Domino C-F Bond Activation of the CF3 Group: Synthesis of Fluorinated Dibenzo[a,c][7]annulenes from 2-(Trifluoromethyl)-1-alkenes and 2,2′-Diceriobiaryls

Article abstract of DOI:10.1021/acs.orglett.6b03743

The construction of ring-fluorinated seven-membered carbocycles was readily achieved via the domino S_N2′-type/S_NV reaction between 2-(trifluoromethyl)-1-alkenes and 1,4-carbodianions. The S_N2′-type reaction of 2-(trifluoromethyl)-1-alkenes with 2,2′-diceriobiaryls generated the intermediary 1,1-difluoro-1-alkenes bearing a monoceriobiaryl moiety, which in turn underwent intramolecular S_NV reaction to afford fluorinated 5H-dibenzo[a,c][7]annulenes.

Full text of DOI:10.1021/acs.orglett.6b03743

Letter
pubs.acs.org/OrgLett
Domino C−F Bond Activation of the CF3 Group: Synthesis of
Fluorinated Dibenzo[a,c][7]annulenes from 2‑(Trifluoromethyl)-1-
alkenes and 2,2′-Diceriobiaryls
Takeshi Fujita, Marina Takazawa, Kazuki Sugiyama, Naoto Suzuki, and Junji Ichikawa*
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
S
* Supporting Information
ABSTRACT: The construction of ring-fluorinated seven-
membered carbocycles was readily achieved via the domino
SN2′-type/SNV reaction between 2-(trifluoromethyl)-1-alkenes
and 1,4-carbodianions. The SN2′-type reaction of 2-(trifluor-
omethyl)-1-alkenes with 2,2′-diceriobiaryls generated the
intermediary 1,1-difluoro-1-alkenes bearing a monoceriobiaryl
moiety, which in turn underwent intramolecular SNV reaction
to afford fluorinated 5H-dibenzo[a,c][7]annulenes.
arbon−fluorine (C−F) bonds are generally considered to
be difficult to cleave because of their high bond energy,1
a CF3 group and retention of one C−F bond, which has long
been considered troublesome because of the shielding effect of
the CF3 group.4 In fact, we have reported 2-fluoroquinoline
synthesis from 2-(trifluoromethyl)-1-alkenes via the SN2′-type/
SNV sequence, initiated by treatment with ortho-lithiated aniline
derivatives.5 Similarly, we have also achieved 3-fluoropyrazole
synthesis via the formal [3 + 2]-cyclization between 2-
(trifluoromethyl)-1-alkenes and hydrazines, in which the ring
closure was not completed by a simple SNV reaction.6 Most
recently, following our results, Xiao and Zhang et al. reported a
one-pot synthesis of 2-fluoro-4H-pyrans in which 1,3-
dicarbonyl compounds were used as binucleophiles in the
presence of K2CO3.7
C
whereas 2-(trifluoromethyl)-1-alkenes and 1,1-difluoro-1-al-
kenes exhibit unique reactivities in defluorinative addition−
elimination processes. Nucleophilic attack to 2-(trifluorometh-
yl)-1-alkenes typically proceeds at the carbon atom γ to the
fluorine substituents and is followed by fluoride elimination to
afford 1,1-difluoro-1-alkenes (SN2′-type reaction, Scheme 1, eq
Scheme 1. Allylic and Vinylic C−F Bond Activation in SN2′-
Type and SNV Reactions
To take full advantage of the sequence, we embarked on the
construction of seven-membered carbocycles by using
binucleophiles containing two carbanion moieties (Scheme
2). As a result, we succeeded in a one-pot synthesis of 7-fluoro-
5H-dibenzo[a,c][7]annulenes8 by treatment of 2-(trifluoro-
methyl)-1-alkenes with 2,2′-dimetallobiaryls.9 The cyclohepta-
triene core is widely used in bioactive agents10 and functional
materials.11 In spite of their utility, their conventional synthetic
methods typically required harsh conditions, expensive
Scheme 2. Seven-Membered Carbocycle Construction via
Domino SN2′-Type/SNV Reactions
1).1,2 On the other hand, 1,1-difluoro-1-alkenes are susceptible
to nucleophilic substitution at the carbon atom α to the fluorine
substituents to give monofluoroalkenes (SNV reaction, Scheme
1, eq 2).1,3
Thus, appropriate choice of binucleophiles enables straight-
forward ring construction via double activation of C−F bonds
by the sequential SN2′-type/SNV process (Scheme 1, eq 3).
This protocol enables selective activation of two C−F bonds in
Received: December 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03743
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Letter
Table 1. Screening of Conditions for Domino SN2′-Type/SNV Reaction between 1a and 2a
a
a
entry
MXn
solvent
conditions
3aa (%)
4aa (%)
1
2
THF
55 °C, 4 h
55 °C, 4 h
55 °C, 4 h
55 °C, 4 h
55 °C, 4 h
40 °C, 5 h
55 °C, 6 h
−78 °C, 15 min then 55 °C, 4 h
0 °C, 15 min then 55 °C, 4 h
rt, 15 min then 55 °C, 4 h
58
27
b
b
MgBr2
ZnCl2
CuBr
THF
ND
ND
b
b
3
THF
N.D.
ND
b
b
4
THF
ND
ND
5
CeCl3
CeCl3
CeCl3
CeCl3
CeCl3
CeCl3
THF
82
7
6
Et2O
71
16
22
trace
12
6
7
1,4-dioxane
THF
29
8
40
9
THF
37
10
THF
91 (90)
a
b
Yield was determined by 19F NMR measurement using PhCF3 as an internal standard. Isolated yield is given in parentheses. ND = not detected.
reagents, and/or multiple steps.8 In contrast, our approach
enables a short-step synthesis of dibenzo[7]annulenes by using
readily available substrates and reagents.
Table 2. Synthesis of Dibenzo[7]annulenes 3
First, we sought suitable conditions for the domino SN2′-
type/SNV reaction using α-(trifluoromethyl)styrene (1a) and
2,2′-dibromobiphenyl (2a) as model substrates (Table 1).
Dibromobiphenyl 2a was treated with 2.1 equiv of n-BuLi and
N,N,N′,N′-tetramethylethylenediamine (TMEDA) in THF at
room temperature for 15 min. Then, the mixture was reacted
with (trifluoromethyl)styrene 1a at 55 °C for 4 h to give
dibenzo[7]annulene 3aa in 58% yield, as well as difluoroalkene
4aa, formed only by the SN2′-type reaction, in 27% yield (entry
1). To improve the reactivities of the intermediary di- and
monometallobiphenyls, several other metallic species were
examined (entries 2−5). When MgBr2, ZnCl2, or CuBr was
employed for transmetalation, the reaction was seriously
inhibited (entries 2−4). However, the use of CeCl3, which
would generate 2,2′-diceriobiphenyl, drastically promoted the
domino SN2′-type/SNV reaction to afford 3aa in 82% yield,
suppressing the formation of 4aa (entry 5).12 Since cerium
reagents generally exhibit reduced basicity along with
substantial nucleophilicity, the reaction of 2,2′-diceriobiphenyl
with 1a seems to proceed as expected, suppressing deproto-
nation of the solvent. Although the solvent effects of other
ether solvents, such as diethyl ether and 1,4-dioxane, were
examined, THF served as the best medium (entries 6 and 7).
For further improvement in the yield of 3aa, we changed the
temperature at the initial stage of the reaction between 1a and
the diceriobiphenyl, as that is less stable to heating (entries 8−
10). After addition of 1a, stirring at −78 or 0 °C for 15 min
followed by raising the temperature to 55 °C retarded the
reaction (entries 8 and 9). Finally, when the temperature was
kept at room temperature for 15 min to consume the
diceriobiphenyl and then raised to 55 °C, 3aa was obtained
in 90% isolated yield (entry 10).
a
entry
1, R
1a, Ph
x (equiv)
2
3 (yield, %)
1
2
3
4
5
6
7
1.2
1.3
1.2
1.2
1.4
1.1
1.4
1.0
1.2
1.2
1.4
1.2
1.4
1.2
2.0
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
2c
3aa (90)
3ba (77)
3ca (72)
3da (78)
3ea (80)
3fa (83)
3ga (80)
3ha (44)
3ia (44)
3ja (57)
3ka (79)
3ab (80)
3kb (72)
3ac (80)
3kc (70)
1b, 4-MeC6H5
1c, 3-MeC6H5
1d, 4-FC6H5
1e, 3-FC6H5
1f, 4-ClC6H5
1g, 3-ClC6H5
1h, 4-MeOC6H5
1i, 3-MeOC6H5
1j, 4-CF3C6H5
1k, SiMe2Ph
1a, Ph
b
8
b
9
b
10
b
11
12
b
13
1k, SiMe2Ph
1a, Ph
14
b
15
1k, SiMe2Ph
b
a
Isolated yield. BF3·OEt2 (2.0 equiv) was added 5 min after addition
of 1. After being stirred at room temperature for 10 min, the mixture
was heated to 55 °C.
the substituent, leading to the corresponding dibenzo[7]-
annulenes 3ba and 3ca in 77% and 72% yields, respectively
(entries 2 and 3). Reactions of (trifluoromethyl)styrenes 1d−g
bearing a fluorine or chlorine substituent also proceeded
without loss of the C−F or C−Cl bond on the benzene ring
(entries 4−7). Methoxy-bearing (trifluoromethyl)styrenes 1h
and 1i, (trifluoromethyl)styrene 1j bearing another CF3 group,
and 2-silylated trifluoropropene 1k participated in the reaction
with the aid of BF3·Et2O (entries 8−11). Not only 2a but also
di-tert-butylated and tetramethylated biphenyls 2b and 2c
underwent diceriation followed by the domino SN2′-type/SNV
With the optimized conditions in hand, we have investigated
the scope of 2-(trifluoromethyl)-1-alkenes 1 and 2,2′-
dibromobiaryls 2 (Table 2). Trifluoromethylstyrenes 1b and
1c, bearing a methyl group on the phenyl group, effectively
underwent the domino reaction with the in situ generated
diceriobiphenyl derived from 2a, regardless of the position of
B
DOI: 10.1021/acs.orglett.6b03743
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reaction with (trifluoromethyl)alkenes 1a and 1k to afford the
corresponding dibenzo[7]annulenes 3ab, 3kb, 3ac, and 3kc in
high yields (entries 12−15).
Unambiguous structural characterization of dibenzo[7]-
annulenes 3 was achieved by X-ray crystallographic analysis
of 3fa (Figure 1). The bond lengths of C5−C6 and C6−C7 are
more, the obtained fluorine-containing dibenzo[7]annulenes
are less accessible by other methods.13
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03743.
Experimental details, characterization data, and NMR
spectra (PDF)
X-ray crystallographic data of 3fa (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: junji@chem.tsukuba.ac.jp.
ORCID
Junji Ichikawa: 0000-0001-6498-326X
Notes
The authors declare no competing financial interest.
Figure 1. ORTEP drawing of dibenzo[7]annulene 3fa with 50%
ellipsoid probability.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
No. JP16H01002 (J.I.) for Precisely Designed Catalysts with
Customized Scaffolding and JSPS KAKENHI Grant No.
JP16K20939 (T.F.) for a Grant-in-Aid for Young Scientists
(B). We acknowledge Tosoh F-Tech, Inc., for a generous gift of
ethyl trifluoroacetate.
1.519(2) and 1.339(2) Å, respectively. Moreover, the bond
angles of C6−C5−C12, C5−C6−C7, and C6−C7−C13 are
109.8(1)°, 116.3(1)°, and 128.6(1)°, respectively. These data
indicate that the hybridization modes of C5, C6, and C7 are
sp3, sp2, and sp2, respectively, and C6−C7 is a double bond.
Thus, in the domino SN2′-type/SNV reaction of trifluorome-
thylalkenes 1 with diceriobiaryls, the latter SNV reaction
proceeded without migration of C−C double bonds.
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