Direct β-Selective Cross-Coupling of Alkenyl Gold Complexes with Alkyl Electrophiles

Article abstract of DOI:10.1002/ejoc.201601149

Alkenyl gold complexes are common intermediates in gold-catalyzed transformations of allenes and alkynes, and numerous methods for their functionalization have been explored. Particularly valuable are cross-coupling reactions, which result in the formation of a new C–C bond. Several strategies are known that enable α-selective cross-coupling of alkenyl gold complexes with aryl, allyl, or acyl coupling partners. We describe the direct β-selective cross-coupling of alkenyl gold complexes with simple alkyl electrophiles. We also describe the effects of the steric and electronic properties of alkenyl gold complexes on the selectivity of the cross-coupling reaction.

Full text of DOI:10.1002/ejoc.201601149

A Journal of
Accepted Article
Title: Direct β-Selective Cross-Coupling of Alkenyl Gold Complexes with Alkyl Elec-
trophiles
Authors: Gojko Lalic; Julia Nguyen; Nicole Duncan
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601149
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Direct -Selective Cross-Coupling of Alkenyl Gold Complexes
with Alkyl Electrophiles
Julia Nguyen, Nicole Duncan, and Gojko Lalic*[a]
coupling reactions with alkenyl gold-complexes.[10] It is known
Abstract: Alkenyl gold complexes are common intermediates in
that gold can facilitate trapping of an electrophile at the -carbon
of alkenyl gold complexes through backbonding (eq 1). After a
hydride shift, the resulting gold carbenoid provides the desired
alkene product.[11] The formation of gold carbenoid intermediates
has been postulated in several examples of intramolecular
reactions of alkenyl gold complexes with electrophiles.[12]
Inspired by these examples, we hypothesised that the same
reactivity can be used to accomplish -selective cross-coupling
of alkenyl gold complexes with simple alkyl electrophiles. Here,
we demonstrate a direct -selecitve cross-coupling of alkenyl
gold complex with alkyl triflates. We also show that the mode of
reactivity of the alkenyl gold complexes with alkyl triflates varies
dramatically as we change the electronic and steric properties of
the gold complexes.
gold-catalyzed transformations of allenes and alkynes, and
numerous methods for their functionalization have been explored.
Particularly valuable are cross-coupling reactions, which result in the
formation of a new C-C bond. Several strategies are known that
allow -selective cross-coupling of alkenyl gold complexes with aryl,
allyl, or acyl coupling partners. We describe a direct -selective
cross-coupling of alkenyl gold complexes with simple alkyl
electrophiles. We also describe effects that the steric and electronic
properties of alkenyl gold complexes have on the selectivity of the
cross-coupling reaction.
One of the most common themes in gold catalysis is the
use of gold’s exceptional carbophilic π acidity to activate alkynes
and allenes towards nucleophilic attack.[1] Belying the wide
variety of products accessible through this reactivity is the fact
that most of these reactions preceed through an alkenyl gold
intermediate.[2] In a vast majority of reactions, the alkenyl gold
complex either undergoes protodeauration or is intercepted by
an electrophile in an intramolecular reaction.[3] More recently,
several examples of intermolecular interception of alkenyl gold
intermediates have been reported, further expanding the scope
and utility of gold catalysis. Particularly valuable are methods
that enable direct cross-coupling of alkenyl gold intermediates
and lead to the formation of a new carbon-carbon bond.[4]
So far, three strategies have been developed to achieve
cross-coupling reactions of alkenyl gold complexes.
One
approach is to use a second metal, such as palladium or nickel,
to catalyze cross-coupling between alkenyl gold complexes and
an organohalide, such as aryl iodide, acyl chloride, and methyl
iodide.[5] Another method is to access Au(I)/Au(III) redox cycles
using Selectfluor as an oxidant. This strategy has been
successfully applied to homocoupling[6] and to cross-coupling
with aryl boronic acids.[7] The third approach also involves
Au(I)/Au(III) redox cycles, but instead of a stoichiometric oxidant,
a ruthenium photoredox catalyst is used to generate a Au(III)
species. This dual gold-ruthenium catalytic system has been
used to accomplish coupling of alkenyl gold intermediates with
aryl diazonium salts.[8]
Scheme 1. Intermolecular Cross-Coupling of Alkenyl Gold Complexes
All three strategies for cross-coupling of alkenyl gold
complexes have been mostly focused on aryl and acyl coupling
In our initial attempts to intercept alkenyl gold complexes
with alkyl triflate, we used triphenylphosphine as the ligand on
gold. Unfortunately, with such complexes, we saw significant
formation of the products of protodeauration and negligible
formation of desired products. Hypothesizing that a better σ
donor ligand was needed to increase the electron density on the
gold center, we switched to N,N’-bis(2,6-diisopropylphenyl)-
imidazol-2-ylidene (IPr) supported complexes.[13] This change
proved to be constructive, and treatment of alkenyl gold complex
1 with alkyl triflate 2 in C6D6 at room temperature generated the
partners, generating C(sp2)-C(sp2) bonds.
Exceptions are
methyl and allyl electrophiles, which have been used palladium-
catalyzed cross-coupling of alkenyl gold complexes.[9] Another
common feature of these three strategies is that the new C-C
bond is formed at the -carbon of the alkenyl gold complex.
The relativistically expanded 5d orbitals of gold suggest
another possible mode of reactivity and an opportunity to
change the regioselectivity and expand the scope of cross-
[a]
J. Nguyen, N. Duncan, G. Lalic
Department of Chemistry, University of Washington
E-mail: lalic@chem.washington.edu
URL: http://faculty.washington.edu/lalic/index.shtml
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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expected alkene product 3, with the E isomer being the major
product (Scheme 2A). Though initially product formation occurs
relatively rapidly, upon approaching 50% yield, the rate of
product formation dramatically decreases and the final yield
generally does not rise above 50%. Curiously, 1H NMR showed
complete consumption of the alkenyl gold 1 and there was no
evidence of the protodeauration product, propylene. We made
several efforts to increase the yield, including conducting a
solvent screen, increasing the temperature, increasing the
equivalents of alkyl triflate, and adding 2,6-lutidine as a proton
scavenger. None of these changes significantly increased yield
of the desired product.
species 1 through the generation of (bis)gold species 4, thus
limiting yields of the final alkene product to 50%.
Formation of unreactive alkenyl (bis)metal species have
several precedents in the literature. Previous work in our lab
had found that in stoichiometric reactions between alkenyl Cu
complex and alkyl triflate, formation of a dinuclear alkenyl
copper complex also limited the yield of the desired product to
approximately 50%.[14] Additionally, Widenhoefer et al. found an
alkenyl bis(gold) species to be an off cycle catalyst resevoir in
their gold catalyzed allene hydroalkoxylation reaction.[15]
Notably, in catalytic variants of these reactions, the formation of
an alkenyl bis(metal) species did not prevent complete
conversion of the starting material to the desired products and
excellent yields (>90%) were achieved. In catalytic reactions, the
presence of a turnover reagent (CsF) or the presence of an
additional substrate facilitate further transformation of the alkenyl
bis(metal) complex. Thus, the reactivity revealed in this
stoichiometric study of alkenyl gold and alkyl triflate offers insight
for the development of a catalytic reaction that does not need to
be limited by the formation of bis(gold) complexes.
While monitoring the reaction by 1H NMR, we had observed
the appearance of two doublets between 4.3 to 4.6 ppm, which
grew during the start of the reaction and disappeared towards
the end. This development was accompanied by the formation
of a white solid in the NMR tube. We suspected that those
peaks corresponded to alkenyl bis(gold) complex
4 and
disappeared as 4 crystallized out of solution. Alkenyl bis(gold)
complex 4 could be generated by a reaction between IPrAuOTf
5, a presumed product of the reaction between alkenyl gold and
alkyl triflate, and alkenyl gold 1. To test this idea, alkenyl gold 1
1
and excess 5 were combined in C6D6, and based on H NMR, 1
was completely consumed within 5 minutes (Scheme 2B). 1H
NMR spectrum of the newly formed complex featured the
characteristic doublets (see above) we had previously observed
in a reaction shown in Scheme 2A. X-ray crystallography
confirmed the structure of complex 4.
Scheme 3. Reactivity of Alkenyl Gold Complexes
Having confirmed that alkyl triflate can intercept 2-propenyl
gold, we next explored the scope of alkenyl gold species that
can undergo this electrophilic interception. Treatment of ethenyl
gold 6 with dodecyl triflate 7 afforded expected alkene product 8
(Scheme 3A). Interestingly, both the yield and rate of the
reaction were significantly reduced as compared to those of the
2-propenyl gold complex reaction (eq 1). It seems that the
additional methyl on the 2-propenyl gold complex plays an
important role in facilitating electrophilic interception, possibly
by stabilizing the cationic intermediate generated upon trapping
of the alkenyl gold species (eq. 1).
Scheme 2. Cross-Coupling of Alkenyl Gold Complex with Alkyl Triflate
Hypothesizing that the low yield of the cross-coupling
product in reaction shown in Scheme 2A is due to the lower
nucleophilicity of the alkenyl (bis)gold species 4, we treated 4
with alkyl triflate and did not observe significant product
formation after 4 days. These results suggest that IPrAuOTf 5,
which is formed as a side product of the alkenyl gold and alkyl
triflate reaction, can sequester any remaining alkenyl gold
Based on the formation of product 8, it is unclear whether
the new C-C bond is formed at the  or the  carbon. In an
effort to probe the regioselectivity of the reaction, we
synthesized (E)-alkenyl gold species 9 and found that after
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European Journal of Organic Chemistry
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COMMUNICATION
treatment with alkyl triflate 10, only trace amounts of the 1,1
disubstituted alkene (the expected product based on the
mechanism detailed in eq 1) were formed. Instead, the major
products were trans cyclopropane product 12 and alkene 11,
together with a dinuclear alkenyl gold complex analogous to 4.
A plausible mechanism for the formation of alkene 11 is an
oxidative addition/reductive elimination sequence. In a classic
paper by Kochi et al., methyl Au(I) was found to cross-couple
with MeI in a sequence that involves oxidative addition and
reductive elimination.[16] Formation of compound 11 through an
oxidative addition/reductive elimination mechanism is consistent
with the generation of a C-C bond at the -carbon and the
conservation of the double bond geometry seen in product 11.
A plausible mechanism for the formation of 12 is shown in
Scheme 4 and involves the formation of a gold carbenoid
intermediate, followed by C-H insertion reaction. While the
insertion is possible at both postions a and b (products 15 and
16, respectively), only the product from the insertion at position a
has been observed in reaction shown in Scheme 3C. We have
prepared the autentic sample of the product analogous to 16
and confirmed that this product is not present in the crude
reaction mixture. This selectivity of the proposed C-H insertion
step is difficult to explain.
selecitve cross-coupling is observed, together with the formation
of the dinuclear alkenyl gold complex. The substitution at the 
position facilitates the cross-coupling reaction, presumably by
stabilizing the cationic intermediate. The substitution at the 
position, on the other hand, hinders the -selective cross-
coupling, presumably by steric hindrance. Finally, in the absence
of an  substituent, we observe a reactivity consistent with the
formation of the gold carbene intermediates. Overall, reactions
with alkyl triflates broaden the synthetic potential of alkenyl gold
intermediates, which are ubiquitous in the field of homogeneous
gold catalysis, and provide an opportunity for the development of
new catalytic processes.
Acknowledgements
Financial support by NSF is greatfully aknowldeged (CAREER
Award #1254636).
Keywords: catalysis 1 • gold 2 • alkenes 3 • alkylation 4 • cross-
coupling 5
The divergent reactivity of the - and -substituted alkenyl
gold complexes is interesting in the context of the recent
investigation of gold carbenoids and the contribution the carbene
form (represented by structure 14a) makes to their structure and
[1]
[2]
(a) A. Furstner, P. Davies, Angew. Chem. Int. Ed. 2007,
46, 3410-3449; (b) D. J. Gorin, F. D. Toste, Nature 2007,
446, 395-403; (c) M. Rudolph, A. Hashmi, Chem. Soc.
Rev. 2012, 41, 2448-2462; (d) L. Liu, G. Hammond, Chem.
Soc. Rev. 2012, 41, 3129-3139; (e) D. Pflästerer, A. S.
Hashmi, Chem. Soc. Rev. 2016, 45, 1331-1367.
(a) W. Yang, A. Hashmi, Chem. Soc. Rev. 2014, 43, 2941-
2955; (b) J. Akana, K. Bhattacharyya, P. Muller, J. Sadighi,
J. Am. Chem. Soc. 2007, 129, 7736-7738; (c) O. Egorova,
H. Seo, Y. Kim, D. Moon, Y. Rhee, K. Ahn, Angew. Chem.
Int. Ed. 2011, 50, 11446-11450; (d) A. Hashmi, A.
Schuster, S. Gaillard, L. Cavallo, A. Poater, S. Nolan,
Organometallics 2011, 30, 6328-6337.
reactivity.[17]
The reactivity of the disubstituted carbenoid
derived from -substituted alkenyl gold complex is consistent
with the idea that the dominant form of the carbenoid is the gold
stabilized carocation represented by resonance structure A in eq
1. However, the C-H insertion observed with monosubstituted
carbenoids derived from complex
contribution of the carbene form.[18]
9 suggests significant
[3]
(a) J. Teles, S. Brode, M. Chabanas, Angew. Chem. Int.
Ed. 1998, 37, 1415-1418; (b) C. Nieto-Oberhuber, M.
Munoz, E. Bunuel, C. Nevado, D. Cardenas, A.
Echavarren, Angew. Chem. Int. Ed. 2004, 43, 2402-2406;
(c) L. Zhang, J. Am. Chem. Soc. 2005, 127, 16804-16805;
(d) C. Li, K. Pati, G. Lin, S. Abu Sohel, H. Hung, R. Liu,
Angew. Chem. Int. Ed. 2010, 49, 9891-9894.
[4]
[5]
M. Johnson, J. van Rensburg, M. Axelsson, M. Ahlquist, O.
Wendt, Chem. Sci. 2011, 2, 2373-2377.
Scheme 4. Mechanism of formation of 12
(a) Y. Shi, S. Ramgren, S. Blum, Organometallics 2009,
28, 1275-1277; (b) A. Hashmi, C. Lothschutz, R. Dopp, M.
Rudolph, T. Ramamurthi, F. Rominger, Angew. Chem. Int.
Ed. 2009, 48, 8243-8246; (c) J. Hirner, S. Blum,
Finally, we synthesized , -disubstituted alkenyl gold
complex 13 (Scheme 3C). Combining 13 with alkyl triflate
generated at least seven different products. These results
suggests that sterics play an important role in modulating the
reactivity of alkenyl gold complexes.
In summary, we described the reactions of various alkenyl
gold complexes with alkyl triflates. We demonstrated that the
efficiency and product distribution of the reaction strongly
depend on the structure of the gold complexes. With -
subsitutied alkenyl gold complexes, an efficient and highly -
Organometallics 2011, 30, 1299-1302; (d) A. Hashmi, C.
Lothschutz, R. Dopp, M. Ackermann, J. Becker, M.
Rudolph, C. Scholz, F. Rominger, Adv. Synth. Catal. 2012,
354, 133-147; (e) M. Pena-Lopez, L. Sarandeses, J.
Sestelo, Eur. J. Org. Chem. 2013, 2545-2554.
[6]
H. Wegner, S. Ahles, M. Neuburger, Chem. Eur. J. 2008,
14, 11310-11313.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601149
COMMUNICATION
[7]
(a) G. Zhang, Y. Peng, L. Cui, L. Zhang, Angew. Chem. Int.
Ed. 2009, 48, 3112-3115; (b) M. Hopkinson, J. Ross, G.
Giuffredi, A. Gee, V. Gouverneur, Org. Lett. 2010, 12,
4904-4907.
[16]
[17]
[18]
A. Tamaki, S. Magennis, J. Kochi, J. Am. Chem. Soc.
1974, 96, 6140-6148.
G. Seidel, A. Furstner, Angew. Chem. Int. Ed. 2014, 53,
4807-4811.
[8]
(a) X. Shu, M. Zhang, Y. He, H. Frei, F. Toste, J. Am.
Chem. Soc. 2014, 136, 5844-5847; (b) D. Patil, H. Yun, S.
Shin, Adv. Synth. Catal. 2015, 357, 2622-2628; (c) J. Um,
H. Yun, S. Shin, Org. Lett. 2016, 18, 484-487; (d) A.
Tlahuext-Aca, M. Hopkinson, R. Garza-Sanchez, F.
Glorius, Chem. Eur. J. 2016, 22, 5909-5913.
A. Hashmi, T. Ramamurthi, F. Rominger, Adv. Synth.
Catal. 2010, 352, 971-975.
(a) M. Fructos, P. de Fremont, S. Nolan, M. Diaz-Requejo,
P. Perez, Organometallics 2006, 25, 2237-2241; (b) Y.
Horino, T. Yamamoto, K. Ueda, S. Kuroda, F. Toste, J.
Am. Chem. Soc. 2009, 131, 2809-2811.
[9]
[10]
[11]
P. Pyykko, Chem. Soc. Rev. 2008, 37, 1967-1997.
C. Obradors, A. Echavarren, Chem. Commun. 2014, 50,
16-28.
[12]
(a) X. Shi, D. Gorin, F. Toste, J. Am. Chem. Soc. 2005,
127, 5802-5803; (b) P. Dube, F. Toste, J. Am. Chem. Soc.
2006, 128, 12062-12063; (c) I. Nakamura, T. Sato, Y.
Yamamoto, Angew. Chem. Int. Ed. 2006, 45, 4473-4475;
(d) G. Lemiere, V. Gandon, K. Cariou, A. Hours, T.
Fukuyama, A. Dhimane, L. Fensterbank, M. Malacria, J.
Am. Chem. Soc. 2009, 131, 2993-3006; (e) I. Alonso, B.
Trillo, F. Lopez, S. Montserrat, G. Ujaque, L. Castedo, A.
Lledos, J. Mascarenas, J. Am. Chem. Soc. 2009, 131,
13020-13030.
[13]
[14]
N. Marion, S. Nolan, Chem. Soc. Rev. 2008, 37, 1776-
1782.
(a) M. Uehling, A. Suess, G. Lalic, J. Am. Chem. Soc.
2015, 137, 1424-1427; (b) A. Suess, M. Uehling, W.
Kaminsky, G. Lalic, J. Am. Chem. Soc. 2015, 137, 7747-
7753.
[15]
T. J. Brown, D. Weber, M. R. Gagné, R. A. Widenhoefer, J.
Am. Chem. Soc. 2012, 134, 9134-9137.
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Title
Direct -selective alkylation of alkenyl gold complexes is achieved using alkyl
triflates as electrophiles. Steric and electronic properties of the alkenyl gold
complexes are shown to effect both the selectivity and the reactivity of the
alkylation. The observed selectivity to the alkylation reaction, and the formation of
cyclopropane-containing by-products suggest the formation of a gold carbene
intermediates.
Key topic: gold catalysis
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