Mild and direct access to 7-substituted-4-trifluoromethylpyrimido[1,2- b ]pyridazin-2-one systems

Article abstract of DOI:10.1055/s-0033-1340664

New and efficient methods for the synthesis of 7-substituted-4- trifluoromethylpyrimido[1,2-b]pyridazin-2-one derivatives using either two-step Suzuki/heterocyclization, or two-step heterocyclization/substitution sequences are developed. A variety of substituted products are obtained in good to excellent yields from 3-amino-6-chloropyridazine and ethyl 4,4,4-trifluorobut-2- ynoate. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340664

PAPER
▌947
paper
Mild and Direct Access to 7-Substituted-4-trifluoromethylpyrimido[1,2-b]py-
ridazin-2-one Systems
Direct Access to Pyrimido[1,2-b]pyridazin-2-ones
Julien Petrignet, Emilie Thiery, Laurence Silpa, Mohamed Abarbri*
Laboratoire d’Infectiologie et Santé Publique (UMR Université François Rabelais/INRA 1282), Université François Rabelais,
Faculté des Sciences, Parc de Grandmont, 37200 Tours, France
Fax +33(2)47367073; E-mail: mohamed.abarbri@univ-tours.fr
Received: 18.11.2013; Accepted after revision: 20.12.2013
heterocyclic pattern of biological interest is therefore like-
Abstract: New and efficient methods for the synthesis of 7-substi-
ly to have a valuable effect and might improve the biolog-
ical activity. We report here a very straightforward and
mild method for the preparation of trifluoromethylated
tuted-4-trifluoromethylpyrimido[1,2-b]pyridazin-2-one
tives using either two-step Suzuki/heterocyclization, or two-step
heterocyclization/substitution sequences are developed. A variety
deriva-
of substituted products are obtained in good to excellent yields from pyrimido[1,2-b]pyridazin-2-ones functionalized with var-
3-amino-6-chloropyridazine and ethyl 4,4,4-trifluorobut-2-ynoate.
ious substituents at position 7.
Key words: ethyl 4,4,4-trifluorobutynoate, aminopyridazine, het-
erocyclization,
Suzuki reaction
trifluoromethylpyrimido[1,2-b]pyridazin-2-one,
N
O
N
O
N
N
F
F
N
N
The pyrimido[1,2-b]pyridazin-2-one system has been de-
scribed as a valuable N-heterocyclic family of compounds
for use in various pharmacological areas. As an example
of bioactive molecules with this fused ring system, com-
pound 1 has been reported to be a potent and selective in-
hibitor of serine protease dipeptyl peptidase IV (DPP-4),
a novel therapeutic target for the treatment of type 2 dia-
betes.1 Compound 2 was found to be an allosteric inhibitor
of activation of serine threonine kinase (AKT), a studied
pathway for many cancer treatments.2 Mesoionic com-
pound 3 has also been tested as a potential inhibitor of the
Wnt signaling pathway, as a representative of a family of
glycoproteins involved in some types of tumors (Figure
1).3
N
NH3+ TFA–
NH2
F
2
1
Cl
N
O
N
N
pyrimido[1,2-b]pyridazin-2-one
N
O
N
Cl
N
O
3
The first access to a pyrimido[1,2-b]pyridazin-2-one was
reported in 1971 by Pilgram et al.4 Products 4 were ob-
tained via a two-step process involving the condensation
of 3-amino-6-chloropyridazine with β-chloroacrylic acid
derivatives, followed by cyclization carried out in xylene
at reflux temperature. In 1983, Mátyus et al. reported a
one-step access to compound 5 by direct condensation of
a substituted 3-aminopyridazine with methyl propiolate or
dimethyl acetylenedicarboxylate in refluxing ethanol
(Scheme 1).5–7 The latter is currently the most commonly
used method for the preparation of the pyrimido[1,2-
b]pyridazin-2-one core.
Figure 1 Examples of bioactive pyrimido[1,2-b]pyridazin-2-ones
R1
R2
OH(Cl)
1)
N
O
Cl
O
DMF, 70 °C
N
Cl
N
R1
2) xylene, 145 °C
70–84%
R2
4
R1 = Cl, H, 2,4-Cl2C6H3
R2 = Cl, H
NH2
N
It has been demonstrated that the incorporation of a triflu-
oromethyl (CF3) group into organic compounds can play
an important role in the search for new active pharmaceu-
tical compounds.8 Indeed, the trifluoromethyl moiety is
known to influence metabolic stability, binding activity
and lipophilicity.9,10 The introduction of such a group to a
X
N
X = H, Cl, Mph,
Me, CONH2
N
O
R3
CO2Me
N
X
N
EtOH, reflux
10–54%
R3
5
R
3 = H, CO2Me
SYNTHESIS 2014, 46, 0947–0954
Advanced online publication: 30.01.2014
DOI: 10.1055/s-0033-1340664; Art ID: SS2013-Z0751-OP
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Reported procedures for the preparation of pyrimido[1,2-
b]pyridazin-2-ones; Mph = morpholino
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

948
J. Petrignet et al.
PAPER
Our group has developed various methods utilizing ethyl mation of the corresponding pyrido[1,2-a]pyrimidin-2-
4,4,4-trifluorobut-2-ynoate (6), a small and simple build- ones.19
ing block, which presents unusual reactivity due to the
As product 7 bears a reactive carbon–chloride bond at po-
presence of the trifluoromethyl group. This commercially
sition 7, it seemed important to us to test the reactivity of
available but expensive alkyne can be prepared on multi-
this bond in order to achieve further transformations. The
gram scale using a well-known procedure.11 Its synthetic
literature reports one example of a Suzuki–Miyaura cross-
potential as a very electron-deficient alkyne has been ex-
coupling of a 7-chloropyrimido[1,2-b]pyridazin-2-one
plored in hydroiodation12,13 and hydrostannation process-
core, as a step involved in the synthesis of compound 2.2
es, followed by palladium-free cross-coupling
Typical Suzuki cross-coupling conditions were therefore
reactions.14,15 The addition of primary and secondary
employed on our substrate, using phenylboronic acid as
the coupling agent. In each case, the starting material was
completely recovered despite the use of high temperatures
and long reaction times.
amines to alkyne 6 was also performed under very mild
conditions, yielding the corresponding (E)- or (Z)-per-
fluorinated β-enaminoesters in a totally stereoselective
manner.16,17
An alternative strategy was therefore employed to prepare
the desired pyrimido[1,2-b]pyridazin-2-ones functional-
ized with an aryl group at position 3. As the literature de-
As a result of its enhanced reactivity, we initially decided
to explore the reaction between alkyne 6 and 3-amino-6-
chloropyridazine, using similar, but milder conditions
scribes several examples of Suzuki–Miyaura cross-
than those reported by Mátyus.5 The reaction was there-
coupling reactions of 3-amino-6-chloropyridazine with
fore performed in ethanol at room temperature employing
aryl boronic acids,20–23 various 3-amino-6-arylpyridazines
a slight excess of 6. This led to the formation of the ex-
8 were prepared using similar reaction conditions
pected product, 7-chloro-4-trifluoromethylpyrimido[1,2-
(Scheme 3). The reactions were performed in a mixture of
1,2-dimethoxyethane and water with tetrakis(triphe-
nylphosphine)palladium(0) [Pd(PPh3)4] (2 mol%) as the
b]pyridazin-2-one (7) in 70% yield (Scheme 2). More-
over, the reaction proceeded very cleanly, and the desired
product was obtained as a solid in pure form after filtra-
catalyst and sodium carbonate (2 equiv) as the base. Prod-
tion. Indeed, no trace of the formation of a five-membered
ucts 8a–h were isolated in 42–54% overall yields. These
moderate results may be explained by the presence of the
ring18 or the regioisomeric pyrimido[1,2-b]pyridazin-4-
one were observed. It is noteworthy that similar reactivity
free amino group.
was observed by Harriman et al. during the condensation
In the next step, 3-amino-6-arylpyridazines 8 were trans-
of 2-aminopyridines and alkynoate 6, leading to the for-
formed into the corresponding trifluoromethylpyrimi-
do[1,2-b]pyridazin-2-ones 9a–h. The reactions were
performed in ethanol at room temperature using a slight
excess of ethyl 4,4,4-trifluorobut-2-ynoate (6) (1.1 equiv).
The conversion was found to be complete after 16 hours
and the desired products were obtained in good overall
yields (60–78%). The results are summarized in Table 1.
F3C
CO2Et
N
O
NH2
6
N
N
EtOH
20 °C, 16 h
Cl
N
Cl
N
CF3
7 (70%)
As already observed for compound 7, this step proceeded
very cleanly and all the products were isolated by simple
Scheme 2 Preparation of 7-chloro-4-trifluoromethylpyrimido[1,2-
b]pyridazin-2-one (7)
ArB(OH)2
Na2CO3, Pd(PPh3)4
NH2
NH2
N
N
DME–H2O (2:1)
90 °C, 48 h
Cl
N
Ar
N
8
NH2
NH2
NH2
NH2
N
N
N
N
N
N
N
N
Cl
F
MeO
8a (51%)
8b (52%)
8c (51%)
8d (42%)
NH2
NH2
NH2
NH2
N
N
N
N
N
N
N
N
O
O
S
8g (54%)
8f (48%)
8h (48%)
NO2
8e (42%)
Scheme 3 Preparation of 3-amino-6-arylpyridazines 8
Synthesis 2014, 46, 947–954
© Georg Thieme Verlag Stuttgart · New York

PAPER
Direct Access to Pyrimido[1,2-b]pyridazin-2-ones
949
Table 1 Condensation of Alkyne 6 and 3-Amino-6-arylpyridazines 8a
7 position of substrate 7 to provide the desired products
10a–g in good yields (Table 2, entries 1–7).
NH2
N
O
6 (1.1 equiv)
Table 2 Nucleophilic Substitution of 7-Chloro-4-trifluoromethyl-
pyrimido[1,2-b]pyridazin-2-one (7)a
N
N
EtOH
20 °C, 16 h
Ar
N
8
Ar
N
CF3
NuH (1.2 equiv)
9
N
O
N
O
Et3N (5 equiv)
Yield (%)b
74
N
Entry Substrate Product
N
EtOH
Nu
N
Cl
N
reflux, 16 h
CF3
CF3
N
O
10
7
N
1
8a
9a
N
Entry Nucleophile
Product
Yield
(%)b
CF3
N
N
O
N
O
N
N
2
3
4
8b
8c
8d
9b
9c
9d
78
74
60
N
N
N
N
1
63
NH2
H
CF3
CF3
Cl
N
O
10a
O
N
N
NH2
CF3
N
N
2
3
4
72
45
55
F
H
CF3
N
N
O
10b
N
O
N
CF3
N
MeO
N
N
NH2
H
N
O
CF3
N
N
10c
N
5
8e
9e
65
O
CF3
HO
N
NH2
NO2
N
N
HO
H
CF3
N
O
10d
N
6
7
8f
9f
68
71
N
N
O
CF3
N
S
N
O
N
N
5
98
NH
CF3
N
N
8g
9g
N
10e
10f
O
CF3
N
O
N
O
N
N
N
NH
6
7
75
64
8
8h
9h
71
N
CF3
N
O
CF3
a Reaction conditions: 3-amino-6-arylpyridazine 8 (1.24 mmol), ethyl
4,4,4-trifluorobutynoate (6) (1.37 mmol), 20 °C, EtOH (2 mL), 16 h.
b Yield of isolated product.
O
N
N
N
O
NH
O
CF3
10g
filtration. Various aryl and heteroaryl groups were tolerat-
ed in this reaction.
8c
9c
–
–
0
0
NH
Next, we continued our investigations in order to synthe-
size new pyrimido[1,2-b]pyridazin-2-one derivatives by
SNAr displacement of the chloride moiety. Indeed, various
amines (as shown in Table 2) were incorporated at the C-
NH2
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 947–954

950
J. Petrignet et al.
PAPER
Table 2 Nucleophilic Substitution of 7-Chloro-4-trifluoromethyl-
pyrimido[1,2-b]pyridazin-2-one (7)a (continued)
Additionally, we attempted to prepare compounds 10 us-
ing a one-pot procedure starting from 3-amino-6-chloro-
pyridazine and ethyl 4,4,4-trifluorobut-2-ynoate (6).
Indeed, the condensation of 3-amino-6-chloropyridazine
and 6, performed under the same conditions as those de-
scribed above, followed by in situ addition of previously
employed representative nucleophiles (i.e., primary and
secondary amines and a thiol), led to the formation of
compounds 10a, 10f and 10h in yields comparable to
those obtained via the two-step procedure (Table 3).
NuH (1.2 equiv)
Et3N (5 equiv)
N
O
N
O
N
N
EtOH
reflux, 16 h
Nu
N
Cl
N
CF3
CF3
10
7
Entry Nucleophile
Product
Yield
(%)b
N
O
Table 3 One-Pot Procedure for the Preparation of Compounds 10a,
10f and 10ha
N
S
N
10
82
SH
6 (1.1 equiv), 10 h, then
NuH (1.3 equiv), Et3N (5 equiv)
NH2
N
O
CF3
N
10h
N
N
EtOH
20 °C to reflux, 16 h
Cl
N
Nu
N
Br
O
CF3
Br
10
N
S
N
11
90
SH
Entry
1
Nucleophile
Product
Yield (%)b,c
44 (44)
CF3
10i
10a
10f
NH2
a Reaction conditions: 7 (0.4 mmol), NuH (0.48 mmol), Et3N
(2 mmol), EtOH (10 mL), reflux, 16 h.
b Yield of isolated product.
NH
2
3
48 (52)
53 (57)
c Starting material was recovered.
SH
10h
As shown in Table 2, treatment of compound 7 with n-bu-
tylamine provided amino-pyrimido[1,2-b]pyridazin-2-
one 10a in 63% yield (Table 2, entry 1), whilst reaction
a Reaction conditions: 2-chloroaminopyridazine (0.5 mmol), ethyl
4,4,4-trifluorobutynoate (6) (0.55 mmol), EtOH (1 mL), 20 °C, 10 h,
then NuH (0.65 mmol), Et3N (2.5 mmol), EtOH (3 mL), 70 °C, 16 h.
with allylamine provided 10b in 72% yield under the b Yield of isolated product.
c Yield in brackets corresponds to that obtained via the two-step pro-
same reaction conditions (Table 2, entry 2). However,
treatment of 7 with propargylamine, under the standard
conditions, provided the expected product 10c, but only in
45% yield (Table 2, entry 3). It is also interesting to note
that an unprotected β-aminoalcohol provided only the N-
amination reaction product in a reasonable yield (Table 2,
entry 4). Reaction of pyridazin-2-one 7 with pyrrolidine
gave 7-(pyrrolidin-1-yl)-4-trifluoromethylpyrimido[1,2-
b]pyridazin-2-one (10e) in very high yield (Table 2, entry
5), and a similar reaction with piperidine provided 10f in
75% yield (Table 2, entry 6). Morpholine also afforded
the expected product (10g) in an acceptable 64% yield.
However, an aromatic amine (aniline) showed no reactiv-
ity in the amination reaction (Table 2, entry 9). These re-
sults demonstrate that the nucleophilicity of the amine
was a crucial parameter in this substitution reaction. Like-
wise, the hindered amine, diisopropylamine, was found to
be unreactive (Table 2, entry 8), despite heating the reac-
tion at a higher temperature (100 °C, DMF).
cedure.
The flexibility of our strategy allows the synthesis of a li-
brary of new fluorinated pyrimido[1,2-b]pyridazin-2-ones
under mild and simple conditions. This work demonstrat-
ing nucleophilic addition reactions shows that an SNAr
displacement with 7-chloro-4-trifluoromethylpyrimi-
do[1,2-b]pyridazin-2-one (7) offers a simple route to dif-
ferent 7-substituted 4-trifluoromethylpyrimido[1,2-
b]pyridazin-2-ones 10.
In summary, we have developed a practical and general
method for the straightforward access to an important
range of 4-trifluoromethylated 7-substituted pyrimi-
do[1,2-b]pyridazin-2-ones using two different approach-
es. The first involves direct condensation of various 3-
amino-6-arylpyridazines with ethyl 4,4,4-trifluorobut-2-
ynaote (6), and the second proceeds via an efficient SNAr
displacement reaction of the chloride at position 7 of the
substrate. The overall yields were good to excellent. The
process holds promise as a valuable tool for the construc-
tion of complex heterocycles. This versatile strategy is be-
ing applied to the production of a wide range of
compounds that are currently under biological evaluation,
in particular as a new group of anticoccidian drugs.
In contrast to aromatic amines, thiophenols were found to
be reactive, providing the desired products 10h and 10i in
excellent yields (Table 2, entries 10 and 11). These sulfur-
containing compounds may have valuable synthetic po-
tential and would appear to be worthy intermediates for
future investigations to synthesize, for example, new tet-
racyclic compounds.
Synthesis 2014, 46, 947–954
© Georg Thieme Verlag Stuttgart · New York

PAPER
Direct Access to Pyrimido[1,2-b]pyridazin-2-ones
951
All reactions were carried out under an argon atmosphere. Absolute
EtOH and DME were obtained from commercial sources and were
used without further purification. Et3N was distilled from KOH. Pe-
troleum ether (PE) refers to the fraction boiling in the 40–60 °C
range. Column chromatography was performed using Merck silica
gel (40–63 m) or Merck neutral aluminum oxide (150 mesh). TLC
was performed using Merck silica gel sheets, and spots were made
visual under UV light. Melting points were obtained using a Stuart
SMP3 melting point apparatus. IR spectra were recorded on a Per-
3-Amino-6-(4-fluorophenyl)pyridazine (8c)25
The product was purified by chromatography on neutral aluminum
oxide using CH2Cl2–MeOH (99:1) as the eluent.
Yield: 193 mg (51%); yellow solid; mp 167–169 °C.
IR (neat): 3409–3105, 1641, 1598, 1446, 1134–1017, 832 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.95 (dd, J = 9.0 Hz, 3.6 Hz, 2 H),
7.62 (d, J = 9.3 Hz, 1 H), 7.18 (t, J = 8.7 Hz, 2 H), 6.85 (d, J = 9.3
Hz, 1 H), 4.81 (s, 2 H).
13C NMR (75 MHz, CDCl3): δ = 163.4 (d, J = 247 Hz), 158.3,
151.7, 133.0 (d, J = 4 Hz), 127.9 (d, J = 8 Hz, 2 C), 125.8, 115.8 (d,
J = 22 Hz, 2 C), 114.8.
1
kin-Elmer ATR spectrophotometer. H (300 MHz), 13C (75 MHz)
and 19F (282 MHz) NMR spectra were obtained using a Bruker
Avance 300 spectrometer. Chemical shifts are given in parts per
million (δ) relative to the residual chloroform (7.26 ppm) or dimeth-
yl sulfoxide (2.50 ppm) signals. Electrospray ionization high-reso-
lution mass spectrometry experiments (HRMS) were run on a
hybrid tandem quadrupole/time-of-flight (Q-TOF) instrument,
equipped with a pneumatically-assisted electrospray (Z-spray) ion
source (Micromass, Manchester, UK) operating in positive mode.
3-Amino-6-(4-methoxyphenyl)pyridazine (8d)25
The product was purified by chromatography on neutral aluminum
oxide using CH2Cl2–MeOH (99:1) as the eluent.
Yield: 167 mg (42%); yellow solid; mp 138–140 °C.
IR (neat): 3410–3292, 3095, 2958, 1644, 1600, 1509, 1452, 1246
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 9.0 Hz, 2 H), 7.62 (d,
J = 9.3 Hz, 1 H), 7.02 (d, J = 9.0 Hz, 2 H), 6.83 (d, J = 9.3 Hz, 1 H),
4.65 (s, 2 H), 3.88 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 160.3, 158.1, 152.3, 129.4, 127.4
(2 C), 125.6, 114.9, 114.2 (2 C), 55.3.
3-Amino-6-chloropyridazine24
A solution of 3,6-dichloropyridazine (16 g, 107 mmol) in an aq so-
lution of NH3 (25% w/w, 160 mL) was heated in a sealed tube at
150 °C for 4 h. After cooling to r.t., the solution was stirred for an
additional 12 h. The mixture was filtered and the solid washed with
H2O (2 × 60 mL) and dried under reduced pressure to afford the
product.
Yield: 9.7 g (78%); beige solid; mp 234–235 °C.
IR (KBr): 3351, 3290, 3161, 1644, 1457 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 7.35 (br s, 1 H), 6.83 (br s, 1
3-Amino-6-(3-nitrophenyl)pyridazine (8e)26
The product was purified by chromatography on neutral aluminum
oxide using Et2O–MeOH (94:6) as the eluent.
H), 6.62 (br s, 2 H).
Yield: 181 mg (42%); yellow solid; mp 194–196 °C.
13C NMR (100 MHz, DMSO-d6): δ = 160.7, 145.5, 129.4, 118.0.
IR (neat): 3459–3127, 3095, 1632, 1522, 1347, 1187, 1137, 1095
cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.80 (t, J = 1.8 Hz, 1 H), 8.41
(ddd, J = 8.0 Hz, 1.8 Hz, 0.9 Hz, 1 H), 8.24 (ddd, J = 8.1 Hz, 2.1 Hz,
0.9 Hz, 1 H), 7.99 (d, J = 9.3 Hz, 1 H), 7.77 (t, J = 8.1 Hz, 1 H), 6.89
(d, J = 9.3 Hz, 1 H), 6.72 (s, 2 H).
Suzuki–Miyaura Cross-Coupling; General Procedure
A reaction tube filled with Ar was loaded with 3-amino-6-chloro-
pyridazine (260 mg, 2 mmol), boronic acid (2.4 mmol, 1.2 equiv),
Pd(PPh3)4 (46 mg, 0.04 mmol, 0.02 equiv) and DME (2 mL).
Na2CO3 (424 mg, 4 mmol, 2 equiv) dissolved in H2O (1 mL) was
added. The tube was sealed and the mixture heated for 2 d at 90 °C.
After cooling, the mixture was diluted with H2O (15 mL) and the aq
layer extracted with CH2Cl2 (3 × 15 mL). The organic layers were
combined, dried over MgSO4, filtered and concentrated under re-
duced pressure. The residue was purified by flash column chroma-
tography on silica gel or neutral aluminum oxide.
13C NMR (75 MHz, CDCl3): δ = 160.8, 148.9, 148.1, 139.2, 131.9,
130.8, 126.1, 123.2, 119.9, 114.5.
3-Amino-6-(thiophen-3-yl)pyridazine (8f)25
The product was purified by chromatography on silica gel using
CH2Cl2–MeOH (95:5) as the eluent.
Yield: 170 mg (48%); yellow solid; mp 150–151 °C.
3-Amino-6-phenylpyridazine (8a)25
The product was purified by chromatography on silica gel using
EtOAc–PE (95:5) as the eluent.
1H NMR (300 MHz, CDCl3): δ = 7.83 (dd, J = 3.0 Hz, 1.3 Hz, 1 H),
7.75 (dd, J = 5.1 Hz, 1.3 Hz, 1 H), 7.62 (d, J = 9.1 Hz, 1 H), 7.45
(dd, J = 5.1 Hz, 3.0 Hz, 1 H), 6.85 (d, J = 9.0 Hz, 1 H), 4.87 (s, 2 H).
13C NMR (75 MHz, CDCl3): δ = 158.7, 150.0, 139.9, 127.1, 126.5,
126.4, 122.7, 115.3.
Yield: 174 mg (51%); yellow solid; mp 142–143 °C.
1H NMR (300 MHz, CDCl3): δ = 7.98 (m, 2 H), 7.69 (d, J = 9.2 Hz,
1 H), 7.57–7.45 (m, 3 H), 4.94 (d, J = 9.2 Hz, 1 H), 5.06 (s, 2 H).
3-Amino-6-(furan-2-yl)pyridazine (8g)25
The product was purified by chromatography on silica gel using
CH2Cl2–MeOH (97:3) as the eluent.
13C NMR (75 MHz, CDCl3): δ = 159.1, 153.1, 137.3, 129.5 (3 C),
126.9, 126.8 (2 C), 115.7.
3-amino-6-(4-chlorophenyl)pyridazine (8b)25
The product was purified by chromatography on neutral aluminum
oxide using Et2O–MeOH (95:5) as the eluent.
Yield: 174 mg (54%); yellow solid; mp 131–132 °C.
IR (neat): 3313, 3154, 1640, 1463, 1158, 1008 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 7.80–7.75 (m, 1 H), 7.63 (d,
J = 9.2 Hz, 1 H), 6.98–6.85 (m, 1 H), 6.84 (d, J = 9.2 Hz, 1 H), 6.64–
6.60 (m, 1 H), 6.58 (s, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 160.5, 152.5, 144.5, 144.1,
124.8, 114.9, 112.9, 107.1.
Yield: 213 mg (52%); yellow solid; mp 177–179 °C.
IR (neat): 3407–3274, 3109–3059, 1592–1487, 1186, 1138, 1093,
1037, 1018 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.92 (d, J = 6.8 Hz, 2 H), 7.63 (d,
J = 9.3 Hz, 1 H), 7.46 (d, J = 6.8 Hz, 2 H), 6.85 (d, J = 9.3 Hz, 1 H),
4.85 (s, 2 H).
13C NMR (75 MHz, CDCl3): δ = 158.6, 151.5, 135.2, 134.9, 129.0,
127.3, 125.7, 114.6.
3-Amino-6-(benzofuran-2-yl)pyridazine (8h)
The product was purified by chromatography on neutral aluminum
oxide using Et2O–MeOH (95:5) as the eluent.
Yield: 203 mg (48%); yellow solid; mp 214–216 °C.
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IR (neat): 3460–3130, 1629, 1594, 1160, 1120, 1083 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C14H8F4N3O: 310.0604;
found: 310.0596 (0.6 ppm).
1H NMR (300 MHz, DMSO-d6): δ = 7.81 (d, J = 9.2 Hz, 1 H), 7.70–
7.62 (m, 2 H), 7.43 (s, 1 H), 7.34–7.27 (m, 2 H), 6.88 (d, J = 9.2 Hz,
1 H), 6.78 (s, 2 H).
7-(4-Methoxyphenyl)-4-(trifluoromethyl)-2H-pyrimido[1,2-
b]pyridazin-2-one (9d)
Yield: 117 mg (60%); white solid; mp 277–279 °C.
13C NMR (75 MHz, DMSO-d6): δ = 160.1, 154.3, 153.7, 143.2,
128.6, 125.0, 124.8, 123.4, 121.4, 113.8, 111.3, 102.2.
HRMS (ESI): m/z [M + H]+ calcd for C12H10N3O: 212.0824; found:
IR (neat): 3079, 2961–2839, 1650, 1606, 1551–1477, 1328, 1234
cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 8.35 (d, J = 9.8 Hz, 1 H), 8.03
(d, J = 9.0 Hz, 2 H), 7.79 (d, J = 9.8 Hz, 1 H), 7.17 (d, J = 9.0 Hz, 2
H), 7.04 (s, 1 H), 3.85 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 166.7, 162.3, 149.8, 149.6,
138.3 (q, J = 35 Hz), 133.4, 128.9 (2 C), 128.0, 125.2, 119.1 (q, J =
273 Hz), 116.3 (q, J = 3 Hz), 115.2 (2 C), 55.9.
19F NMR (282 MHz, DMSO-d6): δ = –64.8.
HRMS (ESI): m/z [M + H]+ calcd for C15H11F3N3O2: 322.0803;
212.0817 (0.5 ppm).
Cyclization; General Procedure
To a solution of a 3-aminopyridazine 8 (1 equiv) in absolute EtOH
was added dropwise ethyl 4,4,4-trifluorobutynoate (6) (1.1 equiv).
The mixture was stirred at r.t. for 1 h, after which an additional por-
tion of 6 (0.5 equiv) was added and the reaction was stirred over-
night. The solvent was evaporated in vacuo and the resulting solid
washed with Et2O to afford the expected pyrimido[1,2-b]pyridazin-
2-one.
found: 322.0799 (0.6 ppm).
7-Chloro-4-(trifluoromethyl)-2H-pyrimido[1,2-b]pyridazin-2-
one (7)
7-(3-Nitrophenyl)-4-(trifluoromethyl)-2H-pyrimido[1,2-b]pyr-
idazin-2-one (9e)
Yield: 1.35 g (70%); white solid; mp 235–236 °C.
Yield: 96 mg (65%); yellow solid; mp 238–240 °C.
IR (neat): 3040, 1653, 1601, 1482, 1240 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 7.87 (d, J = 9.7 Hz, 1 H), 7.81
(d, J = 9.7 Hz, 1 H), 7.06 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 166.4, 149.6, 146.0, 137.9 (q,
J = 35 Hz), 136.0, 131.8, 119.4 (q, J = 274 Hz), 116.2 (q, J = 4 Hz).
19F NMR (282 MHz, DMSO-d6): δ = –65.10 (s).
IR (neat): 3160, 1660, 1552–1494, 1353, 1199–1107 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 8.85 (s, 1 H), 8.54–8.44 (m, 3
H), 7.96–7.91 (m, 2 H), 7.13 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 166.7, 149.9, 149.0, 148.5,
138.3 (q, J = 35 Hz), 134.8, 134.1, 133.5, 131.6, 128.3, 126.2,
121.9, 119.1 (q, J = 273 Hz), 116.8 (q, J = 3 Hz).
19F NMR (282 MHz, DMSO-d6): δ = –64.8.
HRMS (ESI): m/z [M + H]+ calcd for C14H8F3N4O3: 337.0549;
HRMS (ESI): m/z [M + H]+ calcd for C8H4ClF3N3O: 249.9995;
found: 249.9987 (1 ppm).
found: 337.0541 (0.5 ppm).
7-Phenyl-4-(trifluoromethyl)-2H-pyrimido[1,2-b]pyridazin-2-
one (9a)
7-(Thien-3-yl)-4-(trifluoromethyl)-2H-pyrimido[1,2-b]pyrid-
azin-2-one (9f)
Yield: 183 mg (68%); white solid; mp 284–286 °C.
IR (neat): 3063, 1651, 1553–1480, 1234, 1153–1134 cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.76 (dd, J = 2.8 Hz, 1.2 Hz, 1 H),
7.82 (d, J = 9.5 Hz, 1 H), 7.69 (d, J = 9.5 Hz, 1 H), 7.67 (dd, J = 5.2
Hz, 1.2 Hz, 1 H), 7.51 (dd, J = 5.2 Hz, 2.8 Hz, 1 H), 7.02 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 166.8, 149.0, 146.8, 139.1 (q, J =
35 Hz), 135.0, 133.3, 128.2, 127.5, 127.4, 125.6, 119.1 (q, J = 274
Hz), 116.4 (q, J = 3 Hz).
Yield: 54 mg (74%); white solid; mp 303–305 °C.
IR (neat): 3067, 1651, 1603, 1548–1441 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.96–7.92 (m, 3 H), 7.75 (d, J =
9.7 Hz, 1 H), 7.59–7.57 (m, 3 H), 7.05 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 166.8, 150.7, 149.1, 139.2 (q, J =
35 Hz), 133.5, 132.3, 131.8, 129.6 (2 C), 127.1, 126.9 (2 C), 119.1
(q, J = 273 Hz), 116.6 (q, J = 3 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C14H9F3N3O: 292.0698;
found: 292.0690 (0.7 ppm).
HRMS (ESI): m/z [M + H]+ calcd for C12H7F3N3OS: 298.0262;
found: 298.0255 (0.4 ppm).
7-(4-Chlorophenyl)-4-(trifluoromethyl)-2H-pyrimido[1,2-
b]pyridazin-2-one (9b)
Yield: 142 mg (78%); white solid; mp 302–304 °C.
7-(Furan-2-yl)-4-(trifluoromethyl)-2H-pyrimido[1,2-b]pyrid-
azin-2-one (9g)
Yield: 166 mg (71%); white solid; mp 297–299 °C.
IR (neat): 3070, 1659, 1605, 1545–1478, 1165–1139 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.91–7.87 (m, 3 H), 7.75 (d, J =
9.7 Hz, 1 H), 7.55 (d, J = 8.7 Hz, 2 H), 7.06 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 166.7, 149.7, 148.9, 139.2 (q, J =
35 Hz), 138.4, 133.7, 130.7, 129.9 (2 C), 128.1 (2 C), 126.7, 119.1
(q, J = 273 Hz), 116.7 (q, J = 3 Hz).
IR (neat): 3099–3065, 1652, 1606, 1578–1463, 1148, 1068, 1012
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.88 (d, J = 9.7 Hz, 1 H), 7.70–
7.67 (m, 2 H), 7.22 (dd, J = 3.6 Hz, 0.6 Hz, 1 H), 7.01 (s, 1 H), 6.65
(dd, J = 3.6 Hz, 1.8 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C14H8ClF3N3O: 326.0308;
13C NMR (75 MHz, CDCl3): δ = 166.7, 148.9, 147.1, 146.2, 143.3,
139.1 (q, J = 35 Hz), 133.2, 125.9, 119.0 (q, J = 274 Hz), 116.4 (q,
J = 3 Hz), 113.2, 113.1.
found: 326.0301 (0.4 ppm).
7-(4-Fluorophenyl)-4-(trifluoromethyl)-2H-pyrimido[1,2-
b]pyridazin-2-one (9c)27
Yield: 180 mg (74%); white solid; mp 331–333 °C.
HRMS (ESI): m/z [M + H]+ calcd for C12H7F3N3O2: 282.0490;
IR (neat): 3070, 1650, 1606, 1550–1401, 1237, 1183 cm–1.
found: 282.0483 (0.8 ppm).
1H NMR (300 MHz, DMSO-d6): δ = 8.38 (d, J = 9.8 Hz, 1 H), 8.13
(dd, J = 9.0 Hz, 5.4 Hz, 2 H), 7.86 (d, J = 9.8 Hz, 1 H), 7.48 (t, J =
9.0 Hz, 2 H), 7.08 (s, 1 H).
7-(Benzofuran-2-yl)-4-(trifluoromethyl)-2H-pyrimido[1,2-
b]pyridazin-2-one (9h)27
Yield: 292 mg (71%); white solid; mp 339–341 °C.
19F NMR (282 MHz, DMSO-d6): δ = –108.8, –64.8.
IR (neat): 3084–3022, 1652, 1608–1538, 1176, 1150, 1131, 1054,
755 cm–1.
Synthesis 2014, 46, 947–954
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PAPER
Direct Access to Pyrimido[1,2-b]pyridazin-2-ones
953
1H NMR (300 MHz, CDCl3): δ = 8.30 (d, J = 9.7 Hz, 1 H), 7.96 (s,
1 H), 7.86–7.83 (m, 2 H), 7.75 (d, J = 9.7 Hz, 1 H), 7.50 (ddd, J =
8.4 Hz, 7.3 Hz, 1.3 Hz, 1 H), 7.40–7.35 (m, 1 H), 7.08 (s, 1 H).
IR (neat): 3238, 3146, 3085, 1638, 1604, 1497 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 7.70 (t, J = 5.4 Hz, 1 H), 7.41
(d, J = 9.9 Hz, 1 H), 7.26 (d, J = 9.9 Hz, 1 H), 6.79 (s, 1 H), 4.82 (t,
J = 5.4 Hz, 2 H), 3.58 (q, J = 5.4 Hz, 2 H).
19F NMR (282 MHz, CDCl3): δ = –64.7.
HRMS (ESI): m/z [M + H]+ calcd for C16H9F3N3O2: 332.0647;
found: 332.0639 (0.8 ppm).
13C NMR (75 MHz, DMSO-d6): δ = 166.8, 151.5, 148.2, 137.9 (q,
J = 34 Hz), 132.3, 126.0, 119.8 (q, J = 274 Hz), 114.5 (q, J = 4 Hz),
58.7, 44.1.
19F NMR (282 MHz, DMSO-d6): δ = –65.2.
HRMS (ESI): m/z [M + H]+ calcd for C10H10F3N4O2: 275.0756;
Nucleophilic Substitution; General Procedure
To a solution of pyridazin-2-one 7 (100 mg, 0.4 mmol) in EtOH (10
mL) were added an amine or thiol (0.48 mmol, 1.2 equiv) and Et3N
(280 μL, 2 mmol, 5 equiv). The mixture was stirred at 80 °C over-
night. The solvent was then evaporated in vacuo and the residue was
purified by flash column chromatography on silica gel (CH2Cl2–
MeOH, 97:3).
found: 275.0748 (0.9 ppm).
7-(Pyrrolidin-1-yl)-4-(trifluoromethyl)-2H-pyrimido[1,2-b]pyr-
idazin-2-one (10e)
Yield: 103 mg (98%); yellow solid; mp 259–260 °C.
IR (neat): 3073, 2865, 1643, 1602, 1550, 1484, 1454 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.44 (d, J = 9.9 Hz, 1 H), 7.15 (d,
J = 9.9 Hz, 1 H), 6.85 (s, 1 H), 3.49 (m, 4 H), 2.06 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 167.4, 149.6, 147.4, 138.7 (q, J =
34 Hz), 132.7, 122.4, 119.2 (q, J = 274 Hz), 115.1 (q, J = 4 Hz), 47.1
(2 C), 25.3 (2 C).
7-(Butylamino)-4-(trifluoromethyl)-2H-pyrimido[1,2-b]pyrid-
azin-2-one (10a)
Yield: 72 mg (63%); white solid; mp 264–266 °C.
IR (neat): 3291, 3083, 2960, 2933, 2478, 1636, 1607, 1573, 1492,
1409 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 7.64 (t, J = 5.4 Hz, 1 H), 7.40
(d, J = 9.8 Hz, 1 H), 7.19 (d, J = 9.8 Hz, 1 H), 6.78 (s, 1 H), 3.21–
3.14 (m, 2 H), 1.55 (quin, J = 7.3 Hz, 2 H), 1.35 (sext, J = 7.3 Hz, 2
H), 0.90 (t, J = 7.3 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 167.4, 151.7, 148.5, 138.2 (q,
J = 34 Hz), 132.4, 126.3, 120.0 (q, J = 274 Hz), 114.6 (q, J = 4 Hz),
41.2, 30.3, 20.3, 14.2.
19F NMR (282 MHz, CDCl3): δ = –66.5.
HRMS (ESI): m/z [M + H]+ calcd for C12H12F3N4O: 285.0963;
found: 285.0956 (0.7 ppm).
7-(Piperidin-1-yl)-4-(trifluoromethyl)-2H-pyrimido[1,2-b]pyr-
idazin-2-one (10f)
Yield: 89 mg (75%); yellow solid; mp 270–272 °C.
19F NMR (282 MHz, DMSO-d6): δ = –65.3.
HRMS (ESI): m/z [M + H]+ calcd for C12H14ON4F3: 287.1120;
found: 287.1114 (0.3 ppm).
IR (neat): 3074, 2922, 2856, 1637, 1600, 1548, 1450 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.46 (d, J = 9.9 Hz, 1 H), 7.33 (d,
J = 9.9 Hz, 1 H), 6.89 (s, 1 H), 3.56–3.49 (m, 4 H), 1.75–1.60 (m, 6
H).
13C NMR (75 MHz, CDCl3): δ = 167.4, 151.6, 147.3, 138.0 (q, J =
35 Hz), 132.9, 122.1, 119.8 (q, J = 274 Hz), 115.2 (q, J = 4 Hz), 46.9
(2 C), 25.1 (2 C), 24.2.
19F NMR (282 MHz, CDCl3): δ = –65.1.
HRMS (ESI): m/z [M + H]+ calcd for C13H14F3N4O: 299.1120;
7-(Allylamino)-4-(trifluoromethyl)-2H-pyrimido[1,2-b]pyrid-
azin-2-one (10b)
Yield: 43 mg (72%); white solid; mp 230–232 °C.
IR (neat): 3218, 2926, 1638, 1586, 1501, 1407 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 7.83 (t, J = 5.4 Hz, 1 H), 7.44
(d, J = 9.9 Hz, 1 H), 7.26 (d, J = 9.9 Hz, 1 H), 6.79 (s, 1 H), 5.93
(ddt, J = 17.1 Hz, 10.2 Hz, 5.4 Hz, 1 H), 5.26 (dq, J = 17.1 Hz, 1.5
Hz, 1 H), 5.15 (dq, J = 10.2 Hz, 1.5 Hz, 1 H), 3.82 (tt, J = 5.7 Hz,
1.5 Hz, 2 H).
found: 299.1113 (0.5 ppm).
13C NMR (75 MHz, DMSO-d6): δ = 166.8, 151.1, 148.2, 138.0 (q,
J = 35 Hz), 134.2, 132.6, 125.8, 119.8 (q, J = 274 Hz), 116.8, 114.5
(q, J = 4 Hz), 43.6.
7-Morpholino-4-(trifluoromethyl)-2H-pyrimido[1,2-b]pyrid-
azin-2-one (10g)
Yield: 77 mg (64%); yellow solid; mp 240 °C.
IR (neat): 3074, 2981, 2858, 1640, 1601, 1548, 1481, 1449, 1426
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.57 (d, J = 9.9 Hz, 1 H), 7.38 (d,
J = 9.9 Hz, 1 H), 6.93 (s, 1 H), 3.85 (t, J = 4.8 Hz, 4 H), 3.53 (t, J =
4.8 Hz, 4 H).
13C NMR (75 MHz, CDCl3): δ = 166.9, 151.8, 147.5, 138.5 (q, J =
35 Hz), 133.4, 121.7, 119.8 (q, J = 274 Hz), 115.2 (q, J = 4 Hz), 66.0
(2 C), 45.7 (2 C).
19F NMR (282 MHz, DMSO-d6): δ = –65.2.
HRMS (ESI): m/z [M + H]+ calcd for C11H10F3N4O: 271.0807;
found: 271.0798 (1 ppm).
7-(Prop-2-yn-1-ylamino)-4-(trifluoromethyl)-2H-pyrimido[1,2-
b]pyridazin-2-one (10c)
Yield: 48 mg (45%); yellow solid; mp 244–246 °C.
IR (neat): 3290, 2925, 1638, 1500, 1406 cm–1.
19F NMR (282 MHz, CDCl3): δ = –66.4.
HRMS (ESI): m/z [M + H]+ calcd for C12H12F3N4O2: 301.0912;
1H NMR (300 MHz, DMSO-d6): δ = 8.04 (t, J = 5.4 Hz, 1 H), 7.48
(d, J = 9.9 Hz, 1 H), 7.23 (d, J = 9.9 Hz, 1 H), 6.81 (s, 1 H), 3.98
(dd, J = 5.4 Hz, 2.5 Hz, 2 H), 3.19 (t, J = 2.5 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 166.8, 151.1, 148.2, 138.0 (q,
J = 35 Hz), 133.0, 125.5, 119.8 (q, J = 274 Hz), 114.5 (q, J = 4 Hz),
80.4, 74.0, 30.5.
19F NMR (282 MHz, DMSO-d6): δ = –65.1.
HRMS (ESI): m/z [M + H]+ calcd for C11H8F3N4O: 269.0650;
found: 301.0904 (0.8 ppm).
7-(Phenylthio)-4-(trifluoromethyl)-2H-pyrimido[1,2-b]pyrid-
azin-2-one (10h)
Yield: 106 mg (82%); white solid; mp 164–165 °C,
IR (neat): 3074, 2995, 1641, 1602, 1548, 1478, 1450 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.60–7.45 (m, 6 H), 7.24 (d, J =
found: 269.0642 (0.9 ppm).
9.9 Hz, 1 H), 6.93 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 166.5, 156.1, 148.4, 138.7 (q, J =
35 Hz), 135.6 (2 C), 132.0, 130.7, 129.8 (2 C), 128.4, 125.2, 117.8
(q, J = 274 Hz), 115.4 (q, J = 4 Hz).
7-[(2-Hydroxyethyl)amino]-4-(trifluoromethyl)-2H-pyrimi-
do[1,2-b]pyridazin-2-one (10d)
Yield: 72 mg (55%); white solid; mp 262 °C.
© Georg Thieme Verlag Stuttgart · New York
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954
J. Petrignet et al.
PAPER
19F NMR (282 MHz, CDCl3): δ = –66.3.
(5) Mátyus, P.; Kasztreiner, E.; Szilágyi, G.; Sóti, M.
Heterocycles 1983, 20, 2225.
(6) Mátyus, P.; Szilágyi, G.; Kasztreiner, E.; Rabloczky, G.
J. Heterocycl. Chem. 1988, 25, 1535.
HRMS (ESI): m/z [M + H]+ calcd for C14H9F3N3OS: 324.0418;
found: 324.0411 (0.6 ppm).
(7) Pollak, A.; Stanovnik, B.; Tisler, M. J. Org. Chem. 1971, 36,
245; this report described access to pyrimido[1,2-b]pyrid-
azin-2-ones, but the structures were subsequently revised to
pyrimido[1,2-b]pyridazin-4-ones.
(8) Ojima, I. Fluorine in Medicinal Chemistry and Chemical
Biology; Wiley-Blackwell: Chichester, 2009.
(9) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320.
(10) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(11) Hamper, B. C. Org. Synth. 1991, 70, 246.
(12) Prié, G.; Thibonnet, J.; Abarbri, M.; Duchêne, A.; Parrain,
J.-L. Synlett 1998, 839.
(13) Thibonnet, J.; Prié, G.; Abarbri, M.; Duchêne, A.; Parrain,
J.-L. Tetrahedron Lett. 1999, 40, 3151.
7-[(2-Bromophenyl)thio]-4-(trifluoromethyl)-2H-pyrimido[1,2-
b]pyridazin-2-one (10i)
Yield: 144 mg (90%); white solid; mp 224–225 °C.
IR (neat): 2978, 2947, 2603, 2495, 1652, 1605, 1548, 1478, 1443
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.79–7.76 (m, 1 H), 7.70–7.68 (m,
1 H), 7.52 (d, J = 9.9 Hz, 1 H), 7.45–7.38 (m, 2 H), 7.29 (d, J = 9.9
Hz, 1 H), 6.81 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 166.7, 154.3, 148.4, 138.8 (q, J =
35 Hz), 137.8, 134.1, 132.4, 132.3, 130.9, 128.6, 128.2, 127.0,
119.8 (q, J = 274 Hz), 115.2 (q, J = 4 Hz).
19F NMR (282 MHz, CDCl3): δ = –66.4.
HRMS (ESI): m/z [M + H]+ calcd for C14H881BrF3N3OS: 403.9524;
(14) Carcenac, Y.; Zine, K.; Kizirian, J.-C.; Thibonnet, J.;
Duchene, A.; Parrain, J.-L.; Abarbri, M. Adv. Synth. Catal.
2010, 352, 949.
found: 403.9495 (0.7 ppm).
(15) Zine, K.; Petrignet, J.; Thibonnet, J.; Abarbri, M. Synlett
2012, 23, 755.
(16) Richard, S.; Prié, G.; Guignard, A.; Thibonnet, J.; Parrain, J.-
L.; Duchêne, A.; Abarbri, M. Helv. Chim. Acta 2003, 86,
726.
Acknowledgment
We thank the ‘Région Centre’ and INRA for financial support to
L.S. We thank P. Emond and the ‘Laboratoire d’Analyse Chimique
Biologique et Médicale’ (Tours) for the high-resolution mass spec-
tral analysis.
(17) Prié, G.; Richard, S.; Parrain, J.-L.; Duchêne, A.; Abarbri,
M. J. Fluorine Chem. 2002, 117, 35.
(18) Zeng, J.; Tan, Y. T.; Leown, M. L.; Liu, X.-W. Org. Lett.
2012, 14, 4386.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(19) Harriman, G. C. B.; Chi, S.; Zhang, M.; Crowe, A.; Bennett,
R. A.; Parsons, I. Tetrahedron Lett. 2003, 44, 3659.
(20) Maes, B. U. W.; Lemière, G. L. F.; Dommisse, R.;
Augustyns, K.; Hammers, A. Tetrahedron 2000, 56, 1777.
(21) Guery, S.; Parrot, I.; Rival, Y.; Wermuth, C. G. Tetrahedron
Lett. 2001, 42, 2115.
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Synthesis 2014, 46, 947–954
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