Application of 1-(3-bromo-3,3-difluoroprop-1-ynyl)benzenes in Diels-Alder reactions: Synthesis of ortho-CF2Br-substituted biaryls

Article abstract of DOI:10.1055/s-2008-1067221

1-(3-Bromo-3,3-difluoroprop-1-ynyl)benzenes were found to be good dienophiles in Diels-Alder reactions. Based on this key reaction a new pathway towards biaryls with an ortho-CF₂Br group was elaborated. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067221

PAPER
2899
Application of 1-(3-Bromo-3,3-difluoroprop-1-ynyl)benzenes in Diels–Alder
Reactions: Synthesis of ortho-CF2Br-Substituted Biaryls
B
iaryls with anort
a
ho-CF Br
G
2 sroup iliy M. Muzalevskiy,a Valentine G. Nenajdenko,*a Aleksey V. Shastin,b Elizabeth S. Balenkova,a Günter Haufe*c
a
b
c
Department of Chemistry, Moscow State University, Leninskie Gory, Moscow 119992, Russian Federation
E-mail: nen@acylium.chem.msu.ru
Institute of Problems of Chemical Physics, Chernogolovka, Moscow Region 142432, Russian Federation
E-mail: shastin@icp.ac.ru
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Correnstr. 40, 48149 Münster, Germany
Fax +49(251)8339772; E-mail: haufe@uni-muenster.de
Received 26 March 2008; revised 21 May 2008
Ph
O
O
Ar
Ph
Abstract: 1-(3-Bromo-3,3-difluoroprop-1-ynyl)benzenes
were
Ar
100 °C
toluene
found to be good dienophiles in Diels–Alder reactions. Based on
this key reaction a new pathway towards biaryls with an ortho-
CF2Br group was elaborated.
Ph
CF2Br
CF2Br
Ph
2
1
Key words: alkynes, biaryls, bicyclic compounds, Diels–Alder
reaction, fluorine
Scheme 1 Reactions of acetylenes 1 with 1,3-diphenylisobenzo-
furan
The Diels–Alder reaction1 is one of the fundamental trans-
formations in organic synthesis providing a broad variety
of cyclohexene derivatives leading to the development of
a rich downstream chemistry.2 A variety of fluorinated
compounds were prepared using this methodology.3 Two
strategies are suitable, either placing a fluorine substituent
in the diene4 or in the dienophile.3,5 Moreover, trifluoro-
methylated or perfluoroalkylated starting materials can be
applied.6 Several [4+2] cycloaddition reactions of 1,3-
dienes with 1-(3,3,3-trifluoroprop-1-ynyl)benzene, which
are similar to those described in this paper have been exe-
cuted.7
Table 1 Reactions of Acetylenes 1 with 1,3-Diphenylisobenzofuran
Entry
1
a
b
c
d
e
f
Ar
Time (h)
Yield of 2 (%)
1
2
3
4
5
6
4-O2NC6H4
4-ClC6H4
Ph
4
72
95
83
87
–
36
100
8
3-O2NC6H4
2-O2NC6H4
4-MeOC6H4
8
170
–
Our interest was focused on the application of the Diels–
Alder strategy for the preparation of biaryls. Historically,
the first method for the preparation of these compounds
was the well-known Ulmann reaction.8 Nowadays, substi-
tutive aryl–aryl coupling reactions, such as the Suzuki9 or
the Stille10 coupling, are the most general synthetic routes
towards such molecules. However, active halogen atoms
in the side chains might be incompatible with the reaction
conditions. Thus, we were interested to develop a new
pathway towards this important group of compounds. Bi-
aryls are present in a variety of biologically active com-
pounds, which have demonstrated activity across many
therapeutic classes, including anti-inflammatory, anti-
rheumatic, and antitumor agents.11 In addition, some
ortho-substituted biphenyl homologues have been pro-
posed as potential mimetics of a protein a-helix.12 Fur-
thermore, it is well known that fluorine substituents in
organic compounds change the physicochemical
properties13 as well as the biological activity compared to
the fluorine-free parent compounds.14
1-(3-Bromo-3,3-difluoroprop-1-ynyl)benzenes 1, which
were obtained by a catalytic olefination reaction,15,16 are
particularly interesting. They are expected to be good di-
enophiles because of the strong electron withdrawing ef-
fect of the CF2Br group. On the other hand, there is a
principal possibility of further modification of the formed
Diels–Alder adducts by reduction or substitution of the
bromine atom in the CF2Br group. Consequently, Diels–
Alder reactions of 1-(3-bromo-3,3-difluoroprop-1-
ynyl)benzenes 1 represent interesting transformations.
The very reactive 1,3-diphenylisobenzofuran, which is a
stabilized o-quinodimethane17 reacted smoothly with the
above mentioned acetylenes 1 and gave the expected
Diels–Alder adducts 2 in high yields (Scheme 1, Table 1).
In contrast, the reactions of 1,3-diphenylisobenzofuran
with acetylenes 1e and 1f led to complex mixtures of uni-
dentified products.
SYNTHESIS 2008, No. 18, pp 2899–2904
x
x.
x
x
.
2
0
0
8
It is well known that the activity of dienophiles depends
strongly on the electronic properties of substituents at the
Advanced online publication: 06.08.2008
DOI: 10.1055/s-2008-1067221; Art ID: T05008SS
© Georg Thieme Verlag Stuttgart · New York

2900
V. M. Muzalevskiy et al.
PAPER
Ar
O
Ar
Ar
Ar
O
150 °C
toluene
150 °C, 6 h
78%
O
CF2Br
O
CF2Br
CF2Br
CF2Br
1a (Ar = 4-O2NC6H4)
3
6
1
Scheme 2 Reaction of 1a with furan
Scheme 5 Reactions of acetylenes 1 with 2-pyrone
Ar
Ar
Subsequently, we examined the reactivity of other acety-
lenes. The rate of reactions of 1b and 1c with furan, 2,3-
dimethylbutadiene, and cyclohexa-1,3-diene dropped dra-
matically. Even after a longer reaction time the starting
materials were not completely consumed. Moreover, the
formation of complex mixtures and considerable amount
of tars was observed.
150 °C, 6 h
89%
CF2Br
CF2Br
4
1a (Ar = 4-O2NC6H4)
Scheme 3 Reaction of 1a with 2,3-dimethylbutadiene
Ar
Ar
Our further investigations were focused on the application
of acetylenes 1 for the synthesis of biaryls. Diels–Alder
reactions of 2-pyrones with acetylenes are known to lead
to thermolabile cycloadducts, which easily extrude carbon
dioxide to give biaryls at elevated temperature.19 Substi-
tuted biaryls are central components of fine chemicals for
a diverse range of applications. In particular, pharmaceu-
ticals and herbicides with biaryl substructures are of gen-
eral interest.20 In addition, biaryls were applied as chiral
ligands in catalysis, as liquid crystals, or organic conduc-
tors.21
Ar
∆
CF2Br
CF2Br
CF2Br
5
6a
1a Ar = 4-O2NC6H4
120 °C, 24 h
150 °C, 6 h
150 °C, 24 h
43%
34%
-
-
28%
52%
Scheme 4 Reaction of 1a with cyclohexa-1,3-diene
multiple bonds. Thus, for less reactive dienes such as fu-
ran more reactive dienophiles have to be applied. The
most active dienophiles in Diels–Alder reactions with
normal electron demand contain strong electron-with-
drawing groups. Consequently, we first investigated the
nitro-substituted acetylene 1a, which should be the most
active among the acetylenes under consideration. Even for
this acetylene quite harsh conditions were needed for suc-
cessful cycloaddition with common dienes. The reaction
with furan was complete at 150 °C within 6 hours, giving
Initially, we investigated reactions of the unsubstituted 2-
pyrone with acetylenes 1, bearing a nitro group in differ-
ent positions of the aryl ring. The acetylenes 1a and 1d re-
acted with 2-pyrone at 150 °C in toluene giving the
desired biaryls 6a and 6d in good yields (Scheme 5,
Table 2). In the case of the 2-nitrophenyl acetylene 1e the
yield dropped dramatically, obviously because of steric
hindrance in the transition state of the cycloaddition.
the oxanorbornadiene derivative
3 in high yield
The reactions of three more 2-pyrones 7a–c with acety-
lenes were also examined. We found that the 2-pyrones 7a
and 7b gave the corresponding biaryls 8a and 8b, respec-
tively, in moderate yields. Compared to the unsubstituted
2-pyrone longer reaction times were needed for complete
consumption of the starting materials. After heating for 4
days, we still found starting materials in both cases. Ex-
tending the reaction time to one week led to completion
and the yield of biaryl 8b rose to 40%. In contrast to 2-py-
rone 7a, the yield of biaryl 8a dropped to trace amounts
because of sudden tarring of the reaction mixture. The re-
action of pyrone 7c with acetylene 1a was not successful,
probably because of decomposition of pyrone 7c at high
temperature; only traces of 8c were found (Scheme 6,
Table 3).
(Scheme 2). The corresponding reaction of 1-(3,3,3-tri-
fluoroprop-1-ynyl)benzene with furan is described to give
a complex mixture of products containing an oxanorbor-
nadiene formed by successive Diels–Alder and retro-
Diels–Alder reactions.18
The reaction of 1a with 2,3-dimethylbutadiene at 150 °C
led to the corresponding Diels–Alder adduct 4 in high
yield (Scheme 3).
Surprisingly, the reaction of 1a with cyclohexa-1,3-diene
gave a mixture of two products. The expected Diels–
Alder adduct 5 was accompanied by the biaryl 6a after
heating for 6 hours at 150 °C. At 120 °C, the reaction was
incomplete after 24 hours and compound 5 was the sole
product, while after continued heating at 150 °C for 24
hours, only 6a was isolated (Scheme 4). The formation of
the unexpected product 6a can be explained by formal ex-
trusion of ethylene from the adduct 5 by retro-Diels–Alder
reaction.
Table 2 Synthesis of Biaryls 6
Entry
1
a
d
e
Ar
Time (h)
Yield of 6 (%)
1
2
3
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
53
70
70
76
72
22
The reactions of 1a with cyclopentadiene and Danishef-
sky’s diene were also investigated. But unfortunately,
these dienes did not react at 120 °C and gave only tars at
higher temperatures.
Synthesis 2008, No. 18, 2899–2904 © Thieme Stuttgart · New York

PAPER
Biaryls with an ortho-CF2Br Group
2901
Me
1-(3-Bromo-3,3-difluoroprop-1-ynyl)-4-nitrobenzene (1a)
Yield: 4.14 g (75%); yellow oil.
Me
Ar
R1
R2
Ar
R1
O
150 °C
toluene
1H NMR (300 MHz, CDCl3): d = 7.76 (d, J = 8.9 Hz, 2 H), 8.28 (d,
J = 8.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 84.2 (t, J = 39.1 Hz, C≡CCF2Br),
86.9 (t, J = 5.8 Hz, C≡CCF2Br), 101.6 (t, J = 289.8 Hz, CF2Br),
123.9, 133.3, 140.1 (t, J = 7.6 Hz), 148.8.
CF2Br
R2
O
CF2Br
8a–c
7a–c
1a (Ar = 4-O2NC6H4)
7a R1 = H
R2 = Me
7b R1 = CO2Me R2 = Me
7c R1 = H
R2 = MeO
19F NMR (282 MHz, CDCl3): d = –33.41 (s, CF2Br).
ESI-MS: m/z calcd for C9H4BrF2NO2 + Na [M+ + Na]: 297.9291;
found: 297.9293.
Scheme 6 Reactions of acetylenes 1a with 2-pyrones 7
Table 3 Synthesis of Biaryls 8a–c
Anal. Calcd for C9H4BrF2NO2: C, 39.16; H, 1.46. Found: C, 39.31;
H, 1.52.
Entry
2-Pyrone
Time (d)
Product
8a
Yield (%)
1-(3-Bromo-3,3-difluoroprop-1-ynyl)-4-chlorobenzene (1b)
Yield: 3.82 g (71%); colorless oil.
1
2
3
4
5
7a
7a
7b
7b
7c
4
7
4
7
4
17
8a
traces
20
1-(3-Bromo-3,3-difluoroprop-1-ynyl)benzene (1c)
Yield: 2.96 g (64%); colorless oil.
8b
1H NMR (300 MHz, CDCl3): d = 7.36 (t, J = 7.2 Hz, 1 H), 7.44 (d,
J = 7.2 Hz, 1 H), 7.51 (d, J = 7.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 81.0 (t, J = 38.3 Hz, C≡CCF2Br),
90.0 (t, J = 5.8 Hz, C≡CCF2Br), 102.1 (t, J = 289.3 Hz, CF2Br),
118.8, 128.7, 130.9, 132.3.
8b
40
8c
traces
19F NMR (282 MHz, CDCl3): d = –31.22 (s, CF2Br).
H
Me
R
Anal. Calcd for C9H5BrF2: C, 46.79; H, 2.18. Found: C, 46.92; H,
2.25.
8a (R = H)
8b (R = CO2Me)
O2N
Me
BrF2C
H5
1-(3-Bromo-3,3-difluoroprop-1-ynyl)-3-nitrobenzene (1d)
Yield: 3.92 g (71%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.67 (t, J = 8.0 Hz, 1 H), 7.90 (d,
J = 8.0 Hz, 1 H), 8.34 (d, J = 8.0 Hz, 1 H), 8.41 (s, 1 H).
Figure 1 Observed NOEs in compound 8a
13C NMR (75 MHz, CDCl3): d = 82.3 (t, J = 39.1 Hz, C≡CCF2Br),
86.6 (t, J = 5.6 Hz, C≡CCF2Br), 101.6 (t, J = 290.2 Hz, CF2Br),
125.5, 127.0, 130.0, 135.3 (t, J = 7.4 Hz), 137.8, 148.0.
19F NMR (282 MHz, CDCl3): d = –33.20 (s, CF2Br).
The configuration of the biaryls 8a and 8b was deter-
mined by nuclear Overhauser effect (NOE) experiments.
Irradiation of the ortho-proton of the 4-nitrophenyl ring
caused increase of the singlets of one of the methyl groups
in 8a and 8b, while irradiation of the H5 frequency in-
creased the singlet of the other methyl group of compound
8a (Figure 1).
Anal. Calcd for C9H4BrF2NO2: C, 39.16; H, 1.46. Found: C, 39.39;
H, 1.57.
1-(3-Bromo-3,3-difluoroprop-1-ynyl)-2-nitrobenzene (1e)
In summary, we have investigated the reactions of 1-(3-
bromo-3,3-difluoroprop-1-ynyl)benzenes 1 with a series
of active dienes such as 1,3-diphenylisobenzofuran, furan,
2,3-dimethylbutadiene, and cyclohexa-1,3-diene. Also a
new approach to biaryls, containing a CF2Br group in
ortho-position was elaborated using the Diels–Alder reac-
tion of pyrones with 1 as the key step.
Yield: 3.09 g (56%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.66–7.80 (m, 3 H), 8.22 (d,
J = 7.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 85.0 (t, J = 6.3 Hz, C≡CCF2Br),
86.3 (t, J = 39.1 Hz, C≡CCF2Br), 101.8 (t, J = 290.1 Hz, CF2Br),
125.2, 131.7, 133.7, 135.4, 138.2, 149.5.
19F NMR (282 MHz, CDCl3): d = –33.51 (s, CF2Br).
Anal. Calcd for C9H4BrF2NO2: C, 39.16; H, 1.46. Found: C, 39.28;
H, 1.50.
NMR spectra were recorded on Bruker ARX 300, Bruker AMX
400, and Varian Inova 500 MHz spectrometers in CDCl3 with TMS
and CCl3F as internal standards. Mass spectra (ESI-MS) were mea-
sured on a MicroTof Bruker Daltonics. Column and TLC chroma-
tography were performed on silica gel Merck 60 or Merck 60F254
plates, respectively. All dienes were distilled before use.
1-(3-Bromo-3,3-difluoroprop-1-ynyl)-4-methoxybenzene (1f)
Yield: 3.55 g (68%); colorless oil.
Cycloaddition of the 1-(3-Bromo-3,3-difluoroprop-1-ynyl)ben-
zenes 1 with 1,3-Diphenylisobenzofuran; General Procedure
A solution of the corresponding 1-(3-bromo-3,3-difluoroprop-1-
ynyl)benzene 1 (2 mmol) and 1,3-diphenylisobenzofuran (550 mg,
2.05 mmol) in toluene (2 mL) was heated in a sealed glass tube with
a Young-tap at 100 °C for an appropriate time. Toluene was evapo-
rated at reduced pressure and the residue was purified by column
chromatography on silica gel (cyclohexane–EtOAc, 20:1).
1-(3-Bromo-3,3-difluoroprop-1-ynyl)benzenes
The 1-(3-bromo-3,3-difluoroprop-1-ynyl)benzenes 1 were synthe-
sized according to previously reported procedures.16d Reactions
were carried out in 20 mmol scale. 1H and 19F NMR data of com-
pounds 1b,1f are in agreement with literature values.16d
Synthesis 2008, No. 18, 2899–2904 © Thieme Stuttgart · New York

2902
V. M. Muzalevskiy et al.
PAPER
2-[Bromo(difluoro)methyl]-3-(4-nitrophenyl)-1,4-diphenyl-1,4-
dihydro-1,4-epoxynaphthalene (2a)
19F NMR (282 MHz, CDCl3): d = –38.45 (d, J = 163.0 Hz, 1 F,
CF2Br), –42.50 (d, J = 163.0 Hz, 1 F, CF2Br).
Obtained from 1a by heating with 1,3-diphenylisobenzofuran at
100 °C for 4 h; yield: 786 mg (72%); white crystals; mp 147–
148 °C.
ESI-MS: m/z calcd for C29H18BrF2NO3 + Na [M+ + Na]: 568.0330;
found: 568.0333.
1H NMR (300 MHz, CDCl3): d = 7.03 (d, J = 8.7 Hz, 2 H), 7.18–
7.24 (m, 2 H), 7.32–7.40 (m, 5 H), 7.43–7.60 (m, 4 H), 7.83–7.88
(m, 1 H), 8.06 (d, J = 7.6 Hz, 2 H), 8.11 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 92.7 (C–O), 94.7 (C–O), 115.3 (t,
J = 303.9 Hz, CF2Br), 121.5, 122.5, 123.7, 126.6, 126.7, 127.9,
128.86, 128.91, 129.2, 129.3 (all CH), 132.9, 134.0, 139.8, 148.1,
148.2, 149.9 (t, J = 22.9 Hz, C–CF2Br), 150.3, 156.7.
Cycloaddition of the 1-(3-Bromo-3,3-difluoroprop-1-ynyl)ben-
zenes 1 with Dienes; General Procedure
The corresponding 1-(3-bromo-3,3-difluoroprop-1-ynyl)benzene 1
(1 mmol) and the corresponding diene (1.5 mL) were heated in a
sealed glass tube with a Young-tap. The excess of the diene was
evaporated at reduced pressure and the residue was purified by col-
umn chromatography on silica gel (cyclohexane–EtOAc, 20:1).
19F NMR (282 MHz, CDCl3): d = –38.38 (d, J = 162.1 Hz, 1 F,
CF2Br), –42.43 (d, J = 162.1 Hz, 1 F, CF2Br).
ESI-MS: m/z calcd for C29H18BrF2NO3 + Na [M+ + Na]: 568.0330;
2-[Bromo(difluoro)methyl]-3-(4-nitrophenyl)-7-oxabicy-
clo[2.2.1]hepta-2,5-diene (3)
Obtained from 1a by heating with furan at 150 °C for 6 h; yield: 268
mg (78%); white crystals; mp 117–119 °C.
found: 568.0314.
1H NMR (300 MHz, CDCl3): d = 5.60–5.63 (m, 1 H), 5.67–5.70 (m,
1 H), 7.24 (dd, J = 5.3, 1.8 Hz, 1 H), 7.43–7.48 (m, 3 H), 8.27 (d,
J = 8.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 86.4 (CH–O), 89.9 (CH–O), 118.3
(t, J = 300.1 Hz, CF2Br), 125.8, 130.1, 142.4, 146.2, 136.4 (t,
J = 15.3 Hz, C–CF2Br), 140.1, 149.9, 153.5.
19F NMR (282 MHz, CDCl3): d = –39.92 (d, J = 159.2 Hz, 1 F,
CF2Br), –47.92 (d, J = 159.2 Hz, 1 F, CF2Br).
ESI-MS: m/z calcd for C13H8BrF2NO3 + Na [M+ + Na]: 388.9454;
2-[Bromo(difluoro)methyl]-3-(4-chlorophenyl)-1,4-diphenyl-
1,4-dihydro-1,4-epoxynaphthalene (2b)
Obtained from 1b by heating with 1,3-diphenylisobenzofuran at
100 °C for 36 h; yield: 1.018 g (95%); white crystals; mp 62–63 °C.
1H NMR (500 MHz, CDCl3): d = 6.78 (d, J = 8.4 Hz, 2 H), 7.11–
7.19 (m, 2 H), 7.21 (d, J = 8.4 Hz, 2 H), 7.30–7.48 (m, 7 H), 7.52 (t,
J = 7.6 Hz, 2 H), 7.81 (d, J = 7.1 Hz, 1 H), 8.06 (d, J = 7.7 Hz, 2 H).
13C NMR (150 MHz, CDCl3): d = 92.0 (C–O), 94.0 (C–O), 115.3 (t,
J = 304.0 Hz, CF2Br), 121.0, 121.7, 127.4, 127.6, 128.2, 128.25,
128.27, 128.4, 128.6, 128.8 (all CH), 130.7, 132.8, 133.9, 134.6,
147.7 (t, J = 22.4 Hz, C–CF2Br), 148.1, 150.0, 157.3.
19F NMR (470 MHz, CDCl3): d = –37.41 (d, J = 160.3 Hz, 1 F,
CF2Br), –41.74 (d, J = 160.3 Hz, 1 F, CF2Br).
ESI-MS: m/z calcd for C29H18BrClF2O + Na [M+ + Na]: 557.0096;
found: 388.9443.
Anal. Calcd for C13H8BrF2NO3: C, 45.37; H, 2.34; N, 4.07. Found:
C, 45.55; H, 2.21; N, 4.03.
1-{2-[Bromo(difluoro)methyl]-4,5-dimethylcyclohexa-1,4-dien-
1-yl}-4-nitrobenzene (4)
Obtained from 1a by heating with 2,3-dimethylbutadiene at 150 °C
for 6 h; yield: 319 mg (89%); white solid; mp 72–73 °C.
1H NMR (300 MHz, CDCl3): d = 1.67 (s, 3 H, CH3), 1.76 (s, 3 H,
CH3), 2.83 (t, J = 7.2 Hz, 2 H, CH2), 3.02 (t, J = 7.2 Hz, 2 H, CH2),
7.37 (d, J = 8.7 Hz, 2 H), 8.22 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 17.6 (CH3), 18.0 (CH3), 26.9
(CH2), 42.0 (CH2), 121.7, 122.1, 123.6, 127.8, 118.3 (t, J = 307.3
Hz, CF2Br), 129.4 (t, J = 19.4 Hz, C–CF2Br), 136.1 (t, J = 3.5 Hz),
147.0, 148.2.
found: 557.0090.
Anal. Calcd for C29H18BrClF2O: C, 65.01; H, 3.39. Found: C, 65.09;
H, 3.28.
2-[Bromo(difluoro)methyl]-3-phenyl-1,4-diphenyl-1,4-dihy-
dro-1,4-epoxynaphthalene (2c)
Obtained from 1c by heating with 1,3-diphenylisobenzofuran at
100 °C for 100 h; yield: 832 mg (83%); viscous oil.
1H NMR (600 MHz, CDCl3): d = 6.88–7.77 (m, 17 H), 8.02–8.06
(m, 1 H), 8.11–8.15 (m, 1 H).
13C NMR (150 MHz, CDCl3): d = 94.2 (C–O), 94.7 (C–O), 115.5 (t,
J = 303.8 Hz, CF2Br), 125.8, 125.8, 126.6, 127.1, 127.3, 127.5,
127.6, 127.9, 128.0, 128.2, 128.4, 128.7, 128.9 (all CH), 133.1,
134.1, 135.0, 148.5, 147.1 (t, J = 22.6 Hz, C–CF2Br), 150.2, 158.5.
19F NMR (470 MHz, CDCl3): d = –37.47 (d, J = 159.3 Hz, 1 F,
CF2Br), –41.54 (d, J = 159.3 Hz, 1 F, CF2Br).
19F NMR (282 MHz, CDCl3): d = –41.79 (s, CF2Br).
ESI-MS: m/z calcd for C15H14BrF2NO2 + Na [M+ + Na]: 380.0074;
found: 380.0069.
Anal. Calcd for C15H14BrF2NO2: C, 50.30; H, 3.94; N, 3.91. Found:
C, 50.27; H 3.95; N, 3.96.
2-[Bromo(difluoro)methyl]-3-(4-nitrophenyl)bicyclo[2.2.2]oc-
ta-2,5-diene (5)
Obtained from 1a by heating with cyclohexa-1,3-diene at 120 °C
ESI-MS: m/z calcd for C29H19BrF2O + Na [M+ + Na]: 525.0463;
found: 525.0451.
for 24 h; yield: 153 mg (43%);
2-[Bromo(difluoro)methyl]-3-(3-nitrophenyl)-1,4-diphenyl-1,4-
dihydro-1,4-epoxynaphthalene (2d)
white solid; mp 55–57 °C.
Obtained from 1d by heating with 1,3-diphenylisobenzofuran at
100 °C for 8 h; yield: 950 mg (87%); viscous oil.
1H NMR (300 MHz, CDCl3): d = 1.46–1.74 (m, 4 H, CH2), 3.72–
3.78 (m, 1 H, CH), 3.96–4.02 (m, 1 H, CH), 6.48 (td, J = 6.6, 1.3
Hz, 1 H, CH=CH), 6.56 (td, J = 6.6, 1.3 Hz, 1 H, CH=CH), 7.39 (d,
J = 8.7 Hz, 2 H), 8.20 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 24.8 (CH2), 25.2 (CH2), 38.2 (CH),
45.7 (CH), 117.0 (t, J = 304.9 Hz, CF2Br), 123.3, 128.5, 133.6,
134.5 (all CH), 138.1 (t, J = 21.0 Hz, C–CF2Br), 144.3, 145.4,
147.0.
1H NMR (300 MHz, CDCl3): d = 7.13–7.24 (m, 3 H), 7.30–7.51 (m,
8 H), 7.55 (d, J = 7.4 Hz, 2 H), 7.73 (br s, 1 H), 7.85 (d, J = 7.5 Hz,
1 H), 8.08 (d, J = 7.6 Hz, 2 H), 8.13 (d, J = 8.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 92.7 (C–O), 94.6 (C–O), 115.4 (t,
J = 303.9 Hz, CF2Br), 121.5, 122.4, 122.8, 123.8, 126.7, 127.8,
127.9, 128.85, 128.9, 129.2, 129.3, 129.6 (all CH), 132.9, 134.0,
134.5, 135.6, 148.2, 149.8 (t, J = 22.9 Hz, C–CF2Br), 150.3, 156.3.
19F NMR (282 MHz, CDCl3): d = –42.73 (d, J = 149.0 Hz, 1 F,
CF2Br), –43.96 (d, J = 149.0 Hz, 1 F, CF2Br).
Synthesis 2008, No. 18, 2899–2904 © Thieme Stuttgart · New York

PAPER
Biaryls with an ortho-CF2Br Group
2903
ESI-MS: m/z calcd for C15H12BrF2NO2 + Na [M+ + Na]: 377.9912;
found: 377.9921.
2-[Bromo(difluoro)methyl]-4,6-dimethyl-4¢-nitro-1,1¢-biphenyl
(8a)
Obtained from 1a by heating with 2-pyrone 7a at 150 °C for 4 d;
yield: 61 mg (17%); viscous oil.
1H NMR (400 MHz, CDCl3): d = 1.93 (s, 3 H, CH3), 2.43 (s, 3 H,
CH3), 7.25 (s, 1 H), 7.39 (s, 1 H), 7.41 (d, J = 8.8 Hz, 2 H), 8.29 (d,
J = 8.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 20.8 (CH3), 21.2 (CH3), 117.3 (t,
J = 305.2 Hz, CF2Br), 123.1 (t, J = 7.6 Hz), 123.2, 130.9, 133.9,
135.7 (t, J = 20.8 Hz, C–CF2Br), 137.8, 138.4, 145.6, 147.2.
2-[Bromo(difluoro)methyl]-4¢-nitro-1,1¢-biphenyl (6a)
Obtained from 1a by heating with cyclohexa-1,3-diene at 150 °C
for 24 h; yield: 171 mg (52%); yellow crystals; mp 75–76 °C.
1H NMR (300 MHz, CDCl3): d = 7.21–7.28 (m, 1 H), 7.51–7.61 (m,
4 H), 7.71–7.78 (m, 1 H), 8.28 (d, J = 8.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 117.1 (t, J = 305.8 Hz, CF2Br),
122.9, 125.3 (t, J = 7.0 Hz), 128.7, 130.4, 131.2, 131.7, 135.6 (t,
J = 21.6 Hz, C–CF2Br), 137.3, 146.8, 147.4.
19F NMR (282 MHz, CDCl3): d = –39.30 (s, CF2Br).
ESI-MS: m/z calcd for C15H12BrF2NO2 + Na [M+ + Na]: 377.9912;
found: 377.9915.
ESI-MS: m/z calcd for C13H8BrF2NO2 + Na [M+ + Na]: 349.9604;
found: 349.9605.
19F NMR (470 MHz, CDCl3): d = –39.37 (s, CF2Br).
Methyl 6-[Bromo(difluoro)methyl]-2,4-dimethyl-4¢-nitro-1,1¢-
biphenyl-3-carboxylate (8b)
Obtained from 1a by heating with 2-pyrone 7b at 150 °C for 7 d;
Anal. Calcd for C13H8BrF2NO2: C, 47.59; H, 2.46; N, 4.27. Found:
C, 47.59; H, 2.28; N, 4.21.
yield: 166 mg (40%); yellowish crystals; mp 88–89 °C.
Cycloaddition of the 1-(3-Bromo-3,3-difluoroprop-1-ynyl)ben-
zenes 1 with 2-Pyrones; General Procedure
1H NMR (500 MHz, CDCl3): d = 1.81 (s, 3 H, CH3), 2.33 (s, 3 H,
CH3), 3.89 (s, 3 H, CO2CH3), 7.34 (d, J = 8.6 Hz, 2 H), 7.38 (s, 1
H), 8.23 (d, J = 8.6 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 18.1 (CH3), 19.6 (CH3), 52.5
(CO2CH3), 116.6 (t, J = 306.2 Hz, CF2Br), 123.3, 124.1 (t, J = 7.4
Hz), 130.9, 134.5, 134.6, 135.3, 136.4 (t, J = 21.3 Hz, C–CF2Br),
137.8, 144.6, 169.4.
The corresponding 1-(3-bromo-3,3-difluoroprop-1-ynyl)benzene (1
mmol) and the corresponding 2-pyrone (1.05 mmol) in anhyd tolu-
ene (1 mL) were heated in a sealed glass tube with a Young-tap at
150 °C during appropriate time. Toluene was evaporated at reduced
pressure and the residue was purified by column chromatography
on silica gel (cyclohexane–EtOAc, 20:1).
19F NMR (470 MHz, CDCl3): d = –40.68 (s, CF2Br).
ESI-MS: m/z calcd for C17H14BrF2NO4 + Na [M+ + Na]: 435.9966;
2-[Bromo(difluoro)methyl]-4¢-nitro-1,1¢-biphenyl (6a)
Obtained from 1a by heating with 2-pyrone at 150 °C for 53 h;
yield: 249 mg (76%). Data see above.
found: 435.9961.
2-[Bromo(difluoro)methyl]-3¢-nitro-1,1¢-biphenyl (6d)
Obtained from 1d by heating with 2-pyrone at 150 ° for 70 h; yield: Acknowledgment
236 mg (72%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.28 (dd, J = 7.0, 1.9 Hz, 1 H),
7.51–7.66 (m, 3 H), 7.70–7.78 (m, 2 H), 8.24–8.30 (m, 2 H).
This project was supported by the Deutsche Forschungsgemein-
schaft (DFG) through grant Gz: 436 RUS 113/858/0-1 and RFBR-
DFG 07-03-91562-NNIO_a and 08-03-00736_a.
13C NMR (75 MHz, CDCl3): d = 117.6 (t, J = 305.8 Hz, CF2Br),
123.1, 124.8, 125.6 (t, J = 7.0 Hz), 129.0, 129.1, 131.7, 132.5,
135.9, 136.1 (t, J = 21.6 Hz, C–CF2Br), 138.2, 141.9, 148.0.
References
19F NMR (282 MHz, CDCl3): d = –39.51 (s, CF2Br).
ESI-MS: m/z calcd for C13H8BrF2NO2 + Na [M+ + Na]: 349.9599;
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1H NMR (500 MHz, CDCl3): d = 7.21 (dd, J = 6.4, 1.9 Hz, 1 H),
7.43 (d, J = 7.6 Hz, 1 H), 7.49–7.61 (m, 4 H), 7.66 (td, J = 7.5, 1.1
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Synthesis 2008, No. 18, 2899–2904 © Thieme Stuttgart · New York

2904
V. M. Muzalevskiy et al.
PAPER
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