Pd-catalyzed direct arylation of 3-fluorofurans utilizing the neighboring effect of fluorine atom: facile synthesis of tetrasubstituted monofluoro furans

Article abstract of DOI:10.1016/j.tet.2008.12.026

Pd-catalyzed direct arylation of 3-fluorofurans with a variety of aryl bromides was facilitated by the neighboring effect of fluorine atom to provide tetrasubstituted monofluoro furans in moderate to good yields.

Full text of DOI:10.1016/j.tet.2008.12.026

Tetrahedron 65 (2009) 1673–1678
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pd-catalyzed direct arylation of 3-fluorofurans utilizing the neighboring effect
of fluorine atom: facile synthesis of tetrasubstituted monofluoro furans
,
,
a,
*
Peng Li a b, Zhuo Chai b, Gang Zhao b , Shi-Zheng Zhu
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
b Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 October 2008
Received in revised form 6 December 2008
Accepted 9 December 2008
Available online 13 December 2008
Pd-catalyzed direct arylation of 3-fluorofurans with a variety of aryl bromides was facilitated by the
neighboring effect of fluorine atom to provide tetrasubstituted monofluoro furans in moderate to good
yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Arylation
C–H activation
Fluorinated furans
Neighboring effect
Aryl bromide
1. Introduction
monofluoro compounds. Based on these studies and our own ex-
perience9 with the chemistry of 3-fluorofurans, we reasoned that
Transition-metal-catalyzed direct arylation of aromatic com-
pounds via C–H bond activation enables facile synthesis of useful
biaryl compounds, and thus has become one of the focuses of or-
ganic synthesis in recent years.1 In this field, heterocyclic arenes
have received particular attentions as substitutes for the pre-
activated organometallic partners typically used in conventional
cross-coupling reactions due to their peculiar electronic and
structural properties.1 However, in contrast to the numerous re-
lated studies on nitrogen-1c,2 or sulfur-containing3 heterocyclic
arenes, there are only rather limited examples dealing with furans
and the reactive sites are mostly restricted to the C2 or C5 postion.4
Very recently, Hammond et al.5 has realized arylation at the C4-
position of 3-fluorofurans via a microwave promoted Suzuki cross-
coupling reaction between 4-iodo-3-fluorofurans and aryl boronic
acids, which adds to the limited methods available for the synthesis
of multi-substituted fluorous furans.6 On the other hand, Fagnou
et al.7 and Do and Daugulis8 have recently realized palladium- and
copper-catalyzed direct arylation of perfluoroarenes, respectively,
which well demonstrated the special role that the fluorine atom
could play in this type of reactions. However, examples with fluoro-
heterocyclic compounds are rare, especially in the cases of
the direct arylation at the C4-position of these compounds may be
possible and would provide a more atom-economical alternative to
existing methods. Herein, we report the details of our research with
this strategy.
2. Results and discussion
As a test reaction, the coupling of 3-fluoro-2,5-diphenylfuran 1a
with 1-bromo-4-chlorobenzene was initially studied with several
different Pd catalysts, bases, and solvents at varied temperatures
(Table 1). It was found that Pd(OAc)2, the most frequently used Pd
catalyst for this type of reactions,1 failed to effect the reaction (Table
1, entries 1 and 2). PdCl2 or Pd(PPh3)4 also proved unsuitable under
the examined reaction conditions (Table 1, entries 3 and 6). In-
complete conversion of 1a was observed with PdCl2(PhCN)2 or
Pd3(dba)2, which provided the desired product 2e in 10% and 26%
yields, respectively (Table 1, entries 4 and 5). To our delight, when
the reaction was performed with 10 mol % of PdCl2(PPh3)2 and
2 equiv of KOAc in DMF, the desired product was obtained in 60%
yield (Table 1, entry 8). A slight higher yield (62% yield) was
obtained when NMP was employed as the solvent (Table 1, entry 9).
Contrastingly, when apolar toluene was used as the solvent or
K2CO3 was used as the base, the reaction hardly proceeded (Table 1,
entries 7 and 12). Moreover, either reducing the amount of
PdCl2(PPh3)2 to 5 mol % or employing NaOAc as the base led to
* Corresponding authors. Tel.: þ86 21 54925182; fax: þ86 21 64166128.
E-mail addresses: zhaog@mail.sioc.ac.cn (G. Zhao), zhusz@mail.sioc.ac.cn
(S.-Z. Zhu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.026

1674
P. Li et al. / Tetrahedron 65 (2009) 1673–1678
Table 1
Table 2
Optimization studies for the Pd-catalyzed arylation of 1aa
Scope study of different aryl bromides with 3-fluoro-2,5-diphenylfuran (1a)a
O
Ph
Ph
PdCl2(PPh3)2 (10 mol%)
KOAc (2 equiv)
O
O
Ph
O
Br
F
Ph
Ar-X
PdXn (10 mol%)
Solvent, Temp.
+
+
NMP, 110 °C-120 °C
12-16 h
F
F
Ar
2a-2g
Cl
F
Cl
1a
1a
2e
Entry
1
Catalytic system
Temp
Solvent
DMSO
Yieldb
n.r.
Entry
ArX
Product
Yieldb
51 (%)
Pd(OAc)2 (10 mol %)þ3 equiv
NaOAc
80 ꢀ
C
2
Pd(OAc)2 (10 mol %)þ2 equiv
80 ꢀ
C
CH3CN/H2O
¼9:1
Trace
O
K2CO3þ50 mol % TBABcþ20 mol % PPh3
PdCl2 (10 mol %)þ2 equiv KOAc
Br
1
3
4
5
6
7
8
9
10
11
12
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
C
C
C
C
C
C
C
C
C
C
DMF
n.r.
10%
F
2a
PdCl2(PhCN)2 (10 mol %)þ2 equiv KOAc
Pd3(dba)2 (10 mol %)þ2 equiv KOAc
Pd(PPh3)4 (10 mol %)þ2 equiv K2CO3
PdCl2(PPh3)2 (10 mol %)þ2 equiv KOAc
PdCl2(PPh3)2 (10 mol %)þ2 equiv KOAc
PdCl2(PPh3)2 (10 mol %)þ2 equiv KOAc
PdCl2(PPh3)2 (5 mol %)þ2 equiv KOAc
PdCl2(PPh3)2 (10 mol %)þ2 equiv NaOAc
PdCl2(PPh3)2 (10 mol %)þ2 equiv K2CO3
DMF
DMF
DMF
26%
Trace
Trace
60%
62%
61%
Toluene
DMF
NMPc
NMP
O
2
64 (%)
NMP
NMP
59%
Trace
F
Br
a
Compound 1a/1-bromo-4-chlorobenzene¼1:2.
2b
b
c
Isolated yields.
TBAB: tetrabutylamine bromide; NMP: N-methyl pyrrolidone.
O
F
slightly lower yields (Table 1, entries 10 and 11). Thus, the optimum
reaction conditions for the present transformation are 10 mol % of
PdCl2(PPh3)2 and 2 equiv of KOAc in NMP at 110 ꢀC.
F
3
73 (%)
With the optimized conditions in hand, the coupling reactions
of 3-fluoro-2,5-diphenylfuran 1a with a series of aryl halides were
then examined (Table 2). In general, most of the examined aryl
halides participated in the reaction smoothly and the reaction
completed in 12–16 h providing the desired products 2a–2g in 51–
73% yields (Table 2, entries 1–8). Neither the electronic nature nor
the positions of the substituents on the phenyl ring exerted any
considerable influence on the yields. However, in the case of 4-
nitrophenyl bromide, a complex mixture was obtained (Table 2,
entry 9).
2c
Br
F
O
F
4
52 (%)
Subsequently, we explored the arylation of different fluoro-
substituted furans with 1-bromo-4-chlorobenzene and the results
are summarized in Table 3. For substrates 1b–1g bearing
substituted groups with different electronic natures on the differ-
ent positions of R2, no marked difference in yields (51–65%) was
observed (Table 3, entries 1–6). Furthermore, when R1 or R2 was an
alkyl group, the reaction still proceeded smoothly to provide the
desired products without apparent drop in yields (Table 3, entries
7 and 8). Notably, the substrate 2,5-diphenylfuran 1j without
a fluorine atom failed to undergo the reaction, which was in sup-
port of the activating role of the neighboring fluorine atom in the
present system (Table 3, entry 9). To examine the reaction scope
further, substrate 3-fluoro-2,5-diphenylthiophene 1k, the thio-
phene counterpart of 1a, was also prepared and subjected to the
same reaction conditions, but no reaction was detected (Table 3,
entry 10).
Based on the above experimental results, an electrophilic
mechanism similar to those of previous studies on the arylation of
heterocycles11 may be invoked for the present reaction (Scheme 1).
The key step may involve the electrophilic attack on 1 to form the
Pd(II) intermediate A,2a which may explain the failure of substrate
1k to undergo the reaction for that thiophenes in general are more
electron-deficient than furans.12 Subsequent abstraction of the
acidic hydrogen atom in A with the help of a base would generate
another intermediate B, which would then undergo reductive
elimination to deliver the desired products 2 and release the Pd
catalyst. The presence of the fluorine atom in 1 may not only
Br
2d
O
Cl
Br
F
5
62 (%)
2e
Cl
O
O
6
70 (%)
Cl
F
Br
Cl
2f
7
55 (%)
F
Br
2g
(continued)

P. Li et al. / Tetrahedron 65 (2009) 1673–1678
1675
Table 2 (continued )
Entry
ArX
Product
Yieldb
Table 3
Scope study of different 1 with 1-bromo-4-chlorobenzenea
R2
F
O
X
I
R1
Cl
Cl
Br
8
53 (%)c
PdCl2(PPh3)2 (10 mol%)
KOAc (2 eq)
NMP, 110 °C-120 °C
12-16 h
R2
F
F
2a
X
R1
+
NO2
Br
1b-1j X = O
1k X = S
3b-3i
9
dd
dd
Entry Reactant
R1
Product
Yieldb
R2
a
Compound 1a/ArX¼1:2.
Isolated yields.
The reaction time was 9 h.
b
c
d
The reaction system was complicated.
O
F
1
Ph (1b)
p-CH3C6H4
60 (%)
facilitate the formation of intermediate A through conjugative do-
nation of the lone electron pairs, but also could increase the acidity
of the hydrogen atom in A to form B due to its high electronega-
tivity. However, the determination of the exact reaction mechanism
as well as the role of the fluorine atom still requires further
investigation.
3b
Cl
OCH3
O
3. Conclusion
F
2
Ph (1c)
p-CH3OC6H4
51 (%)
In summary, we have successfully utilized the neighboring ef-
fect of the fluorine atom for functionalization at the C4 position of
3-fluorofurans to synthesize tetrasubstituted monofluoro furans
via direct Pd-catalyzed arylation reactions. Using 10 mol % of
PdCl2(PPh3)2 as the catalyst, 2 equiv of KOAc as the base, and NMP
as the solvent, the desired products were obtained in 51–73% yields
within 12–16 h at 110 ꢀC.
3c
Cl
O
F
4. Experimental
4.1. General
F
3
Ph (1d)
o-FC6H4
57 (%)
3d
1H and 13C NMR spectra were recorded at 300 and 100 MHz,
respectively, with TMS as the internal standard. 19F NMR spectra
were recorded at 282 MHz with CFCl3 as the external standard. IR
spectra were recorded in cmꢁ1. Melting points were uncorrected.
All solvents were distilled prior to use unless otherwise noted. All
reactions sensitive to moisture or oxygen were conducted under an
atmosphere of nitrogen or argon.
Cl
F
O
F
4
Ph (1e)
m-FC6H4
60 (%)
Compounds 1a–1j were prepared according to the known
procedures.9,10
3e
Cl
4.2. General procedure for the preparation of 2,4,5-
trisubstituted 3-fluorofurans 2
F
Under an atmosphere of argon, compound 1 (0.2 mmol), aryl
bromide (0.4 mmol), PdCl2(PPh3)2 (14 mg, 0.02 mmol), and KOAc
(39.2 mg, 0.4 mmol) were mixed together. Then 3 mL of N-methyl
pyrrolidin-2-one (NMP) was added, the system was then heated to
120 ꢀC for appropriate times. When the reaction was completed
(monitored by TLC), the reaction system was cooled to room tem-
perature and 3 mL of saturated aqueous NH4Cl was added to
quench the reaction. After extraction with Et2O and drying with
Na2SO4, the organic layer was concentrated under reduced pressure
and the residue was purified by column chromatography on silica
gel to afford the desired products.
O
F
5
Ph (1f)
p-FC6H4
59 (%)
3f
Cl
(continued on next page)

1676
P. Li et al. / Tetrahedron 65 (2009) 1673–1678
Table 3 (continued )
4.2.3. 3-Fluoro-4-(4-fluorophenyl)-2,5-diphenylfuran (2c)
Yield: 73%; white solid; mp: 127–128 ꢀC; IR (CH2Cl2, film):
Entry Reactant
R1
Product
Yieldb
3056, 1641, 1512, 1494, 1225, 1159, 944, 842 cmꢁ1
;
1H NMR
R2
(300 MHz, CDCl3):
d
¼7.80 (d, 3J¼7.5 Hz, 2H), 7.56–7.11 (m, 12H);
Cl
1
13C NMR (100 MHz, CDCl3):
d
¼162.5 (d, JCF¼246.4 Hz), 148.6 (d,
1JCF¼254.6 Hz), 146.8 (d, JCF¼5.3 Hz), 135.5 (d, JCF¼19.4 Hz),
3
2
O
131.4, 131.3, 130.4, 128.8, 128.5, 128.2, 127.2, 125.8, 123.6 (d,
3JCF¼5.2 Hz), 116.0 (d, JCF¼20.8 Hz), 114.6 (d, JCF¼16.7 Hz); 19F
2
2
F
6
Ph (1g)
p-ClC6H4
65 (%)
NMR (CDCl3):
d¼ꢁ113.9 (dd, 1F), ꢁ165.1 (s, 1F); MS (EI) (m/z): 332
(Mþ). Anal. Calcd for C22H14F2O (%): C, 79.51; H, 4.25. Found: C,
79.39; H, 4.39.
3g
Cl
4.2.4. 3-(Biphenyl-4-yl)-4-fluoro-2,5-diphenylfuran (2d)
Yield: 52%; white solid; mp: 174–175 ꢀC; IR (CH2Cl2, film): 1680,
O
1598, 1448, 1278, 989, 846, 764 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
¼7.82 (d, 3J¼7.8 Hz, 2H), 7.69–7.26 (m, 17H); 13C NMR (100 MHz,
F
1
3
7
Ph (1h)
Et
57 (%)
CDCl3):
d
¼148.7 (d, JCF¼254.6 Hz), 145.7 (d, JCF¼6.0 Hz), 140.7,
140.5, 135.5 (d, 2JCF¼19.4 Hz), 130.6, 130.5, 129.9, 128.8, 128.7, 128.5,
3
3h
128.1, 127.5, 127.4, 127.2, 127.0, 125.9, 124.8, 123.6 (d, JCF¼5.2 Hz),
Cl
115.2 (d, 2JCF¼16.4 Hz); 19F NMR (CDCl3):
¼ꢁ164.7 (s, 1F); MS (EI)
d
(m/z): 390 (Mþ); HRMS calcd for C28H19FO: 390.1420, found:
390.1424.
O
4.2.5. 3-(4-Chlorophenyl)-4-fluoro-2,5-diphenylfuran (2e)
Yield: 62%; pale yellow solid; mp: 109–110 ꢀC; IR (CH2Cl2, film):
F
1643, 1493, 1392, 1194, 1093, 944, 836, 691 cmꢁ1
;
1H NMR
8
n-Pentyl(1i)
Ph
61 (%)
(300 MHz, CDCl3):
d
¼7.79 (d, 3J¼7.8 Hz, 2H), 7.57–7.26 (m, 12H); 13
C
3i
1
NMR (100 MHz, CDCl3):
d
¼148.3 (d, JCF¼254.6 Hz), 145.8 (d,
Cl
3JCF¼5.9 Hz), 135.7 (d, JCF¼19.4 Hz), 134.0, 130.87, 130.85, 130.3,
2
3
129.1, 128.8, 128.7, 128.6, 128.3, 127.3, 125.9, 123.6 (d, JCF¼6.1 Hz),
Ph
O
114.4 (d, 2JCF¼15.6 Hz); 19F NMR (CDCl3):
¼ꢁ165.0 (s, 1F); MS (EI)
d
Ph
(m/z): 348 (Mþ); HRMS calcd for C22H14ClFO: 348.0717, found:
9
dc
dc
348.0720.
1j
4.2.6. 3-(4-Chlorophenyl)-4-fluoro-2,5-diphenylfuran (2f)
Yield: 70%; colorless oil; IR (CH2Cl2, film): 3059, 1642, 1598,
Ph
F
S
1494, 1153, 1219, 944, 692 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d¼7.83
dc
dc
Ph
10
(d, 3J¼7.2 Hz, 2H), 7.58–7.26 (m, 12H); 13C NMR (100 MHz, CDCl3):
1
3
1k
d
¼149.1 (d, JCF¼255.3 Hz), 146.3 (d, JCF¼6.0 Hz), 135.6 (d,
a
2JCF¼18.6 Hz), 135.1, 132.6, 130.6, 130.3, 130.2, 129.4, 129.0, 128.8,
Compound 1/1-bromo-4-chlorobenzene¼1:2.
Isolated yields.
No reaction was detected.
b
c
128.3, 127.5, 127.4, 125.2, 123.9, 123.8, 113.5 (d, JCF¼17.9 Hz); 19F
2
NMR (CDCl3):
d
¼ꢁ162.4 (s, 1F); MS (EI) (m/z): 348 (Mþ); HRMS
calcd for C22H14ClFO: 348.0717, found: 348.0715.
: B
4.2.7. 3-Fluoro-4-(naphthalen-1-yl)-2,5-diphenylfuran (2g)
Ar
Yield: 55%; yellow oil; IR (CH2Cl2, film): 3057, 1807, 1597,
H
F
F
LnPd
R1
ArPd
R1
1495, 1264, 1155, 932, 765, 690 cmꢁ1 1H NMR (300 MHz,
.
ArPdX
+
O
1
CDCl3):
d
¼7.87–7.85 (m, 5H), 7.56–7.45 (m, 9H), 7.18–7.16 (m,
2
R2
R2
1
3H); 13C NMR (100 MHz, CDCl3):
d
¼149.5 (d, JCF¼254.6 Hz),
2
O
B
3
A
146.2 (d, JCF¼6.0 Hz), 135.2 (d, JCF¼19.3 Hz), 133.8, 132.0,
4
129.0, 128.7, 128.6, 128.3, 127.7, 127.5 (d, JCF¼1.6 Hz), 127.1 (d,
Scheme 1. A plausible mechanism for the reaction of 1 with aryl halides.
4JCF¼1.4 Hz), 126.6, 126.2, 125.6, 125.5, 124.9, 123.5 (d,
4.2.1. 3-Fluoro-2,4,5-triphenylfuran (2a)
Yield: 51%; white solid; the 1H NMR spectra agree well with that
reported.6b
3JCF¼5.2 Hz), 113.8 (d, 2JCF¼17.9 Hz); 19F NMR (CDCl3):
¼ꢁ162.7
d
(s, 1F); MS (EI) (m/z): 364 (Mþ); HRMS calcd for C26H17FO:
364.1263, found: 364.1262.
4.2.2. 3-Fluoro-2,5-diphenyl-4-o-tolylfuran (2b)
4.2.8. 3-(4-Chlorophenyl)-4-fluoro-2-phenyl-5-p-tolylfuran (3b)
Yield: 64%; colorless oil; IR (CH2Cl2, film): 1640, 1495, 1167, 1126,
Yield: 60%; white solid; mp: 136–137 ꢀC; IR (CH2Cl2, film): 1641,
1068, 944, 850, 763, 691 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d¼7.82
1600, 1509, 1088, 943, 842, 817, 763, 694, 648, 525 cmꢁ1 1H NMR
;
(d, 3J¼8.1 Hz, 2H), 7.48–7.24 (m, 12H), 2.25 (s, 3H); 13C NMR
(300 MHz, CDCl3):
(100 MHz, CDCl3):
d
¼7.70–7.25 (m, 13H), 2.39 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d
¼149.4 (d, 1JCF¼253.8 Hz), 146.2 (d,
d
¼148.0 (d, 1JCF¼253.1 Hz), 145.3 (d,
3JCF¼5.3 Hz), 137.9, 135.4 (d, 2JCF¼19.3 Hz), 131.0, 130.7, 129.5, 129.0,
3JCF¼5.2 Hz), 137.2, 136.0 (d, 2JCF¼19.4 Hz), 133.9, 130.8, 130.4, 129.5,
3
128.9, 128.8, 128.0, 127.4, 126.5, 124.9, 123.8 (d, JCF¼5.2 Hz), 115.4
129.1, 128.7, 128.6, 128.2, 125.9, 123.62, 123.58, 114.4 (d,
2
(d, JCF¼17.9 Hz), 20.2; 19F NMR (CDCl3):
d
¼ꢁ163.0 (s, 1F); MS (EI)
2JCF¼15.6 Hz), 21.4; 19F NMR (CDCl3):
¼ꢁ166.1 (s, 1F); MS (EI)
d
(m/z): 328 (Mþ); HRMS calcd for C23H17FO: 328.1263, found:
(m/z): 362 (Mþ); HRMS calcd for C23H16ClFO: 362.0874, found:
328.1266.
362.0877.

P. Li et al. / Tetrahedron 65 (2009) 1673–1678
1677
4.2.9. 3-(4-Chlorophenyl)-4-fluoro-5-(4-methoxyphenyl)-2-
phenylfuran (3c)
d
¼7.46–7.24 (m, 9H), 2.75 (q, 3J¼7.8 Hz, 2H), 1.31 (t, 3J¼7.8 Hz,
3H); 13C NMR (100 MHz, CDCl3):
d
¼147.3 (d, 1JCF¼246.4 Hz), 144.7
3
2
Yield: 52%; light yellow solid; mp: 109–110 ꢀC; IR (CH2Cl2,
(d, JCF¼6.0 Hz), 138.9 (d, JCF¼14.6 Hz), 133.5, 130.7, 129.0, 128.9,
film): 1599, 1508, 1249, 1177, 1073, 942, 694 cmꢁ1
;
1H NMR
128.5, 128.2, 127.8, 125.7, 113.1 (d, JCF¼16.4 Hz), 18.4 (d,
2
(300 MHz, CDCl3):
d
¼7.74–7.29 (m, 11H), 7.10–6.98 (m, 2H), 3.86
3JCF¼3.7 Hz), 11.9; 19F NMR (CDCl3):
¼ꢁ174.3 (s, 1F); MS (EI) (m/
d
(s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼158.9, 147.3 (d,
z): 300 (Mþ); HRMS calcd for C18H14ClFO: 300.0717, found:
1JCF¼252.3 Hz), 144.9 (d, 3J ¼6.0 Hz), 135.8 (d, JCF¼19.1 Hz),
300.0716.
2
CF
4
133.9, 130.8, 130.4 (d, JCF¼2.3 Hz), 129.4, 128.5, 128.4 (d,
4JCF¼3.0 Hz), 128.0, 125.6, 125.13, 125.08, 121.6 (d, JCF¼5.2 Hz),
4.2.15. 3-(4-Chlorophenyl)-4-fluoro-2-pentyl-5-phenylfuran (3i)
3
2
114.3 (d, JCF¼15.6 Hz), 55.3; 19F NMR (CDCl3):
d¼ꢁ167.7 (s, 1F);
Yield: 61%; yellow oil; IR (CH2Cl2, film): 2959, 1558, 1495, 1454,
MS (EI) (m/z): 378 (Mþ). Anal. Calcd for C23H16ClFO2 (%): C, 72.92;
1091, 1004, 959, 761, 692 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d¼7.71–
H, 4.26. Found: C, 73.01; H, 4.11.
7.24 (m, 9H), 2.72 (t, J¼7.8 Hz, 2H), 1.74–1.69 (m, 2H), 1.34–1.31 (m,
4H), 0.89 (t, J¼6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3):
¼150.4 (d,
d
4.2.10. 3-(4-Chlorophenyl)-4-fluoro-5-(2-fluorophenyl)-2-
phenylfuran (3d)
3JCF¼5.2 Hz), 147.8 (d, 1JCF¼254.6 Hz), 134.8 (d, 2JCF¼20.1 Hz), 133.4,
130.1,129.3, 129.1,128.9,128.4, 127.0,123.5 (d, 3JCF¼4.4 Hz),114.0 (d,
Yield: 57%; light yellow solid; mp: 106–107 ꢀC; IR (CH2Cl2,
2JCF¼14.9 Hz), 31.6, 28.7, 27.5, 22.6 14.2; 19F NMR (CDCl3):
¼ꢁ166.5
d
film): 1639, 1494, 1449, 1233, 842, 766, 691 cmꢁ1
;
1H NMR
(s, 1F); MS (EI) (m/z): 342 (Mþ); HRMS calcd for C21H20ClFO:
(300 MHz, CDCl3):
d
¼7.75–7.13 (m, 13H); 13C NMR (100 MHz,
342.1187, found: 342.1190.
1
1
CDCl3):
d
¼158.2 (d, JCF¼251.9 Hz), 148.6 (d, JCF¼256.9 Hz), 147.1
(d, 3JCF¼5.1 Hz), 134.1, 131.4 (d, 2JCF¼20.5 Hz), 130.9, 130.1, 129.4 (d,
4.2.16. Preparation of 3-fluoro-2,5-diphenylthiophene (1k)
3JCF¼8.1 Hz), 129.1, 128.6, 128.5, 128.2 (d, JCF¼2.2 Hz), 127.3 (m,
To a solution of 2,2-difluoro-1,4-diphenylbut-3-yn-1-ol (4)6b
(258 mg, 1 mmol) in 5 mL of CH2Cl2 in an ice bath was added
0.33 mL of Et3N (2.3 mmol), and the solution was stirred for about
10 min before methanesulfonyl chloride (0.12 mL, 1.5 mmol) was
added slowly. Then the mixture was stirred at this temperature for
3 h (monitored by TLC). Saturated NH4Cl (2 mL) was added to
quench the reaction and the reaction mixture was extracted with
CH2Cl2. After removal of the solvent in vacuum, the residue was
dissolved in 3 mL of acetone and NaSH (90 mg, 1.6 mmol) was
added at room temperature. After stirring for one day, 5 mL of
NH4Cl was added to quench the reaction. After removal of the
volatile substance, the remaining aqueous layer was extracted with
ether acetate, dried over Na2SO4, concentrated in vacuum, and
purified by column chromatography on silica gel to afford 3-fluoro-
2,5-diphenylthiophenerd (1k) in 28% yield.
4
4
2
J¼3.0 Hz), 126.0, 124.3 (d, JCF¼3.6 Hz), 116.8 (dd, JCF¼14.2 Hz,
3JCF¼5.1 Hz), 116.4 (d, JCF¼21.2 Hz), 114.2 (d, JCF¼16.0 Hz); 19F
2
2
NMR (CDCl3):
d¼ꢁ113.0 (m, 1F), ꢁ161.0 (d, JFF¼244.5 Hz, 1F); MS
(EI) (m/z): 366 (Mþ); HRMS calcd for C22H13ClF2O: 366.0623,
found: 366.0627.
4.2.11. 3-(4-Chlorophenyl)-4-fluoro-5-(3-fluorophenyl)-2-
phenylfuran (3e)
Yield: 60%; light yellow solid; mp: 86–87 ꢀC; IR (CH2Cl2, film):
1638, 1500, 1430, 1269, 1198, 882, 778, 682 cmꢁ1
;
1H NMR
(300 MHz, CDCl3):
d
¼7.56–6.95 (m, 13H); 13C NMR (100 MHz,
1
1
CDCl3):
d
¼161.1 (d, JCF¼244.6 Hz), 149.0 (d, JCF¼256.2 Hz), 146.4
3
2
(d, JCF¼5.8 Hz), 134.6 (d, JCF¼21.9 Hz), 130.8, 130.5, 130.4, 130.0,
4
129.2, 128.64, 128.57, 127.9 (d, JCF¼2.2 Hz), 126.0, 119.2 (m), 114.4
2
2
2
(d, JCF¼16.1 Hz) 114.1 (d, JCF¼21.1 Hz), 110.4 (dd, JCF¼24.1 Hz,
Yield: 28%; white solid; mp: 95–96 ꢀC; IR (CH2Cl2, film): 1573,
3JCF¼5.1 Hz); 19F NMR (CDCl3):
d
¼ꢁ113.0 (dd, JFF¼15.8, 9.9 Hz, 1F),
1561, 1395, 1011, 819, 719, 691 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
ꢁ163.2 (s, 1F); MS (EI) (m/z): 366 (Mþ); HRMS calcd for
d
¼7.68–7.58 (m, 4H), 7.44–7.26 (m, 6H), 7.11 (s, 1H); 13C NMR
C22H13ClF2O: 366.0623, found: 366.0626.
(100 MHz, CDCl3):
d
¼153.9 (d, 1JCF¼260.5 Hz), 139.8 (d,
2JCF¼9.0 Hz), 133.6, 131.4, 129.1, 129.0, 128.3, 127.5, 126.7 (d,
3
2
4.2.12. 3-(4-Chlorophenyl)-4-fluoro-5-(4-fluorophenyl)-2-
phenylfuran (3f)
3JCF¼5.8 Hz), 125.2, 120.8 (d, JCF¼11.9 Hz), 114.6 (d, JCF¼27.5 Hz);
19F NMR (CDCl3):
d
¼ꢁ126.9 (s, 1F); MS (EI) (m/z): 254 (Mþ); HRMS
Yield: 59%; white solid; mp: 113–114 ꢀC; IR (CH2Cl2, film): 1508,
calcd for C16H11FS: 254.0566, found: 254.0567.
1235, 1093, 943, 831, 816, 761, 689, 653, 510 cmꢁ1 1H NMR
;
(300 MHz, CDCl3):
(100 MHz, CDCl3):
d
¼7.77–7.53 (m, 2H), 7.52–7.15 (m,11H); 13C NMR
Acknowledgements
d
¼161.8 (d, 1JCF¼246.4 Hz), 148.0 (d,
1JCF¼255.3 Hz), 145.7 (d, 3JCF¼5.2 Hz), 134.9 (d, 2JCF¼19.3 Hz), 134.0,
Generous financial support from the National Natural Science
Foundation of China, QT Program and Shanghai Natural Science
Council is gratefully acknowledged.
3
130.7, 130.1, 129.0, 128.5, 128.3, 128.0, 125.8, 125.4 (d, JCF¼5.2 Hz),
125.3 (d, 3JCF¼5.3 Hz),115.8 (d, 2JCF¼21.6 Hz),114.3 (d, 2JCF¼16.4 Hz);
19F NMR (CDCl3):
d
¼ꢁ113.9 (s, 1F), ꢁ165.9 (s, 1F); MS (EI) (m/z): 366
(Mþ); HRMS calcd for C22H13ClF2O: 366.0623, found: 366.0624.
References and notes
4.2.13. 2,4-Bis(4-chlorophenyl)-3-fluoro-5-phenylfuran (3g)
1. For reviews: (a) Lautens, M.; Scott, M. E.; Alberico, D. Chem. Rev. 2007, 107, 174;
(b) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 1173; (c) Lewis, J. C.;
Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013.
2. For recent examples: (a) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan,
V. Org. Lett. 2007, 9, 2333; (b) Lebrasseur, N.; Larrosa, L. J. Am. Chem. Soc. 2008,
130, 2926; (c) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
127, 18020; (d) Bellina, F.; Benelli, F.; Rossi, R. J. Org. Chem. 2008, 73, 5529; (e)
Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403; (f) Hartwig, J. F.;
Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org.
Chem. 1999, 64, 5575.
3. For recent examples: (a) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K. J. Am.
Chem. Soc. 2006, 128, 11748; (b) Campeau, L.-C.; Bertrand-Laperle, M.; Leclerc,
J.-P.; Villemure, E.; Gorelsky, S.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3276; (c)
Battace, A.; Lemhadri, M.; Zair, T.; Doucet, H.; Santelli, M. Adv. Synth. Catal. 2007,
349, 2507.
4. (a) Besselie`vre, F.; Mahuteau-Betzer, F.; Grierson, D. S.; Piguel, S. J. Org. Chem.
2007, 72, 3278; (b) Fujiwara, Y.; Maruyama, O.; Yoshidomi, M.; Taniguchi, H.
J. Org. Chem. 1981, 46, 851.
Yield: 65%; light yellow solid; mp: 140–142 ꢀC; IR (CH2Cl2, film):
1639, 1501, 1392, 1090, 942, 826, 702, 691, 505 cmꢁ1 1H NMR
;
(300 MHz, CDCl3):
d
¼7.70 (d, 3J¼7.5 Hz, 2H), 7.55–7.26 (m, 11H); 13
C
1
NMR (100 MHz, CDCl3):
d
¼148.6 (d, JCF¼256.1 Hz), 146.1 (d,
3JCF¼6.0 Hz), 134.8 (d, JCF¼19.3 Hz), 134.1, 132.9, 130.8, 130.0 (d,
2
4JCF¼2.4 Hz), 129.1, 129.0, 128.6, 128.5, 127.9 (d, J CF¼2.2 Hz), 127.1
4
(d, 4JCF¼4.5 Hz), 126.0, 124.7 (d, 3JCF¼5.2 Hz), 114.4 (d,
2JCF¼15.7 Hz); 19F NMR (CDCl3):
¼ꢁ164.1 (s,1F); MS (EI) (m/z): 382
d
(Mþ); HRMS calcd for C22H13Cl2FO: 382.0327, found: 382.0328.
4.2.14. 3-(4-Chlorophenyl)-5-ethyl-4-fluoro-2-phenylfuran (3h)
Yield: 57%; yellow oil; IR (CH2Cl2, film): 2976, 3939, 1704, 1676,
1588, 1448, 1092, 1016, 813, 693 cmꢁ1; 1H NMR (300 MHz, CDCl3):

1678
P. Li et al. / Tetrahedron 65 (2009) 1673–1678
5. Arimitsu, S.; Jacobsen, J. M.; Hammond, G. B. J. Org. Chem. 2008, 73, 2886.
6. (a) Sham, H.-L.; Betebenner, D.-A. J. Chem. Soc., Chem. Commun. 1991, 1134; (b)
Arimitsu, S.; Hammond, G. B. J. Org. Chem. 2007, 72, 8559.
7. Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
8754.
10. (a) Ceylan, M.; Gu¨rdere, M. B.; Budak, Y.; Kazaz, V.; Seçen, H. Synthesis 2004, 11,
1750; (b) Amarnath, V.; Amarnath, K. J. Org. Chem. 1995, 60, 301.
11. (a) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449; (b) Park, C.-H.; Ryabova,
V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett. 2007, 9, 2333; (c) Lane,
B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050.
12. Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Addison Wesley Longman: Lon-
don, 1997.
8. Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128.
9. Li, P.; Chai, Z.; Zhao, G.; Zhu, S.-Z. Synlett 2008, 2547.