Catalytic Synthesis of Chiral Phosphole Oxides via Desymmetric C-H Arylation of o -Bromoaryl Phosphine Oxides

Article abstract of DOI:10.1055/s-0036-1588983

A palladium-catalyzed intramolecular direct arylation reaction of o -bromoaryl phosphine oxides was developed to afford a variety of P-stereogenic phosphole oxides in good yields. The enantioselectivities were closely associated with the specific structures of substrates, which ranged from 4-94%. As a result of ready availability of starting materials and simple operation to improve the enantioselectivities of the products with low ee values, the method provides a simple and straightforward procedure for the synthesis of P-stereogenic phosphole oxides.

Full text of DOI:10.1055/s-0036-1588983

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
Y. Lin et al.
Letter
Synlett
Catalytic Synthesis of Chiral Phosphole Oxides via Desymmetric
C–H Arylation of o-Bromoaryl Phosphine Oxides
Yan Lin
Me
R'
Wei-Yang Ma
Qiao-Ying Sun
Yu-Ming Cui*
Li-Wen Xu*
H
R'
P
P
Pd(OAc)2 (5 mol%)
ligand (10 mol%)
Br
O
O
Me
Me
P
H
P
R
R'
R
Cs2CO3 (1.5 equiv)
xylene, 140 °C, 4 h
R'
Me
(S,S)-Me-Duphos
up to: 78% yield
94% ee
Key Laboratory of Organosilicon Chemistry and Material Technology
of Ministry of Education, Hangzhou Normal University, Hangzhou
311121, P. R. of China
R = alkyl, alkoxy, halide, ester
R' = alkyl
ligand
ym_cui@hznu.edu.cn
liwenxu@hznu.edu.cn
Received: 08.02.2017
Accepted after revision: 05.03.2017
Published online: 11.04.2017
fins10 and to benzoquione.11 Meanwhile, other more effi-
cient and atom-economical routes to these compounds
have been developed by several groups through asymmet-
ric C–H activation in which the P-stereogenic compounds
can be constructed in excellent enantioselectivities for both
intra- and intermolecular desymmetrization reactions
(Scheme 1).12 Notably, the substrates have common struc-
tural units of phosphinamides that provided the nitrogen
atoms to coordinate to metals to facilitate the C–H cleavage.
However, the successful examples on asymmetric catalytic
C–H functionalization of substrates without directing
groups, unlike phosphinamides, have not appeared until
now.
DOI: 10.1055/s-0036-1588983; Art ID: st-2017-w0094-l
Abstract A palladium-catalyzed intramolecular direct arylation reac-
tion of o-bromoaryl phosphine oxides was developed to afford a variety
of P-stereogenic phosphole oxides in good yields. The enantioselectivi-
ties were closely associated with the specific structures of substrates,
which ranged from 4–94%. As a result of ready availability of starting
materials and simple operation to improve the enantioselectivities of
the products with low ee values, the method provides a simple and
straightforward procedure for the synthesis of P-stereogenic phosphole
oxides.
Key words asymmetric catalysis, C–H activation, direct arylation,
phosphole oxides, palladium
Previous: asymmetric cycloaddition
O
Ph
Ph
Ph
Ph
Chiral phosphorus compounds have found a plethora of
applications in asymmetric synthesis, typically as useful li-
gands1 in transition-metal catalysis and as versatile organo-
catalysts.2 Owing to the remarkable chiral induction during
the catalytic transformation by a stereogenic phosphorus
atom stemming from its closer proximity to the catalytic
center,3 those with P-chiral centers are particularly attrac-
tive. In fact, P-chiral compounds have proven very efficient
and stable as ligands and even some have been applied in
the pharmaceuticals and agrochemicals. The conventional
methods for the preparation of P-stereogenic compounds
need stoichiometric amounts of chiral auxiliaries, including
resolution of diastereomeric mixtures4 and enantioselec-
tive deprotonation5 of prochiral phosphines. Recently,
metallo-, organo-, and biocatalytic synthetic methods have
been reported, such as enantioselective cycloaddition of
symmetric dialkynylphosphine oxides,6 asymmetric ring-
closing metathesis of symmetric dialkenylphosphine ox-
ides,7 and asymmetric alkylation8 and arylation9 of alkyl
and aryl halide with secondary phosphines as well as their
catalytic asymmetric addition to electron-deficient ole-
P
O
Ph
O
Rh cat.
[2+2+2]
P
+
2
O
O
Ph
helically chiral
This work: asymmetric C-H activation
Me
Br
Me
O
O
Me
Pd cat.
P
P
C-H arylation
Me
P-chiral
Scheme 1 Transition-metal-catalyzed synthesis of chiral phosphole ox-
ides
It was recognized that phospholes are valuable building
blocks for tailoring organic π-conjugated materials, and
their photophysics and redox properties can be efficiently
tuned through the diverse and reversible phosphorus
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
Y. Lin et al.
Letter
Synlett
chemistry.13 In addition, chiral phosphole oxides have the
vast potential in asymmetric catalysis as Lewis base cata-
lysts or precursors of chiral ligands.2,14 Despite the utilities
of chiral phosphole oxides in organic synthesis, the effec-
tive approaches to them are extremely limited in number,
especially for their catalytic synthesis. Previously, we re-
ported a practical method for the synthesis of dibenzo-
phosphole oxides via a palladium-catalyzed direct arylation
strategy from the readily available ortho-haloarylphos-
phine oxides.15 We envision that the P-stereogenic phos-
pholes might be obtained in a catalytic C–H arylation via
desymmetrization of prochiral ortho-haloarylphosphine
oxides in the presence of chiral palladium catalyst.
The substrates were readily synthesized by the reac-
tions of proper chlorophosphines with aryl Grignard re-
agents followed by oxidation with hydrogen peroxide.16 Ini-
tially, 1a was chosen as a model substrate to enact our pro-
posed enantioselective C–H arylation strategy. To obtain
the optimal reaction conditions, several reaction parame-
ters related to this transformation including metal salt, li-
gand, base, solvent, and temperature were screened in de-
tail (Table 1). Among the six commercially available chiral
ligands tested in this reaction, bidentate ligands gave supe-
Table 1 Optimization of Reaction Conditionsa
Me
Me
palladium (5 mol%)
ligand (10 mol%)
Br
O
O
Me
P
P
base (1.5 equiv)
solvent
Me
1a
2a
Me
PCy2
PPh2
i-Pr
P
P
P
Ph Ph
i-Pr
O
O
Me
Me
PPh2
PPh2
PPh2
PPh2
Me
Me
O
O
Me
Me
O
O
P
N
P
Fe
i-Pr
Me
Ph Ph
i-Pr
(R,R)-DIOP
(R,Sp)-Josiphos
(S,S)-Me-Duphos
(R)-BINAP
L2
L3
L5
L4
L6
L1
Entry
Ligand
Metal
Base
Solvent
Temp (°C)
Time (h)
Yield (%)b
ee (%)c
1
2
L1
L2
L3
L4
L5
L6
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
Pd(OAc)2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMAc
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
120
140
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
4
70
33
27
24
70
43
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd(acac)2
Pd(OAc)2
Pd(OAc)2
75
3
62
4
68
5
52
6
73
7
80
22
2
8
K3PO4
58
9
KOAc
trace
95
n.d.
0
10
11
12
13
14
15
16
17
18
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
hexane
dioxane
benzene
xylene
53
11
20
n.d.
36
35
62
60
75
45
trace
55
toluene
toluene
xylene
20
75
68
xylene
4
74
a Unless otherwise specified, the reaction was carried out using 1a (0.25 mmol), base (1.5 equiv), PivOH (0.4 equiv), Pd(OAc)2 (5 mol%), ligand (10 mol%) in
solvent (1 mL) under N2.
b Isolated yield.
c The ee values were determined by HPLC analysis.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
Y. Lin et al.
Letter
Synlett
rior level of chiral induction to that with monodentate li-
gand (Table 1, entries 1–6), which is in contrast to the re-
sults of the intramolecular arene C–H activation of
phosphinamide substrate.12d,e (S,S)-Me-Duphos (L4) com-
bined with Pd(OAc)2 gave the satisfactory yield and better
enantioselectivity (Table 1, entry 4). We then turned our at-
tention to base and reaction medium that proved to have
major influence on the reaction. Although replacement of
Cs2CO3 by K2CO3 led to slightly improvement of product
yield, the enantioselectivity decreased markedly from 70%
to 22%. Other bases proved ineffective for this reaction, and
the C–H activation did not happened at all with KOAc as a
base (Table 1, entries 7–9). The similar trend was observed
when surveying the other solvents instead of toluene. Al-
though excellent yield (up to 95%) was obtained in DMAc,
unfortunately, racemic compound was produced (Table 1,
entry 10). Likewise, the change of Pd(OAc)2 to other palladi-
um precursors did not result in further improvement of re-
action result (Table 1, entries 15 and 16). To our delight,
higher yield and ee were achieved by conducting the intra-
molecular arylation reaction in xylene at higher tempera-
ture and shorter time (Table 1, entries 17 and 18).
Me
Me
Me
O
O
O
Me
Me
Me
P
P
P
Me
2a
2c
75% yield
24% ee
2b
74% yield
75% ee
55% yield
50% ee
O
P
O
P
O
P
Cl
F
EtO2C
2d
2f
2e
78% yield
46% ee
68% yield
32% ee
72% yield
29% ee
Me
O
Me
O
Me
O
Me
Me
Me
P
P
P
F3C
t-Bu
Me
2h
2i
2g
With the optimized conditions in hand, the steric and
electronic influence of substituents on the aromatic rings
was investigated, and the results are summarized in Figure
1.17 Compared with 2a, a substrate with larger steric hin-
drance on phenyl group bearing C–H bonds to be cleaved
caused lower yield and ee of the desired product 2b. On the
other hand, it was found that the reaction of 1c with the
methyl group at bromoarene moiety furnished the product
2c in comparable yield but with much lower ee, which sug-
gested that substitution at the arenes with cleavable C–H
bonds is beneficial for construction of P-stereogenic mole-
cules with a higher degree of enantiotopic differentiation.
For example, the substrates with electron-withdrawing
groups at para position to phosphorus atom gave the corre-
sponding products 2d–f in good yields and low ee values
under the present catalytic system. The compound 2g hav-
ing a CF3 group para to P atom was obtained in satisfactory
yield but with poor enantioselectivity. The developed cata-
lytic system tolerated the bulky tertiary butyl and phenyl
groups well, thus affording the 2h and 2j in moderate enan-
tioselectivities, respectively. It is worth noting that the re-
action of 1i, comprising a methyl substituent at para posi-
tion to P atom, underwent smooth asymmetric arylation,
giving 2i in good yield with excellent enantioselectivity
(94% ee). Strongly electron-donating group such as OMe at
the bromoaryl moiety will be detrimental for this class of
chiral induction in spite of its position. As demonstrated by
the reactions of 1k and 1l, the desired products were ob-
tained in comparable yields but with much lower ee values,
especially for 2l whose enantioselectivity decreased to only 4%.
67% yield
50% ee
71% yield
94% ee
72% yield
30% ee
Me
Me
O
O
P
O
P
Me
Me
P
MeO
Ph
MeO
2j
2l
2k
73% yield
32% ee
74% yield
4% ee
65% yield
60% ee
Figure 1 Substrate scope. Reagents and conditions: phosphine oxide
1b–l (1 mmol), Cs2CO3 (1.5 mmol), PivOH (0.4 mmol), Pd(OAc)2
(5 mol%), L4 (10 mol%) in xylene (4 mL) at 140 °C for 4 h under N2.
It needs to be emphasized that the resulting coupling
products have good ability to crystallize, which provided a
simple and effective method to obtain optically pure P-ste-
reogenic phospholes. As illustrated in Scheme 2, the ee val-
ue of 2a can be improved from 75–97% in high yield after
once recrystallization in CH2Cl2. Furthermore, a single crys-
tal suitable for X-ray diffraction analysis was collected, and
the absolute configuration of 2a was determined to be (S)
by X-ray crystallographic analysis with Cu Kα radiation
(Figure 2).18
In summary, we have developed a novel method for the
synthesis of P-stereogenic phosphole oxides through enan-
tioselective C–H bond functionalization of o-bromoaryl
phosphine oxides in the presence of in situ formed chiral
palladium catalyst. The resulting active catalytic system
showed high reactivity for most substrates, and up to 78%
yield and 94% ee can be achieved under optimal conditions.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
Y. Lin et al.
Letter
Synlett
Leeuwen, P. W. N. M.; Kamer, P. C. J.; Claver, C.; Pàmies, O.;
Diéguez, M. Chem. Rev. 2011, 111, 2077. (f) Xie, J.-H.; Zhu, S.-F.;
Zhou, Q.-L. Chem. Soc. Rev. 2012, 41, 4126. (g) Xie, J.-H.; Zhou,
Q.-L. Acta Chim. Sin. 2014, 72, 778.
Me
Me
O
O
Me
Me
P
P
recrystalllization
CH2Cl2
(2) (a) Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47,
1560. (b) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38,
2190. (c) Mahlau, M.; List, B. Angew. Chem. Int. Ed. 2013, 52, 518.
(d) Brak, K.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2013, 52, 534.
(e) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem. 2012, 4,
603. (f) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev.
2014, 114, 9047.
2a
(75% ee)
(97% ee)
2a
Scheme 2 Further improvement of ee value of the product 2a
(3) (a) Crépy, K. V. L.; Imamoto, T. Top. Curr. Chem. 2003, 229, 1.
(b) Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005,
127, 11934. (c) Tang, W.; Patel, N. D.; Xu, G.; Xu, X.; Savoie, J.;
Ma, S.; Hao, M.-H.; Keshipeddy, S.; Capacci, A. G.; Wei, X.;
Zhang, Y.; Gao, J. J.; Li, W.; Rodriguez, S.; Lu, B. Z.; Yee, N. K.;
Senanayake, C. H. Org. Lett. 2012, 14, 2258. (d) Luo, R.; Liao, J.;
Xie, L.; Tang, W.; Chan, A. S. Chem. Commun. 2013, 49, 9959.
(e) Liu, G.; Liu, X.; Cai, Z.; Jiao, G.; Xu, G.; Tang, W. Angew. Chem.
Int. Ed. 2013, 52, 4235. (f) Xu, G.; Fu, W.; Liu, G.; Senanayake, C.
H.; Tang, W. J. Am. Chem. Soc. 2014, 136, 570.
(4) Pietrusiewicz, K. M.; Zablocka, M. Chem. Rev. 1994, 94, 1375.
(5) (a) Bergin, E.; O’Connor, C. T.; Robinson, S. B.; McGarrigle, E. M.;
O’Mahony, C. P.; Gilheany, D. G. J. Am. Chem. Soc. 2007, 129,
9566. (b) Popovici, C.; Ona-Burgos, P.; Fernández, I.; Roces, L.;
García-Granda, S.; Iglesias, M. J.; Ortiz, F. L. Org. Lett. 2010, 12,
428. (c) Granander, J.; Secci, F.; Canipa, S. J.; O’Brien, P.; Kelly, B.
J. Org. Chem. 2011, 76, 4794. (d) Gammon, J. J.; Gessner, V. H.;
Barker, G. R.; Granander, J.; Whitwood, A. C.; Strohmann, C.;
O’Brien, P.; Kelly, B. J. Am. Chem. Soc. 2010, 132, 13922.
(e) Gatineau, D.; Giordano, L.; Buono, G. J. Am. Chem. Soc. 2011,
133, 10728. (f) Bayardon, J.; Laureano, H.; Diemer, V.; Dutartre,
M.; Das, U.; Rousselin, Y.; Henry, J.-C.; Colobert, F.; Leroux, F. R.;
Jugé, S. J. Org. Chem. 2012, 77, 5759. (g) Casimiro, M.; Roces, L.;
García-Granda, S.; Iglesias, M. J.; Ortiz, F. L. Org. Lett. 2013, 15,
2378.
Figure 2 X-ray crystal structure of 2a18
In addition, the enantioselectivities for the products with
low ee values can be improved to some extent after simple
crystallization, thus providing an alternative and conve-
nient route to chiral phosphole oxides.
(6) (a) Nishida, G.; Noguchi, K.; Hirano, M.; Tanaka, K. Angew. Chem.
Int. Ed. 2008, 47, 3410. (b) Fukawa, N.; Osaka, T.; Noguchi, K.;
Tanaka, K. Org. Lett. 2010, 12, 1324. (c) Sawada, Y.; Furumi, S.;
Takai, A.; Takeuchi, M.; Noguchi, K.; Tanaka, K. J. Am. Chem. Soc.
2012, 134, 4080.
Funding Information
(7) Harvey, J. S.; Malcolmson, S. J.; Dunne, K. S.; Meek, S. J.;
Thompson, A. L.; Schrock, R. R.; Hoveyda, A. H.; Gouverneur, V.
Angew. Chem. Int. Ed. 2009, 48, 762.
(8) (a) Chan, V. S.; Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am.
Chem. Soc. 2006, 128, 2786. (b) Scriban, C.; Glueck, D. S. J. Am.
Chem. Soc. 2006, 128, 2788. (c) Scriban, C.; Glueck, D. S.; Golen,
J. A.; Rheingold, A. L. Organometallics 2007, 26, 1788. (d) Chan,
V. S.; Chiu, M.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2009,
131, 6021.
National Natural Science Foundation of China Grant / Award numbers
‘51303043’, ‘21472031’, ‘21503060’
Science and Technology Department of Zhejiang Province Grant /
Award number ‘2015C31138’
Supporting Information
(9) (a) Brauer, D. J.; Hingst, M.; Kottsieper, K. W.; Liek, C.; Nickel, T.;
Tepper, M.; Stelzer, O.; Sheldrick, W. S. J. Organomet. Chem.
2002, 645, 14. (b) Moncarz, J. R.; Laritcheva, N. F.; Glueck, D. S. J.
Am. Chem. Soc. 2002, 124, 13356. (c) Brunker, T. J.; Anderson, B.
J.; Blank, N. F.; Glueck, D. S.; Rheingold, A. L. Org. Lett. 2007, 9,
1109. (d) Blank, N. F.; Moncarz, J. R.; Brunker, T. J.; Scriban, C.;
Anderson, B. J.; Amir, O.; Glueck, D. S.; Zakharov, L. N.; Golen, J.
A.; Incarvito, C. D.; Rheingold, A. L. J. Am. Chem. Soc. 2007, 129,
6847. (e) Korff, C.; Helmchen, G. Chem. Commun. 2004, 530.
(f) Chan, V. S.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2007,
129, 15122. (g) Harvey, J. S.; Gouverneur, V. Chem. Commun.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588983.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References and Notes
(1) (a) Phosphorus Ligands, In Asymmetric Catalysis: Synthesis and
Applications;1-3
V
o.
l
Börner, A. Wiley-VCH: Weinheim, 2008.
(b) Phosphorus(III) Ligands in Homogeneous Catalysis: Design
and Synthesis; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Wiley:
Hoboken, 2012. (c) Tang, W.; Zhang, X. Chem. Rev. 2003, 103,
3029. (d) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005. (e) van
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
Y. Lin et al.
Letter
Synlett
2010, 46, 7477. (h) Anderson, B. J.; Guino-o, M. A.; Glueck, D. S.;
Golen, J. A.; DiPasquale, A. G.; Liable-Sands, L. M.; Rheingold, A.
L. Org. Lett. 2008, 10, 4425.
ucts were purified by using flash chromatography with EtOAc
as eluent, giving the pure products.
Compound 1a: 1H NMR (400 MHz, CDCl3): δ = 7.67 (dddd, J =
12.9, 5.8, 4.8, 3.4 Hz, 2 H), 7.48–7.37 (m, 4 H), 7.31 (dd, J = 7.5,
4.3 Hz, 2 H), 7.26–7.14 (m, 4 H), 2.50 (s, 6 H). 31P NMR (202
MHz, CDCl3): δ = 35.37 (s). 13C NMR (101 MHz, CDCl3): δ =
143.45 (d, J = 7.9 Hz), 135.82 (d, J = 9.8 Hz), 134.89 (d, J = 7.4 Hz),
133.63 (t, J = 9.5 Hz), 133.14 (d, J = 2.2 Hz), 132.70 (s), 132.19–
131.79 (m), 130.00 (s), 128.95 (s), 127.24 (d, J = 10.8 Hz), 126.88
(d, J = 4.4 Hz), 125.40 (d, J = 13.2 Hz), 21.92 (d, J = 4.1 Hz).
(17) (a) General Procedure for the Synthesis of P-Stereogenic
Phosphole Oxide
(10) (a) Join, B.; Mimeau, D.; Delacroix, O.; Gaumont, A.-C. Chem.
Commun. 2006, 3249. (b) Li, C.; Bian, Q.-L.; Xu, S.; Duan, W.-L.
Org. Chem. Front. 2014, 1, 541. (c) Huang, Y.; Pullarkat, S. A.; Li,
Y.; Leung, P.-H. Inorg. Chem. 2012, 51, 2533. (d) Kovacik, I.;
Wicht, D. K.; Grewal, N. S.; Glueck, D. S.; Incarvito, C. D.; Guzei, I.
A.; Rheingold, A. L. Organometallics 2000, 19, 950.
(11) Huang, Y.; Li, Y.; Leung, P.-H.; Hayashi, T. J. Am. Chem. Soc. 2014,
136, 4865.
(12) (a) Cui, Y.-M.; Lin, Y.; Xu, L.-W. Coord. Chem. Rev. 2017, 330, 37.
(b) Sun, Y.; Cramer, N. Angew. Chem. Int. Ed. 2017, 56, 364.
(c) Du, Z.; Guan, J.; Wu, G.; Xu, P.; Gao, L.; Han, F. J. Am. Chem.
Soc. 2015, 137, 632. (d) Lin, Z. Q.; Wang, W. Z.; Yan, S. B.; Duan,
W. L. Angew. Chem. Int. Ed. 2015, 54, 6265. (e) Liu, L.; Zhang, A.-
A.; Wang, Y.; Zhang, F.; Zuo, Z.; Zhao, W.-X.; Feng, C.-L.; Ma, W.
Org. Lett. 2015, 17, 2046.
(13) (a) Ren, Y.; Baumgartner, T. Dalton Trans. 2012, 41, 7792.
(b) Bouit, P.-A.; Escande, A.; Szűcs, R.; Szieberth, D.; Lescop, C.;
Nyulászi, L.; Réau, R. J. Am. Chem. Soc. 2012, 134, 6524. (c) Ren,
Y.; Kan, W. H.; Thangadurai, V.; Baumgartner, T. Angew. Chem.
Int. Ed. 2012, 51, 3964.
To a mixture of ortho-bromoarylphosphine oxides 1a–l (1.0
mmol), Cs2CO3 (489 mg, 1.5 mmol), Pd(OAc)2 (11.2 mg, 5 mol%),
and L4 (30.6 mg, 10 mol%) under nitrogen atmosphere was
added 4 mL of xylene in a 25 mL Schlenk tube equipped with a
magnetic stir bar. The Schlenk tube was stirred at r.t. for 20 min
and then at 140 °C for 4 h. The reaction mixture was cooled to
r.t. and quenched with water and then extracted with CH2Cl2.
The extraction was washed with brine and dried over Na2SO4.
The solvent was then evaporated in vacuo, and the residue was
purified by using SiO2 column with EtOAc as eluent to afford the
final products.
(14) Yavari, K.; Aillard, P.; Zhang, Y.; Nuter, F.; Retailleau, P.;
Voituriez, A.; Marinetti, A. Angew. Chem. Int. Ed. 2014, 53, 861.
(15) Cui, Y.; Fu, L.; Cao, J.; Deng, Y.; Jiang, J. Adv. Synth. Catal. 2014,
356, 1217.
(16) (a) General Procedure for the Synthesis of o-Bromoarylphos-
phine Oxide
Compound 2a: 1H NMR (400 MHz, CDCl3): δ = 8.20 (dd, J = 13.7,
7.6 Hz, 1 H), 7.72 (d, J = 7.7 Hz, 1 H), 7.57 (t, J = 8.6 Hz, 2 H), 7.48
(t, J = 7.6 Hz, 1 H), 7.43–7.32 (m, 2 H), 7.29 (t, J = 7.5 Hz, 2 H),
7.04 (dd, J = 12.1, 6.0 Hz, 2 H), 2.25 (s, 3 H), 1.79 (s, 3 H). 31P
NMR (202 MHz, CDCl3): δ = 31.93 (s). 13C NMR (101 MHz,
CDCl3): δ = 142.53 (s), 142.26 (d, J = 10.5 Hz), 142.11 – 141.87
(m), 141.02 (d, J = 11.0 Hz), 134.31 (d, J = 9.5 Hz), 133.55 (d, J =
7.9 Hz), 133.14 (d, J = 2.0 Hz), 132.54 (s), 132.23 (d, J = 2.7 Hz),
131.40 (t, J = 11.3 Hz), 130.83 (d, J = 9.8 Hz), 130.24 (s), 129.33
(t, J = 11.0 Hz), 128.72 (s), 127.74 (s), 126.01 (d, J = 11.9 Hz),
121.31 (d, J = 10.0 Hz), 118.75 (d, J = 10.1 Hz), 20.10 (d, J = 4.4
Hz), 19.42 (d, J = 4.6 Hz). Enantiomeric excess was determined
by HPLC with a Chiralpak OD column (hexanes–2-PrOH = 70:30,
0.5 mL/min, 254 nm); major enantiomer tR = 12.3 min, minor
To a stirred solution of o-bromoiodobenzene (1.3 mL, 10 mmol)
in THF (10 mL) was added dropwise a solution of isopropylmag-
nesium chloride (2.0 M in THF, 5 mL, 10 mmol) at –40 °C. After
1 h, PCl3 (0.9 mL, 10 mmol) was added and stirred for 40 min at
the same temperature. The mixture was then allowed to stand
at r.t. for 12 h and cooled at –40 °C again. A solution of proper
arylmagnesium bromide (1.0 M in THF, 22 mL, 22 mmol) was
added dropwise. After 1 h, the resulting mixture was then
stirred at r.t. overnight. A sat. aq solution of NH4Cl was added,
and the reaction mixture was extracted three times with Et2O.
The combined organic layer was washed with water and brine
and dried over MgSO4. The solvent was then evaporated in
vacuo, and the residue was purified by silica gel column chro-
matography with hexane as eluent to afford the corresponding
phosphines. After oxidation by H2O2 in acetone, the crude prod-
enantiomer tR = 25.9 min. ESI-HRMS: m/z: [M + H]+ calcd for
20
C
20H17OP: 305.1090; found: 305.1094. [α]D –36.2 (c 1.21,
CHCl3).
(18) CCDC 1524935 (2a) contains the supplementary crystallo-
graphic data for this paper. The data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E