Diamidophosphite–oxazolines with a pyridine core in Pd-catalyzed asymmetric reactions

Article abstract of DOI:10.1016/j.tetasy.2016.10.008

We have designed and synthesized a small library of readily available P,N,N-diamidophosphite–oxazoline ligands containing 1,3,2-diazaphospholidine rings and a pyridine moiety. The use of these ligands provides up to 96% ee in Pd-catalyzed asymmetric allyl

Full text of DOI:10.1016/j.tetasy.2016.10.008

Tetrahedron: Asymmetry 27 (2016) 1260–1268
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diamidophosphite–oxazolines with a pyridine core in Pd-catalyzed
asymmetric reactions
a
a
a
Konstantin N. Gavrilov a, , Sergey V. Zheglov , Ivan M. Novikov , Victor V. Lugovsky ,
⇑
Vladislav S. Zimarev a, Igor S. Mikhel b
a Department of Chemistry, Ryazan State University, 46 Svoboda Street, 390000 Ryazan, Russian Federation
b A. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninskiy prospekt 31/4, 119071 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
We have designed and synthesized a small library of readily available P,N,N-diamidophosphite–oxazoline
ligands containing 1,3,2-diazaphospholidine rings and a pyridine moiety. The use of these ligands pro-
vides up to 96% ee in Pd-catalyzed asymmetric allylations of (E)-1,3-diphenylallyl acetate; up to 80% ee
in the Pd-catalyzed asymmetric alkylation of cinnamyl acetate with ethyl 2-oxocyclohexane-1-carboxy-
late and up to 94% ee in the Pd-catalyzed desymmetrization of N,N0-ditosyl-meso-cyclopent-4-ene-1,3-
diol biscarbamate. The influence of the structural modules, such as the nature of the phosphorus contain-
ing ring or pyridine substituent as well as of the addition of zinc(II) 5,10,15,20-tetraphenylporphyrin on
the catalytic activity and enantioselectivity is discussed.
Received 27 September 2016
Accepted 13 October 2016
Available online 2 November 2016
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
solid-phase synthetic procedures. These key advantages allow the
preparation and screening of extensive series of P–O and/or P–N
Chiral phosphorus containing compounds are excellent asym-
metric inductors, thousands of which have been successfully
explored in various transition metal catalyzed reactions.1 More-
over, a large number of chiral trivalent P-ligands are commercially
available. Despite this situation, finding an efficient stereoselector
for a given catalytic process is often an arduous task. The vast
majority of chiral phosphorus ligands are able to provide high
enantiomeric control either in certain types of chemical transfor-
mation, or in one particular reaction. There are very few ‘‘privi-
leged ligands” that are useful for a wide range of substrates and
for different types of reactions, while their high cost significantly
limits their wide application. Consequently, the search for efficient
and structurally novel phosphorus containing asymmetric induc-
tors, which can be readily obtained from available enantiopure
precursors, is still a cutting-edge research goal.1h,2
bond containing ligands to obtain high activities and enantioselec-
tivities for each particular reaction.1c,d,h,i,2f,3 In the case of P⁄-chiral
phosphite-type ligands, the presence of an asymmetric donor
phosphorus atom significantly promotes the successful transfer
of chirality in the key step of the catalytic cycle.1a,2d,f,4
The P,N-bidentate ligands are one important subset of phos-
phite-type chiral ligands, and have been utilized in conjunction
with a range of transition metals to efficiently promote numerous
asymmetric transformations.1c,3f,5 At the same time, the use of P,N,
N-ligands is rarely reported. Only a few such compounds based on
TADDOL or biphenols (LA–E, Fig. 1) have been described and
employed in enantioselective Pd-catalyzed allylations, Nazarov-
type cyclizations, intermolecular Heck reactions and Rh-catalyzed
hydroformylations.6 Therefore, more effort should be made to
expand this set of stereoselectors. Herein we report on the prepa-
ration of a small series of diamidophosphite/oxazoline/pyridine
ligands, which we subsequently explored in Pd-catalyzed asym-
metric allylic substitution and desymmetrization reactions.
The Pd-catalyzed asymmetric allylic substitutions have become
classic, powerful and useful tools for carbon–carbon and carbon–
heteroatom bond formation, and have found wide application in
the enantioselective synthesis of valuable natural products and
biologically important building blocks.1b,4a,7 Furthermore, these
reactions are reliable methods for ligand benchmark testing,
while the enantiomeric excesses obtained are the easiest way for
Optically active phosphite-type compounds, which have many
successful applications in enantioselective catalysis processes,
have proven to be extremely attractive chiral ligands. Some of their
advantageous characteristics include stability to oxidation, pro-
nounced
p-acidity and low cost. They can also be easily prepared
in large quantities from inexpensive starting materials via simple
condensation processes, including those involving parallel and
⇑
Corresponding author. Tel.: +7 4912 280580; fax: +7 4912 281435.
E-mail address: k.gavrilov@rsu.edu.ru (K.N. Gavrilov).
http://dx.doi.org/10.1016/j.tetasy.2016.10.008
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.

K. N. Gavrilov et al. / Tetrahedron: Asymmetry 27 (2016) 1260–1268
1261
Ph
O
Ph
N
O
N
O
O
O
Ph
Ph
N
N
R
O
N
N
O
O
O
O
P
N
Ph
P
O
Ph
O
O
O
O
Ph
Ph
P
O
LB
Ph
Ph
R = Me, Bn
L
(S,S)- or (R,R)-
A
LC
N
R1
R2
Ph
O
N
N
O
O
P
P
O
X
O
R2
R1
R1 = R2 = t-Bu
N
R
R
1 = t-Bu, R2 = OMe
1 = SiMe3, R2 = H
X = OR, N(Me)R
LE
LD
Figure 1. Structures of reported P,N,N-phosphite-type ligands.
evaluating new inductors of chirality.7a,g,8 It should be noted that
the formation of quaternary carbon stereocenter via Pd-
a
catalyzed enantioselective synthesis is a fairly complex problem.
From a natural compound preparation and a pharmaceutical
agents discovery perspective, this approach provides access to
useful precursors with a single quaternary stereocenter.1b,9 Both
enantiomers of the desymmetrization product of N,N0-ditosyl-
meso-cyclopent-4-ene-1,3-diol biscarbamate are key building
blocks for pharmacologically active compounds mannostatin A
and (ꢀ)-swainsonine.1b,7c
N
Ph
O
N
P
N
Cl
Z
Y
N
7
O
X
2
4
P
N
5
6
8
4a-d
O
2 Et3N, DMAP, PhCH3
- R3N.HCl
N
Z
HO
X
2. Results and discussion
Y
1a-d
X = Y = Z = CH a
X = N, Y = Z = CH b
Y = N, X = Z = CH
Z= N, X = Y = CH d
Novel diamidophosphites 4a–d and 5 were synthesized in one
step, starting from the corresponding hydroxy-oxazolines 1a–d,
which are readily obtained from the commercially available
(1S,2S)-2-amino-1-phenylpropane-1,3-diol. Compounds 1a–c are
well-known,10 while 1d has been prepared analogously to 1a.10a
Hydroxy-oxazolines 1a–d already incorporate the desired
diversity in the substituents at the C(2) atom. Treating the
relevant compound 1a–d with one equivalent of the appropriate
phosphorylating reagent 2 or 3 in the presence of an excess of
Et3N as an HCl scavenger and DMAP as a catalyst provided direct
access to the diamidophosphite ligands 4a–d and 5 (Scheme 1).
Compounds 4a–d and 5 were purified by flash chromatography
on Al2O3/SiO2 and isolated in good yields (73–86%) as white
solids; they could be prepared on a gram scale. It is noteworthy
O
N
N
P
O
c
N
N
N
Ph
Ph
N
P
Cl
5
3
Scheme 1. Synthesis of diamidophosphite–oxazolines 4a–d and 5.
coupling constants 2JC(8),P (37.9–38.3 Hz, see Experimental section),
which are indicative of the syn-orientation of the phosphorus lone
pair with respect to the C(8) atom. The pseudoequatorial exocyclic
substituent at the phosphorus atom and the –(CH2)3– part of the
pyrrolidine fragment of the phosphabicyclic skeleton are in the
anti-arrangement (Fig. 2).2f,11–13 Additionally, 1H,1H-COSY, 1H,1H-
ROESY, 13C,1H-HSQC and 13C,1H-HMBC 2D-NMR measurements
were used to characterize 4c, which gave us an opportunity to
that the chiral phosphorylating reagent
2 can be easily
synthesized11 in high yield from readily accessible (S)-glutamic
acid anilide.12 All ligands were found to be sufficiently stable
enough to allow for manipulation in the air and could be stored
under dry conditions at room temperature for at least a few
months with negligible decomposition. They were fully character-
ized by 31P, 1H, and 13C NMR spectroscopy as well as by elemental
analysis.
H
(
)
S
According to the 31P and 13C NMR spectroscopy data, the exclu-
sive formation of the stereodefined diamidophosphites 4a–d with
an (R)-configuration at the P⁄-stereocentres occurred. In particular,
the presence of narrow singlets at dP 121.2–121.9 ppm in the 31P
NMR spectra of their solutions in CDCl3 should be noted. The 13C
NMR spectra of these ligands are characterized by large spin–spin
..
8
N
N
P (R)
X
Figure 2. Stereochemistry of the phosphabicyclic part in ligands 4a–d (X = exo-
cyclic substituent).

1262
K. N. Gavrilov et al. / Tetrahedron: Asymmetry 27 (2016) 1260–1268
make a complete assignment of all 1H and 13C resonances (Figs. 3
and 4).
1.83-1.90, m
1.75-1.83, m
2.02-2.09, m
1.61-1.68, m
3.58-3.64, m
3.16-3.22, m
7.31-7.35, m
7.32-7.36, m
In a first set of catalytic experiments, the new ligands 4a–d and
5 were applied to Pd-catalyzed asymmetric allylic substitutions
using (E)-1,3-diphenylallyl acetate 6 as the model substrate and
sodium para-toluene sulfinate, dimethyl malonate or pyrrolidine
as common nucleophilic agents (Tables 1–3). We started our inves-
tigation by employing p-TolSO2Na as the S-nucleophile and THF as
a solvent for standard conditions (Table 1). The catalysts were pre-
pared in situ from [Pd(allyl)Cl]2 and the corresponding ligand with
a molar ratio L/Pd = 1 and 2. The desired product (S)-7a was
obtained with 92% ee using diamidophosphite 4c (Table 1, entry
5), which is superior to all of the results obtained with the other
P⁄-chiral ligands 4a, 4b and 4d (up to 82%, 80%, and 76% ee, respec-
tively, entries 1, 3 and 7). Compound 5 with an achiral diazaphos-
pholidine ring provided moderate enantioselectivity (up to 52% ee).
It is clear that the molar ratio L/Pd = 1 was undoubtedly preferable
in all cases.
Table 2 shows the results obtained in the Pd-catalyzed asym-
metric allylic alkylation of substrate 6. Ligand 4b with pyridin-2-
yl substituent provided enantioselectivities of up to 96% and quan-
titative conversion of the starting substrate; CH2Cl2 was the sol-
vent of choice and the molar ratio L/Pd = 2 was preferable
(Table 2, entries 5–8). Diamidophosphite–oxazolines 4a, 4c and
4d allowed for the synthesis of the desired product (S)-7b with a
somewhat lower enantioselectivity (up to 87%, 90% and 86% ee,
respectively, Table 2, entries 2, 12 and 22). In general, there is no
obvious trend in the influence of the nature of the solvent on the
asymmetric induction for these three stereoselectors. The best L/
Pd molar ratio was 2 in most cases (Table 2, entries 1–4, 9–12
and 19–22). Ligand 5 was practically inefficient (ee is no higher
than 24%). It should be noted that the solvent change resulted in
an inversion of the absolute configuration of the product 7b (see
entries 29–32 in Table 2).
4.15-4.20, m
N
7.18-7.22, m
P
3.83, dd,
J = 7.2
J = 8.4
O
4.27, dt,
N
J = 3.6,
J = 6.6
3.21-3.26, m
5.53, d, J = 6.6
3.89, ddd,
J = 4.2,
J = 10.2
J = 6.0
O
7.06, d,
J = 7.8
N
3.93, dt,
J = 6.0,
J = 10.2
7.25, t,
J = 7.8
9.25, d,
J = 1.8
6.87, t,
J = 7.8
N
8.29, dt,
J = 1.8,
J = 7.8
8.76, dd
J = 1.8,
J = 4.8
7.39, dd,
J = 4.8,
J = 7.8
Figure 4. Full assignment of all H-1 resonances for ligand 4c.
of an equimolar amount of Zn-TPP to catalytic compositions [Pd
(allyl)Cl]2/2L or [Pd(allyl)(cod)]BF4/L (L = 4c,d, L/Zn = 1) had a
pronounced influence on both the conversion and asymmetric
induction (Table 2), i.e., the conversion noticeably increases after
incorporation of the Zn-porphyrin complex. It is interesting to
note that in the case of 4c and [Pd(allyl)Cl]2 as a palladium
source, the addition of Zn-TPP gave rise to compound 7b with
lower enantiomeric purity and an opposite absolute
configuration (Table 2, cf. entries
9 and 13, 11 and 14).
Conversely, the catalytic system [Pd(allyl)(cod)]BF4/4c in
presence of Zn-TPP allowed the synthesis of (S)-7b with
practically equal or higher enantioselectivity (Table 2, entries 15,
16 and 17, 18). An additive of metalloporphyrin enhanced the
asymmetric induction and was achieved with the participation of
the palladium catalyst based on ligand 4d and [Pd(allyl)Cl]2 in
both solvents (Table 2, cf. entries 19 and 23, 21 and 24). At the
same time, when [Pd(allyl)(cod)]BF4 was used as the precatalyst,
this additive had no significant effect on the transfer of chirality
(Table 2, entries 25–28).
The results achieved with pyrrolidine as the N-nucleophile are
summarized in Table 3. As a whole, the catalytic performance in
this process followed the same trend as for the allylic alkylation
of 6. In particular, the amination process with participation of
ligand 4b resulted in quantitative conversion and enantioselectiv-
ity up to 95% ee (Table 3, entries 5–8). The best result was obtained
in THF as reaction medium at L/Pd = 2. Diamidophosphites 4a, 4c
and 4d provided lower levels of asymmetric induction (82%, 86%
and 82% ee, respectively, Table 3, entries 4, 10 and 22). The influ-
ence of the solvent nature on the reaction rate was not straightfor-
ward, but a higher enantioselectivity was observed in THF in most
cases. It is clear that for all ligands, the optimal L/Pd molar ratio
was 2 (Table 2, entries 1–12 and 19–22). Ligand 5 allowed for
the synthesis of product (R)-7c with excellent conversion, but with
low enantiomeric purity (no more than 18% ee); THF was the sol-
vent of choice (Table 3, entries 29–32). In further studies we
explored palladium catalysts based on diamidophosphite-oxazoli-
nes 4c,d and [Pd(allyl)Cl]2 or [Pd(allyl)(cod)]BF4 in combination
with Zn-TPP, with the aim of further studying the properties of
such assemblies. The results show contra directional trends: an
increase in activity and a decrease in enantioselectivity were
observed in the presence of Zn-porphyrin in all cases (Table 3,
entries 9, 11, 13–18; 19, 21, 23–28).
It is worthwhile noting that ligands LE (Fig. 1) coordinated zinc
(II) 5,10,15,20-tetraphenylporphyrin (Zn-TPP) exclusively to the
nitrogen donor atoms and 1:2 assemblies LE-(Zn-TPP)2 are formed.
In Rh-catalyzed asymmetric hydroformylations, these assemblies
are more efficient chiral inductors than free ligands LE.6e,f We can
speculate that the presence of phosphorus and oxazoline
nitrogen donor atoms in 4a–d and 5 makes it possible for the P,
N-chelate to form. If so, such complexes with diamidophosphite–
oxazolines bearing pyridin-3-yl or pyridin-4-yl moieties are
suitable for the binding of Zn-TPP. We observed that the addition
26.24, d,
J = 3.8
48.68, d,
J = 38.2
128.23
32.27
128.75
125.66
63.33, d,
N
J = 8.9
P
55.02, d,
J = 7.2
O
140.49
N
83.87
O
62.95, d
145.46, d,
J = 15.5
J = 5.4
75.52, d,
J = 2.6
114.85, d,
J = 12.2
162.25
123.84
135.82
N
129.22
149.79
N
119.10
152.21
123.21
Figure 3. Full assignment of all C-13 resonances for ligand 4c.

K. N. Gavrilov et al. / Tetrahedron: Asymmetry 27 (2016) 1260–1268
1263
Table 1
Pd-catalyzed allylic sulfonylation of (E)-1,3-diphenylallyl acetate 6 with sodium para-toluene sulfinatea
OAc
O
S
*
O
NaSO2pTol, cat
Ph
Ph
Ph
Ph
THF
7a
6
Entry
Ligand
L/Pd
Yield (%)
ee (%)b,c
1
2
3
4
5
6
7
8
9
10
4a
4a
4b
4b
4c
4c
4d
4d
5
1
2
1
2
1
2
1
2
1
2
92
85
80
66
75
54
49
44
62
48
82 (S)
77 (S)
80 (S)
72 (S)
92 (S)
74 (S)
76 (S)
64 (S)
52 (S)
44 (S)
5
a
b
c
Reactions were carried out with 2 mol % of [Pd(allyl)Cl]2 in THF at 20 °C for 48 h.
The enantiomeric excess of 7a was determined by HPLC (Kromasil 5-CelluCoat, C6H14/i-PrOH = 4/1, 0.5 mL/min, 254 nm, t(R) = 18.2 min, t(S) = 20.0 min).
The absolute configuration was assigned by comparison of the HPLC retention times reported in the literature.14
Table 2
Pd-catalyzed allylic alkylation of (E)-1,3-diphenylallyl acetate 6 with dimethyl malonatea
MeO2C
CO2Me
Ph
OAc
CH2(CO2Me)2, cat
Ph
Ph
Ph
*
solvents
BSA, KOAc
6
7b
Entry
Ligand
L/Pd
Solvent
Conversion (%)
ee (%)b,c
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4b
4b
4b
4b
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
4d
4d
4d
4d
4d
4d
4d
4d
4d
4d
5
1
2
1
2
1
2
1
2
1
2
1
2
1
1
1
1
1
1
1
2
1
2
1
1
1
1
1
1
1
2
1
2
CH2Cl2
CH2Cl2
THF
100
100
99
100
100
100
64
83
55
57
99
100
70
100
100
73
100
80
63
34
38
61
100
71
40 (S)
87 (S)
56 (S)
68 (S)
90 (S)
96 (S)
82 (S)
93 (S)
85 (S)
88 (S)
68 (S)
90 (S)
65 (R)d
50 (R)d
73 (S)e
76 (S)e
72 (S)d,e
88 (S)d,e
76 (S)
70 (S)
74 (S)
86 (S)
82 (S)d
78 (S)d
68 (S)e
THF
CH2Cl2
CH2Cl2
THF
THF
9
CH2Cl2
CH2Cl2
THF
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
THF
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
THF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
100
85
e
66 (S)
100
100
100
100
60
66 (S)d,e
64 (S)d,e
24 (R)
16 (R)
10 (S)
5
5
5
THF
86
14 (S)
a
Reactions were carried out with 2 mol % of [Pd(allyl)Cl]2 at 20 °C for 48 h (BSA, KOAc).
The conversion of substrate 6 and enantiomeric excess of 7b were determined by HPLC (Kromasil 5-CelluCoat, C6H14/i-PrOH = 99/1, 0.6 mL/min, 254 nm, t(R) = 18.6 min, t
b
(S) = 20.7 min).
c
The absolute configuration was assigned by comparison of the HPLC retention times reported in the literature.14,15
In the presence of Zn-TPP.
With complex [Pd(allyl)(cod)]BF4 as the precatalyst.
d
e

1264
K. N. Gavrilov et al. / Tetrahedron: Asymmetry 27 (2016) 1260–1268
Table 3
Pd-catalyzed allylic amination of (E)-1,3-diphenylallyl acetate 6 with pyrrolidinea
OAc
N
*
HN(CH2)4, cat
solvents
Ph
Ph
Ph
Ph
6
7c
Entry
Ligand
L/Pd
Solvent
Conversion (%)
ee (%)b,c
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4b
4b
4b
4b
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
4d
4d
4d
4d
4d
4d
4d
4d
4d
4d
5
1
2
1
2
1
2
1
2
1
2
1
2
1
1
1
1
1
1
1
2
1
2
1
1
1
1
1
1
1
2
1
2
CH2Cl2
CH2Cl2
THF
100
100
86
60 (R)
72 (R)
76 (R)
82 (R)
81 (R)
83 (R)
83 (R)
95 (R)
79 (R)
86 (R)
74 (R)
80 (R)
46 (R)d
49 (R)d
54 (R)e
74 (R)e
52 (R)d,e
64 (R)d,e
73 (R)
74 (R)
78 (R)
82 (R)
61 (R)d
40 (R)d
64 (R)e
72 (S)e
40 (R)d,e
44 (R)d,e
4 (R)
THF
96
CH2Cl2
CH2Cl2
THF
100
100
100
100
69
THF
9
CH2Cl2
CH2Cl2
THF
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
THF
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
THF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
85
99
100
100
100
100
67
100
79
100
100
62
73
100
76
79
67
100
92
100
100
100
97
5
5
5
3 (R)
14 (R)
18 (R)
THF
a
Reactions were carried out with 2 mol % of [Pd(allyl)Cl]2 at 20 °C for 48 h.
The conversion of substrate 6 and enantiomeric excess of 7c were determined by HPLC (Kromasil 5-AmiCoat, C6H14/i-PrOH = 200/1, 1.0 mL/min, 254 nm, t(R) = 5.5 min, t
b
(S) = 6.0 min).
c
The absolute configuration was assigned based on the literature data.16
In the presence of Zn-TPP.
With complex [Pd(allyl)(cod)]BF4 as the precatalyst.
d
e
Table 4
Pd-catalyzed allylic alkylation of cinnamyl acetate 8 with ethyl 2-oxocyclohexane-1-carboxylate 9a
EtO
O
O
O
Ph
OEt
cat
*
Ph
OAc
+
O
PhCH3
8
9
10
Entry
Ligand
L/Pd
Conversion (%)
ee (%)b,c
1
2
3
4
5
6
7
8
9
10
4a
4a
4b
4b
4c
4c
4d
4d
5
1
2
1
2
1
2
1
2
1
2
100
100
100
100
100
100
87
94
100
100
77 (S)
72 (S)
68 (S)
78 (S)
66 (S)
80 (S)
68 (S)
72 (S)
28 (S)
25 (S)
5
a
Reactions were carried out with 2 mol % of [Pd(allyl)Cl]2 in toluene at 20 °C for 48 h (BSA, Zn(OAc)2).
The conversion of substrate 8 and enantiomeric excess of 10 were determined by HPLC (Kromasil 5-CelluCoat, C6H14/i-PrOH = 95/5, 0.4 mL/min, 254 nm, t(R) = 14.3 min, t
b
(S) = 16.4 min).
c
The absolute configuration was assigned by comparison of the HPLC retention times reported in the literature.9a,b

K. N. Gavrilov et al. / Tetrahedron: Asymmetry 27 (2016) 1260–1268
1265
Table 5
Pd-catalyzed desymmetrization of N,N0-ditosyl-meso-cyclopent-4-ene-1,3-diol biscarbamate 12a
Ts
Ts
NH
HN
O
O
HO
OH
TsNCO
THF
O
O
11
12
Ts
Ts
N
H
H
H
H
N
cat
O
O
+
THF, Et3N
O
O
- CO2, - TsNH2
13
(R,S)-
(S,R)-13
Entry
Ligand
L/Pd
Yield (%)
ee (%)b,c
1
2
3
4
5
6
7
8
9
10
4a
4a
4b
4b
4c
4c
4d
4d
5
1
2
1
2
1
2
1
2
1
2
62
59
46
49
66
73
70
67
80
74
70 (S,R)
93 (S,R)
84 (S,R)
91 (S,R)
72 (S,R)
94 (S,R)
66 (S,R)
88 (S,R)
4 (R,S)
5
6 (R,S)
a
b
c
Reactions were carried out with 5 mol % of [Pd2(dba)3]ꢁCHCl3 in THF at 20 °C for 24 h.
The enantiomeric excess of 13 was determined by HPLC (Knauer AG 250, C6H14/i-PrOH = 1/1, 1.0 mL/min, 245 nm, t(R,S) = 16.0 min, t(S,R) = 23.0 min).
The absolute configuration was assigned by comparison of the HPLC retention times reported in the literature.17b
Next, we tested ligands 4a–d and 5 in the Pd-catalyzed allylic
diamidophosphite nature and the 1,3,2-diazaphospholidine rings
with balanced electronic characteristics; and (3) the presence of
the P⁄-stereogenic phosphorus atoms and/or the pyridine cores.
Overall, diamidophosphite–oxazolines 4a–d bearing P⁄- and C⁄-
stereocenters in the 1,3,2-diazaphospholidine rings are relatively
efficient asymmetric inducers, and 4b,c with pyridin-2-yl or pyri-
din-3-yl substituents are the best. In contrast, ligand 5 containing
achiral diamidophosphite moiety provided much lower enantiose-
lectivities. In the allylic substitution of (E)-1,3-diphenylallyl acet-
ate, the addition of Zn-TPP to palladium catalysts based on 4c,d
resulted in the conversion growth, but the enantioselectivity was
highly sensitive to the nucleophile nature. As a whole, diami-
dophosphite–oxazolines with stereogenic phosphorus atoms were
very attractive for further screening in asymmetric transition-
metal catalysis. Such investigations are currently in progress in
our laboratories.
alkylation of cinnamyl acetate 8 with ethyl 2-oxocyclohexane-1-
carboxylate 9 (Table 4); this is a challenging transformation where
a quaternary stereogenic center is generated in the nucleophile.
Diamidophosphites 4a–c provided practically equal good results:
enantiomeric quaternary-substituted b-keto ester (S)-10 was
obtained in 100% conversion and with 77%, 78% and 80% ee, respec-
tively (Table 4, entries 1, 4 and 6). Catalysts based on 4d proved to
be slightly less efficient with 94% conversion and 72% ee for (S)-10
being achieved in this instance (Table 4, entry 8). The most favor-
able L/Pd molar ratio was generally 2. Again, ligand 5 was a poor
stereoselector: compound (S)-10 was formed with up to 28% enan-
tioselectivity (Table 4, entries 9 and 10).
We also screened novel diamidophosphites in the Pd-catalyzed
desymmetrization of N,N0-ditosyl-meso-cyclopent-4-ene-1,3-diol
biscarbamate 12 (Table 5). This process is formally an intramolec-
ular allylic substitution reaction of a meso-substrate with two
enantiotopic leaving groups. The catalytic compositions were gen-
erated in situ from [Pd2(dba)3]ꢁCHCl3, the corresponding ligand and
using Et3N as a base in THF solution, which are used as the stan-
dard conditions.17 Enantioselectivities were best with ligands 4a–
c (up to 91–94% ee Table 5, entries 1–6). The analogous catalysts
based on diamidophosphite 4d showed somewhat lower asym-
metric induction: up to 88% ee for (S,R)-13 was achieved in this
case (Table 2, entries 7 and 8). Unfortunately, the use of ligand 5
generated an almost racemic product 13 (Table 5, entries 9 and
10). As a whole, the ligand to palladium molar ratios do not have
a clear impact on the chemical yields, but the enantiomeric
excesses were higher at L/Pd = 2.
4. Experimental
4.1. General
31P, 13C and 1H NMR spectra were recorded on a Bruker AMX
400 (162.0 MHz for 31P, 100.6 MHz for 13C and 400.13 MHz for
1H) and a Bruker Avance III 600 (242.9 MHz for 31P, 150.9 MHz
for 13C and 600.13 MHz for 1H) instruments in CDCl3 medium.
Complete assignment of all of the resonances in the 1H and 13C
NMR spectra was achieved by the use of APT and DEPT techniques
(together with COSY, ROESY, HSQC and HMBC techniques) and
published data.13,14 Chemical shifts (parts per million, ppm) were
given relative to Me4Si (1H and 13C) and 85% H3PO4 (31P NMR). Data
are represented as follows: chemical shift, multiplicity (br = broad,
s = singlet, d = doublet, t = triplet, m = multiplet); coupling con-
stants nJ in Hertz (Hz), ‘n’ values are reported in the case of their
unambiguous determination. Optical rotations were measured on
an Atago AP-300 polarimeter. HPLC analyses were performed on
a Stayer instrument using KromasilÒ and KnauerÒ columns. Ele-
3. Conclusion
A new P,N,N-ligand series was designed and synthesized for the
Pd-catalyzed allylic substitution and desymmetrization processes.
These stereoselectors have the following main advantages: (1) effi-
cient preparation from readily accessible hydroxy-oxazolines; (2)

1266
K. N. Gavrilov et al. / Tetrahedron: Asymmetry 27 (2016) 1260–1268
mental analyses were performed on a CHN-microanalyzer Carlo
Erba EA1108 CHNS-O.
hydroxy-oxazoline 1a–g (2 mmol) in one portion. The mixture
was then heated at reflux, stirred for 20 min, and cooled to 20 °C.
The resulting suspension was filtered through a short plug of
Al2O3/SiO2, the column was washed twice with toluene (6 mL),
and the solvent was evaporated under reduced pressure (40 Torr).
The product was dried in vacuum (1 Torr) for 1 h.
All reactions were carried out under a dry argon atmosphere in
flame-dried glassware and in freshly dried and distilled solvents.
For example, toluene and tetrahydrofuran were freshly distilled
from sodium benzophenone ketyl before use; dichloromethane
was distilled from NaH. Triethylamine and pyrrolidine were dis-
tilled over KOH and then over a small amount of LiAlH4 before
use. Thin-layer chromatography was performed on E. Merck pre-
coated silica gel 60 F254 and Macherey-Nagel Alugram Alox N/
UV254 plates. Column chromatography was performed using silica
gel MN Kieselgel 60 (230–400 mesh) and MN-Aluminum oxide,
basic, Brockmann Activity 1. Hydroxy-oxazolines 1a–c were
prepared as published.10 Phosphorylating reagents (5S)-2-
4.3.1. (2R,5S)-2-[((4S,5S)-2,5-Diphenyl-4,5-dihydrooxazol-4-yl)
methoxy]-3-phenyl-1,3-diaza-2-phosphabicyclo[3.3.0]octane
4a
Colorless viscous oil (0.79 g, yield 86%). [
a
]
25 = ꢀ157.7 (c 1.0,
D
THF). 1H NMR (400.13 MHz, 27 °C): d = 1.59–1.69 (m, 1H, NCHCH2),
1.72–1.91 (m, 2H, NCH2CH2), 1.99–2.09 (m, 1H, NCHCH2), 3.14–
3.26 (m, 2H, PNCH2 and NCH2CH2), 3.56–3.66 (m, 1H, NCH2CH2),
3.82 (dd, J = 7.6, J = 8.8, 1H, PNCH2), 3.86–3.95 (m, 2H, OCH2),
chloro-3-phenyl-1,3-diaza-2-phosphabicyclo[3.3.0]octane
2 and
3
2-chloro-1,3-diphenyl-1,3,2-diazaphospholidine 3 were prepared
analogously to known procedures.11,18 The [Pd(allyl)Cl]2, (E)-1,3-
diphenylallyl acetate 6, [Pd(allyl)(cod)]BF4 and [Pd2(dba)3]ꢁCHCl3
were obtained as published.19 Zinc(II) 5,10,15,20-tetraphenylpor-
phyrin (Zn-TPP) was prepared as published.20 Pd-catalyzed
reactions: allylic sulfonylation of (E)-1,3-diphenylallyl acetate 6
with sodium para-toluene sulfinate, alkylation with dimethyl
malonate and amination with pyrrolidine, allylic alkylation of cin-
namyl acetate 8 with ethyl 2-oxocyclohexane-1-carboxylate 9 and
desymmetrization of N,N0-ditosyl-meso-cyclopent-4-ene-1,3-diol
biscarbamate 12 were performed according to the appropriate
procedures.11,21,9a,9b,17,14a
4.12–4.21 (m, 1H, PNCH), 4.25 (dt, JH,H = 6.4, J = 4.4, 1H, OCHCH),
3
3
4
5.52 (d, JH,H = 6.8, 1H, OCH), 6.85 (dt, JH,H = 7.2, JH,H = 1.0, 1H,
CHPh), 7.03–7.08 (m, 2H, CHPh), 7.17–7.26 (m, 4H, CHPh), 7.29–
7.35 (m, 3H, CHPh), 7.42–7.48 (m, 2H, CHPh), 7.49–7.55 (m, 1H,
CHPh), 8.03–8.07 (m, 2H, CHPh). 13C NMR (100.6 MHz, 27 °C):
3
2
d = 26.1 (d, JC,P = 3.8, NCH2CH2), 32.1 (s, NCHCH2), 48.6 (d, JC,
2
2
P = 38.3, NCH2CH2), 54.9 (d, JC,P = 7.3, PNCH2), 63.1 (d, JC,P = 5.4,
2
3
POCH2), 63.2 (d, JC,P = 8.8, PNCH), 75.4 (d, JC,P = 2.3, POCH2CH),
3
83.6 (s, OCH), 114.7 (d, JC,P = 11.9, PNCCH), 118.9 (s, CHPh), 125.5
(s, CHPh), 127.5 (s, CPh), 127.9 (s, CHPh), 128.3 (s, CHPh), 128.4 (s,
CHPh), 128.6 (s, CHPh), 129.1 (s, CHPh), 131.5 (s, CHPh), 140.9 (s,
2
OCHC), 145.4 (d, JC,P = 15.7, PNC), 164.1 (s, OC). 31P NMR
(1S,2S)-2-Amino-1-phenylpropane-1,3-diol, isonicotinonitrile,
4-dimethylamino-pyridine (DMAP), sodium para-toluene sulfinate,
dimethyl malonate, N,O-bis(trimethylsilyl) acetamide (BSA), cin-
namyl acetate 8, ethyl 2-oxocyclohexane-1-carboxylate 9, meso-
cyclopent-4-ene-1,3-diol 11 and tosyl isocyanate were purchased
from Aldrich and Acros Organics and used without further
purification.
(162.0 MHz, 27 °C): dP = 121.6. Anal. Calcd for C27H28N3O2P: C,
70.88; H, 6.17; N, 9.18. Found: C, 71.13; H, 6.27; N, 9.14.
4.3.2. (2R,5S)-2-[((4S,5S)-5-Phenyl-2-(pyridin-2-yl)-4,5-dihy-
drooxazol-4-yl)methoxy]-3-phenyl-1,3-diaza-2-phosphabicyclo
[3.3.0]octane 4b
Colorless viscous oil (0.73 g, yield 80%). [
a
]
25 = ꢀ151.1 (c 1.0,
D
THF). 1H NMR (400.13 MHz, 27 °C): d = 1.57–1.67 (m, 1H, NCHCH2),
1.71–1.90 (m, 2H, NCH2CH2), 1.97–2.08 (m, 1H, NCHCH2), 3.12–
3.26 (m, 2H, PNCH2 and NCH2CH2), 3.54–3.65 (m, 1H, NCH2CH2),
3.80 (dd, J = 7.6, J = 8.8, 1H, PNCH2), 3.92 (t, J = 5.6, 2H, OCH2),
4.2. Procedure for the preparation of hydroxy-oxazoline 1d
To a vigorously stirred solution of (1S,2S)-2-amino-1-phenyl-
propane-1,3-diol (1 g, 6 mmol) and K2CO3 (0.14 g, 1 mmol) in a
mixture of ethylene glycol (2.1 mL) and glycerol (1.1 mL) was
added isonicotinonitrile (0.63 g, 6 mmol) in one portion. The resul-
tant mixture was then heated to 110 °C, stirred for 24 h, and cooled
to 20 °C. Water (10 mL) was added and the precipitate was col-
lected by filtration, washed with water and hexane and dried in
vacuum (1 Torr, 2 h). The product was additionally purified by
flash chromatography (Al2O3/SiO2, CH2Cl2/EtOAc, 1:1) and crystal-
lization from heptane/toluene.
3
4.10–4.18 (m, 1H, PNCH), 4.32 (dt, JH,H = 6.8, J = 5.6, 1H, OCHCH),
3
3
5.59 (d, JH,H = 7.2, 1H, OCH), 6.84 (t, JH,H = 7.2, 1H, CHPh), 7.04
3
4
(dt, JH,H = 7.6, JH,H = 1.0, 2H, CHPh), 7.15–7.26 (m, 5H, CHPh),
7.28–7.34 (m, 2H, CHPh), 7.43 (ddd, JH,H = 4.8, JH,H = 7.6, JH,
3
3
4
3
4
H = 1.2, 1H, CHpy), 7.81 (dt, JH,H = 7.6, JH,H = 1.6, 1H, CHpy), 8.08
(br. d, JH,H = 7.6, 1H, CHpy), 8.76 (br. d, JH,H = 4.8, 1H, NCHpy). 13C
3
3
3
NMR (100.6 MHz, 27 °C): d = 26.1 (d, JC,P = 3.4, NCH2CH2), 32.2 (s,
NCHCH2), 48.5 (d, 2JC,P = 38.3, NCH2CH2), 54.9 (d, 2JC,P = 7.2, PNCH2),
2
2
3
63.0 (d, JC,P = 5.3, POCH2), 63.2 (d, JC,P = 8.8, PNCH), 75.4 (d, JC,
3
P = 2.3, POCH2CH), 84.5 (s, OCH), 114.7 (d, JC,P = 12.3, PNCCH),
4.2.1. ((4S,5S)-5-Phenyl-2-(pyridin-4-yl)-4,5-dihydrooxazol-4-
118.9 (s, CHPh), 124.0 (s, CHarom), 125.6 (s, CHarom), 125.7 (s,
CHarom), 128.0 (s, CHarom), 128.5 (s, CHarom), 129.1 (s, CHarom),
yl)methanol 1d
2
White powder (0.93 g, yield 61%). [
NMR (400.13 MHz, 27 °C): d = 3.08 (t, JH,H = 6.0, 1H, OH), 3.79–
a
]
25 = +83.1 (c 1.0, THF). 1H
136.5 (s, CHarom), 140.4 (s, OCHC), 145.3 (d, JC,P = 15.7, PNC),
D
3
146.5 (s, NCpy), 149.9 (s, NCHpy), 163.1 (s, OC). 31P NMR
(162.0 MHz, 27 °C): dP = 121.2. Anal. Calcd for C26H27N4O2P: C,
68.11; H, 5.94; N, 12.22. Found: C, 68.30; H, 5.99; N, 12.38.
3
3.88 (m, 1H, OCH2), 4.08–4.16 (m, 1H, OCH2), 4.32 (dt, JH,H = 8.0,
3JH,H = 4.0, 1H, OCHCH), 5.63 (d, JH,H = 8.4, 1H, OCH), 7.33–7.45
3
3
3
(m, 5H, CHPh), 7.78 (d, JH,H = 5.6, 2H, CHpy), 8.70 (d, JH,H = 6.0,
2H, NCHpy). 13C NMR (150.9 MHz, 25 °C): d = 62.9 (s, OCH2), 76.9
(s, NCH), 83.2 (s, OCH), 122.0 (s, CHPh), 125.8 (s, CHPh), 128.7 (s,
CHPh), 129.0 (s, CHpy), 134.3 (s, Cpy), 139.8 (s, OCHC), 150.2 (s,
NCHpy), 163.0 (s, OC). Anal. Calcd for C15H14N2O2: C, 70.85; H,
5.55; N, 11.02. Found: C, 71.01; H, 5.60; N, 10.91.
4.3.3. (2R,5S)-2-[((4S,5S)-5-Phenyl-2-(pyridin-3-yl)-4,5-dihy-
drooxazol-4-yl)methoxy]-3-phenyl-1,3-diaza-2-phosphabicyclo
[3.3.0]octane 4c
Colorless viscous oil (0.72 g, yield 78%). [
a
]
25 = ꢀ164.5 (c 1.0,
D
THF). 1H NMR (600.13 MHz, 26 °C): d = 1.61–1.68 (m, 1H, NCHCH2),
1.75–1.90 (m, 2H, NCH2CH2), 2.02–2.09 (m, 1H, NCHCH2), 3.16–
3.22 (m, 1H, NCH2CH2), 3.21–3.26 (m, 1H, PNCH2), 3.58–3.64 (m,
1H, NCH2CH2), 3.83 (dd, J = 7.2, J = 8.4, 1H, PNCH2), 3.89 (ddd,
4.3. General procedure for the preparation of ligands 4a–d and 5
2
2
To a vigorously stirred solution of the appropriate phosphory-
lating reagent 2 or 3 (2 mmol), Et3N (0.56 mL, 4 mmol) and DMAP
(0.025 g, 0.2 mmol) in toluene (15 mL) was added the relevant
J = 6.0, JH,H = 10.2, J = 4.2, 1H, OCH2), 3.93 (dt, J = 6.0, JH,H = 10.2,
3
1H, OCH2), 4.15–4.20 (m, 1H, PNCH), 4.27 (dt, JH,H = 6.6, J = 3.6,
3
3
1H, OCHCH), 5.53 (d, JH,H = 6.6, 1H, OCH), 6.87 (t, JH,H = 7.8, 1H,

K. N. Gavrilov et al. / Tetrahedron: Asymmetry 27 (2016) 1260–1268
1267
3
CHPh), 7.06 (d, JH,H = 7.8, 2H, CHPh), 7.18–7.22 (m, 2H, CHPh), 7.25
was stirred for 40 min. (E)-1,3-Diphenylallyl acetate (0.05 mL,
0.25 mmol) was then added and the solution was stirred for
15 min, after which sodium para-toluene sulfinate (0.089 g,
0.5 mmol) was added and the reaction mixture stirred for a further
48 h, quenched with brine (3 mL), and extracted with THF
(3 ꢂ 2 mL). The organic layer was washed with brine (2 ꢂ 2 mL)
and dried over MgSO4. The solvent was evaporated at reduced
pressure (40 Torr). Crystallization of the residue from EtOH, fol-
lowed by desiccation in a vacuum (10 Torr, 12 h), gave (E)-1,3-
diphenyl-3-tosylprop-1-ene 7a as white crystals.22
3
3
(t, JH,H = 7.8, 2H, CHPh), 7.31–7.36 (m, 3H, CHPh), 7.39 (dd, JH,
H = 4.8, JH,H = 7.8, 1H, CHpy), 8.29 (dt, JH,H = 7.8, JH,H = 1.8, 1H,
3
3
4
3
4
4
CHpy), 8.76 (dd, JH,H = 4.8, JH,H = 1.8, 1H, NCHpy), 9.25 (d, JH,
H = 1.8, 1H, NCHpy). 13C NMR (150.9 MHz, 27 °C): d = 26.2 (d, JC,
3
P = 3.8, NCH2CH2), 32.3 (s, NCHCH2), 48.7 (d, 2JC,P = 38.2, NCH2CH2),
2
2
2
55.0 (d, JC,P = 7.2, PNCH2), 63.0 (d, JC,P = 5.4, POCH2), 63.3 (d, JC,
P = 8.9, PNCH), 75.5 (d, JC,P = 2.6, POCH2CH), 83.9 (s, OCH), 114.9
(d, JC,P = 12.2, PNCCH), 119.1 (s, CHPh), 123.2 (s, CHpy), 123.8 (s,
3
3
C
py), 125.7 (s, CHPh), 128.2 (s, CHPh), 128.8 (s, CHPh), 129.2 (s, CHPh),
135.8 (s, CHpy), 140.5 (s, OCHC), 145.5 (d, 2JC,P = 15.5, PNC), 149.8 (s,
NCHpy), 152.2 (s, NCHpy), 162.3 (s, OC). 31P NMR (162.0 MHz,
27 °C): dP = 121.7. Anal. Calcd for C26H27N4O2P: C, 68.11; H, 5.94;
N, 12.22. Found: C, 68.41; H, 5.82; N, 12.11.
4.4.2. The Pd-catalyzed allylic alkylation of (E)-1,3-diphenylallyl
acetate 6 with dimethyl malonate
A solution of [Pd(allyl)Cl]2 (0.0019 g, 0.005 mmol) or [Pd(allyl)
(cod)]BF4 (0.0034 g, 0.01 mmol) and the appropriate ligand
(0.01 mmol or 0.02 mmol) in the appropriate solvent (1.5 mL) was
stirred for 40 min. For the experiments carried out in the presence
of Zn-TPP, this compound (0.0068 g, 0.01 mmol) was added and
stirring was continued for 20 min. (E)-1,3-Diphenylallyl acetate
(0.05 mL, 0.25 mmol) was added and the solution stirred for
15 min. Dimethyl malonate (0.05 mL, 0.44 mmol), BSA (0.11 mL,
0.44 mmol), and potassium acetate (0.002 g) were added. The
reaction mixture was stirred for 48 h, diluted with CH2Cl2 or
THF (2 mL), and filtered through a thin layer of SiO2. The filtrate
was evaporated at reduced pressure (40 Torr) and dried in
vacuum (10 Torr, 12 h) affording a residue containing (E)-dimethyl
2-(1,3-diphenylallyl)malonate 7b.23 In order to evaluate the ee and
conversion, the obtained residue was dissolved in an appropriate
eluant mixture (8 mL) and a sample was taken for HPLC analysis.
4.3.4. (2R,5S)-2-[((4S,5S)-5-Phenyl-2-(pyridin-4-yl)-4,5-dihy-
drooxazol-4-yl)methoxy]-3-phenyl-1,3-diaza-2-phosphabicyclo
[3.3.0]octane 4d
Colorless viscous oil (0.78 g, yield 85%). [
a]
D
25 = ꢀ124.1 (c 1.0,
THF). 1H NMR (600.13 MHz, 27 °C): d = 1.62–1.68 (m, 1H, NCHCH2),
1.75–1.90 (m, 2H, NCH2CH2), 2.02–2.09 (m, 1H, NCHCH2), 3.16–
3.26 (m, 2H, PNCH2 and NCH2CH2), 3.58–3.65 (m, 1H, NCH2CH2),
3.83 (dd, J = 7.8, J = 9.0, 1H, PNCH2), 3.85–3.90 (m, 1H, OCH2),
3.92–3.97 (m, 1H, OCH2), 4.14–4.19 (m, 1H, PNCH), 4.26–4.31 (m,
3
3
1H, OCHCH), 5.54 (d, JH,H = 7.2, 1H, OCH), 6.67 (t, JH,H = 7.2, 1H,
3
3
CHPh), 7.06 (d, JH,H = 7.2, 2H, CHPh), 7.18 (d, JH,H = 7.2, 2H, CHPh),
3
3
7.25 (t, JH,H = 7.2, 2H, CHPh), 7.32–7.37 (m, 3H, CHPh), 7.87 (d, JH,
H = 6.0, 2H, CHpy), 8.76 (d, JH,H = 6.0, 2H, NCHpy). 13C NMR
3
3
(150.9 MHz, 25 °C): d = 26.2 (d, JC,P = 3.5, NCH2CH2), 32.3 (s,
NCHCH2), 48.6 (d, 2JC,P = 37.9, NCH2CH2), 55.0 (d, 2JC,P = 6.9, PNCH2),
2
62.8 (br. s, POCH2), 63.3 (d, JC,P = 9.2, PNCH), 75.6 (s, POCH2CH),
84.0 (s, OCH), 114.9 (d, JC,P = 12.5, PNCCH), 119.1 (s, CHPh), 122.2
4.4.3. The Pd-catalyzed allylic amination of (E)-1,3-diphenylallyl
acetate 6 with pyrrolidine
3
(s, CHPh), 125.6 (s, CHPh), 128.3 (s, CHPh), 128.8 (s, CHPh), 129.2 (s,
A solution of [Pd(allyl)Cl]2 (0.0019 g, 0.005 mmol) or [Pd(allyl)
(cod)]BF4 (0.0034 g, 0.01 mmol) and the appropriate ligand
(0.01 mmol or 0.02 mmol) in the appropriate solvent (1.5 mL)
was stirred for 40 min. For the experiments carried out in the pres-
ence of Zn-TPP, this compound (0.0068 g, 0.01 mmol) was added
and stirring was continued for 20 min. (E)-1,3-Diphenylallyl acet-
ate (0.05 mL, 0.25 mmol) was then added and the solution stirred
for 15 min, after which freshly distilled pyrrolidine (0.06 mL,
0.75 mmol) was added. The reaction mixture was stirred for 48 h,
diluted with CH2Cl2 or THF (2 mL), and filtered through a thin layer
of SiO2. The filtrate was evaporated at reduced pressure (40 Torr)
and dried in a vacuum (10 Torr, 12 h) affording a residue contain-
ing (E)-1-(1,3-diphenylallyl)pyrrolidine 7c.16,24 In order to evaluate
the ee and conversion, the obtained residue was dissolved in an
appropriate eluant mixture (8 mL) and a sample was taken for
HPLC analysis.
2
CHpy), 135.0 (s, Cpy), 140.3 (s, OCHC), 145.4 (d, JC,P = 14.9, PNC),
150.3 (s, NCHpy), 162.5 (s, OC). 31P NMR (162.0 MHz, 27 °C):
dP = 121.9. Anal. Calcd for C26H27N4O2P: C, 68.11; H, 5.94; N,
12.22. Found: C, 68.34; H, 5.88; N, 12.40.
4.3.5. 2-[((4S,5S)-5-Phenyl-2-(pyridin-3-yl)-4,5-dihydrooxazol-
4-yl)methoxy]-1,3-diphenyl-1,3,2-diazaphospholidine 5
White paraffin-like compound (0.72 g, yield 73%). [
a
]
25 = ꢀ2.8
D
(c 1.0, THF). 1H NMR (600.13 MHz, 25 °C): d = 3.76–3.81 (m, 1H,
PNCH2), 3.82–3.88 (m, 2H, PNCH2 and OCH2), 3.92–3.99 (m, 3H,
3
PNCH2 and OCH2), 4.22 (dt, JH,H = 6.6, J = 4.2, 1H, OCHCH), 5.37
3
(d, JH,H = 6.6, 1H, OCH), 6.93–6.97 (m, 2H, CHPh), 7.15–7.21 (m,
3
3
6H, CHPh), 7.27–7.36 (m, 7H, CHPh), 7.37 (ddd, JH,H = 4.8, JH,
3
4
H = 8.4, JH,H = 1.2, 1H, CHpy), 8.20 (dt, JH,H = 7.8, JH,H = 1.8, 1H,
3
4
4
CHpy), 8.75 (dd, JH,H = 4.8, JH,H = 1.2, 1H, NCHpy), 9.16 (dd, JH,
H = 1.2, JH,H = 2.4, 1H, NCHpy). 13C NMR (150.9 MHz, 26 °C):
4
2
2
d = 47.4 (d, JC,P = 10.1, PNCH2), 47.5 (d, JC,P = 10.3, PNCH2), 64.5
(d, JC,P = 2.4, POCH2), 75.2 (d, JC,P = 2.3, NCH), 83.9 (s, OCH),
4.4.4. The Pd-catalyzed allylic alkylation of cinnamyl acetate 8
with ethyl 2-oxocyclohexane-1-carboxylate 9
A solution of [Pd(allyl)Cl]2 (0.0019 g, 0.005 mmol) and the
appropriate ligand (0.01 mmol or 0.02 mmol) in toluene (1.5 mL)
2
3
3
3
115.3 (d, JC,P = 14.0, PNCCH), 115.5 (d, JC,P = 14.0, PNCCH), 120.3
(d, JC,P = 1.5, CHPh), 120.4 (d, JC,P = 1.4, CHPh), 123.3 (s, CHpy),
123.7 (s, Cpy), 125.6 (s, CHPh), 128.3 (s, CHPh), 128.8 (s, CHPh),
129.39 (s, CHPh), 129.4 (s, CHPh), 135.9 (s, CHpy), 140.2 (s, OCHC),
144.8 (d, JC,P = 5.4, PNC), 144.9 (d, JC,P = 6.2, PNC), 149.6 (s,
NCHpy), 152.1 (s, NCHpy), 162.3 (s, OC). 31P NMR (242.9 MHz,
25 °C): dP = 103.7. Anal. Calcd for C29H27N4O2P: C, 70.43; H, 5.50;
N, 11.33. Found: C, 70.71; H, 5.58; N, 11.49.
was stirred for 40 min or the appropriate complex
6 or 7
(0.01 mmol) was dissolved in toluene (1.5 mL). Cinnamyl acetate
(0.04 mL, 0.25 mmol) was added and the solution stirred for
2
2
15 min.
Ethyl
2-oxocyclohexane-1-carboxylate
(0.06 mL,
0.375 mmol), BSA (0.25 mL, 1 mmol) and Zn(OAc)2 (0.005 g) were
added. The reaction mixture was stirred for 48 h, diluted with
toluene (2 mL) and filtered through a thin layer of SiO2. The filtrate
was evaporated at reduced pressure (40 Torr) and dried in vacuum
(10 Torr, 12 h) affording a residue containing ethyl 1-cinnamyl-2-
oxocyclohexanecarboxylate 10.9a,9b In order to evaluate the ee
and conversion, the obtained residue was dissolved in an
appropriate eluent mixture (8 mL) and a sample was taken for
HPLC analysis.
4.4. Catalytic reactions
4.4.1. The Pd-catalyzed allylic sulfonylation of (E)-1,3-dipheny-
lallyl acetate 6 with sodium para-toluene sulfinate
A solution of [Pd(allyl)Cl]2 (0.0019 g, 0.005 mmol) and the
appropriate ligand (0.01 mmol or 0.02 mmol) in THF (1.5 mL)

1268
K. N. Gavrilov et al. / Tetrahedron: Asymmetry 27 (2016) 1260–1268
4.4.5. The Pd-catalyzed desymmetrization of N,N0-ditosyl-meso-
cyclopent-4-ene-1,3-diol biscarbamate 12
A solution of [Pd2(dba)3]ꢁCHCl3 (0.005 g, 0.005 mmol) and the
appropriate ligand (0.01 mmol or 0.02 mmol) in THF (1 mL) was
stirred for 40 min. A solution of N,N0-ditosyl-meso-cyclopent-4-
ene-1,3-diol biscarbamate 12 and Et3N (14 lL, 0.099 mmol) in
THF (0.5 mL) was added (compound 12 was prepared in situ as fol-
lows: to a solution of the meso-cyclopent-4-ene-1,3-diol 11 (0.01 g,
0.099 mmol) in THF (0.5 mL), tosyl isocyanate (35 lL, 0.232 mmol)
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was added; the mixture was stirred at 20 °C for 15 min, heated to
55 °C for 1 h, and cooled down to 20 °C). The reaction mixture was
stirred for 24 h. The solvent was removed at reduced pressure
(40 Torr) and the residue was purified by flash chromatography
on a short pad of SiO2 (EtOAc/hexane, 1:4). The residue was sus-
pended in CH2Cl2/hexane (1:10) and filtered. The filtrate was evap-
orated at reduced pressure (40 Torr) and dried in vacuum (1 Torr,
2 h) gave the desired 3-tosyl-3,3a,6,6a-tetrahydro-2H-cyclopenta
[d]oxazol-2-one 13 as a slightly yellow oil that solidified on stand-
17c,25
ing.
8. Nemoto, T.; Hamada, Y. Tetrahedron 2011, 67, 667–687.
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Acknowledgement
We acknowledge the financial support from the Russian Science
Foundation (Grant No. 14-13-01383).
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