Enantioselective allylic alkylation catalyzed by novel C2-symmetric bisphosphinites

Article abstract of DOI:10.1002/hlca.201400223

In this article, we present our results concerning new C₂-symmetric bisphosphinites with a (1R,2R)-1,2-bis([1,1: 3,1-terphenyl]-5-yl)ethane backbone. For the given chirality of the backbone, derivatives with aromatic and aliphatic substituents

Full text of DOI:10.1002/hlca.201400223

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Helvetica Chimica Acta – Vol. 98 (2015)
Enantioselective Allylic Alkylation Catalyzed by Novel C2-Symmetric
Bisphosphinites
by Yas¸ar Gçk* and Halil Zeki Gçk
Department of Chemistry, Faculty of Arts and Sciences, Osmaniye Korkut Ata University, TR-80000
Osmaniye (phone: þ 90-328-8271000/2541; fax: þ 90-328-8250097; e-mail: yasargok@osmaniye.edu.tr)
In this article, we present our results concerning new C2-symmetric bisphosphinites with a (1R,2R)-
1,2-bis([1,1’:3’,1’’-terphenyl]-5’-yl)ethane backbone. For the given chirality of the backbone, derivatives
with aromatic and aliphatic substituents at the donor P-atoms were synthesized with moderate yields in a
straightforward manner. These compounds were evaluated in the Pd0-catalyzed enantioselective allylic
alkylations (up to 67% ee).
Introduction. – Designing an appropriate ligand is one of the challenges in the field
of asymmetric transition-metal catalysis [1]. Given the complexity of most catalytic
processes, a rational design of a chiral ligand is seldom straightforward. Therefore, the
development of new ligands is often the result of a knowledge-based intuition or of
serendipity. A chiral ligand has to fulfill suitable electronic and steric requirements for
a wide variety of catalytic reactions for excellent enantioselective inductions [2].
Phosphorus compounds play an important role in several fields of synthesis,
especially as ligands in transition metal catalysis. Starting from 1968, tens of thousands
of phosphorus compounds have been developed and evaluated as ligands in several
enantioselective transformations [3]. Among the P-based ligands, phosphines and
phosphinites attracted increased interest due to their wide range of steric and electronic
properties [4]. Phosphinites are easier to synthesize and also provide different
chemical, electronic, and structural properties as compared with phosphines [3]. The
metalÀP bonds of phosphinites are often stronger than related in phosphines due to the
presence of the electron-withdrawing PÀOR group [5].
As part of our ongoing interest in the development of enantioselective catalysts [6],
we synthesized new C2-symmetric bisphosphinites with a (1R,2R)-1,2-bis([1,1’:3’,1’’-
terphenyl]-5’-yl)ethane backbone (Fig.). A C2-symmetry axis minimizes the number of
possible diastereoisomeric transition states [7]. Due to the elimination of less-selective
Figure. Bisphosphinite ligands
ꢀ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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491
reaction pathways, the enantioselectivity can be very high. For the given sense of
chirality of the backbone, Ph and cyclohexyl substituents at the P donor groups were
synthesized with moderate yields in a straightforward manner. These compounds were
evaluated in Pd0-catalyzed enantioselective allylic alkylations.
Results and Discussion. – The synthetic route towards enantiomerically pure C2-
symmetric bisphosphinites 1 and 2 started with (1R,2R)-1,2-bis([1,1’:3’,1’’-terphenyl]-
5’-yl)ethane-1,2-diol (3), which was earlier described by our group (Scheme) [8]. In
general, bisphosphinite ligands are synthesized very efficiently in one step by reacting
the corresponding enantiomerically pure diol with 2 equiv. of the desired chlorophos-
phine in the presence of a base. According to this general procedure, chiral diol 3 was
treated with Ph2PCl and chloro(dicyclohexyl)phosphine (Cy2PCl) to obtain the
corresponding bisphosphinite ligands. Unfortunately, from both reactions, oxidation
products instead of the desired bisphosphinites were obtained and confirmed by 31P-
Scheme. Synthesis of Bisphosphinite Ligands 1 and 2

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Helvetica Chimica Acta – Vol. 98 (2015)
NMR spectrum. To overcome this problem, temporary protection with BH3 was
required, which allowed isolation, purification, and storage of the adduct for a longer
time [6d][9]. BisphosphiniteÀborane 4 and 5 were easily derived from the diol 3. When
diol 3 was treated with Ph2PCl (3.5 equiv.) or Cy2PCl (3.5 equiv.) in the presence of
BuLi and subsequently protected in situ with BH3 · Me2S, bisphosphinite-boranes 4 and
5 were obtained in moderate yields. The last step of our synthetic route, i.e.,
deprotection, could be accomplished by treatment with 1,4-diazabicyclo[2.2.2]octane
(DABCO; 4.5 equiv.) in benzene at 608.
We investigated the Pd0-catalyzed enantioselective allylic alkylation in the presence
of the newly synthesized bisphosphinite ligands 1 and 2 (Table). The transition metal-
catalyzed allylic alkylation reaction, which has become part of modern organic
synthesis, is one of the most versatile and flexible methods for the enantioselective
formation of CÀC and CÀheteroatom bonds [10]. We focused our attention on the
allylic substitution of racemic (2E)-1,3-diphenylallyl acetate (6) with dimethyl
malonate (DMM), which served as test reaction to determine the efficiency of the
newly synthesized enantioselective catalysts (Table) [6a][11]. The nucleophile was
generated from DMM (3 equiv.) in the presence of N,O-bis(trimethylsilyl)acetamide
(BSA; 3 equiv.) and BSA activator AcOLi (0.1 mol-%). The best result was obtained
with ligand 1 (Table, Entry 1). When we decreased the amount of the ligand 1
(0.025 equiv.), a slightly lower enantioselectivity was observed, accompanied by a
decrease in yield (Table, Entry 2). We observed also a pronounced BSA activator
effect (Table, Entry 3). When AcOK was used, no reaction occurred (Table, Entry 3).
To our disappointment, we found no conversion at all when we used THF as solvent
Table. Pd0-Catalyzed Enantioselective Allylic Alkylation of 6 with Dimethyl Malonate in the Presence of
Bisphosphinite Ligands 1 and 2
Entry
Ligand
BSA Activator
Solvent
Yield [%]a)
ee [%]b)c)
1
2d)
3
4
5
6
7d)
8
9
10
1
1
1
1
1
2
2
2
2
2
AcOLi
AcOLi
AcOK
AcOLi
AcOK
AcOLi
AcOLi
AcOK
AcOLi
AcOK
CH2Cl2
CH2Cl2
CH2Cl2
THF
25
15
n.d.e)
n.d.e)
n.d.e)
35
67 (R)
64 (R)
–
–
THF
–
CH2Cl2
CH2Cl2
CH2Cl2
THF
18 (S)
17 (S)
–
18 (S)
–
40
n.d.e)
10
THF
n.d.e)
a) Yield of isolated product. b) Determined by HPLC analysis with a chiral stationary phase (Chiralcel
c
OD-H). ) The absolute configuration was assigned by the sign of the optical rotation. d) 2.5 mmol-% of
ligand was used. e) n.d., Not determined.

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493
(Table, Entries 4 and 5). When we performed the reaction with ligand 2, we observed
moderate yield and poor enantioselectivity (Table, Entry 6). The enantioselectivity and
the yield were slightly changed when 0.025 equiv. of the ligand 2 was used (Table,
Entry 7). In the presence of AcOK, no reaction occured (Table, Entry 8). Switching to
THFas solvent resulted in a sharp decrease of the yield; however, the enantioselectivity
was roughly the same (Table, Entry 9). We determined no conversion when AcOK was
used as BSA activator (Table, Entry 10).
In conclusion, we have synthesized new C2-symmetric bisphosphinites with
(1R,2R)-1,2-bis([1,1’:3’,1’’-terphenyl]-5’-yl)ethylene backbone. For the given sense of
chirality of the backbone, bearing Ph-substituted P-atoms, i.e., 1, and cyclohexyl-
substituted P-atoms 2 were synthesized with moderate yields in a straightforward
manner. Their effectiveness was illustrated in Pd0-catalyzed enantioselective allylic
alkylations. The best catalytic results were obtained in the presence of Ph-substituted
bisphosphinite ligand 1 (up to 67% ee). Making the ligand electron-rich led to lower
enantioselectivity, as shown in the case of cyclohexyl-substituted bisphosphinite ligand
2. It is noteworthy that opposite enantiomers were obtained when the electronic
properties of the P-atoms were changed.
Y. G. and H. Z. G. wish to thank the Scientific & Technological Research Council of Turkey
(TUBITAK) (Project No: TBAG-112T017).
Experimental Part
General. All reactions were carried out under Ar in dry solvents under anh. conditions, unless stated
otherwise. All reagents were purchased and used without further purification, unless noted otherwise.
Anal. TLC: MachereyÀNagel SIL G-25 UV254 plates. Flash chromatography (FC): ROCC silica gel (SiO2;
0.040 – 0.063 mm). Anal. chiral HPLC: VWR Hitachi series, with DAD detection. M.p.: Thermo Scientific
9200 melting-point apparatus. Optical rotations: Krüss P3000 series polarimeter. IR Spectra:
PerkinElmer Spectrum 65 FT-IR spectrometer; n˜ in cmÀ1 1H- and 13C-NMR spectra: Bruker Avance
.
400 spectrometer; d in ppm rel. to Me4Si; 31P-NMR chemical shifts rel. to an external standard of 85%
H3PO4 ; J in Hz. 13C-NMR spectra were recorded using the attached-proton test. ESI-MS: Agilent
LC/MSD and Bruker Daltonics MALDI-TOF mass spectrometer; in m/z.
(1R,2R)-1,2-Di(1,1’:3’,1’’-terphenyl-5’-yl)ethane-1,2-diyl Bis[diphenyl(phosphinite)]Àborane (1:2)
(4). To a soln. of (1R,2R)-1,2-bis([1,1’:3’,1’’-terphenyl]-5’-yl)ethane-1,3-diol (3; 25 mg, 0.048 mmol) in
dry THF was added BuLi (0.240 ml, 0.386 mmol) at 08, and the mixture was stirred for 1 h at r.t. Ph2PCl
(0.035 ml, 0.168 mmol) was added dropwise to the resulting mixture. After stirring for 3 h, BH3 · Me2S
(0.06 ml, 0.578 mmol) was carefully added, and stirring was continued for 2 h. Evaporation in vacuo and
purification by FC (SiO2; hexane/AcOEt 85 :15) afforded 4 (20 mg, 45%). White foam. M.p. 156 – 1578.
[a]2D0 ¼ þ20 (c ¼ 1.0, CHCl3). IR: 3537, 3057, 3032, 2924, 2854, 2377, 1595, 1576, 1497, 1435, 1029, 758, 696.
1H-NMR (400 MHz, DMSO): 0.7 – 1.0 (br. m, 2 BH3); 5.9 – 6.01 (m, 2 H); 7.23 – 7.24 (m, 4 H); 7.3 – 7.5 (m,
34 H); 7.57 – 7.67 (m, 8 H). 13C-NMR (100 MHz, DMSO): 82.45 (d, J ¼ 6.5); 124.95 (d, J ¼ 46); 127.2 (d,
J ¼ 67); 128.5 (d, J ¼ 10.6); 128.73 (t, J ¼ 6.5); 130.2 (d, J ¼ 11); 130.6 (d, J ¼ 11); 131 (d, J ¼ 11); 131.2 (d,
J ¼ 18); 132 (d, J ¼ 33); 137.8, 139.7, 140.2. 31P-NMR (162 MHz, DMSO): 106.62. MALDI-TOF-MS:
938.84 ([M þ H þ Na]þ), 981.81 ([M À 2 H þ 3 Na]þ). Anal. calc. for C62H54B2O2P2 (914.66): C 81.41, H
5.95, found: C 81.20, H 6.00.
(1R,2R)-1,2-Di(1,1’:3’,1’’-terphenyl-5’-yl)ethane-1,2-diyl Bis[dicyclohexyl(phosphinite)]Àborane
(1:2) (5). To a soln. of 3 (25 mg, 0.048 mmol) in dry THF was added BuLi (0.240 ml, 0.386 mmol) at
08, and the mixture was stirred for 1 h at r.t. Then, Cy2PCl (0.039 ml, 0.168 mmol) was added dropwise.
After stirring for 3 h, BH3 · Me2S (0.06 ml, 0.578 mmol) was added carefully to the mixture, and stirring
was continued for 2 h. Evaporation in vacuo and purification by FC (SiO2; hexane/AcOEt 85 :15)

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Helvetica Chimica Acta – Vol. 98 (2015)
afforded in 5 (28 mg, 62%). White foam. M.p. 114 – 1158. [a]2D0 ¼ þ8 (c ¼ 1.07, CHCl3). IR: 3365, 3055,
2931, 2855, 2382, 2358, 1624, 1452, 1443, 1182, 1171, 1124, 1098, 1059, 1047, 1003, 914, 897, 883, 760, 611.
1H-NMR (400 MHz, DMSO): 1.2 – 1.35 (br. m, 20 H); 1.69 – 1.75 (m, 8 H); 1.8 – 1.9 (m, 22 H); 5.35 – 5.36
(m, 2 H); 7.35 – 7.4 (m, 4 H); 7.41 – 7.45 (m, 8 H); 7.54 – 7.55 (m, 4 H); 7.59 – 7.64 (m, 8 H); 7.77 – 7.79 (m,
2 H). 13C-NMR (100 MHz, DMSO): 24.7 (d, J ¼ 2.76); 25.6 (d, J ¼ 1.8); 25.9 (d, J ¼ 1.2); 26.3 (d, J ¼ 4);
26.4 (d, J ¼ 6.6); 34.5 (d, J ¼ 38.5); 86.4 (d, J ¼ 2.3); 123.5, 126.2 (d, J ¼ 4); 127.3, 127.6, 128.8, 140.7, 141.3,
(d, J ¼ 10.8); 142.5. 31P-NMR (162 MHz, DMSO): 119.26. ESI-MS: 956.2 ([M þ NH4]þ), 957.2 ([M þ
NH4 þ H]þ). Anal. calc. for C62H78B2O2P2 (938.85): C 79.32, H 8.37, found: C 79.71, H 8.45.
(1R,2R)-1,2-Di(1,1’:3’,1’’-terphenyl-5’-yl)ethane-1,2-diyl Bis[diphenyl(phosphinite)] (1). A mixture
of 4 (60 mg, 0.066 mmol) and 1,4-diazabicyclo[2.2.2]octane (DABCO; 34 mg, 0.29 mmol) in dry benzene
(3 ml) was heated to 608 for 12 h under Ar. Evaporation in vacuo and purification by FC (dry Al2O3; dry
CH2Cl2) gave 1.
(1R,2R)-1,2-Di(1,1’:3’,1’’-terphenyl-5’-yl)ethane-1,2-diyl Bis[dicyclohexyl(phosphinite)] (2). A mix-
ture of 5 (70 mg, 0.074 mmol) and DABCO (349 mg, 0.34 mmol) in dry benzene (3 ml) was heated to 608
for 12 h under Ar. Evaporation in vacuo and purification by FC (dry Al2O3; dry CH2Cl2) gave 2.
Pd0-Catalyzed Enantioselective Allylic Alkylation: General Procedure. Ligand 1 (0.05 mmol) and
[Pd(h3-C3H5)Cl]2 (0.02 mmol) were dissolved in degassed CH2Cl2 under Ar using Schlenk techniques.
The mixture was stirred for 1 h at 508 and cooled to r.t. Then, (2E)-1,3-diphenylprop-2-enyl acetate (6;
1 mmol) in CH2Cl2 was added, and the mixture was stirred at r.t. for 30 min. Finally, a soln. of N,O-
bis(trimethylsilyl)acetamide (BSA; 3 mmol), AcOLi (0.1 mmol), and dimethyl malonate (DMM;
3 mmol) was added to the mixture. The mixture was stirred for 16 h at r.t. Next, Et2O was added, and the
mixture was washed with a sat. NH4Cl soln., dried (MgSO4), and concentrated in vacuo. The crude
product was purified by FC (SiO2; hexane/AcOEt 90 :10) to afford the target compound.
All adducts were fully characterized by comparison of their spectral data with those reported in the
literature. The absolute configurations were assigned via correlation of their optical rotation with
literature values [12]. The enantiomeric excess (ee) was determined by chiral HPLC analysis: Chiralcel
OD-H column (250 Â 4.6 mm, particle size, 10 mm); solvent, hexane/iPrOH 99 :1, flow rate, 1 ml/min; T,
358, tR 25.60 and 27.26 min for (À)-(R)-7 and (þ)-(S)-7, resp.
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Received July 02, 2014