Synthesis of Chiral-Bridged Atropisomeric Monophosphine Ligands with Tunable Dihedral Angles and their Applications in Asymmetric Suzuki–Miyaura Coupling Reactions

Article abstract of DOI:10.1002/adsc.201700020

Precise chiral recognition was firstly realized in the construction of diastereomeric biaryl monophosphines by means of the substrate-directed asymmetric annulation reactions. A series of new chiral-bridged atropisomeric biphenyl monophosphine ligands with tunable dihedral angles was accordingly synthesized successfully without a resolution step being needed. Using these ligands, different kinds of axially chiral 1,1′-biaryl-2-phosphonates including the first reported quinolyl biaryl phosphonates were prepared in 42–97% yields with up to 96% ee via palladium-catalyzed asymmetric Suzuki coupling reactions. (Figure presented.).

Full text of DOI:10.1002/adsc.201700020

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
COMMUNICATIONS
DOI: 10.1002/adsc.201700020
Synthesis of Chiral-Bridged Atropisomeric Monophosphine
Ligands with Tunable Dihedral Angles and their Applications in
Asymmetric Suzuki–Miyaura Coupling Reactions
Wang Xia,a Yongsu Li,a Zihong Zhou,a Huixuan Chen,a Hao Liang,a Sifan Yu,a
Xuefeng He,a Yaqi Zhang,a Jiyan Pang,a Zhongyuan Zhou,b and Liqin Qiua,*
a
School of Chemistry, The Key Laboratory of Low-carbon Chemistry & Energy Conservation of Guangdong Province,
South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center, Guangdong Engineering
Research Center of Chiral Drugs, Sun Yat-Sen University, No. 135 Xingangxi Road, Guangzhou 510275, Peopleꢀs
Republic of China
Fax : +(86)-20-8411-0996; e-mail: qiuliqin@mail.sysu.edu.cn
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Peopleꢀs
b
Republic of China
Received: January 7, 2017; Revised: February 24, 2017; Published online: && &&, 0000
Supporting information for this article can be found under http://dx.doi.org/10.1002/adsc.201700020.
Abstract: Precise chiral recognition was firstly real-
ized in the construction of diastereomeric biaryl
monophosphines by means of the substrate-directed
asymmetric annulation reactions. A series of new
chiral-bridged atropisomeric biphenyl monophos-
phine ligands with tunable dihedral angles was ac-
cordingly synthesized successfully without a resolu-
tion step being needed. Using these ligands, differ-
ent kinds of axially chiral 1,1’-biaryl-2-phosphonates
including the first reported quinolyl biaryl phospho-
nates were prepared in 42–97% yields with up to
96% ee via palladium-catalyzed asymmetric Suzuki
coupling reactions.
P,N ligands[6] and P,O ligands,[7] which were successful-
ly used in the asymmetric Suzuki coupling. The effect
of alkoxy groups at the 2’-position of the ligands on
the catalytic performance was also studied preliminar-
ily.[7] However, the true function of the groups at the
2’-position is still unclear in the asymmetric reactions.
A breakthrough in asymmetric Suzuki coupling came
with the report of Buchwald and co-worker in 2000.[5]
Since then, Cammidge,[8] Colobert,[9] Espinet,[10]
Fernꢁndez and Lassaletta,[11] Fujihara,[12] Uozumi,[13]
Suginome,[14] and other groups[6,7,15] have made their
contributions in this field. However, the substrate
scope still remains very limited until now. Halogenat-
ed benzenes or naphthalenes were generally em-
ployed as the halide partners in previous works. Ap-
plications of heterocyclic aromatic halides in asym-
metric Suzuki–Miyaura coupling reactions were
rare.[16] The synthesis of different kinds of novel axial-
ly chiral heterocyclic biaryls is anticipated. Based on
the importance of chiral monophosphine ligands and
the significant influence of the dihedral angle of
Keywords: asymmetric catalysis; diastereoselective
synthesis; heterocyclic biaryls; monophosphine li-
gands; quinoline derivatives; Suzuki coupling
Axially chiral biaryls are key structural motifs in biaryl diphosphine ligands on asymmetric catalysis,[17]
a number of natural products and have also proved to we accordingly began to develop dihedral angle-tuna-
be efficient ligands in asymmetric catalysis.[1] During ble monophosphine ligands and investigated their
the past three decades, the development of novel ax- asymmetric catalytic performance. Herein, we disclose
ially chiral ligands has received considerable atten- a strategy for the preparation of novel chiral-bridged
tion, especially 2,2’-difunctionalized biaryl ligands atropisomeric monophosphine ligands without a 2’-
such as axially chiral BINOL,[2] BINAP,[3] and MOP- substituent and their applications in asymmetric
type ligands.[4] Atropisomeric biaryl monophosphine Suzuki–Miyaura coupling reactions.
ligands are highly effective for many catalytic asym-
The new and concise synthetic route to dihedral
metric reactions,[5] however, the development of prac- angle-tunable monophosphine ligands 9a–9l is depict-
tical and simple preparation methods for chiral mono- ed in Scheme 1. Racemic (6,6’)-dimethoxy-2-hydroxy-
phosphine ligands still remains challenging. Recently, (1,1’)-biphenyl 3 was first prepared in 74% yield by
our group synthesized two classes of chiral-bridged a Suzuki–Miyaura coupling reaction of 2-iodo-3-me-
Adv. Synth. Catal. 0000, 000, 0 – 0
1
ꢂ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
COMMUNICATIONS
asc.wiley-vch.de
Scheme 1. Synthesis of ligands. Reagents and conditions: (a) K2CO3, Pd(OAc)2, DMF, H2O, 50 8C; (b) Tf2O, Py, 0 8C to room
temperature; (c) Ar2P(O)H, dppb, Pd(OAc)2, DIPEA, DMSO, 1108C; (d) HSiCl3, DIPEA, toluene, 1108C; (e) BBr3, DCM,
À788C to room temperature; (f) Cs2CO3, DMF, 808C.
thoxyphenol 1 and 2-methoxybenzeneboronic acid 2 turally confirmed by X-ray crystallographic analysis
under mild conditions. Then trifluoromethanesulfonic (Figure 1). To the best of our knowledge, these are
anhydride was added to a solution of 3 in pyridine at the first successful examples to obtain single diaste-
08C. The resulting system was stirred at room temper- reomeric biaryl monophosphine ligands by a sub-
ature for 12 h and gave product 4 in 95% yield. An strate-directed asymmetric annulation reaction. Gen-
arylphosphine oxide moiety was introduced to com- erally tedious and sometimes difficult resolution pro-
pound 4 by reaction with Ar2P(O)H in DMSO at cesses are therefore avoided.
1108C for 12 h in a Pd(OAc)2, 1,4-bis(diphenylphos-
After successful preparation of the ligands, the di-
phino)butane and N,N-diisopropylethylamine catalyst hedral angles of 9a, 9e, 9i, 9c, 9g and 9k were estimat-
system; monophosphine oxides 5a–5d were afforded ed by Chem 3D MM2 Modelling.[18] As shown in
in 88–96% yields. Phosphines 6a–6d were accordingly Table 1, the corresponding values were 49.78 [(S,S,Ra)-
obtained via reduction of 5a–5d with trichlorosilane 9a], 61.38 [(R,R,Sa)-9e] and 55.08 [(R,R,Sa)-9i], respec-
and N,N-diisopropylethylamine. Subsequent removal tively. This shows significant dependence of the dihe-
of the methyl groups of 6a–6d with a solution mixture dral angles on the length of the chiral bridge on the
of BBr3 and DCM gave 7a–7d. Chiral ligands 9a–9l ligand backbone.
were finally prepared successfully via an SN2 substitu-
With the developed ligands in hand, we first select-
tion and annulation reaction with racemates 7a–7d ed quinolyl bromides as the coupling partners. Cou-
and chiral compounds 8a–8c. It is noted that this an- pling of diethyl 8-bromo-7-quinolinylphosphonate
nulation reaction shows precise chiral recognition (12a) with 1-naphthylboronic acid was chosen as the
ability. Central chirality from the linking unit of 8 di- model reaction (Table 2). Ligands 9a–9l (Scheme 1)
rected and determined the axial chirality of the prod- along with 10a–10d (Figure 2) and the well-known
uct. No matter what was used for chiral 8a, 8b or 8c, 11a–11d (Figure 2) were employed for evaluation of
only the corresponding single configurational diaste- the catalytic efficacy. Ligand (R,R,Sa)-9i complexed
reomers 9 were obtained according to NMR analysis. with Pd2(dba)3 was found to be the best choice for the
As a proof, (S,S,Ra)-9c and (R,R,Sa)-9i were also struc- reaction. With the combination of THF, K3PO4,
Adv. Synth. Catal. 0000, 000, 0 – 0
2
ꢂ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
COMMUNICATIONS
asc.wiley-vch.de
Table 2. Optimization experiments.[a]
En-
L*
Solvent Temp. Yield[b] ee[c]
try[a]
[oC]
[%]
[%]
1
2
3
4
5
6
7
8
(S,S,Ra)-9a
(S,S,Ra)-9b
(S,S,Ra)-9c
(S,S,Ra)-9d
(R,R,Sa)-9e THF
(R,R,Sa)-9f THF
(R,R,Sa)-9g THF
(R,R,Sa)-9h THF
(R,R,Sa)-9i
(R,R,Sa)-9j
(R,R,Sa)-9k THF
(R,R,Sa)-9l
10a
10b
10c
10d
11a
11b
11c
11d
THF
THF
THF
THF
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
65
35
30
30
73
59
58
48
75
64
65
63
82
66
72
74
65
73
78
64
80
66
76
71
77
81
52
82
64 (À)
43 (À)
34 (À)
55 (À)
73 (+)
55 (+)
52 (+)
52 (+)
81 (+)
66 (+)
71 (+)
51 (+)
49 (À)
61 (À)
61 (À)
66 (À)
32 (À)
52 (À)
45 (À)
23 (À)
71[d] (+)
84[e] (+)
84[e] (+)
84[e] (+)
Figure 1. Single-crystal X-ray structures of (S,S,Ra)-9c and
(R,R,Sa)-9i.
9
THF
THF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Table 1. Calculated dihedral angles of ligands 9a, 9e, 9i.
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DME[f]
Ligand
(S,S,Ra)-9a
49.78
(R,R,Sa)-9e
61.38
(R,R,Sa)-9i
55.08
Dihedral angle
Pd2(dba)3 and (R,R,Sa)-9i, the target product 13a was
obtained in 82% yield and 81% ee (Table 2, entry 9).
When the reaction was conducted with chiral ligands
9a–9d, coupling product 13a was provided with 64%,
43%, 34% and 55% ees, respectively (Table 2, en-
tries 1–4). This shows that chiral ligand 9a linked with
two phenyl groups on the P-atom provided higher
enantioselection than those ligands having two substi-
tuted phenyl groups. Similar phenomena were also
observed for 9e–9h (Table 2, entries 5–8) and 9i–9l
(Table 2, entries 9–12). Combining the dihedral angles
listed in Table 1 with the catalytic data in Table 2 (en-
tries 1, 5 and 9), it can been inferred that a moderate
dihedral angle is appropriate for acquiring better cat-
alytic results in this reaction. Ligands 10a–10d were
also used for investigating the influence of the MeO
group linked at the 2’-site of the ligands, affording 13a
with moderate enantioselectivities in a range of 49–
66% ee (Table 2, entries 13–16). As a comparison,
BINOL-derived MOPs 11a–11d provided the product
only with lower ees than most of the chiral-bridged bi-
phenyl ligands (Table 2, entries 17–20). All of these
findings demonstrate that the chiral-bridged biphenyl
skeleton in 9a–9l and 10a–10d is beneficial for acquir-
ing high enantioselectivity in this reaction and the
MeO group linked at the 2’-site of the ligands is not
(R,R,Sa)-9i
(R,R,Sa)-9i
(R,R,Sa)-9i
(R,R,Sa)-9i
[a]
Reaction conditions: 1 equiv. of aryl bromide, 2 equiv. of
naphthyl boronic acid, 4% of Pd, 4.8% of ligand, 3 equiv.
of K3PO4, solvent, 36 h.
Yield of isolated product.
Determined by HPLC with a Chiralcel OD-H column.
Reaction time is 24 h.
[b]
[c]
[d]
[e]
[f]
Reaction time is 72 h.
DME=1,2-dimethoxyethane.
necessary for the reaction coordination. This further Figure 2. Monophosphine ligands 10a–10d and 11a–11d.
Adv. Synth. Catal. 0000, 000, 0 – 0
3
ꢂ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
COMMUNICATIONS
asc.wiley-vch.de
deepens insight into the coordination behavior of pal- the coupling partner, coupling products 13a
ladium-monophosphine-catalyzed Suzuki reactions.[19] (Figure 3), 13b, 13c and 13d were obtained in good
Commonly available solvents combined with reaction enantioselectivities (84%, 75%, 81%, and 66% ees, re-
temperature optimization showed that 358C was the spectively). Various arylboronic acids reacted with
best choice with use of THF as the solvent (Table 2, 12a smoothly and a series of chiral biaryl compounds
entry 22). When DME was employed as the solvent, (13e–13p) was obtained in moderate to good yields
308C was appropriate (Table 2, entry 24).
with good to excellent enantioselectivities (up to 96%
With Pd2(dba)3-(R,R,Sa)-9i as the chiral catalyst, we ee). Coupling of 12a with different 1-naphthylboronic
next explored the substrate scope for coupling reac- acids possessing an electron-donating group such as
tion I (Scheme 2). Using 1-naphthylboronic acid as Me, OMe, OBn, or Ph at the 4-position provided
Scheme 2. Asymmetric Suzuki–Miyaura coupling I. Reaction conditions: 12 (1.0 mmol), ArB(OH)2 (2.0 mmol), K3PO4
(3.0 mmol), ligand (4.8 mol%), Pd (4 mol%), THF (6 mL) or DME (6 mL). Yields are combined isolated values; ee values
were determined by HPLC.
Adv. Synth. Catal. 0000, 000, 0 – 0
4
ꢂ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!