Phase-transfer catalyzed asymmetric arylacetate alkylation

Article abstract of DOI:10.1016/j.tetlet.2009.05.090

Phenethyl arylacetates are alkylated under phase-transfer conditions with cinchona catalysts with alkyl halides in high yield with excellent enantioselectivity (84-99% ee) following recrystallization. Cinchonidine (CD) derived catalyst gave the (R)-product and cinchonine (CN) catalyst produced the (S)-product. The phenethyl (PE) ester group is removed, using ammonium formate and catalytic Pd/C, to give alkylated carboxylic acid products in high selectivity. The utility of the approach is demonstrated by a direct synthesis of (S)-naproxen.

Full text of DOI:10.1016/j.tetlet.2009.05.090

Tetrahedron Letters 50 (2009) 4541–4544
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Phase-transfer catalyzed asymmetric arylacetate alkylation
*
Merritt B. Andrus , Kaid C. Harper, Michael A. Christiansen, Meisha A. Binkley
Department of Chemistry and Biochemistry, Brigham Young University, C100 BNSN, Provo, UT 84602, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Phenethyl arylacetates are alkylated under phase-transfer conditions with cinchona catalysts with alkyl
halides in high yield with excellent enantioselectivity (84–99% ee) following recrystallization. Cinchoni-
dine (CD) derived catalyst gave the (R)-product and cinchonine (CN) catalyst produced the (S)-product.
The phenethyl (PE) ester group is removed, using ammonium formate and catalytic Pd/C, to give alkyl-
ated carboxylic acid products in high selectivity. The utility of the approach is demonstrated by a direct
Received 5 May 2009
Revised 20 May 2009
Accepted 22 May 2009
Available online 28 May 2009
TM
synthesis of (S)-naproxen .
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Phase-transfer catalysis
Alkylation
Asymmetric synthesis
Phenylacetate phenethyl ester
Cinchona alkaloid catalyst
R*4N+
Asymmetric alkylation is a key transformation for carbon–car-
bon bond formation, typically performed using chiral auxiliaries.1
Recent developments are focused on the development of chiral cat-
alysts with simple achiral substrates. While there have been some
advances, successful examples remain limited. Koga pioneered cat-
alytic enolate alkylation with chiral amine catalysts and cyclic
silylenol ethers.2 Jacobsen and Doyle recently reported selective
O-
O
O
R*4N+
base
Ar
Ar
R'X
Ar
OR
OR
OR
2
R'
1
3
Scheme 1.
stannylenol ether alkylation using chromium-salen catalysis.3
A
droxy products with good selectivity, including applications to the
syntheses of ragaglitazar and kurasoin A.8 2-Acylimidazoles were
subsequently developed as more efficient PTC substrates for asym-
metric glycolate alkylations.9 We now report an approach to ary-
lacetate alkylation performed under simple PTC conditions to
metal-free organocatalytic approach for intramolecular alkylation
was reported using iodo-aldehyde bis-esters by List with meth-
ylproline catalysis.4 SOMO activation of enamine adducts has been
reported by MacMillan for enantioselective alkylation with allylsi-
lanes.5 We now report an approach to asymmetric arylacetate
alkylation using phenethyl esters 1 under mild phase-transfer con-
ditions with cinchona alkaloid-derived catalysts. Reversible eno-
late formation provides non-covalent catalyst interaction via
electrostatic ion-pairing 2. This approach produces a range of prod-
ucts 3 with good selectivity which can be enhanced through simple
recrystallization and is suitable for multi-step applications
(Scheme 1). Following alkylation, the phenethyl moiety can be con-
verted to various products, including the corresponding carboxylic
acid in high yield upon hydrogenolysis.
access both (R)- and (S)-products.
prise a wide range of compounds, many of which possess impor-
tant biological Common approaches for
activity.10
a-Alkylated arylacetates com-
enantioselective arylacetate alkylation rely primarily on chiral
auxiliaries.11 The utility of the new PTC route focusing on naphthyl
acetates is further demonstrated by a synthesis of the nonsteroidal
12
TM
anti-inflammatory agent (S)-naproxen .
Cinchona-derived PTC catalysts were initially screened for reac-
tivity and selectivity including N-arylmethyl cinchonidines 4 and
5, developed previously for PTC glycine alkylation (Scheme 2).6,7
The N-trifluorobenzyl hydrocinchonidine (HCD) catalyst 4 and
the HCD dimer catalyst 5, based on a 2,7-dimethylnaphthalene lin-
ker, proved to be most efficient as previously found with aryl ke-
tone and acyl imidazoles.7f,9 These catalysts are available in three
steps from inexpensive cinchonidine and the complementary
pseudo-enantiomeric cinchonine (CN). The route to 5 reported by
Park and Jew was modified to insure high catalyst purity and to
avoid the production of non-selective ammonium salts formed by
incomplete quinuclidine N-arylmethylation and 2,7-bis-bromo-
Phase-transfer catalyzed (PTC) alkylation, performed under li-
quid–liquid or solid–liquid conditions,6 has become a practical ap-
proach to amino acid synthesis using the well-known
diphenylimine t-butyl glycine ester of O’Donnell.7 We recently re-
ported a PTC alkylation method with aryl ketones to provide a-hy-
* Corresponding author. Tel.: +1 801 422 8171; fax: +1 801 422 0153.
E-mail address: mbandrus@chem.byu.edu (M.B. Andrus).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.090

4542
M. B. Andrus et al. / Tetrahedron Letters 50 (2009) 4541–4544
Table 1
HCD
Br-
Catalyst 5 (10 mol%)
R'X (5 equiv.)
CsOH•H2O (4 equiv.)
O
N+
N+
O
2Br-
2-Nap
R
HCD
HCD
R
F
CH2Cl2, -40 °C, 24 hr
O
O
R'
3
1
F
N
F
N
4
5
Entry
1
R =
R’X
%Yield
73
% ee
0a
Ar
Ar
Br-
CH3
R
R
N
BnBr
N+
N+
N
O
OMe
Ar
Ar
6 Ar=1-naph.
2
3
4
5
BnBr
BnBr
MeI
86
98
0
0
24
0a
8
7 Ar=3,4,5-F3Ph
R=n-butyl
Scheme 2.
O-4-PMB
methyl naphthalene.7e,f,9 Bis-binaphthyl ammonium bromide 6
and the N,N-di-n-butyl catalyst 7, developed by Maruoka and co-
workers,7d,13 were also screened for PTC arylacetate alkylation.
PTC reactions were performed under various conditions for
naphthyl acetate alkylation using 2-naphthyl 1 variations and cat-
alyst CD-5 (Table 1). Solid–liquid conditions were found to be
superior using insoluble cesium hydroxide hydrate as base in
dichloromethane (DCM) at ꢀ40 °C (24 h). Liquid–liquid PTC condi-
tions with aqueous KOH-toluene were unproductive in this case.
With acylimidazole 1 (entry 1), product 3 was produced in moder-
ate yield (73%) and no selectivity (0% ee, chiral HPLC) using either
catalyst 4 or 5 (10 mol %) with benzyl bromide. In contrast, the pre-
viously investigated glycolate acylimidazoles were found to react
with excellent selectivity under these conditions.9 Esters were also
explored and good reactivity in most cases was obtained (entries 2,
3, and 5), however the selectivity was low using benzyl bromide,
allyl bromide, or methyl iodide. The t-butyl ester variant (entry
4) gave no reaction even after extended reaction times (48 h).14
Acyl oxazolidinone (entry 6) showed poor reactivity while the
phenethyl amide (entry 7) showed excellent reactivity (92%) and
low selectivity (34% ee). The related 2-naphthyl acetyl phenethyl
ester (entry 8) showed excellent reactivity (99%) with improved
selectivity (56% ee) for the R-product. Extension of the ester chain
lowered the selectivity and reactivity (entry 9). Extended aromatic
functionality with the 1-naphthyl homolog (entry 10) and the
addition of a second phenyl (entry 11) produced product with
comparable selectivities and lower yields. The 6-methoxynaphthyl
acetyl ester (entry 12) also showed excellent reactivity with mod-
erate selectivity.
O-t-Bu
t-Bu
O
Allyl-Br
54
t-Bu
O
6
7
Allyl-Br
Allyl-Br
Allyl-Br
Allyl-Br
Allyl-Br
Allyl-Br
Allyl-Br
48
92
99
67
78
78
82
8
34
56
28
59
54
43a
O
N
N
Ph
Ph
CH3
8
O
9
Ph
O
1-Nap
Ph
10
11
O
O
Ph
The phenylacetyl phenethyl (PE) ester 1 was also investigated
under the solid–liquid PTC conditions (Scheme 3). With allyl bro-
mide as electrophile the R-product 3 was obtained in 77% yield
with high selectivity, 93% ee using CD-dimer 5. In contrast to pre-
vious arylketone and acylimidazole substrates, which highly favor
Z-enolate intermediates, phenylacetate esters give E and Z enolates
2 with comparable energies.8a
Ph
12
O
a
6-MeO-naphthyl acetate as substrate 1.
O
Additional catalysts and conditions were explored to further
improve the selectivity with naphthyl acetyl ester 1 (Table 2).
Other catalysts, trifluorobenzyl 4, and the binaphthyl ammonium
bromides 6 and 7 were found to produce lower yields and selectiv-
ities using allyl bromide.
Catalyst 5 (10 mol%)
allyl-Br (5 equiv.)
CsOH•H2O (4 equiv.)
CH2Cl2, -40 °C, 8 hr
O
OPE
OPE
3
1
77%, 93%ee
While the naphthyl acetates are limited with only modest selec-
tivities, the crystalline nature of the phenethyl ester products 3 al-
lowed for subsequent recrystallization to provide improved
selectivity in most cases. The naphthyl acetyl phenethyl ester 1
substrate was reacted with various electrophiles under the optimal
conditions using CD-catalyst 5 (Table 3). Allyl bromides reacted
with moderate initial selectivity (entries 1–3). Following recrystal-
Scheme 3.
lization from warm ether/hexanes, selectivities were shown to be
greatly improved (70–93% ee) and overall yields were modest for
this two-step operation, involving chromatography and recrystalli-
zation (63–68%). Benzyl bromides (entries 4–7) produced products
that were obtained in excellent selectivity (92–99% ee) and good

M. B. Andrus et al. / Tetrahedron Letters 50 (2009) 4541–4544
4543
Table 2
1) Sx, p-TsOH
Morph. 98%
2) NaOH, MeOH
3) 2-PhEtOH,
EDCI, i-Pr2NEt
MeO
MeO
O
O
Catalyst (10 mol%)
allyl-Br (5 equiv.)
CsOH•H2O (4 equiv.)
CH2Cl2
O
COCH3
2-Nap
OPE
OPE
Ph
8
2-Nap
76% (2 steps)
9
O
3
HCN
1
2Br-
N+
HCN
HCN
Entry
Cat.
Temp (°C)
Time (h)
%Yield
% ee
O
MeO
1
2
3
4
5
6
4
5
6
7
5
5
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ20
ꢀ60
8
8
8
8
4
72
99
81
52
84
76
48
56
44
46
22
49
N
O
10
(10mol%)
OPE
S
MeI (5 equiv.)
CsOH•H2O (4 equiv.)
CH2Cl2, -30 °C, 23 hr
71%, 92%ee
Me
11
50
MeO
Pd(OAc)2 5mol%
Pd/C
O
S-naproxen™
-
NH4+HCO2
OH
Table 3
Me
91%
[α]D +56°
12
Scheme 4.
O
Catalyst 5 (10 mol%)
RBr (5 equiv.)
CsOH•H2O (4 equiv.)
CH2Cl2, -40°
O
2-Nap
Ph
2-Nap
OPE
O
1
R
3
excellent overall yield. The pseudo-enantiomeric cinchonine (CN)
dimer catalyst 10 was produced using the optimized route devel-
oped for CD-5. PTC methylation now using 10 under the solid–li-
quid conditions with methyl iodide (23 h) gave product (S)-11,
initially in 99% yield (64% ee, 230 mg scale). Recrystallization
(Et2O/hex.) gave 11 in 71% overall yield with 92% ee. Notably this
methylated product 11 is produced with high selectivity using
the CN catalyst to give the complementary S-product. The PE ester
was converted to the carboxylic acid 12 using the reported condi-
tions of Carpino (Pd(OAc)2, Pd/C 5 mol %) with ammonium formate,
/ recryst. Et2O/hex.
Entry
1
RBr
Time (h)
47
Crude % ee
46
% Yielda
63
% ee
93
Br
2
3
26
28
57
59
68
68
86
70
Br
Br
91% yield, ½a D
ꢁ
+56.16
Commercially obtained S-naproxen 12 was independently con-
verted to the PE ester 11 and the optical rotation and the chiral
Br
Br
4
5
6
28
23
28
27
48
71
89
63
81
72
81
73
97
99
92
94
Br
HPLC trace were compared with the PTC-derived product (½a D
ꢁ
+27.5 to +29 for PTC-derived 11). The comparable selectivity, (R)-
product from CD and (S)-product from CN catalyst, suggests a com-
plementary mode of interaction for the enolate 2 and the pseudoe-
nantiomeric catalysts. Selectivities for previous glycolate
substrates were not complementary, where CD catalysts gave (S)-
products and the CN catalyst also produced (S)-products but with
much lower selectivity.8 A kinetic effect with preferential eno-
late-catalyst pairing and alkylation, via E or Z-2, may also be oper-
ative in this case.
t-Bu
Ph
Br
Br
7
8
Arylacetate PTC alkylation is a general approach to enantioen-
riched a-alkylated products using simple substrates and catalysts.
Complementary enantiomeric products are produced from either
CD or CN catalysts in high selectivities following recrystallization.
The phenethyl ester products are readily converted to useful
products.
MeI
18
19
55
43
71
62
92
Br
9
85b
a
Yields shown are for products purified by short-path silica gel chromatography
and recrystallized from ether/hexanes.
Acknowledgments
b
6-MeO-naphthyl acetate as substrate 1.
We are grateful for support provided by the American Chemical
Society, Petroleum Research Fund-AC (41552-AC1), Research Cor-
poration Research Opportunity Award, and the Brigham Young
University Cancer Research Center. We are also grateful to Erik J.
Hicken, David T. Harris, Jeffrey C. Stephens, D. Karl Bedke, and Mor-
gan J. Gainer for preliminary experiments.
overall yields (72–81%). Reaction with methyl iodide (entry 8) also
gave high selectivity (92% ee) with modest overall yield (71%) for
the R-product 3. The 6-methoxynaphthyl acetyl PE ester (entry 9)
showed good reactivity and selectivity (85% ee).
A short, five-step synthesis of the well-known anti-inflamma-
TM
tory agent (S)-naproxen was performed to demonstrate utility of
Supplementary data
aryl acetate PTC (Scheme 4).12 The requisite aryl acetyl PE ester
was generated from 2-acetyl-6-methoxynaphthalene 8. Willg-
erodt–Kindler reaction with precipitated sulfur, p-TsOH, and mor-
pholine gave the acetylthioamide, which was hydrolyzed to the
corresponding acid.15 Esterification generated phenethyl 9 in
Supplementary data (experimental procedures, characteriza-
tion, and NMR and HPLC data for all compounds) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.05.090.

4544
M. B. Andrus et al. / Tetrahedron Letters 50 (2009) 4541–4544
8. (a) Andrus, M. B.; Hicken, E. J.; Stephens, J. C.; Bedke, D. K. J. Org. Chem. 2005, 70,
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