Selective synthesis of poly-substituted fluorine-containing pyridines and dihydropyrimidines via cascade C-F bond cleavage protocol

Article abstract of DOI:10.1039/c1ob05371j

Fluorinated azaheterocycles are frequently found in pharmaceuticals, drug candidates, ligands for transition metal catalysts, and other molecular functional materials, so efficient methods for the synthesis of these compounds are of significant value. We

Full text of DOI:10.1039/c1ob05371j

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Selective synthesis of poly-substituted fluorine-containing pyridines and
dihydropyrimidines via cascade C–F bond cleavage protocol†
Zixian Chen,a,b Jiangtao Zhu,a Haibo Xie,a Shan Li,a Yongming Wu*a and Yuefa Gong*b
Received 10th March 2011, Accepted 11th May 2011
DOI: 10.1039/c1ob05371j
Fluorinated azaheterocycles are frequently found in pharmaceuticals, drug candidates, ligands for
transition metal catalysts, and other molecular functional materials, so efficient methods for the
synthesis of these compounds are of significant value. We herein describe a selective strategy for the
synthesis of poly-substituted pyridines and fluoroalkyl dihydropyrimidines based on C–F bond
breaking of the anionically activated fluoroalkyl group. An array of pyridines and dihydropyrimidines
were prepared through this domino process in high yields under noble metal catalyst-free conditions,
making this method a valuable supplement to azaheterocycle synthesis.
makes it a property imparting building block in the designing of
Introduction
bioactive molecules.
Nitrogen-containing heterocycles, such as pyridines and
In general, it is hard to cleave a C–F bond due to its large bond
pyrimidines,1 frequently show up as substructures in lots of
natural products, biologically relevant compounds and ligands of
transition metal catalysis. Therefore, there has been much interest
in the development of new methods for the synthesis of these types
of cyclic subunits.
It is well known that the incorporation of fluorine or fluorine-
containing groups into an organic molecule often drastically alters
its chemical, pharmacological and biological properties,2 and
many organofluorine compounds exhibit unique properties in life
science and materials science-related applications. The rationale
behind fluorine substitution has been discussed extensively in the
literature.3 Studies suggest that the van der Waals radius of fluorine
energy (ca. 552 kJ mol-1). However, reports published recently
showed that C–F bond cleavage easily occurs when the CF3
group is attached to a p-electron system, because of electron
pair acceptance into the p-system and subsequent extrusion of
a fluoride ion providing the driving force.7 The formed inter-
mediary gem-difluorovinyl can react with various nucleophiles,8
or react with electrophiles when it is attached to an anion,9
leading to various difluoromethylene building blocks (Scheme 1).
This methodology has great utility in the synthesis fluorine-
containing compounds,10 which provides us an opportunity to
synthesize some nonfluorinated products or partially fluorinated
compounds.11
˚
˚
˚
(1.47 A) is between that of oxygen (1.52 A) and hydrogen (1.2 A),
and thus fluorine appears to have a particularly close isosteric
relationship to oxygen, and is the smallest substituent to replace
hydrogen in C–H bonds.4 The high electronegativity of fluorine has
been commonly used in many ways to develop enzyme inhibitors
or to induce resistance to chemical degradation,5 because the
fluorine substitutions of the natural compounds are generally
recognized by macromolecular recognition sites. Similarly, the
CF2H moiety is known to be isosteric and isopolar with a carbinol
(CH2OH) unit and can also act as a more lipophilic hydrogen bond
donor (rather than typical donors such as OH and NH),6 which
Scheme 1 Nucleophilic or electrophilic attack of gem-difluorovinyl
substrates.
On the other hand, domino reactions have recently attracted
considerable attention due to their high efficiency in constructing
complex molecular architectures from readily available building
blocks.12 Multiple new bonds are formed in a single step under
identical reaction conditions minimizing requisite reagents, sepa-
ration processes, waste, energy, time, and cost. Hence, developing
new domino processes with high efficiency is of great significance
to the synthetic community. Despite significant efforts being de-
voted to azaheterocycles preparation,13 certain lines of fluorinated
aKey laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai
200032, China. E-mail: ymwu@mail.sioc.ac.cn; Fax: (+86) 21-54925192
bSchool of Chemistry and Chemical Engineering, Huazhong University of
Science and Technology, Wuhan, Hubei 430074, China. E-mail: gongyf@
mail.hust.edu.cn
† Electronic supplementary information (ESI) available: NMR data. See
DOI: 10.1039/c1ob05371j
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Table 1 Synthesis of various pyridinesa
Entry
Rf
R1
R2
R3
X
Product
Yieldb (%)
1
2
3
4
5
6
7
8
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Ph
4-MeC6H4
4-FC6H4
n-Butyl
COOMe
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
98
99
84
59
60
97
96
98
89
85
50
96
62
80
64
80
74
82
69
70
65
65
92
60
Ph
4-MeOC6H4
4-CNC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
2-MeC6H4
4-ClC6H4
2-CF3C6H4
2-Thienyl
2-Pyridyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-ClC6H4
2-Thienyl
Ph
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3j
3k
3l
CF3
3m
3a
3a
3n
3o
3p
3q
3r
3s
3t
CF2Br
CF2Cl
CF2H
CF3CF2
CF3CF2
CF3CF2
CF3CF2
CF3CF2
CF3CF2
CF3CF2
CF3CF2 CF2
Ph
Ph
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3CF2
4-BrC6H4
3-MeOC6H4
2-Naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
3u
3v
a Reactions were carried out on a 0.4 mmol scale in THF (2 mL) with 2a (3.0 equiv.) and base (2.5 equiv.) at 80 ◦C unless otherwise stated. b Isolated
yields.
heterocycles are still in need of effective synthetic methods,14
especially domino based ones.
As part of our ongoing program on the synthesis of fluorine-
Results and discussion
The starting fluoroalkyl alkynylimines 1 were prepared from the
containing heterocycles,15 we have reported several efficient meth-
ods for the synthesis of fluorinated indoles, quinolines, benzoth-
iazoles and benzimidazoles. Very recently, we communicated a
new cascade process for the synthesis of an array of fluoro-
substituted pyridines.16 By reacting fluoroalkyl alkynylimines 1
with primary amines 2 we obtained intermediary 4 which under-
went one-pot fluorine elimination and nucleophilic cyclization in
the presence of a base affording the desired pyridines 3 in high
yields (Scheme 2), and two dihydropyrimidine compounds 5 were
also obtained through an unexpected pathway during the previous
investigations. Herein, we wish to report a detailed investigation
of the scope and limitations of this chemoselective process.
CuI-catalyzed coupling of terminal alkynes with fluoroalkylim-
idoyl chlorides in high yields,15a and primary amines 2 were all
commercially available.
Synthesis of 3-F, 3-CF3, 3-H pyridines
As we previously communicated, the optimal reaction conditions
for pyridine synthesis were using alkynylimines and amine (3
equiv.) in THF at 80 ◦C, with 2.5 equiv. of Cs2CO3 as the base.
We examined the generality of the reaction. All alkynylimine
substrates with various alkynyl moieties and N-aryl groups
could provide the target molecules in moderate to good yields
(Table 1, entries 1–7). When a hexyne group is attached, a longer
reaction time (24 h) was required with reduced yield (Table 1,
entry 4). An ester group also afforded the desired products
in moderate yield (Table 1, entry 5). A variety of substituted
benzylamines and hetarylmethylamines tested revealed that the
reactivity was induced by electronic effects. Amines with electron-
donating groups gave good yields (Table 1, entries 8–9), while
electron-withdrawing groups slightly less (Table 1, entries 10–11).
Alkynylimines containing CF2Br and CF2Cl groups were also ex-
amined; the corresponding product was formed in acceptable yield
(Table 1, entries 14–15). Interestingly, when CF2H and CF3CF2
substrates were examined, 3-H pyridine and 3-trifluoromethyl
Scheme 2 Chemoselective synthesis of fluorinated azines.
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Table 2 Optimization for dihydropyrimidine synthesisa
pyridine were obtained, respectively, in favorable yields (Table 1,
entries 16–17). Then we synthesized a series of 3-CF3 pyridines
through this process, and yields for all the substrates tested were
moderate to good (Table 1, entries 18–23). Alkynylimine with a
perfluoropropyl group also gave an acceptable yield (Table 1, entry
24).
Next, we sought to investigate the possibility of the process
with an alkyl amine; when the reaction of 1a with n-butylamine
was examined, the cyclization process did not occur, providing
4w as a sole product in quantitative yield. Obviously, a stronger
base is needed to deprotonate the a-H of the n-butyl group;
indeed, pyridine 3w was formed when NaH was used as the
base (Scheme 3). However, a byproduct dihydropyrimidine 5w
was isolated in 32% yield in addition to the desired compound,
while use of a soluble base t-BuOK yield 5w as the sole product.
Attempts to improve the yield for 3w using LDA, LiHMDS and
n-butyllithium as the base were unsuccessful, suggesting that 4w
was inert to them. Then we went back to study the cyclization
reaction of 4a under the above conditions. Amazingly, cyclization
of 4a at room temperature also gave a mixture of 3a and 5a in a
different ratio as expected (confirmed by crystal diffraction).
Yield (%)b
Entry
Base
T/◦C
Time/min
3
5
1
2
3
4
5
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
80
rt
-20
-40
-40
<1
<1
<1
5
3a/47
3a/33
3a/15
0
5a/53
5a/66
5a/85
5a/98
5a/98
10
0
a Reactions were carried out on a 0.4 mmol scale in THF (2 mL) with base
(2.0 equiv.) unless otherwise stated. b Isolated yields.
only detectable product as seen on the crude 19F NMR spectrum,
indicating the good selectivity of this process.
A possible mechanism of this transformation is suggested in
Scheme 4. After hydroamination of alkynylimine with amine
forming the intermediate vinylogous amidine 4, the deprotonation
and dehydrofluorination process occurs generating an anion and
an imine coexisting in one molecule. When the reaction is carried
out at a low temperature with a soluble base (path a), the in
situ generated amide nucleophilic attacks the imine immediately
without isomerization to form dihydropyrimidine through a kinet-
ically controlled pathway. However, carbon nucleophilic addition
becomes an option when the reaction temperature rises (path
b), providing a 1,2-dihydropyridine ring under thermodynamic
control, and the subsequent proton migration, b-F elimination
and final aromatization to form the pyridine ring also provides a
driving force. Meanwhile, an insoluble base can effectively inhibit
the kinetic pathway.
Scheme 3 Base-controlled cyclization reaction.
Synthesis of fluoroalkyl dihydropyrimidines
The previous results encouraged us to investigate the chemose-
lective synthesis of this dihydropyrimidine product. After opti-
mization (Table 2), a stepwise procedure was established as the
starting material is sensitive to stronger bases. The first step is
the hydroamination of alkynylimines in THF at 80 ◦C. After
the completion of the hydroamination as i◦ndicated on TLC, the
reaction mixture was cooled down to -40 C, then t-BuOK was
added, to give the dihydropyrimidines immediately.
The scope of this reaction pathway was also explored. Sub-
strates formerly used for the synthesis of pyridines gave the
dihydropyrimidine products in good to excellent yields. As shown
in Table 3, most of the alkynylimines could give the desired
products with high yields (Table 3, entries 2–7). Remarkably, a
CH2F- dihydropyrimidine was also obtained, although with a
moderate yield (Table 3, entry 1). However, the alkynyl moiety with
an n-butyl group was not an ideal candidate (Table 2, substrate
in entry 4), as there are two hydrogens sensitive to the base in the
intermediate, complicating the reaction. The result for alkynylim-
ine with an acetylenecarboxylate group was disappointing as well
(Table 2, substrate in entry 5). Compared with the electron-rich
amines, the amines with electron-withdrawing groups consistently
gave reduced yields (Table 3, entries 8–12). As expected, various
hetarylmethylamines also afforded the products in 70–92% yields
(Table 3, entries 13–15). In most cases, dihydropyrimidine was the
Scheme 4 Proposed mechanism.
Conclusion
In conclusion, we have synthesized a series fluorine-containing
azaheterocycles through a selective domino process based on
anionic C–F bond cleavage. A lot of products with one or
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Table 3 Synthesis of various dihydropyrimidinesa
Table 3 (Contd.)
Entry
1
1
2
Product
Yield (%)b
Entry
14
1
2
Product
Yield (%)b
(5b) 67
(5o) 70
2
3
(5c) 97
(5d) 92
15
16
(5p) 92
(5q) 99c
a Reactions were carried out on a 0.3 mmol scale in THF (2 mL) with
amines (2.0 equiv.) and base (2.0 equiv.) unless otherwise stated. b Isolated
yields. c The second step of the reaction was conducted at rt.
4
5
(5e) 88
(5f) 96
two fluorine atoms were formed in good yields from easily
accessible trifluoromethyl-containing materials. Substrates with
various substituents can be tolerated in this reaction, which can
be introduced stepwise from initial fluoroalkyl acids in high yields
(Scheme 5).15a,17 Further investigations of the intermolecular gem-
difluoromethylation based on this strategy are currently underway
in our laboratory.
6
(5g) 93
7
8
(5h) 98
(5i) 94
Scheme 5 Stepwise synthesis of fluorinated azines.
1a
Experimental section
General experimental
9
(5j) 97
Melting points were measured on a Melt-Temp apparatus and
are uncorrected. H NMR spectra were recorded in CDCl3 and
1
d-DMSO on a Bruker AM-300 spectrometer (300 MHz) with
TMS as internal standard. 19F NMR spectra were taken on a
Bruker AM-300 (282 MHz) spectrometer using CFCl3 as external
standard. 13C NMR spectra were taken on a Bruker AM-400 (100
MHz) spectrometer. IR spectra were obtained with a Nicolet
AV-360 spectrophotometer. Elemental analysis was performed
by the Analytical Laboratory of Shanghai Institute of Organic
Chemistry. Mass spectra were recorded by EI and ESI methods,
HRMS (ESI) was measured on Bruker Daltonics APEXIII 7.0
TESLA FTMS. Solvents and reagents were purchased from
commercial sources and used as received. All reactions were
monitored by TLC with silica gel coated plates. Flash column
chromatography was carried out using 300–400 mesh silica gel at
increased pressure and petroleum ether/ethyl acetate combination
was used as the eluent.
10
(5k) 89
11
(5l) 74
12
13
(5m) 89
(5n) 87
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Representative procedure for pyridine 3 synthesis
129.7, 128.9 (d, J = 5.1 Hz), 128.7, 128.3, 124.3, 121.9, 106.0, 38.1,
32.1, 22.5, 14.0; LRMS (EI) m/z (relative intensity) 320 (4) [M+],
305 (9), 291 (14), 278 (100); Anal. Calcd. for C21H21FN2: C, 78.72;
H, 6.61; N, 8.74. Found: C, 79.13; H, 6.89; N, 8.72. IR(KBr): 3227,
2954, 2866, 1610, 1589, 1517, 1490, 1442, 1222, 1017, 698 cm-1.
Alkynylimine 1 (0.4 mmol) was added to a solution of amines 2
(3 equiv.), Cs2CO3 (2.5 equiv.) in THF (2.0 mL). The solution was
then stirred at 80 ◦C. After completion of reaction as indicated by
TLC, the reaction crude was filtered and the filtrate evaporated.
The residue was purified by flash chromatography on silica gel to
provide the desired product 3.
Methyl-5-fluoro-6-phenyl-4-(phenylamino)picolinate (3e)
Light green solid, mp 213–214 ◦C; 1H NMR (300 MHz, d-DMSO)
d 9.05 (br, 1H), 7.85 (d, 2H), 7.65 (d, 1H), 7.57–7.25 (m, 7H), 7.17
(t, 1H), 3.80 (s, 3H); 19F NMR (282 MHz, d-DMSO) d -141.25;
13C NMR (100 MHz, d-DMSO) d 165.4, 148.4 (d, J = 258.9 Hz),
144.8 (d, J = 10.3 Hz), 144.1 (d, J = 4.4 Hz), 141.5 (d, J = 11.8 Hz),
139.8, 135.3 (d, J = 4.4 Hz), 130.0, 129.8, 129.2 (d, J = 5.9 Hz),
128.9, 124.9, 122.9, 109.7, 52.9; HRMS-ESI (m/z): C19H16FN2O2
[M + H]+ calcd 323.11903; found 323.11997; IR(KBr): 3314, 3058,
2949, 1703, 1614, 1597, 1587, 1524, 1494, 1445, 1424, 1376, 1298,
1238, 1121, 1015, 696 cm-1.
3-Fluoro-N,2,6-triphenylpyridin-4-amine (3a)
White solid, mp 127–129 ◦C; 1H NMR (300 MHz, CDCl3) d 8.02
(d, J = 7.1 Hz, 2H), 7.95 (d, J = 7.6 Hz, 2H), 7.56–7.14 (m, 12H),
6.34 (d, J = 3.3 Hz, 1H); 19F NMR (282 MHz, CDCl3) d -152.37;
13C NMR (100 MHz, CDCl3) d 153.3 (d, J = 5.9 Hz), 146.9 (d,
J = 253.1 Hz), 144.0 (d, J = 8.1 Hz), 140.6 (d, J = 10.2 Hz),
139.5, 139.2, 136.0 (d, J = 5.1 Hz), 129.8, 129.0, 129.0 (d, J = 5.9
Hz), 128.7, 128.6, 128.4, 127.0, 124.7, 122.2, 104.3; LRMS (EI)
m/z (relative intensity) 340 (99) [M+], 39 (100); Anal. Calcd. for
C23H17FN2: C, 81.16; H, 5.03; N, 8.23. Found: C, 80.89; H, 5.14;
N, 8.15. IR(KBr): 3409, 3060, 1610, 1595, 1579, 1514, 1498, 1466,
1409, 1242, 694 cm-1.
3-Fluoro-N-(4-methoxyphenyl)-2,6-diphenylpyridin-4-amine (3f)
Yellow solid, mp 110–112 ◦C; 1H NMR (300 MHz, CDCl3) d 8.08
(d, J = 7.9 Hz, 2H), 7.92 (d, J = 6.7 Hz, 2H), 7.57–7.29 (m, 6H),
7.27–7.18 (m, 3H), 6.95 (d, J = 8.8 Hz, 2H), 6.18 (d, J = 3.5 Hz,
1H), 3.83 (s, 3H); 19F NMR (282 MHz, CDCl3) d -153.53; 13C
NMR (100 MHz, CDCl3) d 157.4, 153.2 (d, J = 5.1 Hz), 146.6 (d,
J = 251.6 Hz), 143.6 (d, J = 8.8 Hz), 142.0 (d, J = 11.0 Hz), 139.6,
136.2 (d, J = 5.2 Hz), 131.7, 129.0 (d, J = 5.9 Hz), 128.9, 128.6,
128.5, 128.3, 126.9, 125.6, 115.0, 103.7, 55.6; LRMS-ESI (m/z):
C24H20FN2O [M + H]+ calcd 371.2; found 371.1; Anal. Calcd. for
C24H19FN2O: C, 77.82; H, 5.17; N, 7.56. Found: C, 78.22; H, 5.20;
N, 7.50. IR(KBr): 3413, 3035, 2951, 2835, 1606, 1578, 1515, 1500,
1434, 1240, 1033, 831, 770, 735, 691 cm-1.
3-Fluoro-N,2-diphenyl-6-p-tolylpyridin-4-amine (3b)
White solid, mp 166–168 ◦C; 1H NMR (300 MHz, CDCl3) d 8.08
(d, J = 7.6 Hz, 2H), 7.84 (d, J = 7.9 Hz, 2H), 7.58–7.12 (m, 11H),
6.32 (d, J = 3.0 Hz, 1H), 2.37 (s, 3H); 19F NMR (282 MHz, CDCl3)
d -152.69; 13C NMR (100 MHz, CDCl3) d 153.3 (d, J = 5.8 Hz),
146.8 (d, J = 252.3 Hz), 143.9 (d, J = 8.8 Hz), 140.5 (d, J = 11.0 Hz),
139.3, 138.6, 136.7, 136.1 (d, J = 5.1 Hz), 129.8, 129.3, 129.0 (d,
J = 5.8 Hz), 129.0, 128.4, 126.8, 124.5, 122.1, 104.0, 21.3; LRMS-
ESI (m/z): C24H20FN2 [M + H]+ calcd 355.2; found 355.0; Anal.
Calcd. for C24H19FN2: C, 81.33; H, 5.40; N, 7.90. Found: C, 81.61;
H, 5.36; N, 7.85. IR(KBr): 3420, 1610, 1593, 1573, 1510, 1466,
1242, 1207, 817, 697 cm-1.
4-(3-Fluoro-2,6-diphenylpyridin-4-ylamino)benzonitrile (3g)
Yellow solid, mp 199–201 ◦C; 1H NMR (300 MHz, CDCl3) d 8.07
(d, J = 7.9 Hz, 2H), 7.97 (d, J = 6.8 Hz, 2H), 7.70–7.57 (m, 3H),
7.56–7.26 (m, 8H), 6.61 (d, J = 2.9 Hz, 1H); 19F NMR (282 MHz,
CDCl3) d -149.15; 13C NMR (100 MHz, CDCl3) d 153.4 (d, J =
5.9 Hz), 147.4 (d, J = 254.5 Hz), 144.9 (d, J = 9.5 Hz), 144.1, 138.8,
138.0 (d, J = 11.1 Hz). 135.5 (d, J = 5.1 Hz), 134.0, 129.4, 129.1,
129.0 (d, J = 5.9 Hz), 128.7, 128.5, 126.9, 119.3, 118.9, 106.0, 106.0;
LRMS-ESI (m/z): C24H17FN3 [M + H]+ calcd 366.1; found 366.0;
Anal. Calcd. for C24H16FN3: C, 78.89; H, 4.41; N, 11.50. Found: C,
78.88; H, 4.59; N, 11.48. IR(KBr): 3329, 3058, 2222, 1615, 1598,
1516, 1433, 1398, 1176, 956, 831, 766, 690 cm-1.
3-Fluoro-6-(4-fluorophenyl)-N,2-diphenylpyridin-4-amine (3c)
White solid, mp 154–156 ◦C; 1H NMR (300 MHz, CDCl3) d 8.06
(d, J = 7.3 Hz, 2H), 7.92 (dd, J = 8.5 Hz, J = 5.5 Hz, 2H); 7.56–7.03
(m, 11H), 6.34 (d, J = 3.5 Hz, 1H); 19F NMR (282 MHz, CDCl3)
d -113.91–-114.13 (m, 1F), -152.47 (s, 1F); 13C NMR (100 MHz,
CDCl3) d 163.4 (d, J = 247.9 Hz), 152.2 (d, J = 5.1 Hz), 146.8 (d,
J = 253.1 Hz), 144.0 (d, J = 8.8 Hz), 140.7 (d, J = 11.0 Hz), 139.1,
135.9 (d, J = 5.1 Hz), 135.6 (d, J = 2.9 Hz), 129.8, 129.1, 129.0 (d,
J = 5.9 Hz), 128.7 (d, J = 8.1 Hz), 128.4, 124.8, 122.3, 115.4 (d,
J = 22.0 Hz), 103.8; LRMS (EI) m/z (relative intensity) 358 (100)
[M+], 359 (24), 357 (95); Anal. Calcd. for C23H16F2N2: C, 77.08; H,
4.50; N, 7.82. Found: C, 77.24; H, 4.66; N, 7.75. IR(KBr): 3409,
1612, 1585, 1508, 1465, 1444, 1398, 1221, 1205, 827, 754, 701 cm-1.
3-Fluoro-N,6-diphenyl-2-p-tolylpyridin-4-amine (3h)
◦
1
White solid, mp 135–137 C; H NMR (300 MHz, CDCl3) d
8.05–7.90 (m, 4H), 7.52–7.10 (m, 11H), 6.31 (d, J = 6.7 Hz, 1H),
2.42 (s, 3H); 19F NMR (282 MHz, CDCl3) d -152.28; 13C NMR
(100 MHz, CDCl3) d 153.1 (d, J = 5.1 Hz), 146.8 (d, J = 252.4
Hz), 144.0 (d, J = 8.8 Hz), 140.5 (d, J = 11.0 Hz), 139.6, 139.3,
139.0, 133.3 (d, J = 5.1 Hz), 129.8, 129.1, 128.9 (d, J = 6.6 Hz),
128.6, 128.6, 127.0, 124.6, 122.1, 104.1, 21.4; LRMS (EI) m/z
(relative intensity) 354 (96) [M+], 355 (24), 353 (100); Anal. Calcd.
for C24H19FN2: C, 81.33; H, 5.40; N, 7.90. Found: C, 81.03; H,
6-Butyl-3-fluoro-N,2-diphenylpyridin-4-amine (3d)
White solid, mp 79–80 ◦C; 1H NMR (300 MHz, CDCl3) d 7.92 (d,
J = 7.0 Hz, 2H), 7.52–7.35 (m, 5H), 7.29–7.12 (m, 3H), 6.92 (d,
J = 5.9 Hz, 1H), 6.27 (d, J = 2.1 Hz, 1H), 2.68 (t, J = 7.7 Hz, 2H),
1.76–1.62 (m, 2H), 1.46–1.31 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H);
19F NMR (282 MHz, CDCl3) d -154.47; 13C NMR (100 MHz,
CDCl3) d 158.4 (d, J = 6.6 Hz), 145.9 (d, J = 249.4 Hz), 143.8 (d,
J = 8.8 Hz), 139.9 (d, J = 10.2 Hz), 139.4, 136.1 (d, J = 5.2 Hz),
5686 | Org. Biomol. Chem., 2011, 9, 5682–5691
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5.54; N, 7.80. IR(KBr): 3431, 1611, 1594, 1581, 1520, 1504, 1461,
1407, 1242, 828, 757, 748, 693 cm-1.
3-Fluoro-N,6-diphenyl-2,2¢-bipyridin-4-amine (3m)
Light yellow solid, mp 153–155 ◦C; 1H NMR (300 MHz, CDCl3)
d 8.78 (d, J = 4.4 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.97–7.79
(m, 3H), 7.54 (d, J = 5.6 Hz, 1H), 7.48–7.12 (m, 9H), 6.48 (s, 1H);
19F NMR (282 MHz, CDCl3) d -151.98; 13C NMR (100 MHz,
CDCl3) d 155.4 (d, J = 6.6 Hz), 153.3 (d, J = 5.9 Hz), 149.1, 147.2
(d, J = 257.5 Hz), 143.2 (d, J = 6.6 Hz), 141.3 (d, J = 9.5 Hz),
139.3, 139.1, 136.6, 129.8, 128.7, 128.6, 127.0, 124.8, 124.1, 123.4,
122.4, 105.2; LRMS-ESI (m/z): C22H17FN3 [M + H]+ calcd 342.1;
found 342.0; Anal. Calcd. for C22H16FN3: C, 77.40; H, 4.72; N,
12.31. Found: C, 77.21; H, 4.97; N, 12.48. IR(KBr): 3412, 3033,
1611, 1578, 1565, 1496, 1468, 1410, 1247, 749, 694 cm-1.
3-Fluoro-N,6-diphenyl-2-o-tolylpyridin-4-amine (3i)
White solid, mp 129–130 ◦C; 1H NMR (300 MHz, CDCl3) d 7.87
(d, J = 6.7 Hz, 2H), 7.55–7.15 (m, 13H), 6.35 (s, 1H), 2.40 (s, 3H);
19F NMR (282 MHz, CDCl3) d -150.56; 13C NMR (100 MHz,
CDCl3) d 153.5 (d, J = 5.8 Hz), 146.3 (d, J = 13.2 Hz), 146.1 (d,
J = 248.7 Hz), 140.1 (d, J = 11.0 Hz), 139.5, 139.1, 136.9, 135.5 (d,
J = 2.2 Hz), 130.5, 130.0 (d, J = 2.2 Hz), 129.8, 128.8, 128.7, 128.6,
127.1, 125.7, 124.7, 122.2, 104.4, 20.0 (d, J = 2.2 Hz); HRMS-ESI
(m/z): C24H20FN2 [M + H]+ calcd 355.16050; found 355.16009;
IR(KBr): 3409, 3060, 1612, 1596, 1581, 1513, 1497, 1462, 1408,
1240, 750, 697 cm-1.
N,2,6-Triphenylpyridin-4-amine (3n)
◦
1
White solid, mp 92–94 C; H NMR (300 MHz, CDCl3) d 8.05
(d, J = 7.9 Hz, 4H), 7.49–7.07 (m, 13H), 6.13 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 158.1, 152.0, 140.1, 140.0, 129.7, 128.9, 128.6,
127.1, 123.9, 121.5. 105.2; HRMS-ESI (m/z): C23H19N2 [M + H]+
calcd 323.15428; found 323.15368; IR(KBr): 3394, 3060, 3035,
1607, 1590, 1577, 1509, 1496, 1417, 1267, 987, 776, 694 cm-1.
2-(4-Chlorophenyl)-3-fluoro-N,6-diphenylpyridin-4-amine (3j)
White solid, mp 140–141 ◦C; 1H NMR (300 MHz, CDCl3) d 8.04
(d, J = 7.0 Hz, 2H), 7.92 (d, J = 6.4 Hz, 2H), 7.55–7.16 (m, 11H),
6.33 (d, J = 3.2 Hz, 1H); 19F NMR (282 MHz, CDCl3) d -152.06;
13C NMR (100 MHz, CDCl3) d 153.4 (d, J = 5.9 Hz), 146.8 (d,
J = 253.1 Hz), 142.6 (d, J = 8.8 Hz), 140.7 (d, J = 10.3 Hz), 139.3,
139.1, 135.0, 134.5 (d, J = 5.8 Hz), 130.3 (d, J = 5.9 Hz), 129.9,
128.8, 128.6, 128.6, 126.9, 124.8, 122.3, 104.4; LRMS (EI) m/z
(relative intensity) 374 (100) [M+], 377 (7), 376 (34), 375 (51), 373
(88); Anal. Calcd. for C23H16ClFN2: C, 73.70; H, 4.30; N, 7.47.
Found: C, 73.86; H, 4.33; N, 7.32. IR(KBr): 3421, 1611, 1596,
1581, 1492, 1462, 1409, 1243, 1082, 751, 696 cm-1.
N,2,6-Triphenyl-3-(trifluoromethyl)pyridin-4-amine (3o)
◦
1
White solid, mp 113–114 C; H NMR (300 MHz, CDCl3) d
7.93–7.81 (m, 2H), 7.61–7.19 (m, 14H), 6.73 (s, 1H); 19F NMR
(282 MHz, CDCl3) d -52.82; 13C NMR (100 MHz, CDCl3) d
160.0, 158.6, 151.6, 141.6, 139.0, 138.6, 130.0, 129.6, 128.7, 128.6
(q, J = 1.5 Hz), 128.3, 127.8, 127.3, 125.9, 125.5 (q, J = 273.6 Hz),
124.3, 107.9 (q, J = 29.4 Hz), 104.2; HRMS-ESI (m/z): C24H18F3N2
[M + H]+ calcd 391.14166, found 391.14130; IR(KBr): 3464, 3060,
3036, 1578, 1563, 1498, 1446, 1418, 1405, 1302, 1257, 1225, 1091,
1022, 764, 697 cm-1.
3-Fluoro-N,6-diphenyl-2-(2-(trifluoromethyl)phenyl)pyridin-4-
amine (3k)
◦
1
White solid, mp 157–158 C; H NMR (300 MHz, CDCl3) d
7.89–7.77 (m, 3H), 7.68–7.15 (m, 12H), 6.33 (s, 1H); 19F NMR
(282 MHz, CDCl3) d -58.86 (s, 3F), -150.44 (s, 1F); 13C NMR
(100 MHz, CDCl3) d 153.6 (d, J = 5.8 Hz), 146.0 (d, J = 249.4
Hz), 144.4 (d, J = 13.2 Hz), 139.9 (d, J = 10.3 Hz), 139.4, 138.9,
134.7 (d, J = 2.2 Hz), 131.6, 131.5 (d, J = 7.3 Hz), 129.8, 129.4
(q, J = 30.8 Hz), 128.9, 128.7, 128.6, 127.1, 126.7 (q, J = 4.2 Hz),
124.9, 124.1 (q, J = 273.7 Hz), 122.3, 105.1; LRMS-ESI (m/z):
C24H17F4N2 [M + H]+ calcd 409.1; found 409.0; Anal. Calcd. for
C24H16F4N2: C, 70.58; H, 3.95; N, 6.86. Found: C, 70.60; H, 3.91;
N, 6.78. IR(KBr): 3421, 3064, 1615, 1596, 1579, 1518, 1498, 1465,
1409, 1315, 1267, 1171, 1131, 1035, 762, 697 cm-1.
6-(4-Bromophenyl)-N,2-diphenyl-3-(trifluoromethyl)pyridin-4-
amine (3p)
Light yellow solid, mp 93–96 ◦C; 1H NMR (300 MHz, CDCl3) d
7.74 (d, J = 8.5 Hz, 2H), 7.57–7.39 (m, 9H), 7.36–7.25 (m, 4H) 6.74
(br, 1H); 19F NMR (282 MHz, CDCl3) d -52.14 (s, 3F); 13C NMR
(100 MHz, CDCl3) d 160.1, 157.3, 151.7, 141.5, 138.8, 137.4, 131.8,
130.0, 128.9, 128.5 (q, J = 1.4 Hz), 128.4, 127.8, 126.1, 125.4 (q, J =
274.4 Hz), 124.4, 124.1, 108.1 (q, J = 29.3 Hz), 103.8; HRMS-ESI
(m/z): C24H17BrF3N2 [M + H]+ calcd 469.0522; found 469.0511;
IR(KBr): 3462, 3060, 1576, 1558, 1489, 1426, 1385, 1301, 1256,
1223, 1178, 1132, 1091, 1022, 700 cm-1.
3-Fluoro-N,6-diphenyl-2-(thiophen-2-yl)pyridin-4-amine (3l)
6-(3-Methoxyphenyl)-N,2-diphenyl-3-(trifluoromethyl)-pyridin-4-
amine (3q)
White solid, mp 108–110 ◦C; 1H NMR (300 MHz, CDCl3) d 7.94
(d, J = 6.5 Hz, 2H), 7.83 (s, 1H), 7.50–7.11 (m, 11H), 6.31 (d, J =
3.0 Hz, 1H); 19F NMR (282 MHz, CDCl3) d -150.07; 13C NMR
(100 MHz, CDCl3) d 153.0 (d, J = 5.1 Hz), 145.2 (d, J = 254.6
Hz), 140.8 (d, J = 8.1 Hz), 140.4 (d, J = 9.6 Hz), 139.1, 139.1 (d,
J = 9.5 Hz), 139.0, 129.8, 128.8, 128.6, 128.1, 127.9 (d, J = 3.7
Hz), 127.6 (d, J = 12.5 Hz), 126.9, 124.7, 122.2, 103.6; LRMS (EI)
m/z (relative intensity) 346 (100) [M+], 348 (7), 347 (27), 345 (83);
Anal. Calcd. for C21H15FN2S: C, 72.81; H, 4.36; N, 8.09. Found:
C, 72.92; H, 4.74; N, 7.77. IR(KBr): 3410, 3061, 1611, 1594, 1579,
1509, 1497, 1466, 1406, 1246, 745, 695 cm-1.
◦
1
White solid, mp 136–138 C; H NMR (300 MHz, CDCl3) d
7.61–7.20 (m, 14H), 6.91 (dd, J = 8.1 Hz, J = 1.8 Hz, 1H) 6.73
(br, 1H); 19F NMR (282 MHz, CDCl3) d -52.04 (s, 3F); 13C NMR
(100 MHz, CDCl3) d 159.9, 159.9, 158.4, 151.5, 141.6, 140.1, 139.0,
130.0, 129.6, 128.6 (q, J = 1.5 Hz), 128.3, 127.8, 125.9, 125.5 (q, J =
274.3 Hz), 124.3, 119.7, 115.1, 113.1, 108.0 (q, J = 28.6 Hz), 104.3,
55.4; HRMS-ESI (m/z): C25H20F3N2O [M + H]+ calcd 421.1522;
found 421.1512; IR(KBr): 3446, 3060, 1583, 1558, 1494, 1397,
1300, 1264, 1128, 1095, 1047, 1023, 700 cm-1.
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6-(Naphthalen-2-yl)-N,2-diphenyl-3-(trifluoromethyl)pyridin-4-
amine (3r)
calcd 441.1385; found 441.1380; IR(KBr): 3484, 3057, 1578, 1560,
1498, 1413, 1257, 1203, 1161, 1051, 960, 699 cm-1.
White solid, mp 143–145 ◦C; 1H NMR (300 MHz, CDCl3) d 8.39
(s, 1H), 8.00–7.94 (m, 1H), 7.90–7.76 (m, 3H), 7.61–7.40 (m, 10H),
7.38–7.25 (m, 3H), 6.75 (br, 1H); 19F NMR (282 MHz, CDCl3) d
-52.00 (s, 3F); 13C NMR (100 MHz, CDCl3) d 160.1, 158.5, 151.5,
141.7, 139.0, 135.8, 134.0, 133.3, 130.0, 128.9, 128.6, 128.6, 128.3,
127.8, 127.7, 127.1, 126.8, 126.3, 125.9, 125.5 (q, J = 274.4 Hz),
124.6, 124.3, 108.0 (q, J = 28.7 Hz), 104.4; HRMS-ESI (m/z):
C28H20F3N2 [M + H]+ calcd 441.1573; found 441.1569; IR(KBr):
3463, 3059, 1602, 1576, 1561, 1498, 1439, 1417, 1300, 1190, 1133,
1086, 1023, 702 cm-1.
Procedure for pyridine 3w synthesis
1a (0.4 mmol) and n-butylamine (2 equiv.) were added to 2.0 mL
THF, the mixture was stirred at 80 ◦C for two hours, then cooled to
room temperature, and NaH (2.5 equiv.) was added. The solution
was then stirred at 80 ◦C for 20 min, and quenched with ice
water. The mixture was partitioned between ethyl acetate and
water, the organic layer was washed with brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel to provide product 3w as a yellow
oil.
1H NMR (300 MHz, CDCl3) d 7.81 (d, J = 2.9 Hz, 2H), 7.43–
7.03 (m, 9H), 6.23 (s, 1H), 2.90–2.79 (m, 2H), 1.92–1.75 (m, 2H),
1.04 (t, J = 7.4 Hz, 3H); 19F NMR (282 MHz, CDCl3) d -154.11;
13C NMR (100 MHz, CDCl3) d 153.3 (d, J = 5.9 Hz), 148.5 (d, J =
14.0 Hz), 146.9 (d, J = 246.5 Hz), 139.9, 139.4, 139.2 (d, J = 10.3
Hz), 129.7, 128.6, 128.5, 127.0, 124.4, 121.9, 103.9, 33.7, 22.0, 14.1;
HRMS-ESI (m/z): C20H20FN2 [M + H]+ calcd 307.16050; found
307.16035; IR(KBr): 3415, 3036, 2961, 2930, 2870, 1615, 1597,
1580, 1512, 1496, 1467, 1408, 1249, 1179, 696 cm-1.
N,6-Diphenyl-2-(p-tolyl)-3-(trifluoromethyl)pyridin-4-amine (3s)
White solid, mp 121–123 ◦C; 1H NMR (300 MHz, CDCl3) d 7.91–
7.85 (m, 2H), 7.50–7.40 (m, 4H), 7.40–7.34 (m, 4H), 7.33–7.21 (m,
5H), 6.71 (br, 1H), 2.42 (s, 3H); 19F NMR (282 MHz, CDCl3) d
-52.00 (s, 3F); 13C NMR (100 MHz, CDCl3) d 160.0, 158.5, 151.5,
139.1, 138.9, 138.6, 138.1, 130.0, 129.5, 128.6, 128.5, 128.5, 127.3,
125.8, 125.6 (q, J = 274.4 Hz), 124.3, 107.9 (J = 29.3 Hz), 104.0,
21.4; HRMS-ESI (m/z): C25H20F3N2 [M + H]+ calcd 405.1573;
found 405.1572; IR(KBr): 3466, 3059, 3036, 2922, 1582, 1561,
1498, 1412, 1301, 1257, 1130, 1090, 1021, 695 cm-1.
Procedure for 4a synthesis
1a (0.4 mmol) and benzylamine (2 equiv.) were added to 2.0 mL
THF, the mixture was stirred at 80 ◦C for two hours. Then
the solvent was evaporated, and the residue was purified by
flash chromatography on silica providing 4a as a yellow solid in
quantitative yield.
Mp 76–77 C; H NMR (300 MHz, CDCl3) d 11.28 (br, 1H),
7.46–6.79 (m, 15H), 5.24 (s, 1H), 4.40 (s, 2H); 19F NMR (282 MHz,
CDCl3) d -62.63; 13C NMR (100 MHz, CDCl3) d 163.0, 152.6 (q,
J = 26.4 Hz), 149.1, 139.0, 135.9, 129.5, 128.7, 128.6, 128.4, 128.0,
127.3, 126.6, 123.1, 120.3, 119.0 (q, J = 290.5 Hz), 89.9 (q, J =
3.7 Hz), 48.4; HRMS-ESI (m/z): C23H20F3N2 [M + H]+ calcd
381.15731; found 381.15759; IR(KBr): 3029, 2927, 1616, 1554,
1483, 1281, 1231, 1182, 1137, 1089, 695 cm-1.
2-(4-Chlorophenyl)-N,6-diphenyl-3-(trifluoromethyl)pyridin-4-
amine (3t)
◦
1
White solid, mp 137–139 C; H NMR (300 MHz, CDCl3) d
7.92–7.80 (m, 2H), 7.55–7.24 (m, 13H), 6.73 (br, 1H); 19F NMR
(282 MHz, CDCl3) d -52.32 (s, 3F); 13C NMR (100 MHz, CDCl3)
d 158.7, 151.7, 140.1, 138.8, 138.4, 134.4, 130.0, 130.0, 130.0, 129.7,
128.7, 128.1, 127.3, 126.1, 125.4 (q, J = 274.3 Hz), 124.4, 107.8 (q,
J = 28.6 Hz), 104.2; HRMS-ESI (m/z): C24H17ClF3N2 [M + H]+
calcd 425.1027; found 425.1018; IR(KBr): 3460, 3062, 1581, 1558,
1497, 1410, 1304, 1257, 1224, 1087, 1022, 835, 695 cm-1.
◦
1
N,6-Diphenyl-2-(thiophen-2-yl)-3-(trifluoromethyl)pyridin-4-
amine (3u)
Representative procedure for dihydropyrimidine 5 synthesis
White solid, mp 88–90 ◦C; 1H NMR (300 MHz, CDCl3) d 7.94–
7.84 (m, 2H), 7.50–7.21 (m, 11H), 7.12–7.05 (m, 1H) 6.76 (br,
1H); 19F NMR (282 MHz, CDCl3) d -52.01 (s, 3F); 13C NMR
(100 MHz, CDCl3) d 158.2, 153.1, 151.9, 143.3, 138.9, 138.1, 130.0,
129.7, 128.7, 128.3 (q, J = 3.6 Hz), 127.6, 127.2, 126.9, 126.0, 125.6
(q, J = 274.3 Hz), 124.4, 107.1 (q, J = 30.1 Hz), 104.0; HRMS-ESI
(m/z): C22H16F3N2S [M + H]+ calcd 397.0981; found 397.0976;
IR(KBr): 3466, 3063, 1580, 1558, 1497, 1447, 1417, 1404, 1299,
1256, 1221, 1156, 1106, 1089, 1021, 695 cm-1.
1 (0.4 mmol) and amine (2 equiv.) were added to 2.0 mL THF,
◦
the mixture was stirred at 80 C for two hours, and then cooled
to -40 ◦C (rt for 5q, 5w), and t-BuOK (2.0 equiv.) was added
slowly, and quenched with ice water after 5 min. The mixture was
partitioned between ethyl acetate and water, the organic layer was
washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
to provide 5.
3-(Perfluoroethyl)-N,2,6-triphenylpyridin-4-amine (3v)
6-(Difluoromethyl)-1,2,4-triphenyl-1,2-dihydropyrimidine (5a)
◦
◦
1
1
White solid, mp 146–148 C; H NMR (300 MHz, CDCl3) d
7.88–7.78 (m, 2H), 7.49–7.20 (m, 14H), 6.83 (br, 1H); 19F NMR
(282 MHz, CDCl3) d -82.59 (s, 3F), -101.54 (s, 2F); 13C NMR
(100 MHz, CDCl3) d 161.7, 158.5, 152.5, 142.3, 139.2, 138.4, 130.0,
129.6, 128.6, 128.2, 127.6, 127.4, 127.3, 126.0, 124.4, 119.7 (qt, J =
288.3 Hz, J = 38.9 Hz), 115.7 (tq, J = 257.4 Hz, J = 40.4 Hz), 105.6
(t, J = 23.5 Hz), 105.0; HRMS-ESI (m/z): C25H18F5N2 [M + H]+
Yellow solid, mp 106–107 C; H NMR (300 MHz, CDCl3) d
7.96–7.85 (m, 2H), 7.64 (d, J = 7.5 Hz, 2H), 7.50–7.11 (m, 11H),
6.64 (s, 1H), 6.57 (d, J = 2.5 Hz, 1H), 6.28 (t, J = 54.4 Hz, 1H); 19
NMR (282 MHz, CDCl3) d -112.22 (dd, JF–F = 301.3 Hz, JH–F
55.5 Hz, 1F), -121.41 (dd, JF–F = 301.2 Hz, JH–F = 53.5 Hz, 1F); 13
NMR (100 MHz, CDCl3) d 160.1, 143.7, 142.9 (dd, J = 27.9 Hz,
J = 22.0 Hz), 140.6, 137.2, 130.5, 129.6, 128.6, 128.3, 128.1, 127.2,
F
=
C
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126.5, 126.4, 124.7, 110.2 (t, J = 242.1 Hz), 103.1 (t, J = 5.1 Hz),
79.8; HRMS-ESI (m/z): C23H19F2N2 [M + H]+ calcd 361.15108;
found 361.14966; IR(KBr): 3060, 3032, 2925, 1629, 1580, 1492,
1446, 1376, 1352, 1264, 1125, 1047, 765, 695 cm-1.
(282 MHz, CDCl3) d -112.86 (dd, JF–F = 301.1 Hz, JH–F = 54.6 Hz,
1F), -122.03 (dd, JF–F = 301.1 Hz, JH–F = 53.6 Hz, 1F); 13C NMR
(100 MHz, CDCl3) d 155.2, 143.7, 143.0, 142.9 (dd, J = 27.2 Hz,
J = 22.8 Hz), 140.5, 129.7, 129.3, 128.3, 128.1, 128.0, 127.8, 126.5,
126.4, 124.8, 110.0 (t, J = 242.1 Hz), 102.4 (t, J = 5.9 Hz), 79.4;
LRMS (EI) m/z (relative intensity) 366 (13) [M+], 289 (58), 262
(100), 104 (28), 77 (42); HRMS-EI (m/z) calcd for C21H16F2N2S
366.1002; found 366.1006; IR(KBr): 3063, 1625, 1594, 1492, 1427,
1265, 1124, 1049, 697 cm-1.
6-(Fluoromethyl)-1,2,4-triphenyl-1,2-dihydropyrimidine (5b)
Red oil; 1H NMR (300 MHz, CDCl3) d 8.01–7.82 (m, 2H), 7.62 (d,
J = 7.3 Hz, 2H), 7.48–7.14 (m, 11H), 6.62 (s, 1H), 6.26 (s, 1H), 5.02
(dAB, JF–H = 47.9 Hz, JH–H = 12.3 Hz, 2H); 19F NMR (282 MHz,
CDCl3) d -215.55 (t, J = 47.4 Hz, 1F); 13C NMR (100 MHz,
CDCl3) d 160.7, 145.9 (d, J = 15.4 Hz), 143.6, 141.0, 137.5, 130.2,
129.4, 128.5, 128.2, 127.9, 127.2, 126.6, 126.1, 125.1, 102.8 (d, J =
5.8 Hz), 80.1 (d, J = 173.1 Hz), 79.3; LRMS (EI) m/z (relative
intensity) 342 (11) [M+], 341 (15), 265 (100), 104 (19), 77 (34);
HRMS-EI (m/z) calcd for C23H19FN2 342.1532; found 342.1535;
IR(KBr): 3059, 2925, 1623, 1596, 1542, 1493, 1266, 1069, 757,
696 cm-1.
6-(Difluoromethyl)-1-(4-methoxyphenyl)-2,4-diphenyl-1,2-
dihydropyrimidine (5f)
Red oil; 1H NMR (300 MHz, CDCl3) d 8.03–7.80 (m, 2H), 7.63 (d,
J = 7.1 Hz, 2H), 7.53–7.26 (m, 6H), 7.14 (d, J = 8.7 Hz, 2H), 6.85 (d,
J = 8.7 Hz, 2H), 6.52 (s, 1H), 6.46 (s. 1H), 6.21 (t, J = 54.2 Hz, 1H),
3.78 (s, 3H); 19F NMR (282 MHz, CDCl3) d -113.53 (dd, JF–F
301.0 Hz, JH–F = 54.7 Hz, 1F), -121.49 (dd, JF–F = 301.0 Hz, JH–F
=
=
53.7 Hz, 1F); 13C NMR (100 MHz, CDCl3) d 160.3, 158.5, 143.4
(dd, J = 27.1 Hz, J = 22.7 H), 140.9, 137.4, 136.3, 130.4, 128.6,
128.4, 128.1, 127.2, 127.2, 126.6, 114.8, 110.5 (t, J = 242.1 Hz),
101.0 (t, J = 5.9 Hz), 80.5, 55.5; LRMS (EI) m/z (relative intensity)
390 (18) [M+], 339 (27), 313 (100), 134 (34), 77 (20); HRMS-
EI (m/z) calcd for C24H20F2N2O 390.1544; found 390.1548;
IR(KBr): 3060, 2933, 1626, 1578, 1509, 1247, 1125, 1037,
695 cm-1.
6-(Difluoromethyl)-1,2-diphenyl-4-p-tolyl-1,2-dihydropyrimidine
(5c)
◦
1
Yellow solid, mp 80–83 C; H NMR (300 MHz, CDCl3) d 7.81
(d, J = 8.1 Hz, 2H), 7.63 (d, J = 7.3 Hz, 2H), 7.42–7.10 (m, 10H),
6.63 (s, 1H), 6.56 (d, J = 2.6 Hz, 1H), 6.27 (t, J = 54.5 Hz, 1H),
2.37 (s, 3H); 19F NMR (282 MHz, CDCl3) d -112.49 (dd, JF–F
=
300.0 Hz, JH–F = 54.7 Hz, 1F), -121.53 (dd, JF–F = 301.0 Hz,
JH–F = 53.7 Hz, 1F); 13C NMR (100 MHz, CDCl3) d 159.9,
143.8, 142.8 (dd, J = 28.6 Hz, J = 22.8 Hz), 140.8, 140.7, 134.3,
129.6, 129.3, 128.3, 128.0, 127.2, 126.5, 126.3, 124.7, 110.2 (t,
J = 242.1 Hz), 103.2 (t, J = 5.1 Hz), 79.7, 21.4; LRMS (EI) m/z
(relative intensity) 374 (15) [M+], 373 (20), 297 (100), 104 (25),
77 (34); HRMS-EI (m/z) calcd for C24H20F2N2 374.1595; found
374.1591; IR(KBr): 3030, 1634, 1492, 1448, 1377, 1183, 1041, 813,
742 cm-1.
4-(6-(Difluoromethyl)-2,4-diphenylpyrimidin-1(2H)-yl)benzonitrile
(5g)
Yellow solid, mp 52–54 ◦C; 1H NMR (300 MHz, CDCl3) d 8.03–
7.03 (m, 14H), 6.74–6.67 (m, 2H), 6.30 (t, J = 54.7 Hz, 1H); 19F
NMR (282 MHz, CDCl3) d -110.44 (dd, JF–F = 302.1 Hz, JH–F
=
C
54.7 Hz, 1F), -120.73 (dd, JF–F = 302.1 Hz, JH–F = 54.6 Hz, 1F); 13
NMR (100 MHz, CDCl3) d 159.7, 148.1, 141.3 (dd, J = 27.2 Hz,
J = 22.8 Hz), 139.4, 136.3, 133.6, 130.9, 128.7, 128.5, 128.5, 127.1,
126.2, 123.4, 118.5, 110.3 (t, J = 243.6 Hz), 108.6, 107.6 (t, J = 5.1
Hz), 79.3; LRMS (EI) m/z (relative intensity) 385 (18) [M+], 384
(21), 308 (100), 281 (28), 129 (41), 102 (37); HRMS-EI (m/z) calcd
for C24H17F2N3 385.1391; found 385.1389; IR(KBr): 3061, 2226,
1633, 1603, 1504, 1267, 1049, 695 cm-1.
6-(Difluoromethyl)-4-(4-fluorophenyl)-1,2-diphenyl-1,2-
dihydropyrimidine (5d)
Red oil; 1H NMR (300 MHz, CDCl3) d 7.96–7.83 (m, 2H), 7.70–
7.56 (m, 2H), 7.42–6.98 (m, 10H), 6.62 (s, 1H), 6.51 (d, J = 2.5 Hz,
1H), 6.28 (t, J = 54.7 Hz, 1H); 19F NMR (282 MHz, CDCl3) d
-110.20–-110.40 (m, 1F), -112.78 (dd, JF–F = 301.0 Hz, JH–F
=
54.7 Hz, 1F), -121.57 (dd, JF–F = 301.1 Hz, JH–F = 53.6 Hz,
1F); 13C NMR (100 MHz, CDCl3) d 164.4 (d, J = 250.9 Hz),
159.0, 143.6, 143.3 (dd, J = 27.2 Hz, J = 23.5 Hz), 140.5,
133.3 (td, J = 2.9 Hz), 129.7, 129.3 (d, J = 8.1 Hz), 128.4,
128.2, 126.5, 126.4, 124.8, 115.5 (d, J = 22.0 Hz), 110.1 (t, J =
242.1 Hz), 102.4 (t, J = 5.1 Hz), 79.8; LRMS (EI) m/z (relative
intensity) 378 (10) [M+], 327 (16), 301 (100), 104 (33), 77 (47);
HRMS-EI (m/z) calcd for C23H17F3N2 378.1344; found 378.1345;
IR(KBr): 3063, 1628, 1602, 1510, 1501, 1263, 1157, 1048, 845,
697 cm-1.
6-(Difluoromethyl)-2,4-diphenyl-1-m-tolyl-1,2-dihydropyrimidine
(5h)
1
Red oil; H NMR (300 MHz, CDCl3) d 7.97–7.87 (m, 2H), 7.65
(d, J = 7.3 Hz, 2H), 7.46–7.25 (m, 6H), 7.20 (t, J = 7.5 Hz, 1H),
7.06–6.93 (m, 3H), 6.64 (s, 1H), 6.56 (d, J = 2.8 Hz, 1H), 6.29 (t,
J = 54.5 Hz, 1H), 2.30 (s, 3H); 19F NMR (282 MHz, CDCl3) d
-112.48 (dd, JF–F = 300.0 Hz, JH–F = 54.7 Hz, 1F), -121.65 (dd,
JF–F = 300.0 Hz, JH–F = 53.6 Hz, 1F); 13C NMR (100 MHz, CDCl3)
d 160.2, 143.7, 143.1 (dd, J = 27.2 Hz, J = 22.0 H), 140.7, 139.8,
137.1, 130.5, 129.4, 128.6, 128.3, 128.1, 127.3, 127.2, 126.5, 125.3,
121.9, 110.2 (t, J = 241.3 Hz), 102.9 (t, J = 5.9 Hz), 79.7; LRMS
(EI) m/z (relative intensity) 374 (15) [M+], 373 (17), 323 (18), 297
(100), 118 (22), 91 (41); HRMS-EI (m/z) calcd for C24H20F2N2
374.1595; found 174.1594; IR(KBr): 3060, 2923, 1627, 1604, 1490,
1265, 1122, 1064, 695 cm-1.
6-(Difluoromethyl)-1,2-diphenyl-4-(thiophen-2-yl)-1,2-
dihydropyrimidine (5e)
Yellowish brown solid, mp 97–99 ◦C; 1H NMR (300 MHz, CDCl3)
d 7.70 (d, J = 7.2 Hz, 2H), 7.60–7.19 (m, 10H), 7.13 (t, J = 4.8 Hz,
1H), 6.68–6.55 (m, 2H), 6.35 (t, J = 54.5 Hz, 1H); 19F NMR
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6-(Difluoromethyl)-1,4-diphenyl-2-p-tolyl-1,2-dihydropyrimidine
(5i)
(22), 377 (24), 283 (100), 104 (21), 77 (29); HRMS-EI (m/z) calcd
for C24H17F5N2 428.1312; found 428.1313; IR(KBr): 3063, 2928,
1629, 1595, 1493, 1328, 1167, 1129, 1067, 796, 695 cm-1.
Reddish brown oil; 1H NMR (300 MHz, CDCl3) d 7.98–7.84 (m,
2H), 7.62–7.07 (m, 12H), 6.61 (s, 1H), 6.58–6.53 (m, 1H), 6.26 (t,
J = 54.1 Hz, 1H), 2.32 (s, 3H); 19F NMR (282 MHz, CDCl3) d
-112.39 (dd, JF–F = 301.0 Hz, JH–F = 54.7 Hz, 1F), -121.34 (dd,
JF–F = 301.0 Hz, JH–F = 53.6 Hz, 1F); 13C NMR (100 MHz, CDCl3)
d 160.0, 143.8, 142.9 (dd, J = 27.9 Hz, J = 24.3 Hz), 137.8, 137.7,
137.2, 130.4, 129.6, 129.0, 128.6, 127.2, 126.4, 126.3, 124.7, 110.3
(t, J = 241.4 Hz), 103.0 (t, J = 5.1 Hz), 79.8, 21.2; LRMS (EI) m/z
(relative intensity) 374 (26) [M+], 373 (29), 323 (33), 283 (100),
256 (27), 104 (28), 77 (31); HRMS-EI (m/z) calcd for C24H20F2N2
374.1595; found 374.1600; IR(KBr): 3060, 2922, 1626, 1538, 1491,
1262, 1120, 1046, 695 cm-1.
6-(Difluoromethyl)-2-(naphthalen-1-yl)-1,4-diphenyl-1,2-
dihydropyrimidine (5m)
Red oil; 1H NMR (300 MHz, CDCl3) d 8.88 (d, J = 8.5 Hz, 1H),
8.01–6.97 (m, 17H), 6.52 (d, J = 2.3 Hz, 1H), 6.45 (t, J = 54.8 Hz,
1H); 19F NMR (282 MHz, CDCl3) d -113.05 (dd, JF–F = 301.1 Hz,
JH–F = 54.7 Hz, 1F), -121.08 (dd, JF–F = 302.1 Hz, JH–F = 53.7 Hz,
1F); 13C NMR (100 MHz, CDCl3) d 158.8, 143.8 (dd, J = 27.1 Hz,
J = 22.0 Hz), 143.4, 137.3, 135.0, 134.4, 130.5, 130.3, 129.5, 128.9,
128.6, 128.4, 127.2, 126.7, 126.2, 126.1, 125.8, 125.4, 125.2, 123.8,
110.5 (t, J = 242.1 Hz), 100.0 (t, J = 5.9 Hz), 79.6; LRMS (EI)
m/z (relative intensity) 410 (26) [M+], 359 (28), 283 (100), 256 (45),
104 (28), 77 (28); HRMS-EI (m/z) calcd for C27H20F2N2 410.1595;
found 410.1593; IR(KBr): 3058, 2925, 1632, 1596, 1493, 1359,
1265, 1129, 1045, 766, 695 cm-1.
6-(Difluoromethyl)-1,4-diphenyl-2-o-tolyl-1,2-dihydropyrimidine
(5j)
1
Red oil; H NMR (300 MHz, CDCl3) d 7.94–7.76 (m, 2H), 7.55
(d, J = 6.2 Hz, 1H), 7.45–6.99 (m, 11H), 6.62 (s, 1H), 6.53–6.45 (m,
1H), 6.32 (t, J = 54.0 Hz, 1H), 2.68 (s, 3H); 19F NMR (282 MHz,
CDCl3) d -113.56 (dd, JF–F = 301.0 Hz, JH–F = 54.7 Hz, 1F), -120.53
(dd, JF–F = 302.1 Hz, JH–F = 52.6 Hz, 1F); 13C NMR (100 MHz,
CDCl3) d 158.8, 144.2 (dd, J = 26.4 Hz, J = 22.0 Hz), 143.2, 138.1,
137.4, 135.9, 131.2, 130.2, 129.5, 128.4, 128.0, 127.1, 126.8, 126.4,
125.8, 125.8, 110.4 (t, J = 241.4 Hz), 99.6 (t, J = 5.8 Hz), 79.5,
20.2; LRMS (EI) m/z (relative intensity) 374 (18) [M+], 323 (21),
283 (100), 256 (32), 104 (31), 77 (33); HRMS-EI (m/z) calcd for
C24H20F2N2 374.1595; found 374.1603; IR(KBr): 3062, 1632, 1595,
1492, 1264, 1109, 1047, 762, 696 cm-1.
6-(Difluoromethyl)-1,4-diphenyl-2-(thiophen-2-yl)-1,2-
dihydropyrimidine (5n)
◦
1
Yellow solid, mp 127–129 C; H NMR (300 MHz, CDCl3) d
8.00–7.85 (m, 2H), 7.56–7.13 (m, 10H), 7.03–6.94 (m, 1H), 6.78 (s,
1H), 6.63 (d, J = 2.5 Hz, 1H), 6.22 (t, J = 53.9 Hz, 1H); 19F NMR
(282 MHz, CDCl3) d -113.25 (dd, JF–F = 302.0 Hz, JH–F = 54.6 Hz,
1F), -120.62 (dd, JF–F = 302.0 Hz, JH–F = 53.6 Hz, 1F); 13C NMR
(100 MHz, CDCl3) d 160.9, 144.4, 143.1, 142.6 (dd, J = 27.8 Hz,
J = 22.7 Hz), 137.0, 130.6, 129.7, 128.6, 127.3, 126.7, 126.4, 125.5,
125.2, 125.1, 110.1 (t, J = 242.1 Hz), 102.9 (t, J = 5.9 Hz), 77.4;
LRMS (EI) m/z (relative intensity) 366 (69) [M+], 365 (84), 315
(100), 289 (29), 256 (40), 104 (45), (60); HRMS-EI (m/z) calcd
for C21H16F2N2S 366.1002; found 366.1004; IR(KBr): 3063, 2926,
1627, 1579, 1493, 1375, 1263, 1117, 1047, 694 cm-1.
2-(4-Chlorophenyl)-6-(difluoromethyl)-1,4-diphenyl-1,2-
dihydropyrimidine (5k)
Red oil; 1H NMR (300 MHz, CDCl3) d 8.00–7.82 (m, 2H), 7.66–
7.10 (m, 12H), 6.63–6.53 (m, 2H), 6.29 (t, J = 54.1 Hz, 1H); 19F
6-(Difluoromethyl)-1,4-diphenyl-2-(pyridin-2-yl)-1,2-
dihydropyrimidine (5o)
NMR (282 MHz, CDCl3) d -112.66 (dd, JF–F = 301.1 Hz, JH–F
=
C
54.7 Hz, 1F), -122.40 (dd, JF–F = 301.1 Hz, JH–F = 53.6 Hz, 1F); 13
Yellowgreen solid, mp 117–119 ◦C; 1H NMR (300 MHz, CDCl3)
NMR (100 MHz, CDCl3) d 160.3, 143.5, 142.9 (dd, J = 27.9 Hz,
J = 24.3 Hz), 139.1, 136.9, 133.9, 130.6, 129.7, 128.6, 128.5, 127.9,
127.1, 126.6, 124.8, 110.1 (t, J = 242.1 Hz), 103.2 (t, J = 5.1 Hz),
79.3; LRMS (EI) m/z (relative intensity) 394 (22) [M+], 393 (28),
343 (26), 283 (100), 104 (28), 77 (35); HRMS-EI (m/z) calcd for
C23H17ClF2N2 394.1048; found 394.1052; IR(KBr): 3062, 1629,
1595, 1490, 1446, 1262, 1092, 1049, 696 cm-1.
d 8.67 (d, J = 4.5 Hz, 1H), 8.05–7.93 (m, 2H), 7.66–7.13 (m, 11H),
6.68 (s, 1H), 6.59 (d, J = 1.8 Hz, 1H), 6.15 (t, J = 54.0 Hz, 1H); 19
NMR (282 MHz, CDCl3) d -113.96 (dd, JF–F = 303.1 Hz, JH–F
F
=
54.6 Hz, 1F), -118.05 (dd, JF–F = 303.1 Hz, JH–F = 53.6 Hz, 1F);
13C NMR (100 MHz, CDCl3) d 161.4, 158.8, 149.5, 143.4, 143.3
(dd, J = 27.2 Hz, J = 24.2 Hz), 137.0, 136.1, 130.6, 129.4, 128.6,
127.2, 126.4, 125.7, 123.0, 122.0, 110.0 (t, J = 241.4 Hz), 101.5 (t,
J = 5.1 Hz), 80.7; LRMS (EI) m/z (relative intensity) 361 (3) [M+],
283 (100), 207 (19), 77 (13); HRMS-EI (m/z) calcd for C22H17F2N3
361.1391; found 361.1394; IR(KBr): 3058, 2926, 1625, 1593, 1492,
1374, 1261, 1126, 1048, 764, 696 cm-1.
6-(Difluoromethyl)-1,4-diphenyl-2-(4-(trifluoromethyl)phenyl)-1,2-
dihydropyrimidine (5l)
Red oil; 1H NMR (300 MHz, CDCl3) d 7.91 (d, J = 7.4 Hz, 2H),
7.78 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.54–7.14 (m,
8H), 6.66 (s, 1H), 6.61 (s, 1H), 6.34 (t, J = 53.8 Hz, 1H); 19F NMR
(282 MHz, CDCl3) d -62.40 (s, 3F), -112.56 (dd, JF–F = 301.0 Hz,
JH–F = 54.7 Hz, 1F), -122.85 (dd, JF–F = 301.0 Hz, JH–F = 52.6 Hz,
1F); 13C NMR (100 MHz, CDCl3) d 160.5, 144.7, 143.5, 143.0
(dd, J = 27.2 Hz, J = 22.1 Hz), 136.8, 130.7, 130.3 (q, J = 32.3
Hz), 129.8, 128.7, 127.2, 126.8, 126.7, 125.3 (q, J = 4.4 Hz), 124.7,
124.1 (q, J = 272.1 Hz), 110.0 (t, J = 242.1 Hz), 103.4 (t, J = 5.9
Hz), 79.4; LRMS (EI) m/z (relative intensity) 428 (17) [M+], 427
6-(Difluoromethyl)-2-(furan-2-yl)-1,4-diphenyl-1,2-
dihydropyrimidine (5p)
yellowish brown solid, mp 121–123 ◦C; 1H NMR (300 MHz,
CDCl3) d 7.95 (d, J = 5.1 Hz, 2H), 7.60–7.11 (m, 9H), 6.65 (d,
J = 9.1 Hz, 1H), 6.39–6.19 (m, 3H), 6.11 (t, J = 54.2 Hz, 1H); 19
NMR (282 MHz, CDCl3) d -113.38 (dd, JF–F = 302.1 Hz, JH–F
F
=
54.7 Hz, 1F), -119.17 (dd, JF–F = 302.1 Hz, JH–F = 53.6 Hz, 1F);
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13C NMR (100 MHz, CDCl3) d 161.9, 151.3, 143.0, 142.9, 142.1
(dd, J = 28.7 Hz, J = 23.5 Hz), 137.0, 130.6, 129.6, 128.6, 127.2,
126.6, 125.6, 110.2, 109.9 (t, J = 241.3 Hz), 109.4, 101.6 (t, J = 5.9
Hz), 75.1; LRMS (EI) m/z (relative intensity) 350 (38) [M+], 349
(57), 299 (100), 273 (27), 104 (24), 77 (44); HRMS-EI (m/z) calcd
for C21H16F2N2O 350.1231; found 350.1228; IR(KBr): 3062, 2926,
1626, 1579, 1496, 1373, 1263, 1121, 1048, 693 cm-1.
Cucinotta, J. D. DiMarco, J. Gougoutas, A. Hedberg, M. Malley and
J. P. McCarthy, J. Med. Chem., 1995, 38, 119–129.
2 T. Yamazaki, T. Taguchi and I. Ojima, in Fluorine in Medicinal Chem-
istry and Chemical Biology, ed. I. Ojima, Wiley-Blackwell, Weinheim,
2009, pp. 3–46.
3 K. Uneyama, Organofluorine Chemistry, Oxford, Blackwell Publishing
Ltd, 2006.
4 B. E. Smart, In Organofluorine Chemistry: Principles and Commercial
Applications; ed. R. E. Banks, B. E. Smart and J. C. Tatlow, Plenum,
New York, 1994, pp. 57–88.
5 (a) K. L. Kirk, J. Fluorine Chem., 2006, 127, 1013–1029; (b) J. P. Be´gue´
and D. Bonnet-Delpon, J. Fluorine Chem., 2006, 127, 992–1012; (c) C.
Isanbor and D. O’Hagan, J. Fluorine Chem., 2006, 127, 303–319.
6 (a) Y. Li and J. Hu, Angew. Chem., Int. Ed., 2005, 44, 5882–5886;
(b) G. K. S. Prakash, C. Weber, S. Chacko and G. A. Olah, Org. Lett.,
2007, 9, 1863–1866; (c) J. A. Erickson and J. I. McLoughlin, J. Org.
Chem., 1995, 60, 1626–1631.
7 (a) T. Kobayashi, T. Nakagawa, H. Amii and K. Uneyama, Org. Lett.,
2003, 5, 4297–4300; (b) H. Amii, T. Kobayashi, H. Terasawa and K.
Uneyama, Org. Lett., 2001, 3, 3103–3105.
8 J. Ichikawa, Y. Wada, H. Miyazaki, T. Mori and H. Kuroki, Org. Lett.,
2003, 5, 1455–1458.
9 H. Amii and K. Uneyama, Chem. Rev., 2009, 109, 2119–2183.
10 A. S. Kiselyov, E. L. Piatnitski and J. Doody, Org. Lett., 2004, 6, 4061–
4063 and references therein.
6-(Difluoromethyl)-2-ethyl-1,4-diphenyl-1,2-dihydropyrimidine
(5q)
Dark red oil; 1H NMR (300 MHz, CDCl3) d 7.93–7.78 (m, 2H),
7.57–7.06 (m, 8H), 6.68 (d, J = 2.7 Hz, 1H), 6.11 (t, J = 54.0 Hz,
1H), 5.46 (t, J = 6.6 Hz, 1H), 2.00–1.78 (m, 2H), 1.15 (t, J = 7.3 Hz,
3H); 19F NMR (282 MHz, CDCl3) d -111.94 (dd, JF–F = 300.0 Hz,
JH–F = 54.6 Hz, 1F), -122.27 (dd, JF–F = 300.0 Hz, JH–F = 53.6 Hz,
1F); 13C NMR (100 MHz, CDCl3) d 129.1, 143.9, 142.7 (dd, J =
26.4 Hz, J = 23.5 Hz), 137.0, 130.4, 129.6, 128.6, 127.1, 126.2,
125.0, 109.9 (t, J = 241.3 Hz), 102.7, 80.6, 24.0, 9.8; HRMS-ESI
(m/z): C19H19F2N2 [M + H]+ calcd 313.15108; found 313.15144;
IR(KBr): 3061, 2967, 2933, 1627, 1602, 1539, 1492, 1262, 1118,
1046, 695 cm-1.
11 (a) K. Uneyama, In Organofluorine Chemistry, Blackwell Publishing
Ltd, Oxford, 2006; p 107; (b) H. Amii, T. Kobayashi, Y. Hatamoto and
K. Uneyama, Chem. Commun., 1999, 1323–1324.
12 L. F. Tietze, G. Brasche and G. Gericke, Domino Reactions in Organic
Synthesis, Wiley-VCH, Weinheim, 2006.
6-(Difluoromethyl)-1,4-diphenyl-2-propyl-1,2-dihydropyrimidine
(5w)
13 (a) M. Balasubramanian and J. G. Keay, in Comprehensive Heterocyclic
Chemistry II, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven,
Pergamon, Oxford, 1996, Vol. 5, p 245; (b) K. Parthasarathy, M.
Jeganmohan and C.-H. Cheng, Org. Lett., 2008, 10, 325–328; (c) J. Hu,
Q. Zhang, H. Yuan and Q. Liu, J. Org. Chem., 2008, 73, 2442–2445;
(d) M. Movassaghi, M. D. Hill and O. K. Ahmad, J. Am. Chem. Soc.,
2007, 129, 10096–10097; (e) M. Movassaghi and M. D. Hill, J. Am.
Chem. Soc., 2006, 128, 4592–4593; (f) J. Barluenga, C. d. Pozo and
B. Olano, Synthesis, 1996, 133–140; (g) C. Oliver Kappe, Tetrahedron,
1993, 49, 6937–6963; (h) J. Barluenga, M. Toma´s, J. Jardo´n, E. Rubio
and V. Gotor, Synthesis, 1989, 230–232.
14 (a) S. C. Fields, W. C. Lo, W. K. Brewster and C. T. Lowe, Tetrahedron
Lett., 2010, 51, 79–81; (b) F. von Kieseritzky and J. Lindstro¨m,
Synthesis, 2010, 63–66; (c) W. R. Dolbier and Y.-L. Xu, J. Fluorine
Chem., 2003, 123, 71–73; (d) T. Fukuhara, N. Yoneda and A. Suzuki,
J. Fluorine Chem., 1988, 38, 435–438; (e) R. G. Pews and Z. Lysenko,
J. Org. Chem., 1985, 50, 5115–5119; (f) M. M. Boudakian, J. Fluorine
Chem., 1981, 18, 497–506; (g) P. Bannwarth, A. Valleix, D. Gre e and
R. Gre e, J. Org. Chem., 2009, 74, 4646–4649; (h) X.-J. Yang, L.-S.
Zhang and J.-T. Liu, Tetrahedron, 2007, 63, 5643–5648; (i) E. Okada,
T. Kinomura and Y. Higashiyama, Heterocycles, 1998, 48, 2347–2352;
(j) N. Zanatta, M. B. Fagundes, R. Ellensohn, M. Marques, H. G.
Bonacorso and M. A. P. Martins, J. Heterocycl. Chem., 1998, 35, 451–
455.
1
Yellow oil; H NMR (300 MHz, CDCl3) d 7.90–7.79 (m, 2H),
7.50–7.05 (m, 8H), 6.71 (d, J = 2.9 Hz, 1H), 6.12 (t, J = 53.9 Hz,
1H), 5.53 (t, J = 6.8 Hz, 1H), 1.97–1.74 (m, 2H), 1.73–1.55 (m,
2H), 1.03 (t, J = 7.4 Hz, 3H); 19F NMR (282 MHz, CDCl3) d
-112.58 (dd, JF–F = 299.2 Hz, JH–F = 55.5 Hz, 1F), -122.76 (dd,
JF–F = 299.2 Hz, JH–F = 53.5 Hz, 1F); 13C NMR (100 MHz, CDCl3)
d 158.9, 144.1, 142.3 (dd, J = 27.8 Hz, J = 22.7 Hz), 137.3, 130.2,
129.5, 128.5, 127.0, 126.0, 124.9, 110.0 (t, J = 241.4 Hz), 102.9 (t,
J = 5.1 Hz), 79.5, 33.4, 18.5, 14.1; HRMS-ESI (m/z): C20H21F2N2
[M + H]+ calcd 327.16673; found 327.16673; IR(KBr): 3064, 2959,
2931, 2872, 1629, 1595, 1580, 1493, 1376, 1269, 1118, 1047, 762,
694 cm-1.
Acknowledgements
This work was supported by the National Science Foundation of
China (Nos. 20772145).
15 (a) Z. X. Chen, J. T. Zhu, H. B. Xie, S. Li, Y. M. Wu and Y. F. Gong,
Adv. Synth. Catal., 2010, 352, 1296–1300; (b) Z. X. Chen, J. T. Zhu,
H. B. Xie, S. Li, Y. M. Wu and Y. F. Gong, Chem. Commun., 2010, 46,
2145–2147; (c) Z. X. Chen, J. T. Zhu, H. B. Xie, S. A. Li, Y. M. Wu and
Y. F. Gong, Synlett, 2010, 1418–1420; (d) S. Li, Y. Yuan, J. Zhu, H. Xie,
Z. Chen and Y. Wu, Adv. Synth. Catal., 2010, 352, 1582–1586; (e) J. T.
Zhu, Z. X. Chen, H. B. Xie, S. Li and Y. M. Wu, Org. Lett., 2010, 12,
2434–2436; (f) J. T. Zhu, H. B. Xie, Z. X. Chen, S. Li and Y. M. Wu,
Synlett, 2009, 3299–3302; (g) J. T. Zhu, H. B. Xie, Z. X. Chen, S. Li and
Y. M . Wu , Chem. Commun., 2009, 2338–2340.
16 A portion of these studies have been previously communicated. See:
Z. X. Chen, J. T. Zhu, H. B. Xie, S. Li, Y. M. Wu and Y. F. Gong, Org.
Lett., 2010, 12, 4376–4379.
17 (a) Y. M. Wu, M. Zhang and Y. Q. Li, J. Fluorine Chem., 2006, 127,
218–222; (b) Y. M. Wu, Y. Li and J. Deng, J. Fluorine Chem., 2005, 126,
791–795; (c) K. Tamura, H. Mizukami, K. Maeda, H. Watanabe and
K. Uneyama, J. Org. Chem., 1993, 58, 32–35; (d) K. Uneyama and H.
Watanabe, Tetrahedron Lett., 1991, 32, 1459–1462.
Notes and references
1 (a) G. D. Henry, Tetrahedron, 2004, 60, 6043–6061; (b) D. O’Hagan,
Nat. Prod. Rep., 2000, 17, 435–446; (c) R. K. Anchoori, M. S. Q.
Kortenhorst, M. Hidalgo, T. Sarkar, G. Hallur, R. Bai, P. J. Van Diest,
E. Hamel and S. R. Khan, J. Med. Chem., 2008, 51, 5953–5957; (d) G.-
H. Kuo, C. Prouty, A. Wang, S. Emanuel, A. DeAngelis, Y. Zhang, F.
Song, L. Beall, P. J. Connolly, P. Karnachi, X. Chen, R. H. Gruninger,
J. Sechler, A. Fuentes-Pesquera, S. A. Middleton, L. Jolliffe and W. V.
Murray, J. Med. Chem., 2005, 48, 4892–4909; (e) Y.-W. Kim, J. C.
Hackett and R. W. Brueggemeier, J. Med. Chem., 2004, 47, 4032–4040;
(f) R. T. Skerlj, Y. Zhou, T. Wilson and G. J. Bridger, J. Org. Chem., 2002,
67, 1407–1410; (g) T. J. Anderson, G. D. Jones and D. A. Vicic, J. Am.
Chem. Soc., 2004, 126, 8100–8101; (h) A. Tsuboyama, H. Iwawaki, M.
Furugori, T. Mukaide, J. Kamatani, S. Igawa, T. Moriyama, S. Miura,
T. Takiguchi, S. Okada, M. Hoshino and K. Ueno, J. Am. Chem. Soc.,
2003, 125, 12971–12979; (i) G. C. Rovnyak, S. D. Kimball, B. Beyer, G.
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