N -heteroarylation of chiral α-aminoesters by means of palladium-catalyzed buchwald-hartwig reaction

Article abstract of DOI:10.1021/jo4011427

N-Heteroaryl-α-amino acid derivatives are valuable pharmacological agents as peptidomimetics. Classical S_NAr methods using acid catalysis and elevated temperatures could not be extended to various α-amino acids and fairly electrophilic heterocyclic partners. Here, we report a mild and versatile method of N-heteroarylation of chiral α-aminoesters without racemization, involving Buchwald-Hartwig conditions. It could be extended to various α-amino acids and azines. This efficient N-heteroarylation leads to (i) a chemical library of putative peptidomimetics combining diverse azaheterocycles with the chiral α-aminoesters and their corresponding derivatives (amides, alcohols, etc.) and (ii) arginine derivatives designed as NPFF receptor ligands.

Full text of DOI:10.1021/jo4011427

Article
pubs.acs.org/joc
N‑Heteroarylation of Chiral α‑Aminoesters by Means of Palladium-
Catalyzed Buchwald−Hartwig Reaction
Hassan Hammoud, Martine Schmitt,* Emilie Blaise, Frederic Bihel, and Jean-Jacques Bourguignon
́
́
́ ́ ́
Laboratoire d’Innovation Therapeutique, UMR 7200, Faculte de Pharmacie, Universite de Strasbourg, 74, route du Rhin, BP 60024,
67401 Illkirch, France
S
* Supporting Information
ABSTRACT: N-Heteroaryl-α-amino acid derivatives are
valuable pharmacological agents as peptidomimetics. Classical
SNAr methods using acid catalysis and elevated temperatures
could not be extended to various α-amino acids and fairly
electrophilic heterocyclic partners. Here, we report a mild and
versatile method of N-heteroarylation of chiral α-aminoesters
without racemization, involving Buchwald−Hartwig conditions. It could be extended to various α-amino acids and azines. This
efficient N-heteroarylation leads to (i) a chemical library of putative peptidomimetics combining diverse azaheterocycles with the
chiral α-aminoesters and their corresponding derivatives (amides, alcohols, etc.) and (ii) arginine derivatives designed as NPFF
receptor ligands.
salt of the title α-aminoester was used systematically, we added
to the reaction medium increasing amounts of triethylamine to
obtain increasing amounts of α-aminoester as the free base. The
reaction was monitored by HPLC. The highly reactive glycine
ester was first used in the model reaction. The α-aminoester
was used in excess (2 equiv), since it is known that it may self-
condense and provide the corresponding diketopiperazine.4
After 2 h and without addition of triethylamine, we observed a
complete consummation of the starting 2-chloro-4-methylqui-
noline 1 (Figure 1).
INTRODUCTION
■
Synthesis of metabolically stable peptidomimetics constitutes
an efficient approach in drug design.1 The latter may result
from the replacement of a critical peptidic bond by an
heterocyclic amidine III. These compounds are prepared by
classical peptidic coupling reaction of the corresponding
carboxylic acid with different amines (or peptides). The critical
N-heteroaryl-α-aminoesters II generally result from amination
reaction of 2-chloroazines I with various chiral α-aminoesters
(Scheme 1).
Surprisingly, the reaction medium was composed of 50% of
the expected quinoline-2-yl glycinate 2a, and 50% of the
corresponding carboxylic acid identified by mass spectroscopy
and resulting from important H+ catalyzed hydrolysis of 2a
(detailed data shown in Supporting Information page S2). It
clearly shows the catalytic role played by H+ ions and their
ability to partially protonate the starting iminochloride and then
exacerbate its electrophilic character.5 The best experimental
conditions providing the expected α-aminoester 2a were found
with stoichiometric neutralization of the starting hydrochloride
salt of ethyl glycinate (2 equiv of both glycinate salt and
triethylamine), affording 2a in a satisfactory yield (∼70%) after
8 h reaction. With a large excess of triethylamine (glyOEt salt/
Et3N 2/4), the velocity of the reaction was dramatically
reduced, as evidenced by both disappearance of 1 and
formation of 2a. Figure 1 clearly demonstrates (i) an acid
catalytic effect for the amination reaction and (ii) an important
H+-catalyzed hydrolysis of α-amidinoester 2a into the
corresponding acid in the reaction medium.
In general, the preparation of these compounds requires
relatively drastic experimental conditions such as high reaction
temperatures, basic solvents (NMP, DMF, DMSO) and results
in low to fair yields. It is also proven or suspected to racemize,
when using an optically pure α-aminoester.2 However, if the
heterocyclic iminochloride is highly reactive (i.e., heterocycles
bearing electron-withdrawing groups such as nitro or cyano
groups, or electrophilic azines such as pyrimidines and
quinazolines), the reaction could be performed in protic
solvents in milder experimental conditions.3
Here we describe a method of N-heteroarylation of different
chiral α-aminoesters including Phe as a highly sterically
hindered representative. The 2-chloro-4-methylquinoline 1
was chosen as a reference for our study, and then the
methodology was extended to various azine systems.
RESULTS AND DISCUSSION
■
Before developing a palladium-catalyzed method, the scope and
the limitations of the classical SNAr amination reaction of the
quinoline 1 in thermic conditions were carefully checked. In
order to better estimate the different parameters of the
amination reaction, we first examined the reactivity of this
system in ethanol with various α-aminoesters by heating the
mixture in a sealed tube at 140 °C for 8 h. As the hydrochloride
In a second set of experiments, the influence of different α-
aminoesters on reactivity was checked (see Table 1). We were
Received: May 24, 2013
© XXXX American Chemical Society
A
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Scheme 1. Synthesis of N-Heteroaryl-α-aminoesters and Amides
Figure 1. Influence of acid catalysis in N-heteroarylation of α-aminoesters. [Solid lines indicate the disappearance of starting 2-chloroquinoline 1.
Dashed lines indicate the formation of quinoline-2-yl ethylglycinate 2a.]
copper iodide in presence of N-phenylhydrazone as catalyst and
K3PO4 as a base in DMF solution. The method was efficient
since it allowed N-arylation of various α-amino acids in good
yields. The critical need of iodoaromatics as starting reagents in
this reaction may limit the extension of the method to a large
variety of aromatics and heteroaromatics. We focused our
interest on palladium-catalyzed amination reactions, as largely
introduced by Buchwald and Hartwig.8 Recently, the
Buchwald−Hartwig reaction was used for N-arylation of α-
aminoesters by means of various chloro- and bromo-benzenes.9
The yields were satisfactory, but as the authors were using a
strong base such as sodium tert-butoxide or potassium
hydroxide, they observed important racemization of resulting
α-amino acid derivatives. It is noteworthy that the use of
cesium carbonate as a milder base gave no reaction in their
conditions. We decided to reinvestigate the palladium-catalyzed
reaction, by replacing aromatic by heteroaromatic systems. In
order to clearly prove the beneficial catalytic effect, we chose as
a model reaction the substitution of the already used 2-chloro-
4-methylquinoline 1 with the phenylalanine ethyl ester. It is
important to note that in this latter case, no reaction occurred
in thermic conditions (entry 5 in Table 1). A systematic
evaluation by HPLC (using caffeine as an internal standard) of
the ligand, catalyst, base, solvent and temperature parameters
was performed at different reaction times (2−8 h). Results are
summarized in Table 2. In general the use of Pd(OAc)2 as
catalyst in dioxane in presence of cesium carbonate was proved
to be efficient in Buchwald−Hartwig reactions.10 Different
ligands were used (entries 1−5), and the best results were
obtained with BINAP giving a yield of 86% (isolated product).
The use of other Pd-catalysts was less satisfactory (entries 6−
8). No reaction was observed with a milder base (entry 10).
The use of more (entry 11) or less (entries 12−14) basic
aprotic solvents was disappointing. Finally, the reaction velocity
was significantly reduced at 80 or 60 °C (entries 15−16).
Table 1. Influence of Steric Hindrance of Starting α-
Aminoesters in N-Heteroarylation Reactions
a
yield (%)
entry
no.
R
starting 1
2
1
2
3
4
5
2a
2b
2c
2d
2e
H
0
47
70
39
40
26
0
CH3
(CH2)2SMe
CH2CH(Me)2
CH2Ph
45
56
100
a
Isolated product.
able to observe a clear decrease in reactivity of α-aminoesters
bearing increasing steric hindrance (entries 2−5). In the case of
phenylalanine (entry 5), 100% of the starting iminochloride
could be recovered after 12 h of reaction, whereas moderately
hindered α-aminoesters (R = Me, (CH2)2-SMe) led to about
50% completion of the reaction giving the expected compounds
2b and 2c in 40% yield (entries 2 and 3). Finally, this method
using acid catalysis was proven to be efficient in the amination
reactions of 2-chloroquinoline 1 with only fairly hindered α-
aminoesters (glycine, alanine). However it was not satisfactory
for N-heteroarylation of phenylalanine, leucine and other
relatively bulky α-aminoesters.
We decided to explore alternative methods by replacing the
acid catalyst by other catalysts such as palladium, or copper.
These catalysts were particularly developed in the recent years
and applied to various fields of aromatic and heteroaromatic
chemistry.6 An Ullmann-type N-arylation of α-amino acids and
esters has been recently described.7 The authors were using
B
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Table 2. Optimization of N-Heteroarylation of Phenylalanine Ethylester with 2-Chloroquinoline 1
yield (%)
4 h
entry
catalyst
ligand
base
solvent
T °C
2 h
8 h
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd(PPh3)4
PdCl2
X-phos
S-phos
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
0
4
4
0
6
0
6
2
3
Davephos
Xantphos
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
4
4
a
4
68
−
−
60
64
4
−
−
−
−
5
a
5
86
6
54
56
0
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
5
9
10
0
10
11
12
13
14
15
16
Et3N
0
0
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
−
33
13
57
53
12
−
33
15
67
64
DCM
41
30
11
43
33
toluene
MeCN
dioxane
dioxane
60
a
Isolated product.
Using the optimized reaction conditions (Pd(OAc)2, BINAP,
Table 3. Extension of the Reaction to Other 2-Chloroazines
Cs2CO3, dioxane), we checked extension of the reaction to
other 2-chloroazines (Table 3). After a short reaction time (2
h), the reaction gave satisfactory yields (66−84% of expected
amidine 3−8) with electron-rich (entries 2, 3, 5) or electron-
deficient (entries 4, 6, 7) 2-chloroazines.
Moreover we examined the generalization of the reaction to
other α-aminoesters (Table 4). Besides the expected reaction
products 2, a second compound resulting from an additional N-
heteroarylation of quinoline-2-α-aminoesters 2 took place in a
significant manner with the less hindered glycinate (entry 1,
61% of 10a). Only 20% of 10b was observed with alanine, and
no side product was observed with the most hindered α-
aminoesters (entries 4−7). Our experimental conditions could
be successfully applied to N-heteroarylation of proline and
serine ethylesters, whereas no reaction occurred in the above-
discussed conditions.9
In order to avoid this side reaction observed with fairly
hindered α-aminoesters, the Buchwald−Hartwig reaction was
performed with their corresponding N-carbamates (examples
given with the most reactive glycine and alanine in Table 5).
With N-boc-α-aminoesters, the reaction gave satisfactory yields,
and subsequent deprotection of intermediates 11 with TFA was
nearly quantitative. 2a and 2b obtained from this method have
the same physical characteristics (1H and 13C NMR for 2a and
2b, and [α]D20 for 2b) as that found with the previous method.
The goal of this paper is to describe a methodology that can
be generalized to various heterocyclic iminochlorides, as well as
to all the α-aminoesters and with no racemization. We
systematically checked the optically active novel compounds
(2a−g, 3, 4, 5, 6, 7, 8, 14, 17) resulting from coupling different
pure α-aminoesters with various azines. Preparation of the
corresponding diastereomeric salts by means of S-Mosher acid
as a chiral solvating agent was particularly useful for our
a
Isolated product.
purposes.11 Comparison of H NMR spectra of both the pure
and racemic diastereomeric salts clearly showed the optical
1
C
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purity of our compounds (ee ≥ 99%), as illustrated in the
Supporting Information (pages S60−S78).
Table 4. Palladium-Catalyzed N-Heteroarylation of α-
Aminoesters with 1
A similar approach was used for phenylalanine derivatives 2−
8 suspected to be the α-amino acids most sensitive to
racemization. The method involves the preparation of the
diastereomeric esters 14 and 17, as illustrated in Scheme 2. We
synthesized for this purpose the optically pure S,S diaster-
eoisomer 14 by first preparing the optically pure S,S-Fmoc-Phe-
O-phenylethyl 13 and reacting it with 2-chloroquinoline. In a
similar manner the use of racemic phenylalanine yielded the
diastereomeric mixture 16, which was reacted with 1 to provide
the quinoline derivative 17 as a diastereomeric mixture.
Comparison of 1H NMR spectra of both compounds 14 and
17 (detailed in the Supporting Information page S79) clearly
showed the optical purity of 14 (ee ≥ 99%).
Both methods confirmed that N-heteroarylation of optically
pure α-aminoesters in experimental conditions as described in
this paper, fully conserved optical purity of the resulting N-
heteroaryl-α-aminoester derivatives.
This efficient methodology can be used for preparing
optically pure arginine derivatives as ligands of NPFF
receptors.12 The synthesis of the quinoline derivative 20 is
illustrated in Scheme 3. In particular, the highly sterically
hindered arginine amide 22 could be directly submitted to N-
heteroarylation with 1, and afforded the final compound 20 in a
good yield (73%, 2 steps).
Table 5. Efficient Use of N-Boc-α-aminoesters Derivatives of
Fairly Hindered α-Aminoesters
CONCLUSION
■
In summary, we described an efficient, versatile and non-
racemizing method of N-heteroarylation of diverse α-amino-
esters with various azines (pyridines, pyridazines, quinolines),
which might be extended to other heterocyclic iminochlorides
(azoles, azepines, etc). It is important to note that our method
is mild and conserves chirality of the most sensitive α-amino
acid esters such as phenylalanine. Therefore it constitutes a
valuable method for building original chiral chemical libraries
combining the domain of azaheterocycles (scaffolds) with that
of chiral α-aminoesters and corresponding derivatives (deco-
rations). These compounds may serve as intermediates leading
to the corresponding carboxylic acids, amides and alcohols of
great interest in medicinal chemistry (drug design, or in silico
screening of libraries of peptidomimetics).
a
yield (%)
entry
R
no.
11
no.
2
1
2
H
11a
11b
82
88
2a
2b
92
91
CH3
a
Isolated product.
Scheme 2. Preparation of Diastereomeric Esters of 2e
D
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Scheme 3. Synthesis of Quinoline-2-yl Arginine Derivative 20
(400 MHz, CDCl3, 25 °C) δ 7.29−7.23 (m, 5H), 7.22−7.11 (m, 3H),
7.00−6.97 (m, 2H), 5.87 (q, 1H, J = 6.8 Hz), 3.70−3.66 (m, 1H),
3.01−2.96 (m, 1H), 2.76−2.73 (m, 1H), 1.49−1.46 (m, 5H); 13C
NMR (100 MHz, CDCl3, 25 °C) δ 174.2, 141.2, 137.0, 129.3, 128.5,
128.4, 128.0, 126.7, 126.3, 73.0, 55.8, 40.9, 22.0; HRMS (ESI) calcd
for C17H20NO2 [M + H]+ 270.1488, found 270.1485.
EXPERIMENTAL SECTION
■
General Experimental Methods. All reactions were carried out
in flame-dried screw cap test tubes with magnetic stirring. Reactions
were run under an inert atmosphere of argon gas. Yields refer to
isolated compounds, estimated to be >97% pure as determined H
NMR, HPLC.
1
(S)-1-Phenylethyl 2-amino-3-phenylpropanoate 16. Follow-
ing the procedure of 13 starting from 15, the product was obtained by
silica gel chromatography (DCM/MeOH 95/5) to give 16 as yellow
1H NMR and 13C NMR were recorded at 400 and 100 MHz,
respectively, for CDCl3 solutions. Chemical shifts (δ) are reported in
parts per million (ppm) for 1H and for 13C NMR spectra. The
coupling constants, J, are reported in Hertz (Hz). TMS was used as
the internal reference. High-resolution mass spectra (HRMS) were
recorded on a QTOF mass analyzer with electrospray ionization (ESI,
Resolving Power 17000). Melting points (mp [°C]) were taken on
samples in open capillary tubes. Anhydrous solvents were supplied in
Sureseal bottles and were used as received avoiding further
purification.
1
oil (1 g, 94%): H NMR (400 MHz, CDCl3, 25 °C) δ 7.29−7.11 (m,
9H), 6.98 (d, 1H, J = 7.2 Hz), 5.87−5.78 (m, 1H), 3.70−3.64 (m,
1H), 3.03−2.96 (m, 1H), 2.88−2.71 (m, 1H), 1.49−1.39 (m, 5H); 13C
NMR (100 MHz, CDCl3, 25 °C) δ 174.4, 174.3, 141.3, 141.2, 137.3,
137.0, 129.4, 129.3, 128.5, 128.4, 128.0, 126.8, 126.7, 126.3, 126.2,
73.0, 73.0, 55.9, 55.8, 41.2, 40.8, 22.0, 22.0; HRMS (ESI) calcd for
C17H20NO2 [M + H]+ 270.1488, found 270.1485.
General Procedure for the Synthesis of α-Heteroarylami-
noesters (Method A). A 5 mL microwave tube was charged with 4-
methyl-2-chloroquinoline 1 (1 mmol), aminoester (2 mmol), Et3N (2
mmol) and EtOH (2 mL). The tube was sealed, and the mixture was
stirred at 140 °C for 12 h. The resulting solution was cooled to room
temperature. The ethanol was evaporated, and the crude residue was
purified by column chromatography using EtOAc/heptane (20−80 to
30−70) as eluent to give the expected product 2a−d.
General Procedure for the Synthesis of α-Heteroarylami-
noesters (Method B). Reactions were carried out under argon. As a
typical experiment, iminochloride (1.0 mmol, 1 equiv), amino acid
ethyl ester (1.00 mmol, 1 equiv), Cs2CO3 (3.0 mmol, 3 equiv), BINAP
(0.06 mmol, 0.06 equiv) and Pd(OAc)2 (0.03 mmol, 0.03 equiv) were
added to a flamed-dried microwaves tube in anhydrous dioxane (3
mL). The reaction mixture was nitrogen-flushed and then stirred at
100 °C for 3 h. Upon completion, the reaction mixture was cooled and
then evaporated to dryness. The residue was diluted in water and
extracted twice with EtOAc. The organic layers were combined, dried
over Na2SO4, and then evaporated. The residue was purified by flash
chromatography using EtOAc/heptane (20−80 to 60−40) as eluent to
afford pure products 2−8.
(S),(S)-1-Phenylethyl 2-((((9H-fluoren-9-yl)methoxy)-
carbonyl)amino)-3-phenylpropanoate 12. To a solution of
Fmoc-phenylalanine (2 g, 5.10 mmol) in dry DCM (15 mL) were
added DCC (5.10 mmol, 1 equiv) and DMAP (0.50 mmol, 0.1 equiv).
The reaction mixture was first stirred at 0 °C for 10 min, and then
(1S)-1-phenylethanol (5.10 mmol, 1 equiv) in DCM (10 mL) was
added dropwise. After 2 h of stirring at room temperature, the
resulting mixture was washed with water H2O (3 × 20 mL). The
organic layer was dried over Na2SO4, and the crude mixture was
purified by flash chromatography by using EtOAc/heptane (10−90 to
40−60) as eluent to give 12 as a white solid (2 g, 80%): [α]D
20
=
−78.5 (c 1.0, CHCl3); mp 154−156 °C; 1H NMR (400 MHz, CDCl3,
25 °C) δ 7.69 (d, 2H, J = 6.8 Hz), 7.47 (t, 2H, J = 6.8 Hz), 7.34−7.19
(m, 9H), 7.17−7.03 (m, 3H), 6.78 (d, 2H, J = 6.8 Hz), 5.89 (q, 1H, J =
5.6 Hz), 5.15 (d, 1H, J = 6.8 Hz), 4.65 (q, 1H, J = 5.6 Hz), 4.37−4.22
(m, 2H), 4.12 (t, 1H, J = 6.8 Hz), 3.06−2.90 (m, 2H), 1.50 (d, 3H, J =
6.8 Hz); 13C NMR (100 MHz, CDCl3, 25 °C) δ 170.7, 155.5, 143.9,
141.3, 140.6, 135.4, 129.4, 128.6, 128.4, 128.3, 127.7, 127.1, 126.5,
125.2, 125.1, 120.0, 73.9, 67.0, 54.7, 47.2, 38.0, 21.8; HRMS (ESI)
calcd for C32H29NO4Na [M + Na]+ 514.1991, found 514.1984.
(S)-1-Phenylethyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)-
amino)-3-phenylpropanoate 15. Following the procedure of 12
starting from L,D-phenylalanine, the product 15 was obtained as a
Ethyl 2-((4-methylquinolin-2-yl)amino)acetate 2a. Following
the general procedure for the synthesis of α-heteroarylaminoesters and
starting from 4-methyl-2-chloroquinoline and ethyl glycinate, 2a was
obtained as a white solid. Method A (170 mg, 70%), Method B (35
1
white solid (2.05 g, 82%): mp 153−155 °C; H NMR (400 MHz,
CDCl3, 25 °C) δ 7.69 (d, 2H, J = 7.0 Hz), 7.49 (t, 2H, J = 7.0 Hz),
7.34−7.17 (m, 11H), 7.08−7.06 (m, 2H), 6.76 (d, 1H, J = 7.0 Hz),
5.87−5.79 (m, 1H), 5.22−5.14 (m, 1H), 4.64−4.59 (m, 1H), 4.37−
4.22 (m, 2H), 4.13 (t, 1H, J = 7.0 Hz), 3.09−2.92 (m, 2H), 1.50−1.42
(m, 3H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 170.8, 170.6, 155.6,
155.5, 143.9, 143.8, 143.6, 141.3, 141.2, 129.5, 129.4, 128.6, 128.5,
128.4, 128.3, 128.1, 127.7, 127.7, 127.1, 127.0, 126.6, 126.1, 125.1,
125.0, 120.0, 119.9, 73.9, 73.8, 67.0, 66.9, 54.9, 54.7, 47.2, 47.2, 38.5,
38.0, 22.0, 21.8; HRMS (ESI) calcd for C32H29NO4Na [M + Na]+
514.1991, found 514.1997.
1
mg, 14%): mp 131−133 °C; H NMR (400 MHz, CDCl3, 25 °C) δ
7.68 (d, 1H, J = 8.2 Hz), 7.63 (d, 1H, J = 8.0 Hz), 7.44 (td, 1H, J = 7.6
Hz, J = 2.2 Hz), 7.17 (td, 1H, J = 7.8 Hz, J= 2.0 Hz), 6.46 (s, 1H), 5.14
(s, 1H), 4.25 (s, 2H), 4.18 (q, 2H, J = 7.20 Hz), 2.45 (s, 3H), 1.24 (t,
3H, J = 6.0 Hz); 13C NMR (100 MHz, CDCl3, 25 °C) δ 171.5, 155.6,
147.6, 145.2, 129.2, 126.9, 124.1, 123.6, 122.3, 112.2, 61.2, 43.4, 18.71,
14.3; HRMS (ESI) calcd for C14H17N2O2 [M + H]+ 245.1284, found
245.1285.
(S)-Ethyl 2-((4-methylquinolin-2-yl)amino)propanoate 2b.
Following the general procedure for the synthesis of α-heteroar-
ylaminoesters and starting from 4-methyl-2-chloroquinoline and ethyl
2-aminopropanoate, 2b was obtained as a white solid. Method A (100
mg, 39%), Method B (150 mg, 58%): [α]D20 = −23.4 (c 1.0, MeOH);
(S),(S)-1-Phenylethyl 2-amino-3-phenylpropanoate 13. A
solution of the protected aminoester 12 (2 g, 4.00 mmol) and DBU
(8.10 mmol, 2 equiv) was dissolved in DCM (30 mL). The resulting
mixture was stirred at room temperature for 2 h and then evaporated
to dryness. The crude product was purified by column chromatog-
raphy on silica gel by using DCM/MeOH (95/5) as eluent to give 13
1
mp 135−137 °C; H NMR (400 MHz, CDCl3, 25 °C) δ 7.69−7.59
(m, 2H), 7.43 (td, 1H, J = 8.3 Hz, J = 2.2 Hz), 7.16 (td, 1H, J = 8.3 Hz,
J = 2.2 Hz), 6.45 (s, 1H), 5.09 (bs, 1H), 4.81−4.77 (m, 1H), 4.19−
20
1
as yellow oil (1.04 g, 97%): [α]D = +9.7 (c 0.8, CHCl3); H NMR
E
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4.11 (m, 2H), 2.47 (s, 3H), 1.44 (d, 3H, J= 7.2 Hz), 1.19 (t, 3H, J= 7.2
Hz); 13C NMR (100 MHz, CDCl3, 25 °C) δ 174.9, 155.4, 147.8,
144.8, 129.1, 127.1, 124.1, 123.5, 122.1, 112.3, 61.1, 49.7, 29.7, 18.6,
18.6, 14.3; HRMS (ESI) calcd for C15H19N2O2 [M + H]+ 259.1441,
found 259.1440.
13C NMR (100 MHz, CDCl3, 25 °C) δ 174.3, 154.7, 148.1, 144.8,
129.03, 127.06, 123.5, 123.3, 121.5, 110.1, 60.6, 59.9, 47.2, 30.1, 24.4,
19.1, 14.3; HRMS (ESI) calcd for C17H21N2O2 [M + H]+ 285.1597,
found 285.1604.
Ethyl 2-(bis(4-methylquinolin-2-yl)amino)acetate 10a. Fol-
lowing the general procedure for the synthesis of α-heteroarylami-
noesters (Method B) and starting from 4-methyl-2-chloroquinoline
and ethyl glycinate, 10a was obtained as a white solid (120 mg, 61%):
mp 189−191 °C; 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.77 (d, 4H, J
= 8.2 Hz), 7.51 (td, 2H, J = 8.2 Hz, J= 2.2 Hz), 7.32 (td, 2H, J = 8.2
Hz, J = 2.2 Hz), 7.16 (s, 2H), 5.11 (s, 2H), 4.12 (q, 2H, J = 8.0 Hz),
2.51 (s, 6H), 1.68 (t, 3H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3,
25 °C) δ 171.2, 155.2, 147.5, 145.3, 129.43, 128.4, 125.5, 124.3, 123.6,
115.6, 60.8, 50.6, 19.1, 14.3; HRMS (ESI) calcd for C24H24N3O2 [M +
H]+ 386.1861, found 386.1859.
Ethyl 2-(bis(4-methylquinolin-2-yl)amino)propanoate 10b.
Following the general procedure for the synthesis of α-heteroar-
ylaminoesters (Method B) and starting from 4-methyl-2-chloroquino-
line and ethyl 2-aminopropanoate, 10b was obtained as a white solid
(75 mg, 19%): mp 197−199 °C; 1H NMR (400 MHz, CDCl3, 25 °C)
δ 7.93 (d, 4H, J = 7.6 Hz), 7.63 (td, 2H, J = 7.6 Hz, J = 2.2 Hz), 7.61
(td, 2H, J = 7.6 Hz, J = 2.2 Hz), 7.27 (s, 2H), 4.22 (q, 2H, J = 7.2 Hz),
3.67−3.59 (m, 1H), 2.61 (s, 6H), 1.27 (t, 3H, J = 7.2 Hz), 1.13 (d, 3H,
J = 8.4 Hz); 13C NMR (100 MHz, CDCl3, 25 °C) δ 171.4, 155.3,
147.6, 145.5, 129.5, 128.6, 125.7, 124.5, 123.7, 111.9, 60.9, 55.8, 50.7,
23.7, 16.9, 14.4; HRMS (ESI) calcd for C25H26N3O2 [M + H]+
400.2020, found 400.2026.
Ethyl 2-((tert-butoxycarbonyl)(4-methylquinolin-2-yl)-
amino)acetate 11a. Following the general procedure for the
synthesis of α-heteroarylaminoesters (Method B) and starting from
4-methyl-2-chloroquinoline and N-boc-ethyl glycinate, 11a was
obtained as a white solid (282 mg, 82%): mp 102−104 °C; 1H
NMR (400 MHz, CDCl3, 25 °C) δ 7.81−7.74 (m, 3H), 7.35 (td, 1H, J
= 8.2 Hz, J = 1.8 Hz), 7.17 (td, 1H, J = 8.2 Hz, J = 1.8 Hz), 4.77 (s,
2H), 4.14 (q, 2H, J = 7.2 Hz), 2.58 (s, 3H), 1.41 (s, 9H), 1.18 (t, 3H, J
= 7.2 Hz); 13C NMR (100 MHz, CDCl3, 25 °C) δ 170.2, 153.9, 152.9,
146.2, 145.0, 129.1, 128.8, 125.9, 125.1, 123.5, 118.1, 82.1, 60.9, 48.2,
28.2, 19.0, 14.3; HRMS (ESI) calcd for C19H25N2O4 [M + H]+
345.1809, found 345.1806.
(S)-Ethyl 2-((4-methylquinolin-2-yl)amino)-4-(methylthio)-
butanoate 2c. Following the general procedure for the synthesis of
α-heteroarylaminoesters and starting from 4-methyl-2-chloroquinoline
and ethyl 2-amino-4-(methylthio)butanoate, 2c was obtained as a
white solid. Method A (127 mg, 40%), Method B (232 mg, 73%):
20
1
[α]D = −6.5 (c 0.85, MeOH); mp 130−132 °C; H NMR (400
MHz, CDCl3, 25 °C) δ 7.69 (d, 1H, J = 8.4 Hz), 7.61 (d, 1H, J = 8.4
Hz), 7.45 (td, 1H, J = 8.4 Hz, J = 2.0 Hz), 7.19−7.15 (m, 1H), 6.47 (s,
1H), 5.16 (s, 1H), 4.95−4.94 (m, 1H), 4.17−4.14 (m, 2H), 2.59−2.54
(m, 2H), 2.46 (s, 3H), 2.30−2.21 (m, 1H), 2.09−2.02 (m, 4H), 1.23−
1.18 (m, 3H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 173.6, 155.4,
147.6, 145.0, 129.2, 127.1, 124.1, 123.5, 122.2, 112.3, 61.3, 53.2, 32.2,
30.3, 18.7, 15.6, 14.3; HRMS (ESI) calcd for C17H23N2O2S [M + H]+
319.1474, found 319.1469.
(S)-Ethyl 4-methyl-2-((4-methylquinolin-2-yl)amino)-
pentanoate 2d. Following the general procedure for the synthesis
of α-heteroarylaminoesters and starting from 4-methyl-2-chloroquino-
line and ethyl 2-amino-4-methylpentanoate, 2d was obtained as a
white solid. Method A (168 mg, 56%), Method B (210 mg, 70%):
20
1
[α]D = −49.4 (c 1.0, MeOH); mp 142−144 °C; H NMR (400
MHz, CDCl3, 25 °C) δ 7.68 (d, 1H, J = 8.4 Hz), 7.61 (d, 1H, J =8.4
Hz), 7.43 (td, 1H, J = 8.4 Hz, J = 2.2 Hz), 7.18 (td, 1H, J = 8.4 Hz, J =
2.2 Hz), 6.44 (s, 1H), 4.83−4.78 (m, 2H), 4.17−4.07 (m, 2H), 2.46 (s,
3H), 1.75−1.58 (m, 3H), 1.21 (t, 3H, J = 7.8 Hz), 1.01−0.91 (m, 6H);
13C NMR (100 MHz, CDCl3, 25 °C) δ 174.8, 155.7, 147.8, 144.8,
129.0, 127.1, 124.1, 123.5, 122.1, 112.2, 60.9, 52.6, 42.2, 25.1, 23.0,
22.3, 18.7, 14.3; HRMS (ESI) calcd for C18H25N2O2 [M + H]+
301.1909, found 301.1907.
(S)-Ethyl 2-((4-methylquinolin-2-yl)amino)-3-phenylpropa-
noate 2e. Following the general procedure for the synthesis of α-
heteroarylaminoesters and starting from 4-methyl-2-chloroquinoline
and ethyl 2-amino-3-phenylpropanoate, 2e was obtained as a white
20
solid. Method A (0%), Method B (287 mg, 86%): [α]D = −14.6 (c
0.8, MeOH); mp 115−117 °C; 1H NMR (400 MHz, CDCl3, 25 °C) δ
7.67−7.61 (m, 2H), 7.44 (td, 1H, J = 8.2 Hz, J = 1.8 Hz), 7.21−7.11
(m, 6H), 6.38 (s, 1H), 5.11−5.06 (m, 1H), 4.97 (s, 1H), 4.14−4.05
(m, 2H), 3.21 (qd, 2H, J = 8.2 Hz, J = 2.0 Hz), 2.42 (s, 3H), 1.15 (t,
3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3, 25 °C) δ 173.2, 155.1,
147.8, 144.9, 136.8, 129.5, 129.1, 128.4, 127.1, 126.8, 124.1, 123.5,
122.2, 112.4, 61.1, 54.9, 38.1, 18.7, 14.2; HRMS (ESI) calcd for
C21H23N2O2 [M + H]+ 335.1754, found 335.1753.
Ethyl 2-((tert-butoxycarbonyl)(4-methylquinolin-2-yl)-
amino)propanoate 11b. Following the general procedure for the
synthesis of α-heteroarylaminoesters (Method B) and starting from 4-
methyl-2-chloroquinoline and N-boc-ethyl 2-aminopropanoate, 11b
1
was obtained as a white solid (315 mg, 88%): mp 131−134 °C; H
NMR (400 MHz, CDCl3, 25 °C) δ 7.91−7.84 (m, 3H), 7.35 (td, 1H, J
= 7.2 Hz, J = 1.8 Hz), 7.17 (td, 1H, J = 7.2 Hz, J = 1.8 Hz), 4.24 (q,
2H, J = 7.2 Hz), 3.25−3.17 (m, 1H), 2.68 (s, 3H), 1.56 (s, 9H), 1.30
(t, 3H, J = 7.2 Hz), 1.09 (d, 3H, J = 8.0 Hz); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 171.9, 154.01, 153.0, 146.3, 145.2, 129.2, 128.9,
126.1, 125.3, 123.6, 115.5, 82.2, 67.8, 48.3, 36.9, 28.3, 19.2, 14.4;
HRMS (ESI) calcd for C20H27N2O4 [M + H]+ 359.1965, found
359.1966.
(S)-Ethyl 3-hydroxy-2-((4-methylquinolin-2-yl)amino)-
propanoate 2f. Following the general procedure for the synthesis
of α-heteroarylaminoesters and starting from 4-methyl-2-chloroquino-
line and ethyl 2-amino-3-hydroxypropanoate, 2f was obtained as a
20
brown solid. Method A (0%), Method B (142 mg, 52%): [α]D
=
+15.8 (c 1.0, MeOH); mp 111−115 °C; 1H NMR (400 MHz, CDCl3,
25 °C) δ 7.69 (dd, 1H, J = 7.2 Hz, J = 1.2 Hz), 7.58 (dd, 1H, J = 7.2
Hz, J = 1.2 Hz), 7.46 (td, 1H, J = 7.2 Hz, J = 1.2 Hz), 7.21−7.17 (m,
1H), 6.52 (s, 1H), 5.68 (s, 1H), 4.81 (t, 1H, J = 2.8 Hz), 4.23−4.15
(m, 3H), 3.85−3.81 (m, 1H), 2.46 (s, 3H), 1.35 (t, 3H, J = 2.0 Hz);
13C NMR (100 MHz, CDCl3, 25 °C) δ 171.3, 155.7, 146.5, 145.8,
(S)-Ethyl 3-phenyl-2-(pyridin-2-ylamino)propanoate 3. Fol-
lowing the general procedure for the synthesis of α-heteroarylami-
noesters (Method B) and starting from 2-chloropyridine and ethyl 2-
amino-3-phenylpropanoate, 3 was obtained as a white solid (189 mg,
70%): [α]D20 = −19.7 (c 1.0, MeOH); mp 89−91 °C; 1H NMR (400
MHz, CDCl3, 25 °C) δ 8.02 (dd, 1H, J = 5.0 Hz, J = 2.0 Hz), 7.31 (td,
1H, J = 8.5 Hz, J = 2.0 Hz), 7.22−7.09 (m, 5H), 6.53−6.51 (m, 1H),
6.33 (d, 1H, J = 8.5 Hz), 4.82−4.74 (m, 2H), 4.08 (q, 2H, J = 8.5 Hz),
3.14 (qd, 2H, J = 8.5 Hz, J = 5.6 Hz), 1.13 (t, 3H, J = 5.6 Hz); 13C
NMR (100 MHz, CDCl3, 25 °C) δ 173.1, 157.2, 147.9, 137.2, 136.6,
129.4, 128.5, 126.9, 113.6, 108.7, 61.1, 55.3, 38.3, 14.2; HRMS (ESI)
calcd for C16H19N2O2 [M + H]+ 271.1441, found 271.1446.
(S)-Ethyl 2-((6-methylpyridin-2-yl)amino)-3-phenylpropa-
noate 4. Following the general procedure for the synthesis of α-
heteroarylaminoesters (Method B) and starting from 6-methyl-2-
chloropyridine and ethyl 2-amino-3-phenylpropanoate, 4 was obtained
129.5, 126.2, 123.9, 123.5, 122.6, 112.6, 66.2, 62.01, 58.2, 18.7, 14.2;
HRMS (ESI) calcd for C15H19N2O3 [M + H]+ 275.1390, found
275.1394.
(S)-Ethyl 1-(4-methylquinolin-2-yl)pyrrolidine-2-carboxylate
2g. Following the general procedure for the synthesis of α-
heteroarylaminoesters and starting from 4-methyl-2-chloroquinoline
and ethyl pyrrolidine-2-carboxylate, 2f was obtained as a brown solid.
20
Method A (0%), Method B (207 mg, 73%): [α]D = +26.1 (c 0.9,
1
MeOH); mp 131−134 °C; H NMR (400 MHz, CDCl3, 25 °C) δ
7.65 (dd, 1H, J = 8.0 Hz, J = 1.2 Hz), 7.54 (d, 1H, J = 8.0 Hz), 7.41−
7.36 (m, 1H), 7.11−7.06 (m, 1H), 6.49 (s, 1H), 4.61−4.58 (m, 1H),
4.15−4.02 (m, 2H), 3.67−3.63 (m, 1H), 3.51−3.49 (m, 1H), 2.46 (s,
3H), 2.21−2.19 (m, 1H), 2.07−1.93 (m, 3H), 1.15 (t, 1H, J = 6.8 Hz);
20
as a white solid (221 mg, 78%): [α]D = −23.7 (c 1.0, MeOH); mp
1
98−100 °C; H NMR (400 MHz, CDCl3, 25 °C) δ 7.22−7.11 (m,
F
dx.doi.org/10.1021/jo4011427 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6H), 6.39 (d, 1H, J = 8.5 Hz), 6.13 (d, 1H, J = 8.5 Hz), 4.75−4.71 (m,
2H), 4.10−4.02 (m, 2H), 3.54−3.09 (m, 2H), 2.28 (s, 3H), 1.12 (t,
3H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3, 25 °C) δ 173.1, 156.7,
137.6, 136.7, 129.4, 128.4, 126.8, 112.8, 104.9, 60.9, 55.7, 38.4, 24.3,
14.2; HRMS (ESI) calcd for C17H21N2O2 [M + H]+ 285.1600, found
285.1605.
(S)-Ethyl 3-phenyl-2-(pyrimidin-2-ylamino)propanoate 5.
Following the general procedure for the synthesis of α-heteroar-
ylaminoesters (Method B) and starting from 2-chloropyrimidine and
ethyl 2-amino-3-phenylpropanoate, 5 was obtained as a pink solid
(192 mg, 71%): [α]D20 = −12.5 (c 1.0, MeOH); mp 103−105 °C; 1H
NMR (400 MHz, CDCl3, 25 °C) δ 8.21 (d, 2H, J = 8.0 Hz), 7.21−
7.11 (m, 5H), 6.49 (t, 1H, J = 4.0 Hz), 5.53 (d, 1H, J = 8.0 Hz), 4.87−
4.83 (m, 1H), 4.09 (q, 2H, J = 8.0 Hz), 3.13 (qd, 2H, J = 4.0 Hz, J =
8.2 Hz), 1.12 (t, 3H, J = 8.2 Hz); 13C NMR (100 MHz, CDCl3, 25 °C)
δ 172.3, 161.4, 158.0, 136.3, 129.4, 128.5, 126.9, 111.5, 61.2, 55.2, 38.2,
14.1; HRMS (ESI) calcd for C15H18N3O2 [M + H]+ 272.1393, found
272.1397.
(R,S)-(S)-1-Phenylethyl 2-((4-methylquinolin-2-yl)amino)-3-
phenylpropanoate 17. Following the general procedure for the
synthesis of α-heteroarylaminoesters (Method B) and starting from 4-
methyl-2-chloroquinoline and 16, 17 was obtained as a white solid
1
(233 mg, 57%): mp 105−107 °C; H NMR (400 MHz, CDCl3, 25
°C) δ 7.65−7.59 (m, 3H), 7.54−7.51 (m, 1H), 7.44−40 (m, 2H),
7.23−7.12 (m, 17H), 7.06−7.04 (m, 3H), 6.89−6.87 (m, 2H), 6.33 (s,
1H), 6.27 (s, 1H), 5.86−5.78 (m, 2H), 5.13−4.96 (m, 4H), 3.21−3.16
(m, 3H), 3.07−3.04 (m, 1H), 2.36 (s, 3H), 2.29 (s, 3H), 1.48 (d, 3H, J
= 6.8 Hz), 1.34 (d, 3H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3, 25
°C) δ 172.8, 172.6, 155.3, 155.2, 147.8, 147.7, 146.6, 144.9, 144.8,
141.3, 141.1, 136.9, 136.5, 129.6, 129.5, 129.2, 129.1, 128.8, 128.5,
128.4, 127.9, 127.8, 127.2, 126.8, 126.7, 126.5, 126.1, 125.3, 124.2,
124.1, 123.7, 123.5, 123.4, 122.2, 122.1, 114.7, 112.5, 112.4, 73.2, 73.1,
55.3, 55.0, 38.2, 37.8, 22.0, 21.9, 18.9, 18.6; HRMS (ESI) calcd for
C27H27N2O2 [M + H]+ 411.2067, found 411.2066.
General Procedure for N-Boc Deprotection of 11. Compound
11 (0.5 mmol) and trifluoroacetic acid (2 mL) were mixed in DCM (2
mL). After 1 h, TFA and DCM were evaporated, the crude sample was
washed with saturated aqueous NaHCO3 solution (20 mL), and the
product was extracted with ethyl acetate (3 × 15 mL). On drying with
sodium sulfate, the filtrate was evaporated to dryness to afford 2a or 2b
as white solids.
(S)-Ethyl 2-((6-methoxypyridin-2-yl)amino)-3-phenylpropa-
noate 6. Following the general procedure for the synthesis of α-
heteroarylaminoesters (Method B) and starting from 6-methoxy-2-
chloropyridine and ethyl 2-amino-3-phenylpropanoate, 6 was obtained
20
as a white solid (225 mg, 75%): [α]D = +38.9 (c 1.0, MeOH); mp
1
Ethyl 2-((4-methylquinolin-2-yl)amino)acetate 2a. Following
139−141 °C; H NMR (400 MHz, CDCl3, 25 °C) δ 7.24−7.09 (m,
the general procedure for N-Boc deprotection, 2a was obtained as a
6H), 5.97 (d, 1H, J = 7.8 Hz), 5.91 (d, 1H, J = 7.8 Hz), 4.77−4.65 (m,
3H), 4.08 (q, 2H, J = 7.8 Hz), 3.76 (s, 3H), 3.89−3.11 (m, 2H), 1.12
(t, 3H, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3, 25 °C) δ 173.2,
163.5, 156.1, 139.8, 136.7, 129.9, 128.5, 126.9, 99.7, 98.14, 60.9, 55.6,
53.1, 38.4, 14.2; HRMS (ESI) calcd for C17H21N2O3 [M + H]+
301.1547, found 301.1553.
1
white solid (91 mg, 75%): mp 130−133 °C; H NMR (400 MHz,
CDCl3, 25 °C) δ 7.69 (d, 1H, J = 8.0 Hz), 7.64 (d, 1H, J = 8.0 Hz),
7.45 (td, 1H, J = 7.6 Hz, J = 2.2 Hz), 7.19 (td, 1H, J = 7.6 Hz, J= 2.2
Hz), 6.46 (s, 1H), 5.68 (s, 1H), 4.26 (s, 2H), 4.18 (q, 2H, J = 7.2 Hz),
2.45 (s, 3H), 1.23 (t, 3H, J = 6.2 Hz).
(S)-Ethyl 2-((4-methylquinolin-2-yl)amino)propanoate 2b.
(S)-Ethyl 3-phenyl-2-((5-(trifluoromethyl)pyridin-2-yl)-
amino)propanoate 7. Following the general procedure for the
synthesis of α-heteroarylaminoesters (Method B) and starting from 5-
trifuloromethyl-2-chloropyridine and ethyl 2-amino-3-phenylpropa-
noate, 7 was obtained as a white solid (284 mg, 84%): [α]D20 = −31.3
Following the general procedure for N-Boc deprotection, 2b was
20
obtained as a white solid (103 mg, 80%): [α]D = −23.8 (c 1.0,
1
MeOH); mp 136−139 °C; H NMR (400 MHz, CDCl3, 25 °C) δ
7.65 (d, 1H, J = 8.0 Hz), 7.60 (d, 1H, J = 8.0 Hz), 7.44 (td, 1H, J = 8.0
Hz, J = 2.2 Hz), 7.13 (td, 1H, J = 8.0 Hz, J = 2.2 Hz), 6.40 (s, 1H),
5.08−5.10 (m, 1H), 4.88−4.76 (m, 1H), 4.09−4.18 (m, 2H), 2.40 (s,
3H), 1.46 (d, 3H, J= 7.0 Hz), 1.22 (t, 3H, J= 7.2 Hz).
1
(c 1.0, MeOH); mp 143−145 °C; H NMR (400 MHz, CDCl3, 25
°C) δ 8.25 (s, 1H), 7.45−7.41 (m, 1H), 7.21−7.12 (m, 3H), 7.06 (d,
1H, J = 7.8 Hz), 6.33−6.29 (m, 1H), 5.27−5.19 (m, 1H), 4.89−4.84
(m, 1H), 4.09 (q, 2H, J = 7.8 Hz), 3.63−3.14 (m, 2H), 1.16 (t, 3H, J =
7.8 Hz); 13C NMR (100 MHz, CDCl3, 25 °C) δ 172.6, 172.5, 158.9,
145.8, 145.8, 136.3, 134.1, 129.3, 128.5, 127.5, 125.8, 123.2, 120.5,
116.7, 116.4, 116.1, 115.7, 108.2, 61.4, 55.1, 38.0, 29.7, 14.1; HRMS
(ESI) calcd for C17H18F3N2O2 [M + H]+ 339.1305, found 339.1306.
(S)-Ethyl 3-phenyl-2-((6-phenylpyridazin-3-yl)amino)-
propanoate 8. Following the general procedure for the synthesis
of α-heteroarylaminoesters (Method B) and starting from 6-phenyl-3-
chloropyridazine and ethyl 2-amino-3-phenylpropanoate, 8 was
(S)-2-Amino-N-(pbf)-5-guanidino-N-phenethylpentanamide
22. BOP (4 mmol, 1.3 equiv) was added to a solution of Fmoc-L-Arg
(Pbf)-OH (3 mmol) and NMM (4 mmol, 1.3 equiv) in DCM (12
mL). The resulting mixture was then stirred at rt for 10 min, and after
this time, phenethylamine (4 mmol, 1.3 equiv) was added to the
solution. After 12 h at rt, the mixture was washed with a saturated
solution of NaHCO3 (20 mL), HCl 1 N (20 mL), and then H2O (20
mL). The organic phase was dried (Na2SO4) and filtered, and then the
solvent was removed under reduced pressure. The crude residue was
redissolved in anhydrous DCM (30 mL), and DBU (5.2 mmol, 2
equiv) was added. The final solution was stirred at rt until TLC
showed complete consumption of starting material (1 h). The solvent
was evaporated under a vacuum, and the residue was purified by
chromatography on silica gel (DCM, then DCM/MeOH 95/5) to give
20
obtained as a white solid (230 mg, 66%): [α]D = −165.7 (c 1.0,
1
MeOH); mp 253−255 °C; H NMR (400 MHz, CDCl3, 25 °C) δ
8.16 (d, 1H, J = 9.6 Hz), 7.81−7.79 (m, 2H), 7.56 (d, 1H, J = 9.6 Hz),
7.46−7.45 (m, 3H), 7.21−7.12 (m, 5H), 4.87−4.81 (m, 1H), 4.13 (q,
2H, J = 7.2 Hz), 3.28 (dd, 1H, J = 12.0 Hz, J = 4.0 Hz), 3.11 (dd, 1H, J
= 12.0 Hz, J = 8.0 Hz), 1.16 (t, 3H, J = 8.0 Hz); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 171.6, 156.4, 151.9, 137.5, 133.0, 132.9, 132.5, 130.5,
130.4, 129.7, 128.3, 128.0, 125.3, 63.1, 57.7, 38.6, 14.4; HRMS (ESI)
calcd for C21H22N3O2 [M + H]+ 348.1709, found 348.1715.
(S)-(S)-1-Phenylethyl 2-((4-methylquinolin-2-yl)amino)-3-
phenylpropanoate 14. Following the general procedure for the
synthesis of α-heteroarylaminoesters (Method B) and starting from 4-
methyl-2-chloroquinoline and 13, 14 was obtained as a white solid
(250 mg, 61%): [α]D20 = −15.5 (c 1.0, CHCl3); mp 111−113 °C; 1H
NMR (400 MHz, CDCl3, 25 °C) δ 8.03 (d, 1H, J = 8.2 Hz), 7.88 (d,
1H, J = 8.2 Hz), 7.69−7.60 (m, 3H), 7.47 (t, 2H, J = 7.6 Hz), 7.17−
7.04 (m, 7H), 6.53 (s, 1H), 5.97 (q, 1H, J = 7.6 Hz), 5.53 (s, 1H), 4.19
(t, 1H, J = 7.6 Hz), 3.45−3.40 (m, 1H), 3.25−3.20 (m, 1H), 2.42 (s,
1H), 1.48 (d, 3H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3, 25 °C) δ
171.5, 155.6, 147.4, 144.3, 138.0, 129.7, 129.5, 129.3, 129.0, 128.1,
127.4, 126.3, 125.9, 123.7, 123.6, 121.9, 121.1, 112.1, 58.3, 42.1, 29.8,
22.8, 18.8; HRMS (ESI) calcd for C27H27N2O2 [M + H]+ 411.2067,
found 411.2069.
20
the desired product as a white solid (1.22 g, 81%): [α]D = +3.9 (c
0.35, CHCl3); mp 89.2−91.3 °C; 1H NMR (400 MHz, CDCl3, 25 °C)
δ 7.40 (bs,1H), 7.18−7.06 (m, 5H), 6.23 (s, 3H), 3.42−3.35 (m, 3H),
3.08 (bs, 2H) 2.89−2.85 (m, 5H), 2.71 (t, 2H, J = 7.2 Hz), 2.48 (s,
3H), 2.41 (s, 3H), 2.00 (s, 3H), 1.63 (bs, 2H), 1.42−1.49 (m, 2H),
1.37 (s, 6H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 173.9, 169.1,
158.8, 156.6, 138.8, 138.2, 132.9, 132.2, 128.8, 128.7, 128.5, 126.4,
124.9, 117.6, 86.4, 60.8, 54.1, 43.3, 40.5, 35.6, 31.6, 28.6, 25.3, 19.3,
17.9, 12.5; HRMS (ESI) calcd for C27H40N5O4S [M + H]+ 530.2795,
found 530.2800.
(S)-2-(6-Chloro-4-methylquinolin-2-yl)amino)-5-guanidino-
N-phenethylpentanamide 20. Following the general procedure for
the synthesis of α-heteroarylaminoesters (Method B) and starting
from 6-chloro-4-methyl-2-chloroquinoline and 22, pbf derivatives were
obtained as a brown solid without further purification. This product
(0.5 mmol) and trifluoroacetic acid (3 mL) were mixed in DCM (3
mL). After 1 h, TFA and DCM were evaporated, and the crude sample
was purified by inverse flash chromatography using methanol 10−80%
G
dx.doi.org/10.1021/jo4011427 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
20
in water as eluent to give 20 as a white solid (331 mg, 73%): [α]D
=
Louw, J.; Vogel, G.; Webb, M.; Wijkmans, J.; You, M. Bioorg. Med.
Chem. Lett. 2006, 16, 2724.
1
+13.3 (c 0.8, CHCl3); mp 198.3−199.9 °C; H NMR (400 MHz,
CDCl3, 25 °C) δ 7.58 (d, 1H, J = 2.2 Hz), 7.48 (d, 1H, J = 7.4 Hz),
7.39 (dd, 1H, J = 7.4 Hz, J = 2.2 Hz), 7.12−7.07 (m, 4H), 7.04−7.00
(m, 1H), 6.94 (s, 1H), 3.92 (t, 1H, J = 6.8 Hz), 3.45−3.52 (m, 1H),
3.29−3.34 (m, 3H), 2.69−2.78 (m, 2H), 2.36 (s, 3H), 1.87−1.95 (m,
2H), 1.59−1.68 (m, 2H); 13C NMR (100 MHz, CDCl3, 25 °C) δ
172.7, 158.4, 155.7, 151.1, 146.6, 142.7, 134.5, 134.2, 132.6, 132.4,
132.0, 129.9, 129.6, 126.5, 118.2, 56.3, 44.6, 44.2, 38.9, 32.3, 26.9, 21.2;
HRMS (ESI) calcd for C24H30ClN6O [M + H]+ 453.2164, found
453.2165.
Use of S-Mosher Acid As a Chiral Solvation Agent.
Diastereomeric salts were prepared directly in an NMR tube by
mixing 10 mg of the α-aminoester derivatives with 1 equiv of a
standard solution of S-Mosher acid in CDCl3 or in MeOD. All salts
except for that of 8 were dissolved in CDCl3. Because of the low
solubility in CDCl3, the salt of 8 was dissolved in MeOD. Racemic and
enantiomerically pure compounds 2b−g and enantiomerically pure
compounds of phenylalanine derivatives 3−8 were used as a starting
material for syntheses of those salts.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Influence of acid catalysis, optical purity studies, H and 13C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
AUTHOR INFORMATION
Corresponding Author
*E-mail: mschmitt@unistra.fr.
■
(9) Ma, F.; Xie, X.; Ding, L.; Gao, J.; Zhang, Z. Tetrahedron 2011, 67,
9405.
(10) (a) Salome,
2012, 53, 1033. (b) Salome,
Tetrahedron Lett. 2009, 50, 3798.
́
C.; Schmitt, M.; Bourguignon, J. J. Tetrahedron Lett.
́
C.; Schmitt, M.; Bourguignon, J. J.
Notes
The authors declare no competing financial interest.
(11) (a) Navratilova, H. Chirality 2001, 13, 731. (b) Parker, D. Chem.
Rev. 1991, 91, 1441.
ACKNOWLEDGMENTS
This project was supported by the Alsace region (Reg
Alsace), the University of Strasbourg (UdS), and the National
Center of Scientific Research (CNRS). We thank Mr. Patrick
Wehrung for providing the high-resolution mass spectra.
■
(12) Simonin, F.; Schmitt, M.; Laulin, J. P.; Laboureyras, E.;
Jhamandas, J. H.; MacTavish, D.; Matifas, A.; Mollereau, C.; Laurent,
P.; Parmentier, M.; Kieffer, B. L.; Bourguignon, J. J.; Simonnet, G.
Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 466.
́
ion
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dx.doi.org/10.1021/jo4011427 | J. Org. Chem. XXXX, XXX, XXX−XXX