Synthesis of a new bulky phosphite ligand and its application in the enantioselective hydrogenation

Article abstract of DOI:10.1016/j.jorganchem.2018.02.038

A new bulky phosphite ligand was synthesized and tested in the asymmetric Rh-catalyzed hydrogenation of a series of substrates, including dimethyl itaconate (up to 95% ee), α- and β-dehydroamino acid derivatives (up to 88% and 76% ee, respectively). In th

Full text of DOI:10.1016/j.jorganchem.2018.02.038

Accepted Manuscript
Synthesis of a new bulky phosphite ligand and its application in the enantioselective
hydrogenation
Marina V. Sokolovskaya, Sergey E. Lyubimov, Igor S. Mikhel, Kirill P. Birin, Vadim A.
Davankov
PII:
S0022-328X(18)30137-2
10.1016/j.jorganchem.2018.02.038
JOM 20337
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 30 January 2018
Revised Date: 20 February 2018
Accepted Date: 21 February 2018
Please cite this article as: M.V. Sokolovskaya, S.E. Lyubimov, I.S. Mikhel, K.P. Birin, V.A. Davankov,
Synthesis of a new bulky phosphite ligand and its application in the enantioselective hydrogenation,
Journal of Organometallic Chemistry (2018), doi: 10.1016/j.jorganchem.2018.02.038.
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Graphical abstract:
O
O
O
H2
R
O
Y
R
O
Y
X
X
[Rh(COD) ]BF /2L
2
4
O
P
O
O
O
H2
Me
Me
N
N
[Ir(COD)Cl]2/4L
H
H
Synopsis.
A new bulky phosphite ligand was synthesized and tested in the asymmetric Rh-catalyzed
hydrogenation of a series of substrates, including dimethyl itaconate (up to 95% ee), α- and β-
dehydroamino acid derivatives (up to 88% and 76% ee, respectively).

ACCEPTED MANUSCRIPT
Synthesis of a new bulky phosphite ligand and its application in the
enantioselective hydrogenation.
Marina V. Sokolovskayaa, Sergey E. Lyubimova,*, Igor S. Mikhelb, Kirill P. Birinb, Vadim
A. Davankova
a A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
Vavilov Street 28, 119991 Moscow, Russia
b A.N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of
Sciences,
Leninskiy prospect 31/4, 119071 Moscow, Russia
Abstract
A new bulky phosphite ligand was synthesized and tested in the asymmetric Rh-catalyzed
hydrogenation of a series of substrates, including dimethyl itaconate (up to 95% ee), α- and β-
dehydroamino acid derivatives (up to 88% and 76% ee, respectively). In the Ir-catalyzed
hydrogenation of 2-methylindole, the use of iodine as an additive led to a significant increase in
the enantioselectivity and conversion. The best result (64% ee) was obtained with [Ir(COD)Cl]2
as precatalyst.
Keywords: asymmetric hydrogenation; amino acids; phosphite ligand; 2-methylindole.
* Corresponding author. Tel.: +7 499 1352548; e-mail: lssp452@mail.ru
1. Introduction.
Enantioselective homogenous hydrogenation catalyzed by chiral transition metal complexes has
become one of the most wide-spread methods for obtaining of optically active organic
compounds, more commonly utilizing complexes based on Ru, Rh or Ir and including
phosphorous-containing chiral ligands.1 This method is attractive due to low catalyst loadings,
high reliability, mild reaction conditions and perfect atom economy. Complexes bearing

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phosphine ligands have attracted much attention as a result of their high activity and good
enantioselective control.2 By using ruthenium, rhodium or iridium catalysts with chiral
phosphine ligands in the asymmetric hydrogenation of α- and β-dehydroamino acids and
heterocyclic compounds, good to excellent enantioselectivities have been obtained.3,4 However,
in the past few years, monodentate phosphites and phosphoramidites were shown to be excellent
and sometimes superior alternatives to the phosphine ligands, in terms of enantioselectivity,
simplicity of synthesis, stability, ease of structural variation.5,6 The use of sterically hindered O-
alkyl substituents in such ligands is shown to increase stereogenic activity of a metal-complex
catalyst in a range of examples.7-10 Motivated by this observation, we have prepared a novel
sterically congested adamantane-containing monodentate phosphite ligand for application in the
asymmetric hydrogenation of dimethylitaconate, α- and β-enamides and 2-methylindole.
2. Materials and methods.
2.1. General.
13
1
31P, C and H NMR spectra were recorded with a Bruker Avance 400 (162.0 MHz for
13
1
31P, 100.6 MHz for C and 400.13 MHz for H) and a Bruker Avance III 600 (242.9 MHz for
13
1
31P, 150.9 MHz for C and 600.13 MHz for H) instruments. Complete assignment of all the
1
resonances in H and 13C NMR spectra was achieved by the use of DEPT, COSY, ROESY,
HSQC, and HMBC techniques. Chemical shifts δ are quoted in parts per million (ppm)
downfield of tetramethylsilane. 31P NMR chemical shifts were referenced externally to 85%
H3PO4 (δ 0.0). Coupling constants J are given in Hz.
NEt3 was freshly distilled on CaH2. All other commercially available reagents were used
without further purification. Solvents were purified by standard procedures: CH2Cl2 and CDCl3
were distilled from CaH2.
(Rax)-2-chlorodinaphtho[2,1-d:1’,2’-f][1,3,2] dioxaphosphepine (1)11, substrates 3b-d12-14
5a15 were prepared according to the published procedures. Enamide 5b was synthesized
,

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analogously to 5a by refluxing ethyl 3-phenylpropiolate in DMF with catalytic amount of KOH
and succinimide.
1
5b. 52% yield after recrystallization of crude product in Et2O. White solid, mp 81-82 °C. H
NMR (400.13 MHz, CDCl3): 1.31 (t, J = 7.2, 3Н, CH3), 2.88-3.06 (m, 4H, CH2-CH2), 4.19 (q, J
= 7.2, 2Н, CH2CH3), 6.63 (s, 1Н, =CH), 7.36-7.53 (m, 5H, Ph). 13C NMR (100.6 MHz, CDCl3):
14.1 (CH3), 29.1 (CH2CH2), 60.8 (OCH2CH3), 117.2 (=CH), 126.2 (Ph), 129.1 (Ph), 131.1 (Ph),
133.8 (Ph), 144.2 (=C-N), 163.8 (COO), 175.9 (C(O)N). Anal. calcd. for C15H15NO4 C, 65.92;
H, 5.53; N, 5.13. Found: C, 66.19; H, 5.76; N, 5.01.
1
6b. White solid, mp 81-82 °C. H NMR (400.13 MHz, CDCl3): 1.23 (t, J = 7.2 Hz, 3Н, CН3),
2.67 (br. s, 4Н, СН2-СН2), 3.13 (dd, J = 5.6, J = 16.4, 1H, CH-CH2), 3.76 (dd, J = 10.4, J = 16.4,
1H, CH-CH2), 4.06-4.18 (m, 2Н, OСН2-CH3), 5.68 (dd, J = 5.6 Hz, J = 10.4, 1H, СНN), 7.29-
7.39 (m, 3Н, Ph), 7.46-7.55 (m, 2Н, Ph). 13C NMR (100.6 MHz, CDCl3): 14.1 (CH3), 28.0 (CH2-
CH2), 34.8 (NCH-CH2), 51.5 (NCH-CH2), 60.8 (OCH2CH3), 128.0 (Ph), 128.3 (Ph), 128.7 (Ph),
138.0 (Ph), 170.6 (COO), 177.1 (C(O)N). Anal. calcd. for C15H17NO4 C, 65.44; H, 6.22; N, 5.09.
Found: C, 65.68; H, 6.44; N, 4.91.
Preparation
of
(Rax)-2-(adamantyl-1-ylmethyloxy)-chlorodinaphtho[2,1-d:1’,2’-
f][1,3,2]dioxaphosphepine (L).
A solution of 1-adamantylmethanol 174 mg (1.05 mmol) and 0.18 mL (1.3 mmol) NEt3 in
CH2Cl2 (5 mL) was added to a vigorously stirred solution of the (Rax)-2-chlorodinaphtho[2,1-
d:1’,2’-f][1,3,2]dioxaphosphepine 368 mg (1.05 mmol) in CH2Cl2 (10 mL). The mixture was
stirred for additional 20 min. The obtained solution was washed with water (20 mL), dried over
Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel,
CH2Cl2), the solution was evaporated to give the desired product; yield 413 mg 82%. White
1
solid, mp 113-115 °C. 31P{H} NMR (242.9 MHz, CDCl3): = 143.21. H NMR (600.13 MHz,
CDCl3): 1.54 (s, 6H, ad), 1.67 (d, J = 12.0, 3H, ad), 1.75 (d, J = 12.0, 3H, ad), 2.01 (s, 3H, ad),

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3.40 (dd, JHP = 7.8 Hz, JHH = 10.2 Hz, 1H, POCH2), 3.60 (dd, JHP = 7.2 Hz, JHH = 10.2 Hz, 1H,
POCH2), 7.27-7.31 (m, 2H, ar), 7.39 (d, J = 7.2, 1H, ar), 7.40 (d, J = 7.8, 1H, ar), 7.44-7.48 (m,
1H, ar), 7.45 (t, J = 7.5, 1H, ar), 7.46 (d, J = 9.0, 1H, ar), 7.54 (d, J = 9.0, 1H, ar), 7.95 (d, J =
7.8, 1H, ar), 7.953 (d, J = 7.2, 1H, ar), 7.97 (d, J = 9.0, 1H, ar), 8.00 (d, J =8.4, 1H, ar). 13C NMR
(150.9 MHz, CDCl3): 28.10 (Cq, ad), 34.07 (d, JCP = 4.2, OCH2C), 37.03 (CH2, ad), 39.01 (CH2,
ad), 75.09 (d, JCP = 6.3, OCH2), 121.92 (CH, ar), 121.97 (d, JCP = 1.7, CH, ar), 122.77 (d, JCP
=
2.4, Cq, ar), 124.25 (d, JCP = 5.1, Cq, ar), 124.79 (CH, ar), 124.99 (CH, ar), 126.11 (CH, ar),
126.21 (CH, ar), 127.07 (CH, ar), 127.08 (CH, ar), 128.31 (CH, ar), 128.37 (CH, ar), 129.80
(CH, ar), 130.32 (CH, ar), 131.03 (Cq, ar), 131.53 (Cq, ar), 132.69 (d, JCP = 1.2, Cq, ar), 132.90
(d, JCP = 1.5, Cq, ar), 147.70 (d, JCP = 2.1, POC), 148.87 (d, J = 5.1, POC). Anal. calcd. for
C31H29O3P C, 77.48; H, 6.08; P, 6.45. Found: C, 77.75; H, 6.36; P, 6.31.
Synthesis of rhodium complex 2.
A solution of the ligand 0.024 g, (0.050 mmol) in CH2Cl2 (0.5 mL) was added to a stirred
solution of [Rh(COD)2]BF4 0.010 g, (0.025 mmol) in CH2Cl2 (0.2 mL). The mixture was stirred
for additional 2 min and concentrated at reduced pressure to a volume of ca. 0.15 mL, and
hexane (8 mL) was added. The precipitated solid was separated by centrifugation and dried in
vacuo. Yellow solid, yield 25.1 mg (92 %). 31P{H} NMR (162.0 MHz, CDCl3): = 120.23 (d, JPRh
= 259.0). Anal. calcd. for C70H70BF4O6P2Rh C, 66.78; H, 5.60; P, 4.92. Found: C, 67.02; H,
5.88; P, 4.76.
3. Results and discussion.
A new monodentate phosphite ligand (L) was synthesized by a convenient one-step
phosphorylation of 1-adamantylmethanol in CH2Cl2 (scheme 1).
Scheme 1.
All 1H and 13C NMR signals of L were located by a combination of NMR spectroscopic methods
1
1
(1H, 13C{1H}, 13C{1H} DEPT135, 13C-1H HSQC, 13C-1H HMBC, H-1H COSY, and H-1H
ROESY) (see Figure 1 and Supplementary data for details).

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Figure 1.
Reaction of the phosphite ligand with [Rh(COD)2]BF4 afforded cationic rhodium complex 2
31
(scheme 2). P NMR data for the complex 2 showed chemical shift and coupling constant (see
experimental part) similar to those for rhodium complexes with monodentate phosphite
ligands.16,17
Scheme 2.
The phosphite ligand was firstly used in the Rh-catalyzed hydrogenation of dimethyl itaconate
3a (Scheme 3).
Scheme 3.
The catalyst was formed in situ by mixing [Rh(COD)2]BF4 with 2 equivalents of the chiral
ligand in CH2Cl2 under argon. The catalyst exhibited excellent enantioselectivity (95 % ee) and
complete conversion of 3a (Table 1, entry 1). The use of isolated complex 2 in the hydrogenation
of 3a showed the same activity and enantioselectivity as the catalyst formed in situ (table 1, entry
2). To expand the utility of the ligand, we also examined the Rh-catalyzed enantioselective
hydrogenation of α-dehydroamino acids esters: (Z)-methyl 2-acetamido-3-phenylacrylate 3b,
(Z)-methyl 2-acetamido-3-(4-fluorophenyl)acrylate 3c and (Z)-methyl 2-acetamido-3-(3,4-
dimethoxyphenyl)acrylate 3d. In the hydrogenation of 3b the ligand showed complete
conversion and ee up to 82% (Table 1, entry 3). Reduction of the substrate 3c with electron-
withdrawing fluorine-containing substituent on the phenyl ring gave a lower enantioselectivity
(76 % ee) (Table 1, entry 4). Hydrogenation of a more sterically hindered substrate 3d with
electron-donating methoxy groups gave complete conversion to the L-DOPA derivative and 88%
ee (Table 1, entry 5).
Table 1.
The ligand was also tested in the asymmetric hydrogenation of β-unsaturated amino acid
precursors (5a,b, scheme 4) containing easy leaving phtalimide and succinimide groups.
Scheme 4.

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Firstly we have checked hydrogenation of 5a in ethanol, 2,2,2-trifluoroethanol and CH2Cl2 at 40
°C. A better enantioselectivity was obtained in CH2Cl2, the reaction in alcohols showed lower
conversion and ee`s (table 2, entries 1-3). It should be noted that in the strongly acidic 2,2,2-
trifluoroethanol racemic product was obtained. Lowering the temperature from 40 to 25 °C led
not only to decrease of reaction rate, but also decrease of enantioselectivity (table 2, entry 4).
The hydrogenation of enamide 5b containing a less bulky succinimide group showed that the
process is critically temperature depending. Rising of temperature from 25 to 50 °C led to
decrease of selectivity (table 2, entries 5-7).
Table 2.
The ligand was also tested in the iridium catalyzed hydrogenation of 2-methylindole (scheme 5).
Using the catalysts prepared in situ from [Ir(COD)Cl]2 and the ligand no conversion was
obtained (table 3, entry 1). We next examined [Ir(COD)2]BARF as a precatalyst. In this case
31% conversion was obtained, but a low enantioselectivity was observed (table 3, entry 2).
Considering remarkable positive impact of addition of iodine in the Ir-catalyzed hydrogenation
of heterocyclic compounds18-21, the hydrogenation of 6 was carried out in presence of iodine (5
mol %). In the case of the catalyst based on [Ir(COD)2]BARF enantiomeric excess was increased
up to 16% (table 3, entry 3). The use of [Ir(COD)Cl]2 gave 55 % conversion and 64% ee (table 3,
entry 4).
Scheme 5.
Table 3.
4. Conclusions.
In conclusion, we have prepared a new bulky phosphite ligand for the use in asymmetric
hydrogenation. The ligand proved to be efficient in the Rh-catalyzed asymmetric hydrogenation
of dimethyl itaconate and α- and β-dehydroamino acid derivatives. In the hydrogenation of 2-
methylindole the use of iodine as additive led to a significant increase in the enantioselectivity
and conversion.

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Acknowledgement. This work was supported by RFBR grant № 17-03-00483.
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FIGURES CAPTIONS.
Scheme 1. Ligand synthesis.
Figure 1. Full assignment of all 13C resonances for ligand L.
Scheme 2. Synthesis of rhodium complex.
Scheme 3. Rh-catalyzed hydrogenation of 3a-d.
Scheme 4. Rh-catalyzed hydrogenation of 5a,b.
Scheme 5. Ir-catalyzed hydrogenation of 7.
HO
O
O
P
NEt3
P Cl +
O
O
O
- HNEt3Cl
L
1
Scheme 1.
128.31
129.80
131.03
121.92
124.99
126.11
148.87, d,
2JCP = 5.1
O
28.10
37.03
132.69, d,
4JCP = 1.2
122.77, d,
127.07
34.07, d,
3JCP = 4.2
3JCP = 2.4
124.25, d,
3JCP
P
132.90, d,
127.08 4
JCP = 1.5
= 5.1 O
O
75.09, d,
2JCP = 6.3
39.01
126.21
124.79
147.70, d,
2JCP = 2.1
121.97, d,
3JCP = 1.7
131.53
130.32
128.37
Figure 1.

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+
BF4
L
+ 2 L
BF4
Rh
Rh
L
- COD
2
Scheme 2.
O
O
O
H2
R
O
R
O
Y
*
[Rh(COD)2]BF4/2L
X
Y
X
O
3a, R = H, X = CH2, Y = OMe
3b, R = Ph, X = NH, Y = Me
4a-d
3c, R = 4-F-Ph, X = NH, Y = Me
3d, R = 3,4-OMe-Ph, X = NH, Y = Me
Scheme 3.
X
O
X
O
H2
OEt
[Rh(COD)2]BF4/2L
OEt
*
6 a-b
5a X =
5b X =
O
O
O
O
N
N
Scheme 4.
H2
Me
Me
*
[Ir(COD)Cl]2/4L
N
H
N
H
8
7
Scheme 5.

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Table 1. Asymmetric hydrogenation of 3a-d.a
entry catalyst
substrate
conversion, % ee, %b
1
2
3
4
5
[Rh(COD)2]BF4/2L
100
100
100
100
100
95 (R)
3a
3a
3b
3c
3d
95 (R)
82 (S)
76 (S)
88 (S)
2
[Rh(COD)2]BF4/2L
[Rh(COD)2]BF4/2L
[Rh(COD)2]BF4/2L
a T = 50 °C, P H2 = 55 atm, t = 2 h, CH2Cl2, [Rh(COD)2]BF4/substrate = 1/100.
b determined according to chiral HPLC (see Supplementary data for details).
Table 2. Asymmetric hydrogenation of 5a,b.a
entry catalyst
substrate
t, h
solvent conversion, % ee, %b,c
T, °C
1
2
3
4
5
6
7
[Rh(COD)2]BF4/2L
40
40
40
25
25
40
50
6
EtOH
13
16
50 (+)
0
5a
5a
5a
5a
5b
5b
5b
[Rh(COD)2]BF4/2L
[Rh(COD)2]BF4/2L
[Rh(COD)2]BF4/2L
[Rh(COD)2]BF4/2L
[Rh(COD)2]BF4/2L
[Rh(COD)2]BF4/2L
6
TFE
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
100
44
76(+)
58 (+)
34 (+)
26 (+)
10 (+)
24
24
6
100
65
6
75
a P H2 = 55 atm, [Rh(COD)2]BF4/substrate = 3/100.
b Determined according to chiral HPLC (see Supplementary data for details).
c The sign of optical rotation given in parenthesis.
Table 3. Asymmetric hydrogenation of 7.a
entry catalyst
solvent conversion, % ee, %b
1
2
3
4
[Ir(COD)Cl]2/4L
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
31
7
-
[Ir(COD)2]BARF/2L
[Ir(COD)2]BARF/2L/I2
[Ir(COD)Cl]2/4L/4I2
2 (S)
16 (S)
64 (S)
55
aT = 40 °C, P H2 = 55 atm, t = 24 h, [Ir(COD)Cl]2/substrate = 1/100.
b determined according to chiral HPLC (see Supplementary data for details).

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•
•
•
A new phosphite ligand was tested in the asymmetric Rh- and Ir-catalyzed
hydrogenation.
The ligand showed up to 95% ee in the Rh-catalyzed asymmetric hydrogenation of
dimethyl itaconate and α- and β-dehydroamino acid derivatives.
In the hydrogenation of 2-methylindole the use of iodine as additive led to a significant
increase in the enantioselectivity and conversion.