Convenient synthesis of perfluoroalkyl substituted 2-oxopyridine-fused 1,3-diazaheterocycles via a one-pot three-component reaction

Article abstract of DOI:10.1016/j.tet.2013.03.080

An efficient one-pot synthesis of perfluoroalkylated ring-fused 2-pyridones by three-component reaction of diamine, ketene dithioacetal, and methyl 2-perfluoroalkynoate in EtOH is reported. This protocol has the advantages of easiness, higher yields, and

Full text of DOI:10.1016/j.tet.2013.03.080

Tetrahedron 69 (2013) 4270e4275
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient synthesis of perfluoroalkyl substituted 2-oxopyridine-
fused 1,3-diazaheterocycles via a one-pot three-component reaction
,
Zewei Wang a, Tianqi Sun a, Jie Chen a, Hongmei Deng d, Min Shao d, Hui Zhang a
,
*
,b,c,
Weiguo Cao a
*
a Department of Chemistry, Shanghai University, Shanghai 200444, PR China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China
c Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China
d Instrumental Analysis and Research Center of Shanghai University, Shanghai 200444, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot synthesis of perfluoroalkylated ring-fused 2-pyridones by three-component reaction
of diamine, ketene dithioacetal, and methyl 2-perfluoroalkynoate in EtOH is reported. This protocol has
the advantages of easiness, higher yields, and shorter reaction time. A plausible mechanism for this type
of cyclization is proposed.
Received 18 January 2013
Received in revised form 11 March 2013
Accepted 19 March 2013
Available online 25 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Methyl 2-perfluoroalkynoate
Perfluoroalkylated ring-fused 2-pyridone
Ketene dithioacetal
One-pot synthesis
Multicomponent reaction
1. Introduction
On considering the importance of the introduction of tri-
fluoromethyl or the perfluoroalkyl groups in many biologically active
Many ring-fused 2-pyridones show biological activities.1 Among
these compounds, 2-oxopyridine-fused 1,3-diazaheterocycle moi-
eties are of general interest as a basis for analgesics and antiin-
flammatory agents in medicinal chemistry.2 Although a variety of
methods for the synthesis of such ring-fused 2-pyridinones are
available,2e6 a survey of literatures shows that the preparation of
fluorinated 2-oxopyridine-fused 1,3-diazaheterocycles is challeng-
ing because of the paucity of synthetic access.
pharmaceutical and agrochemical compounds,10 and in continuation
of our interest in exploiting methyl 2-perfluoroalkynoate as fluori-
nated building block for the synthesis of perfluoroalkylated
heterocycles,11 herein, we describe an efficient synthesis of per-
fluoroalkylated 2-oxopyridine-fused 1,3-diazaheterocycles via a new
and one-pot three-component reaction between ketene dithioace-
tal,12 various diamines and methyl 2-perfluoroalkynoates.13
Multicomponent reactions (MCRs) are powerful tools in creating
fused heterocycles because of the inherent molecular diversity,
efficiency, and atom-economy.7
The ketene dithioacetals of the type 2 are well known as two-
carbon synthons and for their pushepull electronic nature.8 The
Michael acceptor characteristics of the ethylene portion of 2 and
the possibility of substitution of the two alkylsulfanyl groups with
nucleophiles have been well exploited for the synthesis of a variety
of heterocycles.9
2. Results and discussion
Initially, the three-component reaction of 1,3-propyldiamine 1a
and 1,1-bis(methylthio)-2-nitroethylene 2a in the presence of
methyl 4,4,4-trifluorobut-2-ynoate 3a as a simple model reaction
was investigated to establish the feasibility of the strategy and to
optimize the reaction conditions. The reaction was performed in
a one-pot two-step process. A mixture of 1a (1.0 mmol) and 1,1-
bis(methylthio)-2-nitroethylene 2a (1.5 mmol) was stirred in
refluxing solvent (5 mL) for 0.5 h, then methyl 4,4,4-trifluorobut-2-
ynoate 3a (1.1 mmol) was added and continued to be stirred for the
rest of the designated time. Since the choice of an appropriate
reaction medium is of crucial importance for successful syn-
thesis, different solvents, such as methanol, ethanol, acetonitrile,
* Corresponding authors. Fax: þ86 21 66134856; e-mail addresses: wgcao@
staff.shu.edu.cn, yehao7171@shu.edu.cn (W. Cao).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.080

Z. Wang et al. / Tetrahedron 69 (2013) 4270e4275
4271
tetrahydrofuran (THF), toluene, and dichloromethane (DCM) were
explored. The results are summarized in Table 1. As can be seen
from the table, the best results were obtained by refluxing the
reaction mixture in EtOH to yield product 4a in excellent yield
(Table 1, entry 7).
yields. However, to synthesize 2-oxopyridine-fused eight-
membered 1,3-diazaheterocycle 4e, only a trace amount of con-
version with respect to 1e was observed even when the reaction
was conducted for 48 h. The results also suggested that the cis or
trans configuration of the corresponding diamine had some
Table 1
Optimization of reaction conditions
Entry
Solvent
Temperature
Time (h)
Yielda (%)
1
2
3
4
5
6
7
DCM
DCM
rt
12
12
12
12
12
4
34
39
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Acetonitrile
Toluene
THF
MeOH
EtOH
14b
Trace
40
60
95
4
Bold entry signifies best result for the reaction condition optimization.
a
Isolated yield.
The unreacted starting material was recovered.
b
To test the generality of the conversion, ketene dithioacetal 2
was subjected to reaction with a variety of diamines 1 and methyl
2-perfluoroalkynoates 3. Using the combinations of 2a with 3a
and a variety of diamines 1aej, as shown in Table 2, almost all of
the tested combinations successfully produced the desired 2-
oxopyridine-fused 1,3-diazaheterocycles with good to excellent
influence on this cascade process. For example, ring-closure to
compound 4f was accomplished with cis-cyclohexanediamine 1f
while the use of its trans-isomer 1g gave no product. Aliphatic di-
amines were proven to be more reactive than aryl diamines.
Moreover, these studies clearly reveal that aryl diamines having
electron-withdrawing groups on benzene ring are not compatible
Table 2
Synthesis of perfluoroalkylated 2-oxopyridine-fused 1,3-diazaheterocyclesa
H
N
N
O
R2
H
NH2
R2
R1S
R1S
R2
N
3
RF
CO2Me
+
RF
NH2
N
H
1
2
4
1a
1b
1c
1,3-propyldiamine
1,2-ethyldiamine
2,2-dimethy-1,3-propyldiamine
1d 1,4-butyldiamine
1e 1,5-pentanediamine 1f cis-1,2-cyclohexanediamine
1h 1,2-benzenediamine
1g trans-1,2-cyclohexanediamine
1i
1j
4,5-dichloro-1,2-benzenediamine
4,5-dimethyl-1,2-benzenediamine
2a R1 = Me, R2 = NO2
3a
2b R1 = Et, R2 = COPh
3c
3b
R
F = CF3
R
F = C2F5
R
F = n- C3F7
Entry
Diamine 1
Ketene dithioacetal 2
2-Perfluoroalkynoate 3
Time (h)
Product 4
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2a
2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3c
3c
3c
3c
4
4
4
4
48
4
48
4
48
48
8
8
8
4
4
4
4
4
4
4a
4b
4c
4d
4e
4f
4g
4h
4i
91
95
90
87
Trace
92
0
76
0
9
10
11
12
13
14
15
16
17
18
19
20
1j
4j
4k
4l
53
78
85
81
80
85
80
67
75
70
63
1a
1b
1c
1a
1b
1c
1a
1b
1c
1f
4m
4n
4o
4p
4q
4r
4s
4t
4
a
Reaction conditions: a mixture of 1 (1.0 mmol) and ketene dithioacetal 2 (1.5 equiv) was stirred in refluxing solvent (5 mL) for 0.5 h, then methyl 2-perfluoroalkynoate 3
(1.1 equiv) was added and continued to be stirred for the rest of the designated time.
b
Isolated yield.

4272
Z. Wang et al. / Tetrahedron 69 (2013) 4270e4275
with this process (Table 2, entry 9). This might be due to the fact
that the NH2 groups in 1i were less nucleophilically active than
those in 1h or 1j. Sterically demanding diamines, such as 1c
were also successfully converted into the corresponding products
(Table 2, entries 3, 13, and 19). In order to expand the scope of the
cyclocondensation reaction, 2a was replaced by ketene dithioacetal
2b. The reaction proceeded smoothly and afforded the similar re-
sults as 2a after extending reaction time from 4 h to 8 h (Table 2,
entries 11e13). Generally, the formation of ring-fused 2-pyridone
was less favored with methyl 2-perfluoroalkynoates 3 containing
longer carbon chain of perfluoroalkyl group (Table 2, compared
entry 1 to entries 14 and 17). However, no corresponding product
was obtained under the same reaction conditions when methyl
4,4,4-trifluorobut-2-ynoate was replaced by methyl but-2-ynoate.
to afford intermediate C. Another elimination of R1SH from C af-
fords cyclic ene-1,1-diamine D, which can be isolated and identi-
fied.6g The aza-ene reaction of D with 2-perfluoroalkynoate 3 gives
E, which undergoes an intramolecular imineeenamine tautome-
rization, followed by an intramolecular nucleophilic attack of the
secondary amino group at the CO group of the ester function to
close the six membered ring to form compound 4.
3. Conclusions
We have developed a concise approach to the synthesis of per-
fluoroalkyl substituted 2-oxopyridine-fused 1,3-diazaheterocycles
by one-pot reaction between diamines, ketene dithioacetals, and
2-perfluoroalkynoates. Characteristics of this method are good to
excellent yields of the products, mild reaction conditions, and use of
easily available starting materials. A plausible mechanism of the
ring-closure cascade reaction including nucleophilic substitution,
aza-ene reaction, intramolecular imineeenamine tautomerization,
followed by cyclization, is proposed.
The structures of compounds 4aet were deduced from their 1H, 19
F
and 13C NMR, IR, and mass spectra. Further confirmation of the
structure of 4 came from the analysis of single-crystal X-ray data of
4a (Fig. 1).14
4. Experimental
4.1. General information
Unless otherwise noted, all reagents were purchased from
commercial sources and used without further purification. Solvents
were distilled before use. Melting points were recorded on a SGW
X4 instrument and uncorrected. 1H, 19F, and 13C NMR spectra were
recorded on a Bruker DRX-500 MHz spectrometer. All chemical
shifts are reported in parts per million downfield (positive) of the
standard: C6F6 for 19F, TMS for 1H and 13C NMR spectra. IR spectra
were obtained on an AVATAR370 FT-IR spectrometer. LRMS (lower
resolution mass spectra) and HRMS (high resolution mass spectra)
were obtained on an Agilent LC/MSD SL and Bruker Daltonics
APEXIII 7.0 TESALA FTMS instrument, respectively. X-ray analysis
was performed on a Bruker Smart Apex2 CCD spectrometer. All
Fig. 1. X-ray structure of compound 4a.
On the basis of all results mentioned above and the related
report,6f a plausible mechanism was proposed (Scheme 1). Diamine
1 undergoes nucleophilic attack at C(1) of the tautomer 20 of ketene
dithioacetal 2 to give the adduct A. Elimination of one molecule of
R1SH from A forms B, which cyclizes by a second nucleophilic attack
2
R2
1
R1S
SR1
2
Tautomerization
2 R2
SR1
H
NH2
N
NH2
NH2
NH2
H
-R1SH
R2
R2
H
N
R1S
H
1 R2
N
H
R1S
1
HSR
N
H
SR1
SR1
1
2'
A
B
C
H
RF
H
RF
H
N
N
Intramolecular
-R1SH
Aza-ene type reaction
OMe
acid-base
R2
neutralization
N
H
R2 O
N
H
O
OMe
3
D
H
N
R2
H
N
H
R
R
N
RF
H
H
N
Imine-enamine
tautomerization
Cyclization
-MeOH
RF
H
N
RF
O
N
O
RF
N
OMe
R2
O
N
HO OMe
MeO
E
F
4
Scheme 1. Proposed mechanism for the formation of 4.

Z. Wang et al. / Tetrahedron 69 (2013) 4270e4275
4273
yields reported in this publication referred to isolated ones of
compounds and their purity was determined by 1H NMR.
(m, 1H), 1.33e1.49 (m, 2H), 1.49e1.58 (m, 2H), 1.66e1.73 (m, 1H),
2.08e2.11 (m, 1H), 2.19e2.23 (m, 1H), 4.21e4.24 (m, 1H), 4.57e4.67
(m, 1H), 6.22 (s, 1H), 9.65 (s, 1H) ppm. 13C NMR (125 MHz, DMSO-
3
4.2. General procedure for the preparation of 2-oxopyridine-
fused 1,3-diazaheterocycles 4
d6)
d
19.0, 19.6, 24.2, 24.7, 55.5, 55.7, 110.5, 110.6 (q, JCeF¼7.5 Hz),
1
2
122.2 (q, JCeF¼272.0 Hz), 135.0 (q, JCeF¼32.0 Hz), 153.3,
158.4 ppm; 19F NMR (470 MHz, DMSO-d6)
d
ꢁ59.7 (s, CF3) ppm. IR
Diamine 1 (1.0 mmol) and ketene dithioacetal 2 (1.5 equiv) was
mixed and dissolved in EtOH (5 mL). After stirring for 0.5 h under
reflux, methyl 2-perfluoroalkynoate 3 (1.1 equiv) was added
dropwise into the solution. The reaction mixture was then allowed
to stir under reflux for the rest of the designated time (see Table 2).
Evaporation of the solvent under reduced pressure resulted in
crude product, which was subjected to column chromatography on
silica gel for further purification using ethyl acetate/petroleum
ether as eluent.
(KBr): n 3335, 3123, 2945, 2857, 1685, 1597, 1568, 1438, 1331, 1268,
1186, 1154, 1110, 989, 883 cmꢁ1; MS (ESI) m/z (%): 326 [(MþNa)]þ.
HRMS (ESI) calcd for C12H12F3N3O3 [(MþNa)]þ: 326.0736; found:
326.0723.
4.2.6. 4-Nitro-3-(trifluoromethyl)benzo[4,5]imidazo[1,2-a]pyridin-
1(5H)-one 4h. Yellow solid; yield: 76%, mp: 120.2e120.3 ꢀC; 1H
NMR (500 MHz, DMSO-d6)
d 6.63 (s, 1H), 7.53e7.56 (m, 1H),
7.65e7.68 (m, 1H), 7.84e7.85 (m, 1H), 8.60e8.61 (m, 1H), 13.86 (s,
3
1H). 13C NMR (125 MHz, DMSO-d6)
d
107.8 (q, JCeF¼7.0 Hz), 111.6,
1
4.2.1. 9-Nitro-8-(trifluoromethyl)-3,4-dihydro-1H-pyrido[1,2-a]pyr-
imidin-6(2H)-one 4a. Light yellow solid; yield: 95%, mp:
113.7, 116.6, 122.4 (q, JCeF¼272.0 Hz), 124.8, 127.4, 128.0, 132.0,
133.2 (q, JCeF¼32.5 Hz, CF2), 143.0, 158.0. 19F NMR (470 MHz,
2
251.6e251.8 ꢀC; 1H NMR (500 MHz, CDCl3)
d
2.11e2.16 (m, 2H),
DMSO-d6)
d
ꢁ59.20 (s, CF3) ppm. IR (KBr):
n 3292, 3127, 3043, 1685,
3.59e3.62 (m, 2H), 4.06 (t, J¼6.0 Hz, 2H), 6.35 (s, 1H), 10.37 (s, 1H)
1606, 1427, 1327, 1292, 1261, 1164, 1142, 1108, 858 cmꢁ1; MS (EI) m/z
(%): 296 [(MꢁH)]ꢁ. HRMS (ESI) calcd for C12H6F3N3O3 [(MꢁH)]ꢁ:
296.0286; found: 296.0288.
ppm; 13C NMR (125 MHz, DMSO-d6)
d 18.0, 41.1, 108.2 (q,
1
3JCeF¼7.4 Hz), 111.0, 122.4 (q, JCeF¼272.0 Hz), 135.2 (q,
2JCeF¼32.0 Hz), 150.7, 160.0 ppm; 19F NMR (470 MHz, DMSO-d6)
d
ꢁ59.9 (s, CF3) ppm. IR (KBr):
n
3180, 3121, 2964, 1692, 1582, 1419,
4.2.7. 7,8-Dimethyl-4-nitro-3-(trifluoromethyl)benzo[4,5]imidazo
[1,2-a]pyridin-1(5H)-one 4j. Yellow solid; yield: 53%, 264.7 ꢀC
1380, 1344, 1255, 1220, 1152, 1025, 983, 874 cmꢁ1; MS (EI) m/z (%):
262 [(MꢁH)]ꢁ. HRMS (ESI) calcd for C9H8F3N3O3 [(MꢁH)]ꢁ:
262.0444; found: 262.0445.
(sublimated); 1H NMR (500 MHz, DMSO-d6)
d
2.39 (s, 6H), 6.54 (s,
1H), 7.55 (s, 1H), 8.32 (s, 1H), 13.65 (s, 1H) ppm; 19F NMR (470 MHz,
DMSO-d6)
d
ꢁ59.2 (s, CF3) ppm. IR (KBr):
n 3459, 3297, 2958, 1683,
4.2.2. 8-Nitro-7-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyridin-
5(1H)-one 4b. Light yellow solid; yield: 91%, 254.3 ꢀC (decom-
1601, 1424, 1305, 1268, 1178, 1139, 1097, 855 cmꢁ1; MS (ESI) m/z (%):
348 [(MþNa)]þ. HRMS (ESI) calcd for C14H10F3N3O3 [(MþNa)]þ:
348.0580; found: 348.0567.
posed); 1H NMR (500 MHz, DMSO-d6)
d
3.88 (t, J¼9.5 Hz, 2H), 4.11
(t, J¼9.5 Hz, 2H), 6.20 (s, 1H), 9.68 (s, 1H) ppm; 13C NMR (125 MHz,
3
DMSO-d6)
d
43.9, 44.4, 110.0, 110.1 (q, JCeF¼7.3 Hz), 122.2 (q,
4.2.8. 8-Benzoyl-7-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyr-
idin-5(1H)-one 4k. Light yellow solid; yield: 78%, mp:
1JCeF¼272.0 Hz),135.1 (q, 2JCeF¼32.1 Hz),153.6,158.6 ppm; 19F NMR
(470 MHz, DMSO-d6)
d
ꢁ59.7 (s, CF3) ppm. IR (KBr):
n
3329, 3117,
193.3e193.9 ꢀC; 1H NMR (500 MHz, CDCl3)
d
3.84 (t, J¼9.0 Hz, 2H),
2932, 1682, 1596, 1570, 1435, 1337, 1274, 1184, 1155, 1037, 984,
880 cmꢁ1; MS (EI) m/z (%): 248 [(MꢁH)]ꢁ. HRMS (ESI) calcd for
C8H6F3N3O3 [(MꢁH)]ꢁ: 248.0287; found: 248.0288.
4.24 (t, J¼9.0 Hz, 2H), 6.15 (s, 1H), 7.20 (s, 1H), 7.36e7.40 (m, 2H),
7.49e7.52 (m, 1H), 7.56e7.58 (m, 2H) ppm; 13C NMR (125 MHz,
3
CDCl3)
d
42.7, 44.1, 93.5, 107.5 (q, JCeF¼5.0 Hz), 122.2 (q,
1JCeF¼275.0 Hz), 128.1, 128.6, 132.5, 140.0, 141.9 (q, 2JCeF¼32.0 Hz),
4.2.3. 3,3-Dimethyl-9-nitro-8-(trifluoromethyl)-3,4-dihydro-1H-pyr-
ido[1,2-a]pyrimidin-6(2H)-one 4c. Light yellow solid; yield: 90%,
155.9, 159.8, 193.7 ppm; 19F NMR (470 MHz, CDCl3)
d
ꢁ58.2 (s, CF3)
ppm. IR (KBr):
n 3369, 3085, 2980, 2901, 1681, 1611, 1558, 1458,
mp: 175.3e176.2 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d
1.02 (s, 6H),
1328, 1293, 1276, 1167, 1136, 1018, 867 cmꢁ1; MS (ESI) m/z (%): 331
[(MþNa)]þ. HRMS (ESI) calcd for C15H11F3N2O2 [(MþNa)]þ:
331.06620; found: 331.06648.
3.26 (s, 2H), 3.65 (s, 2H), 6.28 (s, 1H), 10.30 (s, 1H) ppm; 13C NMR
(125 MHz, DMSO-d6)
d 23.7, 25.8, 50.4, 51.1, 108.3, 110.9, 122.3 (q,
2
1JCeF¼272.0 Hz), 135.3 (q, JCeF¼32.0 Hz), 149.7, 159.8 ppm; 19F
NMR (470 MHz, DMSO-d6)
d
ꢁ59.8 (s, CF3) ppm. IR (KBr):
n
3439,
4.2.9. 9-Benzoyl-8-(trifluoromethyl)-3,4-dihydro-1H-pyrido[1,2-a]
pyrimidin-6(2H)-one 4l. Light yellow solid; yield: 85%, mp:
3200, 3161, 2968, 2880, 1679, 1596, 1417, 1355, 1273, 1257, 1202,
1161, 1143, 1017, 971, 865 cmꢁ1; MS (EI) m/z (%): 290 [(MꢁH)]ꢁ.
HRMS (ESI) calcd for C11H12F3N3O3 [(MꢁH)]ꢁ: 290.0758; found:
290.0758.
224.5e224.8 ꢀC; 1H NMR (500 MHz, CDCl3)
d 2.04e2.09 (m, 2H),
3.40e3.43 (m, 2H), 4.07 (t, J¼5.8 Hz, 2H), 6.11 (s, 1H), 7.34e7.37 (m,
2H), 7.47e7.49 (m, 1H), 7.55e7.57 (m, 2H), 8.92 (s, 1H) ppm. 13C
NMR (125 MHz, CDCl3)
d 19.2, 39.0, 40.0, 93.8, 104.2, 122.3 (q,
2
4.2.4. 10-Nitro-9-(trifluoromethyl)-2,3,4,5-tetrahydropyrido[1,2-a]
[1,3]diazepin-7(1H)-one 4d. Light yellow solid; yield: 87%, mp:
1JCeF¼275.0 Hz), 128.0, 129.1, 132.4, 141.1, 141.3 (q, JCeF¼32.0 Hz),
152.2, 161.0, 195.1 ppm. 19F NMR (470 MHz, CDCl3)
d
ꢁ57.6 (s, CF3)
156.7e156.9 ꢀC; 1H NMR (500 MHz, CDCl3)
d
1.99e2.00 (m, 4H),
ppm. IR (KBr): n 3317, 3092, 2973, 1677, 1607, 1560, 1471, 1338, 1278,
3.62e3.65 (m, 2H), 4.27e4.30 (m, 2H), 6.42 (s,1H), 9.34 (s,1H) ppm;
1156,1134,1044, 860 cmꢁ1; MS (ESI) m/z (%): 345 [(MþNa)]þ. HRMS
(ESI) calcd for C16H13F3N2O2 [(MþNa)]þ: 345.0825; found:
345.0821.
13C NMR (125 MHz, DMSO-d6)
d 23.4, 24.0, 46.0, 46.8, 111.2 (q,
1
3JCeF¼6.3 Hz), 114.6, 122.3 (q, JCeF¼274.0 Hz), 135.4 (q,
2JCeF¼32.0 Hz),155.2, 161.0 ppm. 19F NMR (470 MHz, CDCl3)
ꢁ60.0
d
(s, CF3) ppm. IR (KBr):
n
3437, 3257, 3069, 2966, 2941, 2868, 1687,
4.2.10. 9-Benzoyl-3,3-dimethyl-8-(trifluoromethyl)-3,4-dihydro-1H-
pyrido[1,2-a]pyrimidin-6(2H)-one 4m. Light yellow solid; yield:
1568, 1440, 1380, 1269, 1241, 1193, 1148, 1096, 984, 886 cmꢁ1; MS
(EI) m/z (%): 276 [(MꢁH)]ꢁ. HRMS (ESI) calcd for C10H10F3N3O3
[(MꢁH)]ꢁ: 276.0598; found: 276.0601.
81%, mp: 271.0e271.9 ꢀC; 1H NMR (500 MHz, CDCl3)
d 1.09 (s, 6H),
3.08e3.09 (m, 2H), 3.76 (s, 2H), 6.15 (s, 1H), 7.36e7.39 (m, 2H),
7.48e7.52 (m, 1H), 7.56e7.58 (m, 2H), 8.93 (s, 1H) ppm; 13C NMR
4.2.5. 4-Nitro-3-(trifluoromethyl)-5a,6,7,8,9,9a-hexahydrobenzo[4,5]
imidazo[1,2-a]pyridin-1(5H)-one 4f. Light yellow solid; yield: 92%,
(125 MHz, CDCl3) d 24.0, 26.5, 50.4, 50.8, 93.5, 104.3, 122.3 (q,
2
1JCeF¼275.0 Hz), 128.1, 129.1, 132.4, 141.1, 141.4 (q, JCeF¼32.0 Hz),
mp: 209.5e210.6 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d
1.19e1.31
151.4, 161.2, 195.1 ppm; 19F NMR (470 MHz, CDCl3)
d
ꢁ57.7 (s, CF3)

4274
Z. Wang et al. / Tetrahedron 69 (2013) 4270e4275
ppm. IR (KBr):
n
3322, 3119, 2960, 1677, 1619, 1547, 1470, 1324, 1279,
mp: 215.6e215.7 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 1.01 (s, 6H),
1174, 1150, 1042, 857 cmꢁ1; MS (ESI) m/z (%): 373 [(MþNa)]þ. HRMS
3.25 (s, 2H), 3.66 (s, 2H), 6.14 (s, 1H), 10.24 (s, 1H) ppm; 13C NMR
(ESI) calcd for C18H17F3N2O2 [(MþNa)]þ: 373.1134; found: 373.1134.
(125 MHz, DMSO-d6)
d
23.8, 25.8, 50.4, 51.2, 108.8 (t, 3JCeF¼11.2 Hz),
1
109.4 (m, CF2), 111.3, 116.0 (m, CF2), 118.0 (qt, JCeF¼290.8 Hz,
2
4.2.11. 8-Nitro-7-(pentafluoroethyl)-2,3-dihydroimidazo[1,2-a]pyr-
idin-5(1H)-one 4n. Yellow solid; yield: 80%, mp: 150.6e151.2 ꢀC; 1H
2JCeF¼38.1 Hz, CF3), 136.0 (t, JCeF¼23.9 Hz), 149.7, 159.6 ppm; 19F
NMR (470 MHz, DMSO-d6)
d
ꢁ80.5 (t, J¼10.1 Hz, CF3), ꢁ98.7 (m,
NMR (500 MHz, CDCl3)
d
8.25 (s, 1H), 6.30 (s, 1H), 4.35 (t, J¼9.5 Hz,
CF2), ꢁ117.6 (s, CF2) ppm. IR (KBr):
n 3439, 3230, 2925, 1677, 1595,
2H), 4.10 (t, J¼9.5 Hz, 2H) ppm; 13C NMR (125 MHz, DMSO-d6)
d
43.9,
1419, 1354, 1228, 1196, 1133, 1117, 1104, 926 cmꢁ1; MS (ESI) m/z (%):
414 [(MþNa)]þ. HRMS (ESI) calcd for C13H12F7N3O3 [(MþNa)]þ:
414.0668; found: 414.0659.
3
44.4, 110.6, 111.1 (t, JCeF¼11.1 Hz), 113.6 (m, CF2), 119.3 (qt,
1JCeF¼288.4 Hz, JCeF¼35.8 Hz, CF3), 135.2 (t, JCeF¼23.7 Hz), 153.5,
2
3
158.3 ppm; 19F NMR (470 MHz, CDCl3)
d
ꢁ77.8 (s, CF3), ꢁ102.7 (s, CF2)
ppm. IR (KBr):
n
3381, 3015, 2913, 1680, 1615, 1569, 1426, 1342, 1227,
4.2.17. 4-Nitro-3-(n-heptafluoropropyl)-5a,6,7,8,9,9a-hexahy-
drobenzo[4,5]imidazo[1,2-a]pyridin-1(5H)-one 4t. Yellow solid;
yield: 63%, mp: 193.3e193.5 ꢀC; 1H NMR (500 MHz, CDCl3)
1146, 1113, 1054, 961 cmꢁ1; MS (EI) m/z (%): 298 [(MꢁH)]ꢁ. HRMS
(ESI) calcd for C9H6F5N3O3 [(MꢁH)]ꢁ: 298.0251; found: 298.0257.
d
1.28e1.88 (m, 6H), 2.13e2.16 (m, 1H), 2.37e2.40 (m, 1H),
4.2.12. 9-Nitro-8-(pentafluoroethyl)-3,4-dihydro-1H-pyrido[1,2-a]
pyrimidin-6(2H)-one 4o. Yellow solid; yield: 85%, mp:
4.27e4.30 (m, 1H), 4.67e4.72 (m, 1H), 6.25 (s, 1H), 8.16 (s, 1H) ppm;
13C NMR (125 MHz, CDCl3)
d 19.0, 20.0, 25.4, 55.5, 56.1, 109.6 (m,
3
131.1e131.4 ꢀC; 1H NMR (500 MHz, CDCl3)
d
2.17 (t, J¼6.0 Hz, 2H),
CF2), 111.8, 112.8 (t, JCeF¼11.6 Hz), 115.1 (m, CF2), 118.0 (qt,
3.62e3.65 (m, 2H), 4.09 (t, J¼6.0 Hz, 2H), 6.29 (s, 1H), 10.15 (s, 1H)
1JCeF¼286.5 Hz, 2JCeF¼34.6 Hz, CF3), 136.7 (t, 2JCeF¼23.8 Hz), 153.0,
ppm; 13C NMR (125 MHz, DMSO-d6)
d
18.0, 41.1, 108.7 (t,
158.0 ppm; 19F NMR (470 MHz, CDCl3)
d
ꢁ80.9 (t, J¼10.2 Hz,
3357, 3071,
3JCeF¼10.3 Hz), 111.4, 113.8 (m, CF2), 119.2 (qt, JCeF¼287.0 Hz,
CF3), ꢁ99.81 (m, CF2), ꢁ119.1 (s, CF2) ppm. IR (KBr):
n
1
2JCeF¼36.4 Hz, CF3), 135.5 (t, JCeF¼23.8 Hz), 150.4, 159.4 ppm; 19F
2951, 1679, 1594, 1439, 1334, 1225, 1200, 1112, 1083, 940 cmꢁ1; MS
(ESI) m/z (%): 426 [(MþNa)]þ. HRMS (ESI) calcd for C14H12F7N3O3
[(MþNa)]þ: 426.0663; found: 426.0659.
2
NMR (470 MHz, CDCl3)
d
ꢁ77.0 (s, CF3), ꢁ102.6 (s, CF2) ppm. IR
(KBr):
n 3438, 3267, 2925, 1689, 1589, 1408, 1382, 1345, 1206, 1147,
1120, 1057, 999 cmꢁ1; MS (EI) m/z (%): 312 [(MꢁH)]ꢁ. HRMS (ESI)
calcd for C10H8F5N3O3 [(MꢁH)]ꢁ: 312.0412; found: 312.0413.
Acknowledgements
4.2.13. 3,3-Dimethyl-9-nitro-8-(pentafluoroethyl)-3,4-dihydro-1H-
pyrido[1,2-a]pyrimidin-6(2H)-one 4p. Yellow solid; yield: 81%, mp:
The authors are grateful to the National Natural Science Foun-
dation of China (Grant Nos. 21072126, 21272152) and Leading Ac-
ademic Discipline Projects of Shanghai Municipal Education
Commission (Grant No. J50102) for their financial support.
209.1e209.4 ꢀC; 1H NMR (500 MHz, CDCl3)
d 1.15 (s, 6H), 3.27e3.28
(m, 2H), 3.76 (s, 2H), 6.31 (s, 1H), 10.16 (s, 1H) ppm; 13C NMR
3
(125 MHz, DMSO-d6)
d
23.74, 111.3, 108.8 (t, JCeF¼10.6 Hz), 51.18,
50.34, 25.83, 113.8 (m, CF2), 119.3 (qt, 1JCeF¼287.6 Hz, 2JCeF¼37.8 Hz,
CF3), 135.6 (t, 2JCeF¼23.8 Hz), 149.6, 159.6 ppm; 19F NMR (470 MHz,
Supplementary data
CDCl3)
d
ꢁ77.0 (s, CF3), ꢁ102.5 (s, CF2) ppm. IR (KBr):
n 3262, 3074,
2972,1687,1582,1434,1356,1198,1134,1041, 956 cmꢁ1; MS (EI) m/z
(%): 340 [(MꢁH)]ꢁ. HRMS (ESI) calcd for C12H12F5N3O3 [(MꢁH)]ꢁ:
340.0723; found: 340.0726.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.03.080.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.2.14. 8-Nitro-7-(n-heptafluoropropyl)-2,3-dihydroimidazo[1,2-a]
pyridin-5(1H)-one 4q. Yellow solid; yield: 67%, mp: 161.9e162.3 ꢀC;
References and notes
1H NMR (500 MHz, CDCl3)
d
4.07 (t, J¼9.5 Hz, 2H), 4.32 (t, J¼9.5 Hz,
2H), 6.26 (s, 1H), 8.25 (s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6)
1. (a) Kollmannsberger, C.; Mross, K.; Jakob, A.; Kanz, L.; Bokemeyer, C. Oncology
1999, 56, 1; (b) Liu, J. S.; Zhu, Y. L.; Yu, C. M.; Zhou, Y. Z.; Han, Y. Y.; Wu, F. W.; Qi,
3
d
43.9, 44.4, 109.6 (m, CF2), 110.6, 111.0 (t, JCeF¼11.7 Hz), 115.7 (m,
€
1
2
B. F. Can. J. Chem. 1986, 64, 837; (c) Svensson, A.; Larsson, A.; Emtenas, H.;
CF2), 117.8 (qt, JCeF¼288.4 Hz, JCeF¼35.3 Hz, CF3), 135.6 (t,
€
Hedenstrom, M.; Fex, T.; Hultgren, S. J.; Pinkner, J. S.; Almqvist, F.; Kihlberg, J.
2JCeF¼23.1 Hz), 153.5, 158.3 ppm; 19F NMR (470 MHz, CDCl3)
ChemBioChem 2001, 2, 915.
2. (a) Kubo, K.; Ito, N.; Isomura, Y.; Sozu, I.; Homma, H.; Murakami, M. Chem.
Pharm. Bull. 1979, 27, 1207; (b) Frohn, M. J.; Hong, F.-T.; Liu, L.; Lopez, P.;
Siegmund, A. C.; Tadesse, S.; Tamayo, N. WO 2005070932, 2005. (c)
Alonso-Alija, C.; Michels, M.; Schirok, H.; Schlemmer, K. H.; Dodd, S.; Fitzgerald,
M.; Bell, J.; Gill, A. WO 2003053967, 2003.
3. (a) Huang, Z. T.; Liu, Z. R. Heterocycles 1986, 24, 2247; (b) Jones, R. C. F.; Patel, P.;
Hirst, S. C.; Smallridge, M. J. Tetrahedron 1998, 54, 6191; (c) Jones, R. C. F.;
Smallridge, M. J. Tetrahedron Lett. 1988, 29, 5005; (d) Hehemann, D. G.; Winnik,
W. J. Heterocycl. Chem. 1994, 31, 393.
4. (a) Cheng, D. C.; Croft, L.; Abdi, M.; Lightfoot, A.; Gallagher, T. Org. Lett. 2007, 9,
5175; (b) Cheng, D. C.; Gallagher, T. Org. Lett. 2009, 11, 2639; (c) Qacemi, M. E.;
Ricard, L.; Zard, S. Z. Chem. Commun. 2006, 4422; (d) Podhorez, D. E. J.
Heterocycl. Chem. 1991, 28, 971; (e) Sylvia, S.; Daniel, S.; Simon, S.; Zhang, X.;
Volkhard, A. Synthesis 2005, 3107.
5. (a) Tilak, B. D.; Ayyangar, N. R.; Rao, U. S. Indian J. Chem., Sect. B 1984, 23, 24; (b)
Jones, R. C. F.; Dimopoulos, P.; Coles, S. C.; Light, M. E.; Hursthouse, M. B. J. Chem.
Soc., Perkin Trans. 1 2000, 2331; (c) Masahiko, T.; Chiyoshi, N.; Yoshio, S. Chem.
Lett. 1987, 1229; (d) Al-Afaleq, E. Synth. Commun. 2001, 31, 3557.
6. (a) Yan, S.; Huang, C.; Su, C.; Ni, Y.; Lin, J. J. Comb. Chem. 2010, 12, 91; (b) Yan, S.
J.; Niu, Y. F.; Huang, R.; Lin, J. Synlett 2009, 2821; (c) Wang, M. X.; Miao, W. S.;
Cheng, Y.; Huang, Z. T. Tetrahedron 1999, 55, 14611; (d) Zhang, J. H.; Wang, M. X.;
Huang, Z. T. J. Chem. Soc., Perkin Trans. 1 1999, 2087; (e) Zhao, H.; Zeng, A. Q.;
Liao, W. L.; Jia, Y. M.; Wang, L. B.; Huang, Z. T.; Yu, C. Y. Heterocycles 2010, 82,
619; (f) Alizadeh, A.; Mikaeili, A.; Firuzyar, T.; Ahmadi, M. Helv. Chim. Acta 2011,
94, 1343; (g) Henryk, F.; Danuta, P. Phosphorus, Sulfur, and Silicon 2005, 180,
2291.
d
ꢁ80.8 (t, J¼10.3 Hz, CF3), ꢁ99.8 (m, CF2), ꢁ119.2 (s, CF2) ppm. IR
(KBr):
n 3431, 3099, 2918, 1681, 1616, 1594, 1440, 1337, 1225, 1191,
1134, 1117, 927 cmꢁ1; MS (EI) m/z (%): 348 [(MꢁH)]ꢁ. HRMS (ESI)
calcd for C10H6F7N3O3 [(MꢁH)]ꢁ: 348.0218; found: 348.0225.
4.2.15. 9-Nitro-8-(n-heptafluoropropyl)-3,4-dihydro-1H-pyrido[1,2-
a]pyrimidin-6(2H)-one 4r. Yellow solid; yield: 75%, mp:
125.2e125.7 ꢀC; 1H NMR (500 MHz, CDCl3)
d
2.18e2.23 (m, 2H),
3.65e3.68 (m, 2H), 4.13 (t, J¼6.0 Hz, 2H), 6.32 (s, 1H), 10.32 (s, 1H)
ppm; 13C NMR (125 MHz, CDCl3)
d 18.4, 39.3, 40.5, 109.6 (t,
3JCeF¼11.4 Hz), 110.1 (m, CF2), 111.8, 115.5 (m, CF2), 118.0 (qt,
1JCeF¼290.1 Hz, 2JCeF¼36.0 Hz, CF3), 137.4 (t, 2JCeF¼24.4 Hz), 150.4,
159.2 ppm; 19F NMR (470 MHz, CDCl3)
d
ꢁ81.0 (t, J¼10.5 Hz,
3433, 3129,
CF3), ꢁ99.5 (m, CF2), ꢁ119.2 (s, CF2) ppm. IR (KBr):
n
2924, 1686, 1577, 1428, 1343, 1234, 1197, 1173, 1142, 1086, 952 cmꢁ1
;
MS (EI) m/z (%): 362 [(MꢁH)]ꢁ. HRMS (ESI) calcd for C11H8F7N3O3
[(MꢁH)]ꢁ: 362.0386; found: 362.0381.
4.2.16. 3,3-Dimethyl-9-nitro-8-(n-heptafluoropropyl)-3,4-dihydro-
1H-pyrido[1,2-a]pyrimidin-6(2H)-one 4s. Yellow solid; yield: 70%,

Z. Wang et al. / Tetrahedron 69 (2013) 4270e4275
4275
7. Reviews: (a) Akritopoulou, Z. I.; Djuric, S. W. Top. Heterocycl. Chem. 2010, 25,
231; (b) Jiang, B.; Rajale, T.; Wever, W.; Tu, S. J.; Li, G. Chem.dAsian J. 2010, 5,
2318; (c) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083; (d)
Zhang, J.; Chen, J.; Deng, H.; Wu, X.; Zhang, H.; Cao, W. Chem. Commun. 2011,
3607; (e) Lu, L.; Cao, W.; Chen, J.; Zhang, H.; Zhang, J.; Chen, H.; Wei, J.; Deng, H.;
Shao, M. J. Fluorine Chem. 2009, 130, 295; (f) Yu, H.; Han, J.; Chen, J.; Deng, H.;
Shao, M.; Zhang, H.; Cao, W. Eur. J. Org. Chem. 2012, 3142.
€
Marson, C. M. Chem. Soc. Rev. 2012, 41, 7712.
8. Metzner, P.; Thullier, A. Sulfur Reagents in Organic Synthesis; Academic:
12. (a) Hong, Y.; Mang, W. Chem.dEur. J. 2010, 16, 13450; (b) Karl, D. R. J. Org. Chem.
New York, NY, 1994.
1981, 46, 5031.
9. (a) Kolb, M. Synthesis 1990, 171; (b) Tominaga, Y.; Matsuda, Y. J. Heterocycl.
Chem. 1985, 22, 937.
13. Hamper, B. C. Org. Synth. 1992, 70, 246.
14. CCDC 875267 (4a) contains all crystallographic details of this publication and is
available free of charge at www.ccdc.cam.ac.uk/consts/retrieving.html or can
be ordered from the following address: Cambridge Crystallographic Data
Centre, 12 Union Road, GB-Cambridge CB21EZ; fax: þ44 1223 336 033; or
10. Gladysz, J. A.; Curran, D. P. Tetrahedron 2002, 58, 3823.
11. (a) Wei, J.; Chen, J.; Xu, J.; Cao, L.; Deng, H.; Sheng, W.; Zhang, H.; Cao, W. J.
Fluorine Chem. 2012, 133, 146; (b) Qian, J.; Cao, W.; Zhang, H.; Chen, J.; Zhu, S. J.
Fluorine Chem. 2007, 128, 207; (c) Lu, L.; Wei, J.; Chen, J.; Zhang, J.; Deng, H.; Shao,
M.; Zhang, H.; Cao, W. Tetrahedron 2009, 65, 9152; (d) Xu, J.; Wei, J.; Bian, L.;
ꢀ
deposit@ccdc.cam.ac.uk. Unit cell parameters (4a): a: 7.7031(18) A; b: 7.
ꢀ
ꢀ
b
1192(17) A; c: 9.495(2) A; : 104.330(2); g: 110.65(2); space group: P21/m.