Organocopper cross-coupling reaction for C-C bond formation on highly sterically hindered structures

Article abstract of DOI:10.1039/c9sc00891h

We describe a powerful, broadly applicable cross-coupling protocol that enables carbon-carbon bond formation at highly sterically hindered carbon centers (both sp² and sp³) by employing organocopper reagents under palladium catalysis. Experimental studies and theoretical calculations indicated that the key to the unique reactivity of copper is the relatively low activation energy of the compact transmetalation transition state, due to Cu(i)-Pd(ii) interaction, which is associated with small values of deformation energy of the reactants. This reaction is applicable to a variety of bulky substrates, including compounds inert to previous cross-coupling chemistry and has high functional group tolerance.

Full text of DOI:10.1039/c9sc00891h

View Article Online
View Journal
Chemical
Science
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Oi, R. TAKITA,
J. Kanazawa, A. Muranaka, C. Wang and M. Uchiyama, Chem. Sci., 2019, DOI: 10.1039/C9SC00891H.
This is an Accepted Manuscript, which has been through the
Volume
7 Number 1 January 2016 Pages 1–812
Royal Society of Chemistry peer review process and has been
accepted for publication.
Chemical
Science
Accepted Manuscripts are published online shortly after
www.rsc.org/chemicalscience
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 2041-6539
EDGE ARTICLE
Francesco Ricci et al.
Electronic control of DNA-based nanoswitches and nanodevices
rsc.li/chemical-science

Please do not adjust margins
Page 1 of 7
Chemical Science
View Article Online
DOI: 10.1039/C9SC00891H
EDGE ARTICLE
Organocopper Cross-coupling Reaction for C–C Bond Formation
on Highly Sterically Hindered Structures
Miku Oi,a,b Ryo Takita,*a,b Junichiro Kanazawa,a Atsuya Muranaka,b Chao Wanga and Masanobu
Received 00th January 20xx,
Accepted 00th January 20xx
Uchiyama*a,b
DOI: 10.1039/x0xx00000x
We describe a powerful, broadly applicable cross-coupling protocol that enables carbon–carbon bond formation at highly
sterically hindered carbon centers (both sp2 and sp3) by employing organocopper reagents under palladium catalysis.
Experimental studies and theoretical calculations indicated that the key to the unique reactivity of copper is the relatively
low activation energy of the compact transmetalation transition state, due to Cu(I)–Pd(II) interaction, which is associated
with small values of deformation energy of the reactants. This reaction is applicable to a variety of bulky substrates, including
compounds inert to previous cross-coupling chemistry and has high functional group tolerance.
compact and well-organized transition state in the
transmetalation step.
Introduction
Three-dimensionally (3D) bulky carbon frameworks and other
bulky substrates have become important scaffolds of a broad
range of functional molecules (Scheme 1A). They are useful in
vast fields due to such as the improved solubility, enhanced
stability, and increased control of molecular stacking.1-4 While
transition metal-catalyzed cross-coupling reactions are among
the most developed of C–C bond-forming reactions,5 bond
A
Three-dimensionally (3D) bulky carbon frameworks of functional molecules
t-Bu
t-Bu
O
O
CO2Me
Me
t-Bu
HN
O
N
N
O
P
R2
N
N
O
O
OH
HO
R2
N
t-Bu
t-Bu
t-Bu
CN
Drugs
Organic dyes
Catalysts
Pd
Molecular motors
B
Metal-mediated cross-coupling reactions
formation at sterically hindered structures remains
a
Recent improvements focus on these steps.
challenging task in cross-coupling chemistry, even with sp2- or
sp3-carbon substrates. Recent improvements have focused
mostly on the design of (pre)catalysts and customized ligands in
order to achieve efficient generation of the active palladium
species, and on the oxidative addition/reductive elimination
step in the catalytic cycle (Scheme 1B).6 These “state-of-the-art”
systems, in particular with customized ligands, enable bond
formation on sterically hindered substrates.7 However,
Precatalyst
R
R’
X
R’
Precatalyst
Pd0Ln
Customized ligands
Oxidative addition
Reductive elimination
Minor advances
R’
R
PdIILn
LnPdII
R’
X
Transmetalation
+ M– X
Sterically hindered
structures
R
R’
M
R
Still difficult
M
PdIILn
X
C
This work
transmetalation,
a fundamental step in cross-coupling
FG
FG
Pd
Pd cat., Ligand
reactions,8 can also be targeted to address this challenge.
Herein, we report a powerful and broadly applicable (to
both sp2- and sp3-carbons) Pd-catalyzed cross-coupling reaction
of organocopper reagents that enables efficient C–C bond
formation even on 3D bulky carbon frameworks (Scheme 1C).
Notably, this reaction proceeds under mild conditions using
readily available reagents, and has high functional group
tolerance. Experimental and theoretical studies revealed that
copper(I)–palladium(II) interaction facilitates formation of a
+
Cu
X
Cu
3D bulky substrates
Both C(sp2) and C(sp3
)
Readily available reagents
Well-organized
Transmetalation TS
Scheme 1. (A) Three-dimensionally (3D) bulky carbon frameworks in a broad range
of disciplines. (B) Fundamental steps in cross-coupling reactions and recent
developments in the catalytic cycle. (C) Pd-catalyzed organocopper cross-coupling
reaction on highly sterically hindered structures (This work).
Results & discussion
We commenced our search to develop potent methodology by
focusing on the triptycene framework,9 due to its extremely
hindered tertiary sp3-carbon at the bridgehead 9-position and
unprecedent use in cross-coupling chemistry. The cross-
coupling reactions using a boronate ester or zinc(II) complex of
9-triptycene (1a and 1b) failed to afford any coupled product
a. Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo 7-3-1,
Bunkyo-ku, Tokyo, Japan. E-mail: takita@mol.f.u-tokyo.ac.jp, uchiyama@mol.f.u-
tokyo.ac.jp
b. Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable
Resource Science, Elements Chemistry Laboratory, RIKEN, Wako-shi, Saitama 351-
0198, Japan.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 2 of 7
ARTICLE
under the representative palladium-catalyzed conditions (run 1-
Journal Name
Other sterically hindered tertiary sp3-carbon compounds
View Article Online
3, Table 1).7e,g,h On the other hand, we found that the cross- were also competent substrates for this DreOaI:c1t0io.1n03(9S/cCh9eSCm0e0829B1H).
coupling reaction of 9-triptycenylcopper(I) complex 1c10 with 2 The adamantyl group was successfully introduced not only on a
smoothly proceeded using 5 mol% of Pd(OAc)2 and tris(o- simple aryl group (21), but also onto aryl halide moieties on a
methoxyphenyl)phosphine (L1) at 80 °C to afford the coupling sugar skeleton and in a steroid backbone, affording the
product 3 in 86% yield (run 4). The direct use of organocopper corresponding products 22 and 23 in good yields. These results
reagents in Pd-catalyzed cross-coupling reaction are limited,11 indicate that the present methodology would be suitable for
and a copper co-catalyst,12 as well as relay catalysis using late-stage functionalization of biologically relevant compounds
palladium and copper,13 have been employed. The absence of and functional molecules with bulky tertiary alkyl moieties.
palladium catalyst yielded no desired product (run 5). Under Similarly, the introduction of a tert-butyl group having β-
similar reaction conditions, other organometallic reagents (1a, hydrogen was achieved, affording 24 in 63% yield. A secondary
1b, 1d, and 1e) were also not competent (run 6-9).
2-adamantyl group was also introduced onto an aromatic ring
to give 25 in 88% yield.
Table 1 Screening of 9-metalated triptycene derivatives.
Further examination revealed that this methodology was
also applicable to sterically hindered sp2-carbon using
conditions essentially identical to those employed for sp3-
substrates (Scheme 2C). The reaction between mesitylcopper(I)
and 2 proceeded efficiently at room temperature, affording the
coupled product 26 in quantitative yield. The same
organocopper(I) reagent reacted smoothly under these
conditions with various electrophiles, affording the
corresponding biaryl products 27-32 in good yields, including
hindered ortho-substituted substrates. Further, the present
protocol realized the reactions with much bulkier copper
reagents, such as “super-mesityl”15 (35) and EMind16 (36)
substrates. Importantly, this reaction could also be applied to
the cubane skeleton (i.e. 37). Though the cubane motif has
recently attracted great attention as a bioisostere of benzene in
pharmaceuticals,17 there have only been two examples of cross-
coupling chemistry, and the yields were not high with respect
to the catalyst loading.18 In contrast, the present organocopper
cross-coupling reaction enabled catalytic C–C bond formation
with an iodocubane derivative for the first time, installing the
sterically hindered mesityl group in 49% yield using 10 mol% of
Pd catalyst. 14
Run
1
Metal
Bpin (1a)
ZnCl (1b)
ZnCl (1b)
Cu (1c)
Conditions
Yield (%)a
Pd(OAc)2, SPhos, K3PO4, toluene, 100 °Cb
Pd(OAc)2, RuPhos, THF-toluene, 100 °Cc
XPhos G3, XPhos, THF-toluene, 100 °Cd
Pd(OAc)2, L1e, THF-toluene, 80 °C
L1e, THF-toluene, 80 °C
0
0
2
3
0
4
86
0
5
Cu (1c)
6
Bpin (1a)
ZnCl (1b)
MgCl (1d)
Li (1e)
Pd(OAc)2, L1e, K3PO4, THF-toluene, 100 °C
Pd(OAc)2, L1e, THF-toluene, 100 °C
Pd(OAc)2, L1e, THF-toluene, 100 °C
Pd(OAc)2, L1e, THF-toluene, 100 °C
0
7
trace
0
8
9
0
a NMR yields determined using dimethylsulfone as an internal standard. Reaction
b
c
d
e
time: 4 h (Run 4, 5) or 20 h (other runs) Ref 7e. Ref 7g. Ref 7h. L1: Tris(o-
methoxyphenyl)phosphine.
The optimized conditions of the present organocopper
cross-coupling reaction were then applied to bond formation
using a variety of electrophiles (Scheme 2A). Both electron-
withdrawing and -donating groups on aryl halides, containing
CO2Me, CF3, CN, acetyl, and MeO groups, were compatible with
the reaction conditions, and the desired products were
obtained in good yields (3-8). Moreover, sterically demanding
ortho-substituted substrates gave 9-arylated triptycene
derivatives 9 and 10. X-Ray crystallography of 9 confirmed the
desired C–C bond formation. A straightforward, one-step
synthesis of 9-ferrocenyltriptycene 114b was accomplished with
the present coupling strategy. Various heteroaromatic moieties
were successfully coupled (12-18), and bond formation was also
achieved with sp-carbon of an alkynyl substrate 19. The
coupling reaction with ethyl bromoacetate proceeded in 76%
yield to give the product 20 having a C(sp3)–C(sp3) bond.14 Since
existing syntheses of 9-functionalized triptycenes are rather
lengthy,9 the present methodology offers substantial synthetic
advantages, including high functional group tolerance.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 7
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
View Article Online
DOI: 10.1039/C9SC00891H
MeO PCy2
Pd(OAc)2 (5 mol%)
L1 (15 mol%)
O
FG
FG
+
X
P
P
R
Cu
R
THF(-toluene)
Temp., 4– 48 h
3
3
MeO
MeO
(1.0 eq.)
(1.1 eq.)
L2
L3
L1
A 9-Triptycene derivatives : Temp. (80 ºC – 140 ºC)
X-Ray structure
MeO2C
Ac
OMe
8 : X = I, 82%
CO2Me
CF3
4 : X = I, 83%
CN
9 : X = I, 67%a
3 : X = I, 83%
5 : X = I, 83%
6 : X = I, 81%
7 : X = I, 53% (77%)
X =Br, 69%a
MeO
S
S
N
N
Fe
N
N
Ac
EtO2C
13 : X = Br, 60%
11 : X = Br, 39% (66%)a
10 : X = I, 31%a
15 : X = I, 45%
16 : X = I, 73%
17 : X = Br, 74%
12 : X = Br, 66%
14 : X = I, 64%
B Other sp3– carbon substrates : Temp. (100 ºC)
Me
Me
MeO
Me
Tertiary
O
O
CO2Me
H
H
H
O
O
H
O
O
CO2Me
Me
Me
O
N
Ph
MeO
23 : X = I, 54% (70%)b
18 : X = Br, 90%
19 : X = I, 24%
20 : X = Br, 76%a,b
21 : X = I, 43%c
22 : X = I, 79%c
C sp2– Carbon substrates : Temp. (rt – 120 ºC)
Secondary
CO2Me
CO2Me
CO2Me
OMe
CO2Me
24 : X = I, 55%d
25 : X = I, 88%c
27 : X = I, 55%a
26 : X = I, 97%
: X = Br, 77%
30 : X = Br, 71%a
31 : X = Br, 31%a
28 : X = I, p-, 96%
29 : X = I, �-, 91%
Me
Me
CO2Me
O
N
CO2Me
CO2Me
Et
Et
N
Me
Me
Et
Et
36 : X = I, 53%a
32 : X = Br, 58%a
33 : X = Br, 41%a
34 : X = I, 85%
35 : X = I, 34%a
37 : X = I, 31% (49%)a,e
Scheme 2 Organocopper cross-coupling reaction of sp3- and sp2-carbon substrates with sterically-hindered structures. Isolated yields are shown (1H NMR yields in
parentheses). a L2 was used instead of L1. b Ni(acac)2 was used instead of Pd(OAc)2. c L2 was used instead of L1 and 3 eq. of TMEDA were added. d L3 was used instead
of L1 at –20 °C and 3 eq. of TMEDA were added. e 10 mol% of Pd catalyst and 30 mol% L2 were used.
Given that the nature of the metal species should have the structure (TSB1), resulting in a high activation energy (∆G‡ =
greatest influence on the transmetalation step (Scheme 1B), +46.4 kcal/mol, Figure 1A). Although a lower activation barrier
and taking into account the mechanistic implications of (∆G‡ = +28.0 kcal/mol) was observed with 9-triptycenylzinc
experimental findings,19 we performed theoretical calculations chloride via TSZn1, this reaction (IMZn1–TSZn1–IMZn2) is
for the ligand transfer process from 9-metalated triptycene thermodynamically unfavorable; the transmetalated product
(boron, zinc, and copper) to arylpalladium complex as a model IMZn2 is quite unstable (+25.5 kcal/mol, compared with IMZn1),
of the transmetalation step (Figure 1) at the ωB97X-D/SDD & 6- suggesting that efficient transmetalation is improbable (Figure
31+G* level of theory. DFT calculation for the reaction of 9- 1B). These findings are consistent with the experimental results
triptycenylboronate with trans-Pd(Ph)OH(PMe3)20 indicated shown in Table 1.
that the bulky triptycene group distorts the transition-state
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 4 of 7
View Article Online
DOI: 10.1039/C9SC00891H
EDGE ARTICLE
TS Structures
D
A
B
∆G (kcal/mol)
∆G (kcal/mol)
B
Cu
Zn
B
Zn
2.52
PMe3
+30
+10
+5
Pd
B
TSB
1
Pd
Br
PMe3
TSZn
1
PMe3
2.48
Pd
Pd
B
OH
Pd
Br
Pd
Cu
PMe3
Zn
IMZn2
PMe3
2.48
(+24.6)
+20
(+6.7)
Cl
OH
O
Zn
O
– 2.5
B
O
Cl
(+4.2)
Br
O
+10
0
0
RTZn
Ph
Ph
Pd
Pd
Zn
– 5
X
PMe3
+46.4
– 46.1
Pd
Pd
RTB
PMe3
+28.0
Pd
PMe3
+
M
OH
Pd
PMe3
Br
PMe3
+25.5
Ph
– 10
– 20
– 30
Br
PMe3
B
Cl
O
X
M
– 10
– 15
– 20
– 21.8
– 21.3
Pd
+
O
TripM
DEF
ArPdX
X
+
HO
PMe3
IMB2
IMB
1
INT
M
PMe3
(– 26.1)
(– 21.8)
TS
Pd
Br
IMZn1
PMe3
INTB
Pd
IMZn
1
∆E
ZnCl
RT
OH
Zn
Cl
B
O
O
B
(kcal/mol)
(– 21.3)
O
O
1
– 25
M
DEFTripM
DEFArPdX DEFtotal
INT
∆E
∆G
B
131.6
75.3
32.5
16.5
27.3
14.9
148.1
102.6
47.4
– 140.7
– 111.7
– 73.1
7.4
24.6
6.7
C
∆G (kcal/mol)
Cu
Zn
Cu
– 9.1
2.52
– 25.7
– 10.0
Pd
2.75
Pd
PMe3
NBO (overlap):
E
Pd
Cu
PMe3
Cu
Br
TSCu
+10
0
Cu (3dxy) →
Cu (3dxy) →
*(Pd-P): 2.59 kcal/mol
Cu

*(Pd-CPh): 1.24 kcal/mol
Cu
Br
2
RTCu
2.52
TSCu
1
(– 5.8)
– 10
– 20
– 30
Ph
(– 10.0)
Pd
Cu
PMe3
+19.8
Pd
Pd
– 31.4
Pd
+
P
P
– 15.6
+21.4
Br
PMe3
Cu
Cu
Br
TSCu
IMCu2
– 51.3
Br
Br
1
IMCu
1
(– 25.6)
Pd
2.45
(– 31.4)
PMe3
Cu
– 40
– 50
– 60
Br
Cu
Pd
Br
Pd
PMe3
IMCu3
Cu
Cu
PMe3
Pd
Br
Pd
(– 57.1)
Cu
Cu
NBO (donor):
NBO (acceptor):
*(Pd-P)
NBO (acceptor):
*(Pd-CPh
2.69


)
Cu LP(5) (3dxy
)
transmetalation
reductive elimination
Fig. 1 Theoretical calculations for the transmetalation step between arylpalladium complex and 9-metalated triptycene complexes (A) with 9-triptycenylboronate
reagent, (B) with 9-triptycenylzinc chloride reagent, and (C) with 9-triptycenylcopper reagent (the reductive elimination step is also shown). Energy changes and bond
lengths at the ωB97X-D/SDD (for Pd, Cu, Zn, and Br) & 6-31+G* (for other atoms) level of theory are shown in kcal/mol and Å, respectively. (D) Results of EDA. (E) Results
of NBO analysis.
The situation with the copper reagent is completely transmetalation transition-state structures of arylpalladium
different; initial coordination of 9-triptycenylcopper and trans- complex with these organometalic reagents. Energy
Pd(Ph)Br(PMe3) (RTCu) affords IMCu1 with a large stabilization decomposition analysis (EDA)25 of these transition-state
energy (–31.4 kcal/mol) (Figure 1C). Further, the distance structures clearly indicates that small values of the deformation
between the copper and palladium atoms is shorter (2.69 Å) energy (DEF) are mainly responsible for the low activation
than the sum of their van der Waals radii (3.03 Å), supporting barrier in the case of the copper reagent (Figure 1D). In
the existence of strong metal–metal interaction.21 This Cu–Pd particular, the 9-triptycenylcopper unit involves a much lower
interaction results in the formation of a compact transition- DEFTripM than those in the cases of boron and zinc, probably due
state structure (TSCu1, Cu–Pd: 2.52 Å) that facilitates delivery of to the favorable Cu(I)–Pd(II) interaction, as well as the
the bulky triptycenyl group from the copper to the palladium abundance of vacant sites around the copper center.
center with a reasonable activation energy (∆G‡ = +21.4 Interestingly, the Zn(II) center also shows some interaction with
kcal/mol). The resultant IMCu2 having both phenyl and Pd(II), but the DEFs of both 9-triptycenyl zinc reagent and
triptycenyl ligands on palladium in a cis-fashion then undergoes arylpalladium complex are much larger. In the less-distorted
reductive elimination. The reductive elimination also TSCu1, smooth delivery of the triptycenyl ligand is facilitated by
reasonably proceeds (∆G‡ = +19.8 kcal/mol) to achieve the C–C the well-organized triangular arrangement of copper–
bond formation on the triptycene framework (IMCu3).
palladium–carbon (Cu(I)–Pd(II)–C). In addition, natural bond
Thus, the unique observed reactivity of the copper complex, orbital (NBO)26 analysis showed that electron donation from
in contrast to the boron or zinc complex, is supported by the Cu(I) to Pd(II) is predominant in IMCu1 and TSCu1 (Figure 1E),
theoretical calculations. Although the possibility of a similar while the reverse donation from the Pd(II) center to Lewis acidic
metal–metal interaction in transmetalation has been suggested Zn(II) was observed in TSZn1.14,23d,e These results reflect the
previously,22-24 our DFT calculations directly compare the characteristic reactivity of organocopper reagents arising from
Please do not adjust margins

Page 5 of 7
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
5
6
7
(a) C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot
and V. Snieckus, Angew. Chem. Int. EdD.,O2I:01102.1,053V19ie,/Cw590ASr6tCic20le;0O(8bn9)l1inHJe.
Choi and G. C. Fu, Science, 2017, 356, eaaf7230.
(a) P. G. Gildner and T. J. Colacot, Organometallics, 2015, 34,
5497; (b) N. Hazari, P. R. Melvin and M. M. Beromi, Nat. Rev.
Chem., 2017, 1, 0025.
the high-energy d orbitals and vacant coordination sites of
copper. Thus, transfer of the bulky triptycenyl ligand is
promoted not only by the adjacency of the two metal centers,
but also by the favorable electronic interaction between them.
For the representative examples of the Pd-catalyzed reactions
of sterically hindered substrates with bulky phosphine or NHC
ligands, see: (a) N. Marion and S. P. Nolan, Acc. Chem. Res.,
2008, 41, 1440; (b) R. Martin and S. L. Buchwald, Acc. Chem.
Res., 2008, 41, 1461; (c) S. Würtz and F. Glorius, Acc. Chem.
Res., 2008, 41, 1523; (d) G. C. Fu, Acc. Chem. Res., 2008, 41,
1555. See also: (e) J. E. Milne and S. L. Buchwald, J. Am. Chem.
Soc., 2004, 126, 13028; (f) W. Su, S. Urgaonkar, P. A.
McLaughlin and J. G. Verkade, J. Am. Chem. Soc., 2004, 126,
16433; (g) T. E. Barder, S. D. Walker, J. R. Martinerlli and S. L.
Buchwald, J. Am. Chem. Soc., 2005, 127, 4685; (h) Y. Yang, N.
J. Oldenhuis and S. L. Buchwald, Angew. Chem. Int. Ed., 2013,
52, 615; (i) C. Li, T. Chen, B. Li, G. Xiao and W. Tang, Angew.
Chem. Int. Ed., 2015, 54, 3792; (j) H. Zhang and S. L. Buchwald,
J. Am. Chem. Soc., 2017, 139, 11590.
For a book and reviews, see: a) J. F. Hartwig, Organotransition
Metal Chemistry: From Bonding to Catalysis; University
Science Books: Sausalito, CA. 2010; b) P. Espinet and A. M.
Echavarren, Angew. Chem. Int. Ed., 2004, 43, 4704; c) A. J. J.
Lennox and G. C. Lloyd-Jones, Angew. Chem. Int. Ed., 2013, 52,
7362.
Conclusions
In conclusion, the experimental results and DFT calculations
confirm that this organocopper cross-coupling reaction is a
potent C–C bond-forming methodology with unprecedented
applicability to 3D bulky molecules. The unique ability of copper
to facilitate efficient transmetalation via a compact transition
state arising from an efficient metal–metal interaction is the key
to the success of this reaction. Thus, this reaction is quite
efficient with high functional group tolerance, and applicable to
both sp2- and sp3-substrates. Further investigations on
substrate scope and detailed reaction mechanism are the
subjects of ongoing research.
8
9
Conflicts of interest
There are no conflicts to declare.
For representative utilization of triptycene derivatives, see:
(a) T. M. Swager, Acc. Chem. Res., 2008, 41, 1181; (b) S. A.
Barros and D. M. Chenoweth, Angew. Chem. Int. Ed., 2014, 53,
13746; (c) N. Seiki, Y. Shoji, T. Kajitani, F. Ishiwari, A. Kosaka,
T. Hikima, M. Takata, T. Someya and T. Fukushima, Science,
2015, 348, 1122. See also Ref 4.
Acknowledgements
This work was supported by grants from JSPS KAKENHI (S)
(17H06173), Asahi Glass Foundation, Kobayashi International
10 1c was prepared by the addition of CuI to 9-lithiated
triptycene in THF-toluene solution. Much of copper reagents
in Table 2 were prepared from the corresponding lithiated
substrates. 1- and 2-adamantyl reagents were prepared from
the commercially available zinc bromide solutions. For details,
see the ESI.
11 (a) N. Jabri, A. Alexakis and J. F. Normant, Tetrahedron Lett.,
1981, 22, 959; (b) J. Kanazawa, R. Takita, A. Jankowiak, S. Fujii,
H. Kagechika, D. Hashizume, K. Shudo, P. Kaszyński and M.
Uchiyama, Angew. Chem. Int. Ed., 2013, 52, 8017.
Scholarship Foundation, NAGASE Science
& Technology
Development Foundation, and Sumitomo Foundation (to M.U.),
as well as a JSPS Grant-in-Aid for Young Scientists (A)
(25713001) and grants from Tokyo Biochemical Research
Foundation, Takeda Science Foundation, The FUGAKU Trust for
Medicinal Research, and Uehara Memorial Foundation (to R.T.).
M.O. is grateful for the Graduate Program for Leaders in Life
Innovation (GPLLI) of the University of Tokyo and a JSPS
Research Fellowship for Young Scientists. The computations
were performed using HOKUSAI GreatWave at RIKEN and
Research Center for Computational Science at Okazaki, Japan.
12 (a) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron
Lett., 1975, 16, 4467; (b) L. S. Liebeskind and R. W. Fengl, J.
Org. Chem., 1990, 55, 5359.
13 For a review, see: (a) D. R. Pye and N. P. Mankad, Chem. Sci.,
2017, 8, 1705. See also: (b) L. J. Gooßen, G. Deng and L. M.
Levy, Science, 2006, 313, 662; (c) K. M. Logan, K. B. Smith and
M. K. Brown, Angew. Chem. Int. Ed., 2015, 54, 5228; (d) K.
Semba, K. Ariyama, H. Zheng, R. Kameyama, S. Sakaki and Y.
Nakao, Angew. Chem. Int. Ed., 2016, 55, 6275; (e) S. D. Friis,
M. T. Pirnot and S. L. Buchwald, J. Am. Chem. Soc., 2016, 138,
8372; (f) A. Saito, N. Kumagai and M. Shibasaki, Angew. Chem.
Int. Ed., 2017, 56, 5551; (g) H. Zheng, K. Semba, Y. Nakao and
S. Sakaki, J. Am. Chem. Soc., 2017, 139, 14065; (h) Z. Kuang, B.
Li and Q. Song, Chem. Commun., 2018, 54, 34; (i) M. Takeda,
K. Yabushita, S. Yasuda and H. Ohmiya, Chem. Commun.,
2018, 54, 6776; (j) K. Yabushita, A. Yuasa, K. Nagao and H.
Ohmiya J. Am. Chem. Soc., 2019, 141, 113; (k) A. M.
Bergmann, S. K. Dorn, K. B. Smith, K. M. Logan and M. K.
Brown, Angew. Chem. Int. Ed., 2019, 58, 1719.
Notes and references
1
(a) G. L. Patrick, An Introduction to Drug Synthesis; Oxford
University Press, 2015; (b) F. Lovering, J. Bikker and C.
Humblet, J. Med. Chem., 2009, 52, 6752.
2
3
For a recent representative example, see: Y. Wada, S. Kubo
and H. Kaji, Adv. Mater., 2018, 30, 1705641.
For representative reviews, see: (a) T. Akiyama and K. Mori,
Chem. Rev., 2015, 115, 9277; (b) C. Valente, S. Çalimsiɀ, K. H.
Hoi, D. Mallik, M. Sayah and M. G. Organ, Angew. Chem. Int.
Ed., 2012, 51, 3314.
(a) T. R. Kelly, H. De Silva and R. A. Silva, Nature, 1999, 401,
150; (b) K. Nikitin, H. Müller-Bunz, Y. Ortin, J. Muldoon and M.
J. McGlinchey, J. Am. Chem. Soc., 2010, 132, 17617. For
reviews, see: (c) G. S. Kottas, L. I. Clarke, D. Horinek and J.
Michl, Chem. Rev., 2005, 105, 1281; (d) S. Erbas-Cakmak, D. A.
Leigh, C. T. McTernan and A. L. Nussbaumer, Chem. Rev.,
2015, 115, 10081.
4
14 For details, see the ESI.
15 (a) S. Ito, H. Miyake and M. Yoshifuji, ARKIVOC 2012, 6, and
cited therein; (b) F. Ozawa and Y. Nakajima, Chem. Rec., 2016,
16, 2314.
16 M. Kobayashi, T. Matsuo, T. Fukunaga, D. Hashizume, H.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 6 of 7
ARTICLE
Journal Name
Fueno, K. Tanaka and K. Tamao, J. Am. Chem. Soc., 2010, 132,
15162.
View Article Online
DOI: 10.1039/C9SC00891H
17 (a) K. F. Biegasiewicz, J. R. Griffiths, G. P. Savage, J.
Tsanaktsidis and R. Priefer, Chem. Rev., 2015, 115, 6719; (b)
B. A. Chalmers, H. Xing, S. Houston, C. Clark, S. Ghassabian, A.
Kuo, B. Cao, A. Reitsma, C.-E. P. Murray, J. E. Stok, G. M. Boyle,
C. J. Pierce, S. W. Littler, D. A. Winkler, P. V. Bernhardt, C.
Pasay, J. J. De Voss, J. McCarthy, P. G. Parsons, G. H. Walter,
M. T. Smith, H. M. Cooper, S. K. Nilsson, J. Tsanaktsidis, G. P.
Savage and C. M. Williams, Angew. Chem. Int. Ed., 2016, 55,
3580; (c) T. A. Reekie, C. M. Williams, L. M. Rendina and M.
Kassiou,
J.
Med.
Chem.,
ASAP
(doi:
10.1021/acs.jmedchem.8b00888.)
18 (a) F. Toriyama, J. Cornella, L. Wimmer, T.-G. Chen, D. D.
Dixon, G. Creech and P. S. Baran, J. Am. Chem. Soc., 2016, 138,
11132; b) S. S. R. Bernhard, G. M. Locke, S. Plunkett, A. Meindl,
K. J. Flanagan and M. O. Senge, Chem. Eur. J., 2018, 24, 1026.
19 Control experiments gave some mechanistic insights,
including the necessity of Pd catalyst (run 5, Table 1), no
effects on the reaction outcome in the presence of radical
scavengers, and the product formation in the reaction of the
prepared 1c and Pd(Ar)I(PPh3)2 complex at 80 °C (Ar = p-
MeO2C-C6H4-). For details, see the ESI.
20 (a) A. A. Thomas and S. E. Denmark, Science, 2016, 352, 329;
(b) A. A. Thomas, H. Wang, A. F. Zahrt and S. E. Denmark, J.
Am. Chem. Soc., 2017, 139, 3805; (c) A. A. Thomas, A. F. Zahrt,
C. P. Delaney and S. E. Denmark, J. Am. Chem. Soc., 2018, 140,
4401.
21 (a) P. Pyykkö, Chem. Rev., 1997, 97, 597; (b) J. Bauer, H.
Braunschweig and R. D. Dewhurst, Chem. Rev., 2012, 112,
4329; (c) I. G. Powers and C. Uyeda, ACS Catal., 2017, 7, 936.
22 (a) R. J. Oeschger and P. Chen, J. Am. Chem. Soc., 2017, 139,
1069; (b) R. J. Oeschger, D. H. Ringger and P. Chen,
Organometallics, 2015, 34, 3888.
23 (a) D. G. Musaev and L. S. Liebeskind, Organometallics, 2009,
28, 4639; (b) A. Fromm, C. van Wüllen, D. Hackenberger and
L. J. Gooßen, J. Am. Chem. Soc., 2014, 136, 10007. See also: (c)
B. Fuentes, M. García-Melchor, A. Lledós, F. Maseras, J. A.
Casares, G. Ujaque and P. Espinet, Chem. Eur. J., 2010, 16,
8596; (d) J. delPozo, D. Carrasco, M. H. Pérez-Temprano, M.
García-Melchor, R. Álvarez, J. A. Casares and P. Espinet,
Angew. Chem. Int. Ed., 2013, 52, 2189; (e) J. delPozo, G. Salas,
R. Álvarez, J. A. Casares and P. Espinet, Organometallics, 2016,
35, 3604; (f) R. J. Oeschger and P. Chen, Organometallics,
2017, 36, 1465.
24 During the preparation of the manuscript, it was reported that
the ligand transfer between Rh(I) and Au(I) species should
proceed via an oxidative addition/reductive elimination
pathway, see: M. N. Peñas-Defrutos, C. Bartolomé, M. García-
Melchor and P. Espinet, Angew. Chem. Int. Ed., 2019,
EarlyView (doi: 10.1002/anie.201813419).
25 K. Morokuma, J. Chem. Phys., 1971, 55, 1236.
26 (a) NBO 6.0. E. D. Glendening, J. K. Badenhoop, A. E. Reed, J.
E. Carpenter, J. A. Bohmann, C. M. Morales, C. R. Landis and
F. Weinhold, Theoretical Chemistry Institute, University of
Wisconsin, Madison, 2013; (b) the NBO analysis was carried
out at the ωB97X-D/LanL2DZ & 6-31G* level of theory.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 7
Chemical Science
View Article Online
DOI: 10.1039/C9SC00891H
TOC scheme
A potent cross-coupling methodology that enables efficient carbon–carbon bond
formation at sterically hindered sp2- and sp3-carbons has been developed.