Dual copper- and photoredox-catalysed C(sp2)-C(sp3) coupling

Article abstract of DOI:10.1039/c9cc01718f

The use of copper catalysis with visible light photoredox catalysis in a cooperative fashion has recently emerged as a versatile means of developing new C-C bond forming reactions. In this work, dual copper and photoredox catalysis is exploited to effect C(sp²)-C(sp³) cross-couplings between aryl boronic acids and benzyl bromides.

Full text of DOI:10.1039/c9cc01718f

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Dual Copper- and Photoredox-Catalysed C(sp2)-C(sp3) Coupling
Euan B. McLean,a Vincent Gauchot,a Sebastian Brunen,a David J. Burnsb and Ai-Lan Lee*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The use of copper catalysis with visible light photoredox catalysis in arylboronic acids 1 can undergo transmetallation in dual
a cooperative fashion has recently emerged as a versatile means of copper- and photoredox-catalysed systems, providing literature
developing new C-C bond forming reactions. In this work, dual precedence for steps 6→I→II.5 Additionally, oxidation and
copper- and photoredox catalysis is exploited to effect C(sp2)-C(sp3) reduction potentials from literature support the oxidation of
I/II
2+*
*II/I
cross-couplings between aryl boronic acids and benzyl bromides.
Cu(I) to Cu(II) (E1/2 = -0.161 V)9 by Ru(bpy)3 (E1/2 = 0.77
V).1b For the sp3 cross-partner, we opted for benzyl bromides 4,
since it has been shown that benzylic radicals IV can be
The synergistic combination of transition metal catalysis with
photoredox catalysis has in recent years proven itself to be a
versatile way to effect C-C cross-couplings.1 Since its
conception, the field has mainly been dominated by
methodologies which utilise nickel in synergy with photoredox
catalysts, including seminal contributions from Molander and
MacMillan, which elegantly demonstrate the synthetic utility of
this approach.2 Nevertheless, commonly used nickel catalysts
in dual-catalysis reactions are toxic and carcinogenic,3 so
alternatives with lower toxicity would be beneficial. An
emerging, though much less-explored alternative is the use
of relatively non-toxic copper salts.4 These have an added
benefit in that cheap inorganic copper salts can be used,
without the need for ligands. For example, Sanford’s seminal
work in the area uses CuOAc in conjunction with a photoredox
catalyst to effect mild trifluoromethylation of aryl boronic acids
(Scheme 1A).5,6 Nevertheless, a dual-copper and photoredox-
catalysed C(sp2)-C(sp3) cross-coupling which involves standard,
non-fluorinated C(sp3) centres such as alkyls or benzyls was,
surprisingly, yet to be developed.7 We therefore set out to
explore and develop the first dual copper- and photoredox-
catalysed C(sp2)-C(sp3) cross-couplings of aryls with benzylic sp3
centres (Scheme 1B), and its successful development is
described herein.8
generated from electron-defficient benzyl bromides 4 (Ered
=
-0.95 V)10 under photoredox catalysis (E1/2 = -1.33 V for
Ru(bpy)32+).1b,11 Thus, we surmised that IV could plausibly react
with II to form the intermediate III and subsequently the desired
cross-coupled product 5, following reductive elimination. At this
stage, we envisaged that competing homocoupling of the
benzylic radical (from 4) may be a potential major challenge to
successful cross-coupling.
I/II
A) Sanford's Seminal Trifluoromethylations:5
OH
CuOAc (20-100 mol%)
B
CF3
Ru(bpy)3Cl2.6H2O (1 mol%)
K2CO3 (1 equiv.)
OH
+
CF3I
DMF, 60 °C, 12 h
26 W light bulb
R
R
1
2
3
B) This Work: C(sp2)-C(sp3) cross-couplings
R1
Br
R3
R1
Cu2O (cat.)
R3
Ru(bpy)3(PF6)2 (cat.)
+
KF, H2O
R2
B(OH)2
Toluene, 50 °C
5
4
1
R2
Scheme 1 Dual Copper- and Photoredox-catalysed C(sp2)-C(sp3) Cross-couplings
Firstly, a mechanistic design was constructed for the dual
copper- and photoredox-catalysed C(sp2)-C(sp3) cross-coupling
(Scheme 2). As discussed above, Sanford has shown that
With this proposal in hand, we screened a variety of
conditions on model substrates 1a and 4a (Table 1, see ESI for
full optimisation studies). Initial screens using CuI,
Ru(bpy)3(PF6)2 and K2CO3, provided our first promising result
(10% 5aa, Entry 1). Subsequent solvent screen (see ESI)
identified toluene as the most promising solvent (Entry 2). The
yield of desired product 5aa could be increased from 23% to
a. Institute of Chemical Sciences, School of Engineering and Physical Sciences,
Heriot-Watt University, Edinburgh EH14 4AS, UK. Email: A.Lee@hw.ac.uk
b. Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42
6EY, UK.
Electronic Supplementary Information (ESI) available: Experimental procedures, full
optimisation and control studies, mechanistic studies, characterisation data and
copies of NMR spectra of new compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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29% by reversing the stoichiometry (4a as limiting reagent, of water was optimal, improving the yields asViweweAlrlticalesOntlhinee
DOI: 10.1039/C9CC01718F
Entry 3). Next, a base screen (see ESI) identified KF as the reproducibility of the reaction (Entry 3, Table 2).
optimum base (Entry 5), while increasing the equivalents of
base improves the yield of 5aa (Entry 6). The counterion of the
Table 1 Selected Initial Optimisation Reactions
O2N
base appears to have an effect: for example, the use of LiF or
p-Tolylboronic acid 1a
NaF resulted in no reaction while NH4F produced only
homocoupled side product 7a (Entry 4). Further investigations
showed that the photocatalyst loading could be lowered to 1
mol% (40% 5aa, Entry 7). Finally, a screen of copper catalysts
(see ESI) identified Cu2O to be optimal (55% 5aa, Entry 8). Initial
results in Table 1 show that while the yield of the competing
homocoupling product (7a) appears to remain fairly constant
throughout, the yield of desired cross-coupling product 5aa can
nevertheless be successfully optimised to be the major product.
Control reactions confirmed that the cross-coupling does not
occur in the absence of light, photocatalyst or base respectively
and also shows poor reactivity in the absence of Cu2O (see ESI).
Br
(3 equiv.)
Cu Catalyst (30 mol%)
Ru(bpy)3(PF6)2
(2.5 mol%)
Base, Solvent
50 oC, 16 h
NO2
7a
NO2
4a
5aa
NO2
Entrya Sol.
Base
Ru
(mol%) cat.
Cu 4a (%)a 5aa (%)a 7a (%)a,b
1c,d,e MeCN K2CO3 (1 equiv.)
2 d,e PhMe K2CO3 (1 equiv.)
2.5
2.5
2.5
2.5
2.5
2.5
1
CuI
CuI
CuI
CuI
CuI
N/Af
N/Af
28
45
13
0
10
23
29
0
37
45
40
55
24
17
20
26
22
28
26
20
3
4
5
6
7
8
PhMe K2CO3 (3 equiv.)
PhMe NH4F (3 equiv.)
PhMe
PhMe
PhMe
PhMe
KF (3 equiv.)
KF (6 equiv.)
KF (3 equiv.)
KF (4 equiv.)
CuI
CuI
7
0
Ar2
IV
1
Cu2O
Ar2
aDetermined by 1H NMR analysis using mesitylene as internal standard, 0.1 mmol scale.
bYields with respect to theoretical maximum formation of 7a. cReaction carried out at
R.T. dCuI (20 mol%). eStoichiometry of 1a/4a reversed. fNot applicable as 4a is in excess.
OH
Radical
Addition
HO
Ar1 CuII
X
B
X
CuIII
III
Base
II
X
Ar1
Table 2 Selected Further Optimisation Studies
Copper
Catalysis
Transmet-
allation
Reductive
Elimination
R1
Arylboronic acid 1
R2
Br
(3 equiv.)
Cu2O (15 mol%)
Ru(bpy)3(PF6)2
(1 mol%)
CuIX
6
OH
CuIIX2
I
HO
B
SET
Base
Ar1
Ar1
Ar2
KF (4 equiv.)
Toluene, 16 h
H2O
V
5
2+
Ru(bpy)3
*
R1
Base
+
Ru(bpy)3
R1
Ar1B(OH)2
R1
4
5
7
Photoredox
Catalysis
1
SET
Entry
1
2
3
4
R1
R2
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
H2O equiv. 4 (%)a 5 (%)a 7 (%)a,b
NO2
NO2
NO2
NO2
NO2
NO2
NO2
CN
0
89
33
3
8
4
Ar2
IV
Ar2
2+
20
30
40
30
30
30
30
30
30
30
38
53
45
59
14
20
42
60
66
65
16
28
22
24
22
10
28
30
34
28
Ru(bpy)3
Br
4
9
3
8
Scheme 2 Mechanistic Design
5
6c
7d,e
8
62
41
6
0
0
Up until this point, all optimisation had been carried out
using model arylboronic acid 1a. Much to our surprise and
dismay, when any other arylboronic acids 1 were utilised under
this set of initial optimised conditions (Entry 8, Table 1), the
reaction failed to produce appreciable amounts of cross-
coupled 5 and/or suffered from reproducibility issues.
Therefore, a second series of optimisation studies had to be
carried out in order to develop a set of more general and
reproducible conditions (Table 2, see ESI for full studies).
We hypothesised that this unexpected and stark difference
in reactivity between different arylboronic acids was due to the
corresponding difference in positions of equilibrium between
the arylboronic acid and its dehydrated arylboroxine.12 Since
the position of equilibrium is influenced by the presence of
water,12,13 the addition of controlled quantities of water was
screened against phenylboronic acid 1b (see ESI). From these
experiments, we discovered that the addition of 30 equivalents
9f
CN
CN
NO2
10e,f
11e
aDetermined by 1H NMR analysis with 1,3,5-trimethoxybenzene as internal standard; 0.1
mmol scale. bYields with respect to theoretical maximum formation of 7. cIr(ppy)3 as
photocatalyst. dFluorescein as photocatalyst. eCu2O (30 mol%). f72 h
A number of other photocatalysts were investigated in the
reaction (see ESI), including organic dyes, but none were found
to be as efficient as Ru(bpy)3(PF6)2 (e.g. Entry 3 vs. Entries 6-7).
In order to quickly assess the generality of these conditions,
preliminary investigations into the benzyl bromide scope was
carried out. In general, it was found that when the benzyl
bromide substituent R1 is less electron-withdrawing (CN vs.
NO2), longer reaction times were required for the reaction to
reach completion (Entries 8-9). Finally, increasing the copper
catalyst loading to 30 mol% increased the yield of reaction to
2 | J. Name., 2012, 00, 1-3
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66% and 65% for the -NO2 and -CN substrates respectively and further functionalisation. This protocol also tolVeireawtAersticlehOignhlinlye
also improved reproducibility (Entries 10 and 11).
fluorinated moieties, giving the product 5bh DinO5I:11%0.1y0ie3l9d/.CS9uCbCs0t1ra71t8eFs
bearing a mixture of various electron-withdrawing groups are also
tolerated, furnishing the desired products 5bi and 5aj in moderate
yields. In particular, the formation of 5bi highlights that the reaction
is tolerant of steric hindrance on the benzyl bromide substrate.
As expected, attempts to expand the scope beyond electron-
poor benzyl bromides proved challenging due to the higher reduction
potentials, with benzyl bromide 4k providing only 24% yield of
desired product (5ak) despite extended reaction times (72 h).15
Surprisingly, reducing the reduction potential even further (e.g. by
having two electron-withdrawing nitro groups) does not necessarily
improve the cross-coupling (35% 5al), due to competing proto-
debromination of starting material 4l (31%). Secondary benzyl
bromide 4m successfully cross-couples, albeit less efficiently than its
primary counterpart under these conditions (5am vs. 5aa). Having
ascertained the substrate scope and limitations, we proceeded to
demonstrate that the reaction can be successfully scaled up to 1
mmol, albeit with a slightly reduced yield and increased reaction time
(51% 5aa after 96 h, see ESI).
Table 3 Benzyl Bromide Scope
R3
Cu2O (30 mol%)
Ru(bpy)3(PF6)2
(1 mol%)
R1
R3
Br
R1
+
KF (4 equiv.)
H2O (30 equiv.)
Toluene, 50 °C
B(OH)2
(3 equiv.)
R2
1a R1=Me or
1b R1=OMe
R2
5
4
Ar1: R1=Me; Ar2: R1=OMe
NO2
Ar1
Ar1
Ar1
Ar1
NO2
CN
5aa 16 h
5ad 72 h
66%a (60%)b
5ab 16 h
5ac 96 h
NO2
65%a (62%)b
68%a (65%)b
44%a,c
Br
F
Ar1
Ar1
Ar1
CN
CO2Et
CN
5af 72 h
60%a (55%)b
5ae 96 h
44%a,c
5ag 96 h
65%a (60%)b
F
Ar2
CO2Me
Cl
Ar2
Ar1
Table 4 Arylboronic Acid Scope
F
F
F
Cu2O (30 mol%)
Ru(bpy)3(PF6)2
(1 mol%)
X
Br
R2
X
O2N
R2
F
CO2Et
R3
+
5aj 96 h
47%a,c
5bh 48 h
51%a (51%)b
5bi 20 h
54%a (54%)b
KF (4 equiv.)
H2O (30 equiv.)
Toluene, 50 °C
R3
B(OH)2
3 equiv.
R1
4a or 4i
NO2
Me
Ar1
R1
5
Limitations:
1
Ar1
Ar1
Ar3 R1=NO2, R2=R3=H; Ar4 R1=H, R2=CO2Me, R3=NO2
Me
Me
5am 40 h
45%a (27%)b
NO2
5ak 72 h
24%a
5al 16 h
35%a
NO2
Me
aDetermined by 1H NMR analysis of the crude product using 1,3,5
trimethoxybenzene as an internal standard.bIsolated yield. cIsolated yields not
available due to co-elution with unreacted 4.
Ar3
Ar3
Ar3
Ar3
5ba 16 h
62%a (57%)b
5aa 16 h
65%a (62%)b
5da 16 h
5ca 96 h
51%a,c
58%a (58%)b
Me
With a more general optimised protocol in hand, our attention
turned to investigating the benzyl bromide substrate scope (Table 3).
It should be noted that electron-defficient benzyl bromides, which
have lower reduction potentials than their electron-rich
counterparts,14 have previously been required for efficient benzyl
radical IV formation under photoredox catalysis.11 Consequently,
strongly electron-withdrawing substituents (e.g. NO2) are tolerated
well in the para and ortho positions, furnishing the corresponding
products 5aa and 5ab in good yields (62% and 65%). However, when
the NO2 substituent is moved to the meta position (5ac), the reaction
becomes sluggish and the yield is modest even at prolonged reaction
times (44%, 96 h). The sluggish reaction with 4c is consistent with the
higher reduction potential14 of benzyl bromide 4c (vs. 4a-b) as NO2
exerts a smaller withdrawing effect in the meta position. Increasing
the reaction time allows for the use of benzyl bromides bearing more
moderately electron withdrawing substituents (e.g. CN and ester
groups), furnishing the desired products 5ad and 5ae in good and
moderate yields respectively (60% and 44%). Halogenated benzyl
bromides are also good substrates providing products 5af and 5ag in
yields of 55% and 60% respectively. The selectivity in activating the
C(sp3)-Br bond preferentially over the C(sp2)-Br bond (5af) is
significant as it renders this protocol orthogonal in reactivity to
traditional palladium cross-couplings and provides a platform for
Cl
MeO
F
Cl
Ar3
50%a (44%)b
Ar3
Ar3
5fa 72 h
5ga 72 h
5ea 16 h
5ha 96 h
50%a (50%)b
Ar3
53%a (52%)b
57%a,d
NO2
I
Cl
MeO
Ar3
Ar3
3
5ib 72 h
50%a (50%)b
5ja 72 h
0%a,e
5ka 72 h
3%a,f
5la 72 h
44%a,c,f,g
Ar4
Ar
aYield determined by 1H NMR analysis using 1,3,5 trimethoxybenzene as an internal
standard.bIsolated yield. cIsolated yields not available due to co-elution with
unreacted 4. dIsolated yields not available due to co-elution with homocoupling
product. e1j consumed to form insoluble polymers. fPoor solubility of arylboronic
acid. gUsing boroxine instead of boronic acid, portionwise addition.
The aryboronic acid scope was investigated next (Table 4).
Electron-rich tolylboronic acids perform well as substrates,
furnishing the desired products 5aa-5ca with a slight and gradual
reduction in yield when moving from para (62%) to meta (57%) to
(51%) ortho, presumably reflecting the gradual increase in sterics.
Unsubstituted phenylboronic acid 1d and electron rich p-
anisyboronic acid 1e also proved to be good coupling partners,
yielding products 5da and 5ea in 58% and 57% respectively. Electron-
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N. Hoffmann, ChemCatChem, 2015, 7, 393; (f) J. Twilton, C. Le,
withdrawing substituents are also tolerated in the reaction, with 5fa
and 5ga formed in 44 and 52% respectively. Arylboronic acids bearing
View Article Online
P. Zhang, M. H. Shaw, R. W. Evans anDdODI:.1W0.1.0C39./MC9aCcCM01il7la18nF,
Nat. Rev. Chem., 2017, 1, 0052; (g) M. N. Hopkinson, B. Sahoo,
J.-L. Li and F. Glorius, Chem. Eur. J., 2014, 20, 3874.
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Molander, Science, 2014, 345, 433; (b) Z. Zuo, D. T. Ahneman,
L. Chu, J. A. Terrett, A. G. Doyle and D. W. C. MacMillan,
Science, 2014, 345, 437.
a
combination of electron-withdrawing and electron-donating
groups are also amenable to the coupling conditions: 5ha and 5ib are
formed in 50% yields. Unsurprisingly, alkene moieties, which are
liable to react with intermediate radicals, are not tolerated (e.g. 5ja).
Although the reaction is tolerant of both electron-rich and electron-
poor arylboronic acids, some arylboronic acids, especially ones
containing highly polar substituents (e.g. NO2) suffer from poor
solubility in the reaction mixture, which detrimentally affects their
ability as coupling partners (5ka). Any polar groups such as NO2 are
thus best introduced via the benzyl bromide coupling partner
instead. In some cases, such as with 5la, the solubility problem can
be partially overcome by utilising the arylboroxine (44% 5la).
2
3
4
For example, nickel(II) chloride ethylene glycol dimethyl ether
complex and bis(1,5-cyclooctadiene)nickel(0) are known
carcinogens.
For review on dual copper- and photoredox catalysis, see: E.
B. McLean and A.-L. Lee, Tetrahedron, 2018, 74, 4881.
Y. Ye and M. S. Sanford, J. Am. Chem. Soc., 2012, 134, 9034.
5
6
For
selected
recent
dual
copper-catalysed
perfluoroalkylations, see also: (a) J. A. Kautzky, T. Wang, R. W.
Evans and D. W. C. MacMillan, J. Am. Chem. Soc., 2018, 140,
6522; (b) C. Le, T. Q. Chen, T. Liang, P. Zhang and D. W. C.
MacMillan, Science, 2018, 360, 1010; (c) D. B. Bagal, G.
Kachkovskyi, M. Knorn, T. Rawner, B. M. Bhanage and O.
Reiser, Angew. Chem. Int. Ed., 2015, 54, 6999; (d) Q.-Y. Lin, Y.
Ran, X.-H. Xu and F.-L. Qing, Org. Lett., 2016, 18, 2419; (e) H.-
R. Zhang, D.-Q. Chen, Y.-P. Han, Y.-F. Qiu, D.-P. Jin and X.-Y.
Liu, Chem. Commun., 2016, 52, 11827; (f) T. Rawner, E.
Lutsker, C. A. Kaiser and O. Reiser, ACS Catal., 2018, 8, 3950.
For examples of other dual copper- and photoredox C-C bond
forming reactions, see: (a) M. Rueping, R. M. Koenigs, K.
Poscharny, D. C. Fabry, D. Leonori and C. Vila, Chem. Eur. J.,
2012, 18, 5170; (b) I. Perepichka, S. Kundu, Z. Hearne and C.-
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and L. Ackermann, Angew. Chem. Int. Ed., 2016, 55, 4759; (d)
H. Zhang, P. Zhang, M. Jiang, H. Yang and H. Fu, Org. Lett.,
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Zhu, J. Org. Chem., 2017, 82, 8455; (f) D. Wang, N. Zhu, P.
Chen, Z. Lin and G. Liu, J. Am. Chem. Soc., 2017, 139, 15632;
(g) R. Jin, Y. Chen, W. Liu, D. Xu, Y. Li, A. Ding and H. Guo,
Chem. Commun., 2016, 52, 9909; (h) S.-Y. Hsieh and J. W.
Bode, ACS Cent. Sci., 2017, 3, 66; (i) W. Deng, W. Feng, Y. Li
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TEMPO (2 equiv.)
Cu2O (30 mol%)
Ru(bpy)3(PF6)2
(1 mol%)
Me
O2N
O2N
+
KF (4 equiv.)
H2O (30 equiv.)
Toluene, 50 °C
O
4a
Br
B(OH)2
N
8 64%
(5aa not detected)
1a (3 equiv.)
7
Scheme 3 Radical Trap Experiment
Having investigated the scope of both coupling partners,
preliminary mechanistic investigations were conducted next.
Carrying out the reaction under our optimised conditions in the
presence of known radical trap TEMPO results in complete inhibition
of the reaction, with no observed formation of desired product 5aa
(Scheme 3). In addition, the TEMPO trapped benzylic radical adduct
8 can be isolated in 64% yield. This result supports our hypothesis
that the mechanism is radical based and most likely involves benzylic
radicals IV as intermediates. Experiments to determine the quantum
yield of the reaction were also carried out (see ESI). The quantum
yield of the reaction was calculated to be φ = 0.012, which rules out
the presence of any radical chain mechanisms in the reaction.16
In conclusion, we have successfully developed the first dual
copper- and photoredox-catalysed C(sp2)-C(sp3) cross-couplings of
aryls with benzylic sp3 centres. Surprisingly, addition of water was
found to be necessary for the generality and reproducibility of the
reaction, thereby allowing the successful cross-coupling of a variety
of arylboronic acids with electron-defficient benzyl bromides.
We would like to thank the Engineering and Physical
Sciences Research Council, Heriot-Watt University and CRITICAT
Centre for Doctoral Training and Syngenta [Ph.D. studentship to
EM; Grant code: EP/L016419/1] and Leverhulme Trust (RPG-
2014-345) for financial support. Mass spectrometry data were
acquired at the EPSRC UK National Mass Spectrometry Facility
at Swansea University.
8
9
For examples of other dual metal- and photoredox-catalysed
reactions developed in our group, see: (a) V. Gauchot and A.-
L. Lee, Chem. Commun., 2016, 52, 10163; (b) V. Gauchot, D. R.
Sutherland and A. L. Lee, Chem. Sci., 2017, 8, 2885.
S. G. Bratsch, J. Phys. Chem. Ref. Data, 1989, 18, 1.
10 E. M. Kosower and M. Mohammad, J. Am. Chem. Soc., 1971,
93, 2713.
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15 The reaction was also attempted using the more reducing fac-
Ir(ppy)3 photocatalyst, but this resulted in only trace amounts
of the desired product 5ak, see ESI.
References
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For selected reviews, see: (a) X. Lang, J. Zhao and X. Chen,
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4 | J. Name., 2012, 00, 1-3
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Abstract
View Article Online
DOI: 10.1039/C9CC01718F
Dual Copper- and Photoredox-Catalysed C(sp2)-C(sp3) Coupling
Euan B. McLean, Vincent Gauchot, Sebastian Brunen, David J. Burns and Ai-Lan Lee*
R1
Ru
Cu
Br
R3
R1
Cu2O (cat.)
Ru(bpy)3(PF6)2 (cat.)
R3
+
KF, H2O
Toluene, 50 °C
B(OH)2
R2
R2
The use of copper catalysis with visible light photoredox catalysis in a cooperative fashion has
recently emerged as a versatile means of developing new C-C bond forming reactions. In this work,
dual copper- and photoredox catalysis is exploited to effect C(sp2)-C(sp3) cross-couplings between
aryl boronic acids and benzyl bromides.