Asymmetric catalytic arylation of ethyl glyoxylate using organoboron reagents and Rh(i)-phosphane and phosphane-phosphite catalysts

Article abstract of DOI:10.1039/c3ra47000h

Herein we report the first application of Rh(i)-phosphane and phosphane-phosphite catalysts in the enantioselective catalytic arylation of ethyl glyoxylate with organoboron reagents, providing access to ethyl mandelate derivatives in high yield (up to 99%) and moderate to very good enantioselectivities (up to 75% ee). Commercial phosphane ligands, such as (R)-MonoPhos and (R)-Phanephos were tested, as well as non-commercial (R,R)-TADDOL-derived phosphane-phosphite ligands. Those ligands containing bulky substituents in the ortho-and para-positions of the chiral phosphite moiety were found to be the most selective.

Full text of DOI:10.1039/c3ra47000h

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PAPER
Asymmetric catalytic arylation of ethyl glyoxylate
using organoboron reagents and Rh(I)–phosphane
and phosphane–phosphite catalysts†
Cite this: RSC Adv., 2014, 4, 6035
Carolina Silva Marques,a Mehmet Dindaroglu,b Hans-Gunther Schmalzb
˘
¨
a
*
and Anthony J. Burke
Herein we report the first application of Rh(I)–phosphane and phosphane–phosphite catalysts in the
enantioselective catalytic arylation of ethyl glyoxylate with organoboron reagents, providing access to
ethyl mandelate derivatives in high yield (up to 99%) and moderate to very good enantioselectivities (up
to 75% ee). Commercial phosphane ligands, such as (R)-MonoPhos and (R)-Phanephos were tested, as
well as non-commercial (R,R)-TADDOL-derived phosphane–phosphite ligands. Those ligands containing
bulky substituents in the ortho-and para-positions of the chiral phosphite moiety were found to be the
most selective.
Received 25th November 2013
Accepted 16th December 2013
DOI: 10.1039/c3ra47000h
www.rsc.org/advances
Introduction
The formation of C–C bonds, despite its long history and interest
to organic chemists, still remains a challenge. Our group has
worked exhaustively on this transformation as a means to easily
access important key structural units, present in biologically
active compounds, such as chiral amines,1a–c a-hydroxyesters,1d,e
and a-amino acids.1f With regard to the synthesis of a-hydrox-
yesters – which are structural moieties widespread in natural
products2 – our group has been a pioneer in the implementation
of the catalytic arylation of glyoxylates with Rh(I)–NHC catalysts
giving mandelate derivatives in excellent yields. Unfortunately,
the principle downside was the moderate enantioselectivities
that were achieved (up to 34% ee).1e
There is still an ever increasing demand for single enan-
tiomer products. Over the past few decades, phosphorous-based
ligands, which are almost indispensable in asymmetric organ-
ometallic catalysis,3 have been used with much success in a
plethora of transformations, including the catalytic addition of
the phenyl group to activated imine substrates1b and aldehydes4
with the aid of organoboron reagents. Phosphite ligands are a
very important class of phosphorous ligands, which were
successfully applied in the Rh-catalyzed hydroformylation of
aldehydes5 and in Cu-catalysed 1,4-additions6 as well as in
several other asymmetric catalytic transformations.7 Some of us
Fig.
1 General structure of the modular phosphane–phosphite
ligands introduced by Schmalz's group.10
have recently developed a class of modular chiral phosphane–
phosphite ligands (Schmalz ligands), prepared from TADDOL8
and TARTROL9 building blocks (Fig. 1), and which have been
used in several transition metal-catalysed reactions.10 We
decided to test these ligands for the rst time, in the transition
metal-catalysed arylation of ethyl glyoxylate, using organoboron
reagents and Rh(I) pre-catalysts.
Results and discussion
a
´
´
´
Department of Chemistry and Centro de Quımica de Evora, University of Evora, Rua
´
˜
Romao Ramalho 59, 7000 Evora, Portugal. E-mail: ajb@dquim.uevora.pt; Fax: +351
Miyaura and co-workers already reported a non-asymmetric
rhodium-catalysed addition of organoboronic acids to alde-
hydes using several racemic phosphane ligands.11a,b With regard
to the synthesis of mandelate derivatives, Francesco and co-
workers reported a non-asymmetric Suzuki–Miyaura coupling
266 745 303; Tel: +351 266 745 311
bDepartment of Chemistry, University of Cologne, Greinstrasse 4, 50939 Koln,
¨
Germany
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra47000h
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Table 1 Rh(I) catalysed enantioselective arylation of ethyl glyoxylate
with phenylboronic acid
reaction of organoboronic acids and ethyl glyoxylate using Pd(0)
catalysts.12 In 2012, Yamamoto and co-workers reported the
addition of arylboronic acids to ethyl glyoxylate catalysed by a
Ru/Me–BIPAM complex, giving mandelate derivatives in high
yields and enantioselectivities.13
Based on our previous work on the synthesis of ethyl man-
delate derivatives using Rh(I)–NHC catalysts,1d,e and our
unsuccessful attempts at obtaining high enantioselectivities, we
initiated a focused program at screening various chiral phos-
phorous ligands in an attempt at increasing the enantiose-
lectivities. The study was based on the same methodology
previously employed1d,e and besides the commercial bidentate
phosphane ligands (Fig. 2): (R)-Phanephos (1), commonly used
for asymmetric hydrogenations,14 (R,R)-Chiraphos (2), (R)-
MonoPhos (3) and other phosphoramidite type derivatives (4)
and (5) were also employed. The results can be seen in Table 1.
In the case of (R)-Phanephos (1) (Fig. 2), full conversion into
ethyl mandelate was observed (Table 1, entry 1) but with poor
enantiocontrol (<5% ee). Rh(acac)(C2H4)2 is a pre-catalyst,
which was already applied with success by Hayashi's group in
the rhodium-catalyzed asymmetric 1,4-addition of aryl- and
alkenylboronic acids to enones.15a When we used this pre-
catalyst, only a moderate yield and a poor enantioselectivity was
obtained (Table 1, entry 2). By testing the same reaction
conditions at room temperature in an attempt to improve the
enantioselectivity, a good enantioselectivity of 75% ee was
obtained, unfortunately with a low yield (see Table 1, entry 3).
We decided to test the less bulkier commercial (R,R)-Chiraphos
(2) ligand (Fig. 2) using the same reaction conditions, since it
was successfully applied by Miyaura's group for the conjugate
addition of organoboron, organosilicon, and organobismuth
reagents to a,b-unsaturated ketones.11c The reaction was non-
enantioselective, and the racemic ethyl mandelate product was
obtained, with moderate yield (48% yield) (see Table 1, entry 4).
Inspired by the work developed by Yamamoto and co-
workers,13 we decided to use the chiral commercial phosphor-
amidite ligand (R)-MonoPhos (3) (Fig. 2) under these reaction
conditions. These ligands reported by Feringa's group were
shown to be privileged in several asymmetric catalytic reac-
tions.16 Excellent yields were obtained with this ligand, using
several Rh(I) pre-catalysts (see Table 1, entries 5 to 8), but only
Entrya
Rh(I)
Ligand
Yieldb/%
eec/%
1
[Rh(COD)OH]2
Rh(acac)(C2H4)2
Rh(acac)(C2H4)2
[Rh(COD)OH]2
[Rh(COD)OH]2
Rh(COD)2BF4
[Rh(COD)Cl]2
Rh(acac)(C2H4)2
[Rh(nbd)Cl]2
1
>99
66
12
<5
2
<10 (R)
75 (R)
<5
19 (S)
10 (S)
<10 (S)
26 (S)
28 (S)
23 (S)
19 (S)
3d
4
2
3
48
5
6
7
8
9
10
11
>99
>99
>99
>99
33
[Rh(COD)OH]2
[Rh(COD)OH]2
4
5
>99
>99
a
Reaction conditions: 1.5 mol% [Rh(I)]2 or 3 mol% [Rh(I)], 3.3 mol%
Ligand, 2 equivalents PhB(OH)2, 2 equivalents KOtBu, 1 ml t-amyl
b
alcohol, 100 ml ethyl glyoxylate. Isolated yield aer silica gel
c
chromatography. Determined by chiral stationary phase HPLC.
d
Reaction run at room temperature.
low enantioselectivities were observed. Since this reaction
appeared to be highly dependent on the rhodium complex, the
bulky Rh(I) pre-catalyst [Rh(nbd)Cl]2 was tested with this ligand
(Table 1, entry 9), but only a 33% yield was obtained and an
enantioselectivity of only 28% ee with (R)-MonoPhos (3). In a
nal attempt to improve the enantioselectivity, we decided to
test the commercial chiral MonoPhos derivatives (4) and (5)
(Fig. 2). Full conversion to the ethyl mandelate product was
obtained, but the enantioselectivity was poor (see Table 1,
entries 10 and 11).
Recently we have successfully developed a family of phos-
phane–phosphite chiral ligands containing the TADDOL back-
bone, which were evaluated in this work in catalytic arylation
reactions with organoboron reagents and transition metal
catalysts. The ligands are schematized in Fig. 3.10
Zhou and co-workers reported the rst asymmetric Rh
spirophosphite-catalysed addition of arylboronic acids to
a-ketoesters in aqueous media.17 At this point, we decided to
use our TADDOL-phosphane–phosphite ligands (see Fig. 3),
Fig. 2 Commercial phosphorous containing ligands.
6036 | RSC Adv., 2014, 4, 6035–6041
Fig. 3 (R,R)-TADDOL-derived chiral phosphane–phosphite ligands.10
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along with [RhCl(C2H4)2]2 and Rh(acac)(C2H4)2 pre-catalysts (Table 2, entries 1, 4, 6, 10, 12 and 14, ranging from 44–61% ee).
and NaF as additive, in toluene and water. The application of The lowest enantioselectivity value obtained with the use of this
inorganic uorinated bases seemed to improve signicantly the Rh-pre-catalyst and the less bulky TADDOL-phosphane–phos-
yield.1f,17 The results are shown in Table 2. Generally, moderate phite ligand (7) was 23% ee (Table 2, entry 3). So, it seems that
to excellent yields were obtained with [RhCl(C2H4)2]2 (see the size of the substituents on the phenyl ring in the ligand
Table 2, entries 3, 4, 8, 10 and 12). This Rh pre-catalyst type has backbone has an effect on the reaction enantioselectivity.
already been used successfully in several catalytic reactions.18
No big difference between aliphatic and aromatic substitu-
Despite its successful application in several other catalytic ents was observed, for example compare ligand (8) with (10)
reactions,15 the use of Rh(acac)(C2H4)2 leads to a signicant (Table 2, entries 4 and 8), where the enantioselectivities
decrease in the reaction yield (see Table 2, entries 2, 11, 13 and obtained were practically the same. The (S)-enantiomer of the
15). Apparently, the substitution pattern on the aromatic moiety ethyl mandelate product was the major isomer obtained in most
of the TADDOL-derived phosphane–phosphite ligand backbone of the reactions.
(see Fig. 3) doesn't seem to have a pronounced inuence on the
Aer these preliminary test studies, we decided to select
efficiency of the reaction. A maximum enantioselectivity of 69% [RhCl(C2H4)2]2 as the pre-catalyst and the TADDOL-phosphane–
ee was obtained for the arylation of ethyl glyoxylate with Rh(a- phosphite ligands (8) and (12) (see Fig. 3) for further studies.
cac)(C2H4)2 and the TADDOL-phosphane–phosphite ligand (10) The use of different phenyl-organoboron sources and bases was
(Table 2, entry 17). It seems that there is a slight temperature evaluated. The results can be seen in Table 3.
effect on the reaction enantioselectivity, since on conducting
The highest obtained enantioselectivity was 56% ee with
ꢀ
the experiment at 50 C and room temperature no signicant C9H11BO2. It was observed that the yields for the ethyl man-
difference was noted (Table 2, compared entries 9 and 17), but delate product decreased signicantly (Table 3). In fact, the
when the experiment was conducted at 0 ꢀC there was a more anhydrous arylboron reagents, like potassium tri-
signicant difference in the enantioselectivity and in the yield uoro(phenyl)borate (PhBF3K), triphenylborane (Ph3B), sodium
(Table 2, compare entries 9 and 17 with entry 18). In general, the tetraphenylborate (Ph4BNa) and 1,3-propanediol boronic ester
use [RhCl(C2H4)2]2 afforded the highest enantioselectivities (C9H11BO2) (Table 3, entries 1 to 4, respectively), previously
evaluated in the enantioselective arylation of activated imines
with Ru catalysts,1c gave poorer results than phenylboronic acid,
and thus phenylboronic acid was identied as the organoboron
reagent of choice in this reaction (compare Table 2 with Table
Table 2 Rh(I)–phosphane–phosphite enantioselective catalytic ary-
lation of ethyl glyoxylate with phenylboronic acid
Table 3 Screening of different phenyl-organoboron reagents and
bases in the Rh(I)–phosphane–phosphite enantioselective arylation of
ethyl glyoxylate
Entrya
Rh(I)
Ligand (Fig. 3)
Yieldb/%
eec/%
1
2
3
4
5
6
7
8
[RhCl(C2H4)2]2
Rh(acac)(C2H4)2
[RhCl(C2H4)2]2
[RhCl(C2H4)2]2
Rh(acac)(C2H4)2
[RhCl(C2H4)2]2
Rh(acac)(C2H4)2
[RhCl(C2H4)2]2
Rh(acac)(C2H4)2
[RhCl(C2H4)2]2
Rh(acac)(C2H4)2
[RhCl(C2H4)2]2
Rh(acac)(C2H4)2
[RhCl(C2H4)2]2
Rh(acac)(C2H4)2
[RhCl(C2H4)2]2
Rh(acac)(C2H4)2
Rh(acac)(C2H4)2
6
88
26
93
>99
79
36
92
>99
90
89
33
>99
23
43
17
57
51 (S)
14 (S)
23 (S)
60 (S)
60 (S)
49 (S)
30 (S)
57 (S)
67 (S)
61 (S)
15 (S)
56 (S)
33 (R)
44 (S)
26 (R)
10 (S)
69 (S)
51 (S)
7
8
Entrya
Ligand (Fig. 3)
PhB
Base
Yieldb/%
eec/%
9
1
2
3
4
5
6
7
8
12
PhBF3K
Ph3B
Ph4BNa
NaF
NaF
NaF
NaF
KF
CsF
KHF2
KPF6
ZnF2
LiF
NaOH
K3PO4
K2CO3
KHF2
12
35
36
38
18
25
<10
33
70
45
14
17
26
11
50 (S)
40 (S)
<5
56 (S)
15 (S)
24 (R)
<5
32 (R)
23 (R)
11 (R)
43 (S)
47 (S)
52 (S)
28 (S)
10
11
12
13
10
9
C9H11BO2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
10
11
12
13
14
15
16d
17d
18e
9
10
11
12
13
14
8
>99
18
a
Reaction conditions: 1.5 mol% [RhCl(C2H4)2]2 or
mol% Ligand,
equivalents NaF, 2 ml solvent, 100 ml ethyl glyoxylate. Isolated yield
3
mol%
Rh(acac)(C2H4)2,
6
2 equivalents PhB(OH)2, 2
b
a
Reaction conditions: 1.5 mol% [RhCl(C2H4)2]2, 6 mol% Ligand, 2
c
aer silica gel chromatography. Determined by chiral stationary equivalents phenyl-organoboron reagent, 2 equivalents base, 2 ml
phase HPLC. Reaction run at room temperature. Reaction run at solvent, 100 ml ethyl glyoxylate. Isolated yield aer silica gel
0
d
e
b
ꢀC.
chromatography. c Determined by chiral stationary phase HPLC.
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3). In the case of the base, NaF was undoubtedly the right choice were evaluated. Method A consisted in the use of Rh(a-
(compare Table 2, entry 12 with Table 3, entries 5 to 10 and cac)(C2H4)2 along with (R)-MonoPhos ligand (3) (Fig. 2), KOtBu
Table 2, entry 4 with Table 3, entries 11 to 14). Curiously, when as base and t-amyl-alcohol as solvent (optimized conditions
other uoride derivatives like CsF, ZnF2 or LiF where used, the from Table 1). Method B consisted in the use of [RhCl(C2H4)2]2
major enantiomer of ethyl mandelate was determined to have along with (R,R)-TADDOL-phosphane–phosphite ligands (8)
the (R) absolute conguration, contrary to when NaF was used and (11) (Fig. 3), with NaF as base in toluene and water (4/1)
(see Table 2). At this juncture, we do not have a plausible (optimized conditions from Table 2). In general, method A
explanation to account for these facts. We decided to screen afforded the best results (Table 5, entries 5, 7, 11, 13, 15 and 16).
other commercially available Rh(I) pre-catalysts, including With the exception of 2-naphthylboronic acid and 4-uo-
screening various solvents, using our optimized procedure (see rophenylboronic acid, which worked better in the case of
Table 2, entry 17). The results are given in Table 4.
method B (Table 5, entries 4 and 10). As regards electronic
The results were quite disappointing, since in general both effects, apparently no signicant differences were found when
yield and enantioselectivity decreased signicantly (compare electron-withdrawing or electron-donating substituents were
Table 2, entry 17 with Table 4, entries 1 to 5). Curiously, upon present in the phenyl ring of the organoboron reagent (see
using acetone as solvent, the absolute conguration of the Table 5, compare for instance entry 8 with entry 12, and entry 1
major product enantiomer switched from (S) to (R) (Table 4, with entry 3). On the other hand, the reaction seems to suffer
entry 4, last column). Toluene was undoubtedly the solvent of from steric hindrance. For instance, in the case of 1 or
choice for this transformation. We decided to evaluate the effect 2-naphthylboronic acid method A worked best for the former
of silver salts on this transformation, since we already reported and method B for the latter (Table 5, compare entries 4 and 12
their success in similar arylation reactions using organoboron (method B)). The reaction enantioselectivity was generally poor,
reagents.1c In fact, a pronounced counter-ion effect was noted
since there was an increase in both the yield and the enantio-
selectivity (Table 4, compare entries 5 and 6). To evaluate the
Table 5 Reaction scope for the Rh(I)-catalytic arylation of ethyl
effect of AgBF4 on the reaction, we decided to test it using all the glyoxylate with various arylboronic acidsa
Rh pre-catalysts and ligand (8) (Fig. 3). [Rh(nbd)Cl]2 gave
the best balanced overall results.
In order to probe the reaction scope, we decided to screen
several arylboronic acids bearing electron-donating and elec-
tron-withdrawing substituents in the ortho, meta and para-
positions of the phenyl ring (Table 5). Two methods (A and B)
Table 4 Solvent and catalyst screening study for the Rh(I)-catalysed
enantioselective arylation of ethyl glyoxylate
Entrya
R
(14)
a
Method
Yieldb/%
eec/%
<10
13
<5
1
3-AcC6H4
2-Naphthyl
4-ClC6H4
3-MeOC6H4
4-FC6H4
1-Naphthyl
2-Furyl
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
A
A
16
<10
16
82
23
13
32
11
18
50
76
12
71
39
30
18
Traces
2d
3
b
4d
5
35
c
32 (S)
12 (S)
<5
29
<5
28 (R)
14
55
<10
<10
n.d.
6d
7
d
e
Entrya
Rh(I)
Solvent
Yieldb/%
eec/%
8d
9
10e
11
12e
13
14e
15
16
17
1
2
3
4
Rh(acac)(C2H4)2
Rh(acac)(C2H4)2
Rh(acac)(C2H4)2
Rh(acac)(C2H4)2
[RhCl(COD)]2
[RhCl(COD)]2
Rh(acac)(C2H4)2
[RhCl(C2H4)2]2
[Rh(nbd)Cl]2
THF
1,4-Dioxane
DME
Acetone
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
27
25
0
14
46
70
9
16
24
43
54 (S)
37 (S)
—
35 (R)
<5
37 (R)
41 (S)
60 (S)
54 (S)
61 (S)
f
g
5
6e
2-MeOC6H4
4-MeOC6H4
3-NH2C6H4
h
i
j
7d,e,f
8d,e,f
9d,f
10d,e,f
15
n.d.
a
Reaction conditions: Method A: 3 mol% Rh(acac)(C2H4)2, 3.3 mol% (R)-
MonoPhos (3), 2 equivalents R–B(OH)2, 2 equivalents KOtBu, 1 ml t-
[Rh(nbd)Cl]2
a
Reaction conditions: 1.5 mol% [Rh(I)]2 or 3 mol% [Rh(I)], 6 mol% amyl alcohol, 100 ml ethyl glyoxylate. Method B: 1.5 mol%
Schmalz Ligand (10), 2 equivalents PhB(OH)2, 2 equivalents NaF, 2 ml [RhCl(C2H4)2]2, 6 mol% Ligand (8) or (11), 2 equivalents R–B(OH)2, 2
b
b
solvent, 100 ml ethyl glyoxylate. Isolated yield aer silica gel equivalents NaF, 2 ml solvent, 100 ml ethyl glyoxylate. Isolated yield
c
c
chromatography. Determined by chiral stationary phase HPLC. aer silica gel chromatography. Determined by chiral stationary
d
e
d
e
Reaction run at 50 ꢀC. 3.3 mol% AgBF4 was added to the reaction phase HPLC. Ligand (8) was used. Ligand (11) was used. n.d. ¼ not
vessel. f Ligand (8) was used.
determined.
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(Table 5, last column), but the highest enantioselectivity (55% 0.98 mmol), KOtBu (1 equiv., 0.49 mmol), and t-amyl alcohol
ee) was obtained with the 1-naphthylboronic acid reagent (1 ml) were added sequentially. Finally, ethyl glyoxylate (50% in
(Table 5, entry 12).
toluene, 0.49 mmol, 100 ml) was added and the reaction was
stirred at the desired temperature, and monitored by TLC. The
crude mixture was passed through a porous ceramic glass lter
and eluted with CH2Cl2. The solvents were concentrated under
reduced pressure and the residue puried by liquid chroma-
tography (SiO2 gel, hexane/AcOEt (5/1)), yielding the desired
ethyl mandelate derivative product.
Conclusions
We have developed an efficient Rh(I)-catalysed glyoxylate aryla-
tion reaction allowing the synthesis of mandelate derivatives in
excellent yields and good enantioselectivities (up to 75% ee for a
virtually unexplored reaction). This procedure was applied for
the rst time with chiral phosphorous-containing Rh(I) cata-
lysts. Several ethyl mandelate derivatives were synthesized,
using two different catalytic protocols. We are currently devel-
oping an intra-molecular version of this reaction in order to
access families of very interesting pharmacologically active
chiral cyclo-alkanol compounds for HTS studies.
Method B. [RhCl(C2H4)2]2 (1.5 mol%, 7.34 ꢂ 10ꢁ3 mmol) or
Rh(acac)(C2H4)2 (3 mol%, 0.015 mmol) was added to a round
bottom ask, under a nitrogen atmosphere. The chiral TAD-
DOL-phosphane–phosphite ligands (6 mol%, 0.030 mmol) and
toluene (1.6 ml) were added to the reaction vessel. The mixture
ꢀ
was stirred at 50 C during 30 minutes, which was followed by
the sequential addition of the arylboronic acid or derivative
(2 equiv., 0.98 mmol), NaF (2 equiv., 0.98 mmol), and water (0.4
ml). Finally, ethyl glyoxylate (50% in toluene, 0.49 mmol, 100 ml)
was added and the reaction was stirred at the desired temper-
ature, and monitored by TLC. The reaction was quenched with
water (10 ml) and extracted with AcOEt (3 ꢂ 10 ml). The
combined organic layers were dried with anhydrous MgSO4,
ltered and concentrated under reduced pressure. The crude
residue was puried by liquid chromatography (SiO2 gel,
hexane/AcOEt (5/1)), yielding the desired ethyl mandelate
derivative product.
Experimental
General procedures
All the reagents were obtained from Aldrich, Fluka, Acros and
Alfa Aeser. The solvents used were dried using current laboratory
techniques.19 All the reagents applied in this work were used as
received. All reactions were conducted under a nitrogen atmo-
sphere. Column chromatography was carried out on silica gel
(sds, 70–200 mm). Thin layer chromatography (TLC) was carried
out on aluminium backed Kiselgel 60 F254 plates (Merck). Plates
were visualized either by UV light or with phosphomolybdic acid
in ethanol. The NMR analyses were recorded on a Bruker Avance
instrument (400 MHz) using CDCl3 as solvent and the signal from
the residual CHCl3 as an internal standard. Mass spectra were
recorded on a Waters-Micromass instrument (MaldiTOF, Micro-
TOF, ESI). High performance liquid chromatographic (HPLC)
analyses were performed with an Agilent 1100 series instrument.
The conditions used were, ux ¼ 1 ml minꢁ1, detector ¼ wave-
length light (l ¼ 210 nm), eluent ¼ hexane/2-propanol (90/10),
and column ¼ Chiralcel OD-H (0.46 cm ꢂ 25 cm) tted with a
guard column composed of the same stationary phase. Racemic
mixtures were prepared using the followed procedure:
[RhCl(COD)]2 (1.5 mol%, 7.34 ꢂ 10ꢁ3 mmol) was added to a
round bottom ask, under an inert atmosphere. PPh3 (3.3 mol%,
0.015 mmol), arylboronic acid (2 equiv., 0.98 mmol), KOtBu
(1 equiv., 0.49 mmol) and t-amyl alcohol (1 ml) were added
sequentially. Finally, ethyl glyoxylate (50% in toluene, 0.49 mmol,
100 ml) was added and the reaction was stirred at 60 ꢀC, and
monitored by TLC. The crude mixture was passed through a
porous ceramic glass lter and eluted with CH2Cl2. The solvents
were concentrated under reduced pressure and the residue
puried by liquid chromatography (SiO2 gel, hexane/AcOEt (5/1)),
yielding the desired racemic ethyl mandelate derivative product.
Ethyl mandelate:.1d,e Colorless oil. 1H NMR (CDCl3, 400 MHz)
d ppm: 1.21 (m, 3H, CH3), 3.56 (br s, 1H, OH), 4.17–4.26 (m, 2H,
CH2), 5.16 (s, 1H, CH), 7.34–7.42 (m, 5H, Ar). 13C NMR (CDCl3,
100 MHz) d ppm: 14.14, 62.33, 73.01, 126.63, 128.49, 128.66,
138.53, 173.76. HPLC: tR: 7.4 min (S) and 12.1 min (R).
Ethyl 2-(3-acetylphenyl)-2-hydroxyacetate (12a):.1d,e Colorless
oil. 1H NMR (CDCl3, 400 MHz) d: 1.25 (m, 3H, CH3), 2.62 (s, 3H,
CH3 (Ac)), 4.19–4.41 (m, 2H, CH2), 5.35 (s, 1H, CH), 7.32–7.66
(m, 2H, Ar), 7.69–8.04 (m, 2H, Ar). 13C NMR (CDCl3, 100 Hz) d:
14.03, 22.62, 62.83, 72.39, 128.41, 128.66, 129.01, 131.30,
137.55, 139.17, 173.06, 198.14. ESI-TOF MS (m/z) 223.10 (M + 1).
HPLC: tR: 18.5 min and 20.9 min.
Ethyl 2-hydroxy-2-(naphthalen-2-yl)acetate (12b):.1d,e White
solid. 1H NMR (CDCl3, 400 MHz) d: 1.20 (m, 3H,CH3), 3.71 (br s,
1H, OH), 4.13–4.19 (m, 1H, CH2), 4.21–4.30 (m, 1H, CH2), 5.33
(s, 1H, CH), 7.47–7.54 (m, 3H, Ar), 7.83–7.85 (m, 3H, Ar), 7.91 (s,
1H, Ar). 13C NMR (CDCl3, 100 MHz) d: 14.45, 62.40, 73.08,
124.17, 125.90, 126.06, 126.33, 127.91, 128.34, 128.62, 133.28,
133.38, 135.89, 173.84. ESI-TOF MS (m/z): 213.10 (–OH), 231.10
(M + 1). HPLC: tR: 11.0 min and 13.5 min.
Ethyl 2-(4-chlorophenyl)-2-hydroxyacetate (12c):.1d,e Light
1
yellow solid. H NMR (CDCl3, 400 MHz) d: 1.06 (m, 3H, CH3),
4.00–4.05 (m, 2H, CH2), 4.99 (s, 1H, CH), 7.15–7.25 (m, 2H, Ar),
7.63–7.65 (m, 2H, Ar). 13C NMR (CDCl3, 100 MHz) d: 14.12,
64.06, 71.82, 128.02, 128.36, 129.18, 129.55, 137.11, 137.14,
169.66. ESI-TOF MS (m/z): 213.11. HPLC: tR: 7.1 min (S) and 8.1
min (R).
Catalytic reactions
Method A. [Rh(I)]2 (1.5 mol%, 7.34 ꢂ 10ꢁ3 mmol) or [Rh(I)]
Ethyl 2-hydroxy-2-(3-methoxyphenyl)acetate (12d):.1d,e Yellow
(3 mol%, 0.015 mmol) was added to a round bottom ask, oil. 1H NMR (CDCl3, 400 MHz) d: 1.21 (m, 3H, CH3), 3.63 (br s,
under an inert atmosphere. Commercial phosphane ligand 1H, OH), 3.78 (s, 3H, OCH3), 4.14–4.19 (m, 1H, CH2), 4.20–4.28
(3.3 mol%, 0.015 mmol), arylboronic acid or derivative (2 equiv., (m, 1H, CH2), 5.12 (s, 1H, CH), 6.83–6.85 (m, 1H, Ar), 6.96–6.98
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(m, 2H, Ar), 7.23–7.27 (m, 1H, Ar). 13C NMR (CDCl3, 100 MHz) d:
13.96, 55.29, 62.14, 72.61, 111.85, 114.32, 118.92, 129.46,
140.23, 159.73, 173.97. ESI-TOF MS (m/z): 193.09 (–OH), 211.10
(M + 1). HPLC: tR: 14.3 min and 17.6 min.
Notes and references
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1639–1643; (b) C. S. Marques and A. J. Burke,
ChemCatChem, 2011, 3, 635–645; (c) C. S. Marques and
A. J. Burke, Eur. J. Org. Chem., 2012, 4232–4239; (d)
C. S. Marques and A. J. Burke, Tetrahedron, 2012, 68, 7211–
7216; (e) C. S. Marques and A. J. Burke, Tetrahedron:
Asymmetry, 2013, 24, 628–632; (f) C. S. Marques and
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2 G. M. Copola and H. F. Schuster, a-Hydroxy Acids in
Enantioselective Synthesis, Wiley-VCH, Weinheim, 1997.
3 (a) Privileged Chiral Ligands and Catalysts, ed. Q.-L. Zhou,
Wiley-VCH, 2011; (b) Phosphorus Ligands in Asymmetric
Ethyl 2-(4-uorophenyl)-2-hydroxyacetate (12e):.1d,e Colorless
oil. 1H NMR (CDCl3, 400 MHz) d: 1.16 (m, 3H, CH3), 3.88 (br s,
1H, OH), 4.12–4.18 (m, 1H, CH2), 4.20–4.24 (m, 1H, CH2), 5.11
(s, 1H, CH), 6.99–7.03 (m, 2H, Ar), 7.36–7.40 (m, 2H, Ar). 13C
NMR (CDCl3, 100 MHz) d: 14.15, 62.36, 71.47, 115.49, 115.61,
128.24, 134.37, 161.42, 164.06, 173.67. ESI-TOF MS (m/z): 181.07
(–OH), 199.08 (M + 1). HPLC: tR: 6.9 min (S) and 8.2 min (R).
Ethyl 2-hydroxy-2-(naphthalen-1-yl)acetate (12f):.1d,e White
solid. 1H NMR (CDCl3, 400 MHz) d: 1.26 (m, 3H, CH3), 4.12–4.32
(m, 2H, CH2), 5.81 (s, 1H, CH), 7.44–7.70 (m, 4H, Ar), 7.84–7.96
(m, 2H, Ar), 8.11–8.18 (m, 1H, Ar). 13C NMR (CDCl3, 100 MHz) d:
14.17, 62.06, 71.33, 123.46, 123.70, 125.13, 125.68, 125.78,
126.48, 127.84, 128.80, 129.36, 134.07, 174.48. ESI-TOF MS
(m/z): 233.08 (M + 2). HPLC: tR: 55.8 min and 36.2 min. (HPLC
eluent: hexane/2-propanol (98/2)).
¨
Catalysis, ed. A. Borner, Wiley-VCH, 2008, vol. 1–3.
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1
Ethyl 2-(furan-2-yl)-2-hydroxyacetate (12g):.1d,e Yellow oil. H
NMR (CDCl3, 400 MHz) d: 1.20 (m, 3H, CH3), 4.27–4.30 (m, 2H,
CH2), 5.18 (s, 1H, CH), 6.37 (m, 2H, CH–CH), 7.40 (m, 1H, OCH).
13C NMR (CDCl3, 100 MHz) d: 14.10, 62.60, 67.03, 108.45,
110.55, 143.09, 151.05, 171.47. ESI-TOF MS (m/z): 153.05 (–OH),
171.06 (M + 1). HPLC: tR: 8.9 min and 10.8 min.
´
´
5 M. Dieguez, O. Pamies and C. Claver, Tetrahedron:
Asymmetry, 2004, 15, 2113–2122.
Ethyl 2-hydroxy-2-(2-methoxyphenyl)acetate (12h):.1d Color-
less oil. 1H NMR (CDCl3, 400 MHz) d: 1.20 (m, 3H, CH3), 3.91 (s,
3H, OCH3), 4.17–4.26 (m, 2H, CH2), 5.28 (s, 1H, CH), 6.89–6.96
(m, 2H, Ar), 7.01–7.05 (m, 1H, Ar), 7.42–7.47 (m, 1H, Ar). 13C
NMR (CDCl3, 100 MHz) d: 14.31, 55.64, 61.52, 71.45, 110.01,
121.46, 129.51, 132.60, 137.17, 164.75, 174.01. ESI-TOF MS
(m/z): 193.10 (–OH), 211.10 (M + 1). HPLC: not determined.
Ethyl 2-hydroxy-2-(4-methoxyphenyl)acetate (12i):.12 Color-
less oil. 1H NMR (CDCl3, 400 MHz) d: 1.25 (m, 3H, CH3), 3.39 (br
s, 1H, OH), 3.81 (s, 3H, OCH3), 4.15–4.28 (m, 2H, CH2), 5.10 (s,
1H, CH), 6.88–6.90 (m, 2H, Ar), 7.32–7.34 (m, 2H, Ar). 13C NMR
(CDCl3, 100 MHz) d: 14.10, 55.53, 62.36, 72.39, 114.13, 127.70,
130.36, 159.95, 173.82. ESI-TOF MS (m/z): 193.08 (–OH), 233.08
(M + 1 plus Na). HPLC: tR: 10.2 min and 14.4 min.
¨
´
6 A. Alexakis, J. E. Backvall, N. Krause, O. Pamies and
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M. Dieguez, Chem. Rev., 2008, 108, 2796–2823.
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´
´
´
´
¨
¨
Ethyl 2-(3-aminophenyl)-2-hydroxyacetate (12j):.1d Obtained
in vestigial quantities. Colorless oil.
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Acknowledgements
¨
J. Wassenaar, A. J. Sandee, S. Romanski, J.-M. Neudor,
We are grateful for the award of a PhD grant to C.S.M. (SFRH/
H.-G. Schmalz and J. N. H. Reek, Organometallics, 2010, 29,
˜
ˆ
BD/45132/2008) from the Fundaçao para a Ciencia e a Tecno-
logia (FCT) 2010. We are grateful for funding from strategic
project PEst-OE/QUI/UI0619/2011 (CQE-UE). We acknowledge
LabRMN at FCT-UNL for the acquisition of the NMR spectra; the
NMR spectrometers are part of the National NMR Network and
were purchased within the framework of the National Pro-
gramme for Scientic Re-equipment (contract REDE/1517/
RMN/2005), with funds from POCI 2010 (FEDER) and FCT.
The C.A.C.T.I. at the University of Vigo (Spain) is gratefully
acknowledged for MS analysis.
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