Evans auxiliary' based P-N ligands for Pd-catalyzed asymmetric allylic alkylation reactions

Article abstract of DOI:10.1055/s-0031-1290404

A new type of chiral P-N ligands has been prepared which incorporates the Evans auxiliary as chiral ligand. They were found to act as effective ligands in the Pd-catalyzed allylic alkylation reactions. Using these ligands with allylpalladium chloride dimer as catalyst, the coupling of 1,3-diphenyl-3- acetoxyprop-1-ene and dimethyl malonate proceeded smoothly at -10°C providing the desired product with enantiomeric excess up to 87% and excellent yield.

Full text of DOI:10.1055/s-0031-1290404

LETTER
▌1805
letter
‘Evans Auxiliary’ Based P–N Ligands for Pd-Catalyzed Asymmetric Allylic
Alkylation Reactions
Novel P–N ligand
Yun Li,a Fang Liang,a Rui Wu,a Qian Li,a Quan-Rui Wang,b Yao-Chang Xu,a Lei Jiang*a
a
China Novartis Institutes for BioMedical Research Co.,Ltd. , Building 8, Lane 898 Halei Road, 201203, Shanghai, P. R. of China
b
Department of Chemistry, Fudan University, 220 Handan Road, 200433, Shanghai, P. R. of China
Fax +86(21)61606155; E-mail: lei-1.jiang@novartis.com
Received: 16.04.2012; Accepted after revision: 06.05.2012
Inspired by the phosphine oxazoline ligand (PHOX) for
Abstract: A new type of chiral P–N ligands has been prepared
their excellent enatioselectivity and high reaction rate
which incorporates the Evans auxiliary as chiral ligand. They were
shown in the allylic alkylation reactions,3,9 we envisaged
incorporating the Evans chiral auxiliary next to the imino
found to act as effective ligands in the Pd-catalyzed allylic alkyla-
tion reactions. Using these ligands with allylpalladium chloride di-
mer as catalyst, the coupling of 1,3-diphenyl-3-acetoxyprop-1-ene group that could lead to novel P–N ligand 1. This new
and dimethyl malonate proceeded smoothly at –10 °C providing the
desired product with enantiomeric excess up to 87% and excellent
yield.
class of ligands was designed to possess two independent
parts: an Evans auxiliary moiety providing a chiral recog-
nition environment and a phosphinoimine unit coordinat-
ing with the metal center for catalysis.
Key words: asymmetric allylic alkylation, palladium catalysis,
P–N ligand, Evans auxiliary
The synthesis of ligand 1a(b) proved to be rather straight-
forward from the commercially available Evans auxiliary.
Compound 4a(b) was converted into N-aryl oxazolidin-2-
One of the most powerful approaches for the formation of
one 5a(b) via a SNAr reaction10 with 2-fluoronitroben-
carbon–carbon or carbon–heteroatom bond is the metal-
zene. Reduction of the nitro group with Pd/C provided the
catalyzed asymmetric allylic alkylation (AAA) reaction.1
corresponding aniline 6a(b). Condensation of anilines
This reaction has been broadly studied and has become a
6a(b) with phosphinoaldehyde 7 in the presence of 4 Å
model reaction to evaluate new chiral ligands.2 Over the
MS and a catalytic amount of zinc chloride resulted in the
past several years, many useful chiral ligands such as
efficient formation of ligands 1a(b) as shown in Scheme
C2,C1-symmetric bidentate chiral ligands3,4 have been ex-
1.
tensively applied in this field.
The Evans auxiliary has been employed in a number of
O
NO2
synthetic transformations including aldol condensation,5
Diels–Alder reaction,6 and alkylation7 and a high level of
enantio- and diastereoselectivity has been achieved.8
However, to the best of our knowledge, no example of a
P–N ligand incorporating the Evans auxiliary has been re-
ported. Considering their ease of synthesis and commer-
cial availability, it would be ideal to design a chiral ligand
that links the Evans auxiliary with a phosphino fragment
for metal-catalyzed asymmetric transformations. Herein,
we report the preparation of this new class of ligands 1
(Figure 1) and evaluate them in the palladium-catalyzed
AAA reactions.
O
NO2
F
b
a
O
+
N
O
N
R
H
R
3
4a, R = Ph
4b, R = i-Pr
5a, R = Ph
5b, R = i-Pr
O
NH2
O
O
c
N
R
O
+
N
R
Ph
N
P
Ph
PPh2
O
7
6a, R = Ph 82% from 4a
6b, R = i-Pr 69% from 4b
1a, R = Ph 76%
1b, R = i-Pr 52%
chelation part
O
Scheme 1 Reagents and conditions: (a) NaH, DMF, 100 °C, 10 h;
(b) H2, Pd/C, MeOH; (c) ZnCl2, 4 Å MS, THF, r.t., 10 h.
O
O
N
R
In order to investigate the potential application of this new
type of ligands in asymmetric catalysis, we first carried
out the AAA reaction of 1,3-diphenylprop-2-enyl acetate
(8) with dimethylmalonate as the prototypical substrate.
Using 1a and [Pd(η3-C3H5)Cl]2 as catalyst with N,O-bis-
(trimethylsilyl)acetamide (BSA) and a catalytic amount
of LiOAc as additives in CH2Cl2, the reaction proceeded
well, and the desired product was isolated in 95% yield
with 63% ee (Table 1, entry 1).
N
P
N
P
chirality part
R
P-N ligand (1)
PHOX (2)
Figure 1 New type of P–N ligands and Pfaltz scaffolds
SYNLETT 2012, 23, 1805–1808
Advanced online publication: 14.06.2012
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6
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5
2
1
4
1
4
3
7
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2
0
9
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DOI: 10.1055/s-0031-1290404; Art ID: ST-2012-W0332-L
© Georg Thieme Verlag Stuttgart · New York

1806
Y. Li et al.
LETTER
The solvent effect has also been investigated. Among the improved the ee value to 82% (Table 1, entry 17). These
five solvents (CH2Cl2, THF, toluene, MeCN, and diox- data suggest that the extra lithium cation is beneficial to
ane) examined, the reaction with THF gave the product in the enantioselectivity of this reaction. Using Pd(OAc)2 as
superior yield and enantiomeric excess.
Pd precursor instead of [Pd(η3-C3H5)Cl]2 required longer
reaction time and gave the product in lower yield (Table
1, entry 8). Combining all the findings, the reaction was
performed under the optimized reaction conditions (8
mol% of 1a, 2 mol% of [Pd(η3-C3H5)Cl]2 as catalyst, 2.0
equiv of BSA as base and 1.0 equiv of LiOAc as additive
in THF). Switching to the more hindered isopropyl-substi-
tuted ligand 1b under the same reaction conditions yielded
the desired product with slightly better enantioselectivity
(Table 1, entry 19).
Variations of the ligand-to-palladium ratio had minimal
impact on the reaction outcome. Lowering the reaction
temperature to –10 °C resulted in slightly improved yield
and enantioselectivity (80%). Further lowering of the re-
action temperature led to longer reaction time and mini-
mum benefit of the ee value. Changing the base from BSA
to other organic or inorganic bases resulted in a significant
drop of yield and enantiomeric excess of the product.
When switching the additive from LiOAc to KOAc, a sig-
nificant drop of ee value was observed. Increasing the Next, we examined the substrate scope for this new proto-
amount of LiOAc from catalytic to stoichiometric amount col, and the reaction results are summarized in Table 2.
Table 1 Optimization of the Asymmetric Allylic Alkylation Using Pd/Ligand 112,13
MeO2C
CO2Me
OAc
O
O
Pd
P–N ligand
base
Ph
Ph OMe
OMe
Ph
Ph
8
9
10
Entrya
Ligand (L/Pd)
Base (additives)b
Solvent
Temp (°C)
Time (h)
Yield (%)c ee (%)d
1
2
1a (2:1)
1a (2:1)
1a (2:1)
1a (2:1)
1a (2:1)
1a (1:1)
1a (3:1)
1a (2:1)
1a (2:1)
1a (2:1)
1a (2:1)
1a (2:1)
1a (2:1)
1a (2:1)
1a (2:1)
1a (2:1)
1a (2:1)
1a (2:1)
1b (2:1)
BSA, LiOAc
BSA, LiOAc
BSA, LiOAc
BSA, LiOAc
BSA, KOAc
BSA, LiOAc
BSA, LiOAc
BSA, LiOAc
BSA, LiOAc
BSA, LiOAc
BSA, LiOAc
TBAF
CH2Cl2
toluene
THF
20
20
2.0
2.0
1.5
2.0
1.5
3.0
2.0
8.0
2.0
5.0
15
95
96
98
94
97
97
98
62
97
98
70
87
0
63 (S)
53 (S)
70 (S)
51 (S)
51 (S)
45 (S)
63 (S)
69 (S)
69 (S)
80 (S)
82 (S)
9 (S)
3
20
4
MeCN
THF
20
5
20
6
dioxane
THF
20
7
20
8e
9
THF
20
THF
0
10
11
12
13
14
15
16
17f
18g
19
THF
–10
–20
–10
–10
–10
–10
–10
–10
–10
–10
THF
THF
5.0
5.0
8.0
5.0
10
Ba(OH)2
THF
–
Cs2CO3
THF
95
98
90
98
99
99
48 (S)
65 (S)
32 (S)
55 (S)
82 (S)
87 (S)
LiOH
THF
Li2CO3
THF
BSA, LiOAc, LiCl
BSA, LiOAc
BSA, LiOAc
THF
5.0
5.0
20
THF
THF
a Reaction run with (η3-C3H5PdCl)2 (2 mol%) as catalyst unless otherwise noted.
b Using base (2 equiv) and additives (2 mol%).
c Isolated yields.
d The ee value was determined by SFC with a chiral column, Daicel chiralcel AD-H column (20% MeOH in liquid CO2). The absolute config-
uration was determined by comparing the sign of optical rotation.11
e Using Pd(OAc)2 as palladium source.
f Using LiOAc (2 mol%) and LiCl (1 equiv) as additive.
g Using LiOAc (1.0 equiv) as additive.
Synlett 2012, 23, 1805–1808
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel P–N ligand
1807
References
Table 2 Asymmetric Allylic Alkylation with Several Nucleophiles
PdCl2(allyl)2
OAc
Nu
(1) (a) Trost, B. M.; Vanvranken, D. L. Chem. Rev. 1996, 96,
395. (b) Guiry, P. J.; McCarthy, M.; Lacey, P. M.; Saunders,
C. P.; Kelly, S.; Connolly, D. J. Curr. Org. Chem. 2000, 4,
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3809. (d) Kazmaier, U. Curr. Org. Chem. 2003, 7, 317.
(e) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103,
2921. (f) Tsuji, J. Palladium Reagents and Catalysis:
Innovations in Organic Synthesis; Wiley: New York, 1995.
(g) Ojima, I. Catalytic Asymmetric Synthesis; Wiley: New
York, 2000. (h) Guerrero Rios, I.; Rosas-Hernandez, A.;
Martin, E. Molecules 2011, 16, 970. (i) Trost, B. M.; Zhang,
T.; Sieber, J. D. Chem. Sci. 2010, 1, 427. (j) Transition Metal
Catalyzed Enantioselective Allylic Substitution in Organic
Synthesis, In Topics in Organometallic Chemistry; Vol. 38;
Kazmaier, U., Ed.; Springer: Berlin, 2012, 95–153.
(2) Guerrero, Rios. I.; Rosas-Hernandez, A.; Martin, E.
Molecules 2011, 16, 970.
(3) (a) Gualandi, A.; Manoni, F.; Monari, M.; Savoia, D.
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M.; Dechert, S.; Meyer, F. Organometallics 2010, 29, 1117.
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(d) Zhang, W.; Shimanuki, T.; Kida, T.; Nakatsuji, Y.;
Ikeda, I. J. Org. Chem. 1999, 64, 6247. (e) Savoia, D.;
Alvaro, G.; Di Fabio, R.; Fiorelli, C.; Gualandi, A.; Monari,
M.; Piccinelli, F. Adv. Synth. Catal. 2006, 348, 1883.
(f) Trost, B. M.; Pan, Z.; Zambrano, J.; Kujat, C. Angew.
Chem. Int. Ed. 2002, 41, 4691.
(4) (a) Steinhagen, H.; Reggelin, M.; Helmchen, G. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2108. (b) You, S.-L.; Hou,
X.-L.; Dai, L.-X.; Cao, B.-X.; Sun, J. Chem. Commun. 2000,
1933. (c) Prétôt, R.; Pfaltz, A. Angew. Chem. Int. Ed. 1998,
37, 323. (d) Hoshi, T.; Sasaki, K.; Sato, S.; Ishii, Y.; Suzuki,
T.; Hagiwara, H. Org. Lett. 2011, 13, 932. (e) Widhalm, M.;
Abraham, M.; Arion, V. B.; Saarsalu, S.; Maeorg, U.
Tetrahedron: Asymmetry 2010, 21, 1971. (f) Noel, T.; Bert,
K.; Van der Eycken, E.; Van der Eycken, J. Eur. J. Org.
Chem. 2010, 4056. (g) Jin, L.; Nemoto, T.; Nakamura, H.;
Hamada, Y. Tetrahedron: Asymmetry 2008, 19, 1106.
(h) Cao, Z.; Liu, Y.; Liu, Z.; Feng, X.; Zhuang, M.; Du, H.
Org. Lett. 2011, 13, 2164. (i) Thiesen, K. E.; Maitra, K.;
Olmstead, M. M.; Attar, S. Organometallics 2010, 29, 6334.
(5) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127.
Nu
+
1b, base
solvent
Ph
Ph
Ph
Ph
8
10b–d
Entry Nucleophiles
Products
Yield ee
(%)a
(%)b
O
O
MeO2C
CO2Me
1
96
82
MeO
BnO
OMe
OBn
Ph
Ph
CO2Bn
BnO2C
O
O
2
86
67
80
48
Ph
O
Ph
O
S
Ph
3c
PhSO2Na
Ph
Ph
a Isolated yields.
b The ee value was determined by SFC with a chiral column.
c This reaction was performed in THF without any additional base and
using 1a as the ligand.
When the sterically more hindered 2-methylmalonate was
employed, the product was isolated in excellent yield with
slightly diminished ee value (82%). Benzyl malonate gave
comparable result as the corresponding methyl ester. Un-
der the same reaction conditions, when PhSO2Na was
used as the nucleophile, poor yield and lower ee was ob-
tained (ca. 27%). Interestingly, much better yield and en-
antiomeric excess was obtained (Table 2, entry 3) after
removing the additive LiOAc. It is possible that the lithi-
um ion may act as a Lewis acid that coordinates with the
bicarbonyl group of the malonate substrates.
In summary, a novel class of Evans auxiliary incorporat-
ing imino-type P–N ligands was synthesized from the in-
expensive Evans auxiliary in three steps. This new class of
ligands was successfully applied into palladium-catalyzed
asymmetric allylic alkylation with several nucleophiles,
under the optimal reaction conditions; the desired product
could be obtained in excellent yields and good enantiose-
lectivity. Further improvement and applications in asym-
metric synthesis are in progress and will be reported in
due course.
(6) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc.
1988, 110, 1238.
(7) (a) McLeod, M. C.; Wilson, Z. E.; Brimble, M. A. J. Org.
Chem. 2012, 77, 400. (b) Garcia-Fandino, R.; Codesido, E.
M.; Sobarzo-Sanchez, E.; Castedo, L.; Granja, J. R. Org.
Lett. 2004, 6, 193. (c) Lerm, M.; Gais, H.-J.; Cheng, K.;
Vermeeren, C. J. Am. Chem. Soc. 2003, 125, 9653.
(8) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737.
(9) Hayashi, T.; Hayashi, C.; Uozumi, Y. Tetrahedron:
Asymmetry 1995, 6, 2503.
(10) Bunce, R. A.; Smith, C. L.; Lewis, J. R. J. Heterocycl. Chem.
2004, 41, 963.
Acknowledgment
We thank Dr. Jiangwei Zhang of China Novartis for the MS and
HRMS analytical support. We also thank Dr. Barry Toure for proof
reading this manuscript. Y.L. is grateful for the financial support for
postdoctoral program from the Educational Office of Novartis Insti-
tutes for Bio-Medical Research.
(11) Von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993,
32, 566.
(12) Typical Procedure for the Preparation of 1a
The reaction mixture of 6a (1.75 g, 6.89 mmol) and ZnCl2
(0.188 g, 1.378 mmol) and 4 Å MS (2.0 g) in THF (34.4 mL)
was added 7 (2.00 g, 6.90 mmol) and stirred for 12 h at r.t.
After that, the reaction mixture was filtered and diluted with
CH2Cl2. The organic phase was washed 3 times with H2O
and brine and then separeted and dried over Na2SO4. Organic
phase was then concentrated and chromatographed on silica
Supporting Information for this article is available online at
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1805–1808

1808
Y. Li et al.
LETTER
119.0, 63.5, 61.2, 54.8, 28.6, 17.1, 14.8. 31P NMR (162
MHz, DMSO-d6): δ = –14.3 (s). ESI-MS: m/z = 493.2 [M +
H+]. ESI-HRMS: m/z calcd for C31H30N2O2P [M + H+]:
493.2044; found: 493.2048.
gel, eluted with hexane–EtOAc (2:1) which afford 1a (2.358
g, 65% yield) as a yellowish solid; mp 144–145 °C; [α]D
25
+224 (c 0.76, CHCl3). 1H NMR (400 MHz, DMSO-d6): δ =
8.90 (d, J = 5.0 Hz, 1 H), 8.27 (dd, J = 3.6, 7.4 Hz, 1 H), 7.62
(t, J = 7.5 Hz, 1 H), 7.52 (t, J = 7.4 Hz, 1 H), 7.42 (d, J = 3.3
Hz, 6 H), 7.36–7.16 (m, 11 H), 7.16–7.03 (m, 2 H), 6.93 (dd,
J = 4.8, 7.5 Hz, 1 H), 6.40 (d, J = 7.5 Hz, 1 H), 5.50 (t, J =
8.4 Hz, 1 H), 4.81 (t, J = 8.7 Hz, 1 H), 4.16 (t, J = 8.3 Hz, 1
H). 13C NMR (100 MHz, DMSO-d6): δ = 160.2 (d, J = 22
Hz), 156.7, 148.6, 139.1 (d, J = 5 Hz), 138.8 (d, J = 4 Hz),
138.5, 136.4 (d, J = 5 Hz), 136.3 (d, J = 6 Hz), 134.2 (d, J =
3 Hz), 134.0 (d, J = 3 Hz), 133.6, 132.1, 130.3, 130.0, 129.8,
129.46 (d, J = 1 Hz), 129.4 (d, J = 1 Hz), 129.1, 128.9, 127.9,
126.6, 119.3, 70.5, 62.2. 31P NMR (162 MHz, DMSO-d6):
δ = –14.4 (s). ESI-MS: m/z = 526.2 [M + H+]. ESI-HRMS:
m/z calcd for C34H28N2O2P [M + H+]: 527.1888; found:
527.1882.
(13) General Procedure for the Asymmetric Allylic
Alkylation
To a Schlenk tube containing allyl palladium(II) chloride
dimer (2.90 mg, 0.008 mmol), 1b (15.3 mg, 0.032 mmol),
and LiOAc (2.62 mg, 0.040 mmol) were evacuated and
backfilled with nitrogen for 3 times, after that, THF (2 mL)
was added and stirred for 0.5 h at r.t. Then (E)-1,3-
diphenylallyl acetate (100 mg, 0.396 mmol) was added, and
the mixture was stirred for another 10 min, dimethyl
malonate (157 mg, 1.189 mmol) was added to the reaction
mixture followed by BSA (242 mg, 1.189 mmol). The
resultant mixture was stirred at –10 °C for 10 h. The reaction
was diluted with CH2Cl2 and quenched by sat. aq NH4Cl.
The organic layer was washed by H2O and brine 3 times,
concentrated and purified with silica gel (EtOAc–hexane,
1:10) afforded 10a (121 mg, 99% yield) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.20 (m, 10 H), 6.51–
6.46 (d, J = 15.6 Hz, 1 H), 6.37–6.29 (dd, J = 8.4, 15.9 Hz, 1
H), 4.30–4.24 (dd, J = 8.7, 10.8 Hz, 1 H), 3.98–3.94 (d, J =
10.8 Hz, 1 H), 3.71–3.70 (d, J = 3.0 Hz, 3 H), 3.52–3.51 (d,
3 H, J = 3.3 Hz, 3 H). The ee value was determined by SFC
(Daicel CHIRALCEL AD-H, column size: 0.46 cm I.D. × 25
cm L, liquid CO2/MeOH = 85:15, flow rate: 2.0 mL/min, λ =
254 nm): tR (major) = 8.0 min; tR (minor) = 16.77 min; 87% ee .
Compound 1b: 54%; mp 125–126 °C. [α]D25 +174 (c 1.0,
CHCl3). 1H NMR (400 MHz, DMSO-d6): δ = 8.92 (d, J = 5.0
Hz, 1 H), 8.12 (dd, J = 3.6, 6.9 Hz, 1 H), 7.68–7.53 (m, 1 H),
7.49 (t, J = 7.4 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 6 H), 7.37 (dd,
J = 3.5, 5.8 Hz, 1 H), 7.33–7.19 (m, 6 H), 6.89 (dd, J = 5.0,
6.8 Hz, 1 H), 6.46 (dd, J = 3.5, 5.8 Hz, 1 H), 4.53–4.30 (m,
2 H), 4.18 (dd, J = 4.6, 7.2 Hz, 1 H), 1.78–1.53 (m, 1 H), 0.79
(d, J = 6.8 Hz, 3 H), 0.74 (d, J = 6.8 Hz, 3 H). 13C NMR (100
MHz, DMSO-d6): δ = 159.4 (d, J = 22 Hz), 156.3, 148.1,
138.5, 138.3, 138.2, 135.7 (d, J = 9 Hz), 135.6 (d, J = 9 Hz),
133.6 (d, J = 8 Hz), 133.4 (d, J = 8 Hz), 132.9, 131.5, 130.0,
129.3, 129.2, 128.8 (d, J = 7 Hz), 128.1 (d, J = 4 Hz), 126.2,
Synlett 2012, 23, 1805–1808
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