Concise synthesis of ω-fluoroalkylated ketoesters. A building block for the synthesis of six-, seven-, and eight-membered fluoroalkyl substituted 1,2-diaza-3-one heterocycles

Article abstract of DOI:10.1016/j.tet.2009.03.029

A concise and general synthetic route toward the small and medium-sized fluoroalkyl substituted 1,2-diaza-3-one heterocyclic ring skeletons via a sequential reaction of condensation and ring-closure reaction of ω-fluoroalkylated ketoesters 4 with hydrazin

Full text of DOI:10.1016/j.tet.2009.03.029

Tetrahedron 65 (2009) 4212–4219
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Concise synthesis of
u-fluoroalkylated ketoesters. A building block for the
synthesis of six-, seven-, and eight-membered fluoroalkyl substituted
1,2-diaza-3-one heterocycles
,
c
a,b,
*
Wen Wan a, Jie Hou a, Haizhen Jiang a, Yangli Wang a, Shizheng Zhu b , Hongmei Deng , Jian Hao
*
a Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
c Instrumental Analysis & Research Center, Shanghai University, 99 Shangda Road, Shanghai 200444, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and general synthetic route toward the small and medium-sized fluoroalkyl substituted
1,2-diaza-3-one heterocyclic ring skeletons via a sequential reaction of condensation and ring-closure
Received 29 December 2008
Received in revised form 11 March 2009
Accepted 13 March 2009
reaction of
u
-fluoroalkylated ketoesters 4 with hydrazines 5 catalyzed by 10–20 mol % TsOH has been
-fluoroalkylated ketoesters 4, which were
developed. A practical preparation of biologically interested
u
Available online 20 March 2009
subsequently subjected as a fluorine-containing building block to the synthesis of 1,2-diaza-3-one het-
erocycles has been optimized. Trifluoromethyl substituted seven- and eight-membered 1,2-diazapinone
8, 1,2-diazocinone 10 were also obtained via this sequential reaction of
ketoesters with hydrazine hydrates in acidic condition. In contrast, the sequential reaction of
roalkylated - or -ketoesters with aryl hydrazines under the same conditions did not result in the
d
- (or
3
-) trifluoromethyl
u
-fluo-
d
3
formation of diazepinones and diazocinones, and instead, the reaction provided a direct access to the
biologically important 2-fluoroalkyl-indole-3-carboxylate derivatives via a Fisher indole synthesis.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
a reliable and efficient method for such preparation and further
investigation into their synthetic applications is still remaining as
Small and medium-sized nitrogen-containing heterocyclic
skeletons, such as 1,2-diaza-3-one heterocyclic frameworks have
recently drawn much attention due to their potential applications
either as the key intermediates in the synthesis of more complex
structures or as core structures for the synthesis of pharmaceuti-
cally important molecules.1
Many 1,2-diaza-3-one heterocycles have been found to have
potent anticonvulsant, antituberculosis, antitumor, and herbicidal
activities.2 It’s quite interesting that the electronic substituent
effects on the bioactivity changes at certain positions of such het-
erocycles have been observed. For instance, the bioactivities of
pyridazinone and its 4,5-dihydro derivatives were found to be quite
sensitive to the electronic effects of substituent group at specific 2-
or 6-position.3 To the best of our knowledge, however, the struc-
tures of fluoroalkyl substituted analogies, especially 6-fluoroalkyl
substituted pyridazinones, and their expected potential bio-
activities are still far from understanding. Moreover, the method for
a challenge.
In general, a sequential condensation and ring-closure reaction
of ketoesters or ketocarboxylic acids with hydrazines is one of the
practical processes toward the construction of nonfluoroalkyl
substituted 1,2-diaza-3-one heterocyclic ring system.4 Other
methods, such as oxidation followed by ring-expansion reaction of
N-amino-lactam,5 and intramolecular cyclization of hydrazides of
vic-acetylenylbenzoic6 have also been reported to produce corre-
sponding pyridazinones and diazepinones.
Our approach toward the construction of fluoroalkyl substituted
1,2-diaza-3-one heterocycles with different ring sizes is based on
the development and optimization of a practical preparation of
u-fluoroalkyl substituted ketoesters. As
a fluorine-containing
building block, -fluoroalkyl substituted ketoesters can be then
u
subjected to a sequential process of condensation and ring-closure
reaction with various hydrazines under catalysis of 10–20 mol %
TsOH, and lead to the formation of 1,2-diaza-3-one heterocycles.
the preparation of biologically equal important various
u
-fluoro-
Interestingly, such sequential reaction of
u-fluoroalkylated d- or
alkyl ketoesters is also less well-investigated. The development of
3-ketoesters with aryl hydrazines under the same acidic conditions
cannot provide the formation of diazepinones and diazocinones,
and instead, the reaction provides us a possibility to directly access
to the biologically interested 2-fluoroalkyl-indole-3-carboxylate
derivatives via a Fisher indole synthesis.
* Corresponding authors. Tel./fax: þ86 21 66133380.
E-mail address: jhao@staff.shu.edu.cn (J. Hao).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.029

W. Wan et al. / Tetrahedron 65 (2009) 4212–4219
4213
Table 1
The overall yields of
2. Results and discussion
u-fluoroalkylated ketoesters 4
As for the key fluorine-containing building block for the syn-
thesis of 1,2-diaza-3-one heterocycles, fluoroalkylated ketoesters
were prepared in moderate yields through a condensation of
Entry
Compd.
n
RF
R1
Overall yield (%)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
1
1
1
1
2
3
CF3
CF3
CF2H
C3F7
CF3
Me
Et
Et
Et
Me
Me
57
65
34
17
55
50
fluorinated methyl acetate 1 with various a,u-diesters 2, such as
dimethyl succinate, followed by decarboxylation with H3BO3,7 as
outlined in Scheme 1. NaOCH3, NaH, t-BuOK, or metal sodium was,
respectively, employed as a base in a model reaction of Claisen
condensation of methyl trifluoroacetate with dimethyl succinate in
dry ether to produce trifluoromethylated ketodiester 3a (n¼1). It
was found that commonly used NaOCH3, NaH, or t-BuOK was not an
ideal base for this condensation reaction, reaction treated with
these bases resulted either a lower yield (less than 50%) with longer
reaction time (more than 24 h) or more complicated mixture.
Treatment of dimethyl succinate with metal sodium, however,
produced 75% isolated yield of 3a within 12 h. Nevertheless, the
yield could not be further improved remarkably even when the
reaction time was prolonged over 72 h. It’s quite certain that small
amount of alcohol (methanol or ethanol), which was existed in
diester as an impurity reacted with metal sodium and produced
corresponding NaOCH3 or NaOEt in situ, respectively, such in situ
generated base accelerated the condensation reaction. The sub-
sequential decarboxylation of 3a in the presence of boric acid
(1.1 equiv) at 150–180 ꢀC yielded, after a quick aqueous work-up,
CF3
proportion of desired products of corresponding hydrazone and
4,5-dihydro-6-trifluoromethyl pyridazinone (Table 2). High con-
versions of substrates were successfully realized when the con-
densations were carried out in refluxed toluene under the catalysis
of Bronsted acids. In particular, an almost quantitative yield of the
desired 4,5-dihydropyridazinone was obtained when the amount
of catalyst of TsOH, or CF3COOH, was increased from 10 to 20 mol %
(entries 8 and 10, Table 2), the reaction time was significantly
shortened from 36 h to 12 h. In the case of using concentrated
H2SO4 as a catalyst (either 10 or 20 mol %), reaction could yield the
desired 4,5-dihydropyridazinone products in high yield (entry 11,
Table 2), however, the partial carbonization of substrates was also
clearly observed. In the case of using Lewis acids as catalysts, for
instance Ti(OEt)4, AlCl3, CuI2, ZnBr2, reaction generally resulted
lower yield of 4,5-dihydropyridazinone but higher yield of hydra-
zone even with longer reaction time (48 h). TiCl4 (10%) could not
promote such condensation reaction. The optimization study of this
sequential process revealed an interesting result that the ratio of
product 6b and 7b was also dominated by the molar ratio of the
starting materials of ketoester 4 and hydrazine 5; 1:1 molar ratio of
4a and phenyl hydrazine 5b could result the N-phenyl-4,5-dihydro-
6-trifluoromethyl-pyridazinones 7b as a major product under the
catalysis of 10% TsOH, while 1:2 molar ratio of same substrates
could efficiently terminate the reaction at first step and prevent the
subsequential ring-closure reaction to the formation of dihy-
dropyridazinone product 7b. In addition, the hydrazone 6b could
the desired trifluoromethyl substituted g-ketoester 4a in 76% yield.
The overall yield of two steps was 57% and was higher than that was
reported in literature. After optimization of reaction conditions, the
scope of this sequential process was then successfully extended to
the synthesis of other fluoroalkyl substituted
4-difluoromethyl- -ketoester 4c, 4-heptafluoropropanyl
4d, 5-trifluoromethyl- -ketoester 4e, and 6-trifluoromethyl-3-
u
-ketoesters, such as
g
g-ketoester
d
ketoester 4f, under the similar conditions described above
(Table 1). This sequential reaction generally undergoes smoothly
even in 100-g scale in laboratory and provides reasonable overall
yield. However, in the case of using difluoroacetate as a starting
material, the base could directly affect the difluoromethyl group,
and result partial decomposition of either difluoroacetate or con-
densation product 3c. As a result, the overall yield for difluoro-
methyl ketoester 4c was only 34%. As for the parafluoroalkyl
ketoester 4d (Table 1, entry 4), decomposition was observed at the
stage of decarboxylation at high temperature, though a high yield of
condensation reaction was obtained at first step. The reason for this
decomposition is not clear yet.
Table 2
Catalyst effects on the condensation and ring-closure reaction of phenyl hydrazine
with trifluoromethyl
g
-ketoester 4a
O
catalyst
toluene, reflux
OCH3
F3C
+
Ph-NHNH2
O
4a
5b
Ph
N
Ph
NH
O
O
O
N
N
O
OR1
1. Na/Et2O
2. H+
+
OCH3
OR1
OR1
n
RF
n
F3C
F3C
RF
OMe
O
O
O
OR1
3
6b
7b
O
1
2
20% TsOH
toluene, reflux
93%
O
RF = CF3, HCF2, C3F7
R1 = Me, Et
n = 1, 2, 3
H3BO3
RF
CO2R1
n
150°C-180°C
4
Entry
Catalyst
mol %
Yield (6b)
Yield (7b)
Scheme 1. Optimized route toward
u
-fluoroalkylated ketoesters 4.
1
2
3
4
5
6
7
8
TiCl4
Ti(OEt)4
CuI2
ZnBr2
AlCl3
TsOH
TsOH
TsOH
CF3COOH
CF3COOH
H2SO4
HOAc/NaOAc
10
10
10
10
10
5
10
20
10
20
10
10
d
d
97%
87%
94%
73%
80%
40%
0
1%
0
2%
25%
1%
10%
1%
The condensation of fluoroalkyl substituted ketoester 4 with
hydrazine followed by ring-closure reaction is a simple and typical
route toward 1,2-diaza-3-one compounds.8 This sequential process,
however, is sensitive and chemoselectively controlled by either the
ratio of ketoester 4 and hydrazine or the percentage of acidic cat-
alyst that is added to catalyze this reaction. A variety of catalysts
including Lewis acids, Bronsted acid, and acidic buffer (pH¼5.0,
entry 12, Table 2) were employed in a model reaction of 4a with
phenyl hydrazine (1:1 mole ratio) to examine their effects on the
20%
15%
55%
98%
95%
99%
90%
67%
9
10
11
12
All reactions were carried out on a 1 mmol scale and giving isolated yields.

4214
W. Wan et al. / Tetrahedron 65 (2009) 4212–4219
be readily converted to 7b with 100% conversion and 93% isolated
yield under the catalysis of 20% TsOH.9
substrates, which results the formations of dihydropyridazinones 7,
20 mol % TsOH as catalyst and 1:1 molar ratio of -fluoroalkyl
u
For better understanding the mechanism of this sequential
process, the reaction of 4-methoxyphenyl hydrazine 5j with tri-
ketoester 4 and hydrazine 5 were finally determined as a standard
condition. Moreover, 10 mol % of TsOH catalyst with 1:2 ratio of
fluoromethyl-
g
-ketoester 4j was selectively monitored by 19F NMR
fluoroalkylated
g-ketoesters (n¼1) and hydrazines could be an ef-
and 1H NMR. The formation of hydrazone intermediate 6j was
clearly observed during the course of 19F NMR study. The first
condensation step of this sequential process was relatively slower
than the second ring-closure step. Once hydrazone 6j was formed,
the following ring-closure reaction toward dihydropyridazinone
product would be formed in a shorter period. This phenomenon
was also observed in all other examined cases. The plausible
mechanistic interpretation of formation of 7 is explained by the
condensation of hydrazine with ketone and ring-closure reaction of
hydrazone, as shown in Scheme 2.
fective condition to improve the yield of hydrazone product 6 if the
hydrazone 6 is demanded to be a dominated product. Results from
substituent effects on the ring-closure reaction in Table 3 indicated
that the electron rich hydrazine, such as 4-methoxyphenyl hydra-
zine 5j, provided higher yield of dihydropyridazinone product 7j
(entry 10 of Table 3), reaction process was difficult to be terminated
at first step. Whereas, reaction process with electron deficient hy-
drazine, for instance NO2 substituted hydrazine 5f (entry 6, Table
3), could either be selectively terminated at first step and form the
hydrazone 6 as a major product or directly form the final dihy-
dropyridazinone 7 as a major product depending on the different
molar ratio of ketoester 4 and hydrazine 5. Furthermore, no
cyclized product could be detected by 19F NMR in reaction of dinitro
substituted hydrazines (7g and 7h, entries 7 and 8, Table 3) even
under the catalysis of stoichiometric TsOH. Only hydrazone prod-
ucts 6g, 6h were obtained. It was also found that treatment of
acetohydrazide 5k (entry 11, Table 3) with 4a mainly afforded N-
deprotected 6-trifluoromethyl dihydropyridazinone 7a due to the
hydrolysis of acetyl group under the acetic condition. With the
intent of expanding the spectrum of this sequential reaction to
accommodate more diverse substituents, the heptafluoropropyl
+OH
O
H+
OCH3
OCH3
-H2O
Condensation
F3C
F3C
O
O
4a
4-CH3OPh-NHNH2
4-CH3OPh
NH
4-CH3OPh
N
O
N
N
ring-closure reaction
OCH3
F3C
F3C
and difluoromethyl substituted g-ketoester were also investigated
O
6j
7j
(entries 12 and 13, Table 3). The reaction conditions were proved to
be compatible with hydrazines in good yields. In general, the
hydrazone product 6 could be isolated if it was clearly detected
during the reaction. Subsequential ring-closure reaction was suc-
cessfully implemented for the transformation from hydrazone 6 to
dihydropyridazinone 7. The base promoted ring-closure reaction,
for instance by using NaH, could partially result the formation of
Scheme 2. Plausible reaction pathway from ketoester to dihydropyridazinones.
With optimization of reaction conditions, we applied this pro-
tocol to a range of hydrazine substrates, including aryl hydrazines,
alkyl hydrazines, and acetyl hydrazines (Table 3). To ensure a good
performance with a wide range of both ketoester 4 and hydrazine 5
Table 3
Synthesis of hydrazones 6 and pyridazinones 7a
R2
R2
O
NH
10-20% TsOH
N
O
N
OR1
+
+
H2N NH R2
N
RF
Toluene
OR1
RF
O
reflux, 1-2 days
RF
O
4a-d
5
6
7
Entry
RF
R1
R2
Ratio of 4 and 5b
Product (s)
Yield (%)
6
7
1
2
CF3
CF3
Me
Me
H (5a)
Ph (5b)
1:1
1:1
1:2
1:1
1:2
1:1
1:1
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:1
1:1
1:1
1:1
6a and 7a
6b and 7b
Tracec
Tracec
70
83
92
20
80
25
85
dd
80e
10
3
CF3
Me
4-Cl-Ph (5c)
6c and 7c
0
67
4
5
6
CF3
CF3
CF3
Me
Me
Me
4-F-Ph (5d)
PhCO (5e)
4-NO2-Ph (5f)
6d and 7d
6e
6f and 7f
Tracec
82
15
85
15
81
30
85
7
8
CF3
CF3
Me
Et
2,4-NO2-Ph (5g)
2,4-NO2-Ph (5h)
6g
6h
dd
dd
dd
dd
77
94
76
9
CF3
CF3
CF3
C3F7
CF2H
Et
4-CH3-Ph (5i)
4-CH3O-Ph (5j)
CH3CO (5k)
H (5l)
6i and 7i
6j and 7j
6k and 7k
6l and 7l
6m and 7m
Tracec
Tracec
Tracec
Tracec
Tracec
10
11
12
13
Me
Me
Et
72
82
Et
H (5m)
a
All reactions were carried out on a 5 mmol scale and giving isolated yields.
The reaction was conducted at molar ratio of 1:1 (4:5) catalyzed by 20% TsOH or at molar ratio of 1:2 (4:5) catalyzed by 10% TsOH, respectively.
Trace product was detected by 19F NMR.
Dihydropyridazinone was not detected.
The yield of 7j could be further improved to 93% if 25% TsOH was employed.
b
c
d
e

W. Wan et al. / Tetrahedron 65 (2009) 4212–4219
4215
product 7,10 however, reaction was generally complicated even in
lower temperature (lower than ꢁ60 ꢀC), the isolated yield of
product 7 was commonly less than 20%.
The assignment of configuration of 7j (CCDC 704552) was un-
ambiguously confirmed by X-ray crystallographic analysis (Fig. 1).
In the diagram of crystal structure of 7j, the molecules are linked
firstly into centrosymmetric dimmers, and then into infinite chains.
The dipole–dipole and van der Waals interaction may be effective
in this molecular packing.
COOMe
O
H
N
O
N
(
)
n
Ph-NHNH2
100%TsOH
NH2NH2 H2O
10% TsOH
OMe
N
(
)
n
F3C
CF3
O
F3C
N
H
4e, 4f
8, 85%
n = 2
11
(n = 2, 3)
NH2NH2 H2O
10% TsOH
NH2
11a (n = 2) 72%
11b (n = 3) 78%
O
H
N
100% TsOH
N
Taking into account the good results obtained from the previous
OMe
F3C
n
condensation and ring-closure reaction, other
ketoester possessing longer carbon chain, for instance, tri-
fluoromethyl -ketoester 4e and trifluoromethyl -ketoester 4f
u-fluoroalkyl
O
F3C
9, 92%
10, 45%
n = 3
d
3
n = 3
were also envisaged. Similar condensation and ring-closure re-
action of 4e or 4f with hydrazine were also experimented toward
the synthesis of 1,2-diazaone derivatives. With previously opti-
Scheme 3. The methods for the synthesis of fluoroalkylated 1,2-diazaones and indoles.
mized condition, reaction of
u
-trifluoromethyl ketoester (4e, n¼2)
interested trifluoromethylated triazolopyridazine derivative 15
(Scheme 4). Triazolopyridazine derivatives play an important role
in pharmaceuticals and have received much attention in related
fields for long time.12 Fluoroalkylated analogs are also expected to
have the potential biological significance and unique chemical
properties. The synthetic route toward 6-trifluoromethyl
substituted triazolopyridazine 15 was fulfilled starting from 4,5-
dihydro-6-trifluoromethyl pyridazinones 7a according to the pro-
cedures in literatures. Compound 7a was initially oxidized and
formed 6-fluoroalkyl pyridazinones 12 in 95% yield in the presence
of Br2/AcOH.13 The subsequential chlorination of hydroxyl group in
12 by POCl3 in MeCN resulted the formation of 13 in 88% yield.14
Substitution of Cl atom in 13 and followed by the cyclization of 14
resulted the formation of 6-trifluoromethyl substituted tri-
azolopyridazine 15 (Scheme 4).15 Bioactivity assay for 6-tri-
fluoromethyl triazolopyridazine 15 is currently in progress.
with hydrazine hydrate 5a was successfully carried out in refluxed
toluene and produced the desired trifluoromethylated dihy-
drodiazepinone 8 in 85% yield (Scheme 3). However, the reaction of
u
-trifluoromethyl ketoester (4f, n¼3) with hydrazine hydrate 5a
under same condition was stopped at the first step and formed
hydrazone 9 in 92% yield when 10% TsOH was applied. The trace
amount of desired 1,2-diazocinone 10 was only detected by 19F NMR
in this case. 1,2-Diazocinone 10 could only be obtained stepwise if
the catalytic amount of TsOH is employed in the condensation step,
the ring-closure reaction of hydrazone 9 to form 1,2-diazocinone 10
required the existence of stoichmetric TsOH, and could be accom-
plished in 45% yield. In addition, ring-closure reaction promoted by
base, such as NaH, could not produce desired 1,2-diazocinone 10 in
good yield (less than 10% isolated yield) even in low reaction tem-
perature, and instead, reaction was complicated. It’s worth to be
mentioned that reaction of 4e or 4f with aryl hydrazines catalyzed
by stoichiometric TsOH could not yield desired diazepinone or
diazocinone derivatives, instead, 2-trifluoromethyl indole-3-prop-
anoate 11a or 2-trifluoromethyl indole-3-butanoate 11b was
obtained in 72% or 78%, respectively, through a Fischer indole
synthesis (Scheme 3). Catalytic amount of TsOH, for instance 10%,
could also stop the reaction at condensation step and form the
corresponding hydrazone product. In such circumstance, trace
amount of indole product could only be detected by 19F NMR.11
It should be pointed out that indole ring could only be formed in
the cases of using 4e and 4f (n¼2, 3) with N-aryl hydrazines cata-
lyzed by stoichiometric TsOH. This phenomenon of indole forma-
tion was not clearly observed in the condensation of fluoroalkylated
H
N
H
N
O
N
Cl
Br2
HOAc
POCl3
MeCN
O
N
N
N
F3C
F3C
F3C
F3C
7a
12, 95%
13, 88%
O
O
N
NHNH2
N
N
NH2NH2 H2O
K2CO3, THF
N
O
N
TsOH, MeOH
N
F3C
14, 90%
15, 85%
Scheme 4. A transformation of 4,5-dihydro-6-trifluoromethyl pyridazinone 7a to tri-
azolopyridazine 15.
g
-ketoesters 4a–4d (n¼1) with N-aryl hydrazines even under the
catalysis of 100% TsOH. Ring-closure reaction to form six-mem-
bered dihydropyridazinone 7 became a dominative process in this
sequential reaction.
3. Conclusions
A concise and general synthetic route toward the small and
medium-sized fluoroalkyl substituted 1,2-diaza-3-one heterocyclic
ring skeletons via a sequential reaction of condensation and ring-
One application of 4,5-dihydro-6-trifluoromethyl-pyridazinone
7a was successfully subjected to the synthesis of pharmaceutically
closure reaction of
5 catalyzed by 10%–20 mol % TsOH has been successfully developed.
A practical preparation of -fluoroalkylated ketoesters 4, which are
recognized as an important fluorinated building blocks has been
optimized. Initial application of -fluoroalkylated ketoesters 4 was
u-fluoroalkylated ketoesters 4 with hydrazines
u
u
also succeeded in the synthesis of 2-trifluoromethyl-indole-3-car-
boxylate via a Fischer indole synthesis.
4. Experimental section
4.1. General
Reactions were conducted in an appropriate round bottom
three-necked flask equipped with magnetic stirring bar and
Figure 1. ORTEP diagram of 7j and its packing diagram.

4216
W. Wan et al. / Tetrahedron 65 (2009) 4212–4219
condenser under nitrogen protection. Thin layer chromatography
(TLC) was performed on a silica gel. All melting points were taken
on WRS-1 digital melting point apparatus made by Shanghai
physical instrument factory (SPOIF), China, and were uncorrected.
1H, 13C, and 19F NMR spectra were recorded on Bruker AV-500
spectrometer. Chemical shifts for 1H NMR spectra are reported in
parts per million downfield from TMS, chemical shifts for 13C NMR
spectra are reported in parts per million relative to internal chlo-
4.2.2. Ethyl 5,5,5-trifluoro-4-oxopentanoate (4b)
Compound 4b was obtained as a colorless liquid in 65% yield
(72 ꢀC/10 mmHg); 1H NMR (500 MHz, CDCl3, ppm)
d 4.16 (q, 2H,
J¼7.0 Hz, –OCH2–), 3.04 (t, 2H, J¼6.0 Hz, –CH2–), 2.71 (t, 2H,
J¼6.0 Hz, –CH2–), 1.27 (t, 3H, J¼7.0 Hz, –CH3); 13C NMR (125 MHz,
CDCl3, ppm)
d
190.1 (q, J¼35.0 Hz), 171.2, 115.5 (q, J¼290.0 Hz), 61.1,
31.4, 26.8, 13.9; 19F NMR (CDCl3, 470 MHz, ppm)
(KBr) 2961, 1747, 1445, 1216, 1141, 1086, 914.
d
ꢁ74.98 (s, 3F); IR
n
roform (d
77.2 ppm for 13C), and chemical shifts for 19F NMR spectra
are reported in parts per million downfield from internal fluoro-
trichloromethane (CFCl3). Coupling constants (J) are given in hertz
(Hz). The terms m, s, d, t, q refer to multiplet, singlet, doublet,
triplet, quartet; br refers to a broad signal. Infrared spectra (IR) were
recorded on AVATAR 370 FT-IR spectrometer, absorbance frequen-
cies are given at maximum of intensity in cmꢁ1. Elemental analyses
were performed with Elemental Vario EL III instrument. High
resolution mass spectra were obtained on a CONCEPT 1H spec-
trometer, using EI at 70 eV. Single-crystal XRD was performed with
4.2.3. Ethyl 5,5-difluoro-4-oxopentanoate (4c)
Compound 4c was obtained as a colorless liquid in 34% yield by
reduced pressure distillation (71 ꢀC/10 mmHg); 1H NMR (500 MHz,
CDCl3, ppm)
d
5.78 (t, 1H, J¼53.5 Hz, –CF2H–), 4.13 (q, 2H, J¼7.0 Hz,
–OCH2–), 2.96 (t, 2H, J¼6.5 Hz, –CH2–), 2.66 (t, 2H, J¼6.5 Hz, –CH2–),
1.25 (t, 3H, J¼7.0 Hz, –CH3); 13C NMR (125 MHz, CDCl3)
d 198.5 (t,
J¼25.0 Hz), 172.0, 109.8 (t, J¼250.0 Hz), 61.1, 31.2, 27.2, 14.2; 19F
NMR (470 MHz, CDCl3)
d
ꢁ127.85 (d, 2F, J¼51.7 Hz); IR (KBr)
n 2968,
1742, 1445, 1198, 1119, 998.
graphite-monochromatic Mo Ka radiation
(
l
¼0.71073 Å) on
a Bruker Smart ApexII CCD diffractometer at T¼273(2) K. The
structures were solved by direct method with SHELXS-97 program
and refined by full matrix least-squares on F2 with SHELXL-97
program. All non-hydrogen atoms were refined anisotropically, and
hydrogen atoms were located and included at their calculated
position.
4.2.4. Ethyl 5,5,6,6,7,7,7-heptafluoro-4-oxoheptanoate (4d)
Compound 4d was obtained as a colorless liquid in 17% yield by
reduced pressure distillation (78 ꢀC/10 mmHg); 1H NMR (500 MHz,
CDCl3, ppm)
–CH2–), 2.63 (t, 2H, J¼6.0 Hz, –CH2–), 1.27 (t, 3H, J¼7.5 Hz, –CH3);
13C NMR (125 MHz, CDCl3)
d
4.16 (q, 2H, J¼7.5 Hz, –OCH2–), 2.69 (t, 2H, J¼6.0 Hz,
d
198.5 (t, J¼26.3 Hz), 172.0, 121.5–114.1
The syntheses of some main products are shown below.
(q, t, J¼286.3 Hz, JF¼33.8 Hz), 111.3–109.6 (t, t, J¼263.8, 32.5 Hz),
109.3–105.5 (t, t, q, J¼267.5, 35, 33.8 Hz), 66.0, 35.3, 32.2, 13.4; 19F
NMR (CDCl3, 470 MHz, ppm)
d
ꢁ80.85 (t, 3F, J¼9.4 Hz), ꢁ119.55 (q,
4.2. Procedure for the synthesis of
ketoesters (4)
u-fluoroalkylated
2F, J¼9.4 Hz), ꢁ127.13 (s, 2F); IR (KBr)
n 2987, 1811, 1716, 1410, 1378,
1349, 1232,1021.
To a 250 mL three-necked round bottom flask equipped with
condenser and magnetic stir bar was added dry ether (80 mL), so-
dium wire (0.5 mol), and methyl (or ethyl) 2,2,2-trifluoroacetate
(0.5 mol) at 0 ꢀC under nitrogen atmosphere and stirred for 10 min.
A solution of dimethyl succinate (1 mol) in ether (200 mL) was
added dropwisely to the reaction mixture, keeping the temperature
at 0–5 ꢀC. The reaction continued until all the sodium wire had
dissolved. After the solution was refluxed for 36 h, the ether and
excess of dimethyl succinate were then distilled off in vacuo to
leave a black tarry residue of sodio-derivative. The free ketoester
was liberated by treatment with sulfuric acid (100 mL, 5 N) and was
extracted with ether (3ꢂ100 mL). Distillation of the dried extracts
(over anhydrous MgSO4) gave crude dimethyl trifluoro-
acetosuccinate, bp 90–120 ꢀC/5 mmHg. This crude material was
used without purification in further hydrolysis experiments. Di-
methyl trifluoroacetosuccinate (0.5 mol) and boric acid (0.55 mol)
in flask were heated to 150 ꢀC (oil bath, magnetic stirring, Claisen
condenser connected with a gas collected device). As the temper-
ature was raised to 180 ꢀC, the rate of CO2 evolution increased and
the reaction mixture became a clear, light yellow appearance after
3 h. The contents of the flask were cooled to room temperature,
poured onto ice water (350 mL), and extracted with ether
(3ꢂ100 mL). After the combined organic layers were dried over
anhydrous MgSO4, the solvent was removed in vacuo and the res-
idue was distilled through a 10 mm Vigreux apparatus. A main
fraction was collected.
4.2.5. Methyl 6,6,6-trifluoro-5-oxohexanoate (4e)
Compound 4e was obtained as a colorless liquid in 55% yield by
reduced pressure distillation (80 ꢀC/10 mmHg); 1H NMR (500 MHz,
CDCl3, ppm)
d
3.69 (s, 3H, –OCH3), 2.84 (t, 2H, J¼7.0 Hz, –CH2–), 2.41
(t, 2H, J¼7.0 Hz, –CH2–), 2.04–1.98 (m, 2H, –CH2–); 13C NMR
(125 MHz, CDCl3)
d
190.9 (q, J¼35.0 Hz), 172.9, 115.4 (q, J¼291.3 Hz),
51.6, 35.3, 32.2, 17.5; 19F NMR (CDCl3, 470 MHz, ppm)
3F); IR (KBr) 2958, 1764, 1736, 1441, 1209, 1172.
d
ꢁ79.31 (s,
n
4.2.6. Methyl 7,7,7-trifluoro-6-oxoheptanoate (4f)
Compound 4f was obtained as a colorless liquid in 50% yield by
reduced pressure distillation (83 ꢀC/10 mmHg); 1H NMR (500 MHz,
CDCl3, ppm)
d
3.68 (s, 3H, –OCH3), 2.75 (t, 2H, J¼6.5 Hz, –CH2–),
2.36 (t, 2H, J¼7.0 Hz, –CH2–), 1.74–1.65 (m, 4H, –CH2–); 13C NMR
(125 MHz, CDCl3)
d
191.1 (q, J¼35.0 Hz), 173.4, 115.5 (q, J¼291.3 Hz),
51.6, 36.0, 33.5, 24.4, 23.9; 19F NMR (CDCl3, 470 MHz, ppm)
ꢁ79.35 (s, 3F); IR (KBr) 2942, 1768, 1741, 1445, 1210, 1186.
d
n
4.3. General procedure for the synthesis of 6, 7, 8, 9, and 10
To a 100 mL three-necked round bottom flask equipped with
condenser and magnetic stir bar was added phenyl hydrazine,
methyl 5,5,5-trifluoro-4-oxopentanoate, TsOH, and toluene (50 mL)
under nitrogen atmosphere, stirred in reflux for 24 h. Once the
reaction was completed, the precipitation was removed via filtra-
tion, the residue was then carefully washed with ethyl acetate for
three times, the solvent was removed by rotary evaporator. The
residue was then purified by column chromatography product.
4.2.1. Methyl 5,5,5-trifluoro-4-oxopentanoate (4a)
Compound 4a was obtained as a colorless liquid in 57% yield
(65 ꢀC/10 mmHg); 1H NMR (CDCl3, 500 MHz, ppm)
d
3.73 (s, 3H,
4.3.1. 6-(Trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one (7a)
Compound 7a was obtained as a pale colorless solid in 83% yield
by column chromatography (6:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 75–77 ꢀC; 1H NMR (500 MHz, CDCl3,
–OCH3), 3.06 (t, 2H, J¼6.5 Hz, –CH2–), 2.74 (t, 2H, J¼6.5 Hz,
–CH2–); 13C NMR (CDCl3, 125 MHz, ppm)
d
190.3 (q, J¼35.0 Hz),
172.0, 115.6 (q, J¼290.0 Hz), 52.3, 31.6, 26.8; 19F NMR (CDCl3,
470 MHz, ppm)
1207, 1147, 1072.
d
ꢁ68.26 (s, 3F); IR (KBr):
n
2960, 1741, 1442,
ppm)
d
8.76 (s, 1H, –NH), 2.78 (t, 2H, J¼8.5 Hz, –CH2–), 2.64 (t, 2H,
J¼8.5 Hz, –CH2–); 13C NMR (125 MHz, CDCl3)
d 166.8, 140.6 (q,

W. Wan et al. / Tetrahedron 65 (2009) 4212–4219
4217
J¼36.3 Hz), 120.3 (q, J¼272.5 Hz), 25.3, 19.6; 19F NMR (470 MHz,
3F), ꢁ114.21 to 114.25 (m, 1F); IR (KBr)
n
3026, 2917, 1706, 1651,
CDCl3)
d
ꢁ71.29 (s, 3F); IR (KBr)
n
3285, 1703, 1652, 1212, 1133.
1599, 1506, 1204, 1120, 842. Anal. Calcd for C11H8F4N2O (260.19): C,
50.78; H, 3.10; N, 10.77. Found: C, 50.59; H, 3.15; N, 10.69.
4.3.2. Methyl 5,5,5-trifluoro-4-(2-phenylhydrazono)-
pentanoate (6b)
4.3.7. Methyl 4-(2-benzoylhydrazono)-5,5,5-trifluoropentanoate (6e)
Compound 6e was obtained as a colorless solid in 82% yield by
column chromatography (6:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 102–105 ꢀC; 1H NMR (500 MHz,
Compound 6b was obtained as a brick red liquid in 70% yield by
column chromatography (8:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide; 1H NMR (500 MHz, CDCl3, ppm)
d 9.29 (s,
1H, –NH), 7.29 (t, 2H, J¼7.5 Hz, –ArH), 7.16 (d, 2H, J¼7.5 Hz, –ArH),
6.94 (t, 1H, J¼7.5 Hz, –ArH), 3.73 (s, 3H, –OCH3), 2.74 (t, 2H,
J¼7.0 Hz, –CH2–), 2.69 (t, 2H, J¼7.0 Hz, –CH2–); 13C NMR (125 MHz,
CDCl3, ppm)
d
11.28 (s, 1H, –NH), 8.01 (d, 2H, J¼5.5 Hz, –ArH), 7.56
(t, 1H, J¼7.5 Hz, –ArH), 7.47 (t, 2H, J¼7.5 Hz, –ArH), 3.72 (s, 3H,
–OCH3), 2.83 (t, 2H, J¼4.0 Hz, –CH2–), 2.80 (t, 2H, J¼4.0 Hz, –CH2–);
CDCl3)
d
175.2, 144.1, 131.0 (q, J¼32.5 Hz), 129.4, 122.3 (q,
13C NMR (125 MHz, CDCl3)
d 175.2, 166.1, 132.6, 132.5, 128.5 (q,
J¼271.3 Hz), 121.7, 113.8, 52.7, 30.9, 19.0; 19F NMR (470 MHz, CDCl3)
J¼31.3 Hz), 127.8, 127.0, 121.2 (q, J¼273.8 Hz,), 53.1, 30.6, 25.5; 19F
d
ꢁ68.26 (s, 3F); IR (KBr)
n
3316, 3023, 1723, 1602, 1526, 1497, 754,
NMR (470 MHz, CDCl3)
d
ꢁ69.21 (s, 3F); IR (KBr)
n 3325, 3087, 2962,
696. MS (ESI): m/z 275.09 [MþH]þ; HRMS [Mþ1] calcd for
1734, 1666, 1123, 728, 697. Anal. Calcd for C13H13F3N2O3 (302.25):
C, 51.66; H, 4.34; N, 9.27. Found: C, 51.43; H, 4.33; N, 9.01. MS
(ESI): m/z 303.0 [MþH]þ; HRMS [Mþ1] calcd for C13H13F3N2O3:
302.0878; found 302.0887.
C12H13F3N2O2: 274.0929; found 274.0785.
4.3.3. 2-Phenyl-6-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-
one (7b)
Compound 7b was obtained as a chocolate brown solid in 92%
yield by column chromatography (8:1 petroleum ether/ethyl ace-
tate) on neutral aluminum oxide: mp 83–85 ꢀC; 1H NMR (500 MHz,
4.3.8. Methyl 5,5,5-trifluoro-4-(2-(4-nitrophenyl)hydrazono)-
pentanoate (6f)
Compound 6f was obtained as a red-brown solid in 85% yield by
column chromatography (10:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 92–93 ꢀC; 1H NMR (500 MHz, CDCl3,
CDCl3, ppm)
d
7.46–7.40 (m, 4H, –ArH), 7.31 (t, 1H, J¼7.0 Hz, –ArH),
2.88 (t, 2H, J¼7.0 Hz, –CH2–), 2.81 (t, 2H, J¼7.0 Hz, –CH2–); 13C NMR
(125 MHz, CDCl3)
d
164.3, 141.0 (q, J¼36.3 Hz), 140.1, 128.8, 127.4,
ppm)
d
10.17 (s, 1H, –NH), 8.17 (d, 2H, J¼7.5 Hz, –ArH), 7.21 (d, 2H,
124.9, 120.4 (q, J¼272.5 Hz), 26.9, 20.2; 19F NMR (470 MHz, CDCl3)
J¼7.5 Hz, –ArH), 3.76 (s, 3H, –OCH3), 2.80 (t, 2H, J¼6.0 Hz, –CH2–),
d
ꢁ70.95 (s, 3F); IR (KBr)
n
3067, 2923,1709, 1596, 1494, 1393, 765,
2.76 (t, 2H, J¼6.0 Hz, –CH2–); 13C NMR (125 MHz, CDCl3)
d 175.5,
693. Anal. Calcd for C11H9F3N2O (242.2): C, 54.55; H, 3.75; N, 11.57.
Found: C, 54.28; H, 3.88; N, 11.29.
149.3, 141.6, 135.5 (q, J¼33.8 Hz), 125.8, 121.6 (q, J¼272.5 Hz), 113.0,
52.9, 30.8, 19.3; 19F NMR (470 MHz, CDCl3)
3308, 3041, 1733, 1594, 1533, 1110, 851.
d
ꢁ68.89 (s, 3F); IR (KBr)
n
4.3.4. Methyl 4-(2-(4-chlorophenyl)hydrazono)-5,5,5-trifluoro-
pentanoate (6c)
Compound 6c was obtained as a red-brown solid in 67% yield by
column chromatography (10:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 92–93 ꢀC; 1H NMR (500 MHz, CDCl3,
4.3.9. 2-(4-Nitrophenyl)-6-(trifluoromethyl)-4,5-dihydro-
pyridazin-3(2H)-one (7f)
Compound 7f was obtained as a red-brown solid in 80% yield by
column chromatography (8:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 96–99 ꢀC; 1H NMR (500 MHz, CDCl3,
ppm)
d
10.17 (s, 1H, –NH), 8.18 (d, 2H, J¼9.0 Hz, –ArH), 7.22 (d, 2H,
J¼9.0 Hz, –ArH), 3.77 (s, 3H, –OCH3), 2.79 (t, 2H, J¼2.5 Hz, –CH2–),
ppm)
d
8.27 (d, 2H, J¼7.0 Hz, –ArH), 7.78 (d, 2H, J¼7.0 Hz, –ArH),
2.76 (t, 2H, J¼2.5 Hz, –CH2–); 13C NMR (125 MHz, CDCl3)
d
175.0,
2.94 (t, 2H, J¼7.5 Hz, –CH2–), 2.88 (t, 2H, J¼7.5 Hz, –CH2–); 13C NMR
143.9, 130.9 (q, J¼32.5 Hz), 129.3, 122.2 (q, J¼272.5 Hz), 121.5, 113.6,
(125 MHz, CDCl3)
d
164.4, 145.6, 145.1, 142.8 (q, J¼36.3 Hz), 125.9,
52.6, 30.8, 18.9; 19F NMR (470 MHz, CDCl3)
3326, 3031, 1738, 1590, 1527, 1109, 847.
d
ꢁ69.06 (s, 3F); IR (KBr)
124.1, 120.1 (q, J¼272.5 Hz), 27.2, 20.4; 19F NMR (470 MHz, CDCl3)
n
d
ꢁ71.10 (s, 3F); IR (KBr)
n 3051, 2924, 1713, 1594, 1519, 1132, 854.
Anal. Calcd for C11H8F3N3O3 (287.19): C, 46.00; H, 2.81; N, 14.63.
Found: C, 45.94; H, 2.79; N, 14.43.
4.3.5. 2-(4-Chlorophenyl)-6-(trifluoromethyl)-4,5-dihydro-
pyridazin-3(2H)-one (7c)
Compound 7c was obtained as a pale yellow solid in 80% yield by
column chromatography (6:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 88–92 ꢀC; 1H NMR (500 MHz, CDCl3,
4.3.10. Methyl 4-(2-(2,4-dinitrophenyl)hydrazono)-5,5,5-trifluoro-
pentanoate (6g)
Compound 6g was obtained as a yellow solid in 81% yield by
column chromatography (6:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 99–101 ꢀC; 1H NMR (500 MHz, CDCl3,
ppm)
d
7.42 (d, 2H, J¼9.0 Hz, –ArH), 7.37 (d, 2H, J¼9.0 Hz, –ArH),
2.87 (t, 2H, J¼7.0 Hz, –CH2–), 2.80 (t, 2H, J¼7.0 Hz, –CH2–); 13C NMR
(125 MHz, CDCl3)
d: 164.1, 141.3 (q, J¼36.3 Hz), 138.5, 132.6, 128.7,
ppm)
d
11.78 (s, 1H, –NH), 9.10 (s, 1H, –ArH), 8.40 (d, 1H, J¼9.5 Hz,
125.9, 120.2 (q, J¼271.3 Hz), 26.7, 20.1; 19F NMR (470 MHz, CDCl3)
–ArH), 8.04 (d, 1H, J¼9.5 Hz, –ArH), 3.75 (s, 3H, –OCH3), 2.94 (t, 2H,
d
ꢁ71.00 (s, 3F); IR (KBr)
n 3097, 2963, 1907, 1709, 1655, 1590, 1489,
J¼7.0 Hz, –CH2–), 2.86 (t, 2H, J¼7.0 Hz, –CH2–); 13C NMR (125 MHz,
1457, 1205, 1126, 833. Anal. Calcd for C11H8ClF3N2O (276.64): C,
47.76; H, 2.91; N, 10.13. Found: C, 47.74; H, 2.99; N, 10.34. (EI): m/z
276 [M]þ.
CDCl3)
d
172.4, 144.4, 142.0 (q, J¼32.5 Hz), 139.7, 131.3, 130.0, 122.8,
120.9 (q, J¼273.8 Hz,), 117.2, 52.4, 29.5, 20.6; 19F NMR (470 MHz,
CDCl3)
d
ꢁ68.75 (s, 3F); IR (KBr)
n 3314, 3108, 2957,1734, 1616, 1597,
1547, 1435, 1334, 837. Anal. Calcd for C12H11F3N4O6 (364.23): C,
39.57; H, 3.04; N, 15.38. Found: C, 39.51; H, 3.03; N, 15.26.
4.3.6. 2-(4-Fluorophenyl)-6-(trifluoromethyl)-4,5-dihydro-
pyridazin-3(2H)-one (7d)
Compound 7d was obtained as a pale colorless solid in 85% yield
by column chromatography (8:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 105–107 ꢀC; 1H NMR (500 MHz,
4.3.11. Ethyl 4-(2-(2,4-dinitrophenyl)hydrazono)-5,5,5-trifluoro-
pentanoate (6h)
Compound 6h was obtained as a brilliant yellow solid in 85%
yield by column chromatography (8:1 petroleum ether/ethyl ace-
tate) on neutral aluminum oxide: mp: 101–103 ꢀC; 1H NMR
CDCl3, ppm)
d
7.44–7.41 (m, 2H, –ArH), 7.10 (t, 2H, J¼8.5 Hz, –ArH),
2.87 (t, 2H, J¼8.0 Hz, –CH2–), 2.79 (t, 2H, J¼8.0 Hz, –CH2–); 13C NMR
(125 MHz, CDCl3)
136.1 (d, J¼2.5 Hz), 126.8 (d, J¼8.8 Hz), 120.3 (q, J¼271.3 Hz), 115.6
d
164.3, 161.4 (d, J¼245.0 Hz),141.2 (q, J¼36.3 Hz),
(500 MHz, CDCl3, ppm) d 11.97 (s, 1H, –NH), 9.13 (s, 1H, –ArH), 8.41
(d, 1H, J¼9.5 Hz, –ArH), 7.97 (d, 1H, J¼9.5 Hz, –ArH), 4.19 (q, 2H,
(d, J¼22.5 Hz), 26.8, 20.2; 19F NMR (470 MHz, CDCl3)
d
ꢁ70.99 (s,
J¼7.5 Hz, –OCH2–), 2.97 (t, 2H, J¼6.5 Hz, –CH2–), 2.78 (t, 2H,

4218
W. Wan et al. / Tetrahedron 65 (2009) 4212–4219
J¼6.5 Hz, –CH2–), 1.29 (t, 3H, J¼7.5 Hz, –CH3); 13C NMR (125 MHz,
4.3.17. Methyl 7,7,7-trifluoro-6-hydrazonoheptanoate (9)
CDCl3)
d
172.0, 144.4, 142.1 (q, J¼33.8 Hz), 139.8, 131.4, 130.0, 122.9,
Compound 9 was obtained as a pale yellow solid in 92% yield by
column chromatography (2:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 92–96 ꢀC; 1H NMR (400 MHz, CDCl3,
120.9 (q, J¼273.8 Hz,), 117.2, 61.6, 29.8, 20.7, 14.0; 19F NMR
(470 MHz, CDCl3)
1617,1593, 1567, 1425, 835.
d
ꢁ68.55 (s, 3F); IR (KBr)
n 3323, 3118, 2943, 1738,
ppm)
d 5.93 (s, 2H, –NH2), 3.67 (s, 3H, –OCH3), 2.39–2.31 (m, 4H,
–CH2–), 1.71 (t, 2H, J¼7.0 Hz, –CH2–), 1.60 (t, 2H, J¼6.5 Hz, –CH2–);
4.3.12. 2-p-Tolyl-6-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-
one (7i)
Compound 7i was obtained as a pale red solid in 77% yield by
column chromatography (6:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 89–90 ꢀC; 1H NMR (500 MHz, CDCl3,
13C NMR (400 MHz, CDCl3)
d
173.8, 136.8 (q, J¼32.5 Hz), 115.1 (q,
J¼271.3 Hz), 51.5, 33.2, 24.7, 23.4, 23.0; 19F NMR (470 MHz, CDCl3)
d
ꢁ69.60 (s, 3F); IR (KBr)
n 3258, 1712, 1645, 1237, 1131.
4.3.18. 8-(Trifluoromethyl)-4,5,6,7-tetrahydro-1,2-diazocin-3(2H)-
one (10)
Compound 10 was obtained as a yellow solid in 45% yield by
column chromatography (4:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 103–105 ꢀC; 1H NMR (500 MHz,
ppm)
d
7.31 (d, 2H, J¼8.5 Hz, –ArH), 7.22 (d, 2H, J¼8.5 Hz, –ArH),
2.86 (t, 2H, J¼8.5 Hz, –CH2–), 2.79 (t, 2H, J¼8.5 Hz, –CH2–), 2.36 (s,
3H, –CH3); 13C NMR (125 MHz, CDCl3)
d
164.3, 140.7 (q, J¼36.3 Hz),
137.6, 137.5, 129.4, 124.9, 120.3 (q, J¼272.5 Hz), 27.0, 21.1, 20.3; 19F
NMR (470 MHz, CDCl3)
d
ꢁ70.93 (s, 3F); IR (KBr)
n
3010, 2918, 1714,
CDCl3, ppm)
d
8.36 (s, 1H, –NH), 2.44 (t, 2H, J¼7.5 Hz, –CH2–), 2.34
1650, 1511, 1426, 1131, 818. Anal. Calcd for C12H11F3N2O (256.22): C,
56.25; H, 4.33; N, 10.93. Found: C, 56.08; H, 4.47; N, 10.75.
(q, 4H, J¼7.0 Hz, –CH2–), 1.60–1.54 (m, 2H, –CH2–); 13C NMR
(125 MHz, CDCl3)
d
179.0,140.6 (q, J¼36.3 Hz),126.1 (q, J¼281.3 Hz),
33.5, 29.3, 25.0, 24.2; 19F NMR (470 MHz, CDCl3)
(KBr) 3275, 1706, 1658, 1217, 1129.
d
ꢁ70.68 (s, 3F); IR
4.3.13. 2-(4-Methoxyphenyl)-6-(trifluoromethyl)-4,5-dihydro-
pyridazin-3(2H)-one (7j)
n
Compound 7j was obtained as a colorless solid in 94% yield by
column chromatography (4:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 92–94 ꢀC; 1H NMR (500 MHz, CDCl3,
4.4. General procedure for the synthesis of indoles (11)
To a 100 mL three-necked round bottom flask equipped with
condenser and magnetic stir bar was added phenyl hydrazine
(2.7 mmol), methyl 6,6,6-trifluoro-5-oxohexanoate (2.7 mmol),
TsOH (0.27 mmol), and toluene (50 mL) under nitrogen atmo-
sphere, the solution was heated to 90 ꢀC and stirred for 24 h. Once
the reaction was completed, the precipitation was removed via
filtration, the residue was then carefully washed with ethyl
acetate for three times, the solvent was removed by rotary
evaporator. The residue was then purified by column chroma-
tography product 11.
ppm)
d
7.33 (d, 2H, J¼6.5 Hz, –ArH), 6.93 (d, 2H, J¼6.5 Hz, –ArH),
3.82 (s, 3H, –OCH3), 2.87 (t, 2H, J¼8.0 Hz, –CH2–), 2.80 (t, 2H,
J¼8.0 Hz, –CH2–); 13C NMR (125 MHz, CDCl3)
d 164.4, 158.7, 140.7
(q, J¼36.3 Hz), 133.1, 126.5, 120.3 (q, J¼271.3 Hz), 114.1, 55.5, 26.9,
20.3; 19F NMR (470 MHz, CDCl3)
d
ꢁ70.92 (s, 3F); IR (KBr)
n 3007,
2963, 1705, 1606, 1508, 1198, 1120, 834. Anal. Calcd for
C12H11F3N2O2 (272.08): C, 52.94; H, 4.07; N, 10.29. Found: C, 52.67;
H, 4.05; N, 10.10.
4.3.14. 6-(1,1,2,2,3,3-Hexafluoropropyl)-4,5-dihydropyridazin-
3(2H)-one (7l)
Compound 7l was obtained as a chocolate brown solid in 72%
yield by column chromatography (8:1 petroleum ether/ethyl ace-
tate) on neutral aluminum oxide: mp 105–107 ꢀC; 1H NMR
4.4.1. Methyl 3-(2-(trifluoromethyl)-1H-indol-3-yl)-
propanoate (11a)
Compound 11a was obtained as a pale yellow solid in 72% yield
by column chromatography (6:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 151–154 ꢀC; 1H NMR (500 MHz,
(500 MHz, CDCl3, ppm)
d
: 8.99 (s, 1H, –NH), 2.78 (t, 2H, J¼8.0 Hz,
–CH2–), 2.62 (t, 2H, J¼8.0 Hz, –CH2–); 13C NMR (125 MHz, CDCl3)
CDCl3, ppm)
d
8.38 (s, 1H, –NH), 7.68 (d, 1H, J¼8.0 Hz, –ArH), 7.41 (d,
d
164.4, 154.3 (t, J¼25.0 Hz), 121.5–111.4 (q, t, J¼286.3, 33.8 Hz),
1H, J¼8.0 Hz, –ArH), 7.33 (t, 1H, J¼7.5 Hz, –ArH), 7.20 (t, 1H,
113.5–110.4 (t, t, J¼257.5, 32.5 Hz), 109.3–106.7 (t, t, q, J¼267.5,
J¼8.0 Hz, –ArH), 3.68 (s, 3H, –OCH3), 3.26–3.22 (m, 2H, –CH2–), 2.67
32.5 Hz, J¼33.8 Hz), 26.9, 19.6; 19F NMR (470 MHz, CDCl3)
d
ꢁ80.12
(t, 2H, J¼8.0 Hz, –CH2–); 13C NMR (125 MHz, CDCl3)
d 173.8, 135.5,
(t, 3F, J¼9.4 Hz), ꢁ109.96 (q, 2F, J¼9.4 Hz), ꢁ125.24 (s, 2F); IR (KBr)
n
127.0, 124.9, 122.2 (q, J¼266.3 Hz), 121.9 (q, J¼36.3 Hz), 120.7, 120.0,
2995, 1813, 1381, 1359, 1228, 1022.
116.4 (q, J¼2.5 Hz), 112.0, 51.9, 35.4, 19.5; 19F NMR (CDCl3, 470 MHz,
ppm)
d
ꢁ58.44 (s, 3F); IR (KBr)
n 3363, 3031, 1718, 1592, 1570, 1115,
4.3.15. 6-(Difluoromethyl)-4,5-dihydropyridazin-3(2H)-one (7m)
742. Anal. Calcd for C13H12F3NO2 (271.24): C, 57.57; H, 4.46; N, 5.16.
Found: C, 57.34; H, 4.70; N, 5.07.
Compound 7m was obtained as a pale colorless solid in 82%
yield by column chromatography (4:1 petroleum ether/ethyl ace-
tate) on neutral aluminum oxide: mp 71–73 ꢀC; 1H NMR (500 MHz,
4.4.2. Methyl 4-(2-(trifluoromethyl)-1H-indol-3-yl)butanoate (11b)
Compound 11b was obtained as a yellow solid in 68% yield by
column chromatography (6:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 156–159 ꢀC; 1H NMR (500 MHz,
CDCl3, ppm)
d
9.81 (s, 1H, –NH), 6.13 (t,1H, J¼53.5 Hz, –CF2H–), 2.72
(t, 2H, J¼8.0 Hz, –CH2–), 2.60 (t, 2H, J¼8.0 Hz, –CH2–); 13C NMR
(125 MHz, CDCl3)
d
167.8, 146.3 (t, J¼31.3 Hz), 113.5 (t, J¼235.0 Hz),
25.4, 17.9; 19F NMR (470 MHz, CDCl3)
(KBr) 2978, 1714, 1648, 1202, 1143.
d
ꢁ119.38 (d, 2F, J¼51.7 Hz); IR
CDCl3, ppm) d 8.43 (s, 1H, –NH), 7.68–7.67 (m, 1H, –ArH), 7.39–7.37
n
(m, 1H, –ArH), 7.32–7.29 (m, 1H, –ArH), 7.20–7.16 (m, 1H, –ArH),
3.67 (s, 3H, –CH3), 2.96–2.93 (m, 2H, –CH2–), 2.93–2.40 (m, 2H,
–CH2–), 2.06–2.00 (m, 2H, –CH2–); 13C NMR (125 MHz, CDCl3)
4.3.16. 7-(Trifluoromethyl)-5,6-dihydro-2H-1,2-diazepin-3(4H)-
one (8)
Compound 8 was obtained as a pale colorless solid in 85% yield
by column chromatography (8:1 petroleum ether/ethyl acetate) on
neutral aluminum oxide: mp 102–105 ꢀC; 1H NMR (400 MHz,
d
174.2, 135.5, 127.4, 124.9, 122.2 (q, J¼266.3 Hz), 121.8 (q,
J¼24.0 Hz), 120.6, 120.4, 117.7 (q, J¼2.5 Hz), 111.9, 51.7, 33.6, 25.9,
23.2; 19F NMR (470 MHz, CDCl3)
2953, 1720, 1585, 1544, 1123, 751.
d
ꢁ58.15 (s, 3F); IR (KBr)
n 3341,
CDCl3, ppm)
d
8.61 (s, 1H, –NH), 2.70 (t, 2H, J¼7.2 Hz, –CH2–), 2.62
(t, 2H, J¼6.8 Hz, –CH2–), 2.22–2.15 (m, 2H, –CH2–); 13C NMR
4.4.3. 6-(Trifluoromethyl)pyridazin-3(2H)-one (12)
(400 MHz, CDCl3)
d
172.7, 150.7 (q, J¼33.8 Hz), 120.8 (q,
To a 100 mL three-necked round bottom flask equipped with
condenser and magnetic stir bar was added 6-(trifluoromethyl)-
4,5-dihydropyridazin-3(2H)-one (0.5 g, 3 mmol), and bromine
J¼273.7 Hz), 35.3, 27.6, 22.6; 19F NMR (470 MHz, CDCl3)
ꢁ71.55 (s,
d
3F); IR (KBr)
n 3258, 1712, 1645, 1237, 1131.

W. Wan et al. / Tetrahedron 65 (2009) 4212–4219
4219
(0.53 g, 3.3 mmol) in glacial acetic acid (50 mL) under nitrogen
atmosphere. Then the solution was heated to 80 ꢀC and refluxed for
1 h. Once the reaction was completed, the ice water (100 mL) was
added and extract with ethyl acetate (80 mL). Washed with satu-
rated sodium bicarbonate (150 mL) until pH¼7. The solvent was
removed by rotary evaporator. The residue was white powder, yield
in 95% yield by column chromatography (4:1 petroleum ether/ethyl
acetate) on neutral aluminum oxide: mp 80–81 ꢀC; 1H NMR
Calcd for C6H3F3N4 (188.11): C, 38.31; H, 1.61; N, 29.78. Found: C,
38.28; H,1.628; N, 29.49. MS (ESI): m/z 189.2 [MþH]þ; HRMS [Mþ1]
calcd for C6H3F3N4: 188.0310; found 188.0303.
Acknowledgements
This work has been financially supported by National Natural
Science Foundation of China (20772079), Science and Technology
Commission of Shanghai Municipality (07JC14020, 07ZR14040,
08JC1409900) and Shanghai Municipal Education Commission.
(500 MHz, CDCl3, ppm)
d
9.13 (s, 1H, –NH), 7.54 (d, 1H, J¼10.0 Hz,
–CH]), 7.14 (d, 1H, J¼10.0 Hz, –CH]); 13C NMR (125 MHz, CDCl3)
d
162.1, 137.4 (q, J¼37.5 Hz), 113.4, 129.5, 120.5 (q, J¼271.3 Hz); 19F
NMR (470 MHz, CDCl3)
1707, 1346, 848.
d
ꢁ67.41 (s, 3F); IR (KBr)
n 3134, 3079, 2978,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.03.029.
4.4.4. 3-Chloro-6-(trifluoromethyl)pyridazine (13)
To a 100 mL three-necked round bottom flask equipped with
condenser and magnetic stir bar was added 6-(trifluoromethyl)
pyridazin-3(2H)-one (0.5 g, 3 mmol), and phosphoryl trichloride
(1.84 g, 12 mmol), cyanide as solvent. Then the solution was heated
to 130 ꢀC and refluxed for 8 h. TLC traced. Once the reaction was
completed, excessive phosphoryl trichloride and cyanide were re-
moved by rotary evaporator. The ice water (50 mL) was added into
system and washed with saturated sodium bicarbonate (aq,
100 mL) until pH¼7 and extract with ethyl acetate. The solvent was
removed by rotary evaporator. The residue was red-brown powder,
yield 88% by column chromatography (10:1 petroleum ether/ethyl
acetate) on neutral aluminum oxide: mp 92–96 ꢀC; 1H NMR
References and notes
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(500 MHz, CDCl3, ppm)
d
7.92 (d, 1H, J¼9.0 Hz, –CH]), 7.85 (d, 1H,
J¼9.0 Hz, –CH]); 13C NMR (125 MHz, CDCl3)
d 159.7, 151.0 (q,
J¼35.0 Hz), 129.6, 126.2 (d, J¼1.3 Hz), 121.1 (q, J¼272.5 Hz); 19F
NMR (470 MHz, CDCl3)
1571, 868.
d
ꢁ66.86 (s, 3F); IR (KBr)
n 3063, 2962, 2011,
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4.4.5. 3-Hydrazinyl-6-(trifluoromethyl)pyridazine (14)
To a 100 mL three-necked round bottom flask equipped with
condenser and magnetic stir bar was added 3-chloro-6-(tri-
fluoromethyl)pyridazine (0.5 g, 2.7 mmol) with hydrazine hy-
drate(85%) (0.32 g, 5.5 mmol), potassium carbonate (20 mol %), THF
as solvent. Then the solution was heated to 130 ꢀC and refluxed for
8 h, TLC traced. Once the reaction was completed, THF removed by
rotary evaporator. The product was chocolate brown solid, yield
90% by column chromatography (1:4 methanol/ethyl acetate) on
neutral aluminum oxide: mp 102–104 ꢀC; 1H NMR (500 MHz,
DMSO, ppm)
d
8.82 (s, 1H, –NH), 7.71 (d, 1H, J¼8.5 Hz, –CH]), 7.16
(d, 1H, J¼8.5 Hz, –CH]), 4.53 (s, 2H, –NH2); 13C NMR (125 MHz,
DMSO)
d
164.2, 141.8 (q, J¼32.5 Hz), 125.2, 123.0 (q, J¼271.3 Hz),
111.8; 19F NMR (470 MHz, DMSO)
d
ꢁ66.19 (s, 3F); IR (KBr)
n 3455,
1607,1354, 1184, 1135, 852, 588. MS (ESI): m/z 179.0 [MþH]þ; HRMS
[Mþ1] calcd for: C5H5F3N4: 178.0466; found 178.0455.
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175–186; (b) Breukelman, S. P.; Meakins, G. D.; Roe, A. M. J. Chem. Soc., Perkin
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4.4.6. 6-(Trifluoromethyl)-7H-pyrazolo[4,3]pyridazine (15)
To a 100 mL three-necked round bottom flask equipped with
condenser and magnetic stir bar was added 3-hydrazinyl-6-(tri-
fluoromethyl)pyridazine (0.5 g, 2.8 mmol) with trimethoxy-
methane (0.89 g, 8.4 mmol), 5 mol % TsOH, methanol as solvent.
Then the solution was heated to 80 ꢀC and refluxed for 36 h, TLC
traced. Once the reaction was completed, the system was washed
by ethyl acetate (80 mL) then filtered. The filtrate was collected
then removed solvent by rotary evaporator. The product was yellow
solid, yield 85% by column chromatography (6:1 petroleum ether/
ethyl acetate) on neutral aluminum oxide: mp 112–113 ꢀC; 1H NMR
(500 MHz, CDCl3, ppm)
d 9.31 (s, 1H, –CH]N–), 8.44 (d, 1H,
J¼9.5 Hz, –CH]), 7.49 (d, 1H, J¼9.5 Hz, –CH]); 13C NMR (125 MHz,
CDCl3)
d
145.7 (q, J¼37.5 Hz), 142.9, 139.2, 127.2, 120.0 (q,
15. (a) Albright, J. D.; Moran, D. B.; Wright, W. B.; Collins, J. B.; Beer, B.; Lippa, A. S.;
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J. Org. Chem. 1980, 45, 2320–2324.
J¼273.8 Hz), 116.8; 19F NMR (470 MHz, CDCl3)
d
ꢁ67.25 (s, 3F); IR
(KBr)
n 3095, 3065, 3043, 2986, 1543, 1387, 1199, 1153, 840. Anal.