Copper-catalyzed dehydrogenative borylation of terminal alkynes with pinacolborane

Article abstract of DOI:10.1039/c6sc02668k

LCuOTf complexes [L = cyclic (alkyl)(amino)carbenes (CAACs) or N-heterocyclic carbenes (NHCs)] selectively promote the dehydrogenative borylation of C(sp)-H bonds at room temperature. It is shown that σ,π-bis(copper) acetylide and copper hydride complexes are the key catalytic species.

Full text of DOI:10.1039/c6sc02668k

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DOI: 10.1039/C6SC02668K
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Copper-Catalyzed Dehydrogenative Borylation of Terminal
Alkynes with Pinacolborane
Received 00th January 20xx,
Accepted 00th January 20xx
Erik A. Romero, Rodolphe Jazzar, Guy Bertrand*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Scheme 1. Hypothetical mechanism for the LCuOTf induced dehydrogenative
LCuOTf complexes [L = cyclic (alkyl)(amino)carbenes (CAACs) or N-
heterocyclic carbenes (NHCs)] selectively promote the
dehydrogenative borylation of C(sp)-H bonds at room
temperature. It is shown that σ,π-bis(copper) acetylide and copper
hydride complexes are the key catalytic species.
borylation of terminal alkynes.
L =
Dipp
Et
Et
Et3N
N
L
Cu
OTf
R
H
Popularized by the Suzuki-Miyaura reaction, organoboronic
esters and acids are now regarded as key building blocks for
compounds with applications ranging from material to life
sciences. Consequently, numerous methodologies have been
developed to access these valuable substrates.1 Following
ground-breaking reports by Hartwig et al.,2 and Smith et al.,3
the catalytic dehydrogenative borylation of C(sp3)-H bonds and
C(sp2)-H bonds are now well documented.4 In contrast, for
C(sp)-H bonds there are only a few reports by Ozerov et al.5
using iridium and palladium complexes supported by pincer
ligands, and one by Tsuchimoto et al.6 with zinc triflate, which
is only effective with 1,8-naphthalenediaminatoborane as the
boron partner. One of the difficulties of the dehydrogenative
borylation of terminal alkynes is the competing hydroboration
of the triple bond, which affords alkenyl boronic esters.7
H-H
Et3NH.OTf
L
L
TfO
Cu
H
C
Cu
+
LCuOTf
L Cu
R
A
R
B
H
B
L
Cu
O
O
TfO
O
O
L Cu
H
R
B
O
B
TS
O
dinuclear complexes A, the triple bond is protected which
should prevent the classical hydroboration reaction leading to
alkenyl boronic esters. Instead, the highly polarized copper-
carbon bond could undergo a σ-bond metathesis with
pinacolborane (TS) to afford the desired alkynyl boronic ester
B, as well as the copper hydride C. The latter should react with
triethylammonium triflate to regenerate LCuOTf and
triethylamine with elimination of dihydrogen.
We first checked that in the absence of catalyst no reaction
occurred between p-tolylacetylene 1a and pinacolborane in
C6D6 at room temperature for 2 hours (Table 1, Entry 1). In the
presence of 1 mol% of L1CuOTf, no significant reaction
occurred either because of the difficulty of the triflate to
deprotonate the alkyne8 (Entry 2). In order to promote the
deprotonation of the alkyne, 1 mol% of Et3N was added which
resulted in immediate hydrogen evolution (as characterized by
We recently reported8 on the role of the X ligand in the
mechanism of the LCuX catalyzed azide-alkyne cycloaddition
(CuAAC reaction) [L = cyclic (alkyl)(amino)carbene].9,10 Herein
we show that these results allow for the rational design of
copper catalysts that selectively promote the dehydrogenative
borylation of terminal alkynes with pinacolborane.
In the above mentioned study, we found that in the presence
of triethylamine, LCuOTf reacts with terminal alkynes to give
the catalytically active σ,π-bis(copper) acetylides A,8,11 along
with ammonium triflate (Scheme 1). We hypothesized that in
1
a singlet at 4.47 ppm in H NMR). The major product was the
alkynyl boronic ester B1 (48 %), but the alkenyl boronic ester
D1 (11 %), and the styrene derivative E1 (7 %) were also formed
(Entry 3).
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Scheme 2. Scope of the dehydrogenative borylation of terminal alkynes.
Table 1. Optimization of the dehydrogenative borylation reaction[a]
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DOI: 10.1039/C6SC02668K
R
H
L1CuOTf (2.5 mol%)
BPin
Tol
H
Tol
BPin
R
BPin
Et
+
N
Et3N (5 mol%),
L1
Dipp
Et
cat.
1a
PinB-H
B
B1
D1
+
Tol
Benzene (0.1 M), 2-12 h, RT
iPr
Base, Solvent
RT, 2 h
O
N
N
L2
L3
Dipp
Dipp
B-H
Tol
BPin
BPin
BPin
E1
O
N
Dipp
Dipp: 2,6-Diisopropylphenyl
B1 99%a
B2 98%a
B3 99%a
gram scale : 3.95 g (95%)
Entry
Cat.
(mol%)
Base Solvent Conc.
1a
B1
D1
E1
(mol%)
(M)
(%)b (%)b (%)b (%)b
OMe
BPin
BPin
BPin
BPin
1
2
-
-
C6D6
C6D6
C6D6
C6D6
C6D6
1.4
100
86
14
100
1
0
0
0
L1CuOTf (1)
-
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
0.1
0.1
0.1
0
6
6
3
L1CuOTf (1) Et3N (1)
CuOTf Et3N (1)
L1CuOTf (1) Et3N (2)
48
0
11
0
7
NC
F
B4 88%a
B5 85%a
B6 85%a
4
0
BPin
5
70
42
64
38
5
14
6
12
26
17
6
BPin
BPin
BPin
6
L1CuOTf (1) Et3N (2) CD2Cl2
L1CuOTf (1) Et3N (2) THF-d8
L1CuOTf (1) Et3N (2) CD3CN
L1CuOTf (1) iPrNH2 (2) C6D6
L1CuOTf (1) iPr2NH (2) C6D6
L1CuOTf (1) iPr2NEt (2) C6D6
L1CuOTf (1) BnNEt2 (2) C6D6
L1CuOTf (1) DABCO (2) C6D6
12
5
Cl
7
12
0
B7 82%a
B8 81%a
B9 85%a
8
18
67
47
10
14
18
37
20
4
BPin
9
12
13
45
8
10
7
TMS
B11 99%b
BPin
Cl
O
Me3Si
10
11
12
13
11
28
53
60
36
54
83
98
96
92
B10 89%a
B12 99%b
3
BPin
O
BPin
7
MeO
1
7
B13 99%b
B14 96%b
B15 95%b
[a] reaction time 2 h. [b] reaction time 12 h.
14 L1CuOTf (0.25) Et3N (0.5) C6D6
15
15
4
6
15
16
17
18
19
L1CuOTf (0.5) Et3N (1)
L1CuOTf (2.5) Et3N (5)
C6D6
C6D6
9
terminal alkynes bearing functionalities such as OMe, CN, F, Cl,
TMS and CO2Me. It is worth noting that electron-rich terminal
alkynes require longer reaction times (12 h instead of 2 h) (B11-
15). Alkynyl boronic esters B1-15 were isolated in good to
excellent yields by filtration through a short plug of dry neutral
alumina using pentane as the eluent. This straightforward
protocol allows for gram-scale synthesis, as shown with B3.
With these results in hand, we performed a set of experiments
in order to verify our mechanistic hypothesis. When the 2.5
mol% mononuclear complex F was used, with or without Et3N,
no traces of the dehydrogenative borylation product B1 were
observed, instead the hydroboration product D1 was
quantitatively formed (Fig. 1, Scheme 3) (See also the kinetic
profile in the Supplementary Information). In marked contrast,
when 2.5 mol% Et3NH.OTf was added as a proton source, we
observed the rapid formation of B1, and the kinetic profile was
comparable with those obtained using our standard catalytic
conditions (LCuOTf/Et3N) or the bis(copper) acetylide A. Since
we already proved that LCuOTf/Et3N reacts with terminal
alkynes to afford the dinuclear species A,8 we verified that
similarly complex F reacts with Et3NH.OTf to give A. These
experiments as a whole strongly suggest that the dinuclear
complex A is pivotal in the dehydrogenative process.
7
L1CuOTf (2.5) Et3N (5) C6D6
1
0
1
L2CuOTf (2.5) Et3N (5)
L3CuOTf (2.5) Et3N (5)
C6D6
C6D6
0
0
4
0
0
8
[a] Reactions were carried out in a test tube for 2 h at RT under an argon
atmosphere using 1:1 mixture (0.69 mmol) of p-tolylacetylene and
pinacolborane. [b] Measured by NMR using 1,4-dioxane as an internal standard.
a
Note that no reaction occurred under ligand-free conditions
(Entry 4). Encouraged by these preliminary results, we further
optimized the dehydrogenative borylation leading to B1. We
found that a two-fold excess of Et3N with respect to
(CAAC)CuOTf was beneficial (Entry 5). By screening solvents
(Entries 5-8) and base additives (Entries 9-13), we identified
benzene and Et3N as most appropriate for the reaction. When
we increased the catalyst loading to 2.5 mol% (Entries 14-16),
and decreased the concentration of the solution from 1.4 to
0.1 mol/L (Entry 17) there was quantitative formation of the
desired alkynyl boronic ester B1 with excellent selectivity
within two hours at room temperature. Notably, substitution
of ligand L1 for the more bulky menthyl CAAC L2 or even IPr-
NHC12 L3 gave comparable results.
The other important species in our postulated mechanism is
the copper hydride C, a type of complex that has been
proposed to play a major role in a number of catalytic
The scope of the dehydrogenative borylation reaction was
then studied at room temperature in a benzene solution (0.1
M) using a stoichiometric mixture of alkyne and borane (1.82
mmol), 5 mol% of Et3N and 2.5 mol% L1CuOTf (Scheme 2). This
methodology is readily applicable to a broad range of
transformations.13 While there is still no report of
a
monomeric mono-ligated Cu hydride,14 a range of dimeric
species have been described by us and others.15 An indication
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Figure 1. Kinetic profiles of the formation of B1 using various catalytic systems
In summary, we have disclosed the first examplVeiewofArtaiclehOignhlinlye
selective dehydrogenative borylation ofDteOrI:m10in.1a0l39a/lCk6ySnCe0s26w6i8thK
pinacolborane, using an inexpensive metal center supported
by readily accessible ligands.16 Preliminary mechanistic studies
suggest the pivotal role of a σ,π-bis(copper) acetylide A and a
copper hydride C.
Acknowledgments
The authors gratefully acknowledge financial support from the
DOE (DE-FG02-13ER16370).
Notes and References
[1]
J. F. Hartwig, Acc. Chem. Res. 2012, 45, 864; A. J. Lennox and G. C.
Lloyd-Jones, Chem. Soc. Rev. 2014, 43, 412.
[a] Reactions were carried out in a J-Young NMR tube at RT under an argon atmosphere
using a 1:1 mixture (0.45 mmol) of p-tolylacetylene and pinacolborane in 1 mL of C6D6.
[b] 2.5 mol% of F and 5 mol% Et3N; no trace of B1 was observed, instead D1 was
obtained quantitatively. [c] 2.5 mol% of F, Et3N and Et3NH.OTf. [d] 2.5 mol% of A, 1.25
mol% Et3N and 3.75 mol% Et3NH.OTf. [e] 2.5 mol% of L1CuOTf and 5 mol% of Et3N.
[2]
H. Chen, S. Schlecht, T. C. Semple and J. F. Hartwig, Science 2000,
287, 1995.
[3]
[4]
J. Y. Cho, M. K. Tse, D. Holmes, R. E. Maleczka Jr. and M. R. Smith III,
Science 2002, 295, 305.
J. F. Hartwig, Chem. Soc. Rev. 2011, 40, 1992; I. A. Mkhalid, J. H.
Barnard, T. B. Marder, J. M. Murphy and J. F. Hartwig, Chem. Rev. 2010,
110, 890.
Scheme 3. Evidence for the pivotal role of the dinuclear copper complex A
F (2.5 mol%)
BPin
[5]
C. I. Lee, J. Zhou and O. V. Ozerov, J. Am. Chem. Soc. 2013, 135, 3560;
C. I. Lee, N. A. Hirscher, J. Zhou, N. Bhuvanesh and O. V. Ozerov,
Organometallics 2015, 34, 3099; C. I. Lee, W. C. Shih, J. Zhou, J. H.
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and O. V. Ozerov, Chem. Sci. 2015, 6, 6572; C. J. Pell and O. V. Ozerov,
Inorg. Chem. Front. 2015, 2, 720.
Tol
D1
Et3N (5 mol%)
RT, C6D6
95% (NMR yield)
Tol
H
+
PinBH
F (2.5 mol%)
Tol
BPin
B1
Et3N (2.5 mol%)
Et3NH.OTf (2.5 mol%)
RT, C6D6
96% (NMR yield)
[6]
[7]
[8]
T. Tsuchimoto, H. Utsugi, T. Sugiura and S. Horio, Adv. Synth. Catal.
2015, 357, 77.
L
TfO
Ph
Et3NH.OTf (0.5 eq)
RT, CDCl3, 1 min
R. Barbeyron, E. Benedetti, J. Cossy, J. J. Vasseur, S. Arseniyadis and
M. Smietana, Tetrahedron 2014, 70, 8431.
Cu
+
+
H
Ph
L
Cu
Ph
F
L
Cu
Et3N
L. Jin, D. R. Tolentino, M. Melaimi and G. Bertrand, Sci. Adv. 2015, 1,
e1500304; L. Jin, E. A. Romero, M. Melaimi and G. Bertrand, J. Am.
Chem. Soc. 2015, 137, 15696.
A
Scheme 4. Evidence for the formation of the copper hydride C
[9]
For reviews on CAACs, see: M. Melaimi, M. Soleilhavoup and G.
Bertrand, Angew. Chem., Int. Ed. 2010, 49, 8810; D. Martin, M. Melaimi,
M. Soleilhavoup and G. Bertrand, Organometallics 2011, 30, 5304; M.
Soleilhavoup and G. Bertrand, Acc. Chem. Res. 2015, 48, 256.
O
O
LCuOTf (2.5 mol%)
H
D
D
B3
BH
+
D
+
Ph
Et3N (5 mol%)
CD2Cl2, RT, 3h
Ph
90% D-incorporation
[10] For the synthesis of CAACs, see: V. Lavallo, Y. Canac, C. Präsang, B.
Donnadieu and G. Bertrand, Angew. Chem., Int. Ed. 2005, 44, 5705; R.
Jazzar, R. D. Dewhurst, J. B. Bourg, B. Donnadieu, Y. Canac and G.
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R. D. Dewhurst, B. Donnadieu and G. Bertrand, J. Org. Chem. 2007, 72,
3492.
Styrene-D
75% D-incorporation
L
Cu
H
L
Cu
C
H
D
Ph
D
Ph
or
[11] For other mechanistic studies, involving the transient formation of σ,π-
bis(copper) acetylides, see: V. O.Rodionov, V. V. Fokin and M. G. Finn,
Angew. Chem., Int. Ed. 2005, 44, 2210; F. Himo, T. Lovell, R. Hilgraf, V.
V. Rostovtsev, L. Noodleman, K. B. Sharpless and V. V. Fokin, J. Am.
Chem. Soc. 2005, 127, 210; M. Ahlquist and V. V. Fokin, Organometallics
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Mayer and B. F. Straub, Angew. Chem., Int. Ed. 2007, 46, 2101; A.
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2015, 54, 7431; B. T. Worrell, J. A. Malik and V. V. Fokin, Science 2013,
340, 457.
Et3ND.OTf
of L1CuH formation in this process is the observation of a small
amount of styrene derivatives E in our experiments (Table 1).
Indeed, copper hydrides are known to undergo 1,2-addition
across alkynes to generate copper vinyl complexes, which by
protonolysis give the alkenes.15 Consistent with this
hypothesis, a catalytic experiment using deuterium labelled
phenyl acetylene under our optimized conditions, but in CD2Cl2
instead of C6D6 (Table 1, entry 6), afforded B3 and Styrene-D
(75% D-incorporation) (Scheme 4).
[12] A. J. Arduengo, R. Krafczyk and R. Schmutzler, Tetrahedron 1999, 55,
14523.
[13] For reviews, see: J. D. Egbert, C. S. J. Cazin and S. P. Nolan, Catal. Sci.
Technol. 2013, 3, 912; C. Deutsch, N. Krause and B. H. Lipshutz, Chem.
Rev. 2008, 108, 2916. B. H. Lipshutz, Synlett 2009, 509.
[14] For an example of diligated copper hydride, see: B. H. Lipshutz and B. A.
Frieman, Angew. Chem., Int. Ed. 2005, 44, 6345.
Conclusions
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[15] G. D. Frey, B. Donnadieu, M. Soleilhavoup and G. Bertrand, Chem. Asian
J. 2011, 6, 402; N. Cox, H. Dang, A. M. Whittaker and G. Lalic,
Tetrahedron 2014, 70, 4219; M. R. Uehling, R. P. Rucker and G. Lalic, J.
Am. Chem. Soc. 2014, 136, 8799; A. M. Suess, M. R. Uehling, W.
Kaminsky and G. Lalic, J. Am. Chem. Soc. 2015, 137, 7747; N. P.
Mankad, D. S. Laitar and J. P. Sadighi, Organometallics 2004, 23, 3369;
K. Semba, T. Fujihara, T. H. Xu, J. Terao and Y. Tsuji, Adv. Synth. Catal.
2012, 354, 1542. A. J. Jordan, C. M. Wyss, J. Bacsa and J. P. Sadighi,
Organometallics 2016, 35, 613; A. M. Suess and G. Lalic, Synlett 2016
27, 1165; L. R. Collins, I. M. Riddlestone, M. F. Mahon and M. K.
Whittlesey, Chem. Eur. J. 2015, 21, 14075. C. M. Wyss, B. K. Tate, J.
Bacsa, T. G. Gray and J. P. Sadighi, Angew. Chem., Int. Ed. 2013, 52,
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[16] CAAC and NHC precursors are commercially available.
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