Synthesis and biological evaluation of new bicyclic fluorinated uracils through ring-closing metathesis

Article abstract of DOI:10.1021/jo0601765

Two families of bicyclic fluorinated uracils have been prepared starting from a gem-difluorinated unsaturated nitrile, by means of a ring-closing metathesis reaction to form the new ring, which is fused at the C-5/C-6 or N-1/C-6 positions of the uracil mo

Full text of DOI:10.1021/jo0601765

CHART 1. Examples of Fluorinated Nucleosides and Bases
Synthesis and Biological Evaluation of New
Bicyclic Fluorinated Uracils through
Ring-Closing Metathesis§
Santos Fustero,*,†,‡ Silvia Catala´n,† Julio Piera,†
Juan F. Sanz-Cervera,†,‡ Begon˜a Ferna´ndez,† and
Jose´ Luis Acen˜a‡
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia,
E-46100 Burjassot, Spain, and Laboratorio de Mole´culas
Orga´nicas, Centro de InVestigacio´n Pr´ıncipe Felipe, E-46013
Valencia, Spain
More examples of biologically active compounds formed in
this fashion include C-6 fluorinated uracils, which have
important applications as agrochemicals, especially as herbi-
cides, insecticides, and acaricides.4 In fact, we recently reported
our preparation of uracils 3 with a fluoroalkyl substituent at
C-6, in which fluorinated nitriles (RFCN) 1 and esters 2 were
used as precursors (Scheme 1).5,6 As an extension of this
methodology, we now describe the preparation of two new
classes of bicyclic fluorinated uracils,7 both of which have a
fused ring either between C-5 and C-6 (4) or between N-1 and
C-6 (5) (Scheme 2). The starting material for both 4 and 5
is 2,2-difluoropent-4-enenitrile 6, and the key step is a ring-
closing metathesis (RCM) reaction,8,9 which is carried out after
suitable olefin substituents have been introduced within the
uracil framework. In addition, we have also undertaken a
preliminary evaluation of the acaricidal activity of the resulting
derivatives.
santos.fustero@uV.es
ReceiVed January 25, 2006
Two families of bicyclic fluorinated uracils have been
prepared starting from a gem-difluorinated unsaturated nitrile,
by means of a ring-closing metathesis reaction to form the
new ring, which is fused at the C-5/C-6 or N-1/C-6 positions
of the uracil moiety. The selective formation of olefin
regioisomers in the metathesis process can be controlled
according to the reaction conditions (catalyst, solvent, and
temperature). The acaricidal activities of the resulting
compounds have also been investigated.
(2) (a) Ozaki, S. Med. Res. ReV. 1996, 16, 51-86. (b) Ojima, I.;
McCarthy, J. R.; Welch, J. T. In Biomedical Frontiers of Fluorine
Chemistry; ACS Symposium Series 639; American Chemical Society:
Washington, DC, 1996. (c) Filler, R.; Kobayashi, Y. Biomedicinal Aspects
of Fluorine Chemistry; Elsevier Biomedical Press: New York and Kodansha
Ltd: Tokyo, 1982. (d) Pankiewicz, K. W. Carbohydr. Res. 2000, 327, 87-
105.
(3) (a) Kotra, L. P.; Xiang, Y.; Newton, M. G.; Schinazi, R. F.; Cheng,
Y.-C.; Chu, C. K. J. Med. Chem. 1997, 40, 3635-3644. (b) Hertel, L. W.;
Kroin, J. S.; Misner, J. W.; Tustin, J. M. J. Org. Chem. 1988, 53, 2406-
2409.
(4) As examples, see: (a) Tohyama, Y.; Sanemitsu, Y. PCT Int. Appl.
EP 1122244 A1, 2001; Chem. Abst. 2001, 135, 152820. (b) Theodoridis,
G.; Crawford, S. D. PCT Int. Appl. US 6277847 B1, 2001; Chem. Abst.
2001, 135, 180781. (c) Drewes, M.-W.; Andree, R.; Dollinger, M. PCT
Int. Appl. DE 19632005 A1, 1998; Chem. Abst. 1998, 128, 167437. (d)
Koiso, T.; Ono, S.; Kondo, H.; Asada, T. PCT Int. Appl. JP 09241245 A2,
1997; Chem. Abst. 1997, 127, 274174. (e) Kameswaran, V. PCT Int. Appl.
US 6191275 B1, 2001; Chem. Abst. 2001, 134, 178567. (f) Yagi, K.;
Akimoto, K.; Mimori, N.; Miyake, T.; Kudo, M.; Arai, K.; Ishii, S. Pest.
Manag. Sci. 2000, 56, 65-73.
Disrupting the biological mechanisms associated with nucleic
acids in order to develop effective agents with antitumoral and/
or antiviral activities has become a major field in drug discovery
research. In this context, the preparation of molecules that mimic
the structures of nucleic acids or their building blocks has
provided many therapeutically useful compounds.1 In addition,
because the introduction of fluorine atoms into organic mol-
ecules usually promotes dramatic changes in their biological
properties, this particular strategy has been used successfully
to synthesize biologically active fluorinated nucleotides and
nucleosides.2 Two emblematic examples of this are 5-fluoro-
uracil and trifluridine (Chart 1), both potent inhibitors of
thymidylate synthase. Thus, 5-fluorouracil is now a widely used
drug in the treatment of several types of cancer, and trifluridine
has proven to be an effective antiviral agent against Herpes
simplex infections. By carefully positioning the fluorine atoms,
compounds with different effects can be formed, as is the case
with the antitumoral compound gemcitabine, in which the
fluorine atoms are positioned in the sugar moiety.3
(5) Fustero, S.; Piera, J.; Sanz-Cervera, J. F.; Catala´n, S.; Ram´ırez de
Arellano, C. Org. Lett. 2004, 6, 1417-1420.
(6) For a different synthetic approach leading to C-6 fluorinated uracils,
see: Fustero, S.; Salavert, E.; Sanz-Cervera, J. F.; Piera, J.; Asensio, A.
Chem. Commun. 2003, 844-845.
(7) The synthesis of nonfluorinated, polycyclic uracils has been previously
reported. For some examples, see: (a) Garc´ıa Mart´ınez, A.; Herrera
Ferna´ndez, A.; Moreno Jime´nez, F.; Mun˜oz Mart´ınez, P. J.; Alonso Mart´ın,
C.; Subramanian, L. R. Tetrahedron 1996, 52, 7973-7982. (b) Macchia,
M.; Antonelli, G.; Balsamo, A.; Barontini, S.; Calvani, F.; Gentili, D.;
Martinelli, A.; Rossello, A.; Turriziani, O.; Tesoro, R. Il Farmaco 1999,
54, 242-247.
(8) For reviews of the metathesis reaction, see: (a) Grubbs, R. H. In
Handbook of Metathesis; Wiley-VCH Verlag Gmbh and Co. KGaA:
Weinheim, 2003; Vols. 1-3. (b) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413-4450. (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3012-3043. (d) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2003, 42, 4592-4633. (e) Grubbs, R. H. Tetrahedron 2004, 60, 7117-
7140.
§ In Memoriam of Professor Marcial Moreno-Man˜as.
† Universidad de Valencia.
(9) The metathesis reaction has been widely used for the preparation of
nucleosides and analogues, mostly for building the sugar ring. For a recent
review, see: Amblard, F.; Nolan, S. P.; Agrofolio, L. A. Tetrahedron 2005,
71, 7067-7080.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) Nucleosides and Nucleotides as Antitumor and AntiViral Agents; Chu,
C. K., Baker, D. C., Eds.; Plenum Press: New York, 1993.
10.1021/jo0601765 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/15/2006
4010
J. Org. Chem. 2006, 71, 4010-4013

SCHEME 1
SCHEME 2
CHART 2. Structures of First (10) and Second (11)
Generation Grubbs’ Catalysts
SCHEME 4
SCHEME 3
TABLE 1. Reaction Conditions for the RCM of 9c
catalyst
(15 mol %)
temp
(°C)
4b:4b′
ratio
yield
(%)a
entry
solvent
1
2
3
11
10
11
CH2Cl2
CH2Cl2
PhMe
50
50
120
72:28
100:0
0:100
74
71
70
a Isolated yield of pure products.
The starting nitrile 6 was obtained from the known10 2,2-
difluoropent-4-enoic acid 7 in three standard steps, namely, ethyl
ester formation, transformation to the corresponding primary
amide, and dehydration to the nitrile11 (Scheme 3). Next, 6 was
treated at -78 °C with the lithium enolates derived from ethyl
acetate (R1 ) H), ethyl but-3-enoate (R1 ) vinyl),12 or ethyl
pent-4-enoate (R1 ) allyl), all of which were generated by their
reaction with LDA, to afford â-enamino esters 8a-c. The latter
compounds, isolated solely in their enamino tautomeric form,
were then deprotonated with NaH, and further addition of phenyl
isocyanate gave uracils 9a-c.13
Uracils 9b and 9c, which already contained two olefinic
moieties, were the direct precursors of bicyclic uracils 4. Thus,
the RCM reaction of compound 9b was carried out in the
presence of Grubbs’ second generation catalyst 11 (Chart 2)
and CH2Cl2 as solvent by heating (50 °C) in a sealed flask to
obtain the six-membered cyclized product 4a in good yield
(Scheme 4). However, when the same reaction conditions were
used on substrate 9c, a mixture of the seven-membered isomeric
uracils 4b and 4b′ was obtained (72:28 ratio), with the minor
product coming from the isomerization of the double bond after
the metathesis reaction14 (Table 1, entry 1). We found, however,
that by fine-tuning the reaction conditions,15 we could success-
fully carry out the regioselective preparation of either bicyclic
uracil. Thus, the use of Grubbs’ first generation catalyst 10 in
CH2Cl2 yielded only 4b (entry 2), whereas heating in the
presence of the second generation catalyst 11 in toluene (120
°C in a sealed flask) led to the isomerization of the double bond
to give 4b′ as a single product (entry 3). It should be noted that
the other possible isomer (coming from the migration of the
double bond toward the fluorine atoms) was not detected,
apparently due to a stereoelectronic effect of the contiguous
difluoromethylene moiety.15 Furthermore, the metathesis reac-
tion proceeded much faster than the isomerization since no ring-
contraction product, namely 4a, was formed from 9c. Finally,
we found that a two-step procedure involving metathesis
followed by isomerization was also efficient for the preparation
of compound 4b′.16
We next focused on the preparation of the second family of
bicyclic uracils 5, which was accessible from compound 9a after
the introduction of a second olefinic substituent at N-1.
(10) (a) Greuter, H.; Lang, R. W.; Romann, A. J. Tetrahedron Lett. 1988,
29, 3291-3294. (b) Xu, F.; Simmons, B.; Armstrong, J., III; Murry, J. J.
Org. Chem. 2005, 70, 6105-6107.
(14) (a) These isomerizations usually take place before the metathesis
process and are promoted by the presence of ruthenium hydride species
formed by decomposition of catalyst 11; see: Hong, S. H.; Day, M. W.;
Grubbs, R. H. J. Am. Chem. Soc. 2004, 126, 7414-7415. (b) For a review,
see: Schmidt, B. Eur. J. Org. Chem. 2004, 1865-1880.
(15) We have also been able to control these RCM reaction conditions
with or without the double bond isomerization in a variety of fluorinated
and non-fluorinated substrates. For a mechanistic explanation, see: Fustero,
S.; Sa´nchez-Rosello´, M.; Jime´nez, D.; Sanz-Cervera, J. F.; del Pozo, C.;
Acen˜a, J. L. J. Org. Chem. 2006, 71, 2706-2714.
(11) An alternative access to nitrile 6 from ethyl difluoroiodoacetate has
been reported; see: Hung, M.-H.; Logothetis, A. L. PCT Int. Appl. WO
9705122 A1, 1997; Chem. Abst. 1997, 126, 239542.
(12) The lithium enolate of ethyl but-3-enoate also afforded the γ-alky-
lation product as a side reaction (30% yield).
(13) Yields of uracils 9 are sometimes compromised as a result of their
difficult separation from byproducts formed when isocyanates react with
liberated EtOH.
J. Org. Chem, Vol. 71, No. 10, 2006 4011

SCHEME 5
at a concentration of 4.0-5.0 mg/mL, in terms of both mortality
and fecundity inhibition (4b inhibited fecundity only, entry 2).
Although promising, these results did not establish a clear
structure-activity relationship but nevertheless served to con-
firm the potential of C-6 fluorinated uracils as acaricides.4
In summary, we have prepared a small library of two new
families of fused bicyclic fluorinated uracils, through a straight-
forward synthetic route starting from a simple fluorinated nitrile,
using either a RCM or a tandem RCM-isomerization to
construct the second ring. More experiments to determine the
usefulness of these compounds are underway.
Experimental Section
General Procedure for Ring-Closing Metathesis Reaction
(Method A). Grubbs’ first generation catalyst 10 (15% molar equiv,
0.045 mmol) was added to a solution of compound 9 or 12 (0.3
mmol) in CH2Cl2 (0.02 M) at room temperature. The reaction
mixture was stirred at 50 °C in a sealed flask under inert atmosphere
for 2 h. The solvent was then removed under vacuum. The crude
product 4 or 5 was purified through a silica gel column with solvent
mixtures as indicated in each case.
General Procedure for Tandem RCM-Isomerization Reac-
tion (Method B). Grubbs’ second generation catalyst 11 (15%
molar equiv, 0.045 mmol) was added to a solution of compound 9
or 12 (0.3 mmol) in toluene (0.02 M) at room temperature. The
reaction mixture was stirred at 120 °C in a sealed flask under inert
atmosphere for 3 h. The solvent was then removed under vacuum.
The crude product 4′ or 5′ was purified through a silica gel column
with solvent mixtures as indicated in each case.
Unfortunately, the reaction of 9a with allyl bromide and NaH
afforded mixtures of N- and O-allylation products that were
difficult to separate. After some experimentation, we finally
discovered that treatment of 9a with allyl acetate under Pd(0)
catalysis17 yielded the desired N-allyl uracil 12a as the only
product (Scheme 5). When we subjected this compound to the
previously optimized RCM conditions using Grubbs’ first
generation catalyst 10, bicyclic uracil 5a was obtained as a single
isomer. However, in sharp contrast to bicyclic uracils 4, the
double bond was only partially isomerized in the presence of
the second generation catalyst 11 in toluene, resulting in a
mixture of 5a and 5a′ (33:67 ratio). These were subsequently
separated by means of column chromatography. Forcing the
reaction conditions18 did not improve the yield of the isomerized
product 5a′. Moreover, treatment of 5a with catalyst 11 only
produced a mixture of both isomers 5a and 5a′ (50:50 ratio). It
would thus seem that the electron-withdrawing group attached
to the N-1 nitrogen atom precludes the isomerization, despite
the effect of the difluoromethylene group.15
After optimizing this synthetic strategy, we then proceeded
to prepare a small library of different bicyclic uracils 4 and 5,
all with a seven-membered fused ring, using a variety of
isocyanates in the reaction with enamino esters 8. In this manner,
different substituents R2 can be introduced at the N-3 position,
including aliphatic, aromatic, electron-withdrawing, electron-
donating, and chiral groups (Chart 3).
Finally, representative examples of these bicyclic uracils and
their precursors (4b, 4e, 4e′, 5a, 5a′, 5d, 9b, and 9g) were tested
as acaricides against Tetranychus urticae (twospotted spider
mite), a parasite of crops and common houseplants, using the
commercially available miticide tebufenpyrad19 as reference
standard. Preliminary results from a 24-, 96-, and 144-h assay20
showed that only those compounds shown in Table 2 were active
8,8-Difluoro-7,8-dihydro-3-phenylquinazoline-2,4(1H,3H)-di-
one (4a). Starting from 9b, and after subsequent purification of
the crude product by means of flash chromatography (n-hexane/
EtOAc, 2:1), use of Method A with catalyst 11 gave 4a as a white
solid (78% yield): Rf ) 0.23 (n-hexane/EtOAc, 2:1); mp 204-
206 °C; 1H NMR (400 MHz, CDCl3) δ 3.06 (tq, J ) 21.0, 2.0 Hz,
2H), 5.88-5.92 (m, 1H), 6.65 (dt, J ) 10.0, 2.0 Hz, 1H), 7.23-
7.25 (m, 2H), 7.39-7.54 (m, 3H), 8.69 (br, 1H); 13C NMR (75.5
MHz, CDCl3) δ 34.5 (t, 2JCF ) 24.9 Hz), 110.2 (t, 3JCF ) 6.0 Hz),
116.9 (t, 1JCF ) 243.1 Hz), 118.3 (t, 4JCF ) 3.0 Hz), 119.7 (t, 3JCF
2
) 5.7 Hz), 128.1, 129.1, 129.4, 134.0, 136.1 (t, JCF ) 25.7 Hz),
150.4, 161.0; 19F NMR (282.4 MHz, CDCl3) δ -95.1 (t, JHF
)
21.0 Hz, 2F); IR (film) 3079, 2995, 1723, 1664, 1429, 1350, 1173,
1042 cm-1; HRMS (EI) calcd for C14H10F2N2O2 (M+) 276.0710,
found 276.0679.
9,9-Difluoro-8,9-dihydro-3-phenyl-1H-cyclohepta[d]pyrimi-
dine-2,4(3H,5H)-dione (4b). Starting from 9c, and after subsequent
purification of the crude product by means of flash chromatography
(n-hexane/EtOAc, 2:1), Method A gave 4b as a white solid (71%
1
yield): Rf ) 0.25 (n-hexane/EtOAc, 2:1); mp 213-215 °C; H
NMR (300 MHz, CDCl3) δ 2.94 (tdd, J ) 15.1, 6.0, 1.5 Hz, 2H),
3.34-3.37 (m, 2H), 5.62-5.69 (m, 1H), 6.00-6.07 (m, 1H), 7.14-
7.19 (m, 2H), 7.35-7.47 (m, 3H), 7.93 (br, 1H); 13C NMR (75.5
MHz, CDCl3) δ 23.2, 35.2 (t, 2JCF ) 25.8 Hz), 112.6 (t, 3JCF ) 5.8
1
3
Hz), 116.5 (t, JCF ) 243.7 Hz), 121.9 (t, JCF ) 6.3 Hz), 128.4,
129.5, 129.9, 131.7, 134.8, 141.3 (t, 2JCF ) 27.0 Hz), 150.2, 163.6;
(16) Structural assignation of both isomers 4b and 4b′ was carried out
on the basis of their 1H NMR spectra: compound 4b presents two signals
(5.65 and 6.05 ppm) corresponding to an isolated double bond, whereas
their chemical shifts in 4b′ (5.96 and 6.58 ppm) indicates the conjugation
of the double bond with the uracil ring.
(17) (a) Moreno-Man˜as, M.; Pleixats, R.; Villarroya, M. Tetrahedron
1993, 49, 1457-1464. (b) Goux, C.; Sigismondi, S.; Sinou, D.; Pe´rez, M.;
Moreno-Man˜as, M.; Pleixats, R.; Villarroya, M. Tetrahedron 1996, 52,
9521-9534.
(18) These modifications included longer reaction times, higher amounts
of catalyst (up to 25 mol %), or the use of different solvents, e.g.,
trifluorotoluene.
(20) Acaricide Assay. Bean leaf disks (2 cm diameter) were sprayed
by using a Potter tower with an aqueous solution of the compound, a
commercial solution of tebufenpyrad [N-(4-tert-butylbenzyl)-4-chloro-3-
ethyl-1-methyl-1H-pyrazole-5-carboxamide, containing 1.5 mg/mL of active
component] or H2O as control (0.1% of a wetting agent was added to all
solutions). Adult female mites were transferred to the disks (3 mites per
disk) and placed on Petri dishes supported by wet cotton pads. The mites
were kept at 20-25 °C, 50-80% relative humidity and a 16:8 h photoperiod
(light:dark). The number of surviving mites and eggs were counted after
24, 96, and 144 h, and percent mortality was calculated using Abbott’s
equation, which corrects for mortality in the controls: [(number surviving
in control - number surviving treatment)/number surviving in control] ×
100.
(19) Kim, Y.-J.; Lee. H.-S.; Lee, S.-W.; Kim, G.-H.; Ahn, Y.-J. J. Econ.
Entomol. 1999, 92, 187-192.
4012 J. Org. Chem., Vol. 71, No. 10, 2006

CHART 3. Bicyclic Uracils (Yields of the RCM Reaction in Brackets)
3
1
4JCF ) 5.4 Hz), 102.1 (t, JCF ) 7.7 Hz), 117.2 (t, JCF ) 246.3
TABLE 2. Acaricide Activities of Fluorinated Uracils
3
Hz), 117.3, 121.4, 125.6 (t, JCF ) 5.2 Hz), 126.9, 128.0, 128.4,
[M]
mortality
(%)
fecundity
130.8, 133.6, 145.8 (t, JCF ) 27.6 Hz), 150.7, 160.5; 19F NMR
2
entry compd (mg/mL)
inhibition (%)
(282.4 MHz, CDCl3) δ -95.5 (t, J ) 16.5 Hz, 2F); IR (film) 1720,
1675, 1451, 1381, 1226 cm-1. HRMS (EI) calcd for C17H16F2N2O2
(M+) 318.1180, found 318.1212.
24 h 96 h 144 h 24 h 96 h 144 h
58.8 70.4 86.7 96.8 99.6 100.0
1
tebufen-
pyrad
4b
1.5
2
3
4
5
5.0
4.0
4.5
5.0
0.0
0.0
0.0 15.5 57.0
86.7 78.6 46.7
81.5
68.3
74.7
84.5
5,5-Difluoro-5,6-dihydro-2-phenylpyrimido[1,6a]azepine-1,3-
(2H,9H)-dione (5a). Starting from 12a, and after subsequent
purification of the crude product by means of flash chromatography
(n-hexane/EtOAc, 2:1), Method A gave 5a as a white solid (93%
4e
38.2 66.7
4e′
5d
11.8 56.6 100.0 57.1 53.3
33.8 16.7 73.3 70.2 72.8
1
yield): Rf ) 0.36 (n-hexane/EtOAc, 2:1); mp 136-138 °C; H
19F NMR (282.4 MHz, CDCl3) δ -92.7 (t, JHF ) 15.4 Hz, 2F); IR
NMR (300 MHz, CDCl3) δ 3.00 (tq, J ) 15.6, 1.9 Hz, 2H), 4.70
(dt, J ) 4.3, 1.4 Hz, 2H), 5.63-5.69 (m, 1H), 5.87-5.94 (m, 1H),
6.19 (s, 1H), 7.12-7.15 (m, 2H), 7.35-7.44 (m, 3H); 13C NMR
(75.5 MHz, CDCl3) δ 37.6 (t, 2JCF ) 27.6 Hz), 39.6 (t, 4JCF ) 5.1
(film) 3186, 3128, 1723, 1652, 1495, 1423, 1329, 1193 cm-1
.
HRMS (EI) calcd for C15H12F2N2O2 (M+) 290.0867, found 290.0816.
9,9-Difluoro-8,9-dihydro-3-phenyl-1H-cyclohepta[d]pyrimi-
dine-2,4(3H,7H)-dione (4b′). Starting with 9c, and after subsequent
purification of the crude product by means of flash chromatography
(n-hexane/EtOAc, 2:1), Method B gave 4b′ as a white solid (70%
3
1
Hz), 99.5 (t, JCF ) 8.6 Hz), 116.1 (t, JCF ) 245.1 Hz), 123.6,
123.8 (t, 3JCF ) 6.3 Hz), 126.9, 127.9, 128.4, 133.9, 147.2 (t, 2JCF
) 28.4 Hz), 150.4, 160.6; 19F NMR (282.4 MHz, CDCl3) δ -97.1
(t, J ) 15.9 Hz, 2F); IR (film) 1716, 1690, 1452, 1365, 1205, 1101
cm-1. HRMS (EI) calcd for C15H12F2N2O2 (M+) 290.0866, found
290.0950.
1
yield): Rf ) 0.32 (n-hexane/EtOAc, 2:1); mp 247-249 °C; H
NMR (300 MHz, CDCl3) δ 2.35-2.44 (m, 2H), 2.47-2.54 (m,
2H), 5.96 (dt, J ) 12.4, 5.0 Hz, 1H), 6.58 (dt, J ) 12.4, 1.8 Hz,
1H), 7.16-7.19 (m, 2H), 7.36-7.48 (m, 3H), 8.09 (br, 1H); 13C
5,5-Difluoro-5,6-dihydro-2-phenylpyrimido[1,6a]azepine-1,3-
(2H,5H)-dione (5a′). Starting from 12a, and after subsequent
purification of the crude product by means of flash chromatography
(n-hexane/EtOAc, 2:1), Method B gave a mixture of 5a (33% yield)
and 5a′ (67% yield). Data for 5a′: Rf ) 0.30 (n-hexane/EtOAc,
2:1); mp 98-100 °C; 1H NMR (300 MHz, CDCl3) δ 2.36 (q, J )
7.1 Hz, 2H), 2.58 (tt, J ) 15.1, 7.1 Hz, 2H), 5.74 (dt, J ) 7.1, 6.8
Hz, 1H), 6.22 (s, 1H), 6.67 (d, J ) 8.3 Hz, 1H), 7.16-7.19 (m,
2H), 7.36-7.39 (m, 3H); 13C NMR (75.5 MHz, CDCl3) δ 19.4 (t,
3JCF ) 5.3 Hz), 38.8 (t, 2JCF ) 24.6 Hz), 100.9 (t, 3JCF ) 9.1 Hz),
117.4 (t, 1JCF ) 245.6 Hz), 120.3, 126.2, 127.9, 129.1, 129.4, 134.2,
3
2
NMR (75.5 MHz, CDCl3) δ 23.3 (t, JCF ) 6.4 Hz), 32.5 (t, JCF
) 24.6 Hz), 109.3, 118.0 (t, 1JCF ) 243.8 Hz), 118.6, 128.0, 129.1,
129.5, 131.9, 134.3, 139.8 (t, JCF ) 26.9 Hz), 149.2, 162.9; 19F
2
NMR (282.4 MHz, CDCl3) δ -93.2 (t, JHF ) 14.4 Hz, 2F); IR
(film) 3122, 2983, 1720, 1657, 1436, 1411, 1340, 1205, 1116, 1064
cm-1; HRMS (EI) calcd for C15H12F2N2O2 (M+) 290.0867, found
290.0872.
General Procedure for Preparation of Compounds 12. A
solution of allyl acetate (4.0 mmol) in THF (1.5 mL) was transferred
to a flask containing bis(dibenzylideneacetone)palladium (0.08
mmol) and 1,4-bis(diphenylphosphino)butane (0.16 mmol). This
solution was added to a mixture of compound 9 (1.0 mmol) in water
(4 mL). After being heated at 60 °C for 27 h, the mixture was
partitioned between CH2Cl2 and water. The organic layer was then
dried and concentrated. The residue was digested with Et2O, the
ethereal filtrate was concentrated, and the residue was purified by
means of column chromatography on silica gel with n-hexanes/
ethyl acetate mixtures of increasing polarity to afford 1-allyluracils
12.
2
147.4 (t, JCF ) 28.6 Hz), 150.4, 161.2; 19F NMR (282.4 MHz,
CDCl3) δ -91.8 (t, J ) 14.6 Hz, 2F); IR (film) 1719, 1675, 1468,
1383, 1349, 1148, 1128 cm-1. HRMS (EI) calcd for C15H12F2N2O2
(M+) 290.0866, found 290.0856.
Acknowledgment. The authors wish to thank the Ministerio
de Educacio´n y Ciencia (BQU2003-01610) and the Generalitat
Valenciana of Spain (GR03-193 and GV05/079) for financial
support. S.C. and B.F. thank the Ministerio de Educacio´n y
Ciencia for predoctoral (FPU) fellowships.
1-Allyl-6-(1,1-difluorobut-3-enyl)-3-phenylpyrimidine-2,4-
(1H,3H)-dione (12a). Flash chromatography (n-hexane/EtOAc, 4:1
to 2:1) of the crude reaction mixture on silica gel gave 12a as a
white solid (60% yield): Rf ) 0.42 (n-hexane/EtOAc, 2:1); mp
Supporting Information Available: Characterization data for
compounds 4c-g, 4c′, 4e′, 5b-e, 8a-c, 9a-l, and 12b-e; copies
of the NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
86-88 °C; H NMR (300 MHz, CDCl3) δ 2.95 (td, J ) 17.6, 7.0
Hz, 2H), 4.54 (d, J ) 5.4 Hz, 2H), 5.15-5.30 (m, 4H), 5.67-5.89
(m, 2H), 6.08 (s, 1H), 7.12-7.16 (m, 2H), 7.36-7.46 (m, 3H);
2
13C NMR (75.5 MHz, CDCl3) δ 40.1 (t, JCF ) 25.6 Hz), 47.8 (t,
JO0601765
J. Org. Chem, Vol. 71, No. 10, 2006 4013