β-Bromodifluoromethyl β-enaminoketones: Versatile synthetic intermediates for synthesis of CF2-containing compounds

Article abstract of DOI:10.1016/j.tetlet.2005.06.002

A series of N-aryl β-bromodifluoromethyl β-enaminoketones were regioselectively synthesized in good yield by the reaction of N-aryl bromodifluoroacetimidoyl chlorides with methyl ketones. β- Bromodifluoromethyl β-enaminoketones smoothly cyclized to give a novel class of cyclic (2,2-difluoro-5-phenyl-furan-3-ylidene)-aryl-amines under basic condition. An intramolecular halophilic substitution mechanism was proposed.

Full text of DOI:10.1016/j.tetlet.2005.06.002

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5357–5360
b-Bromodifluoromethyl b-enaminoketones: versatile
synthetic intermediates for synthesis of CF2-containing compounds
Yong-Ming Wu,* Ya Li and Juan Deng
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Received 25 March 2005; revised 31 May 2005; accepted 2 June 2005
Available online 27 June 2005
Abstract—A series of N-aryl b-bromodifluoromethyl b-enaminoketones were regioselectively synthesized in good yield by the
reaction of N-aryl bromodifluoroacetimidoyl chlorides with methyl ketones. b-Bromodifluoromethyl b-enaminoketones smoothly
cyclized to give a novel class of cyclic (2,2-difluoro-5-phenyl-furan-3-ylidene)-aryl-amines under basic condition. An intramolecular
halophilic substitution mechanism was proposed.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1.Introduction
because of the existence of BrCF2 moiety. Herein, we
would like to report the regioselective synthesis of b-bro-
modifluoromethyl b-enaminoketones and further con-
version to some interesting CF2-containing compounds.
The synthesis and reactivity of b-enaminoketones repre-
sent an active investigation area in organic chemistry.1
These compounds have remarkable properties and they
are valuable intermediates for the synthesis of several
interesting compounds.2 They can also be used as start-
ing materials for the stereoselective preparation of
c-amino alcohol.3
2.Regioselective synthesis of b-bromodifluoromethyl
b-enaminoketones
The b-bromodifluoromethyl b-enaminoketones can be
prepared by the reaction of bromodifluoroacetimidoyl
chlorides 18 with the carbanion of methyl ketones.9
The treatment of bromodifluoroacetimidoyl chloride 1
and acetophenone with NaH as base in dry Et2O at
0 ꢁC for 24 h, gave the desired b-enaminoketone in
78% isolated yield (Scheme 1).
b-Enaminoketones can usually be prepared in several
ways. The simplest is the direct condensation of the
appropriate amine with symmetrical b-dicarbonyl com-
pounds,4 while the acylation of lithium imines with ester
is another approach to the regioselective preparation.5
In recent years, the introduction of the difluoromethyl-
ene segmentinot organic compounds has been proved
to be attractive due to the potential biological activities
of such molecules.6 Bromodifluoroacetate, chlorodifluo-
romethyl ketones and bromodifluoromethyl acetylene
are widely used as reagents for the introduction of a
CF2 moiety.7 In search for new CF2-containing reactive
synthetic intermediates,8 we have found that b-bromo-
difluoromethyl b-enaminoketones showed unique prop-
erties compared with their non-fluorinated analogues
This method is successfully extended to the synthesis of
other b-bromodifluoromethyl b-enaminoketones,10 as
illustrated in Table 1. However, the reaction of 3,3-di-
methyl-2-butanone or acetone with NaH as base was
inefficient, and the desired product was isolated in low
yield. Interestingly, when LDA was used instead of
NaH, the reaction worked very well. It was worth
noting that bromodifluoroacetimidoyl chlorides
1
reacted with methyl ketones under basic conditions to
provide the enamino tautomer exclusively, but the
possible imine tautomer was not observed in product 2
1
according to the H, 19F NMR analysis.
Keywords: Bromodifluoromethyl; Enaminoketones; Cyclization; Halo-
philic substitution.
*
The configuration of the enamino double bond in prod-
uct 2 was also studied. The down-field chemical shift of
Corresponding author. Tel.: +86 21 54925190; fax: +86 21
64166128; e-mail: ymwu@mail.sioc.ac.cn
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.002

5358
Y.-M. Wu et al. / Tetrahedron Letters 46 (2005) 5357–5360
PMP
Cl
PMP
H
1) NaH(2.0equiv)
N
O
N
O
Et2O, 0oC
+
BrF2C
Ph
2) NH4Cl sat.
BrF2C
Ph
2a
Scheme 1. Synthesis of b-bromodifluoromethyl b-enaminoketones.
Table 1. The reaction of bromodifluoroacetimidoyl chlorides with methyl ketones
R
Cl
base
H
R
N
O
R'COCH3
+
BrF2C
N
BrF2C
R'
2
Entry
R
R0
Base
ProductYield (%)
1
2
3
4
5
6
7
p-OCH3
o-Br
o-Cl
Ph
Ph
NaH
NaH
NaH
NaH
LDA
LDA
LDA
2a
2b
2c
2d
2e
2f
78
62
74
71
67
63
54
Ph
Ph
o-CH3, p-Br
p-OCH3
o-CH3, p-Br
p-OCH3
t-Bu
t-Bu
CH3
2g
R1
H
speaking, the CF2Br group could undergo two different
types of reactions, that is, substitution via single electron
transfer (SET) course or halophilic mechanism,11 and
radical addition to unsaturated compounds. We rea-
soned that b-enaminoketones 2 could be readily con-
verted to enolate (I) under basic conditions
(Fig. 2).12 Once enolate (I) is formed in proper
reaction conditions, intramolecular cyclization might
occur.
N
O
BrF2C
R'
Z (s-cis)
1
Figure 1.
the N–H proton (d >12 ppm) is a typical feature of a
hydrogen bond with oxygen in carbonyl group, showing
a chelated configuration, Z, s-cis form (Fig. 1).
When a mixture of b-enaminoketones 2a and triethyl-
amine was heated in dry DMF at 100 ꢁC for 12 h, no
reaction occurred and 2a was recovered quantitatively.
However, when DMAP was used as a base, a crystalline
solid was isolated in 22% yield after standard work up.
An X-ray diffraction study confirmed the unique struc-
ture of the product (Fig. 3).13 So the intramolecular
cyclization indeed occurred.
3.Cyclization of b-bromodifluoromethyl b-enamino-
ketones
Because of the unique properties of CF2Br moiety in
b-bromodifluoromethyl b-enaminoketones 2, generally
R1
N
Further experimental study revealed that K2CO3 was a
suitable base for the intramolecular cyclization14
(Scheme 2). When the reaction was carried out under
strong basic conditions (NaH or NaOH as base), the
reaction mixture turned dark and the desired product
I
R'
BrF2C
-O
Figure 2.
Figure 3. Crystal structure of the cyclization product.

Y.-M. Wu et al. / Tetrahedron Letters 46 (2005) 5357–5360
5359
R
K2CO3 (1.2 equiv)
DMF, 100oC
R
CHCOPh
CF2Br
N
N
H
F
O
F
p-OCH3
o-Br
86%
82%
3a
3b
R:
2a
2b
Scheme 2.
R1
N
R1
R1
H
O
N
N
base
-F2C
R'
BrF2C
R'
BrF2C
R'
-O
R'
BrO
R1
N-
R1
N
R1
Br
N
F2C
R'
+
Br
F
F2C
BrO
-O
R'
O
F
Scheme 3. Possible mechanism of the intramolecular cyclization reaction.
was isolated in low yield (20–30%). This might be due to
the decomposition of the product in strong basic condi-
tions. The results of intramolecular cyclization are
described in Scheme 2.
References and notes
´
´
1. (a) Fustero, S.; Carcıa de la Torre, M.; Simon Fuenters, A.
J. Org. Chem. 1999, 64, 5551–5556; (b) Cimarelli, C.;
Palmieri, G.; Volpini, E. Tetrahedron Lett. 2004, 45, 6629–
6631; (c) Yu, H. B.; Zhang, Q. S.; Huang, W. Y. Chin. J.
Chem. 1997, 15, 278–282; (d) Ollinger, P.; Remp, W.;
Junck, H. Monatch. Chem. 1974, 105, 346–353.
To understand the reaction mechanism, 1,4-dinitrobenz-
ene was added to the reaction mixture. Inhibition by
1,4-dinitrobenzene was not observed. So a halophilic
process was mostlikely involved, as shown in Scheme 3.
Of course, a simple intramolecule nucleophilic substitu-
tion mechanism was also possible.
2. Cimarelli, C.; Palmieri, G. Res. Dev. Org. Chem. 1997, 1,
179–189.
3. Bartoli, G.; Cimarelli, G.; Palmieri, G. J. Chem. Soc.,
Perkin Trans. 1 1994, 537–543.
4. (a) Braibante, M. E. F.; Braibante, H. S.; Missio, L.;
Andricopulo, A. Synthesis 1994, 9, 898–900; (b) Baraldi,
P. G.; Simoni, D.; Manfredini, S. Synthesis 1983, 902; (c)
Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277–294.
5. Bartoli, G.; Cimarelli, C.; Palmieri, G.; Bosco, M.;
Dalpozzo, R. Synthesis 1990, 10, 895–897.
6. (a) Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M.
J. Org. Chem. 1988, 53, 2406–2409; (b) Chen, J.; Hu, Q.
M. J. Chem. Soc., Perkin Trans. 1 1994, 1111–1114; (c)
In conclusion, an efficientprocedure for regioselecitve
synthesis of b-bromodifluoromethyl b-enaminoketones
by the reaction of bromodifluoro-acetimidoyl chlorides
with methyl ketones was described. These enamino-
ketones were smoothly cyclized by treatment with
K2CO3 in DMF to give a novel class of gem-
difluorinated cyclic (2,2-difluoro-5-phenyl-furan-3-
ylidene)-aryl-amines. Further studies of the synthetic
applications of this enaminoketones are in progress.
´
´
Fustero, S.; Bartolome, A.; Garcıa Soler, J. Org. Lett.
2003, 5, 2523–2526; (d) Suzuki, A.; Mae, M.; Amii, H.;
Uneyama, K. J. Org. Chem. 2004, 69, 5132–5134.
7. (a) Burton, D. J.; Yang, Z. Y. Tetrahedron 1992, 48, 189–
275; (b) Yang, Z. Y.; Burton, D. J. J. Org. Chem. 1991, 56,
1037–1041.
Acknowledgements
8. Wu, Y. M.; Li, Y.; Deng, J. J. Fluorine Chem. 2005, 126,
791–795.
9. (a) Yu, H. B.; Huang, W. Y. J. Fluorine Chem. 1997, 84,
The authors thank the National Natural Science Foun-
dation of China (NNSFC) (No. 20472104) for financial
support.
´
65–67; (b) Fustero, S.; Salavert, E.; Navarro, A.; Simon
Fuentes, A. J. Org. Chem. 2002, 67, 4667–4679.
10. Typical procedure: A flask fitted with a nitrogen inlet was
charged with acetophenone (132 mg, 1.1 mmol), N-(p-
Supplementary data
methoxyphenyl) bromodifluoroacetimidoyl chloride
1
(298 mg, 1 mmol), sodium hydride (80 mg, 60% dispersion
in mineral oil, 2 mmol) and 8 mL dry diethyl ether. The
mixture was stirred for 24 h at 0 ꢁC. After standard work-
up, the crude product was purified by flash column
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2005.
06.002.

5360
Y.-M. Wu et al. / Tetrahedron Letters 46 (2005) 5357–5360
chromatography (5% ethyl acetate in petroleum) to give 2a
(298 mg, 78%).
11. (a) Peng, W. M.; Zhu, S. Z. Tetrahedron 2003, 59, 4395–
4404; (b) Medebielle, M.; Kato, K.; Dolbier, W. R., Jr.
Synlett 2002, 1541–1543; (c) Burkholder, C. D.; Dolbier,
tion: 1.19–25.50ꢁ; Completeness to theta = 25.50%, 98.3%;
data/restraints/parameters: 10541/0/798; goodness-of-fit
on F2: 0.986; final R indices [I > 2sigma(I)]:R1 = 0.1116,
wR2 = 0.3220;
wR2 = 0.3619; extinction coefficient: 0.0082(18); largest
R
indices (all data): R1 = 0.2083,
W. R., Jr.; Medebielle, M. J. Org. Chem. 1998, 63, 5385–
´
diff. Peak and hole: 0.419 and ꢀ0.390 e Aꢀ3
.
´
5394; (d) Burkholder, C. D.; Dolbier, W. R., Jr.; Mede-
14. Typical procedure: anhydrous potassium carbonate
(50 mg, 0.36 mmol) was added to b-bromodifluoromethyl
enaminoketone 2a (115 mg, 0.30 mmol) in 3 mL dried
DMF. The mixture was heated at about 80 ꢁC for 5 h.
Then, 10 mL water was added to the mixture. The mixture
was extracted with ethyl acetate (2 · 10 mL). The com-
bined organic layer was dried over Mg2SO4, concentrated
and subjected to a column chromatography (5% ethyl
acetate in petroleum) to give 3a (77 mg, 86%).
bielle, M. J. Fluorine Chem. 2001, 109, 39–48.
12. Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277–294.
13. Crystal data for 3a: crystal system: triclinic; space group: p-
˚
˚
1; unitcell dimension: a = 9.859(5) A, b = 17.793(9) A, c =
18.419(10), a = 101.068(13)ꢁ, b = 104.880(9)ꢁ,c = 105.865(10)ꢁ;
volume: 2882(3) A3; Z, calculated density: 8, 1.389 Mg/m3;
absorption coefficient: 0.109 mm3; F(000): 1248; crystal
size: 0.478 · 0.453 · 0.207 mm; theta range for data collec-