Organocatalytic conversion of arylglyoxals into optically active mandelic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.01.114

A novel protocol for the organocatalytic conversion of arylglyoxals into the corresponding α-hydroxy arylacetic acid methyl esters has been developed. The catalyst consists of a combination of a commercially available cinchona alkaloid derivative and an a

Full text of DOI:10.1016/j.tetlet.2009.01.114

Tetrahedron Letters 50 (2009) 3185–3188
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Tetrahedron Letters
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Organocatalytic conversion of arylglyoxals into optically active mandelic
acid derivatives
Ellen Schmitt, Ingo Schiffers, Carsten Bolm *
Institut für Organische Chemie der RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel protocol for the organocatalytic conversion of arylglyoxals into the corresponding a-hydroxy
Received 14 January 2009
Accepted 21 January 2009
Available online 25 January 2009
arylacetic acid methyl esters has been developed. The catalyst consists of a combination of a commer-
cially available cinchona alkaloid derivative and an achiral thiol and leads to enantiomerically enriched
products (eemax 83%) under mild reaction conditions. The alkaloid can be easily recovered and reused
without loss in activity and selectivity.
Ó 2009 Elsevier Ltd. All rights reserved.
5
The synthesis of
molecular Cannizzaro reactions of the corresponding
a
-hydroxy arylacetic acids by means of intra-
-keto alde-
Franzen, who investigated the mechanism of the glyoxalase path-
6
a
way. This enzyme carries out the detoxification of methylglyoxal,
hydes is a process, which is known since the end of the 19th
century. The resulting mandelic acid derivatives are chiral mole-
which is produced in the metabolism of living organisms, by con-
verting it into lactic acid. It consists of two enzymes (glyoxalase I
and II) and catalytic amounts of the important coenzyme glutathi-
one, a tripeptidic thiol. In the first step, a hemithioacetal is formed
from the glyoxal and glutathione, which then isomerizes enanti-
oselectively to the thioester by a base-mediated proton transfer
catalyzed by glyoxalase I. Subsequently, glyoxalase II converts this
1
cules, which in the last decades proved to be versatile building
blocks in the preparation of natural and biologically active com-
2
pounds. Stereoselective versions of intramolecular Cannizzaro
reactions are rare since the conversion of the glyoxals commonly
requires drastic reaction conditions such as strong bases in stoichi-
ometric amounts and high temperatures, which limits the possibil-
ities to render the process asymmetric. The use of Lewis acids
7
thioester into the acid and glutathione. Franzen utilized this con-
cept in the conversion of phenylglyoxal to mandelic acid or the cor-
responding mandelates employing substoichiometric amounts of
aminothiols as mediators.
3
allows for milder reaction conditions. In combination with chiral
ligands, enantioselective Lewis acid catalysts are formed, and up
to now three systems have been reported.4 Nishinaga found that
cobalt(II) Schiff-base complexes (20 mol %) catalyzed the conver-
sion of phenylglyoxal in a dichloroethane/isopropanol mixture at
The highest reaction rates were observed when N,N-dialkylcy-
5
b
steines were employed in methanol. Application of 20 mol % of
a chiral aminothiol stemming from the reaction of thiiran with
enantiopure N-methyl methamphetamin delivered methyl man-
6
0 °C, leading to 97% of isopropyl mandelate within 8 h. With a chi-
ral Co-complex bearing a binaphthyl backbone, the product had
3.5% enantiomeric excess (ee).4a In 2000, Morken described the
use of a Cu(II)/PhBox system as catalyst. In the presence of
mol % of a 1:1 complex of Cu(OTf) and the phenyl-substituted
8
delate with 9% ee. Franzen proposed the classical Cannizzaro
5a
1
mechanism involving a 1,2-hydride shift. Later, this was dis-
proved by means of solvent isotope incorporation NMR experi-
9
1
2
ments,
and it was shown that the rearrangement of
-hydroxy thiocarboxylic ester 4 pro-
general base-catalyzed enediol proton transfer
bisoxazoline, phenylglyoxal hydrate was converted at room tem-
perature to give mandelic acid isopropylester with 28% ee in 56%
yield.4 Recently, this system was optimized by Ishihara, who em-
hemithioacetal 2 to the
ceeded by
(Scheme 1). Subsequently, the intermediacy of enediol 3 was
confirmed by flavin-trapping experiments. Our ongoing research
in the field of asymmetric organocatalysis
a
a
b
10
1
1
ployed 11 mol % of a bisoxazoline and 10 mol % of Cu(SbF
)
6 2
in
1
2,13
combination with tert-butanol instead of isopropanol. Under anhy-
drous conditions, the corresponding tert-butyl mandelate with 54%
ee was obtained in 71% yield.4 With enantiopure menthol as
nucleophile, diastereomeric interactions led to mandelic acid men-
thyl ester having up to 90% de.
encouraged us to
search for an improved enantioselective version of Franzen’s Can-
nizzaro-type reaction. Herein, we describe the development of a
metal-free procedure for the synthesis of mandelic acid derivatives
5 with easily accessible mediators leading to products with up to
83% ee.
The conversion of phenylglyoxal hydrate (6a) to methyl man-
delate (5a) was selected as test reaction (Scheme 2). Based on Fran-
zen’s results, we initially varied the aminothiol structure, but to
our disappointment all attempts to apply 7a–c as chiral mediators14
c
Already from the 1950s stems another approach for the conver-
sion of phenylglyoxal to mandelic acid esters. It was developed by
*
Corresponding author. Tel.: +49 241 809 4675; fax: +49 241 809 2391.
E-mail address: Carsten.Bolm@oc.rwth-aachen.de (C. Bolm).
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.114

3
186
E. Schmitt et al. / Tetrahedron Letters 50 (2009) 3185–3188
proton transfer
O
OH
OH
SR
SR
SR
H
OH
3
O
O
OH
H
H
SR
R N
3
O
RSH
H
O
OH
1
2
O
H
SR
O
OH
4 (4a R = Ph)
OR
hydride shift
ROH
transesterification
O
5
a R = Me
5
5b R = H
Scheme 1. Proposed mechanisms for the rearrangement of hemithioacetal 2 to thioester 4.
with thiols),16 quinidine (8a) and its easily accessible derivatives
O
OH
(Fig. 1) appeared attractive for further tests.
7
a-c (20 mol%)
OH
OH
OMe
In order to prevent oligomerization, phenylglyoxal hydrate (6a)
MeOH, rt
O
was first converted into its hemiacetal by stirring in methanol
1 mmol of 6a in 2 mL of solvent). Subsequently, the alkaloid and
(
6a
5a
NMe2
SH
the thiol (20 mol % each) were added. In the initial experiments,
the presence of dichloromethane (DCM, 0.6 mL) ensured the com-
plete dissolution of quinidine. Under standard reaction conditions,
the resulting mixture was stirred at room temperature for 72 h.
The results are summarized in Table 1.
Ph
Ph
SH
N
Me
N
Me
SH
Me
7
a
7b
7c
Scheme 2. Conversion of phenylglyoxal hydrate (6a) in the presence of enantio-
pure aminothiols 7a–c.
Table 1
Catalyst screening in the enantioselective conversion of phenylglyoxal hydrate (6a)
with chiral amines and achiral aromatic thiols .
a
(
in methanol) led to low product yields (up to 40%) and
O
8 (20 mol%),
9 (20 mol%
OH
unsatisfying enantioselectivities (eemax 12%). Since the access to
enantiopure aminothiols is preparatively demanding, it appeared
desirable to separate both functionalities, the amino and the thiol
group. In preliminary experiments employing DABCO as amine and
methanol as reaction media, aliphatic thiols gave only marginal
yields of 5a. In contrast, the use of thiophenols led to reasonable
conversions in acceptable reaction times. Noting that the quinucli-
dine moiety of cinchona alkaloids contained a tertiary amino group
and that various compounds of this substrate class have very suc-
OH
OH
OMe
MeOH, DCM
O
6
a
5a
1
2
a R = H, R = H
SH
R2
1
2
b R = Me, R = H
1
2
c R = t-Bu, R = H
R1
1
2
d R = OMe, R = H
9a-e
e R = H, R = t-Bu
1
2
Entry
Alkaloid
Thiol
Yieldb (%)
eec (%)
15
cessfully been applied in organocatalysis (also in combination
1
2
3
4
5
6
7
8
9
QD (8a)
QD (8a)
QD (8a)
QD (8a)
QD (8a)
CPD (8b)
QD-Bn (8c)
QD-Me (8d)
DHQD-PHN (8e)
9a
9b
9c
9d
9e
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9e
60
58
59
57
40
60
37
43
41
48
53
39
41
49
58
35
9 (R)
9 (R)
9 (R)
11 (R)
13 (R)
7 (R)
34 (S)
50 (S)
55 (S)
55 (R)
53 (S)
63 (R)
69 (S)
56 (S)
58 (S)
83 (S)
1
R O
Ph
2
N
R
R
R O
N
N
N
(
S)
O
(
R)
N
N
Ph
PYR
10
(DHQ)
(DHQD)
(DHQ) PHAL (8h)
(DHQD) PHAL (8i)
(DHQD) PHAL (8i)
2
PYR (8f)
1
2
8
8
8
8
a
R = Me R = H QD
b R = H R = H CPD
R = Me R = Bn QD-Bn
d R = Me R = Me QD-Me
OMe
11
12
13
14
2
PYR (8g)
1
2
N
N
2
1
2
c
R
R
2
1
2
8e DHQD-PHN
d
e
2
1
1
5
6
(DHQD)
(DHQD)
2
PHAL (8i)
PHAL (8i)
2
MeO
N
MeO
O
PHAL
f (DHQ)2PYR
a
Unless otherwise noted, the reactions were carried out with phenylglyoxal
hydrate (6a, 1 mmol) and 20 mol % of both chiral amine and thiol in a mixture of
MeOH (2 mL; 50 equiv) and DCM (0.6 mL) for 72 h at rt.
Yield of isolated product after column chromatography.
Determined by HPLC analysis using a Chiralcel OD-H column (90:10 hep-
tane:isopropanol, 0.85 mL/min, 20 °C, 230 nm, t
O
8
8
8
8
N
N
g (DHQD)2PYR
b
N
c
h (DHQ) PHAL
2
DHQD
DHQ
i
(DHQD)2PHAL
R
(S) = 9.3 min, t
R
(R) = 15.6 min).
d
Reaction was performed without DCM.
Reaction was run 168 h.
e
Figure 1. Cinchona alkaloid catalysts.

E. Schmitt et al. / Tetrahedron Letters 50 (2009) 3185–3188
3187
Application of a mixture of quinidine (8a) and thiophenol (9a)
afforded methyl mandelate (5a) in 60% yield after 72 h (Table 1,
As mentioned earlier, Franzen had observed high reaction rates
5
a,22
by using achiral dialkylcysteamines as catalysts.
Assuming that
1
7
entry 1). Although the ee of the product was very low (9%),
the experiment showed that the alkaloid was involved in the
asymmetric protonation step and was capable to form an enanti-
omerically enriched product. Since in the studies of Ishihara the
the transesterification step in this system was accelerated by an
anchimeric assistance of the amine function, we wondered
whether the addition of an achiral b-aminothiol would increase
the rate of the alkaloid catalysis. For evaluating this hypothesis, a
combination of 15 mol % of 2-(N,N-dimethylamino)ethanthiol and
4c
exclusion of water gave higher yields, anhydrous reaction condi-
tions were tested next. Here, however, performing the reaction
under argon in the presence of molecular sieves did not result
in an improvement. The formation of significant amounts of man-
delic acid (5b) by hydrolysis of the thioester was excluded by
NMR spectroscopy. Small quantities of 5b were only detected
when water (2 equiv) was added. By reducing the catalyst loading
or diluting the reaction mixture with other solvents such as DCM
or toluene, slightly higher enantioselectivities were observed, and
the reaction rate decreased significantly. Next, a set of thiophenol
derivatives was tested under the standard reaction conditions
2
20 mol % of (DHQD) PHAL (8i) was applied under standard condi-
tions, and to our delight, after only 24 h methyl mandelate was ob-
tained in 47% yield (Table 2, entry 1). Although the enantiomeric
excess (57%) was slightly lower in comparison to the correspond-
ing thiophenol experiment (Table 1, entry 13), the result was
remarkable. It showed that even in the presence of considerable
amounts of an achiral catalyst the alkaloid was the more active
species in the thioester formation. Use of the commercially avail-
able hydrochloric salt 10a, which is more stable toward oxidation
and easier to handle, led to a slight increase in yield and ee (Table
2, entry 2). Prolonging the reaction time to 72 h had no significant
beneficial effect on the yield, indicating that the conversion had
nearly reached its maximum after 24 h (entry 3). Analogous results
were observed by applications of the hydrochloric salts of 2-(N,N-
diethylamino)ethanthiol (10b) and 2-(piperidino)ethanthiol (10c)
(Table 1, entries 2–5). Even under argon, 2-thionaphthol and 4-
nitrothiophenol were oxidized rapidly to the corresponding disul-
fides, resulting in termination of the catalysis at the initial stage.
Electron-donating substituents in the para-position of the thio-
phenol had no influence on activity and selectivity (Table 1, en-
tries 2–4). Only ortho-substituted 2-tert-butylthiophenol (9e) led
to 5a with a slightly higher ee (entry 5). In several other organo-
catalytic transformations, for example, Baylis–Hillman and Henry
reactions, cinchona alkaloids with a phenolic hydroxy group in
2
3
(Table 2, entries 4 and 5). In accordance with the observations
of Franzen, use of the morpholino derivative 10d led to a lower
5
b
yield. Interestingly, this was accompanied by an increase in
enantioselectivity (entry 6). Although the Sharpless’ ligands are
0
the C6 -position of the quinoline backbone showed superior selec-
2
commercially available, it is important to note that (DHQD) PHAL
tivities in comparison to their natural analogs.1 In contrast,
8
could be recovered and reused without loss of neither activity
nor selectivity (entry 7). Reducing the catalyst loading at constant
solvent volume resulted in a lower yield of 5a. In contrast, by
nearly identical results were observed in the present system (en-
1
9
try 6). A considerable improvement of enantioselectivity could
be achieved with simple quinidine ethers, but it was accompanied
by decreased yields (entries 7–9). Next, the effects of other cin-
chona alkaloid ethers, which nowadays are known as Sharpless’ li-
Table 2
Catalyst screening of the enantioselective conversion of arylglyoxal hydrates 6 with
2
0
a
alkaloid 8i and achiral aminothiols.
gands, were studied in the model reaction (entries 10–16). By
employing (DHQD) PHAL (8i) under standard conditions, methyl
2
O
8i
(
20 mol%),
OH
1
0 (15 mol%)
mandelate with up to 69% ee was isolated (entry 13). In contrast
to quinidine (8a), the bisalkaloid ether was completely soluble in
methanol. Attempts to perform the reaction without the co-sol-
vent DCM led to a slightly decreased enantioselectivity (entry
OH
OH
OMe
Ar
Ar
MeOH, DCM
O
6
5
a Ar = Phenyl; b Ar = 2-Naphthyl; c Ar = 1-Naphthyl
1
4). Interestingly, the bisalkaloid ether of dihydroquinidine affor-
1
1
1
0a R = -Me
0b R = -Et
ded methyl mandelate 5a with opposite absolute configuration in
comparison to the product obtained with the natural alkaloid (Ta-
ble 1, entry 1 vs entry 13), a phenomenon that was also observed
NR2 HCl
0c R = -C H -
HS
4 8
10
10d R = -C H OC H -
2 4 2 4
20
in other organocatalytic reactions. Either enantiomer of methyl
mandelate could be prepared by using quinine- or quinidine-de-
rived catalysts (entries 10–13). By combining bisalkaloid 8i with
ortho-substituted thiophenol 9e, the enantiomeric excess of the
methyl mandelate could be further improved to 83% (entry 16).
To the best of our knowledge, this result represents currently the
highest enantioselectivity achieved for the non-enzymatic conversion
of phenylglyoxal to a mandelic acid derivative. The yield was in-
creased by prolonging the reaction time, but then the ee of the
product was lower (entry 13 vs entry 15). Control experiments
with enantiopure methyl mandelate excluded a racemization un-
der the standard reaction conditions. On the other hand, highly
enantiomerically enriched thiophenolester 4a,21 which was the
initially formed product of the catalytic reaction (Scheme 1),
showed a considerably lower enantiomeric excess after treatment
with quinidine. Thus, the presence of this intermediate, which
was detected in the model reaction as a by-product in significant
amounts, and its slow (rate determining) transesterification with
methanol to give the final product (5a) appeared responsible for
the decrease of the ee with time (by rapid racemization). It also
accounted for the low rate of the overall reaction, since significant
amounts of the catalytically important thiol were trapped in an
inactive form.
Entry
Substrate
Aminothiol
Yieldb (%)
eec (%)
1d
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
10a
10a
10a
10b
10c
10d
10b
10b
10b
10b
47
52
55
48
46
27
46
42
44
66
57 (S)
63 (S)
59 (S)
59 (S)
59 (S)
72 (S)
61 (S)
63 (S)
2
e
3
4
5
6
f
7
g
8
h
9
56 (S)
10
65 (S) i
a
Unless otherwise noted the reactions were carried out with arylglyoxal hydrate
1 mmol), (DHQD) PHAL (20 mol %), and aminothiol hydrochloride (15 mol %) in
(
2
MeOH (2 mL; 50 equiv) for 24 h at rt.
b
Yield of isolated product after column chromatography.
Determined by HPLC analysis using a Chiralcel OD-H column (90:10 heptane/
c
isopropanol, 0.85 mL/min, 20 °C, 230 nm, t (S) = 9.3 min, t (R) = 15.6 min).
R
R
d
e
f
The aminothiol was used as free base.
Reaction run for 72 h.
Reaction run with recycled catalyst.
Use of 10 mol % of (DHQD)
g
h
2
PHAL and 7.5 mol % of 10b in 1 mL of MeOH.
Determined by HPLC analysis using a Chiralcel OD–H column (90:10 hep-
tane:isopropanol, 1 mL/min, 20 °C, 230 nm, t (S) = 11.8 min, t (R) = 14.1 min).
R
R
i
Determined by HPLC analysis using a Chiralcel AD-H column (90:10 hep-
tane:isopropanol, 0.8 mL/min, 20 °C, 230 nm, t (S) = 20.1 min, t (R) = 22.1 min).
R
R

3
188
E. Schmitt et al. / Tetrahedron Letters 50 (2009) 3185–3188
halving both the amount of solvent and the catalyst quantity no
significant change of yield and enantioselectivity was observed
transesterification of a-hydroxythiolphenol ester 4 under standard reaction
conditions. This proved that the
and could easily be exchanged.
a-hydrogen in the primary product was acidic
(Table 2, entry 8). To extend the substrate scope, 1-naphthylglyox-
1
1
1. (a) Shinkai, S.; Yamashita, T.; Kusano, Y.; Manabe, O. Chem. Lett. 1979, 1323; (b)
Shinkai, S.; Yamashita, T.; Kusano, Y.; Manabe, O. J. Am. Chem. Soc. 1981, 103,
al hydrate (6b) and 2-naphthylglyoxal hydrate (6c) were prepared
by Riley oxidation of the corresponding methyl ketone. Subjected
2
070.
2. For recent examples, see: (a) Bolm, C.; Atodiresei, I.; Schiffers, I. Org. Synth.
005, 82, 120; (b) Rodriguez, B.; Bolm, C. J. Org. Chem. 2006, 71, 2888; (c)
to the alkaloid catalysis with (DHQD)
0b, the corresponding -hydroxy arylacetic acid methylesters
were formed with 56% ee and 65% ee, respectively (Table 2, entries
2
PHAL and hydrochloride
2
1
a
Rodriguez, B.; Rantanen, T.; Bolm, C. Angew. Chem. 2006, 118, 7078. Angew.
Chem., Int. Ed. 2006, 45, 6924; (d) Rantanen, T.; Schiffers, I.; Bolm, C. Org. Process
Res. Dev. 2007, 592; (e) Rodriguez, B.; Bruckmann, A.; Bolm, C. Chem. Eur. J.
9
and 10).
2007, 13, 4710; (f) Bruckmann, A.; Pena, M.; Bolm, C. Synlett 2008, 900.
In summary, we have developed a novel organocatalytic proto-
13. For recent reviews on asymmetric organocatalysis, see: (a) Dalko, P. I.
Enantioselective Organocatalysis: Reactions and Experimental Procedures;
Wiley-VCH: Weinheim, 2007; (b) Pellissier, H. Tetrahedron 2007, 63, 9267;
col for the conversion of arylglyoxals to the corresponding
a-hy-
droxy arylacetic acid methyl esters. Readily available cinchona
alkaloid catalysts in combination with achiral thiols deliver enan-
tiomerically enriched products with good ees. The reaction rate
could be accelerated by presence of achiral b-aminothiols as the
thiol component.
(
c) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416; (d)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (e)
Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606; (f) Doyle, A.
G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713; (g) Davie, E. A. C.; Mennen, S. M.;
Xu, Y.; Miller, S. Chem. Rev. 2007, 107, 5759; (h) Massi, A.; Dondoni, A. Angew.
Chem. 2008, 120, 4716. Angew. Chem. Int. Ed. 2008, 47, 4638; (i) Gruttadauria,
M.; Giacalone, F.; Noto, R. Chem. Soc. Rev. 2008, 37, 1666; (k) Bartoli, G.;
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Bartoli, G. Angew. Chem. 2008, 120, 6232. Angew. Chem., Int. Ed. 2008, 47, 6138.
4. For the use of these aminothiols as ligands in asymmetric alkenylzinc additions
to aldehydes, see: (a) Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6453; (b) Tseng,
S.-L.; Yang, T.-K. Tetrahedron: Asymmetry 2005, 16, 773; (c) Wipf, P.; Jayasuriya,
N. Chirality 2008, 20, 425.
Acknowledgments
1
We are grateful to the Deutsche Forschungsgemeinschaft (DFG;
SPP 1179) and the Fonds der Chemischen Industrie for financial
support. We thank PD. Dr. L. Hintermann for many stimulating dis-
cussions and Professor Dr. H. Perl for her kind comments on this
manuscript.
15. For reviews, see: (a) Kacprzak, K.; Gawronski, J. Synthesis 2001, 961; (b) Ó
Dálaigh, C. Synlett 2005, 875.
1
6. (a) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417; (b) Faber, W. S.;
Kok, J.; de Lange, B.; Feringa, B. L. Tetrahedron 1994, 50, 4775; (c) McDaid, P.;
Chen, Y.; Deng, L. Angew. Chem. 2002, 114, 348. Angew. Chem., Int. Ed. 2002, 41,
338.
References and notes
1
7. Prolongation of the reaction time did not further increase the product yields.
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of methyl mandelate.
1
.
.
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1
1
09; (d) El Nimr, A. E.; Salama, H. A.; Khalil, R. M.; Kassem, M. A. Pharmazie
983, 38, 728.
3
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For recent examples, see: (a) Curini, M.; Epifano, F.; Genovese, S.; Marcotullio,
M. C.; Rosati, O. Org. Lett. 2005, 7, 1331; (b) Abaee, M. S.; Sharifi, R.; Mojtahedi,
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1
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Calter, M. A.; Phillips, R. M.; Flaschenriem, C. J. Am. Chem. Soc. 2005, 127, 14566;
(
d) Likhar, P. R.; Bandyopadhyay, A. K. Synlett 2000, 538.
4
(a) Maruyama, K.; Murakami, Y.; Yoda, K.; Mashino, T.; Nishinaga, A. J. Chem.
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(
f) Poulsen, T. B.; Bella, M.; Jørgensen, K. A. Org. Biomol. Chem. 2006, 4, 63; (g)
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2
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(a) Franzen, V. Chem. Ber. 1955, 88, 1361; (b) Franzen, V. Chem. Ber. 1957, 90,
23; (c) Franzen, V. Chem. Ber. 1957, 90, 2036.
5
.
.
2
2
1. For the synthesis of mandelic acid thiophenolester from L-mandelic acid, see:
6
Yang, H.; Liebeskind, L. S. Org. Lett. 2007, 9, 2993.
6
(a) Neuberg, C. Biochem. Z. 1913, 49, 502; (b) Dakin, H. D.; Dudley, H. W. J. Biol.
Chem. 1913, 14, 155.
Racker, E. J. Biol. Chem. 1951, 190, 685.
Determined by optical rotation, see Ref. 5c Unfortunately, no yields were given
for the catalysis.
(a) Hall, S. S.; Doweyko, A. M.; Jordan, F. J. Am. Chem. Soc. 1976, 98, 7460; (b)
Hall, S. S.; Doweyko, A. M.; Jordan, F. J. Am. Chem. Soc. 1978, 100, 5934.
2. According to Ref. 5a, the conversion of phenylglyoxal in the presence of 5 mol %
of 2-(N,N-diethylamino)ethanthiol afforded methyl mandelate in 72% yield
after 12 h at room temperature. In our hands, use of 20 mol % of the same
amino thiol led to a maximum yield of 60% after 48 h.
7
8
.
.
23. The hydrochloric salts of 2-(piperidino)ethanthiol (10c) and 2-
9
.
(
morpholino)ethanthiol (10d) were prepared from ethylenesulfide and the
corresponding amines. See: Snyder, H. R.; Stewart, J. M.; Ziegler, J. B. J. Am.
Chem. Soc. 1947, 69, 2672.
1
0. We also detected the incorporation of solvent protons into the product when
using deuterated methanol. Furthermore, deuterium was incorporated in a