Regioselective synthesis of CF2Cl-substituted biaryls by [3+3] cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 4-aryl-1-chloro-1,1-difluoro-4-(trimethylsilyloxy)-3-en-2-ones

Article abstract of DOI:10.1007/s00706-012-0795-4

The TiCl₄-mediated [3+3] cyclocondensation of various 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 4-aryl-1-chloro-1,1-difluoro-4- (trimethylsilyloxy)-3-en-2-ones provides a regioselective approach to novel 4-aryl-6-(chlorodifluoromethyl)salicylates (CF₂Cl-substituted biar-yls) with very good regioselectivity.

Full text of DOI:10.1007/s00706-012-0795-4

Monatsh Chem (2012) 143:1151–1156
DOI 10.1007/s00706-012-0795-4
ORIGINAL PAPER
Regioselective synthesis of CF2Cl-substituted biaryls by [3+3]
cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes
with 4-aryl-1-chloro-1,1-difluoro-4-(trimethylsilyloxy)-3-en-2-ones
•
Verena Specowius Nazken Kelzhanova
•
•
Zharylkasyn A. Abilov Peter Langer
Received: 26 March 2012 / Accepted: 10 May 2012 / Published online: 12 June 2012
Ó Springer-Verlag 2012
Abstract The TiCl4-mediated [3?3] cyclocondensation
of various 1,3-bis(trimethylsilyloxy)-1,3-butadienes with
4-aryl-1-chloro-1,1-difluoro-4-(trimethylsilyloxy)-3-en-2-ones
provides a regioselective approach to novel 4-aryl-6-
(chlorodifluoromethyl)salicylates (CF2Cl-substituted biar-
yls) with very good regioselectivity.
(trimethylsilyloxy)-1,3-butadienes (for a review of [3?3]
cyclizations, see [11]; for a review of 1,3-bis(silyl enol
ethers), see [12]; [13–18]). Herein, we report, for the first
time, the synthesis of 4-aryl-6-(chlorodifluoromethyl)salic-
ylates by regioselective [3?3] cyclocondensation of various
1,3-bis(trimethylsilyloxy)-1,3-butadienes with 4-aryl-1-chloro-
1,1-difluoro-4-(trimethylsilyloxy)-3-en-2-ones. The products
are not readily available by other methods and are formed
with very good regioselectivity.
Keywords Arenes ꢀ Cyclizations ꢀ Organofluorine
compounds ꢀ Regioselectivity ꢀ Silyl enol ethers
Introduction
Results and discussion
Aromatic molecules containing a CF2Cl group have been
reported to show pharmacological activity, e.g., as tyrosine
kinase inhibitors [1–3]. A number of synthetic approaches
to CF2Cl-substituted arenes, based on the fluorination or
chlorination of suitable benzene derivatives, have been
reported [4–10]. These methods are limited with regard to
scope and toxicity and availability of the required halo-
genation agents and aromatic substrates. In recent years,
we developed the synthesis of various fluorinated arenes
based on TiCl4-mediated [3?3] cyclizations of 1,3-bis
1,3-Bis(trimethylsilyloxy)-1,3-butadienes 2a–2g were pre-
pared in two steps from the corresponding b-ketoesters
[19–21]. Silyl enol ethers 1a, 1b were prepared by silyla-
tion of the corresponding 1-chloro-1,1-difluorobenzoyl-
acetones (Scheme 1). The TiCl4-mediated cyclization of 1a,
1b with 1,3-bis(trimethylsilyloxy)-1,3-butadienes 2a–2g
afforded the 4-aryl-6-(chlorodifluoromethyl)salicylates 3a–
3k in 29–62 % yields (Scheme 2; Table 1). The relatively
low yield of 3k can be explained by the fact that 1,3-
bis(trimethylsilyloxy)-1,3-butadienes derived from 1,3-
diketones are less nucleophilic compared to those derived
from b-ketoesters.
The reactions proceeded with very good regioselectivity.
It is noteworthy that the cyclization of 1,3-bis(trimethylsi-
lyloxy)-1,3-butadienes with silyl enol ethers derived from
non-fluorinated benzoylacetone has been reported to pro-
ceed with opposite regioselectivity [21].
V. Specowius ꢀ N. Kelzhanova ꢀ P. Langer (&)
Institut fu
18059 Rostock, Germany
e-mail: peter.langer@uni-rostock.de
¨r Chemie, Universita¨t Rostock, Albert Einstein Str. 3a,
P. Langer
Leibniz-Institut fu
¨r Katalyse an der Universita¨t Rostock e.V.,
Albert Einstein Str. 29a, 18059 Rostock, Germany
The formation of products 3 can be explained by anal-
ogy to the synthesis of the corresponding CF3-substituted
analogues [18] by formation of allylic cation A, reaction
with the terminal carbon atom of 2a to give intermediate B,
cyclization via intermediate C to give D, and subsequent
N. Kelzhanova ꢀ Z. A. Abilov
Al-Farabi Kazakh National University, Al-Farabi ave. 71,
050040 Almaty, Kazakhstan
123

1152
V. Specowius et al.
Me3SiO
OSiMe3
Me3SiO
O
O
O
i
O
OH
CF2Cl
1) TiCl4
CH2Cl2
20 °C
CF2Cl
OMe
2a
R
OMe
CF2Cl
-78
R
+
1a (R = Cl, 86%)
1b (R = OMe, 81%)
Me3SiO
O
2) H+, H2O
Ar
3a
(51%)
_
Ar
CF2Cl
i, TMSCl (1.5 equiv.), NEt3 (1.3 equiv.), pentane, 20 °C, 62 h.
1
TiCl3OH
O
Scheme 1
O
TiCl4
Me3SiO
Ar
O
Me3SiO
OSiMe3
R2
OMe
OH
O
CF2Cl
OTiCl3
R1
Ar
R1
2a 2g
-
CF2Cl
i
R2
CF2Cl
A
D
+
Me3SiO
O
Me3SiCl
Me3SiCl
2a
R3
CF2Cl
3a-3k
O
O
R3
1a, 1b
Me3SiO
OMe
Me3SiO
OMe
+ Me3SiCl
(Me3Si)2O
CF2Cl
O
OTiCl3
CF2Cl
i, TiCl4 (1.0 equiv.), CH2Cl2, -78 to 20 °C, 12 h.
Ar
Ar
Scheme 2
OSiMe3
TiCl4
B
Table 1 Synthesis of 3a–3k
C
1
2
3
R1
R2
R3
Yield/%a
Scheme 3
a
a
a
a
a
b
b
b
b
b
b
a
a
b
c
d
e
a
b
c
d
f
a
b
c
d
e
f
H
OMe
OMe
OMe
OMe
OCH2Ph
OMe
OMe
OMe
OMe
OEt
Cl
51
35
48
45
40
49
62
41
41
40
29
Me
Et
Cl
OH
O
Cl
OH
O
n-Pr
H
Cl
OMe
CF2
OMe
i
Cl
CF2Cl
H
OMe
OMe
OMe
OMe
OMe
OMe
MeO
g
h
i
Me
Et
MeO
3f
4
(90%)
n-Pr
Cl
i, Allyl-SnBu3 (2.5 equiv.), AIBN, benzene, reflux, 16 h.
j
Scheme 4
g
k
Me
Et
Yields of isolated products
cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-but-
adienes with 4-aryl-1-chloro-1,1-difluoro-4-(trimethylsilyl-
oxy)-3-en-2-ones. It was demonstrated that the CF2Cl
group can be transformed into a CF2-allyl group by a free
radical reaction.
aromatization (before or during the aqueous work-up)
(Scheme 3).
The CF2Cl group could be successfully used for further
synthetic transformations. The free radical reaction of 3f
with allyltributylstannane, following a known procedure
[22], resulted in replacement of the chlorine atom by an
allyl group and formation of product 4 in 90 % yield
(Scheme 4).
Experimental
1H NMR spectra were taken in CDCl3 at 300 and
400 MHz; 13C NMR spectra were taken in CDCl3 at 75 and
100 MHz. Chemical shifts are reported in parts per million
using the solvent internal standard (chloroform, 7.26 and
77.0 ppm, respectively). Infrared spectra were recorded on
an FTIR spectrometer. Mass spectrometric data (MS) were
Conclusions
We reported a convenient and regioselective synthesis
of CF2Cl-substituted biaryls by TiCl4-mediated [3?3]
123

Regioselective synthesis of CF2Cl-substituted biaryls
1153
C15H10Cl2F2O3 ([M?], [35Cl] [35Cl]) 345.99696, found
345.996551.
obtained by electron ionization (EI, 70 eV), chemical
ionization (CI, isobutane), or electrospray ionization (ESI).
CH2Cl2 (anhydrous, 99.8 %) was purchased directly from
ACROS and used without further purification, TiCl4 was
purchased from Aldrich. Analytical thin-layer chromatog-
raphy was performed on 0.20 mm 60 A silica gel plates.
Column chromatography was performed on 60 A silica gel
(60–200 mesh). All cyclization reactions were carried out
in Schlenk tubes under an argon atmosphere using dried
solvents. 1,3-Bis(trimethylsilyloxy)-1,3-butadienes 2 were
prepared according to the literature from the corresponding
b-ketoesters in two steps [19–21]. Silyl enol ethers 1a, 1b
were also prepared by analogy to reported procedures
[19–21].
Methyl 6-(chlorodifluoromethyl)-4-(4-chlorophenyl)-2-
hydroxy-3-methylbenzoate (3b, C16H12Cl2F2O3)
Starting with 0.678 g 1a (2.0 mmol), 0.577 g 1-methoxy-
1,3-bis(trimethylsilyloxy)-1,3-pentadiene (2b, 2.0 mmol),
and 0.22 cm3 TiCl4 (2.0 mmol) in 4 cm3 CH2Cl2, product
3b was isolated as a white solid (n-heptane/EtOAc =
30:1). Yield 0.252 g (35 %); m.p.: 84–86 °C; 1H NMR
(300 MHz, CDCl3): d = 2.19 (s, 3H, CH3), 4.00 (s, 3H,
OCH3), 7.16 (s, 1H, CH), 7.23–7.26 (m, 2H, CH), 7.41–
7.49 (m, 2H, CH), 10.69 (s, 1H, OH) ppm; 13C NMR (75
MHz, CDCl3): d = 13.6 (CH3), 52.6 (OCH3), 109.1 (t, JC,F
2.2 Hz, C), 118.9 (t, JC,F = 8.8 Hz, CH), 125.2 (t, JC,F
=
=
290 Hz, CF2Cl), 128.6 (CH), 128.7 (C), 130.2 (CH), 133.0
(t, JC,F = 26.4 Hz, C-CF2Cl), 134.1, 138.2, 145.4 (C),
159.7 (C–O), 170.1 (C=O) ppm; 19F NMR (282 MHz,
General procedure for the synthesis of 3a–3k
ꢀ
CDCl3): d = -44.90 (CF2Cl) ppm; IR (ATR): m = 3,401
To 1a, 1b (1.0 equiv.) and 2 (1.0 equiv.) in dichloro-
methane (2.0 cm3 per 1 mmol of 1) was added TiCl4 (1.0
equiv.) at -78 °C. The solution was slowly allowed to
warm to 20 °C with stirring. To the solution was added
10 % hydrochloric acid and the organic and the aqueous
layer were separated. The latter was extracted with
dichloromethane. The combined organic layers were dried
(sodium sulfate), filtered, and the filtrate was concentrated
in vacuo. The residue was purified by chromatography
(silica gel, n-heptane/EtOAc).
(w), 3,095 (w), 3,063 (w), 3,040 (w), 3,011 (w), 2,970 (w),
2,958 (w), 2,924 (w), 2,855 (w), 2,637 (w), 1,694 (s), 1,604
(w), 1,574 (w), 1,553 (w), 1,503 (w), 1,483 (m), 1,440 (m),
1,411 (m), 1,387 (w), 1,345 (w), 1,315 (m), 1,297 (w),
1,272 (w), 1,260 (w), 1,226 (w), 1,201 (w), 1,186 (m),
1,138 (s), 1,110 (s), 1,090 (m), 1,020 (w), 1,011 (w) cm-1
;
MS (EI, 70 eV): m/z (%) = 364 ([M?], [37Cl] [37Cl], 7),
362 ([M?], [37Cl] [35Cl], 41), 360 ([M?], [35Cl] [35Cl], 59),
331 (21), 330 (46), 329 (50), 328 (66), 327 (44), 295 (34),
293 (100), 273 (60), 257 (36), 201 (39); HRMS (EI,
70 eV): calcd. for C16H12Cl2F2O3 ([M?], [35Cl] [35Cl])
360.01261, found 360.011788.
Methyl 6-(chlorodifluoromethyl)-4-(4-chlorophenyl)-2-
hydroxybenzoate (3a, C15H10Cl2F2O3)
Starting with 0.678 g 1a (2.0 mmol), 0.521 g 1-methoxy-
1,3-bis(trimethylsilyloxy)-1,3-butadiene (2a, 2.0 mmol),
and 0.22 cm3 TiCl4 (2.0 mmol) in 4 cm3 CH2Cl2, product
3a was isolated as a red solid (n-heptane/EtOAc = 50:1).
Yield 0.356 g (51 %); m.p.: 86–87 °C; 1H NMR (300
MHz, DMSO-d6): d = 3.44 (s, 3H, OCH3), 6.97 (s, 1H,
CH), 6.99 (s, 1H, CH), 7.16 (d, 3J = 8.3 Hz, 1H, CH), 7.30
(d, 3J = 8.3 Hz, 1H, CH) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 52.7 (OCH3), 114.0 (t, JC,F = 6.0 Hz,
Methyl 6-(chlorodifluoromethyl)-4-(4-chlorophenyl)-3-
ethyl-2-hydroxybenzoate (3c, C17H14Cl2F2O3)
Starting with 0.678 g 1a (2.0 mmol), 0.605 g 1-methoxy-
1,3-bis(trimethylsilyloxy)-1,3-hexadiene (2c, 2.0 mmol),
and 0.22 cm3 TiCl4 (2.0 mmol) in 4 cm3 CH2Cl2, product
3c was isolated as a white solid (n-heptane/EtOAc =
30:1). Yield 0.361 g (48 %); m.p.: 84–86 °C; 1H NMR
(300 MHz, CDCl3): d = 1.23 (t, 3J = 7.4 Hz, 3H, CH2
3
CH3), 2.45 (q, J = 7.4 Hz, 2H, CH2CH3), 4.15 (s, 3H,
CH), 117.4 (CH), 118.1 (t, JC,F = 2.8 Hz, C), 128.4 (t, JC,F
249 Hz, CF2Cl), 128.9, 129.3 (CH), 133.6 (t, JC,F
=
OCH3), 7.35–7.40 (m, 2H, CH), 7.54–7.58 (m, 2H, CH),
10.74 (s, 1H, OH) ppm; 13C NMR (75 MHz, CDCl3):
d = 13.7 (CH2CH3), 20.8 (CH2CH3), 52.7 (OCH3), 109.6
(t, JC,F = 2.2 Hz, C), 119.2 (t, JC,F = 8.8 Hz, CH), 125.2
=
25.9 Hz, C-CF2Cl), 133.8, 137.2, 142.0 (C), 155.7 (C–O),
166.1 (C=O) ppm; 19F NMR (282 MHz, DMSO-d6):
ꢀ
d = -46.62 (CF2Cl) ppm; IR (ATR): m = 3,070 (w),
(t, JC,F = 290 Hz, CF2Cl), 128.6, 129.9 (CH), 133.0 (t, JC,F
26.4 Hz, C-CF2Cl), 134.1, 134.7, 138.3, 145.3 (C), 159.4
=
2,961 (w), 2,856 (w), 1,905 (w), 1,678 (br, s), 1,615 (m),
1,595 (w), 1,578 (w), 1,556 (m), 1,485 (s), 1,438 (s), 1,354
(w), 1,332 (m), 1,305 (w), 1,278 (s), 1,231 (w), 1,208 (s),
1,184 (w), 1,148 (s), 1,121 (w), 1,107 (w), 1,092 (w), 1,051
(s), 1,014 (s) cm-1; MS (EI, 70 eV): m/z (%) = 350
([M?], [37Cl] [37Cl], 5), 348 ([M?], [37Cl] [35Cl], 27), 246
([M?], [35Cl] [35Cl], 46), 316 (66), 315 (28), 314 (100),
188 (31), 157 (10), 126 (22); HRMS (EI, 70 eV): calcd. for
(C–O), 170.1 (C=O) ppm; 19F NMR (282 MHz, CDCl3):
ꢀ
d = -44.89 (CF2Cl) ppm; IR (ATR): m = 3,401 (w), 2,981
(w), 2,957 (w), 2,875 (w), 1,906 (w), 1,690 (br, s), 1,605
(w), 1,557 (w), 1,496 (w), 1,479 (w), 1,460 (w), 1,440 (s),
1,402 (w), 1,392 (w), 1,373 (w), 1,353 (w), 1,327 (w),
1,312 (w), 1,277 (w), 1,247 (s), 1,219 (w), 1,198 (w), 1,182
(m), 1,135 (s), 1,110 (s), 1,088 (m), 1,058 (s), 1,014
123

1154
V. Specowius et al.
(m) cm-1; MS (EI, 70 eV): m/z (%) = 378 ([M?], [37Cl]
[37Cl], 4), 376 ([M?], [37Cl] [35Cl], 27), 374 ([M?], [35Cl]
[35Cl], 42), 344 (14), 343 (25), 342 (21), 341 (25), 307
(100); HRMS (EI, 70 eV): calcd. for C17H14Cl2F2O3
([M?], [35Cl] [35Cl]) 374.02826, found 374.027536; calcd.
for C17H14Cl2F2O3 ([M?] [35Cl] [37Cl]) 376.02531, found
376.025071.
(282 MHz, CDCl3): d = -44.94 (CF2Cl) ppm; IR (ATR):
ꢀ
m = 3,090 (w), 3,067 (w), 3,032 (w), 2,958 (w), 2,927 (w),
2,896 (w), 2,856 (w), 1,722 (w), 1,660 (s), 1,614 (m), 1,594
(w), 1,461 (w), 1,454 (w), 1,422 (w), 1,385 (s), 1,353 (m),
1,316 (w), 1,304 (w), 1,272 (w), 1,265 (w), 1,202 (s), 1,185
(w), 1,151 (m), 1,106 (s), 1,091 (w), 1,054 (m), 1,030 (w),
1,011 (m) cm-1; MS (EI, 70 eV): m/z (%) = 426 ([M?],
[37Cl] [37Cl], 6), 424 ([M?], [37Cl] [35Cl], 39), 422 ([M?],
[35Cl] [35Cl], 61), 188 (17), 92 (55), 91 (100), 65 (20);
HRMS (EI, 70 eV): calcd. for C21H14Cl2F2O3 ([M?] [35Cl]
[35Cl]) 422.02826, found 422.027865; calcd. for C21H14
Cl2F2O3 ([M?] [35Cl] [37Cl]) 424.02531, found 424.
025393; calcd. for C21H14Cl2F2O3 ([M?] [37Cl] [37Cl])
426.02236, found 426.023495.
Methyl 6-(chlorodifluoromethyl)-4-(4-chlorophenyl)-2-
hydroxy-3-propylbenzoate (3d, C18H16Cl2F2O3)
Starting with 0.678 g 1a (2.0 mmol), 0.605 g 1-methoxy-
1,3-bis(trimethylsilyloxy)-1,3-heptadiene (2d, 2.0 mmol),
and 0.22 cm3 TiCl4 (2.0 mmol) in 4 cm3 CH2Cl2, product
3d was isolated as an orange oil (n-heptane/EtOAc =
30:1). Yield 0.348 g (45 %); 1H NMR (300 MHz, CDCl3):
d = 0.82 (t, 3J = 7.4 Hz, 3H, CH2CH3), 1.43–1.56 (m, 2H,
CH2CH3), 2.53–2.59 (m, 2H, CH2), 4.00 (s, 3H, OCH3),
Methyl 6-(chlorodifluoromethyl)-2-hydroxy-4-(4-methoxy-
phenyl)benzoate (3f, C16H13ClF2O4)
3
7.01 (s, 1H, CH), 7.19–7.22 (m, J = 8.5 Hz, 2H, CH),
3
Starting with 0.670 g 1b (2.0 mmol), 0.521 g 1-methoxy-
1,3-bis(trimethylsilyloxy)-1,3-butadiene (2a, 2.0 mmol),
and 0.22 cm3 TiCl4 (2.0 mmol) in 4 cm3 CH2Cl2, product
3f was isolated as an orange solid (n-heptane/EtOAc =
7.39–7.42 (m, J = 8.5 Hz, 2H, CH), 10.50 (s, 1H, OH)
ppm; 13C NMR (75 MHz, CDCl3): d = 14.0 (CH2CH3),
22.5 (CH2CH3), 29.5 (CH2CH3), 52.7 (OCH3), 109.5
(t, JC,F = 2.2 Hz, C), 119.2 (t, JC,F = 8.8 Hz, CH), 125.2
(t, JC,F = 290 Hz, CF2Cl), 128.6 (CArH), 130.0 (CArH),
132.9 (t, JC,F = 26.0 Hz, C-CF2Cl), 133.5, 134.0, 138.5,
145.7 (C), 159.5 (C–O), 170.1 (C=O) ppm; 19F NMR
(282 MHz, CDCl3): d = -44.91 (CF2Cl) ppm; IR (ATR):
1
30:1). Yield 0.335 g (49 %); m.p.: 98–100 °C; H NMR
(300 MHz, CDCl3): d = 3.85 (s, 3H, OCH3), 3.99 (s, 3H,
OCH3), 6.96–7.01 (m, J = 8.9 Hz, 2H, CArH), 7.32 (d,
3
3J = 1.9 Hz, 1H, CArH), 7.47 (d, 3J = 1.7 Hz, 1H, CArH),
3
7.53–7.58 (m, J = 8.9 Hz, 2H, CArH), 10.41 (s, 1H, OH)
m = 2,959 (w), 2,932 (w), 2,872 (w), 1,904 (w), 1,749 (w),
ppm; 13C NMR (75 MHz, CDCl3): d = 52.5 (OCH3), 55.4
(OCH3), 108.9 (t, JC,F = 2.2 Hz, C), 114.5 (CArH), 116.5
ꢀ
1,672 (br, s), 1,605 (m), 1,564 (w), 1,489 (m), 1,464 (w),
1,438 (s), 1,402 (w), 1,380 (w), 1,329 (w), 1,300 (w), 1,272
(s), 1,345 (w), 1,218 (m), 1,181 (w), 1,153 (w), 1,139 (w),
1,102 (w), 1,090 (s), 1,071 (w), 1,015 (s) cm-1; MS (EI,
70 eV): m/z (%) = 392 ([M?], [37Cl] [37Cl], 5), 390 ([M?],
[37Cl] [35Cl], 25), 388 ([M?], [35Cl] [35Cl], 39), 358 (15),
357 (23), 356 (22), 355 (24), 323 (36), 322 (23), 321 (100),
305 (10), 293 (14), 201 (21); HRMS (EI, 70 eV): calcd. for
C18H16Cl2F2O3 ([M?], [35Cl] [35Cl]) 388.04391, found
388.044006; calcd. for C18H16Cl2F2O3 ([M?] [35Cl] [37Cl])
390.04096, found 390.041345.
(t, JC,F = 8.8 Hz, CH), 118.3 (CArH), 125.4 (t, JC,F
=
290.5 Hz, CF2Cl), 128.3 (CArH), 130.6 (C), 136.5
(t, JC,F = 25.9 Hz, C-CF2Cl), 146.0 (C), 160.5 (C), 161.4
(C–O), 169.6 (C=O) ppm; 19F NMR (282 MHz, CDCl3):
ꢀ
d = -45.23 (CF2Cl) ppm; IR (ATR): m = 3,062 (w), 3,038
(w), 3,013 (w), 2,954 (w), 2,930 (w), 2,839 (w), 2,054 (w),
1,897 (w), 1,666 (s), 1,605 (m), 1,583 (w), 1,562 (w), 1,513
(s), 1,454 (w), 1,437 (s), 1,365 (w), 1,333 (m), 1,307 (w),
1,271 (w), 1,252 (w), 1,235 (w), 1,211 (m), 1,174 (m),
1,146 (m), 1,109 (m), 1,056 (w), 1,029 (s) cm-1; MS (EI,
70 eV): m/z (%) = 344 ([M?] [37Cl] 27), 342 ([M?] [35Cl]
74), 312 (33), 311 (27), 310 (100), 247 (47), 124 (26);
HRMS (EI, 70 eV): calcd. for C16H13ClF2O4 ([M?] [35Cl])
342.04649, found 342.046469.
Benzyl 6-(chlorodifluoromethyl)-4-(4-chlorophenyl)-2-
hydroxybenzoate (3e, C21H14Cl2F2O3)
Starting with 0.678 g 1a (2.0 mmol), 0.673 g 1-benzyloxy-
1,3-bis(trimethylsilyloxy)-1,3-butadiene (2e, 2.0 mmol),
and 0.22 cm3 TiCl4 (2.0 mmol) in 4 cm3 CH2Cl2, the
product 3e was isolated as an orange solid (n-heptane/
EtOAc = 30:1). Yield 0.339 g (40 %); m.p.: 92–94 °C; 1H
NMR (300 MHz, CDCl3): d = 5.44 (s, 2H, CH2), 7.32–
7.53 (m, 11H, CArH), 10.34 (s, 1H, OH) ppm; 13C NMR
Methyl 6-(chlorodifluoromethyl)-2-hydroxy-3-methyl-4-(4-
methoxyphenyl)benzoate (3g, C17H15ClF2O4)
Starting with 0.670 g 1b (2.0 mmol), 0.577 g 1-methoxy-
1,3-bis(trimethylsilyloxy)-1,3-pentadiene (2b, 2.0 mmol),
and 0.22 cm3 TiCl4 (2.0 mmol) in 4 cm3 CH2Cl2, product
3g was isolated as a white solid (n-heptane/EtOAc =
30:1). Yield 0.446 g (62 %); m.p.: 56–58 °C; 1H NMR
(250 MHz, CDCl3): d = 2.22 (s, 3H, CH3), 3.86 (s, 3H,
(125 MHz, CDCl3): d = 68.5 (CH2), 110.1 (t, JC,F
=
2.2 Hz, C), 116.7 (t, JC,F = 8.8 Hz, CH), 119.0 (CArH),
124.9 (t, JC,F = 290 Hz, CF2Cl), 125.3 (C), 126.3 (C),
128.5 (CArH), 128.6 (CArH), 128.8 (CArH), 129.3 (CArH),
134.1 (C), 135.3 (C), 136.8 (t, JC,F = 26.0 Hz, C-CF2Cl),
145.1 (C), 161.4 (C–O), 168.8 (C=O) ppm; 19F NMR
3
OCH3), 3.99 (s, 3H, OCH3), 6.94–7.00 (m, J = 8.8 Hz,
2H, CArH), 7.18 (s, 1H, CArH), 7.21-7.27 (m, 3J = 8.8 Hz,
2H, CArH), 10.70 (s, 1H, OH) ppm; 13C NMR (75 MHz,
123

Regioselective synthesis of CF2Cl-substituted biaryls
1155
CDCl3): d = 13.7 (CH3), 52.5 (OCH3), 55.3 (OCH3),
Yield 0.312 g (41 %); m.p.: 38–40 °C; 1H NMR
3
108.4 (t, JC,F = 2.2 Hz, C), 113.8 (CArH), 119.3 (t, JC,F
=
(300 MHz, CDCl3): d = 0.83 (t, J = 7.4 Hz, 3H, CH3),
1.48–1.58 (m, J = 7.4 Hz, 2H, CH2), 2.57–2.62 (m, 2H,
3
8.8 Hz, CH), 125.3 (t, JC,F = 290.5 Hz, CF2Cl), 128.6 (C),
130.1 (CArH), 132.1 (C), 132.7 (t, JC,F = 26.0 Hz, C-
CF2Cl), 146.4 (C), 159.4 (C), 159.7 (C–O), 170.2 (C=O)
ppm; 19F NMR (282 MHz, CDCl3): d = -44.73 (CF2Cl)
ppm; IR (ATR): ꢀm = 3,005 (w), 2,972 (w), 2,960 (w),
2,940 (w), 2,844 (w), 1,661 (br, s), 1,606 (br, s), 1,562 (w),
1,513 (s), 1,457 (w), 1,439 (m), 1,418 (w), 1,384 (w), 1,337
(m), 1,306 (w), 1,290 (w), 1,270 (m), 1,245 (m), 1,207 (w),
1,176 (w), 1,164 (w), 1,132 (m), 1,094 (m), 1,022 (m),
1,011 (w) cm-1; MS (EI, 70 eV): m/z (%) = 358 ([M?],
[37Cl], 36), 356 ([M?], [35Cl], 100), 325 (27), 324 (33), 323
(28), 293 (61), 261 (30); HRMS (EI, 70 eV): calcd. for C17
H15ClF2O4 ([M?] [35Cl]) 356.06214, found 356.062022.
CH2), 3.86 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 6.94-6.98
(m, 3J = 8.7 Hz, 2H, CArH), 7.14 (s, 1H, CArH), 7.19–7.22
3
(m, J = 8.7 Hz, 2H, CArH), 10.59 (s, 1H, OH) ppm; 13C
NMR (75 MHz, CDCl3): d = 13.3 (CH3), 22.5 (CH2), 29.5
(CH2), 52.5 (OCH3), 55.3 (OCH3), 108.9 (t, JC,F = 2.2 Hz,
C), 113.7 (CArH), 119.7 (t, JC,F = 8.8 Hz, CH), 125.3
(t, JC,F = 290.0 Hz, CF2Cl), 129.8 (CArH), 132.4 (C),
132.6 (t, JC,F = 25.9 Hz, C-CF2Cl), 133.5 (C), 146.6 (C),
159.3 (C), 159.5 (C–O), 170.2 (C=O) ppm; 19F NMR
(282 MHz, CDCl3): d = -44.70 (CF2Cl) ppm; IR (ATR):
ꢀ
m = 3,037 (w), 3,003 (w), 2,958 (w), 2,936 (w), 2,873 (w),
2,839 (w), 1,671 (br, s), 1,608 (br, s), 1,578 (w), 1,557 (w),
1,513 (s), 1,464 (w), 1,438 (m), 1,414 (w), 1,382 (w), 1,328
(m), 1,300 (w), 1,288 (w), 1,272 (m), 1,243 (m), 1,218 (w),
1,175 (m), 1,153 (w), 1,137 (w), 1,103 (s), 1,072 (w), 1,034
(s), 1,013 (w) cm-1; MS (EI, 70 eV): m/z (%) = 386
([M?], [37Cl], 34), 384 ([M?], [35Cl], 95), 326 (34), 324
(100), 323 (39), 221 (69), 295 (30), 287 (13); HRMS (EI,
70 eV): calcd. for C19H19ClF2O4 ([M?] [35Cl]) 384.09344,
found 384.093282.
Methyl 6-(chlorodifluoromethyl)-3-ethyl-2-hydroxy-4-(4-
methoxyphenyl)benzoate (3h, C18H17ClF2O4)
Starting with 0.670 g 1b (2.0 mmol), 0.605 g 1-methoxy-
1,3-bis(trimethylsilyloxy)-1,3-hexadiene (2c, 2.0 mmol),
and 0.22 cm3 TiCl4 (2.0 mmol) in 4 cm3 CH2Cl2, product
3h was isolated as a white solid (n-heptane/EtOAc =
30:1). Yield 0.306 g (41 %); m.p.: 64–66 °C; 1H NMR
3
(300 MHz, CDCl3): d = 1.08 (t, J = 7.4 Hz, 3H, CH3),
3
2.65 (q, J = 7.4 Hz, 2H, CH2), 3.86 (s, 3H, OCH3), 3.99
Ethyl 3-chloro-6-(chlorodifluoromethyl)-2-hydroxy-4-(4-
methoxyphenyl)benzoate (3j, C17H14Cl2F2O4)
(s, 3H, OCH3), 6.94-6.99 (m, 3J = 8.7 Hz, 2H, CArH), 7.14
(s, 1H, CArH), 7.20–7.23 (m, 3J = 8.7 Hz, 2H, CArH),
10.60 (s, 1H, OH) ppm; 13C NMR (75 MHz, CDCl3):
d = 13.7 (CH3), 20.8 (CH2), 52.5 (OCH3), 55.3 (OCH3),
Starting with 0.670 g 1b (2.0 mmol), 0.618 g 4-chloro-1-
ethoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene (2f, 2.0
mmol), and 0.22 cm3 TiCl4 (2.0 mmol) in 4 cm3 CH2Cl2,
product 3j was isolated as an orange solid (n-heptane/
EtOAc = 30:1). Yield 0.339 g (40 %); m.p.: 92–94 °C; 1H
108.9 (t, JC,F = 2.2 Hz, C), 113.7 (CArH), 119.7 (t, JC,F
=
8.8 Hz, CH), 125.3 (t, JC,F = 290.0 Hz, CF2Cl), 129.8
(CArH), 132.3 (C), 132.7 (t, JC,F = 25.9 Hz, C-CF2Cl),
134.7 (C), 136.4 (C), 159.3 (C), 159.9 (C–O), 170.2 (C=O)
ppm; 19F NMR (282 MHz, CDCl3): d = -44.72 (CF2Cl)
3
NMR (300 MHz, CDCl3): d = 1.45 (t, J = 7.2 Hz, 3H,
CH3), 3.86 (s, 3H, OCH3), 4.49 (t, 3J = 7.2 Hz, 2H, CH2),
6.98–7.02 (m, 3J = 8.9 Hz, 2H, CArH), 7.27 (s, 1H, CArH),
3
ꢀ
ppm; IR (ATR): m = 3,437 (w), 3,041 (w), 3,009 (w),
7.39–7.43 (m, J = 8.9 Hz, 2H, CArH), 10.26 (s, 1H, OH)
2,968 (w), 2,940 (w), 2,879 (w), 2,842 (w), 1,668 (br, s),
1,608 (m), 1,579 (w), 1,555 (w), 1,513 (s), 1,486 (w), 1,466
(w), 1,440 (m), 1,414 (w), 1,384 (w), 1,355 (w), 1,336 (w),
1,315 (w), 1,284 (s), 1,243 (s), 1,199 (w), 1,176 (m), 1,149
(w), 1,139 (m), 1,103 (s), 1,059 (m), 1,030 (s), 1,013 (w),
1,000 (w) cm-1; MS (EI, 70 eV): m/z (%) = 372 ([M?],
[37Cl], 36), 370 ([M?], [35Cl], 100), 337 (20), 335 (12), 312
(28), 310 (84), 307 (75), 302 (40), 287 (16); HRMS (EI,
70 eV): calcd. for C18H17ClF2O4 ([M?] [35Cl]) 370.07779,
found 370.077603.
ppm; 13C NMR (75 MHz, CDCl3): d = 13.6 (CH3), 55.3
(OCH3), 63.0 (CH2), 111.8 (t, JC,F = 2.2 Hz, C), 113.8
(CArH), 119.6 (t, JC,F = 8.8 Hz, CH), 124.3 (C), 124.9
(t, JC,F = 290.0 Hz, CF2Cl), 129.8 (C), 130.4 (CArH),
136.4 (t, JC,F = 26.0 Hz, C-CF2Cl), 144.6 (C), 156.0 (C),
160.0 (C–OH), 168.2 (C=O) ppm; 19F NMR (282 MHz,
ꢀ
CDCl3): d = -45.45 (CF2Cl) ppm; IR (ATR): m = 2,983
(w), 2,962 (w), 2,937 (w), 2,907 (w), 2,838 (w), 1,738 (m),
1,667 (br, s), 1,608 (s), 1,579 (w), 1,562 (w), 1,542 (w),
1,515 (s), 1,465 (m), 1,443 (w), 1,419 (w), 1,394 (w), 1,374
(m), 1,304 (w), 1,287 (w), 1,248 (m), 1,228 (w), 1,177 (m),
1,153 (w), 1,137 (w), 1,099 (s), 1,031 (w), 1,014 (w) cm-1
;
Methyl 6-(chlorodifluoromethyl)-2-hydroxy-4-(4-methoxy-
phenyl)-3-propylbenzoate (3i, C19H19ClF2O4)
MS (EI, 70 eV): m/z (%) = 394 ([M?], [37Cl] [37Cl], 5),
392 ([M?], [37Cl] [35Cl], 31), 390 ([M?], [35Cl] [35Cl], 45),
348 (13), 347 (18), 346 (68), 344 (100), 281 (43); HRMS
(EI, 70 eV): calcd. for C17H14Cl2F2O4 ([M?] [35Cl] [35Cl])
390.02317, found 390.023407.
Starting with 0.670 g 1b (2.0 mmol), 0.605 g 1-methoxy-
1,3-bis(trimethylsilyloxy)-1,3-heptadiene (2d, 2.0 mmol),
and 0.22 cm3 TiCl4 (2.0 mmol) in 4 cm3 CH2Cl2, product
3i was isolated as an orange solid (n-heptane/EtOAc = 30:1).
123

1156
V. Specowius et al.
1-[5-(Chlorodifluoromethyl)-3-hydroxy-40-methoxy-2-
methylbiphenyl-4-yl]propan-1-one (3k, C18H16ClF2O3)
Starting with 0.670 g 1b (2.0 mmol), 0.673 g 4-ethyl-1-
methyl-1,3-bis(trimethylsilyloxy)-1,3-butadiene (2g, 2.0
mmol), and 0.22 cm3 TiCl4 (2.0 mmol) in 4 cm3 CH2Cl2,
product 3k was isolated as an orange oil (n-heptane/
EtOAc = 30:1). Yield 0.200 g (29 %); 1H NMR (250
NMR (75 MHz, CDCl3): d = 43.4 (t, J = 27.0 Hz, CH2),
52.6 (OCH3), 55.4 (OCH3), 111.5 (t, JC,F = 2.8 Hz, C),
114.4 (CH), 116.5 (CH), 117.6 (t, JC,F = 9.4 Hz, CH),
120.4 (CH2), 122.0 (t, JC,F = 244.8 Hz, CF2), 128.3 (CH),
129.3 (t, JC,F = 4.4 Hz, CH), 131.2 (C), 138.2 (t, JC,F
25.9 Hz, C-CF2), 145.4 (C), 159.9 (C–O), 160.2 (C–O),
170.0 (C=O) ppm; 19F NMR (282 MHz, CDCl3): d =
=
3
ꢀ
! MHz, CDCl3): d = 1.24 (t, J = 7.3 Hz, 3H, CH2CH3),
2.24 (CH3), 3.01 (q, J = 7.3 Hz, 2H, CH2CH3), 3.91 (s,
-88.99 (CF2) ppm; IR (ATR): m = 3,402 (s), 3,088 (w),
3
3,057 (w), 3,022 (w), 2,958 (w), 2,840 (w), 1,719 (s), 1,643
(w), 1,607 (w), 1,590 (w), 1,573 (w), 1,520 (m), 1,498 (w),
1,467 (w), 1,433 (s), 1,415 (w), 1,400 (m), 1,366 (m), 1,334
(w), 1,318 (w), 1,293 (w), 1,274 (m), 1,250 (m), 1,226 (m),
1,179 (m), 1,161 (w), 1,140 (w), 1,126 (w), 1,114 (w),
1,059 (w), 1,015 (s) cm-1; HRMS (ESI/TOF): calcd. for
C19H18NaF2O4 [(M ? Na)?] 371.1065, found 371.1063.
3H, OCH3), 7.00–7.31 (m, 5H, CArH), 7.70 (s, 1H, OH)
ppm; 13C NMR (75 MHz, CDCl3): d = 8.3 (CH3), 13.5
(CH3), 37.9 (t, JC,F = 3.8 Hz, CH2), 55.3 (OCH3), 113.8
(CArH), 119.6 (t, JC,F = 8.8 Hz, CH), 122.4 (t, JC,F
1.7 Hz, C), 125.9 (t, JC,F = 290.5 Hz, CF2Cl), 130.1
(CArH), 130.6 (t, JC,F = 26.4 Hz, C-CF2Cl), 132.1 (C),
=
144.7 (C), 152.6 (C), 159.2 (C–OH), 208.5 (C=O) ppm; 19
F
Acknowledgments Financial support by the State of Mecklenburg-
Vorpommern is gratefully acknowledged.
NMR (282 MHz, CDCl3): d = -42.48 (CF2Cl) ppm; IR
ꢀ
(ATR): m = 3,391 (br, w), 2,962 (w), 2,937 (w), 2,912 (w),
2,837 (w), 1,693 (s), 1,608 (m), 1,678 (w), 1,564 (w), 1,515
(s), 1,456 (w), 1,443 (w), 1,419 (w), 1,399 (w), 1,379 (w),
1,346 (s), 1,308 (w), 1,298 (w), 1,289 (w), 1,248 (m), 1,225
(w), 1,175 (m), 1,144 (w), 1,118 (w), 1,109 (w), 1,095 (w),
1,069 (w), 1,033 (w), 1,017 (w), 1,008 (w) cm-1; MS (EI,
70 eV): m/z (%) = 356 ([M?], [37Cl], 12), 354 ([M?],
[35Cl], 37), 327 (31), 325 (100), 305 (12), 277 (28); HRMS
(ESI/TOF): calcd. for C18H16ClF2O3 ([M - H] [35Cl])
353.07615, found 353.07685.
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methoxyphenyl)benzoate (4, C19H18F2O4)
To a benzene suspension (10 cm3/1 mmol of 3f) of 3f (1.0
mmol) in a pressure tube was added Bu3SnCH2CH=CH2
(5.0 mmol) and azobisisobutyronitrile (AIBN, 0.12 mmol)
and the resultant solution was degassed by bubbling argon
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to 90 °C under argon atmosphere for 20 h with stirring.
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pressure tube was rinsed with benzene and the organic
solution was concentrated in vacuo. The residue was
purified by column chromatography (n-heptane/EtOAc).
Starting with 0.171 g 3f (0.5 mmol), 0.414 g allylstanne
(1.25 mmol), and AIBN (0.06 mmol) in 10 cm3 benzene,
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Tetrahedron 48:8523
1
50:1). Yield 0.156 g (90 %); m.p.: 150–151 °C; H NMR
(300 MHz, CDCl3): d = 3.10–3.23 (m, 2H, CH2), 3.85 (s,
3H, OCH3), 3.96 (s, 3H, OCH3), 5.18–5.26 (m, 2H, CH2),
3
5.84–5.98 (m, 1H, CH), 6.97–6.99 (m, J = 8.9 Hz, 2H,
CArH), 7.24–7.26 (m, 2H, CArH), 7.53–7.57 (m,
3J = 8.9 Hz, 2H, CArH), 9.61 (s, 1H, OH) ppm; 13C
123