Asymmetric Suzuki-Miyaura cross-coupling of aryl chlorides with enhancement of reaction time and catalyst turnover

Article abstract of DOI:10.1016/j.tetlet.2011.03.051

A series of new chiral phosphonite ligands were evaluated for the palladium-catalyzed asymmetric Suzuki-Miyaura cross-coupling reactions of aryl chlorides. Ligand 4 gave 91% yield and 78% ee with 0.5 mol % catalyst loading for the coupling of aryl boronic

Full text of DOI:10.1016/j.tetlet.2011.03.051

Tetrahedron Letters 52 (2011) 2638–2641
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Tetrahedron Letters
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Asymmetric Suzuki–Miyaura cross-coupling of aryl chlorides
with enhancement of reaction time and catalyst turnover
⇑
Toshinori Kamei, Akihiro H. Sato, Tetsuo Iwasawa
Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University, Otsu, Shiga 520-2194, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new chiral phosphonite ligands were evaluated for the palladium-catalyzed asymmetric
Suzuki–Miyaura cross-coupling reactions of aryl chlorides. Ligand 4 gave 91% yield and 78% ee with
0.5 mol % catalyst loading for the coupling of aryl boronic acid and aryl chloride in 5 h. When the catalyst
loading was lowered to 0.1 mol % the same reaction gave 75% yield and 76% ee.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 19 January 2011
Revised 7 March 2011
Accepted 9 March 2011
Available online 16 March 2011
The Suzuki–Miyaura cross-coupling reaction is one of the most
widely used method for preparing biaryl bonds.1 The widespread
availability of aryl chlorides contributes to the utility of this reac-
tion in synthetic organic chemistry.1a–d The asymmetric variant re-
mains an important challenge2 due to the importance of axially
chiral biaryls in synthetic applications,3a–d including pharmaceuti-
cal,3e,f material,3g and supramolecular3h chemistry. So far a few
examples on catalytic enantioselective versions have been re-
ported.4–6
Recently, Lassaletta and Uozumi reported on highly efficient
asymmetric cross-couplings. Lassaletta and co-workers utilized a
novel C2-symmetric bis-hydrazone ligand,7a and Uozumi devel-
oped a polymer-supported catalyst.7b While their procedures
achieved valuable enantioselectivities there is still room for
improvement especially in terms of catalyst loadings and reaction
times. In these prior works a minimum of 5 mol % of catalyst and
24 h of reaction time was necessary, though Uozumi was able to
reuse their catalyst 4 times.
We previously reported on the pentaarylbenzene phosphine
ligand 1 palladium-catalyzed Suzuki–Miyaura coupling of aryl chlo-
rides.8 The well-organized array of aromatic rings was demon-
strated to play an enhancing role in the catalytic cycle.9,10
Phosphine 1 catalyzed the reaction of 2-chloro-3-methoxybenzal-
dehyde with ortho-tolylboronic acid to form the unsymmetrical
tri-ortho-substituted biaryl11 in >99% yield with 0.1 mol % catalyst
loading (Scheme 1).
In this Letter, we describe three new phophonites that promote
the asymmetric cross-coupling of aryl chlorides with low catalyst
loading and short reaction time. The pentatolylbenzene moiety
feature found in 1 was appended with chiral biaryls to give 2, 3,
and 4 (Fig. 1). Phosphonite 4 was found to give the axially chiral
tri-ortho-substituted biaryl12 in 75% yield and 76% ee with a
0.1 mol % catalyst loading (catalyst turnover = 750) and 5 h reac-
tion time.
The chiral phosphonite 2,13 3,14 and 415 were synthesized from
bromide 616 via iodide 510a as shown in Scheme 2. Lithiation of io-
dide 5 smoothly occurred in toluene at ꢀ78 °C, and it was followed
by reaction with 1,2-dibromobenzene, giving 6 in 89% yield.8 Initial
efforts to convert 6 to the desired ligands 2, 3, and 4 proved diffi-
cult presumably due to the sterically hindered carbanion.17 After
several attempts, the use of phosphorous trichloride was found
to give access to desired phophonites. The addition of PCl3 followed
by (R)-1,10-binaphthyl-2,20-diol was conducted in one-pot under
an argon atmosphere. Purification by silica gel column chromatog-
raphy gave 2 in 43% yield. Similarly the reactions of (R)-3,30-di-
methyl-1,10-binaphthyl-2,20-diol14 and (S)-9,100-biphenanthrene-
90,10-diol15 afforded 3 in 69% yield and 4 in 70% yield. These
compounds readily dissolved in CHCl3, CH2Cl2, benzene, toluene,
and THF. Compounds 2, 3, and 4 proved to be stable solids as con-
firmed by the lack of observed phosphorous oxide in 31P NMR after
workup and purification. Presumably the large pentatolylbenzene
moiety provides a degree of robustness to these ligands, protecting
the phosphorous lone-pair from oxidation.18
At the outset of our study the availability of 2 led us to investi-
gate its performance as a chiral ligand in palladium-catalyzed
asymmetric Suzuki–Miyaura reactions. The reactions were carried
out in the presence of [Pd2(dba)3ꢁCHCl3] (dba = dibenzylideneace-
tone) and 2 (Scheme 3). As coupling partners, 2-(2-chloro-3-
methoxyphenyl)-1,3-dioxolane 7 and ortho-tolylboronic acid 8
were chosen because of their availability. The chemical yield and
enantiomeric excess of the axially chiral product (S)-2-(6-meth-
oxy-20-methyl biphenyl-2-yl)-1,3-dioxolane19 were surveyed in
several conditions (Table 1).20
In entries 1 and 2, the catalyst system at 75 °C in THF and KF
smoothly gave the coupling adduct in 96% yield, although the yield
at 50 °C decreased to 44%. In entries 2–4, the ratio of 2 to palladium
(P/Pd ratio) was varied between 1.2, 2.0, and 3.0 to little effect. In
entry 5 the reaction proceeded with 0.1 mol % catalyst loading,
⇑
Corresponding author. Tel.: +81 77 543 7461; fax: +81 77 543 7483.
E-mail address: iwasawa@rins.ryukoku.ac.jp (T. Iwasawa).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.051

T. Kamei et al. / Tetrahedron Letters 52 (2011) 2638–2641
2639
Scheme 1. Synthesis of a biaryl in the presence of 1.
giving 99% yield and 40% ee. Of the bases evaluated in entries 6–11,
the significance of CsF is striking, giving coupling in 96% yield and
46% ee. In entry 14, 92% yield and 45% ee were produced with a
catalyst loading of 0.1 mol %.
within 5 h, and the product was given in 69% ee and 72% ee, respec-
tively (entries 3 and 4). Conducting the reaction in toluene with
CsF the % ee values were 74 with 3 and 78 with 4 (entries 5 and
6). This is slightly better as compared with the % ee using THF
and KF. In entry 7, the catalyst loading of 0.1 mol % with 4 achieved
75% yield and 76% ee, consuming the starting material 7 within 5 h.
The coupling partners of arylboronic acid were changed to o-anis-
ylboronic acid 10 (entries 8 and 9)21 and 1-naphthylboronic acid
11 (entries 10 and 11). Although the starting halide 7 was
consumed within 5 h through entries 8–11, the highest enantiose-
lectivities recorded was 52% ee.22 Asymmetric cross-coupling of
2-chloro-3-methoxy benzonitrile 923 with 1-naphthylboronic acid
11 in entry 12 was carried out with phosphonite 4, and the reaction
proceeded within 3 h in 87% yield and 33% ee.
The configurational stability of (S)-2-(6-methoxy-20-methyl
biphenyl-2-yl)-1,3-dioxolane at the reaction temperature of the
coupling was surveyed. The mixture of (S)/(R) = 66:34 ratio was re-
fluxed in THF for 12 h, to give 68:32. In addition, (S)/(R) = 68:32 was
heated in toluene for 12 h at 90 °C, to give 66:34. There is virtually no
erosion of ee under these conditions thus we presume that the biaryl
has kept its configuration under the reaction conditions.
Next, we evaluated the performance of ligands 2, 3, and 4 (Table
2). In the reaction of halide 7 with boronic acid 8 with THF and KF
under P/Pd = 2, phosphonite 3 gave 65% ee compared to 2 (41% ee)
(entries 1 and 2). When the mol % of ligand 3 and 4 rose to 1.5 (P/
Pd = 3) the starting material 7 disappeared by TLC monitoring
In summary, chiral phosphonite 2, 3, and 4 were developed and
evaluated for the asymmetric Suzuki–Miyaura cross-coupling
Figure 1. Phosphonite 2, 3, and 4.
Scheme 2. Synthetic routes to 2, 3, and 4.
Scheme 3. Asymmetric Suzuki–Miyaura reaction of 7 with 8.

2640
T. Kamei et al. / Tetrahedron Letters 52 (2011) 2638–2641
Scheme 4. Asymmetric Suzuki–Miyaura reaction with aryl chlorides.
Table 1
Effect of chiral ligand 2 on the asymmetric coupling conducted via Scheme 3a
Entry
Mol % of Pd2(dba)3
Mol % of 2
Base
Solvent
Tempb (°C)
Timec (h)
Yield (%)
eed (%)
1
2
3
0.5
0.5
0.5
0.5
0.05
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.05
1.2
1.2
2.0
3.0
0.12
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0.12
KF
KF
KF
KF
KF
KF
K2CO3
Na2CO3
Cs2CO3
(C2H5)3N
CsF
CsF
CsF
CsF
THF
THF
THF
THF
50
75
75
75
75
75
75
75
75
75
75
90
110
90
5
5
7
5
7
3.5
4
4
6
5
5
4
4
44
96
99
97
99
84
37
24
16
33
96
99
>99
92
30 (S)
33 (S)
42 (S)
34 (S)
40 (S)
47 (S)
48 (S)
50 (S)
59 (S)
43 (S)
46 (S)
48 (S)
42 (S)
45 (S)
4
5e
6
THF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
7
8
9f
10
11
12
13
14
4
a
b
c
d
e
f
All reactions were performed in accordance with the representative procedure in Ref. 20, unless otherwise noted.
Oil bath temperature.
The reactions were stopped when the complete formation of Pd black was observed and/or when the starting materials disappeared on TLC monitoring.
The absolute configuration is shown in parenthesis.
The concentration of the aryl chloride was 0.83 M.
The starting aryl chloride was recovered in 79%.
Table 2
Effect of 2, 3, and 4 on the asymmetric coupling conducted via Scheme 4a
Entry
Base/solvent
Ligand
Mol % of Pd2(dba)3
Mol % of ligand
Halide
Arylboronic acid
Tempb (°C)
Timec (h)
Yield (%)
eed (%)
1
2
3
4
5
6
7
KF/THF
KF/THF
KF/THF
KF/THF
CsF/toluene
CsF/toluene
CsF/toluene
CsF/toluene
CsF/toluene
CsF/toluene
CsF/toluene
CsF/toluene
2
3
3
4
3
4
4
3
4
3
4
4
0.25
0.25
0.25
0.25
0.25
0.25
0.05
0.25
0.25
0.25
0.25
0.25
1.0
1.0
1.5
1.5
1.0
1.0
0.2
1.0
1.0
1.0
1.0
1.0
7
7
7
7
7
7
7
7
7
7
7
9
8
8
8
8
8
8
8
10
10
11
11
11
75
75
75
75
90
90
90
90
90
90
90
90
7
6
4
5
4
5
5
5
5
4
4
3
84
79
90
94
93
91
75
92
91
63
55
87
41 (S)
65 (S)
69 (S)
72 (R)
74 (S)
78 (R)
76 (R)
37 (S)
e
8
9
e
g
47 (R)
10f
11f
12
47
52
33
h
i
a
b
c
d
e
f
All reactions were performed in accordance with the representative procedure in Ref. 20, unless otherwise noted.
Oil bath temperature.
The reactions were stopped when the starting aryl chloride was consumed on TLC monitoring.
The absolute configuration is shown in parenthesis.
The absolute configuration was determined on the basis of the proline-derived diamine in Ref. 21
The values of % yield and % ee were calculated after the recrystallization was operated.
½
½
½
a 2D1
ꢂ
= ꢀ16.9 (c 0.50, CDCl3).
= ꢀ2.24 (c 0.49, CDCl3).
= +39.8 (c 0.50, CDCl3).
g
h
i
a 2D2
a 2D2
ꢂ
ꢂ
reaction of aryl chlorides. These new phosphonite ligands afforded
a catalytic system with very low loading (0.5 mol %) and with
shortened reaction times compared to previous studies (now ca.
5 h). Under these conditions up to 91% yield and 78% ee were
achieved for one set of coupling partners. Additionally, the asym-
metric coupling of 7 with 8 with 0.1 mol % catalyst loading and li-
gand 4 within 5 h gave the resulting chiral biaryl in 75% yield and
76% ee. These results demonstrate a significant advance in the effi-
ciency of the asymmetric cross-coupling reaction of aryl chlorides
with aryl boronic acids to give chiral biaryls. Ongoing efforts to en-

T. Kamei et al. / Tetrahedron Letters 52 (2011) 2638–2641
2641
10. (a) Ito, S.; Wehmeier, M.; Brand, J. D.; Kübel, C.; Epsch, R.; Rabe, J. P.; Müllen, K.
Chem. Eur. J. 2000, 6, 4327–4342; (b) Li, D.; Kaner, R. B. Science 2008, 320, 1170–
1171.
11. Myers, A. I.; Himmelsbach, R. J. J. Am. Chem. Soc. 1985, 107, 682–685.
12. The phosphonite 2, 3, and 4 were applied in the formation of tetra-ortho-
hance the enantiomeric excess capability of chiral phosphonite li-
gands while retaining low catalyst loading and shortened reaction
times will be reported in due course.
substituted biaryl:
methoxyphenyl)-1,3-dioxolane
However, any coupling adduct was not observed.
a
cross-coupling reaction with 2-(2-chloro-3-
of 2,4,6-trimethylphenylboronic acid.
Acknowledgments
13. Synthetic procedure for phosphonite 2, 3 and 4: To a solution of 6 (136 mg,
0.20 mmol) in THF (3 mL) at ꢀ78 °C was added n-BuLi (0.21 mmol, 1.59 M in
hexane) dropwise over 3 min, and the mixture was stirred for 2 h. PCl3 (29 mg,
0.21 mmol) was slowly added over 2 min, and the reaction was allowed to
warm to room temperature. After stirring for 4.5 h, the solvent was thoroughly
removed in vacuo, and to the residue was added THF (2 mL) and appropriate
chiral diol (0.24 mmol), and then Et3N (42 mg, 0.42 mmol). After stirring for
10 h at ambient temperature, all the volatiles were evaporated. The mixture
was dissolved in benzene (30 mL), and washed with water (30 mL ꢃ 2), and
brine (30 mL), and dried over Na2SO4. Purification by silica gel column
chromatography gave a desired molecule. Data of 4 are as follows: yield 70%
We are very grateful to Professor Michael P. Schramm at Cali-
fornia State University Long Beach for helpful discussion. We also
thank Dr. Ken-ichi Yamada for assistance with polarimeter and
useful discussion. We are grateful for the financial support from
the Research Foundation for Pharmaceutical Sciences, and Ryukoku
University Science and Technology Fund, and Grant-in-Aid for
Young Scientists (B).
as a white solid material; ½a D26
ꢂ
–272 (c 1.00, C6H6). 1H NMR (400 MHz, C6D6) d
Supplementary data
9.06 (d, J = 7.9 Hz, 1H), 8.54–8.44 (m, 4H), 7.79 (t, J = 7.2, 7.2 Hz, 1H), 7.72 (d,
J = 7.2 Hz, 1H), 7.57–6.51 (m, 32H), 5.95 (t, J = 7.5, 7.5 Hz, 1H), 1.98 (s, 3H), 1.81
(s, 3H), 1.75 (s, 3H), 1.70 (d, J = 5.6 Hz, 6H). 13C NMR (100 MHz, C6D6) d 148.4,
148.36, 147.0, 146.6, 143.0, 142.7, 142.0, 141.9, 141.50, 141.46, 140.5, 140.1,
139.5, 139.4, 139.2, 139.14, 139.1, 139.0, 136.2, 135.58, 135.57, 135.42, 135.37,
134.1, 133.4, 133.33, 133.28, 133.1, 132.9, 132.82, 132.76, 132.7, 132.5, 132.3,
132.1, 132.0, 131.2, 130.1, 130.1, 129.8, 129.5, 129.3, 129.18, 129.16, 129.14,
129.13, 129.0, 128.9, 127.8, 128.6, 128.5, 128.4, 128.0, 127.5, 127.3, 126.6,
126.3, 126.0, 124.2, 124.0, 123.94, 123.90, 123.8, 123.0, 121.5, 121.4, 22.0, 21.6,
21.5. 31P NMR (162 MHz, C6D6) d 184.1. MS (FAB) m/z: 1019 ([M+H]+), 927
([MꢀC7H7]+). Anal. Calcd for C75H55O2P: C, 88.38; H, 5.44. Found: C, 88.28; H,
5.46.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.051.
References and notes
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20. The typical procedure of asymmetric cross-coupling reactions (Table 1, entry 2): KF
(87 mg, 1.5 mmol) was dried in vacuo in a Schlenk flask with heating (heat
gun), then 2-(2-chloro-3-methoxyphenyl)-1,3-dioxolane (107 mg, 0.5 mmol),
o-tolylboronic acid (102 mg, 0.75 mmol), Pd2(dba)3ꢁCHCl3 (2.6 mg,
0.0025 mmol), and phosphonite
2 (5.5 mg, 0.006 mmol) were added. The
whole system was evacuated and backfilled with argon three times, and 1 mL
of THF was added. The reaction mixture was stirred at room temperature for
10 min, and then conducted in refluxing THF (oil bath temperature 75 °C) for
5 h. After the reaction, the mixture was diluted with 10 mL of EtOAc, and
filtered through a pad of celite and florisil. Purification by silica gel column
chromatography gave a desired biaryl19 (129 mg, 96%) as white needles. The ee
was determined by HPLC analysis to be 33% with Daicel Chiralcel OJ (eluted
with hexane/iPrOH 75:25, 270 nm, flow rate 0.5 mL/min, column temperature
298 K, and retention times: 14.24 min for R with 33.7%; 18.95 min for S with
66.3%). 1H NMR (400 MHz, CDCl3) d 7.41–7.37 (m, 1H), 7.32 (d, J = 7.8 Hz, 1H),
7.28–7.21 (m, 3H), 7.16 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 5.35 (s, 1H),
4.04–3.95 (m, 2H), 3.80–3.72 (m, 2H), 3.67 (s, 3H), 2.08 (s, 3H). 13C NMR
(100 MHz, CDCl3) d 156.7, 137.6, 137.2, 135.6, 130.68, 130.65, 129.7, 128.9,
127.8, 125.5, 118.8, 111.5, 101.6, 65.69, 65.57, 56.0, 20.3. MS (EI) m/z: 270 (M+,
100%). Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.52; H, 6.75.
21. (a) Bracegirdle, A.; Clayden, J.; Lai, L. W. Beilstein J. Org. Chem. 2008, 4, 47; b
According to Ref. 21a, the product in Table 2 of entry 9 reacted with (S)-(+)-2-
(anilinomethyl)pyrrolidine to be transformed into diastereo-mixtures. The
major isomer afforded the identical assignment with 1H NMR data of a biaryl
bearing axial chirality (R).
22. The biaryl product in entries 10 and 11 was purified by recrystallization one
time to remove small amounts of unclear byproducts.
23. Unfortunately, the derivatives from the cross-coupling reactions of 2-chrolo-3-
methoxy benzonitrile
9
with ortho-tolylboronic acid 8, ortho-
methoxyphenlylboronic acid 10, and ortho-formylphenylboronic acid did not
have enough rotation barriers to maintain the axial chirality. The spectra of
HPLC indicate that these bialys are racemic compounds even at 298 K.