Asymmetric synthesis of deuterated and fluorinated aromatic α,α-disubstituted amino acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2010.04.026

We herein present organocatalytic approaches to synthesize fluorinated and deuterated α-substituted phenylglycine derivatives. Whereas the addition of diethyl azodicarboxylate to fluorinated α-substituted aldehydes furnishes chiral non-racemic compounds, the use of chloramine-T as a nitrogen source represents a rapid access to sulfamidated fluorinated amino acid precursors. Additionally, further functionalization was achieved through the palladium-catalyzed coupling of a p-bromosubstituted aldehyde with a range of fluorine or deuterium-containing boronic acids. Oxidation of the aldehyde function and cleavage of the protection group of the nitrogen give way to the free fluorinated unnatural amino acids.

Full text of DOI:10.1016/j.tetasy.2010.04.026

Tetrahedron: Asymmetry 21 (2010) 1341–1349
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of deuterated and fluorinated aromatic
a,a-disubstituted amino acid derivatives
Caroline E. Hartmann a, Thomas Baumann b, , Michael Bächle b, , Stefan Bräse a,
*
a Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany
b Cynora GmbH, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
We herein present organocatalytic approaches to synthesize fluorinated and deuterated
phenylglycine derivatives. Whereas the addition of diethyl azodicarboxylate to fluorinated
a
a
-substituted
-substituted
Received 24 February 2010
Accepted 12 April 2010
Available online 19 June 2010
aldehydes furnishes chiral non-racemic compounds, the use of chloramine-T as a nitrogen source repre-
sents a rapid access to sulfamidated fluorinated amino acid precursors. Additionally, further functional-
ization was achieved through the palladium-catalyzed coupling of a p-bromosubstituted aldehyde with a
range of fluorine or deuterium-containing boronic acids. Oxidation of the aldehyde function and cleavage
of the protection group of the nitrogen give way to the free fluorinated unnatural amino acids.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Henri Kagan on the occasion of
his 80th birthday
1. Introduction
rine itself and reagents derived from it, numerous fluorinated
compounds have gained influence in the development of bioactive
Chiral amino compounds, among them particularly
acids and their derivatives, play a central role in the emergence
of life. Numerous examples of non-proteinogenic -amino acids
and related compounds have moved into the focus of biochemical
research and drug discovery. They differ from their ‘natural’ rela-
a
-amino
molecules.6 Therefore, the introduction of fluorine has become a
very important strategy to overcome serious problems of newly
designed active compounds, such as insufficient bioavailability as
a result of fast in vivo metabolism or poor transportation or diffu-
sion through the body.7 The substitution of carbon-bound hydro-
gen by fluorine to significantly enhance the metabolic stability
caused by the strength and chemical stability of the C–F bond
can thus improve the pharmacokinetic properties of drugs that
are based on a peptide structure. In this context, it has been shown
that the incorporation of even one fluorinated amino acid instead
of its hydrocarbon analogue can not only have a strong impact
on protein structure8 but does also tremendously increases peptide
and protein stability by forming very strong non-natural side chain
interaction cores.9 The modification by fluorine results in a high
polarizability of the C–F bond and, consequently, of the entire car-
bon skeleton, while on the other hand the steric demand of the
molecule is not significantly increased. Thus, the replacement of
hydrogen with fluorine generally enhances lipophilicity, resulting
in improved membrane permeability that facilitates transport
through the blood–brain barrier, a property of particular impor-
tance in the development of peptide-based drugs.10 These effects
can best be measured by performing a so-called ‘fluorine scan’,
which means systematically exchanging one or more hydrogen
for fluorine.11 Due to the sensitivity of 19F NMR spectroscopy along
with large 19F–1H coupling constants and chemical-shift anisot-
ropy, fluorine incorporation has proved to be a particularly power-
ful tool for dynamic NMR studies of biological processes.12
a
tives in the composition of the
opposite stereochemistry or untypical substitution patterns.
Thus, the presence of a fully substituted -carbon centre im-
a-carbon centre, displaying either
a
poses severe conformational restrictions on the molecule and
exhibits a pronounced helix-inducing potential when incorporated
into peptides.1 These specific peculiarities of the secondary struc-
ture were found to be responsible for the membrane destabiliza-
tion exerted by peptaibols, a class of peptidic broad-spectrum
antibiotics.2,3
Since some of the major drawbacks in the application of pep-
tides as pharmaceuticals deal with their conformational flexibility,
a,a
-disubstituted amino acid derivatives4 can be used to minimize
the nonselective interactions with different receptors. The concept
of forcing conformational constraint on otherwise flexible struc-
tures was carried further in the targeted synthesis of peptoids,
where it was utilized in the design of non-peptidic small molecules
to conformationally and functionally mimic biologically active
peptides.5
The incorporation of fluorine in fluorocarbon compounds
clearly demonstrates the unique properties of this outstanding ele-
ment in organic chemistry. Besides the synthetic potential of fluo-
Moreover, fluorinated amino acids have attracted considerable
attention as synthetic targets for pharmaceutical and other biolog-
ical applications.13 Nevertheless, their application remains strongly
* Corresponding author. Tel.: +49 721 608 2902; fax: +49 721 608 8581.
E-mail address: braese@kit.edu (S. Bräse).
www.cynora.de.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.026

1342
C. E. Hartmann et al. / Tetrahedron: Asymmetry 21 (2010) 1341–1349
Table 1
a
limited to date. The main reasons for this are the restricted syn-
thetic availability of fluorinated building blocks as well as the elab-
orate methods often required for their incorporation. For this
reason, fast and convenient access to this class of interesting mol-
ecules is highly desirable.
-Sulfamidation of 2-arylpropionaldehydes with chloramine-Ta
chloramine-T
2 mol% L-proline
O
O
NHTos
MeCN, MW,60 min
R
R
Therefore, we decided to investigate the scope of two different
4a-g
5a-g
organocatalytic approaches toward
a,a-disubstituted fluorinated
Entry
R
Tempb (°C)
Powerc (W)
Product
Yieldd (%)
amino acids. Herein, we report the synthesis of a library of fluori-
nated and deuterated amino acid precursors via organocatalytic
amination of aryl aldehydes.14
1
2
3
4
5
6
7
2-F–C6H4
3-F–C6H4
4-F–C6H4
3-CF3–C6H4
4-CF3–C6H4
4-D-C6H4
60
60
60
60
60
60
60
200
200
200
200
200
200
200
5a
70
62
85
73
79
86
74
5b
5c17
5d
2. Results and discussion
5e17
5f
a-CD3–C6H4
5g
The aldehydes were synthesized according to the literature
from the commercially available acetophenones.15 In the first step
a Wittig reaction was carried out with the corresponding acetoph-
enones to yield enol ethers. These could then easily be cleaved by
protonation and tautomerized with aq HBr resulting in the desired
aldehydes. In the case of the deutero-substituted aldehyde 4f
(Scheme 1), the bromo substituent was supposed to be exchanged
with organomagnesium reagents. As the lability of the carbonyl
function of the ketone and the aldehyde renders them not useful
for Grignard addition, the transformation was performed at this
stage in 89% yield. Acidic opening of 3 delivered the p-deuterated
substrate 4f in 97% yield.
a
Reaction conditions: 1.0 equiv aldehyde, 1.5 equiv chloramine-T, 2 mol %
proline.
For cooling, compressed air with a constant pressure of 0.7 bar (10 psi) was
used during the entire experiment.
L-
b
c
Application of constant microwave power.
Isolated yields.
d
esterification is performed with trimethylsilyldiazomethane to de-
liver the fully protected amino acid 7 (Scheme 2). In a last step
hydrogen bromide in acetic acid20 was used to furnish the free
a
-methylphenylglycine 8 (81% overall yield).
With the
a
-substituted aldehydes in hand,16 we turned our
-sulfamidation of 2-arylpropionaldehydes
In most cases, however, it is necessary to install enantiomeri-
attention toward the
a
cally pure amino acids. With this goal in mind, a different organo-
catalytic strategy was considered. We have previously reported the
microwave-enhanced addition of diethyl azodicarboxylate to aro-
with the inexpensive and environmentally benign reagent chlora-
mine-T. Under these conditions, we had previously been able to
show that electron-withdrawing groups or atoms such as fluorine
have a stabilizing effect on the reaction which results in higher
yields. Electron-donating groups on the other hand lower the yield,
most likely because of a halogenation of the electron-rich aromatic
ring. The reactions were carried out under microwave conditions
according to a literature-known procedure at 60 °C within 60 min
matic
a
-methylaldehydes.21 When screening the most commonly
used solvents, the incapability of low-absorbing solvents such as
1,4-dioxane or chloroform became visible. On the other hand, ace-
tonitrile was found to be the solvent with the best conversion and
the best enantiomeric ratio.
In this study, therefore, the amidation reactions were per-
formed with 50 mol % L-proline, 1.5 equiv diethyl azodicarboxylate
and using only 2 mol % L
-proline.17
In this manner we were able to produce a range of fluoro-con-
taining sulfamidated aldehydes with different aromatic substitu-
ents (Table 1).
in acetonitrile under microwave irradiation at 60 °C within 30–
60 min (Table 2).
While the unsubstituted 2-phenylpropionaldehyde gave the
amidated product 9l with complete conversion and good enanti-
oselectivity, moving to 2-naphthylpropionaldehyde resulted in a
decrease of yield to 76% for 9m whereas the enantioselectivity re-
mained the same (90% and 89% ee). A variety of fluoro-substituted
aromatic aldehydes were subjected to the reaction conditions. The
substitution patterns played a significant role, as electron-with-
drawing groups have a stronger impact when they are positioned
closer toward the reaction centre. Consequently, when moving
from the ortho- over meta- to the para-position, the yield rose sig-
nificantly from 38% to 91% and the enantioselectivity increased
from 69% to 89% (Table 2, 9a to 9c). In the case of the trifluoro-
methyl-substituent, the yield and the ee stayed in the same range
(Table 2, entries 6 and 7). Although fluorinated compounds are par-
ticularly prone to self-disproportionation of the enantiomers dur-
ing achiral chromatography, this could not be observed here.22
Here, however, all the substituents on the aromatic backbone
seem to have only a small impact on the resulting yields as they
all lay in the range between 62% and 85%. Altogether, no trend is
perceptible. Apart from fluoro-substituted aldehydes we also sub-
mitted deuterated aldehydes to the process (Table 1, entries 6 and
7). Regardless of the altered electronic properties, yields of 86% for
5f and 74% for 5g were achieved. Nevertheless, the resulting prod-
ucts could only be obtained as racemic mixtures. It is possible that
the reaction proceeds via enolate-intermediates rather than enam-
ines. If so, the chiral catalyst loses its influence on the side of the
attack. Recently, other methods for a-functionalization (e.g., chlo-
rination) were published which can be used for the same pur-
pose.18 The racemic aldehydes can subsequently be oxidized to
the corresponding amino acids. In a first step the aldehyde is oxi-
dized with sodium chlorite/hydrogen peroxide.19 The following
OMe
O
OMe
O
KOtBu,
CH3OCH2PPh3Cl
1) Mg,
dibromoethane, THF
HBr
acetone/H2O, 0 °C,
2) D2O, 89%
THF, −78 °C - r.t.,
97%
88%
D
D
Br
Br
1
2
3
4f
Scheme 1. Synthesis of deuterated aldehyde 4f.

C. E. Hartmann et al. / Tetrahedron: Asymmetry 21 (2010) 1341–1349
1343
1) NaClO2, H2O2,
KH2PO4
MeCN / H2O
O
O
O
HBr / AcOH
phenol
NHTos
NHTos
NH2
MeO
HO
2) Me3SiCHN2
MeOH / toluene
92%
80 °C, 10 h
88%
6
8
7
Scheme 2. Oxidation and deprotection of sulfamidated aldehydes.
Table 2
-Amination of 2-arylpropionaldehydes with dialkyl azodicarboxylatesa
Furthermore, the products obtained have, despite their fluorine
content, a very low vapor pressure, thus change of enantioselectiv-
ity due to volatility did not occur in our case.23
Besides diethyl azodicarboxylate, also dibenzyl azodicarboxyl-
ate could be utilized as nitrogen-transfer reagent under microwave
irradiation (Table 2, entries 11–13).
a
O
CO2R
O
DEAD or DBAD,
50 mol-% L-proline
N
NH
MeCN , MW
R
CO2R
R
4a-j
9a-m
Further functionalization of the aromatic backbone was
achieved by introduction of different units through the bromine
substituent. Therefore, aldehyde 9h was first converted to the
methylester followed by a Suzuki reaction. In this way the amount
of required and the often costly boronic acids could be kept at a
minimum.
For the next step, a literature-known procedure for the Suzuki–
Miyaura reaction in the microwave was applied (Table 3).24 The
reaction of 10 with phenyl boronic acid in a mixture of toluene/
ethanol/water 3:3:1 with tetrakis(triphenylphosphine)-palladium
at 100 °C did not result in the formation of the desired product
11a. Changing the solvent to 1,4-dioxane and raising the tempera-
ture to 150 °C, however, resulted in 61% product after 30 min (Ta-
ble 3, entry 1).25 By increasing the reaction time to 2 h, 82% of the
coupling product 11a could be obtained. When assigning the reac-
tion conditions to 4-fluorophenyl boronic acid, the level of reactiv-
ity remained the same (Table 3, entry 4, 11b).
Entry
R
Azo-
compound
Time
(min)
Product Yieldb
(%)
eec,d
(%)
1
2
3
4
5
6
C6H5
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
30
30
60
60
60
60
9l21
9m21
9a
97
76
38
77
91
65
89 (R)
90 (R)
69 (R)
87 (R)
89 (R)
72 (R)
2-Naph
2-F–C6H4
3-F–C6H4
4-F–C6H4
3-CF3–
C6H4
9b
9c21
9d
7
4-CF3–
C6H4
DEAD
60
9e21
63
56 (R)
8
9
4-D–C6H4
DEAD
DEAD
60
60
9f
9g
68
88
n.d.
n.d.
a-CD3–
C6H4
4-Br–
C6H4
4-Br–
C6H4
4-F–C6H4
C6H5
10
11
DEAD
DBAD
60
60
9h21
9i21
75
72
86 (R)
53 (R)
12
13
DBAD
DBAD
60
60
9j21
85
83
59 (R)
9k21
81 (R)e
Moving to phenyl boronic acids bearing more of the electron-
withdrawing fluorine atoms, a drop in yield could be observed
which derives from the decreased reactivity of the electronically
deactivated boronic acids in the coupling process. The formation
of 11f as a last example goes in line with the unsubstituted com-
pound 11a.
a
Reaction conditions: 1.0 equiv aldehyde, 0.5 equiv L-proline, 1.5 equiv DEAD,
T = 60 °C, application of constant microwave power of 200 W. For cooling, com-
pressed air with a constant pressure of 0.7 bar (10 psi) was used during the entire
experiment.
b
Isolated yields.
c
Determined by HPLC analysis using a chiral column (Chiracel AD); see Sec-
The deprotection of hydrazino acid precursors can be achieved
in very good yields (Scheme 3).16 Oxidation of the aldehyde 9k
with sodium chlorite and subsequent treatment with trimethylsi-
tion 4.1 for details. n.d. not determined.
d
Absolute configuration according to correlation with related systems.16,17,21
e
Reaction conditions: solvent = dichloromethane, rt, 5 d.
Table 3
Suzuki–Miyaura reaction of an aminoacid precursor with functionalized phenyl boronic acida
O
O
CO2Et
CO2Et
N
N
NH
CO2Et
NH
CO2Et
MeO
MeO
K3PO4, 10 mol% Pd(PPh3)4
1,4-dioxane, MW
R
B
(OH)2
Br
10
R
11a-f
Entry
R
Time (h)b
Product
Yieldc (%)
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
4-F–C6H4
3,4,5-F–C6H2
2,3,4,5,6-F–C6
4-CF3–C6H4
0.5
1
2
2
2
2
2
2
11a
11a
11a
11b
11c
11d
11e
11f
61
79
82
88
61
69
69
81
2,3,4,5,6-D-C6
a
Reaction conditions: 1.0 equiv 10, 1.5 equiv boronic acid, 3 equiv K3PO4, 10 mol % Pd(PPh3)4, 6 mL 1,4-dioxane per mmol substrate, T = 150 °C, application of constant
microwave power of 200 W.
b
For cooling, compressed air with a constant pressure of 0.7 bar (10 psi) was used during the entire experiment.
Isolated yields.
c

1344
C. E. Hartmann et al. / Tetrahedron: Asymmetry 21 (2010) 1341–1349
The specified reaction time corresponds to the irradiation time.
O
O
O
The temperature was monitored by an infrared temperature sensor
positioned below the reaction vessel. The indicated temperature
corresponds to the maximum temperature reached during each
experiment.
1) NaClO2, H2O2,
O
HN
N
OBn
OBn
O
HN
N
OBn
OBn
MeCN/H2O, r.t., 15 h
MeO
2) Me3SiCHN2,
MeOH/toluene, r.t., 10 min,
87% over two steps
O
1H NMR spectra were recorded at 400 MHz on Bruker AM400,
the 13C NMR spectra were recorded at 100 MHz, respectively. The
chemical shifts are reported in parts per million (ppm) relative to
the solvent residual peak.27 HPLC was performed on an Agilent
1100 Series using Diacel Chiralpak AS (250 ꢀ 4.6 mm) or Diacel
9k
12
1) pyridine, 40 °C, 15 h,
then TFAA, r.t., 48 h
2) SmI2, THF/MeOH, r.t., 30 min
O
NH2
HO
Chiracel OD (250 ꢀ 4.0 mm, 10
lm). Rotational values were deter-
3) 6 M HCl, reflux, 48 h, then
propylene oxide
71% over three steps
mined on a Perkin Elmer 241 Polarimeter at k = 589 nm (sodium D-
Line). The concentration c is given in (g/100 mL). The ee’s were
determined by comparison with the racemic products obtained
by application of DL-proline as a catalyst.
8
Scheme 3. Oxidation of the aldehyde 9k and cleavage of the protecting groups.
4.1.1. GP 1: General procedure for the proline-catalyzed
famidation under microwave irradiation
a-sul-
In a 10 mL vessel were placed 1.00 mmol (1.0 equiv) of the alde-
hyde, 0.02 mmol (2 mol %) -proline, 1.50 mmol (1.5 equiv) chlora-
lyldiazomethane furnished the completely protected methyl ester
12 in 87% yield.
Applying then a selective benzyloxycarbonyl deprotection using
trifluoroacetanhydride (TFAA), cleavage of the hydrazine with SmI2
and finally hydrolysis of the ester function gave 71% of the phenyl-
glycine derivative 8.
L
mine-T, 5 mL acetonitrile, and a magnetic stir bar. The vessel was
sealed with a septum, placed in a MW cavity, and locked with
the pressure device. Constant microwave irradiation of 200 W as
well as simultaneous air-cooling (0.7 bar, 10 psi) was used during
the entire reaction time (30 min, 60 °C). After cooling to rt, the sol-
vent was removed under reduced pressure, and the product was
purified by column chromatography (diethyl ether/n-pentane) to
3. Conclusions
afford the a-sulfamidated aldehyde as a colorless solid.
In summary, we presented an easy and fast method to access a
variety of fluorinated or deuterated configurationally stable
a,a-
4.1.2. GP 2: General procedure for the synthesis of N,N0-bis
(ethoxycarbonyl)-2-hydrazino-2-phenylpropionaldehyde under
microwave irradiation
In a 10 mL vessel were placed 1.0 mmol (1.0 equiv) of the alde-
hyde, 0.5 mmol (50 mol %) L-proline, 1.5 mmol (1.5 equiv) diethyl
azodicarboxylate, 5 mL acetonitrile, and a magnetic stir bar. The
vessel was sealed with a septum, placed in a MW cavity, and
locked with the pressure device. Constant microwave irradiation
of 200 W as well as simultaneous air-cooling (0.7 bar, 10 psi) was
used during the entire reaction time (60 min, 60 °C). After cooling
to rt, the solvent was removed under reduced pressure and the
product was purified by column chromatography (n-pentane/
disubstituted amino acid precursors. Starting from easily accessi-
ble aromatic aldehydes, different organocatalytic strategies could
be applied successfully to fluorinated and deuterated aromatic
aldehydes. Using chloramine-T as a nitrogen source, the racemic
sulfamidated products could be obtained in good to very good
yields within 1 h. For enantiomerically enriched compounds, the
addition of diethyl azodicarboxylate to the above-mentioned alde-
hydes could be performed under microwave irradiation to furnish
the amidated compounds in good to excellent yields and up to 90%
ee. Further functionalities could be introduced through a Suzuki–
Miyaura reaction on the aromatic backbone to deliver the biphe-
nyl-bearing amino acid precursor in 61–82% yield. These products
can easily be oxidized and deprotected to the corresponding
unnatural amino acids, thus opening a way to a range of substi-
tuted amino acid moieties which then can be further utilized or
manipulated.
diethyl ether) to afford the a-aminated aldehyde as an oil.
4.1.3. GP 3: General procedure for the synthesis of N,N0-
bis(ethoxycarbonyl)-2-hydrazino-2-phenylpropionaldehyde at
room temperature
In a 10 mL vessel was placed 1.0 mmol of the aldehyde
(1.0 equiv), 1.5 mmol diethyl azodicarboxylate (1.5 equiv),
0.5 mmol L-proline (50 mol %), 5 mL acetonitrile, and a magnetic
stir bar. The reaction mixture was vigorously stirred at rt until
TLC indicated complete conversion. The solvent was removed un-
der reduced pressure and the product was purified by column
4. Experimental section
4.1. General
All chemicals were purchased and used without further purifi-
cation. The aldehydes and the enol ether 3 were synthesized
according to the literature.17 The products were purified by flash
chromatography26 using silica 60 from SDS (0.035–0.070 mm) or
Merck (0.040–0.063 mm) and sea sand (purified with acid and
calcined) from Merck. The solvents were purified by distillation
and were determined by volume. The microwave-assisted reac-
tions were conducted using a focused microwave unit (DiscoverÒ
Reactor from CEM Corporation). The instrument consists of a
continuous focused microwave power delivery system with opera-
tor-selectable power output from 0 to 300 W. In all experiments,
the microwave power was held constant to ensure reproducibility.
Reactions were performed in 10 mL glass vessels, which were
sealed with a septum and locked into a pressure device, which
controlled the pressure in the reaction vessel (maximum 10 bar).
chromatography (n-pentane/diethyl ether) to afford the a-aminat-
ed carbonyl compound as an oil.
4.1.4. GP 4: General procedure for the esterification of
famidated or -aminated aldehydes
a-sul-
a
At first, 1.00 mmol (1.00 equiv) of the aldehyde was dissolved in
5.0 mL of acetonitrile along with 0.28 mmol (0.28 equiv) KH2PO4 in
2.0 mL water and 0.5 mL (1.00 mmol, 1.00 equiv) 35% H2O2. To the
resulting mixture was added a solution of 1.74 mmol (1.74 equiv)
NaClO2 in 5.0 mL of water dropwise, keeping the temperature of
the mixture below 10 °C. After the mixture was stirred for 12 h,
0.08 mmol (0.08 equiv) of Na2SO3 was added and the resulting
mixture was partitioned between brine and dichloromethane, the
layers were separated, and the aqueous layer was extracted with

C. E. Hartmann et al. / Tetrahedron: Asymmetry 21 (2010) 1341–1349
1345
dichloromethane. The combined organic extracts were washed
with brine, dried, and concentrated under reduced pressure to give
a residue that was taken up in toluene/methanol 1:2 and treated
with an ethereal solution of trimethylsilyldiazomethane at 0 °C
for five minutes until bubbling subsided. The excess trimethylsilyl-
diazomethane was quenched with a few drops of acetic acid and
the solvent was removed in vacuo. Column chromatography (n-
pentane/diethyl ether) delivered the product as a colorless solid.
phy on silica with n-pentane/diethyl ether 5:1 delivered 409 mg
(4.16 mmol, 99%) of a colorless oil. Rf = 0.35 (pentane/diethyl ether
5:1). 1H NMR (400 MHz, CDCl3): d = 1.36 (d, J = 7.1 Hz, 3H, CHCH3),
3.55 (dq, J = 7.1, 1.3 Hz, 1H, CHCH3), 7.13 (d, J = 8.1 Hz, 2H, 30-H, 50-
H), 7.30 (d, J = 8.1 Hz, 2H, 20-H, 60-H), 9.60 (d, J = 1.3 Hz, 1H, CHO)
ppm. 13C NMR (100 MHz, CDCl3): d = 14.6 (CHCD3), 53.0 (CHCD3),
127.3 (t, J = 24.4 Hz, C-40), 129.0 (C-30, C-50), 129.1 (C-20, C-60),
137.8 (C-10), 201.1 (CHO) ppm. IR (KBr): vꢁ1 = 3078 (m), 2978
(m), 2934 (m), 2817 (m), 2719 (w), 1920 (w), 1722 (s), 1599 (m),
1492 (m), 1454 (m), 1417 (w), 1371 (m), 1211 (w), 1065 (m),
1020 (m), 856 (m) cmꢁ1. MS (EI, 70 eV): m/z (%): 135 (13) [M+],
106 (100) [M+ꢁCO], 78 (14) [C6H4D+]. HRMS (C9H9DO): calcd:
135.0794, found: 135.797.
4.1.5. GP 5: General procedure for the Suzuki-coupling of
diethyl 1-(2-(4-bromophenyl)-1-methoxy-1-oxopropan-2-yl)
hydrazine-1,2-dicarboxylate with phenyl boronic acids under
microwave irradiation
In
a 10 mL vessel under argon were placed 0.50 mmol
(1.0 equiv) of the ester, 0.75 mmol (1.5 equiv) phenyl boronic acid,
1.00 mmol (2.0 equiv) K3PO4, 0.05 mmol (10 mol %) tetrakis(tri-
phenylphosphine)palladium, 3 mL dioxane, and a magnetic stir
bar. The vessel was sealed with a septum, placed in a MW cavity,
and locked with the pressure device. Constant microwave irradia-
tion of 200 W as well as simultaneous air-cooling (0.7 bar, 10 psi)
was used during the entire reaction time (120 min, 150 °C). After
cooling to rt, the resulting mixture was partitioned between brine
and dichloromethane, the layers were separated, and the aqueous
layer was extracted with dichloromethane. The combined organic
extracts were washed with brine, dried, and the solvent was re-
moved in vacuo. The product was purified by column chromatog-
raphy (n-pentane/diethyl ether) to afford the coupling product as
an oil.
4.4. N-(2-(20-Fluorophenyl)-1-oxopropan-2-yl)-4-
methylbenzenesulfonamide 5a (Table 1, entry 1)
The product was synthesized following GP 1, using 0.152 g
(1.00 mmol) of 2-(20-fluorophenylphenyl)propanal, 0.423 g
(1.50 mmol) chloramine-T, 3 mg (0.02 mmol) L-proline, and 5 mL
acetonitrile. Flash chromatography on silica with n-pentane/
diethyl ether 2:1 delivered 0.223 g (0.70 mmol, 70%) of a colorless
solid. Rf = 0.12 (n-pentane/diethyl ether 2:1). Mp = 138 °C. 1H NMR
00
(400 MHz, CDCl3): d = 1.85 (s, 3H, CCH3), 2.24 (s, 3H, C4 TsCH3), 6.00
(br s, 1H, NH), 6.44 (dd, J = 11.3, 7.9 Hz, 1H, 30-H), 6.89 (d, J = 8.0 Hz,
2H, 300-HTs, 500-HTs), 7.07–7.13 (m, 2H, 40-H, 50-H), 7.16 (d, J = 8.1 Hz,
2H, 200-HTs, 600-HTs), 7.42 (d, J = 7.8 Hz, 1H, 60-H), 9.11 (s, 1H, CHO)
00
ppm. 13C NMR (100 MHz, CDCl3): d = 20.5 (CCH3), 21.4 (C4 TsCH3),
66.4 (CCH3), 115.6 (d, J = 21.7 Hz, C-30), 121.6 (d, 3J = 11.3 Hz, C-
40), 124.5 (d, J = 2.9 Hz, C-50), 126.5 (CTs-200, CTs-600), 128.9 (CTs-300,
4.2. 4-Deutero-4-(2-methoxy-1-methylvinyl)-benzene 3
C
Ts-500), 129.57 (d, J = 3.1 Hz, C-60), 131.28 (d, J = 8.8 Hz, C-10),
Under argon, 90 mg (40 mmol) of magnesium and 20 mL of dry
THF were placed together in a column fixed with a reflux con-
denser and a magnetic stir bar. To activate magnesium, five drops
of dibromoethane were added and the mixture was quickly heated
with the heat gun. Then 1130 mg (5.0 mmol) of 1-bromo-4-(1-
methoxyprop-1-en-2-yl)-benzene was added and the reaction
mixture was stirred at rt for three hours. After this time 1.01 mL
D2O was added and after three more hours of stirring at rt the reac-
tion mixture was filtered over Celite and the solvent was removed
in vacuo. Flash chromatography on silica with n-pentane/diethyl
ether 40:1 delivered 669 mg (4.45 mmol, 89%) of a mixture of E/
Z-isomers (E/Z 1.48:1, determined by integration of the methyl sig-
nals) a colorless oil. Rf = 0.32 (n-pentane/diethyl ether 40:1). 1H
NMR (400 MHz, CDCl3): d = 2.02, 2.10 (d, J = 1.4 Hz, 3H, CH3),
3.75, 3.80 (s, 3H, OCH3), 6.21, 6.51 (q, J = 1.4 Hz, 1H, CHvinyl),
7.39–7.43 (m, 4H) ppm. 13C NMR (125 MHz, CDCl3): d = 12.6, 18.3
(CCH3), 59.9, 60.1 (OCH3), 110.9, 114.5 (CCH3), 127.1, 127.8 (C-30,
C-50), 125.0, 128.2 (C-20, C-60), 132.1 (t, J = 17.5 Hz, C-40), 138.4
(C-10), 140.7 (CHOCH3), 144.6, 145.2 (CHOCH3) ppm. IR (KBr):
vꢁ1 = 3027 (w), 2932 (w), 2833 (w), 1654 (m), 1595 (w), 1493
(w), 1458 (w), 1409 (w), 1223 (m), 1135 (m), 1113 (w), 1010
(w), 982 (vw), 860 (w) cmꢁ1. MS (EI, 70 eV): m/z (%): 149 (100)
[M+], 134 (18) [C9H8DO+], 196 (85) [C8H7D+], 78 (17) [C8H7D+].
HRMS (C10H11DO): calcd: 149.0951, found: 149.0956.
138.1 (CTs-100), 142.5 (CTs-400), 160.3 (d, J = 249.6 Hz, C-20), 193.4
(CHO) ppm. 19F NMR (400 MHz, CDCl3): d = ꢁ111.9 ppm. IR (KBr):
vꢁ1 = 3259 (m), 3070 (w), 2984 (w), 2835 (w), 1742 (m), 1599
(w), 1487 (w), 1445 (w), 1365 (w), 1328 (m), 1164 (m), 816 (w),
765 (m), 706 (w) cmꢁ1. FAB-MS: m/z (%) = 322 (90) [M+H+], 292
(100) [M+–CHO], 172 (87) [C7H8NO2S+], 154 (98) ½C7H7SO2þꢂ, 136
(75) [C8H8FN+] HRMS (C16H17FNO3S): calcd: 322.0913, found:
322.0916. Anal. Calcd for C16H16FNO3S (321.08 g/mol): C, 59.80;
H, 5.02; N, 4.36; S, 9.98. Found: C, 58.96; H, 4.88; N, 4.78; S, 10.04.
4.5. N-(2-(30-Fluorophenyl)-1-oxopropan-2-yl)-4-methylben 5b
(Table 1, entry 2)
The product was synthesized following GP 1, using 0.152 g
(1.00 mmol) of 2-(30-fluorophenyl)propanal, 0.423 g (1.50 mmol)
chloramine-T, 0.003 g (0.02 mmol)
L-proline, and 5 mL acetonitrile.
Flash chromatography on silica with n-pentane/diethyl ether 2:1
delivered 0.189 g (0.62 mmol, 62%) of
a
colorless solid.
Mp = 101 °C. Rf = 0.12 (n-pentane/diethyl ether 2:1). 1H NMR
00
(400 MHz, CDCl3): d = 1.86 (s, 3H, CCH3), 2.35 (s, 3H, C4 TsCH3),
6.05 (br s, 1H, NH), 6.76–6.79 (m, 1H, 40-H), 6.89–6.95 (m, 2H, 50-
H, 60-H), 7.08 (d, J = 8.0 Hz, 2H, 200-HTs, 600-HTs), 7.17 (dt, J = 8.1,
5.9 Hz, 1H, 20-H), 7.38 (d, J = 8.1 Hz, 2H, 300-HTs, 500-HTs), 9.11 (s,
1H, CHO) ppm. 13C NMR (100 MHz, CDCl3): d = 20.0 (CCH3), 21.3
00
(C4 TsCH3), 66.4 (CCH3), 114.8 (d, J = 22.8 Hz, C-40), 115.6 (d,
4.3. 2-(40-Deuterophenyl)propanal 4f
J = 22.0 Hz, C-20), 126.6 (CTs-200, CTs-600), 123.1 (C-60), 129.2 (CTs-300,
C
Ts-500), 129.4 (C-10), 130.3 (d, J = 8.3 Hz, C-50), 138.8 (CTs-100),
A solution of 639 mg (4.20 mmol) 4-deutero-4-(2-methoxy-1-
methylvinyl)-benzene in 80 mL acetone/water 4:1 was treated
with 4.6 mL aq HBr at 0 °C. The reaction mixture was stirred for
24 h and the procedure was repeated, until no further change of
product/starting material ratio could be seen by TLC. The aqueous
phase was neutralized with satd NaHCO3 and then extracted with
dichloromethane. The organic phase was dried over MgSO4 and the
solvent was removed under reduced pressure. Flash chromatogra-
143.1 (CTs-400), 162.8 (d, J = 247.7 Hz, C-30), 193.7 (CHO) ppm. 19F
NMR (400 MHz, CDCl3): d = ꢁ111.3 ppm. IR (KBr): vꢁ1 = 3274 (m),
3067 (w), 2985 (w), 2867 (w), 2710 (vw), 1731 (s), 1612 (m),
1592 (s), 1489 (s), 1384 (s), 1329 (s), 1161 (vs), 1093 (s), 964
(m), 815 (m), 787 (m), 739 (w), 696 (w) cmꢁ1. FAB-MS: m/z (%):
322 (36) [M+H+], 292 (51) [M+–CHO], 172 (55) [C7H8NO2S+], 155
(63) ½C7H7SO2þꢂ, 136 (100) [C8H8FN+], 107 (34) [C7H4F+], 91 (59)
½C7H7þꢂ, 77 (29) ½C6H4þꢂ. HRMS (C16H17FNO3S): calcd: 322.0913,

1346
C. E. Hartmann et al. / Tetrahedron: Asymmetry 21 (2010) 1341–1349
found: 322.0916. Anal. Calcd for C16H16FNO3S (321.08 g/mol): C,
59.80; H, 5.02; N, 4.36; S, 9.98. Found: C, 59.38; H, 5.34; N, 4.03;
S, 9.39.
2H, CHPh), 7.09–7.19 (m, 3H, CHPh), 7.28 (d, J = 8.2 Hz, 2H, 200-HTs
,
600-HTs), 9.06 (s, 1H, CHO) ppm. 13C NMR (100 MHz, CDCl3):
0
d = 19.8–20.0 (m, CD3), 21.4 (C4 TsCH3), 66.7 (CCD3), 126.6 (C-40),
127.5 (CTs-200, CTs-600), 128.6 (C-20, C-60), 128.8 (C-30, C-50), 129.2
(CTs-300, CTs-500), 134.1 (C-10), 139.1 (CTs-100), 142.8 (CTs-400), 194.4
(CHO) ppm. IR (KBr): vꢁ1 = 3254 (m), 3069 (w), 2951 (w), 2843
(w), 2727 (w), 1732 (m), 1599 (w), 1583 (w), 1495 (m), 1449
(m), 1405 (m), 1378 (w), 1329 (m), 1167 (m), 818 (m), 764 (m)
cmꢁ1. FAB-MS: m/z (%): 277 (100) [M+], 155 (48) ½C7H7SO2þꢂ, 91
(74) ½C7H7þꢂ. HRMS (C16H14D3NO3S): calcd: 307.1195, found:
307.1191. Anal. Calcd for C16H15D3NO3S (306.11 g/mol): C, 62.72;
H, 6.58; N, 4.57; S, 10.47. Found: C, 62.35; H, 5.69; N, 4.93; S,
10.42.
4.6. 4-Methyl-N-(1-oxo-2-(3-(trifluoromethyl)phenyl)propan-2-
yl)benzenesulfonamide 5d (Table 1, entry 4)
The product was synthesized following GP 1, using 0.202 g
(1.00 mmol) of 2-(30-trifluoromethy)propanal, 0.423 g (1.50 mmol)
chloramine-T, 0.003 g (0.02 mmol) L-proline, and 5 mL acetonitrile.
Flash chromatography on silica with n-pentane/diethyl ether 2:1
delivered 0.269 g (0.73 mmol, 73%) of a colorless solid. Rf = 0.10
(n-pentane/diethyl ether 2:1). 1H NMR (400 MHz, CDCl3): d = 1.88
00
(s, 3H, CCH3), 2.25 (s, 3H, C4 TsCH3), 6.04 (br s, 1H, NH), 6.96 (d,
J = 8.0 Hz, 2H, 300-HTs, 500-HTs), 7.14 (s, 1H, 20-H), 7.23 (d, J = 8.3 Hz,
4.9. Diethyl (R)-1-(2-(20-fluorophenyl)-1-oxopropan-2-yl)hydra-
1,2-dicarboxylate 9a (Table 2, entry 3)
2H, 200-HTs
,
600-HTs), 7.30 (d, J = 7.7 Hz, 1H, 50-H), 7.36 (d,
3
J = 8.0 Hz, 1H, 40-H), 7.40 (d, J = 7.7 Hz, 1H, 60-H), 9.05 (s, 1H,
CHO) ppm. 13C NMR (100 MHz, CDCl3): d = 20.2 (CCH3), 21.3
The product was synthesized following GP 2, using 0.152 g
00
(C4 TsCH3), 66.4 (CCH3), 124.5 (C-40), 126.9 (C-30), 126.4 (CTs-200,
(1.00 mmol) of 2-(20-fluorophenyl)propanal, 0.261 g (1.50 mmol)
C
Ts-600), 129.3 (C-50), 129.4 (CTs-300, CTs-500), 131.1 (q, J = 32.7 Hz, C-
diethyl azodicarboxylate, 0.058 g (0.50 mmol) L-proline, and 5 mL
acetonitrile. Flash chromatography on silica with n-pentane/
diethyl ether 2:1 delivered 0.124 g (0.38 mmol, 38%) of a colorless
40), 135.1 (C-10), 138.6 (CTs-100), 143.3 (CTs-400), 193.7 (CHO) ppm.
IR (KBr): vꢁ1 = 3239 (m), 3067 (w), 2978 (w), 2844 (w), 2730 (w),
1738 (m), 1598 (m), 1496 (m), 1441 (m), 1402 (m), 1330 (s),
oil in 69% ee. Rf = 0.16 (n-pentane/diethyl ether 2:1). [
a]
D = ꢁ3.0 (c
1148 (m), 1093 (m), 1072 (m), 878 (m), 811 (m), 704 (m) cmꢁ1
.
2.9, CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.16–1.33 (m, 6H,
OCH2CH3), 1.84 (s, 3H, CCH3), 4.19 (q, J = 7.1 Hz, 4H, OCH2CH3),
6.70 (br s, 1H, NH rotamers), 7.05–7.44 (m, 4H, 30-H, 40-H, 50-H,
60-H), 9.80, 9.93 (2 ꢀ s, 1H, CHO rotamers) ppm. 13C NMR
(100 MHz, CDCl3): d = 14.1, 14.4 (OCH2CH3), 18.5 (CCH3), 62.3,
63.2 (OCH2CH3), 77.1 (CCH3), 116.0 (d, J = 23.4 Hz, C-30), 116.4 (d,
J = 23.0 Hz, C-10), 124.7 (C-50), 129.0 (d, J = 22.1 Hz, C-40), 130.4
(d, J = 8.4 Hz, C-60), 156.0 (q, NCO2), 160.4 (d, J = 247.0 Hz, C-20),
194.1 (CHO) ppm. 19F NMR (376 MHz, CDCl3): d = ꢁ115.47 ppm.
IR (KBr): vꢁ1 = 3301 (m), 2984 (m), 1734 (s), 1613 (w), 1582 (w),
1489 (m), 1448 (m), 1379 (s), 1341 (s), 1244 (s), 1176 (m), 1096
(m), 1065 (s), 925 (vw), 819 (w), 762 (m) cmꢁ1. FAB-MS: m/z
(%) = 297 (26) [M+–CHO], 225 (100) ½C11H15FN2O2þꢂ, 210 (29)
½C11H13FNO2þꢂ, 179 (54), 176 (41), 136 (55) [C9H8F+], 123 (93),
104 (91) ½C8H8þꢂ. HRMS (C15H20FN2O5): calcd: 327.1356, found:
327.1353. Anal. Calcd for C15H19FN2O5 (326.13 g/mol): C, 55.21;
H, 5.87; N, 8.58. Found: C, 54.21; H, 5.85; N, 8.83.
FAB-MS: m/z (%): 372 (35) [M+], 342 (100) [M+–CHO], 239 (52),
188 (49), 172 (93) ½C9H7F3þꢂ, 155 (74) ½C7H7SO2þꢂ, 139 (27), 91
(82) ½C7H7þꢂ. HRMS (C17H17F3NO3S): calcd: 372.0881, found:
372.0883. Anal. Calcd C17H16F3NO3S (371.08 g/mol): C, 54.98; H,
4.34; N, 3.77; S, 8.63. Found: C, 54.47; H, 4.43; N, 4.02; S, 8.24.
4.7. N-(2-(4-Deuterophenyl)-1-oxopropan-2-yl)-4-
methylbenzene 5f (Table 1, entry 6)
The product was synthesized following GP 1, using 0.125 g
(0.93 mmol) of 2-(40-deuterophenyl)propanal, 0.391 g (1.40 mmol)
chloramine-T, 0.003 g (0.02 mmol)
L-proline, and 5 mL acetonitrile.
Flash chromatography on silica with n-pentane/diethyl ether 1:1
delivered 0.242 g (0.80 mmol, 86%) of
a
colorless solid.
Mp = 105 °C. Rf = 0.25 (n-pentane/diethyl ether 1:1). 1H NMR
0
(400 MHz, CDCl3): d = 1.88 (s, 3H, CCH3), 2.34 (s, 3H, C4 TsCH3),
5.98 (br s, 1H, NH), 7.05 (d, J = 7.9 Hz, 2H, 300-HTs, 500-HTs), 7.11 (d,
J = 8.4 Hz, 2H, 20-H, 60-H), 7.18 (d, J = 8.4 Hz, 2H, 30-H, 50-H), 7.35
(d, J = 8.4 Hz, 2H, 200-HTs, 600-HTs), 9.13 (s, 1H, CHO) ppm. 13C NMR
4.10. Diethyl (R)-1-(2-(30-fluorophenyl)-1-oxopropan-2-yl)
hydra-1,2-dicarboxylate 9b (Table 2, entry 4)
0
(100 MHz, CDCl3): d = 19.6 (CH3), 21.4 (C4 TsCH3), 66.8 (CCH3),
126.6 (C-40), 127.5 (C-30, C-50), 128.7 (CTs-200, CTs-600), 129.2 (C-20,
C-60), 129.5 (CTs-300, CTs-500), 134.1 (C-10), 139.1 (CTs-100), 142.8
(CTs-400), 194.3 (CHO) ppm. IR (KBr): vꢁ1 = 3253 (m), 3068 (w),
2975 (w), 2842 (w), 2722 (w), 1743 (m), 1599 (w), 1495 (w),
1403 (m), 1365 (m), 1328 (m), 1160 (m), 902 (m), 817 (m), 707
The product was synthesized following GP 2, using 0.152 mg
(1.00 mmol) of 2-(30-fluorophenyl)propanal, 0.261 g (1.50 mmol)
diethyl azodicarboxylate, 0.058 g (0.50 mmol) L-proline, and 5 mL
acetonitrile. Flash chromatography on silica with n-pentane/
diethyl ether 2:1 delivered 0.250 g (0.77 mmol, 77%) of a colorless
ꢁ
(m) cmꢁ1. FAB-MS: m/z (%): 305 (36) [M+H+], 275 (100) [M+
CHO], 239 (50), 172 (55) [C7H8NO2S+], 155 (42) ½C7H7SO2þꢂ, 91
(33) ½C7H7þꢂ. HRMS (C16H17DNO3S): calcd: 305.1070, found:
305.1066. Anal. Calcd for C16H16DNO3S (304.10 g/mol): C, 63.13;
H, 5.96; N, 4.60; S, 10.53. Found: C, 62.42; H, 5.89; N, 4.81; S, 10.33.
oil in 87% ee. Rf = 0.13 (n-pentane/diethyl ether 2:1). [
a
]
D = ꢁ5.0 (c
4.4, CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.14–1.33 (m, 6H,
OCH2CH3), 1.83 (s, 3H, CCH3), 4.18 (q, J = 7.1 Hz, 4H, OCH2CH3),
6.59 (br s, 1H, NH rotamers), 7.03–7.43 (m, 4H, 20-H, 40-H, 50-H,
60-H), 9.78, 9.92 (2 ꢀ d, 3J = 6.8, 2.9 Hz, 1H, CHO rotamers) ppm.
13C NMR (100 MHz, CDCl3): d = 14.1, 14.4 (OCH2CH3), 18.5
(CCH3), 62.3, 63.2 (OCH2CH3), 77.1 (q, CCH3), 116.3 (C-20, C-40),
124.7 (C-50, C-60), 129.5 (q, C-10), 156.0 (q, NCO2), 160.4 (d,
J = 246.5 Hz, C-30), 194.1 (CHO) ppm. 19F NMR (376 MHz, CDCl3):
4.8. N-(2-Phenyl-1-oxo-2-trideutero-propan-2-yl)-4-methyl 5g
(Table 1, entry 7)
The product was synthesized following GP 1, using 0.085 g
d = ꢁ112.52 ppm. IR (KBr): vꢁ1 = 3302 (m,
v[NH]), 2984 (m,
(0.62 mmol) of
a,a
,a-trideutero-2-phenylpropanal, 0.262 g
v
[CH3]), 1734 (s, v[CO]), 1613 (w), 1582 (w), 1489 (s), 1448 (s),
(0.93 mmol) chloramine-T, 0.002 g (0.01 mmol)
L-proline, and
1378 (s), 1341 (s), 1244 (s), 1176 (m), 1096 (m), 1065 (s), 924
(w), 819 (w), 762 (s) cmꢁ1. MS (EI, 70 eV): m/z (%): 297 (31) [M+–
CHO], 225 (100) ½C11H15FN2O2þꢂ, 210 (16) ½C11H13FNO2þꢂ, 179
(47), 176 (25), 136 (32) [C9H8F+], 123 (28). HRMS (C15H20FN2O5):
calcd: 327.1356, found: 327.1353.
5 mL acetonitrile. Flash chromatography on silica with n-pen-
tane/diethyl ether 2:1 delivered 0.140 g (0.46 mmol, 74%) of a col-
orless solid. Mp = 112 °C. Rf = 0.17 (n-pentane/diethyl ether 2:1).
0
1H NMR (400 MHz, CDCl3): d = 2.27 (s, 3H, C4 TsCH3), 5.93 (br s,
1H, NH), 6.98 (d, J = 8.2 Hz, 2H, 300-HTs, 500-HTs), 7.05 (d, J = 7.6 Hz,

C. E. Hartmann et al. / Tetrahedron: Asymmetry 21 (2010) 1341–1349
1347
4.11. Diethyl (R)-1-(1-oxo-2-(3-(trifluoromethyl)phenyl)
propan-2-yl)hydrazine-1,2-dicarboxylate 9d (Table 2, entry 6)
(w), 2985 (w), 2937 (w), 1735 (m), 1602 (vw), 1584 (vw), 1449
(w), 1408 (w), 1340 (m), 1241 (w), 1187 (w), 1095 (w), 1060 (w),
928 (w), 866 (w), 762 (w) cmꢁ1. FAB-MS: m/z (%) = 312 (100)
[M+H+], 282 (24) [M+–CHO], 210 (22) ½C10H8D3N2O3þꢂ, 154 (31),
137 (50) [C9H6D3O+]. HRMS (C15H18D3N2O5): calcd: 312.1639,
found: 312.1642.
The product was synthesized following GP 3, using 0.202 g
(1.00 mmol) of 2-(30-trifluoromethylphenyl)propanal, 0.261 g
(1.50 mmol) diethyl azodicarboxylate, 0.058 g (0.50 mmol) L-pro-
line, and 5 mL acetonitrile. Flash chromatography on silica with
n-pentane/diethyl ether 1:1 delivered 0.243 g (0.65 mmol, 65%)
of a colorless oil in 72% ee. Rf = 0.20 (n-pentane/diethyl ether
4.14. Diethyl (R)-1-(2-(4-bromophenyl)-1-methoxy-1-
oxopropan-2-yl)hydrazine-1,2-dicarboxylate 10
1:1). [
a
]D = +31.6 (c 1.2, CHCl3). HPLC (Chiralcel OD, n-heptane/iso-
propanol 70:30, 0.5 mL/min): Rt(maj)
=
10.1 min, Rt(min)
=
The product was synthesized following GP 4, using 5.20 g
(13.47 mmol) of diethyl 1-(1-oxo-2-(4-bromophenyl)propan-2-
yl)hydrazine-1,2-dicarboxylate. Flash chromatography on silica
with n-pentane/diethyl ether 5:1 delivered 4.68 g (11.26 mmol,
84%) of a colorless oil. Rf = 0.32 (n-pentane/diethyl ether 5:1).
12.2 min. 1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 7.1 Hz, 6H,
OCH2CH3), 1.73 (s, 3H, CCH3), 4.14 (q, J = 7.1 Hz, 4H, OCH2CH3),
6.89, 7.01 (2 ꢀ br s, 1H, NH rotamers), 7.45–7.61 (m, 4H, 20-H, 40-
H, 50-H, 60-H), 9.61, 9.69 (2 ꢀ s, 1H, CHO rotamers) ppm. 13C NMR
(100 MHz, CDCl3): d = 14.0, 14.2 (OCH2CH3), 18.8 (CCH3), 62.2,
62.5 (OCH2CH3), 72.6 (CCH3), 123.9 (q, 1J = 275.0 Hz, CF3), 123.4
(C-40), 124.87 (C-50), 124.90 (C-20), 129.3 (C-60), 131.1 (q,
2J = 32.4 Hz, C-30), 138.6 (C-10), 156.0, 156.9 (NCO2), 194.3 (CHO)
ppm. IR (KBr): vꢁ1 = 3301 (m), 2987 (w), 1736 (s), 1515 (m),
1446 (m), 1406 (m), 1330 (s), 1241 (m), 1169 (m), 1127 (m),
1072 (m), 923 (w), 805 (w), 766 (w) cmꢁ1. MS (EI, 70 eV): m/z
(%): 347 (14) [M+–CHO], 303 (16), 275 (100) ½C12H14F3N2O2þꢂ, 215
(31), 188 (19) [C9H9F3N+], 173 (44) ½C9H8F3þꢂ, 145 (37) ½C7H4F3þꢂ,
104 (87) ½C8H7þꢂ. HRMS (C16H20F3N2O5): calcd: 377.1324, found:
377.1328.
[a
]
D = ꢁ53.4 (c 1.75, CHCl3) 1H NMR (400 MHz, CDCl3): d = 1.14
(t, J = 7.1 Hz, 3H, OCH2CH3), 1.23 (t, J = 7.1 Hz, 3H, OCH2CH3),
1.64, 1.97 (2 ꢀ br s, 3H, CCH3 rotamers), 3.64 (s, 3H, OCH3), 3.89–
3.99 (m, 2H, OCH2CH3), 4.05–4.17 (m, 2H, OCH2CH3), 6.20, 6.54
3
(2 ꢀ br s, 1H, NH rotamers), 7.33 (d, J = 8.4 Hz, 2H, 20-H, 60-H),
7.36 (d, 3J = 8.7 Hz, 2H, 30-H, 50-H) ppm. 13C NMR (100 MHz, CDCl3):
d = 14.35, 14.44 (CH2CH3), 21.8 (CCH3), 52.9 (OCH3), 62.1, 62.9
(OCH2CH3), 70.5 (CCH3), 122.6 (C-40), 128.2 (C-20, C-60), 131.0 (C-
30, C-50), 137.1 (C-10), 157.0, 155.9 (NCO2), 172.2 (COOCH3) ppm.
IR (KBr): vꢁ1 = 3305 (m), 2985 (m), 2910 (w), 1744 (m), 1492
(m), 1400 (m), 1376 (m), 1242 (m), 1062 (m), 1010 (m), 916 (w),
829 (w), 764 (w) cmꢁ1. FAB-MS: m/z (%) = 417 (48) [M+1], 241
(97) ½C10H10BrO4þꢂ, 177 (100) ½C6H11N2O4þꢂ. HRMS (C16H22BrN2O6):
calcd: 417.0661, found: 417.0665. Anal. Calcd for C16H21BrN2O6
(416.06 g/mol): C, 46.06; H, 5.07; N, 6.71. Found: C, 45.64; H,
5.50; N, 6.97.
4.12. Diethyl (R)-1-(1-oxo-2-(4-deuterophenyl)propan-2-
yl)hydrazine-1,2-dicarboxylate 9f (Table 2, entry 8)16
The product was synthesized following GP 2, using 0.154 g
(1.14 mmol) of 2-(40-deuteromethylphenyl)propanal, 0.298 g
(1.71 mmol) diethyl azodicarboxylate, 0.066 g (0.75 mmol)
L-pro-
4.15. Diethyl (R)-1-(2-(biphenyl-4-yl)-1-methoxy-1-oxopropan-
line, and 5 mL acetonitrile to afford 0.240 g (0.77 mmol, 68%) of a
colorless oil. 1H NMR (400 MHz, CDCl3): d = 1.26 (t, J = 7.1 Hz, 6H,
OCH2CH3), 1.75 (s, 3H, CCH3), 4.16 (q, J = 7.1 Hz, 4H, OCH2CH3),
6.93 (br s, 1H, NH), 7.25–7.52 (m, 4H, 20-H, 30-H, 50-H, 60-H), 9.55,
9.70 (2 ꢀ s, 1H, CHO rotamers) ppm. 13C NMR (100 MHz, CDCl3):
d = 14.1, 14.4 (OCH2CH3), 17.6 (CCH3), 62.3, 63.2 (OCH2CH3), 73.2
(CCH3), 124.7 (C-20, C-60), 126.9–128.8 (C-30, C-50), 136.7 (C-10),
156.6 (NCO2R), 193.1 (CHO) ppm. IR (KBr): vꢁ1 = 3302 (m), 2985
(m), 1733 (vs), 1513 (m), 1493 (m), 1410 (m), 1378 (s), 1241 (s),
2-yl)hydrazine-1,2-dicarboxylate 11a (Table 3, entry 1–3)
The product was synthesized following GP 5, using 0.208 g
(0.50 mmol) of a diethyl 1-(2-(4-bromophenyl)-1-methoxy-1-oxo-
propan-2-yl)hydrazine-1,2-dicarboxylate and 0.092 g (0.75 mmol)
phenyl boronic acid. Flash chromatography on silica with n-pen-
tane/diethyl ether 1:1 delivered 0.176 g (0.42 mmol, 82%) of a col-
orless oil. Rf = 0.17 (n-pentane/diethyl ether 1:1). [
a
]D = ꢁ56.8 (c
6.4, CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.02 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.17 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.76, 2.08 (2 ꢀ br s,
3H, CCH3 rotamers), 3.68, 3.73 (2 ꢀ br s, 3H, OCH3 rotamers),
3.89–3.90 (m, 2H, OCH2CH3), 4.07–4.17 (m, 2H, OCH2CH3), 6.41,
6.72 (2 ꢀ br s, 1H, NH rotamers), 7.23–7.28 (m, 1H, CHar), 7.31–
7.36 (m, 2H, CHar), 7.44–7.51 (m, 6H, CHar) ppm. 13C NMR
(100 MHz, CDCl3): d = 14.37, 14.43 (CH2CH3), 21.9 (CCH3), 52.8,
52.9 (OCH3), 61.9, 62.2 (OCH2CH3), 70.6, 70.9 (CCH3), 126.5 (C-30,
C-50), 127.1 (C-200, C-600), 127.9 (C-400), 128.7 (C-20, C-60), 128.9 (C-
300, C-500), 136.9 (C-40), 140.2 (C-100), 141.1 (C-10), 155.9, 156.1
(NCO2), 172.4, 172.6 (q, COCH3) ppm. IR (KBr): vꢁ1 = 3309 (m),
2983 (m), 1723 (s), 1517 (m), 1488 (m), 1447 (m), 1402 (m),
1376 (m), 1336 (m), 1238 (m), 1097 (m), 1063 (m), 1008 (m),
842 (w), 763 (w) cmꢁ1. FAB-MS: m/z (%) = 415 (25) [M+H+], 239
(100) ½C16H15O2þꢂ, 179 (21) ½C14H12þꢂ, 154 (12) ½C12H9þꢂ. HRMS
(C22H26N2O6): calcd: 415.1869, found: 415.1866.
1185 (m), 1065 (m), 1028 (m), 925 (w), 858 (w), 766 (m) cmꢁ1
.
FAB-MS: m/z (%) = 310 (100) [M+H+], 280 (18) [M+ꢁCHO], 208
(18) ½C10H8DN2O3þꢂ, 177 (32) ½C9H7DN2O2þꢂ, 154 (25). HRMS
(C15H20DN2O5): calcd: 310.1513, found: 310.1517. Anal. Calcd for
C15H19DN2O5 (309.14 g/mol): C, 58.24; H, 6.84; N, 9.06. Found: C,
57.33; H, 6.48; N, 9.13.
4.13. Diethyl (R)-1-(1-oxo-2-trideuteromethyl-2-phenyl)
propan-2-yl)hydrazine-1,2-dicarboxylate 9g (Table 2, entry 9)
The product was synthesized following GP 2, using 0.137 g
(1.00 mmol) of
(1.50 mmol) diethyl azodicarboxylate, 0.058 g (0.50 mmol)
a
,
a
,
a
-trideutero-2-phenylpropanal, 0.261 g
-pro-
L
line, and 5 mL acetonitrile. Flash chromatography on silica with
n-pentane/diethyl ether 2:1 delivered 0.290 g (0.93 mmol, 88%)
of
a
colorless solid. Rf = 0.08 (n-pentane/diethyl ether 2:1).
[
a
]
D = +11.2 (c 4.8, MeOH). 1H NMR (400 MHz, CDCl3): d = 1.30 (t,
4.16. Diethyl (R)-1-(2-(40-fluorobiphenyl-4-yl)-1-methoxy-1-
J = 7.2 Hz, 6H, OCH2CH3), 4.16 (q, J = 7.1 Hz, 4H, OCH2CH3), 6.71,
6.80 (2 ꢀ br s, 1H, NH, rotamers), 7.28–7.37 (m, 5H, 20-H, 30-H,
40-H, 50-H, 60-H), 9.58, 9.73 (2 ꢀ s, 1H, CHO rotamers) ppm. 13C
NMR (100 MHz, CDCl3): d = 14.2, 14.4 (OCH2CH3), 14.1–14.35 (m,
CCD3), 14.35, 15.2 (OCH2CH3, rotamers), 62.2, 64.2 (OCH2CH3),
73.1 (CCD3), 126.9 (C-20), 128.2 (C-40), 129.0 (C-30), 136.8 (C-10),
156.5 (NCO2), 192.9 (CHO) ppm. IR (KBr): vꢁ1 = 3300 (w), 3060
oxopropan-2-yl)hydrazine-1,2-dicarboxylate 11b (Table 3, entry
4)
The product was synthesized following GP 5, using 0.208 g
(0.50 mmol) of diethyl 1-(2-(4-bromophenyl)-1-methoxy-1-oxo-
propan-2-yl)hydrazine-1,2-dicarboxylate and 0.105 g (0.75 mmol)
4-fluorophenyl boronic acid. Flash chromatography on silica with

1348
C. E. Hartmann et al. / Tetrahedron: Asymmetry 21 (2010) 1341–1349
n-pentane/diethyl ether 1:1 delivered 0.190 g (0.44 mmol, 88%) of
62.9 (OCH2CH3, rotamers), 70.6 (CCH3), 121.2 (J = 142.1 Hz, C-100),
128.3 (C-30, C-50), 129.3 (C-10), 130.9 (C-20, C-60), 131.5 (C-40),
140.6–141.0 (m, CarF), 155.9 (m, CarF), 156.0 (m, Car-F), 156.1
(NCO2), 157.0 (NCO2), 172.1 (COCH3) ppm. 19F NMR (376 MHz,
CDCl3): d = ꢁ143.2, ꢁ155.0, ꢁ160.2 ppm. IR (KBr): vꢁ1 = 3311 (m),
2984 (m), 2955 (m), 1724 (m), 1572 (w), 1512 (m), 1467 (m),
1378 (m), 1237 (m), 1063 (m), 1010 (w), 869 (w), 830 (w), 764
(w) cmꢁ1. FAB-MS: m/z (%) = 505 (7) [M+H+], 417 (63), 241 (96),
177 (100). HRMS (C22H22F5N2O6): calcd: 505.1401, found:
505.1398.
a
[a]
light yellow oil. Rf = 0.14 (n-pentane/diethyl ether 1:1).
D = ꢁ54.5 (c 1.50, MeOH) 1H NMR (400 MHz, CDCl3): d = 1.02
(t, J = 7.1 Hz, 3H, OCH2CH3), 1.17 (t, J = 7.1 Hz, 3H, OCH2CH3),
1.75, 2.06 (s, 3H, CCH3 rotamers), 3.68, 3.73 (s, 3H, OCH3, rotamers),
3.88–4.00 (m, 2H, OCH2CH3), 4.01–4.20 (m, 2H, OCH2CH3), 6.44,
6.76 (2 ꢀ br s, 1H, NH rotamers), 6.99–7.04 (m, 2H, CHar), 7.40–
7.46 (m, 4H, CHar), 7.67–7.79 (m, 2H, CHar) ppm. 13C NMR
(100 MHz, CDCl3): d = 14.4, 14.5 (OCH2CH3 rotamers), 21.8 (C-
CH3), 52.8, 52.9 (s, OCH3, rotamers), 61.9, 62.1 (s, OCH2CH3, rota-
mers), 62.7, 62.8 (s, OCH2CH3, rotamers), 79.8 (C-CH3), 114.5 (d,
J = 21.4 Hz, C-300), 114.7 (d, J = 21.4 Hz, C-500), 125.4 (C-30, C-50),
126.0 (C-20, C-60) 127.6 (d, J = 8.0 Hz, C-200, C-600), 135.1 -135.9 (m,
C-100), 137.8 (C-40), 139.0 (C-10), 155.9, 157.0 (s, NCO2, rotamers),
162.8 (C-400), 171.4 (d, COCH3) ppm. 19F-NMR (376 MHz, CDCl3):
d = ꢁ114.3 ppm. IR (KBr): vꢁ1 = 3310 (w), 2983 (w), 1736 (m),
1497 (m), 1400 (w), 1376 (m), 1336 (m), 1238 (m), 1160 (w),
4.19. Diethyl (R)-1-(1-methoxy-1-oxo-2-(40-
(trifluoromethyl)biphenyl-4-yl)propan-2-yl)hydrazine-1,2-
dicarboxylate 11e (Table 3, entry 7)
The product was synthesized following GP 5, using 0.208 g
(0.50 mmol) of diethyl 1-(2-(4-bromophenyl)-1-methoxy-1-oxo-
propan-2-yl)hydrazine-1,2-dicarboxylate and 0.143 g (0.75 mmol)
4-trifluoromethylphenyl boronic acid. Flash chromatography on
silica with n-pentane/diethyl ether 1:1 delivered 0.163 g
(0.34 mmol, 69%) of a light yellow oil. Rf = 0.16 (n-pentane/diethyl
1063 (w), 1007 (w), 826 (w), 763 (w) cmꢁ1
. FAB-MS: m/z
(%) = 433 (4) [M+H+], 258 (17), 257 (100) ½C16H14FO2þꢂ, 197 (18)
[C14H11F+]. HRMS (C22H26FN2O6): calcd: 433.1775, found:
433.1772.
ether 1:1). [
a]
D = ꢁ46.2 (c 7.0, CHCl3). 1H NMR (400 MHz, CDCl3):
4.17. Diethyl (R)-1-(1-methoxy-1-oxo-2-(30,40,50-
trifluorobiphenyl-4-yl)propan-2-yl)hydrazine-1,2-
dicarboxylate 11c (Table 3, entry 5)
d = 1.10 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.21–1.33 (m, 3H, OCH2CH3),
1.82, 2.14 (s, 3H, CCH3, rotamers), 3.77, 3.82 (s, 3H, OCH3, rota-
mers), 3.97–4.09 (m, 2H, OCH2CH3), 4.14–4.32 (m, 2H, OCH2CH3),
6.49, 6.80 (2 ꢀ br s, 1H, NH rotamers), 7.41–7.46 (m, 2H, 30-H, 50-
H), 7.6 (d, J = 8.7 Hz, 2H, 200-H, 600-H), 7.67 (s, 2H, 20-H, 60-H), 7.91
(d, J = 7.8 Hz, 2H, 300-H, 500-H) ppm. 13C NMR (100 MHz, CDCl3):
d = 14.0, 14.3 (OCH2CH3 rotamers), 21.8 (CCH3), 52.7, 52.9 (s,
OCH3, rotamers), 61.8, 62.1 (s, OCH2CH3, rotamers), 62.7, 62.8 (s,
OCH2CH3, rotamers), 70.6 (CCH3), 122.9 (q, J = 271.8 Hz, CF3),
125.7, 125.8 (q, J = 3.7 Hz, C-300, C-500), 127.1, 127.3 (C-30, C-50),
128.1, 128.3 (C-200, C-600), 129.6 (q, J = 32.7 Hz, CCF3), 130.9, 131.5
(C-20, C-60), 138.1, 138.3 (C-40), 139.6 (C-10), 143.8 (C-100), 156.0
(NCO2), 157.1 (NCO2), 172.2 (COCH3) ppm. 19F NMR (376 MHz,
CDCl3): d = ꢁ62.35 ppm. IR (KBr): vꢁ1 = 3309 (m), 2986 (m), 1741
(m), 1500 (m), 1400 (m), 1377 (m), 1242 (m), 1070 (m), 1008
(m), 859 (m), 828 (m), 764 (m) cmꢁ1. FAB-MS: m/z (%) = 483 (17)
[M+H+], 307 (100) ½C17H14F3O2þꢂ. HRMS (C23H26F3N2O6): calcd:
483.1742, found: 483.1741.
The product was synthesized following GP 5, using 0.208 g
(0.50 mmol) of diethyl 1-(2-(4-bromophenyl)-1-methoxy-1-oxo-
propan-2-yl)hydrazine-1,2-dicarboxylate and 0.132 g (0.75 mmol)
2,3,4-trifluorophenyl boronic acid. Flash chromatography on silica
with n-pentane/diethyl ether 1:1 delivered 0.143 g (0.31 mmol,
61%) of a light yellow oil. Rf = 0.14 (n-pentane/diethyl ether 1:1).
[a
]
D = ꢁ41.9 (c 7.0, MeOH). 1H NMR (400 MHz, CDCl3): d = 1.06 (t,
J = 7.0 Hz, 3H, OCH2CH3), 1.18–1.27 (m, 3H, OCH2CH3), 1.74, 2.06
(s, 3H, CCH3, rotamers), 3.71, 3.77 (s, 3H, OCH3, rotamers), 3.90–
4.04 (m, 2H, OCH2CH3), 4.11–4.26 (m, 2H, OCH2CH3), 6.25, 6.38
(2 ꢀ br s, 1H, NH rotamers), 7.11 (ddd, J = 6.8 Hz, 2H, 200-H, 600-H),
7.38–7.84 (m, 4H, 20-H, 30-H, 50-H, 60-H) ppm. 13C NMR (100 MHz,
CDCl3): d = 14.1, 14.4 (OCH2CH3, rotamers), 22.0 (CCH3), 52.9,
53.0 (s, OCH3, rotamers), 62.2, 62.9 (OCH2CH3, rotamers), 70.7
(CCH3), 110.8–111.2 (m, C-200, C-600), 126.3 (C-30, C-50), 127.2 (C-
20, C-60), 128.1 (C-100), 136.4–137.0 (m, C-40), 136.9 (C-10), 150.1–
150.3 (m, C-400), 152.6 (m, C-300), 155.9–156.0 (m, C-500), 157.0
(NCO2), 171.4 (COCH3) ppm. 19F NMR (376 MHz, CDCl3):
d = ꢁ133.55, ꢁ161.75 ppm. IR (KBr): vꢁ1 = 3313 (w), 2986 (w),
1742 (m), 1536 (m), 1509 (m), 1443 (w), 1376 (m), 1247 (m),
4.20. Diethyl (R)-1-(1-methoxy-1-oxo-2-(20,30,40,50,60-
pentadeuterobiphenyl-4-yl)propan-2-yl)hydrazine-1,2-
dicarboxylate 11f (Table 3, entry 8)
The product was synthesized following GP 5, using 0.208 g
(0.50 mmol) of diethyl 1-(2-(4-bromophenyl)-1-methoxy-1-oxo-
propan-2-yl)hydrazine-1,2-dicarboxylate and 0.960 g (0.75 mmol)
phenyl-d5 boronic acid. Flash chromatography on silica with n-
pentane/diethyl ether 1:1 delivered 0.170 g (0.41 mmol, 81%) of a
light yellow oil. Rf = 0.17 (n-pentane/diethyl ether 1:1).
1108 (w), 1049 (m), 1018 (w), 865 (w), 834 (w), 767 (w) cmꢁ1
.
FAB-MS: m/z (%) = 469 (13) [M+H+], 293 (100) ½C16H12F3O2þꢂ. HRMS
(C22H24F3N2O6): calc.: 469.1587, found: 469.1593.
4.18. Diethyl (R)-1-(1-methoxy-1-oxo-2-(20,30,40,50,60-penta-4-
yl)propan-2-yl)hydrazine-1,2-di 11d (Table 3, entry 6)
[a]
D = ꢁ54.1 (c 4.2, MeOH) 1H NMR (400 MHz, CDCl3): d = 1.22–
1.29 (m, 6H, OCH2CH3), 2.03, 2.16 (s, 3H, CCH3, rotamers), 3.76,
3.82 (s, 3H, OCH3, rotamers), 3.97–4.28 (m, 4H, OCH2CH3), 6.48,
6.80 (2 ꢀ br s, 1H, NH rotamers), 7.48–7.87 (m, 4H, 20-H, 30-H, 50-
H, 60-H) ppm. 13C NMR (100 MHz, CDCl3): d = 14.1, 14.4 (OCH2CH3,
rotamers), 21.0, 21.8 (CCH3, rotamers), 52.8, 52.9 (s, OCH3, rota-
mers), 61.8, 62.7 (OCH2CH3, rotamers), 62.1, 62.8 (OCH2CH3, rota-
mers), 70.7 (CCH3), 126.5 (C-30, C-50), 127.9 (C-20, C-60), 128.1–
128.6 (C-200, C-300, C-400, C-500, C-600), 136.9 (C-40), 140.0 (C-100),
141.0 (C-10), 156.0 (NCO2), 156.7 (NCO2), 171.8 (COCH3) ppm. IR
(KBr): vꢁ1 = 3309 (m), 2983 (m), 2910 (w), 1740 (s), 1611 (w),
1514 (m), 1402 (m), 1376 (w), 1336 (m), 1174 (m), 1064 (m),
849 (m), 762 (m) cmꢁ1. FAB-MS: m/z (%) = 420 (18) [M+H+], 244
(100) [C15H8D5N2O+]. HRMS (C22H22D5N2O6): calcd: 420.2183,
found: 420.2185.
The product was synthesized following GP 5, using 0.208 g
(0.50 mmol) of diethyl 1-(2-(4-bromophenyl)-1-methoxy-1-oxo-
propan-2-yl)hydrazine-1,2-dicarboxylate and 0.159 g (0.75 mmol)
pentafluorophenyl boronic acid. Flash chromatography on silica
with n-pentane/diethyl ether 1:1 delivered 0.174 g (0.35 mmol,
69%) of a light yellow oil. Rf = 0.20 (n-pentane/diethyl ether 1:1).
[a
]
D = ꢁ100.0 (c 2.45, CHCl3). 1H NMR (400 MHz, CDCl3):
d = 1.18–1.31 (m, 6H, OCH2CH3), 1.98, 2.04 (s, 3H, CCH3, rotamers),
3.71, 3.77 (s, 3H, OCH3, rotamers), 3.95–4.06 (m, 2H, OCH2CH3),
4.11–4.24 (m, 2H, OCH2CH3), 6.50, 6.80 (2 ꢀ br s, 1H, NH rotamers),
7.30–7.80 (m, 4H, 20-H, 30-H, 50-H, 60-H) ppm. 13C NMR (100 MHz,
CDCl3): d = 14.1, 14.4 (OCH2CH3, rotamers), 21.7 (CCH3), 52.9,
53.0 (s, OCH3, rotamers), 61.9, 62.1 (OCH2CH3, rotamers), 62.8,

C. E. Hartmann et al. / Tetrahedron: Asymmetry 21 (2010) 1341–1349
1349
11. Olsen, J. A.; Banner, D. W.; Seiler, P.; Obst Sander, U.; D’Arcy, A.; Stihle, M.;
Müller, K.; Diederich, F. Angew. Chem., Int. Ed. 2003, 42, 2507–2511.
12. Berkowitz, D. B.; Karukurichi, K. R.; de la Salud-Bea, R. L.; Nelson, D.; McCune,
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Acknowledgments
We wish to thank the Deutsche Forschungsgemeinschaft (DFG)
(SPP 1191), the Fonds der Chemischen Industrie and the Karlsruhe
House of Young Scientists (KHYS) from the Karlsruhe Institute of
Technology (grant to C.E.H.) for financial support. The microwave
was funded by the German Federal Excellence Initiative (FYS grant
to C.E.H.).
13. For fluorinated amino acids, several reviews have already been published: (a)
Tolman, V. Amino Acids 1996, 11, 15–36; (b) Kröger, S.; Haufe, G. Amino Acids
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15. For ortho-fluoro-substituted aromatic compounds: Makosza, M.; Surowiec, M.;
Szczepanska, A.; Sulikowski, D.; Maltsev, O. Synlett 2007, 470–474; for para-
substituted aromatic compounds: (a) Wang, M.-X.; Lin, S.-J.; Liu, J.; Zheng, Q.-Y.
Adv. Synth. Catal. 2004, 346, 439–445; (b) Cali, P.; Begtrup, M. Synthesis 2002,
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Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 5507–5510; (b) Halland, N.; Lie,
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