Synthesis of novel chiral biquinolyl diphosphine ligand and its applications in palladium-catalyzed asymmetric allylic substitution reactions

Article abstract of DOI:10.1016/j.tetlet.2016.01.007

A novel chiral diphosphine ligand, 6,6′-bis(diphenylphosphino)-5,5′-biquinoline (BIQAP) was synthesized via two step reactions using optical pure BIQOL as starting material and the molecular structure of (R)-BIQAP was determined by single-crystal X-ray diffraction. The ligand was used for Pd-catalyzed asymmetric allylic substitution reactions. High enantioselectiveties were obtained in the corresponding C-C and C-N bond formation of 1,3-diphenyl-2-propenyl acetate, with dimethyl malonate (up to 94% ee) and with potassium phthalimide (up to 96% ee).

Full text of DOI:10.1016/j.tetlet.2016.01.007

Tetrahedron Letters 57 (2016) 845–848
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel chiral biquinolyl diphosphine ligand and its
applications in palladium-catalyzed asymmetric allylic substitution
reactions
a
a
a
b
a,
⇑
Rui Zhang , Bin Xie , Guo-Shu Chen , Liqin Qiu , Yi-Xin Chen
a
School of Chemistry and Chemical Engineering, Guangzhou University, 230 Wai Huan Xi Road, GuangZhou Higher Education Mega Center, Guangzhou 510006, China
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135, Xin Gang Xi Road, Guangzhou 510275, China
b
a r t i c l e i n f o
a b s t r a c t
0
0
Article history:
A novel chiral diphosphine ligand, 6,6 -bis(diphenylphosphino)-5,5 -biquinoline (BIQAP) was synthesized
via two step reactions using optical pure BIQOL as starting material and the molecular structure of
(
Received 21 October 2015
Revised 30 December 2015
Accepted 5 January 2016
Available online 6 January 2016
R)-BIQAP was determined by single-crystal X-ray diffraction. The ligand was used for Pd-catalyzed
asymmetric allylic substitution reactions. High enantioselectiveties were obtained in the corresponding
C–C and C–N bond formation of 1,3-diphenyl-2-propenyl acetate, with dimethyl malonate (up to 94% ee)
and with potassium phthalimide (up to 96% ee).
Keywords:
Ó 2016 Elsevier Ltd. All rights reserved.
Diphosphine ligand
Pd-catalyzed
Allylic alkylation
BIQAP
Introduction
Pd-catalyzed asymmetric allylic substitution reactions (see
Scheme 1 and Scheme 2).
Chiral phosphine ligands are a very successful type of ligands
used in asymmetric catalysis.1 Among them, BINAP is no doubt
one of the most effective chiral diphosphine ligands. So far
Results and discussion
2
diphosphine–metal complexes have been found to be versatile in
The chiral BIQAP ligand was obtained through a straightforward
two-step synthetic route using optical pure BIQOL as the starting
material. At first, ditriflate of (R)-BIQOL was prepared using
3
many catalytic reactions such as asymmetric hydrogenation, ary-
4
5
lation, allylic alkylation, etc. Moreover, a large number of exam-
ples of industrialization have been reported.6
(R)-BIQOL and triflate in an ice bath. Then, a coupling reaction
Pd-catalyzed asymmetric allylic alkylation7 is
a powerful
between ditriflate L2 and diphenylphosphine was carried out with
approach to stereoselective C–C, C–N, and C–O bonds formation
in synthetic organic chemistry. As such its asymmetric version
using a chiral ligand has also been extensively studied in the past
a Ni-based catalyst and 1,4-diaza[2.2.2]bicyclooctane (DABCO) in
DMF at 120 °C for 72 h. Numerous nickel catalysts such as NiCl
NiCl /dppp, NiCl ꢀ(Ph P) were screened and it is found
ꢀdppe, NiCl
that only NiCl
2
,
2
2
2
3
2
8
decades. In order to achieve high enantioselectivity from racemic
2
ꢀdppe catalyzed (R)-BIQAP formation.
or achiral allylic substrates, the development of a novel chiral
X-ray single crystal diffraction analysis of (R)-BIQAP revealed
the presence of diphenylphosphino moiety in the ligand via C–P
binding in an orthorhombic crystal system and the space-group
ligand is an essential and challenging task.9 In 2000, Chan and
2
co-workers once reported a C -symmetric, heterocyclic chiral
0
0
10
ligand, 6,6 -dihydroxy-5,5 -biquinoline (BIQOL)
which has a
1 1 1
is P2 2 2 (19). The interplanar angle of the least-squares of the
biquinoline is 90° (Fig. 1).
With chiral ligand BIQAP in hand, we first examined its catalytic
activity under the Pd-catalyzed asymmetric allylic alkylation reac-
tion. rac-1,3-Dipenylpropen-1-yl acetate reacted with dimethyl
skeleton similar to that of BINOL. Since then the BIQOL ligand
has been applied to many kinds of reactions and showed good
1
0,11
enantioselectivity.
Herein we report its further development
0
for the preparation of novel BIQAP ligand 6,6 -bis(diphenylphos-
phino)-5,5 -biquinoline and the corresponding application in
0
malonate (3.0 equiv) in the presence of (S)-BIQAP (5.0 mol %), [Pd
3
(
3
g
-C
3
H
5
)Cl]
2
(2.5 mol %), N,O-bis(trimethylsilyl)acetamide (BSA,
(0.1 equiv). The latter was acted as BSA
equiv) and Zn(OAc)
2
⇑
Corresponding author. Tel.: +86 203 936 6902; fax: +86 203 936 6903.
E-mail address: y.xin.chen@163.com (Y.-X. Chen).
activator.
http://dx.doi.org/10.1016/j.tetlet.2016.01.007
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

8
46
R. Zhang et al. / Tetrahedron Letters 57 (2016) 845–848
OH
OH
PPh
PPh
2
2
BINOL
BINAP
N
N
OH
OH
PPh
PPh
2
2
N
N
BIQOL
BIQAP
2
Scheme 1. C -symmetric chiral ligands.
N
N
Tf
2
O ,Pyridine
OTf
OTf
PHPh
Triethylenediamine
DMF,
2 2
, NiCl ·dppe
OH
OH
CH
2
Cl
2
, r.t.
Δ
N
N
N
L1
L2
N
Figure 1. The crystal structure of (R)-BIQAP.
PPh
PPh
2
PPh2
PPh2
or
2
N
N
precursors. Decreasing the catalyst loading of ligand 3 from
L3
L4
5
9
.0 mol % to 2.5 mol % afforded almost the same result (99% yield,
1% ee, Table 1, entry 10). 1 mol % catalyst loading still gave the
Scheme 2. Synthesis of chiral BIQAP ligand.
product in 99% yield with 92% ee (Table 1, entry 11). Similar results
were obtained using (R)-or (S)-BIQAP as the ligand under the same
conditions (Table 1, entries 11 and 12). An interesting phe-
nomenon was also observed that there was no influence in enan-
Solvent screening experiments showed that toluene, THF or
EtOAc as solvent provided good enantioselection. Yet, CH Cl was
the best one with ee value up to 90% (Table 1, entries 1–5). After
selecting CH Cl as the solvent, we then investigated the effect of
palladium sources (Table 1, entries 2, 6–9) and found that [Pd
2
2
2
tioselectivity without Zn(OAc) as the activator (Table 1, entries
2
2
13 and 14). In addition, temperature decrease from 25 °C to
ꢁ10 °C brought about an enantioselectivity increase from 92% to
94% ee (Table 1, entries 14–16). The catalytic activity was further
3
(g
-C
H
3 5
)Cl]
2
was the most favorable choice among the studied
Table 1
The Pd-catalyzed asymmetric allylic alkylation reaction
a,12
Ligand 3 (5 mmol %)
H
3
CO
2
C
CO
2 3
CH
3
OAc
Ph
CO CH
[Pd(η -C H )Cl] (2.5 mmol %)
2
3
3
5
2
+
Ph
CO
2
CH
3
BSA (3.0 equiv)
Zn(OAc) (0.1 equiv)
Ph
Ph
*
2
5
6
7
Entry
Solvent
Toluene
[Pd]
Ligand (%)
Activator
Temp (°C)
Time (h)
Yieldb (%)
eec (%)
3
3
3
3
3
1
2
3
4
5
6
7
8
9
[Pd(
[Pd(
[Pd(
[Pd(
[Pd(
g
g
g
g
g
-C
3
3
3
3
3
H
5
5
5
5
5
)Cl]
)Cl]
)Cl]
)Cl]
)Cl]
2
2
2
2
2
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
2.5
1.0
1.0
5.0
1.0
1.0
1.0
1.0
1.0
Zn(OAc)
Zn(OAc)
Zn(OAc)
Zn(OAc)
Zn(OAc)
Zn(OAc)
Zn(OAc)
Zn(OAc)
Zn(OAc)
Zn(OAc)
Zn(OAc)
Zn(OAc)
—
2
2
2
2
2
2
2
2
2
2
2
2
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
ꢁ10
ꢁ10
ꢁ10
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
6
99
99
75
99
97
29
87
8
84 (S)
90 (S)
83 (S)
84 (S)
7 (S)
81 (S)
78 (S)
79 (S)
n.d.
91 (S)
92 (S)
92 (R)
91 (S)
92 (S)
93 (S)
94 (S)
94 (S)
94 (S)
CH
THF
EtOAc
2
Cl
2
-C
-C
-C
-C
H
H
H
H
CH
3
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CN
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Pd(bda)
Pd (bda)
Pd(OAc)
PdCl
2
2
3
2
2
0
3
3
3
3
3
3
3
3
3
10
11
12
13
14
15
16
17
18
[Pd(
[Pd(
[Pd(
[Pd(
[Pd(
[Pd(
[Pd(
[Pd(
[Pd(
g
g
g
g
g
g
g
g
g
-C
-C
-C
-C
-C
-C
-C
-C
-C
3
H
3
H
3
H
3
H
3
H
3
H
3
H
3
H
3
H
5
)Cl]
5
)Cl]
5
)Cl]
5
)Cl]
5
)Cl]
5
)Cl]
5
)Cl]
5
)Cl]
5
)Cl]
2
2
2
2
2
2
2
2
2
99
99
99
99
99
99
99
99
99
d
—
—
—
—
—
a
b
c
Reaction conditions: 0.5 mmol 1,3-dipenylpropen-1-yl acetate, 1.5 mmol BSA, 1.5 mmol dimethyl malonate, 2.0 mL of solvent.
Yield of isolated product.
Determined by HPLC on a Chiralcel OD-H column.
d
(R)-BIQAP as ligand.

R. Zhang et al. / Tetrahedron Letters 57 (2016) 845–848
847
Table 2
Acknowledgments
a,13,14
The Pd-catalyzed asymmetric allylic amination reaction
We thank the National Natural Science Foundation of China
No. 21072036) and Guang Zhou University for financial support.
1
0a
N
H
Ligand 4 (5 mmol %)
Pd(η -C H )Cl] (2.5 mmol %)
3 5 2
(
OAc
Ph
3
X
[
Ph
benzylamine 8
or
potassium phthalimide 9
Ph
Ph
O
N
O
*
Supplementary data
5
10
10b
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.01.
Entry Nucleophile [Pd]
Temp
Yieldb
(%)
eec (%)
0
07.
(°C)
1
2
8
8
Pd
[Pd(
Cl]
[Pd(
Cl]
[Pd(
Cl]
Pd
[Pd(
Cl]
[Pd(
Cl]
[Pd(
Cl]
2
(bda)
3
0
0
0
3
n.d.
91 (R)
3
References and notes
g
g
g
-C
3
3
3
H
H
H
5
5
5
)
)
)
2
3-C
1.
(a) Hayashi, T. Acc. Chem. Res. 2000, 33, 354–362; (b) Genet, J. P. Acc. Chem. Res.
003, 36, 908–918; (c) Tang, W. J.; Zhang, X. Chem. Rev. 2003, 103, 3029–3070.
3
4
8
8
25
40
7
90 (R)
88 (R)
2
2
2
3
.
.
Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345–350.
3-C
62
(a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori,
R. J. Am. Chem. Soc. 1980, 102, 7932–7934; (b) Qiu, L.; Qi, J.; Pai, C.-C.; Chan, S.;
Zhou, Z.; Choi, M. C. K.; Chan, A. S. C. Org. Lett. 2002, 4, 4599–4602; (c) Qiu, L.;
Wu, J.; Chan, S.; Au-Yeung, T. T.-L.; Ji, J.-X.; Guo, R.; Pai, C.-C.; Zhou, Z.; Li, X.;
Fan, Q.-H.; Chan, A. S. C. Proc. Natl. Acad. Sci. USA 2004, 101, 5815–5820; (d) Qiu,
L.; Kwong, F. Y.; Wu, J.; Lam, W. H.; Chan, S.; Yu, W.-Y.; Li, Y.-M.; Guo, R.; Zhou,
Z.; Chan, A. S. C. J. Am. Chem. Soc. 2006, 128, 5955–5965; (e) Pai, C.-C.; Lin, C. W.;
Lin, C.-C.; Chen, C.-C.; Chan, A. S. C. J. Am. Chem. Soc. 2000, 122, 11513–11514;
(f) Jeulin, S.; Paule, S.; Vidal, V. R.; Genet, J. P.; Champion, N.; Dellis, P. Angew.
Chem., Int. Ed. 2004, 43, 320–325; (g) Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X.
J. Org. Chem. 2000, 65, 6223–6226; (h) Schmid, R.; Cereghetti, M.; Heiser, B.;
Schonholzer, P.; Hansen, H. J. Helv. Chim. Acta 1988, 71, 897–929; (I) Saito, T.;
Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.; Kumobayashi, H. Adv.
Synth. Catal. 2001, 343, 264–267; (J) Xie, J. H.; Wang, L. X.; Fu, Y.; Zhu, S. F.; Fan,
B. M.; Duan, H. F.; Zhou, Q. L. J. Am. Chem. Soc. 2003, 125, 4404–4405.
(a) Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113, 1417–1419; (b)
Wang, S.; Li, J.; Miao, T.; Wu, W.; Li, Q.; Zhuang, Y.; Zhou, Z.; Qiu, L. Org. Lett.
2
5
6
9
9
2
(bda)
3
0
0
0
32
n.d.
96 (R)
3
g
g
g
-C
3-C
3-C
3
3
3
H
H
H
5
)
5
)
5
)
2
7
8
9
9
25
40
97
99
91 (R)
2
91 (R) (94)d
(R)
2
a
Reaction conditions: 0.5 mmol 1,3-dipenylpropen-1-yl acetate, 1.5 mmol
nucleophilc, 5.0 mol % (R)-BIQAP, 2.0 mL of solvent, 24 h.
b
Yield of isolated product.
Determined by HPLC on Chiralcel OD-H column.
After a single recrystallization.
c
d
4.
5.
6.
7.
2012, 14, 1966–1969.
(a) Gladiali, S.; Dore, A.; Fabbri, D.; Medici, S.; Pirri, G.; Pulacchini, S. E. J. Org.
Chem. 2000, 16, 2861–2865; (b) Xing, A. P.; Pang, Z. B.; Li, H. F.; Wang, L. L.
Tetrahedron 2014, 70, 8822–8828.
(a) Chan, A. S. C. ChemTech 1993, 23, 46–51; (b) Blaser, H. U. Chem. Commun.
2003, 293–296; (c) Berqbreiter, D. E.; Kobayashi, S. Chem. Rev. 2009, 109, 257–
surveyed (Table 1, entries 16–18). To our delight, the reaction still
takes place as usual even shortening the reaction time to 6 hours.
Under the optimal experimental conditions, product
obtained in 99% yield with 94% ee.
After realizing the above-mentioned enantioselective C–C bond
formation, we turned to evaluate BIQAP ligand in a C–N bond for-
mation reaction. Preliminary tests showed that asymmetric allylic
amination of rac-1,3-dipenylpropen-1-yl acetate with benzylamine
didn’t proceed by employing (R)-BIQAP as the ligand and Pd (bda)
2 3
as the palladium source at 0 °C (Table 2, entry 1). In contrast, pro-
duct 10a was obtained in 91% ee and 3% yield (Table 2. entry 1)
with [Pd(
from 0 °C to 40 °C, the yield of product 10a had a significant
increase, but the enantioselectivity decreased from 91% to 88%
Table 2, entries 2–4). To improve the reactivity and stereoselectiv-
ity, the reaction was further explored by using potassium phthal-
imide 9 as a bulky and reactive nitrogen-containing nucleophile
Table 2, entries 5–8). Similar results to that in the preparation of
0a were given under the same conditions. Product 10b was
7 was
2
58.
(a) Forst, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron: Asymmetry 1992, 3,
089–1122; (b) Heumann, A.; Reglier, M. Tetrahedron 1995, 51, 975–1015; (c)
1
Trost, B. M.; van Vranken, D. L. Chem. Rev. 1996, 96, 395–422; (d) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921–2944; (e) Lu, Z.; Ma, S. Angew. Chem.,
Int. Ed. 2007, 47, 258–297.
8.
(a) Chen, Z.; Jiang, Q.; Zhu, G.; Xiao, D.; Cao, P.; Guo, C.; Zhang, X. J. Org. Chem.
1997, 62, 4521–4523; (b) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–
345; (c) Uenishi, J.; Hamada, M. Tetrahedron: Asymmetry 2001, 12, 2999–3006;
(
d) Hu, X.; Dai, H.; Hu, X.; Chen, H.; Wang, J.; Bai, C.; Zheng, Z. Tetrahedron:
Asymmetry 2002, 13, 1687–1693; (e) Anderson, J. C.; Osborme, J. Tetrahedron:
Asymmetry 2005, 16, 931–934; (f) Zhang, K.; Peng, Q.; Hou, X. L.; Wu, Y. D.
Angew. Chem., Int. Ed. 2008, 47, 1741–1744; (g) Yuan, H.; Zhou, Z.; Xiao, J.;
Liang, L.; Dai, L. Tetrahedron: Asymmetry 2010, 21, 1874–1884; (h) Liu, Y.; Cao,
Z.; Du, H. J. Org. Chem. 2012, 77, 4479–4483.
3
g
-C
3
H
5
)Cl]
2
instead. When the temperature was raised
(
9.
(a) Fuji, K.; Kinoshita, N.; Tanaka, K. Chem. Commun. 1999, 1895–1896; (b) You,
S. L.; Hou, X. L.; Dai, L. X.; Yu, Y. H.; Xia, W. J. Org. Chem. 2002, 67, 4684–4695;
(
2
c) Bayardon, J.; Sinou, D.; Guala, M.; Desimoni, G. Tetrahedron: Asymmetry
004, 15, 3195–3200.
(
1
1
1
1
0. Chen, Y. X.; Yang, L. W.; Zhou, Z. Y.; Chan, A. S. C.; Kwong, H. L. Chirality 2000,
12, 510–513.
1. Chen, Q.; Ou, J.; Chen, G. S.; Liu, T. S.; Xie, B.; Liang, H. B.; Xie, L. Q.; Chen, Y. X.
Chirality 2014, 26, 268–271.
obtained with 96% ee at 0 °C despite in only 32% yield. When the
temperature was raised to 40 °C, the reaction gave satisfactory
results for product 10b (99% yield and 91% ee) (Table 2, entry 8).
The product can be enantioenriched to 94% ee after a single
recrystallization.
2. General procedure for the Pd-catalyzed allylic alkylation of rac-1,3-dipenylpropen-
3
1-yl acetate
5
with dimethyl malonate 6: [Pd(
g
-C H )Cl] (4.6 mg,
3
5
2
0.0125 mmol) and (S)-BIQAP (15.0 mg, 0.025 mmol) were dissolved in dry
solvent (1 mL) in a dried Schlenk tube under nitrogen atmosphere, and then
stirred at room temperature. After 20 min, rac-1,3-dipenylpropen-1-yl acetate
(
126.5 mg, 0.5 mmol) was added and the mixture was stirred for another
min. Finally, the mixture was kept at proper temperature. To this solution
were added dimethyl malonate (171 L, 1.5 mmol), N,O-bis(trimethylsilyl)
acetamide (365 L, 1.5 mmol), and Zn(OAc) (8.5 mg, 0.05 mmol). The reaction
mixture was diluted with CH Cl (20 mL) and washed twice with saturated
aqueous NH Cl. The organic layer was dried over anhydrous Na SO and then
5
Conclusion
l
l
2
2
2
In conclusion, a novel chiral diphosphine ligand BIQAP based on
biquinoline skeleton was successfully prepared, and the ligand
structure was also determined via single-crystal X-ray diffraction.
The ligand was applied to the Pd-catalyzed asymmetric allylic
alkylation and aminations. The corresponding products were pro-
vided in very high yields and with excellent enantioselectivities
4
2
4
concentrated under reduced pressure. The residue was purified by preparative
TLC (PE/EA = 10/1) to give the pure product 7.
1
3. General procedure for the Pd-catalyzed allylic amination of rac-1,3-dipenylpropen-
3
1
-yl acetate 5 with benzylamine 8: [Pd(
g
-C
3
H
5
)Cl]
2
(4.6 mg, 0.0125 mmol) and
(S)-BIQAP (15.0 mg, 0.025 mmol) were dissolved in dry CH Cl2 (1 mL) in a
2
dried Schlenk tube under nitrogen atmosphere, and then stirred at room
temperature. After 20 min, rac-1,3-dipenylpropen-1-yl acetate (126.5 mg,
(
upto 94% and 96% ee respectively). Further applications and mod-
0.5 mmol) was added and the mixture was stirred for another 5 min. Finally,
ification of the ligand are in progress in our laboratory.
the mixture was kept at proper temperature. To this solution were added

8
48
R. Zhang et al. / Tetrahedron Letters 57 (2016) 845–848
benzylamine (164
l
L, 1.5 mmol) and N,O-bis(trimethylsilyl)acetamide (365
l
L,
stirred at room temperature. After 20 min, rac-1,3-dipenylpropen-1-yl acetate
(126.5 mg, 0.5 mmol) was added and the mixture was stirred for another
5 min. Finally, the mixture was kept at proper temperature. To this solution
was added potassium phthalimide (0.278 g, 1.5 mmol). The reaction mixture
was diluted with ether (20 mL) and washed twice with brine. The organic layer
was dried over anhydrous Na SO and then concentrated under reduced
2 4
pressure. The residue was chromatographed on silica gel (PE/EA = 15:1 as
eluent) to give the pure product 10b.
1
.5 mmol). The reaction mixture was subjected directly to column
chromatography on silica gel (PE/EA = 15:1 as eluent) to give the pure
product 10a.
1
4. General procedure for the Pd-catalyzed allylic amination of rac-1,3-dipenylpropen-
3
1
0
CH
-yl acetate
.0125 mmol) and (S)-BIQAP (15.0 mg, 0.025 mmol) were dissolved in dry
Cl (1 mL) in a dried Schlenk tube under nitrogen atmosphere, and then
5
with potassium phthalimide 9: [Pd(
g
-C
3
H
5
)Cl]
2
(4.6 mg,
2
2