First P*,S-bidentate diamidophosphite ligand in Pd-catalyzed asymmetric reactions

Article abstract of DOI:10.1016/j.mencom.2020.01.010

A novel P*,S-bidentate diamidophosphite ligand with a 1,3,2-diazaphospholidine core and an exocyclic thioether fragment provided up to 86% ee in the Pd-catalyzed alkylation of rac-(E)-1,3-diphenylallyl acetate with dimethyl malonate, as well as up to 73 a

Full text of DOI:10.1016/j.mencom.2020.01.010

Mendeleev
Communications
Mendeleev Commun., 2020, 30, 31–33
First P*,S-bidentate diamidophosphite ligand
in Pd-catalyzed asymmetric reactions
Konstantin N. Gavrilov,*a Ilya V. Chuchelkin,a Sergey V. Zheglov,a Ilya D. Firsin,a Vladislav S. Zimarev,a
Vladislav K. Gavrilov,a Alexander V. Maximychev,b Alexander M. Perepukhovb and Nataliya S. Goulioukina*a,c,d
a Department of Chemistry, S. A. Esenin Ryazan State University, 390000 Ryazan, Russian Federation.
Fax: +7 4912 281 435; e-mail: k.gavrilov@365.rsu.edu.ru
b Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Moscow Region, Russian Federation.
Fax: +7 495 408 4257; e-mail: aleksandr-iv@mail.ru
c Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 939 1854; e-mail: goulioukina@org.chem.msu.ru
d A. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences,
119071 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2020.01.010
A novel P*,S-bidentate diamidophosphite ligand with a 1,3,2-
Nu
diazaphospholidine core and an exocyclic thioether fragment
Me
Ph
Ph
ꢄ
O
provided up to 86% ee in the Pd-catalyzed alkylation of rac-
(E)-1,3-diphenylallyl acetate with dimethyl malonate, as well
as up to 73 and 75% ee in the amination of this substrate
with pyrrolidine and diethyl (aminomethyl)phosphonate,
respectively. For the Pd-catalyzed alkylation of cinnamyl
acetate with b-keto esters, ee values up to 76% were achieved.
EtO2C
AcꢀN
uꢁ to ꢅꢆꢃ ee
O
ꢄ
N
O
P
Me
CO2Et
N
S
ꢄ
ꢉ ꢊn
Ph
uꢁ to ꢂꢂꢃ ee
Ph
uꢁ to ꢇꢆꢃ ee
Pdꢈcatalysis
Keywords: chiral diamidophosphites, chiral P,S-ligands, palladium-catalyzed asymmetric reactions.
Diamidophosphites (with characteristic unit PON2) constitute a
very promising group of asymmetric inducers with significant
differences from more common phosphites (PO3) and phosphor-
amidites (PO2N). In particular, the replacement of bivalent oxygen
atoms in the first coordination sphere of the phosphorus atom for
the trivalent nitrogen atoms bearing certain substituents increases
the electron density and steric hindrances on phosphorus. The
modular structure of diamidophosphites allows one to vary substi-
tuents at the phosphorus and/or nitrogen atoms (thereby finely
tuning the steric and electronic parameters of a ligand), as well
as the configuration of P*- and C*-stereocenters. The presence of
asymmetric phosphorus atom can significantly favor a successful
chiralitytransferinacatalyticcycle.Incorporationofthephosphorus
and nitrogen atoms into the 1,3,2-diazaphospholidine ring leads to a
higherdegreeofrigidityandresistancetooxidationand hydrolysis.
Therefore, known P*-monodentate, P*,N- and P*,P-bidentate
diamidophosphite ligands have found a successful application in
the asymmetric Pd-catalyzed allylation and cycloaddition, Rh-
catalyzed hydrogenation and hydroformylation, as well as in the
Ni-catalyzed hydrovinylation.1 There are no data on the synthesis
of P*,S-bidentate diamidophosphites and their use in asymmetric
catalysis, while P*,S-bidentate phosphites and phosphoramidites
are well-known.2
carboxylic acids derivatives,4 and allylic amines are important star-
ting compounds for many natural products and drugs.5 The Pd-
catalyzed enantioselective synthesis of a quaternary carbon center
ishighlychallenging and provides access to practically significant
building blocks.6 Note that in the case of Pd-π-allyl catalytic
intermediates based on P*,S-ligands, the nucleophilic attack occurs
trans to P-atom, thus sulfide donor center can serve as an important
stereocontrolling element, primarily when S-atom becomes a
stereogenic center if coordinated to a metal.2(c)-(e),3(b),7
As illustrated in Scheme 1, novel P*,S-bidentate diamidophos-
phite ligand, viz., (2R,5S)-2-(2-methylthioethoxy)-3-phenyl-1,3-di-
aza-2-phosphabicyclo[3.3.0]octane, 1 was efficiently prepared by
the reaction of 2-(methylthio)ethan-1-ol with (5S)-2-chloro-3-
phenyl-1,3-diaza-2-phosphabicyclo[3.3.0]octane in toluene in the
presence of excess Et3N as the hydrochloride scavenger. After
vacuum distillation, compound 1 was obtained as clear oil, quite
stable for manipulations in air and storage under dry conditions at
room temperature for several months with negligible degradation.
The structure of compound 1 was confirmed by elemental
analysis and 1H, 13C, and 31P NMR spectroscopy. The complete
1
assignment of H and 13C chemical shifts was performed by
1
1
2D NMR techniques, including H-1H COSY, H-1H NOESY,
1H-13C HSQC and 1H-13C HMBC spectra (see Figure S1, Online
Supplementary Materials). The 31P{1H} spectrum featured a
Herein we report on the synthesis of the first P*,S-bidentate
diamidophosphite ligand bearing an asymmetric phosphorus atom
in the 1,3,2-diazaphospholidine ring and its application in the
Pd-mediated asymmetric allylic substitution processes such as
alkylation and amination. These catalytic transformations are
reliable methods to evaluate the efficiency of new chiral
ligands.1(d),2(e),3 The products of alkylation using dimethyl malonate
are convenient precursors of enantioenriched unsaturated
Ph
Ph
ꢁO
EtꢀNꢃ PhMe
N
P
N
P
ꢂ
− EtꢀN ꢁCl
N
N
SMe
O
Cl
SMe
ꢀ
Scheme 1
© 2020 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 31 –

Mendeleev Commun., 2020, 30, 31–33
single sharp singlet at dP 123.1 ppm indicating that ligand 1 is
stereoindividual. Its P*-stereocenter has (R) absolute configu-
ration, which is supported by a large value JC(8),P of 38.1 Hz
N
i
2
Ph
Ph
Ph
Ph
suggesting that the lone pair of the phosphorus atom and the C(8)
atom of the pyrrolidine –(CH2)3– fragment are located in the syn-
orientation relative to the 1,3,2-diazaphospholidine ring plane
(Figure S2).1(a),(b),(m),(o),(p),8
OAc
Ph
ꢁꢀ ꢁꢂꢃ ee
Ph
ꢄN
ꢆ
PꢇOꢈꢇOEtꢈ2
ꢀa
Initially the efficiency of ligand 1 was examined in the allylic
alkylation of rac-(E)-1,3-diphenylallyl acetate 2a with dimethyl
malonate as the C-nucleophile using [Pd(π-allyl)Cl]2 as the pre-
catalyst with a combined base of N,O-bis(trimethylsilyl)acetamide
(BSA) and a catalytic amount of KOAc (Scheme 2). Represen-
tative results of the optimization study are highlighted in Table 1,
demonstrating high catalytic activity of ligand 1; irrespective of the
experimental conditions applied, quantitative conversions were
observed in all cases. In all cases, the (S)-enantiomer of the reaction
product 3 was predominant. However, the value of the enantio-
selectivity strongly depended on the solvent and the ratio of ligand
to palladium (entries 1-4). The best ee of 84% was achieved using
CH2Cl2 as the solvent and 1:Pd molar ratio of 2:1 (entry 4). The
catalyst loading can be reduced to 0.2 or 0.1 mol% without any
loss in activity or selectivity (entries 5, 6). Running the reaction at
-20°C provided 86% ee (entry 7). The replacement of KOAc
with weaker Lewis basic LiOAc (entries 8, 9), the use of Cs2CO3
asthebase(entry10),NaB[C6H3(CF3)2-3,5]4 asanoncoordinating
counterion source (entry 11) or ethyl carbonate derivative 2b as
the electrophile (entry 12) did not cause any improvement. Never-
theless, it should be pointed out that new heterodonor P*,S-
ligand 1 provided superior or comparable efficiency to P*-mono,
P*,P- and P*,N-bidentate 1,3,2-diazaphospholidine-based ligands
reported to date (see Table S1).1(a),(b),(i),(l)
ii
ꢂꢀ ꢁꢅꢃ ee
Scheme 3 Reagents and conditions: i, pyrrolidine, [Pd(π-allyl)Cl]2, 1, THF;
ii, (EtO)2P(O)CH2NH2, [Pd(π-allyl)Cl]2, 1, CH2Cl2.
phile, ligand 1 provided high catalytic activity, the corresponding
product 4 being obtained with 73% ee (R). In contrast to the
allylic alkylation, THF was the solvent of choice and the 1:Pd
molar ratio of 1:1 was preferable (see Table S2).
WhenamorechallengingN-nucleophile,diethyl(aminomethyl)-
phosphonate, was used, the conversion of substrate 2a and the
enantioselectivity were higher in CH2Cl2 as the reaction medium
and with the 1:Pd molar ratio of 2:1 (see Table S3). a-Amino phos-
phonate 5 was obtained with 75% ee, but its absolute configuration
has not yet been ascertained. Note that this reaction offers an addi-
tionalscopeforthesynthesisofnonracemica-aminophosphonates.10
The next step was an attempt to use ligand 1 in the Pd-catalyzed
allylic alkylation of non-symmetric cinnamyl acetate 6 with b-keto
esters 7a and 7b (Scheme 4). In this process, a quaternary C*-
stereocenter is formed at the carbon atom belonging to the
nucleophile. To the best of our knowledge, there are only three
examples for the synthesis of the enantioenriched compound
8a.6(g),11 When ligand 1 was used, the reactions proceeded with
the quantitative conversion providing (S)-isomers of the desired
products 8a,b with 62 and 76% ee, respectively (see Tables S4
and S5). For both the reactions, 1:Pd molar ratio of 2:1 was
optimal.
We further tested ligand 1 in Pd-catalyzed allylic amination
reactions (Scheme 3). In the case of pyrrolidine as the N-nucleo-
CO2Me
CO2Me
MeO2C
Ph
CO2Me
Ph
OCꢀOꢁꢂ
i
ꢃ
Ph
Ph
O
O
ꢀa ꢂ ꢄ Me
ꢀb ꢂ ꢄ OEt
ꢁ
CO2Et
CO2Et
i
ꢀ
OAc
Ph
ꢁ ꢂn
Scheme 2 Reagents and conditions: i, [Pd(π-allyl)Cl]2 (2.0 mol%), 1 (4.0 or
8.0 mol%), 2 (0.25 mmol), dimethyl malonate (1.8 equiv.), BSA (1.8 equiv.),
KOAc (8 mol%), solvent (1.5 ml), room temperature, 48 h.
ꢁ ꢂn
ꢀ
Ph
ꢁa n ꢃ ꢄ
ꢁb n ꢃ 2
ꢂa n ꢃ ꢄꢅ ꢆ2ꢇ ee
ꢂb n ꢃ 2ꢅ ꢈꢆꢇ ee
Table 1 Pd-catalyzed allylic alkylation of substrates 2 with dimethyl
malonate.
Scheme 4 Reagents and conditions: i, [Pd(π-allyl)Cl]2, 1, BSA, Zn(OAc)2,
PhMe.
Molar ratio
1:Pd
Conversion
of 2 (%)
Entry Substrate
Solvent
ee of 3 (%)a
We also examined the Pd-catalyzed asymmetric allylic substitu-
tion using b-keto ester 9 with acetamido group at the a-carbon as
the prochiral nucleophile (Scheme 5). This is one of the most
straightforward approaches to chiral quaternary a-amino acid
derivatives.12 Product (R)-10 was obtained with 55% ee and
quantitative conversion of substrate 6 (see Table S6).
In summary, P*,S-bidentate diamidophosphite ligand 1 turned
to be a promising chiral inducer being rather sensitive to the
nature of nucleophile and reaction conditions. This ligand exhibits
noticeable advantages over P*-mono, P*,P- and P*,N-bidentate
1
2
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
1:1
2:1
1:1
2:1
2:1
2:1
2:1
1:1
2:1
2:1
2:1
2:1
THF
THF
100
100
66 (S)
76 (S)
43 (S)
84 (S)
85 (S)b
85 (S)c
86 (S)d
79 (S)e
83 (S)e
82 (S)f
85 (S)g
83 (S)
3
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
4
5
6
7
8
9
10
11
12
O
O
CO2Et
CH2Cl2
99
i
CO2Et
NꢀAc
Me
ꢁ
OAc
ꢅRꢆ
Ph
Me
a The conversion of 2 and ee values of 3 were determined by HPLC analysis. The
absolute configuration was assigned by comparison of the HPLC retention times
[Kromasil 5-CelluCoat, C6H14 /PriOH = 99:1, 0.6 ml min-1, 254 nm, t(R) =
= 18.8 min, t(S) = 20.2 min] with reported data.1(p),9 b 0.2 mol% [Pd(π-allyl)Cl]2.
c 0.1 mol% [Pd(π-allyl)Cl]2. d Performed at -20°C. e With LiOAc instead of
KOAc. f With Cs2CO3 (2 equiv.) as the base. g NaB[C6H3(CF3)2-3,5]4 (5 mol%)
was used as the additive.
NꢀAc
ꢀ
Ph
ꢁ
ꢂꢃꢂ ꢃꢃꢄ ee
Scheme 5 Reagents and conditions: i, [Pd(π-allyl)Cl]2, 1, BSA, KOAc or
BSA, Zn(OAc)2, PhMe.
– 32 –

Mendeleev Commun., 2020, 30, 31–33
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This work was supported by the Russian Science Foundation
(project no. 19-13-00197).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2020.01.010.
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– 33 –