Bismuth- and Iron-Catalyzed Three-Component Synthesis of α-Amino Acid Derivatives: A Simple and Convenient Route to α-Arylglycines

Article abstract of DOI:10.1055/s-0035-1561499

Efficient bismuth- and iron-catalyzed three-component syntheses of α-arylglycines have been developed. These methods provide a general, atom-economic route to various N-protected α-arylglycines starting from readily available amides (or carbamates), glyoxalates, and (hetero)arenes with water as the only by-product. Scope and limitations of bismuth- and iron-catalyzed reactions are discussed and compared. In addition, mechanistic investigations as well as initial forays into stereoselective three-component reactions are presented.

Full text of DOI:10.1055/s-0035-1561499

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–AE
paper
A
J. Halli et al.
Paper
Synthesis
Bismuth- and Iron-Catalyzed Three-Component Synthesis of
α-Amino Acid Derivatives: A Simple and Convenient Route to
α-Arylglycines
Juliette Halli‡
Angelika E. Schneider‡
Bi3+ or Fe3+
catalysis
O
O
O
CO2R'
(Het)Ar-H
+
+
Tamara Beisel
R
NH2
H
CO2R'
R
N
(Het)Ar
H
Philipp Kramer
arylglycines
64 examples
8–95% yield
Andrej Shemet
R = aryl, alkyl, alkoxy
R' = Et, i-Pr, H
Georg Manolikakes*
Department of Organic Chemistry and Chemical Biology,
Goethe-University Frankfurt, Max-von-Laue-Straße 7, 60439
Frankfurt am Main, Germany
g.manolikakes@chemie.uni-frankfurt.de
‡ These authors contributed equally to this study.
Received: 07.06.2016
Accepted: 13.06.2016
Published online: 29.07.2016
DOI: 10.1055/s-0035-1561499; Art ID: ss-2016-z0412-op
chemist’s tool box with novel efficient, modular and practi-
cal methods for the synthesis of the α-arylglycine structure
is therefore of great interest.8,9 Common procedures for the
preparation of these compounds are based on the addition
of a nucleophile to an imine species, such as the Mannich
reaction,10 the Strecker reaction,11 the Petasis–(Borono–
Mannich) reaction,12 or aza-Friedel–Crafts-type reactions13
(Scheme 1).
Abstract Efficient bismuth- and iron-catalyzed three-component syn-
theses of α-arylglycines have been developed. These methods provide a
general, atom-economic route to various N-protected α-arylglycines
starting from readily available amides (or carbamates), glyoxalates, and
(hetero)arenes with water as the only by-product. Scope and limita-
tions of bismuth- and iron-catalyzed reactions are discussed and com-
pared. In addition, mechanistic investigations as well as initial forays
into stereoselective three-component reactions are presented.
HO
OH
N
H
H
OH
N
Key words multicomponent reactions, iron, bismuth, aza-Friedel–
Crafts reaction, amino acids, homogeneous catalysis
NH2
N
O
HN
O
O
H
H
CO2H
α-Amino acids are of fundamental importance for biolo-
gy, biochemistry, and chemistry.1,2 They form the backbone
of proteins, an essential part of every living organism, and
are used as common feedstock for the production of biode-
gradable plastics, fertilizers, nutritional supplements, or
drugs.1,2 Many proteinogenic and nonproteinogenic α-ami-
no acids have important biological, nonprotein-related
functions, such as glutamate,1 an important neurotransmit-
ter or glycine,3 the starting material for the biosynthesis of
porphyrin-type cofactors. With the expansion of the genet-
ic code and the discovery of protein-based drugs, nonpro-
teinogenic (or unnatural) α-amino acids have gained in-
creasing attention.1,2 Among these nonproteinogenic α-
amino acids, α-arylglycines are of particular importance, as
they are building blocks for various drugs, such as cardio-
vascular agents4 and β-lactam antibiotics5 like amoxicillin
and norcardicin A (Figure 1). The α-arylglycine moiety is
also part of numerous natural products, such as vancomy-
cin6 or chloropeptin I7 (Figure 1). Expanding the organic
O
N
S
HO2C
NH2
Me
HO2C
Me
H
Norcardicin A
Amoxicillin
OH
H
N
O
H
O
O
H
H
N
HO2C
N
N
O
N
N
N
H
H
O
Me
O
O
Cl
Cl
Cl
Cl
Cl
Cl
OH
OH
OH
OH
Chloropeptin I
Figure 1 α-Arylglycine moiety in biologically active substances
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

B
J. Halli et al.
Paper
Synthesis
arene to the in situ formed N-acylimine. Small quantities of
water formed in the condensation step should not lead to a
significant catalyst deactivation. For the sake of practicality
the glyoxalate was used in its more stable polymeric or hy-
drated form.17
To identify a suitable catalyst system, the reaction of
benzamide (1a) with commercially available ethyl
glyoxalate (2a)18 and the moderately reactive m-xylene
(3a)19 was chosen using only 1 mol% of the catalyst (Table
1). Preliminary results revealed that several Lewis and
Brønsted acids are able to catalyze this reaction, albeit with
various degrees of efficiency (Table 1). Water-sensitive
Lewis acids, such as BF3·OEt2 and AlCl3, or weak Brønsted
acids, for example, TFA or (PhO)2P(O)OH, did not catalyze
the reaction at all (yields <10%, results not shown).
NHR2
CN
path A: Strecker
R1 = Ar
Ar
Nu = CN
hydrolysis
NHR2
CO2H
R2-NH2
+
R1-CHO
NR2 path B: Mannich
– H2O
R1 = CO2R
R1
imine
H
Ar
Nu = Ar-H or Ar-B(OH)2
NHR2
path C:
aza-Friedel-Crafts
R1 = CO2Et
(Het)Ar
CO2Et
Nu = (Het)Ar-H
Scheme 1 Different synthetic routes to α-arylglycines
However, these methods have some decisive drawbacks.
Cyanides used in the Strecker reaction are highly toxic and
the subsequent hydrolysis of the nitrile function under
acidic conditions curtails the functional group tolerance
(Scheme 1, path A). The Petasis–(Borono–Mannich) reac-
tion and related processes require prefunctionalized and of-
ten expensive boronic acid derivatives (Scheme 1, path B).
Another important approach is the direct amino- and ami-
doalkylation of unfunctionalized (hetero)arenes (Scheme 1,
path C).13,14 These aza-Friedel–Crafts-type reactions are
based on nucleophilic addition of arenes to highly electro-
philic imines and especially N-acylimines. In combination
with the in situ formation of the reactive N-acylimine spe-
cies via condensation of an aldehyde and an amide, these
methods enable the preparation of α-arylglycines with wa-
ter as only by-product and offer a promising opportunity
for the sustainable and atom-economic synthesis of this
important compound class.15 However, reported aza-
Friedel–Crafts-type reactions are often limited to very reac-
tive (hetero)arenes or require stoichiometric amounts of
strong Brønsted or Lewis acids.14 These restrictions lead to
a rather small substrate scope and the formation of consid-
erable amounts of waste and by-products.
Table 1 Initial Screening of Different Catalysts
Me
Me
O
1 mol% cat.
BzNH2
+
80 °C, 18 h
MeNO2
+
Me
H
CO2Et
Me
BzHN
CO2Et
1a
2a
3a
4a
Entry
Catalyst
Yield (%)a
1
2
3
4
5
6
7
8
Fe(ClO4)3·xH2O
Bi(OTf)3
91
88
72
54
16
18
49
12
In(OTf)3
Yb(OTf)3
Sc(OTf)3
TfOH
TfOH (5 mol%)
TsOH
a Yields are given for the isolated product. The product was obtained as a
98:2 mixture of regioisomers. Only the major regioisomer is shown.
In the course of our research on imine-based multicom-
ponent reactions,16 we were able to develop three-compo-
nent reactions for the synthesis of α-arylglycines using in-
expensive and nontoxic bismuth and iron catalysts.16a,b
These reactions provide straightforward access to a broad
scope of α-(hetero)arylglycines. They utilize readily avail-
able starting materials and water is generated as the only
by-product. Herein we report the full scope and limitations
of both methods, together with comparison of the specific
advantages and disadvantages as well as detailed mechanis-
tic investigations.
The stronger Brønsted acids TfOH and TsOH provided
the desired product in <20% yield (Table 1, entries 6 and 8).
A higher loading of TfOH did not lead to a greatly improved
yield (entry 7). Most promising results were obtained with
Bi(OTf)3, In(OTf)3, and Yb(OTf)3 (entries 2–4). Other metal
triflates such as Sc(OTf)3, Mg(OTf)2, or Zn(OTf)2 did not
show a similar catalytic activity. Surprisingly, 1 mol%
Fe(ClO4)3 furnished the α-arylglycine 4a in 91% yield (entry
1).
From an ecological and economic point of view, readily
available, cheap, and nontoxic iron salts would be an ideal
catalyst system for this three-component reaction.20,21
Therefore, iron-based catalysts were investigated in more
detail. During our previous research on amidoalkylation re-
actions, Bi(OTf)3 was identified as a very active, nontoxic,
and relatively cheap catalyst.22,23 Thus, we decided to take
Optimization and Scope
At the onset of our studies, we hypothesized that an
ideal catalyst should be able to catalyze both the formation
of a reactive N-acylimine via condensation of an amide with
a glyoxylic acid derivative and the addition of an unreactive
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

C
J. Halli et al.
Paper
Synthesis
focus on bismuth-catalyzed reactions as well. Although
In(OTf)3 and Yb(OTf)3 showed promising catalytic activity
(Table 1, entries 3 and 4), In- and Yb-based catalysts were
not examined due to the toxicity and teratogenic potential
of In(III) and Yb(III) salts.24
with similar efficiency (entries 6 and 11). However, as
judged by the observed rapid color change, we assume a
fast oxidation of Fe2+ to Fe3+ under our aerobic reaction con-
ditions. To rule out a possible ‘hidden’ catalysis by Brønsted
acids, the reaction was performed in the presence of the
proton scavenger 2,6-di-tert-butylpyridine (dbpy, entry
12).25 No significant decrease in yield was observed. There-
fore, we concluded that a Fe3+ species is the active catalyst.
Next, different solvents were examined for our three-
component reaction (Table 2, entries 13–16). Best results
were obtained in nitromethane. All other tested solvents
led to lower yields (1,2-dichloroethane, dichloromethane,
or 1,4-dioxane) or complete shutdown of the reaction (THF,
H2O, EtOAc). A similar screening of reaction parameters was
performed with the Bi-catalyzed three-component synthe-
sis. As shown in Table 3, Bi(OTf)3 proved to be the optimal
catalyst. Other bismuth salts like BiCl3 or BiBr3 afforded the
product in lower yields (Table 3, entries 5 and 6). Notably,
the catalyst loading of Bi(OTf)3 could be reduced to only
1 mol% without a significant change in yield and even with
only 0.5 mol% of Bi(OTf)3 the product could be isolated in
77%. As shown in Table 1, TfOH, a possible by-product from
the hydrolysis of Bi(OTf)3, did not display a similar catalytic
activity. To further exclude a possible Brønsted acid cataly-
sis a control reaction with the proton scavenger dbpy was
performed also in the case of Bi(OTf)3 (entry 7). Again no
significant decrease in the catalytic activity was observed,
indicating a Bi(III)-species as the active catalyst. In the case
of the Bi-catalyzed reaction, nitromethane also proved to be
To optimize the reaction conditions for both bismuth-
and iron-based conversions, the initial model reaction be-
tween benzamide (1a), ethyl glyoxalate (2a), and m-xylene
(3a) was chosen. The results for the optimization of the iron
catalyst are depicted in Table 2. Both, iron chloride either in
its anhydrous form or as hexahydrate, as well as iron per-
chlorate displayed high catalytic activities. Despite the fact
that both Fe(ClO4)3 and FeCl3·6H2O gave similar yields
during the initial optimization reactions (Table 2, entries 1
and 7), Fe(ClO4)3 led to higher yields in general. Additional-
ly, for Fe(ClO4)3 the catalyst loading can be decreased with-
out significant loss of efficiency (entry 9). Whereas 1 mol%
Fe(ClO4)3 led to the desired product in 91% yield (entry 8),
the yield with 1 mol% FeCl3 dropped to 18% (entry 5). The
corresponding Fe2+ salts could catalyze the model reaction
Table 2 Optimization of the Reaction Parameters for Fe-Catalyzed
Three-Component Reaction for the Synthesis of α-Arylglycine 4a
Me
Me
Fe2+/3+
O
BzNH2
+
80 °C, 16 h
MeNO2
+
Me
H
CO2Et
Me
BzHN
CO2Et
1a
2a
3a
4a
Table 3 Optimization of the Reaction Parameters for Bi-Catalyzed
Three-Component Reaction for the Synthesis of α-Arylgylcine 4a
Entry Catalyst
Solvent
Yield (%)a
1
2
FeCl3·6H2O (5 mol%)
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
84
84
86
87
18
82
91
91
75
37
82
86
39
23
Me
FeCl3·6H2O (2 mol%)
Me
Bi3+
3
anhyd FeCl3 (5 mol%)
anhyd FeCl3 (2 mol%)
anhyd FeCl3 (1 mol%)
FeCl2·4H2O (2 mol%)
O
BzNH2
+
4
80 °C, 16 h
MeNO2
+
Me
H
CO2Et
5
Me
BzHN
CO2Et
6
1a
2a
Catalyst
3a
4a
7
Fe(ClO4)3·xH2O (5 mol%)
Fe(ClO4)3·xH2O (1 mol%)
Fe(ClO4)3·xH2O (0.5 mol%)
Fe(ClO4)3·xH2O (0.1 mol%)
Fe(ClO4)2·xH2O (2 mol%)
Entry
Solvent
Yield (%)a
8
9
1
2
3
4
5
6
7
8
Bi(OTf)3 (5 mol%)
Bi(OTf)3 (2 mol%)
Bi(OTf)3 (1 mol%)
Bi(OTf)3 (0.5 mol%)
BiCl3 (5 mol%)
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
DCE
84
89
88
77
72
69
84
52
10
11
12
13
14
15
16
Fe(ClO4)3·xH2O (5 mol%) + dbpy (10 mol%) MeNO2
FeCl3·6H2O (2 mol%)
FeCl3·6H2O (2 mol%)
FeCl3·6H2O (2 mol%)
FeCl3·6H2O (2 mol%)
DCE
CH2Cl2
BiBr3 (5 mol%)
1,4-dioxane <10
MeCN 10
Bi(OTf)3 (5 mol%) + dbpy (10 mol%)
Bi(OTf)3 (5 mol%)
a Yields are given for the isolated product. The product was obtained as a
98:2 mixture of regioisomers. Only the major regioisomer is shown.
a Yields are given for the isolated product. The product was obtained as a
98:2 mixture of regioisomers. Only the major regioisomer is shown.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

D
J. Halli et al.
Paper
Synthesis
the ideal solvent. While yields in 1,2-dichloroethane were
still acceptable (entry 8), the use of other solvents led to
significant lower yields (results not shown).
arenes led to the formation of glycine derivatives 4q and 4r,
useful building blocks for the synthesis of fluorescence la-
bels,26 in 49–64% yield. Less reactive arenes, such as ben-
zene, did not react, even under harsh reaction conditions. In
most cases only one regioisomer was obtained. However, in
some cases, such as in the reaction with anisole, a mixture
of regioisomers was isolated. To our surprise, the use of
Bi(OTf)3, supposedly the more active catalyst, always led to
higher regioselectivities. In certain cases, such as with
anisole, only a small, negligible difference in the regioselec-
tivity was observed (75:25 vs. 71:29 para/ortho). However,
for reactions with other arenes, Bi(OTf)3 furnished the de-
sired products with a significantly higher regioselectivity.
This fact is exemplified by the arylglycines 4e (86:14 vs.
Scope of (Hetero)Arenes, Amides, and Glyoxalates
After identification of the ideal reaction conditions, the
scope of our methods was explored. First, reactions of dif-
ferent arenes with benzamide (1a), and ethyl glyoxalate
(2a) were investigated. Various electron-rich arenes are
suitable substrates for both the Fe- and the Bi-catalyzed
aza-Friedel–Crafts reaction (Scheme 2). The combined re-
sults are shown in Scheme 2. Both types of catalyst fur-
nished different α-arylglycine derivatives in good to excel-
lent yields. Interestingly N-pivalolyl-protected aniline 3m
reacted chemoselectively and α-arylglycine 4m was isolat-
ed in 67% (Bi) and 80% (Fe) yield. The reactions of polycyclic
1–5 mol%
Bi3+ or Fe3+
O
O
CO2Et
+
+
Ar-H
Ph
NH2
H
CO2Et
BzHN
Ar
2a
4
1a
3
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Mes
Me
Me
BzHN
BzHN
BzHN
BzHN
MeO
BzHN
OMe
OMe
Me
OMe
4b
Bi3+: 95%
Fe3+: 94%
4c
4d
4e
4f
Bi3+: 75% (r.r. 75:25)
Fe3+: 67% (r.r. 71:29)
Bi3+: 70%
Bi3+: 59% (r.r. 86:14)
Fe3+: 63% (r.r. 75:25)
Bi3+: 62%
Fe3+: 63%
Fe3+: 68% (r.r. 94:6)
CO2Et
CO2Et
Br
CO2Et
CO2Et
CO2Et
Cl
I
Br
I
BzHN
BzHN
BzHN
BzHN
MeO
BzHN
MeO
OMe
OMe
OMe
4g
Bi3+: 77%
Fe3+: 68%
4h
Bi3+: 88%
Fe3+: 74%
4i
4j
4k
Bi3+: 81%
Fe3+: 76%
Bi3+: 41%
Fe3+: 34%
Bi3+: 59%
Fe3+: 50%
OMe
CO2Et
CO2Et
CO2Et
CO2Et
OMe
OMe
Me
CO2Et
BzHN
BzHN
Me
BzHN
PivHN
BzHN
MeO
Me
Me
CO2Et
Me
OMe
BzHN
4l
4m
4n
Bi3+: 40%
Fe3+: 66%
4o
Bi3+: 68%
Fe3+: 58%
4p
Bi3+: 40%
Fe3+: 32%
Bi3+: 67% (r.r. 95:5)
Fe3+: 80% (r.r. 71:29)
Bi3+: 50% (r.r. 67:33)
Fe3+: 62% (r.r. 50:50)
CO2Et
CO2Et
CO2Et
BzHN
BzHN
BzHN
MeO
4q
Bi3+: 49%
Fe3+: 64%
4r
4s
Bi3+: 0%
Fe3+: 0%
Bi3+: 54%
Fe3+: 57%
Scheme 2 Substrate scope: arene component. Yields are given for isolated products. Unless otherwise mentioned, the corresponding α-arylglycine
was observed as one single regioisomer (d.r. >98:2). In the case of regioisomers, only the major one is shown. Bz = benzoyl, Piv = pivalolyl.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

E
J. Halli et al.
Paper
Synthesis
75:25), 4m (95:5 vs. 71:29), or 4p (67:33 vs 50:50). So far
we do not have a conclusive explanation for this phenome-
non.
Not only arenes but also heteroaromatic compounds are
suitable substrates for the three-component reaction
(Scheme 4). The corresponding heteroarylglycines 7a–l
were obtained in good to excellent yields with both Fe and
Bi catalysis. In general, lower reaction temperatures were
necessary to avoid direct addition of the heteroarene to the
aldehyde (Scheme 5).27 Reaction of benzamide (1a) with
ethyl glyoxalate (2a) and a heteroarene 6 as the nucleophil-
ic component furnished different heteroarylglycines in 47
to 88% yield (Scheme 4). Interestingly, reactions with carba-
mates, such as urethane, as the amide component, led to
overall higher yields as well as improved regioselectivities.
Improved regioselectivities can be rationalized by the de-
creased reactivity of the in situ formed N-carbamoylimine
compared to the N-acylimine in the benzamide case. The
low yields with benzamides are most probably associated
with the instability of the formed amidoalkylated products
under acidic conditions. We assume that these compounds
decompose under acidic conditions via dissociation of the
benzamide, thereby forming a stabilized heterobenzylic
cation 9, which can react with excess of the heteroarene to
the corresponding diarylmethane derivative 10.
Next, the reactions of different amides and carbamates
with ethyl glyoxalate (2a) and mesitylene (3b) were exam-
ined (Scheme 3). To our delight different benzamide deriva-
tives were compatible with both catalysts systems and the
desired products 5a–c were obtained in excellent yields
(68–94%). Alkyl-substituted primary amides are also suit-
able substrates and arylglycine derivatives 5d–f were ob-
tained in 70–88% yield with iron catalysis and in 79–81%
yield with bismuth catalysis. Even acid-sensitive amides
such as acrylamide were transformed into the desired prod-
uct 5g in 82% (Bi) or 85% (Fe) yield. Carbamates are suitable
substrates for the bismuth- and the iron-catalyzed three-
component reactions. Different N-protected α-arylglycines
5h–k, such as 5i bearing a Cbz-protecting group or the
Fmoc-derivative 5k, were obtained in high yields. Unfortu-
nately reaction with tert-butyl carbamate did not furnish
the desired Boc-protected arylglycine 5l. Sterically more
demanding secondary amides or electron-deficient trifluo-
roacetyl amide proved to be unsuitable for our method and
the desired products 5m and 5n could not be obtained.
Me
1–5 mol%
Bi3+ or Fe3+
O
CO2Et
Mes
O
O
+
+
R
N
R
NH2
H
CO2Et
H
Me
Me
1
2a
3b
5
O
CO2Et
Mes
O
CO2Et
O
CO2Et
Mes
O
CO2Et
O
CO2Et
Mes
Cl
N
N
Mes
N
H
H
H
N
Mes
Me
N
H
H
O2N
MeO
Br
O
5a
5b
5c
5d
5e
Bi3+: 81%
Fe3+: 94%
Bi3+: 80%
Fe3+: 85%
Bi3+: 68%
Fe3+: 89%
Bi3+: 81%
Fe3+: 88%
Bi3+: 79%
Fe3+: 70%
O
CO2Et
CO2Et
O
CO2Et
Mes
O
CO2Et
Mes
O
CO2Et
Mes
CO2Et
Mes
Fmoc
t-Bu
N
Mes
N
Mes
EtO
N
BnO
N
H
O
N
N
H
H
H
H
H
5f
5g
5h
5i
5j
5k
Bi3+: 81%
Fe3+: 80%
Bi3+: 82%
Fe3+: 85%
Bi3+: 86%
Fe3+: 83%
Bi3+: 65%
Fe3+: 51%
Bi3+: 84%
Fe3+: 70%
Bi3+: 83%
Fe3+: 75%
O
CO2Et
Mes
O
CO2Et
Mes
O
CO2Et
Mes
Ph
N
O
N
F3C
N
H
H
5l
5m
5n
Bi3+: 0%
Fe3+: 0%
Bi3+: 0%
Fe3+: 0%
Bi3+: 0%
Fe3+: 0%
Scheme 3 Substrate scope: amide component. Yields are given for the isolated products. Mes = mesityl (2,4,6-trimethylphenyl), Bn = benzyl, Fmoc =
[9H-fluoren-9-yl)methoxy]carbonyl.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

F
J. Halli et al.
Paper
Synthesis
2–5 mol%
Bi3+ or Fe3+
O
CO2Et
N HetAr
O
O
+
+
HetAr-H
R
R
NH2
H
CO2Et
2a
H
1
6
7
CO2Et
O
CO2Et
O
CO2Et
O
CO2Et
S
O
CO2Et
O
O
CO2Et
S
O
R
N
R
N
R
N
R
N
R
N
R
N
H
H
H
H
H
H
S
N
N
Ts
Br
Cl
Me
Ts
7a: R = Ph
Bi3+: 55%
Fe3+: 60%
7c: R = Ph
7e: R = Ph
Bi3+: 64% (r.r. 89:11)
7g: R = Ph
Bi3+: <5%
Fe3+: 51%
7i: R = Ph
Bi3+: <5%
Fe3+: 62%
7k: R = Ph
Bi3+: 37%
Bi3+: <5%
Fe3+: 50% (r.r. 63:37) Fe3+: 47% (r.r. 88:12)
Fe3+: 74% (r.r. 82:18)
7b: R = OEt
Bi3+: 77%
Fe3+: 74%
7d: R = OEt
Bi3+: 52%
Fe3+: 75%
7f: R = OEt
Bi3+: 72%
Fe3+: 78% (r.r. 93:7)
7h: R = OEt
Bi3+: 88%
Fe3+: 75% (r.r. 80:20)
7j: R = OEt
Bi3+: 62%
Fe3+: 75%
7l: R = OEt
Bi3+: 78%
Fe3+: 83%
Scheme 4 Substrate scope: heteroarenes. Yields are given for isolated products. Unless otherwise mentioned, the corresponding α-arylglycine was
observed as one single regioisomer (d.r. >98:2). Yields are given for the isolated product. In the case of regioisomers, only the major one is shown.
Ts = tosyl.
L.A.
L.A.
(Het)Ar
CO2Et
Bi3+ or Fe3+
(Het)Ar-H
H
HO
O
(Het)Ar-H
– H2O
(Het)Ar
(Het)Ar
(Het)Ar
CO2Et
(Het)Ar
CO2Et
H
CO2Et
2a
8
9
10
– Bz-NH2
NHBz
CO2Et
4, 7 or 12
Scheme 5 Mechanistic rationale for the formation of the observed by-products with very electron-rich (hetero)arenes
O
CO2R'
Mes
O
O
Indeed, Bi(OTf)3-catalyzed reactions of very electron-
rich heterocycles, such as benzofuran, N-tosylpyrrole, or
-indole, with benzamide (1a) and ethyl glyoxalate (2a) led
to the selective formation of the double addition products
of type 10 (Scheme 5). Using the less active iron catalyst,
heteroarylglycines 7g, 7i, and 7k could be isolated in 51, 62,
and 74% yield, respectively. Both methods are not limited to
ethyl glyoxalate as the aldehyde component (Scheme 6).28
Reactions with different glyoxalates, such as isopropyl gly-
oxalate (2b) furnished the desired amino acid derivative
11a in 50 and 83% yield. Even free glyoxylic acid, used as
aqueous solution, can be employed as aldehyde source,
thereby providing the free acid 11b in 71 and 81% yield. Re-
actions with carbamates, such as urethane or the Fmoc-
derivative, afforded the N-protected arylglycines 11c and
11d in 45–92% yield. Especially, the Fmoc-protected acid
11d would be an ideal starting material for solid-phase
peptide synthesis with unnatural amino acid derivatives. In
the case of the carbamates, iron catalysis proved to be more
reliable and furnished the desired products in higher yields
and purity.
Bi3+ or Fe3+
+
Mes-H
+
R
N
H
R
NH2
H
CO2R'
1
2
3b
11
CO2i-Pr
CO2H
Mes EtO
O
CO2H
Mes
CO2H
Mes
Bz
Bz
Fmoc
N
Mes
N
N
H
N
H
H
H
11a
11b
11d
Bi3+: 45%
Fe3+: 85%
11c
Bi3+: 50%
Fe3+: 92%
Bi3+: 50%
Fe3+: 83%
Bi3+: 71%
Fe3+: 81%
Scheme 6 Reaction of benzamide (1a) and different carbamates with
glyoxylic acid derivatives 2 and mesitylene (3b). Yields are given for iso-
lated products.
Limitations
In general, similar yields were obtained with bismuth
and iron catalysis. In the case of competing regioisomer for-
mation, reactions with Bi(OTf)3 gave consistently higher re-
gioselectivities. During our studies on the scope of the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

G
J. Halli et al.
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Synthesis
arene component, a significant difference was observed in
the reactivity for very electron-rich as well as for unreactive
aromatics (Scheme 7). These differences in reactivity are
most probably associated with the activity of the used cata-
lyst. For very reactive, electron-rich arenes, such as dimeth-
oxybenzenes, anthracene, or anisidine derivatives, the less
active iron catalyst proved to be advantageous. The amido-
alkylated arenes 12a–j were obtained in 63–89% yield. Re-
actions of electron-rich arenes in combination with the
more active Bi(OTf)3 gave the corresponding products in
lower yields or did not afford the product at all. In these
cases, the competing formation of diarylmethane deriva-
tives was observed in significant quantities (cf. Scheme 5).
For free phenols, such as 4-bromophenol, bismuth catalysis
proved to be advantageous and furnished the glycine deriv-
ative 12g in 65% yield (vs 11% with Fe3+). With iron catalysts
oxidative coupling reactions of the phenol were observed.
In the case of less reactive arenes, such as o-xylene, the
more active bismuth catalyst proved to be more efficient
and afforded the arylglycine in 89% yield (vs 54% with Fe3+
catalysis). Bi(OTf)3 could even catalyze the reaction of tolu-
ene, furnishing product 12j in 50% yield. In the case of iron
catalysis no product formation was observed with toluene.
Although the lower catalytic activity of the iron salts might
look like a disadvantage at the first glance, it proved to be a
major advantage in terms of practicability. Commercially
available, technical ethyl glyoxalate, is commonly provided
as a solution of the polymer form in toluene. In the case of
Bi-catalyzed reactions, toluene has to be removed prior to
the reaction to avoid the formation of 12j as side-product.
For iron-catalyzed reactions the commercially available
solution can be used without further processing, thereby
leading to a more straightforward procedure.
Also in the case of less reactive amide components, the
higher catalytic activity of Bi(OTf)3 proved to be beneficial
(Scheme 8). Bi(OTf)3-catalyzed reactions with cyclic sec-
ondary amides or carbamates afforded the desired products
14a and 14b in 63 and 80% yield. No product formation
2–5 mol%
O
O
CO2Et
Mes
O
Bi3+ or Fe3+
+
+
Mes-H
N
X
NH
X
H
CO2Et
2a
13
3b
14
14b
X = O
Bi3+: 63% Bi3+: 80%
Fe3+: 8% Fe3+: 0%
14a
X = CH2
Scheme 8 Substrate scope: reactions with cyclic secondary amides
and carbamates. Yields are given for the isolated products.
Fe3+ or Bi3+
CO2Et
O
O
Ar-H
+
+
Ph
NH2
H
CO2Et
2a
BzHN
Ar
1a
3
12
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
NHPiv
BzHN
BzHN
OMe
BzHN
BzHN
MeO
BzHN
MeO
OMe
Me
OMe
NHPiv
NHPiv
OMe
12a
12b
12c
12d
12e
Bi3+: 62%
Bi3+: 0%
Bi3+: 45%
Bi3+: 0%
Bi3+: 0%
Fe3+: 63%
Fe3+: 89%
Fe3+: 80% (r.r. 67:33)
Fe3+: 77% (r.r. 91:9)
Fe3+: 74%
CO2Et
BzHN
CO2Et
CO2Et
CO2Et
CO2Et
Br
BzHN
Cl
BzHN
BzHN
MeO
BzHN
Me
HO
Me
Me
12f
12g
12h
12i
12j
Bi3+: 48%
Fe3+: 82%
Bi3+: 65%
Bi3+: 89% (r.r. 89:11)
Fe3+: 54% (r.r. 80:20)
Bi3+: 89%
Fe3+: 34%
Bi3+: 50% (r.r. 75:25)
Fe3+: 11%
Fe3+: 0%
Scheme 7 Substrate scope: limitation for Bi3+ and Fe3+. Yields are given for the isolated products. Unless otherwise mentioned, the corresponding α-
arylglycine was observed as one single regioisomer (d.r. >98:2). In the case of regioisomers, only the major one is shown.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

H
J. Halli et al.
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Synthesis
with iron catalysts was observed. Acyclic secondary amides
or carbamates proved to be unreactive using either bismuth
or iron catalysis.
Interestingly, Bi(OTf)3 was able to catalyze reactions
with different sulfonamides as amide component (Scheme
9). The corresponding N-sulfonylated arylglycines 16a–c
were obtained in 54–79% yield. Presumably, Bi(OTf)3 is ac-
tive enough to catalyze the addition of arenes to in situ less
electrophilic N-sulfonylimines.14
Since no enantioselective version of the three-compo-
nent reaction could be realized with chiral catalysts, we de-
cided to explore diastereoselective reactions with chiral
amide components (Schemes 11–13).
For first tests chiral carbamates based on the Evans aux-
iliary were selected (Scheme 11).30 However, chiral oxazo-
lidinones, such as 20a or 20b, did not furnish the desired
products under our standard reaction conditions. Whereas
20b did not react at all, an interesting reactivity was ob-
served for oxazolidinone 20a. The bismuth-catalyzed reac-
tion of 20a furnished cyclic amino acid derivative 21 in 84%
yield as single diastereomer (Scheme 12). Formation of the
cyclic product can be rationalized by an intramolecular ad-
dition of the phenyl moiety to the formed N-acylimine.
Even in the presence of excess of mesitylene no intermolec-
ular addition was observed. Therefore, we next selected
chiral primary amides as potential chiral starting materials
for our three-component reaction.
O
CO2Et
Mes
O
O
2 mol% Bi(OTf)3
O
R
O
R
+
+
Mes-H
S
S
N
MeNO2
80 °C, 16 h
NH2
H
CO2Et
2a
H
15
3b
16
O
CO2Et
O
CO2Et
Mes
O
CO2Et
Mes
O
O
O
S
S
S
S
N
Mes
Me
N
H
N
H
H
R
16b
16c
67%
16a
R = Me: 79%
R = Br: 54%
Fe3+: 0%
Bi3+: 54%
O
CO2Et
Mes
O
2 mol%
Bi(OTf)3
O
R = OMe: 64%
O
NH
N
+
+
Mes-H
O
Scheme 9 Substrate scope with sulfonamides. Yields are given for the
80 °C, 16 h
MeNO2
H
CO2Et
isolated products.
R
R
20
2a
3b
R = Bn: 0%
R = i-Pr: 0%
Investigations into Stereoselective Reactions
Since most of the natural α-arylglycines exist in one en-
antiomeric form, stereoselective synthesis of these com-
pounds would be highly desirable. Therefore, we decided to
investigate a possible asymmetric version of our three-
component reactions (Scheme 10). The most obvious ap-
proach would be the use of chiral ligands in our transforma-
tion. Hence various common chiral ligands were tested in
combination with different Bi3+ or Fe3+ salts (Scheme 10).29
Unfortunately, no asymmetric induction was observed us-
ing various metal–ligand combinations, solvents, or tem-
peratures (Scheme 10). In further studies using different li-
gands and variations of the amide or arene component as
well as In3+ and Yb3+, promising Lewis acids in our initial
screening, were studied. Again no asymmetric induction
was observed.
Scheme 11 Unsuccessful diastereoselective approach using Evans-
type carbamates
O
CO2Et
2 mol%
Bi(OTf)3
O
O
O
NH
+
N
O
80 °C, 16 h
MeNO2
H
CO2Et
Ph
20a
84%
21
2a
Scheme 12 Intramolecular amidoalkylation of 20a. Yield is given for
the isolated product.
Reaction of phthalimide-protected valine amide 22
with ethyl glyoxalate (2a) and mesitylene (3b) furnished
the expected product 23 in 84% with Bi(OTf)3 and 78% yield
with FeCl3·6H2O (Scheme 13). Only moderate diastereose-
lectivities (67:33 and 65:35) were observed. Variation of
the temperature, solvent, or catalyst did not improve the
stereoselectivity. Replacing the amide protecting group by a
carbamate, led to a diminished diastereoselectivity and a
drastic decrease in isolated yields. Reactions with amide-
protected valine amides did not furnish any desired prod-
uct at all. In summary, all our approaches to stereoselective
reactions did not lead to the expected results. Only in the
case of chiral amide components moderate stereoselectivi-
metal salts
O
CO2Et
Mes
ligands
+
+
Mes-H
BzNH2
different conditions
H
CO2Et
2a
BzHN
1a
3a
4a
0% ee
Me
N
Me
O
O
O
O
O
O
N
N
N
N
N
N
R
R
R
R
R
R
17
18
19
Scheme 10 Unsuccessful enantioselective approaches
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

I
J. Halli et al.
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Synthesis
ties could be achieved. Therefore, further studies into the
field of asymmetric three-component reactions were not
pursued.
and 5 mol% Fe(ClO4)3. In both cases an interesting observa-
tion was made: the rates of benzamide conversion and
product formation deviate significantly from each other at
the onset of the reaction (Figure 2).
iPr
In the case of Fe(ClO4)3, a fast conversion of the benz-
amide (20% conversion after 10 min and 70% after 45 min)
was observed. However, the rate of product formation was
slower (<1% yield after 10 min and 50% yield after 45 min).
Similar observations were made with 5 mol% of Bi(OTf)3
(20% and 45% conversion vs 2% yield and 30% yield after 10
and 45 min, respectively). Since in both cases the yield of α-
arylglycine 4b exceeded 90% after 24 hours reaction time,
no unproductive side-reactions of benzamide can account
for the fast conversion of the amide component. Therefore,
formation of some kind of productive intermediate, most
probably by the reaction of two of the three components,
has to take place.
O
2 mol%
Bi(OTf)3
PG
O
O
iPr
N
Mes-H
NH2
H
+
+
EtO2C
NH
80 °C, 16 h
MeNO2
H
CO2Et
N
PG
Mes
23
22
2a
3b
PG = Phth:
2 mol% Bi(OTf)3: 87%, d.r. 67:33
2 mol% FeCl3: 78%, d.r. 65:35
PG = Cbz: <10%, d.r. 50:50
Scheme 13 Reaction of N-protected valine amide 22. Yields are given
for the isolated products. Phth = phthaloyl, PG = protecting group.
Mechanistic Investigations
As can be seen from Figure 3, Fe(ClO4)3 catalyzes the re-
action with a higher efficiency than Bi(OTf)3, both at high
(5 mol%) and low (1 mol%) catalyst loading. With 5 mol%
Fe(ClO4)3 64% of the amidoalkylated product is observed af-
ter 60 minutes, compared to only 28% with 5 mol% Bi(OTf)3.
As expected, reduction of the catalyst loading to 1 mol%
leads to a considerable decrease in the reaction rate (Figure
3).
In order to gain further insight into the reaction mecha-
nism and the different catalytic activities of Bi(OTf)3 and
Fe3+ salts, a series of experiments were performed. First the
progress of the reaction between benzamide (1a), ethyl gly-
oxalate (2a), and mesitylene (3b) in the presence of differ-
ent catalysts as well as catalyst loadings was monitored by
gas chromatographic analysis (Scheme 14, Figures 2 and 3).
Interestingly, FeCl3·6H2O displays the lowest catalytic
activity. After 50 minutes at 60 °C, only 5% product forma-
tion was observed with 5 mol% FeCl3·6H2O. Presumably, a
facile dissociation of the noncoordinating counterions to
form an active metal catalyst is crucial for a high activity.31
We have to emphasize that under our standard reaction
conditions (80 °C; 16 h, 24 h, respectively) all three cata-
lysts [Fe(ClO4)3, FeCl3·6H2O, and Bi(OTf)3] give similar yields
at 5 mol% and even 2 mol% loadings (>90% in all cases). To
our surprise, Bi(OTf)3, the catalyst with the best perfor-
mance with less reactive arenes, displayed an inferior activ-
ity compared to Fe(ClO4)3 in the reaction with mesitylene
1–5 mol% Bi3+
O
or Fe3+
CO2Et
Mes
+
+
Mes-H
BzNH2
60 °C
MeNO2
H
CO2Et
2a
BzHN
1a
3b
4b
Scheme 14 Model reaction for kinetic experiments
In order to obtain a clearer distinction between the dif-
ferent systems, the reaction was performed at a slightly de-
creased temperature of 60 °C. Initially we compared the
rates for conversion of the limiting starting material, ben-
zamide (1a), and product formation with 5 mol% of Bi(OTf)3
Figure 2 Comparison of the rates of benzamide conversion and product formation
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

J
J. Halli et al.
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Synthesis
ponent reaction of mesitylene (3b) with ethyl glyoxalate
(2a) was investigated next. Both 2 mol% Bi(OTf)3 and
2 mol% Fe(ClO4)3 furnished the double addition product 26
in 70–74% yield. Formation of such diarylmethane products
was already observed in the case of more reactive (hete-
ro)arenes (cf. Scheme 5) and is described in the literature.27
Addition of a ligand, 2,2′-bipyridine (bipy) to the iron-cata-
lyzed reaction, enabled the controlled synthesis of
monoaddition product 27 in 66% yield. Alcohol 27 is the
presumed intermediate in the synthesis of diarylmethane
products of type 26. We next examined alcohol 27 as a pos-
sible intermediate in our three-component reaction. Treat-
ment of 27 with 1.0 equivalent of benzamide and
2.0 equivalents of mesitylene under our standard reaction
conditions did furnish the expected product 4b and diaryl-
methane derivative 26 in less than 5% yield, using either
Bi(OTf)3 or Fe(ClO4)3. These experiments indicate that alco-
hol 27 is not involved in the main reaction pathway. On the
basis of these results, we assume the following mechanism
(Scheme 15). In the first step, the amide adds to the glyox-
ylic acid derivative 2 to form hemiaminal 24. Elimination of
water furnishes a reactive acylimine species 28. Trapping of
this highly electrophilic imine with a second molecule of
the amide gives bisamide 25, observed intermediate in
some of our three-component reactions. The fast addition
of a second amide is not surprising, if one considers the
higher nucleophilicity of the amide nitrogen.18 Under the
reaction conditions, bisamide 25, favored under kinetic
control, can decompose to yield the reactive N-acylimine
28. In the presence of a suitable, nucleophilic arene, the N-
acylimine can undergo an aza-Friedel–Crafts type reaction
to afford the desired α-arylglycine product 4 containing a
thermodynamically more stable C–C bond. The catalytic ac-
tivity of the used catalyst greatly depends on two factors.
On the one hand, the catalyst has to be stable in the pres-
ence of significant amounts of water, since up to 100 equiv-
alents of water are generated during the course of the reac-
tion (with respect to the catalyst).
On the other hand the catalyst has to promote the addi-
tion of the amide 1 to the glyoxalate 2 over the direct addi-
tion of the arene 3 to the aldehyde 2. Only the right combi-
nation of both reactivities leads to an efficient catalyst for
these three-component reactions. In addition, the Lewis
acidic catalyst could further activate the N-acylimine to-
wards the addition of a nucleophile. This might partially ex-
plain the higher activity of Bi(OTf)3, a strong Lewis acid, in
reactions with less nucleophilic arenes.28 Another possible
explanation for the high catalytic efficiency of bismuth as
well as the observed improved regioselectivities is the acti-
vation of the arene component by the bismuth catalyst. Al-
though Bi(III)-arene complexes have been reported in liter-
ature, we do not have any solid experimental evidence for
an additional activation of the arene component.33 We as-
sume that two factors contribute to the observed low stereo-
selectivities in our asymmetric approaches. The high intrin-
Figure 3 Rates of product formation with different catalyst loadings
(Figure 3). Therefore, Fe(ClO4)3 is the catalyst of choice for
more reactive arenes, considering the activity and the eco-
nomic and ecologic aspects of iron(III) salts.
As outlined in the introduction, our first rationale for
the development of these three-component reactions was
the in situ formation of a reactive N-acylimine species. Ini-
tial experiments indicated the formation of a two-compo-
nent adduct of benzamide with one of the other starting
materials (Figure 2). Therefore, we examined the reaction
between benzamide (1a) and ethyl glyoxalate (2a) in the
presence of 5 mol% Fe(ClO4)3 or 5 mol% Bi(OTf)3
(Scheme 15). At room temperature quantitative formation
of N,O-hemiaminal 24a is observed within 24 hours
(Scheme 15). Longer reaction times (96 h) or heating to
80 °C led to the formation of bisamide 25a, insoluble in
most common organic solvents, in almost quantitative
yields. Indeed, the formation and precipitation of bisamide
25 could be observed in some of our three-component re-
actions. During the reaction bisamide 25a is consumed
completely and at the end the reaction mixture becomes
homogenous again. Due to the insolubility of bisamide 25a
and the instability of bisamide 25a and hemiaminal 24a,
we were not able to quantify the amount of both interme-
diates during the course of the reaction with the analytical
methods available at our department (GC, HPLC, React-IR,
or NMR). Neither were we able to detect any reactive N-
acylimine species.32 As expected, the reaction of benzamide
(1a) and mesitylene (3b) in the presence of an iron or bis-
muth catalyst did not furnish any new product at all
(Scheme 15). Treatment of either hemiaminal 24a or bis-
amide 25a, both known precursors for acylimines,14 with
Bi(OTf)3 or Fe(ClO4)3 and mesitylene (3b) led to the expect-
ed formation of the aryl glycine derivative 4b in 85 and 83%
yield. To elucidate further reaction pathways, the two-com-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

K
J. Halli et al.
Paper
Synthesis
O
OH
O
CO2Et O
O
O
Bi3+ or Fe3+
+
NH2
Ph
N
CO2Et
r.t., 96 h
Ph
N
N
H
Ph
r.t., 24 h
MeNO2
Ph
H
CO2Et
2a
H
H
1a
1.0 equiv
24a
25a
bisamide
1.2 equiv
N,O-hemiaminal
>95%
O
CO2Et O
O
O
O
Bi3+ or Fe3+
Bi3+ or Fe3+
no conversion
observed
Mes-H
+
+
Ph
N
N
Ph
80 °C, 24 h
MeNO2
Ph
NH2
H
CO2Et
2a
Ph
NH2
H
H
1a
2.0 equiv
25a
bisamide
>95%
1a
1.0 equiv
3b
3.0 equiv
1.0 equiv
O
OH
O
CO2Et O
CO2Et
CO2Et
Mes
Bi3+ or Fe3+
Bi3+ or Fe3+
Ph
N
CO2Et
Ph
N
N
H
Ph
80 °C, 18 h
MeNO2
80 °C, 18 h
MeNO2
BzHN
Mes
BzHN
H
H
24a
4b
5 mol% Bi(OTf)3: 85%
5 mol% Fe(ClO4)3: 83%
25a
bisamide
4b
N,O-hemiaminal
5 mol% Bi(OTf)3: 79%
5 mol% Fe(ClO4)3: 78%
2 mol% Fe(ClO4)3
3 mol% bipy
O
O
OH
CO2Et
Bi3+ or Fe3+
+
Mes-H
Mes-H
+
80 °C, 24 h
MeNO2
80 °C, 24 h
MeNO2
H
CO2Et
H
CO2Et
Mes
CO2Et
Mes
Mes
2a
1.0 equiv
3b
2.5 equiv
26
2a
1.0 equiv
3b
2.5 equiv
27
66%
2 mol% Bi(OTf)3: 70%
2 mol% Fe(ClO4)3: 74%
5 mol% Bi(OTf)3 or
5 mol% Fe(ClO4)3
OH
O
CO2Et
Mes
CO2Et
Mes
+
+
+
Mes-H
80 °C, 24 h
MeNO2
Mes
CO2Et
Ph
NH2
Mes
BzHN
27
1.0 equiv
1a
3b
2.0 equiv
26
<5%
4b
<5%
1.0 equiv
Mes-H
5 mol%
Bi3+ or Fe3+
CO2Et
Mes
CO2Et
CO2Et
+
+
80 °C, 24 h
MeNO2
BzHN
BzHN
Mes
Mes
Mes
4b
1.0 equiv
3b
3.0 equiv
4b
26
6%
Postulated Mechanism:
L.A.
O
CO2R'
N (Het)Ar
Lewis acid
(L.A.)
O
O
+
+ (Het)Ar-H
R
H
R
NH2
H
CO2R'
1
2
3
4
arylglycine
slow
fast
Lewis acid (L.A.)
(Het)Ar-H rate-determining step
3
O
+/–
– H2O
elimination
L.A.
R
NH2
O
OH
O
CO2R'O
O
1
R
N
CO2R'
fast
equilibrium
R
N
N
H
R
+ H2O
R
N
CO2R'
H
H
addition
fast
24
N,O-hemiaminal
28
25
N-acylimine
bisamide
Scheme 15 Mechanistic studies and postulated reaction pathway
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

L
J. Halli et al.
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Synthesis
sic reactivity of N-acylimines leads to a low selectivity in
general, both for the diastereoselective and enantioselec-
tive reactions. As reported in the literature, coordination of
a Lewis acid to the N-acylimine takes place at the oxygen
atom.34 This places the catalyst far away from the reactive
center, thereby severely hampering any stereochemical in-
duction by the ligand. Based on this assumption, one can
rationalize that tailor-made sterically very demanding li-
gands should offer a solution to this problem. However, the
catalytic activity of such encumbered systems might be too
low for these types of multicomponent reactions.
mobenzenesulfonamide, thiophene-2-sulfonamide, and 2-(1,3-diox-
oisoindolin-2-yl)-3-methylbutanamide were synthesized according
to literature.16 Ethyl glyoxalate was obtained as 50 wt% solution in tol-
uene. Glyoxylic acid was obtained as 50 wt% solution in H2O and used
as received. All other starting materials were purchased from com-
mercial sources and used without further purification. Fe(ClO4)3 was
obtained as undefined hydrate (Fe(ClO4)3·xH2O, yellow form, reagent
grade) from different providers. The exact H2O content was deter-
mined by elemental analysis. Depending on the provider and storage
time (or even the time for weighting out a defined amount for ele-
mental analysis) Fe(ClO4)3 contained from one up to ten molecules of
H2O. Therefore, the amount of Fe(ClO4)3 used is always calculated on
anhyd Fe(ClO4)3. No changes in catalytic activity were observed for
different batches of Fe(ClO4)3 or upon prolonged storage times. No
special precautions were taken to avoid exposure of Fe(ClO4)·xH2O to
moisture. Caution! Perchlorate salts are known to be shock-sensitive
and are potential explosives. They should be handled with care and
the necessary precautions. Since most of these properties are associ-
ated with anhyd perchlorate salts, we strongly advise to use the hy-
drated form of Fe(ClO4)3. Under no circumstances should Fe(ClO4)3
be dried or handled in its anhydrous form. Since similar yields are
obtained even with the decahydrate Fe(ClO4)3·10H2O, this is not nec-
essary. Special precautions should be taken to avoid accidental drying
of the perchlorate, for example, by accidental evaporation of the sol-
vent from the reaction. During our studies we never encountered
problems associated with Fe(ClO4)3. Even prolonged heating of
Fe(ClO4)3 in MeNO2 up to 120 °C did not lead to any decomposition.
(In fact it is known the anhydrous LiClO4 is stable in Et2O at tempera-
tures up to 140–150 °C. For further information on perchlorate safety
and stability, we recommend the article of Long.35
Conclusion and Outlook
In summary, two general Bi(OTf)3- and Fe3+-catalyzed
three-component reactions between amides, (hete-
ro)arenes, and glyoxylic acid derivatives have been devel-
oped. Scope and limitations as well as advantages and dis-
advantages of both catalyst systems were investigated in
detail. These investigations show that very cheap Fe3+ salts
are the catalysts of choice in most reactions. The lower ac-
tivity of iron-based catalysts offers an additional advantage
in the case of very reactive arene components. On the other
hand, the high activity of Bi(OTf)3 significantly expands the
scope of the three-component reaction and allows the utili-
zation of less reactive arenes and sulfonamides. Investiga-
tions into potential asymmetric versions of the three-com-
ponent reaction were unsuccessful. No enantioselective re-
action was realized and the diastereoselective induction
with chiral amide components was low to moderate. Mech-
anistic investigations indicate a reaction pathway via for-
mation of a reactive, highly electrophilic acylimine followed
by an aza-Friedel–Crafts-type reaction with the arene as
nucleophilic component. These practical and operationally
simple reactions enable the efficient and straightforward
synthesis of N-protected arylglycines from simple commer-
cial available starting materials and nontoxic catalysts.
With water as the only generated side-product, these meth-
ods constitute a promising approach towards the sustain-
able synthesis of important α-amino acids.
Anhyd Bi(OTf)3 was obtained from different providers and used di-
rectly. No special precautions were taken to avoid exposure of
Bi(OTf)3 to moisture. Therefore, we cannot rule out the formation of
Bi(OTf)3·xH2O during storage. Indeed, depending on the provider and
storage time (or even the time for weighting out a defined amount for
elemental analysis) Bi(OTf)3 contained up to six molecules of water.
However, no changes in catalytic activity and yield even upon pro-
longed storage (>1 year) were observed. Therefore, the amount of
Bi(OTf)3 used is always calculated on anhyd Bi(OTf)3. The actual cata-
lyst loading for particular reactions might be slightly lower, depend-
ing on the batch quality and storage time.
1H and 13C NMR spectra were recorded at 300, 400, or 500 MHz and
75, 101, or 126 MHz, respectively. Chemical shifts are reported as δ-
values relative to the residual CDCl3 or DMSO-d6 peak (δ = 7.26 for 1H
1
and δ = 77.16 for 13C; δ = 2.50 for H and δ = 39.52 for 13C). Coupling
constants (J) are given in Hz and standard abbreviations are used for
signal multiplicities.
For reactions and column chromatography, solvents were obtained
from different commercial suppliers in >97% purity and used as re-
ceived.
Mass spectra (MS) were measured using ESI (electrospray ionization)
techniques. High-resolution mass spectra (HRMS) were measured us-
ing MALDI (Matrix-assisted Laser Desorption/Ionization) techniques.
All reactions were performed without any precautions to exclude am-
bient air or moisture. TLC was performed on precoated aluminum
sheets (silica gel 60 F254). The spots were visualized by using UV ra-
diation, I2, or cerium(IV) ammonium molybdate. Flash column chro-
matography was performed by using Silica 60 (0.04–0.063 mm, 230–
400 mesh). All yields refer to isolated yields of compounds estimated
to be >95% pure, as determined by 1H NMR spectroscopy. Melting
points are uncorrected.
IR spectra were recorded on an FTIR (Fourier transform infrared spec-
troscopy) spectrophotometer including a diamond universal ATR
sampling technique (attenuated total reflectance) from 4000–400
cm–1. The absorption bands were reported in wave numbers (cm–1).
Three-Component Synthesis of α-Arylglycines; General Procedure
(GP)
N-(m-Tolyl)pivalamide, N-(3-methoxyphenyl)pivalamide, 1-methoxy-
3,5-dimethylbenzene, 2-methoxy-naphthalene, 1-tosyl-1H-pyrrole,
1-tosyl-1H-indole, N-(o-tolyl)pivalamide, N-(2-methoxy-phenyl)piv-
alamide, N-(4-methoxyphenyl)pivalamide, methanesulfonamide, 4-
methylbenzenesulfonamide, 4-methoxybenzenesulfonamide, 4-bro-
A 10 mL screw cap vial was charged with the respective iron salt (1–
5 mol%) or Bi(OTf)3 (1–5 mol%), the appropriate amide (1.0 equiv),
and MeNO2 (4.0 mL/mmol amide) (or DCE wherever applicable). Ethyl
glyoxalate (1.2 equiv) and the appropriate aromatic compound
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

M
J. Halli et al.
Paper
Synthesis
(3.0 equiv) were added under vigorous stirring. Ethyl glyoxalate was
used as a 50 wt% solution in toluene (technical form) and used as re-
ceived for the reactions with iron(III) salts. For the reaction with
Bi(OTf)3 toluene was removed in vacuo (1 mbar, 3 h) in order to avoid
side reactions. The resulting oil was redissolved in MeNO2. The reac-
tion mixture was heated to 40–100 °C and stirred at this temperature.
After cooling to r.t., the reaction mixture was diluted with EtOAc and
filtered through a short plug of Celite and silica gel. The plug was
rinsed with additional EtOAc. The combined filtrates were concen-
trated under reduced pressure. Purification of the crude residue by
column chromatography (cyclohexane/EtOAc, then n-hexane/EtOAc)
afforded the analytically pure product.
tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 4:1) yielded the product as a colorless
solid (153 mg, 94%).
Mp 77.6 °C; Rf = 0.50 (cyclohexane/EtOAc = 7:3)
IR (ATR): 3320 (m), 2980 (w), 1727 (s), 1632 (s), 1579 (m), 1525 (s),
1488 (m), 1382 (w), 1339 (w), 1311 (m), 1242 (s), 1136 (m), 1082
(m), 1020 (s), 929 (m), 852 (m), 800 (m), 713 (m), 689 (s), 622 cm–1
(s).
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 7.5 Hz, 2 H), 7.47 (dt, J =
15.0, 7.2 Hz, 3 H), 7.18 (d, J = 6.1 Hz, 1 H), 6.85 (d, J = 7.8 Hz, 2 H), 6.19
(d, J = 6.6 Hz, 1 H), 4.34–4.12 (m, 2 H), 2.48 (s, 6 H), 2.25 (s, 3 H), 1.22
(t, J = 7.1 Hz, 3 H).
Ethyl 2-Benzamido-2-(2,4-dimethylphenyl)acetate (4a)
13C NMR (101 MHz, CDCl3): δ = 171.9, 166.6, 137.8, 137.1, 134.1,
131.8, 131.0, 130.2, 128.7, 127.2, 62.2, 52.8, 21.0, 20.5, 14.2.
MS (ESI): m/z [M + H]+ calcd for C20H24NO3: 326.2; found: 326.1.
HRMS (MALDI): m/z [M + H]+ calcd for C20H24NO3: 326.1751; found:
326.1751.
Bi Catalysis: Compound 4a was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,
1.2 mmol, 1.2 equiv), m-xylene (0.37 mL, 3.0 mmol, 3.0 equiv), and
Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction
mixture was stirred for 24 h at 80 °C. Purification by chromatography
(n-hexane/EtOAc = 4:1) yielded the product as a colorless solid [276
mg, 89%; ratio of regioisomers (r.r.) = >98:2].
Ethyl 2-Benzamido-2-(4-methoxyphenyl)acetate (4c)
Bi Catalysis: Compound 4c was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,
1.2 mmol, 1.2 equiv), anisole (0.32 mL, 3.0 mmol, 3.0 equiv), and
Bi(OTf)3 (7 mg, 0.01 mmol, 1 mol%) in MeNO2 (4.0 mL). The reaction
mixture was stirred for 16 h at 80 °C. Purification by chromatography
(n-hexane/EtOAc = 4:1) yielded the product as a colorless solid
(236 mg, 75%; r.r. = 75:25).
Fe Catalysis: Compound 4a was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
0.6 mmol, 1.2 equiv), m-xylene (0.18 mL, 1.5 mmol, 3.0 equiv), and
Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reac-
tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 4:1) yielded the product as a colorless
solid (141 mg, 91%; r.r. = >98:2). Further purification of the major re-
gioisomer could be achieved by precipitation from hexane/CH2Cl2
(only major regioisomer, as judged by 1H NMR). Analytical data were
obtained for this purified regioisomer.
Fe Catalysis: Compound 4c was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
0.6 mmol, 1.2 equiv), anisole (0.16 mL, 1.5 mmol, 3.0 equiv), and
Fe(ClO4)3 (9 mg, 0.050 mmol, 5 mol%) in MeNO2 (2.0 mL). The reac-
tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 4:1) yielded the product as a colorless
solid (105 mg, 67%; r.r. = 75:25). Further purification of the major re-
gioisomer could be achieved by precipitation from hexane/CH2Cl2
(r.r. = 78:22, as judged by 1H NMR analysis). Analytical data were ob-
tained for this purified mixture.
Mp 98.2 °C; Rf = 0.54 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3304 (w), 2985 (w), 2360 (w), 1745 (s), 1635 (s), 1601 (w),
1580 (w), 1523 (s), 1487 (m), 1371 (w), 1348 (m), 1324 (w), 1212 (s),
1189 (m), 1150 (m), 1095 (m), 1021 (m), 929 (w), 872 (w), 810 (w),
774 (w), 722 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.80 (dd, J = 5.3, 3.3 Hz, 2 H), 7.52–7.40
(m, 3 H), 7.17 (d, J = 7.8 Hz, 1 H), 7.07–6.96 (m, 3 H), 5.93 (d, J = 7.1 Hz,
1 H), 4.31–4.11 (m, 2 H), 2.52 (s, 3 H), 2.30 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3
H).
13C NMR (101 MHz, CDCl3): δ = 171.8, 166.7, 138.4, 136.9, 133.9,
132.5, 131.9, 131.8, 128.7, 127.33, 127.3, 126.4, 62.0, 53.5, 21.2, 19.6,
14.2.
MS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.2; found: 312.2.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found:
Mp 65.6 °C; Rf = 0.49 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3319 (w), 2964 (w), 1737 (s), 1633 (s), 1578 (w), 1530 (m),
1512 (s), 1490 (m), 1462 (w), 1366 (w), 1317 (m), 1248 (s), 1022 (m),
801 (m), 762 (m), 692 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.78–7.72 (m, 2
H), 7.47–7.28 (m, 5 H), 7.03 (d, J = 6.6 Hz, 1 H), 6.85–6.79 (m, 2 H),
5.63 (d, J = 7.0 Hz, 1 H), 4.24–4.07 (m, 2 H), 3.72 (s, 3 H), 1.20–1.14 (m,
3 H).
13C NMR (101 MHz, CDCl3): δ = 171.3, 166.5, 159.7, 133.8, 131.8,
131.6, 130.8, 129.8, 128.9, 128.7, 128.5 128.4, 127.1, 121.1, 114.4,
111.1, 62.0, 61.6, 56.3, 55.6, 55.3, 53.9, 14.0 (peaks not assigned to re-
gioisomers).
MS (ESI): m/z [M + Na]+ calcd for C18H19NO4Na: 336.1; found: 336.4.
HRMS (MALDI): m/z [M + H]+ calcd for C18H20NO4 314.1387, found
312.1596.
Ethyl 2-Benzamido-2-mesitylacetate (4b)
Bi Catalysis: Compound 4b was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,
1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and
Bi(OTf)3 (7 mg, 0.01 mmol, 1 mol%) in MeNO2 (2.0 mL). The reaction
mixture was stirred for 16 h at 80 °C. Purification by chromatography
(n-hexane/EtOAc = 4:1) yielded the product as a colorless solid
(308 mg, 95%).
314.1384.
Ethyl 2-Benzamido-2-(4-methoxy-3-methylphenyl)acetate (4d)
Bi Catalysis: Compound 4d was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,
Fe Catalysis: Compound 4b was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and
FeCl3·6H2O (3 mg, 0.010 mmol, 2 mol%) in MeNO2 (2.0 mL). The reac-
0.6 mmol,
1.2 equiv),
1-methoxy-2-methylbenzene
(0.19 mL,
1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 5 mol%) in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

N
J. Halli et al.
Paper
Synthesis
MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C.
Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded
the product as a colorless solid (115 mg, 70%; r.r. = >98:2).
MS (ESI): m/z [M + H]+ calcd for C19H22NO4: 328.2; found: 328.3.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO4: 328.1543; found:
328.1543.
Fe Catalysis: Compound 4d was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
Ethyl 2-Benzamido-2-(2-methoxy-5-methylphenyl)acetate (4f)
1.2 mmol,
1.2 equiv),
1-methoxy-2-methylbenzene
(0.37 mL,
Bi Catalysis: Compound 4f was synthesized according to the GP from
3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in
MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C.
Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded
the product as a colorless solid (223 mg, 68%; r.r. = 94:6). Further pu-
rification of the major regioisomer could be achieved by precipitation
from hexane/CH2Cl2 (only major regioisomer, as judged by 1H NMR
analysis). Analytical data were obtained for this purified regioisomer.
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,
0.6 mmol,
1.2 equiv),
1-methoxy-4-methylbenzene
(0.19 mL,
1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C.
Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded
the product as a colorless solid (102 mg, 62%; r.r. = >98:2).
Fe Catalysis: Compound 4f was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
Mp 95.0 °C; Rf = 0.51 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3323 (w), 2361 (w), 1733 (s), 1635 (s), 1579 (m), 1531 (m),
1508 (m), 1451 (w), 1347 (m), 1315 (m), 1278 (m), 1249 (s), 878 (m),
800 (m), 751 (m), 691 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.4 Hz, 2 H), 7.51 (t, J = 7.3
Hz, 1 H), 7.43 (t, J = 7.5 Hz, 2 H), 7.26 (m, 2 H), 7.06 (d, J = 6.6 Hz, 1 H),
6.80 (d, J = 8.4 Hz, 1 H), 5.66 (d, J = 7.0 Hz, 1 H), 4.34–4.13 (m, 2 H),
3.82 (s, 3 H), 2.21 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.5, 166.6, 158.1, 134.0, 131.9,
129.7, 128.7, 128.4, 127.5, 127.3, 126.1, 110.3, 62.0, 56.5, 55.5, 16.4,
14.2.
1.2 mmol,
1.2 equiv),
1-methoxy-4-methylbenzene
(0.38 mL,
3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in
MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C.
Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded
the product as a colorless solid (205 mg, 63%; r.r. = >98:2).
Mp 100.3 °C; Rf = 0.51 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3263 (m), 2908 (w), 2832 (w), 1732 (s), 1637 (s), 1579 (w),
1524 (m), 1506 (m), 1461 (m), 1390 (w), 1365 (m), 1323 (s), 1254 (s),
1206 (s), 1135 (s), 1091 (s), 1033 (s), 978 (w), 874 (m), 805 (s), 761
(m), 717 (s), 690 (s), 604 cm–1 (m).
MS (ESI): m/z [M + Na]+ calcd for C19H21NO4Na: 350.1; found: 350.3.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO4: 328.1543; found:
1H NMR (400 MHz, CDCl3): δ = 7.82–7.77 (m, 2 H), 7.52–7.46 (m, 1 H),
7.42 (t, J = 7.4 Hz, 2 H), 7.29 (d, J = 8.1 Hz, 1 H), 7.25 (d, J = 1.9 Hz, 1 H),
7.10 (dd, J = 8.3, 1.7 Hz, 1 H), 6.80 (d, J = 8.3 Hz, 1 H), 5.89 (d, J = 8.3 Hz,
1 H), 4.25–4.16 (m, 2 H), 3.83 (s, 3 H), 2.30 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3
H).
13C NMR (101 MHz, CDCl3): δ = 171.3, 166.7, 155.1, 134.4, 131.7,
131.6, 130.6, 130.2, 128.6, 127.3, 125.5, 111.2, 61.7, 55.8, 54.1, 20.6,
14.3.
328.1543.
Ethyl 2-Benzamido-2-(4-methoxy-2-methylphenyl)acetate (4e)
Bi Catalysis: Compound 4e was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,
0.6 mmol,
1.2 equiv),
1-methoxy-3-methylbenzene
(0.19 mL,
1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C.
Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded
the product as a colorless solid (97 mg, 59%; r.r. = 80:20).
MS (ESI): m/z [M + Na]+ calcd for C19H21NO4Na: 350.1; found: 350.2.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO4: 328.1543; found:
328.1543.
Fe Catalysis: Compound 4e was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
Ethyl 2-Benzamido-2-(3-chloro-4-methoxyphenyl)acetate (4g)
Bi Catalysis: Compound 4g was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,
1.2 mmol, 1.2 equiv), 2-chloroanisole (0.38 mL, 3.0 mmol, 3.0 equiv),
and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The re-
action mixture was stirred for 16 h at 80 °C. Purification by chroma-
tography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless
solid (266 mg, 77%; r.r. = >98:2).
0.6 mmol,
1.2 equiv),
1-methoxy-3-methylbenzene
(0.19 mL,
1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C.
Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded
the product as a colorless solid (121 mg, 63%; r.r. = 75:25). Further
purification of the major regioisomer could be achieved by precipita-
tion from hexane/CH2Cl2 (84:16 mixture of regioisomers, as judged
by 1H NMR analysis). Analytical data were obtained for this purified
mixture.
Fe Catalysis: Compound 4g was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
1.2 mmol, 1.2 equiv), 2-chloroanisole (0.38 mL, 3.0 mmol, 3.0 equiv)
and FeCl3∙6H2O (14 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The
reaction mixture was stirred for 24 h at 80 °C. Purification by chro-
matography (n-hexane/EtOAc = 4:1) yielded the product as colorless
solid (235 mg, 68%; r.r. = >98:2).
Mp 90.2 °C; Rf = 0.51 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3343 (w), 2937 (w), 1732 (s), 1638 (s), 1611 (m), 1579 (m),
1486 (m), 1347 (m), 1293 (m), 1252 (s), 1111 (m), 1079 (m), 925 (w),
862 (m), 761 (m), 691 (s), 626 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.89–7.73 (m, 2
H), 7.55–7.38 (m, 3 H), 7.23–7.15 (m, 1 H), 7.00 (d, J = 6.5 Hz, 1 H),
6.82–6.70 (m, 2 H), 5.89 (d, J = 6.9 Hz, 1 H), 4.32–4.11 (m, 2 H), 3.79 (s,
3 H), 2.53 (s, 3 H), 2.35 (s, 1 H), 1.27–1.16 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.8, 166.7, 159.6, 138.7, 133.9,
131.9, 131.7, 130.7, 128.7, 128.6, 128.6, 127.8, 127.7, 127.3, 127.3,
121.8, 116.6, 112.2, 111.9, 62.0, 55.7, 55.4, 53.3, 21.8, 19.9, 14.2
(peaks not assigned to regioisomers).
Mp 89.0 °C; Rf = 0.49 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3310 (w), 2976 (w), 1730 (s), 1634 (s), 1604 (m), 1578 (m),
1525 (s), 1489 (s), 1372 (w), 1342 (m), 1292 (s), 1255 (s), 1188 (s),
1093 (s), 1063 (s), 1023 (s), 919 (w), 875 (m), 795 (m), 689 cm–1 (s).
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1H NMR (400 MHz, CDCl3): δ = 7.85–7.79 (m, 2 H), 7.55–7.41 (m, 4 H),
7.33 (dd, J = 8.5, 2.2 Hz, 1 H), 7.19 (d, J = 6.6 Hz, 1 H), 6.93–6.89 (m, 1
H), 5.67 (d, J = 6.8 Hz, 1 H), 4.32–4.15 (m, 2 H), 3.89 (s, 3 H), 1.25 (t, J =
7.1 Hz, 3 H).
IR (ATR): 3390 (w), 2362 (w), 1840 (s), 1655 (s), 1600 (w), 1579 (w),
1518 (m), 1483 (s), 1367 (w), 1343 (w), 1286 (m), 1259 (m), 1214 (s),
1180 (s), 1153 (m), 1097 (w), 1048 (m), 1012 (s), 927 (w), 799 (m),
714 cm–1 (s).
13C NMR (101 MHz, CDCl3): δ = 170.8, 166.4, 155.1, 133.5, 131.9,
130.0, 128.9, 128.7, 127.2, 127.0, 123.0, 112.2, 62.3, 56.2, 55.9, 14.03.
MS (ESI): m/z [M + H]+ calcd for C18H19ClNO4: 348.1; found: 348.0.
HRMS (MALDI): m/z [M + H]+ calcd for C18H19ClNO4: 348.0997; found:
1H NMR (400 MHz, CDCl3): δ = 7.86–7.78 (m, 3 H), 7.56–7.38 (m, 4 H),
7.17 (d, J = 6.6 Hz, 1 H), 6.80 (d, J = 8.5 Hz, 1 H), 5.65 (d, J = 6.8 Hz, 1 H),
4.32–4.15 (m, 2 H), 3.87 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.0, 166.6, 158.4, 138.2, 133.7,
132.1, 131.1, 129.0, 128.8, 127.3, 111.1, 86.5, 62.4, 56.6, 55.7, 14.1.
348.0996.
MS (ESI): m/z [M]+ calcd for C18H18INO4: 439.0; found: 439.2.
HRMS (MALDI): m/z [M + H]+ calcd for C18H19INO4: 440.0353; found:
Ethyl 2-Benzamido-2-(3-bromo-4-methoxyphenyl)acetate (4h)
440.0345.
Bi Catalysis: Compound 4h was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol), ethyl glyoxalate (122 mg, 1.2 mmol),
2-bromoanisole (0.37 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg,
0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was
stirred for 16 h at 80 °C. Purification by chromatography (n-hex-
ane/EtOAc = 4:1) yielded the product as a colorless solid (344 mg,
88%; r.r. = >98:2).
Ethyl 2-Benzamido-2-(5-bromo-2-methoxyphenyl)acetate (4j)
Bi Catalysis: Compound 4j was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol), ethyl glyoxalate (122 mg, 1.2 mmol),
4-bromoanisole (0.38 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (33 mg,
0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was
stirred for 16 h at 100 °C. Purification by chromatography (n-hex-
ane/EtOAc = 4:1) yielded the product as a colorless solid (161 mg,
41%; r.r. = >98:2).
Fe Catalysis: Compound 4h was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.30 mL,
1.5 mmol, 1.5 equiv), 2-bromoanisole (0.37 mL, 3.0 mmol, 3.0 equiv),
and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The re-
action mixture was stirred for 24 h at 80 °C. Purification by chroma-
tography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a
colorless solid (289 mg, 74%; r.r. = >98:2).
Fe Catalysis: Compound 4j was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol), ethyl glyoxalate (0.24 mL, 1.2 mmol),
4-bromoanisole (0.38 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg,
0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was
stirred for 16 h at 100 °C. Purification by chromatography (cyclohex-
ane/EtOAc = 9:1 → 4:1) yielded the product as a colorless solid
(132 mg, 34%; r.r. = >98:2).
Mp 103.7 °C; Rf = 0.51 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3387 (w), 2992 (w), 2942 (w), 1739 (s), 1654 (s), 1602 (w),
1580 (w), 1519 (m), 1498 (m), 1484 (s), 1443 (m), 1367 (w), 1342 (w),
1286 (m), 1261 (s), 1213 (s), 1179 (s), 1152 (m), 1096 (w), 1055 (m),
799 (m), 713 (s), 688 (m), 665 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.85–7.80 (m, 2 H), 7.61 (d, J = 2.2 Hz, 1
H), 7.52 (m, 1 H), 7.44 (dd, J = 10.2, 4.6 Hz, 2 H), 7.38 (dd, J = 8.5, 2.2
Hz, 1 H), 7.18 (d, J = 6.6 Hz, 1 H), 6.90–6.86 (m, 1 H), 5.68 (d, J = 6.7 Hz,
1 H), 4.32–4.16 (m, 2 H), 3.89 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.9, 166.6, 156.2, 133.7, 132.1,
132.1, 130.6, 128.8, 127.9, 127.3, 112.3, 112.2, 62.4, 56.5, 55.9, 14.2.
MS (ESI): m/z [M + H]+ calcd for C18H19BrNO4: 392.0; found: 392.9.
HRMS (MALDI): m/z [M + H]+ calcd for C18H19BrNO4: 392.0492; found:
Mp 129.2 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).
IR (ATR): 1738 (m), 1638 (s), 1576 (m), 1520 (m), 1486 (s), 1365 (s),
1337 (m), 1315 (s), 1247 (s), 1188 (s), 1176 (s), 1131 (m), 1087 (s),
1026 (s), 900 (m), 868 (m), 801 (s), 759 (w), 718 (m), 688 (s), 669 (s),
653 (s), 618 (s), 590 (s), 539 (m), 500 cm–1 (w).
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 7.3 Hz, 2 H), 7.56 (d, J = 2.4
Hz, 1 H), 7.53–7.38 (m, 4 H), 7.28–7.24 (m, 1 H), 6.82–6.75 (m, 1 H),
5.88 (d, J = 8.0 Hz, 1 H), 4.27–4.17 (m, 2 H), 3.84 (s, 3 H), 1.21 (t, J = 7.1
Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.7, 166.7, 156.4, 134.1, 133.5,
132.5, 131.9, 128.7, 128.0, 127.3, 113.3, 113.0, 62.0, 56.1, 53.4, 14.2.
MS (ESI): m/z [M + H]+ calcd for C18H19BrNO4 392.1; found: 392.1.
392.0491.
Ethyl 2-Benzamido-2-(3-iodo-4-methoxyphenyl)acetate (4i)
Anal. Calcd for C18H18BrNO4: C, 55.12; H, 4.63; N, 3.57. Found: C,
54.86; H, 4.50; N, 3.42.
Bi Catalysis: Compound 4i was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,
1.2 mmol, 1.2 equiv), 2-iodoanisole (0.40 mL, 3.0 mmol, 3.0 equiv),
and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The re-
action mixture was stirred for 16 h at 80 °C. Purification by chroma-
tography (n-hexane/EtOAc = 4:1) yielded the product as a colorless
solid (355 mg, 81%; r.r. = >98:2).
Ethyl 2-Benzamido-2-(5-iodo-2-methoxyphenyl)acetate (4k)
Bi Catalysis: Compound 4k was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,
1.2 mmol, 1.2 equiv), 4-iodoanisole (702 mg, 3.0 mmol, 3.0 equiv),
and Bi(OTf)3 (33 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The re-
action mixture was stirred for 16 h at 100 °C. Purification by chroma-
tography (n-hexane/EtOAc = 4:1) yielded the product as a colorless
solid (261 mg, 59%; r.r. = >98:2).
Fe Catalysis: Compound 4i was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,
1.2 mmol, 1.2 equiv), 2-iodoanisole (0.40 mL, 3.0 mmol, 3.0 equiv),
and Fe(ClO4)3 (7 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reac-
tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 4:1) yielded the product as a colorless
solid (333 mg, 76%; r.r. = >98:2).
Fe Catalysis: Compound 4k was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
1.2 mmol, 1.2 equiv), 4-iodoanisole (702 mg, 3.0 mmol, 3.0 equiv),
and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The re-
action mixture was stirred for 24 h at 80 °C. Purification by chroma-
tography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless
solid (221 mg, 50%; r.r. = >98:2).
Mp 120.6 °C; Rf = 0.54 (cyclohexane/EtOAc = 7:3).
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Mp 102.4 °C; Rf = 0.46 (cyclohexane/EtOAc = 7:3).
Mp 157–159 °C; Rf = 0.5 (n-hexane/EtOAc = 1:1).
IR (ATR): 3277 (w), 3054 (w), 2933 (w), 2835 (w), 1739 (s), 1637 (s),
1602 (w), 1578 (w), 1523 (m), 1486 (s), 1456 (m), 1391 (w), 1366 (w),
1336 (m), 1317 (m), 1294 (m), 1247 (s), 1188 (s), 1134 (m), 1093 (m),
1025 (s), 800 (m), 689 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.83–7.75 (m, J = 13.0, 7.6 Hz, 2 H),
7.75–7.68 (m, 1 H), 7.63–7.37 (m, 4 H), 7.31–7.20 (m, 1 H), 6.71–6.64
(m, 1 H), 5.86 (d, J = 8.0 Hz, 1 H), 4.26–4.15 (m, 2 H), 3.82 (s, 3 H), 1.21
(t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.7, 166.7, 157.2, 139.2, 138.6,
134.1, 131.9, 128.7, 128.4, 127.3, 113.5, 83.2, 62.0, 55.9, 53.3, 14.3.
MS (ESI): m/z [M + Na]+ calcd for C18H18INO4Na: 462.0; found: 462.2.
HRMS (MALDI): m/z [M + H]+ calcd for C18H19INO4: 440.0353; found:
IR (ATR): 3244 (w), 2962 (w), 1742 (s), 1666 (m), 1638 (s), 1600 (m),
1582 (w), 1524 (s), 1505 (s), 1481 (m), 1443 (m), 1399 (m), 1387 (m),
1369 (m), 1335 (s), 1252 (m), 1194 (s), 1158 (s), 1105 (m), 1076 (m),
1019 (m), 949 (w), 911 (m), 872 (m), 839 (w), 829 (w), 814 (w), 796
(w), 769 (m), 691 (s), 665 (m), 596 (m), 567 (w), 519 (w), 489 cm–1
(w).
1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.80–7.78 (m, 2
H), 7.52–7.48 (m, 1 H), 7.44–7.37 (m, 4 H), 7.31 (br s, 1 H), 7.23 (d, J =
8.2 Hz, 1 H), 7.08 (br d, J = 6.7 Hz, 1 H), 5.90 (d, J = 6.9 Hz, 1 H), 4.27–
4.12 (m, 2 H), 2.53 (s, 3 H), 1.30 (s, 9 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ (major regioisomer) = 176.8, 171.6,
166.7, 138.2, 138.1, 133.8, 131.9, 131.2, 128.7, 127.2, 127.2, 122.3,
118.1, 62.1, 53.4, 39.7, 27.7, 19.7, 14.1.
440.0347.
MS (ESI): m/z [M + H]+ calcd for C23H28N2O4: 396.2; found: 419.1.
HRMS (MALDI): m/z [M + H]+ calcd for C23H28N2O4: 397.2122; found:
397.2182.
Ethyl 2-Benzamido-2-(2,5-dimethylphenyl)acetate (4l)
Bi Catalysis: Compound 4l was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,
0.6 mmol, 1.2 equiv), p-xylene (0.19 mL, 1.5 mmol, 3.0 equiv), and
Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction
mixture was stirred for 16 h at 80 °C. Purification by chromatography
(cyclohexane/EtOAc = 4:1) yielded the product as a colorless oil
(62 mg, 40%).
Ethyl 3-(1-Benzamido-2-ethoxy-2-oxoethyl)-4-methoxybenzoate
(4n)
Bi Catalysis: Compound 4n was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,
0.6 mmol, 1.2 equiv), ethyl 4-methoxybenzoate (360 mg, 2.0 mmol,
4.0 equiv), and Bi(OTf)3 (16 mg, 0.025 mmol, 5 mol%) in MeNO2
(2.0 mL). The reaction mixture was stirred for 72 h at 100 °C. Purifica-
tion by chromatography (n-hexane/EtOAc = 4:1) yielded the product
as a yellow oil (77 mg, 40%; r.r. = >98:2).
Fe Catalysis: Compound 4l was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
0.6 mmol, 1.2 equiv), p-xylene (0.19 mL, 1.5 mmol, 3.0 equiv), and
Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reac-
tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 4:1) yielded the product as a colorless oil
(53 mg, 32%); Rf = 0.38 (cyclohexane/EtOAc = 7:3).
Fe Catalysis: Compound 4n was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
0.6 mmol, 1.0 equiv), ethyl 4-methoxybenzoate (270 mg, 1.5 mmol,
3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2
(2.0 mL). The reaction mixture was stirred for 24 h at 100 °C. Purifica-
tion by chromatography (n-hexane/EtOAc = 4:1) yielded the product
as a yellow oil (128 mg, 66%; r.r. = 71:28); Rf = 0.3 (hexane/EtOAc =
7:3).
IR (ATR): 3338 (w), 2977 (w), 2925 (w), 2869 (w), 1737 (s), 1638 (s),
1578 (w), 1531 (s), 1489 (m), 1366 (w), 1344 (s), 1285 (m), 1219 (m),
1198 (s), 1077 (w), 1021 (m), 808 (w), 689 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.4 Hz, 2 H), 7.55–7.41 (m, 3
H), 7.13–7.01 (m, 4 H), 5.93 (d, J = 7.0 Hz, 1 H), 4.35–4.11 (m, 2 H),
2.51 (s, 3 H), 2.30 (s, 3 H), 1.29–1.19 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.6, 166.5, 136.1, 135.0, 133.8,
133.7, 131.8, 130.9, 129.2, 128.6, 127.2, 127.0, 61.9, 53.6, 21.0, 19.1,
14.0.
IR (ATR): 3342 (w), 2981 (w), 2843 (w), 1741 (m), 1711 (s), 1650 (s),
1608 (m), 1580 (m), 1506 (m), 1484 (m), 1465 (m), 1445 (m), 1391
(w), 1368 (m), 1322 (m), 1297 (m), 1265 (s), 1238 (s), 1204 (s), 1188
(s), 1130 (s), 1103 (m), 1023 (s), 913 (m), 862 (m), 831 (m), 801 (m),
771 (m), 713 (s), 692 (m), 647 (m), 630 (m), 589 (m), 541 (m), 473
cm–1 (m).
MS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.2; found: 312.2.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found
312.1595.
1H NMR (300 MHz, CDCl3): δ = 8.13 (d, J = 2.1 Hz, 1 H), 8.04 (dd, J = 8.6,
2.2 Hz, 1 H), 7.82–7.79 (m, 2 H), 7.53–7.43 (m, 3 H), 7.27 (br s, 1 H),
6.93 (d, J = 8.7 Hz, 1 H), 6.00 (d, J = 8.0 Hz, 1 H), 4.35 (q, J = 7.1 Hz, 2 H),
4.20 (q, J = 7.1 Hz, 2 H), 3.92 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H), 1.20 (t, J =
7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.86, 166.73, 166.11, 160.76, 134.16,
132.20, 132.13, 131.84, 128.69, 127.31, 125.93, 123.56, 110.71, 61.98,
61.01, 56.06, 53.61, 14.53, 14.23.
Ethyl 2-Benzamido-2-(3-methyl-5-pivalamidophenyl)acetate (4m)
Bi Catalysis: Compound 4m was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), 3-methylpivalanilide (287 mg,
1.5 mmol, 3.0 equiv), and Bi(OTf)3 (16 mg, 0.025 mmol, 5 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C.
Purification by chromatography (n-hexane/EtOAc 4:1) yielded the
product as a yellow solid (13 mg, 67%; r.r. = >98:2).
MS (ESI): m/z [M + Na]+ calcd for C21H23NO6Na: 408.1; found: 408.1.
HRMS (MALDI): m/z [M + H]+ calcd for C21H24NO6 386.1598; found:
386.1600.
Fe Catalysis: Compound 4m was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.0 equiv), 3-methylpivalanilide (287 mg,
1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C.
Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the
product as a yellow solid (158 mg, 80%; r.r. = 71:29).
Ethyl 2-Benzamido-2-(3,4,5-trimethoxyphenyl)acetate (4o)
Bi Catalysis: Compound 4o was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,
0.6 mmol, 1.2 equiv), 1,2,3-trimethoxybenzene (253 mg, 3.0 mmol,
3.0 equiv), Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%), and in MeNO2
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(2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 9:1 → 7:3) yielded the
product as a colorless oil (127 mg, 68%; r.r. = >98:2).
MS (ESI): m/z [M + H]+ calcd for C20H24NO4: 342.1; found: 342.2.
HRMS (MALDI): m/z [M + H]+ calcd for C20H24NO4: 342.1053; found:
342.1696.
Fe Catalysis: Compound 4o was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
1.2 mmol, 1.2 equiv), 1,2,3-trimethoxybenzene (505 mg, 3.0 mmol,
3.0 equiv), Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%), and 2,2′-bipyridine
(0.06 mmol, 6 mol%, 9 mg) in MeNO2 (4.0 mL). The reaction mixture
was stirred for 24 h at 100 °C. Purification by chromatography (cyclo-
hexane/EtOAc = 9:1 → 7:3) yielded the product as a colorless oil
(216 mg, 58%; r.r. = >98:2); Rf = 0.23 (cyclohexane/EtOAc = 7:3).
Ethyl 2-Benzamido-2-(2-methoxynaphthalen-1-yl)acetate (4q)
Bi Catalysis: Compound 4q was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6
mmol, 1.2 equiv), 2-methoxynaphthalene (237 mg, 1.5 mmol, 3.0
equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).
The reaction mixture was stirred for 16 h at 80 °C. Purification by
chromatography (n-hexane/EtOAc = 4:1) yielded the product as an or-
ange oil (89 mg, 49%).
IR (ATR): 3347 (w), 2979 (w), 2939 (w), 2837 (w), 1721 (m), 1670 (m),
1600 (m), 1581 (m), 1516 (m), 1494 (s), 1465 (w), 1418 (m), 1369
(m), 1313 (m), 1278 (s), 1244 (s), 1203 (s), 1172 (s), 1092 (s), 1055 (s),
1015 (s), 964 (m), 909 (m), 873 (m), 798 (m), 746 (m), 713 (m), 692
(m), 667 (m), 570 (m), 514 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.83–7.79 (m, 2 H), 7.52–7.47 (m, 1 H),
7.45–7.40 (m, 2 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.12 (d, J = 8.6 Hz, 1 H),
6.67–6.64 (m, 1 H), 5.86 (d, J = 7.9 Hz, 1 H), 4.31–4.15 (m, 2 H), 3.95 (s,
3 H), 3.86 (s, 3 H), 3.86 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).
Fe Catalysis: Compound 4q was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
0.6 mmol, 1.2 equiv), 2-methoxynaphthalene (237 mg, 1.5 mmol, 3.0
equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL).
The reaction mixture was stirred for 24 h at 80 °C. Purification by
chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the prod-
uct as an orange oil (123 mg, 64%); Rf = 0.31 (cyclohexane/EtOAc =
7:3).
13C NMR (101 MHz, CDCl3): δ = 171.5, 166.7, 154.3, 151.8, 142.2,
134.3, 131.8, 128.7, 127.3, 124.6, 123.5, 107.3, 61.9, 61.1, 60.9, 56.1,
53.6, 14.3.
MS (ESI): m/z [M + Na]+ calcd for C20H23NO6Na: 396.1; found: 396.3.
HRMS (MALDI): m/z [M + H]+ calcd for C21H24NO6: 374.1598; found:
IR (ATR): 3446 (w), 2979 (w), 2841 (w), 2099 (w), 1739 (s), 1651 (s),
1626 (m), 1598 (m), 1580 (m), 1560 (m), 1512 (s), 1482 (s), 1473 (s),
1445 (m), 1386 (s), 1367 (m), 1319 (m), 1267 (s), 1251 (s), 1204 (s),
1185 (s), 1147 (s), 1086 (s), 1024 (s), 906 (m), 888 (w), 864 (m), 848
(m), 810 (s), 783 (m), 709 (s), 692 (s), 672 (m), 645 (m), 605 (m), 589
(m), 546 (m), 526 (m), 502 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 8.36 (d, J = 8.7 Hz, 1 H), 7.88 (d, J = 9.0
Hz, 1 H), 7.84–7.78 (m, 3 H), 7.62–7.57 (m, 1 H), 7.50–7.36 (m, 5 H),
7.30 (d, J = 9.0 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 4.23–4.16 (m, 2 H),
3.99 (s, 3 H), 1.16 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.8, 167.0, 155.3, 134.4, 132.6,
131.7, 130.8, 129.6, 128.7, 128.6, 127.8, 127.4, 124.1, 123.1, 119.5,
113.1, 61.7, 56.6, 49.0, 14.3.
MS (ESI): m/z [M + H]+ calcd for C22H22NO4: 364.2; found: 364.3.
HRMS (MALDI): m/z [M + H]+ calcd for C22H22NO4: 364.1543; found:
374.15988.
Ethyl 2-Benzamido-2-(4-methoxy-2,6-dimethylphenyl)acetate
(4p)
Bi Catalysis: Compound 4p was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6
mmol,
1.2 equiv),
1-methoxy-3,5-dimethylbenzene
(204 mg,
1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C.
Purification by chromatography (n-hexane/EtOAc = 9:1 → 4:1) yielded
the product as a colorless oil (84 mg, 50%; r.r. = 67:33).
364.1544.
Fe Catalysis: Compound 4p was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
0.6 mmol, 1.2 equiv), 1-methoxy-3,5-dimethylbenzene (204 mg,
1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C.
Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1)
yielded the product as a yellowish oil (106 mg, 62%; r.r. = 50:50); Rf =
0.57 (cyclohexane/EtOAc = 7:3).
Ethyl 2-Benzamido-2-(pyren-4-yl)acetate (4r)
Bi Catalysis: Compound 4r was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,
0.6 mmol, 1.2 equiv), pyrene (303 mg, 1.5 mmol, 3.0 equiv), and
Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction
mixture was stirred for 16 h at 80 °C. Purification by chromatography
(n-hexane/EtOAc = 4:1) yielded the product as a colorless solid
(111 mg, 54%; r.r. = >98:2).
IR (ATR): 3449 (w), 3319 (s), 2977 (m), 2840 (w), 2099 (s), 1739 (s),
1655 (s), 1651 (s), 1624 (m), 1599 (m), 1580 (m), 1512 (s), 1482 (s),
1446 (m), 1367 (m), 1318 (s), 1251 (s), 1207 (s), 1186 (s), 1147 (s),
1094 (s), 1024 (s), 1002 (m), 973 (m), 931 (m), 906 (m), 887 (m), 862
(m), 848 (m), 810 (s), 745 (m), 709 (s), 691 (s), 672 (m), 645 (m), 608
(m), 590 (m), 546 (m), 526 (m), 502 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.82–7.77 (m, 2 H), 7.50–7.39 (m, 3 H),
7.17 (d, J = 6.1 Hz, 1 H), 6.75–6.44 (m, 2 H), 6.23–6.12 (m, 1 H), 4.32–
4.10 (m, 2 H), 3.85–3.74 (m, 3 H), 2.56 (s, 2 H), 2.49 (s, 2 H), 2.31 (s, 2
H), 1.28–1.15 (m, 3 H) (peaks not assigned to regioisomers).
13C NMR (101 MHz, CDCl3): δ = 171.9, 171.5, 166.6, 166.4, 158.7,
157.5, 139.0, 138.3, 134.5, 133.9, 131.7, 131.5, 128.6, 128.5, 127.2,
127.1, 126.3, 124.2, 122.2, 114.4, 109.7, 62.0, 61.4, 55.5, 55.0, 52.5,
50.2, 21.5, 20.8, 19.9, 14.2, 14.1 (peaks not assigned to regioisomers).
Fe Catalysis: Compound 4r was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
0.6 mmol, 1.2 equiv), pyrene (303 mg, 1.5 mmol, 3.0 equiv), and
Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction
mixture was stirred for 24 h at 80 °C. Purification by chromatography
(cyclohexane/EtOAc = 20:1 → 9:1 → 4:1) yielded the product as a col-
orless solid (115 mg, 57%; r.r. = >98:2).
Mp 207.3 °C; Rf = 0.48 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3331 (w), 2985 (w), 2360 (w), 2342 (w), 1740 (s), 1635 (s),
1602 (w), 1579 (w), 1517 (w), 1489 (m), 1374 (w), 1349 (m), 1313
(w), 1204 (s), 1183 (m), 1150 (m), 1089 (m), 1021 (m), 845 (s), 824
(m), 692 cm–1 (s).
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1H NMR (400 MHz, CDCl3): δ = 8.61–8.54 (m, 1 H), 8.25–8.01 (m, 8 H),
7.86–7.79 (m, 2 H), 7.49 (dd, J = 14.0, 6.6 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 2
H), 7.26 (s, 1 H), 6.83 (d, J = 7.3 Hz, 1 H), 4.36–4.15 (m, 2 H), 1.18 (t, J =
7.1 Hz, 3 H).
IR (ATR): 3427 (w), 2969 (w), 1731 (s), 1660 (s), 1607 (w), 1588 (m),
1566 (w), 1506 (s), 1473 (s), 1366 (m), 1352 (w), 1309 (s), 1256 (m),
1212 (w), 1189 (s), 1159 (m), 881 (m), 848 (m), 777 (m), 751 (s), 613
cm–1 (m).
13C NMR (101 MHz, CDCl3): δ = 171.8, 166.9, 133.8, 132.0, 131.8,
131.4, 130.9, 130.1, 129.3, 128.9, 128.7, 128.2, 127.4, 127.3, 126.4,
125.8, 125.7, 125.4, 125.2, 125.1, 124.8, 122.8, 62.3, 54.3, 14.2.
1H NMR (400 MHz, CDCl3): δ = 7.71–7.51 (m, 4 H), 7.14 (d, J = 6.2 Hz, 1
H), 6.86 (s, 2 H), 6.15 (d, J = 6.5 Hz, 1 H), 4.33–4.12 (m, 2 H), 2.46 (s, 6
H), 2.25 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
MS (ESI): m/z [M]+ calcd for C27H21NO3: 407.2; found: 407.2.
13C NMR (101 MHz, CDCl3): δ = 171.8, 165.6, 137.9, 137.1, 132.89,
132.0, 130.8, 130.2, 128.8, 126.6, 62.3, 52.9, 21.0, 20.5, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C20H22BrNO3Na: 428.1; found 428.2.
HRMS (MALDI): m/z [M]+ calcd for C27H21NO3: 407.1516; found:
407.1513.
HRMS (MALDI): m/z [M + H]+ calcd for C20H23BrNO3: 404.0856; found:
404.0854.
Ethyl 2-Mesityl-2-(4-methoxybenzamido)acetate (5a)
Bi Catalysis: Compound 5a was synthesized according to the GP from
4-methoxybenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).
The reaction mixture was stirred for 16 h at 80 °C. Purification by
chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a
colorless solid (145 mg, 81%).
Ethyl 2-Mesityl-2-(4-nitrobenzamido)acetate (5c)
Bi Catalysis: Compound 5c was synthesized according to the GP from
4-nitrobenzamide (83 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).
The reaction mixture was stirred for 16 h at 80 °C. Purification by
chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a
colorless solid (125 mg, 68%).
Fe Catalysis: Compound 5a was synthesized according to the GP from
4-methoxybenzamide (73 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2
(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 4:1 → 7:3) yielded the
product as a colorless solid (166 mg, 94%).
Fe Catalysis: Compound 5c was synthesized according to the GP from
4-nitrobenzamide (166 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate
(0.24 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol,
3.0 equiv), and FeCl3·6H2O (14 mg, 0.050 mmol, 5 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the
product as a colorless solid (329 mg, 89%).
Mp 109.8 °C; Rf = 0.36 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3432 (w), 2921 (m), 2851 (m), 1726 (m), 1652 (s), 1605 (m),
1524 (w), 1486 (s), 1366 (m), 1349 (m), 1306 (m), 1252 (s), 1214 (w),
1193 (s), 1175 (s), 1088 (m), 1021 (s), 845 (m), 767 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.7 Hz, 2 H), 7.08 (d, J = 6.3
Hz, 1 H), 6.92 (d, J = 8.7 Hz, 2 H), 6.85 (s, 2 H), 6.18 (d, J = 6.5 Hz, 1 H),
4.32–4.11 (m, 2 H), 3.84 (s, 3 H), 2.47 (s, 6 H), 2.25 (s, 3 H), 1.22 (t, J =
7.1 Hz, 3 H).
Mp 119.2 °C; Rf = 0.36 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3349 (w), 2978 (w), 1731 (s), 1634 (m), 1598 (m), 1525 (s),
1488 (m), 1460 (w), 1343 (m), 1297 (m), 1240 (s), 1148 (w), 1077
(m), 1024 (m), 928 (w), 876 (m), 853 (m), 799 (m), 761 (w), 720 (s),
679 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 8.7 Hz, 2 H), 7.95 (d, J = 8.7
Hz, 2 H), 7.27–7.22 (m, 1 H), 6.87 (s, 2 H), 6.15 (d, J = 6.4 Hz, 1 H),
4.34–4.12 (m, 2 H), 2.46 (s, 6 H), 2.26 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 172.1, 166.1, 162.5, 137.7, 137.1,
131.1, 130.1, 129.0, 126.3, 113.9, 62.1, 55.5, 52.8, 21.0, 20.5, 14.2.
MS (ESI): m/z [M + H]+ calcd for C21H26NO4 356.2; found: 356.2.
13C NMR (101 MHz, CDCl3): δ = 171.6, 164.6, 149.9, 139.6, 138.2,
137.1, 130.4, 130.3, 128.4, 124.0, 62.5, 53.1, 21.0, 20.5, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C20H22N2O5Na: 393.1; found: 393.3.
HRMS (MALDI): m/z [M + H]+ calcd for C21H26NO4 356.1856; found:
356.1856.
HRMS (MALDI): m/z [M + Na]+ calcd for C20H22N2O5Na: 393.1421;
found: 393.1421.
Ethyl 2-(4-Bromobenzamido)-2-mesitylacetate (5b)
Bi Catalysis: Compound 5b was synthesized according to the GP from
4-bromobenzamide (100 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).
The reaction mixture was stirred for 16 h at 80 °C. Purification by
chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a
colorless solid (161 mg, 80%).
Ethyl 2-(2-Chloroacetamido)-2-mesitylacetate (5d)
Bi Catalysis: Compound 5d was synthesized according to the GP from
2-chloroacetamide (47 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The
reaction mixture was stirred for 16 h at 80 °C. Purification by chro-
matography (cyclohexane/EtOAc = 4:1 → 7:3) yielded the product as a
colorless oil (121 mg, 81%).
Fe Catalysis: Compound 5b was synthesized according to the GP from
4-bromobenzamide (100 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2
(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the
product as a colorless solid (172 mg, 85%).
Fe Catalysis: Compound 5d was synthesized according to the GP from
2-chloroacetamide (47 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and FeCl3·6H2O (3 mg, 0.010 mmol, 2 mol%) in MeNO2 (2.0
mL). The reaction mixture was stirred for 24 h at 80 °C. Purification
by chromatography (cyclohexane/EtOAc = 4:1 → 7:3) yielded the
product as a colorless oil (131 mg, 88%); Rf = 0.30 = (cyclohexane/
EtOAc = 7:3).
Mp 89.5 °C; Rf = 0.70 (cyclohexane/EtOAc = 7:3).
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IR (ATR): 3307 (w), 2975 (w), 1733 (s), 1660 (m), 1519 (m), 1463 (w),
1370 (w), 1311 (m), 1195 (s), 1150 (m), 1096 (m), 1017 (s), 925 (w),
853 (m), 769 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 6.83 (s, 2 H), 6.68 (d, J = 6.0 Hz, 1 H),
5.96 (d, J = 6.7 Hz, 1 H), 4.30–4.06 (m, 2 H), 2.40 (s, 6 H), 2.24 (s, 3 H),
1.24–1.16 (m, 12 H).
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 6.2 Hz, 1 H), 6.87–6.82 (m, 2
H), 5.99 (d, J = 7.2 Hz, 1 H), 4.32–3.97 (m, 4 H), 2.40 (s, 6 H), 2.25 (s, 3
H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.1, 165.3, 138.4, 137.1, 130.4,
130.2, 129.9, 69.3, 62.2, 52.5, 42.7, 21.0, 20.4, 20.1, 14.2.
13C NMR (101 MHz, CDCl3): δ = 177.7, 172.0, 137.60, 137.0, 131.1,
130.1, 62.0, 52.4, 38.9, 27.7, 21.0, 20.4, 14.2.
MS (ESI): m/z [M + H]+ calcd for C18H28NO3: 306.2; found: 306.2.
HRMS (MALDI): m/z [M + H]+ calcd for C18H28NO3: 306.2064; found:
306.2064.
MS (ESI): m/z [M + Na]+ calcd for C15H20ClNO3Na: 320.1; found: 320.2.
HRMS (MALDI): m/z [M + H]+ calcd for C15H21ClNO3: 298.1205; found:
Ethyl 2-Acrylamido-2-mesitylacetate (5g)
298.1202.
Bi Catalysis: Compound 5g was synthesized according to the GP from
acrylamide (71 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,
1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and
Bi(OTf)3 (7 mg, 0.01 mmol, 1 mol%) in MeNO2 (2.0 mL). The reaction
mixture was stirred for 16 h at 80 °C. Purification by chromatography
(cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid
(226 mg, 82%).
Ethyl 2-Acetamido-2-mesitylacetate (5e)
Bi Catalysis: Compound 5e was synthesized according to the GP from
acetamide (59 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,
1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and
Bi(OTf)3 (33 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction
mixture was stirred for 16 h at 80 °C. Purification by chromatography
(cyclohexane/EtOAc = 4:1 → 1:1) yielded the product as a colorless
solid (209 mg, 79%).
Fe Catalysis: Compound 5g was synthesized according to the GP from
acrylamide (71 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and
FeCl3·6H2O (7 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reac-
tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 7:3) yielded the product as a colorless
solid (233 mg, 85%).
Fe Catalysis: Compound 5e was synthesized according to the GP from
acetamide (30 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
0.6 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and
FeCl3·6H2O (7 mg, 0.020 mmol, 2 mol%) in MeNO2 (4.0 mL). The reac-
tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 4:1 → 1:1) yielded the product as a color-
less solid (93 mg, 70%).
Mp 117.2 °C; Rf = 0.43 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3304.43 (s), 2983 (s), 1748 (s), 1652 (m), 1614 (m), 1519 (s),
1404 (m), 1368 (s), 1311 (s), 1209 (m), 1187 (s), 1148 (m), 1113 (m),
1072 (s), 1023 (m), 990 (m), 958 (s), 856 (m), 810 (m), 604 cm–1 (m).
Mp 95.8 °C; Rf = 0.29 (cyclohexane/EtOAc = 1:1).
IR (ATR): 3302 (m), 2976 (w), 2360 (w), 1748 (s), 1649 (s), 1524 (s),
1366 (m), 1310 (w), 1281 (w), 1211 (s), 1192 (s), 1149 (m), 1124 (m),
1022 (m), 855 (m), 832 (w), 797 (w), 644 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 6.40 (d, J = 6.4 Hz, 1 H),
6.02 (d, J = 7.2 Hz, 1 H), 4.28–4.07 (m, 2 H), 2.38 (s, 6 H), 2.25 (s, 3 H),
2.01 (s, 3 H), 1.19 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 6.59 (t, J = 16.2 Hz, 1 H),
6.29 (dd, J = 16.9, 1.0 Hz, 1 H), 6.16 (dd, J = 17.0, 10.1 Hz, 1 H), 6.07 (d,
J = 6.9 Hz, 1 H), 5.66 (dd, J = 10.1, 1.0 Hz, 1 H), 4.30–4.09 (m, 2 H), 2.40
(s, 6 H), 2.24 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.8, 164.7, 137.8, 137.1, 130.9,
130.4, 130.1, 127.4, 62.1, 52.4, 21.0, 20.4, 14.2.
13C NMR (101 MHz, CDCl3): δ = 171.9, 169.4, 137.8, 137.0, 131.2,
MS (ESI): m/z [M + H]+ calcd for C16H22NO3: 276.2; found: 276.2.
130.1, 62.0, 52.2, 23.2, 21.0, 20.4, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C15H21NO3Na: 286.1; found: 286.2.
HRMS (MALDI): m/z [M + H]+ calcd for C16H22NO3: 276.1594; found:
276.1595.
HRMS (MALDI): m/z [M + H]+ calcd for C15H22NO3: 264.1594; found:
264.1597.
Ethyl 2-[(Ethoxycarbonyl)amino]-2-mesitylacetate (5h)
Bi Catalysis: Compound 5h was synthesized according to the GP from
ethyl carbamate (45 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).
The reaction mixture was stirred for 16 h at 80 °C. Purification by
chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the prod-
uct as colorless crystals (126 mg, 86%).
Ethyl 2-Mesityl-2-pivalamidoacetate (5f)
Bi Catalysis: Compound 5f was synthesized according to the GP from
pivalamide (100 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,
1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and
Bi(OTf)3 (7 mg, 0.01 mmol, 1 mol%) in MeNO2 (4.0 mL). The reaction
mixture was stirred for 16 h at 80 °C. Purification by chromatography
(cyclohexane/EtOAc = 4:1) yielded the product as a colorless oil
(248 mg, 81%).
Fe Catalysis: Compound 5h was synthesized according to the GP from
ethyl carbamate (45 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2
(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the
product as a colorless solid (121 mg, 83%).
Fe Catalysis: Compound 5f was synthesized according to the GP from
pivalamide (50 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv) and
FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reac-
tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 4:1) yielded the product as a colorless oil
(122 mg, 80%); Rf = 0.44 (cyclohexane/EtOAc = 7:3).
Mp 54.1 °C; Rf = 0.40 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3374 (m), 2964 (s), 1705 (s), 1612 (w), 1509 (m), 1391 (w),
1366 (m), 1308 (s), 1263 (w), 1220 (m), 1173 (w), 1091 (m), 1053 (s),
947 (w), 847 (w), 781 (m), 732 (w), 694 (w), 639 cm–1 (w).
IR (ATR): 3448 (w), 2961 (m), 1731 (s), 1670 (s), 1611 (w), 1494 (s),
1395 (w), 1366 (m), 1308 (m), 1257 (m), 1185 (s), 1100 (m), 1016
(m), 907 (w), 852 (m), 770 cm–1 (w).
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1H NMR (500 MHz, CDCl3): δ = 6.84 (s, 2 H), 5.83–5.71 (m, 1 H), 5.67
(d, J = 6.1 Hz, 1 H), 4.16 (d, J = 91.0 Hz, 4 H), 2.37 (s, 6 H), 2.25 (s, 3 H),
1.27–1.17 (m, 6 H).
1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 5.98–5.68 (m, 3 H), 5.35–
5.15 (m, 2 H), 4.63–4.47 (m, 2 H), 4.30–4.07 (m, 2 H), 2.37 (s, 6 H),
2.25 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 171.6, 155.8, 137.5, 136.7, 131.2,
13C NMR (75 MHz, CDCl3): δ = 171.8, 155.6, 137.8, 136.9, 132.8, 131.3,
129.8, 61.7, 61.0, 53.3, 20.7, 20.0, 14.4, 14.0.
130.1, 118.0, 66.0, 62.0, 53.7, 21.0, 20.3, 14.2.
MS (ESI): m/z [M + H]+ calcd for C16H24NO4: 294.2; found: 294.2.
MS (ESI): m/z [M + H]+ calcd for C17H24NO4: 306.2; found: 306.2.
HRMS (MALDI): m/z [M + H]+ calcd for C16H24NO4: 294.1700; found:
HRMS (MALDI): m/z [M + H]+ calcd for C17H24NO4: 306.1700; found:
294.1700.
306.1700.
Ethyl 2-{[Benzyloxy)carbonyl]amino}-2-mesitylacetate (5i)
Ethyl 2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-2-mesityl-
acetate (5k)
Bi Catalysis: Compound 5i was synthesized according to the GP from
benzyl carbamate (76 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).
The reaction mixture was stirred for 16 h at 80 °C. Purification by
chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the prod-
uct as a colorless solid (116 mg, 65%).
Bi Catalysis: Compound 5k was synthesized according to the GP from
(9H-fluoren-9-yl)methyl carbamate (120 mg, 0.5 mmol, 1.0 equiv),
ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL,
3.0 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in
MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C.
Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the
product as a colorless oil (185 mg, 83%).
Fe Catalysis: Compound 5i was synthesized according to the GP from
benzyl carbamate (76 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2
(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the
product as a colorless solid (91 mg, 51%).
Fe Catalysis: Compound 5k was synthesized according to the GP from
(9H-fluoren-9-yl)methyl carbamate (239 mg, 1.0 mmol, 1.0 equiv),
ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL,
3.0 mmol, 3.0 equiv), and FeCl3·6H2O (5 mg, 0.020 mmol, 2 mol%) in
MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C.
Purification by chromatography (cyclohexane/EtOAc = 9:1) yielded
the product as a colorless oil (332 mg, 75%); Rf = 0.69 (cyclohex-
ane/EtOAc = 7:3).
Mp 73.5 °C; Rf = 0.38 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3363 (m), 2957 (s), 2360 (m), 1728 (m), 1701 (s), 1521 (s),
1479 (w), 1455 (w), 1370 (w), 1306 (m), 1231 (s), 1048 (s), 986 (m),
916 (w), 824 (m), 794 (m), 752 (s), 700 (s), 606 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.43–7.01 (m, 5 H), 6.85 (s, 2 H), 5.88–
5.55 (m, 2 H), 5.17–4.99 (m, 2 H), 4.29–4.06 (m, 2 H), 2.38 (s, 6 H),
2.26 (s, 3 H), 1.19 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.7, 155.8, 137.8, 136.9, 136.4,
131.3, 130.1, 130.1, 128.7, 128.3, 67.2, 62.0, 53.7, 21.0, 20.3, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C21H25NO4Na: 378.2; found: 378.3.
HRMS (MALDI): m/z [M + Na]+ calcd for C21H25NO4Na: 378.1677;
IR (ATR): 3368 (w), 2956 (w), 1718 (s), 1611 (w), 1498 (m), 1448 (m),
1305 (m), 1195 (s), 1050 (s), 852 (m), 739 (s), 621 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.75 (d, J = 7.5 Hz, 2 H), 7.63–7.47 (m, 2
H), 7.45–7.26 (m, 4 H), 6.86 (s, 2 H), 5.90–5.49 (m, 2 H), 4.44–4.11 (m,
5 H), 2.35 (s, 6 H), 2.27 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.7, 155.7 144.1, 143.9, 141.4, 137.9,
137.0, 131.1, 130.2, 127.8, 127.2, 125.2, 120.1, 67.3, 62.1, 53.8, 47.3,
21.0, 20.4, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C28H29NO4Na: 466.2; found: 466.0.
HRMS (MALDI): m/z [M + Na]+ calcd for C28H29NO4Na: 466.1989;
found: 378.1681.
found: 466.1993.
Ethyl 2-{[(Allyloxy)carbonyl]amino}-2-mesitylacetate (5j)
Ethyl 2-Benzamido-2-(5-bromothiophen-2-yl)acetate (7a)
Bi Catalysis: Compound 5j was synthesized according to the GP from
allyloxycarbamate (51 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (4.0 mL).
The reaction mixture was stirred for 16 h at 80 °C. Purification by
chromatography (n-hexane/EtOAc = 4:1) yielded the product as a col-
orless oil (128 mg, 84%).
Bi Catalysis: Compound 7a was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,
0.6 mmol, 1.2 equiv), 2-bromothiophene (0.15 mL, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).
The reaction mixture was stirred for 16 h at 60 °C. Purification by
chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the prod-
uct as a yellow solid (102 mg, 55%; r.r. = >98:2).
Fe Catalysis: Compound 5j was synthesized according to the GP from
allyloxycarbamate (102 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate
(0.24 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol,
3.0 equiv), and FeCl3·6H2O (14 mg, 0.05 mmol, 5 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 20:1 → 9:1 → 4:1)
yielded the product as a colorless oil (215 mg, 70%); Rf = 0.63 (cyclo-
hexane/EtOAc = 7:3).
Fe Catalysis: Compound 7a was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
1.2 mmol, 1.2 equiv), 2-bromothiophene (0.29 mL, 3.0 mmol,
3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the
product as a yellow solid (219 mg, 60%; r.r. = >98:2).
Mp 95.2 °C; Rf = 0.58 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3376 (w), 2981 (w), 1831 (w), 1718 (s), 1649 (w), 1611 (w),
1498 (m), 1369 (m), 1305 (m), 1195 (s), 1093 (m), 1053 (s), 932 (m),
852 (m), 775 cm–1 (m).
IR (ATR): 3309 (w), 2995 (w), 2929 (w), 1738 (s), 1636 (s), 1604 (w),
1570 (w), 1525 (s), 1488 (m), 1371 (m), 1292 (s), 1205 (s), 1171 (m),
1123 (w), 1083 (m), 1012 (m), 810 (m), 755 (m), 716 (s), 691 cm–1 (s).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

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1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.7 Hz, 2 H), 7.57–7.51 (m, 1
H), 7.49–7.43 (m, 2 H), 7.16–7.08 (m, 1 H), 6.94–6.77 (m, 2 H), 5.99–
5.92 (m, 1 H), 4.37–4.23 (m, 2 H), 1.32 (t, J = 7.1 Hz, 3 H) (peaks not
assigned to regioisomers).
13C NMR (75 MHz, CDCl3): δ = 169.6, 166.7, 140.7, 137.8, 133.4, 132.3,
130.0, 128.8, 127.3, 126.6, 126.2, 125.7, 112.7, 62.8, 52.6, 14.2 (peaks
not assigned to regioisomers).
Rf = 0.58 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3300 (w), 2978 (w), 2929 (w), 1983 (w), 1983 (w), 1739 (s),
1635 (s), 1604 (w), 1579 (w), 1525 (s), 1587 (m), 1443 (m), 1369 (m),
1324 (m), 1290 (s), 1204 (s), 1166 (m), 1125 (m), 1086 (m), 1021 (m),
989 (m), 881 (m), 810 (m), 754 (m), 715 (s), 690 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.6 Hz, 2 H), 7.57–7.42 (m, 3
H), 7.12 (d, J = 6.3 Hz, 1 H), 6.95–6.76 (m, 2 H), 5.99–5.91 (m, 1 H),
4.37–4.23 (m, 2 H), 1.32 (t, J = 7.1 Hz, 3 H).
MS (ESI): m/z [M + Na]+ calcd for C15H14BrNO3SNa: 390.0; found:
390.1.
13C NMR (101 MHz, CDCl3): δ = 169.7, 166.7, 140.7, 137.8, 133.4,
132.3, 130.5, 130.0, 128.9, 127.3, 126.6, 126.2, 125.7, 62.8, 52.6, 52.6,
14.2 (peaks not assigned to regioisomers).
HRMS (MALDI): m/z [M + H]+ calcd for C15H14BrNO3S: 367.9952;
found: 367.9951.
MS (ESI): m/z [M + Na]+ calcd for C15H14ClNO3SNa: 346.0; found:
346.2.
HRMS (MALDI): m/z [M + H]+ calcd for C15H15ClNO3S: 324.0456;
Ethyl 2-(5-Bromothiophen-2-yl)-2-[(ethoxycarbonyl)amino]ace-
tate (7b)
Bi Catalysis: Compound 7b was synthesized according to the GP from
urethane (67 mg, 0.75 mmol, 1.5 equiv), ethyl glyoxalate (51 mg, 0.5
mmol, 1.0 equiv), 2-bromothiophene (0.16 mL, 1.5 mmol), and
Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (1.0 mL). The reaction
mixture was stirred for 16 h at 60 °C. Purification by chromatography
(cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid
(130 mg, 77%; r.r. = >98:2).
found: 324.0454.
Ethyl 2-(5-Chlorothiophen-2-yl)-2-[(ethoxycarbonyl)amino]ace-
tate (7d)
Bi Catalysis: Compound 7d was synthesized according to the GP from
urethane (67 mg, 0.75 mmol, 1.5 equiv), ethyl glyoxalate (51 mg, 0.5
mmol, 1.0 equiv), 2-chlorothiophene (0.16 mL, 1.5 mmol), and
Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (1.0 mL). The reaction
mixture was stirred for 16 h at 60 °C. Purification by chromatography
(cyclohexane/EtOAc 9:1 → 4:1) yielded the product as a yellow solid
(76 mg, 52%; r.r. = >98:2).
Fe Catalysis: Compound 7b was synthesized according to the GP from
urethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
1.2 mmol, 1.2 equiv), 2-bromothiophene (0.28 mL, 3.0 mmol), and
Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reac-
tion mixture was stirred for 48 h at 40 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yel-
low solid (249 mg, 74%; r.r. = >98:2).
Fe Catalysis: Compound 7d was synthesized according to the GP from
urethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
1.2 mmol, 1.2 equiv), 2-chlorothiophene (0.29 mL, 3.0 mmol,
3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 48 h at 40 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the
product as a yellow solid (219 mg, 75%; r.r. = >98:2).
Mp 48.8 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3305 (m), 2983 (w), 2951 (w), 2904 (w), 1741 (s), 1686 (s),
1526 (m), 1499 (w), 1433 (m), 1372 (m), 1312 (m), 1295 (m), 1257
(m), 1216 (s), 1107 (s), 1061 (s), 1038 (s), 963 (s), 810 (w), 800 (w),
780 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 6.91 (d, J = 3.8 Hz, 1 H), 6.82 (d, J = 3.7
Hz, 1 H), 5.68 (s, 1 H), 5.53 (d, J = 7.4 Hz, 1 H), 4.31–4.20 (m, 2 H),
4.19–4.11 (m, 2 H), 1.31–1.23 (m, 6 H).
13C NMR (101 MHz, CDCl3): δ = 169.5, 155.6, 141.1, 129.9, 126.3,
112.6, 62.6, 61.7, 53.8, 14.6, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C11H14BrNO4SNa: 358.0; found:
Mp 46.9 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3310 (m), 2985 (w) 1741 (s), 1686 (s), 1528 (m), 1443 (m),
1371 (m), 1355 (m), 1206 (s), 1045 (s), 986 (s), 964 (w), 869 (w), 780
(m), 664 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 6.84–6.82 (m, 1 H), 6.77 (d, J = 3.8 Hz, 1
H), 5.68 (s, 1 H), 5.51 (d, J = 7.3 Hz, 1 H), 4.31–4.10 (m, 4 H), 1.34–1.14
(m, 6 H).
358.1.
13C NMR (75 MHz, CDCl3): δ = 169.5 155.6, 138.2, 130.4, 126.2, 125.4,
62.6, 61.7, 53.9, 14.6, 14.1.
HRMS (MALDI): m/z [M + K]+ calcd for C11H14BrNO4SK: 373.9464;
found: 373.9453.
MS (ESI): m/z [M + Na]+ calcd for C11H14ClNO4SNa: 314.0; found:
314.2.
Ethyl 2-Benzamido-2-(5-chlorothiophen-2-yl)acetate (7c)
HRMS (MALDI): m/z [M + K]+ calcd for C11H14ClNO4SK: 329.9964;
Bi Catalysis: Compound 7c was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,
0.6 mmol, 1.2 equiv), 2-chlorothiophene (0.15 mL, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).
The reaction mixture was stirred for 16 h at 60 °C. Purification by
chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the prod-
uct as a yellow solid (119 mg, 37%; r.r. = >98:2).
found: 329.9970.
Ethyl 2-Benzamido-2-(5-methylthiophen-2-yl)acetate (7e)
Bi Catalysis: Compound 7e was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,
0.6 mmol, 1.2 equiv), 2-methylthiophene (0.15 mL, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (1.0 mL).
The reaction mixture was stirred for 16 h at r.t. Purification by chro-
matography (cyclohexane/EtOAc = 4:1) yielded the product as a color-
less solid (97 mg, 64%; r.r. = 89:11).
Fe Catalysis: Compound 7c was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
1.2 mmol, 1.2 equiv), 2-chlorothiophene (0.28 mL, 3.0 mmol,
3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the
product as a yellow low-melting solid (161 mg, 50%; r.r. = 63:37).
Fe Catalysis: Compound 7e was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
0.6 mmol, 1.2 equiv), 2-methylthiophene (0.15 mL, 1.5 mmol,
3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

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Synthesis
(2.0 mL). The reaction mixture was stirred for 24 h at 60 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 4:1) yielded the prod-
uct as a yellow solid (72 mg, 47%; r.r. = 88:12).
tion mixture was stirred for 24 h at 60 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 9:1) yielded the product as a yellow solid
(166 mg, 51%, r.r. = >98:2).
Mp 66–68 °C; Rf = 0.3 (cyclohexane/EtOAc = 4:1).
Mp 79.4 °C; Rf = 0.59 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3315 (w), 2981 (w), 2917 (w), 1737 (s), 1637 (s), 1603 (m),
1579 (m), 1523 (s), 1486 (s), 1446 (m), 1369 (m), 1327 (m), 1294 (m),
1229 (m), 1204 (s), 1172 (s), 1122 (m), 1083 (m), 1019 (s), 976 (m),
929 (w), 883 (w), 803 (m), 754 (m), 714 (s), 691 (s), 672 (s), 622 (m),
601 (s), 579 (s), 557 (s), 537 (s), 522 (s), 505 (m), 480 (m), 472 cm–1
(m).
1H NMR (300 MHz, CDCl3): δ (major regioisomer) = 7.83–7.79 (m, 2
H), 7.54–7.41 (m, 3 H), 7.05 (br d, J = 5.5 Hz, 1 H), 6.92–6.89 (m, 1 H),
6.64–6.60 (m, 1 H), 5.95 (d, J = 7.4 Hz, 1 H), 4.36–4.18 (m, 2 H), 2.44 (s,
3 H), 1.32–1.22 (m, 3 H).
IR (ATR): 3299 (w), 3057 (w), 2991 (w), 1751 (s), 1639 (s), 1602 (w),
1579. (w), 1526 (s), 1488 (m), 1454 (m), 1369 (w), 1336 (m), 1241
(m), 1206 (s), 1156 (s), 1094 (m), 1016 (m), 961 (m), 820 (m), 749 (s),
716 (s), 689 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.89–7.82 (m, 2 H), 7.60–7.42 (m, 5 H),
7.35–7.19 (m, 3 H), 6.85 (s, 1 H), 6.09 (d, J = 7.7 Hz, 1 H), 4.37–4.21 (m,
2 H), 1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 168.7, 166.8, 155.1, 151.5, 133.6,
132.2, 128.8, 128.1, 127.4, 124.9, 123.3, 121.5, 111.5, 106.1, 62.8, 51.3,
14.2.
13C NMR (75 MHz, CDCl3): δ (major regioisomer) = 171.21, 170.29,
166.66, 140.68, 136.33, 133.80, 133.68, 132.04, 131.94, 128.73,
127.32, 127.25, 126.37, 125.81, 125.26, 122.71, 62.39, 62.09, 52.63,
50.95, 15.43, 14.17, 13.25.
MS (ESI): m/z [M + Na]+ calcd for C19H17NO4Na: 346.1; found: 346.2.
HRMS (MALDI): m/z [M + H]+ calcd for C19H18NO4: 324.1230; found:
324.1229.
MS (ESI): m/z [M + H]+ calcd for C16H18NO3: 303.1; found: 304.3.
HRMS (MALDI): m/z [M + Na]+ calcd for C16H17NO3SNa: 326.0821;
Ethyl 2-(Benzofuran-2-yl)-2-[(ethoxycarbonyl)amino]acetate (7h)
Bi Catalysis: Compound 7h was synthesized according to the GP from
urethane (46 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,
0.6 mmol, 1.2 equiv), benzofuran (0.16 mL, 1.5 mmol, 3.0 equiv), and
Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction
mixture was stirred for 16 h at 60 °C. Purification by chromatography
(cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid
(128 mg, 88%; r.r. = >98:2).
found: 326.0821.
Ethyl 2-[(Ethoxycarbonyl)amino]-2-(5-methylthiophen-2-yl)ace-
tate (7f)
Bi Catalysis: Compound 7f was synthesized according to the GP from
urethane (67 mg, 0.75 mmol, 1.5 equiv), ethyl glyoxalate (51 mg,
0.5 mmol, 1.0 equiv), 2-methylthiophene (0.15 mL, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in DCE (4.0 mL).
The reaction mixture was stirred for 16 h at 60 °C. Purification by
chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product
as a colorless oil (97 mg, 72%; r.r. = >98:2).
Fe Catalysis: Compound 7h was synthesized according to the GP from
urethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
1.2 mmol, 1.2 equiv), benzofuran (0.32 mL, 3.0 mmol, 3.0 equiv), and
Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reac-
tion mixture was stirred for 24 h at 60 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yel-
low solid (219 mg, 75%; r.r. = 80:20). Further purification of the major
regioisomer could be achieved by precipitation from hexane/CH2Cl2
(91:9 mixture of regioisomers, as judged by 1H NMR analysis). Analyt-
ical data were obtained for this purified mixture.
Fe Catalysis: Compound 7f was synthesized according to the GP from
urethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2
mmol, 1.2 equiv), 2-methylthiophene (0.29 mL, 3.0 mmol, 3.0 equiv)
and Fe(ClO4)3 (18 mg, 0.050 mmol, 5 mol%) in MeNO2 (4.0 mL). The
reaction mixture was stirred for 48 h at 40 °C. Purification by chro-
matography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a
yellow oil (211 mg, 78%; r.r. = 93:7); Rf = 0.56 cyclohexane/EtOAc =
7:3).
Mp 60.3 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3263 (w), 2983 (w), 1742 (m), 1688 (s), 1605 (w), 1533 (m),
1453 (m), 1369 (m), 1319 (s), 1245 (s), 1200 (s), 1093 (m), 1049 (s),
953 (m), 937 (m), 753 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.57–7.52 (m, 1
H), 7.49–7.42 (m, 1 H), 7.32–7.19 (m, 2 H), 6.76 (s, 1 H), 5.85–5.72 (m,
1 H), 5.71–5.58 (m, 1 H), 4.32–4.10 (m, 4 H), 1.29–1.22 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 168.7, 155.8, 155.0, 151.8, 128.0, 124.9,
123.2, 121.4, 111.5, 105.5, 62.6, 61.7, 52.6, 14.6, 14.2 (peaks not as-
signed to regioisomers).
IR (ATR): 3326 (w), 2985 (w), 2933 (w), 1710 (s), 1506 (s), 1370 (m),
1317 (m), 1200 (s), 1094 (w), 1053 (s), 862 (w), 798 (m), 778 cm–1
(m).
1H NMR (300 MHz, CDCl3): δ (major regioisomer) = 6.87–6.77 (m, 1
H), 6.62–6.51 (m, 1 H), 5.66–5.41 (m, 2 H), 4.31–4.09 (m, 4 H), 2.44 (s,
3 H), 1.29–1.19 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ (major regioisomer) = 170.3, 155.7,
140.6, 136.6, 126.1, 125.2, 62.2, 61.5, 53.8, 15.4, 14.6, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C12H17NO4SNa: 294.1; found: 294.4.
HRMS (MALDI): m/z [M + K]+ calcd for C12H17NO4SK: 310.0510; found:
MS (ESI): m/z [M + Na]+ calcd for C15H17NO5Na: 314.1; found: 314.2.
HMRS (MALDI): m/z [M + H]+ calcd for C15H18NO5: 292.1180; found:
292.1177.
310.0511.
Ethyl 2-(Benzamido)-2-(1-tosyl-1H-pyrrol-2-yl)acetate (7i)
Ethyl 2-Benzamido-2-(benzofuran-2-yl)acetate (7g)
Fe Catalysis: Compound 7i was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
1.2 mmol, 1.2 equiv), N-tosylpyrrole (664 mg, 3.0 mmol, 3.0 equiv),
and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The re-
action mixture was stirred for 24 h at 60 °C. Purification by chroma-
tography (cyclohexane/EtOAc = 9:1) yielded the product as a yellow
oil (265 mg, 62%; r.r. = >98:2); Rf = 0.57 (cyclohexane/EtOAc = 7:3).
Fe Catalysis: Compound 7g was synthesized according to the GP from
benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,
1.2 mmol, 1.2 equiv), benzofuran (0.33 mL, 3.0 mmol, 3.0 equiv), and
Fe(ClO4)3 (18 mg, 0.050 mmol, 5 mol%) in MeNO2 (4.0 mL). The reac-
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IR (ATR): 3365 (w), 1725 (m), 1662 (m), 1599 (w), 1505 (w), 1482 (m),
1404 (w), 1363 (m), 1345 (m), 1281 (w), 1246 (w), 1211 (m), 1188
(m), 1172 (s), 1155 (s), 1123 (m), 1091 (m), 1056 (m), 1017 (m), 864
(w), 808 (m), 750 (s), 716 (m), 702 (m), 673 (s), 627 (m), 584 (s), 562
(s), 542 (s), 511 cm–1 (m).
IR (ATR): 1739 (w), 1644 (w), 1520 (w), 1486 (w), 1447 (w), 1367 (m),
1171 (s), 1120 (m), 1089 (m), 1019 (m), 979 (m), 812 (w), 746 (m),
703 (s), 666 (s), 570 (s), 536 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 8.00–6.90 (m, 15 H), 6.05 (d, J = 7.4 Hz,
1 H), 4.40–4.12 (m, 2 H), 2.33 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.68–7.58 (m, 4 H), 7.53–7.36 (m, 3 H),
7.33–7.28 (m, 1 H), 7.18–7.11 (m, 2 H), 6.88 (d, J = 7.5 Hz, 1 H), 6.48–
6.41 (m, 1 H), 6.31–6.22 (m, 2 H), 4.23–4.06 (m, 2 H), 2.26 (s, 3 H),
1.19 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 169.6, 166.5, 145.2, 136.4, 133.5,
131.9, 130.1, 129.7, 128.6, 127.3, 126.8, 124.6, 116.9, 112.1, 62.3, 50.1,
21.6, 14.1.
13C NMR (101 MHz, CDCl3): δ = 170.6, 166.9, 145.4, 135.3, 135.1,
133.6, 132.1, 130.1, 129.9, 128.8, 127.3, 127.1, 125.4, 125.1, 123.8,
120.2, 118.0, 113.9, 62.4, 49.6, 21.7, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C26H24N2O5SNa: 499.1; found: 499.1.
HRMS (MALDI): m/z [M + Na]+ calcd for C26H24N2O5SNa: 499.1298;
found: 499.1291.
MS (ESI): m/z [M + Na]+ calcd for C22H22N2O5SNa: 449.1; found: 449.1.
HRMS (MALDI): m/z [M + Na]+ calcd for C22H22N2O5SNa: 449.1142;
Ethyl 2-[(Ethoxycarbonyl)amino]-2-(1-tosyl-1H-indol-3-yl)ace-
tate (7l)
found: 449.1146.
Bi Catalysis: Compound 7l was synthesized according to the GP from
urethane (46 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6
mmol, 1.2 equiv), N-tosylindole (203 mg, 0.75 mmol, 1.5 equiv), and
Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in DCE (4.0 mL). The reaction
mixture was stirred for 16 h at 60 °C. Purification by chromatography
(cyclohexane/EtOAc = 9:1 → 4.1) yielded the product as a colorless oil
(171 mg, 78%; r.r. = >98:2).
Ethyl 2-[(Ethoxycarbonyl)amino]-2-(1-tosyl-1H-pyrrol-2-yl)ace-
tate (7j)
Bi Catalysis: Compound 7j was synthesized according to the GP from
urethane (46 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6
mmol, 1.2 equiv), N-tosylpyrrole (332 mg, 1.5 mmol, 3.0 equiv), and
Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in DCE (2.0 mL). The reaction
mixture was stirred for 16 h at 60 °C. Purification by chromatography
(cyclohexane/EtOAc = 9:1 → 4.1) yielded the product as a yellow solid
(123 mg, 62%; r.r. = >98:2).
Fe Catalysis: Compound 7l was synthesized according to the GP from
urethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2
mmol, 1.2 equiv), N-tosylindole (814 mg, 3.0 mmol, 3.0 equiv), and
Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reac-
tion mixture was stirred for 24 h at 60 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 9:1 → 4.1) yielded the product as a color-
less oil (369 mg, 83%; r.r. = >98:2). Compound 7l is very sensitive, es-
pecially towards light or acid and decomposes rapidly. Partial
decomposition (<5%) is observed upon silica gel chromatography. An-
alytically pure 7l could be obtained by preparative HPLC (column:
Fe Catalysis
Compound 7j was synthesized according to the GP from urethane
(89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol,
1.2 equiv), N-tosylpyrrole (664 mg, 3.0 mmol, 3.0 equiv), and
Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reac-
tion mixture was stirred for 24 h at 40 °C. Purification by chromatog-
raphy (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yel-
low solid (302 mg, 75%; r.r. = >98:2).
Machery Nagel Nuc 50-100/250 × 20 mm, hexane/EtOAc/CH2Cl2
10:1.5:2, flow rate 8 mL/min) and has to be stored under argon, pro-
tected from light at or below –20 °C.
=
Mp 138.9 °C; Rf = 0.63 (cyclohexane/EtOAc = 7:3).
Rf = 0.59 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3367 (w), 3161 (w), 2985 (w), 1722 (m), 1709 (s), 1596 (w),
1515 (m), 1469 (m), 1407 (w), 1364 (m), 1329 (m), 1213 (m), 1176
(s), 1154 (s), 1124 (m), 1090 (m), 1048 (s), 899 (m), 813 (m), 739 (m),
702 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.3 Hz, 2 H), 7.31–7.21 (m, 3
H), 6.30 (s, 1 H), 6.25–6.22 (m, 1 H), 5.84 (d, J = 8.1 Hz, 1 H), 5.43 (d, J =
6.5 Hz, 1 H), 4.22–4.03 (m, 4 H), 2.40 (s, 3 H), 1.20 (m, 6 H).
13C NMR (101 MHz, CDCl3): δ = 169.9, 155.7, 145.2, 136.3, 130.0,
129.9, 127.1, 124.3, 116.1, 111.9, 62.1, 61.4, 51.3, 21.7, 14.7, 14.1.
MS (ESI): m/z [M + Na]+ calcd for C18H22N2O6SNa: 417.1; found: 417.2.
HRMS (MALDI): m/z [M + Na]+ calcd for C18H22N2O6SNa: 417.1096;
IR (ATR): 3383 (w), 2981 (w), 1714 (m), 1596 (w), 1514 (w), 1446 (m),
1368 (m), 1301 (m), 1218 (m), 1171 (s), 1200 (m), 1093 (m), 1050
(m), 1019 (m), 976 (m), 856 (w), 812 (m), 745 (s), 704 (m), 663 cm–1
(s).
1H NMR (500 MHz, CDCl3): δ = 7.95 (d, J = 8.3 Hz, 1 H), 7.75 (d, J = 8.4
Hz, 2 H), 7.64 (d, J = 7.9 Hz, 1 H), 7.58 (s, 1 H), 7.27 (t, J = 32.8 Hz, 4 H),
5.68–5.42 (m, 2 H), 4.27–4.08 (m, 4 H), 2.34 (s, 3 H), 1.27–1.16 (m, 6
H).
13C NMR (126 MHz, CDCl3): δ = 170.5, 155.8, 145.3, 135.3, 135.1,
130.1, 128.6, 127.0, 125.3, 124.8, 123.6, 120.2, 118.2, 113.8, 62.2, 61.5,
50.8, 21.7, 14.6, 14.1.
found: 417.1099.
MS (ESI): m/z [M + Na]+ calcd for C22H24N2O6SNa: 467.1; found: 467.2.
HRMS (MALDI): m/z [M + Na]+ calcd for C22H24N2O6SNa: 467.1247;
found: 467.1239.
Ethyl 2-Benzamido-2-(1-tosyl-1H-indol-3-yl)acetate (7k)
Fe Catalysis: Compound 7k was synthesized according to the GP from
benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,
0.6 mmol, 1.2 equiv), N-tosylindole (407 mg, 1.5 mmol, 3.0 equiv),
and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The re-
action mixture was stirred for 24 h at 60 °C. Purification by chroma-
tography (n-hexane/EtOAc = 9:1 → 4.1 → 7:3) yielded the product as a
white low-melting foam (177 mg, 74%; r.r. = 82:18).
Isopropyl 2-Benzamido-2-mesitylacetate (11a)
Bi Catalysis: Compound 11a was synthesized according to the GP
from benzamide (66 mg, 0.55 mmol, 1.0 equiv), isopropyl 2-oxoace-
tate (75 mg 0.65 mmol, 1.18 equiv), mesitylene (0.21 mL, 3.0 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).
The reaction mixture was stirred for 16 h at 80 °C. Purification by
chromatography (cyclohexane/EtOAc = 4:1 → 1:1) yielded the prod-
uct as colorless solid (94 mg, 50%).
Rf = 0.40 (n-hexane/EtOAc = 7:3).
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Fe Catalysis: Compound 11a was synthesized according to the GP
from benzamide (121 mg, 1.0 mmol, 1.0 equiv), isopropyl 2-oxoace-
tate (174 mg, 1.5 mmol, 1.5 equiv), mesitylene (0.42 mL, 3.0 mmol,
3.0 equiv), and Fe(ClO4)3 (18 mg, 0.050 mmol, 5 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 24 h at 60 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 4:1 → 1:1) yielded the
product as a colorless solid (281 mg, 83%).
Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction
mixture was stirred for 24 h at 80 °C. Purification by chromatography
(CH2Cl2/MeOH = 50:1 → 20:1) yielded the product as a colorless solid
(66 mg, 50%).
Fe Catalysis: Compound 11c was synthesized according to the GP
from urethane (45 mg, 0.5 mmol, 1.0 equiv), glyoxylic acid (0.07 mL,
0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and
FeCl3·6H2O (7 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reac-
tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-
raphy (CH2Cl2/MeOH = 50:1 → 20:1) yielded the product as a colorless
solid (122 mg, 92%).
Mp 101.2 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3317 (m), 2975 (w), 2932 (w), 1747 (s), 1633 (s), 1579 (w),
1530 (s), 1490 (m), 1462 (m), 1360 (m), 1212 (s), 1154 (m), 1108 (s),
1089 (s), 973 (w), 852 (m), 828 (w), 787 cm–1 (m).
Mp 144.5 °C; Rf = 0.23 (CH2Cl2/MeOH = 9:1).
1H NMR (400 MHz, CDCl3): δ = 7.82–7.78 (m, 2 H), 7.53–7.39 (m, 3 H),
7.18 (d, J = 6.2 Hz, 1 H), 6.83 (s, 2 H), 6.15 (d, J = 6.6 Hz, 1 H), 5.08
(hept, J = 6.3 Hz, 1 H), 2.47 (s, 6 H), 2.25 (s, 3 H), 1.25 (d, J = 6.3 Hz, 3
H), 1.12 (d, J = 6.2 Hz, 3 H).
IR (ATR): 3267 (w), 3027 (w), 2918 (w), 2530 (w), 1725 (s), 1655 (m),
1613 (m), 1513 (w), 1426 (w), 1336 (m), 1226 (w), 1196 (m), 1067
(m), 925 (m), 851 cm–1 (m).
13C NMR (101 MHz, CDCl3): δ = 171.4, 166.6, 137.6, 137.0, 134.2,
131.8, 131.1, 130.1, 128.7, 127.2, 69.9, 53.0, 21.8, 21.6, 21.0, 20.5.
MS (ESI): m/z [M + Na]+ calcd for C21H25NO3Na: 362.2; found: 362.3.
HRMS (MALDI): m/z [M + H]+ calcd for C21H26NO3: 340.1907; found:
1H NMR (400 MHz, DMSO): δ = 12.78 (s, 1 H), 7.42 (d, J = 7.2 Hz, 1 H),
6.81 (s, 2 H), 5.52 (d, J = 7.7 Hz, 1 H), 4.09–3.94 (m, 2 H), 2.26 (s, 6 H),
2.19 (s, 3 H), 1.16 (t, J = 7.0 Hz, 3 H).
13C NMR (101 MHz, DMSO): δ = 172.8, 156.1, 136.7, 136.4, 132.0,
129.2, 60.0, 52.9, 20.4, 19.9, 14.6.
340.1905.
MS (ESI): m/z [M]+ calcd for C14H19NO4: 265.1; found: 264.2.
HRMS (MALDI): m/z [M + Na]+ calcd for C14H19NO4Na: 288.1206;
2-Benzamido-2-mesitylacetic Acid (11b)
found: 288.1208.
Fe Catalysis: Compound 11b was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), glyoxylic acid (50%
w/w in H2O, 0.07 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL,
1.5 mmol, 3.0 equiv), and FeCl3·6H2O (7 mg, 0.025 mmol, 5 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C.
Purification by chromatography (CH2Cl2/MeOH = 20:1 → 9:1) yielded
the product as a low-melting solid (120 mg, 81%).
2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-2-mesitylacetic
Acid (11d)
Bi Catalysis: Compound 11d was synthesized according to the GP
from 9H-fluoren-9-yl carbamate (113 mg, 0.5 mmol, 1.0 equiv), gly-
oxylic acid (0.07 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL,
1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in Me-
NO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Puri-
fication by chromatography (cyclohexane/EtOAc =7:3 → 1:1) yielded
the product as a colorless oil (94 mg, 45%).
Bi Catalysis: Compound 11b was synthesized according to the GP
from benzamide (121 mg, 1.0 mmol, 1.0 equiv), glyoxylic acid (50%
w/w in H2O, 0.13 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL,
3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in
MeNO2 (4.0 mL). The reaction mixture was stirred for 21 h at 80 °C.
After cooling to r.t., aq 1 M NaOH (15 mL) was added to the reaction
mixture. The aqueous phase was washed with EtOAc (2 × 10 mL),
acidified with aq 2 N HCl to pH 4, and extracted with EtOAc (3 ×
10 mL). The combined organic layers were dried (anhyd MgSO4), fil-
tered, and evaporated to dryness. Purification by chromatography
(CH2Cl2/MeOH = 20:1 → 9:1) yielded the product as a low-melting sol-
id (211 mg, 71%).
Fe Catalysis: Compound 11d was synthesized according to the GP
from 9H-fluoren-9-yl carbamate (113 mg, 0.5 mmol, 1.0 equiv), gly-
oxylic acid (0.07 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL,
1.5 mmol, 3.0 equiv), and FeCl3·6H2O (9 mg, 0.025 mmol, 5 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C.
Purification by chromatography (cyclohexane/EtOAc =7:3 → 1:1)
yielded the product as a colorless oil (177 mg, 85%); Rf = 0.35 (EtOAc).
IR (ATR): 3347 (w), 2953 (w), 1717 (s), 1598 (w), 1512 (m), 1443 (m),
1323 (m), 1194 (s), 1052 (s), 853 (m), 747 (s), 616 cm–1 (m).
Mp <30 °C; Rf = 0.41 (CH2Cl2/MeOH = 9:1).
IR (ATR): 3412 (w), 2920 (w), 2520 (w), 1732 (m), 1612 (s), 1575 (m),
1514 (s), 1485 (s), 1344 (w), 1308 (w), 1240 (m), 1193 (m), 1085 (w),
976 (w), 851 (m), 746 (m), 713 cm–1 (s).
1H NMR (300 MHz, DMSO-d6): δ = 8.50 (d, J = 6.7 Hz, 1 H), 7.88 (d, J =
7.0 Hz, 2 H), 7.56–7.42 (m, 3 H), 6.85 (s, 2 H), 5.94 (d, J = 6.7 Hz, 1 H),
2.35 (s, 6 H), 2.21 (s, 3 H).
1H NMR (500 MHz, DMSO-d6): δ = 12.84 (s, 1 H), 7.90–7.86 (m, 2 H),
7.86–7.81 (m, 1 H), 7.81–7.70 (m, 2 H), 7.44–7.38 (m, 2 H), 7.35–7.26
(m, 2 H), 6.83 (s, 2 H), 5.52 (d, J = 7.6 Hz, 1 H), 4.32–4.16 (m, 3 H), 2.28
(s, 6 H), 2.20 (s, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 172.8, 156.1, 144.0, 143.7, 140.7,
136.9, 136.5), 131.9, 129.3, 127.7, 127.1, 127.0, 125.5, 120.1, 65.9,
53.1, 46.7, 20.4, 20.0.
13C NMR (75 MHz, DMSO-d6): δ = 172.5, 166.4, 137.2, 136.5, 133.8,
131.4, 131.4, 129.3, 128.2, 127.7, 52.2, 20.4, 20.1.
MS (ESI): m/z [M + H]+ calcd for C18H20NO3: 298.1; found: 298.5.
HRMS (MALDI): m/z [M + H]+ calcd for C18H20NO3: 298.1438; found:
MS (ESI): m/z [M + H]+ calcd for C26H26NO4: 416.2; found: 416.4.
HRMS (MALDI): m/z [M + Na]+ calcd for C26H25NO4Na: 438.1676;
found: 438.1674.
298.1440.
Ethyl 2-Benzamido-2-(2-methoxy-5-pivalamidophenyl)acetate
(12a)
2-[(Ethoxycarbonyl)amino]-2-mesitylacetic Acid (11c)
Bi Catalysis: Compound 11c was synthesized according to the GP
from urethane (45 mg, 0.5 mmol, 1.0 equiv), glyoxylic acid (0.07 mL,
0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and
Fe Catalysis: Compound 12a was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.2 equiv), N-(4-methoxyphenyl)pivalamide
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Synthesis
(311 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol,
5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h
at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 →
4:1 → 7:3 → 1:1) yielded the product as a colorless solid (184 mg,
89%; r.r.= >98:2).
Ethyl 2-Benzamido-2-(4-methyl-3-pivalamidophenyl)acetate
(12c)
Bi Catalysis: Compound 12c was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), 2-methylpivalanilide (287 mg,
1.5 mmol, 3.0 equiv), and Bi(OTf)3 (16 mg, 0.025 mmol, 5 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C.
Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the
product as a yellow solid (89 mg, 45%; r.r. = >98:2).
Bi Catalysis: Compound 12a was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), N-(4-methoxyphenyl)pivalamide
(311 mg, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.025 mmol,
5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h
at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 →
4:1 → 7:3 → 1:1) yielded the product as a colorless solid (128 mg,
62%; r.r. = >98:2).
Fe Catalysis: Compound 12c was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.2 equiv), 2-methylpivalanilide (287 mg,
1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C.
Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the
product as a yellow solid (152 mg, 77%; r.r. = 91:9).
Mp 90.2 °C; Rf = 0.20 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3302 (w), 2948 (w), 1743 (m), 1638 (s), 1603 (w), 1526 (s),
1414 (w), 1369 (w), 1328 (m), 1216 (s), 1149 (m), 1096 (m), 1029
(m), 932 (w), 859 (w), 806 (w), 725 (m), 693 cm–1 (s).
Mp 123–125 °C; Rf = 0.5 (n-hexane/EtOAc = 1:1).
1H NMR (400 MHz, CDCl3): δ = 7.84–7.76 (m, 3 H), 7.52–7.39 (m, 3 H),
7.34–7.30 (m, 2 H), 6.86 (d, J = 8.9 Hz, 1 H), 5.84 (d, J = 8.0 Hz, 1 H),
4.25–4.16 (m, 2 H), 3.83 (s, 3 H), 1.30 (s, 9 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 176.7, 171.9, 166.7, 153.8, 134.2,
131.8, 131.5, 128.7, 127.3, 126.1, 123.2, 122.2, 111.7, 61.9, 56.0, 53.9,
39.6, 27.8, 14.3.
IR (ATR): 2959 (w), 2923 (m), 2853 (w), 1744 (s), 1661 (s), 1643 (s),
1615 (w), 1602 (w), 1580 (w), 1519 (s), 1489 (s), 1446 (m), 1417 (w),
1399 (w), 1367 (m), 1340 (s), 1299 (s), 1265 (s), 1218 (m), 1194 (s),
1170 (s), 1092 (m), 1023 (m), 947 (w), 923 (w), 880 (w), 800 (w), 777
(m), 749 (w), 714 (s), 691 (s), 620 (s), 608 (s), 584 (s), 540 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.91 (d, J = 9.0 Hz, 1 H), 7.82–7.79 (m, 2
H), 7.51–7.41 (m, 3 H), 7.28 (s, 2 H), 7.23 (br s, 1 H), 7.12 (br d, J = 6.8
Hz, 1 H), 5.68 (d, J = 6.9 Hz, 1 H), 4.30–4.13 (m, 2 H), 2.26 (s, 3 H), 1.33
(s, 9 H), 1.24 (t, J = 5.8 Hz, 3 H).
MS (ESI): m/z [M + H]+ calcd for C23H29N2O5: 413.2; found: 413.9.
HRMS (MALDI): m/z [M + H]+ calcd for C23H29N2O5: 413.2071; found:
413.2071.
13C NMR (75 MHz, CDCl3): δ = 176.6, 171.2, 166.6, 136.3, 133.9, 133.1,
132.0, 129.7, 129.14, 128.7, 127.3, 125.8, 123.2, 62.2, 56.6, 40.0, 27.8,
17.8, 14.2.
Ethyl 2-Benzamido-2-(4-methoxy-3-pivalamidophenyl)acetate
(12b)
MS (ESI): m/z [M + Na]+ calcd for C23H28N2O4Na: 420.0; found: 420.0.
Fe Catalysis: Compound 12b was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.2 equiv), N-(2-methoxyphenyl)pivalamide
(311 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mol,
5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h
at 100 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1
→ 4:1 → 7:3 → 1:1) yielded the product as a colorless solid (164 mg,
80%, obtained as a 1.6:1 mixture of regioisomers). Further purifica-
tion of the major regioisomer could be achieved by precipitation from
hexane/CH2Cl2 (92:8 mixture of regioisomers, as judged by 1H NMR
analysis). Analytical data were obtained for this purified mixture.
HRMS (MALDI): m/z [M + K]+ calcd for C23H28N2O4K: 435.1681; found:
435.1674.
Ethyl 2-Benzamido-2-(2,5-dimethoxyphenyl)acetate (12d)
Fe Catalysis: Compound 12d was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.2 equiv), 1,4-dimethoxybenzene (207 mg,
1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C.
Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded
the product as a colorless solid (128 mg, 74%).
Mp 127.6 °C; Rf = 0.34 (cyclohexane/EtOAc = 7:3).
Mp 75.4 °C; Rf = 0.33 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3443 (w), 3283 (w), 2959 (w), 2361 (w), 1743 (m), 1668 (m),
1632 (m), 1600 (w), 1579 (w), 1525 (s), 1484 (s), 1430 (m), 1394 (w),
1339 (m), 1267 (m), 1198 (m), 1153 (m), 1122 (m) 1093 (w), 1027
cm–1 (m).
IR (ATR): 3299 (w), 2954 (w), 2835 (w), 1727 (m), 1636 (m), 1581 (w),
1503 (s), 1458 (m), 1327 (m), 1207 (s), 1153 (s), 1045 (s), 1022 (s),
925 (m), 822 (m), 755 (m), 715 (m), 635 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 8.54 (d, J = 2.2 Hz, 1 H), 8.10 (s, 1 H),
7.85–7.79 (m, 2 H), 7.52–7.39 (m, 3 H), 7.19–7.11 (m, 2 H), 6.86 (d, J =
8.4 Hz, 1 H), 5.68 (d, J = 7.0 Hz, 1 H), 4.33–4.12 (m, 2 H), 3.89 (s, 3 H),
1.31 (s, 9 H), 1.24 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.82–7.78 (m, 2 H), 7.51–7.46 (m, 1 H),
7.42 (t, J = 7.4 Hz, 2 H), 7.31 (d, J = 8.1 Hz, 1 H), 7.01 (s, 1 H), 6.84 (d, J =
1.3 Hz, 2 H), 5.90 (d, J = 8.3 Hz, 1 H), 4.26–4.16 (m, 2 H), 3.82 (s, 3 H),
3.78 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 176.6, 171.1, 166.7, 148.1, 134.0,
131.8, 129.7, 128.7, 128.5, 127.4, 123.10, 118.2, 110.1, 62.1, 56.9, 56.1,
40.2, 27.8, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C23H28N2O5Na: 435.2; found: 435.3.
HRMS (MALDI): m/z [M + H]+ calcd for C23H29N2O5: 413.2071; found:
13C NMR (101 MHz, CDCl3): δ = 171.1, 166.7, 153.9, 151.4, 134.3,
131.7, 128.7, 127.3, 126.7, 116.7, 114.5, 112.4, 61.8, 56.3, 55.9, 54.1,
14.3.
MS (ESI): m/z [M + Na]+ calcd for C19H21NO5Na: 366.1; found: 366.2.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO5: 344.1493; found:
413.2072.
344.1491.
Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found: C, 66.20,
H, 6.11; N, 3.80.
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Synthesis
Ethyl 2-Benzamido-2-(3,4-dimethoxyphenyl)acetate (12e)
Ethyl 2-Benzamido-2-(5-bromo-2-hydroxyphenyl)acetate (12g)
Fe Catalysis: Compound 12e was synthesized according to the GP
from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate
(0.24 mL, 1.2 mmol, 1.2 equiv), veratrole (0.38 mL, 3.0 mmol,
3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the
product as a colorless oil (216 mg, 63%; r.r. = >98:2).
Bi Catalysis: Compound 12g was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), 4-bromophenol (260 mg, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (3 mg, 0.005 mmol, 1 mol%) in DCE (2.0 mL).
The reaction mixture was stirred for 16 h at 80 °C. Purification by
chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product
as a low-melting solid (123 mg, 65%; r.r. = >98:2).
Rf = 0.32 (cyclohexane/EtOAc = 7:3).
Fe Catalysis: Compound 12g was synthesized according to the GP
from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate
(0.24 mL, 1.2 mmol, 1.2 equiv), 4-bromophenol (516 mg, 3.0 mmol,
3.0 equiv), and Fe(ClO4)3 (7 mg, 0.02 mmol, 2 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the
product as a low-melting solid (39 mg, 11%; r.r. = >98:2).
IR (ATR): 3338 (w), 2980 (w), 1732 (s), 1634 (s), 1595 (w), 1578 (w),
1520 (s), 1488 (m), 1467 (m), 1356 (m), 1332 (m), 1255 (s), 1238 (m),
1203 (m), 1183 (m), 1165 (m), 1139 (s), 1097 (m), 1017 (s), 923 (w),
878 (w), 851 (m), 799 (m), 752 (m), 714 (s), 691 (m), 633 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.3 Hz, 2 H), 7.51 (t, J = 7.3
Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.11 (d, J = 6.7 Hz, 1 H), 7.02–6.94 (m,
2 H), 6.85 (d, J = 8.2 Hz, 1 H), 5.69 (d, J = 7.0 Hz, 1 H), 4.33–4.15 (m, 2
H), 3.89 (s, 3 H), 3.87 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).
Rf = 0.46 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3368, 3099, 2920, 2852, 1736, 1622, 1576, 1530 (s), 1488
(m), 1430 (m), 1363, 1344 (m), 1310 (m), 1278 (s), 1236 (m), 1198
(m), 1120 (m), 1090 (s), 1022 (m), 877 (m), 813 (s), 727 (s), 692 cm–1
(m).
13C NMR (101 MHz, CDCl3): δ = 171.3, 166.7, 149.4, 149.4, 133.9,
132.0, 129.3, 128.8, 127.3, 119.7, 111.5, 110.7, 62.1, 56.7, 56.1, 56.1,
14.2.
1H NMR (400 MHz, CDCl3): δ = 9.47 (s, 1 H), 7.86–7.76 (m, 2 H), 7.61
(d, J = 6.7 Hz, 1 H), 7.58–7.52 (m, 1 H), 7.49–7.43 (m, 2 H), 7.35–7.31
(m, 1 H), 7.13 (d, J = 2.4 Hz, 1 H), 6.92 (d, J = 8.7 Hz, 1 H), 5.83 (d, J = 6.9
Hz, 1 H), 4.39–4.30 (m, 2 H), 1.30 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.6, 168.3, 155.0, 133.3, 132.7,
132.0, 129.9, 128.8, 127.3, 126.1, 121.3, 112.6, 62.9, 51.8, 14.0.
MS (ESI): m/z [M + Na]+ calcd for C19H21NO5Na: 366.1; found: 366.3.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO5: 344.1493; found:
344.1490.
Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found: C, 66.31;
H, 6.18; N, 3.98.
MS (ESI): m/z [M + Na]+ calcd for C17H16BrNO4Na: 400.0; found: 400.1.
HRMS (MALDI): m/z [M + H]+ calcd for C17H17BrNO4: 378.0335; found:
Ethyl 2-(Anthracen-9-yl)-2-benzamidoacetate (12f)
Bi Catalysis: Compound 12f was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), anthracene (267 mg, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).
The reaction mixture was stirred for 16 h at 80 °C. Purification by
chromatography (cyclohexane/EtOAc = 20:1 → 9:1 → 4:1) yielded the
product as a yellow solid (92 mg, 48%; r.r. = >98:2).
378.0335.
Ethyl 2-Benzamido-2-(3,4-dimethylphenyl)acetate (12h)
Bi Catalysis: Compound 12h was synthesized according to the GP
from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate
(122 mg, 1.2 mmol, 1.2 equiv), o-xylene (0.36 mL, 3.0 mmol,
3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purifica-
tion by chromatography (n-hexane/EtOAc = 4:1) yielded the product
as a colorless solid (278 mg, 89%; r.r. = 89:11).
Fe Catalysis: Compound 12f was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.2 equiv), anthracene (267 mg, 1.5 mmol,
3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2
(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 20:1 → 9:1 → 4:1)
yielded the product as a yellow solid (157 mg, 82%; r.r. = >98:2).
Fe Catalysis: Compound 12h was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.2 equiv), o-xylene (0.18 mL, 1.5 mmol,
3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2
(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 4:1) yielded the prod-
uct as a colorless solid (88 mg, 54%; r.r. = 80:20). Further purification
of the major regioisomer could be achieved by precipitation from
hexane/CH2Cl2 (87:13 mixture of regioisomers, as judged by 1H NMR
analysis). Analytical data were obtained for this purified mixture.
Mp 128.6 °C; Rf = 0.59 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3355 (w), 3058 (w), 2979 (w), 1721 (s), 1640 (s), 1579 (w),
1520 (s), 1488 (m), 1450 (m), 1367 (w), 1314 (s), 1210 (s), 1142 (m),
1092 (m), 1044 (m), 901 (m), 845 (m), 727 (s), 713 (s), 690 cm–1 (s).
1H NMR (500 MHz, CDCl3): δ = 8.55–8.43 (m, 3 H), 8.06 (d, J = 8.4 Hz, 2
H), 7.78 (d, J = 8.5 Hz, 2 H), 7.64–7.34 (m, 9 H), 7.31 (d, J = 7.2 Hz, 1 H),
4.25–4.09 (m, 2 H), 1.04 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 172.3, 167.3, 133.8, 131.9, 131.8,
130.3, 129.8, 129.4, 128.7, 128.1, 127.37, 127.3, 125.3, 123.6, 62.3,
51.4, 14.1.
Mp 70–72 °C; Rf = 0.31 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3285 (w), 2981 (w), 1741 (s), 1635 (s), 1602 (w), 1579 (w),
1527 (s), 1488 (s), 1446 (w), 1370 (w), 1345 (m), 1302 (m), 1263 (m),
1189 (s), 1153 (s), 1093 (m), 1022 (m), 819 (w), 689 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.82 (d, J = 7.3 Hz,
2 H), 7.54–7.39 (m, 3 H), 7.22–6.95 (m, 4 H), 5.71 (d, J = 7.1 Hz, 1 H),
4.34–4.10 (m, 2 H), 2.26 (s, 3 H), 2.25 (s, 3 H), 1.27–1.21 (m, 3 H).
MS (ESI): m/z [M + H]+ calcd for C25H22NO3: 384.2; found: 385.0.
HRMS (MALDI): m/z [M] calcd for C25H21NO3: 383.1521; found:
383.1501.
13C NMR (101 MHz, CDCl3): δ (major regioisomer) = 171.4, 166.6,
137.5, 137.2, 134.3, 134.0, 131.9, 130.3, 128.7, 127.3, 124.8, 124.4,
62.1, 56.8, 20.0, 19.6, 14.2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE

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Synthesis
MS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.2; found: 312.2.
Ethyl 2-Mesityl-2-(2-oxopyrrolidin-1-yl)acetate (14a)
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found:
312.1595.
Bi Catalysis: Compound 14a was synthesized according to the GP
from pyrrolidin-2-one (85 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate
(122 mg, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol,
3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 4:1) yielded the prod-
uct as a colorless solid (182 mg, 63%).
Ethyl 2-Benzamido-2-(5-chloro-2-methoxyphenyl)acetate (12i)
Bi Catalysis: Compound 12i was synthesized according to the GP
from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate
(122 mg, 1.2 mmol, 1.2 equiv), 4-chloroanisole (0.49 mL, 4.0 mmol,
4.0 equiv), and Bi(OTf)3 (32 mg, 0.05 mmol, 5 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 16 h at 100 °C. Purifica-
tion by chromatography (n-hexane/EtOAc = 4:1) yielded the product
as a colorless solid (310 mg, 89%; r.r. = >98:2).
Fe Catalysis: Compound 14a was synthesized according to the GP
from pyrrolidin-2-one (43 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2
(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 4:1) yielded the prod-
uct as a colorless solid (12 mg, 8%).
Fe Catalysis: Compound 12i was synthesized according to the GP
from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate
(0.24 mL, 1.2 mmol, 1.2 equiv), 4-chloroanisole (0.37 mL, 3.0 mmol,
3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the
product as a colorless solid (116 mg, 34%; r.r. = >98:2).
Mp 141–142 °C; Rf = 0.2 (cyclohexane/EtOAc = 7:3).
IR (ATR): 2988 (w), 2926 (w), 1743 (s), 1681 (s), 1610 (m), 1491 (m),
1460 (m), 1245 (m), 1187 (s), 1023 (m), 903 (w), 860 (m), 673 cm–1
(m).
1H NMR (300 MHz, CDCl3): δ = 6.87 (s, 2 H), 6.12 (s, 1 H), 4.33–4.11
Mp 88.8 °C; Rf = 0.55 (cyclohexane/EtOAc = 7:3).
(m, 2 H), 3.66 (m, 1 H),
IR (ATR): 3257 (w), 2959 (w), 1737 (s), 1638 (s), 1602 (w), 1579 (w),
1523 (m), 1488 (s), 1458 (m), 1365 (w), 1320 (m), 1247 (s), 1190 (s),
1130 (m), 1093 (s), 1026 (s), 979 (w), 804 (m), 719 (m), 658 cm–1 (s).
2.93 (m, 1 H), 2.56–2.35 (m, 2 H), 2.26 (d, J = 4.5 Hz, 9 H), 2.10–1.99
(m, 1 H), 1.86–1.79 (m,
1H NMR (400 MHz, CDCl3): δ = 7.79 (dd, J = 5.2, 3.3 Hz, 2 H), 7.53–7.40
(m, 4 H), 7.30–7.23 (m, 2 H), 6.83 (d, J = 8.8 Hz, 1 H), 5.88 (d, J = 8.0 Hz,
1 H), 4.24–4.17 (m, 2 H), 3.85 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.6, 166.5, 155.7, 134.0, 131.7,
130.6, 129.4, 128.6, 127.4, 127.2, 125.9, 112.3, 61.9, 56.0, 53.3, 14.1.
MS (ESI): m/z [M + H]+ calcd for C18H19ClNO4: 348.1; found: 348.2.
HRMS (MALDI): m/z [M + H]+ calcd for C18H19ClNO4: 348.0997; found:
1 H), 1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 175.3, 171.7, 138.1, 130.1, 128.2, 61.8,
54.0, 44.2, 30.8, 21.0, 20.6, 18.3, 14.2.
MS (ESI): m/z [M + H]+ calcd for C17H24NO3: 290.2; found: 290.2.
Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.47;
H, 7.97; N, 4.66.
348.0995.
Ethyl 2-Mesityl-2-(2-oxooxazolidin-3-yl)acetate (14b)
Bi Catalysis: Compound 14b was synthesized according to the GP
from oxazolidin-2-one (87 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate
(122 mg, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol,
3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2
(4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purifica-
tion by chromatography (cyclohexane/EtOAc = 4:1) yielded the prod-
uct as a colorless solid (234 mg, 80%).
Ethyl 2-Benzamido-2-(p-tolyl)acetate (12j)
Bi Catalysis: Compound 12j was synthesized according to the GP
from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate
(61 mg, 0.6 mmol, 1.2 equiv), toluene (0.22 mL, 2.1 mmol, 4.2 equiv),
and Bi(OTf)3 (7 mg, 0.005 mmol, 2 mol%) in DCE (2.0 mL). The reac-
tion mixture was stirred for 16 h at 100 °C. Purification by chroma-
tography (n-hexane/EtOAc = 4:1) yielded the product as a colorless
solid (74 mg, 50%; r.r. = 75:25).
Mp 127–128 °C; Rf = 0.2 (cyclohexane/EtOAc = 7:3).
IR (ATR): 2921 (w), 1732 (s), 1611 (w), 1486 (w), 1447 (m), 1239 (m),
1144 (w), 1023 (s), 884 (m), 738 (w), 699 (m), 676 cm–1 (m).
Mp 99–101 °C; Rf = 0.4 (n-hexane/EtOAc 4:1).
IR (ATR): 3290 (w), 1743 (s), 1636 (s), 1603 (m), 1581 (m), 1527 (s),
1488 (s), 1447 (m), 1372 (m), 1348 (m), 1330 (m), 1300 (w), 1275
(w), 1252 (m), 1206 (s), 1178 (s), 1153 (s), 1096 (m), 1075 (w), 1021
(s), 928 (w), 815 (m), 803 (w), 791 (w), 759 (m), 723 (s), 711 (s), 691
(s), 634 (m), 615 (m), 587 (s), 573 (m), 512 (m), 487 (m), 459 cm–1
(w).
1H NMR (300 MHz, CDCl3): δ (major regioisomer) = 7.83–7.80 (m, 2
H), 7.54–7.40 (m, 3 H), 7.35–7.32 (m, J = 8.1 Hz, 2 H), 7.24–7.16 (m, J =
15.2, 5.8 Hz, 2 H), 7.11 (br d, J = 6.9 Hz, 1 H), 5.73 (d, J = 7.0 Hz, 1 H),
4.33–4.11 (m, 2 H), 2.34 (s, 3 H), 1.29–1.19 (m, 3 H).
1H NMR (300 MHz, CDCl3): δ = 6.89 (s, 2 H), 5.88 (s, 1 H), 4.45–4.14
(m, 4 H), 3.93 (m, 1 H), 3.13 (m, 1 H), 2.28 (d, J = 2.7 Hz, 9 H), 1.26 (t,
J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.4, 158.4, 138.6, 137.9, 130.3, 127.8,
62.5, 62.1, 55.6, 41.9, 21.0, 20.5, 14.3.
MS (ESI): m/z [M + H]+ calcd for C16H22NO4: 292.2; found: 292.2.
Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C, 65.82;
H, 7.25; N, 4.69.
13C NMR (75 MHz, CDCl3): δ = 171.33, 166.61, 138.51, 137.19, 135.48,
133.94, 131.93, 131.17, 129.81, 128.73, 128.60, 127.34, 127.28,
126.67, 126.45, 62.12, 56.75, 53.71, 21.30, 19.68, 14.18. (peaks are not
assigned to regioisomers).
Ethyl 2-Mesityl-2-(methylsulfonamido)acetate (16a)
Bi Catalysis: Compound 16a was synthesized according to the GP
from methanesulfonamide (49 mg, 0.5 mmol, 1.0 equiv), ethyl glyox-
alate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,
3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).
MS (ESI): m/z [M + H]+ calcd for C18H20NO3: 298.5; found: 298.5.
HRMS (MALDI): m/z [M + H]+ calcd for C18H20NO3: 298.1438; found:
298.1439.
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The reaction mixture was stirred for 20 h at 80 °C. Purification by
chromatography (n-hexane/EtOAc = 4:1) yielded the product as a col-
orless solid (81 mg, 54%).
IR (ATR): 3309 (w), 2965 (w), 1732 (s), 1610 (w), 1577 (w), 1473 (w),
1449 (w), 1391 (m), 1370 (m), 1323 (s), 1299 (m), 1278 (s), 1247 (m),
1223 (m), 1200 (m), 1159 (s), 1147 (s), 1090 (s), 1071 (s), 1033 (m),
1012 (m), 975 (w), 925 (m), 852 (m), 818 (s), 764 (w), 740 (s), 724
(m), 703 (w), 615 (s), 593 (m), 562 (s), 553 (s), 532 (m), 475 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.37–7.30 (m, 4 H), 6.63 (s, 2 H), 5.84
(br d, J = 4.2 Hz, 1 H), 5.57 (d, J = 4.3 Hz, 1 H), 4.23–4.06 (m, 2 H), 2.20
(s, 6 H), 2.19 (s, 3 H), 1.14 (t, J = 7.1 Hz, 3 H).
Mp 126–128 °C; Rf = 0.5 (n-hexane/EtOAc 7:3).
IR (ATR): 3298 (w), 2966 (w), 2927 (w), 2111 (w), 1732 (s), 1609 (w),
1464 (w), 1413 (m), 1401 (m), 1366 (w), 1327 (s), 1311 (s), 1289 (s),
1254 (m), 1219 (s), 1199 (s), 1161 (s), 1145 (s), 1096 (s), 1021 (m),
987 (s), 970 (s), 909 (w), 872 (m), 855 (s), 827 (m), 784 (w), 762 (s),
721 (w), 636 (w), 602 (m), 555 (m), 528 (s), 513 (s), 475 cm–1 (m).
13C NMR (75 MHz, CDCl3): δ = 170.65, 139.23, 138.40, 137.17, 131.58,
129.83, 128.78, 128.32, 127.12, 62.68, 55.01, 20.88, 20.01, 14.09.
MS (ESI): m/z [M + Na]+ calcd for C19H22BrNO4SNa: 462.0; found:
462.0.
1H NMR (300 MHz, CDCl3): δ = 6.86 (s, 2 H), 5.64 (d, J = 4.0 Hz, 1 H),
5.41 (br d, J = 3.5 Hz, 1 H), 4.29–4.13 (m, 2 H), 2.61 (s, 3 H), 2.35 (s, 6
H), 2.26 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.21, 138.51, 137.35, 130.28, 129.78,
HRMS (MALDI): m/z [M + K]+ calcd for C19H22BrNO4SK: 478.0085;
62.68, 55.24, 42.03, 21.04, 20.10, 14.20.
found: 478.0069.
MS (ESI): m/z [M + Na] calcd for C14H21NO4SNa: 322.1; found: 322.0.
HRMS (MALDI): m/z [M + K]+ calcd for C14H21NO4SK: 338.0823; found:
338.0823.
Ethyl 2-Mesityl-2-(4-methoxyphenylsulfonamido)acetate (16b, R =
OMe)
Bi Catalysis: Compound 16b (R = OMe) was synthesized according to
the GP from 4-methoxybenzenesulfonamide (196 mg, 0.5 mmol,
1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene
(0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol,
2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 18 h
at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1)
yielded the product as a colorless solid (126 mg, 64%).
Ethyl 2-Mesityl-2-(4-methylphenylsulfonamido)acetate (16b, R =
Me)
Bi Catalysis: Compound 16b was synthesized according to the GP
from 4-methylbenzenesulfonamide (87 mg, 0.5 mmol, 1.0 equiv),
ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL,
1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C.
Purification by chromatography (n-hexane/EtOAc = 9:1 → 4:1) yielded
the product as a colorless solid (148 mg, 79%).
Mp 173–175 °C; Rf = 0.5 (n-hexane/EtOAc 4:1).
IR (ATR): 3274 (w), 2923 (w), 1738 (m), 1594 (m), 1496 (m), 1437 (w),
1412 (m), 1329 (m), 1311 (w), 1288 (w), 1263 (s), 1228 (m), 1183
(m), 1157 (m), 1119 (w), 1096 (m), 1063 (m), 1024 (s), 939 (w), 913
(m), 870 (m), 828 (s), 801 (m), 779 (m), 722 (m), 674 (s), 628 (w), 585
(s), 559 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.50–7.45 (m, 2 H), 6.75–6.70 (m, 2 H),
6.66 (s, 2 H), 5.67 (br d, J = 4.5 Hz, 1 H), 5.51 (d, J = 4.6 Hz, 1 H), 4.20–
4.04 (m, 2 H), 3.80 (s, 3 H), 2.21 (s, 6 H), 2.19 (s, 3 H), 1.13 (t, J = 7.1 Hz,
3 H).
13C NMR (75 MHz, CDCl3): δ = 170.95, 162.74, 137.90, 137.17, 131.85,
129.87, 129.42, 129.09, 113.71, 62.55, 55.66, 55.00, 20.92, 20.13,
14.12.
MS (ESI): m/z [M + Na]+ calcd for C20H25NO5SNa: 414.1; found:
414.08.
Mp 138–140 °C; Rf = 0.3 (cyclohexane/EtOAc = 4:1).
IR (ATR): 3275 (w), 2923 (w), 1735 (s), 1611 (w), 1597 (w), 1451 (w),
1407 (w), 1367 (w), 1330 (m), 1289 (m), 1265 (m), 1228 (m), 1187
(w), 1163 (s), 1119 (w), 1095 (w), 1065 (m), 1023 (m), 972 (w), 938
(w), 911 (m), 870 (m), 838 (w), 825 (w), 809 (s), 778 (w), 721 (m),
705 (w), 670 (m), 586 (s), 552 (s), 530 (m), 486 cm–1 (w).
1H NMR (300 MHz, CDCl3): δ = 7.44 (d, J = 8.3 Hz, 2 H), 7.07 (d, J = 8.1
Hz, 2 H), 6.65 (s, 2 H), 5.69 (d, J = 4.6 Hz, 1 H), 5.51 (d, J = 4.7 Hz, 1 H),
4.20–4.03 (m, 2 H), 2.34 (s, 3 H), 2.21 (s, 6 H), 2.21 (s, 3 H), 1.12 (t, J =
7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.93, 143.13, 137.99, 137.18, 137.13,
129.84, 129.46, 129.17, 126.99, 62.55, 55.01, 21.59, 20.92, 20.12,
14.10.
HRMS (MALDI): m/z [M + Na]+ calcd for C20H25NO5SNa: 414.1346;
found: 414.1338.
MS (ESI): m/z [M + Na]+ calcd for C20H25NO4SNa: 398.1; found: 398.1.
HRMS (MALDI): m/z [M + K]+ calcd for C20H25NO4SK: 414.1136; found:
414.1133.
Ethyl 2-Mesityl-2-(thiophene-2-sulfonamido)acetate (16c)
Bi Catalysis: Compound 16c was synthesized according to the GP
from 2-thiophenesulfonamide (82 mg, 0.5 mmol, 1.0 equiv), ethyl
glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL,
1.5 mmol, 1.5 equiv) and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in
MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C.
Purification by chromatography (n-hexane/EtOAc 9:1 → 4:1) yielded
the product as a colorless solid (123 mg, 67%).
Ethyl 2-(4-Bromophenylsulfonamido)-2-mesitylacetate (16b, R =
Br)
Bi Catalysis: Compound 16b (R = Br) was synthesized according to
the GP from 4-bromobenzenesulfonamide (120 mg, 0.5 mmol,
1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene
(0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol,
2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h
at 100 °C. Purification by chromatography (n-hexane/EtOAc 4:1 →
7:3) yielded the product as a colorless solid (118 mg, 54%).
Mp 158–160 °C; Rf = 0.3 (n-hexane/EtOAc = 4:1).
IR (ATR): 3314 (w), 3115 (w), 2967 (w), 2083 (w), 1739 (s), 1612 (w),
1509 (w), 1480 (w), 1463 (w), 1407 (m), 1367 (w), 1329 (s), 1287 (s),
1225 (m), 1197 (m), 1157 (s), 1144 (s), 1091 (s), 1033 (m), 1014 (s),
976 (w), 925 (w), 852 (s), 828 (m), 782 (w), 739 (m), 729 (s), 666 (s),
641 (w), 608 (s), 589 (s), 570 (s), 546 (s), 528 (s), 468 cm–1 (m).
Mp 114–116 °C; Rf = 0.6 (n-hexane/EtOAc = 4:1).
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1H NMR (300 MHz, CDCl3): δ = 7.44 (dd, J = 5.0, 1.2 Hz, 1 H), 7.24 (dd,
J = 3.8, 1.3 Hz, 1 H), 6.88–6.85 (m, 1 H), 6.72 (s, 2 H), 5.87 (br d, J = 4.9
Hz, 1 H), 5.59 (d, J = 5.0 Hz, 1 H), 4.22–4.05 (m, 2 H), 2.26 (s, 6 H), 2.21
(s, 3 H), 1.14 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.78, 141.13, 138.13, 137.21, 132.19,
131.93, 129.96, 129.35, 127.00, 62.67, 55.28, 20.96, 20.16, 14.11.
1H NMR (300 MHz, CDCl3): δ = 8.10 (br d, J = 7.2 Hz, 1 H), 7.90–7.88
(m, 2 H), 7.77–7.74 (m, 2 H), 6.83 (s, 2 H), 5.99 (d, J = 7.3 Hz, 1 H), 4.44
(d, J = 11.5 Hz, 1 H), 4.20–4.03 (m, 2 H), 2.86–2.74 (m, 1 H), 2.39 (s, 6
H), 2.25 (s, 3 H), 1.11 (t, J = 7.1 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.83
(d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.38, 168.61, 168.33, 137.69, 137.05,
134.54, 131.57, 130.90, 130.01, 123.88, 63.58, 61.85, 52.40, 27.89,
21.01, 20.29, 19.62, 14.11.
MS (ESI): m/z [M + H]+ calcd for C17H22NO4S2: 368.1; found: 368.5.
HRMS (MALDI): m/z [M + K]+ calcd for C17H21NO4S2K: 406.0544;
found: 406.0543.
Diastereomer b
Mp 136–138 °C; Rf = 0.3 (n-hexane/EtOAc = 4:1).
Ethyl 3,5,10,10a-Tetrahydro-3-oxo-1H-oxazolo[3,4-b]isoquinoline-
1H NMR (300 MHz, CDCl3): δ = 7.95 (br d, J = 7.4 Hz, 1 H), 7.85–7.82
(m, 2 H), 7.74–7.71 (m, 2 H), 6.79 (s, 2 H), 6.04 (d, J = 7.5 Hz, 1 H), 4.45
(d, J = 11.3 Hz, 1 H), 4.24–4.09 (m, 2 H), 3.03–2.90 (m, 1 H), 2.36 (s, 6
H), 2.21 (s, 3 H), 1.20–1.14 (m, 6 H), 0.86 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.43, 168.54, 168.50, 137.72, 137.08,
134.52, 131.51, 130.82, 129.99, 123.84, 63.29, 61.88, 52.10, 27.96,
20.97, 20.28, 19.91, 19.72, 14.18.
5-carboxylate (21)
Bi Catalysis: Compound 21 was synthesized according to the GP from
(R)-4-benzyloxazolidin-2-one (59 mg, 0.3 mmol, 1.0 equiv), ethyl gly-
oxalate (61 mg, 0.6 mmol, 2.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol,
2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h
at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1)
yielded the product as a colorless solid (72 mg, 84%).
Mp 58–59 °C; Rf = 0.2 (cyclohexane/EtOAc = 7:3).
MS (ESI): m/z [M + H]+ calcd for C26H31N2O5: 451.2; found: 451.4.
IR (ATR): 2980 (w), 2936 (w), 2084 (w), 1760 (s), 1726 (s), 1477 (m),
1454 (m), 1408 (m), 1393 (m), 1365 (m), 1340 (m), 1322 (m), 1272
(s), 1237 (s), 1227 (s), 1205 (s), 1186 (s), 1167 (m), 1115 (m), 1099
(m), 1063 (s), 1017 (s), 983 (m), 938 (m), 917 (w), 892 (m), 876 (m),
824 (m), 810 (m), 759 (s), 745 (m), 715 (w), 697 (m), 671 (m), 620
(w), 585 (w), 534 (m), 509 (w), 495 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.61–7.56 (m, 1 H), 7.28–7.25 (m, 3 H),
7.18–7.15 (m, 1 H), 5.46 (s, 1 H), 4.72–4.67 (m, 1 H), 4.52–4.45 (m, 1
H), 4.27–4.12 (m, 3 H), 3.06–2.99 (m, 1 H), 2.93–2.84 (m, 1 H), 1.31 (t,
J = 7.1 Hz, 3 H).
HRMS (MALDI): m/z [M + H]+ calcd for C26H31N2O5: 451.2228; found:
451.2224.
Ethyl 2-Benzamido-2-hydroxyacetate (24a)
Fe Catalysis: Compound 24a was synthesized according to the GP
from benzamide (61 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate
(0.12 mL, 1.2 mmol, 1.2 equiv), and FeCl3·6H2O (13 mg, 0.025 mmol,
5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h
at r.t. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded
the product as a colorless solid (96 mg, 99%).
13C NMR (75 MHz, CDCl3): δ = 170.09, 157.14, 132.04, 129.88, 128.95,
Mp 54.8 °C; Rf = 0.30 (n-hexane/EtOAc = 7:3).
128.31, 127.65, 127.31, 69.38, 62.16, 55.07, 49.62, 33.78, 14.25.
1H NMR (400 MHz, CDCl3): δ = 7.84–7.79 (m, 2 H), 7.51 (d, J = 51.2 Hz,
3 H), 7.36 (d, J = 5.8 Hz, 1 H), 5.78 (dd, J = 6.9, 6.0 Hz, 1 H), 4.35 (q, J =
7.1 Hz, 2 H), 4.15 (d, J = 5.8 Hz, 1 H), 1.36 (t, J = 7.1 Hz, 3 H).
The structure was assigned by COSY.
MS (ESI): m/z [M + H]+ calcd for C14H16NO4: 262.1; found: 262.2.
Analytical and spectral data are consistent with those reported in the
literature.36
Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C, 63.95;
H, 5.82; N, 5.20.
Ethyl 2,2-Bis(benzamido)acetate (25a)
Ethyl 2-(3-Methyl-(1,3-dioxoisoindolin-2-yl)butanamido)-2-mesi-
tylacetate (23, PG = Phth)
Fe Catalysis: Compound 25a was synthesized according to the GP
from benzamide (242 mg, 2.0 mmol, 2.0 equiv), ethyl glyoxalate
(0.10 mL, 1.0 mmol, 1.0 equiv), and FeCl3·6H2O (13 mg, 0.025 mmol,
5 mol%) in MeNO2 (2.0 mL). After stirring for 24 h at 80 °C, the white
precipitate was filtered, and dried under reduced pressure. The de-
sired product was isolated as a white solid (325 mg, ~100%).
Bi Catalysis: Compound 23 (PG = Phth) was synthesized according to
the GP from 3-methyl-2(1,3-dioxoisoindolin-2-yl)butanamide
(246 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol,
1.2 equiv), mesitylene (0.41 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3
(13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture
was stirred for 24 h at 80 °C. Purification by chromatography (n-hex-
ane/EtOAc = 4:1) yielded the product as a colorless solid (393 mg,
87%; r.r. = 67:33).
Mp (decomp.); Rf = 0.26 (n-hexane/EtOAc = 7:3).
1H NMR (400 MHz, CDCl3): δ = 8.00–7.70 (m, 6 H), 7.55–7.42 (m, 6 H),
5.88 (t, J = 6.7 Hz, 1 H), 4.33 (dd, J = 14.1, 7.0 Hz, 2 H), 1.30 (t, J = 7.1
Hz, 3 H).
IR (ATR): 3348 (w), 2966 (w), 2873 (w), 2050 (w), 1979 (w), 1776 (w),
1765 (w), 1730 (m), 1705 (s), 1676 (s), 1608 (w), 1525 (s), 1466 (m),
1383 (s), 1360 (m), 1331 (m), 1279 (m), 1240 (s), 1153 (m), 1099 (m),
1063 (s), 1026 (s), 982 (w), 947 (w), 908 (w), 885 (m), 868 (w), 854
(m), 827 (w), 806 (w), 766 (w), 725 (s), 708 (m), 688 (w), 613 (s), 604
cm–1 (s).
Analytical and spectral data are consistent with those reported in the
literature.37
Ethyl 2,2-Dimesitylacetate (26)
Fe Catalysis: Compound 26 was synthesized according to the GP from
ethyl glyoxalate (0.10 mL, 1.0 mmol, 1.0 equiv), mesitylene (0.42 mL,
3.0 mmol, 3.0 equiv), and FeCl3·6H2O (13 mg, 0.025 mmol, 5 mol%) in
MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C.
Purification by chromatography (n-hexane/EtOAc = 20:1 → 9:1) yield-
ed the product as a colorless solid (320 mg, 99%).
Diastereomer a
Mp 63–65 °C; Rf = 0.2 (n-hexane/EtOAc = 4:1).
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Mp 100–106 °C; Rf = 0.72 (n-hexane/EtOAc = 9:1).
1H NMR (400 MHz, CDCl3): δ = 6.79 (s, 4 H), 4.24 (q, J = 7.1 Hz, 2 H),
2.24 (s, 6 H), 2.07 (s, 12 H), 1.27 (t, J = 7.1 Hz, 3 H).
(9) For recent examples, see: (a) Zhao, L.; Basle, O.; Li, C.-J. Proc.
Natl. Acad. Sci. U.S.A. 2009, 106, 4106. (b) Beenen, M. A.; Weix,
D. J.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 6304. (c) Shang,
G.; Yang, Q.; Zhang, X. Angew. Chem. Int. Ed. 2006, 45, 6360.
(d) Lee, E. C.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 12066.
(e) Hirner, S.; Panknin, O.; Edefuhr, M.; Somfai, P. Angew. Chem.
Int. Ed. 2008, 47, 1907. (f) Lee, S.; Beare, N. A.; Hartwig, J. K.
J. Am. Chem. Soc. 2001, 123, 8410. (g) Saaby, S.; Fang, X.;
Gathergood, N.; Jorgensen, K. A. Angew. Chem. Int. Ed. 2000, 39,
4114. (h) Mita, T.; Chen, J.; Sugawara, M.; Sato, Y. Angew. Chem.
Int. Ed. 2011, 50, 1393. For the iron-catalyzed addition of thio-
phenes to preformed glyoxalate imines, see: (i) Huang, Z.;
Zhang, J.; Wang, N.-X. Tetrahedron 2011, 67, 1788.
(10) (a) Mannich, C.; Krösche, W. Arch. Pharm. 1912, 250, 647. For
recent reviews, see: (b) Kobayashi, S.; Ueno, M. In Comprehen-
sive Asymmetric Catalysis, Supplement 1; Jacobsen, E. N.; Pfaltz,
A.; Yamamoto, H., Eds.; Springer: Berlin, 2004, 143–159.
(c) Cordova, A. Acc. Chem. Res. 2004, 37, 102.
(11) (a) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27. For a recent
review, see: (b) Wang, J.; Liu, X.; Feng, X. Chem. Rev. 2011, 111,
6947.
Analytical and spectral data are consistent with those reported in the
literature.38
Ethyl 2-Hydroxy-2-mesitylacetate (27)
Fe Catalysis: Compound 27 was synthesized according to the GP from
ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.0 equiv), mesitylene (0.42 mL,
3.0 mmol, 3.0 equiv), 2,2′-bipyridine (5 mg, 0.03 mmol, 3 mol%), and
Fe(ClO4)3 (7 mg, 0.02 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction
mixture was stirred for 24 h at 80 °C. Purification by chromatography
(hexane/EtOAc = 4:1) yielded the product as a colorless oil (176 mg,
66%).
Rf = 0.51 (n-hexane/EtOAc = 7:3).
1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 5.52 (d, J = 2.8 Hz, 1 H),
4.34–4.11 (m, 2 H), 3.22 (d, J = 2.8 Hz, 1 H), 2.33 (s, 6 H), 2.26 (s, 3 H),
1.22 (t, J = 7.1 Hz, 3 H).
Analytical data are consistent with those reported in the literature.39
(12) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34,
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Acknowledgment
This work was financially supported by the Fonds der Chemischen In-
dustrie (Liebig Fellowship to G.M. and A.E.S.), the Evonik Stiftung (Fel-
lowship to J.H.), the Stiftung Polytechnische Gesellschaft Frankfurt
am Main (Fellowship to T.B.), and the Goethe-University Frankfurt
(Nachwuchs im Fokus-Program). We would like to thank Prof.
Michael Göbel (Goethe-University Frankfurt) for his support as well
as Rockwood Lithium GmbH (Frankfurt) and Evonik Industries AG
(Hanau) for the generous gift of chemicals.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561499.
S
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(16) (a) Schneider, A. E.; Manolikakes, G. Synlett 2013, 24, 2057.
(b) Halli, J.; Manolikakes, G. Eur. J. Org. Chem. 2013, 7471.
(c) Beisel, T.; Manolikakes, G. Org. Lett. 2013, 15, 6046.
(d) Schneider, A. E.; Beisel, T.; Shemet, A.; Manolikakes, G. Org.
Biomol. Chem. 2014, 12, 2356. (e) Schneider, A. E.; Manolikakes,
G. J. Org. Chem. 2015, 80, 6193. (f) Beisel, T.; Manolikakes, G.
Org. Lett. 2015, 17, 3162. (g) Beisel, T.; Manolikakes, G. Synthesis
2016, 48, 379. (h) Beisel, T.; Kirchner, J.; Kaehler, T.; Knauer, J.;
Soltani, Y.; Manolikakes, G. Org. Biomol. Chem. 2016, 14, 5525.
(17) Monomeric glyoxalates are prepared from the corresponding
polymers by pyrolysis. The monomers are so reactive that they
polymerize easily and react readily with water to generate the
hydrated forms. Therefore, they have to be distilled just prior to
use, after pyrolysis, and used under nonaqueous conditions.
(18) Ethyl glyoxalate was obtained in the polymer form (50 wt%
solution) in toluene. Toluene was removed prior to the initial
experiments by applying vacuum (1 mbar) for 2 h.
(19) For an excellent overview of the nucleophilicity of arenes as
well as the reactivity of various other molecules, we recom-
mend the database of Prof. H. Mayr (LMU Munich):
http://www.cup.lmu.de/oc/mayr/reaktionsdatenbank/.
(20) For reviews, see: (a) Bauer, I.; Knölker, H.-J. Chem. Rev. 2015,
115, 3170. (b) Gopalaiah, K. Chem. Rev. 2013, 113, 3248.
(c) Darwish, M.; Wills, M. Catal. Sci. Technol. 2012, 2, 243.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AE