Nickel-Catalyzed Directed Hydroarylation of Alkynes with Boronic Acids

Article abstract of DOI:10.1002/ejoc.201801494

A regio- and stereoselective nickel-catalyzed hydroarylation of alkynes using propargylic carbamates as directing groups has been developed. The reaction proceeds under mild reaction conditions using arylboronic acids in the absence of base. A range of heterocycles and functional groups are tolerated under the reaction conditions, providing high yields of trisubstituted alkenes with control of olefin geometry.

Full text of DOI:10.1002/ejoc.201801494

DOI: 10.1002/ejoc.201801494
Communication
Nickel-Catalyzed Hydroarylation
Nickel-Catalyzed Directed Hydroarylation of Alkynes with
Boronic Acids
Luke E. Hanna,[a] Mikhail O. Konev,[a] and Elizabeth R. Jarvo*[a]
Abstract: A regio- and stereoselective nickel-catalyzed hydro- base. A range of heterocycles and functional groups are toler-
arylation of alkynes using propargylic carbamates as directing
groups has been developed. The reaction proceeds under mild
reaction conditions using arylboronic acids in the absence of
ated under the reaction conditions, providing high yields of
trisubstituted alkenes with control of olefin geometry.
Introduction
Functionalized alkenes are present in pharmaceutical agents
and natural products (Figure 1) and are common building
blocks in synthesis.[1,2] Hydroarylation reactions using arylbor-
onic acids offer a simple and attractive manifold for the prepa-
ration of substituted alkenes from alkyne precursors.[3,4] Pre-
cious metal catalysts have been established for reactions em-
ploying arylboronic acids, beginning with pioneering work of
Hayashi using rhodium complexes (Scheme 1a).[5,6] Control of
regioselectively in reactions of internal alkynes, in the absence
of strong electronic bias, has been accomplished with elegant
use of directing groups, with recent focus on directing groups
that serve as synthetic handles for subsequent manipulation
(Scheme 1c and d).[7,8] Establishing base metal catalysts for alk-
yne hydroarylation is of interest, in part to provide the practical
and synthetic advantages of an earth-abundant metal.[9] For ex-
ample, Hartwig and co-workers reported the use of nickel cata-
lysts (Scheme 1b), providing smooth hydroarylation of symmet-
rical alkynes with arylboronic acids; Reddy and co-workers
developed regioselective hydroarylation of propargylic alcohols
(Scheme 1e).[10,11]
Scheme 1. Transition metal-catalyzed hydroarylation reactions of alkynes with
boronic acids.
carbamates serve as directing groups and could direct oxidative
addition of nickel for stereospecific Suzuki reactions.[12] In this
manuscript, we report a regio- and stereoselective hydroaryl-
ation of propargylic carbamates. These reactions proceed under
mild conditions, at room temperature with no added base
(Scheme 1f).
Figure 1. Examples of stilbene-containing pharmaceutical agents and natural
products.
We hypothesized that carbamates could serve as directing
groups for nickel-catalyzed hydroarylation. This hypothesis was
based on previous work in our laboratory, where we found that
Results and Discussion
We began our investigation by interrogating a range of alkynes,
including those with propargylic directing groups such as pival-
ates, carbonates, and carbamates. The highest yield of hydro-
arylated product 2 was formed when a dimethylcarbamate was
employed as a directing group (Table 1, entry 1). Use of a sim-
ple alkyne (4) with no directing group resulted poor conversion
[a] Department of Chemistry, University of California,
Irvine, CA 92697, USA
E-mail: erjarvo@uci.edu; http://sites.uci.edu/jarvogroup/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201801494.
Eur. J. Org. Chem. 0000, 0–0
1
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
and recovered starting material (entry 2). A mixture of byprod-
Having identified suitable reaction conditions for model sub-
ucts and only 20 % hydroarylated product could be observed strate 1, we interrogated a range of internal alkynes (Table 2).
when propargylic alcohol 5 was used (entry 3). Using pivalates Substrates bearing electron-deficient arenes provided the high-
and carbonates as directing groups lead to formation of allene est yields of hydroarylated product at room temperature (11–
3 and small amounts of desired product 2. The steric properties 15). Electron-rich arenes required heating (8 and 10). Ketone
of the directing group also proved important, as more bulky and ester substituents are well-tolerated (11 and 12), however,
carbamates such as diphenyl carbamate lead to a severe drop free aldehydes were not. Gratifyingly, protection of the alde-
yield (entry 4). A range of ligands was evaluated during the hyde as an acetal restored clean hydroarylation under moder-
course of reaction optimization. The reaction performs well ately elevated reaction temperatures (10). Halides were well tol-
with monodentate phosphine ligands, and bulky Buchwald- erated under the reaction conditions (13–15). Aryl fluorides and
type ligands such as TrixiePhos were uniquely capable of fur- chlorides allow for the potential for subsequent functionaliza-
nishing good yields of product and suppressing the formation tion. X-ray crystallographic analysis of a single crystal of tri-
of allene. Notably, subsequent allylic substitution of the allylic fluoromethyl-substituted 15 established the olefin geometry
carbamate 2 was not observed under our reaction conditions.
and supported that the reaction provides cis hydroarylation.[14]
Benzyl-protected alcohols on the alkyl moiety of the starting
materials were carried through the reaction untouched (16).
Citronellal-derived 17 was obtained in good yield, demonstrat-
ing that pendant alkenes do not diminish reactivity. Surpris-
ingly, aryl-substitution at the propargylic position was also tol-
erated, providing hydroarylation in high yield and no subse-
quent allylic substitution (18).
Table 1. Optimization of reaction conditions.
Table 2. Scope of hydroarylation with respect to alkyne.
[a] Determined by 1H NMR spectroscopy using PhTMS as internal standard.
Typical additives and reaction conditions for hydroarylation
and Suzuki-type coupling reactions were evaluated as part of
reaction optimization. Interestingly, the presence of bases such
as tBuOK and K3PO4 that are commonly used to promote trans-
metallation provide lower yield (Table 1, entry 11). Furthermore,
the addition of just one equivalent of LiCl to the reaction mix-
ture lead to a complete shutdown of reactivity and recovery of
[a] Reaction was heated at 80 °C instead of 24 °C.
Next, we turned our attention to investigating the scope
starting material (entry 12). Additionally, during an investigation with respect to arylboronic acids (Table 3). A similar trend in
of suitable solvents it was found that the use of strongly coordi- sensitivity to electronics was observed and electron-deficient
nating solvents such as DMF also shut down reactivity (entry arylboronic acids provided the highest yields at room tempera-
13). Notably, under optimized reaction conditions, the hydro- ture while electron-rich arylboronic acids typically required
arylation reaction proceeds at room temperature for a majority heating. A variety of functional groups were well-tolerated, al-
of substrates; related hydroarylation reactions frequently re- lowing for the incorporation of trimethylsilyl, ether, thioether,
quire elevated temperatures.[13]
and trifluoromethyl moieties (19–21, 24). Aryl chlorides and
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
fluorides participated cleanly in hydroarylation (22–23), with no 34 (Scheme 2). Base-mediated olefin isomerization provides
observed competitive hydrodehalogenation or cross-coupling. tamoxifen.[16]
Esters, ketones and carbamates were also well-tolerated (25–
27). Furthermore, boronic acids containing heterocycles such
as indole, furan, benzofuran, and thiophene provided smooth
hydroarylation (28–31).
Table 3. Scope of hydroarylation with respect to boronic acid.
Scheme 2. Synthesis of Tamoxifen.
To gain insight into the mechanism of the reaction we
sought to determine the origin of the hydrogen atom in our
hydroarylation reaction. Employing PhB(OD)2 in the reaction
lead to a 68 % yield of product -2 with 88 % deuterium incor-
D
poration (Scheme 3). Alternatively, use of (PhBO)3 and deuter-
ium oxide resulted in 99 % deuterium incorporation, albiet in
low yield of product (17–30 %), presumably by formation of
PhB(OD)2 in situ. One possible mechanism that is consistent
with these results is one where the low-valent nickel catalyst is
first protonated by the boronic acid. Carbamate-directed hydro-
metallation of the alkyne provides vinylnickel intermediate 35
in a regio- and stereoselective manner. This intermediate can
then undergo transmetallation and reductive elimination to fur-
nish the desired product. This mechanism is consistent with the
mechanisms previously proposed for hydoarylation reactions in
the absence of base.[3]
Scheme 3. Deuterium labeled boronic acid reveals the origin of hydrogen in
the reaction.
Conclusions
[a] Reaction was heated at 80 °C instead of 24 °C.
In conclusion, we have developed a regio- and stereoselective
nickel-catalyzed hydroarylation of alkynes with arylboronic
acids using a propargylic carbamate as a directing group. The
reaction is tolerant of a range of functional groups and hetero-
cycles. Application in the synthesis of a representative triaryl-
ethylene, tamoxifen, is demonstrated.
Allylic alcohols are excellent functional handles in synthesis.
Moreover, activated allylic alcohols such as allylic carbamates
have been used as electrophiles in both palladium and copper
catalyzed allylic substitution reactions.[15] Thus, the directing
group employed in this hydroarylation reaction is poised for
subsequent metal-catalyzed transformations. To highlight the
potential application of such a reaction in the preparation of
medicinal agents including selective estrogen receptor modula-
tors, we undertook synthesis of tamoxifen.[1] Sequential nickel-
catalyzed hydroarylation and allylic displacement with a cu-
Experimental Section
In a glove box, a flame dried 7 mL dram vial was charged with
Ni(cod)2 (5.5 mg, 0.020 mmol, 0.10 equiv.), TrixiePhos (8.0 mg,
prate reagent transforms alkyne 32 into trisubstituted alkene 0.020 mmol, 0.10 equiv.), arylboronic acid (0.50 mmol, 2.5 equiv.),
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
P. Forgione, Tetrahedron 2001, 57, 5899–5913; e) For a lead reference,
see: G. D. Kortman, K. L. Hull, ACS Catal. 2017, 7, 6620–6224.
[5] T. Hayashi, K. Inoue, N. Taniguchi, M. Ogasawara, J. Am. Chem. Soc. 2001,
123, 9918–9919.
[6] C. H. Oh, H. H. Jung, K. S. Kim, N. Kim, Angew. Chem. Int. Ed. 2003, 42,
805–808; Angew. Chem. 2003, 115, 829–832.
[7] a) M. Lautens, M. Yoshida, Org. Lett. 2002, 4, 123–125; b) M. Lautens, M.
Yoshida, J. Org. Chem. 2003, 68, 762–769; c) J. Panteleev, R. Y. Huang,
E. K. J. Lui, M. Lautens, Org. Lett. 2011, 13, 5314–5317; d) J. Panteleev, L.
Zhang, M. Lautens, Angew. Chem. Int. Ed. 2011, 50, 9089–9092; Angew.
Chem. 2011, 123, 9255–9258; e) L. Zhang, J. Panteleev, M. Lautens, J. Org.
Chem. 2014, 79, 12159–12176.
[8] Z. Liu, J. Derosa, K. M. Engle, J. Am. Chem. Soc. 2016, 138, 13076–13081.
[9] E. Shirakawa, F. Takahashi, T. Tsuchimoto, Y. Kawakami, Chem. Commun.
2001, 0, 2688–2689.
and the alkyne (0.20 mmol, 1.0 equiv.) and dissolved in THF
(4.0 mL). The reaction was then stirred for 24 h at 24 °C or 80 °C
depending on the substrate and arylboronic acid used. The reaction
mixture was then filtered through a pad of silica and eluted with
Et2O to remove the catalyst and then concentrated under reduced
pressure. The product was purified by flash column chromatogra-
phy.
Acknowledgments
This work was supported by National Science Foundation (NSF)
CHE-1464980 and DoEd GAANN (PA200A120070 to L. E. H.) We
thank Frontier Scientific for generous donations of boronic
acids. Dr. Joseph Ziller and Dr. John Greaves are acknowledged
for X-ray crystallographic and mass spectrometry data, respec-
tively, and Kevin Chen in the Nowick laboratory at UC Irvine for
assistance with HPLC separations.
[10] a) D. W. Robbins, J. F. Hartwig, Science 2011, 333, 1423–1427; b) C. Clark,
C. A. Incerti-Pradillos, H. W. Lam, J. Am. Chem. Soc. 2016, 138, 8068–8071;
c) X. Zhang, X. Xie, Y. Liu, Chem. Sci. 2016, 7, 5815–5820.
[11] M. H. Babu, G. R. Kumar, R. Kant, M. S. Reddy, Chem. Commun. 2017, 53,
3894–3897.
[12] a) M. R. Harris, L. E. Hanna, M. A. Greene, C. E. Moore, E. R. Jarvo, J. Am.
Chem. Soc. 2013, 135, 3303–3306; b) S.-Q. Zhang, B. L. H. Taylor, C.-L. Ji,
Y. Gao, M. R. Harris, L. E. Hanna, E. R. Jarvo, K. N. Houk, X. Hong, J. Am.
Chem. Soc. 2017, 139, 12994–13005.
Keywords: Directed · Hydroarylation · Nickel ·
Trisubstituted alkenes · Boronic acids
[13] See references from Scheme 2.
[1] a) C. Avendano, J. C. Menendez, Medicinal Chemistry of Anticancer Drugs,
Elsevier, Oxford, 2015, pp. 87–95; b) A. S. Levenson, V. C. Jordan, Eur. J.
Cancer 1999, 35, 1628; c) H. Wiseman, Tamoxifen: Molecular Basis of Use
in Cancer Treatment and Prevention, Wiley, Chichester, 1994; d) W. J. Mid-
dleton, D. Metzger, J. A. Snyder, J. Med. Chem. 1971, 14, 1193–1197.
[2] a) F. Orsini, G. Sello, in Studies in Natural Products Chemistry, Vol 34, Elsev-
ier, Oxford, 2008, pp. 77–127; b) C. M. Lin, H. H. Ho, G. R. Pettit, E. Hamel,
Biochemistry 1989, 28, 6984–6991.
[14] CCDC 1862425 (for 15) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre.
[15] a) Top Organomet. Chem: Transition Metal Catalyzed Enantioselective
Allylic Substiution Reactions (Ed.: U. Kazmaier), Springer-Verlag, Berlin Hei-
delberg, 2012; b) J. Tsuji, Palladium Reagents and Catalysts: Perspectives
for the 21st Century, Wiley-VCH, Weinheim, Germany, 2005.
[16] a) I. Shiina, Y. Sano, K. Nakata, M. Suzuki, T. Yokoyama, A. Sasaki, T. Ori-
kasa, T. Miyamoto, M. Ikekita, Y. Nagahara, Y. Hasome, Bioorg. Med. Chem.
2007, 15, 7599–7617; b) G. Danoun, A. Tlili, F. Monnier, M. Taillefer,
Angew. Chem. Int. Ed. 2012, 51, 12815–12819; Angew. Chem. 2012, 124,
12987–12991.
[3] For reviews, see: a) Y. Yamamoto, Chem. Soc. Rev. 2014, 43, 1575–1600;
b) K. Fagnou, M. Lautens, Chem. Rev. 2003, 103, 169–196.
[4] Alternative hydroarylation reaction strategies have been reported that
do not employ arylboronic acids as reagents. For reviews, see: a) Catalytic
Hydroarylation of Carbon-Carbon Multiple Bonds. (Eds.: L. Ackermann, T. B.
Gunnoe, L. G. Habgood) Wiley-VCH, Weinheim, Germany, 2018; b) ref.[3]
;
c) C. Nevado, A. M. Echavarren, Synthesis 2005, 2, 167–182; d) A. G. Fallis,
Received: October 1, 2018
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Nickel-Catalyzed Hydroarylation
L. E. Hanna, M. O. Konev,
E. R. Jarvo* ........................................... 1–5
Nickel-Catalyzed Directed Hydro-
arylation of Alkynes with Boronic
Acids
Stereoselective synthesis of trisubsti- are allylic carbamates that can un-
tuted alkenes using a nickel catalyst dergo further transformation, for ex-
under mild reaction conditions is re- ample, by copper-mediated allylic sub-
ported.
A
propargylic carbamate stitution
serves as a directing group. Products
DOI: 10.1002/ejoc.201801494
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim