Nickel-catalyzed cyclization of difluoro-substituted 1,6-enynes with organozinc reagents through the stereoselective activation of c-f bonds: Synthesis of bicyclo[3.2.0]heptene derivatives

Article abstract of DOI:10.1002/anie.201004543

Quite a gem: A nickel-catalyzed cyclization of 1,6-enynes, bearing a gem-difluoro group at the olefinic terminus, with organozinc reagents gives the title compounds (see scheme). One of the fluorine atoms is stereoselectively replaced by the R group of R<

Full text of DOI:10.1002/anie.201004543

Angewandte
Chemie
DOI: 10.1002/anie.201004543
À
C F Activation
Nickel-Catalyzed Cyclization of Difluoro-Substituted 1,6-Enynes with
À
Organozinc Reagents through the Stereoselective Activation of C F
Bonds: Synthesis of Bicyclo[3.2.0]heptene Derivatives**
Manabu Takachi, Yusuke Kita, Mamoru Tobisu, Yoshiya Fukumoto, and Naoto Chatani*
Multicomponent reactions have been a subject of intense
study because they provide for a variety of transformations
that are not easily achieved by current methods.[1] Among
such reactions, transition-metal-catalyzed three-component
coupling reactions of alkynes (or dienes), electron-deficient
olefins (having ketone, ester, imide, and nitro groups at the
olefinic moiety), and organometallic reagents (or metal
hydrides) have been extensively studied because such alky-
lative (or reductive) coupling results in the stereoselective
formation of synthetically important skeletons in a one-pot
reaction.[2–6] In 1994, Ikeda and Sato reported on the nickel-
catalyzed intermolecular coupling of alkynes, enones, and
organostannanes.[3a] Montgomery and Savchenko also
reported the nickel-catalyzed cyclization of intramolecular
alkynyl enones with organozinc reagents leading to alkylative
cyclization products (Scheme 1).[4a] At the initial stage, a
in the oxidative cyclization step. Thus, an alternate mecha-
nism that involves both the Lewis acid activation of the
carbonyl oxygen atom and the Lewis base activation of a Ni0
species by the organozinc, as shown in A, was proposed.[7] The
involvement of an organozinc species may accelerate the
oxidative cyclization leading to the production of B, which
then undergoes reductive elimination/protonation to give the
final product. Lei and co-workers recently reported the
nickel-catalyzed reductive cyclization of simple, nonactivated
enynes through the use of iPr2Zn, and proposed that the
transmetalation of a C–Ni bond with iPr2Zn occurs.[8]
We became interested in reactions of difluoro-substituted
enynes with organozinc reagents, as a fluorine atom at the
olefinic terminus may also interact with the organozinc (C;
Scheme 2) in a manner analogous to a carbonyl group. The
Scheme 2. Working hypothesis.
fluorine atom would also affect the reactivity of the olefin
component in terms of electronic factors.[9] Herein we report
an unprecedented cyclization of 1,6-enynes bearing a gem-
difluoro group at the olefinic terminus that leads to the
formation of bicyclo[3.2.0]heptene derivatives, in which one
of the fluorine atoms is stereoselectively replaced by the R’’
Scheme 1. Nickel-catalyzed alkylative cyclization of enynes.
À
nickelacycle, simply derived from the oxidative cyclization of
an intramolecular alkynyl enone and Ni0, was proposed as a
potential intermediate. However, based on computational
investigations, they concluded that organozinc is also involved
group of R’’2Zn. Although the cross-coupling reaction of C F
bonds is known,[10] the present reaction involves a new type of
coupling reaction with cyclization.
The reaction of 1a with Et2Zn in the presence of
[Ni(cod)2]/PCy3 (cod = 1,5-cyclooctadiene) as the catalyst in
1,4-dioxane at 508C for 2 hours gave 2a,[11] as the sole
product, in 56% yield (Scheme 3). Products containing an
ethyl group were not detected.[12] The use of PPh3 improved
the product yield to 77%. P(4-MeOC6H4)3 was found to be
the ligand of choice given the following results: P(4-
MeOC6H4)3 gave 83% 2a; P(4-CF3C6H4)3 gave 75% 2a;
PPh3 gave 77% 2a; P(2-MeC6H4)3 and PtBu3 each gave
complex reaction mixtures. A comparable yield (76%) was
observed when THF was used as a solvent. The use of other
solvents also gave the product, albeit in less satisfactory yields
[toluene 60%; DMA 51% (DMA = N,N-dimethylaniline)].
[*] M. Takachi, Dr. Y. Kita, Dr. M. Tobisu, Dr. Y. Fukumoto,
Prof. Dr. N. Chatani
Department of Applied Chemistry, Faculty of Engineering
Osaka University, Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-7396
E-mail: chatani@chem.eng.osaka-u.ac.jp
[**] This work was supported, in part, by Grants-in-Aid from the MEXT
(Japan) and by Daikin Industries Ltd. We also thank the Instru-
mental Analysis Center, Faculty of Engineering, Osaka University, for
their assistance with the HRMS, and elemental analyses.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004543.
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ing cyclobutene 2g (entry 7) in 65% yield. As expected, the
use of Me2Zn resulted in methylative cyclization to give
products 3 (entries 8–11). It was found that a phenyl group
can also be introduced at a bridgehead by the use of Ph2Zn to
give products 4 (entries 12–14). However, the reaction of 1c
with Ph2Zn gave a mixture of 4c and 5 (entry 13). The
reaction of 4c under standard reaction conditions did not give
5. A route to the formation of 5 is not clear at present.
We investigated the reaction of 6, a chloro analogue of 1a,
under the standard reaction conditions, but a complex
mixture was obtained, indicating that the presence of a
fluorine atom is required for the reaction to proceed
(Scheme 4). We next examined whether two fluorine atoms
were required for the reaction to occur by using monofluoro-
substituted enynes 7 and 8. Interestingly, only the trans isomer
Scheme 3.
The results of the reaction of various difluoro-substituted
enynes with organozinc reagents are shown in Table 1.
Enynes bearing internal alkynes served as good substrates
in the reaction with Et2Zn, and the corresponding bicyclo-
[3.2.0]heptene derivatives 2a–2e (entries 1–5) were obtained
in high yields (72–83% yields). The structure of the product
was confirmed by X-ray analysis of 2d.[13] Use of a terminal
alkyne as in 1 f also resulted in the corresponding reductive
cyclization product 2 f (entry 6). An enyne having a nitrogen
functionality in the tether (e.g., 1g) also gave the correspond-
Table 1: Nickel-catalyzed reaction of difluoro-substituted 1,6-enynes with
organozinc reagents.[a]
Entry Difluoro enyne
R2Zn
Product[b]
Et2Zn
1
2
3
4
5
6
R=Me (1a)
R=cyclopropyl (1b)
R=Ph (1c)
R=2-naphthyl (1d)
R=SiMe3 (1e)
R=H (1 f)
2a (83%)
2b (81%)
2c (83%)
2d (72%; 4 h)
2e (77%; 4 h)
2 f (41%)
Et2Zn
Scheme 4. Halogen atom effects. Ts=4-toluenesulfonyl.
7
1g
2g (65%)
8 gave the corresponding product 9, but the cis isomer 7 was
completely unreactive. Although the reaction involves the
Me2Zn
À
stereoselective activation of a trans C F bond, the reaction
required an extended period of time for completion [compare
1g (2 h) and 7 (24 h)], indicating that the presence a cis
fluorine atom also has a significant effect on the reactivity of
the substrate, even though the cis fluorine atom itself does not
appear to participate in the reaction.
A proposed mechanism for the reaction is shown in
Scheme 5. The intermediate 10, corresponding to C as shown
in Scheme 2, is proposed as the key intermediate in which Ni
is activated by a Lewis base interaction with the R’’ group on
the organozinc, and the olefin is activated by a Lewis acid
through coordination of the fluorine atom to Zn.[14] In the
8
9
10
R=Me (1a)
R=Ph (1c)
R=H (1 f)
3a (86%)
3c (63%)
3 f (31%)
Me2Zn
Ph2Zn
11
1g
3g (80%; 6 h)
À
latter activation, only the trans C F bond can coordinate to
12
13
14
R=Me (1a)
R=Ph (1c)
R=H (1 f)
4a (50%; 5 h)
4c (42%) + 5 (14%)
4 f (28%)
Zn. Both activations by organozinc facilitate the oxidative
cyclization leading to the production of the nickelacyclopen-
tene 11,[15] which is then transformed into the s-allyl nickel
complex 12. Reductive elimination directly from 12 or from
the p-allyl nickel complex 13[16] gives the final product. In the
case of Et2Zn, b-hydride elimination occurs in 12 or 13 to
[a] Reaction conditions: difluoro-substituted 1,6-enyne (0.3 mmol),
organozinc (0.636 mmol), [Ni(cod)2] (0.015 mmol), P(4-MeOC6H4)3
(0.06 mmol), 1,4-dioxane (1.5 mL) at 508C for 2 h. [b] Yields of isolated
products.
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introduced into a 10 mL two-necked round-bottom flask, and then
dissolved in 1,4-dioxane (1.5 mL). The organozinc (0.636 mmol;
1.06m Et2Zn in n-hexane, 2.0m Me2Zn in toluene, Ph2Zn solid) was
then added to the flask, and the flask was immersed in an oil bath at
508C. The reaction was monitored by GC methods. After the starting
enyne had disappeared, the flask was cooled to room temperature, the
solvent removed by evaporation, and the product was separated by
flash column chromatography on silica gel (ethyl acetate/n-hexane =
1:1). In the reaction with Me2Zn, a 10 mL screw-top vial was used in
place of a 10 mL two-necked round-bottom flask. When a 10 mL two-
necked round-bottom flask was used, yields were dramatically
decreased.
Scheme 5. Proposed reaction mechanism. Ft =trans F, Fc = cis F.
Received: July 24, 2010
Published online: October 7, 2010
introduce a hydride. This mechanism explains the experi-
mental results showing that the stereoselective cleavage of the
À
Keywords: C F activation · cyclization · enynes · nickel ·
organozinc
.
À
trans C F bond occurred, as shown in Scheme 4.
An alternative mechanism is depicted in Scheme 6. The
reductive elimination from 11 gives cyclobutene 14, which
again reacts with Ni0 in a syn fashion to give the p-allyl nickel
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[6] Instead of electron-deficient olefins, aldehydes have also been
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Cheong, T. F. Jamison, K. N. Houk, J. Am. Chem. Soc. 2009, 131,
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Scheme 6. Alternative steps.
fluoride complex 15. Transmetalation of 14 with R’2Zn
leading to 13 and subsequent reductive elimination affords
the final product. However, the formation of a p-allyl nickel
complex by the reaction of allyl fluorides with Ni0 has been
reported in only one paper and provided no details.[16,17]
Although this alternative mechanism cannot be excluded,
the path from 14 to 15, which proceeds in a syn fashion, is not
likely.
In summary, we report the development of a new catalytic
system based on the assumption that organozinc functions as
both a Lewis base with respect to Ni0 and a Lewis acid with
À
respect to the C F bond. As a result, an unprecedented type
of cyclization using difluoro-substituted 1,6-enynes was
achieved. The nickel-catalyzed reaction of difluoro-substi-
tuted enynes with organozinc reagents gives bicyclo-
[3.2.0]heptene derivatives, in which one of the fluorine
atoms is replaced in a stereoselective manner by the R’’
group of R’’2Zn. The reaction involves the regioselective
[18]
À
activation of C F bonds. The extension of the methodology
to the coupling of difluoro-substituted enynes with other
organometallic reagents and reducing reagents is currently
underway.
[7] H. P. Hratchian, S. K. Chowdhury, V. M. Gutiꢀrrez-Garcꢁa,
K. K. D. Amarasinghe, M. J. Heeg, H. B. Schlegel, J. Montgom-
ery, Organometallics 2004, 23, 4636.
[8] M. Chen, Y. Weng, M. Guo, H. Zhang, A. Lei, Angew. Chem.
2008, 120, 2311; Angew. Chem. Int. Ed. 2008, 47, 2279; See also,
Z. Chai, H.-F. Wang, G. Zhao, Synlett 2009, 1785.
[9] For reviews on gem-difluoroalkenes, see: J. Ichikawa, J. Fluorine
Chem. 2000, 105, 257 and references therein. K. Uneyama,
Organofluorine Chemistry, Blackwell, Oxford, 2006; For a recent
Experimental Section
General procedure for nickel-catalyzed reaction of difluoro-substi-
tuted 1,6-enynes with organozinc reagents: The enyne (0.3 mmol),
[Ni(cod)2] (0.015 mmol), and P(4-MeOC6H4)3 (0.06 mmol) were
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Communications
À
paper, see: Y. Zhao, W. Huang, L. Zhu, J. Hu, Org. Lett. 2010, 12,
1444.
[14] For a review of the coordination chemistry of C F bonds, see: H.
Plenio, Chem. Rev. 1997, 97, 3363.
À
[10] For a recent review on catalytic activation of C F bonds, see: H.
Amii, K. Uneyama, Chem. Rev. 2009, 109, 2119.
[15] W. Kaschube, W. Schrꢂder, K. R. Pꢂrschke, K. Angermund, C.
Krꢃger, J. Organomet. Chem. 1990, 389, 399.
[16] X.-X. Lin, G.-Z. Liu, Hecheng Huaxue 1995, 3, 256; Chem. Abst.
1995, 911757.
[11] For a paper on construction of fluoro-substituted fused cyclo-
butenes, see: Q. Shen, G. B. Hammond, J. Am. Chem. Soc. 2002,
124, 6534.
[12] Use of N,N-tetramethylethylenediamine as a ligand in the
reaction of 1a gave an ethylation product in 52% yield. This
catalytic system was not applicable to other reactions.
[13] CCDC 762355 (2a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/cgi-bin/catreq.cgi..
À
[17] For a paper on allylic C F bond activation by palladium, see: X.
Pigeon, M. Bergeron, F. Barabꢀ, P. Dubꢀ, H. N. Frost, J.-F.
Paquin, Angew. Chem. 2010, 122, 1141; Angew. Chem. Int. Ed.
2010, 49, 1123.
[18] For a recent paper on a Ni/Mg, bimetallic, cooperative system
À
for the activation of a C F bond, see: N. Yoshikai, H. Matsuda,
E. Nakamura, J. Am. Chem. Soc. 2009, 131, 9590.
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