Synthesis of Novel Fluorinated Multisubstituted Pyrimidines and 1,5-Benzodiazepines via Fluorinated N,S-Acetals

Article abstract of DOI:10.1055/s-0036-1588588

An efficient and novel approach using highly versatile but less exploited monofluorinated α-oxoketene N,S-acetals as synthons for the synthesis of novel fluorinated multisubstituted pyrimidines and 1,5-benzodiazepines by cyclization with guanidine nitrate

Full text of DOI:10.1055/s-0036-1588588

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 4495–4508
paper
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Synthesis
Synthesis of Novel Fluorinated Multisubstituted Pyrimidines and
1,5-Benzodiazepines via Fluorinated N,S-Acetals
Nutan Sharmaa
NH2
R1
Tejpal Singh Chundawatb
Subash Chandra Mohapatraa
Sunita Bhagat*a
O
HN
N
N
1) Selectfluor
1) Selectfluor
N
N
SMe
R1
R2
R1
NH
2)
N
NH2
.
N
R2
HNO3
X
H
R2
F
H
2)
X
F
H2N
NH2
a Organic Synthesis Research Laboratory, Department
of Chemistry, A.R.S.D. College, University of Delhi,
New Delhi-110021, India
X
NH2
16 examples
70–80% yields
8 examples
70–78% yields
X = CH, N, O, S
R1 = Ph, 4-MeOC6H4, c-Hex, n-Pr
2 = F, Cl, Br, Me, OMe
sunitabhagat28@gmail.com
b Department of Applied Sciences, The NorthCap Uni-
versity (formerly ITM University), Gurgaon-122017,
Haryana, India
R
Received: 22.04.2016
Accepted after revision: 08.08.2016
Published online: 09.09.2016
bacterial,10 antifungal,11 anti-inflammatory,12 antihyper-
tensive,13 antidiabetic,14 and anticancer activities.15 Thus,
the various biological activities of fluorinated pyrimidines
are very interesting from both a scientific and a practical
perspective.16 Benzodiazepines are another important class
of azaheterocycles17a that constitute the building blocks of a
variety of fused-ring compounds17 and are extensively used
as anticonvulsant, antianxiety, antitumor, psychosis, hyp-
notic, antipyretic, and anti-inflammatory agents.18 In view
of the widespread biological applications and the impor-
tance of fluorine incorporation, molecular skeletons that in-
tegrate the fluorine atom as well as a benzodiazepine moi-
ety might possess properties of both and enhance the activ-
ity. However, in contrast to their non-fluorinated
counterparts,19,20 there are very few reports on the synthe-
sis of fluorinated pyrimidines21 and 1,5-benzodiazepines.22
Thus, the development of novel functionalized fluorinated
pyrimidines and benzodiazepines is of high demand.
α-Oxoketene N,S-acetals, which are useful 1,3-dielec-
trophiles, have been extensively investigated in cyclization
reactions for the synthesis of six- and seven-membered
heterocycles, especially using nitrogen binucleophiles.23–25
In this respect, fluorinated α-oxoketene N,S-acetals offer in-
teresting perspectives for the synthesis of pyrimidines and
1,5-benzodiazepines. To our surprise, fluorinated α-oxoke-
tene N,S-acetals have not been exploited so far for the syn-
thesis of six- and seven-membered heterocycles, except for
their limited use in the construction of five-membered het-
erocycles.26 Thus, in view of previous reports, and given our
continued interest in heterocyclic synthesis,27,28 herein, we
report an efficient synthesis of novel fluorinated multisub-
stituted pyrimidines and 1,5-benzodiazepines (Scheme 1).
A variety of α-oxoketene N,S-acetals 2 were easily synthe-
sized from α-oxoketene dithioacetals28b and substituted
amines by heating to reflux in toluene.29 All the compounds
DOI: 10.1055/s-0036-1588588; Art ID: ss-2016-n0277-op
Abstract An efficient and novel approach using highly versatile but
less exploited monofluorinated α-oxoketene N,S-acetals as synthons for
the synthesis of novel fluorinated multisubstituted pyrimidines and 1,5-
benzodiazepines by cyclization with guanidine nitrate and o-phenylene-
diamine, respectively, has been developed. The synthesized com-
pounds, which carry additional functional groups that allow further
functionalization, are of considerable interest as building blocks in me-
dicinal chemistry. X-ray crystallographic studies confirmed the forma-
tion of the desired cyclized product.
Key words fluorinated compounds, ketene acetals, pyrimidines, ben-
zodiazepines, binucleophiles
Organofluorine compounds, particularly heterocyclic
derivatives, exhibit many desirable properties, and they
have attracted much attention especially in the last decade
in biological and medicinal chemistry.1–4 These properties
arise from the unique features of the fluorine atom, which
can enhance both drug pharmacokinetics by making it
more bioavailable, lipophilic, and metabolically stable, as
well as pharmacodynamics by increasing its affinity for the
target protein without major steric implications.5,6 Further-
more, the selective incorporation of a fluorine atom into bi-
ologically relevant organic molecules has been an active re-
search area in organic chemistry for many years.7 Therefore,
it seems natural that there is a growing demand for the
preparation of selectively fluorinated heterocycles, which
will offer rich possibilities in the future of drug develop-
ment.8
As a privileged fragment, the pyrimidine nucleus is
present in a variety of natural products and in numerous
pharmaceutically important compounds.9 The various de-
rivatives of pyrimidines have been found to possess anti-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 4495–4508

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NH2
R1
O
HN
1)
Selectfluor
NH
N
N
1)
Selectfluor
NH2
N
N
SMe
R1
R2
R1
N
2)
N
.
R2
HNO3
X
H
2a–p
R2
F
H
2)
X
F
7a–h
8 examples
70–78% yields
H2N
NH2
X
5a–p
NH2
6
16 examples
70–80% yields
X = CH, N, O, S
R1 = 4-MeOC6H4, c-Hex, n-Pr
2 = F, Cl, Br, Me, OMe
R
Scheme 1 Synthesis of novel fluorinated multisubstituted pyrimidines and 1,5-benzodiazepines by using fluorinated N,S-acetals
were isolated as single E-stereoisomeric forms of 2, which
was confirmed by 1H NMR and X-ray crystallographic anal-
ysis.
The presence of a significant downfield shift of the NH
1
proton in the H NMR spectra in CDCl3 (presence of broad-
ened signals at δ = 11.9–13.5 ppm) is characteristic of
enaminoketones displaying strong internal H-bonds. The
fact that only one geometric form of enamine 2 was isolated
is demonstrated by the sharp signals of the vinylic proton
and of the thiomethyl moiety in the 1H NMR spectra and is
in accordance with reported data of related N,S-acetals.29
Figure 1 X-ray crystallographic ORTEP drawings of 2e
Furthermore, X-ray crystallographic studies of 2e proved
the assigned E-stereochemistry (Figure 1). Electrophilic fluo-
rination of α-oxoketene N,S-acetal 2 was performed by us-
ing 1.0 equivalent of 1-(chloromethyl)-4-fluoro-1,4-diazo-
niabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor)
in acetonitrile at 0 °C, which resulted in a clean monofluori-
nation toward 3 within 30 minutes with formation of minor
amounts of difluorinated product 4 (<6%) (Scheme 2).26
However, upon addition of Selectfluor in one portion or by
using a slight excess of Selectfluor, an increase in the
amount of difluorinated product 4 was observed, which
was difficult to separate from the monofluorinated product
3 by flash chromatography. As evident from previous re-
ports,26 it should be noted that the fluorinated N,S-acetals 3
exist as three isomers: the enamino form 3, the (E)-imino
form, and the (Z)-imino form 3A, which could not be isolat-
ed as single compounds, so the mixture was used directly
for further transformations.
In the next step, the desired fluorinated pyrimidines 5
were efficiently synthesized by heating monofluorinated
α-oxoketene N,S-acetals 3 and guanidine nitrate using t-BuONa
as base in t-BuOH for 2–3 hours (Scheme 3). The obtained
fluorinated pyrimidines 5, showing a diverse substitution
pattern, were easily purified by flash chromatography
(Scheme 3). Structural assignments were made on the basis
1
of IR, H, 13C, 19F NMR and mass spectra. IR spectra of the
products 5 revealed the presence of absorption peaks for
primary amino groups in the region of 3450–3390 cm–1. In
1
the H NMR spectra (CDCl3), absorptions as broad singlets
at δ = 4.53–5.15 ppm (s, 2 H, NH) were characterized for
primary amino group protons of the cyclized pyrimidine
ring of 5. Furthermore, the presence of a singlet at δ = –163.7
to –174.7 ppm in the 19F NMR spectra confirmed the pres-
ence of one F atom in the final product 5. Additionally, the
R1
R1
O
HN
O
N
SMe
SMe
R2
R2
+
R1
F
F
O
HN
X
X
Selectfluor (1 equiv)
0 °C, 30 min
X
3a–p
3A
SMe
R2
MeCN
R1
X
2a–p
O
F
N
F
SMe
R2
4 (6%)
Scheme 2 Synthesis of fluorinated α-oxoketene N,S-acetals by using Selectfluor
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Synthesis
R1
R1
O
N
O
HN
SMe
R2
SMe
+
R2
F
X
F
X
3A
3a–p
NH2
NH2
NH2
NH
.
HNO3
NH2
N
N
H2N
N
N
6
R1
N
R1
R2
Et3N, toluene
reflux, 120 °C
24 h
NaOt-Bu, t-BuOH
H
N
heat, 2–3 h
R2
F
H
X
F
X
5a–p
7a–h
Scheme 3 Synthesis of novel fluorinated multisubstituted pyrimidines and 1,5-benzodiazepines
structures of the synthesized novel fluorinated pyrimidines
5 were confirmed by single-crystal X-ray diffraction analy-
sis of compounds 5b and 5c (Figure 2 and Figure 3).
A variety of N,S-acetals 2, bearing alkyl, cycloalkyl, and
aryl substituents were used as substrates (Table 1). We ob-
served a yield of 75 and 77% when unsubstituted phenyl
rings were present with R1 as Ph and 4-MeOC6H4, respec-
tively, for the desired products 5a and 5b (entries 1 and 2).
When an electron-withdrawing group was present as R2,
the reaction gave intriguing cyclized products 5c–g, 5l, and
5m in 72–76% yields (entries 3–7, 12, and 13) with R1 as 4-
MeOC6H4 for 5e, 5g and as Ph for other compounds. Yields
of 78–79% were obtained when electron-donating groups
were present as R2 with R1 as Ph (entries 8 and 9).
Interestingly, a comparable yield of 74% was observed
when both electron-withdrawing and electron-donating
groups were present in the same ring (Table 1, entry 10).
When a cyclopropyl group was present, product 5k was ob-
tained in 75% yield with R1 as Ph (entry 10). Furthermore,
when a heteroaromatic nucleus was introduced in sub-
strates 2n–p, the reaction provided the desired cyclized
scaffolds 5n–p in 70–80% yields with R1 as Ph and 4-
MeOC6H4 (entries 14–16).
Figure 2 X-ray crystallographic ORTEP drawings of 5b
We then further exploited fluorinated N,S-acetals 3 to
examine the scope of the reaction with o-phenylenedi-
amine (6; Table 2). The reaction proceeded well with an ar-
omatic group as R2 and Ph or 4-MeOC6H4 groups as R1, pro-
viding the fluorinated 1,5-benzodiazepine scaffolds 7a and
7b in 74 and 72% yield, respectively (entries 1 and 2). When
electron-withdrawing groups were present as R2 the reac-
tion afforded the product in 71–78% yield (entries 3–6).
However, a comparatively low yield of 70% was obtained
when an electron-donating group was used as R2 with R1 as
Ph (entry 7). The reaction accommodated a heteroaromatic
nucleus such as thiophene with R1 as Ph, which provided
the desired heteroaromatic fluorinated product 7h in 71%
yield (entry 8).
Figure 3 X-ray crystallographic ORTEP drawings of 5c
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Table 1 Substrate Scope of the Synthesis of Novel Fluorinated Multisubstituted Pyrimidinesa
NH2
R1
N
N
O
HN
1)
2)
Selectfluor
R1
N
R2
SMe
H
NH
.
R2
F
HNO3
X
X
2a–p
5a–p
H2N
NH2
NaOt-Bu, heat, 2–3 h
Entry
1
Substrate 2
Product 5
Yield (%)b
NH2
N
N
O
HN
2a
5a
5b
75
N
H
SMe
F
OMe
NH2
OMe
N
N
O
HN
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
77
76
72
73
75
76
78
N
H
SMe
F
NH2
N
N
O
HN
5c
N
SMe
H
F
F
F
NH2
N
N
O
HN
5d
5e
5f
N
SMe
H
F
Cl
Cl
Br
Br
Cl
OMe
NH2
OMe
N
N
N
N
O
HN
N
H
SMe
F
Cl
NH2
N
O
HN
N
H
SMe
F
Br
OMe
NH2
OMe
N
O
HN
2g
2h
5g
5h
N
H
SMe
F
Br
NH2
N
N
O
HN
N
SMe
H
F
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Table 1 (continued)
Entry
9
Substrate 2
Product 5
Yield (%)b
NH2
N
N
OMe
OMe
O
HN
2i
5i
79
N
H
SMe
F
NH2
N
N
OMe
OMe
O
HN
10
11
12
2j
5j
74
75
72
N
SMe
H
F
F
F
NH2
N
N
O
HN
2k
2l
5k
5l
N
H
SMe
F
NH2
N
N
O
HN
N
SMe
H
F
Br
Br
NH2
N
N
O
HN
13
14
15
2m
2n
2o
5m
5n
5o
76
80
78
N
SMe
H
F
F
F
NH2
N
N
O
O
HN
N
H
SMe
S
F
S
OMe
NH2
OMe
N
N
HN
N
H
SMe
HN
S
F
S
NH2
N
N
O
16
2p
5p
70
N
SMe
H
O
F
O
a Reactions conditions: 3 (mixture, 1.0 equiv), guanidine nitrate (1.2 equiv), t-BuONa (1.2 equiv), t-BuOH, 80 °C, 2–3 h.
b Isolated yield.
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Table 2 (continued)
Table 2 Substrate Scope of the Synthesis of Novel Fluorinated Multi-
substituted 1,5-Benzodiazepinesa
Entry Substrate Product 7
Yield
(%)b
2
R1
1)
2)
Selectfluor
NH2
O
HN
N
N
R1
N
N
SMe
7
2h
7g
70
N
R2
R2
H
F
7a–h
X
N
X
2a–p
NH2
H
F
6
Et3N, toluene
120 °C, 24 h
Entry Substrate Product 7
Yield
(%)b
N
N
8
2n
7h
71
2
N
H
F
S
a Reaction conditions: 3 (mixture; 1.0 equiv), o-phenylenediamine (6; 1
equiv), Et3N (1.5 equiv), toluene, 120 °C, 24 h.
b Isolated yield.
N
N
1
2
2a
2b
7a
7b
74
72
N
H
F
Structural assignments of 7 were made on the basis of
IR, 1H, 13C, 19F NMR and mass spectra. IR spectra of the
products 7 showed the presence of absorption peaks for
secondary amino groups in the region 3435–3400 cm–1. In
the 1H NMR spectra (CDCl3), a singlet at δ = 4.95–5.80 ppm
(s, 1 H, CHF) was characterized for the methylene proton
between the two imine bonds of the cyclized benzodiaze-
pine ring of 7. The appearance of a peak at δ = 85.0–
90.0 ppm for –CF in the 13C NMR spectra confirms the pres-
ence of a F atom in the cyclized ring of the final product 7,
which was further confirmed by the presence of a singlet at
δ = –82.0 to –106.5 in the 19F NMR data.
N
N
OMe
N
H
F
N
N
3
4
5
6
2c
2d
2e
2g
7c
7d
7e
7f
71
72
78
72
N
H
F
F
The structures of the synthesized novel fluorinated ben-
zodiazepines 7 were further confirmed by single-crystal X-
ray diffraction analysis of 7b (Figure 4).
N
N
N
N
N
H
F
F
F
Cl
Cl
Br
N
OMe
N
H
N
OMe
N
H
Figure 4 X-ray crystallographic ORTEP drawings of 7b
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With these observations in hand, a plausible mecha-
nism is proposed for the formation of 5 (Scheme 4, route A)
and 7 (route B). In the ketene dithioacetal system, the car-
bonyl carbon and β-carbon atoms are regarded as hard and
soft electrophilic centers, since the carbonyl carbon is adja-
cent to the hard-base oxygen whereas the β-carbon is
flanked by the soft-base methylthio group. It is also known
that α-oxoketene-N,O-acetals are more reactive towards
nucleophiles than the corresponding N,S-acetals.30 It is thus
probable that N,O-acetal 8 is formed prior to the attack of
guanidine on 3, which then gives heterocyclic product 5 via
9 by removal of water.
A plausible mechanism involving an enamine–imine
tautomeric intermediate is depicted for compound 7 (route
B) as shown in Scheme 4. The mechanism involves substitu-
tion of the thiomethyl group of fluorinated ketene N,S-ace-
tal 3 by one of the amino groups of reactant 6, resulting in
the formation of intermediate 7A at first. This intermediate
tautomerises to the imine form 7B. The latter is likely to ex-
ist in the anti-configuration due to steric stability and un-
dergo cyclocondensation, yielding 7. This mechanism can
also be used to interpret the previous reported results,31 es-
pecially the reaction between ketene dithioacetals and 2-
aminothiophenol or 2-aminophenol32 and hydrazine.32
In conclusion, we have reported the significance of im-
mensely important but less exploited fluorinated α-oxoke-
tene N,S-acetals as synthons to provide a facile access to
medicinally useful novel fluorinated pyrimidines and 1,5-
benzodiazepines in good yields. These atom-economical
transformations proceed with high functional group toler-
ance. The chemistry outlined here is extremely versatile
and general, accommodating a variety of functional groups,
making it ideal for the generation of libraries of heterocyclic
systems. Further studies should extend the scope and ap-
plication of these synthons and the results will be reported
in due course.
All the reactions were performed in an oven-dried Schlenk flask un-
der a nitrogen atmosphere. Column chromatography was performed
using silica gel (mesh 100–200). TLC analysis was performed on com-
mercially prepared 60 F254 silica gel plates. Visualization of spots on
route B
N
N
R1
N
R2
H
F
X
7a–h
H2N
O
– H2O
N
R1
N
H2N
O
R2
H
F
NH
X
N
7B
H N
R1
O
N
R2
R1
H
H
N
F
R2
H
X
F
7A
X
– MeSH
NH2
NH2
NH2
6
H
N
N
R1
S
– H2O
NH R1
t-Bu
O
HN
R2
O
R2
F
X
10
F
HN
X
R1
O
H
N
H
NaOt-Bu
3a–p
– t-BuOH
NH2
O
HN
H2N
R2
t-Bu
– NaSMe
F
R1
O
X
NH
N
N
9
O
HN
H
R1
t-Bu
N
N
NH2
R2
H
R2
H
F
X
F
X
8
5a–p
route A
Scheme 4 Plausible mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 4495–4508

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Synthesis
the TLC plate was accomplished with UV light (254 nm) and staining
over I2 chamber. IR spectra were recorded in CHCl3 with a Perkin–
Elmer Spectrum RX-1 FT-IR spectrophotometer. CDCl3 was used as
solvent for characterization of compounds 2 and 5, whereas DMSO
was used for compounds 7. 1H NMR spectra were recorded with a Jeol
JNM-ECX400P at 400 MHz. 13C NMR spectra were recorded with a Jeol
JNM-ECX400P at 100 MHz. 19F NMR spectra were recorded with a Jeol
JNM-ECX400P at 376 MHz. Chemical shifts for carbon signals are re-
ported in ppm from tetramethylsilane and are referenced to the car-
bon resonance of the solvent. Data are reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, dd = doublet of doublet, br s = broad singlet), coupling con-
stants in Hertz, and integration. HRMS (ESI) were recorded with a Q-
TOF electrospray mass spectrometer. All purchased chemicals were
used as received. Melting points are uncorrected.
1H NMR (400 MHz, CDCl3): δ = 13.43 (br s, 1 H, NH), 7.89 (dd, J = 8.70,
5.5 Hz, 2 H), 7.36 (t, J = 7.33 Hz, 2 H), 7.30 (d, J = 6.87 Hz, 2 H), 7.23 (t,
J = 7.33 Hz, 1 H), 7.09 (t, J = 8.70 Hz, 2 H), 5.80 (br s, 1 H, vinylic CH),
2.41 (s, 3 H, SCH3).
13C NMR (100 MHz, CDCl3): δ = 184.7, 167.9, 165.7, 138.0, 136.2,
129.3, 129.2, 129.0, 126.5, 125.3, 115.3, 115.1, 87.9 (vinylic CH), 14.7
(SCH3).
HRMS (ESI): m/z [M + H]+ calcd for C16H14FNOS: 288.0858; found:
288.0865.
(E)-1-(4-Chlorophenyl)-3-(methylthio)-3-(phenylamino)prop-2-
en-1-one (2d)
Yield: 0.49 g (84%); yellow viscous material.
IR (CHCl3): 3401, 2925, 1558, 1461 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.05 Hz, 2 H), 7.40–7.35 (m,
4 H), 7.31 (d, J = 7.32 Hz, 2 H), 7.25 (t, J = 7.32 Hz, 1 H), 2.43 (s, 3 H,
SCH3).
13C NMR (100 MHz, CDCl3): δ = 184.4, 158.3, 137.0, 130.5, 128.6,
127.1, 114.1, 14.8 (SCH3).
(E)-α-Oxoketene N,S-Acetals 2; General Procedure29
A mixture of substituted/unsubstituted 3,3-bis(methylthio)-1-phen-
ylprop-2-en-1-one 2 (1 equiv) and amine (1equiv) in toluene was
heated at reflux at 120 °C for 20–24 h, and the progress of the reac-
tion was monitored by TLC. Upon completion, the mixture was cooled
to r.t., water (50 mL) was added and the mixture was extracted with
ethyl acetate (3 × 20 mL) and separated. The organic layer was dried
over sodium sulfate and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel 100–200
mesh size; EtOAc–hexane, 3%) and pure compound was identified as
the (E)-stereoisomeric form of 2.
HRMS (ESI): m/z [M + H]+ calcd for C16H14ClNOS: 304.0563; found:
304.0560.
(E)-1-(4-Chlorophenyl)-3-[(4-methoxyphenyl)amino]-3-(meth-
ylthio)prop-2-en-1-one (2e)
Yield: 0.56 g (87%); yellow solid; mp 58–60 °C.
IR (CHCl3): 3400, 2928, 1556, 1460 cm–1
.
(E)-3-(Methylthio)-1-phenyl-3-(phenylamino)prop-2-en-1-one
1H NMR (400 MHz, CDCl3): δ = 13.33 (br s, 1 H, NH), 7.84 (d, J =
8.54 Hz, 2 H), 7.39 (d, J = 8.54 Hz, 2 H), 7.23 (d, J = 8.54 Hz, 2 H), 6.90
(d, J = 8.54 Hz, 2 H), 3.81 (s, 3 H, Ar-OCH3), 2.42 (s, 3 H, SCH3).
13C NMR (100 MHz, CDCl3): δ = 184.4, 158.4, 136.8, 130.5, 128.3,
127.2, 114.1, 87.6 (vinylic CH), 55.3 (Ar-OCH3), 14.6 (-SCH3).
(2a)26
Yield: 0.49 g (82%); light-yellow solid.
IR (CHCl3): 3400, 2924, 1563, 1473 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 13.2 (br s, 1 H, NH), 7.88 (d, J = 7.33 Hz,
2 H), 7.43 (m, 3 H), 7.35–7.29 (m, 4 H), 7.24 (t, J = 7.32 Hz, 1 H), 5.86
(s, 1 H, vinylic CH), 2.41 (s, 3 H, SCH3).
HRMS (ESI): m/z [M + H]+ calcd for C17H16ClNO2S: 334.0668; found:
334.0670.
13C NMR (100 MHz, CDCl3): δ = 185.6, 163.1, 140.6, 137.8, 130.8,
128.9, 128.2, 127.0, 126.4, 125.2, 90.1 (vinylic CH), 14.7 (SCH3).
HRMS (ESI): m/z [M + H]+ calcd for C16H15NOS: 270.0952; found:
(E)-1-(4-Bromophenyl)-3-(methylthio)-3-(phenylamino)prop-2-
en-1-one (2f)
270.0945.
Yield: 0.48 g (83%); pale-yellow solid; mp 64–66 °C.
IR (CHCl3): 3402, 2921, 1554, 1464 cm–1
.
(E)-3-[(4-Methoxyphenyl)amino]-3-(methylthio)-1-phenylprop-
2-en-1-one (2b)
1H NMR (400 MHz, CDCl3): δ = 13.46 (br s, 1 H, NH), 7.76 (d, J =
7.63 Hz, 2 H), 7.55 (d, J = 8.39 Hz, 2 H), 7.37 (t, J = 8.39 Hz, 2 H), 7.31
(d, J = 8.39 Hz, 2 H), 7.25 (t, J = 6.87 Hz, 1 H), 5.81 (br s, 1 H, vinylic
CH), 2.43 (s, 3 H, SCH3).
Yield: 0.59 g (88%); orange solid; mp 80–82 °C.
IR (CHCl3): 3401, 2926, 1570, 1472 cm–1
.
1H NMR (400 MHz, CDCl3 ): δ = 13.34 (br s, 1 H, NH), 7.92 (dd, J = 7.79,
5.95 Hz, 2 H), 7.43 (d, J = 7.33 Hz, 3 H), 7.22 (d, J = 8.70 Hz, 2 H), 6.89
(d, J = 9.16 Hz, 2 H), 5.85 (s, 1 H, vinylic CH), 3.78 (s, 3 H, Ar-OCH3),
2.38 (s, 3 H, SCH3).
13C NMR (100 MHz, CDCl3): δ = 185.6, 168.4, 158.1, 140.1, 130.6,
128.1, 127.5, 127.0, 126.8, 114.0, 87.7 (vinylic CH), 55.2 (Ar-OCH3),
14.4 (SCH3).
13C NMR (100 MHz, CDCl3): δ = 184.6, 168.2, 138.9, 137.8, 131.4,
129.0, 128.6, 126.6, 125.5, 125.3, 88.0 (vinylic CH), 14.7 (SCH3).
HRMS (ESI): m/z [M + H]+ calcd for C16H14BrNOS: 348.0057; found:
348.0068.
(E)-1-(4-Bromophenyl)-3-[(4-methoxyphenyl)amino]-3-(meth-
ylthio)prop-2-en-1-one (2g)
HRMS (ESI): m/z [M + H]+ calcd for C17H17NO2S: 300.1058; found:
300.1061.
Yield: 0.47 g (82%); dark-yellow solid; mp 70–72 °C.
IR (CHCl3): 3404, 2923, 1557, 1463 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 13.23 (br s, 1 H, NH), 7.77 (d, J =
8.39 Hz, 2 H), 7.56 (d, J = 8.39 Hz, 2 H), 7.23 (d, J = 8.39 Hz, 2 H), 6.90
(d, J = 9.16 Hz, 2 H), 5.78 (br s, 1 H, vinylic CH), 3.82 (s, 3 H, Ar-OCH3),
2.42 (s, 3 H, SCH3).
(E)-1-(4-Fluorophenyl)-3-(methylthio)-3-(phenylamino)prop-2-
en-1-one (2c)
Yield: 0.48 g (81%); pale-yellow solid; mp 65–67 °C.
IR (CHCl3): 3405, 2923, 1560, 1467 cm–1
.
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Synthesis
13C NMR (100 MHz, CDCl3): δ = 184.5, 169.3, 158.4, 139.0, 131.4,
130.6, 128.6, 127.2, 125.3, 114.2, 87.2 (vinylic CH), 55.4 (Ar-OCH3),
14.6 (SCH3).
13C NMR (100 MHz, CDCl3): δ = 194.9, 164.5, 138.2, 128.8, 125.8,
124.8, 91.5 (vinylic CH), 20.3, 14.5 (SCH3), 9.1.
HRMS (ESI): m/z [M + H]+ calcd for C13H15NOS: 234.0952; found:
234.0947.
HRMS (ESI): m/z [M + H]+ calcd for C17H16BrNO2S: 378.0163; found:
378.0152.
(E)-1-(4-Bromophenyl)-3-(cyclohexylamino)-3-(methylthio)prop-
(E)-3-(Methylthio)-3-(phenylamino)-1-(p-tolyl)prop-2-en-1-one
2-en-1-one (2l)
(2h)
Yield: 0.47 g (80%); light-yellow solid; mp 87–89 °C.
Yield: 0.49 g (82%); yellow oil.
IR (CHCl3): 3400, 2928, 1562, 1465 cm–1
1H NMR (400 MHz, CDCl3): δ = 13.50 (s, 1 H, NH), 7.82 (d, J = 8.05 Hz,
2 H), 7.40–7.32 (m, 4 H), 7.27–7.24 (m, 3 H), 5.87 (br s, 1 H, vinylic
CH), 2.44 (s, 3 H, SCH3), 2.41 (s, 3 H, Ar-CH3).
IR (CHCl3): 3403, 2929, 1560, 1468 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 11.98 (br s, 1 H, NH), 7.68 (d, J =
8.54 Hz, 2 H), 7.49 (d, J = 8.54 Hz, 2 H), 5.52 (s, 1 H, vinylic CH), 3.61–
3.57 (m, 1 H), 2.44 (s, 3 H, SCH3), 1.97–1.95 (m, 2 H), 1.77–1.74 (m,
2 H), 1.58–1.55 (m, 1 H), 1.43–1.22 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 185.9, 141.3, 138.2, 137.3, 129.0,
128.9, 127.0, 126.3, 125.2, 88.4 (vinylic CH), 21.4 (Ar-CH3), 14.7
(SCH3).
13C NMR (100 MHz, CDCl3): δ = 183.4, 168.5, 139.3, 131.3, 128.4,
124.9, 85.4 (vinylic CH), 53.1, 32.9, 25.2, 24.2, 14.2 (SCH3).
HRMS (ESI): m/z [M + H]+ calcd for C16H20BrNOS: 354.0527; found:
354.0530.
HRMS (ESI): m/z [M + H]+ calcd for C17H17NOS: 284.1109; found:
284.1122.
(E)-1-(4-Fluorophenyl)-3-(methylthio)-3-(propylamino)prop-2-
(E)-1-(2-Methoxyphenyl)-3-(methylthio)-3-(phenylamino)prop-2-
en-1-one (2m)
en-1-one (2i)
Yield: 0.39 g (75%); yellow viscous material.
Yield: 0.47 g (80%); yellow viscous solid.
IR (CHCl3): 3398, 2925, 1569, 1474 cm–1
.
IR (CHCl3): 3403, 2922, 1572, 1470 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 12.03 (br s, 1 H, NH), 7.86 (t, J =
6.96 Hz, 2 H), 7.06 (t, J = 8.79 Hz, 2 H), 5.50 (s, 1 H, vinylic CH), 3.36 (s,
2 H, CH2CH2CH3), 2.47 (s, 3 H, SCH3), 1.76–1.71 (m, 2 H, CH2CH2CH3),
1.01 (t, J = 7.32 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 184.3, 168.9, 161.4, 133.2, 128.5,
113.3, 85.4 (vinylic CH), 45.6 (CH2CH2CH3), 22.8 (CH2CH2CH3), 14.2
(SCH3), 11.4 (CH3).
1H NMR (400 MHz, CDCl3): δ = 13.31 (s, 1 H, NH), 7.63 (dd, J = 8.05,
2.2 Hz, 1 H), 7.31–7.24 (m, 5 H), 7.17–7.13 (m, 1 H), 6.94 (t, J =
8.05 Hz, 1 H), 6.88 (d, J = 8.05 Hz, 1 H), 5.85 (s, 1 H, vinylic CH), 3.82
(s, 3 H, Ar-OCH3), 2.29 (s, 3 H, SCH3).
13C NMR (100 MHz, CDCl3): δ = 186.2, 166.7, 156.9, 138.2, 131.2,
130.5, 129.9, 128.9, 126.2, 125.1, 120.6, 111.4, 93.4 (vinylic CH), 55.6
(Ar-OCH3), 14.7 (SCH3).
HRMS (ESI): m/z [M + H]+ calcd for C13H16FNOS: 254.1015; found:
254.1026.
HRMS (ESI): m/z [M + H]+ calcd for C17H17NO2S: 300.1058; found:
300.1046.
(E)-3-(Methylthio)-3-(phenylamino)-1-(thiophen-2-yl)prop-2-en-
(E)-1-(4-Fluoro-2-methoxyphenyl)-3-(methylthio)-3-(phenylami-
1-one (2n)
no)prop-2-en-1-one (2j)
Yield: 0.47 g (79%); dark-brown solid; mp 90–92 °C.
Yield: 0.47 g (80%); light-yellow solid; mp 110–112 °C.
IR (CHCl3): 3396, 2925, 1560, 1465 cm–1
.
IR (CHCl3): 3404, 2920, 1570, 1466 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 13.1 (s, 1 H, NH), 7.61 (d, J = 2.93 Hz,
1 H), 7.49 (dd, J = 5.13 Hz, 1 H), 7.36 (t, J = 8.05 Hz, 2 H), 7.30 (d, J =
8.79 Hz, 2 H), 7.23 (t, J = 8.05 Hz, 1 H), 7.09 (t, J = 5.13 Hz, 1 H), 5.78 (s,
1 H, vinylic CH), 2.42 (s, 3 H, SCH3).
13C NMR (100 MHz, CDCl3): δ = 179.0, 167.1, 146.5, 138.0, 130.3,
129.1, 129.0, 128.3, 127.7, 126.3, 125.1, 119.8, 88.2 (vinylic CH), 14.7
(SCH3).
1H NMR (400 MHz, CDCl3): δ = 13.21 (br s, 1 H, NH), 7.68 (t, J =
8.39 Hz, 1 H), 7.42 (t, J = 8.39 Hz, 2 H), 7.27–7.20 (m, 2 H), 6.64 (td, J =
8.39, 2.29 Hz, 1 H), 6.56 (dd, J = 8.39, 2.29 Hz, 1 H), 6.33 (s, 1 H), 5.66
(s, 1 H, vinylic CH), 3.74 (s, 3 H, Ar-OCH3), 2.29 (s, 3 H, SCH3).
13C NMR (100 MHz, CDCl3): δ = 184.2, 166.9, 165.3, 162.9, 136.3,
131.2, 129.9, 126.2, 125.8, 106.7, 99.3, 82.4 (vinylic CH), 55.6 (Ar-
OCH3), 14.6 (SCH3).
HRMS (ESI): m/z [M + H]+ calcd for C14H13NOS2: 276.0517; found:
276.0519.
HRMS (ESI): m/z [M + H]+ calcd for C17H16FNO2S: 318.0964; found:
318.0962.
(E)-3-[(4-Methoxyphenyl)amino]-3-(methylthio)-1-(thiophen-2-
(E)-1-Cyclopropyl-3-(methylthio)-3-(phenylamino)prop-2-en-1-
yl)prop-2-en-1-one (2o)
one (2k)
Yield: 0.50 g (75%); brown solid; mp 94–96 °C.
Yield: 0.49 g (80%); light-yellow solid; mp 44–46 °C.
IR (CHCl3): 3395, 2926, 1559, 1468 cm–1
.
IR (CHCl3): 3399, 2924, 1569, 1460 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 12.8 (s, 1 H, NH), 7.59 (d, J = 3.66 Hz,
1 H), 7.46 (d, J = 4.39 Hz, 1 H), 7.19 (t, J = 9.52 Hz, 2 H), 7.07 (t, J = 5.13,
3.66 Hz, 1 H), 6.87 (d, J = 8.79 Hz, 2 H), 5.70 (s, 1 H, vinylic CH), 3.79
(s, 3 H, Ar-OCH3), 2.39 (s, 3 H, SCH3).
1H NMR (400 MHz, CDCl3): δ = 12.8 (s, 1 H, NH), 7.31 (t, J = 8.05 Hz,
2 H), 7.22 (d, J = 8.05 Hz, 2 H), 7.17 (t, J = 7.32 Hz, 1 H), 5.34 (s, 1 H,
vinylic CH), 2.33 (s, 3 H, SCH3), 1.76–1.72 (m, 1 H), 1.04–1.00 (m, 2 H),
0.81–0.76 (m, 2 H).
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13C NMR (100 MHz, CDCl3): δ = 178.9, 168.4, 158.3, 146.5, 131.8,
130.6, 130.2, 129.4, 127.7, 127.2, 114.1, 87.2 (vinylic CH), 55.3 (Ar-
OCH3), 14.6 (SCH3).
HRMS (ESI): m/z [M + H]+ calcd for C15H15NO2S2: 306.0622; found:
306.0620.
5-Fluoro-6-(4-fluorophenyl)-N4-phenylpyrimidine-2,4-diamine
(5c)
Yield: 0.11 g (76%); fluorescent yellow solid; mp 140–142 °C.
IR (CHCl3): 3420, 1606, 1519, 1446 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.96 (t, J = 8.05 Hz, 2 H), 7.63 (d, J =
7.32 Hz, 2 H), 7.35 (t, J = 8.79, 7.32 Hz, 2 H), 7.16–7.08 (m, 3 H), 6.87
(br s, 1 H, NH), 4.89 (br s, 2 H, NH2).
19F NMR (376 MHz, CDCl3): δ = –108.30 (s, 1 F, CF), –168.27 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 164.9, 162.4, 157.6, 151.5, 146.2,
138.0, 137.1, 130.7, 128.9, 123.8, 120.5, 115.6, 115.3.
HRMS (ESI): m/z [M + H]+ calcd for C16H12F2N4: 299.1108; found:
299.1096.
(E)-1-(Benzofuran-3-yl)-3-(methylthio)-3-(phenylamino)prop-2-
en-1-one (2p)
Yield: 0.44 g (75%); yellow solid; mp 88–90 °C.
IR (CHCl3): 3405, 2922, 1572, 1469 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 13.4 (br s, 1 H, NH), 7.65 (d, J = 8.26 Hz,
1 H), 7.54 (d, J = 8.26 Hz, 1 H), 7.40 (d, J = 6.89 Hz, 2 H), 7.37 (d, J =
8.26, 2 H), 7.32 (d, J = 8.26 Hz, 2 H), 7.26 (d, J = 6.89 Hz, 2 H), 6.07 (s,
1 H, vinylic CH), 2.50 (s, 3 H, SCH3).
13C NMR (100 MHz, CDCl3): δ = 175.6, 169.0, 155.1, 154.8, 137.8,
129.0, 128.0, 126.7, 126.4, 125.2, 123.2, 122.4, 111.8, 108.9, 88.4 (vi-
nylic CH), 14.8 (SCH3).
6-(4-Chlorophenyl)-5-fluoro-N4-phenylpyrimidine-2,4-diamine
(5d)
Yield: 0.10 g (72%); yellow viscous material.
IR (CHCl3): 3418, 1616, 1521, 1446.
HRMS (ESI): m/z [M + H]+ calcd for C18H15NO2S: 310.0901; found:
310.0897.
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.05 Hz, 2 H), 7.63 (d, J =
8.79 Hz, 2 H), 7.42 (d, J = 8.79 Hz, 2 H), 7.34 (t, J = 8.05, 7.32 Hz, 2 H),
7.10 (t, J = 7.32 Hz, 1 H), 6.87 (br s, 1 H, NH), 4.89 (br s, 2 H, NH2).
19F NMR (376 MHz, CDCl3): δ = –167.81 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 157.8, 151.3, 146.2, 139.7, 138.0,
137.4, 136.0, 132.2, 130.0, 129.9, 128.9, 128.6, 123.8, 120.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H12ClFN4: 315.0813; found:
315.0823.
Fluorinated Multisubstituted Pyrimidines 5; General Procedure
To a stirred solution of 3 (1 equiv) in t-BuOH (5 mL), t-BuONa (1.2
equiv) and guanidine nitrate (1.2 equiv) was added. The resulting re-
action mixture was heated at 90 °C for 2–3 h, and the progress of the
reaction was monitored by TLC. Upon completion, the mixture was
cooled to r.t. and filtered over a Celite bed. The filtrate was concen-
trated under reduced pressure and the residue was purified by col-
umn chromatography (silica gel (100–200 mesh size; EtOAc–hexane,
25%) to give the pure 5-fluoro-N4,6-diphenylpyrimidine-2,4-diamine
5.
6-(4-Chlorophenyl)-5-fluoro-N4-(4-methoxyphenyl)pyrimidine-
2,4-diamine (5e)
Yield: 0.11 g (73%); yellow solid; mp 170–172 °C.
IR (CHCl3): 3415, 1615, 1508, 1430 cm–1
.
5-Fluoro-N4,6-diphenylpyrimidine-2,4-diamine (5a)
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.79 Hz, 2 H), 7.48 (d, J =
8.79 Hz, 2 H), 7.42 (d, J = 8.79 Hz, 2 H), 6.81 (br s, 1 H, NH), 4.98 (br s,
2 H, NH2), 3.79 (s, 3 H, Ar-OCH3).
Yield: 0.11 g (75%); light-yellow solid; mp 151–153 °C.
IR (CHCl3): 3411, 1612, 1520, 1442 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 8.05 Hz, 2 H), 7.63 (d, J =
7.32 Hz, 2 H), 7.48–7.43 (m, 3 H), 7.35 (t, J = 8.05 Hz, 2 H), 7.11 (t, J =
7.32 Hz, 1 H), 6.92 (br s, 1 H, NH), 5.01 (br s, 2 H, NH2).
19F NMR (376 MHz, CDCl3): δ = –168.27 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 157.8, 151.3, 138.1, 133.7, 129.9,
19F NMR (376 MHz, CDCl3): δ = –168.39 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 157.9, 156.3, 151.8, 151.7, 145.8,
139.7, 137.2, 135.9, 132.3, 130.9, 129.9, 128.6, 122.8, 114.1, 55.4 (Ar-
OCH3).
HRMS (ESI): m/z [M + H]+ calcd for C17H14ClFN4O: 345.0918; found:
345.0906.
128.9, 128.6, 128.5, 128.4, 123.6, 120.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H13FN4: 281.1202; found:
281.1204.
6-(4-Bromophenyl)-5-fluoro-N4-phenylpyrimidine-2,4-diamine
(5f)
5-Fluoro-N4-(4-methoxyphenyl)-6-phenylpyrimidine-2,4-di-
Yield: 0.11 g (75%); yellow solid; mp 120–122 °C.
amine (5b)
IR (CHCl3): 3413, 1612, 1522, 1445 cm–1
.
Yield: 0.11 g (77%); brown solid; mp 156–158 °C.
IR (CHCl3): 3409, 1612, 1509, 1425 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 8.05 Hz, 2 H), 7.50–7.43 (m,
5 H), 6.89 (d, J = 8.79 Hz, 2 H), 6.79 (br s, 1 H, NH), 4.95 (br s, 2 H,
NH2), 3.79 (s, 3 H, Ar-OCH3).
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.79 Hz, 2 H), 7.62 (d, J =
8.79 Hz, 2 H), 7.58 (d, J = 8.79 Hz, 2 H), 7.35 (t, J = 8.79 Hz, 2 H), 7.11
(t, J = 7.32 Hz, 1 H), 6.87 (br s, 1 H, NH), 4.92 (br s, 2 H, NH2).
19F NMR (376 MHz, CDCl3): δ = –167.81 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 157.8, 151.4, 146.2, 139.7, 138.0,
137.3, 132.7, 131.6, 130.2, 128.9, 124.4, 123.8, 120.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H12BrFN4: 359.0307; found:
359.0297.
.
19F NMR (376 MHz, CDCl3): δ = –168.98 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 157.9, 156.3, 151.7, 147.2, 139.6,
137.2, 133.9, 131.0, 129.8, 128.6, 128.5, 128.3, 122.8, 114.1, 55.4 (Ar-
OCH3).
HRMS (ESI): m/z [M + H]+ calcd for C17H15FN4O: 311.1308; found:
311.1300.
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Synthesis
6-(4-Bromophenyl)-5-fluoro-N4-(4-methoxyphenyl)pyrimidine-
6-Cyclopropyl-5-fluoro-N4-phenylpyrimidine-2,4-diamine (5k)
2,4-diamine (5g)
Yield: 0.11 g (75%); pale-yellow solid; mp 103–105 °C.
Yield: 0.11 g (76%); yellow solid; mp 160–162 °C.
IR (CHCl3): 3400, 1611, 1517, 1443 cm–1
.
IR (CHCl3): 3410, 1607, 1509, 1430 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 8.79 Hz, 2 H), 7.25 (t, J =
8.79 Hz, 2 H), 6.99 (t, J = 7.69 Hz, 1 H), 6.55 (br s, 1 H, NH), 4.53 (br s,
2 H, NH2), 2.10–2.03 (m, 1 H, c-Pr CH), 1.02–1.00 (m, 2 H, c-Pr CH2),
0.89–0.86 (m, 2 H, c-Pr CH2).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 8.05 Hz, 2 H), 7.58 (d, J =
8.05 Hz, 2 H), 7.48 (d, J = 8.79 Hz, 2 H), 6.89 (d, J = 9.52 Hz, 2 H), 6.81
(br s, 1 H, NH), 4.97 (br s, 2 H, NH2), 3.79 (s, 3 H, Ar-OCH3).
19F NMR (376 MHz, CDCl3): δ = –168.15 (s, 1 F, CF).
19F NMR (376 MHz, CDCl3): δ = –174.73 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 157.9, 156.3, 151.7, 151.6, 133.9,
131.0, 129.8, 128.6, 128.5, 128.3, 122.8, 114.1, 55.4 (Ar-OCH3).
13C NMR (100 MHz, CDCl3): δ = 157.9, 154.2, 149.3, 140.6, 138.5,
128.8, 123.2, 120.1, 9.7 (c-Pr CH), 8.5 (c-Pr CH2).
HRMS (ESI): m/z [M + H]+ calcd for C17H14BrFN4O: 389.0413; found:
HRMS (ESI): m/z [M + H]+ calcd for C13H13FN4: 245.1202; found:
389.0419.
245.1211.
5-Fluoro-N4-phenyl-6-(p-tolyl)pyrimidine-2,4-diamine (5h)
6-(4-Bromophenyl)-N4-cyclohexyl-5-fluoropyrimidine-2,4-di-
amine (5l)
Yield: 0.11 g (78%); dark-yellow solid; mp 125–127 °C.
Yield: 0.10 g (72%); light-brown viscous material.
IR (CHCl3): 3406, 1610, 1522, 1444 cm–1
.
IR (CHCl3): 3443, 1596, 1512, 1457 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.24 Hz, 2 H), 7.62 (d, J =
8.70 Hz, 2 H), 7.33 (t, J = 8.24 Hz, 2 H), 7.25 (d, J = 8.24 Hz, 2 H), 7.09
(t, J = 7.33 Hz, 1 H), 6.92 (br s, 1 H, NH), 5.14 (br s, 2 H, NH2), 2.39 (s,
3 H, Ar-CH3).
19F NMR (376 MHz, CDCl3): δ = –168.46 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 157.8, 151.3, 138.1, 129.9, 129.1,
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.79 Hz, 2 H), 7.55 (d, J =
8.79 Hz, 2 H), 4.93 (br s, 1 H, NH), 4.84 (br s, 2 H, NH2), 3.95–3.88 (m,
1 H), 2.04–1.99 (m, 2 H), 1.78–1.73 (m, 2 H), 1.66–1.63 (m, 1 H), 1.45–
1.35 (m, 2 H), 1.26–1.17 (m, 3 H).
19F NMR (376 MHz, CDCl3): δ = –169.35 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 158.0, 153.4, 132.6, 131.5, 130.1,
128.9, 128.6, 123.7, 120.5, 21.4 (Ar-CH3).
124.1, 49.1, 33.1, 25.5, 24.8.
HRMS (ESI): m/z [M + H]+ calcd for C16H18BrFN4: 365.0777; found:
HRMS (ESI): m/z [M + H]+ calcd for C17H15FN4: 295.1359; found:
295.1363.
365.0788.
5-Fluoro-6-(2-methoxyphenyl)-N4-phenylpyrimidine-2,4-di-
amine (5i)
5-Fluoro-6-(4-fluorophenyl)-N4-propylpyrimidine-2,4-diamine
(5m)
Yield: 0.11 g (79%); pale-yellow solid; mp 175–177 °C.
Yield: 0.11 g (76%); off-white solid; mp 90–92 °C.
IR (CHCl3): 3406, 1613, 1518, 1445 cm–1
.
IR (CHCl3): 3450, 1610, 1520, 1469 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 7.79 Hz, 2 H), 7.40 (d, J =
7.79 Hz, 2 H), 7.32 (t, J = 8.24 Hz, 2 H), 7.09–7.01 (m, 2 H), 6.97 (d, J =
8.24 Hz, 1 H), 6.84 (br s, 1 H, NH), 4.97 (br s, 2 H, NH2), 3.82 (s, 3 H,
Ar-OCH3).
1H NMR (400 MHz, CDCl3): δ = 7.88 (q, J = 8.39 Hz, 2 H), 7.09 (t, J =
8.77 Hz, 2 H), 5.05 (br s, 1 H, NH), 4.88 (br s, 2 H, NH2), 3.39 (q, J = 6.87
Hz, 2 H), 1.62 (sext, J = 7.63, 6.87 Hz, 2 H), 0.95 (t, J = 7.63 Hz, 3 H).
19F NMR (376 MHz, CDCl3): δ = –163.85 (s, 1 F, CF).
19F NMR (376 MHz, CDCl3): δ = –111.01 (s, 1 F, CF), –170.63 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 158.0, 157.1, 138.4, 131.0, 130.4,
13C NMR (100 MHz, CDCl3): δ = 164.6, 162.1, 158.2, 154.1, 144.4,
129.0, 123.6, 120.8, 120.5, 111.3, 55.8 (Ar-OCH3).
139.7, 137.3, 130.5, 130.0, 115.3, 115.1, 42.3, 22.7, 11.3.
HRMS (ESI): m/z [M + H]+ calcd for C17H15FN4O: 311.1308; found:
HRMS (ESI): m/z [M + H]+ calcd for C13H14F2N42: 265.1265; found:
311.1299.
265.1252.
5-Fluoro-6-(4-fluoro-2-methoxyphenyl)-N4-phenylpyrimidine-
5-Fluoro-N4-phenyl-6-(thiophen-2-yl)pyrimidine-2,4-diamine
2,4-diamine (5j)
(5n)
Yield: 0.11 g (74%); light-brown solid; mp 176–178 °C.
Yield: 0.12 g (80%); light-yellow solid; mp 130–132 °C.
IR (CHCl3): 3403, 1615, 1520, 1445 cm–1
.
IR (CHCl3): 3401, 1610, 1517, 1444 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 7.32 Hz, 2 H), 7.40 (t, J =
8.05 Hz, 1 H), 7.34 (t, J = 8.79 Hz, 2 H), 7.11 (t, J = 7.32 Hz, 1 H), 6.89
(br s, 1 H, NH), 6.77–6.68 (m, 2 H), 5.12 (br s, 2 H, NH2), 3.83 (s, 3 H,
Ar-OCH3).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 3.66 Hz, 1 H), 7.62 (d, J =
8.05 Hz, 2 H), 7.48 (d, J = 5.13 Hz, 1 H), 7.34 (t, J = 8.05 Hz, 2 H), 7.15
(t, J = 4.39 Hz, 1 H), 7.09 (t, J = 7.32 Hz, 1 H), 6.86 (br s, 1 H, NH), 4.89
(br s, 2 H, NH2).
19F NMR (376 MHz, CDCl3): δ = –108.50 (s, 1 F, CF), –163.69 (s, 1 F, CF).
19F NMR (376 MHz, CDCl3): δ = –165.66 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 165.8, 158.5, 157.8, 150.6, 146.2,
13C NMR (100 MHz, CDCl3): δ = 157.6, 151.0, 138.1, 135.5, 129.6,
137.9, 131.5, 131.4, 128.9, 123.7, 120.4, 107.5, 99.6, 55.9 (Ar-OCH3).
129.5, 128.9, 128.2, 123.6, 120.4.
HRMS (ESI): m/z [M + H]+ calcd for C17H14F2N4O: 329.1214; found:
HRMS (ESI): m/z [M + H]+ calcd for C14H11FN4S: 287.0766; found:
329.1202.
287.0755.
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5-Fluoro-N4-(4-methoxyphenyl)-6-(thiophen-2-yl)pyrimidine-
3-Fluoro-N-(4-methoxyphenyl)-4-phenyl-3H-benzo[b][1,5]diaze-
2,4-diamine (5o)
pin-2-amine (7b)
Yield: 0.11 g (78%); light-brown solid; mp 106–108 °C.
Yield: 0.12 g (72%); light-brown sticky solid.
IR (CHCl3): 3392, 1609, 1508, 1429 cm–1
.
IR (CHCl3): 3408, 2925, 1624, 1599 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.88 (s, 1 H), 7.49–7.46 (m, 3 H), 7.17–
7.14 (m, 1 H), 6.90–6.87 (m, 2 H), 6.81 (br s, 1 H, NH), 4.99 (br s, 2 H,
NH2), 3.79 (s, 3 H, Ar-OCH3).
1H NMR (400 MHz, DMSO-d6): δ = 9.67 (br s, 1 H, NH), 8.06 (d, J =
7.33 Hz, 2 H), 7.65 (d, J = 8.70 Hz, 2 H), 7.52–7.47 (m, 4 H), 7.23 (t, J =
7.79 Hz, 2 H), 7.14 (t, J = 8.24 Hz, 1 H), 6.85 (d, J = 9.16 Hz, 2 H), 3.68
(s, 3 H, Ar-OCH3).
19F NMR (376 MHz, CDCl3): δ = –165.48 (s, 1 F, CF).
19F NMR (376 MHz, DMSO-d6): δ = –84.22 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 157.4, 156.3, 151.5, 151.3, 137.7,
135.2, 130.8, 129.8, 129.6, 129.5, 129.1, 128.2, 122.9, 114.1, 55.4 (Ar-
OCH3).
HRMS (ESI): m/z [M + H]+ calcd for C15H13FN4OS: 317.0872; found:
317.0860.
13C NMR (100 MHz, DMSO-d6): δ = 164.1, 163.1, 155.3, 139.5, 138.6,
135.1, 132.5, 130.6, 128.6, 128.1, 127.0, 126.2, 122.4, 121.2, 113.7,
89.6 (CF), 55.1 (Ar-OCH3).
HRMS (ESI): m/z [M + H]+ calcd for C22H18FN3O: 360.1512; found:
360.1498.
6-(Benzofuran-3-yl)-5-fluoro-N4-phenylpyrimidine-2,4-diamine
(5p)
3-Fluoro-4-(4-fluorophenyl)-N-phenyl-3H-benzo[b][1,5]diazepin-
2-amine (7c)
Yield: 0.10 g (70%); light-brown solid; mp 183–185 °C.
Yield: 0.12 g (71%); orange sticky solid.
IR (CHCl3): 3405, 1607, 1583, 1440 cm–1
.
IR (CHCl3): 3409, 2921, 1582 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 7.63 Hz, 4 H), 7.42 (s, 1 H),
7.33–7.28 (m, 3 H), 7.23–7.18 (m, 1 H), 7.06 (t, J = 7.63 Hz, 1 H), 6.86
(br s, 1 H, NH), 5.00 (br s, 2 H, NH2).
1H NMR (400 MHz, DMSO-d6): δ = 9.80 (br s, 1 H, NH), 8.14 (t, J =
8.05 Hz, 2 H), 7.75 (d, J = 8.05 Hz, 2 H), 7.50 (d, J = 8.05 Hz, 1 H), 7.36
(t, J = 8.79 Hz, 2 H), 7.29–7.24 (m, 4 H), 7.17 (t, J = 8.05 Hz, 1 H), 7.01
(t, J = 7.32 Hz, 1 H).
19F NMR (376 MHz, DMSO-d6): δ = –109.20 (s, 1 F, Ar-CF), –83.40 (s,
1 F, CF).
13C NMR (100 MHz, DMSO-d6): δ = 164.8, 162.4, 139.4, 139.1, 138.5,
131.3, 130.8, 130.7, 128.6, 127.1, 126.3, 123.2, 122.8, 120.9, 119.5,
115.8, 115.6, 89.3 (CF).
19F NMR (376 MHz, CDCl3): δ = –164.13 (s, 1 F, CF).
13C NMR (100 MHz, CDCl3): δ = 158.1, 154.8, 150.9, 148.6, 138.9,
137.9, 136.4, 128.9, 128.1, 126.2, 123.9, 123.4, 121.9, 120.6, 112.0,
111.2, 111.1.
HRMS (ESI): m/z [M + H]+ calcd for C18H13FN4O: 321.1151; found:
321.1136.
HRMS (ESI): m/z [M + H]+ calcd for C21H15F2N3: 348.1312; found:
348.1302.
Synthesis of Fluorinated 1,5-Benzodiazepines 7; General Proce-
dure
Triethylamine (1.5 equiv) was added dropwise to a stirred solution of
3 (1 equiv) and o-phenylenediamine 6 (1 equiv) in toluene (10 mL).
The resulting mixture was heated at reflux at 120 °C for 24 h, and the
progress of the reaction was monitored by TLC. Upon completion, the
mixture was cooled to r.t., water (50 mL) was added and the mixture
was extracted with ethyl acetate (3 × 20 mL) and separated. The or-
ganic layer was dried over sodium sulfate and concentrated under re-
duced pressure. The product was purified by column chromatography
(silica 100–200 mesh size; EtOAc–hexane, 5%) to give (3-fluoro-4-
phenyl-1H-benzo[b][1,5]diazepin-2-yl)phenylamines 7.
4-(4-Chlorophenyl)-3-fluoro-N-phenyl-3H-benzo[b][1,5]diazepin-
2-amine (7d)
Yield: 0.12 g (72%); light-orange sticky solid.
IR (CHCl3): 3420, 2929, 1637, 1601 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.84 (br s, 1 H, NH), 8.04 (d, J =
8.79 Hz, 1 H), 7.93 (d, J = 8.05 Hz, 2 H), 7.87–7.74 (m, 2 H), 7.65 (d, J =
8.79 Hz, 1 H), 7.60–7.51 (m, 2 H), 7.37 (d, J = 8.05 Hz, 1 H), 7.32–7.22
(m, 2 H), 7.08 (t, J = 7.32 Hz, 1 H), 6.96 (d, J = 8.05 Hz, 1 H).
19F NMR (376 MHz, DMSO-d6): δ = –114.51 (s, 1 F, CF).
3-Fluoro-N,4-diphenyl-3H-benzo[b][1,5]diazepin-2-amine (7a)
13C NMR (100 MHz, DMSO-d6): δ = 162.5, 162.0, 143.6, 140.7, 135.4,
132.8, 131.3, 128.8, 125.4, 120.0, 114.5, 89.6 (CF).
HRMS (ESI): m/z [M + H]+ calcd for C21H15ClFN3: 364.1017; found:
364.1005.
Yield: 0.13 g (74%); orange sticky solid.
IR (CHCl3): 3414, 2923, 1629, 1597 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 9.81 (br s, 1 H, NH), 8.08 (d, J =
5.13 Hz, 2 H), 7.76 (d, J = 8.05 Hz, 2 H), 7.53–7.50 (m, 4 H), 7.32–7.25
(m, 4 H), 7.18 (t, J = 8.79 Hz, 1 H), 7.02 (d, J = 7.32 Hz, 1 H), 4.98 (s, 1 H,
CHF).
.
4-(4-Chlorophenyl)-3-fluoro-N-(4-methoxyphenyl)-3H-ben-
zo[b][1,5]diazepin-2-amine (7e)
Yield: 0.13 g (78%); light-yellow oil.
IR (CHCl3): 3406, 2923, 1627, 1592 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 9.68 (s, 1 H, NH), 8.08 (d, J =
8.24 Hz, 2 H), 7.64 (d, J = 8.70 Hz, 2 H), 7.59 (d, J = 8.70 Hz, 2 H), 7.47
(d, J = 7.79 Hz, 1 H), 7.25 (d, J = 4.58 Hz, 2 H), 7.17–7.12 (m, 1 H), 6.85
(d, J = 9.16 Hz, 2 H), 5.73 (s, 1 H, CHF), 3.69 (s, 3 H, Ar-OCH3).
19F NMR (376 MHz, DMSO-d6): δ = –82.81 (s, 1 F, CF).
.
13C NMR (100 MHz, DMSO-d6): δ = 170.3, 165.0, 148.6, 139.4, 139.1,
138.6, 134.9, 130.8, 128.8, 128.6, 128.2, 127.1, 126.3, 123.2, 122.8,
119.4, 115.8, 113.8, 87.2 (CF).
HRMS (ESI): m/z [M + H]+ calcd for C21H16FN3: 330.1406; found:
330.1395.
19F NMR (376 MHz, DMSO-d6): δ = –83.93 (s, 1 F, CF).
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Synthesis
13C NMR (100 MHz, DMSO-d6): δ = 164.2, 155.3, 138.6, 135.5, 132.4,
132.1, 129.9, 128.9, 128.7, 127.1, 126.4, 126.1, 122.5, 122.1, 113.7,
89.2 (CF), 55.1 (Ar-OCH3).
for providing instrumentation facilities. N.S. and T.J. are thankful to
DST for INSPIRE Fellowship and UGC for SPF, respectively.
HRMS (ESI): m/z [M + H]+ calcd for C22H17ClFN3O: 394.1122; found:
394.1112.
Supporting Information
Supporting information for this article is available online at
4-(4-Bromophenyl)-3-fluoro-N-(4-methoxyphenyl)-3H-ben-
zo[b][1,5]diazepin-2-amine (7f)
http://dx.doi.org/10.1055/s-0036-1588588.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Yield: 0.12 g (72%); brown yellow sticky solid.
References
IR (CHCl3): 3407, 1632, 1586 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.68 (br s, 1 H, NH), 8.01 (d, J =
8.79 Hz, 2 H), 7.73 (d, J = 8.05 Hz, 2 H), 7.64 (d, J = 8.79 Hz, 2 H), 7.56
(d, J = 9.52 Hz, 2 H), 6.92 (d, J = 9.52 Hz, 2 H), 6.85 (d, J = 8.79 Hz, 2 H),
5.78 (s, 1 H, CHF), 3.72 (s, 3 H, Ar-OCH3).
(1) Organofluorine Compounds: Chemistry and Applications;
Hiyama T., Yamamoto H. Ed., Springer: New York, 2000, and ref-
erences therein.
(2) (a) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;
Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5,
637. (b) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303.
(c) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013. (d) Müller, K.;
Faeh, C.; Diederich, F. Science 2007, 317, 1881. (e) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008,
37, 320. (f) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071.
(g) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem.
Rev. 2014, 114, 2432.
19F NMR (376 MHz, DMSO-d6): δ = –83.20 (s, 1 F, CF).
13C NMR (100 MHz, DMSO-d6): δ = 164.5, 156.5, 134.6, 131.9, 131.5,
130.1, 129.7, 128.9, 127.1, 126.5, 122.5, 119.1, 113.9, 113.7, 90.0 (CF),
55.2 (Ar-OCH3).
HRMS (ESI): m/z [M + H]+ calcd for C22H17BrFN3O: 438.0617; found:
438.0606.
3-Fluoro-N-phenyl-4-(p-tolyl)-3H-benzo[b][1,5]diazepin-2-amine
(7g)
(3) (a) Jeschke, P. ChemBioChem 2004, 5, 570. (b) Jeschke, P. Pest
Manage. Sci. 2010, 66, 10. (c) Fujiwara, T.; O’Hagan, D. J. Fluorine
Chem. 2014, 167, 16.
Yield: 0.12 g (70%); orange-brown semisolid.
IR (CHCl3): 3432, 2925, 1628, 1584 cm–1
.
(4) (a) Phelps, M. E. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 9226.
(b) Bolton, R. J. Labelled Compd. Radiopharm. 2002, 45, 485.
(c) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Chem. Rev.
2008, 108, 1501. (d) Cai, L.; Lu, S.; Pike, V. W. Eur. J. Org. Chem.
2008, 2853. (e) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D.
Angew. Chem. Int. Ed. 2008, 47, 8998. (f) Littich, R.; Scott, P. J. H.
Angew. Chem. Int. Ed. 2012, 51, 1106.
(5) (a) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (b) Filler, A.;
Kobayashi, Y. Biomedical Aspects of Fluorine Chemistry; Kodan-
sha Ltd: Tokyo, 1981.
1H NMR (400 MHz, DMSO-d6): δ = 9.80 (br s, 1 H, NH), 7.99 (d, J =
8.05 Hz, 2 H), 7.74 (d, J = 6.59 Hz, 2 H), 7.49 (d, J = 7.32 Hz, 1 H), 7.32
(d, J = 8.05 Hz, 2 H), 7.26 (t, J = 8.05 Hz, 4 H), 7.16 (t, J = 8.05 Hz, 1 H),
7.01 (t, J = 7.32 Hz, 1 H), 5.74 (s, 1 H, CHF), 2.36 (s, 3 H, Ar-CH3).
19F NMR (376 MHz, DMSO-d6): δ = –82.50 (s, 1 F, CF).
13C NMR (100 MHz, DMSO-d6): δ = 162.2, 149.7, 141.0, 139.5, 138.7,
132.1, 129.2, 128.6, 128.2, 127.1, 126.0, 123.1, 122.7, 120.9, 119.2,
88.2 (CF), 21.0 (Ar-CH3).
HRMS (ESI): m/z [M + H]+ calcd for C22H18FN3: 344.1563; found:
344.1574.
(6) Welch, J. T. Tetrahedron 1987, 43, 3123.
(7) (a) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305. (b) Perutz, R.
N. Science 2008, 321, 1168. (c) Grushin, V. V. Acc. Chem. Res.
2010, 43, 160. (d) Brabandt, W. V.; Verniest, G.; Smaele, D. D.;
Duvey, G.; De Kimpe, N. J. Org. Chem. 2006, 71, 7100.
(e) Verneist, G.; Surmont, R.; Hende, E. V.; Deweweire, A.;
Deroose, F.; Thuring, J. W.; De Kimpe, N. J. Org. Chem. 2008, 73,
5458. (f) Surmont, R.; Verneist, R.; Colpeart, F.; Macdonald, G.;
Thuring, J. W.; Deroose, F.; De Kimpe, N. J. Org. Chem. 2009, 74,
1377. (g) Surmont, R.; Verneist, R.; De Kimpe, N. Org. Lett. 2009,
11, 2920. (h) Surmont, R.; Verneist, R.; De Kimpe, N. Org. Lett.
2010, 12, 4648.
3-Fluoro-N-phenyl-4-(thiophen-2-yl)-3H-benzo[b][1,5]diazepin-
2-amine (7h)
Yield: 0.12 g (71%); light-brown sticky solid.
IR (CHCl3): 3405, 2920, 1628, 1596 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.80 (s, 1 H, NH), 8.10 (dd, J = 13.18,
3.66 Hz, 1 H), 7.83 (d, J = 5.13 Hz, 1 H), 7.76 (d, J = 8.05 Hz, 2 H), 7.43
(d, J = 8.05 Hz, 1 H), 7.36 (t, J = 5.13 Hz, 1 H), 7.32–7.23 (m, 4 H), 7.16
(t, J = 8.05 Hz, 1 H), 7.01 (t, J = 7.32 Hz, 1 H).
19F NMR (376 MHz, DMSO-d6): δ = –106.50 (s, 1 F, CF).
(8) (a) Petrov, A. V. Fluorinated Heterocyclic Compounds: Synthesis,
Chemistry, and Applications; John Wiley & Sons: New York,
2009. (b) Hu, X. G.; Hunter, L. Beilstein J. Org. Chem. 2013, 9,
2696.
13C NMR (100 MHz, DMSO-d6): δ = 163.1, 145.1, 139.4, 138.2, 136.9,
132.6, 130.7, 129.9, 128.9, 128.6, 128.3, 127.2, 126.1, 125.3, 123.2,
122.9, 120.8, 119.3, 116.0, 89.4 (CF).
(9) (a) Sharma, V.; Chitranshi, N.; Aggarwal, A. K. Int. J. Med. Chem.
2014, ID 202784. (b) Sheibani, H.; Saljoogi, A. S.; Bazgir, A.
ARKIVOC 2008, (ii), 115. (c) Lagoja, I. M. Chem. Biodivers. 2005, 2,
1. (d) Chambhare, R. V.; Khadse, B. G.; Bobde, A. S.; Bahekar, R.
H. Eur. J. Med. Chem. 2003, 38, 89. (e) Shishoo, C. J.; Shirsath, V.
S.; Rathod, I. S.; Yande, V. D. Eur. J. Med. Chem. 2000, 35, 351.
(f) Hassan, N. A. Molecules 2000, 5, 827.
HRMS (ESI): m/z [M + H]+ calcd for C19H14FN3S: 336.0970; found:
336.0983.
Acknowledgment
The authors are thankful to SERB, Department of Science & Technolo-
gy, India for providing financial support and USIC, University of Delhi
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 4495–4508

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(10) (a) Sharma, P.; Rane, N.; Gurram, V. K. Bioorg. Med. Chem. Lett.
2004, 14, 4185. (b) Prakash, O.; Bhardwaj, V.; Kumar, R.; Tyagi,
P.; Aneja, K. R. Eur. J. Med. Chem. 2004, 39, 1073. (c) Marquais-
Bienewald, S.; Holzol, W.; Preuss, A.; Mehlin, A. U. S. Patent
0188453A1, 2006.
(11) (a) Basavaraja, H. S.; Sreenivasa, G. M.; Jayachandran, E. Indian J.
Heterocycl. Chem. 2005, 15, 69. (b) Nakagawa, Y.; Bobrov, S.;
Semer, C. R.; Kucharek, T. A.; Harmoto, M. U. S. Patent
6818631B1, 2004.
(12) (a) Sondhi, S. M.; Jain, S.; Dwivedi, A. D.; Shukla, R.; Raghubir, R.
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2008, 47,
136. (b) Amir, M.; Javed, S. A.; Kumar, H. Indian J. Pharm. Sci.
2007, 68, 337.
Adapa, S. R. Synlett 2006, 1009. (d) Pozarentzi, M.; Stephanidou-
Stephanatou, J.; Tsoleridis, C. A.; Zika, C.; Demopoulos, V. Tetra-
hedron 2009, 65, 7741. (e) Munoz, M.; Sathicq, G.; Romanelli, G.;
Hernandez, S.; Cabello, C. I.; Botto, I. L.; Capron, M. J. Porous
Mater. 2013, 20, 65. (f) Radatz, C. S.; Silva, R. B.; Perin, G.;
Lenardao, E. J.; Jacob, R. G.; Alves, D. Tetrahedron Lett. 2011, 52,
4132.
(21) (a) Heidelberger, C.; Chaudhary, N. K.; Danneberg, P.; Mooren,
D.; Griesbach, L.; Duschinsky, R.; Schnitzer, R. J.; Pleven, E.;
Scheiner, J. Nature 1957, 179, 663. (b) Mertes, M. P.; Saheb, S. E.;
Miller, D. J. Med. Chem. 1966, 9, 876. (c) Popova, L. M.; Trishina,
A. U.; Vershilov, S. V.; Ginak, A. I.; Maksimov, B. N. J. Fluorine
Chem. 1999, 96, 51.
(13) (a) Alam, O.; Khan, S. A.; Siddiqui, N.; Ahsan, W.; Verma, S. P.;
Gilani, S. J. Eur. J. Med. Chem. 2010, 45, 5113. (b) Rana, K.; Kaur,
B.; Kumar, B. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
2004, 43, 1553.
(14) Lee, H. W.; Bok, Y. K.; Joong, B. A.; Sung, K. K.; Jung, H. L.; Shin, J.
S.; Ahn, S. K.; Lee, S. J.; Yoon, S. S. Eur. J. Med. Chem. 2005, 40,
862.
(15) (a) Ghorab, M. M.; Ragab, F. A.; Alqasoumi, S. I.; Alafeefy, A. M.;
Aboulmagd, S. A. Eur. J. Med. Chem. 2010, 45, 171. (b) Xie, F.;
Zhao, H.; Zhao, L.; Lou, L.; Hu, Y. Bioorg. Med. Chem. Lett. 2009,
19, 275.
(22) Prakash, G. K.; Vaghoo, H.; Venkat, A.; Panja, C.; Chacko, S.;
Mathew, T.; Olah, G. A. Future Med. Chem. 2009, 1, 909.
(23) For reviews, see: (a) Dieter, R. K. Tetrahedron 1986, 42, 3029.
(b) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46,
5423.
(24) (a) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am. Chem.
Soc. 2005, 127, 4578. (b) Dong, D.; Bi, X.; Liu, Q.; Cong, F. Chem.
Commun. 2005, 3580. (c) Bi, X.; Dong, D.; Li, Y.; Zhang, Q. J. Org.
Chem. 2005, 70, 10886. (d) Tan, J.; Xu, X.; Zhang, L.; Li, Y.; Liu, Q.
Angew. Chem. Int. Ed. 2009, 48, 2868; Angew. Chem. 2009, 121,
2912.
(16) (a) Kuhn, J. G. Ann. Pharmacother. 2001, 35, 217.
(b) Kreutzberger, A.; Burger, A. J. Fluorine Chem. 1993, 60, 257.
(c) Sreen, V.; Jain, S. J. Fluorine Chem. 1993, 63, 265. (d) Uno, H.;
Matsushima, Y.; Tasaka, T.; Suzuki, H. Bull. Chem. Soc. Jpn. 1990,
63, 293.
(17) (a) Sakata, G.; Makino, K.; Kurasawa, Y. Heterocycles 1988, 27,
2481. (b) Pareek, A.; Kumar, N.; Agarwal, A.; Sharma, P.;
Kishore, D. Res. J. Chem. Sci. 2013, 3, 90. (c) Salve, P. S.; Mali, D. S.
Int. J. Pharm. Bio. Sci. 2013, 4, 345.
(18) (a) Di Braccio, M.; Grossi, G.; Roma, G.; Vargiu, L.; Mura, M.;
Marongiu, M. E. Eur. J. Med. Chem. 2001, 36, 935. (b) Ha, S. K.;
Shobha, D.; Moon, E.; Chari, M. A.; Mukkanti, K.; Kim, S.-H.;
Ahn, K.-H.; Kim, S. Y. Bioorg. Med. Chem. Lett. 2010, 20, 3969.
(c) Ghogare, J. G.; Bhandari, S. V.; Bothara, K. G.; Madgulkar, A.
R.; Parashar, G. A.; Sonawane, B. G.; Inamdar, P. R. Eur. J. Med.
Chem. 2010, 45, 857.
(19) (a) Patel, K. S.; Raval, K. N.; Patel, S. P.; Patel, A. G.; Patel, S. V. Int.
J. Pharm. Biol. Sci. 2012, 2, 170. (b) Chandak, S.; Sharma, D.;
Sharma, V.; Dubey, A. J. Pharm. Biomed. Sci. 2012, 21.
(20) (a) Kurane, R.; Jadhav, J.; Khanapure, S.; Salunkhe, R.; Rashinkar,
G. Green Chem. 2013, 15, 1849. (b) Gibbs, R. A.; De, S. K. Tetrahe-
dron Lett. 2005, 46, 1811. (c) Varala, R.; Enugala, R.; Nuvula, S.;
(25) Xu, X.; Zhang, L.; Liu, X.; Pan, L.; Liu, Q. Angew. Chem. Int. Ed.
2013, 52, 9271; Angew. Chem. 2013, 125, 9441.
(26) Surmont, R.; Verniest, G.; Schrijver, M. D.; Thuring, J. W.; ten
Holte, P.; Deroose, F.; De Kimpe, N. J. Org. Chem. 2011, 76, 4105.
(27) (a) Chundawat, T. S.; Sharma, N.; Kumari, P.; Bhagat, S. Synlett
2016, 27, 404. (b) Chundawat, T. S.; Sharma, N.; Bhagat, S. Med.
Chem. 2014, 10, 409.
(28) (a) Chundawat, T. S.; Sharma, N.; Bhagat, S. Med. Chem. Res.
2014, 23, 1350. (b) Sharma, N.; Chundawat, T. S.; Mohapatra, S.
C.; Bhagat, S. RSC Adv. 2013, 3, 16336.
(29) Yang, C. W.; Bai, Y. X.; Zhang, N. T.; Zeng, C. C.; Hua, L. M.; Tian,
H. Y. Tetrahedron 2012, 68, 10201.
(30) (a) Stachel, H. D. Chem. Ber. 1962, 95, 2166. (b) Zhang, L.; Dong,
J.; Xu, X.; Liu, Q. Chem. Rev. 2016, 116, 287.
(31) (a) Gompper, R.; Toepfl, W. Chem. Ber. 1962, 95, 2871.
(b) Augustin, M.; Doeilling, W. J. Prakt. Chem. 1982, 324, 3.
(32) (a) Huang, Z.-T.; Shi, X. Chem. Ber. 1990, 123, 541. (b) Huang, Z.-
T.; Zhang, P. C. Chin. Chem. Lett. 1990, 1, 167; Chem. Abstr. 1991,
115, 135980. (c) Chauhan, S. M. S.; Junjappa, H. Synthesis 1974,
880. (d) Chauhan, S. M. S.; Junjappa, H. Synthesis 1975, 798.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 4495–4508