Synthesis and substitution reactions of β-alkoxyvinyl bromodifluoromethyl ketones

Article abstract of DOI:10.1016/j.jfluchem.2008.09.001

β-Alkoxyvinyl bromodifluoromethyl ketones 1a, 1b and 1c were synthesized by the reaction of bromodifluoroacetic anhydride with appropriate vinyl ethers in high yields. The acyclic enone 1a reacted with amines to give the corresponding β-aminovinyl bromodi

Full text of DOI:10.1016/j.jfluchem.2008.09.001

Journal of Fluorine Chemistry 129 (2008) 1167–1172
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and substitution reactions of
ketones
b-alkoxyvinyl bromodifluoromethyl
Xiang Fang a, Yang Chen a, Daming He a, Xianjin Yang a, Fanhong Wu a,b,
*
a Laboratory for Advanced Material and Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology,
130 Meilong Road, Shanghai 200237, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history:
b
-Alkoxyvinyl bromodifluoromethyl ketones 1a, 1b and 1c were synthesized by the reaction of
bromodifluoroacetic anhydride with appropriate vinyl ethers in high yields. The acyclic enone 1a reacted
with amines to give the corresponding -aminovinyl bromodifluoromethyl ketones 2 in good yields. The
reaction of 1a with electrophilic reagent ICl yielded -iodoenone 4. The substitution reaction of the cyclic
Received 6 August 2008
Received in revised form 8 September 2008
Accepted 8 September 2008
Available online 17 September 2008
b
a
enones 1b and 1c with thio-nucleophiles gave the corresponding difluoromethylene thioethers 6. The
three-component reactions of 2 with primary amines and formaldehyde gave multifunctional 1,2,3,4-
tetrahydropyrimidine 3 in moderate yields.
Keywords:
Fluorinated synthons
ß 2008 Elsevier B.V. All rights reserved.
b-Alkoxyvinyl bromodifluoromethyl
ketones
Enaminones
1. Introduction
carbon–bromide bond (Fig. 1) were still unknown. Herein we
would like to report our recent research of the reactions of 1 as
The ability of fluorine atom to enhance biological and
therapeutic activities of organic compounds has led to widespread
interest in selective introduction of fluorine atom and fluoroalkyl
groups into organic molecules [1–3], especially those heterocyclic
compounds which have potential biological activities. Recently,
the introduction of the difluoromethylene moiety into organic
compounds has been proved to be attractive due to the potential
biological properties of such molecules [4–6]. This group has been
recognized as an isopolar–isosteric replacement for oxygen. In
searching for new CF2-containing reactive synthetic intermediates
gem-difluorinated synthons with some typical nucleophilic and
electrophilic reagents, together with their further chemical
transformations, especially the SRN1 reactions of 1 with thio-
nucleophiles.
2. Results and discussion
b-Ethyloxyvinyl bromodifluoromethyl ketone 1a was easily
prepared by the procedure of Hojo et al. [12] from bromodifluor-
oacetic anhydride and ethyl vinyl ether in 80% yield (Scheme 1 and
entry 1 in Table 1,). Similarly the cyclic enones 1b and 1c were
readily prepared [12,13] by Friedel–Crafts acylation of dihydro-
furan and dihydropyran in 95% and 99% yields, respectively
(Table 1, entries 2 and 3).
[7], we found that
been widely used as intermediates in heterocyclic synthesis [8–
10], but the reaction of the -alkoxyvinyl bromodifluoromethyl
ketones were poorly investigated [11]. Such bromodifluoromethyl
synthons 1 may take place the same kind reactions of
b-alkoxyvinyl trifluoromethyl ketones have
b
b
-
The use of
b-dialkylamino-a,b-unsaturated trifluoromethyl
alkoxyvinyl trifluoromethyl ketones, e.g., 1,2-nucleophilic Aldol
reaction and 1,4-Michael addition; electrophilic addition in double
bond, but the different radical addition and different kind
substitution (nucleophilic with SET or halophilic) reaction in the
ketones [14,15] in the synthesis of fluorine-containing hetero-
cycles [16] were recently reported. Liu also reported the three-
component reaction of fluorine-containing enaminoketones or 3-
fluoroalkylanilinoacrylic acid esters with primary amines and
formaldehyde [17]. b-Aminovinyl bromodifluoromethyl ketones 2
were prepared from enone 1a in good to excellent yields (Scheme 2
and Table 2) for their further transformation.
N-Monosubstituted enaminones 2a and 2b existed predomi-
nantly in a Z-configuration (cis-position between the bromodi-
fluoroacetyl and the amino groups) due to hydrogen bonding in
* Corresponding author at: Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai
200032, China. Tel.: +86 21 64253530; fax: +86 21 64253074.
E-mail address: wfh@ecust.edu.cn (F. Wu).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.09.001

1168
X. Fang et al. / Journal of Fluorine Chemistry 129 (2008) 1167–1172
Table 2
The reaction of
b-ethyloxyvinyl bromodifluoromethyl ketone 1a with amines.
Entry
1
R1
H
R2
Product
Yield (%)
75
Ph
(2a)
(2b)
2
H
i-Pr
100
Fig. 1. The reactivity of
b-alkoxyvinyl bromodifluoromethyl ketones.
3
4
5
i-Pr
i-Pr
86
91
93
Scheme 1.
Table 1
(2c)
(2d)
(2e)
The preparation of
b-alkoxyvinyl bromodifluoromethyl ketones 1.
CH3
CH3
Entry
1
Substance
Product
Yield (%)
80
(1a)
2
95
(1b)
3
99
Scheme 3.
(1c)
(2:primary amines:HCHO) (Scheme 3) according to the reference
optimum condition [17]. As shown in Table 3, aliphatic primary
amines reacted readily with 2a, 2b and formaldehyde to give
C
OÁ Á ÁHN, which were shown by the coupling constant across the
multifunctional 1,2,3,4-tetrahydropyrimidine 3 in moderate
yields. It were found that the length and bulkiness of the carbon
chain in primary amines had little influence on the reaction. The
3
double bond on 1H NMR spectra. It is well-known that the Jtrans
value in 1,2-substituted ethylenic compounds is always larger than
the Jcis value. For instance, the characteristic features of the 1H
3
NMR in CDCl3 spectra of 2b were the appearances of doublets
centered at 5.32 ppm and 7.23 ppm with 3JH–H = 7.1 Hz for 3-H and
4-H protons, respectively, indicating the cis configuration of the
vicinal two hydrogen atoms. The trans configuration of the N,N-
dimethylenaminone 2d was also based on the appearances of
doublets centered at 5.25 ppm and 7.85 ppm with 3JH–H = 12.2 Hz
in the 1H NMR spectra
The three-component reaction of N-monosubstituted enam-
inoketones 2a and 2b with primary amines and formaldehyde
were proceeded in DMF at 110 8C with a mole ratio of 1:3:6.5
Table 3
The reaction of N-monosubstituted enaminoketones 2 with primary amines and
formaldehyde.
Entry
R2
R3
Product
Yield (%)
1
2
3
Ph
Ph
Ph
i-Pr
t-Bu
Ph
(3a)
(3b)
49
48
Complex
(2a)
4
5
6
i-Pr
i-Pr
i-Pr
i-Pr
t-Bu
Ph
(3c)
(3d)
35
33
Complex
(2b)
Scheme 2.

X. Fang et al. / Journal of Fluorine Chemistry 129 (2008) 1167–1172
1169
Scheme 4.
Table 5
Table 4
The reaction of
a-iodoenone (4) with amines.
Reactions of acyclic enone (1a), cyclic enones (1b) and (1c) with thiolates.
Entry
1
R1
H
R2
Product
Yield (%)
62
Entry
Substance
Thiolate
Product
Yield (%)
Ph
1
2
3
4
5
(1a)
(1b)
(1b)
(1c)
(1c)
C6H4SH
Complex
4-ClC6H4SH
4-CH3C6H4SH
4-ClC6H4SH
4-CH3C6H4SH
(6a)
(6b)
(6c)
(6d)
75
75
78
80
(5a)
2
H
i-Pr
63
corresponding difluoromethylene thioethers 6. The isolated yields
varied from 75% to 80% (Scheme 5 and Table 5). The displacement
of bromide from the CF2Br group was considered by an SRN
1
mechanism [20] involving a SET chain process. Unfortunately, the
attempted reaction of 1a with sodium thiolate led to decomposi-
tion and none of the desired product could be isolated (Table 5,
entry 1).
(5b)
3
CH3
CH3
(5d)
Decomposed
3. Conclusions
reaction yield of aromatic enaminoketones 2a was higher than that
of aliphatic enaminoketones 2b. However, in case of aniline, the
reactions were very complicated and no expected cyclic products
were obtained (Table 3, entries 3 and 6).
The reactions of enone 1a with electrophiles were scarcely
investigated [18]. We found the reaction of 1a with iodine
underwent very slowly. However, the reaction of much more
electrophilic iodine monochloride were effective in the introduc-
b
-Ethyloxyvinyl bromodifluoromethyl enone 1a, cyclic enones
1b and 1c were prepared in high yields. Acyclic enone 1a reacted
with amines to give -aminovinyl bromodifluoromethyl ketones 2.
Meanwhile, the reaction of enone 1a with electrophilic reagent ICl
gave -iodoenone 4, which was also able to be converted to the
b
a
corresponding enaminones 5. The preparations of difluoromethy-
lene thioethers 6 in good yields were realized by the substitute
reaction of the cyclic enones 1b, 1c with thiolates. It provided an
effective method for the synthesis of multifunctional 1,2,3,4-
tetrahydropyrimidines 3 through the three-component reactions
of 2 with primary amines and formaldehyde.
tion of the iodine atom to the
a-position to the carbonyl group of
enone 1a. The addition of ICl to enone 1a in the presence of one
equivalent of pyridine at low temperature gave the corresponding
a
-iodoenone 4 in the isolated yield of 50% with the conversion of
66% (Scheme 4).
Iodoenone 4 showed the similar reactivity of enone 1a. The
reaction of enone 4 with amines produced the corresponding
enaminones 5a and 5b in 62–63% yields (Table 4, entries 1 and 2).
The dimethylamino substituted enaminone 5d was not stable and
decomposed (Table 4, entry 3).
4. Experimental
IR spectra were measured on a Nicolet Magna IR-550 spectro-
meter using potassium bromide pellet. High resolution mass
spectra were carried out on a Finnigan GC–MS-4021 spectrometer.
1H NMR (500 MHz) and 13C (125.8 MHz) spectra were recorded on
a Bruker AC-500 spectrometer with Me4Si as internal standard. 19
F
NMR spectra were obtained on Bruker AC-500 (470 MHz) spectro-
meter in CDCl3 with CFCl3 as external standard, downfield shifts
The Z-configuration was observed in the
a-iodoenaminone 5.
For example, the chemical shift of the NH proton of 5b was
observed at 5.91 ppm. The isomer with trans-disposed bromodi-
fluoroacetyl and amino group becomes more stable presumably
because of steric bulk of the
a
-halogeno substituent [18].
-alkoxyvinyl
being designated as negative. All chemical shifts (d) are expressed
in ppm, coupling constants (J) are given in Hz.
It was assumed that the CF2Br group of
b
bromodifluoromethyl ketones would be reactive with sulfur
nucleophiles [19–21]. In fact, in the presence of NaH, the reactions
of cyclic enones 1b and 1c with thiolates in dimethylformamide
were rapid and exothermic, completed within 30 min, to give the
4.1. General procedure for the preparation of
bromodifluoromethyl ketones
b-alkoxyvinyl
To a stirred solution of 4-dimethylaminopyridine (10 mg) and
bromodifluoroacetic anhydride (10 mmol) which was prepared
according to a previously reported procedure [22] in dichlor-
omethane (15 ml), ethyl vinyl ether (12 mmol) was added
dropwise at À10 8C. The reaction mixture was stirred for 10 h at
0 8C, allowed to warm to room temperature and the solvent was
evaporated in vacuo. The reaction mixture was poured into sodium
bicarbonate solution (the deep violet color changed to the yellow
color), the two phases were separated and the organic phase was
washed with water, dried over anhydrous sodium sulfate. The
Scheme 5.

1170
X. Fang et al. / Journal of Fluorine Chemistry 129 (2008) 1167–1172
solvent was evaporated in vacuo to give the crude compound 1 as a
4.2.4. (E)-1-Bromo-4-(dimethylamino)-1,1-difluorobut-3-en-2-one
light yellow oil.
(2d)
1H NMR (CDCl3, 500 MHz):
d 7.85 (1H, d, J = 12.2 Hz), 5.25 (1H,
4.1.1. 2-Bromo-1-(4,5-dihydrofuran-3-yl)-2,2-difluoroethanone (1b)
d, J = 12.2 Hz), 3.24 (3H, s), 2.98 (3H, s). 19F NMR (CDCl3, 470 MHz):
1H NMR (CDCl3, 500 MHz):
d
7.67 (1H, t, J = 1.6 Hz), 4.7 (2H, t,
d
À61.4 (2F, s). 13C NMR (CDCl3, 125.8 MHz):
d 180.0 (t, J = 23.9 Hz),
J = 9.8 Hz), 3.0 (2H, t, J = 9.8 Hz). 19F NMR (CDCl3, 470 MHz):
d
157.5, 116.7 (t, J = 320.2 Hz), 86.0, 46.2, 38.1. IR (cmÀ1, KBr): 3447,
2925, 1657, 1585, 1070, 868, 682. EI-MS (m/z): 229 (M + 2+, 23),
227 (M+, 23), 98 (100). HRMS calcd for C6H8ONF2Br: 226.9757,
found: 226.9757.
À59.1 (2F, s). 13C NMR (CDCl3, 125.8 MHz):
d 178.8 (t, J = 27.4 Hz),
164.0 (t, J = 7.0 Hz), 114.4 (t, J = 317.6 Hz), 112.6, 74.4, 27.9. IR
(cmÀ1, KBr): 2929, 1779, 1670, 1594, 1151, 818. EI-MS (m/z): 228
(M + 2+, 6), 226 (M+, 6), 97 (100). HRMS calcd for C6H5O2F2Br:
225.9441, found: 225.9441.
4.2.5. (E)-1-Bromo-1,1-difluoro-4-(pyrrolidin-1-yl)but-3-en-2-one
(2e)
4.1.2. 2-Bromo-1-(5,6-dihydro-4H-pyran-3-yl)-2,2-
1H NMR (CDCl3, 500 MHz):
d
8.05 (1H, d, J = 12.2 Hz), 5.22 (1H,
difluoroethanone (1c)
d, J = 12.2 Hz), 3.62 (2H, t, J = 6.8 Hz), 3.32 (2H, t, J = 7.0 Hz), 2.11–
1H NMR (CDCl3, 500 MHz):
d
8.0 (1H, s), 4.2 (2H, t, J = 5.3 Hz),
2.05 (2H, m), 2.03–1.95 (2H, m). 19F NMR (CDCl3, 470 MHz):
d
2.35 (2H, t, J = 6.3 Hz), 1.99–1.94 (2H, m). 19F NMR (CDCl3,
À61.2 (2F, s). 13C NMR (CDCl3, 125.8 MHz):
d 179.9 (t, J = 23.9 Hz),
470 MHz):
d
À55.9 (2F, s). 13C NMR (CDCl3, 125.8 MHz):
d
181.4 (t,
153.3, 116.8 (t, J = 320.2 Hz), 86.9, 53.7, 48.1, 25.7 7, 25.5. IR (cmÀ1
,
J = 25.2 Hz), 162.8 (t, J = 6.9 Hz), 114.4 (t, J = 318.9 Hz), 109.8, 68.3,
21.3, 19.0. IR (cmÀ1, KBr): 2960, 1678, 1609, 1236, 960. EI-MS (m/
z): 242 (M + 2+, 3), 240 (M+, 3), 111 (100), 83 (24). HRMS calcd for
C7H7O2F2Br: 239.9597, found: 239.9597.
KBr): 2924, 2876, 1662, 1579, 1266, 1077, 939, 863. EI-MS (m/z):
255 (M + 2+, 8), 253 (M+, 8), 174 (12), 124 (100). HRMS calcd for
C8H10ONF2Br: 252.9914, found: 252.9915.
4.3. General procedure for the synthesis of 1,2,3,4-
tetrahydropyrimidines
4.2. General procedure for the synthesis of enaminones
PhNH2 (5 mmol) was added dropwise to the solution of enone
1a (4 mmol) in acetonitrile (10 ml) under stirring at 0 8C. The
mixture was stirred at room temperature for 10 h to complete the
reaction, then the mixture was treated with about 30 ml of water
and extracted with 3 Â 20 ml of ether. The combined organic layer
was washed with saturated brine solution and dried over
anhydrous sodium sulfate. After evaporation of ether, the crude
product was subjected to column chromatography to give the pure
product 2a.
To a solution of enaminone 2a (1 mmol) in DMF (5 ml), were
added primary amines (3 mmol) and 37% formaldehyde
(6.5 mmol). The mixture was stirred at 110 8C for 2–5 h (monitored
by TLC or 19F NMR). After completion of the reaction, the mixture
was cooled to room temperature, diluted with water and extracted
with Et2O. The organic layer was washed with saturated NaCl
solution and dried over anhydrous Na2SO4. The residue obtained
after evaporation of the solvent was purified by flash chromato-
graphy on silica gel.
4.2.1. (Z)-1-Bromo-1,1-difluoro-4-(phenylamino)but-3-en-2-one
4.3.1. 2-Bromo-2,2-difluoro-1-(3-isopropyl-1-phenyl-1,2,3,4-
(2a)
tetrahydropyrimidin-5-yl)ethanone (3a)
1H NMR (CDCl3, 500 MHz):
d
11.7 (1H, br), 7.70–7.65 (1H, m),
7.4 (2H, t, J = 8.0 Hz), 7.2 (1H, t, J = 7.9 Hz), 7.13 (2H, d, J = 7.7 Hz),
5.64 (1H, d, J = 7.5 Hz). 19F NMR (CDCl3, 470 MHz):
À61.8 (2F, s).
13C NMR (CDCl3, 125.8 MHz):
182.4 (t, J = 25.6 Hz), 150.3, 139.5,
130.6, 126.3, 118.0, 115.5 (t, J = 317.8 Hz), 88.9. IR (cmÀ1, KBr):
3248, 1606, 1565, 1300, 1137, 751. EI-MS (m/z): 277 (M + 2+, 20),
275 (M+, 20), 146 (100). HRMS calcd for C10H8ONF2Br: 274.9757,
found: 274.9758.
1H NMR (CDCl3, 500 MHz):
d
7.86 (1H, s), 7.27 (2H, t, J = 7.9 Hz),
6.96 (3H, t, J = 7.9 Hz), 4.69 (2H, s), 4.22 (2H, s), 3.55–3.48 (1H, m),
1.18 (6H, d, J = 6.7 Hz); 19F NMR (CDCl3, 470 MHz):
À52.6 (2F, s);
13C NMR (CDCl3, 125.8 MHz):
176.7 (t, J = 23.7 Hz), 149.4, 148.7,
d
d
d
d
130.0, 122.4, 119.1, 115.7 (t, J = 318.9 Hz), 64.8, 56.4, 46.1, 21.8; IR
(cmÀ1, KBr): 2975, 1585, 1129, 694; EI-MS (m/z): 360 (M + 2+, 13),
358 (M+, 13), 279 (100), 105 (44); HRMS calcd for C15H17O2N2F2Br:
358.0492, found: 358.0492.
4.2.2. (Z)-1-Bromo-1,1-difluoro-4-(isopropylamino)but-3-en-2-one
4.3.2. 2-Bromo-1-(3-tert-butyl-1-phenyl-1,2,3,4-
(2b)
tetrahydropyrimidin-5-yl)-2,2-difluoroethanone (3b)
1H NMR (CDCl3, 500 MHz):
d
10.1 (1H, br), 7.23 (1H, q, J = 7.1 Hz),
1H NMR (CDCl3, 500 MHz):
d 8.04 (1H, s), 7.34–6.98 (5H, m),
5.32 (1H, d, J = 7.1 Hz), 3.65–3.57 (1H, m), 1.32 (6H, d, J = 6.6 Hz). 19
NMR(CDCl3, 470 MHz):
F
4.57 (2H, s), 3.68 (2H, s), 1.14 (9H, s); 19F NMR (CDCl3, 470 MHz):
d
d
À60.6(2F,s). 13CNMR(CDCl3, 125.8 MHz):
À53.9 (2F, s); 13C NMR (CDCl3, 125.8 MHz):
d 176.3 (t, J = 23.7 Hz),
d
180.7 (t, J = 24.7 Hz), 156.6, 116.2 (t, J = 318.1 Hz), 85.2, 51.8, 23.9.
145.8, 142.4, 129.0, 124.8, 118.6, 113.5 (t, J = 318.8 Hz), 62.6, 54.6,
41.0, 26.1; IR (cmÀ1, KBr): 2975, 1578, 1149, 757, 695; EI-MS (m/z):
374 (M + 2)+, 11), 372 (M+, 11), 293 (100), 208 (88), 104 (56); HRMS
calcd for C16H19ON2F2Br: 372.0649, found: 372.0649.
IR (cmÀ1, KBr): 3270, 2977, 1644, 1587, 1139, 1072, 875. EI-MS (m/
z): 243 (M + 2+, 16), 241 (M+, 16), 112 (100), 70 (33). HRMS calcd for
C7H10ONF2Br: 240.9914, found: 240.9914.
4.2.3. (E)-1-Bromo-4-(diisopropylamino)-1,1-difluorobut-3-en-2-
4.3.3. 2-Bromo-1-(1,3-diisopropyl-1,2,3,4-tetrahydropyrimidin-5-
one (2c)
yl)-2,2-difluoroethanone (3c)
1H NMR (CDCl3, 500 MHz):
d
7.89 (1H, d, J = 12.4 Hz), 5.35 (1H,
1H NMR (CDCl3, 500 MHz):
d
7.87 (1H, s), 4.14 (2H, s), 3.64 (2H,
s), 3.62–3.54 (1H, m), 2.96–2.88 (1H, m), 1.32 (6H, d, J = 6.7 Hz),
1.16 (6H, d, J = 6.4 Hz); 19F NMR (CDCl3, 470 MHz):
À52.3 (2F, s);
13C NMR (CDCl3, 125.8 MHz):
174.9 (t, J = 23.4 Hz), 147.2, 114.2
(t, J = 319.1 Hz), 96.9, 61.6, 54.7, 49.8, 43.3, 20.2, 19.2; IR (cmÀ1
d, J = 12.4 Hz), 3.96–3.89 (1H, m), 3.66–3.60 (1H, m), 1.24 (6H, d,
J = 6.8 Hz), 1.21 (6H, d, J = 6.8 Hz). 19F NMR (CDCl3, 470 MHz):
d
d
À61.0 (2F, s). 13C NMR (CDCl3, 125.8 MHz):
d
180.1 (t, J = 23.7 Hz),
d
152.6, 117.1 (t, J = 320.2 Hz), 85.8, 51.0, 49.8, 24.2, 20.2. IR (cmÀ1
,
,
KBr): 3451, 2985, 1563, 1308, 935. EI-MS (m/z): 285 (M + 2+, 15),
283 (M+, 15), 204 (43), 154 (100). HRMS calcd for C10H16ONF2Br:
283.0383, found: 283.0383.
KBr): 2974, 1586, 1134, 690; EI-MS (m/z): 326 (M + 2+, 6), 324 (M+,
6), 245 (100), 174 (26), 124 (26); HRMS calcd for C12H19ON2F2Br:
324.0649, found: 324.0648.

X. Fang et al. / Journal of Fluorine Chemistry 129 (2008) 1167–1172
1171
4.3.4. 2-Bromo-1-(3-tert-butyl-1-isopropyl-1,2,3,4-
gas was evolved and the flask became warm. After stirring for
15 min, a clear solution was obtained. Then cyclic enone (1 mmol)
1b was added all at once, and the solution was allowed to stir at
0 8C for 30 min. The reaction mixture was poured into 10 ml of
water, and the mixture was extracted with CHCl3 (3 Â 10 ml). The
combined organic layer was washed with 30 ml water to remove
the DMF, then dried over Na2SO4 and concentrated by rotary
evaporation at reduced pressure. The resulting oil was purified by
flash column chromatography on silica gel.
tetrahydropyrimidin-5-yl)-2,2-difluoroethanone (3d)
1H NMR (CDCl3, 500 MHz):
d 7.78 (1H, s), 3.99 (2H, s), 3.61–3.54
(1H, m), 3.52 (2H, s), 1.26 (6H, d, J = 6.0 Hz), 1.16 (9H, s); 19F NMR
(CDCl3, 470 MHz):
d
À52.5 (2F, s); 13C NMR (CDCl3, 125.8 MHz):
d
174.7 (t, J = 23.6 Hz), 147.1, 114.1 (t, J = 318.8 Hz), 98.5, 59.1, 55.0,
54.3, 41.3, 25.5, 20.2; IR (cmÀ1, KBr): 2973, 1586, 1131, 689; EI-MS
(m/z): 340 (M + 2+, 6), 338 (M+, 6), 259 (100), 203 (32), 124 (25), 70
(50); HRMS calcd for C13H21ON2F2Br: 338.0805, found: 338.0805.
4.4. Procedure for preparation of Iodoenone
4.6.1. 2-(4-Chlorophenylthio)-1-(4,5-dihydrofuran-3-yl)-2,2-
difluoroethanone (6a)
To the stirred solution of enone 1a (19 mmol) in 5 ml CHCl3 was
added a solution of ICl (19 mmol) in 3 ml CHCl3 at 0 8C. After 1 h
pyridine (21 mmol) was added to the reaction mixture with
stirring at 0 8C. The reaction mixture was stirred for 1–2 h at 20 8C,
then water (50 ml) was added, the water phase was extracted with
hexane (3 Â 10 ml). The combined organic layers were dried by
MgSO4 and the slovent was evaporated in vacuo to give the crude
compound 4 as red oil.
1H NMR (CDCl3, 500 MHz):
d 7.64 (1H, s), 7.55 (2H, d, J = 8.5 Hz),
7.38 (2H, d, J = 8.5 Hz), 4.62 (2H, t, J = 9.8 Hz), 2.93 (2H, t, J = 9.8 Hz).
19F NMR (CDCl3, 470 MHz):
125.8 MHz):
d
À78.4 (2F, s). 13C NMR (CDCl3,
d
182.8 (t, J = 27.6 Hz), 165.0 (t, J = 7.5 Hz), 139.6,
135.0, 131.2, 125.5 (t, J = 290.2 Hz), 125.4, 115.9, 75.2, 28.9. IR
(cmÀ1, KBr): 3085, 1647, 1574, 1180, 1074, 822. EI-MS (m/z): 292
(M + 2+, 2), 290 (M+, 5), 97 (100). HRMS calcd for C12H9O2ClF2S:
289.9980, found: 289.9980.
4.4.1. (Z)-1-Bromo-4-ethoxy-1,1-difluoro-3-iodobut-3-en-2-one (4)
4.6.2. 1-(4,5-Dihydrofuran-3-yl)-2,2-difluoro-2-(p-
1H NMR (CDCl3, 500 MHz):
d
7.95 (1H, s), 4.44 (2H, q, J = 7.1 Hz),
tolylthio)ethanone (6b)
1.5 (3H, t, J = 7.1 Hz). 19F NMR (CDCl3, 470 MHz):
NMR (CDCl3, 125.8 MHz):
d
À54.5 (2F, s). 13
C
1H NMR (CDCl3, 500 MHz):
d 7.52 (1H, s), 7.42 (2H, d, J = 8.0 Hz),
d
177.6 (t, J = 26.3 Hz), 169.1 (t,
7.13 (2H, d, J = 8.0 Hz), 4.53 (2H, t, J = 9.7 Hz), 2.84 (2H, t, J = 9.7 Hz),
J = 6.7 Hz), 112.0 (t, J = 319.1 Hz), 75.1, 73.6, 16.1. IR (cmÀ1
,
2.31 (3H, s). 19F NMR (CDCl3, 470 MHz):
(CDCl3, 125.8 MHz): d 180.5 (t, J = 27.6 Hz), 162.2 (t, J = 7.2 Hz),
d
À79.5 (2F, s). 13C NMR
KBr): 2985, 1686, 1598, 1234, 933, 869. EI-MS (m/z): 356
(M + 2+, 15), 354 (M+, 15), 225 (100), 197 (93). HRMS calcd for
C6H6O2F2BrI: 353.8564, found: 353.8564.
139.8, 135.8, 129.0, 122.7 (t, J = 290.0 Hz), 120.6, 113.4, 72.4, 26.3,
20.3. IR (cmÀ1, KBr): 3084, 1651, 1578, 1136, 1072, 814. EI-MS (m/
z): 270 (M+, 17), 97 (100). HRMS calcd for C13H12O2F2S: 270.0526,
found: 270.0526.
4.5. General procedure for the synthesis of
a-iodoenaminones
PhNH2 (8 mmol)wasaddeddropwisetothesolutionofiodoenone
4 (4 mmol) in acetonitrile (10 ml) under stirring at 0 8C. The mixture
was stirred at room temperature for 10 h to complete the reaction,
thenthemixturewastreatedwithabout30 mlofwaterandextracted
with 3 Â 20 ml of ether. The combined organic layer was washed
with saturated brine solution and dried over anhydrous sodium
sulfate.Afterevaporationofether,thecrudeproductwassubjectedto
column chromatography to give the pure product 5a.
4.6.3. 2-(4-Chlorophenylthio)-1-(5,6-dihydro-4H-pyran-3-yl)-2,2-
difluoroethanone (6c)
1H NMR (CDCl3, 500 MHz):
d 7.90 (1H, s), 7.47 (2H, d, J = 8.5 Hz),
7.29 (2H, d, J = 8.5 Hz), 4.08 (2H, t, J = 5.3 Hz), 2.22 (2H, t, J = 6.3 Hz),
1.88–1.82 (2H, m). 19F NMR (CDCl3, 470 MHz):
NMR (CDCl3, 125.8 MHz):
d
À74.3 (2F, s). 13
C
d
182.9 (t, J = 27.2 Hz), 161.5 (t,
J = 7.4 Hz), 136.9, 135.9, 128.4, 123.5 (t, J = 291.4 Hz), 123.0,
110.4, 66.6, 19.8, 17.3. IR (cmÀ1, KBr): 2959, 1653, 1591, 1075,
817. EI-MS (m/z): 306 (M + 2+, 1), 304 (M+, 2), 111 (100). HRMS
calcd for C13H11O2ClF2S: 304.0136, found: 304.0132.
4.5.1. (Z)-1-Bromo-1,1-difluoro-3-iodo-4-(phenylamino)but-3-en-2-
one (5a)
1H NMR (CDCl3, 500 MHz):
d
8.08 (1H, d, J = 13.6 Hz), 7.6 (1H, br),
4.6.4. 1-(5,6-Dihydro-4H-pyran-3-yl)-2,2-difluoro-2-(p-
7.33 (2H, t, J = 7.9 Hz), 7.14 (1H, t, J = 7.4 Hz), 7.05 (2H, d, J = 8.2 Hz).
tolylthio)ethanone (6d)
19F NMR (CDCl3, 470 MHz):
125.8 MHz):
d
À52.6 (2F, s). 13C NMR (CDCl3,
1H NMR (CDCl3, 500 MHz):
d
7.92 (1H, s), 7.42 (2H, d, J = 8.1 Hz),
7.13 (2H, d, J = 8.1 Hz), 4.08 (2H, t, J = 5.3 Hz), 2.3 (3H, s), 2.22 (2H, t,
J = 6.3 Hz), 1.87–1.82 (2H, m). 19F NMR (CDCl3, 470 MHz):
À75.4
(2F, s). 13C NMR (CDCl3, 125.8 MHz):
183.3 (t, J = 27.2 Hz), 161.4
(t, J = 7.2 Hz), 139.7, 135.7, 128.9, 123.3 (t, J = 290.0 Hz), 120.8,
110.6, 66.5, 20.3, 19.8, 17.3. IR (cmÀ1, KBr): 2966, 1652, 1588, 1070,
832. EI-MS (m/z): 284 (M+, 12), 111 (100). HRMS calcd for
d
174.3 (t, J = 25.0 Hz), 147.3 (t, J = 6.7 Hz), 137.3, 129.2,
124.8, 116.7, 110.3 (t, J = 319.6 Hz), 70.6. IR (cmÀ1, KBr): 3292, 1584,
1144, 935. EI-MS (m/z):403 (M + 2+, 18), 401 (M+, 18), 272 (100), 146
(26). HRMS calcd for C10H7ONF2BrI: 400.8724, found: 400.8725.
d
d
4.5.2. (Z)-1-Bromo-1,1-difluoro-3-iodo-4-(isopropylamino)but-3-
en-2-one (5b)
C14H14O2F2S: 284.0683, found: 284.0683.
1H NMR (CDCl3, 500 MHz):
d 7.64 (1H, d, J = 14.1 Hz), 5.91 (1H,
br), 3.88–3.75 (1H, m), 1.39 (6H, d, J = 6.6 Hz). 19F NMR (CDCl3,
Acknowledgement
470 MHz):
d
À52.0 (2F, s). 13C NMR (CDCl3, 125.8 MHz):
d 175.0 (t,
J = 24.7 Hz), 154.0, 112.3 (t, J = 318.1 Hz), 67.8, 51.3, 24.2. IR (cmÀ1
,
This research work was supported by the National Natural
Science Foundation of China (Grant No. 20672034).
KBr): 3289, 2976, 1603, 1136, 909. EI-MS (m/z): 369 (M + 2+, 18),
367 (M+, 18), 238 (100), 196 (28). HRMS calcd for C10H7ONF2BrI:
366.8880, found: 366.8880.
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