Differential Dihydrofunctionalization of Terminal Alkynes: Synthesis of Benzylic Alkyl Boronates through Reductive Three-Component Coupling

Article abstract of DOI:10.1021/jacs.9b02372

The differential dihydrofunctionalization of terminal alkynes is accomplished through the reductive three-component coupling of terminal alkynes, aryl halides, and pinacolborane. The transformation results in hydrofunctionalization of both π-bonds of an alkyne in a single reaction promoted by cooperative action of a copper/palladium catalyst system. The differential dihydrofunctionalization reaction has excellent substrate scope and can be accomplished in the presence of esters, nitriles, alkyl halides, epoxides, acetals, alkenes, aryl halides, and silyl ethers. Mechanistic experiments indicate that the reaction proceeds through copper-catalyzed hydroboration followed by a second hydrocupration. The resulting heterobimetallic complex is the key intermediate that participates in the subsequent palladium-catalyzed cross-coupling, which furnishes benzylic alkyl boronate products.

Full text of DOI:10.1021/jacs.9b02372

Communication
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Differential Dihydrofunctionalization of Terminal Alkynes: Synthesis
of Benzylic Alkyl Boronates through Reductive Three-Component
Coupling
Megan K. Armstrong and Gojko Lalic*
Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
S
* Supporting Information
Scheme 1. Copper Hydride Chemistry in Differential
Functionalization of Alkyne π-Bonds
ABSTRACT: The differential dihydrofunctionalization of
terminal alkynes is accomplished through the reductive
three-component coupling of terminal alkynes, aryl
halides, and pinacolborane. The transformation results
in hydrofunctionalization of both π-bonds of an alkyne in
a single reaction promoted by cooperative action of a
copper/palladium catalyst system. The differential dihy-
drofunctionalization reaction has excellent substrate scope
and can be accomplished in the presence of esters, nitriles,
alkyl halides, epoxides, acetals, alkenes, aryl halides, and
silyl ethers. Mechanistic experiments indicate that the
reaction proceeds through copper-catalyzed hydrobora-
tion followed by a second hydrocupration. The resulting
heterobimetallic complex is the key intermediate that
participates in the subsequent palladium-catalyzed cross-
coupling, which furnishes benzylic alkyl boronate
products.
lkynes are extensively used in organic synthesis as readily
A
available and versatile intermediates. They participate in a
wide range of transformations, the most common of which are
C−H functionalization of terminal alkynes, addition to one of
the π bonds, and a double addition to both π bonds. Also
known, but significantly less common, are reactions that lead
to the differential transformation of the two π bonds. One of
the simplest and oldest1 reactions that mechanistically fits this
description is the hydration of alkynes, which involves initial
hydration followed by a tautomerization.2,3 This trans-
formation has been known for a long time and has inspired
development of differential transformations of alkyne π bonds
using other hydrofunctionalization reactions. However, these
transformations are still rare4 and generally rely on intra-
molecular reactions5 or reactions of alkynes activated by
electron-withdrawing groups.6
The methods developed by the Buchwald and Mankad
groups demonstrate the utility of copper hydride chemistry in
differential transformations of alkyne π bonds. They also
suggest a great potential for the development of reactions that
would combine copper-catalyzed hydrofunctionalization of one
π-bond with a different hydrofunctionalization of the other π-
bond (Scheme 1b). Such reactions would significantly increase
the complexity of the products that can be accessed directly
from alkynes and would enhance their utility as synthetic
intermediates.
In this paper, we describe a method for the differential
dihydrofunctionalization of terminal alkynes that formally
combines hydroboration with hydroarylation (Scheme 1b).
The overall reaction, promoted by synergistic Cu/Pd catalysis,
results in reductive coupling of terminal alkynes, aryl bromides,
Our interest in copper-catalyzed hydrofunctionalization
reactions7 led us to explore the application of copper hydride
chemistry8 in differential functionalization of the two alkyne π-
bonds. Successful applications developed so far have combined
copper-catalyzed hydrofunctionalization of one π-bond with
catalytic reduction of the other (Scheme 1a).9 In 2014,
Buchwald et al. reported the first example of such a reductive
hydrofunctionalization reaction, which combines reduction
and hydroamination.10 More recently, Mankad et al. reported
an interesting example of a hydroacylation reaction followed by
a reduction.11
Received: March 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b02372
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
and pinacolborane and the formation of benzylic alkyl
boronates.12
Table 1. Reaction Development
Inspiration for our approach to differential dihydrofunction-
alization came from a report by Sadighi et al. in 2006.13 The
authors describe the hydrocupration of alkenyl Bpin by
IPrCuH and formation of a heterobimetallic complex (eq 1).
While we7,14 and others15 have previously established that
(NHC)copper hydride complexes are excellent catalysts for
hydrofunctionalization of alkynes,8 this report demonstrated
that these same complexes also participate in the selective
hydrocupration of functionalized alkenes.16 Our plan was to
combine these two facets of the (NHC)CuH chemistry and
develop a differential dihydrofunctionalization of alkynes
(Scheme 2).
Scheme 2. Design of Differential Dihydrofunctionalization
a
All reactions performed on 0.05 mmol scale and monitored by GC
b
with 1,3,5-trimethoxybenzene as an internal standard. Concentration
of alkyne in the reaction mixture, IPr = 1,3-bis(2,6-diisopropyl-
phenyl)imidazol-2-ylidene, dba = dibenzylideneacetone, pin =
pinacolato.
Scheme 3. Preliminary Investigation of Differential
Dihydrofunctionalization
Preliminary investigation of the proposed differential
dihydrofunctionalization reaction began with 5-phenyl-1-
pentyne (1), 4-bromoanisole (2), and pinacolborane as
coupling partners, with IPrCuOt-Bu and a variety of palladium
catalysts. Initially, we observed numerous reactions promoted
by the Cu/Pd catalyst system. In addition to the desired
product (3), products of Miyaura borylation18 (4), hydro-
boration15b,19 (5), hydroarylation20 (6), and geminal dibora-
tion21 (7) of the alkyne were also observed (Scheme 3).
In addition to alkenyl boronate 5, compounds 622 and 712b
could, in principle, also serve as intermediates in the synthesis
of the desired product 3. However, careful monitoring of the
reaction mixture revealed that the formation of either the E-
styrene (6) or alkyl diboronate (7) generally corresponded
with a decreased yield of the desired product (3). On the other
hand, any alkenyl boronate (5) formed was consumed over the
course of the reaction, resulting in the corresponding increase
in yield of the desired product. As a result, we focused on
identifying reaction conditions that would minimize both
hydroarylation and diboration of the terminal alkyne.
We reasoned that the heterobimetallic intermediate IV could
be accessed directly from alkynes through copper-catalyzed
hydroboration and the subsequent hydrocupration of the
alkenyl boronate ester (III). This simple access to the
heterobimetallic intermediate provides an opportunity to
systematically explore a wide range of differential dihydro-
functionalization reactions of alkynes through further function-
alization of this key intermediate. We chose to pursue
palladium-catalyzed cross-coupling of the heterobimetallic
intermediate (IV) with aryl bromides (II), inspired by
known catalytic arylations of related copper(I) alkyl
intermediates.17
Initially, we found that the identity of the palladium catalyst
and the alkoxide additive had the greatest effect on the product
B
DOI: 10.1021/jacs.9b02372
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 2. Scope of Differential Dihydrofunctionalization of Alkynes
a
b
c
d
Reactions performed on 0.5 mmol scale. IPrCuCl instead of IPrCuOt-Bu and NaOt-Bu instead of KOt-Bu. Toluene/isooctane (1:1) used. GC
e
yield, with 1,3,5-trimethoxybenzene as internal standard. KOTMS used instead of KOt-Bu and toluene/THF (1:1) was used. Ar1 = 4-
OMe(C6H4), Ar2 = 4-CF3(C6H4).
distribution. Extensive reaction development focused on these
two parameters led to an efficient differential dihydrofunction-
alization of terminal alkynes shown in Table 1 (entry 1).
During the reaction development, we made several
observations summarized in Table 1. Considering that
Pd2dba3 is rarely used in combination with dialkylbiaryl
phosphine ligands, we were surprised that it was a significantly
better precatalyst than other common palladium sources. For
example, Pd(OAc)2 provided the product in only 54% yield at
the full conversion (Table 1 entry 2) (see Supporting
Information (SI) for further details). IPrCuOt-Bu performed
better than IPrCuCl as a catalyst precursor (entry 3). The
catalyst loading of both palladium and copper proved crucial. A
lower loading of IPrCuOt-Bu resulted in a decreased yield with
full consumption of aryl halide (entry 4). A higher loading of
23
C
DOI: 10.1021/jacs.9b02372
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
the palladium catalyst increased the formation of E-styrene (6)
and lowered the product yield (entry 5).
The reaction outcome was also greatly influenced by the
choice of phosphine ligand. XPhos24 provided significantly
higher selectivity for the desired product than closely related
BrettPhos25 (entry 6) and other dialkylbiaryl ligands (see SI
for details). Bisphosphine ligands, such as (R)-DTBM-
SEGPHOS, formed the product of diboration (7) almost
exclusively (entry 7). The choice of the alkoxide additive also
proved important. KOt-Bu was superior to both NaOt-Bu and
LiOt-Bu (entries 8 and 9), increasing conversion of alkenyl
Bpin (5) to product, while suppressing formation of E-styrene
(6).
High yields of the differentially dihydrofunctionalized
product were obtained in aromatic hydrocarbon solvents
such as toluene and benzene (entries 1 and 10), with lower
yields in isooctane (entry 11) and minimal reactivity in
ethereal solvents (entries 12 and 13) (see SI for details).
Lastly, we observed that the concentration of the reaction
mixture had a significant effect on yield. Doubling the
concentration of the reaction mixture (entry 14) decreased
the yield.26
alkenyl Bpin (5), (b) E-styrene (6), or (c) alkyl diboronate
(7).
We explored the reactivity of each presumed intermediate
under the standard conditions for differential dihydrofunction-
alization (Scheme 4). When alkenyl Bpin (5) was the
a
Scheme 4. Mechanistic Experiments
Having established the conditions for the differential
dihydrofunctionalization of terminal alkynes (Table 1, entry
1), we explored the scope of the reaction (Table 2). A broad
range of aryl bromides serve as coupling partners. Both
electron-rich (3 and 11) and electron-poor (8 and 12) aryl
bromides were viable coupling partners. A variety of functional
groups were tolerated, and the reaction could be performed in
the presence of aryl fluorides (9), aryl chlorides (10), and
acetals (13 and 24). Styrenes (18) were also compatible with
the reaction. Products derived from para- (14), meta- (15),
and ortho- (16) substituted aryl bromides were isolated in
good yields. Notably, a variety of O-, N-, and S-containing
heterocycles were compatible with this reaction (19−23).
We also explored the scope of the alkyne coupling partner.
Alkynes containing nitriles (25), epoxides (27), chlorides (29),
bromides (30), acetals (35), and esters (36) were compatible
with the reaction conditions. Protected alcohols (28, 31, and
32) and functionalized phenyl ethers (26, 40, and 41) were
competent coupling partners in the reaction. Propargylic
substitution of the alkyne also provided products in good
yields (32−34). Finally, electron-rich (38) and electron-
deficient (39) aryl acetylenes can be utilized in this reaction.
We also noted several limitations of the reaction. The
reaction is not compatible with aldehydes, ketones, activated
alkenes (such as enones), free alcohols, or tertiary alkyl amines.
Furthermore, reactions with several aryl chlorides provided no
desired products, suggesting that aryl chlorides are not viable
substrates. Finally, internal alkynes, including differentially
substituted aryl alkyl alkynes, provided no desired product in
the reaction.
a
Reactions performed on 0.05 mmol scale and monitored by GC
b
analysis using 1,3,5-trimethoxybenzene as an internal standard. No
further change even after 24 h; remaining material is unreacted
starting material. No further change even after 24 h; remaining
material is 50% unreacted starting material and 45% alkenyl Bpin 5. R
c
= Ph(CH2)3, Ar = 4-OMe(C6H4).
Considering our preliminary observations and the known
reactivity of both palladium-catalyzed cross-coupling27 and
copper-catalyzed hydrofunctionalization reactions,8 we envi-
sioned three possible pathways for differential dihydrofunc-
tionalization of terminal alkynes (eq 2): (a) copper-catalyzed
hydroboration followed by hydrocupration and electrophilic
functionalization, (b) hydroarylation followed by hydrobora-
tion, or (c) diboration to generate the alkyl diboronate,
followed by monoselective cross-coupling with the aryl halide.
Each pathway proceeds through a unique intermediate: (a)
substrate, the desired product (3) was formed in 43% yield
after 6 h (Scheme 4a), whereas neither E-styrene (6) nor alkyl
diboronate (7) formed the desired product in appreciable
yields even after 24 h (Scheme 4b and c). In both cases,
products of other side reactions were observed and/or starting
material was recovered. These results strongly suggest that the
operative pathway involves hydroboration of the alkyne (2).
We also wanted to verify that the heterobimetallic complex
(IV) could be formed directly from terminal alkynes and is the
key catalytic intermediate in the reaction. The stoichiometric
D
DOI: 10.1021/jacs.9b02372
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
reaction between terminal alkyne, IPrCuOt-Bu, and HBpin
resulted in the formation of hetermobimetallic complex 42, in
excellent yield (Scheme 4d). Additionally, the stoichiometric
cross-coupling between 42 and aryl bromide (2) yielded the
desired benzylalkylboronate in 98% yield (Scheme 4e).
Altogether, these results support our proposed pathway.
Considering the results of these experiments, we propose the
mechanism outlined in Scheme 5. Initial transmetalation
heterobimetallic intermediate provides an exciting opportunity
for a systematic development of other differential dihydro-
functionalization reactions.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b02372.
Experimental procedure and product characterization
(PDF)
Scheme 5. Proposed Catalytic Cycle
AUTHOR INFORMATION
Corresponding Author
*lalic@chem.washington.edu
■
ORCID
Gojko Lalic: 0000-0003-3615-3423
Funding
NIH (1R01GM125791-01A1) is acknowledged.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Prof. Forrest Michael for assistance in preparation of
this manuscript. We also thank the NIH for financial support.
■
REFERENCES
(1) Neumann, B.; Schneider, H. Die Uberfu
Acetaldehyd Und Essigsaure. Angew. Chem. 1920, 33, 189.
■
̈
̈
hrung Von Acetylen in
̈
(2) (a) Halpern, J.; James, B. R.; Kemp, A. L. W. Catalysis of the
Hydration of Acetylenic Compounds by Ruthenium(III) Chloride. J.
Am. Chem. Soc. 1961, 83, 4097. (b) Halpern, J.; James, B. R.; Kemp,
A. L. W. Formation and Properties of Some Chlorocarbonyl
Complexes of Ruthenium(II) and Ruthenium(III). J. Am. Chem.
Soc. 1966, 88, 5142. (c) Blum, J.; Huminer, H.; Alper, H. Alkyne
Hydration Promoted by RhCl3 and Quaternary Ammonium Salts. J.
Mol. Catal. 1992, 75, 153. (d) Hiscox, W.; Jennings, P. W. Catalytic
Hydration of Alkynes with Zeise’s Dimer. Organometallics 1990, 9,
1997. (e) Baidossi, W.; Lahav, M.; Blum, J. Hydration of Alkynes by a
PtCl4−Co Catalyst. J. Org. Chem. 1997, 62, 669.
(3) For examples of anti-Markovnikov hydration of alkynes, see:
(a) Tokunaga, M.; Wakatsuki, Y. The First Anti-Markovnikov
Hydration of Terminal Alkynes: Formation of Aldehydes Catalyzed
by a Ruthenium(II)/Phosphane Mixture. Angew. Chem., Int. Ed. 1998,
37, 2867. (b) Grotjahn, D. B.; Lev, D. A. A General Bifunctional
Catalyst for the Anti-Markovnikov Hydration of Terminal Alkynes to
Aldehydes Gives Enzyme-Like Rate and Selectivity Enhancements. J.
Am. Chem. Soc. 2004, 126, 12232.
between IPrCuOt-Bu and HBpin generates IPrCuH, and
hydrocupration of the terminal alkyne (I) results in alkenyl
copper (VI). Additional transmetalation between a second
equivalent of HBpin and VI delivers alkenyl Bpin (III) and
regenerates IPrCuH. Reinsertion of III into IPrCuH furnishes
heterobimetallic complex (IV).
The heterobimetallic complex (IV) participates in a standard
palladium-catalyzed cross-coupling with the aryl bromide to
produce the differentially dihydrofunctionalized product V and
Pd(0). The IPrCuOt-Bu catalyst is regenerated in the presence
of KOt-Bu.
In conclusion, we have developed a method for the
differential dihydrofunctionalization of alkynes that results in
the reductive three-component coupling of terminal alkynes,
aryl bromides, and pinacolborane. The benzylic alkyl boronate
products are accessed directly from terminal alkynes by
accomplishing two different regioselective hydrofunctionaliza-
tion reactions promoted by a Cu/Pd catalyst system.
The reaction has excellent substrate scope and functional
group compatibility, providing the desired products in high
yields. The results of mechanistic experiments indicate that the
reaction proceeds through copper-catalyzed hydroboration,
followed by a second hydrocupration of the alkenyl boronate,
and palladium-catalyzed arylation of the resulting hetero-
bimetallic intermediate. The most important finding of our
studies is that the heterobimetallic intermediate can be readily
accessed directly from the terminal alkyne in the presence of a
copper catalyst and HBpin. We believe that the access to this
(4) Zeng, X. Recent Advances in Catalytic Sequential Reactions
Involving Hydroelement Addition to Carbon−Carbon Multiple
Bonds. Chem. Rev. 2013, 113, 6864.
(5) (a) Utimoto, K. Palladium Catalyzed Synthesis of Heterocycles.
Pure Appl. Chem. 1983, 55, 1845. (b) Messerle, B. A.; Vuong, K. Q.
Rhodium- and Iridium-Catalyzed Double Hydroalkoxylation of
Alkynes, an Efficient Method for the Synthesis of O,O-Acetals:
Catalytic and Mechanistic Studies. Organometallics 2007, 26, 3031.
(c) Belting, V.; Krause, N. Gold-Catalyzed Tandem Cycloisomeriza-
tion−Hydroalkoxylation of Homopropargylic Alcohols. Org. Lett.
́
́
2006, 8, 4489. (d) Barluenga, J.; Fernandez, A.; Satrustegui, A.;
́
́
Dieguez, A.; Rodríguez, F.; Fananas, F. J. Tandem Intramolecular
̃
Hydroalkoxylation−Hydroarylation Reactions: Synthesis of Enantio-
pure Benzofused Cyclic Ethers from the Chiral Pool. Chem. - Eur. J.
́
́
2008, 14, 4153. (e) Barluenga, J.; Fernandez, A.; Dieguez, A.;
́
̃
Rodríguez, F.; Fananas, F. J. Gold- or Platinum-Catalyzed Cascade
Processes of Alkynol Derivatives Involving Hydroalkoxylation
Reactions Followed by Prins-Type Cyclizations. Chem. - Eur. J.
E
DOI: 10.1021/jacs.9b02372
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
2009, 15, 11660. (f) Bhuvaneswari, S.; Jeganmohan, M.; Cheng, C.-H.
Platinum-Catalyzed Multistep Reactions of Indoles with Alkynyl
Alcohols. Chem. - Eur. J. 2007, 13, 8285. (g) Patil, N. T.; Raut, V. S.;
Kavthe, R. D.; Reddy, V. V. N.; Raju, P. V. K. Thorpe−Ingold Effect
in Copper(II)-Catalyzed Formal Hydroalkoxylation−Hydroarylation
Reaction of Alkynols with Indoles. Tetrahedron Lett. 2009, 50, 6576.
(h) Shibuya, M.; Fujita, S.; Abe, M.; Yamamoto, Y. Brønsted Acid/
Silane Catalytic System for Intramolecular Hydroalkoxylation and
Hydroamination of Unactivated Alkynes. ACS Catal. 2017, 7, 2848.
(i) Shibuya, M.; Okamoto, M.; Fujita, S.; Abe, M.; Yamamoto, Y.
Boron-Catalyzed Double Hydrofunctionalization Reactions of Un-
activated Alkynes. ACS Catal. 2018, 8, 4189. (j) Li, X.; Chianese, A.
R.; Vogel, T.; Crabtree, R. H. Intramolecular Alkyne Hydro-
alkoxylation and Hydroamination Catalyzed by Iridium Hydrides.
Org. Lett. 2005, 7, 5437. (k) Yang, T.; Campbell, L.; Dixon, D. J. A
Au(I)-Catalyzed N-Acyl Iminium Ion Cyclization Cascade. J. Am.
Chem. Soc. 2007, 129, 12070.
(6) (a) Sriramurthy, V.; Barcan, G. A.; Kwon, O. Bisphosphine-
Catalyzed Mixed Double-Michael Reactions: Asymmetric Synthesis of
Oxazolidines, Thiazolidines, and Pyrrolidines. J. Am. Chem. Soc. 2007,
129, 12928. (b) Sriramurthy, V.; Kwon, O. Diphosphine-Catalyzed
Mixed Double-Michael Reaction: A Unified Synthesis of Indolines,
Dihydropyrrolopyridines, Benzimidazolines, Tetrahydroquinolines,
Tetrahydroisoquinolines, Dihydrobenzo-1,4-Oxazines, and Dihydro-
benzo-3,1-Oxazines. Org. Lett. 2010, 12, 1084.
Enantioselective 1,1-Arylborylation of Alkenes: Merging Chiral Anion
Phase Transfer with Pd Catalysis. J. Am. Chem. Soc. 2015, 137, 3213.
(c) Sun, C.; Potter, B.; Morken, J. P. A Catalytic Enantiotopic-Group-
Selective Suzuki Reaction for the Construction of Chiral Organo-
boronates. J. Am. Chem. Soc. 2014, 136, 6534. (d) Feng, X.; Jeon, H.;
Yun, J. Regio- and Enantioselective Copper(I)-Catalyzed Hydro-
boration of Borylalkenes: Asymmetric Synthesis of 1,1-Diborylal-
kanes. Angew. Chem., Int. Ed. 2013, 52, 3989. (e) Lee, J. C. H.;
McDonald, R.; Hall, D. G. Enantioselective Preparation and
Chemoselective Cross-Coupling of 1,1-Diboron Compounds. Nat.
Chem. 2011, 3, 894.
(13) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. Copper(I) β-Boroalkyls
from Alkene Insertion: Isolation and Rearrangement. Organometallics
2006, 25, 2405.
(14) Suess, A. M.; Lalic, G. Copper-Catalyzed Hydrofunctionaliza-
tion of Alkynes. Synlett 2016, 27, 1165.
(15) (a) Fujihara, T.; Xu, T.; Semba, K.; Terao, J.; Tsuji, Y. Copper-
Catalyzed Hydrocarboxylation of Alkynes Using Carbon Dioxide and
Hydrosilanes. Angew. Chem., Int. Ed. 2011, 50, 523. (b) Semba, K.;
Fujihara, T.; Terao, J.; Tsuji, Y. Copper-Catalyzed Highly Regio- and
Stereoselective Directed Hydroboration of Unsymmetrical Internal
Alkynes: Controlling Regioselectivity by Choice of Catalytic Species.
Chem. - Eur. J. 2012, 18, 4179.
(16) Jang, W. J.; Han, J. T.; Yun, J. NHC-Copper-Catalyzed Tandem
Hydrocupration and Allylation of Alkenyl Boronates. Synthesis 2017,
49, 4753.
(17) (a) Friis, S. D.; Pirnot, M. T.; Dupuis, L. N.; Buchwald, S. L. A
Dual Palladium and Copper Hydride Catalyzed Approach for Alkyl−
Aryl Cross-Coupling of Aryl Halides and Olefins. Angew. Chem., Int.
Ed. 2017, 56, 7242. (b) Logan, K. M.; Brown, M. K. Catalytic
Enantioselective Arylboration of Alkenylarenes. Angew. Chem., Int. Ed.
2017, 56, 851. (c) Bergmann, A. M.; Dorn, S. K.; Smith, K. B.; Logan,
K. M.; Brown, M. K. Catalyst-Controlled 1,2- and 1,1-Arylboration of
α-Alkyl Alkenyl Arenes. Angew. Chem., Int. Ed. 2019, 58, 1719.
(d) Semba, K.; Ariyama, K.; Zheng, H.; Kameyama, R.; Sakaki, S.;
Nakao, Y. Reductive Cross-Coupling of Conjugated Arylalkenes and
Aryl Bromides with Hydrosilanes by Cooperative Palladium/Copper
Catalysis. Angew. Chem., Int. Ed. 2016, 55, 6275. (e) Semba, K.;
Nakao, Y. Arylboration of Alkenes by Cooperative Palladium/Copper
Catalysis. J. Am. Chem. Soc. 2014, 136, 7567.
(18) (a) Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-
Catalyzed Cross-Coupling Reaction of Alkoxydiboron with Haloar-
enes: A Direct Procedure for Arylboronic Esters. J. Org. Chem. 1995,
60, 7508. (b) Billingsley, K. L.; Buchwald, S. L. An Improved System
for the Palladium-Catalyzed Borylation of Aryl Halides with Pinacol
Borane. J. Org. Chem. 2008, 73, 5589.
(7) (a) Uehling, M. R.; Suess, A. M.; Lalic, G. Copper-Catalyzed
Hydroalkylation of Terminal Alkynes. J. Am. Chem. Soc. 2015, 137,
1424. (b) Uehling, M. R.; Rucker, R. P.; Lalic, G. Catalytic Anti-
Markovnikov Hydrobromination of Alkynes. J. Am. Chem. Soc. 2014,
136, 8799. (c) Mailig, M.; Hazra, A.; Armstrong, M. K.; Lalic, G.
Catalytic Anti-Markovnikov Hydroallylation of Terminal and
Functionalized Internal Alkynes: Synthesis of Skipped Dienes and
Trisubstituted Alkenes. J. Am. Chem. Soc. 2017, 139, 6969.
(8) Jordan, A. J.; Lalic, G.; Sadighi, J. P. Coinage Metal Hydrides:
Synthesis, Characterization, and Reactivity. Chem. Rev. 2016, 116,
8318.
(9) For selected examples of reductive hydrofunctionalizations of
alkynes using other catalyst systems, see: (a) Li, L.; Herzon, S. B.
Regioselective Reductive Hydration of Alkynes to Form Branched or
Linear Alcohols. J. Am. Chem. Soc. 2012, 134, 17376. (b) Li, L.;
Herzon, S. B. Temporal Separation of Catalytic Activities Allows Anti-
Markovnikov Reductive Functionalization of Terminal Alkynes. Nat.
Chem. 2014, 6, 22. (c) Zeng, M.; Herzon, S. B. Synthesis of 1,3-
Amino Alcohols, 1,3-Diols, Amines, and Carboxylic Acids from
Terminal Alkynes. J. Org. Chem. 2015, 80, 8604. (d) Nayal, O. S.;
Thakur, M. S.; Kumar, M.; Sharma, S.; Kumar, N. Tin-Catalyzed
Selective Reductive Hydroamination of Alkynes for the Synthesis of
Tertiary Amines. Adv. Synth. Catal. 2016, 358, 1103. (e) Tsuchimoto,
T.; Wagatsuma, T.; Aoki, K.; Shimotori, J. Indium-Catalyzed
Reductive Alkylation of Pyrroles with Alkynes and Hydrosilanes:
Selective Synthesis of β-Alkylpyrroles. Org. Lett. 2009, 11, 2129.
(f) Tsuchimoto, T.; Kanbara, M. Reductive Alkylation of Indoles with
Alkynes and Hydrosilanes under Indium Catalysis. Org. Lett. 2011, 13,
912. (g) Zeng, M.; Li, L.; Herzon, S. B. A Highly Active and Air-
Stable Ruthenium Complex for the Ambient Temperature Anti-
Markovnikov Reductive Hydration of Terminal Alkynes. J. Am. Chem.
Soc. 2014, 136, 7058. (h) Heutling, A.; Pohlki, F.; Bytschkov, I.;
Doye, S. Hydroamination/Hydrosilylation Sequence Catalyzed by
Titanium Complexes. Angew. Chem., Int. Ed. 2005, 44, 2951.
(10) Shi, S.-L.; Buchwald, S. L. Copper-Catalysed Selective
Hydroamination Reactions of Alkynes. Nat. Chem. 2015, 7, 38.
(11) Cheng, L.-J.; Mankad, N. P. Cu-Catalyzed Hydrocarbonylative
C−C Coupling of Terminal Alkynes with Alkyl Iodides. J. Am. Chem.
Soc. 2017, 139, 10200.
(19) (a) Jang, W. J.; Lee, W. L.; Moon, J. H.; Lee, J. Y.; Yun, J.
Copper-Catalyzed Trans-Hydroboration of Terminal Aryl Alkynes:
Stereodivergent Synthesis of Alkenylboron Compounds. Org. Lett.
2016, 18, 1390. (b) Bai, T.; Yang, Y.; Han, C. Isolation and
Characterization of Hydrocarbon Soluble NHC Copper((I) Phos-
phoranimide Complex and Catalytic Application for Alkyne Hydro-
boration Reaction. Tetrahedron Lett. 2017, 58, 1523. (c) Hall, J. W.;
Unson, D. M. L.; Brunel, P.; Collins, L. R.; Cybulski, M. K.; Mahon,
M. F.; Whittlesey, M. K. Copper-NHC-Mediated Semihydrogenation
and Hydroboration of Alkynes: Enhanced Catalytic Activity Using
Ring-Expanded Carbenes. Organometallics 2018, 37, 3102. (d) Lip-
̌
̌
́
shutz, B. H.; Boskovic, Z. V.; Aue, D. H. Synthesis of Activated
Alkenylboronates from Acetylenic Esters by CuH-Catalyzed 1,2-
Addition/Transmetalation. Angew. Chem., Int. Ed. 2008, 47, 10183.
(20) Armstrong, M. K.; Goodstein, M. B.; Lalic, G. Diastereodi-
vergent Reductive Cross Coupling of Alkynes through Tandem
Catalysis: Z- and E-Selective Hydroarylation of Terminal Alkynes. J.
Am. Chem. Soc. 2018, 140, 10233.
(12) For a review describing the utility of these compounds, see:
(a) Rygus, J. P. G.; Crudden, C. M. Enantiospecific and Iterative
Suzuki−Miyaura Cross-Couplings. J. Am. Chem. Soc. 2017, 139,
18124. For selected examples of synthesis of benzylic alkyl boronates,
(21) Lee, S.; Li, D.; Yun, J. Copper-Catalyzed Synthesis of 1,1-
Diborylalkanes through Regioselective Dihydroboration of Terminal
Alkynes. Chem. - Asian J. 2014, 9, 2440.
́
see: (b) Nelson, H. M.; Williams, B. D.; Miro, J.; Toste, F. D.
F
DOI: 10.1021/jacs.9b02372
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(22) Noh, D.; Chea, H.; Ju, J.; Yun, J. Highly Regio- and
Enantioselective Copper-Catalyzed Hydroboration of Styrenes.
Angew. Chem., Int. Ed. 2009, 48, 6062.
(23) (a) Amatore, C.; Jutand, A.; Meyer, G.; Atmani, H.; Khalil, F.;
Chahdi, F. O. Comparative Reactivity of Palladium(0) Complexes
Generated in Situ in Mixtures of Triphenylphosphine or Tri-2-
Furylphosphine and Pd(dba)2. Organometallics 1998, 17, 2958.
(b) Zalesskiy, S. S.; Ananikov, V. P. Pd2(dba)3 as a Precursor of
Soluble Metal Complexes and Nanoparticles: Determination of
Palladium Active Species for Catalysis and Synthesis. Organometallics
2012, 31, 2302.
(24) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. Expanding Pd-Catalyzed C−N Bond-Forming
Processes: The First Amidation of Aryl Sulfonates, Aqueous
Amination, and Complementarity with Cu-Catalyzed Reactions. J.
Am. Chem. Soc. 2003, 125, 6653.
(25) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. A
Highly Active Catalyst for Pd-Catalyzed Amination Reactions: Cross-
Coupling Reactions Using Aryl Mesylates and the Highly Selective
Monoarylation of Primary Amines Using Aryl Chlorides. J. Am. Chem.
Soc. 2008, 130, 13552.
(26) Optimal concentration of various components in the reaction
mixture was achieved when the alkyne concetration was 0.05 M. A
further decrease in concentration of reaction components (0.01 M in
alkyne) was found to lower the yield of the desired product, with full
conversion of starting materials being achieved only after 72 h.
(27) (a) Biffis, A.; Centomo, P.; Del Zotto, A.; Zecca, M. Pd Metal
Catalysts for Cross-Couplings and Related Reactions in the 21st
Century: A Critical Review. Chem. Rev. 2018, 118, 2249.
(b) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Palladium-Catalyzed Cross-Coupling: A Historical
Contextual Perspective to the 2010 Nobel Prize. Angew. Chem., Int.
Ed. 2012, 51, 5062.
G
DOI: 10.1021/jacs.9b02372
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX