(2 mL) was added dropwise and the reaction mixture was stirred
for 30 min at this temperature. Once the enolate had been
formed, the reaction was cooled until À78 8C, and a solution of
nitrile 7 (1.3 mmol) in THF (2 mL) was added with the aid of a
syringe pump (2 mL/h). After completing the addition, the
reaction mixture was stirred for 1.5 h, and then quenched with
saturated aqueous NH4Cl (10 mL). The crude mixture was
extracted with ethyl acetate (3 Â 10 mL), and the combined
organic extracts were washed with brine, dried over anhydrous
Na2SO4 and concentrated to dryness under vacuum. After flash
chromatography over silica gel, previously deactivated with a
solution of hexanes/Et3N 2% using mixtures of hexanes:ethyl
acetate as eluent, the corresponding enamino esters 11 were
obtained.
(282.4 MHz, CDCl3)
C
d
À90.4 (s, 2F). HRMS (EI+): m/z calc. for
14H15F2NO2 (M+): 267.1071, found: 231.1045.
1.3. General procedure for the preparation of DHPMs (10)
Sodium hydride (0.9 mmol) was added to a solution of the
corresponding d-enaminoester 11 (0.5 mmol) in DMF (2 mL) at
À10 8C, and the suspension was stirred for 30 min. Then, a solution
of the iso- or isothiocyanate (0.6 mmol) in DMF (1 mL) was added
dropwise, and the reaction mixture was allowed to reach room
temperature. After 2 h (TLC revealed total consumption of the
starting material), DMF was eliminated under reduced pressure
and the crude mixture was quenched with saturated aqueous
NH4Cl (10 mL) and extracted with CH2Cl2 (3 Â 10 mL); the
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4 and concentrated to dryness under vacuum.
The residue was then subjected to flash chromatography over silica
gel using mixtures of hexanes:ethyl acetate as eluent, affording the
desired DHMPs 10.
1.2.1. (2E,4Z)-Ethyl 5-amino-6,6-difluoro-2,4,8-nonatrienoate (11a)
By means of the general procedure previously described, 11a
was obtained from 7a as a yellow oil (120 mg) in 40% yield after
flash chromatography with hexanes:ethyl acetate (4:1) as eluent.
1H NMR (300 MHz, CDCl3)
d
1.22 (t, J = 7.1 Hz, 3H), 2.72 (dt,
1.3.1. 6-(1,1-Difluoro-3-butenyl)-4-(ethoxycarbonylmethyl)-3-
phenyl-3,4-dihydropyrimidin-2(1H)-one (10a)
By means of the general procedure previously described, 10a
was obtained from 11a and phenyl isocyanate as a yellow oil
(70 mg) in 40% yield after flash chromatography with hexane-
s:ethyl acetate (2:1) as eluent. 1H NMR (300 MHz, CDCl3)
d 1.13 (t,
J = 7.2 Hz, 3H), 2.53 (d, J = 7.5 Hz, 1H), 2.53 (d, J = 5.3 Hz, 1H), 2.71
(dt, J = 7.1 Hz, JHF = 16.3 Hz, 2H), 3.97 (q, J = 7.2 Hz, 2H), 4.71–4.78
(m, 1H), 5.11 (d, J = 16.5 Hz, 1H), 5.16 (d, J = 9.5 Hz, 1H), 5.22–5.24
(m, 1H), 5.67 (ddt, 1J = 7.0 Hz, 2J = 10.3 Hz, 3J = 17.2 Hz, 1H), 7.15–
J = 7.2 Hz, JHF = 16.2 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 4.09 (br s, 2H),
5.16 (d, J = 11.7 Hz, 1H), 5.21 (d, J = 14.1 Hz, 1H), 5.26 (d,
J = 12.2 Hz, 1H), 5.72 (d, J = 14.9 Hz, 1H), 5.62–5.75 (m, 1H), 7.37
(dd, 1J = 14.9 Hz, 2J = 12.1 Hz, 1H). 13C NMR (75.5 MHz, CDCl3)
d
13.3, 40.5 (t, 2JCF = 34.5 Hz), 59.1, 96.6 (t, 3JCF = 6.5 Hz), 116.2, 118.7
1
4
(t, JCF = 243.3 Hz), 119.9, 127.1 (t, JCF = 5.1 Hz), 136.2, 143.3 (t,
2JCF = 26.0 Hz), 166.6. 19F NMR (282.4 MHz, CDCl3)
d
À103.5 (t,
JFH = 15.5 Hz, 2F). HRMS (EI+): m/z calc. for C11H15F2NO2 (M+):
231.1071, found: 231.1036.

S. Fustero et al. / Journal of Fluorine Chemistry 130 (2009) 1145–1150
1149
7.26 (m, 3H), 7.24 (br s, 1H), 7.31–7.36 (m, 2H). 13C NMR
s:ethyl acetate (4:1) as eluent. m.p. 84–86 8C. 1H NMR (300 MHz,
CDCl3) 1.23 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 2.64 (d,
J = 7.2 Hz, 1H), 2.64 (d, J = 6.0 Hz, 1H), 3.35 (dq, 1J = 7.0 Hz,
2J = 14.0 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 4.43–4.45 (m, H), 4.46
(dq, 1J = 7.2 Hz, 2J = 14.4 Hz, 1H), 5.14 (ddd, 1J = 1.8 Hz, 2J = 3.9 Hz,
3J = 5.7 Hz, 1H), 7.45–7.50 (m, 5H), 7.52 (br s, 1H). 13C NMR
2
(75.5 MHz, CDCl3)
d
13.9, 39.4, 40.0 (t, JCF = 26.4 Hz), 56.7, 60.7,
d
99.6 (t, 3JCF = 6.9 Hz), 117.6 (t, 1JCF = 243.7 Hz), 121.2, 127.3, 127.9,
127.8 (t, 3JCF = 5.2 Hz), 129.2, 133.2 (t, 2JCF = 29.5 Hz), 139.8, 152.6,
169.8. 19F NMR (282.4 MHz, CDCl3)
d
À102.4 (td, JFH = 16.6 Hz,
JFF = 255 Hz, 1F), À 103.5 (td, JFH = 16.6 Hz, JFF = 255 Hz, 1F). HRMS
(EI+): m/z calc. for C18H20F2N2O3 (M+): 350.1442, found: 350.1422.
(75.5 MHz, CDCl3)
d 12.4, 14.0, 39.0, 46.8, 52.8, 61.1, 102.9 (t,
1
3
3JCF = 5.9 Hz), 116.5 (t, JCF = 242.1 Hz), 125.7 (t, JCF = 5.7 Hz),
1.3.2. 6-(1,1-Difluoro-3-butenyl)-4-(ethoxycarbonylmethyl)-3-
ethyl-3,4-dihydropyrimidin-2(1H)-thione (10b)
128.7, 131.0, 132.8 (t, 2JCF = 26.2 Hz), 133.0 (t, 2JCF = 31.4 Hz), 169.5,
176.1. 19F NMR (282.4 MHz, CDCl3)
d
À97.6 (d, JFF = 266.7 Hz, 1F),
À98.6 (d, JFF = 266.9 Hz, 1F). HRMS (EI+): m/z calc. for
17H20F2N2O2S (M+): 354.1214, found: 354.1298.
By means of the general procedure previously described, 10b
was obtained from 11a and ethyl isothiocyanate as a yellow oil
(97 mg) in 61% yield after flash chromatography with hexane-
C
s:ethyl acetate (5:1) as eluent. 1H NMR (300 MHz, CDCl3)
d
1.26 (t,
1.3.6. 6-Difluoro(phenyl)methyl-4-(ethoxycarbonylmethyl)-3-[(R)-
1-phenylethyl]-3,4-dihydropyrimidin-2(1H)-one (10f)
By means of the general procedure previously described, 10f
was obtained from 11b and (R)-phenyl ethyl isocyanate as a 2:1
mixture of diastereoisomers, as colorless oils (72 + 36 mg) in 52%
combined yield after flash chromatography with hexanes:ethyl
J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 2.59 (dd, 1J = 6.7 Hz,
2J = 14.4 Hz, 1H), 2.66 (dt, 1J = 3.7 Hz, 2J = 14.4 Hz, 1H), 2.76 (dt,
J = 7.1 Hz, JHF = 15.8 Hz, 2H), 3.33 (dq, 1J = 7.0 Hz, 2J = 14.0 Hz, 1H),
4.15 (q, J = 7.1 Hz, 2H), 4.48 (dq, 1J = 7.0 Hz, 2J = 14.0 Hz, 1H), 4.45–
4.51 (m, 1H), 5.22 (d, J = 12.2 Hz, 1H), 5.26 (d, J = 3.7 Hz, 1H), 5.30–
5.33 (m, 1H), 5.70 (ddt, 1J = 7.1 Hz, 2J = 10.4 Hz, 3J = 17.5 Hz, 1H),
acetate (2:1) as eluent. Major diastereoisomer: [
a
]
25: À67.4 (c 1.0;
D
7.51 (br s, 1H). 13C NMR (75.5 MHz, CDCl3)
d
12.4, 14.1, 38.9, 40.6 (t,
CH3Cl). 1H NMR (300 MHz, CDCl3)
d 1.18 (t, J = 7.1 Hz, 3H), 1.59 (d,
3
2JCF = 26.4 Hz) 46.8, 52.6, 61.1, 101.2 (t, JCF = 6.0 Hz), 117.4 (t,
1JCF = 243.9 Hz), 121.7, 127.4 (t, 3JCF = 5.3 Hz), 132.0 (t,
J = 6.7 Hz, 3H), 2.49 (dd, 1J = 3.8 Hz, 2J = 15.3 Hz, 1H), 2.65 (dd,
1J = 10.2 Hz, 2J = 15.4 Hz, 1H), 3.96–4.03 (m, 1H), 4.00 (q, J = 7.1 Hz,
2H), 4.96–4.99 (m, 1H), 5.59 (q, J = 7.1 Hz, 1H), 6.68 (br s, 1H), 7.19–
2JCF = 29.8 Hz), 169.7, 176.1. 19F NMR (282.4 MHz, CDCl3)
d
À102.3 (t, JFH = 15.8 Hz, 2F). HRMS (EI+): m/z calc. for
7.27 (m, 5H), 7.34–7.42 (m, 5H). 13C NMR (75.5 MHz, CDCl3)
d
14.1,
3
C
14H20F2N2O2S (M+): 318.1214, found: 318.1194.
18.4, 40.9, 48.3, 53.2, 60.7, 103.4 (t, JCF = 5.5 Hz), 116.9 (t,
3
1JCF = 240.7 Hz), 125.8 (t, JCF = 5.5 Hz), 127.1, 127.6, 128.5,
2
2
1.3.3. 6-Difluoro(phenyl)methyl-4-(ethoxycarbonylmethyl)-3-
phenyl-3,4-dihydropyrimidin-2(1H)-one (10c)
By means of the general procedure previously described, 10c
was obtained from 11b and phenyl isocyanate as a white solid
(88 mg) in 46% yield after flash chromatography with hexane-
s:ethyl acetate (3:1) as eluent. m.p. 116–118 8C. 1H NMR (300 MHz,
128.6, 130.8, 133.6 (t, JCF = 26.2 Hz), 134.5 (t, JCF = 31.0 Hz),
140.2, 154.0, 169.9. 19F NMR (282.4 MHz, CDCl3)
d
À97.1 (d,
JFF = 264.3 Hz, 1F), À99.7 (d, JFF = 264.3 Hz, 1F). HRMS (EI+): m/z
calc. for C23H25F2N2O3 (M+1): 415.1833, found: 415.1831. Minor
diastereoisomer: [
CDCl3)
1.13 (t, J = 7.1 Hz, 3H), 1.55 (dd, 1J = 3.6 Hz, 2J = 12.0 Hz,
a]
D
25: +126.7 (c 1.0; CH3Cl). 1H NMR (300 MHz,
d
CDCl3)
d
1.09 (t, J = 7.1 Hz, 3H), 2.50 (d, J = 7.0 Hz, 1H), 2.50 (d,
1H), 1.59 (d, J = 7.2 Hz, 3H), 2.21 (dd, 1J = 10.1 Hz, 2J = 15.5 Hz, 1H),
3.96 (dq, 1J = 1.1 Hz, 2J = 7.1 Hz, 2H), 4.34–4.41 (m, 1H), 5.11–5.14
(m, 1H), 5.76 (q, J = 7.1 Hz, 1H), 6.46 (br s, 1H), 7.27–7.36 (m, 3H),
J = 5.6 Hz, 1H), 3.96 (dq, 1J = 1.4 Hz, 2J = 7.1 Hz, 2H), 4.71–4.77 (m,
1H), 5.13–5.15 (m, 1H), 7.01 (br s, 1H), 7.22–7.25 (m, 3H), 7.31–
7.40 (m, 5H), 7.46 (d, J = 7.2 Hz, 2H). 13C NMR (75.5 MHz, CDCl3)
d
7.40–7.50 (m, 7H). 13C NMR (75.5 MHz, CDCl3)
d
14.0, 16.4, 39.4,
1
3
3
13.9, 39.3, 56.8, 60.8, 101.1 (t, JCF = 6.2 Hz), 116.7 (t,
47.9, 52.0, 60.5, 103.1 (t, JCF = 6.0 Hz), 116.9 (t, JCF = 242.1 Hz),
3
3
1JCF = 242.2 Hz), 125.8 (t, JCF = 5.7 Hz), 127.5, 127.9, 128.5,
125.8 (t, JCF = 5.6 Hz), 127.7, 127.9, 128.5, 128.6, 130.8, 134.7 (t,
2
2
2
129.3, 130.7, 133.3 (t, JCF = 26.7 Hz), 134.2 (t, JCF = 31.2 Hz),
139.7, 152.1, 169.7. 19F NMR (282.4 MHz, CDCl3)
2JCF = 31.0 Hz), 133.5 (t, JCF = 36.2 Hz), 140.6, 153.7, 170.0. 19F
d
À98.7 (d,
NMR (282.4 MHz, CDCl3)
JFF = 265.1 Hz, 1F). HRMS (EI+): m/z calc. for C23H25F2N2O3 (M+1):
d
À97.7 (d, JFF = 265.1 Hz, 1F), À98.9 (d,
JFF = 264.0 Hz, 1F), À99.8 (d, JFF = 264.0 Hz, 1F). HRMS (EI+): m/z
calc. for C21H20F2N2O3 (M+): 386.1442, found: 386.1428.
415.1833, found: 415.1830.
1.3.4. 6-Difluoro(phenyl)methyl-4-(ethoxycarbonylmethyl)-3-ethyl-
3,4-dihydropyrimidin-2(1H)-one (10d)
1.3.7. 6-Difluoro(phenyl)methyl-4-(ethoxycarbonylmethyl)-3-[(R)-
1-naphtylethyl]-3,4-dihydropyrimidin-2(1H)-one (10g)
By means of the general procedure previously described, 10d
was obtained from 11b and ethyl isocyanate as a colorless oil
(81 mg) in 48% yield after flash chromatography with hexane-
By means of the general procedure previously described, 10g
was obtained from 11b and (R)-napthyl ethyl isocyanate as a 3:1
mixture of diastereoisomers, as light yellow oils (81 + 27 mg) in
50% combined yield after flash chromatography with hexane-
s:ethyl acetate (2:1) as eluent. 1H NMR (300 MHz, CDCl3)
d 1.17 (t,
J = 7.0 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 2.52–2.68 (m, 2H), 3.01 (dq,
1J = 7.2 Hz, 2J = 14.0 Hz, 1H), 3.76 (dq, 1J = 7.2 Hz, 2J = 14.0 Hz, 1H),
4.11 (q, J = 7.1 Hz, 2H), 4.35–4.40 (m, H), 5.02–5.04 (m, H), 6.48 (br
s, 1H), 7.40–7.50 (m, 3H), 7.52 (d, J = 6.4 Hz, 2H). 13C NMR
s:ethyl acetate (4:1) as eluent. Major diastereoisomer: [
a
]
25: À48.1
D
(c 1.0; CH3Cl). 1H NMR (300 MHz, CDCl3)
d
1.19 (t, J = 7.1 Hz, 3H),
1.82 (d, J = 7.0 Hz, 3H), 2.56 (dd, 1J = 3.8 Hz, 2J = 15.3 Hz, 1H), 2.71
(dd, 1J = 9.3 Hz, 2J = 15.3 Hz, 1H), 3.76–3.83 (m, 1H), 4.06 (q,
J = 7.1 Hz, 2H), 4.74–4.77 (m, 1H), 6.29 (q, J = 7.0 Hz, 1H), 6.72 (br s,
1H), 7.31–7.37 (m, 3H), 7.40–7.54 (m, 5H), 7.62 (d, J = 7.1 Hz, 1H),
(75.5 MHz, CDCl3)
d 13.1, 14.0, 39.6, 40.2, 52.5, 60.9, 101.3 (t,
1
3
3JCF = 5.7 Hz), 116.8 (t, JCF = 240.5 Hz), 125.8 (t, JCF = 5.7 Hz),
128.5, 130.8, 133.4 (t, 2JCF = 26.3 Hz), 134.2 (t, 2JCF = 30.8 Hz), 152,7,
7.85 (dd, 1J = 8.0 Hz, 2J = 15.7 Hz, 3H). 13C NMR (75.5 MHz, CDCl3)
d
170.1. 19F NMR (282.4 MHz, CDCl3)
d
À98.3 (d, JFF = 264.0 Hz, 1F),
À99.5 (d, JFF = 264.0 Hz, 1F). HRMS (EI+): m/z calc. for
17H20F2N2O3 (M+): 338.1442, found: 338.1420.
14.0, 18.7, 40.9, 47.7, 49.9, 60.7, 103.2 (t, JCF = 5.5 Hz), 116.7 (t,
3
3
1JCF = 247.0 Hz), 123.3, 124.8, 125.1, 125.7 (t, JCF = 5.5 Hz), 125.9,
C
126.8, 128.4, 128.7, 129.2, 130.6, 131.6, 133.9, 134.3, 153.8, 169.8.
19F NMR (282.4 MHz, CDCl3)
d
À95.7 (d, JFF = 265.7 Hz, 1F), À100.4
1.3.5. 6-Difluoro(phenyl)methyl-4-(ethoxycarbonylmethyl)-3-ethyl-
3,4-dihydropyrimidin-2(1H)-thione (10e)
By means of the general procedure previously described, 10e
was obtained from 11b and ethyl isothiocyanate as a white solid
(120 mg) in 68% yield after flash chromatography with hexane-
(d, JFF = 265.7 Hz, 1F). HRMS (EI+): m/z calc. for C27H26F2N2O3 (M+):
464.1911, found: 464.1914. Minor diastereoisomer: (it was not
possible to obtain a pure sample of the minor diastereomer, and
the data were extracted for the spectra impurified with the major
product). 1H NMR (300 MHz, CDCl3)
d 1.19 (t, J = 7.1 Hz, 3H), 1.50

1150
S. Fustero et al. / Journal of Fluorine Chemistry 130 (2009) 1145–1150
(d, J = 6.8 Hz, 3H), 1.55–1.62 (m, 1H), 1.83 (dd, 1J = 10.4 Hz,
2J = 15.5 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 4.26–4.31 (m, 1H),
5.09–5.11 (m, 1H), 6.47 (q, J = 6.8 Hz, 1H), 6.92 (br s, 1H), 7.28–
for a predoctoral fellowship, and CP and JLA for Ramon y Cajal
contracts.
´
8.00 (m, 12H). 19F NMR (282.4 MHz, CDCl3)
d
À97.7 (d,
References
JFF = 265.0 Hz, 1F), À98.8 (d, JFF = 265.0 Hz, 1F). HRMS (EI+): m/z
calc. for C27H26F2N2O3 (M+): 464.1911, found: 464.1910.
[1] P. Biginelli, Gazz. Chim. Ital. 23 (1893) 360–416.
[2] C.O. Kappe, Tetrahedron 49 (1993) 6937–6963.
[3] (a) R. Fossheim, K. Svarteng, A. Mostad, C. Romming, E. Shefter, D.J. Triggle, J. Med.
Chem. 25 (1982) 126–131;
1.3.8. 3,4-(Diethoxycarbonylmethyl)-6-difluoro(phenyl)methyl-3,4-
dihydropyrimidin-2(1H)-one (10h)
By means of the general procedure previously described, 10 h
was obtained from 11b and ethoxycarbonyl methyl isocyanate as a
yellow oil (69 mg) in 35% yield after flash chromatography with
hexanes:ethyl acetate (2:1) as eluent. 1H NMR (300 MHz, CDCl3)
1.22 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 2.56 (dd, 1J = 7.1 Hz,
2J = 16.1 Hz, 1H), 2.78 (dd, 1J = 5.5 Hz, 2J = 16.1 Hz, 1H), 3.98 (d,
J = 17.6 Hz, 1H), 4.19 (d, J = 16.7 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H),
4.18 (q, J = 7.1 Hz, 2H), 4.41–4.49 (m, 1H), 5.03–5.08 (m, 1H), 6.73
(br s, 1H), 7.41–7.48 (m, 3H), 7.51–7.54 (m, 2H). 13C NMR
(b) B. Loev, M.M. Goodman, K.M. Snader, R. Tedeschi, E. Macko, J. Med. Chem. 17
(1974) 956–965.
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Acc. Chem. Res. 39 (2006) 451–463; (d) F. Lie´by-Muller, C. Simon, T. Constantieux,
J. Rodriguez, QSAR Comb. Sci. 25 (2006) 432–438; (e) C. Simon, T. Constantieux, J.
Rodriguez, Eur. J. Org. Chem. (2004) 4957–4980; (f) C.O. Kappe, QSAR Comb. Sci.
22 (2003) 630–645.
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(b) C.O. Kappe, Acc. Chem. Res. 33 (2000) 879–888;
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[6] (a) G. Uray, P. Verdino, F. Belaj, C.O. Kappe, W.M.F. Fabian, J. Org. Chem. 66 (2001)
6685–6694, and references cited therein;
d
(75.5 MHz, CDCl3)
d 14.0, 14.0, 39.9, 47.9, 54.5, 60.9, 61.3, 101.7 (t,
1
3
3JCF = 6.1 Hz), 116.8 (t, JCF = 242.1 Hz), 125.8 (t, JCF = 5.3 Hz),
(b) B. Lagu, D. Tian, G. Chiu, D. Nagarathnam, J. Fang, Q. Shen, C. Forray, R.W.
Ransom, R.S.L. Chang, K.P. Vyas, K. Zhang, C. Gluchowski, Bioorg. Med. Chem. Lett.
10 (2000) 175–178.
2
2
128.6, 130.8, 133.7 (t, JCF = 36.3 Hz), 133.8 (t, JCF = 32.7 Hz),
152.8, 169.3, 170.3. 19F NMR (282.4 MHz, CDCl3)
d
À98.1 (d,
[7] (a) E.W. Hurst, R. Hull, J. Med. Pharm. Chem. 3 (1961) 215–229;
(b) E.W. Hurst, Ann. NY Acad. Sci. 98 (1962) 275–286;
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[8] T.U. Mayer, T.M. Kapoor, S.J. Haggarty, R.W. King, S.L. Schreiber, T.J. Mitchison,
Science 286 (1999) 971–974.
JFF = 265 Hz, 1F), À99.7 (d, JFF = 265 Hz, 1F). HRMS (EI+): m/z calc.
for C19H22F2N2O5 (M+): 396.1496, found: 396.1498.
1.3.9. 6-Difluoro(phenyl)methyl-4-(ethoxycarbonylmethyl)-3-(2,4,6-
trichlorophenyl)-3,4-dihydropyrimidin-2(1H)-one (10i)
By means of the general procedure previously described, 10i
was obtained from 11b and 2,4,6-trichlorophenyl isocyanate as a
white solid (98 mg) in 40% yield after flash chromatography with
hexanes:ethyl acetate (3:1) as eluent. m.p. 146–148 8C. 1H NMR
[9] (a) Y.S. Sadanandam, M.M. Shetty, P.V. Diwan, Eur. J. Med. Chem. 27 (1992) 87–
92;
(b) D. Bozing, P. Benko, L. Petocz, M. Szecsey, P. Toempe, G. Gigler, I. Gacsalyi, Eur.
Pat. Appl. EP (1991) 409, 233 [Chem. Abstr. 114 (1991) 247302z].
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Steele, C.F. Homnick, R.M. Freidinger, R.W. Ransom, P. Kling, D. Reiss, T.P. Broten,
T.W. Schorn, R.S.L. Chang, S.S. O’Malley, T.V. Olah, J.D. Ellis, A. Barrish, K. Kassahun,
P. Leppert, D. Nagarathnam, C. Forray, J. Med. Chem. 43 (2000) 2703–2718, and
references cited therein.
[11] (a) W.K. Hagmann, J. Med. Chem. 51 (2008) 4359–4369;
(b) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37 (2008)
320–330;
(300 MHz, CDCl3)
d 1.19 (t, J = 7.1 Hz, 3H), 2.73 (d, J = 7.0 Hz, 2H),
4.03 (q, J = 7.1 Hz, 2H), 4.81 (dtd, 1J = 2.5 Hz, 2J = 4.7 Hz, 3J = 7.0 Hz,
1H), 5.21 (dd, 1J = 1.9 Hz, 2J = 3.9 Hz, 1H), 6.36 (br s, 1H), 7.42–7.59
(m, 7H). 13C NMR (75.5 MHz, CDCl3)
d 14.0, 40.1, 55.9, 60.9, 102.1
(c) K.L. Kirk, Org. Proc. Res. Dev. 12 (2008) 305–321;
(d) K. Mu¨ ller, C. Faeh, F. Diederich, Science 457 (2007) 1881–1886.
[12] For a recent account see: S. Fustero, J.F. Sanz-Cervera, J.L. Acen˜a, M. Sa´nchez-
3
1
3
(t, JCF = 5.9 Hz), 116.8 (t, JCF = 242.1 Hz), 125.9 (t, JCF = 5.5 Hz),
2
128.8, 129.0, 129.3, 131.1, 133.1 (t, JCF = 26.4 Hz), 133.4 (t,
2JCF = 31.0 Hz), 133.9, 135.0, 135.1, 137.8, 150.3, 169.7. 19F NMR
´
Rosello, Synlett (2009) 525–549.
[13] S. Fustero, J. Piera, J.F. Sanz-Cervera, S. Catala´n, C. Ramirez de Arellano, Org. Lett. 6
(2004) 1417–1420.
(282.4 MHz, CDCl3)
d
À97.8 (d, JFF = 265.9 Hz, 1F), À99.7 (d,
JFF = 265.9 Hz, 1F). HRMS (EI+): m/z calc. for C21H17Cl3F2N2O3 (M+):
´
´
˜
[14] S. Fustero, S. Catalan, S. Flores, D. Jimenez, C. del Pozo, J.L. Acena, J.F. Sanz-Cervera,
S. Me´rida, QSAR Comb. Sci. 25 (2006) 753–760.
488.0273, found: 488.0280.
´
´
˜
[15] S. Fustero, S. Catalan, J. Piera, J.F. Sanz-Cervera, B. Fernandez, J.L. Acena, J. Org.
Chem. 71 (2006) 4010–4013.
[16] For the preparation of gem-difluorinated nitriles 7, see: (a) Ref. [14]; (b) W.J.
Middleton, E.M. Bingham, J. Org. Chem. 45 (1980) 2883–2887.
[17] The absolute configuration of the newly created stereocenter was not deter-
mined.
Acknowledgements
´
We thank the Ministerio de Educacion y Ciencia (CTQ2007-
61462) of Spain for their financial support. SC expresses her thanks
[18] R.W. Lang, H. Greuter, A.J. Romann, Tetrahedron Lett. 29 (1988) 3291–3294.