Pd-Catalyzed Asymmetric C-H Bond Activation for the Synthesis of P-Stereogenic Dibenzophospholes

Article abstract of DOI:10.1021/acs.organomet.9b00216

Pd-catalyzed asymmetric C-H bond activation for the synthesis of P-stereogenic dibenzophospholes was efficiently achieved via two types of catalytic systems. Chiral phosphoric amides/acids as ligands provided the products with up to 5:95 er, and (R)-segph

Full text of DOI:10.1021/acs.organomet.9b00216

Communication
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Pd-Catalyzed Asymmetric C−H Bond Activation for the Synthesis of
P‑Stereogenic Dibenzophospholes
Zhen Li,† Zi-Qi Lin,‡ Chao-Guo Yan,† and Wei-Liang Duan*,†
†College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, People’s Republic of China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: Pd-catalyzed asymmetric C−H bond activation
for the synthesis of P-stereogenic dibenzophospholes was
efficiently achieved via two types of catalytic systems. Chiral
phosphoric amides/acids as ligands provided the products
with up to 5:95 er, and (R)-segphos as ligand resulted in
enantioselectivities of up to 98:2.
Scheme 1. Synthesis of P-Stereogenic Phosphorus
Compounds
P-stereogenic phosphorus compounds have attracted consid-
erable interest because of their inherent property as useful
chiral ligands1 in asymmetric catalysis. Although P-stereogenic
compounds are efficient in several catalytic reactions, their
application in catalysis has been less explored in comparison
with phosphorus ligands with chiral carbon centers or axial
chirality, probably because of the difficulty in the preparation
and accessibility of P-chiral ligands.2 Pd-catalyzed asymmetric
C−H bond activation has emerged as an effective method to
synthesize chiral phosphorus compounds.3,4 Our group5 and
Liu, Ma, and co-workers6 independently reported Pd-catalyzed
enantioselective C−H arylation to synthesize P-stereogenic
phosphinic amides by using TADDOL-derived phosphorami-
dites with excellent stereoselectivities (Scheme 1aa). Tang and
co-workers7 also presented an efficient method for the
synthesis of a series of P-chiral biarylphosphonates with good
enantioselectivities from P-chiral biaryl monophosphorus
ligands (Scheme 1ab). Cui, Xu, et al.8 demonstrated the
desymmetrization of o-bromoaryl diarylphosphine oxides to
provide P-stereogenic phosphole oxides with 4−94% ee by
using Me-DuPhos as a ligand (Scheme 1ac); the success of this
transformation built a solid foundation for further improving
the enantioselectivity by the change of ligand or additive in the
reaction. In the above examples (Scheme 1a), trivalent chiral
phosphorus ligands were used in combination with palladium
to control the enantioselectivity in reaction.
asymmetric C−H arylation of ferrocenyl ketones through
Pd(0)/Pd(II) catalysis (Scheme 1ba).13 Baudoin et al.14 also
developed an asymmetric intramolecular arylation to synthe-
size indolines with Pd/chiral phosphoric acid (Scheme 1bb).
Phosphole compounds have attracted considerable attention
because of their π-conjugated systems, which is useful for the
In 2015, we first described the Pd-catalyzed enantioselective
arylation of β-C(sp3)−H bonds in 8-aminoquinoline amides,9
and a chiral phosphoric amide/acid10 was used as the only
chiral source to control stereoselectivity in the reaction. In this
new protocol,11 ligands not only coordinate with metals but
also directly participate in the concerted metalation−
deprotonation12 step to control the enantioselectivity of the
reaction, which is different from the reaction involving Pd/
chiral phosphine catalysts (Scheme 1a). We further used Pd/
chiral phosphoric acid (CPA) systems to carry out the
Special Issue: Asymmetric Synthesis Enabled by Organometallic
Complexes
Received: March 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.9b00216
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
construction of optical electronic materials.15 To continue our
interest in the area of synthesis of chiral phosphorus
compounds.5 Herein, we report the development of two
catalytic systems for the Pd-catalyzed asymmetric C−H
arylation of phosphine oxides, thereby constructing P-stereo-
genic dibenzophospholes with good to excellent enantiose-
lectivities (Scheme 1c).
a
Table 1. Optimization of Reaction Conditions
Diphenyl(2-bromo-4-fluorophenyl)phosphine oxide (1a) as
a model substrate was subjected to cyclization. The chiral
phosphoric acid was initially examined as the ligand in the
reaction. The desired product was generated in 85% yield and
12:88 er with L1 and Pd(PCy3)2 as a catalyst in the presence of
Cs2CO3 in toluene (Table 1, entry 1). An array of R
substituents (steric and electronic influence) at the 3,3′-
position of CPAs was examined. As the steric hindrance
increased, the enantioselectivity of the product became
relatively lower than the initial result (entries 2−7). The
chiral phosphoric amides of the binaphthyl skeleton with
different N-substituents achieved high enantioselectivity and
yields except for L12, which had N-(R)CHMePh (entries 8−
12). The use of a CPA-bearing nitro substituent at the 6,6′-
position, L13, generated a product with 25:75 er (entry 13).
The TADDOL-derived chiral phosphoric acid L14 produced a
racemized product (entry 14). The solvent was changed to
DME, t-amylOH, 1,4-dioxane, DMF, o-xylene, and p-xylene.
Among them, p-xylene provided the highest enantioselectivity
(entries 15−20). The use of chiral phosphoric amides/acids
L1/L8 = 1/1 slightly improved the er to 8:92 (entry 21).16
The enantioselectivity of the product could be maintained even
when the loading of Pd catalyst was reduced to 3 mol %
(entries 22 and 23). Moderate yields and high enantioselec-
tivity could be achieved without the addition of phosphine
ligands to the reaction (entry 24), possibly indicating that the
coordination of the phosphorus ligand with the Pd catalyst is
not essential in this reaction. Finally, L1/L8 was used as a
ligand in 2 mL of m-xylene to furnish the product in 95% yield
and 6:94 er (entry 25). For comparison with CPAs, a chiral
phosphine ligand was applied to control the enantioselectivity
in the current reaction. A survey of different chiral
bisphosphine ligands revealed that (R)-segphos as a chiral
ligand generated a product with 90% ee and 38% yield (entries
26−28). When the amount of ligand was increased to 15 mol
% (5 mol % Pd), the product yield improved to 68%, and the
enantioselectivity was maintained (entry 29).
Under the optimized reaction conditions, the scope of the
substrate was examined using chiral phosphoric amides/acids
as ligands (Table 2). Various substituents on the bromoaryl
ring, such as fluoro, chloro, methyl, and tert-butyl (2a−d),
were used to produce P-stereogenic dibenzophospholes in high
yields with up to 5:95 er. Substrate-bearing and electron-
donating and -withdrawing groups, such as OMe (2e), CN
(2f), and ester (2g), were also examined. The cyclization
products were isolated in good yields and enantioselectivities.
The product having a naphthyl substituent, 2h, was also
isolated in 16.5:83.5 er. A series of substituents on the diphenyl
rings was also tested. Substrates with a methyl substituent at
the ortho, meta, and para positions (2i−k) produced P-
stereogenic dibenzophospholes with good yields and moderate
enantioselectivities. Fluoro, chloro, trifluoromethyl, and
methoxy groups at the para position (2l−o) were tolerated
well, and the enantioselectivity of the product bearing electron-
withdrawing substituents was higher than that of the substrates
containing electron-donating substituents. In addition, a 2
b
ligand
yield
c
entry
Pd cat.
(mol %)
solvent
(%)
er
1
2
3
4
5
6
7
8
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
L1 (10)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DME
85
34
51
49
34
59
62
75
92
72
59
24
34
17
65
75
75
48
98
95
97
12:88
57:43
40:60
49:51
47:53
35:65
49:51
19:81
17:83
14:86
16:84
54:46
25:75
51:49
28:72
26:74
13:87
53:47
12:88
11:89
8:92
L2 (10)
L3 (10)
L4 (10)
L5 (10)
L6 (10)
L7 (10)
L8 (10)
L9 (10)
L10 (10)
L11 (10)
L12 (10)
L13 (10)
L14 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
9
10
11
12
13
14
15
16
17
18
19
20
21
t-amylOH
dioxane
DMF
o-xylene
p-xylene
p-xylene
L1 (10)
L8(10)
L1 (6), L8
(6)
L1 (6), L8
(6)
d
22
Pd(PCy3)2
Pd(PCy3)2
p-xylene
p-xylene
p-xylene
m-xylene
toluene
toluene
toluene
96
95
58
95
25
38
88
8:92
7:93
9:91
6:94
87:13
95:5
63:37
de
,
23
24
25
26
27
28
Pd(CH3CN)2Cl2 L1 (6), L8
(6)
L1 (6), L8
(6)
(R)-binap
(10)
(R)-segphos
(10)
(S,S)-Me-
Duphos
(10)
(R)-segphos
(15)
de
,
Pd(PCy3)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
f
f
f
f
29
Pd(OAc)2
toluene
68
95:5
a
Reaction conditions unless specified otherwise: phosphine oxide 1a
(0.10 mmol, 1.0 equiv), Pd(PCy3)2 or Pd(OAc)2 (5 mol %), L (6−15
b
mol %), Cs2CO3 (2 equiv), solvent (1 mL), 120 °C, 24 h. Isolated
c
d
e
yield. Determined by chiral HPLC. 3 mol % Pd cat. at 110 °C. In 2
f
mL solvent with 3 equiv of Cs2CO3. 30 mol % PivOH, 1.5 equiv of
Cs2CO3.
B
DOI: 10.1021/acs.organomet.9b00216
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Organometallics
Communication
a b
,
Table 2. Substrate Scope Using Chiral Phosphoric Amides/
Acids as Ligands
Table 3. Substrate Scope with (R)-segphos as a Ligand
a b
,
a
Reaction conditions: phosphine oxide 1 (0.10 mmol), Pd(OAc)2 (5
mol %), (R)-segphos (15 mol %), PivOH (30 mol %), Cs2CO3 (1.5
a
Reaction conditions: phosphine oxide 1 (0.10 mmol), Pd(PCy3)2 (3
mol %), L1 (6 mol %), L8 (6 mol %), Cs2CO3 (3 equiv), m-xylene (2
b
equiv), toluene (1 mL), 120 °C, 24 h. Isolated yield and er were
b
mL), 110 °C, 24 h. Isolated yield and er were determined with chiral
HPLC.
determined with chiral HPLC.
mmol scale of reaction was also conducted and the product 2d
was isolated with 2.5:97.5 er after recrystallization (eq 1).
In summary, we have developed two protocols to achieve
Pd-catalyzed asymmetric C−H bond activation for the
synthesis of P-stereogenic dibenzophospholes; both chiral
phosphoric acids/amides and trivalent phosphorus P(III)
compounds are effective ligands for the reaction. The
suitability for gram-scale reactions further enhances the utility
of these methods.
ASSOCIATED CONTENT
Next, we examined the reaction scope by using (R)-segphos
as the ligand (Table 3). The substrates bearing various
functional groups, such as fluoro, chloro, methyl, tert-butyl,
methoxy, cyano, and ethyl ester, on the bromoaryl ring
exhibited compatibility and yielded P-chiral phosphine oxides
with a relatively high er (2a−g). The product 2h with a
naphthyl substituent was obtained with a low yield and a
moderate ee. The methyl substituents at different positions of
diphenyl rings were tolerated well with good yields and high er
(2i−k). Aromatic rings bearing fluoro (2l) had the highest
enantioselectivity (98:2). Finally, the compounds bearing
chloro, trifluoromethyl, and methoxy substituents delivered
dibenzophospholes in useful yields and enantioselectivities
(2m−o). The X-ray crystal diffraction analysis of the product
2a (Table 3) indicated that the absolute configuration of 2a is
R, and other absolute configurations were assigned through
analogy with 2a.17
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.9b00216.
Experimental procedures, analysis data for all new
compounds, and details of X-ray crystallographic analysis
for 2a (PDF)
Accession Codes
CCDC 1870685 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
C
DOI: 10.1021/acs.organomet.9b00216
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
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AUTHOR INFORMATION
Corresponding Author
*E-mail for W.-L.D.: duanwl@yzu.edu.cn.
ORCID
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Wei-Liang Duan: 0000-0003-2791-1931
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the NSFC (21472218,
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Top-notch Academic Programs Project of Jiangsu Higher
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(16) A nonlinear effect was observed in the current reaction; the
results may suggest that more than one phosphoric acid/amide is
involved in the enantioselective C−H palladation step. See the
Supporting Information for details.
(17) See the Supporting Information for X-ray data.
E
DOI: 10.1021/acs.organomet.9b00216
Organometallics XXXX, XXX, XXX−XXX