Double C-F bond activation through β-fluorine elimination: Nickel-mediated [3+2] cycloaddition of 2-trifluoromethyl-1-alkenes with alkynes

Article abstract of DOI:10.1002/anie.201402695

The nickel-mediated [3+2] cycloaddition of 2-trifluoromethyl-1-alkenes with alkynes afforded fluorine-containing multi-substituted cyclopentadienes in a regioselective manner. This reaction involves the consecutive two C-F bond cleavage of a trifluoromethyl or a pentafluoroethyl group through β-fluorine elimination.

Full text of DOI:10.1002/anie.201402695

Angewandte
Chemie
DOI: 10.1002/anie.201402695
À
C F Bond Activation
À
Double C F Bond Activation through b-Fluorine Elimination: Nickel-
Mediated [3+2] Cycloaddition of 2-Trifluoromethyl-1-alkenes with
Alkynes**
Tomohiro Ichitsuka, Takeshi Fujita, Tomohiro Arita, and Junji Ichikawa*
À
Abstract: The nickel-mediated [3+2] cycloaddition of 2-
trifluoromethyl-1-alkenes with alkynes afforded fluorine-con-
taining multi-substituted cyclopentadienes in a regioselective
oxidative addition of a C F bond is not necessarily possible
À
because of its high bond energy. In contrast, C F bond
cleavage by b-fluorine elimination has been considered
a much more reasonable process compared to oxidative
addition because transition-metal-mediated b-heteroatom
elimination typically proceeds under milder conditions
(Scheme 1B).[7,8] Furthermore, b-fluorine elimination is
sometimes even more preferable than b-hydrogen elimina-
tion as an elementary step from complexes with both fluorine
and hydrogen atoms on the b-carbon to the metal center.[7–9]
Although b-fluorine elimination is potentially advantageous,
the literature contains only a few reports on its practical
application to transition-metal-mediated reactions. For exam-
À
manner. This reaction involves the consecutive two C F bond
cleavage of a trifluoromethyl or a pentafluoroethyl group
through b-fluorine elimination.
À
T
ransition-metal-mediated C F bond activation has occu-
pied a significant research area, establishing new synthetic
methodologies.[1–3] In particular, cross-coupling reactions by
À
C F bond cleavage of aryl, vinyl, and allyl fluorides has been
intensively studied in this decade.[4–6] In most cases, cleavage
À
of a C F bond was achieved by its oxidative addition to low-
À
valent transition metal complexes (Scheme 1A). However,
ple, allylic C F bond activation of 2-trifluoromethyl-1-
alkenes proceeded through sequential imino- or carbometa-
lation and b-fluorine elimination to give 1,1-difluoro-1-
alkenes (Scheme 1Ba).[7f,g] In a similar manner, vinylic C F
À
bond activation of 1,1-difluoro-1-alkenes by an imino- or
carbometalation–b-fluorine elimination process provided
monofluorinated alkenes (Scheme 1Bb).[7c,d]
To take complete advantage of these processes, we
À
attempted the double C F bond activation of 2-trifluoro-
methyl-1-alkenes through the sequential use of b-fluorine
elimination (Scheme 2). Because electron-deficient alkenes
À
Scheme 1. C F bond activation by A) oxidative addition and B) b-
fluorine elimination.
[*] T. Ichitsuka, Dr. T. Fujita, T. Arita, Prof. Dr. J. Ichikawa
Division of Chemistry, Faculty of Pure and Applied Sciences,
University of Tsukuba
À
Scheme 2. Double C F bond activation of a CF3 group by a) allylic
À
C F bond activation via nickelacycles and b) intramolecular vinylic
Tsukuba, Ibaraki 305-8571 (Japan)
E-mail: junji@chem.tsukuba.ac.jp
À
C F bond activation.
Homepage: http://www.chem.tsukuba.ac.jp/junji/index.html
readily undergo oxidative cyclization,[10–12] we envisioned that
oxidative cyclization of a 2-trifluoromethyl-1-alkene and an
alkyne on a Ni0 complex would generate a nickelacyclopen-
tene bearing a trifluoromethyl group. b-Fluorine elimination
of this type of nickelacycle would generate organonickel
[**] This work was supported by the Grants-in-Aid for Scientific Research
on Innovative Areas “Organic Synthesis Based on Reaction
Integration. Development of New Methods and Creation of New
Substances” (No. 2105). We acknowledge generous gifts of tert-
butyl 2-(trifluoromethyl)acrylate and 2-bromo-3,3,3-trifluoropro-
pene from Tosoh F-Tech, Inc.
À
complexes having both a vinylic C Ni bond and a difluoro-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402695.
À
alkene moiety. Subsequently, intramolecular vinylic C F
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bond activation of the intermediary difluoroalkene might
occur through normally disfavored 5-endo insertion[7c,d] to
afford 2-fluoro-1,3-cyclopentadienes. Herein we demonstrate
the nickel-mediated [3+2] cycloaddition of 2-trifluoromethyl-
À
1-alkenes with alkynes by double C F bond activation of
a trifluoromethyl group by sequential b-fluorine elimination,
which allowed the efficient synthesis of highly substituted 2-
fluoro-1,3-cyclopentadines.
We selected 2-(4’-acetyl)phenyl-3,3,3-trifluoropropene
(1a) and 4-octyne (2a) as model substrates for optimization
of the reaction conditions (Table 1). Upon treatment of 1a
with 2a in the presence of an equimolar amount of [Ni(cod)2]
Figure 1. List of substrates.
Table 2: Synthesis of 2-fluoro-1,3-cyclopentadienes 3 by Ni-mediated
[3+2] cycloaddition of 2-trifluoromethyl-1-alkenes 1 with alkynes 2.[a]
Table 1: Optimization of reaction conditions in Ni-mediated [3+2]
cycloaddition of 2-trifluoromethyl-1-alkene 1a with alkyne 2a.[a]
Entry
1
2
Solvent
Conditions
Yield [%]
1
2
3
4
5
6
7
8
1a 2a 1,4-dioxane RT, 3 h
1a 2b 1,4-dioxane RT, 10.5 h
1a 2c 1,4-dioxane 608C, 19 h
1a 2d 1,4-dioxane 1008C, 3 h
3aa 74%
3ab 77%
3ac 48%
3ad 86%
3ae 64%
Entry
Ligand
Solvent
Yield [%][b]
1
2
3
4
5
6
7
PPh3
toluene
toluene
toluene
toluene
THF
0
0
1,10-phen
IMes·HCl[c]
PCy3
PCy3
PCy3
26
66[d]
48
56
74[d]
1a 2e toluene
1b 2a toluene
1c 2a toluene
1d 2a toluene
1008C, 3 h
RT, 1.5 h then 808C, 1.5 h 3ba 82%
RT, 9 h
508C, 1 h
3ca 86%
3da 78%
3eb 57%
3 fd 42%
3ga 88%
3gb 93%
DME
1,4-dioxane
PCy3
9
1e 2b 1,4-dioxane 608C, 6 h
1 f 2d toluene 1008C, 3 h
1g 2a 1,4-dioxane RT, 3 h
1g 2b toluene RT, 2 h
10
11
12
[a] Reaction conditions: [Ni(cod)2] (0.20 mmol), ligand (0.20 mmol), 1a
(0.20 mmol), 2a (0.22 mmol), solvent (2.0 mL) at room temperature for
3 h. [b] 19F NMR yield using PhCF3 as an internal standard. [c] tBuOK
(1.0 equiv) was used as a base. [d] Yield of isolated product.
[a] Reaction conditions: [Ni(cod)2] (0.30 mmol), ligand (0.30 mmol),
1 (0.30 mmol), 2 (0.33 mmol), solvent (3.0 mL).
(cod = 1,5-cyclooctadiene) and PPh3 or 1,10-phenanthroline,
no cyclization product was obtained (Table 1, entries 1 and 2).
However, when IMes possessing a strong s-donating ability
was employed as a ligand, the expected [3+2] cycloaddition
proceeded to afford 2-fluoro-1,3-cyclopentadiene 3aa in 26%
tively).[13] The use of diphenylacetylene (2d) resulted in the
formation of the corresponding cycloaddition product 3ad in
86% yield (entry 4). a-Trifluoromethylstyrenes 1b–d bearing
electron-withdrawing cyano, trifluoromethyl, and ethoxycar-
bonyl groups further provided cyclopentadienes 3ba–da in
good to high yields (entries 6–8). Non-substituted a-trifluoro-
methylstyrene (1e) and a-trifluoromethylstyrene 1 f bearing
an electron-donating methoxy group successfully underwent
cycloaddition with 2b or 2d (entries 9 and 10). The reaction of
tert-butyl a-trifluoromethyacrylate (1g) with alkynes 2a and
2b readily proceeded to give 2-fluoro-1,3-cyclopentadiene-1-
carboxylates 3ga and 3gb in 88% and 93% yields, respec-
tively (entries 11 and 12).
Two plausible mechanisms for this reaction are shown in
Scheme 3. Nickelacyclopentene A bearing a trifluoromethyl
group was probably formed by oxidative cyclization of 2-
trifluoromethyl-1-alkene 1 and alkyne 2 with Ni0 (Scheme 3,
path A). Ring-opening of nickelacycle A readily proceeded
by b-fluorine elimination to generate alkenylnickel species B.
Subsequent 5-endo insertion and the second b-fluorine
elimination afforded 2-fluoro-1,3-cyclopentadiene 3 along
with NiF2 species.[14] An alternative mechanism could be the
oxidative addition pathway (Scheme 3, path B), in which 2-
À
yield by cleavage of two C F bonds in the trifluoromethyl
À
group and formation of two C C bonds (Table 1, entry 3). In
the case where PCy3 was used, the yield of 3aa was improved
to 66% (entry 4). These results suggest that highly electron-
rich Ni0 species derived from strong s-donating ligands
promoted oxidative cyclization between 1a and 2a in the
initial step. Next we screened reaction solvents. Both THF
and DME (1,2-dimethoxyethane) gave the product, albeit in
low yields (entries 5 and 6). The best result (74% yield of
3aa) was obtained using 1,4-dioxane (entry 7).
The scope of the [3+2] cycloaddition was examined using
a wide variety of 2-trifluoromethyl-1-alkenes 1a–g and
alkynes 2a–e under the previously described optimal reaction
conditions (Figure 1 and Table 2). Unsymmetrical 4-methyl-
2-pentyne (2b), 1-phenyl-1-propyne (2c), and 1-(4’-methoxy-
phenyl)-1-pentyne (2e) also participated in this reaction to
afford the corresponding 2-fluoro-1,3-cyclopentadienes 3ab,
3ac, and 3ae in 77%, 48%, and 64% yields, respectively, with
complete regioselectivity (Table 2, entries 2, 3, and 5, respec-
2
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Furthermore, the sequential double C F bond activation
was successfully applied to pentafluoroethyl compounds
under the same reaction conditions to give 5-trifluoro-
methyl-1,3-cyclopentadienes (Scheme 5). 2-Pentafluoro-
ethyl-1-alkene 6 readily reacted with 4-octyne (2a) in the
presence of the nickel complex to afford, by isomerization, 5-
trifluoromethyl-1,3-cyclopentadiene 7 in 77% yield. Thus, we
also achieved the direct synthesis of a ring trifluoromethy-
lated cyclopentadiene.
Scheme 3. Plausible reaction mechanisms.
Scheme 5. Synthesis of 5-trifluoromethyl-1,3-cyclopentadiene 7 by Ni-
mediated [3+2] cycloaddition of 2-pentafluoroethyl-1-alkene 6 with
alkyne 2a.
trifluoromethyl-1-alkene 1 initially reacted with Ni0 to gen-
erate p-allylnickel intermediate A’ by oxidative addition of
0 [6]
À
À
a C F bond to Ni . Alkyne insertion into the C Ni bond of
A’ led to B, followed by subsequent 5-endo insertion and b-
fluorine elimination to give the same product 3.
In summary, we have developed a new methodology for
À
allylic and vinylic C F bond activation based on b-fluorine
elimination from nickelacycles generated by oxidative cycli-
zation of 2-trifluoromethyl-1-alkenes with alkynes. The
nickel-mediated [3+2] cycloaddition reaction involves the
To elucidate the mechanism, the stoichiometric reaction
of 2-trifluoromethyl-1-alkene 1 with a Ni0 complex was
conducted in the absence of alkynes (Scheme 4). If the
À
consecutive and regioselective cleavage of two C F bonds of
À
reaction started with oxidative addition of the C F bond to
a trifluoromethyl and a pentafluoroethyl group. This method-
ology simultaneously enables the direct construction of
a multisubstituted cyclopentadiene ring and the introduction
of a fluorine substituent or a trifluoromethyl group in
a regioselective manner.[16] Fluorine-containing, multisubsti-
tuted cyclopentadienes would be useful compounds as ligands
of metallocene-type complexes[17] and as building blocks for
further chemical transformations such as Diels–Alder reac-
tions.[18,19]
Ni0, the corresponding p-allylnickel complex would be
observed. Treatment of 1a with stoichiometric [Ni(cod)2]
Experimental Section
General procedure for nickel-mediated [3+2] cycloaddition of 2-
trifluoromethyl-1-alkenes with alkynes: To a solution of [Ni(cod)2]
(86 mg, 0.31 mmol) and PCy3 (88 mg, 0.31 mmol) in 1,4-dioxane
(3.2 mL) were added 2-trifluoromethyl-1-alkene 1g (61 mg,
0.31 mmol) and alkyne 2a (38 mg, 0.34 mmol) at room temperature.
After stirring for 3 h at the same temperature, the reaction mixture
was filtered through a pad of silica gel (EtOAc). The filtrate was
concentrated under reduced pressure, and the residue was purified by
silica gel column chromatography (hexane/EtOAc = 20:1) to give 2-
fluorocyclopentadiene 3ga (74 mg, 88%).
Scheme 4. Generation and reactions of nickelacyclopropane 4a.
and PCy3 in toluene at room temperature, however, afforded
nickelacyclopropane 4a as the sole product in 92% yield; this
was confirmed by 19F, and 31P NMR spectroscopy.[5f,11c] In this
reaction, no p-allylnickel complexes were observed in the
NMR spectra. The formation of 4a was further supported by
the conversion of 4a to hydrogenated product 5a in 55%
yield upon treatment with an excess of acetic acid.[15] In
addition, 4a readily reacted with 4-octyne to afford 2-fluoro-
1,3-cyclopentadiene 3aa in 81% yield. Therefore, the cyclo-
pentadiene formation probably proceeded through an oxida-
tive cyclization–b-fluorine elimination sequence (path A).
Received: April 22, 2014
Published online: && &&, &&&&
À
Keywords: alkynes · C F bond activation · cycloaddition ·
cyclopentadienes · fluoroalkenes · nickel
.
À
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presumably due to the paramagnetic property of NiII.
[15] For protonolysis of a nickelacyclopentene by treatment with
acetic acid, see: J. J. Eisch, X. Ma, K. I. Han, J. N. Gitua, C.
Krꢂger, Eur. J. Inorg. Chem. 2001, 77 – 88.
4
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Angewandte
Chemie
[16] For a recent report on the direct synthesis of multi-substituted
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.
Angewandte
Communications
Communications
À
C F Bond Activation
T. Ichitsuka, T. Fujita, T. Arita,
J. Ichikawa*
&&&& — &&&&
À
Clear-cut: The nickel-mediated [3+2]
cycloaddition of 2-trifluoromethyl-1-
alkenes with alkynes afforded fluorine-
containing multi-substituted cyclopenta-
dienes. This reaction involves the con-
secutive and regioselective double C F
À
Double C F Bond Activation through b-
Fluorine Elimination: Nickel-Mediated
[3+2] Cycloaddition of 2-Trifluoromethyl-
1-alkenes with Alkynes
bond cleavage of a trifluoromethyl and
a pentafluoroethyl group by b-fluorine
elimination.
6
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These are not the final page numbers!