Synthesis of fluorinated pyrimidinones

Article abstract of DOI:10.1016/j.jfluchem.2013.06.018

A method for the construction of fluorinated pyrimidinones based on the reaction of cyanodifluoromethyl- substituted amines with isocyanates is described. The use of ortho-iodophenylisocyanate in this reaction followed by copper catalyzed intramolecular amination affords fluorinated fused heterocycles - 4-fluoropyrimido[1,6-a]benzimidazol-1(2H)-ones.

Full text of DOI:10.1016/j.jfluchem.2013.06.018

Journal of Fluorine Chemistry 154 (2013) 73–79
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of fluorinated pyrimidinones
Mikhail D. Kosobokov a, Marina I. Struchkova a, Dmitry E. Arkhipov b,
Alexander A. Korlyukov b, Alexander D. Dilman a,
*
a N.D. Zelinsky Institute of Organic Chemistry, Leninsky prosp. 47, 119991 Moscow, Russian Federation
b A.N. Nesmeyanov Institute of Organoelement Compounds, Vavilov str. 28, 119991 Moscow, Russian Federation
A R T I C L E I N F O
A B S T R A C T
Article history:
A method for the construction of fluorinated pyrimidinones based on the reaction of cyanodifluor-
omethyl-substituted amines with isocyanates is described. The use of ortho-iodophenylisocyanate in
this reaction followed by copper catalyzed intramolecular amination affords fluorinated fused
heterocycles – 4-fluoropyrimido[1,6-a]benzimidazol-1(2H)-ones.
Received 22 May 2013
Received in revised form 25 June 2013
Accepted 30 June 2013
Available online 10 July 2013
ß 2013 Elsevier B.V. All rights reserved.
Keywords:
Heterocycles
Isocyanates
Cyclization
Pyrimidinones
Coupling reaction
1. Introduction
nucleophilic amine and an electrophilic nitrile group, and reaction
of this 1,4-bipolar system with an appropriate double or triple
The ability of fluorine to modify biological properties of organic
compounds has sparked the interest to partially fluorinated
molecules [1]. Since heterocycles are ubiquitous in pharmaceu-
ticals, compounds containing one or two fluorine atoms in the ring
have gained significant attention in medicinal chemistry [2].
Among diverse classes of fluorinated heterocycles, derivatives of
pyrimidinones and pyrimidinediones have become particularly
important exhibiting anti-cancer, antiviral, and antifungal activi-
ty [1b,2b,3,4]. Fluorinated uracil and cytosine were the first
examples of successful drugs of this type followed by numerous
analogs (Fig. 1). The conventional synthetic approach toward
mono- and difluorinated pyrimidinones involves fluorination of
parent heterocycles using elemental fluorine or O–F and N–F
reagents [5,6]. An alternative method for the preparation of
difluoro-substituted pyrimidinediones (dihydrouracils) based on
building-block strategy was suggested, but the method has a
limited scope [7].
bond is expected to afford heterocyclic molecule. In this work we
demonstrate this concept by using isocyanates as the AB
component [9]. The process affords pyrimidinones (A = CO,
B = NR3) bearing N-unsubstituted imino-function, which can be
further exploited for constructing more complex heterocyles.
2. Results and discussion
First, the reactions of amines
1 with isocyanates were
investigated (Table 1). Due to the presence of fluorine atoms
O
F
O
F
HN
NH
HN
N
O
NH2
Herein we describe a general approach for making fluorinated
six-membered heterocycles based on coupling of three compo-
nents – imines, difluoroacetonitrile carbanion, and a reagent with
electrophilic multiple bond (Scheme 1). Thus, we have recently
described that imines react with difluoro(trimethylsilyl)acetoni-
trile leading to products 1 [8]. The latter compounds possess a
5-fluorouracil
5-fluorocytosine
O
O
O
"
"
F
HN
NH
HN
NH
HN
NH
or
Y
Y
Y
F
F
F
Y = O, NH
* Corresponding author. fax: +7 499 1355328.
Fig. 1. Fluorinated pyrimidinones.
E-mail addresses: adil25@mail.ru, dilman@ioc.ac.ru (A.D. Dilman).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.06.018

74
M.D. Kosobokov et al. / Journal of Fluorine Chemistry 154 (2013) 73–79
Table 1
A
F
A
R2
F
B
R2
B
R2
R1
A
C
Reaction of 3-amino-2,2-difluoropropanenitriles with isocyanates.
N
B
N
NH
F
O
·
R3
N
N
R2
R1
O
O
R3
R1
N
NH
R3
R2
R1
R2
R1
R3
NH
F
base
F
F
N
(1.2 equiv)
N
N
N
H
CN
F
R1
1
.
i
ii
CN
N
H
O
F
A
1
F
F
F
F
N
this work
B
2
3
i: neat, 130 °C, 1-5 h
ii: NEt3 or DBU (1.2 equiv), MeCN, rt, 1 h
Scheme 1. Approach to six-membered heterocycles.
R1
R2 R3
1
2
Time
Yield
3
Base Yield
for 1 ! 2, h of 2,a
%
of 3,a
%
O
O
O
Me
Ph
Ar
Me
Ph
Ar
O
Me
Ph
Ar
O
Ph
Ph
Me Ph
1a 2a
3
1
3
95
95
83
3a NEt3 95
3b NEt3 97
3c NEt3 98
i
ii
N
N
N
N
N
N
Me 4-ClC6H4 1a 2b
Bn Ph 1b 2c
N
H
S
F
F
F F
F
80b
93
3d NEt3 99
3e DBU 78
4, 91%
i: HCl, dioxane/H2O, rt, 1 h
ii: Cs2CO3, DMF, 100 °C, 2 h
5, 72%
Bn 4-ClC6H4 1b 2d
3
5
3b, Ar = 4-ClC6H4
S
Ph
Me Pr
1a 2ec
a
b
c
Isolated yield.
Scheme 2. Synthesis of fluorouracil 5.
Additionally, ca. 10% of heterocycle 3d was formed.
Performed using 3 equiv. of PrNCO.
Fig. 2. The molecular structures of compounds 3a (left) and 7a (right). Non-hydrogen atoms are presented by thermal ellipsoids at 50% probability.
Table 2
Synthesis of fused heterocycles 7.
OCN
O
O
R2
R1
N
H
i
R2
R1
I
N
I
N
N
1
I
CN
130 °C
N
H
F
F
F
F
2
3
O
O
F
R2
R2
R1
N
N
N
N
R1
N
N
F
F
6
7
i: 10% CuI, 10% proline
Cs2CO3 (3 equiv), DMF, 90 °C, 2 h
.
R1
R2
1
2
Time for 1 ! 2, h
Yield of 2,a
%
7
Yield of 7,a
%
Ph
Me
Bn
1a
1b
2f
2
5
94
67
7a
81
80
2g
7b
S
Me
1c
2h
2
96
7c
77
1-Naphthyl
4-MeOC6H4
Me
Et
1d
1e
2i
2j
2
3
95
92
7d
7eb
79
75
a
Isolated yield.
b
Reaction time 5 h.

M.D. Kosobokov et al. / Journal of Fluorine Chemistry 154 (2013) 73–79
75
and cyano group, amines 1 have decreased nucleophilicity and,
contrary to regular secondary N,N-dialkylamines, required heating
at 130 8C with isocyanates in the absence of solvent. The ureas 2
were isolated in excellent yield and purity, except urea 2d, which
contained about 10% of cyclized heterocycle 3d. Cyclization of
ureas 2a-d into iminopyrimidinones 3a–d occurred readily and
quantitatively in the presence of triethylamine (1.2 equiv.).
However, urea 2e bearing an N-propyl substituent did not react
under standard conditions, and employment of a stronger base 1,8-
diazabicycloundec-7-ene (DBU) was necessary to obtain product
3e. In solution compounds 3 exist as mixtures of geometrical
isomers owing to the C55N bond, whereas X-ray analysis of a single
crystal of the heterocycle 3a showed only one isomer (Fig. 2) [10].
When crystals corresponding to one isomer, for which the
structure was determined by X-ray analysis, were dissolved in
CDCl3, 19F NMR spectrum showed two isomers. This fact suggests
that inversion of nitrogen lone pair within the C55N–H fragment
has moderate activation barrier, and, as a result, the position of
equilibrium between geometrical isomers may depend on the
medium.
electrospray ionization (ESI) and time-of-flight (TOF) mass
analyzer. The measurements were done in a positive ion mode
(interface capillary voltage – 4500 V) or in a negative ion mode
(3200 V); mass range from m/z 50 to m/z 3000 Da. 2,2-Difluoro-
3-(methylamino)-3-phenylpropanenitrile (1a) and difluoro(tri-
methylsilyl)acetonitrile were obtained according to literature
procedures [8]. 2-Iodophenylisocyanate was obtained from 2-
iodoaniline and diphosgene [13]. Imines were obtained by
condensation of aldehydes and imines [14]. Other chemicals
were commercially available (Aldrich, Acros) and were used
as-received. Column chromatography was carried out employ-
ing Merck silica gel (Kieselgel60, 230–400 mesh). Precoated
silica gel plates F-254 were used for thin-layer analytical
chromatography visualizing with UV and/or acidic aq. KMnO4
solution. For microscale distillation, the provided boiling points
correspond to bath temperature.
4.2. Synthesis of amines 1b-e
CF3CO2H (0.96 mL, 12.5 mmol) was added to a mixture of
imine (10 mmol) and KHF2 (580 mg, 7.5 mmol) in acetonitrile
(30 mL) at 0 8C, and the suspension was stirred for 5 min.
Difluoro(trimethylsilyl)acetonitrile (2.24 g, 15 mmol) was
added, and the mixture was stirred for 18 h at room
temperature. Saturated aqueous Na2CO3 (20 mL) was added
dropwise, the mixture was stirred for 2 min, diluted with water
(150 mL) and extracted with ether/hexane (1/1, 3 ꢀ 50 mL). The
combined organic phase was filtered through Na2SO4, concen-
trated, and the residue was purified by chromatography
(hexanes/EtOAc).
The opportunity to synthesize fluorouracils was exemplified
by transformation of the iminopyrimidinone 3b (Scheme 2).
Thus, the imino group of 3b was hydrolyzed under acidic
conditions to give the dione 4, from which one fluorine was
eliminated in the presence of Cs2CO3 furnishing 5-fluoro-
substituted uracil 5.
To demonstrate the utility of the present methodology for
accessing more complex fluorinated heterocycles, we decided to
exploit functionalization of the N–H group of the iminopyrimidi-
nones. The use of isocyanate bearing iodine in ortho-position
provides ureas 2 (Table 2). It was found that heating of iodo-
substituted ureas 2 at 90 8C in the presence of Cs2CO3 and catalytic
amounts of CuI and proline [11] afforded monofluorinated fused
4-fluoropyrimido[1,6-a]benzimidazol-1(2H)-ones 7 in good yields.
The reaction likely involves copper catalyzed cyclization [11] of
iminopyrimidinones 3 generating intermediate 6 followed by
elimination of HF. To support this mechanism, we were able to
isolate difluorinated heterocycle 6e when the copper catalyzed
coupling was performed at 50 8C. The structure of the heterocycle
7a was verified by X-ray analysis (Fig. 2) [10]. Thus, we have
demonstrated that our isocyanate/coupling sequence constitutes a
straightforward construction of pyrimido [1,6-a]benzimidazol-
1(2H)-one heterocycles [12].
4.2.1. 3-(Benzylamino)-2,2-difluoro-3-thien-2-ylpropanenitrile (1b)
Yield: 2.14 g (7.7 mmol, 77%). Colorless crystals. mp 27–28 8C,
bp 123–130 8C (bath temp)/0.2 Torr. Chromatography (hexanes/
EtOAc 20/1 ! 15/1), Rf 0.30 (hexanes/EtOAc 20/1). 1H NMR
(300 MHz, CDCl3) d: 2.16 (s, 1H), 3.89 (d, 1H, J = 13.2), 4.09 (d,
1H, J = 13.2), 4.52 (dd, 1H, J = 12.6, 7.9), 7.15–7.22 (m, 1H), 7.23–
7.29 (m, 1H), 7.40–7.52 (m, 6H). 13C NMR (75 MHz, CDCl3)
: 50.9,
d
60.8 (t, J = 25.4), 110.9 (t, J = 248.8), 111.8 (t, J = 45.3), 127.0, 127.2,
127.5, 128.2, 128.3, 128.5, 135.0 (d, J = 2.2), 138.1. 19F NMR
(282 MHz, CDCl3)
12.6). Calcd for C14H12F2N2S: C, 60.42; H, 4.35; N, 10.07. Found: C,
60.69; H, 4.14; N, 10.28.
d
: ꢁ94.8 (dd, J = 286.1, 7.9), ꢁ100.2 (dd, J = 286.1,
3. Conclusions
4.2.2. 2,2-Difluoro-3-(2-furyl)-3-(methylamino)propanenitrile (1c)
Yield: 1.24 g, (6.7 mmol, 67%). Colorless oil. bp 94–101 8C (bath
temp)/12 Torr. Chromatography (hexanes/EtOAc 20/1 ! 10/1), Rf
We have disclosed
a convenient method for assembling
difluorinated iminopyrimidinones from isocyanates and secondary
amines originating from imines and difluoro(trimethylsilyl)ace-
tonitrile. This methodology can be used for the synthesis of 5-
fluorouracil derivatives, as well as for construction of fluoro-
substituted fused heterocycles.
0.44 (hexanes/EtOAc 10/1). 1H NMR (300 MHz, CDCl3)
d: 1.72 (s,
1H), 2.50 (s, 3H), 4.13 (dd, 1H, J = 12.6, 8.3), 6.42–6.45 (m, 1H),
6.49–6.52 (m, 1H), 7.47–7.50 (m, 1H). 13C NMR (75 MHz, CDCl3)
d
:
34.7, 62.4 (dd, J = 24.8, 25.8), 110.6 (t, J = 249.9), 110.65, 110.72,
111.8 (t, J = 44.9), 143.7, 146.2 (d, J = 3.5). 19F NMR (282 MHz,
CDCl3)
d
: ꢁ100.2 (dd, J = 286.1, 12.6), ꢁ95.9 (dd, J = 286.1, 8.3).
4. Experimental
Calcd for C8H8F2N2O: C, 51.61; H, 4.33; N, 15.05. Found: C, 51.75; H,
4.39; N, 15.19.
4.1. General experimental procedures
4.2.3. 2,2-Difluoro-3-(methylamino)-3-(1-naphthyl)propanenitrile
(1d)
All reactions were performed under an argon atmosphere.
Acetonitrile was distilled from CaH2 and stored under molecular
Yield: 1.82 g (7.4 mmol, 74%). Colorless oil. bp 140–145 8C (bath
temp)/0.25 Torr. Chromatography (hexanes/EtOAc 10/1 ! 5/1), Rf
˚
sieves 4 A. DMF was distilled under vacuum from P2O5 and stored
˚
over MS 4 A. Column chromatography was carried out employing
0.38 (hexanes/EtOAc 10/1). 1H NMR (300 MHz, CDCl3)
d: 1.91 (s,
silica gel (230–400 mesh). For NMR measurements, CDCl3 was
distilled from CaH2. Coupling constants (J) are given in Hz. NMR
1H), 2.54 (s, 3H), 5.08 (t, 1H, J = 9.3), 7.54–7.71 (m, 3H), 7.84–7.91
(m, 1H), 7.94–8.01 (m, 2H), 8.11–8.18 (m, 1H). 13C NMR (75 MHz,
spectra were recorded on
Microanalyses were performed on KarloErba 1106 instrument.
High resolution mass spectra (HRMS) were measured using
a
Bruker AM-300 instrument.
CDCl3)
J = 249.9), 122.4, 125.3, 125.5, 126.0, 126.8, 128.9 (d, J = 3.5), 129.1,
130.0, 132.4, 133.9. 19F NMR (282 MHz, CDCl3)
: ꢁ97.4 (dd,
d: 34.9, 62.6 (t, J = 25.3), 112.0 (t, J = 44.9), 112.7 (t,
d

76
M.D. Kosobokov et al. / Journal of Fluorine Chemistry 154 (2013) 73–79
J = 288.2, 9.3), ꢁ92.8 (dd, J = 288.2, 9.3). Calcd for C14H12F2N2: C,
(hexanes/EtOAc 3/1). 1H NMR (300 MHz, CDCl3)
6.55 (br, 1H), 6.92–7.57 (m, 13H). 13C NMR (75 MHz, CDCl3)
d
: 4.68 (s, 2H),
: 48.3,
68.28; H, 4.91; N, 11.38. Found: C, 68.27; H, 4.80; N, 11.28.
d
56.5 (t, J = 24.2), 110.1 (t, J = 252.2), 111.5 (t, J = 43.8), 121.3, 126.2,
4.2.4. 3-(Ethylamino)-2,2-difluoro-3-(4-
127.5, 128.0, 128.4, 128.6, 128.8, 129.4, 129.9, 131.2, 135.4, 136.4,
methoxyphenyl)propanenitrile (1e)
155.1. 19F NMR (282 MHz, CDCl3)
d
: ꢁ95.9 (dd, J = 287.2, 14.8),
Yield: 1.73 g (7.2 mmol, 72%). Colorless oil. bp 112–120 8C (bath
temp)/0.8 Torr. Chromatography (hexanes/EtOAc 20/1 ! 10/1), Rf
ꢁ94.8 (dd, J = 287.2, 14.8). HRMS (ESI) Calcd for C21H17ClF2N3OS
(M+H): 432.0738. Found: 432.0743.
0.45 (hexanes/EtOAc 10/1). 1H NMR (300 MHz, CDCl3)
d: 1.13 (t,
3H, J = 7.3), 1.54 (s, 1H), 2.61–2.77 (m, 2H), 3.84 (s, 3H), 4.10 (t, 1H,
J = 10.1), 6.96 (d, 2H, J = 8.8), 7.37 (d, 2H, J = 8.8). 13C NMR (75 MHz,
4.3.5. N-(2-Cyano-2,2-difluoro-1-phenylethyl)-N-methyl-N0-
propylurea (2e)
CDCl3)
(t, J = 248.2), 114.3, 125.0 (d, J = 3.5), 129.7, 160.5. 19F NMR
(282 MHz, CDCl3)
10.1). Calcd for C12H14F2N2O: C, 59.99; H, 5.87; N, 11.66. Found: C,
60.02; H, 5.81; N, 11.77.
d
: 15.1, 42.1, 55.2, 66.0 (t, J = 24.2), 112.0 (t, J = 45.5), 112.1
A mixture of amine 1a (196 mg, 1 mmol) and propylisocyanate
(255 mg, 3 mmol) was heated in a tightly closed test tube for 5 h at
130 8C. After cooling to room temperature, the excess of
isocyanate was evaporated under vacuum, and the residue was
purified by chromatography (hexanes/EtOAc, 5/1). Yield: 261 mg
(0.93 mmol, 93%). Colorless oil. Chromatography (hexanes/EtOAc
5/1 ! 3/1), Rf 0.22 (hexanes/EtOAc 5/1). 1H NMR (300 MHz,
d
: ꢁ99.2 (dd, J = 286.1, 10.1), ꢁ95.7 (dd, J = 286.1,
4.3. Reaction of amines 1 with arylisocyanates (general procedure)
CDCl3)
3.31 (m, 2H), 5.10 (t, 1H, J = 4.8), 6.48 (dd, 1H, J = 17.5, 12.8), 7.34–
7.43 (m, 5H). 13C NMR (75 MHz, CDCl3)
: 11.0, 23.1, 30.1, 42.9,
d: 0.90 (t, 3H, J = 7.3), 1.48–1.62 (m, 2H), 2.72 (s, 3H), 3.17–
A mixture of amine 1 (1 mmol) and isocyanate (1.2 mmol) was
heated at 130 8C during a certain time (3 h for 2a,c,d,j; 1 h for 2b;
2 h for 2f,h,i; 5 h for 2g). After cooling, the mixture was subjected
to column chromatography (hexanes/EtOAc).
d
59.5 (dd, J = 22.5, 24.8), 111.1 (dd, J = 251.1, 253.4), 111.8 (t,
J = 44.9), 128.4, 128.80, 128.83, 131.1, 158.0. 19F NMR (282 MHz,
CDCl3)
d
: ꢁ95.9 (dd, J = 290.3, 17.5), ꢁ92.9 (dd, J = 290.3, 12.8).
4.3.1. N-(2-Cyano-2,2-difluoro-1-phenylethyl)-N-methyl-N0-
phenylurea (2a)
HRMS (ESI) Calcd for C14H17F2N3ONa (M+Na): 304.1237. Found:
304.1232.
Yield: 300 mg (0.95 mmol, 95%). Colorless crystals. mp 128–
130 8C. Chromatography (hexanes/EtOAc 5/1), Rf 0.43 (hexanes/
4.3.6. N-(2-Cyano-2,2-difluoro-1-phenylethyl)-N0-(2-iodophenyl)-N-
methylurea (2f)
EtOAc 5/1). 1H NMR (300 MHz, CDCl3)
d
: 2.88 (s, 3H), 6.56 (dd, 1H,
J = 13.9, 16.5), 6.85 (s, 1H), 7.07–7.15 (m, 1H), 7.27–7.36 (m, 2H),
7.40–7.51 (m, 7H). 13C NMR (75 MHz, CDCl3)
: 30.8, 59.5 (dd,
J = 23.0, 25.1), 110.9 (dd, J = 251.1, 253.1), 111.8 (t, J = 44.4), 120.8,
124.0, 128.6 (t, J = 1.7), 128.8, 129.1, 129.2, 130.8, 138.1, 155.7. 19
NMR (282 MHz, CDCl3)
Yield: 415 mg (0.94 mmol, 94%). Colorless crystals. mp 118–
120 8C. Chromatography (hexanes/EtOAc 3/1), Rf 0.22 (hexanes/
d
EtOAc 3/1). 1H NMR (300 MHz, CDCl3)
d
: 3.03 (s, 3H), 6.59 (t, 1H,
J = 15.3), 6.84 (t, 1H, J = 7.3), 7.12 (s, 1H), 7.30–7.56 (m, 6H), 7.78 (d,
1H, J = 7.3), 8.22 (d, 1H, J = 7.3). 13C NMR (75 MHz, CDCl3)
: 31.1,
F
d
: ꢁ95.4 (dd, J = 292.5, 16.5), ꢁ93.2 (dd,
d
J = 292.5, 13.9). Calcd for C17H15F2N3O: C, 64.75; H, 4.79; N, 13.33.
59.5 (t, J = 24.2), 90.6, 110.7 (dd, J = 250.9, 259.0), 111.7 (t, J = 44.4),
121.6, 125.4, 128.6 (t, J = 1.7), 129.15, 129.20, 129.26, 130.7, 138.5,
Found: C, 64.87; H, 4.68; N, 13.31.
138.6, 155.1. 19F NMR (282 MHz, CDCl3)
d
: ꢁ95.2 (dd, J = 292.5,
4.3.2. N0-(4-Chlorophenyl)-N-(2-cyano-2,2-difluoro-1-phenylethyl)-
N-methylurea (2b)
15.3), ꢁ93.4 (dd, J = 292.5, 15.3). Calcd for C17H14F2IN3O: C, 46.28;
H, 3.20; N, 9.52. Found: C, 46.26; H, 3.12; N, 9.53.
Yield: 332 mg (0.95 mmol, 95%). Colorless crystals. mp 141–
144 8C. Chromatography (hexanes/EtOAc 3/1), Rf 0.44 (hexanes/
4.3.7. N-Benzyl-N-(2-cyano-2,2-difluoro-1-thien-2-ylethyl)-N0-(2-
iodophenyl)urea (2g)
EtOAc 3/1). 1H NMR (300 MHz, CDCl3)
d
: 2.88 (s, 3H), 6.50 (dd, 1H,
J = 16.7, 13.1), 6.82 (s, 1H), 7.25 (d, 2H, J = 8.8), 7.36 (d, 2H, J = 8.8),
7.41–7.51 (m, 5H). 13C NMR (75 MHz, CDCl3)
: 30.9, 59.6 (t,
Yield: 350 mg (0.67 mmol, 67%). Colorless crystals. mp 27–
28 8C. Chromatography (hexanes/EtOAc 10/1 ! 5/1), Rf 0.17
d
J = 23.6), 110.8 (t, J = 252.3), 111.8 (t, J = 44.4), 122.0, 128.6, 128.9,
129.1, 129.2, 129.3, 130.6, 136.7, 155.5. 19F NMR (282 MHz, CDCl3)
(hexanes/EtOAc 5/1). 1H NMR (300 MHz, CDCl3)
d: 4.81 (s, 2H),
6.74–6.83 (m, 1H), 6.88 (s, 1H), 7.00–7.17 (m, 2H), 7.22–7.50 (m,
8H), 7.63–7.69 (m, 1H), 8.05–8.11 (m, 1H). 13C NMR (75 MHz,
CDCl3) d: 48.3, 56.6 (t, J = 24.2), 89.7, 110.0 (t, J = 252.2), 111.5 (t,
d
C
: ꢁ95.5 (dd, J = 292.5, 16.7), ꢁ93.5 (dd, J = 292.5, 13.1). Calcd for
17H14ClF2N3O: C, 58.38; H, 4.03; N, 12.01. Found: C, 58.43; H,
4.06; N, 12.10.
J = 44.3), 122.2, 125.3, 126.2, 127.3, 128.0, 128.1, 128.8, 129.1,
130.0, 131.0, 135.0, 138.6, 138.9, 155.3. 19F NMR (282 MHz, CDCl3)
4.3.3. N-Benzyl-N-(2-cyano-2,2-difluoro-1-thien-2-ylethyl)-N0-
phenylurea (2c)
d
C
: ꢁ95.8 (dd, J = 288.2, 14.8), ꢁ94.6 (dd, J = 288.2, 14.8). Calcd for
21H16F2IN3OS: C, 48.20; H, 3.08; N, 8.03. Found: C, 48.35; H, 3.18;
Yield: 330 mg (0.83 mmol, 83%). Colorless crystals. mp 109–
113 8C. Chromatography (hexanes/EtOAc 4/1), Rf 0.25 (hexanes/
N, 7.94.
EtOAc 4/1). 1H NMR (300 MHz, CDCl3)
d
: 4.71 (s, 2H), 6.60 (br, 1H),
4.3.8. N-[2-Cyano-2,2-difluoro-1-(2-furyl)ethyl]-N0-(2-iodophenyl)-
N-methylurea (2h)
7.02–7.53 (m, 14H). 13C NMR (75 MHz, CDCl3)
d
: 48.4, 56.4 (t,
J = 24.2), 110.2 (t, J = 252.2), 111.5 (t, J = 44.3), 120.1, 123.8, 126.2,
Yield: 414 mg (0.96 mmol, 96%). Colorless crystals. mp 91–
93 8C (hexanes). Chromatography (hexanes/EtOAc 3/1), Rf 0.20
127.4, 128.0, 128.4, 128.7, 129.4, 129.9, 131.4, 135.6, 137.8, 155.3.
19F NMR (282 MHz, CDCl3)
J = 286.1, 14.8). HRMS (ESI) Calcd for C21H18F2N3OS (M+H):
d
: ꢁ95.9 (dd, J = 286.1, 14.8), ꢁ94.8 (dd,
(hexanes/EtOAc 3/1). 1H NMR (300 MHz, CDCl3)
d: 3.18 (s, 3H),
6.43–6.73 (m, 3H), 6.84 (t, 1H, J = 7.3), 7.08–7.18 (br, 1H), 7.37 (t,
1H, J = 7.3), 7.50–7.60 (br, 1H), 7.78 (d, 1H, J = 7.3), 8.21 (d, 1H,
J = 7.3). 13C NMR (75 MHz, CDCl3)
d: 31.3, 55.1 (t, J = 25.3), 90.3,
109.4 (t, J = 252.2), 110.7, 111.4 (t, J = 43.8), 112.5, 121.4, 125.3,
129.3, 138.5, 138.6, 143.6, 144.2, 154.7. 19F NMR (282 MHz, CDCl3)
398.1133. Found: 398.1133.
4.3.4. N-Benzyl-N0-(4-chlorophenyl)-N-(2-cyano-2,2-difluoro-1-
thien-2-ylethyl)urea (2d)
Yield: 388 mg (0.90 mmol) of the mixture of 2d and 3d (ca. 9:1),
which corresponds to the 80% yield of 2d. Colorless crystals. mp
112–114 8C. Chromatography (hexanes/EtOAc 3/1), Rf 0.44
d
C
: ꢁ96.8 (dd, J = 290.3, 13.3), ꢁ95.4 (dd, J = 290.3, 13.3). Calcd for
15H12F2IN3O2: C, 41.78; H, 2.81; N, 9.75. Found: C, 41.87; H, 2.77;
N, 9.71.

M.D. Kosobokov et al. / Journal of Fluorine Chemistry 154 (2013) 73–79
77
4.3.9. N-[2-Cyano-2,2-difluoro-1-(1-naphthyl)ethyl]-N0-(2-
iodophenyl)-N-methylurea (2i)
(dd, J = 261.2, 12.5, minor), ꢁ98.2 (dd, J = 256.4, 12.5, major). HRMS
(ESI) Calcd for C17H15ClF2N3O (M+H): 350.0866. Found: 350.0863.
Yield: 466 mg (0.95 mmol, 95%). Colorless crystals. mp 132–
134 8C (hexanes/EtOAc 1/1). Chromatography (hexanes/EtOAc 3/
4.4.3. 1-Benzyl-5,5-difluoro-4-imino-3-phenyl-6-thien-2-
yltetrahydropyrimidin-2(1H)-one (3c)
Yield: 195 mg (0.49 mmol, 98%). Mixture of isomers 1.6/1.
Colorless crystals. mp 142–144 8C. 1H NMR (300 MHz, CDCl3)
d:
3.98–4.16 (m, 1H), 4.96–5.09 (m, 1H), 5.44–5.54 (m, 1H), 7.06–7.18
(m, 2H), 7.33–7.64 (m, 11H), 8.36–8.42 (br). 13C NMR (75 MHz,
1 ! 1/1), Rf 0.25 (hexanes/EtOAc 3/1). 1H NMR (300 MHz, CDCl3)
d:
2.95 (s, 3H), 6.88 (t, 1H, J = 7.3), 7.06 (br, 1H), 7.18 (dd, 1H, J = 16.1,
13.6), 7.44 (t, 1H, J = 7.3), 7.54–7.67 (m, 3H), 7.79 (d, 1H, J = 7.3),
7.88 (d, 1H, J = 7.3), 7.91–8.03 (m, 2H), 8.14 (d, 1H, J = 8.1), 8.33 (d,
1H, J = 8.1). 13C NMR (75 MHz, CDCl3)
d: 30.8, 56.8 (t, J = 23.0), 90.6,
111.2 (dd, J = 250.5, 253.4), 112.0 (t, J = 43.8), 121.8, 123.0, 124.7,
CDCl3) d: 49.9 (major), 50.0 (minor), 57.3 (dd, J = 30.5, 28.5), 57.8 (t,
125.4, 126.6, 127.0 (br), 128.0, 129.1, 129.4, 130.7, 131.7, 134.1,
J = 29.6), 108.7 (dd, J = 247.9, 243.0, major), 110.4 (dd, J = 251.1,
243.6, minor), 127.2, 127.5, 127.61, 127.63, 128.17, 128.20, 128.3,
128.5, 128.58, 128.60, 128.7, 128.9, 129.0, 129.2, 129.29, 129.32,
129.7, 130.3, 133.7 (d, J = 7.5), 134.02 (d, J = 7.5), 134.03 (d, J = 1.1),
135.0, 135.1, 136.4 (d, J = 1.2), 150.5 (minor), 151.1 (dd, J = 27.4,
24.5, minor), 151.5 (major), 155.5 (dd, J = 32.2, 25.9, major). 19F
138.6, 138.8, 154.8. 19F NMR (282 MHz, CDCl3)
d
: ꢁ95.9 (dd,
J = 290.3, 16.1), ꢁ93.2 (dd, J = 290.3, 13.6). Calcd for C21H16F2IN3O:
C, 51.34; H, 3.28; N, 8.55. Found: C, 51.18; H, 3.19; N, 8.58.
4.3.10. N-[2-Cyano-2,2-difluoro-1-(4-methoxyphenyl)ethyl]-N-
ethyl-N0-(2-iodophenyl)urea (2j)
NMR (282 MHz, CDCl3)
d
: ꢁ118.7 (d, J = 259.7, minor), ꢁ117.3 (d,
Yield: 446 mg (0.92 mmol, 92%). Colorless crystals. mp 46–
49 8C (Et2O). Chromatography (hexanes/EtOAc 3/1), Rf 0.30
J = 255.4, major), ꢁ101.32 (dd, J = 259.7, 10.6, minor), ꢁ100.9 (dd,
J = 255.4, 10.6, major). HRMS (ESI) Calcd for C21H18F2N3OS (M+H):
398.1133. Found: 398.1126.
(hexanes/EtOAc 3/1). 1H NMR (300 MHz, CDCl3)
d: 1.16 (t, 3H,
J = 6.6), 3.41–3.51 (m, 2H), 3.83 (s, 3H), 6.51 (t, 1H, J = 15.5), 6.82 (t,
1H, J = 7.3), 6.98 (d, 2H, J = 8.4), 7.12 (s, 1H), 7.36 (t, 1H, J = 7.3), 7.47
(d, 2H, J = 8.4), 7.77 (d, 1H, J = 8.1), 8.27 (d, 1H, J = 8.1). 13C NMR
4.4.4. 1-Benzyl-3-(4-chlorophenyl)-5,5-difluoro-4-imino-6-thien-2-
yltetrahydropyrimidin-2(1H)-one (3d)
(75 MHz, CDCl3)
J = 251.1), 111.8 (t, J = 43.8), 114.5, 121.4, 122.8, 125.0, 129.1,
130.4, 138.5, 138.8, 154.5, 160.1. 19F NMR (282 MHz, CDCl3)
d
: 14.2, 38.9, 55.1, 59.2 (t, J = 24.2), 89.9, 110.8 (t,
Yield: 213 mg (0.49 mmol, 99%). Mixture of isomers 3/1.
Colorless crystals. mp 112–114 8C. 1H NMR (300 MHz, CDCl3)
d:
d
:
3.98–4.14 (m, 1H), 4.95–5.09 (m, 1H), 5.37–5.50 (m, 1H), 7.04–7.16
(m, 2H), 7.24–7.61 (m, 10H), 8.37–8.45 (br). 13C NMR (75 MHz,
CDCl3) d: 50.0 (major), 50.1 (minor), 57.3 (dd, J = 30.5, 28.5, major),
ꢁ94.7 (d, 2F, J = 15.5). Calcd for C19H18F2IN3O2: C, 47.03; H, 3.74; N,
8.66. Found: C, 46.94; H, 3.84; N, 8.58.
57.8 (t, J = 29.2, minor), 108.7 (dd, J = 248.2, 243.3, major), 110.3
(dd, J = 251.5, 244.6, minor), 127.3, 127.6, 127.70, 127.73, 128.3,
128.6, 128.7, 128.9, 129.6, 130.2, 130.6, 130.7, 132.5, 134.6, 133.6
(d, J = 7.5), 133.9 (d, J = 8.1), 134.83, 134.85, 135.0, 135.8, 150.3
(minor), 150.9 (dd, J = 27.6, 24.2, minor), 151.3 (major), 155.4 (dd,
4.4. Synthesis of heterocycles 3a–d (general procedure)
Triethylamine (825
mL, 0.6 mmol) was added to a solution of
urea 2a–d (0.5 mmol) in acetonitrile (1 mL) at 0 8C, and the mixture
was stirred for 1 h at room temperature. The solvent was
evaporated, and the residue was passed through short silica gel
pad eluting with EtOAc. The eluent was evaporated, and the
residue was dried under vacuum.
J = 32.8, 26.5, major). 19F NMR (282 MHz, CDCl3)
d
: ꢁ118.7 (d,
J = 260.7, minor), ꢁ117.3 (d, J = 256.4, major), ꢁ101.4 (dd, J = 260.7,
10.6, minor), ꢁ100.9 (dd, J = 256.4, 10.6, major). HRMS (ESI) Calcd
for C21H16ClF2N3OSNa (M+Na): 454.0563. Found: 454.0558.
4.4.1. 5,5-Difluoro-4-imino-1-methyl-3,6-
4.5. 5,5-Difluoro-4-imino-1-methyl-6-phenyl-3-
diphenyltetrahydropyrimidin-2(1H)-one (3a)
propyltetrahydropyrimidin-2(1H)-one (3e)
Yield: 150 mg (0.48 mmol, 95%). Mixture of isomers 1.8/1.
Colorless crystals. mp 179–181 8C. 1H NMR (300 MHz, CDCl3)
d
:
DBU (91 mg, 0.6 mmol) was added to a solution of urea 2e
(141 mg, 0.5 mmol) in acetonitrile (1 mL) at 0 8C, and the mixture
was stirred for 1 h at room temperature. HCl (5 mL of 0.5M
aqueous solution) was added, the mixture was extracted with Et2O
(3 ꢀ 3 mL), the combined organic phase was dried (Na2SO4),
concentrated, and the residue was purified by chromatography
(hexanes/EtOAc 3/1). Yield: 110 mg (0.39 mmol, 78%). Mixture of
isomers 1.1/1. Colorless oil. Rf 0.51 (hexanes/EtOAc 3/1). 1H NMR
3.13 (s, 3H), 4.81–4.93 (m, 1H), 7.23–7.63 (m, 10H), 8.22–8.32 (br).
13C NMR (75 MHz, CDCl3)
: 35.1, 64.5 (dd, J = 26.5, 28.6), 109.2
d
(dd, J = 246.7, 242.9, major), 110.9 (dd, J = 251.0, 242.7, minor),
127.28, 127.30, 128.4, 128.6, 129.09, 129.14, 129.19, 129.50,
129.58, 129.7, 130.1, 130.7, 130.8, 130.9, 133.9, 136.3, 150.9
(minor), 151.4 (dd, J = 27.6, 24.8, minor), 151.7 (major), 155.6 (dd,
J = 32.1, 26.1, major). 19F NMR (282 MHz, CDCl3)
d
: ꢁ119.0 (d,
J = 260.7, minor), ꢁ117.7 (d, J = 256.4, major), ꢁ98.5 (dd, J = 260.7,
(300 MHz, CDCl3) d: 0.95 (t, 3H, J = 7.7), 1.60–1.78 (m, 2H), 3.03 (s)
12.7, minor), ꢁ98.1 (dd, J = 254.3, 12.7, major). Calcd for
and 3.08 (s) (3H), 3.75–4.08 (m, 2H), 4.66 (dd, J = 13.0, 2.9) and 4.73
(dd, J = 14.7, 3.8) (1H), 7.11–7.20 (m, 2H), 7.35–7.44 (m, 3H), 8.06–
8.24 (br). 13C NMR (75 MHz, CDCl3)
d: 11.0, 11.10, 20.6, 21.3, 35.1,
C17H15F2N3O: C, 64.75; H, 4.79; N, 13.33. Found: C, 64.77; H,
4.86; N, 13.33.
35.2, 43.4, 44.3, 64.4 (d, J = 27.1), 64.8 (dd, J = 26.5, 2.6), 108.7 (dd,
J = 251.1, 247.0), 109.1 (dd, J = 246.3, 241.7), 127.3 (d, J = 1.6), 127.4
(d, J = 1.6), 129.1, 129.2, 129.6, 129.8, 131.0 (d, J = 6.6), 151.3, 151.9,
4.4.2. 1-(4-Ehlorophenyl)-5,5-difluoro-6-imino-3-methyl-4-
phenyltetrahydropyrimidin-2(1H)-one (3b)
Yield: 170 mg (0.49 mmol, 97%). Mixture of isomers 3.4/1.
Colorless crystals. mp 164–166 8C. 1H NMR (300 MHz, CDCl3)
154.5 (t, J = 28.2), 159.6 (t, J = 30.3). 19F NMR (282 MHz, CDCl3)
d:
d
:
ꢁ120.4 (d, J = 272.4), ꢁ117.5 (d, J = 255.4), ꢁ102.1 (dd, J = 272.4,
14.7), ꢁ97.6 (dd, J = 255.4, 13.0). HRMS (ESI) Calcd for C14H18F2N3O
(M+H): 282.1412. Found: 282.1415.
3.13 (s, 3H), 4.84 (br d, 1H, J = 12.5), 7.18–7.58 (m, 9H), 8.22–8.37
(br). 13C NMR (75 MHz, CDCl3)
: 35.18 (major), 35.22 (minor), 64.4
d
(dd, J = 26.5, 28.8), 109.1 (dd, J = 246.5, 243.0) (major), 110.8 (dd,
J = 251.1, 243.0, minor), 127.2, 129.2, 129.3, 129.4, 129.7, 129.8,
130.1, 130.4, 130.53, 130.56, 130.62, 130.7, 132.4, 134.3, 134.8,
135.6, 150.7 (minor), 151.1 (dd, J = 27.6, 25.3, minor), 151.5
(major), 155.4 (dd, J = 32.3, 26.5, major). 19F NMR (282 MHz, CDCl3)
4.6. 3-(4-Chlorophenyl)-5,5-difluoro-1-methyl-6-
phenyldihydropyrimidine-2,4(1H,3H)-dione (4)
HCl (300
mL, 3M aqueous solution) was added to a solution of
d
: ꢁ119.1 (d, J = 261.2, minor), ꢁ117.8 (d, J = 256.4, major), ꢁ98.6
heterocycle 3b (175 mg, 0.5 mmol) in dioxane (1 mL), and the

78
M.D. Kosobokov et al. / Journal of Fluorine Chemistry 154 (2013) 73–79
mixture was stirred for 1 h at room temperature. Saturated
aqueous Na2CO3 (2 mL) was added, and the mixture was extracted
with EtOAc (3 ꢀ 3 mL). The combined organic phase was dried
(Na2SO4), and concentrated. The resulting solid was washed with
hexane/Et2O (2/1, 3 mL) and dried under vacuum. Yield: 160 mg
(0.46 mmol, 91%). Colorless crystals. mp 149–151 8C. 1H NMR
(0.5 mmol) in dimethylformamide (1 mL). The mixture was
stirred at 90 8C during the time given in Table 2. The mixture
was cooled, diluted with water (5 mL) and extracted with EtOAc
(3 ꢀ 3 mL). The combined organic phase was dried (Na2SO4),
concentrated, and the residue was purified by chromatography
(hexanes/EtOAc).
(300 MHz, CDCl3)
7.22 (m, 2H), 7.37–7.38 (m, 2H), 7.42–7.56 (m, 5H). 13C NMR
(75 MHz, CDCl3) : 35.4, 64.5 (dd, J = 27.1, 25.6), 109.0 (dd,
d: 3.15 (s, 3H), 4.90 (dd, 1H, J = 13.9, 3.7), 7.13–
4.9.1. 4-Fluoro-2-methyl-3-phenylpyrimido[1,6-a]benzimidazol-
1(2H)-one (7a)
d
J = 252.8, 247.9), 127.2 (d, J = 1.7), 129.39, 129.47, 129.5, 129.6,
130.1, 132.4, 135.1, 151.0, 159.4 (dd, J = 30.9, 29.9). 19F NMR
Yield: 119 mg (0.41 mmol, 81%). Colorless crystals. mp 212–
214 8C (hexanes/EtOAc 10/1). Chromatography (hexanes/EtOAc 3/
(282 MHz, CDCl3)
d
: ꢁ120.3 (d, J = 273.4), ꢁ102.8 (dd, J = 273.4,
1), Rf 0.32 (hexanes/EtOAc 3/1). 1H NMR (300 MHz, CDCl3)
d
: 3.34
(s, 3H), 7.40–7.62 (m, 7H), 7.88 (d, 1H, J = 8.1), 8.45 (d, 1H, J = 8.1).
13C NMR (75 MHz, CDCl3)
: 33.9, 115.1, 119.7, 124.1, 126.0, 127.7,
13.9). HRMS (ESI) Calcd for C17H14ClF2N2O2 (M+H): 351.0706.
Found: 351.0706.
d
129.2, 129.4 (d, J = 2.3), 130.4, 130.5, 132.8 (d, J = 26.5), 136.2 (d,
J = 235.0), 141.8 (d, J = 30.0), 144.1, 146.7. 19F NMR (282 MHz,
4.7. 3-(4-Chlorophenyl)-5-fluoro-1-methyl-6-phenylpyrimidine-
2,4(1H,3H)-dione (5)
CDCl3)
d
: ꢁ160.9 (s). Calcd for C17H12FN3O: C, 69.62; H, 4.12; N,
14.33. Found: C, 69.44; H, 4.09; N, 14.37.
Cs2CO3 (117 mg, 0.36 mmol) was added to a solution of
heterocycle 4 (105 mg, 0.3 mmol) in dimethylformamide (1 mL),
and the mixture was stirred for 2 h at 100 8C. The mixture was
cooled, diluted with saturated aqueous NH4Cl (2 mL) and water
(3 mL), and extracted with EtOAc (3 ꢀ 3 mL). The combined
organic phase was dried (Na2SO4), concentrated, and the residue
was purified by chromatography (hexane/EtOAc, 1/1). Yield: 71 mg
(0.21 mmol, 72%). Colorless crystals. mp 232–234 8C (hexanes/
EtOAc, 3/1), Rf 0.33 (hexanes/EtOAc 1/1). 1H NMR (300 MHz, CDCl3)
4.9.2. 2-Benzyl-4-fluoro-3-thien-2-ylpyrimido[1,6-a]benzimidazol-
1(2H)-one (7b)
Yield: 150 mg (0.40 mmol, 80%). Yellow crystals. mp 221–
223 8C (hexanes/EtOAc 10/1). Chromatography (hexanes/EtOAc 3/
1 ! 1/1), Rf 0.38 (hexanes/EtOAc 3/1). 1H NMR (300 MHz, CDCl3)
d:
5.23 (s, 2H), 7.00–7.10 (m, 3H), 7.11–7.16 (m, 1H), 7.23–7.31 (m,
3H), 7.45–7.64 (m, 3H), 7.94 (d, 1H, J = 8.1), 8.50 (d, 1H, J = 8.1). 13
NMR (75 MHz, CDCl3) : 49.1, 115.4, 119.9, 124.5, 125.98 (d,
C
d
d
: 3.20 (s, 3H), 7.19–7.34 (m, 2H), 7.38–7.68 (m, 7H). 13C NMR
(75 MHz, CDCl3) : 34.3, 127.1 (d, J = 1.7), 128.6 (d, J = 2.3), 129.3,
J = 1.7), 126.04 (d, J = 25.3), 126.2, 126.6, 124.5, 127.7, 128.6, 129.9,
130.7, 131.8 (d, J = 1.7), 136.2, 137.8 (d, J = 238.4), 141.2 (d,
d
129.6, 129.7, 130.8, 133.0 (d, J = 1.1), 135.0, 137.6 (d, J = 232.1),
140.0 (d, J = 25.6), 150.5, 156.7 (d, J = 26.5). 19F NMR (282 MHz,
J = 28.8), 144.2, 146.7. 19F NMR (282 MHz, CDCl3)
Calcd for C21H14FN3OS: C, 67.18; H, 3.76; N, 11.19. Found: C, 67.31;
H, 3.85; N, 11.24.
d
: ꢁ154.1 (s).
CDCl3)
d
: ꢁ161.2 (s). HRMS (ESI) Calcd for C17H13ClFN2O2 (M+H):
331.0644. Found: 331.0646.
4.9.3. 4-Fluoro-3-(2-furyl)-2-methylpyrimido[1,6-a]benzimidazol-
1(2H)-one (7F)
4.8. 2-Ethyl-4,4-difluoro-3-(4-methoxyphenyl)-3,4-
dihydropyrimido[1,6-a]benzimidazol-1(2H)-one (6e)
Yield: 110 mg (0.39 mmol, 77%). Colorless crystals. mp 177–
179 8C (hexanes/EtOAc 10/1). Chromatography (hexanes/EtOAc 3/
Triethylamine (825
m
L, 0.6 mmol) was added to a solution of
1), Rf 0.39 (hexanes/EtOAc 3/1). 1H NMR (300 MHz, CDCl3)
d
: 3.50
(s, 3H), 6.62 (br, 1H), 6.91 (br, 1H), 7.37–7.53 (m, 2H), 7.68 (br, 1H),
7.84 (d, 1H, J = 8.1), 8.38 (d, 2H, J = 8.1). 13C NMR (75 MHz, CDCl3)
urea 2j (243 mg, 0.5 mmol) in acetonitrile (1 mL) at 0 8C, and the
mixture was stirred for 1 h at room temperature. The flask was
d:
cooled to 0 8C, and HCl (440
m
L of 1.7M dioxane solution) was
34.0, 111.8, 115.1, 116.2 (d, J = 5.8), 119.7, 123.2 (d, J = 23.0), 124.3,
126.0, 130.4, 137.1 (d, J = 241.9), 139.4 (d, J = 3.5), 141.2 (d,
J = 28.8), 144.1, 144.9 (d, J = 1.7), 146.3. 19F NMR (282 MHz, CDCl3)
added. The precipitate was filtered, washed with Et2O, and the
combined filtrate was concentrated. The residue was dissolved
in dimethylformamide (1 mL) followed by addition of L-proline
(30 mg, 0.25 mmol), CuI (10 mg, 0.05 mmol), and Cs2CO3
(489 mg, 1.5 mmol). The mixture was stirred for 3 h at 50 8C,
then cooled, diluted with water (5 mL) and extracted with
EtOAc (3 ꢀ 3 mL). The combined organic phase was dried
(Na2SO4), concentrated, and the residue was purified by
chromatography (hexanes/EtOAc, 5/1). Yield: 121 mg
(0.34 mmol, 68%). Colorless oil. Rf 0.36 (hexanes/EtOAc 5/1).
d
: ꢁ156.8 (s). Calcd for C15H10FN3O2: C, 63.60; H, 3.56; N, 14.83.
Found: C, 63.49; H, 3.56; N, 14.94.
4.9.4. 4-Fluoro-2-methyl-3-(1-naphthyl)pyrimido[1,6-
a]benzimidazol-1(2H)-one (7d)
Yield: 136 mg (0.40 mmol, 79%). Colorless crystals. mp 181–
183 8C (hexanes/CHCl3 10/1). Chromatography (hexanes/EtOAc 3/
1 ! 1/1), Rf 0.40 (hexanes/EtOAc 3/1). 1H NMR (300 MHz, CDCl3)
d:
1H NMR (300 MHz, CDCl3)
d
: 1.27 (t, 3H, J = 7.0), 3.12–3.26 (m,
3.21 (s, 3H), 7.41–7.71 (m, 7H), 7.88–8.09 (m, 2H), 8.47–8.54 (m,
1H), 3.71 (s, 3H), 4.00–4.15 (m, 1H), 4.99 (dd, 1H, J = 12.8, 3.4),
6.80 (d, 2H, J = 8.8), 7.01 (d, 2H, J = 8.8), 7.43 (t, 1H, J = 7.7), 7.52
(t, 1H, J = 7.7), 7.84 (d, 1H, J = 7.7), 8.35 (d, 1H, J = 7.7). 13C NMR
1H). 13C NMR (75 MHz, CDCl3)
d: 33.0, 115.1, 119.7, 123.8, 124.2,
124.9, 125.3, 126.0, 126.8, 127.8, 128.6 (d, J = 2.3), 128.8, 130.5,
131.0, 131.1, 131.3 (d, J = 26.5), 133.6, 136.8 (d, J = 234.9), 141.7 (d,
(75 MHz, CDCl3)
d
: 12.8, 42.1, 55.2, 65.7 (dd, J = 29.4, 26.8),
J = 29.4), 144.1, 146.7. 19F NMR (282 MHz, CDCl3)
Calcd for C21H14FN3O: C, 73.46; H, 4.11; N, 12.24. Found: C, 73.54;
H, 4.09; N, 12.21.
d
: ꢁ158.7 (s).
111.3 (dd, J = 247.3, 241.6), 114.6, 114.9, 121.2, 122.5 (d, J = 7.2),
125.1, 126.6, 128.7 (d, J = 1.4), 131.8, 142.1 (dd, J = 32.3, 29.7),
142.4, 147.4, 160.5. 19F NMR (282 MHz, CDCl3)
d
: ꢁ120.5 (d,
J = 269.2), ꢁ88.4 (dd, J = 269.2, 12.8). HRMS (ESI) Calcd for
19H18F2N3O2 (M+H): 358.1362. Found: 358.1357.
4.9.5. 2-Ethyl-4-fluoro-3-(4-methoxyphenyl)pyrimido[1,6-
a]benzimidazol-1(2H)-one (7e)
C
Yield: 126 mg (0.37 mmol, 75%). Colorless crystals. mp 185–
187 8C (hexanes/EtOAc 10/1). Chromatography (hexanes/EtOAc 5/
4.9. Synthesis of heterocycles 7 (general procedure)
1 ! 3/1), Rf 0.42 (hexanes/EtOAc 3/1). 1H NMR (300 MHz, CDCl3)
d:
L-Proline (6.0 mg, 0.05 mmol), CuI (10 mg, 0.05 mmol), and
Cs2CO3 (489 mg, 1.5 mmol) were added to a solution of urea 2f–j
1.15 (t, 3H, J = 7.0), 3.82–3.94 (m, 2H), 3.85 (s, 3H), 7.05 (d, 2H,
J = 8.8), 7.31–7.53 (m, 4H), 7.83 (d, 1H, J = 8.1), 8.41 (d, 1H, J = 8.1).

M.D. Kosobokov et al. / Journal of Fluorine Chemistry 154 (2013) 73–79
79
13C NMR (75 MHz, CDCl3)
d: 14.0, 41.2, 55.3, 114.5, 115.1, 119.3,
119.5, 123.8, 125.8, 130.4, 130.8 (d, J = 2.3), 132.5 (d, J = 26.5),
136.3 (d, J = 232.6), 141.7 (d, J = 29.9), 144.0, 146.2, 160.9. 19F NMR
(b) S. Fustero, J. Piera, J.F. Sanz-Cervera, S. Catalan, C. Ramirez de Arellano, Org.
Lett. 6 (2004) 1417–1420.
[5] (a) M.J. Robins, S.R. Naik, J. Am. Chem. Soc. 93 (1971) 5277–5278;
(b) R.H. Hesse, D.H.R. Barton, H.T. Toh, M.M. Pechet, J. Org. Chem. 37 (1972)
329–330;
(c) G.W.M. Visser, S. Boele, B.W. Van Halteren, G.H.J.N. Knops, J.D.M. Herscheid,
G.A. Brinkman, A. Hoekstra, J. Org. Chem. 51 (1986) 1466–1471;
(d) S. Stavber, M. Zupan, Tetrahedron 46 (1990) 3093–3100;
(e) G.S. Lal, W. Pastore, R. Pesaresi, J. Org. Chem. 60 (1995) 7340–7342.
[6] For an overview of chemistry of fluorinated five- and six-membered heterocycles,
see:
(282 MHz, CDCl3)
(M+H): 338.1299. Found: 338.1289.
d
: ꢁ160.0 (s). HRMS (ESI) Calcd for C19H17FN3O2
Acknowledgments
This work was supported by the Ministry of Science (project
MD-4750.2013.3), and the Russian Academy of Sciences (program
#8). We thank Dr. B. Lichitskii for helpful discussions.
A.W. Erian, J. Heterocycl. Chem. 38 (2001) 793–808.
[7] F. Olimpieri, S. Fustero, A. Volonterio, M. Zanda, Synthesis (2010) 651–660.
[8] M.D. Kosobokov, A.D. Dilman, V.V. Levin, M.I. Struchkova, J. Org. Chem. 77 (2012)
5850–5855.
[9] For non-fluorinated analogous process, ortho-cyanoanilines have been mainly
employed as 1,4-bipolar system, see:
Appendix A. Supplementary data
(a) J.W. Chern, P.L. Tao, M.H. Yen, G.Y. Lu, C.Y. Shiau, Y.J. Lai, S.L. Chien, C.H. Chan, J.
Med. Chem. 36 (1993) 2196–2207;
Supplementary material related to this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jfluchem.2013.
06.018.
(b) S. Richter, B. Gioffreda, Arch. Pharm. 344 (2011) 810–820;
(c) N. Haider, G. Heinisch, R. Wanko, J. Heterocycl. Chem. 28 (1991) 1441–1444.
[10] CCDC-934724 (3a) and CCDC-934723 (7a) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[11] (a) D. Ma, Q. Cai, Acc. Chem. Res. 41 (2008) 1450–1460;
(b) G. Evano, N. Blanchard, M. Toumi, Chem. Rev. 108 (2008) 3054–3131.
[12] For alternative preparative methods of pyrimido[1,6-a]benzimidazol-1(2H)-ones,
see:
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