Minimizing Aryloxy Elimination in RhI-Catalyzed Asymmetric Hydrogenation of β-Aryloxyacrylic Acids using a Mixed-Ligand Strategy

Article abstract of DOI:10.1002/chem.201503229

The first example of efficient asymmetric hydrogenation of challenging β-aryloxyacrylic acids was realized using a Rh^I-complex based on the heterocombination of a readily available chiral monodentate secondary phosphine oxide (SPO) and an achiral monodentate phosphine ligand as the catalyst. Excellent enantioselectivities (92->99% ee) were achieved for a wide variety of chiral β-aryloxypropionic acids with minor aryloxy elimination in most cases. The resultant products were readily transformed into biologically active compounds through simple synthetic manipulations.

Full text of DOI:10.1002/chem.201503229

DOI: 10.1002/chem.201503229
Communication
&
Asymmetric Catalysis
Minimizing Aryloxy Elimination in RhI-Catalyzed Asymmetric
Hydrogenation of b-Aryloxyacrylic Acids using a Mixed-Ligand
Strategy
Yang Li,[a] Zheng Wang,[a] and Kuiling Ding*[a, b]
municate our results on the first example of highly efficient AH
of b-aryloxyacrylic acids, using a RhI catalyst based on the het-
Abstract: The first example of efficient asymmetric hydro-
genation of challenging b-aryloxyacrylic acids was realized
using a RhI-complex based on the heterocombination of
a readily available chiral monodentate secondary phos-
phine oxide (SPO) and an achiral monodentate phosphine
ligand as the catalyst. Excellent enantioselectivities (92–>
99% ee) were achieved for a wide variety of chiral b-ary-
loxypropionic acids with minor aryloxy elimination in most
cases. The resultant products were readily transformed
into biologically active compounds through simple syn-
thetic manipulations.
erocombination of a readily available chiral monodentate sec-
ondary phosphine oxide (SPO) and an achiral monodentate
phosphine ligand. Excellent enantioselectivities (92–>99% ee)
were attained for a variety of chiral b-aryloxypropionic acids
with minor aryloxy elimination in most cases, some of which
were transformed into biologically active compounds through
simple synthetic manipulations.
Secondary phosphine oxide (SPO) has been widely used as
a preligand in a number of transition metal-catalyzed reac-
tions,[9] and recently our group reported the successful applica-
tions of chiral SPO preligands in RhI-catalyzed AH of unsaturat-
ed phosphonic acids and carboxylic acids.[10] These results in-
spired us to explore the feasibility of using a RhI/SPO system
for AH of b-aryloxyacrylic acids. The initial tests for AH of (E)-3-
phenoxycinnamic acid [(E)-1a] using the catalysts generated in
situ from [Rh(cod)2]BF4 (1.0 mol%) and a variety of chiral SPO
ligands (2.0 mol%) only resulted in poor substrate conversions
and low to moderate enantioselectivities for hydrogenation
product 2a, along with a significant amount of byproduct 3a
generated by phenoxy elimination (Table S1 in the Supporting
Information), indicating the challenging nature of this type of
substrates. A breakthrough in catalyst screening was eventually
realized by using chiral/achiral mixed ligands (Tables S2–S4 vs.
S1 in the Supporting Information). We thus decided to test the
mixed-ligand strategy[10b,c,11,12] for AH of (E)-1a using RhI/SPO/
PPh3 (1.0 mol% Rh) as the catalyst. A comprehensive screening
of chiral SPO ligands L1–L6 and achiral triarylphosphine li-
gands (P1–P7), metal/ligand ratios, H2 pressure, base additives,
and solvents (Tables S2 and S3 in the Supporting Information)
disclosed the importance of fine-tuning stereoelectronic prop-
erties of the component ligands and the reaction conditions
for chemo and enantioselectivities of the catalysis. Ultimately,
the 1:1 combination of SPO ligand (S)-L3 with (4-MeOC6H4)3P
(P5) turned out to be the best partners, affording 2a in high
chemoselectivity (2a/3a=90/10) with >99% ee (Scheme 2).
Under the optimized reaction conditions, AH of an array of
(E)- or (Z)-b-aryloxyacrylic acids 1a–v and (Z)-b-methoxyacrylic
acid 1w were investigated with [Rh(cod)2]BF4/(S)-L3/P5 (1:1:1,
1.0 mol% RhI) as catalyst, and the results are summarized in
Table 1. The AH reaction proceeded smoothly to afford the cor-
responding b-aryloxy- or methoxy-propionic acids 2a–w with
generally good to high chemoselectivities (entries 1–26). It is
remarkable that the catalyst system tolerates both electronic
and steric modifications of the substituents on the b,b-posi-
Asymmetric hydrogenation (AH) of b-aryloxy acrylic acids to di-
rectly afford optically active b-aryloxypropionic acids, one type
of key structural element in a broad range of pharmaceuticals,
bioactive compounds, and natural products (Scheme 1),[1–5] re-
Scheme 1. Representative pharmaceuticals, bioactive molecules, and natural
products derived from b-aryloxypropionic acids.
mains largely unexplored probably due to the difficulty associ-
ated with easy aryloxy elimination in the hydrogenation to
give undesired achiral 3-aryl propionic acid derivatives,[6] de-
spite the fact that a number of chiral catalysts have been suc-
cessfully developed for AH of various substituted acrylic acids[7]
including b-alkoxyacrylic amide or esters.[6,8] Herein, we com-
[a] Dr. Y. Li, Dr. Z. Wang, Prof. Dr. K. Ding
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P. R. China)
Fax: (+21)6416-6128
E-mail: kding@mail.sioc.ac.cn
[b] Prof. Dr. K. Ding
Collaborative Innovation Center of Chemical Science and Engineering
(Tianjin), Tianjin 300071 (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503229.
Chem. Eur. J. 2015, 21, 16387 – 16390
16387
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
dent on the extent of aryloxy elimination. It is noteworthy that
under otherwise identical conditions, AH of the (E)- and (Z)-iso-
mers of 1a, 1i, and 1m gave their corresponding products 2a,
2i, and 2m, respectively, with high ee values (>96%) but in
the opposite sense of chiral induction (entries 1 vs. 2, 10 vs. 11,
and 15 vs. 16). Substrate (E)-1s with a heteroaryl 2-thienyl
group at b-position was also hydrogenated smoothly in
CH2Cl2/THF/H2O (7:2:1) as a mixed solvent, affording the corre-
sponding b-thien-2-yl substituted propanoic acid 2s with 97%
ee (entry 22). Furthermore, the AH of substrates with an alkyl
[methyl, (E)-1t–v] or alkoxy [methoxy, (E)-1w] at b-position
have also been successful, affording the corresponding prod-
ucts 2t–v and 2w, respectively, with excellent ee values (en-
tries 23–25 and 26). Finally, the catalyst loading could be low-
ered to 0.1 mol% for AH of (E)-1a under a higher H2 pressure
(50 atm), affording (R)-2a in high yield with 98% ee (entry 27).
To highlight the synthetic utility of the methodology, the ef-
forts were made using the hydrogenation products for the
asymmetric synthesis of some useful chiral molecules, includ-
ing several pharmaceuticals and bioactive flavanoids. Treat-
ment of product (R)-2a with trifluoroacetic acid and trifluoro-
acetic acid anhydride afforded flavanone (R)-5 through Friedel-
Crafts acylation in 84% yield with 98% ee, which upon reduc-
tion with NaBH4 gave the flavanol (2R,4R)-6 in 87% yield and
95:5 d.r. without loss of optical purity (Scheme 3a).[1c] Intramo-
lecular Friedel–Crafts acylation of (R)-2k under similar condi-
tions furnished 5,7-dimethoxyflavanone (R)-7 (97% ee), which,
on selective demethylation using a literature procedure, would
Scheme 2. A heterocombination of chiral SPO with achiral (p-MeOC6H4)3P
(P5) makes a difference in RhI-catalyzed AH of of b-phenoxy-b-phenyl acrylic
acid (E-1a).
Table 1. RhI/(S)-L3/P5-catalyzed AH of b-aryloxyacrylic acids 1a–w.[a]
Entry Substrate R1
R2
2/3
Yield ee
[%] [%]
1
2
3
4
5
6
7
8
9
(E)-1a
(Z)-1a
(E)-1b
(E)-1c
(E)-1d
(E)-1e
(E)-1 f
(E)-1g
(E)-1h
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
90/10 87
88/12 85
92/8 88
90/10 87
83/17 80
77/23 75
77/23 74
70/30 68
81/19 78
94/6 90
92/8 86
90/10 89
>99(R)
96(S)
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
3-IC6H4
2-MeC6H4
2-MeC6H4
2-MeOC6H4
>99(+)
>99(+)
99(+)
98(+)
99(+)
98(R)
98(À)
>99(R)
98(S)
10[b] (E)-1i
11[b] (Z)-1i
12[b] (E)-1j
>99(+)
99(R)
13
14
(E)-1k
(E)-1l
3,5-di-MeOC6H3 90/10 86
1-naphthyl
88/12 85
96/4 94
79/21 77
92/8 89
88/12 85
83/17 81
86/14 82
81/19 77
70/30 67
97/3 92
97/3 94
98/2 94
98/2 93
89/11 87
99(À)
>99(À)
98(+)
>99(À)
>99(+)
95(+)
98(À)
98(+)
97(R)
15[b] (E)-1m
16[b] (Z)-1m
2-MeC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-FC6H4
3,4-di-MeOC6H3 2-MeOC6H4
2-thienyl
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
17
18
19
20
(E)-1n
(E)-1o
(E)-1p
(E)-1q
21[b] (E)-1r
22[b,c] (E)-1s
23[d] (E)-1t
24[d] (E)-1u
25[d] (E)-1v
1-naphthyl
Ph
4-MeOC6H4
1-naphthyl
Me
97(S)
96(+)
98(+)
92(S)
26
(Z)-1w
27[e] (E)-1a
Ph
98(R)
[a] Reaction conditions: [1]=0.125M. All conversions (>99%) and molar
ratios of 2/3 were determined by 1H NMR analysis of the crude reaction
mixtures. The ee values of 2a–w were determined by chiral HPLC analysis
of their corresponding methyl esters 4a–w, and the yields were based on
the isolated 4a–w. [b] 20 mol% morpholine. [c] CH2Cl2/THF/H2O (7:2:1)
was used as the solvent. [d] The free acids (S)-2t–v were isolated. [e] (E)-
1a (0.6 g), 0.1 mol% catalyst loading, H2 (50 atm), 24 h.
Scheme 3. Transformation of the AH products to flavanone (R)-5 and flava-
nol (2R,4R)-6 (a), (R)-Pinostrobin and (R)-Tephrowatsin E (b), (R)-Atomoxeti-
ne (c), and (R)-Duloxetine (d). Conditions: a) i) TFA/TFAA, CH2Cl2, rt, 0.5 h,
84%; ii) NaBH4, THF, rt, 12 h, 87%. b) i) TFA/TFAA, CH2Cl2, rt, 0.5 h, 70%; ii) Pd/
C (10%), H2, MeOH, 10 h, 85%. c) i) MeNH2, HOBt, EDCI, NMM, CH2Cl2, rt,10 h,
84%; ii) BH3, THF, reflux, 5 h, 69%. d) i) NaBH4/I2, THF, rt, 2 h; ii) p-TsCl/NEt3,
CH2Cl2, rt, 24 h, 61% for two steps; iii) MeNH2, THF, reflux, 24 h, 60%.
tions, affording the corresponding b-aryloxy- or methoxypropi-
onates 4a–w in consistently excellent enantioselectivities (92–
>99% ee), albeit with varied isolated yields (67–94%), depen-
Chem. Eur. J. 2015, 21, 16387 – 16390
www.chemeurj.org
16388
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
give (R)-Pinostrobin (Scheme 3b).[14] Hydrogenolytic removal of
ketone oxygen in (R)-7 with Pd/C catalysis under 10 atm H2 af-
2a, providing the circumstantial evidence for the assumed
pathway above. This mechanistic proposal suggests that the
electron density on the Rh atom would have a significant
effect on the bifurcated reactivity of C, and an electron-rich Rh
center in intermediate C should disfavor the formation of D,
and thus may partially depress the phenoxy elimination path-
way. This implication was verified by a comparison of the re-
sults using a heterocombination of a relatively electron-rich tri-
arylphosphine and an electron-poor SPO ligand (Table S4 in
the Supporting Information) and those using electron-poor
SPO ligand alone (Table S1 in the Supporting Information),
with the former often giving less phenoxy elimination products
than the latter. In addition, comparative reaction profile studies
also established that use of the Rh hetero-ligand complex re-
sulted in a substantial rate enhancement compared to the re-
actions using Rh homo-ligand complexes (Figures S7 and S8 in
the Supporting Information), indicating the synergistic effect of
component ligands with push-pull electronic properties.
forded (R)-Tephrowatsin
E in 85% yield with 96% ee
(Scheme 3b). An efficient route to (R)-Atomoxetin[15] has also
been developed through amidation of (R)-2i with MeNH2 fol-
lowed by reduction with borane (Scheme 3c). Finally, (R)-2s
was readily transformed into (R)-Duloxetine[16] through a three-
step sequence without loss of optical purity (Scheme 3d).
It has been disclosed that switch of substrate configuration
from E- to Z- or vice versa allows the access of both enantio-
mers of the products with the same catalyst (entries 1 vs 2, 10
vs 11, and 15 vs 16 in Table 1). This fact implies that the sub-
strate most likely binds to the Rh center in a chelating mode
through its vinyl and carboxylate moieties, so that the catalyst
can effectively differentiate the enantiotopic faces of the
alkene on the basis of the orientation of the carboxylic
group.[10b,13,17] As shown in Scheme 4, a Rh species (complex A)
In conclusion, a range of challenging b-aryloxyacrylic acids
has been hydrogenated with high chemo- and enantioselectiv-
ities using a catalyst generated in situ from [Rh(cod)2]BF4, an
electron-poor chiral SPO ligand (S)-L3, and an electron-rich
achiral triarylphospine ligand [(4-MeOC6H4)3P], affording vari-
ous b-aryloxypropionic acids with minor aryloxy elimination in
most cases. This methodology has also been successfully ap-
plied to the concise synthesis of several bioactive molecules,
including (R)-Duloxetine, (R)-Atomoxetin, (R)-Pinostrobin, and
(R)-Tephrowatsin E. The mechanistic understanding of the ary-
loxy elimination pathway in combination with the impacts of
component ligands on the phenoxy elimination and catalytic
efficiency of the process disclosed in the present work might
stimulate future efforts to address the issue of aryloxy elimina-
tion in the related catalytic systems.
Scheme 4. Plausible mechanistic pathways for the asymmetric hydrogena-
tion and phenoxy elimination. The relative positions of P* and P in the cata-
lytic intermediates are uncertain and might be reversed.
Experimental Section
Typical procedure for [Rh(cod)2]BF4/(S)-L3/(4-MeOC6H4)3P catalyzed
asymmetric hydrogenation of (E)-3-phenoxy-3-phenylacrylic acid
(E)-1a: To a vial containing a suspension of substrate (E)-1a
(0.5 mmol, 1 equiv) in dichloromethane/H2O (2.6/0.4 mL) was
added morpholine (4.4 mL, 0.05 mmol, 0.1 equiv), and the resulting
mixture was stirred at rt for 10 min to form the substrate solution.
Into a Schlenk tube were added chiral monodentate secondary
phosphine oxide preligand (S)-L3 (2.0 mg, 0.005 mmol, 0.01 equiv),
[Rh(cod)2]BF4 (2.0 mg, 0.005 mmol, 0.01 equiv), tris(4-methoxyphe-
nyl)phosphine (P5, 0.005 mmol, 0.01 equiv), and dichloromethane
(1.0 mL) under argon atmosphere. The resulting mixture was
stirred for 10 min at rt to give the precatalyst solution, which was
transferred into the vial containing the substrate solution. The vial
was transferred into a Parr steel autoclave in a glove box. The au-
toclave was sealed and purged three times with hydrogen, before
finally being pressurized to the specified pressure of hydrogen
(25 atm). The reaction mixture was stirred at rt for the specified
period of time (16 h). The hydrogen gas was released in a hood,
and the conversion of (E)-1a and the relative amount of the hydro-
genation and phenoxide elimination products (2a/3a molar ratio)
generated under the catalytic conditions consisting of a hetero-
combination of a chiral SPO (P*) and an achiral phosphine (P)
is most likely an intermediate step to the chiral hydrogenation
product. In fact, ESI-MS analyses of the reaction systems prior
to hydrogenation have unambiguously established the forma-
tion of hetero-ligand Rh complexes in the solution (Figures S2–
S6 in the Supporting Information). The formation of substrate-
bound Rh dihydride B, the transformation of B to an Rh alkyl
intermediate C, and reductive elimination of C to afford the
normal product (R)-2a and regenerate catalyst A follow the
general pathway of Rh-catalyzed hydrogenation of olefins.
However, on the other hand, the ligand substitution of a sol-
vent molecule (S) in C by phenoxy group would give inter-
mediate D, which undergoes b-phenoxy elimination and hy-
drogenation, leading to the formation of the byproduct 3a.
The control experiments (Scheme S1 in the Supporting Infor-
mation) indicate that phenoxy elimination should have oc-
curred through an intermediate inside the catalytic cycle rather
than through an alternative secondary hydrogenation of (R)-
1
were determined by H NMR analysis of an aliquot of the mixture.
The product mixture was esterified with CH2N2 to give the corre-
sponding methyl esters, which were isolated by silica gel chroma-
Chem. Eur. J. 2015, 21, 16387 – 16390
www.chemeurj.org
16389
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[5] a) H. D. Smolarz, E. Mendyk, A. Bogucka-Kocka, J. Kocki, Z. Naturforsch.,
C: J. Biosci. 2006, 61, 64; b) K. J. Hodgetts, Tetrahedron Lett. 2000, 41,
8655.
[6] a) G. W. Stewart, M. Shevlin, A. D. G. Yamagata, A. W. Gibson, S. P. Keen,
J. P. Scott, Org. Lett. 2012, 14, 5440; b) J.-H. Xie, Q.-L. Zhou, Acta Chim.
Sinica 2012, 70, 1427.
[7] For an elegant review, see: S. Khumsubdee, K, Burgess, ACS Catal.
2013, 3, 237.
[8] Y. Zhu, K. Burgess, Adv. Synth. Catal. 2008, 350, 979.
tography (EA/petroleum ether=1/30) to give 4a. The ee of the
product (R)-2a was determined by chiral HPLC analysis of (R)-4a:
colorless oil, 87% yield, >99% ee; [a]D25 =À3.5 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.39–7.37 (m, 2H), 7.32–7.24 (m, 3H),
7.15 (t, J=8.0 Hz, 2H), 6.87–6.84 (m, 3H), 5.63 (dd, J=9.2, 4.4 Hz,
1H), 3.65 (s, 3H), 3.04 (dd, J=15.6, 9.2 Hz, 1H), 2.76 (dd, J=15.6,
4.4 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): d=170.7, 157.6, 140.3,
129.2, 128.6, 127.9, 125.9, 121.1, 116.1, 76.6, 51.7, 43.5 ppm; FTIR
(neat) n=3087, 3063, 3030, 2951, 2845, 1736, 1596, 1587, 1490,
1226, 1165, 1025, 751, 690 cmÀ1; HRMS (ESI) m/z: calcd. for
C16H20NO3+: 274.1438; found: 274.1442 [M+NH4]+.
[9] For reviews, see: a) L. Ackermann, Synthesis 2006, 1557; b) T. M. Shaikh,
C. M. Weng, F. E. Hong, Coord. Chem. Rev. 2012, 256, 771; for a highlight,
see: c) N. V. Dubrovina, A. Bçrner, Angew. Chem. Int. Ed. 2004, 43, 5883;
Angew. Chem. 2004, 116, 6007; for selected examples of transition
metal catalysis with secondary phosphine oxide as the preligands, see:
d) M. T. Reetz, T. Sell, R. Goddard, Chimia 2003, 57, 290; e) J. Bigeault, L.
Giordano, G. Buono, Angew. Chem. Int. Ed. 2005, 44, 4753; Angew.
Chem. 2005, 117, 4831; f) H. Landert, F. Spindler, A. Wyss, H.-U. Blaser, B.
Pugin, Y. Ribourduoille, B. Gschwend, B. Ramalingam, A. Pfaltz, Angew.
Chem. Int. Ed. 2010, 49, 6873; Angew. Chem. 2010, 122, 7025.
[10] a) K. Dong, Z. Wang, K. Ding, J. Am. Chem. Soc. 2012, 134, 12474; b) L.
Yang, K. Dong, Z. Wang, K. Ding, Angew. Chem. Int. Ed. 2013, 52, 6748;
Angew. Chem. 2013, 125, 6880; c) K. Dong, L. Yang, Z. Wang, K. Ding,
Angew. Chem. Int. Ed. 2013, 52, 14191; Angew. Chem. 2013, 125, 14441;
d) K. Dong, Y. Li, Z. Wang, K. Ding, Org. Chem. Front. 2014, 1, 155; e) X.
Liu, Z. Han, Z. Wang, K. Ding, Acta Chim. Sinica 2014, 72, 849.
[11] For an elegant review, see: M. T. Reetz, Angew. Chem. Int. Ed. 2008, 47,
2556; Angew. Chem. 2008, 120, 2592.
[12] For examples, see: a) M. T. Reetz, G. Mehler, Tetrahedron Lett. 2003, 44,
4593; b) M. T. Reetz, O. Bondarev, Angew. Chem. Int. Ed. 2007, 46, 4523;
Angew. Chem. 2007, 119, 4607; c) D. PeÇa, A. J. Minnaard, J. A. F. Boo-
gers, A. H. M. de Vries, J. G. de Vries, B. L. Feringa, Org. Biomol. Chem.
2003, 1, 1087; d) R. Hoen, J. A. F. Booger, H. Bernsmann, A. J. Minnaard,
A. Meetsma, T. D. Tiemersma-Wegman, A. H. M. De Vries, J. G. de Vries,
B. L. Feringa, Angew. Chem. Int. Ed. 2005, 44, 4209; Angew. Chem. 2005,
117, 4281; e) C. Monti, C. Gennari, U. Piarulli, Tetrahedron Lett. 2004, 45,
6859; f) L. Pignataro, B. Lynikaite, R. Colombo, S. Carboni, M. Krupicka,
U. Piarulli, C. Gennari, Chem. Commun. 2009, 3539; g) M. Weis, C.
Waloch, W. Seiche, B. Breit, J. Am. Chem. Soc. 2006, 128, 4188; h) J. Wie-
land, B. Breit, Nat. Chem. 2010, 2, 832; i) M. Kuil, P. E. Goudriaan,
P. W. N. M. van Leeuwen, J. N. H. Reek, Chem. Commun. 2006, 4679; j) P.-
A. R. Breuil, F. W. Patureau, J. N. H. Reek, Angew. Chem. Int. Ed. 2009, 48,
2162; Angew. Chem. 2009, 121, 2196; k) D. J. Frank, A. Franzke, A. Pfaltz,
Chem. Eur. J. 2013, 19, 2405.
Procedure for asymmetric hydrogenation of (E)-1a under a catalyst
loading of 0.1mol%: the procedure was generally similar to that
described above with a slight modification in conditions: (E)-1a=
0.60 g (2.5 mmol), total dichloromethane/H2O (9:1) volume=
8.0 mL, morpholine (0.5 mmol), with hydrogen pressure of 50 atm
and reaction time of 24 h. (R)-4a was isolated in 87% yield with
98% ee.
Acknowledgements
Funding for this project was provided by NSFC (grant nos.:
21121062, 21232009, 91127041), the Chinese Academy of Sci-
ences, and the Science and Technology Commission of Shang-
hai Municipality.
Keywords: asymmetric catalysis · hydrogenation · rhodium ·
secondary phosphine oxide · b-aryloxyacrylic acids
[1] For examples, see: a) A. LØvai, J. Ott, G. Snatzke, Monatsh. Chem. 1992,
123, 919; b) W. H. Miles, E. S. Fialcowitz, H. S. Halstead, Tetrahedron
2001, 57, 9925; c) M. Kawasaki, H. Kakuda, M. Goto, S. Kawabataa, T. Ko-
metani, Tetrahedron: Asymmetry 2003, 14, 1529; d) A. Kamal, G. B. R.
Khanna, R. Ramu, T. Krishnaji, Tetrahedron Lett. 2003, 44, 4783; e) R. K.
Rej, T. Das, S. Hazra, S. Nanda, Tetrahedron: Asymmetry 2013, 24, 913;
f) C. A. Lipinski, C. E. Aldinger, T. A. Beyer, J. Bordner, D. F. Burdi, D. L.
Bussolotti, P. B. Inskeep, T. W. Siegel, J. Med. Chem. 1992, 35, 2169; g) S.
Wang, R. Beck, T. Blench, A. Burd, S. Buxton, M. Malic, T. Ayele, S. Shaikh,
S. Chahwala, C. Chander, R. Holland, S. Merette, L. Zhao, M. Blackney, A.
Watts, J. Med. Chem. 2010, 53, 1465; h) S. Singh, Chem. Rev. 2000, 100,
925; i) J. Zhao, H.-X. Ding, D.-G. Zhao, C.-M. Wang, K. Gao, J. Pharm.
Pharmacol. 2012, 64, 1785; j) A. K. Ghosh, X. Cheng, B. Zhou, Org. Lett.
2012, 14, 5046.
[13] For an example, see: S. Song, S.-F. Zhu, Y.-B. Yu, Q.-L. Zhou, Angew.
Chem. Int. Ed. 2013, 52, 1556; Angew. Chem. 2013, 125, 1596.
[14] a) K. J. Hodgetts, Tetrahedron 2005, 61, 6860; b) C. Valla, A. Baeza, F.
Menges, A. Pfaltz, Synlett 2008, 3167; c) T. Korenaga, K. Hayashi, Y.
Akaki, R. Maenishi, T. Sakai, Org. Lett. 2011, 13, 2022.
[15] For examples of Atomoxetine synthesis, see: a) M. Srebnik, P. V. Rama-
chandran, H. C. Brown, J. Org. Chem. 1988, 53, 2916; b) C. Xu, C. Yuan,
Tetrahedron 2005, 61, 2169.
[2] a) F. P. Bymaster, E. E. Beedle, J. Findlay, P. T. Gallagher, J. H. Krushinski, S.
Mitchell, D. W. Robertson, D. C. Thompson, L. Wallace, D. T. Wong,
Bioorg. Med. Chem. Lett. 2003, 13, 4477; b) J. R. Cashman, S. Ghirmai,
Bioorg. Med. Chem. 2009, 17, 6890.
[16] Y. Suzuki, M. Iwata, R. Yazaki, N. Kumagai, M. Shibasaki, J. Org. Chem.
2012, 77, 4496; and the references therein.
[3] a) A. K. Christman, J. D. Fermo, J. S. Markowitz, Pharmacotherapy 2004,
24, 1020; b) S. Chumpradit, M.-P. Kung, C. Panyachotipun, V. Prapansiri,
C. Foulon, B. P. Brooks, S. A. Szabo, S. Tejani-Butt, A. Frazer, H. F. Kung, J.
Med. Chem. 1992, 35, 4492.
[17] For a related study of phenoxy elimination, see: M. . Chµvez, S. Vargas,
A. Suµrez, E. lvarez, A. Pizzano, Adv. Synth. Catal. 2011, 353, 2775.
[4] For reviews, see: a) A. E. Nibbs, K. A. Scheidt, Eur. J. Org. Chem. 2012,
449; b) J. K. Lin, S. H. Tsai, S. Y. Lin-Shiau, Drugs Future 2001, 26, 145.
Received: August 15, 2015
Published online on October 1, 2015
Chem. Eur. J. 2015, 21, 16387 – 16390
www.chemeurj.org
16390
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim