Twofold C?H Activation-Based Enantio- and Diastereoselective C?H Arylation Using Diarylacetylenes as Rare Arylating Reagents

Article abstract of DOI:10.1002/anie.202106871

C?H bond activation has been established as an attractive strategy to access axially chiral biaryls, and the most straightforward method is direct C?H arylation of arenes. However, the arylating source has been limited to several classes of reactive and bulky reagents. Reported herein is rhodium-catalyzed 1:2 coupling of diarylphosphinic amides and diarylacetylenes for enantio- and diastereoselective construction of biaryls with both central and axial chirality. This twofold C?H activation reaction stays contrast to the previously explored Miura–Satoh type 1:2 coupling of arenes and alkynes in terms of chemoselectivity and proceeded under mild conditions with the alkyne acting as a rare arylating reagent. Both C?H activation events are stereo-determining and are under catalyst control, with the 2^nd C?H activation being diastereo-determining in a remote fashion. Analysis of the stereochemistry of the major and side products suggests moderate enantioselectivity of the initial C?H activation–desymmetrization process. However, the minor (R) rhodium vinyl intermediate is consumed more readily in undesired protonolysis, eventually resulting in high enantio- and diastereoselectivity of the major product.

Full text of DOI:10.1002/anie.202106871

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How to cite:
International Edition: doi.org/10.1002/anie.202106871
À
C H Activation
German Edition:
doi.org/10.1002/ange.202106871
À
À
Twofold C H Activation-Based Enantio- and Diastereoselective C H
Arylation Using Diarylacetylenes as Rare Arylating Reagents
Panjie Hu, Lingheng Kong, Fen Wang,* Xiaolin Zhu, and Xingwei Li*
À
Abstract: C H bond activation has been established as an
attractive strategy to access axially chiral biaryls, and the most
complexity in a single step starting from readily available
reagents.
À
À
straightforward method is direct C H arylation of arenes.
The effectiveness of C H bond activation-based gener-
ation of axially chirality has been witnessed by the increasing
However, the arylating source has been limited to several
classes of reactive and bulky reagents. Reported herein is
rhodium-catalyzed 1:2 coupling of diarylphosphinic amides
and diarylacetylenes for enantio- and diastereoselective con-
struction of biaryls with both central and axial chirality. This
number of reports in the past decade. Early work focused on
palladium-catalyzed C H activation, and the majority of
[3]
À
recent studies takes advantage of size-increasing effect via
dynamic kinetic transformation of arenes that already bear an
axis.[4] Our group also realized biaryl synthesis by alternative
dynamic kinetic transformation of the coupling reagent
(alkynes).[5] Direct arylation of arenes with concurrent
generation of an axis seems a more straightforward protocol.
In 2012 Yamaguchi and Itami applied naphthyl boronic acids
as an arylating reagent in Pd-catalyzed arylation of thio-
phenes.[6] In 2020, Cramer applied 1-naphthyl bromide as the
À
twofold C H activation reaction stays contrast to the previ-
ously explored Miura–Satoh type 1:2 coupling of arenes and
alkynes in terms of chemoselectivity and proceeded under mild
conditions with the alkyne acting as a rare arylating reagent.
À
Both C H activation events are stereo-determining and are
under catalyst control, with the 2nd C H activation being
À
diastereo-determining in a remote fashion. Analysis of the
stereochemistry of the major and side products suggests
moderate enantioselectivity of the initial C H activation–
desymmetrization process. However, the minor (R) rhodium
vinyl intermediate is consumed more readily in undesired
protonolysis, eventually resulting in high enantio- and diaste-
reoselectivity of the major product.
arylating reagent for biaryl synthesis.[7] Great progress has
[8]
À
À
been made in Rh- or Ir-catalyzed C H activation. In 2017,
Waldmann[9] realized asymmetric C H arylation of sterically
À
hindered benzamides with diazonaphthoquinones catalyzed
by a chiral RhIII cyclopentadienyl (Scheme 1a). Cramer
elegantly realized desymmetrization-arylation of phosphine
oxides using a chiral CpXIr(III) catalyst in combination with
a chiral acid (Scheme 1a).[10] We recently applied o-alkyny-
lanilines as an arylating reagent for 2,3’-biindolyl synthesis.[11]
In 2020, You achieved arylation of arenes via dynamic kinetic
Introduction
Axially chiral compounds represent a large family of
aromatics that have found wide applications as medicinally
important agents, organocatalysts, and chiral ligands or
catalysts. Numerous organocatalytic and metal-catalyzed
synthetic methods have been developed to access atropo-
enriched biaryls.[1] Despite the progress, there is a general
trend to access these synthetic targets by overcoming some
drawbacks such as use of stoichiometric chiral auxiliaries and
the requirement of prefunctionalized starting materials. In
[2]
À
this regard, asymmetric C H bond activation has been
established as an atom- and step-economic approach to
address these limitations, allowing generation of molecular
[*] P. Hu, Dr. L. Kong, Dr. F. Wang, Dr. X. Zhu, Prof. Dr. X. Li
School of Chemistry and Chemical Engineering, Shaanxi Normal
University (SNNU)
Xi’an 710062 (China)
E-mail: fenwang@snnu.edu.cn
lixw@snnu.edu.cn
Prof. Dr. X. Li
Institute of Molecular Sciences and Engineering, Institute of Frontier
and Interdisciplinary Sciences, Shandong University
Qingdao 266237 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202106871.
À
Scheme 1. Axially chiral biaryls via C H arylation of arenes.
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Table 1: Initial optimization of the directing group.[a]
transformation of arenes using heteroarenes as an arylating
reagent.[12]
Despite the progress, generation of axial chirality calls for
employment of more readily available arylating reagents.
Since 1-naphthyl groups represent a typical bulky aryl ring,
formation of 1-naphthyls offers a convenient approach to
biaryl synthesis. In this context, Wang[13] reported in 2019
Satoh-Miura type[14] 1:2 annulation between amides and
alkynes for atroposelective synthesis of naphthalenes (Sche-
me 1a), where the alkyne contributes four carbon atoms to
the naththalene ring (Type I coupling), and the axis preexists
in the arene substrate, which amounts to dinamic kinetic
transformation of the arene substrate. On the other hand,
alternative role of alkynes may be invoked in a different
chemoselectivity (Scheme 1b, Type II reaction) where the
chiral axis is newly constructed. While this reaction also
proceeds via twofold C H activation and 1:2 coupling,[15] the
À
alkyne contributes ten carbon atoms during the naphthalene
ring formation, and one of arene ring in the alkyne unit
À
undergoes C H activation. This unusual selectivity has been
disclosed in several reports.[16] However, no atroposelective
system has been developed. We now report enantio- and
[a] Reaction conditions: 1 (0.05 mmol), 2a (0.15 mmol), (R)-Rh1
(4 mol%), AgOTf (16 mol%), AgOAc (0.15 mmol), CyCO2H (0.1 mmol),
DCM (1 mL), 24 h, 508C. The e.r. was determined by HPLC using a chiral
stationary phase. [b] The yield was determined by 1H NMR analysis.
À
diastereoselective C H activation–desymmetrization of
phosphinamide (Scheme 1c), leading to synthesis of biaryls
À
with axial and P-central chirality, in which both the C H
activation events are stereo-determining.
Table 2: Optimization of the reaction conditions.[a]
Results and Discussion
We embarked on our studies by screening a series of
arenes bearing different directing groups using the Cramer-
type (R)-Rh1 catalyst.[17] While some arenes were found to
undergo the Satoh-Miura type annulation with diphenylace-
Entry Ag additive Oxidant (equiv) Solvent Yield [%]
e.r.
1
2
3
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgSbF6
AgPF6
AgBF4
AgOTf
AgOTf
AgOAc (3.0)
iPrCO2Ag (3.0)
CyCO2Ag (3.0)
AgOAc (3.0)
AgOAc (3.0)
AgOAc (3.0)
AgOAc (3.0)
AgOAc (3.0)
AgOAc (3.0)
AgOAc (2.5)
AgOAc (2.5)
AgOAc (2.5)
AgOAc (2.5)
AgOAc (2.5)
AgOAc (2.5)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
65
30
56
57
23
43
47
12
25
71
67
30
54
52
43
97:3
96:4
97:3
95:5
94:6
87:13
93:7
98:2
97:3
98:2
97:3
95:5
96:4
97:3
90:10
tylene, the desired chemoselectivity was consistently realized
[11,18]
=
when arenes bearing a P O
directing group were used
under oxidative conditions (AgOAc, DCM, Table 1). It was
discovered that phosphinamides with dialkylamino groups
underwent 1:2 coupling with diphenylacetylene in variable
enantioselectivity (77:23 to 97:3 e.r.), and the highest enan-
tioselectivity was observed for a NiPr2 substituent. In contrast,
Ph2P(O)tBu only coupled with lower efficiency and moderate
enantioselectivity. Therefore, this substrate (1a) was retained
for further optimization.
The coupling of 1a and diphenylacetylene (2a) was
further screened (Table 2 and Supporting Information).
Increasing the temperature to 608C improved the reaction
efficiency, while no improvement was made when other silver
carboxylate oxidants were used (entries 1–3). CyCO2H
seemed to be a superior acid additive and other common
carboxylic acids gave less satisfactory outcomes (entries 4–7).
Solvent screening indicated that DCM outperformed other
halogenated solvents. AgOTf and AgSbF6 proved nearly
equally effective in activating the RhIII catalyst (entries 9–10
and Equation 1). While the reaction may afford the undesired
hydroarylation product, the enantio- and diastereoselectivi-
ties were generally high. In contrast to the Rh1 catalyst, Rh2
and Rh3 gave lower efficiency or enantioselectivity. In all
cases, no Type I coupling product was detected. The absolute
4[b]
5[c]
6[d]
7[e]
8
9
PhCl
10
11
12
13
14[f]
15[g]
DCM
DCM
DCM
DCM
DCM
DCM
[a] Reaction conditions: 1a (0.05 mmol), 2a (0.125 mmol), (R)-Rh1
(4 mol%), AgOTf (16 mol%), AgOAc (0.125 mmol) and CyCO2H
(0.1 mmol) in DCM (1 mL), 24 h, 608C, isolated yield. >19:1 d.r. in all
cases. The e.r. was determined by HPLC using a chiral stationary phase.
[b] iPrCO2H (0.1 mmol) instead of CyCO2H. [c] PhCO2H (0.1 mmol)
instead of CyCO2H. [d] tAmCO2H (0.1 mmol) instead of CyCO2H.
[e] AcOH (0.1 mmol) instead of CyCO2H. [f] (R)-Rh2 (4 mol%). [g] (S)-
Rh3 (4 mol%).
configuration of 3 has been determined by X-ray crystallog-
raphy (CCDC 2006608).[19]
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were obtained in much lower enantioselectivity. Significantly
and surprisingly, the absolute configuration of a representative
À
C H olefination product (3’) has been determined to be (R)
configured (CCDC 2085200), which stands in sharp contrast
to the (S) P-central chirality in the final product. These
observations may offer insight into the mechanism of this
coupling system (see below).
The scope of the diarylacetylene was next explored
(Scheme 3). Since the alkyne underwent twofold insertion
À
together with C H activation in one of the arene ring, it is
expected that the electronic and steric effects of the alkyne
Scheme 2. Scope of phosphoric amides in enantioselective arylation.
[a] Reaction conditions: 1 (0.05 mmol), 2a (0.125 mmol), (R)-Rh1
(4 mol%), AgOTf (16 mol%), AgOAc (0.125 mmol), CyCO2H
(0.1 mmol), DCM (1 mL), 608C, 24 h. [b] 1 mmol scale. [c] AgSbF6
(16 mol%). [d] AgPF6 (16 mol%), 408C. [e] 0.1 cmmol scale.
Having established the optimal reaction conditions, we
next examined the scope of the arene substrates (Scheme 2).
Symmetric diarylphosphinic amides bearing an electron-
Scheme 3. Scope of diarylacetylene in enantioselective arylation. [a] Re-
action conditions: 1a (0.05 mmol), 2 (0.125 mmol), (R)-Rh1
(4 mol%), AgOTf (16 mol%), AgOAc (0.125 mmol), and CyCO2H
(0.1 mmol) in DCM (1 mL) at 608C, 24 h. [b] CHCl3. [c] (R)-Rh2
(4 mol%) was used. [d] r.r. was determined by HPLC. [e] 0.1 mmol
scale.
t
donating (Me, Et, Bu, OEt, and OMe), -withdrawing (Ph
and CF3), and halogen groups at the para position of the
benzene ring were generally well tolerated, and the corre-
sponding products (4–13) were isolated in moderate to good
yields and in 93.5:6.5 to 97.5:2.5 e.r. Arenes bearing meta alkyl
À
and alkoxyl groups were also compatible (14–17), and the C
À
H activation took place at the less hindered ortho C H site in
are superposed to give a pronounced effect. Indeed, essen-
tially no desired reaction was detected when di(o-tolyl)ace-
tylene was used. Nevertheless, coupling using various diary-
lacetylene bearing electron-donating (alkyl and OMe) and
-withdrawing (halogen, OCF3, and CF3) at the para position
afforded the desired product in moderate yield and good to
excellent enantioselectivity (24–33, 91.5:8.5 to 97:3 e.r.). In
contrast, the reaction of di-(m-tolyl)acetylene and 1a only
gave complicated product mixtures.
Synthetic applications of product 3 at a 1 mmol scale was
demonstrated (Scheme 4). Treatment of 3 with MeOTf
followed by LAH reduction afforded diarylphosphine oxide
34 in moderate yield and low diastereoselectivity, and each
diastereomer was obtained in 95:5 e.r. Pd-catalyzed phenyl-
ation of the diastereomeric mixture of 34 gave the corre-
excellent enantioselectivity (95:5 to 97:3 e.r.). The reaction
seemed sensitive to steric effect; introduction of an ortho Me
group inhibited the reaction. Other N,N-dialkylphosphina-
mides reacted with slightly lower enantioselectivity (18–21).
Similarly, tertiary alkyl amine-derived phosphinamides also
reacted with attenuated enantioselectivity (22 and 23). This
coupling reaction can be performed at a 0.1 mmol scale and
was readily scaled to 1 mmol scale. All the products obtained
in this work are atropomerically stable and no decrease of
enantiopurity or diastereopurity was observed when they
À
were heated at 1008C. In most cases, competitive 1:1 C H
olefination side products were observed, which accounts for
the moderate isolated yields of the major 1:2 coupling
products in most reactions. These olefination side-products
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Scheme 4. Product transformations and applications.
sponding triarylphosphine oxide. Standard reduction by
SiHCl3 provided the axially chiral phosphine 35 in high yield
and in 95:5 e.r. Phosphine 35 has been applied as a chiral
ligand in palladium-catalyzed asymmetric allylic alkylation of
an allyl acetate, affording product 36 in 95:5 e.r.
Photophysical properties of selected products (3, 4, 7, 9,
and 31) were next examined (Figure 1). These compounds
typically exhibited three absorption bands in the UV–Vis
spectroscopy, ranging from 225 to 317 nm. Fuorescence
emission was observed (excited at 300 nm), and the absolute
quantum yield was determined. The highest quantum yield of
0.5 was found for product 3 (Table 2). These data may indicate
the potentiality of our products as organic semiconductors
(Table 3).
Scheme 5. Mechanistic studies.
that the 1st C H activation is turnover-limiting. In contrast,
À
À
C H activation of the alkyne is likely rapid (KIE = 1.2,
Scheme 5c). This conclusion seems reasonable because the
2nd C H activation leads to a thermodynamically stable
À
rhodacycle (see below) and is probably also kinetically
feasible. In addition, the kinetic isotope effect with respect
À
to the formation of the C H olefination side product was also
determined by parallel reactions, and a consistent value was
obtained, indicating no change of the turnover-limiting step.
A plausible mechanism of the coupling of 1a and 2a is
proposed (Scheme 6). The 1 C H activation likely occurs via
st
À
We next briefly explored the mechanism of this naphthy-
lation reaction. H/D exchange between phosphinamide 1a
and CD3CO2D under the standard conditions gave appreci-
able H/D exchange at the ortho positions (Scheme 5a).
However, only slight exchange was observed when dipheny-
carboxylate-assisted concerted metalation-deprotonation
(CMD) to give rhodacyclic intermediate B, which is enan-
tio-determining with respect to the P-stereogenic center. The
insertion of the 1st diphenylacetylene gives a rhodacycle C.
Subsequent cis–trans isomerization of the RhIII alkenyl
lacetylene was present, indicating that the C H activation
moiety in C is proposed to give RhIII vinyl D. The 2nd ortho
À
[14]
À
was largely irreversible in the catalytic system. Two KIE
experiments were next conducted. The parallel reactions
using 1a and 1a-d10 gave kH/kD = 3.5 (Scheme 5b), suggesting
C H activation then occurs to give a stable rhodacyclic
intermediate E. The Satoh-Miura coupling selectivity was not
observed due to more facile cis–trans isomerization in our
system, which is probably driven by formation of thermody-
namically stable intermediate E. A related signal of m/e =
984.3068 was indeed observed in mass spectrometric analysis
of a reaction mixture. This 2nd C H activation is diastereo-
À
Figure 1. Normalized absorption and emission spectra of 3, 4, 7, 31
and 9 in DCM (1ꢁ10À5 M).
Table 3: Photophysical properties of selected products in CH2Cl2
(1ꢁ10À5 M).
[a]
[b]
[c]
Compound
labs [nm]
lem [nm]
FF
3
4
7
31
9
227, 297 (sh), 317 (sh)
227, 245 (sh), 297 (sh)
227, 297 (sh), 317 (sh)
366
366
363
372
384
0.50
0.48
0.47
0.003
0.005
225, 254 (sh), 303 (sh)
Scheme 6. Proposed catalytic cycle (EDS=enantiodetermining step,
DDS=diastereodetermining step, RDS=rate-determining step).
225, 251(sh), 273 (sh), 316 (sh)
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Conclusion
In summary, we have achieved
the 1:2 coupling of phosphinamides
with diarylacetylenes for enantio-
and diastereoselective synthesis of
axially chiral biaryls bearing a P-
stereogenic center. The reaction
proceeded via desymmetrization
of phosphinamides, with the alkyne
being a rare arylating reagent. Dual
À
activation of C H bonds in the
phosphinamide and the diarylace-
tylene has been invoked, with each
being stereo-determining. The re-
actions proceeded under mild con-
ditions with high enantioselectivity
and excellent diastereoselectivity.
Analysis of the stereochemistry of
the major and side products sug-
gests moderate enantioselectivity
À
of the initial C H activation–de-
symmetrization process. However,
the minor (R) rhodium vinyl inter-
mediate is consumed more readily
Scheme 7. Rationalization of the stereochemistry of the major and side products.
determining, and the axial chirality is retained in the 2nd
in undesired protonolysis, resulting in high enantioselectivity
of the major product (with Horeau amplification effect) at the
cost of the formation of side products. Future studies of axial
chirality using other arylating reagents are underway in our
laboratories.
À
alkyne insertion and C C reductive elimination of F or F’.
The observed stereochemistry of the olefination side
product was taken onto account of the mechanism (Sche-
À
me 7A). The C H activation of the diphenylphosphinic
amide is enantiodetermining and it slightly favors formation
of the (S) configured P-chiral intermediate (B) based on the
stereochemistry of the major 1:2 coupling product. Following
the parallel alkyne insertion, both intermediates (S)-C and
(R)-C’ are generated. Clearly, two competing processes are
existing: these two RhIII vinyl species may undergo undesired
protonolysis and the desired cis–trans isomerization of the
Acknowledgements
Financial support from the NSFC (21525208) and the SNNU
is gratefully acknowledged.
vinyl group to allow for the 2nd C H activation. On the basis
À
of the observed opposite configurations of the major and the
side products, it is possible that protonolysis of (S)-C and (R)-
C’ is competitive and the protonolysis of the latter inter-
mediate likely carries a slightly lower barrier. This eventually
leads to overall moderate enantioselectivity of the (R)-3’ side
product. Accordingly, with the relatively less favored proto-
nolysis of the (S)-C, it rather prefers to undergo cis–trans
Conflict of Interest
The authors declare no conflict of interest.
À
Keywords: alkyne · arylation · axial chirality · C H activation ·
desymmetrization
isomerization to allow formation of D. In the 2nd C H
À
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Manuscript received: May 22, 2021
´
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Accepted manuscript online: June 19, 2021
du Vignꢅ, V. Smal, Y.-X. Cao, N. Cramer, Chem. Rev. 2020, 120,
Version of record online: && &&
,
&&&&
Angew. Chem. Int. Ed. 2021, 60, 2 – 8
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Research Articles
À
C H Activation
P. Hu, L. Kong, F. Wang,* X. Zhu,
X. Li*
&&&& — &&&&
À
Twofold C H Activation-Based Enantio-
À
and Diastereoselective C H Arylation
Using Diarylacetylenes as Rare Arylating
Reagents
Rhodium-catalyzed 1:2 coupling of
bearing a P-stereogenic center. The reac-
À
phosphinamides and diarylacetylenes has
been realized for enantio- and diastereo-
selective synthesis of axially chiral biaryls
tion proceeded via twofold C H bond
activation, with the alkynes being an ary-
lating reagent.
&&&&
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 2 – 8
These are not the final page numbers!