Gold-catalyzed functionalization of unactivated C(sp3)-H bonds by hydride transfer facilitated by alkynylspirocyclopropanes

Article abstract of DOI:10.1002/anie.201205051

A Golden Gate: Alkynylspirocyclopropanes served as a template for the development of gold-catalyzed hydride transfer from unactivated C(sp ³)-H bonds to electronically neutral alkynes. A variety of interesting carbocyclic structures can be accessed selectively with the appropriate choice of the reaction conditions. Mechanistic studies support a sequential gold-catalyzed cleavage of C-H and C-C bonds. Copyright

Full text of DOI:10.1002/anie.201205051

Angewandte
Chemie
DOI: 10.1002/anie.201205051
Gold Catalysis
3
À
Gold-Catalyzed Functionalization of Unactivated C(sp ) H Bonds by
Hydride Transfer Facilitated by Alkynylspirocyclopropanes**
Josꢀ Barluenga,* Rita Sigꢁeiro, Rubꢀn Vicente, Alfredo Ballesteros,* Miguel Tomꢂs, and
Miguel A. Rodrꢃguez
Transition-metal-catalyzed coupling reactions involving unac-
3
À
tivated C(sp ) H bonds constitute one of the most active
research areas in both industry and academia.[1,2] In partic-
À
ular, the development of methods that enable C C bond
formations through the selective cleavage of ubiquitous
3
À
C(sp ) H bonds is highly desirable as it allows for new
retrosynthetic disconnections, thus minimizing the number of
steps and the generation of waste.[2] A major drawback of this
transformation lies in the control of the selectivity. In general,
selective functionalizations are achieved by the assistance of
directing groups that bring the catalyst closer to the desired
C H bond.[3] Alternatively, good control of the selectivity has
À
Scheme 1. Complementary approaches to gold-promoted hydride
been reported by the intramolecular thermal or Lewis acid
catalyzed 1,5-hydride transfer reaction (HT).[4] In contrast to
hydride transfer to electron-poor alkenes,[5] the use of
electronically unbiased alkynes as acceptor partners requires
the assistance of platinum[6] or gold[7] catalysts.[8] Thus,
3
À
transfer from C(sp ) H bonds to alkynes.
hypothesized that this restricted geometry might facilitate the
1,5-hydride transfer to
a
metal-activated alkyne
a
variety of gold- or platinum-catalyzed cleavages of
(Scheme 1b).[11] Herein, we disclose a new gold-catalyzed
3
3
À
À
C(sp ) H bonds through intramolecular HT to alkynes have
been described recently by the groups of Sames, Gagosz, and
hydride transfer from an unactivated C(sp ) H bond to an
alkyne, and the subsequent selective cyclizations.
others. As a carbocation is initially generated, this strategy
Initially, we studied the reactivity of spirane 1a in the
presence of various gold catalysts. We were pleased to find
that a high conversion of 1a was achieved when using cationic
gold complex [(IPr)Au(NTf2)] in 1,2-dichloroethane (708C,
24 h; Scheme 2), thus yielding a mixture of compounds 2–4a
(80% conv., 2a/3a/4a = 2.5:1:1).[12]
3
À
has been limited to C(sp ) H bonds bearing a stabilizing
functionality at the a position (OR, NR2, aryl; Scheme 1a).
Considering this limitation, hydride transfer to alkynes from
aliphatic, nonbenzylic, positions constitutes a challenging
transformation.
As part of our research into the synthesis and reactivity of
alkynylcyclopropane derivatives,[9,10] we have recently
reported the synthesis of spiro[2,4]heptane derivatives
1 whose particular structure makes them amenable for use
in investigations of new metal-catalyzed processes.[11] These
compounds have severe geometrical restrictions that place an
inactive methylene group close to the alkyne moiety. We
Scheme 2. Gold-catalyzed HT cyclizations of alkynylcyclopropane 1a.
IPr=1,3-bis(2,6-diisopropylphenyl)imidazolium, DCE=1,2-dichloro-
ethane.
[*] Prof. Dr. J. Barluenga, Dr. R. Sigꢀeiro, Dr. R. Vicente,
Prof. Dr. A. Ballesteros, Prof. Dr. M. Tomꢁs
Departamento de Quꢂmica Orgꢁnica e Inorgꢁnica e Instituto
Universitario de Quꢂmica Organometꢁlica “Enrique Moles”
Universidad de Oviedo; c/Juliꢁn Claverꢂa 8, 33006 Oviedo (Spain)
E-mail: barluenga@uniovi.es
These transformations are noteworthy because they
3
À
involve a selective cleavage of an unactivated C(sp ) H
abg@uniovi.es
bond, which together with the formation and cleavage of
Prof. Dr. M. A. Rodrꢂguez
Departamento de Quꢂmica, Centro de Investigaciꢃn en Sꢂntesis
Quꢂmica, Universidad de La Rioja
À
unactivated C C bonds results in the formation of the final
products. Further screening of the reaction conditions to
achieve higher selectivity was undertaken using [(IPr)Au-
(NTf2)] as catalyst. Shorter reaction times increased the
amount of 2a, although lower conversion was achieved.
Interestingly, the use of microwave irradiation proved advan-
tageous, as tricycles 2 could be prepared exclusively in
moderate to good yields when irradiating spiranes 1 in the
c/Madre de Dios, 51, 26006 LogroÇo (Spain)
[**] We are grateful to the MINECO (Spain) (Projects CTQ-201020517-
C02 and CTQ2011-24800) for financial support. R.V. is a Ramꢃn
y Cajal fellow. Table-of-contents photo is courtesy of PDPhoto.org.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205051.
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presence of [(IPr)Au(NTf2)] in DCE for 1 hour at 908C
(Scheme 3). Under these reaction conditions, spiro-
[2,5]heptanes 1 (n = 1) bearing various alkyl chains (R2 =
nBu, iBu, and iPr) afforded the corresponding tricycles 2a–c
in moderate yields. In the same way, spiro[2,5]octane 1 (n = 2)
was also converted into the corresponding tricycle 2d.
Scheme 4. Synthesis of bicycles 3 from alkynylcyclopropanes 1. The
yields of the isolated product are in parenthesis. PMP=4-MeOC6H4.
Scheme 3. Synthesis of tricycles 2 from alkynylcyclopropanes 1.
Method A: [(IPr)Au(NTf2)] (5.0 mol%), DCE, 908C, mW, 1 h; method B:
[(JohnPhos)Au(MeCN)][SbF6] (5.0 mol%), DCE, 708C, 1.5–8 h. The
yields of the isolated product are in parenthesis. brsm=based on
recovered starting material, PCP=4-ClC6H4.
Although these reaction conditions were also amenable for
the transformation of aryl- and trimethylsilyl-substituted
substrates 1 (R2 = Ar, TMS) into compounds 2e–h, better
efficiency was achieved using [(JohnPhos)Au(MeCN)][SbF6]
as the catalyst under thermal conditions (DCE, 708C, 1.5–
8 h).[13]
Next, the beneficial effects of microwave irradiation
allowed us to establish a selective route toward bicyclo-
[3.2.1]octenes 3 (Scheme 4). In this case, irradiation in DCE at
1508C in the presence of [(JohnPhos)Au(MeCN)][SbF6] led,
after 1 hour, to cycloadducts 3 in generally high yields. As
depicted, alkynylcyclopropanes 1 bearing a linear alkyl chain
at substituent R2 were efficiently converted into bicycles 3a–
c.[13,14] Likewise, compounds bearing secondary alkyl sub-
stituents such as iPr (3d) or c-pentyl (3e) were obtained in
good yields. Notably, an additional cyclopropyl moiety was
tolerated and remained unchanged in the final product (3 f–
g). As before, the use of electron-poor and electron-rich
arenes (R1 = PCP or PMP), gave 3g–h with similar efficacy.
Moreover, alkynylcyclopropane 1i bearing two phenyl sub-
stituents was converted into compound 3i, albeit in relatively
lower yield.[15]
Scheme 5. Synthesis of pentalenes 4 from alkynylcyclopropanes 1. The
yields of the isolated product are in parenthesis. E/Z ratio was
determined by H NMR spectroscopy.
1
rise to compounds 4 f–h (72–90% yield) featuring a fully
substituted exocyclic double bond.[13,14]
To gain an insight into the mechanism of these trans-
formations we carried out a variety of experiments. To
provide experimental support for a hydride-transfer mecha-
nism, we subjected deuterium-labeled compounds [D4]-1e
and [D4]-1a to cyclization conditions, which gave rise to
[D4]-2e and [D4]-3a, respectively, without loss of the deute-
rium label (Scheme 6a and b). The conversion of [D4]-1a into
[D4]-4a took place with deuterium scrambling probably as
a result of D/H shifts within the dienyl moiety as well as
partial loss of the deuterium label (Scheme 6c).
Finally, the transformation of compounds 1 (R2 = alkyl)
into pentalene derivatives 4 could be selectively accomplished
by microwave heating in DCE at 1508C (1 h) using [(IPr)Au-
(NTf2)] as catalyst (Scheme 5). Thus, we were able to prepare
several bicycles 4a–e from substrates 1 bearing a primary
alkyl substituent, either linear (R2 = nPr, nBu, nC8H17) or
branched (R2 = sBu), in good yields (63–90%) and with
moderate E selectivity (E/Z = 4:1). The use of cyclopropanes
1 bearing a secondary alkyl substituent (R2 = iPr, c-pent) gave
We suspected that tricycles 2, obtained selectively only
under mild reaction conditions, might be a precursor to
compounds 3 and 4, but that the formation of which would
require notably stronger reaction conditions. Indeed, 2a was
2
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Scheme 6. Deuterium-labeling experiments.
Scheme 8. Proposed mechanism.
converted into the corresponding bicycles 3a[16] and 4a under
microwave irradiation in the presence of [(JohnPhos)Au-
(MeCN)][SbF6]
and
[(IPr)Au(NTf2)],
respectively
(Scheme 7). Furthermore, we observed that 3a gave 4a
almost quantitatively when treated with the [(IPr)Au(NTf2)]
catalyst (Scheme 7). The latter transformation might deserve
further attention as it involves an unprecedented gold-
catalyzed rearrangement of a 1,4-diene.[17]
protodemetallation would provide the pentalene 4. Without
further evidence, it is reasonable to assume that IVand III are
the intermediates for the conversion of 3 into 4.[24]
In summary, we have reported the manifold reactivity of
readily available alkynylcyclopropanes 1 that bear a spirane
core. This study led us to discover an unprecedented gold-
catalyzed 1,5-hydride transfer that involves a unactivated
3
[25]
À
C(sp ) H bond and an electronically neutral alkyne.
Interestingly, the diverse fate of the resulting cationic gold
À
species (C C bond formation and bond cleavage of the
unactivated species) can be efficiently controlled under
microwave irradiation by simply selecting the appropriate
catalyst (either [(JohnPhos)Au(MeCN)][SbF6] or [(IPr)Au-
(NTf2)]) and reaction temperature. Thus, a range of cyclic
structures, for example, pentalene derivatives 2 and 4,[26] and
bicycles 3,[27] can be accessed with complete selectively.[28]
Remarkably, it is herein shown that a spirane structure
containing a cyclopropane ring can facilitate the intramolec-
ular hydride transfer between unactivated donor and acceptor
components. These results may open the way to study other
hydride acceptor groups as well as to ascertain whether the
spirane structure is essential or simpler alkynylcyclopropanes
might also be employed.
Scheme 7. Gold-catalyzed conversion of 2a into 3a and 4a, and 3a
into 4a.
Based on these experiments, we propose a tentative
mechanism for these transformations (Scheme 8). The gold-
to-alkyne coordination would trigger the 1,5-hydride transfer
with concomitant cyclopropane ring cleavage.[18] The gener-
ated 1,4-enallenyl gold intermediate I might then undergo
a cyclization via species II to afford tricycle 2.[19] Support for
the proposed mechanism was gained by computational
studies, as a transition state involving the H atom migration
was found.[20,21] The subjection of 2 to harsher reaction
conditions leads to 3 and 4 probably through the common
intermediate III formed by regioselective gold-catalyzed
Experimental Section
Representative procedure (2a, Scheme 3): [(IPr)Au(NTf2)] (17 mg,
0.02 mmol, 5.0 mol%) was added to a solution of alkynylcyclopro-
pane 1a (100 mg, 0.424 mmol) in DCE (4.2 mL, 0.1m) under argon in
a microwave vial. The vessel was sealed with a septum cap, placed into
the microwave cavity, and irradiated to maintain the reaction mixture
at 908C during 1 h. Then, the vial was cooled down to room
temperature and the solvent was removed under reduced pressure.
The resulting residue was purified by flash chromatography on silica
[22]
À
cyclopropane C C bond cleavage.
A pinacol-type rear-
rangement would explain the formation of 3 from III. Thus,
the 1,2-alkyl migration, giving intermediate IV, would be
followed by metal elimination.[23] On the contrary, deproto-
nation of III, giving intermediate V, and a subsequent
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gel (n-pentane) to afford 2a (51 mg, 51%, 79% based on recovered
starting material) as a colourless oil.
Aubert, L. Fensterbank, M. Malacria, Angew. Chem. 2006, 118,
7758; Angew. Chem. Int. Ed. 2006, 45, 7596.
[8] For hydride transfer to alkynes with other catalysts, see: a) T.
Sugiishi, H. Nakamura, J. Am. Chem. Soc. 2012, 134, 2504; b) F.
Cambeiro, S. Lꢄpez, J. A. Varela, C. Saꢅ, Angew. Chem. 2012,
124, 747; Angew. Chem. Int. Ed. 2012, 51, 723.
Received: August 10, 2012
Published online: && &&, &&&&
3
[9] J. Barluenga, E. Tudela, R. Vicente, A. Ballesteros, M. Tomꢅs,
Angew. Chem. 2011, 123, 2155; Angew. Chem. Int. Ed. 2011, 50,
2107.
[10] For other recent studies on the reactivity of alkynylcyclopro-
panes with Au or Pt catalysts, see: a) S. Ye, Z.-X. Yu, Org. Lett.
2010, 12, 804; b) C.-W. Li, K. Pati, G.-Y. Lin, S. M. A. Sohel, H.-
H. Hung, R.-S. Liu, Angew. Chem. 2010, 122, 10087; Angew.
Chem. Int. Ed. 2010, 49, 9891. See also Ref. [7g].
[11] J. Barluenga, E. Tudela, R. Vicente, A. Ballesteros, M. Tomꢅs,
Chem. Eur. J. 2011, 17, 2349 – 2352.
[12] Under otherwise identical reaction conditions, other catalysts
gave rise to less conversion of 1a. Some examples: AuCl3 (20%),
PtCl4 (25%, 1 atm CO), [Pd(PPh)2Cl2] (< 5%), and PtCl2
(< 5%).
[13] The structures of compounds 2 – 4 were established based on 1D
and 2D NMR studies. X-Ray analysis was performed on com-
pounds 2 f and 3g. CCDC 887447 (2 f) and 887448 (3g) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[14] Under otherwise identical reaction conditions, spiro[2.5]octane
derivative 1 (n = 2) gave rise to a complex reaction mixture.
[15] Compound 2e (50%) was also obtained under the reaction
conditions.
[16] Compound 4a (30%, E/Z = 3.6:1) was also obtained under the
reaction conditions.
[17] For a recent example of gold-catalyzed Cope rearrangement of
1,5-dienes, see: R. J. Felix, D. Weber, O. Gutiꢂrrez, D. J. Tantillo,
M. R. Gagnꢂ, Nat. Chem. 2012, 4, 405.
À
Keywords: C(sp ) H bond cleavage · cyclization · gold ·
.
homogeneous catalysis · hydride transfer
À
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[20] See the Supporting Information for details of computational
studies.
[21] One referee suggested a closely related reaction pathway
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formation of a carbocation and a subsequent proton transfer. At
this stage, this hypothesis cannot be ruled out.
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might serve as a driving force of this step. For examples of gold-
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4
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[23] The formation of bicycle 3 through a cyclopropyl gold-carbene
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a
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3
À
C(sp ) H bonds to an activated enone, see Ref. [4g].
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Communications
Gold Catalysis
A Golden Gate: Alkynylspirocyclopro-
panes served as template for the devel-
J. Barluenga,* R. Sigꢁeiro, R. Vicente,
A. Ballesteros,* M. Tomꢂs,
opment of gold-catalyzed hydride transfer
3
À
from unactivated C(sp ) H bonds to
M. A. Rodrꢃguez
&&&& — &&&&
electronically neutral alkynes. A variety of
interesting carbocyclic structures can be
accessed selectively with the appropriate
choice of the reaction conditions. Mech-
anistic studies support a sequential gold-
Gold-Catalyzed Functionalization of
3
À
Unactivated C(sp ) H Bonds by Hydride
Transfer Facilitated by
À
À
Alkynylspirocyclopropanes
catalyzed cleavage of C H and C C
bonds.
6
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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