Copper(I)-Catalyzed [4 + 1] Cycloaddition of Silyl Dienol Ethers with Sodium Bromodifluoroacetate: Access to β,β-Difluorocyclopentanone Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b02085

Silyl dienol ethers readily underwent copper(I)-catalyzed [4 + 1] cycloaddition with sodium bromodifluoroacetate to afford 4,4-difluorocyclopent-1-en-1-yl silyl ethers. On the basis of high-resolution mass spectroscopy analysis, annulation presumably proceeded via a copper(I) difluorocarbene complex, which represents an unprecedented example of [4 + 1] cycloadditions promoted by a transition metal difluorocarbene complex.

Full text of DOI:10.1021/acs.orglett.6b02085

Letter
pubs.acs.org/OrgLett
Copper(I)-Catalyzed [4 + 1] Cycloaddition of Silyl Dienol Ethers with
Sodium Bromodifluoroacetate: Access to
β,β‑Difluorocyclopentanone Derivatives
Kohei Fuchibe, Tatsuya Aono, Ji Hu, and Junji Ichikawa*
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
S
* Supporting Information
ABSTRACT: Silyl dienol ethers readily underwent copper(I)-
catalyzed [4 + 1] cycloaddition with sodium bromodifluor-
oacetate to afford 4,4-difluorocyclopent-1-en-1-yl silyl ethers.
On the basis of high-resolution mass spectroscopy analysis,
annulation presumably proceeded via a copper(I) difluor-
ocarbene complex, which represents an unprecedented
example of [4 + 1] cycloadditions promoted by a transition metal difluorocarbene complex.
Encouraged by this success, we revisited the synthesis of
difluorocyclopentanone derivatives to provide the regioisomers.
We report herein the [4 + 1] cycloaddition of copper
difluorocarbene complexes and silyl dienol ethers, affording
4,4-difluorocyclopent-1-en-1-yl silyl ethers (regioisomer B)
(Scheme 1b). It should be mentioned that the chemistry of [4
+ 1] cyclizations is much less developed for five-membered ring
formation compared to [3 + 2] and [2 + 2 + 1] cyclizations;6,7
furthermore, the [4 + 1] cycloaddition promoted by a transition
metal difluorocarbene complex has not been reported in the
literature.
ransition metal difluorocarbene complexes, LnM = CF2, are
Thighly promising intermediates for the synthesis of
fluorine-containing compounds, considering the significant role
of their fluorine-free counterparts in today’s synthetic organic
chemistry.1 Despite their potential utility, however, only a limited
number of reactions of difluorocarbene complexes have been
reported in the past year.2 Our continuous interest in transition
metal difluorocarbene complexes prompted us to apply them to
catalytic synthesis.
Recently, we reported the synthesis of 5,5-difluorocyclopent-
1-en-1-yl silyl ethers (regioisomer A) via the domino
difluorocyclopropanation/vinylcyclopropane (VCP) rearrange-
ment sequence of silyl dienol ethers (Scheme 1a).3 Silyl dienol
ethers, prepared from α,β-unsaturated ketones, were treated with
trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate
(FSO2CF2CO2SiMe3)4 in the presence of a nickel(II) catalyst,
leading to the α,α-difluorocyclopentanone derivatives in good
yields.5
To conduct the desired [4 + 1] cycloaddition, we adopted a
copper(I) salt as a catalyst and a halodifluoroacetate as a carbene
−
source (XCF2CO2 ) for the following reasons (Scheme 1b): (i)
decarboxylation of copper(I) carboxylate is known to proceed
with an activation energy of ca. 20 kcal/mol (calculated value),8
and elimination of a halide ion (X−) from the resulting
(halodifluoromethyl)copper(I) species would generate the
required difluorocarbene complexes;9 (ii) copper(I) carbene
complexes mediated dihydrofuran formation via a [4 + 1]
pathway.10
An attempted reaction with several copper(I) complexes
realized the desired [4 + 1] cycloaddition as expected (Table 1).
In the absence of a copper(I) complex, silyl dienol ether 1a
reacted with sodium bromodifluoroacetate in acetonitrile at 50
°C to afford vinylcyclopropane 3 and α,α-difluorocyclopenta-
none-derived silyl enol ether 4 in 35 and 5% yields, respectively
(entry 1). While cyclopropane 3 was produced by the reaction
with free difluorocarbene generated in situ,11 the undesired
regioisomer A, silyl enol ether 4, was obtained from 3 via VCP
rearrangement.3,12 Silyl dienol ether 1a afforded the desired 4,4-
difluorocyclopent-1-en-1-yl silyl ether 2a (regioisomer B) in the
presence of copper(I) bromide, (phenylethynyl)copper(I), or
SIMesCuCl in 25, 37, and 10% yields (entries 2−4), respectively.
Scheme 1. Syntheses of gem-Difluorocyclopentanone
Derivatives
Received: July 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02085
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
worked well to afford 2f in 57% yield; however, a longer reaction
time was required (entry 6). A methyl group installed at the
internal position (R2) allowed the reaction to afford the desired
product 2g in 76% yield (entry 7). The reaction was also applied
to a cyclic system. Silyl enol ether 2h, bearing a bicyclo[4.3.0]-
nonane skeleton, was efficiently synthesized from cyclic silyl
dienol ether 1h in 63% yield (entry 8).
Table 1. Effect of Copper(I) Complex
The obtained silyl enol ethers 2 are useful intermediates for β-
fluorocyclopentenones (eq 1). Upon treatment with tetrabuty-
entry
Cu(I) complex
t (h)
2a (%)
3 (%)
4 (%)
1
2
3
4
5
6
7
8
none
15
18
15
15
12
12
18
12
−
25
35
3
5
CuBr
−
−
trace
2
CuCCPh
SIMesCuCl
37
10
10
40
11
4
10
b
5a
39
b
5b
62
−
−
2
b
5c
51
b
c
5d
71 (70)
7
a
19F NMR yield based on an internal standard, (CF3)2C(C6H4p-Me)2,
lammonium fluoride in THF/HCOOH, 2a and 2d underwent
desilylation and dehydrofluorination to provide 4-substituted 3-
fluorocyclopent-2-en-1-ones 6a and 6d in 81 and 85% yields,
respectively. Thus, the copper(I)-catalyzed [4 + 1] cycloaddition
provides a variety of β,β-difluoro- and β-fluorocyclopentanone
derivatives.5
unless otherwise noted. TBS = Sit-BuMe2, SIMes = 1,3-bis(2,4,6-
trimethylphenyl)imidazolin-2-ylidene, and Phen = 1,10-phenanthro-
b
c
line. 5 mol %. Isolated yield.
To elucidate the reaction intermediate, we conducted the
following experiment (Scheme 2). When complex 5d was treated
Scheme 2. HRMS Analysis of Reactive Intermediate
Product 2a was obtained with bipyridyl complex 5a or
phenanthroline complexes 5b,c in 39, 62, or 51% yields (entries
5−7).13,14 Eventually, dimethylphenanthroline-based complex
5d was revealed to be the most effective catalyst for the
cycloaddition reaction, affording 2a in 71% yield (entry 8).15−17
The scope of the [4 + 1] cycloaddition with respect to 4,4-
difluorocyclopent-1-en-1-yl silyl ethers 2 is described in Table
2.18 Electron-donating and -withdrawing groups installed on the
aromatic ring at the terminal position (R1) did not affect the
reaction, leading to the corresponding products 2b−d in 61−
70% yields (entries 2−4). 2-Naphthyl-substituted substrate 1e
also afforded the product 2e in 59% yield (entry 5).
Cycloaddition of alkyl-substituted substrate 1f (R1 = n-Pr)
Table 2. Copper(I)-Catalyzed Synthesis of 4,4-
a
Difluorocyclopent-1-en-1-yl Silyl Ethers
with sodium bromodifluoroacetate (5.0 equiv) in the presence of
butylamine (10 equiv) at room temperature, isocyanide complex
7d+, losing triphenylphosphine, was observed by high-resolution
mass spectroscopy (HRMS).15 This fact suggested that
phenanthroline-based difluorocarbene complex 8d+ was gen-
erated in situ to be trapped as the aminolysis product 7d+.9b,19
There remained a possibility that in situ generated free
difluorocarbene produced the corresponding isocyanide (n-
BuNC) by the reaction with butylamine, leading to the
generation of 7d+. However, this possibility seems unlikely
entry
1
R1
R2
2 (%)
b
1
1a
1b
1c
1d
1e
1f
Ph
H
H
70, 2a
70, 2b
61, 2c
62, 2d
59, 2e
57, 2f
76, 2g
63, 2h
2
3
C6H4p-Me
C6H4p-OMe
C6H4p-Br
2-naphthyl
n-Pr
H
1
c
because isocyanide was not observed by H NMR analysis on
4
H
treatment of sodium bromodifluoroacetate (1.0 equiv) with
butylamine (2.0 equiv) in acetonitrile at room temperature for
12 h.20,21
A plausible mechanism is proposed to account for the [4 + 1]
cycloaddition process (Scheme 3). The key difluorocarbene
complex 8d+Br− is generated from a catalyst precursor 5d and
sodium bromodifluoroacetate through the sequence of anion
5
H
cd
,
6
7
8
H
c
1g
1h
Ph
Me
−(CH2)4−
a
b
c
Isolated yield. TBS = Sit-BuMe2. Table 1, entry 8. 2 mol % of 5d.
36 h.
d
B
DOI: 10.1021/acs.orglett.6b02085
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Scheme 3. Proposed Catalytic Cycle
ACKNOWLEDGMENTS
■
This research is supported by JSPS KAKENHI Grant Number
JP15K05414 (K.F.), JSPS KAKENHI Grant Number
JP16H01002 (J.I.), and Asahi Glass Foundation (K.F.). Kanto
Denka Kogyo Co., Ltd., is acknowledged for the generous gift of
ethyl bromodifluoroacetate.
REFERENCES
■
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2001, 40, 3441 (Ru). (b) Takahira, Y.; Morizawa, Y. J. Am. Chem. Soc.
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exchange, decarboxylation, and α-bromine elimination. Unlike
the nickel(II) difluorocarbene complex that promoted cyclo-
propanation of silyl dienol ethers 1,3 copper(I) difluorocarbene
complex 8d+Br− is electrophilic enough to be nucleophilically
attacked by silyl dienol ethers 1 either (I) directly on its CF2
carbon or (II) on its metal center followed by migratory
insertion,22 to generate alkyl copper(I) species [Cu = Cu(4,7-
dimethylphenanthroline)]. The intermediate 9+Br− in turn
undergoes a Michael-type ring closure10b to afford 4,4-
difluorocyclopent-1-en-1-yl silyl ethers 2 ([4 + 1] cycloadducts).
Thus, complex 8d+Br− serves as a one-carbon component in the
[4 + 1] cycloaddition. The resulting copper(I) species 10 reacts
with the second molecule of the carbene source, BrCF2CO2Na,
regenerating the difluorocarbene complex.23
In summary, [4 + 1] cycloaddition of sodium bromodifluor-
oacetate with silyl dienol ethers was achieved to provide β,β-
difluorocyclopentanone-derived silyl enol ethers under
copper(I) catalysis. High-resolution mass spectroscopy analysis
suggested that the reaction would proceed via a copper(I)
difluorocarbene complex. This is an unprecedented example of a
cycloaddition caused by a transition metal difluorocarbene
complex.
(6) For reported [4 + 1] cycloaddition reactions, see: Coscia, R. W.;
Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 2496 and refs therein.
(7) For reveiws on metal-catalyzed cycloadditions, see: (a) Lautens,
M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49. (b) Fruhauf, H.-W.
̈
Chem. Rev. 1997, 97, 523.
(8) (a) Shang, R.; Fu, Y.; Wang, Y.; Xu, Q.; Yu, H.-Z.; Liu, L. Angew.
Chem., Int. Ed. 2009, 48, 9350. (b) Ambler, B. R.; Altman, R. A. Org. Lett.
2013, 15, 5578.
ASSOCIATED CONTENT
* Supporting Information
(9) Most transition metal difluorocarbene complexes were prepared
via elimination from (trifluoromethyl)metal species. See: (a) Clark, G.
R.; Hoskins, S. V.; Roper, W. R. J. Organomet. Chem. 1982, 234, C9.
(b) Clark, G. R.; Hoskins, S. V.; Jones, T. C.; Roper, W. R. J. Chem. Soc.,
Chem. Commun. 1983, 719. (c) Koola, J. D.; Roddick, D. M.
Organometallics 1991, 10, 591. (d) Hughes, R. P.; Laritchev, R. B.;
Yuan, J.; Golen, J. A.; Rucker, A. N.; Rheingold, A. L. J. Am. Chem. Soc.
2005, 127, 15020. (e) Goodman, J.; Grushin, V. V.; Larichev, R. B.;
Macgregor, S. A.; Marshall, W. J.; Roe, D. C. J. Am. Chem. Soc. 2009, 131,
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02085.
Experimental procedures and spectra of new compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
4236. (f) Martínez-Salvador, S.; Menjon
́ ́
, B.; Fornies, J.; Martín, A.;
Uson, I. Angew. Chem., Int. Ed. 2010, 49, 4286. (g) Harrison, D. J.;
́
Daniels, A. L.; Korobkov, I.; Baker, R. T. Organometallics 2015, 34, 5683
and refs therein.
*E-mail: junji@chem.tsukuba.ac.jp.
Author Contributions
(10) (a) Storm, D. L.; Spencer, T. A. Tetrahedron Lett. 1967, 8, 1865.
(b) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 1046.
(11) Oshiro, K.; Morimoto, Y.; Amii, H. Synthesis 2010, 2010, 2080.
(12) (a) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C.; Tanko, J.;
Hudlicky, T. Chem. Rev. 1989, 89, 165. (b) Baldwin, J. E. Chem. Rev.
2003, 103, 1197.
(13) To exclude the possibility that 2a was obtained via cyclopropane
3, isolated 3 was subjected to the reaction conditions with 5b, which
gave no detectable amount of 2a (19F NMR). The reactivity of copper(I)
J.I. conceived the project and wrote the manuscript with K.F. K.F.
also planned the experiments. T.A. and J.H. carried out the
experiments. All the authors discussed the experiments and
results and have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b02085
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complexes was found to be quite different from that of the nickel(II)
complexes because difluorocyclopropane was not obtained in the
reaction with acetophenone-derived silyl enol ether. See ref 3.
(14) In situ generation of catalyst 5b by mixing their three components
(CuBr, PPh3, and phenanthroline) in acetonitrile did not work.
(15) For more details on catalyst optimization, effect of carbene
sources, and HRMS analysis, see Supporting Information.
(16) For preparation of catalysts 5, see: Ignatenko, V. A.; Deligonul, N.;
Viswanathan, R. Org. Lett. 2010, 12, 3594.
(17) The dimethylphenanthroline ligand in 5d seemed to stabilize the
difluorocarbene complex due to its electron-donating properties and
rigid structure.
(18) Typical procedure. To an acetonitrile suspension (1.8 mL) of
copper(I) catalyst 5d (10 mg, 0.016 mmol) and sodium bromodi-
fluoroacetate (72 mg, 0.37 mmol) was added silyl dienol ether 1a (88
mg, 0.34 mmol) at rt. After the reaction mixture was stirred at 50 °C for
12 h, hexane (5 mL) and saturated aqueous NaHCO3 (5 mL) were
added to quench the reaction at 0 °C. Organic materials were extracted
with hexane five times. The combined extracts were washed with brine
and dried over anhydrous Na2SO4. The sulfate was removed by
filtration, and the filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography (hexane) on silica gel
which was deactivated with 15 vol % of H2O prior to use, yielding 4,4-
difluorocyclopent-1-en-1-yl silyl ether 2a as a colorless oil (74 mg, 70%).
(19) Neutral and cationic copper(I) carbene complexes with trigonal
planar geometry were reported: (a) Dai, X.; Warren, T. H. J. Am. Chem.
Soc. 2004, 126, 10085. (b) Barluenga, J.; Lopez, L. A.; Lober, O.; Tomas,
M.; Garcia-Granda, S.; Alvarez-Rua, C.; Borge, J. Angew. Chem., Int. Ed.
2001, 40, 3392. (c) Hofmann, P.; Shishkov, I. V.; Rominger, F. Inorg.
Chem. 2008, 47, 11755.
1
(20) Free isocyanide was observed by H NMR analysis when the
temperature was increased to 50 °C.
(21) Although copper(I) difluorocarbene complexes have been
proposed as intermediates in some reactions, there was little evidence
of complex formation.
(22) (a) Xiao, Q.; Xia, Y.; Li, H.; Zhang, Y.; Wang, J. Angew. Chem., Int.
Ed. 2011, 50, 1114. (b) Hu, M.; Ni, C.; Hu, J. J. Am. Chem. Soc. 2012,
134, 15257. (c) Xia, Y.; Zhang, Y.; Wang, J. ACS Catal. 2013, 3, 2586 and
refs therein.
(23) From the result of HRMS analysis, a phosphine ligand was
eliminated from the catalyst precursor 5d. The following experiment
indicated that the elimination of phosphine ligand was necessary for the
reaction: the yield of 2a decreased to 32% (19F NMR) when the reaction
was conducted in the presence of 20 mol % of PPh3 for 12 h (vs Table 1,
entry 8).
D
DOI: 10.1021/acs.orglett.6b02085
Org. Lett. XXXX, XXX, XXX−XXX