A cascade process for the synthesis of gem-difluoromethylene compounds

Article abstract of DOI:10.1039/c1ob00027f

An efficient strategy for the synthesis of 2,2-difluoro-2,3-dihydrofuran derivatives from β-fluoroalkyl-β-enaminoketones is described. The reaction occurred via an intramolecular halophilic attack-initiated cascade process. A series of 2,3-dihydrofurans w

Full text of DOI:10.1039/c1ob00027f

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A cascade process for the synthesis of gem-difluoromethylene compounds†
Zixian Chen,a,b Jiangtao Zhu,a Haibo Xie,a Shan Li,a Yongming Wu*a and Yuefa Gong*b
Received 6th January 2011, Accepted 9th March 2011
DOI: 10.1039/c1ob00027f
An efficient strategy for the synthesis of 2,2-difluoro-2,3-dihydrofuran derivatives from
b-fluoroalkyl-b-enaminoketones is described. The reaction occurred via an intramolecular halophilic
attack-initiated cascade process. A series of 2,3-dihydrofurans were prepared in high yields. And an
intermolecular domino process achieved providing polysubstituted furans. The mechanism of the
reaction is discussed.
order to improve their pharmacological properties. The CF2/CH2
transposition has been recognized as a valuable tool in the
Introduction
Halophilic reactions were observed many years ago,1 and
substrates such as halogenated aliphatic nitro-compounds,2
perhaloalkanes,3 N-halo-acetanlides,4 and succinimides,5 and a-
halosulfones6 could be attacked directly by nucleophiles on their
halogen atoms rather than halogen-bound carbon atoms, followed
by the formation of reactive carbanion intermediates, which
diversify into many products (Scheme 1). A lot of nitrogen, oxygen,
sulfur and carbon based nucleophiles can be employed in this
interesting transformation.
blockage of metabolic processes,9 as fluorine is the smallest
replacement for hydrogen in the C–H bond,10 and its substitution
introduces only small steric and geometric perturbations which
are generally recognized by macromolecular recognition sites.
Moreover, the difluoromethylene group has also been regarded
as an isopolar–isosteric replacement for oxygen and extensively
used to modify nucleoside and phosphate analogues.11 In addition,
using this subunit as a surrogate for a carbonyl group was also
reported recently.12
Due to the ongoing interest in the synthesis of fluorinated
compounds,13 our group has communicated a convenient method
for the synthesis of a useful fluorine-containing building block, b-
fluoroalkyl-b-enaminoketones.14 While we tried to investigate the
cyclization reaction of this synthon under conditions involving
a transition-metal, a 2,2-difluoro-2,3-dihydrofuran product was
formed through a halophilic attack initiated cascade process. As
dihydrofuran and furan derivatives are important heterocyclic
compounds commonly found in natural products and biologically
relevant compounds,15 and methods for the synthesis of their
fluoro-analogs are limited, the importance of this strategy becomes
self-explanatory. Herein we wish to report a detailed investigation
of the scope and limitations of this strategy, and the reaction
mechanism is also discussed.
Scheme 1 General equation for halophilic reactions.
Different from carbophilic reactions (SNC) which have a sig-
nificant impact in organic chemistry, the halophilic reaction is
observed only when the reactant 1 contains one or more electron-
withdrawing groups at the a-C atom, thus providing the necessary
stabilization of the active carbanion 3.7 Various fluorinated halides
with structures that satisfy the requirements are particularly suit-
able for this type of reaction. A series of fluorinated compounds
(Rf-OR, Rf-SR, Rf-NR, etc.) are synthesized conveniently through
this halophilic attack-initiated nucleophilic substitution protocol.8
The selective introduction of a gem-difluoromethylene moiety
into organic compounds has attracted a lot of attention in
recent years due to the unique properties of this group. gem-
Difluorination is often used on biologically active compounds in
Results and discussion
Initially, we chose 4-bromo-4,4-difluoro-3-((4-methoxyphenyl)-
amino)-1-phenylbut-2-en-1-one 1a as the model substrate to
optimize the reaction conditions (Table 1).14 As previously com-
municated, the cyclization took place when DMF was used
as the solvent, however, the temperature could be reduced to
60 ◦C. Common inorganic bases such as K3PO4 and K2CO3 could
afford the product in good yields, while Na2CO3 was inefficient
probably due to its poor solubility compared with sylvites. An
organic base which was screened but this only led to recovery of the
material. Among the other solvents evaluated, only CH3CN could
give moderate yield. Further attempts to decrease the amount of
aKey laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai,
200032, China. E-mail: ymwu@mail.sioc.ac.cn; Fax: (+86) 21-54925192
bSchool of Chemistry and Chemical Engineering, Huazhong University of
Science and Technology, Wuhan, Hubei, 430074, China. E-mail: gongyf@
mail.hust.edu.cn
† Electronic supplementary information (ESI) available: NMR data.
CCDC reference number 806367. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1ob00027f
3878 | Org. Biomol. Chem., 2011, 9, 3878–3885
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Table 1 Optimization of reaction conditionsa
Table 3 One-pot synthesis of dihydrofuransa
Entry
R1
R2
Product
Yield (%)b
1
2
3
4
5
6
7
8
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-CF3C6H4
2-CF3C6H4
4-COOEtC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2c
2d
2e
2o
2p
2q
2r
2s
2t
81
82
89
70
66
70
81
60
74
54
Entry
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
K3PO4
K2CO3
Na2CO3
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
CH3CN
Toluene
THF
84
84
15
—
40
—
—
67c
4-MeC6H4
3-MeOC6H4
4-FC6H4
4-BrC6H4
9
10
2u
DMF
a Reactions were carried out on a 0.5 mmol scale with LiHMDS (2.0 eq.)
and methyl ketones (1.0 eq.), then K2CO3 (2.0 eq.) and DMF (4 mL) at
60 ◦C unless otherwise stated. b Isolated yields.
a Reactions were carried out on a 0.2 mmol scale with K2CO3 (2.0 eq.) and
solvent (2 mL) at 60 ◦C unless otherwise stated. b Isolated yields. c K2CO3
(1.2 eq.) was used.
with substituents meta or ortho to the nitrogen both proceeded
well. Modifying the R2 group revealed that both electron-rich
and electron-poor aryl rings could give favourable yields (Table 2,
entries 9–14).
base used under the ascertained conditions led to a decrease in
yield.
Having established suitable reaction conditions, we explored
the scope and generality of the methodology starting with b-
fluoroalkyl-b-enaminoketones, which could be prepared from
the condensation of methyl ketones with fluoroalkylimidoyl
chlorides.16 As displayed in Table 2, when the CF2Cl group was
used in place of CF2Br (Table 2, entry 1), the corresponding
product was formed only in moderate yield due to the inertness
of the C–Cl bond.3c Next, the substituents of the enaminoketones
were investigated. When R1 was an aromatic ring with an electron-
donating group, the products were isolated in good yields (Table 2,
entries 3–5), while electron-withdrawing groups led to a decline in
yields (Table 2, entries 6–8), especially the NO2 group. Substrates
The high efficiency of this cyclization reaction under mild
conditions motivated us to explorer the feasibility of forming
the products through a one-pot process from fluoroalkylimidoyl
chlorides and methyl ketones. However, we soon realized that
these two steps could not be carried out under the same reaction
medium, and a sequential process was established finally based on
the addition of DMF and K2CO3 to the crude mixture derived
from the condensation of methyl ketones with fluoroalkylimidoyl
chlorides in THF after evaporation of the volatile materials. Then
the scope and generality of the consecutive process was studied.
Changing the R1 group still indicated that the reactivity was
affected by the electronic effects of the substituents, as shown
by comparing the results of the electron donating groups (Table 3,
entries 1–3) with the electron withdrawing groups (Table 3, entries
4–6). However, different from the stepwise procedure, the electron-
poor R2 group afforded the products in moderate yields (Table 3,
entries 9–10). This may result from the low conversion of the prior
(condensation) step.
Table 2 Cyclization of b-fluoroalkyl-b-enaminoketonesa
Entry
R1
R2
Product
Yield (%)b
Surprisingly, novel 3,3-difluoroindoline compounds were ob-
tained as the only detectable products (Fig. 1), while expanding
the reaction scope with b-enaminoalkylketone 1v and b-enamino
ester 1w (Scheme 2). However, attempts to improve the yields for
these types of heterocycles were unsuccessful.17
1
2
3
4
5
6
7
8
4-MeOC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
52c
82
84
90
99
87
83
46
71
73
83
81
79
80
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-ClC6H4
3-ClC6H4
4-NO2C6H4
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
9
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
2-Naphthyl
2-Naphthyl
10
11
12
13
14
a Reactions were carried out on a 0.5 mmol scale with K2CO3 (2.0 eq.) and
DMF (4 mL) at 60 ◦C unless otherwise stated. b Isolated yields.
Fig. 1 X-Ray structure of 2v.
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Scheme 2 Synthesis of indolines.
Based on the above observations, a possible mechanism of this
transformation is proposed in Scheme 3. As the 1,4-dinitrobenzene
added could not inhibit the reaction, a single electron transfer
(SET) course can be excluded. The b-enaminoketone is initially
deprotonated by base, and subsequent intramolecular halophilic
attack occurred after the generation of the enolate anion. The
generated active carbanion c is rapidly transformed into vinyl
amide d, forming a six-membered ring to stabilize the Br–O
bond. Then the oxygen anion might be regenerated (e) which
generated dihydrofuran products 2 by nucleophilic addition to the
gem-difluorovinyl.18 In the case of b-enaminoalkylketone and b-
enamino ester, the indoline product 2v/2w may be formed through
nucleophilic addition of the carbanion to the gem-difluorovinyl,
isomerised from the initially formed amide. And the formation
of these products can also exclude the simple intramolecular
nucleophilic substitution pathway, as the CF2Br group is hard
to undergo such a reaction by a carbanion due to its unique
property.19
Scheme 4 Cascade strategy.
With these dihydrofurans in hand and the expectation to
diversify the variety of fluoro-furan compounds, some derivation
reactions were developed (Scheme 5). While we used a standard
Mg participated defluorination reaction to synthesize the aroma-
tized furan ring,21 a mono fluorine dihydrofuran 3a was produced
without aromatization. And reduction of the 2,2-difluoro-2,3-
dihydrofuran with NaBH4 in the presence of trifluoroacetic acid
(TFA) at 0 ◦C yielded the 2,2-difluoro-3-amino-dihydrofuran 4a.22
Scheme 5 Product derivation.
Conclusions
In conclusion, an efficient strategy for the synthesis of fluoro-
furan derivates by the cascade reaction of fluoroalkylimidoyl
chlorides and methyl ketones was developed. A wide variety of
functionalized 2,2-difluoro-2,3-dihydrofurans can be synthesized
in good yields under mild conditions, and several fully substituted
2,3-dihydrofurans were also obtained according to the proposed
mechanism, rendering this method particularly attractive for the
efficient preparation of biologically and medicinally interesting
molecules.
Scheme 3 Proposed mechanism.
We also interested in whether the resonance structure a
(Scheme 3) could react with some electrophilic reagents as reported
in the literature (Scheme 4).20 As expected, an intermolecular
reaction with ethyl propiolate and methyl propiolate was accom-
plished forming the fully substituted dihydrofurans as the major
products besides the intramolecular products. However, when we
introduce the alkynyl moiety into the N-aryl ring of the substrate
in order to synthesis a polycyclic compound, a quinoline product
2z was obtained through a quick aromatization process which
inhibited the formation of the oxygen anion, which complements
our previously reported fluorinated quinoline synthesis.13c The
condition for synthesis of this 2-fluoroalkylquinoline was also
optimized delivering an 84% yield (DBU 2 eq., THF, 60 ◦C).
Experimental section
General experimental
Melting points were measured on a Melt-Temp apparatus and
1
uncorrected. HNMR spectra were recorded in CDCl3 and d-
DMSO on a Bruker AM-300 spectrometer (300 MHz) with TMS
as the internal standard. 19F NMR spectra were taken on a Bruker
AM-300 (282 MHz) spectrometer using CFCl3 as the external
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standard. 13C NMR spectra were taken on a Bruker AM-400
(100 MHz) spectrometer. IR spectra were obtained with a Nicolet
AV-360 spectrophotometer. Elemental analysis was performed
by the Analytical Laboratory of Shanghai Institute of Organic
Chemistry. Mass spectra were recorded by EI and ESI methods,
HRMS (ESI) was measured on a Bruker Daltonics APEXIII
7.0 TESLA FTMS. Solvents and reagents were purchased from
commercial sources and used as received. THF was distilled from
sodium. All reactions were monitored by TLC with silica gel
coated plates. Flash column chromatography was carried out
using 300–400 mesh silica gel at increased pressure and petroleum
ether/ethyl acetate combination was used as the eluent
N, 4.55; IR (KBr): 1651, 1608, 1589, 1449, 1277, 1144, 1119, 1017,
761, 678 cm-1.
N-(2,2-Difluoro-5-phenylfuran-3(2H)-ylidene)-3-methylaniline
(2d)
Yellow solid, mp 74–76 ◦C; 1H NMR (300 MHz, CDCl3) d 7.77–
7.64 (m, 2H), 7.54–7.37 (m, 3H), 7.27 (t, J = 7.8 Hz, 1H), 7.02
(d, J = 7.3 Hz, 1H), 6.91–6.80 (m, 2H), 6.23 (s, 1H), 2.37 (s, 3H);
19F NMR (282 MHz, CDCl3) d -78.86; 13C NMR (100 MHz, d-
DMSO) d 170.9, 158.6 (t, J = 24.2 Hz), 149.3, 139.5, 133.8, 129.9,
129.8, 127.6, 127.4, 127.2, 122.5, 122.3 (t, J = 264.5 Hz), 119.1,
95.4, 21.6; LRMS-EI m/z (relative intensity) 285 (54) [M+], 102
(100); Anal. calcd for C17H13F2NO: C, 71.57; H, 4.59; N, 4.91.
Found: C, 71.56; H, 4.88; N, 4.83; IR (KBr): 3111, 1659, 1597,
1570, 1491, 1449, 1319, 1279, 1149, 1121, 1020, 765 cm-1.
Representative procedure for the synthesis of 2
b-fluoroalkyl-b-enaminoketones 1 (0.5 mmol) was added to a
solution of K2CO3 (2.0 eq.) in DMF (4.0 mL). The solution
was then stirred at 60 ◦C until completion of the reaction as
indicated by TLC, then partitioned between ethyl acetate and
water; the organic layer was washed with brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel to provide 2.
N-(2,2-Difluoro-5-phenylfuran-3(2H)-ylidene)-2-methylaniline
(2e)
Yellow solid, mp 70–72 ◦C; 1H NMR (300 MHz, CDCl3) d 7.80–
7.70 (m, 2H), 7.58–7.41 (m, 3H), 7.29–7.07 (m, 3H), 6.83 (d, J =
7.3 Hz, 1H), 6.12 (s, 1H), 2.25 (s, 3H); 19F NMR (282 MHz,
CDCl3) d -79.10; 13C NMR (100 MHz, d-DMSO) d 170.2, 158.0
(t, J = 24.2 Hz), 147.5, 133.1, 130.5, 129.7, 129.2, 126.9, 126.7,
126.4, 125.7, 121.3 (t, J = 264.4 Hz), 119.0, 94.6, 17.2; LRMS-EI
m/z (relative intensity) 285 (66) [M+], 102 (100); HRMS-EI (m/z)
calcd for C17H13F2NO 285.0965; found 285.0962. IR (KBr): 3123,
1665, 1607, 1593, 1573, 1483, 1451, 1321, 1277, 1150, 1128, 1017,
768 cm-1.
N-(2,2-Difluoro-5-phenylfuran-3(2H)-ylidene)-4-methoxyaniline
(2a)
Yellow solid, mp 70–71 ◦C; 1H NMR (300 MHz, CDCl3) d 7.79–
7.72 (m, 2H), 7.57–7.42 (m, 3H), 7.10 (d, J = 9.1 Hz, 2H), 6.94 (d,
J = 8.7 Hz, 2H), 6.37 (t, J = 1.4 Hz, 1H), 3.84 (s, 3H); 19F NMR
(282 MHz, CDCl3) d -78.44; 13C NMR (100 MHz, d-DMSO) d
170.0, 158.4, 156.3 (q, J = 24.0 Hz), 141.8, 133.3, 129.6, 127.2,
127.1, 124.2, 122.4 (q, J = 263.3 Hz), 115.0, 95.5, 55.8; LRMS-EI
m/z (relative intensity) 301 (100) [M+], 286 (72), 133 (35), 102 (41),
77 (30); Anal. calcd for C17H13F2NO2: C, 67.77; H, 4.35; N, 4.65.
Found: C, 67.70; H, 4.36; N, 4.49; IR (KBr): 3290, 2914, 2836,
1650, 1606, 1570, 1504, 1247, 1153, 1122, 1021, 840, 771 cm-1.
4-Chloro-N-(2,2-difluoro-5-phenylfuran-3(2H)-ylidene)aniline (2f)
Yellow solid, mp 116–118 ◦C; 1H NMR (300 MHz, CDCl3) d 7.81–
7.71 (m, 2H), 7.61–7.42 (m, 3H), 7.37 (d, J = 8.7 Hz, 2H), 7.02
(d, J = 8.7 Hz, 2H), 6.23 (s, 1H); 19F NMR (282 MHz, CDCl3) d
-79.30; 13C NMR (100 MHz, d-DMSO) d 170.8, 158.9 (t, J = 24.0
Hz), 147.4, 133.2, 130.3, 129.2, 129.2, 127.0, 126.4, 123.2, 121.5
(t, J = 265.0 Hz), 94.7; LRMS-EI m/z (relative intensity) 305 (44)
[M+], 102 (100); Anal. calcd for C16H10ClF2NO: C, 62.86; H, 3.30;
N, 4.58. Found: C, 62.97; H, 3.49; N, 4.44; IR (KBr): 1657, 1604,
1571, 1483, 1281, 1175, 1150, 1088, 1017, 849, 677 cm-1.
N-(2,2-Difluoro-5-phenylfuran-3(2H)-ylidene)aniline (2b)
Yellow solid, mp 89–90 ◦C; 1H NMR (300 MHz, CDCl3) d 7.80–
7.70 (m, 2H), 7.59–7.36 (m, 5H), 7.22 (t, J = 7.8 Hz, 1H), 7.08
(d, J = 7.8 Hz, 2H), 6.26 (s, 1H); 19F NMR (282 MHz, CDCl3) d
-79.11; 13C NMR (100 MHz, d-DMSO) d 171.1, 158.8 (t, J = 23.5
Hz), 149.2, 133.8, 130.0, 129.8, 127.6, 127.1, 126.7, 122.3 (t, J =
264.9 Hz), 122.1, 95.3; LRMS-EI m/z (relative intensity) 271 (56)
[M+], 102 (100); Anal. calcd for C16H11F2NO: C, 70.84; H, 4.09;
N, 5.16. Found: C, 70.73; H, 4.36; N, 4.94; IR (KBr): 1662, 1606,
1589, 1572, 1490, 1279, 1155, 1129, 1019, 765, 698 cm-1.
3-Chloro-N-(2,2-difluoro-5-phenylfuran-3(2H)-ylidene)aniline (2g)
Yellow solid, mp 60–61 ◦C; 1H NMR (300 MHz, CDCl3) d 7.81–
7.73 (m, 2H), 7.61–7.43 (m, 3H), 7.33 (t, J = 8.0 Hz, 1H), 7.22–7.16
(m, 1H), 7.07 (t, J = 1.8 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.21
(t, J = 1.4 Hz, 1H); 19F NMR (282 MHz, CDCl3) d -79.48; 13C
NMR (100 MHz, d-DMSO) d 171.8, 160.2 (t, J = 24.2 Hz), 150.8,
134.5, 134.0, 131.7, 129.9, 127.8, 127.0, 126.3, 122.1 (t, J = 264.8
Hz), 121.6, 120.6, 95.3; LRMS-EI m/z (relative intensity) 305 (41)
[M+], 102 (100); Anal. calcd for C16H10ClF2NO: C, 62.86; H, 3.30;
N, 4.58. Found: C, 62.59; H, 3.40; N, 4.40; IR (KBr): 1665, 1605,
1584, 1571, 1492, 1470, 1320, 1280, 1156, 1020, 766 cm-1.
N-(2,2-Difluoro-5-phenylfuran-3(2H)-ylidene)-4-methylaniline
(2c)
Yellow solid, mp 102–104 ◦C; 1H NMR (300 MHz, CDCl3) d 7.74
(d, J = 8.7 Hz, 2H), 7.57–7.41 (m, 3H), 7.21 (d, J = 8.2 Hz, 2H),
7.00 (d, J = 8.2 Hz, 2H), 6.31 (s, 1H), 2.38 (s, 3H); 19F NMR
(282 MHz, CDCl3) d -78.80; 13C NMR (100 MHz, d-DMSO) d
170.0, 157.3 (t, J = 23.4 Hz), 146.0, 135.6, 133.0, 129.8, 129.1,
126.8, 126.5, 121.7 (t, J = 264.8 Hz), 121.6, 94.8, 20.5; LRMS-EI
m/z (relative intensity) 285 (63) [M+], 102 (100); Anal. calcd for
C17H13F2NO: C, 71.57; H, 4.59; N, 4.91. Found: C, 71.41; H, 4.75;
N-(2,2-Difluoro-5-phenylfuran-3(2H)-ylidene)-4-nitroaniline (2h)
◦
1
Yellow solid, mp 199–202 C; H NMR (300 MHz, d-DMSO) d
8.32 (d, J = 9.1 Hz, 2H), 7.99 (d, J = 7.3 Hz, 2H), 7.74–7.53 (m,
3H), 7.36 (d, J = 9.1 Hz, 2H), 6.99 (s, 1H); 19F NMR (282 MHz,
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d-DMSO) d -75.71; 13C NMR (100 MHz, d-DMSO) d 171.9,
160.6 (t, J = 24.0 Hz), 154.7, 144.7, 133.7, 129.3, 127.2, 126.1,
125.1, 121.9, 121.2 (t, J = 264.9 Hz), 94.6; LRMS-EI m/z (relative
intensity) 316 (63) [M+], 102 (100); Anal. calcd for C16H10F2N2O3:
C, 60.76; H, 3.19; N, 8.86. Found: C, 60.72; H, 3.12; N, 8.56; IR
(KBr): 1652, 1596, 1581, 1568, 1509, 1485, 1450, 1338, 1320, 1155,
1126, 1108, 1016, 768 cm-1.
2.67; N, 4.12. Found: C, 56.38; H, 2.79; N, 3.82; IR (KBr): 1590,
1483, 1406, 1279, 1152, 1104, 1089, 1008, 836, 802 cm-1.
N-(2,2-Difluoro-5-(naphthalen-2-yl)furan-3(2H)-ylidene)-4-
methoxyaniline (2m)
◦
1
Yellow solid, mp 153–155 C; H NMR (300 MHz, d-DMSO) d
8.58 (s, 1H), 8.17–7.95 (m, 4H), 7.72–7.59 (m, 2H), 7.32–7.20 (m,
3H), 7.06 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H); 19F NMR (282 MHz,
d-DMSO) d -77.15; 13C NMR (100 MHz, d-DMSO) d 169.4,
158.0, 155.8 (t, J = 23.6 Hz), 141.5, 134.6, 132.3, 129.2, 128.8,
128.7, 127.8, 127.3, 127.2, 124.0, 123.8, 123.0, 122.1 (t, J = 264.2
Hz), 114.5, 95.6, 55.3; LRMS-EI m/z (relative intensity) 351 (100)
[M+], 336 (59), 152 (78); Anal. calcd for C21H15F2NO2: C, 71.79; H,
4.30; N, 3.99. Found: C, 71.73; H, 4.64; N, 3.81; IR (KBr): 2838,
1605, 1561, 1503, 1296, 1245, 1145, 1129, 1030, 792 cm-1.
N-(2,2-Difluoro-5-(4-methoxyphenyl)furan-3(2H)-ylidene)-4-
methoxyaniline (2i)
◦
1
Yellow solid, mp 119–120 C; H NMR (300 MHz, CDCl3) d
7.71 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 7.00–6.90 (m,
4H), 6.23 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H); 19F NMR (282 MHz,
CDCl3) d -79.58; 13C NMR (100 MHz, d-DMSO) d 169.6, 163.0,
157.7, 156.0 (t, J = 23.9 Hz), 141.6, 128.9, 123.6, 122.1 (t, J =
263.3 Hz), 118.9, 114.7, 114.4, 92.9, 55.6, 55.3; LRMS-EI m/z
(relative intensity) 331 (100) [M+], 316 (86), 132 (57); Anal. calcd
for C18H15F2NO3: C, 65.25; H, 4.56; N, 4.23. Found: C, 65.28; H,
4.59; N, 4.02; IR (KBr): 2944, 2838, 1606, 1502, 1264, 1245, 1151,
1117, 1024, 839 cm-1.
4-Chloro-N-(2,2-difluoro-5-(naphthalen-2-yl)furan-3(2H)-
ylidene)aniline (2n)
◦
1
Yellow solid, mp 146–147 C; H NMR (300 MHz, d-DMSO) d
8.60 (s, 1H), 8.20–7.96 (m, 4H), 7.74–7.60 (m, 2H), 7.54 (d, J =
8.7 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.13 (s, 1H); 19F NMR
(282 MHz, d-DMSO) d -78.31; 13C NMR (100 MHz, d-DMSO)
d 166.0, 154.3 (t, J = 24.1 Hz), 142.8, 130.1, 127.5, 125.6, 124.6,
124.6, 124.2, 123.1, 122.9, 122.6, 119.0, 118.6, 118.3, 116.9 (t, J =
265.0 Hz), 90.4; LRMS-EI m/z (relative intensity) 355 (63) [M+],
152 (100); Anal. calcd for C20H12ClF2NO: C, 67.52; H, 3.40; N,
3.94. Found: C, 67.53; H, 3.48; N, 3.78; IR (KBr): 1604, 1590,
1562, 1483, 1294, 1145, 1113, 1032, 790 cm-1.
4-Chloro-N-(2,2-difluoro-5-(4-methoxyphenyl)furan-3(2H)-
ylidene)aniline (2j)
Yellow solid, mp 138–140 ◦C; 1H NMR (300 MHz, CDCl3) d 7.94
(d, J = 9.2 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz,
2H), 7.11 (d, J = 9.1 Hz, 2H), 6.84 (s, 1H), 3.87 (s, 3H); 19F NMR
(282 MHz, CDCl3) d -78.52; 13C NMR (100 MHz, d-DMSO) d
170.8, 163.3, 159.0 (t, J = 24.7 Hz), 147.7, 129.9, 129.2, 123.2, 121.7
(t, J = 264.1 Hz), 118.6, 114.8, 92.5, 55.6; LRMS-EI m/z (relative
intensity) 335 (71) [M+], 132 (100); HRMS-EI (m/z) calcd for
C17H12ClF2NO2 335.0525; found 335.0527; IR (KBr): 1603, 1506,
1485, 1320, 1257, 1150, 1111, 1024, 837, 800 cm-1.
Representative procedure for the one-pot synthesis of 2
Fluoroalkylimidoyl chlorides (0.5 mmol) and methyl ketones (1.0
eq.) were added to 2.0 mL anhydrous THF. Then LiHMDS (2.0
eq. in THF) was added dropwise at 0 ◦C, the solution was stirred
for a further 20 min, then concentrated in vacuo. The residue was
next dissolved with 4 mL DMF, and K2CO3 (2.0 eq.) was added.
The mixture was then stirred at 60 ◦C until completion of reaction
as indicated by TLC, then partitioned between ethyl acetate and
water, the organic layer was washed with brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel to provide 2.
N-(5-(4-Chlorophenyl)-2,2-difluorofuran-3(2H)-ylidene)-4-
methoxyaniline (2k)
Yellow solid, mp 125–127 ◦C; 1H NMR (300 MHz, CDCl3) d 7.69
(d, J = 8.7 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.7 Hz,
2H), 6.95 (d, J = 9.1 Hz, 2H), 6.37 (s,1H), 3.84 (s, 3H); 19F NMR
(282 MHz, CDCl3) d -78.15; 13C NMR (100 MHz, d-DMSO) d
168.3, 158.0, 155.5 (t, J = 23.9 Hz), 141.3, 137.5, 129.3, 128.4,
125.5, 123.8, 121.9 (t, J = 264.0 Hz), 114.5, 95.7, 55.3; LRMS-EI
m/z (relative intensity) 335 (100) [M+], 320 (71), 133 (42); Anal.
calcd for C17H12ClF2NO2: C, 60.82; H, 3.60; N, 4.17. Found: C,
60.69; H, 3.96; N, 4.09; IR (KBr): 1606, 1592, 1503, 1292, 1248,
1153, 1091, 1025, 1009, 836 cm-1.
N-(2,2-Difluoro-5-phenylfuran-3(2H)-ylidene)-4-
(trifluoromethyl)aniline (2o)
◦
1
Yellow solid, mp 105–108 C; H NMR (300 MHz, d-DMSO) d
8.00 (d, J = 8.7 Hz, 2H), 7.81 (d, J = 8.7 Hz, 2H), 7.71–7.52 (m,
3H), 7.32 (d, J = 8.2 Hz, 2H), 6.99 (s, 1H); 19F NMR (282 MHz,
d-DMSO) d -62.78 (s, 3F), -81.18 (s, 2F); 13C NMR (100 MHz,
d-DMSO) d 172.0, 160.6 (t, J = 24.2 Hz), 152.7, 133.9, 129.7,
127.6, 127.0 (t, J = 3.6 Hz), 126.8, 126.5 (t, J = 32.2 Hz), 124.8 (t,
J = 272.2 Hz), 122.1, 121.8 (t, J = 264.8 Hz), 95.0; LRMS-EI m/z
(relative intensity) 339 (81) [M+], 338 (47), 102 (100); Anal. calcd
for C17H10F5NO: C, 60.18; H, 2.97; N, 4.13. Found: C, 60.06; H,
3.05; N, 3.89; IR (KBr): 1657, 1594, 1572, 1491, 1320, 1282, 1163,
1107, 1065, 1012, 861, 766 cm-1.
4-Chloro-N-(5-(4-chlorophenyl)-2,2-difluorofuran-3(2H)-
ylidene)aniline (2l)
Yellow solid, mp 144–146 ◦C; 1H NMR (300 MHz, CDCl3) d 7.69
(d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz,
2H), 7.01 (d, J = 8.6 Hz, 2H), 6.22 (s, 1H); 19F NMR (282 MHz,
CDCl3) d -78.99; 13C NMR (100 MHz, d-DMSO) d 170.2, 159.5 (t,
J = 24.2 Hz), 148.0, 138.7, 131.1, 130.1, 130.0, 129.4, 125.9, 123.9,
122.2 (t, J = 265.2 Hz), 96.0; LRMS-EI m/z (relative intensity) 339
(54) [M+], 136 (100); Anal. calcd for C16H9Cl2F2NO: C, 56.50; H,
3882 | Org. Biomol. Chem., 2011, 9, 3878–3885
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N-(2,2-Difluoro-5-phenylfuran-3(2H)-ylidene)-2-
(trifluoromethyl)aniline (2p)
-105.11 (m, 1F). 13C NMR (100 MHz, d-DMSO) d 169.8, 165.1
(d, J = 252.8 Hz), 158.4 (t, J = 24.0 Hz), 148.9, 130.1 (d, J =
9.3 Hz), 129.7, 126.4, 123.5, 122.0 (t, J = 264.8 Hz), 121.8, 116.8
(d, J = 22.3 Hz), 94.9; LRMS-EI m/z (relative intensity) 289 (84)
[M+], 120 (100); Anal. calcd for C16H10F3NO: C, 66.44; H, 3.48;
N, 4.84. Found: C, 66.52; H, 3.48; N, 4.78; IR (KBr): 3100, 3073,
1658, 1605, 1579, 1504, 1483, 1416, 1242, 1146, 1119, 812, 755,
700 cm-1.
Yellow solid, mp 88–91 ◦C; 1H NMR (300 MHz, d-DMSO) d 7.99
(d, J = 8.6 Hz, 2H), 7.84–7.52 (m, 5H), 7.46 (t, J = 7.8 Hz, 1H), 7.21
(d, J = 8.7 Hz, 1H), 6.88 (s, 1H); 19F NMR (282 MHz, d-DMSO)
d -59.66 (s, 3F), -79.94 (s, 2F); 13C NMR (100 MHz, d-DMSO)
d 172.2, 160.8 (t, J = 24.2 Hz), 147.7, 134.3, 134.0, 129.7, 126.9 (t,
J = 5.2 Hz), 126.7, 126.1, 124.2 (t, J = 272.9 Hz), 121.6 (t, J = 264.8
Hz), 121.3, 120.9, 118.9, 95.0; LRMS-EI m/z (relative intensity)
339 (83) [M+], 102 (100); Anal. calcd for C17H10F5NO: C, 60.18; H,
2.97; N, 4.13. Found: C, 60.23; H, 3.10; N, 4.00; IR (KBr): 1670,
1597, 1572, 1487, 1451, 1319, 1280, 1160, 1131, 1035, 762 cm-1.
N-(5-(4-Bromophenyl)-2,2-difluorofuran-3(2H)-ylidene)aniline
(2u)
◦
1
Yellow solid, mp 57–60 C; H NMR (300 MHz, d-DMSO) d
7.90 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.49 (t, J =
7.3 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 8.2 Hz, 2H),
7.06 (s, 1H); 19F NMR (282 MHz, d-DMSO) d -78.19; 13C NMR
(100 MHz, d-DMSO) d 169.8, 158.4 (t, J = 24.2 Hz), 149.0, 132.8,
129.9, 129.2, 127.4, 126.7, 126.2, 122.0 (t, J = 264.9 Hz), 121.9,
95.9; LRMS-EI m/z (relative intensity) 349 (100) [M+], 351 (100),
182 (77), 180 (76); Anal. calcd for C16H10BrF2NO: C, 54.88; H,
2.88; N, 4.00. Found: C, 54.99; H, 3.16; N, 3.78; IR (KBr): 1604,
1588, 1483, 1404, 1272, 1155, 1070, 1008 cm-1.
Ethyl 4-((2,2-difluoro-5-phenylfuran-3(2H)-
ylidene)amino)benzoate (2q)
Yellow solid, mp 95–97 ◦C; 1H NMR (300 MHz, d-DMSO) d 8.05
(d, J = 8.2 Hz, 2H), 7.99 (d, J = 7.3 Hz, 2H), 7.67 (t, J = 7.3 Hz,
1H), 7.57 (t, J = 7.3 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 6.96 (s,
1H), 4.35 (q, J = 6.9 Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H); 19F NMR
(282 MHz, d-DMSO) d -79.11; 13C NMR (100 MHz, d-DMSO)
d 171.8, 165.8, 160.2 (t, J = 24.2 Hz), 153.4, 133.9, 131.0, 129.7,
127.6, 127.5, 126.8, 121.9 (t, J = 264.9 Hz), 121.7, 95.1, 61.2, 14.7;
LRMS-EI m/z (relative intensity) 343 (100) [M+], 298 (50), 102
(74); Anal. calcd for C19H15F2NO3: C, 66.47; H, 4.40; N, 4.08.
Found: C, 66.48; H, 4.58; N, 4.05; IR (KBr): 3104, 2979, 1698,
1673, 1591, 1570, 1492, 1451, 1411, 1369, 1279, 1157, 1125, 1021,
869, 771 cm-1.
Procedure for the synthesis of 2v/2w
b-Enaminoalkylketone 1v or b-enamino ester 1w (0.5 mmol) was
added to a solution of K2CO3 (6.0 eq.) in CH3CN (4.0 mL). The
solution was then stirred at 60 ◦C. After completion of reaction as
indicated by TLC, the reaction crude was filtered and the filtrate
evaporated. The residue was purified by flash chromatography on
silica gel to provide the desired product 2v/2w.
N-(2,2-Difluoro-5-(p-tolyl)furan-3(2H)-ylidene)aniline (2r)
◦
1
Yellow solid, mp 86–87 C; H NMR (300 MHz, d-DMSO) d
7.85 (d, J = 8.2 Hz, 2H), 7.48 (t, J = 7.7 Hz, 2H), 7.39–7.25 (m,
3H), 7.17 (d, J = 7.3 Hz, 2H), 6.88 (s, 1H), 2.38 (s, 3H); 19F NMR
(282 MHz, d-DMSO) d -78.66; 13C NMR (100 MHz, d-DMSO)
d 171.0, 158.6 (t, J = 24.0 Hz), 149.1, 144.1, 130.2, 129.7, 127.3,
126.3, 124.2, 122.1 (t, J = 264.3 Hz), 121.8, 94.2, 21.6; LRMS-EI
m/z (relative intensity) 285 (100) [M+], 116 (70); Anal. calcd for
C17H13F2NO: C, 71.57; H, 4.59; N, 4.91. Found: C, 71.56; H, 4.80;
N, 4.92; IR (KBr): 1649, 1607, 1483, 1452, 1317, 1282, 1149, 1012,
795, 693 cm-1.
(Z)-1-(3,3-Difluoro-6-methoxyindolin-2-ylidene)propan-2-one (2v)
Yellow solid, mp 124–126 ◦C; 1H NMR (300 MHz, CDCl3) d 9.98
(br, 1H), 7.10 (s, 1H), 6.96–6.89 (m, 1H), 6.79 (d, J = 8.5 Hz,
1H), 5.84 (t, J = 3.0 Hz, 1H), 3.80 (s, 3H), 2.26 (s, 3H); 19F NMR
(282 MHz, CDCl3) d -95.71; 13C NMR (100 MHz, CDCl3) d 199.2,
155.8, 152.3 (t, J = 27.2 Hz), 137.9 (t, J = 7.4 Hz), 121.9 (t, J =
23.5 Hz), 120.6 (t, J = 245.0 Hz), 119.2, 111.6, 110.2, 95.4, 56.0,
29.7; LRMS-EI m/z (relative intensity) 239 (100) [M+], 224 (33),
204 (46); HRMS-EI (m/z) calcd for C12H11F2NO2 239.0758; found
239.0759.
N-(2,2-Difluoro-5-(3-methoxyphenyl)furan-3(2H)-ylidene)aniline
(2s)
(Z)-Ethyl 2-(3,3-difluoro-6-methoxyindolin-2-ylidene)acetate (2w)
◦
1
Yellow oil. 1H NMR (300 MHz, d-DMSO) d 7.57–7.43 (m, 5H),
7.29 (t, J = 7.3 Hz, 1H), 7.23–7.14 (m, 3H), 7.05 (s, 1H), 3.83 (s, 3H);
19F NMR (282 MHz, d-DMSO) d -78.29; 13C NMR (100 MHz, d-
DMSO) d 171.2, 160.6, 159.1 (t, J = 24.0 Hz), 149.5, 131.3, 130.3,
128.7, 127.0, 122.5 (t, J = 264.3 Hz), 122.3, 120.6, 120.1, 112.3,
96.0, 56.5; LRMS-EI m/z (relative intensity) 301 (100) [M+], 132
(59); Anal. calcd for C17H13F2NO2: C, 67.77; H, 4.35; N, 4.65.
Found: C, 67.32; H, 4.72; N, 4.42. IR (KBr): 1666, 1606, 1575,
1486, 1299, 1223, 1155, 1128, 1028, 783 cm-1.
Yellow solid, mp 79–80 C; H NMR (300 MHz, CDCl3) d 8.80
(br, 1H), 7.10 (s, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.76 (d, J =
8.5 Hz, 1H), 5.44 (d, J = 3.5 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H),
3.80 (s, 3H), 1.32 (d, J = 7.0 Hz, 3H); 19F NMR (282 MHz,
CDCl3) d.-93.53; 13C NMR (100 MHz, CDCl3) d 169.1, 155.3,
153.3 (t, J = 27.2 Hz), 138.0 (t, J = 6.6 Hz), 121.8 (t, J = 23.5
Hz), 120.1 (t, J = 245.0 Hz), 119.5, 111.1, 110.0, 87.9, 60.1, 56.0,
14.3; LRMS-EI m/z (relative intensity) 269 (29) [M+], 223 (100),
208 (37); HRMS-EI (m/z) calcd for C13H13F2NO3 269.0864; found
269.0869.
N-(2,2-Difluoro-5-(4-fluorophenyl)furan-3(2H)-ylidene)aniline (2t)
Procedure for the synthesis of 2x/2y
◦
1
Yellow solid, mp 88–90 C; H NMR (300 MHz, d-DMSO) d
8.13–8.00 (m, 2H), 7.54–7.25 (m, 5H), 7.18 (d, J = 7.3 Hz, 2H),
6.99 (s, 1H); 19F NMR (282 MHz, d-DMSO) d -78.31 (s, 3F),
Ethyl propiolate or methyl propiolate (2.0 eq.) was added to a
solution of K3PO4 (2.0 eq.) in CH3CN (4.0 mL), and 1a (0.5 mmol)
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was added after the temperature was raised to 60 ◦C. After
completion of reaction as indicated by TLC, the reaction crude
was filtered and the filtrate evaporated. The residue was purified by
flash chromatography on silica gel to provide the desired product
2x/2y.
Procedure for the synthesis of 3a
A schlenk tube was charged with 2a (0.3 mmol), and Mg (8.0 eq.),
evacuated and back-filled with nitrogen. DMF (2 ml) and TMSCl
(4 eq.) was successively added at 0 ◦C. Then the reaction mixture
was stirred at 0 ◦C for 0.5 h. The mixture was partitioned between
ethyl acetate and water, the organic layer was washed with brine,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel to provide 3a as
a yellow oil.
(E)-Methyl 3-(5,5-difluoro-4-((4-methoxyphenyl)imino)-2-phenyl-
4,5-dihydrofuran-3-yl)acrylate (2x)
◦
1
Yellow solid, mp 153–154 C; H NMR (300 MHz, d-DMSO)
d 7.83–7.64 (m, 5H), 7.49 (d, J = 15.6 Hz, 1H), 7.17 (d, J =
15.6 Hz, 1H), 7.08–6.97 (m, 4H), 3.79 (s, 3H), 3.71 (s, 3H); 19F
NMR (282 MHz, d-DMSO) d -72.61; 13C NMR (100 MHz, d-
DMSO) d 169.4, 167.0, 157.9, 154.8 (t, J = 22.0 Hz), 140.4, 133.8,
131.4, 130.0, 129.2, 126.8, 122.4, 121.9, 118.1 (t, J = 272.9 Hz),
114.6, 109.9, 55.8, 52.1; LRMS-EI m/z (relative intensity) 385 (26)
[M+], 326 (100), 306 (44); HRMS-EI (m/z) calcd for C21H17F2NO4
385.1126; found 385.1121; IR (KBr): 1720, 1631, 1505, 1453, 1310,
1291, 1251, 1172, 1108, 1063, 836 cm-1.
N-(2-Fluoro-5-phenylfuran-3(2H)-ylidene)-4-methoxyaniline (3a)
1
Yellow oil; H NMR (300 MHz, CDCl3) d 7.75 (dd, J = 8.0,
1.6 Hz, 2H), 7.53–7.39 (m, 3H), 7.04 (d, J = 8.7 Hz, 2H), 6.93
(d, J = 8.7 Hz, 2H), 6.36 (d, J = 61.7 Hz, 1H), 6.27 (s, 1H), 3.83
(s, 3H); 19F NMR (282 MHz, CDCl3) d -122.92 (d, J = 61.9 Hz,
1F); 13C NMR (100 MHz, d-DMSO) d 173.7 (d, J = 5.1 Hz),
165.5 (d, J = 10.3 Hz), 157.5, 143.5 (d, J = 4.4 Hz), 132.7, 129.5,
128.3, 127.2, 123.3 (d, J = 2.9 Hz), 114.9, 107.9 (d, J = 230.3 Hz),
94.5, 55.8; LRMS-EI m/z (relative intensity) 283 (29) [M+], 178
(34), 102 (100); HRMS-EI (m/z) calcd for C17H14FNO2 283.1009;
found 283.1010; IR (KBr): 2925, 1648, 1608, 1593, 1571, 1503,
1491, 1449, 1285, 1245, 1031, 1008 cm-1.
(E)-Ethyl 3-(5,5-difluoro-4-((4-methoxyphenyl)imino)-2-phenyl-
4,5-dihydrofuran-3-yl)acrylate (2y)
◦
1
Yellow solid, mp 105–108 C; H NMR (300 MHz, d-DMSO) d
7.84–7.63 (m, 5H), 7.48 (d, J = 15.5 Hz, 1H), 7.15 (d, J = 15.5 Hz,
1H), 7.06–6.95 (m, 4H), 4.17 (q, J = 7.0 Hz, 2H), 3.78 (s, 3H),
1.22 (t, J = 7.0 Hz, 3H); 19F NMR (282 MHz, d-DMSO) d -72.58;
13C NMR (100 MHz, d-DMSO) d 169.3, 166.6, 157.8, 154.9 (t,
J = 21.3 Hz), 140.5, 133.7, 131.3, 130.0, 129.2, 126.8, 122.8, 121.8,
118.1 (t, J = 272.9 Hz), 114.6, 109.9, 60.7, 55.8, 14.6; LRMS-
EI m/z (relative intensity) 399(6) [M+], 326 (39), 301 (100), 286
(72); HRMS-EI (m/z) calcd for C22H19F2NO4 399.1282; found
399.1285; IR (KBr): 2922, 1715, 1633, 1604, 1504, 1290, 1261,
1251, 1178, 1107, 1063, 1028, 839 cm-1.
Procedure for the reduction of 2a
NaBH4 (2 mmol) was slowly added to a solution of the correspond-
ing 2a (0.3 mmol) and TFA (0.1 mL) in THF (2 mL) at 0 ◦C. The
resulting mixture was stirred at 0 ◦C for 3 h, and was then quenched
with an aqueous saturated solution of NaHCO3 (5 mL), extracted
with ethyl acetate (3 ¥ 10 mL), dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel to provide 4a as a yellow solid.
2,2-Difluoro-N-(4-methoxyphenyl)-5-phenyl-2,3-dihydrofuran-3-
amine (4a)
Procedure for the synthesis of 2z
Yellow solid, mp 90–91 ◦C; 1H NMR (300 MHz, CDCl3) d.7.66–
7.58 (m, 2H), 7.47–7.37 (m, 3H), 6.84 (d, J = 9.1 Hz, 2H), 6.72
(d, J = 8.9 Hz, 2H),5.62 (t, J = 2.0 Hz, 1H), 4.94 (ddd, J = 12.4,
6.0, 2.6 Hz, 1H), 3.78 (s, 3H), 3.12 (br, 1H); 19F NMR (282 MHz,
CDCl3) d -68.20 (dd, J = 148.6, 12.4 Hz, 1F), -82.55 (dd, J =
148.6, 5.9 Hz, 1F); 13C NMR (100 MHz, CDCl3) d 155.4 (d, J =
3.0 Hz), 153.3, 140.0, 130.3, 130.2 (t, J = 269.2 Hz), 128.7, 128.1,
125.5, 115.1, 115.1, 97.8 (d, J = 3.0 Hz), 62.1 (dd, J = 37.0, 22.3
Hz), 55.8; LRMS-EI m/z (relative intensity) 303 (31) [M+], 181
(100), 133 (39), 122 (51); HRMS-EI (m/z) calcd for C12H11F2NO2
303.1071; found 303.1060; IR (KBr): 3391, 2997, 2936, 1655, 1512,
1493, 1449, 1260, 1243, 1114, 1090, 1021, 744 cm-1.
1z (0.5 mmol) and DBU (2.0 eq.) was added to 2.0 mL THF, the
mixture was then stirred at 60 ◦C. After completion of reaction as
indicated by TLC, the reaction crude was concentrated in vacuo.
The residue was purified by flash chromatography on silica gel to
provide the desired product 2z
(4-Benzyl-2-(bromodifluoromethyl)quinolin-3-
yl)(phenyl)methanone (2z)
Yellow solid, mp 115–118 ◦C; 1H NMR (300 MHz, CDCl3) d 8.28
(d, J = 8.5 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.82 (t, J = 7.8 Hz,
1H), 7.75 (d, J = 7.0 Hz, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.55 (t,
J = 7.5 Hz, 1H), 7.38 (t, J = 7.8 Hz, 2H), 7.20–7.06 (m, 3H),
7.01 (d, J = 7.0 Hz, 2H), 4.30 (AB, J = 16.1 Hz, 2H); 19F NMR
(282 MHz, CDCl3) d -46.98 (AB, J = 160.8 Hz, 2H); 13C NMR
(100 MHz, d-DMSO) d 194.8, 149.5 (t, J = 24.9 Hz), 146.9, 145.8,
137.8, 137.1, 134.1, 131.0, 131.0, 129.6, 129.4, 129.0, 128.7, 128.7,
128.3, 127.7, 126.7, 124.9, 116.9 (t, J = 307.4 Hz), 35.6; LRMS-
EI m/z (relative intensity) 451 (3) [M+], 279 (28), 193 (88), 55
(100); HRMS-EI (m/z) calcd for C24H16BrF2NO 451.0383; found
451.0387; IR (KBr): 3059, 2921, 2850, 1672, 1596, 1563, 1494,
1450, 1409, 1254, 1144, 1127, 1070, 960, 918, 761 cm-1.
Acknowledgements
This work was supported by the National Science Foundation of
China (Nos. 20772145).
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