Synthesis of Unprotected 2-Arylglycines by Transamination of Arylglyoxylic Acids with 2-(2-Chlorophenyl)glycine

Article abstract of DOI:10.1021/acs.joc.0c01302

The transamination of α-keto acids with 2-phenylglycine is an effective methodology for directly synthesizing unprotected α-amino acids. However, the synthesis of 2-arylglycines by transamination is problematic because the corresponding products, 2-arylglycines, transaminate the starting arylglyoxylic acids. Herein, we demonstrate the use of commercially available l-2-(2-chlorophenyl)glycine as the nitrogen source in the transamination of arylglyoxylic acids, producing the corresponding 2-arylglycines without interference from the undesired self-transamination process.

Full text of DOI:10.1021/acs.joc.0c01302

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Featured Article
Synthesis of Unprotected 2-Arylglycines by Transamination
of Arylglyoxylic Acids with 2-(2-Chlorophenyl)glycine
Haruki Inada, Masatoshi Shibuya, and Yoshihiko Yamamoto
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01302 • Publication Date (Web): 13 Aug 2020
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Synthesis of Unprotected 2-Arylglycines by Transamination of
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Arylglyoxylic Acids with 2-(2-Chlorophenyl)glycine
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Haruki Inada, Masatoshi Shibuya,* and Yoshihiko Yamamoto
Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-
cho, Chikusa, Nagoya 464-8601, Japan
E-mail: m-shibu@ps.nagoya-u.ac.jp
Abstract: The transamination of α-keto acids with 2-phenylglycine is an effective methodology for directly
synthesizing unprotected α-amino acids. However, the synthesis of 2-arylglycines by transamination is problematic
because the corresponding products 2-arylglycines transaminate the starting arylglyoxylic acids. Herein, we
demonstrate the use of commercially available L-2-(2-chlorophenyl)glycine as the nitrogen source in the
transamination of arylglyoxylic acids, producing the corresponding 2-arylglycines without interference from the
undesired self-transamination process.
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INTRODUCTION
2
-Arylglycines comprise an important class of non-proteinogenic α-amino acids, which are found in peptide drugs,
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antibiotics such as amoxicillin, cefprozil and vancomycin, and other biologically active compounds (Figure 1).1,2
Although the Strecker synthesis is their most reliable preparation method, it requires toxic cyanide reagents and harsh
3
conditions for hydrolysis of the α-amino nitriles. Harmless and effective alternative methods have also been
4
developed, including the addition of arylboronic acids to α-imino acids (Petasis reaction), reduction of α-
5
6
iminoesters, α-arylation of glycine derivatives, and carboxylation using CO as a C1 source for benzyl amine
2
derivatives.7,8 These methods afford protected 2-arylglycines, which require an additional step for deprotection to
9
access unprotected 2-arylglycines. There are few methods to directly prepare unprotected 2-arylglycines. Therefore,
the development of a versatile preparation method would be desirable.
In biological systems, the transamination of α-keto acids is used to synthesize α-amino acids; the reaction is catalyzed
10
by transaminases using pyridoxal/pyridoxamine 5'-phosphate as a coenzyme. This process affords unprotected α-
amino acids. In 1934, Herbst and Engel reported thermally promoted biomimetic transaminations between α-keto
acids and 2-phenylglycine without any catalysts to form the corresponding unprotected α-amino acids (Scheme 1a).11
Although related research has been reported, the methods have not been applied to organic synthesis.12,13 Intrigued
14
by the potential usefulness of transamination, we recently reported a modified protocol. Combining transamination
with the oxidation of 1,2-diols to α-keto acids, we established a direct method for the synthesis of unprotected α-
amino acids. Owing to the method’s high functional group compatibility, a variety of unnatural α-amino acids
including fluorescent and photoactivatable species were prepared.14b
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OH
HO
H N
2
NH2
O
HO
H
H
N
S
O
OH
O
O
O
N
HO
O
Cl
CO H
O
O
O
2
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amoxicillin
Cl
HO
OH
H
O
H
N
H
O
H
N
O
N
N
CO H
N
2
N
H
H
H
O
O
O
H
HN
HO C
OH
O
N
O
NH2
2
OH
OH
S
N
H
H
HO
NH2
vancomycin
cefprozil
OH
OH
O
H N
2
OH
O
O
OH
O
O
NH
H
N
H
H
O
N
N
NH
N
N
N
H
H
H
O
O
O
O
O
O
NH
O
O
NH2
H N
2
OH
HN
O
NH
OH
O
O
O
OH
H
H
H
N
N
N
Cl
N
N
N
O
H
H
H
O
O
H N
2
R = -1,2-dimannosyl
OR
OH
ramoplanin
Figure 1. Arylglycine-containing drugs.
In the thermal transamination, 2-phenylglycine is used as a nitrogen source (Scheme 1a). The phenyl group at the 2-
position stabilizes the benzylic anion to promote the decarboxylation of intermediate I under the reaction conditions.
Thus, alkyl-substituted glyoxylic acids efficiently undergo transamination to produce the corresponding α-amino
acids. On the other hand, in the transamination between 2-phenylglycine and arylglyoxylic acids, the formed 2-
arylglycine can undergo transamination with the starting arylglyoxylic acid as the nitrogen source (Scheme 1b). This
self-transamination is a potential problem for the preparation of 2-arylglycines by transamination. Herein, we report
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that L-2-(2-chlorophenyl)glycine efficiently transaminates arylglyoxylic acids as the nitrogen source to afford the
corresponding 2-arylglycines.
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Scheme 1. Transamination of α-Keto Acids with 2-Arylglycines: Prior and Current Work
a) Transamination of -Keto Acids with 2-Phenylglycine11
NH2
OH
O
O
NH2
O
R
OH
R
OH
O
Ph
NH2
Ph
O
HO C
2
HO C
N
2
R
OH
R
OH
-
CO2
-
H O
O
2
O
I
Ph
NH
Ph
NH2
H O
2
NH
R
OH
R
OH
R
OH
-PhCHO
O
O
O
II
III
b) This Work: Transamination of Arylglyoxylic Acid
NH2
OH
R2
O
NH2
O
O
OH
OH
R1
R1
O
self-transamination
(potential problem)
NH2
O
O
OH
+
H
R1
R1
RESULTS AND DISCUSSION
We initially investigated the transamination of 4-chlorophenylglyoxylic acid with 2-phenylglycine (Scheme 2).
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Almost no reaction occurred at 50 °C. This suggests that a higher temperature is required for transamination with 2-
phenylglycine. To identify a more effective nitrogen source, transaminations of phenylglyoxylic acid (1a) with
various 2-arylglycines were examined at 50 °C (Table 1). Gratifyingly, the reaction of 1a with L-2-(2-
chlorophenyl)glycine(1 equiv) produced 2-phenylglycine (2a) in 29% yield after 5 h at 50 °C (entry 1). The reaction
with DL-2-(2-chlorophenyl)glycine afforded 2a in slightly lower yield, presumably because of the lower solubility of
the racemic reagent over the L-isomer (entry 2). Several other 2-(2-substituted-phenyl)glycines exhibited high
reactivities similar to that of L-2-(2-chlorophenyl)glycine (entries 3–7), whereas 2-(2-fluorophenyl)glycine and 2-(2-
methylphenyl)glycine exhibited low reactivities (entries 8 and 9). Interestingly, 2-(3-chlorophenyl)glycine and 2-(4-
chlorophenyl)glycine did not undergo the reaction at 50 °C (entries 10 and 11). According to these results, we selected
L-2-(2-chlorophenyl)glycine as the optimal nitrogen source because of its advantageous commercial availability
among the 2-arylglycines with the high reactivities. Although a nitrogen source is L-2-(2-chlorophenyl)glycine, the
desired 2-arylglycines are obtained in racemic form. The reaction conditions were then optimized. Extending the
reaction time to 24 h improved the yield of 2a to 50% (entry 12). Increasing the quantity of L-2-(2-
chlorophenyl)glycine to 1.5 equiv slightly improved the yield of 2a to 59% (entry 13). Increasing the quantity of L-
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2
-(2-chlorophenyl)glycine to 2.0 equiv further improved the yield to 71% (entry 14).
Scheme 2. Transamination of 4-Chlorophenylglyoxylic Acid with 2-Phenylglycine
NH2
OH
O
O
NH2
(1 equiv)
OH
OH
MeCN/H O
2
O
O
50 °C, 5 h
Cl
Cl
0.2 mmol
not detected
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Table 1. Transamination Using 2-(Substituted-phenyl)glycines and Optimization of Reaction Conditions
NH2
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O
NH2
O
Ar
(1 equiv)
CO H
2
OH
OH
O
MeCN/H O
2
1a
50 °C, 5 h
2a
entry
nitrogen source
yield (%)a
Ar = 2-Cl-C H4b
1
2
29
23
6
c
Ar = 2-Cl-C H4
6
c
3
4
5
6
7
Ar = 2-Br-C H4
29
25
23
28
30
6
c
Ar = 2-MeO-C H4
6
c
Ar = 2-HO-C H4
6
c
Ar = 2-CF -C H
6 4
3
c
Ar = 2-Ph-C H4
6
c
8
9
Ar = 2-F-C H4
7
7
6
c
Ar = 2-CH -C H
6 4
3
c
1
1
1
0
Ar = 3-Cl-C H4
0
6
c
1
2d
Ar = 4-Cl-C H4
0
6
50
59
71
6
Ar = 2-Cl-C H4b
Ar = 2-Cl-C H4b
Ar = 2-Cl-C H4b
1
3d,e
6
4d,f
1
6
a
d
1
b
c
Yields were determined by H NMR using 2,2-dimethyl-2-silapentane-5-sulfonate (DSS) as an internal standard. L-Isomer. Racemate.
e
f
Reaction time was 24 h. 1.5 equiv of nitrogen source was used. 2.0 equiv of nitrogen source was used
1
As the yields were determined by H NMR analysis of the crude products in the foregoing examination, an isolation
protocol was investigated (Scheme 3). The crude products contained unreacted L-2-(2-chlorophenyl)glycine and 2-
chlorobenzaldehyde as the major impurities. Separation of the desired product 2a and unreacted L-2-(2-
chlorophenyl)glycine is a particularly formidable problem owing to their similar physical properties. Eventually, we
found that simply refluxing the reaction mixture induced the degradation of L-2-(2-chlorophenyl)glycine. After 12 h,
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the L-2-(2-chlorophenyl)glycine was almost completely consumed. After precipitation by the addition of diethyl ether
to the reaction mixture, the precipitate was washed with acetonitrile and water to afford the desired racemic product
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1
1
1
1
1
1
1
1
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a in 69% isolated yield.
Scheme 3. Isolation of 2a
NH2
CO H
2
O
NH2
O
(2 equiv)
Cl
OH
OH
MeCN/H O
O
2
5
0 °C, 24 h
then reflux, 12 h
1a
1 mmol
2a
9% (isolated yield)
6
With the optimal reaction conditions and isolation protocol in hand, the substrate scope was investigated (Scheme
4
). First, the effects of the substituents at the 4-position of 1 were examined. The reactions of 4-halo-substituted
phenylglyoxylic acids efficiently proceeded to produce arylglycines 2b–d in 50–62% yields. The reaction of highly
electron-withdrawing 4-trifluoromethyl-substituted phenylglyoxylic acid 1e also efficiently proceeded to produce
arylglycine 2e in 67% NMR yield. However, heating to reflux led to the decomposition of 2e. Thus, the reaction was
stopped without heating to reflux and 2e was isolated by reprecipitation in 38% yield (See the Experimental Section
for details). Highly electron-withdrawing 4-benzyloxycarbonyl-substituted phenylglycine 2f was not obtained
because it readily decomposed under the reaction conditions. Moderately electron-donating methyl-, tert-butyl-, and
phenylglycines 2g and 2h, and phenyl-substituted phenylglycine 2i were obtained in good to high isolated yields (45–
7
9%). The highly electron-donating 4-methoxy-substituted phenylglycine 2j was obtained in 63% isolated yields.
Although the reaction of 4-dimethylamino-substituted phenylglyoxylic acid 1k was slow, the desired product 2k was
obtained in 40% isolated yield after 3 days. Interestingly, labile 4-chloromethyl-substituted phenylglycine 2l was
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1
1
1
1
1
1
1
1
1
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2
2
2
2
2
2
2
2
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obtained in 44% isolated yield without notable decomposition, which suggests high functional group compatibility.
Arylglycines 2m and 2n having moderately electron-withdrawing chloro- and electron-donating methoxy-
substituents at the 3-positions were also efficiently formed in 55% (isolated) and 59% (NMR) yields, respectively.
Because 2n was partly decomposed by heating to reflux, the isolated yield was 38%. 2-Substituted phenylglyoxylic
acids 1o–r were transformed into the corresponding arylglycines 2o–r in high NMR yields. Since 2-(2-
bromophenyl)glycine (2r) exhibited good reactivity as the nitrogen source as shown in Table 1, its self-
transamination was a concern. Nonetheless, 2r was produced in 61% NMR yield. Hence, the transamination of 2-
chlorophenylglyoxylic acid with 2r was also examined (Scheme 5); the reaction afforded L-2-(2-
chlorophenyl)glycine in lower NMR yield (26%). These results suggest that L-2-(2-chlorophenyl)glycine has higher
reactivity as the nitrogen source than 2-(2-bromophenyl)glycine (2r). Because heating at reflux degraded 2o–r, their
isolations were difficult. Only arylglycines 2o and 2p could be isolated in moderate yields. 2-(2-Naphthyl)glycine
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1
2
3
4
5
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(2s) was obtained in 72% isolated yield. Finally, we tried to prepare 2-(4-hydroxyphenyl)glycine and its derivatives,
O-benzylated 2-(3-chloro-4-hydroxyphenyl)glycine and 2-(3,5-dihydroxyphenyl)glycine, which are important
1
unnatural α-amino acids contained in biologically active peptides (Figure 1). Although the reaction to prepare 2-
(3,5-dibenzyloxyphenyl)glycine produced a complex mixture, arylglycines 2t–w were obtained in 48–65% isolated
yields. Phenolic hydroxy group, and allyl and benzyl ethers are compatible. These products are useful building blocks
to synthesize the biologically active peptides. We also examined the reactions of alkylglyoxylic acids. α-Amino acids
3
a-c were obtained in high yields. It suggests that this method is effective to the synthesis of arylglycines as well as
α-amino acids having alkyl side chains.
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Scheme 4. Substrate Scopea
4
5
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9
1
1
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1
1
1
1
1
1
1
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6
NH2
CO H
2
O
NH2
(
2 equiv)
Cl
OH
OH
0
1
2
3
4
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9
0
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2
3
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9
0
1
2
3
4
5
6
7
8
9
0
R
R
MeCN/H O
0 °C, 24 h
then reflux, 12 h
O
2
O
5
1
2
0.5 mmol
NH2
NH2
O
NH2
O
X = F 2b, 50% (62%)b
OH
OH
OH
OH
X = Cl 2c, 61%
X = Br 2d, 62%
O
X
F3C
BnO C
2
e, 38%c,d (67%)b
2
2f, 0%
NH2
NH2
NH2
NH2
O
OH
OH
OH
O
O
O
H C
3
H CO
3
2h, 45% (61%)b
2
g, 62%
2i, 79%
2j, 63%
NH2
NH2
NH2
NH2
OH
OH
Cl
OH
H CO
3
OH
O
Cl
O
O
O
(
H C) N
3
2
2k, 40%e
2n, 38% (59%)b
2l, 44%
2m, 55%
X
NH2
NH2
CH3 NH2
NH2
OH
OH
OH
OH
O
O
O
O
X = F 2q, (82%)b
X = Br 2r, (61%)b
2s, 72%
o, 44% (80%)b
2p, 36%c,d (71%)b
2
NH2
NH2
O
NH2
NH2
OH
Cl
OH
OH
OH
O
O
O
BnO
BnO
O
HO
2v, 50%c
2w, 63%
2
u, 65%
2
t, 48%
From Alkylglyoxylic Acid
NH2
NH2
NH2
OH
OH
OH
O
O
O
3
a, 82%
3b, 80%
3c, 68%
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a
b
1
Isolated yield. Percentages in parentheses are the yields determined by H NMR using DSS as an internal standard.
These reactions were separately conducted on 0.2 mmol scale from the reactions to determine isolated yields, and
c
d
worked up without heating to reflux. Isolated as the HCl salt. The reactions were worked up without heating to
e
reflux. Reaction time was 3 days.
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Scheme 5. Transamination of 2-Chlorophenylglyoxylic Acid with 2-(2-Bromophenyl)glycine (2r)
NH2
OH
O
Br
O
NH2
2r (2 equiv)
OH
OH
MeCN/H O
50 °C, 24 h
2
O
O
Cl
Cl
0.2 mmol
26% (NMR)
Arylglycine 2l has a chloromethylphenyl moiety as a handle for further modification. To demonstrate the utility of
2
l, its coupling with benzene thiolate anion was examined (Scheme 6). The reaction efficiently proceeded in the
presence of the unprotected α-amino acid moiety to afford thioether 4 in 72% isolated yield.
Scheme 6. Derivatization of 2l
NH2
SH
NH2
OH
(2.6 equiv)
OH
S
O
Na CO , H O
Cl
O
2
3
2
rt, 5 h
2l
4
72%
As above, L-2-(2-chlorophenyl)glycine enabled the synthesis of a variety of 2-arylglycines by the transamination of
arylglyoxylic acids. The effect of the chloro substituent at the 2-position is unclear at this time.15 An electron-
withdrawing effect that stabilizes the formed anion intermediate may promote the decarboxylation step. However, as
2
-methoxy- and 2-hydroxyphenylglycines also exhibited high reactivity similar to L-2-(2-chlorophenyl)glycine
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(Table 1), there is not a good correlation between the electronic effect of the substituents and the reactivity as the
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nitrogen source.
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CONCLUSIONS
In conclusion, we have developed a synthetic method of unprotected 2-arylglycines by the transamination of
arylglyoxylic acids. Commercially available L-2-(2-chlorophenyl)glycine was found as an effective nitrogen source,
although further investigation is required to clarify the effect of the chloro substituent. The optimized protocol enables
the preparation of a variety of arylglycines having a free α-amino acid moiety, including labile 2-(4-
chloromethylphenyl)glycine (2l) and medicinally important 2-(4-hydroxyphenyl)glycine and 2-(3-chloro-4-
hydroxyphenyl)glycine derivatives (2t–w). This method would be a useful tool for preparing arylglycines in peptide
drug development.
EXPERIMENTAL SECTION
All reactions were carried out under an argon atmosphere, stirred magnetically, unless otherwise noted. An oil bath
was used as a heating source for all the reactions that required heating in this work. Reactions were monitored by
thin-layer chromatography (TLC: Merck Silica Gel 60 F254). Column chromatography was carried out using neutral
silica gel (Cica silica gel 60N, particle size 0.040–0.050 mm, neutral, KANTO CHEMICAL CO., INC.) or SO H
3
®
silica gel (CHROMATOREX , FUJI SILYSIA CHEMICAL LTD.). NMR spectra were measured by JEOL ECS-
00 ( H NMR (400 MHz), 13C NMR (100 MHz)). 13C{ H} NMR spectra were fully decoupled. H and C{ H}
1
1
1
13
1
4
NMR chemical shifts are reported in parts per million (ppm, δ scale) relative to residual solvents or internal references
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(1
H NMR: CHCl at 7.26 ppm or tetramethylsilane at 0.00 ppm in CDCl , CD HOD at 3.31 ppm in CD OD, DMSO-
3 3 2 3
d at 2.50 ppm in DMSO-d , sodium 2,2-dimethyl-2-silapentane-5-sulfonate (DSS) at 0.00 ppm as an internal
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reference in D O; C NMR: CDCl at 77.0 ppm in CDCl , CD OD at 49.0 ppm in CD OD, DMSO-d at 39.52 ppm
2
3
3
3
3
6
in DMSO-d , DSS at 0.00 ppm as an internal reference in D O). Coupling constants (J) are reported in Hz.
6
2
Multiplicities are reported using the following abbreviations; s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet;
-1
m, multiplet; br, broad. Infrared (IR) spectra were recorded on a JASCO FT-IR-4200 at 4.0 cm resolution and
reported in wavenumbers. Mass spectra were measured by JEOL JMS-T100LP using Electrospray Ionization (ESI)
and Direct Analysis in Real Time (DART).
L-2-(2-Chlorophenyl)glycine,
phenylglyoxylic
acid
(1a),
DL-2-(2-chlorophenyl)glycine,
DL-4-(2-
chlorophenyl)glycine, 2-oxo-4-phenylbutanoic acid, phenylpyruvic acid, and 4-methyl-2-oxovaleric acid were
purchased from Tokyo Chemical Industry Co., Ltd. (TCI) and used as received.
Preparation of 2-(2-Bromophenyl)glycine as the Nitrogen Source
Methyl 2-(2-bromophenyl)glycinate. To a solution of 2-bromobenzaldehyde (5.56 g, 30.1 mmol) and NH Cl (3.39 g,
4
6
3.4 mmol) in MeOH (45 mL) and H O (15 mL) was added KCN (4.12 g, 63.3 mmol) at 0 °C. The reaction mixture
2
was stirred for 24 h at room temperature. After CH Cl and aq. HCl (6 M) were added, the resultant mixture was
2
2
separated into the organic layer and the aqueous layer. After the aqueous layer was washed with CH Cl the two
2
2,
organic layers were combined and extracted with aq. HCl (6 M). The two aqueous layers were combined and refluxed
for 34 h. After it was cooled to room temperature, MeOH was added. The solvents were removed to afford the crude
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material. After it was dissolved into MeOH (150 mL), SOCl (7.58 mL, 105 mmol) was added at 0 °C. The reaction
2
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8
9
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1
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mixture was refluxed for 18 h. It was cooled to room temperature and concentrated in vacuo. After aq. NaHCO was
3
0
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2
3
4
5
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7
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2
3
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0
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2
3
4
5
6
7
8
9
0
added to the residue, it was extracted with AcOEt. The organic layer was dried over Na SO , filtered, and
2
4
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane/AcOEt = 2/1
1
to 3/2) to afford methyl 2-(2-bromophenyl)glycinate (2.41 g, 33%) as a brown oil. H NMR (400 MHz, CDCl ) δ
3
13
1
7
.60–7.56 (m, 1H), 7.36–7.29 (m, 2H), 7.17 (ddd, J = 8.4, 6.4, 2.8 Hz, 1H), 5.03 (s, 1H), 3.73 (s, 3H); C{ H} NMR
-1
(
100 MHz, CDCl ) δ 173.8, 139.8, 133.2, 129.4, 128.4, 128.0, 123.6, 58.2, 52.5; IR (neat, cm ) 1738; HRMS (DART,
3
+
m/z) Calcd. for C H BrNO ·H ([M+H] ): 243.9973, found 243.9975.
9
10
2
2
-(2-Bromophenyl)glycine. After methyl 2-(2-bromophenyl)glycinate (244.1 mg, 1.00 mmol) was dissolved in aq.
KOH (10%, 5.3 mL), the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was
neutralized with aq. HCl (20%) and charged on a cationic ion exchange chromatography (DOWEX 50W–8, 200–
4
00 mesh). The product was eluted with aq.NH (3%). The eluent was concentrated in vacuo to afford 2-(2-
3
1
bromophenyl)glycine as a pale brown solid (198 mg, 86%). Mp 208 °C (decomp.); H NMR (400 MHz, D O with 4
2
13
1
eq of KOH) δ 7.64 (d, J = 8.0 Hz, 1H), 7.42–7.31 (m, 2H), 7.22 (td, J = 8.0, 2.0 Hz, 1H), 4.69 (s, 1H); C{ H} NMR
-1
(
100 MHz, D O with 4 eq of KOH) δ 183.0, 144.0, 135.7, 131.8, 131.7, 130.8, 125.9, 62.8; IR (KBr, cm ) 3300–
2
+
1
900, 1664, 1589, 1508; HRMS (DART, m/z) Calcd. for C H BrNO ·H ([M+H] ): 229.9817, found 229.9793.
8
8
2
Typical Procedure for the Preparation of 2-Arylglycine as a Nitrogen Source.
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2
-(2-Methoxyphenyl)glycine. To a solution of 2-methoxybenzaldehyde (2.07 g, 15.2 mmol) and NH Cl (1.72 g, 32.1
4
mmol) in MeOH (15 mL) and H O (7.6 mL) was added KCN (2.08 g, 32.0 mmol) at 0 °C. The reaction mixture was
2
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stirred for 5 h at room temperature. After CH Cl and aq. HCl (6 M) were added, the resultant mixture was separated
2
2
into the organic layer and the aqueous layer. After the aqueous layer was washed with CH Cl , the two organic layers
2
2
were combined. The organic layer was extracted with aq. HCl (6 M), the two aqueous layers were combined. The
resultant aqueous solution was refluxed for 13 h. After it was cooled to room temperature, MeOH was added. The
solvents were removed to afford the crude material. After it was dissolved into MeOH (76 mL), SOCl (3.84 mL,
2
5
3.3 mmol) was added at 0 °C. The reaction mixture was refluxed for 7 h. It was cooled to room temperature and
concentrated in vacuo. After aq. NaHCO was added to the residue, it was extracted with AcOEt. The organic layer
3
was dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by flash column
2
4
chromatography on silica gel (hexane/AcOEt = 1/1 to 1/2 to 0/1) to afford methyl 2-(2-methoxyphenyl)glycinate.
After methyl 2-(2-methoxyphenyl)glycinate was dissolved in aq. KOH (10%, 14 mL), the reaction mixture was
stirred for 1 h at room temperature. The reaction mixture was neutralized with aq. HCl (20%) and charged on a
cationic ion exchange chromatography (DOWEX 50W–8, 200–400 mesh). The product was eluted with aq. NH3
(3%). The eluent was concentrated to afford 2-(2-methoxyphenyl)glycine as a white solid (504 mg, 18%). Mp 150.1–
1
1
7
1
50.6 °C; H NMR (400 MHz, D O) δ 7.47 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H),
2
.05 (t, J = 8.0 Hz, 1H), 4.81 (s, 1H), 3.85 (s, 3H); 13C{ H} NMR (100 MHz, D O) δ 176.2, 159.9, 134.0, 133.9,
1
2
-1
24.7, 123.7, 114.3, 58.4, 58.0; IR (KBr, cm ) 3600–1900, 1633, 1603, 1498, 1458; HRMS (DART, m/z) Calcd. for
+
C H NO ·H ([M+H] ): 182.0817, found 182.0843.
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-(2-Hydroxyphenyl)glycine. Methyl 2-(2-hydroxyphenyl)glycinate was purified by flash column chromatography
8
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1
1
1
1
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2
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2
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2
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on silica gel (CHCl /MeOH = 20/1 to 10/1 to 8/1). Brown solid (332 mg, 20% yield), mp 161 °C (decomp.); H NMR
3
13
1
(
400 MHz, D O) δ 7.37–7.26 (m, 2H), 7.02–6.90 (m, 2H), 4.87 (s, 1H); C{ H} NMR (100 MHz, D O) δ 176.2,
2
2
-1
1
57.3, 133.7, 133.4, 123.4, 123.2, 118.5, 58.0; IR (KBr, cm ) 3700–2200, 1622, 1595, 1495, 1460; HRMS (DART,
+
m/z) Calcd. for C H NO ·H ([M+H] ): 168.0661, found 168.0649.
8
9
3
2
-(2-Trifluoromethylphenyl)glycine. Methyl 2-(2-trifluoromethylphenyl)glycinate was purified by flash column
chromatography on silica gel (hexane/AcOEt = 4/1 to 3/1). 2-(2-Trifluoromethylphenyl)glycine was isolated by
precipitation; After Et O was added to the reaction mixture, 2-(2-trifluoromethylphenyl)glycine was appeared as a
2
precipitate. It was corrected by filtration and washed with H O and Et O. White solid (128 mg, 4%), mp 260 ºC
2
2
1
(
decomp.); H NMR (400 MHz, D O with 6 eq of KOH) δ 7.74 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.49 (d,
2
13
1
J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 4.72 (s, 1H); C{ H} NMR (100 MHz, D O with 6 eq of KOH) δ 182.9,
2
43.7, 135.6, 130.8, 130.4, 130.2 (q, J = 29.6 Hz), 128.6 (q, J = 5.8 Hz), 127.2 (q, J = 271.8 Hz), 58.7; IR (KBr, cm-1)
1
3
2
+
300–1900, 1658, 1589, 1506, 1315; HRMS (DART, m/z) Calcd. for C H F NO ·H ([M+H] ): 220.0585, found
9
8
3
2
20.0561.
2
-(2-Fluorophenyl)glycine. Methyl 2-(2-fluorophenyl)glycinate was purified by flash column chromatography on
1
silica gel (hexane/AcOEt = 2/1 to 1/1). Brown solid (522 mg, 21%), mp 246 °C (decomp.); H NMR (400 MHz, D O
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with 6 eq of KOH) δ 7.41–7.30 (m, 2H), 7.20 (t, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 4.55 (s, 1H); C{ H}
NMR (100 MHz, D O with 6 eq of KOH) δ 183.1, 163.0 (d, J = 242.2 Hz), 132.0 (d, J = 8.5 Hz), 131.8 (d, J = 14.3
2
0
1
2
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0
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Hz), 131.8 (d, J = 3.8 Hz), 127.3 (d, J = 2.9 Hz), 118.3 (d, J = 21.9 Hz), 57.5; IR (KBr, cm ) 3400–1800, 1662,
+
1
624, 1587, 1537; HRMS (DART, m/z) Calcd. for C H FNO ·H ([M+H] ): 170.0617, found 170.0601.
8
8
2
2
-(2-Methylphenyl)glycine. Methyl 2-(2-methylphenyl)glycinate was purified by flash column chromatography on
1
silica gel (hexane/AcOEt = 1/1). Brown solid (470 mg, 19%), mp 204 ºC (decomp.). H NMR (400 MHz, D O with
2
13
1
4
1
eq of KOH) δ 7.30–7.19 (m, 4H), 4.56 (s, 1H), 2.38 (s, 3H); C{ H} NMR (100 MHz, D O with 4 eq of KOH) δ
2
-1
84.2, 143.3, 139.0, 133.3, 130.1, 129.3, 129.1, 59.8, 21.3; IR (KBr, cm ) 3300–1800; 1628, 1568, 1520; HRMS
+
(
DART, m/z) Calcd. for C H NO ·H ([M+H] ): 166.0868, found 166.0846.
9
11
2
2
-(3-Chlorophenyl)glycine. Methyl 2-(3-chlorophenyl)glycinate was purified by flash column chromatography on
1
silica gel. Pale brown solid (412 mg, 15%), mp 235 ºC (decomp.); H NMR (400 MHz, D O with 4 eq of KOH) δ
2
13
1
7
1
.42–7.26 (m, 4H), 4.34 (s, 1H); C{ H} NMR (100 MHz, D O with 4 eq of KOH) δ 183.0, 146.9, 136.4, 132.9,
2
-1
30.1, 129.5, 127.9, 62.8; IR (KBr, cm ) 3300–1900, 1655, 1631, 1583, 1522; HRMS (DART, m/z) Calcd. for
+
C H ClNO ·H ([M+H] ): 186.0322, found 186.0347.
8
8
2
Methyl N-Boc-2-(2-bromophenyl)glycinate. To a solution of methyl 2-(2-bromophenyl)glycinate (689 mg, 2.82
mmol) prepared by the above procedure and Et N (831 μL, 5.99 mmol) in CH Cl (15 mL) was added di-tert-butyl
3
2
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dicarbonate (826 μL, 3.60 mmol) at 0 °C. After the reaction mixture was stirred for 4 h at room temperature, it was
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quenched with saturated aq. NH Cland extracted with AcOEt. The organic layer was dried over MgSO , filtered, and
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9
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concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane/AcOEt = 15/1
1
to 10/1) to afford methyl N-Boc-2-(2-bromophenyl)glycinate (835 mg, 86%) as a white solid. Mp 95.6–96.1 ºC; H
NMR (400 MHz, CDCl ) δ 7.58 (dd, J = 8.0, 1.2 Hz, 1H), 7.36–7.27 (m, 2H), 7.18 (ddd, J = 8.4, 6.8, 2.4 Hz, 1H),
3
13
1
5
1
.73–5.48 (m, 2H), 3.73 (s, 3H), 1.50–1.21 (m, 9H); C{ H} NMR (100 MHz, CDCl ) δ 171.1, 154.8, 136.9, 133.5,
3
-1
29.8, 129.7, 127.8, 123.7, 80.3, 57.6, 52.9, 28.3; IR (neat, cm ) 1747, 1714; HRMS (DART, m/z) Calcd. for
+
C H BrNO ·H ([M+H] ): 344.0498, found 344.0517.
1
4
18
4
N-Boc-2-(2-phenylphenyl)glycinate. To a flask charged with methyl N-Boc-2-(2-bromophenyl)glycinate (377 mg,
1
.64 mmol), phenylboronic acid (300 mg, 2.46 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloride dichloromethane adduct (67.6 mg, 82.8 μmol), were added THF (6.6 mL) and aq. Na CO (1 M, 1.6 mL).
2
3
The mixture was degassed by freeze–pump–thaw cycles. After it was refluxed for 2 h, it was diluted with AcOEt and
H O and extracted with AcOEt. The organic layer was dried over MgSO , filtered, and concentrated in vacuo. The
2
4
residue was purified by flash column chromatography on silica gel (hexane/AcOEt = 10/1) to afford methyl N-Boc-
2
-(2-phenylphenyl)glycinate with small amount of the starting material. Because it was difficult to separate the
desired product and the starting material, the mixture was exposed to Suzuki-Miyaura coupling conditions again
using phenylboronic acid (155 mg, 1.27 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
dichloromethane adduct (68.5 mg, 83.9 μmol), THF (6.6 mL), and aq. Na CO (1 M, 1.6 mL). After the reaction
2
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mixture was refluxed for 1 h, it was diluted with AcOEt and H O and extracted with AcOEt. The organic layer was
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dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by flash column chromatography
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on silica gel (hexane/AcOEt = 10/1) to methyl N-Boc-2-(2-phenylphenyl)glycinate (356 mg, 64%) in pure form as a
1
white amorphous. H NMR (400 MHz, CDCl ) δ 7.46–7.31 (m, 8H), 7.31–7.26 (m, 1H), 5.45–5.34 (m, 1H), 5.28
3
13
1
(
br s, 1H), 3.63 (s, 3H), 1.50–1.19 (m, 9H); C{ H} NMR (100 MHz, CDCl ) δ 172.1, 154.4, 142.4, 140.2, 134.4,
3
-1
1
30.9, 129.4, 128.3, 128.2, 128.0, 127.4, 126.7, 79.9, 54.5, 52.5, 28.3; IR (neat, cm ) 1745, 1714; HRMS (DART,
+
m/z) Calcd. for C H NO ·H ([M+H] ): 342.1705, found 342.1732.
2
0
23
4
2
-(2-Phenylphenyl)glycine. To a solution of methyl N-Boc-2-(2-phenylphenyl)glycinate (356 mg, 1.04 mmol) in
CH Cl (5.2 mL) was added trifluoroacetic acid (1.76 μL, 22.9 mmol) at room temperature. The reaction mixture was
2
2
stirred for 1 h at room temperature and it was concentrated in vacuo. After the residue was dissolved in aq. KOH
(10%, 5.2 mL), the reaction mixture was stirred for 1 h at room temperature. Then, 1,4-dioxane (5.2 mL) was added
and the reaction mixture was stirred for 30 min at room temperature. After the reaction mixture was neutralized with
aq. HCl (20%), Et O was added. The reaction mixture was separated into organic layer and aqueous layer. The
2
aqueous layer was charged on a cationic ion exchange chromatography (DOWEX 50W–8, 200–400 mesh). The
product was eluted with aq. NH (3%). The eluent was concentrated in vacuo to afford 2-(2-phenylphenyl)glycine as
3
1
a white solid (200 mg, 84%). Mp 182.2–182.8 ºC; H NMR (400 MHz, D O with 5 eq of KOH) δ 7.54–7.34 (m,
2
13
1
8
1
H), 7.27 (d, J = 8.0 Hz, 1H), 4.45 (s, 1H); C{ H} NMR (100 MHz, D O with 4 eq of KOH) δ 183.9, 144.0, 143.5,
2
-1
42.7, 132.8, 132.1, 131.1, 130.9, 130.02, 129.99, 129.3, 59.3; IR (KBr, cm ) 3700–1800, 1626, 1481; HRMS
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(
DART, m/z) Calcd. for C H NO ·H ([M+H] ): 228.1025, found 228.1010.
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Preparation of Arylglyoxylic Acids.
Typical Procedure A: Preparation from the Corresponding Mandelic Acids.16
4
-Fluorophenylglyoxylic acid (1b). To a 200 mL flask charged with 4-fluoromandelic acid (541 mg, 3.18 mmol) and
AZADOL (24.4 mg, 0.159 mmol) in MeCN (16 mL) was added NaNO (44.1 mg, 0.639 mmol) at room temperature.
2
The reaction mixture was stirred under air (balloon) for 2 h. Then, it was quenched with aq. HCl (1 M) and extracted
with AcOEt. The organic layer was dried over MgSO and concentrated under reduced pressure. The crude materials
4
were purified by column chromatography on silica gel (SO H, hexane/AcOEt = 4/1) and azeotropic dried with hexane
3
1
to afford arylglyoxylic acid 1b (518 mg, 97%) as a white solid. Mp 89.7–92.9 °C; H NMR (400 MHz, CDCl ) δ
3
13
1
8
1
1
.55–8.50 (m, 2H), 7.22 (t, J = 9.2 Hz, 2H); C{ H} NMR (100 MHz, CDCl ) δ 182.6, 167.3 (d, J = 259.3 Hz),
3
-1
61.6, 134.4 (d, J = 9.5 Hz), 128.2 (d, J = 2.9 Hz), 116.4 (d, J = 21.9 Hz); IR (neat, cm ) 3800–2300, 1728, 1682,
+
597; HRMS (DART, m/z) Calcd. for C H FO ·NH ([M+NH ] ): 186.0567, found 186.0569.
8
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4
4
16
4
-Bromophenylglyoxylic acid (1d). Purified by column chromatography on silica gel (SO H, hexane/AcOEt = 2/1),
3
1
White solid (681 mg, 99%); H NMR (400 MHz, CDCl ) δ 8.31 (dt, J = 8.8, 2.0 Hz, 2H), 7.70 (dt, J = 8.8, 2.0 Hz,
3
2
H).
4
-(Trifluoromethyl)phenylglyoxylic acid (1e).16 Purified by column chromatography on silica gel (SO H,
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hexane/AcOEt = 2/1), White solid (556 mg, quant.).; H NMR (400 MHz, CDCl ) δ 8.52 (d, J = 8.0 Hz, 2H), 7.81
3
(d, J = 8.0 Hz, 2H).
0
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-Chlorophenylglyoxylic acid (1m). Purified by column chromatography on silica gel (SO H, hexane/AcOEt = 2/1).
3
1
Pale yellow solid (550 mg, 99%), mp 54.5–58.2 °C; H NMR (400 MHz, CDCl ) δ 8.36 (t, J = 1.8 Hz, 1H), 8.32 (dt,
3
13
1
J = 8.0, 1.8 Hz, 1H), 7.69 (dq, J = 8.0, 1.8 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H); C{ H} NMR (100 MHz, CDCl ) δ
3
-1
1
83.3, 162.5, 135.5, 135.3, 133.1, 130.7, 130.3, 129.2; IR (neat, cm ) 3600–2800; 1711, 1682; HRMS (DART, m/z)
+
Calcd. for C H ClO ·NH ([M+NH ] ): 202.0271, found 202.0242.
8
5
3
4
4
2
-(4-Benzyloxyphenyl)-2-hydroxyacetic acid. To a 200 mL flask charged with 2-hydroxy-2-(4-hydroxyphenyl)acetic
acid monohydrate (1.87 g, 10.1 mmol) and K CO (9.79 g, 70.8 mmol) in DMF (14 mL) was added BnBr (3.58 mL,
2
3
3
0.2 mmol) at 0 °C. After the reaction mixture was stirred for 2 h at room temperature, it was quenched with H O
2
and extracted with a solution of hexane and AcOEt (4/1). The organic layer was dried over MgSO and concentrated
4
under reduced pressure. To a solution of the crude material in THF (11 mL) and EtOH (2.9 mL) was added aq. NaOH
(
5.2 M, 14.0 mL, 72.5 mmol) at room temperature. The reaction mixture was stirred for 3 h. Then, the reaction
mixture was acidified with aq. HCl (10%) and extracted with AcOEt. The organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. The solid material was dissolved in hot AcOEt and reprecipitated by an addition
of hexane. After filtration, the precipitate was washed with hexane and dried under reduced pressure. 2-(4-
(
Benzyloxy)phenyl)-2-hydroxyacetic acid (1.26 g) was obtained in 49% yield (2 steps) as a white solid. Mp 133.4–
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36.3 °C; H NMR (400 MHz, CDCl ) δ 7.45–7.32 (m, 7H), 6.99 (d, J = 8.8 Hz, 2H), 5.21 (s, 1H), 5.07 (s, 2H);
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C{ H} NMR (100 MHz, DMSO-d ) δ 174.3, 157.9, 137.1, 132.6, 128.4, 127.9, 127.8, 127.6, 114.4, 71.9, 69.2; IR
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-1
+
(KBr, cm ) 3546, 3489, 3500–2300, 1697; HRMS (DART, m/z) Calcd. for C H O ·NH ([M+NH ] ): 276.1236,
1
5
14
4
4
4
found 276.1251.
4
-Benzyloxyphenylglyoxylic acid (1v). Purified by column chromatography on silica gel (SO H, hexane/AcOEt = 6/1
3
1
to 4/1). Pale yellow solid (646 mg, 83%). Mp 90.8–91.5 °C; H NMR (400 MHz, CDCl ) δ 8.50 (d, J = 8.8 Hz, 2H),
3
13
1
7
1
.46–7.33 (m, 5H), 7.07 (d, J = 8.8 Hz, 2H), 5.19 (s, 2H); C{ H} NMR (100 MHz, CDCl ) δ 181.7, 164.9, 161.0,
3
-1
35.6, 134.5, 128.8, 128.5, 127.5, 124.8, 115.2, 70.4; IR (neat, cm ) 3800–2300, 1741, 1672; HRMS (DART, m/z)
+
Calcd. for C H O ·H ([M+H] ): 257.0814, found 257.0810.
1
5
12
4
2
-Chlorophenylglyoxylic acid. Purified by column chromatography on silica gel (SO H, hexane/AcOEt = 4/1). White
3
1
solid (539 mg, 97%), mp 112.6–114.2 °C; H NMR (400 MHz, CDCl ) δ 7.86 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6
3
13
1
Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H); C{ H} NMR (100 MHz, CDCl ) δ 185.7, 164.0, 134.6,
3
-1
1
34.1, 132.3, 131.9, 130.8, 127.2; IR (neat, cm ) 3700–2300, 1684; HRMS (DART, m/z) Calcd. for C H ClO ·NH
8
5
3
4
+
([M+NH ] ): 202.0271, found 202.0266.
4
Typical Procedure B: Preparation from the Corresponding Styrenes.
1
-(4-Chlorophenyl)ethane-1,2-diol. To a solution of 1-chloro-4-vinylbenzene (1.41 g, 10.2 mmol) and N-
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methylmorpholine N-oxide (1.79 g, 15.3 mmol) in acetone (46 mL) and H O (5.1 mL) was added osmium tetroxide
2
(
4% in H O, 621 μL, 102 μmol) at 0 °C. After the reaction mixture was stirred for 18 h at room temperature, it was
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quenched with saturated aq. Na S O and extracted with AcOEt. The organic layer was dried over MgSO , filtered,
2
2
3
4
and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane/AcOEt
1
=
1/1) to afford 1-(4-chlorophenyl)ethane-1,2-diol (1.57 g, 90%) as a white solid. Mp 79.9–80.6 °C; H NMR (400
MHz, CDCl ) δ 7.36–7.29 (m, 4 H), 4.82 (dt, J = 8.0, 3.6 Hz, 1H), 3.76 (ddd, J = 10.8, 7.2, 3.6 Hz, 1H), 3.63 (ddd,
3
13
1
J = 10.8, 8.0, 4.4 Hz, 1H), 2.53 (d, J = 3.6 Hz, 1H), 1.98 (dd, J = 7.2, 4.4 Hz, 1H); C{ H} NMR (100 MHz, CDCl )
3
-1
δ 138.8, 133.7, 128.7, 127.4, 74.0, 67.8; IR (neat, cm ) 3800–3000, 1082; HRMS (DART, m/z) Calcd. for
+
C H ClNO ·NH ([M+NH ] ): 190.0635, found 190.0662.
8
9
2
4
4
4
-Chlorophenylglyoxylic acid (1c). To a 100 mL flask charged with 1-(4-chlorophenyl)ethane-1,2-diol (345 mg, 2.00
mmol), nor-AZADO (27.7 mg, 0.200 mmol), and AcOH (229 μL, 4.00 mmol) in MeCN (5.0 mL) and H O (5.0 mL)
2
was added NaNO (55.2 mg, 0.800 mmol) at room temperature. After the reaction mixture was stirred under air
2
(balloon) for 18 h, it was quenched with aq. HCl (1 M) and extracted with AcOEt. The organic layer was dried over
MgSO and concentrated under reduced pressure. The crude materials were purified by column chromatography on
4
silica gel (SO H, hexane/AcOEt = 2/1) to afford arylglyoxylic acid 1c (346 mg, 94%) as a white solid. Mp 84.9–87.4
3
1
13
1
°
C; H NMR (400 MHz, CDCl ) δ 8.38 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H); C{ H} NMR (100 MHz,
3
-1
CDCl ) δ 183.4, 162.0, 142.6, 132.5, 130.1, 129.4; IR (neat, cm ) 3800–3000, 1718, 1670; HRMS (DART, m/z)
3
+
Calcd. for C H ClO ·H ([M+H] ): 185.0006, found 185.0020.
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Benzyl 4-(1,2-dihydroxyethyl)benzoate. Benzyl 4-vinylbenzoate was prepared from 4-vinylbenzoic acid according to
8
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the previous report. Benzyl 4-(1,2-dihydroxyethyl)benzoate was purified by flash column chromatography on silica
gel (hexane/AcOEt = 1/1 to 1/2). White solid (2.46 g, 90% (3 steps from benzyl 4-vinylbenzoate)), mp 45.4–45.8 ºC;
1
H NMR (400 MHz, CDCl ) δ 8.07 (d, J = 8.0 Hz, 2H), 7.45–7.31 (m, 7H), 5.36 (s, 2H), 4.89 (dt, J = 7.6, 3.6 Hz,
3
1
H), 3.80 (ddd, J = 11.2, 6.8, 3.6 Hz, 1H), 3.64 (ddd, J = 11.2, 7.6, 4.4 Hz, 1H), 2.66 (d, J = 3.6 Hz, 1H), 2.06 (dd, J
13
1
=
6.8, 4.4 Hz, 1H); C{ H} NMR (100 MHz, CDCl ) δ 166.2, 145.7, 135.9, 129.9, 129.7, 128.6, 128.3, 128.1, 126.0,
3
-1
+
7
2
4
4.2, 67.8, 66.7; IR (neat, cm ) 3800–2800, 1714; HRMS (DART, m/z) Calcd. for C H O ·NH ([M+NH ] ):
1
6
16
4
4
4
90.1392, found 290.1418.
-(Benzyloxycarbonyl)phenylglyoxylic acid (1f). Purified by column chromatography on silica gel (SO H,
3
1
hexane/AcOEt = 5/1 to 4/1). White solid (689 mg, 79%), mp 50.3–52.0 °C; H NMR (400 MHz, CDCl ) δ 8.44 (dt,
3
13
1
J = 8.8, 2.0 Hz, 2H), 8.21 (dt, J = 8.8, 2.0 Hz, 2H), 7.48–7.34 (m, 5H), 5.41 (s, 2H); C{ H} NMR (100 MHz,
-1
CDCl ) δ 184.0, 165.3, 161.1, 135.8, 135.3, 134.9, 131.1, 130.4, 128.7, 128.6, 128.4, 67.5; IR (neat, cm ) 3800–
3
+
2
300, 1722, 1695; HRMS (DART, m/z) Calcd. for C H O ·NH ([M+NH ] ): 302.1029, found 302.1042.
1
6
12
5
4
4
1
-(p-Tolyl)ethane-1,2-diol. Purified by column chromatography on silica gel (hexane/AcOEt = 1/1 to 1/2). White
1
solid (1.47 g, 96%), mp 75.4–75.8 °C; H NMR (400 MHz, CDCl ) δ 7.27 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz,
3
2
H), 4.81 (dt, J = 8.0, 4.0 Hz, 1H), 3.75 (ddd, J = 10.8, 7.2, 4.0 Hz, 1H), 3.67 (ddd, J = 10.8, 8.0, 5.2 Hz, 1H), 2.38
13
1
(
d, J = 4.0 Hz, 1H), 2.35 (s, 3H), 1.98 (dd, J = 7.2, 5.2 Hz, 1H); C{ H} NMR (100 MHz, CDCl ) δ 137.7, 137.5,
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29.2, 126.0, 74.5, 68.1, 21.1; IR (neat, cm ) 3700–2400; HRMS (DART, m/z) Calcd. for C H O ·NH ([M+
9
11
2
4
+
NH ] ): 1701181, found 170.1166.
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
-Methylphenylglyoxylic acid (1g). Purified by column chromatography on silica gel (SO H, hexane/AcOEt = 6/1).
3
1
White solid (417 mg, 84%), mp 92.9–94.3 °C; H NMR (400 MHz, CDCl ) δ 8.34 (d, J = 8.0 Hz, 2H), 7.34 (d, J =
3
.0 Hz, 2H), 2.46 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 183.6, 161.3, 147.4, 131.6, 129.7, 129.2, 22.0; IR
1
8
3
-1
+
(
neat, cm ) 3300–2300, 1724, 1678; HRMS (DART, m/z) Calcd. for C H O ·NH ([M+ NH ] ): 182.0817, found
9
8
3
4
4
1
82.0816.
1
-(4-tert-Butylphenyl)ethane-1,2-diol. Purified by column chromatography on silica gel (hexane/AcOEt = 2/1 to 1/1).
1
White solid (1.77 g, 90%), mp 126.3–127.2 °C; H NMR (400 MHz, CDCl ) δ 7.40 (d, J = 8.0 Hz, 2H), 7.31 (d, J =
3
8
1
1
.0 Hz, 2H), 4.81 (dt, J = 8.0, 4.0 Hz, 1H), 3.77 (ddd, J = 11.6, 8.0, 4.0 Hz, 1H), 3.69 (ddd, J = 11.6, 8.0, 4.8 Hz,
13
1
H), 2.36 (d, J = 4.0 Hz, 1H), 1.99 (dd, J = 8.0, 4.8 Hz, 1H), 1.32 (s, 9H); C{ H} NMR (100 MHz, CDCl ) δ 150.9,
3
-1
37.4, 125.8, 125.4, 74.5, 68.0, 34.5, 31.3; IR (neat, cm ) 3600–3100; HRMS (DART, m/z) Calcd. for C H O ·NH
1
2
18
2
4
+
([M+NH ] ): 212.1651, found 212.1647.
4
4
-tert-Butylphenylglyoxylic acid (1h). Purified by column chromatography on silica gel (SO H, hexane/AcOEt =
3
1
6
/1). White solid (562 mg, 91%), mp 58.9–61.8 °C; H NMR (400 MHz, CDCl ) δ 8.37 (d, J = 8.8 Hz, 2H), 7.55 (d,
3
13
1
J = 8.8 Hz, 2H), 1.36 (s, 9H); C{ H} NMR (100 MHz, CDCl ) δ 183.9, 161.8, 160.0, 131.4, 129.1, 126.0, 35.5,
3
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1
2
3
4
-1
+
3
0.9; IR (neat, cm ) 3800–2300, 1734, 1682; HRMS (DART, m/z) Calcd. for C H O ·NH ([M+NH ] ): 224.1287,
1
2
14
3
4
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
found 224.1263.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
-(4-phenylphenyl)ethane-1,2-diol. Purified by column chromatography on silica gel (hexane/AcOEt = 1/1 to 0/1).
1
Pale brown solid (1.47 g, 99%), mp 144.0–146.0 °C; H NMR (400 MHz, CD OD) δ 7.63–7.55 (m, 4H), 7.46 (d, J
3
=
8.4 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H), 4.73 (dd, J = 7.6, 5.6 Hz, 1H), 3.67–3.62 (m, 2H);
13
1
C{ H} NMR (100 MHz, CD OD) δ 142.4, 142.2, 141.7, 129.8, 128.3, 127.94, 127.92, 127.8, 75.7, 68.7; IR (KBr,
3
-1
+
cm ) 3600–3000; HRMS (DART, m/z) Calcd. for C H O ·NH ([M+NH ] ): 232.1338, found 232.1319.
1
4
14
2
4
4
4
-Phenylphenylglyoxylic acid (1i). Purified by column chromatography on silica gel (SO H, hexane/AcOEt = 6/1).
3
1
Pale yellow solid (638 mg, 79%), mp 100.0–101.9 °C; H NMR (400 MHz, CDCl ) δ 8.53 (d, J = 8.4 Hz, 2H), 7.77
3
13
1
(d, J = 8.4 Hz, 2H), 7.66 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.2 Hz, 2H), 7.44 (t, J = 7.2 Hz, 1H); C{ H} NMR (100
-1
MHz, CDCl ) δ 183.7, 161.7, 148.3, 139.2, 132.0, 130.3, 129.1, 128.9, 127.5, 127.4; IR (neat, cm ) 3600–2200,
3
+
1
730, 1682; HRMS (DART, m/z) Calcd. for C H O ·NH ([M+NH ] ): 244.0974, found 244.0969.
1
4
10
3
4
4
1
-(4-Methoxyphenyl)ethane-1,2-diol. Purified by column chromatography on silica gel (hexane/AcOEt = 1/1 to 2/3).
1
White solid (1.59 g, 94%), mp 77.7–79.7 °C; H NMR (400 MHz, CDCl ) δ 7.30 (d, J = 8.8 Hz, 2H), 6.90 (d, J =
3
8
.8 Hz, 2H), 4.79 (dt, J = 8.0, 3.6 Hz, 1H), 3.81 (s, 3H), 3.74 (ddd, J = 11.2, 7.6, 3.6 Hz, 1H), 3.66 (ddd, J = 11.2,
13
1
8
.0, 4.8 Hz, 1H), 2.39 (d, J = 3.6 Hz, 1H), 2.00 (dd, J = 7.6, 4.8 Hz, 1H); C{ H} NMR (100 MHz, CDCl ) δ 159.2,
3
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
1
32.6, 127.3, 113.8, 74.2, 67.9, 55.2; IR (neat, cm ) 3600–3000; HRMS (DART, m/z) Calcd. for C H O ·NH
9
12
3
4
+
([M+NH ] ): 186.1130, found 186.1144.
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
-Methoxyphenylglyoxylic acid (1j). Purified by column chromatography on silica gel (SO H, hexane/AcOEt = 2/1).
3
1
White solid (352 mg, 86%), mp 81.4–84.4 °C; H NMR (400 MHz, CDCl ) δ 8.53–8.46 (m, 2H), 7.00 (d, J = 8.8
3
13
1
Hz, 2H), 3.92 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 182.2, 166.8, 161.7, 134.3, 124.7, 114.4, 55.7; IR (neat,
3
-1
+
cm ) 3800–2300, 1730, 1670: HRMS (DART, m/z) Calcd. for C H O ·H ([M+H] ): 181.0501, found 181.0497.
9
8
4
1
-(4-(Chloromethyl)phenyl)ethane-1,2-diol. Purified by column chromatography on silica gel (hexane/AcOEt = 1/1
1
to 2/3). White solid (824 mg, 44%), mp 102.2–103.6 °C; H NMR (400 MHz, CDCl ) δ 7.42–7.36 (m, 4H), 4.85 (dt,
3
J = 8.0, 3.2 Hz, 1H), 4.59 (s, 2H), 3.78 (ddd, J = 10.8, 6.8, 3.2 Hz, 1H), 3.66 (ddd, J = 10.8, 8.0, 4.8 Hz, 1H), 2.48
13
1
(
d, J = 3.2 Hz, 1H), 1.97 (dd, J = 6.8, 4.8 Hz, 1H); C{ H} NMR (100 MHz, CDCl ) δ 140.8, 137.2, 128.8, 126.5,
3
-1
+
7
4.3, 68.0, 45.9; IR (neat, cm ) 3500–2800; HRMS (DART, m/z) Calcd. for C H ClO ·NH ([M+NH ] ): 204.0791,
9
11
2
4
4
found 204.0771.
4
-(Chloromethyl)phenylglyoxylic acid (1l). Purified by column chromatography on silica gel (SO H, hexane/AcOEt
3
1
=
6/1 to 4/1). White solid (550 mg, 91%), mp 53.8–57.7 °C; H NMR (400 MHz, CDCl ) δ 8.42 (d, J = 8.4 Hz, 2H),
3
13
1
7
4
.57 (d, J = 8.4 Hz, 2H), 4.64 (s, 2H); C{ H} NMR (100 MHz, CDCl ) δ 183.8, 162.0, 145.1, 131.7, 131.5, 129.0,
3
-1
+
5.0; IR (neat, cm ) 3600–2300, 1718, 1684; HRMS (DART, m/z) Calcd. for C H ClO ·NH ([M+NH ] ): 216.0428,
9
7
3
4
4
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The Journal of Organic Chemistry
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2
3
4
found 216.0426.
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
-(3-Methoxyphenyl)ethane-1,2-diol. Purified by column chromatography on silica gel (hexane/AcOEt = 1/1 to 0/1).
1
White solid (1.34 g, 90%), mp 67.2–67.8 °C; H NMR (400 MHz, CDCl ) δ 7.28 (t, J = 8.0 Hz, 1H), 6.97–6.92 (m,
3
2
H), 6.88–6.83 (m, 1H), 4.82 (dt, J = 7.6, 3.6 Hz, 1H), 3.82 (s, 3H), 3.78 (ddd, J = 11.2, 7.6, 3.6 Hz, 1H), 3.67 (ddd,
13
1
J = 11.2, 7.6, 4.4 Hz, 1H), 2.46 (d, J = 3.6 Hz, 1H), 1.98 (dd, J = 7.6, 4.4 Hz, 1H); C{ H} NMR (100 MHz, CDCl )
3
-1
δ 159.8, 142.2, 129.6, 118.3, 113.4, 111.6, 74.6, 68.0, 56.2; IR (neat, cm ) 3700–3000; HRMS (DART, m/z) Calcd.
+
for C H O ·NH ([M+NH ] ): 186.1130, found 186.1139.
9
12
3
4
4
3
-Methoxyphenylglyoxylic acid (1n). Purified by column chromatography on silica gel (SO H, hexane/AcOEt = 3/1).
3
1
Yellow solid (531 mg, 96%), mp 66.1–66.8 °C; H NMR (400 MHz, CDCl ) δ 8.05 (d, J = 7.6 Hz, 1H), 7.87–7.85
3
13
1
(m, 1H), 7.45 (t, J = 7.6 Hz, 1H). 7.28–7.24 (m, 1H), 3.89 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 184.2, 161.8,
3
-1
1
59.8, 132.8, 130.0, 124.3, 122.7, 114.4, 55.6; IR (neat, cm ) 3800–2400, 1741, 1684; HRMS (DART, m/z) Calcd.
+
for C H O ·NH ([M+H] ): 181.0501, found 181.0506.
9
8
4
4
1
-(o-Tolyl)ethane-1,2-diol. Purified by column chromatography on silica gel (hexane/AcOEt = 1/1). White solid
1
(1.47 g, 94%), mp 107.2–109.0 °C; H NMR (400 MHz, CDCl ) δ 7.50 (d, J = 8.4 Hz, 1H), 7.27–7.13 (m, 3H), 5.08
3
(dt, J = 8.0, 3.2 Hz, 1H), 3.74 (ddd, J = 11.2, 7.2, 3.2 Hz, 1H), 3.62 (ddd, J = 11.2, 8.0, 4.0 Hz, 1H), 2.36 (d, J = 3.2
13
1
Hz, 1H), 2.35 (s, 3H), 2.08 (dd, J = 7.2, 4.0 Hz, 1H); C{ H} NMR (100 MHz, CD OD) δ 141.0, 136.0, 131.1, 128.3,
3
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
1
27.0, 126.9, 72.4, 67.8, 19.2; IR (KBr, cm ) 3600–2300; HRMS (DART, m/z) Calcd. for C H O ·NH
9
12
2
4
+
([M+NH ] ): 170.1166, found 170.1181.
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
-Methylphenylglyoxylic acid (1o). Purified by column chromatography on silica gel (SO H, hexane/AcOEt = 6/1).
3
1
White solid (487 mg, 98%), mp 34.3–35.9 °C; H NMR (400 MHz, CDCl ) δ 8.13 (d, J = 7.6 Hz, 1H), 7.54 (td, J =
3
13
1
7
.2, 1.2 Hz, 1H), 7.39–7.32 (m, 2H), 2.59 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 187.3, 165.3, 141.8, 134.2,
3
-1
1
32.8, 132.3, 130.4, 126.0, 21.5; IR (neat, cm ) 3600–2400, 1739, 1685; HRMS (DART, m/z) Calcd. for
+
C H O ·NH ([M+NH ] ): 182.0845, found 182.0817.
9
8
3
4
4
1
-(1-Naphthalenyl)ethane-1,2-diol. Purified by column chromatography on silica gel (hexane/AcOEt = 1/1 to 0/1).
1
Pale brown solid (1.83 g, 97%), mp 135.8–137.8 °C; H NMR (400 MHz, CD OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.87
3
(
d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 6.8 Hz, 1H), 7.55–7.54 (m, 3H), 5.53 (dd, J = 8.4, 4.0 Hz,
13
1
1
1
H), 3.85 (dd, J = 12.0 4.0 Hz, 1H), 3.69 (dd, J = 12.0, 8.4 Hz, 1H); C{ H} NMR (100 MHz, CD OD) δ 138.7,
3
-1
35.2, 132.1, 129.9, 128.9, 127.0, 126.5, 126.4, 124.7, 124.0, 72.8, 68.4; IR (neat, cm ) 3600–2900, 1676; HRMS
+
(
DART, m/z) Calcd. for C H O ·NH ([M+NH ] ): 206.1181, found 206.1157.
1
2
12
2
4
4
1
-Naphthylglyoxylic acid (1p). Purified by column chromatography on silica gel (SO H, hexane/AcOEt = 4/1). Pale
3
1
yellow solid (516 mg, 86%), mp 92.3–94.3 °C; H NMR (400 MHz, CDCl ) δ 8.83 (d, J = 8.0 Hz, 1H), 8.56 (d, J =
3
6
.4 Hz, 1H), 8.18 (d, J =8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.71 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.64–7.58 (m,
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The Journal of Organic Chemistry
1
2
3
4
13
1
2
H); C{ H} NMR (100 MHz, CDCl ) δ 186.6, 163.5, 136.5, 135.1, 133.9, 131.1, 129.5, 129.0, 127.4, 127.1, 125.4,
3
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
+
1
24.4; IR (neat, cm ) 3800–2300, 1732, 1674; HRMS (DART, m/z) Calcd. for C H O ·NH ([M+NH ] ): 218.0817,
1
2
8
3
4
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
found 218.0822.
Typical Procedure C: Preparation from the Corresponding Arylaldehydes.
1
-(2-Fluorophenyl)ethane-1,2-diol. To a well-dried flask charged with CH PPh Br (5.18 g, 14.5 mmol) and dry THF
3 3
n
(
30 mL) was added BuLi (15wt%, 8.53 mL, 14.5 mmol) dropwise at 0 °C. After the mixture was stirred for 20 min,
a solution of 2-fluorobenzaldehyde (1.50 g, 12.1 mmol) in THF (24 mL) was added at -78 °C. The reaction mixture
was stirred for 3 h at 0 °C. Then, it was quenched with saturated aq. NH Cl and extracted with AcOEt. The organic
4
layer was dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by flash column
4
chromatography on silica gel (hexane/Et O = 20/1) to afford 1-fluoro-2-vinylbenzene containing impurities, which
2
was used to the next reaction without further purification. To a solution of 1-fluoro-2-vinylbenzene and N-
methylmorpholine N-oxide (2.19 g, 18.7 mmol) in acetone (55 mL) and H O (6.1 mL) was added osmium tetroxide
2
(
4% in H O, 739 μL, 121 μmol) at 0 °C. The reaction mixture stirred for 17 h at room temperature. It was quenched
2
with saturated aq. Na S O and extracted with AcOEt. The organic layer was dried over MgSO , filtered, and
2
2
3
4
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane/AcOEt = 1/1)
1
to afford 1-(2-fluorophenyl)ethane-1,2-diol (715 mg, 38% (2 steps)) as a white solid. Mp 80.4–81.2 °C; H NMR
(
400 MHz, CDCl ) δ 7.53 (td, J = 7.6, 2.0 Hz, 1H), 7.32–7.24 (m, 1H), 7.20–7.15 (m, 1H), 7.04 (dd, J = 10.0, 8.4
3
Hz, 1H), 5.16 (dt, J = 7.6, 3.6 Hz, 1H), 3.87 (ddd, J = 10.8, 7.2, 3.6 Hz, 1H), 3.67 (ddd, J = 10.8, 7.6, 5.2 Hz, 1H),
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