Palladium-catalyzed coupling reaction of amino acids (esters) with aryl bromides and chlorides

Article abstract of DOI:10.1016/j.tet.2011.09.109

The bulky and electron-rich MOP type ligands and Pd(dba)₂ combinations showed high efficiency for the coupling reactions of amino acids and inactive aryl halides to give N-aryl amino acids. Under the catalytic conditions, not only α-amino acids, but also β-, γ-, and δ-amino acids have been coupled with aryl chlorides in moderate to high yields; in the case of optically pure β-amino acids as substrates, the optical purities of the coupling products retained.

Full text of DOI:10.1016/j.tet.2011.09.109

Tetrahedron 67 (2011) 9405e9410
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed coupling reaction of amino acids (esters) with aryl bromides
and chlorides
,
b
b
a,c,
Fangfang Ma a, Xiaomin Xie a , Lina Ding , Jinsheng Gao , Zhaoguo Zhang
*
*
a School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
b School of Chemistry, Chemical Engineering & Materials, Heilongjiang University, 74 Xuefu Road, Harbin 150080, China
c Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 May 2011
Received in revised form 22 September 2011
Accepted 23 September 2011
Available online 29 September 2011
The bulky and electron-rich MOP type ligands and Pd(dba)2 combinations showed high efficiency for the
coupling reactions of amino acids and inactive aryl halides to give N-aryl amino acids. Under the catalytic
conditions, not only
a
-amino acids, but also
b
-,
g
-, and
d
-amino acids have been coupled with aryl
-amino acids as substrates, the optical
chlorides in moderate to high yields; in the case of optically pure
purities of the coupling products retained.
b
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Monophosphine ligand
Inactive aryl halide
Amino acid
1. Introduction
reaction of inactive aryl halides with amino acids or esters have
been published.30e32 Therefore, there is still a need to develop
a general and versatile catalyst for coupling inactivated aryl halides
with amino acids (esters).
The major problem encountered with the multi-functionalized
compounds as the substrates of the metal-catalyzed coupling re-
action is: the competitive coordination of the substrates with the
counter anion of the catalyst, which might cause deactivation of the
catalyst, such as in the palladium-catalyzed coupling reaction of
amides or malonates.33e36 Recent studies demonstrate that the
bulky and electron-rich ligands may contribute to carry out the
coupling reaction of the multi-functionalized compounds with in-
active aryl halides.33e36
Palladium-catalyzed cross-coupling reactions of aryl halides and
amines provide an invaluable entry toward the synthesis of a wide
range of compounds, such as, pharmaceutical and agrochemical
products, electronic materials, polymers, and liquid crystals.1e8
These compounds, especially pharmaceuticals and natural prod-
ucts, are always multi-functionalized complex molecules. There-
fore, much attention has also been directed to the seeking of
arylation of more complex amines as a more direct and economical
way.9e11 Among numerous functionalized amines, amino acids are
commercially available and are one of the best building blocks for
the synthesis of peptides, lactams, heterocycles, and physiologically
active substances.12,13 Furthermore, N-aryl amino acids are impor-
tant synthetic intermediates and structural components of medic-
inally molecules.14e20 As a result, amino acids or esters are very
attractive coupling partners for the transition metal-catalyzed
processes. The coupling with amino acids or esters with aryl ha-
lides can be conducted with catalytic amounts of copper, however,
the substrates are generally limited to aryl iodides or bromides and
We recently reported the synthesis of the bulkyand electron-rich
MOP type ligands and their applications in the palladium-catalyzed
arylation of amines and b
-dicarbonyl compounds.36,37 Herein, we
report the application of these ligands in the palladium-catalyzed
arylation of amino acids as functionalized amines.
- or b
-amino acids (esters).21e29 Of the aryl halides, aryl chlorides
2. Results and discussion
a
are generally the most attractive substrates for cross-coupling re-
actions because they are less expensive and more readily available.
Similarly, only a few reports on palladium-catalyzed the coupling
The coupling of PhBr with DL-alanine was chosen as the model
reaction to test the feasibility of palladium-catalyzed coupling re-
action of aryl halides and amino acids. The bidentate aryl phos-
phine ligands, BINAP and DPPF, which are fairly general and
efficient ligands for palladium-catalyzed reaction of PhBr and
amines,38,39 were ineffective in the arylation of the amino acids
* Corresponding authors. Tel./fax: þ86 021 5474 8925; e-mail addresses: xiao-
minxie@sjtu.edu.cn (X. Xie), zhaoguo@sjtu.edu.cn (Z. Zhang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.109

9406
F. Ma et al. / Tetrahedron 67 (2011) 9405e9410
(Table 1, entries 1 and 2). This might be ascribed to the coordination
of the central metal with the carboxyl group of amino acids, which
retained after the formation of PdeN bond, making the aryl-PdeN
complexes too stable to reductive elimination.40,41 Similar results
were also detected in other Pd-catalyzed coupling reactions of
multi-functionalized compounds. For example, in the arylation
12e15). With respect to its low price and easy handling, KOH was
employed as the base in further studies, and the reaction condition
in entry 11, Table 1, was chosen as the optimal reaction condition.
On the basis of these results, the scope of Pd(dba)2/L1 catalyzed
amination of aryl halides with DL-alanine was explored, and the
results were summarized in Table 2. Reactions of aryl chlorides
possessing an electron-withdrawing group, such as trifluoromethyl
or carboxyl group, with amino acids occurred in high yields (entries
1e3). Even with the electron-rich aryl halides (chloride or bromide)
(entries 4e14), coupling reactions occurred in moderate to excel-
lent yields. The coupling reaction of 4-methyl-chlorobenzene was
conducted with 82% yield. In the case of 4-bromoanisole as sub-
strate, the desired product was obtained in 93% yield after re-
crystallization (entry 10). Noticeably, the coupling product was too
unstable to be isolated in the previously reports.9 Moreover, the steric
effect of o-methyl or o-methoxyl group of aryl halide was in-
conspicuous for the coupling reaction (entries 6, 7, and 14). For aryl
halides bearing a base-sensitive functional group, the coupling
reaction was also accomplished in high yields by transforming the
amino acid to amino ester and using Cs2CO3 as base and dioxane as
solvent (Scheme 1). The functional groups, such as esters, were well
tolerated under the reaction conditions.
reaction of
b-dicarbonylate, the coinstantaneous coordination of
two carbonyl groups with Pd prevented the formed aryl palladium
complex from reductive elimination.33 When our sterically hin-
dered electron-rich MOP type ligand (L1) was used, to our pleasure,
the reaction occurred with 69% yield of the desired product (Table 1,
entry 3). However, dramatic decrease of the activity of the catalyst
was observed by lowering the steric hindrance of the alkyl phos-
phine ligands (Table 1, entries 4e6). When L2 with dicyclohexyl
phosphino group was used as ligand, the coupling yield was de-
creased to 14% (Table 1, entry 4); in the cases when the dialkyl-
biarylphosphines (L3 and L4) were used as ligand, hardly any or
only trace product was obtained. These were in accordance with
the reports that increasing the steric hindrance of the ligands
would promote the reductive elimination during the CeN bond-
forming step.41e46 More significantly, the catalytic combination,
Pd(dba)2/L1, was also effective for the coupling reactions of inactive
aryl chlorides with amino acids; a 61% yield was obtained when
PhCl and DL-analine were used as substrates (Table 1, entry 7). We
also found that tBuOH was the optimal solvent for the trans-
formation presumably because amino acids are much more soluble
in a protic solvent rather than in an ethereal or a hydrocarbon
solvent (Table 1, entries 8e10). Finally, stronger bases, such as
tBuONa and KOH (Table 1, entries 10 and 11), were found to be more
effective than phosphates, carbonates and NaOH (Table 1, entries
Table 2
Palladium/L1-catalyzed coupling reaction of aryl halides with DL-alaninea
Entry
ArX
R
Product
Yieldb (%)
X
Table 1
Effect of ligands, solvents and bases on the Pd-catalyzed coupling reaction of aryl
1
2
3
4
5
6
7
8
4-CF3
Cl (1b)
Cl (1c)
Cl (1d)
Br (1e)
Cl (1e0)
Br (1f)
Cl (1f0)
Br (1g)
Br (1h)
Br (1i)
Cl (1i0)
Br (1j)
Cl (1j0)
Cl (1k)
3ba
3ca
3da
3ea
94
88
84
90
82
86
88
84
94
93
67
84
80
79
halide with DL-alaninea
4-COOH
3-COOH
4-Me
2-Me
3fa
3,5-DiMe
4-tBu
4-MeO
3ga
3ha
3ia
Yieldd (%)
9
Entry
Ligand
Base
Solvent
10
11
12
13
14
1b
DPPF
BINAP
L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
L1
L1
L1
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
KOH
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
0
0
69
14
0
Trace
61
80
83
90
85
43
Trace
0
2b
3-MeO
2-MeO
3ja
3b
4b
3ka
5b
6b
a
Reaction conditions: aryl halide (1.0 mmol), DL-alanine (1.2 mmol), KOH
7c
t
(3.0 mmol), Pd(dba)2 (2.0 mmol %), L1 (3.0 mmol %), BuOH (2.5 mL), 90 ꢀC, 20 h.
8c
b
Isolated yield.
9c
Dioxane
10c
11c
12c
13c
14c
15c
tBuOH
tBuOH
NaOH
Cs2CO3
K3PO4
tBuOH
tBuOH
tBuOH
K2CO3
tBuOH
0
a
Reaction conditions: aryl halide (1.0 mmol), DL-alanine (1.2 mmol), KOH
(3.0 mmol), Pd(dba)2 (2.0 mmol %), L1 (3.0 mmol %), tBuOH (2.5 mL), 90 ꢀC, 20 h.
Scheme 1. Palladium/L1-catalyzed coupling reaction of aryl halides with methyl ala-
ninate. Reaction conditions: aryl halide (1.0 mmol), methyl DL-alaninate hydrochloride
(1.2 mmol), Cs2CO3 (3.0 mmol), Pd(dba)2 (2.0 mmol %), L1 (4.0 mmol %), 1,4-dioxane
(2.5 mL), 90 ꢀC, 20 h.
b
X¼Br.
c
X¼Cl.
d
Isolated yield.

F. Ma et al. / Tetrahedron 67 (2011) 9405e9410
9407
We then expanded the applicability of the catalytic system to
diversified amino acids, and the results were summarized in Table
Due to the importance of the chiral amino acids in the
pharmaceutical industry, we expected to extend this methodol-
ogy to the synthesis of optically pure N-aryl amino acids. The
optical purities of the coupling products of chiral amino acids
were investigated by transforming them to the corresponding
methyl esters45e47 and analyzing their esters by HPLC. The re-
3. Not only
a-amino acids and b-amino acids could be arylated in
good yields (Table 3, entries 4 and 14), but also the coupling re-
actions of g-, d-amino acids or 4-aminobenzoic acid, which can-
not be catalyzed by CuI,22 occurred in moderate yields (entries 18,
19, and 21). However, the coupling yields were greatly influenced
by the structure of amino acids. Amino acids without extra co-
ordinating groups gave high coupling yields. For example, the
sults were also summarized in Table 3. The coupling of
a-amino
acids with bulky alkyl group at -carbon, such as valine or iso-
a
leucine, gave corresponding N-arylation products with high op-
tical purities (Table 3, entries 2e4.) However, when it comes to
coupling reaction of the simple
1e8) occurred in excellent yields (80%e96%); the
a
-amino acids (Table 3, entries
-amino acids
b
N-arylation products of
- or -carbon, optical purities of the coupling products de-
creased greatly (entries 6e8). The coupling reaction of chiral
-amino acids, whatever the substituent at -carbon is, afforded
a-amino acids with a phenyl group at
(Table 3, entries 14e17) could be also coupled in moderate to
excellent yields; 4-aminobutanoic acid was arylated in 71% yield.
For amino acids with other adjacent coordinating group, such as
a heteroatom, the coupling yields decreased remarkably. In the
a
b
b
b
the coupling products with their original optical purities (entries
cases of the coupling reaction of
L
-methionine, the yields of
14e17).
N-arylation dropped to 64% (Table 3, entries 9). Moreover, our
catalytic system was ineffective for proline, serine and glutamic
acid (Table 3, entries 11e13). It may also be due to the fact that
such substrates have more heteroatoms or functional groups
binding to Pd, which enhance the stability of the aryl-PdeN
complex and consequently inhibit it from reductive elimination.
In order to solve the problem, we increased the amount of cata-
lyst to 3.0% of Pd(dba)2 and 4.5% of L1, which led to increase the
coupling yield to 84% in the case of methionine (Table 3, entry 9).
We also tried to protect the coordinating group to facilitate the
coupling reaction. The transformation of glutamic acid to the di-
tert-butyl ester (4b) made that the arylation occurred in 31% yield
3. Conclusion
In conclusion, we have developed a general and useful cata-
lytic system for palladium-catalyzed coupling reaction of amino
acids or esters with inactive aryl halides under mild conditions. In
the catalytic system, the bulky and electron-rich MOP type
phosphine was used as ligand; amino acids including
a- and
b
-amino acids, long alkyl aliphatic amino acids and aromatic
amino acids worked well in this reaction to give coupling prod-
ucts in moderate to good yields. Coupling of 4-bromoanisole with
amino acids was realized and decent yields were obtained. Fur-
thermore, this method has been proven useful for preparing
enantiopure N-aryl
a bulk alkyl group at
(Table 3, entry 22). In case of the coupling of L-tryptophan, 2-
amino-3-(1-phenyl-1H-indol-3-yl) propanoic acid (3as) was iso-
lated as coupling product in 36% yield (Table 3, entry 10),
resulting from the coupling with nitrogen atom on indyl-cycle
under the catalytic condition.
b
-amino acids and N-aryl
-carbon.
a-amino acids with
a
4. Experimental sections
4.1. General procedure for the palladium-catalyzed coupling
reaction of amino acids with aryl halides
Table 3
Palladium/L1-catalyzed coupling reaction of amino acid with chlorobenzenea
Entry
Amino acid (ester)
Product
Yield
(%)
eeb
(%)
An oven-dried resealable Schlenk flask was charged with
Pd(dba)2 (11.4 mg, 0.02 mmol), L1 (13.6 mg, 0.03 mmol), base
(3.0 mmol), and amino acid (1.20 mmol) under N2. tBuOH (2.5 mL)
and aryl halides (1.00 mmol) were added in sequence via a syringe.
The flask was sealed, and the mixture was allowed to heat to 90 ꢀC
for 20 h. After being cooled to room temperature, the reaction
mixture was diluted with 2 mL of water and 3 mL of CHCl3, and
then adjusted to pH¼3 with concentrated HCl. The organic layer
was separated, and the aqueous layer was extracted with CHCl3
(5 mLꢁ3). The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated. The residual oil was purified
by column chromatography on silica gel (CHCl3/CH3OH) to afford
the coupling product.
1
2
3
4
5
6
7
8
L
-Alanine 2b
-Valine 2c
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3as
d
83
90
88
80
96
84
87
89
66 (84)c
36
0
0
0
73
78
81
75
96
97
93
78
41
33
1
29
d
d
d
d
97
99
96
L
D-Valine 2d
L
L
L
-Isoleucine 2e
-Leucine 2f
-Phenylalanine 2g
D-Phenylalanine 2h
L
-Phenylglycine 2i
-Methionine 2j
9
L
10
11
12
13
14
15
16
L-Tryptophan 2s
L
L
L
-Proline 2t
-Serine 2u
-Glutamic acid 2v
d
d
(S)-3-Aminobutanoic acid 2k
(R)-3-Aminopentanoic acid 2l
(S)-3-Amino-3-cyclohexylpropanoic
acid 2m
3ak
3al
3am
4.1.1. N-Phenyl alanine (3aa)9. 1H NMR (400 MHz, CDCl3):
d 1.54 (d,
J¼7.2 Hz, 3H), 4.12 (q, J¼6.8 Hz, 1H), 6.40 (d, J¼7.6 Hz, 2H), 6.80 (t,
17
(S)-3-Amino-3-phenylpropanoic
acid 2n
3an
95
>99
J¼7.6 Hz, 1H), 7.21 (td, J¼8.0, 2.0 Hz, 2H); 13C NMR (100 MHz,
18
19
20
21
22d
4-Aminobutanoic acid 2o
5-Aminopentanoic acid 2p
2-Aminobenzoic acid 2q
4-Aminobenzoic acid 2r
Di-tert-butyl
3ao
3ap
3aq
3ar
5ab
71
66
81
75
31
d
d
d
d
d
DMSO):
d 18.5, 51.3, 112.7, 116.7, 129.2, 148.1, 176.5.
4.1.2. (S)-N-Phenyl alanine (3ab)9. ½a D25
ꢃ45.3 (c 1.25, CHCl3); ee%
ꢂ
(the methyl ester): 75 (HPLC: Chiralcel OJ-H Column, hexane/iPrOH
2-aminopentanedioate
hydrochloride 4b
90/10, 0.5 mL/min, 254 nm, t1¼28.3 min, t2¼45.4 min).
a
4.1.3. (S)-N-Phenyl valine (3ac)9. 1H NMR (400 MHz, CDCl3):
d 1.07
Reaction conditions: chlorobenzene (1.0 mmol), amino acid (1.2 mmol), KOH
(3.0 mmol), Pd(dba)2 (2.0 mmol %), L1 (3.0 mmol %), tBuOH (2.5 mL), 90 ꢀC, 20 h.
(d, J¼6.8 Hz, 6H), 2.18e2.26 (m, 1H), 3.86 (d, J¼5.6 Hz, 1H), 6.66 (d,
b
ee of the corresponding methyl ester of the coupling product.
Pd(dba)2 (3.0 mmol %), L1 (4.5 mmol %).
Pd(dba)2 (2.0 mmol %), L1 (4.0 mmol %), Cs2CO3 (3.0 mmol), 1,4-dioxane
J¼8.8 Hz, 2H), 6.78 (t, J¼8.4 Hz, 1H), 7.20 (t, J¼7.6 Hz, 2H); 13C NMR
c
d
(100 MHz, DMSO):
d 19.0, 19.3, 30.4, 61.9, 112.5, 116.2, 128.9, 148.4,
(2.5 mL).
174.9. ½a 2D5
ꢃ75.6 (c 1.02, CHCl3); ee% (the methyl ester): 96 (HPLC
ꢂ

9408
F. Ma et al. / Tetrahedron 67 (2011) 9405e9410
Chiralcel OJ-H column, hexane/iPrOH 90/10, 0.5 mL/min, 254 nm,
t1¼11.0 min, t2¼15.7 min).
column, hexane/iPrOH 99/1, 0.8 mL/min, 254 nm, t1¼19.1 min,
t2¼23.0 min).
4.1.4. (R)-N-Phenyl valine (3ad)9. ½a D25
ꢂ
þ72.9 (c 1.04, CHCl3); ee%
4.1.12. (R)-3-(Phenylamino)pentanoic
(400 MHz, CDCl3):
acid
(3al)49
.
1H
NMR
(the methyl ester): 97 (HPLC: Chiralcel OJ-H column, hexane/iPrOH
d
0.99 (t, J¼7.6 Hz, 3H), 1.64e1.67 (m, 2H),
90/10, 0.5 mL/min, 254 nm, t1¼10.7 min, t2¼16.0 min).
2.57e2.59 (m, 2H), 3.70e3.77 (m, 1H), 6.70 (d, J¼8.4 Hz, 2H), 6.76 (t,
J¼7.2 Hz, 1H), 7.19 (d, J¼8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
4.1.5. (S)-N-Phenyl isoleucine (3ae)11. White solid. Mp: 166e169 ꢀC.
d
10.2, 26.9, 38.1, 52.7, 114.8, 118.9, 129.3, 145.6, 177.5. ½a D25
þ7.6 (c
ꢂ
1H NMR (400 MHz, CDCl3):
d
0.97 (t, J¼7.6 Hz, 3H), 1.03 (d, J¼6.8 Hz,
0.99, CHCl3); ee% (the methyl ester): >99 (HPLC: Chiralcel OD-H
column, hexane/iPrOH 99/1, 0.8 mL/min, 254 nm, t1¼25.1 min,
t2¼29.0 min).
3H), 1.29e1.37 (m, 1H), 1.61e1.67 (m, 1H), 1.91e1.96 (m, 1H),
3,93e3.94 (d, J¼5.6 Hz, 1H), 6.64 (dt, J¼7.6, 1.2 Hz, 2H), 6.77 (tt,
J¼7.6, 1.2 Hz, 1H), 7.16e7.19 (m, 1H), 7.20 (t, J¼6.4 Hz, 2H); 13C NMR
(100 MHz, DMSO):
d
11.8, 16.2, 25.8, 37.3, 61.2, 116.8, 129.5, 148.9,
4.1.13. (S)-3-(Phenylamino)-3-cyclohexyl
propanoic
acid
175.5. IR (cmꢃ1): 3251, 2958, 2871, 2362, 2339, 1748, 1697, 1507,
1230, 942, 896, 763. HRMS: calcd for C12H17NO2: 207.1259; found:
(3am)22 1H NMR (400 MHz, CDCl3):
.
d
1.07e1.27 (m, 5H), 1.56e1.88
(m, 6H), 2.50 (dd, J¼16.0 Hz, 6.8 Hz, 1H), 2.60 (dd, J¼16.0 Hz, 6.0 Hz,
1H), 3.68 (q, J¼6.8 Hz, 1H), 6.66 (d, J¼8.0 Hz, 2H), 6.72 (d, J¼7.6 Hz,
1H), 7.17 (dt, J¼7.2 Hz, 1.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
207.1263. ½a 2D5
ꢃ50.3 (c 1.07, CH3OH); ee% (the methyl ester): 93
ꢂ
(HPLC: Chiralcel OJ-H column, hexane/iPrOH 90/10, 0.8 mL/min,
254 nm, t1¼9.8 min, t2¼14.6 min).
d 26.1, 26.3, 29.1, 29.3, 36.5, 41.6, 55.3, 113.8,117.7, 128.4, 129.3,130.1,
147.1, 178.4. ½a D25
ꢃ5.9 (c 0.74, CHCl3); ee% (the methyl ester): 96
ꢂ
4.1.6. (S)-N-Phenyl leucine (3af)11. White solid. Mp: 115e116 ꢀC. 1H
(Original ee of substrate: 96%. HPLC: Chiralcel OD-H column, hex-
NMR (400 MHz, DMSO):
d
0.85 (d, J¼6.4 Hz, 3H), 0.92 (d, J¼7.2 Hz,
ane/iPrOH 99/1, 0.8 mL/min, 254 nm, t1¼10.9 min, t2¼14.1 min).
3H), 1.49e1.64 (m, 2H), 1.71e1.81 (m, 1H), 3.81 (dd, J¼8.4, 6.0 Hz,
1H), 6.50e6.54 (m, 3H), 7.03 (t, J¼7.2 Hz, 2H); 13C NMR (100 MHz,
4.1.14. (S)-3-(Phenylamino)-3-phenyl propanoic acid (3an)50
NMR (400 MHz, CDCl3):
2.85 (d, J¼6.4 Hz, 2H), 4.85 (t, J¼6.8 Hz,
1H), 6.59 (d, J¼8.0 Hz, 2H), 6.71 (t, J¼7.2 Hz, 1H), 7.12 (t, J¼7.6 Hz,
.
1H
DMSO):
d
22.7, 23.6, 25.4, 42.1, 55.1, 113.2, 117.1,122.9, 149.1,177.0. IR
d
(cmꢃ1): 3246, 2965, 2934, 2876, 2360, 2337, 1684, 1497, 1214, 922,
776, 751. HRMS: calcd for C12H17NO2: 207.1259, found: 207.1262:
2H),7.25e7.38 (m, 5H); 13C NMR (100 MHz, DMSO):
d 44.2, 54.9,
½
a 2D5
ꢂ
ꢃ55.7 (c 0.98, CH3OH); ee% (the methyl ester): 78 (HPLC:
114.2, 117.2, 127.8, 128.1, 129.5, 130.0, 114.8, 148.9, 173.3. ½a D25
ꢃ11.2
ꢂ
Chiralcel OJ-H column, hexane/iPrOH 90/10, 0.8 mL/min, 254 nm,
(c 1.00, CHCl3); ee% (the methyl ester): >99 (HPLC: Chiralcel OD-H
column, hexane/iPrOH 99/1, 0.8 mL/min, 254 nm, t1¼52.3 min,
t2¼60.2 min).
t1¼9.1 min, t2¼12.7 min).
4.1.7. (S)-N-Phenyl phenylalanine (3ag)9. 1H NMR (400 MHz,
DMSO):
d
2.91 (q, J¼8.4 Hz, 1H), 2.95 (q, J¼7.6 Hz, 1H), 4.07 (q,
4.1.15. 4-(Phenylamino)butanoic acid (3ao)51. 1H NMR (400 MHz,
J¼8.4 Hz, 1H), 5.91 (s, 1H), 6.49e6.55 (m, 3H), 7.01e7.05 (m, 2H),
CDCl3):
d
1.93e2.00 (m, 2H), 2.50 (t, J¼7.6 Hz, 2H), 3.21 (t, J¼6.8 Hz,
7.16e7.19 (m, 1H), 7.23e7.29 (m, 4H); 13C NMR (100 MHz, DMSO):
2H), 6.62 (d, J¼8.0 Hz, 2H) 6.71 (t, J¼7.6 Hz, 1H), 7.18 (t, J¼7.6 Hz,
d
37.9, 57.6, 112.7, 116.6, 126.5, 128.3, 129.1, 129.4, 138.1, 147.9, 174.9;
2H); 13C NMR (100 MHz, CDCl3):
129.2, 147.8, 179.2.
d 24.3, 31.6, 43.2, 112.9, 124.2,
½
a 2D5
ꢂ
ꢃ15.4 (c 1.12, CHCl3); ee% (the methyl ester): 41 (HPLC: Chir-
alcel OJ-H column, hexane/iPrOH 90/10, 0.8 mL/min, 254 nm,
t1¼13.3 min, t2¼59.1 min).
4.1.16. 6-(Phenylamino)hexanoic acid (3ap)24
.
1H NMR (400 MHz,
CDCl3):
d
1.44e1.50 (m, 2H), 1.61e1,73 (m, 4H), 2.39 (t, J¼14.0 Hz,
4.1.8. (R)-N-Phenyl phenylalanine (3ah)9. ½a D25
ꢂ
þ12.2 (c 1.02,
2H), 3.12 (t, J¼6.8 Hz, 2H), 5.49 (br, 1H), 6.60 (d, J¼8.0 Hz, 2H), 6.70
CH3OH); ee% (the methyl ester): 33 (HPLC: Chiralcel OJ-H column,
(t, J¼7.6 Hz, 1H), 7.17 (t, J¼8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
hexane/iPrOH
90/10,
0.8 mL/min,
254 nm,
t1¼43.1 min,
d 24.3, 26.4, 28.9, 34.0, 43.9, 113.1, 117.6, 129.1, 147.8, 179.8.
t2¼60.3 min).
4.1.17. 2-(Phenylamino)benzoic acid (3aq)52
CDCl3):
6.76 (t, J¼8.4 Hz, 1H), 7.13 (t, J¼8.4 Hz, 1H), 7.11e7.28 (m,
3H), 7.34e7.39 (m, 3H), 8.04 (dd, J¼8.0 Hz, J¼1.6 Hz, 1H), 9.32 (s,
1H); 13C NMR (100 MHz, DMSO):
112.5, 112.8, 116.4, 116.7, 128.2,
129.1, 129.2, 129.5, 138.1, 147.9, 174.9.
.
1H NMR (400 MHz,
4.1.9. (S)-N-Phenyl phenylglycine (3ai)48
.
1H NMR (400 MHz,
d
DMSO):
d
5.06 (s, 1H), 6.52 (t, J¼6.8 Hz, 1H), 6.63 (d, J¼6.8 Hz, 2H),
7.00 (d, J¼7.6 Hz, 2H), 7.02 (d, J¼7.6 Hz, 1H), 7.27e7.36 (m, 2H), 7.48
d
(d, J¼7.2 Hz, 2H); 13C NMR (100 MHz, DMSO):
d 60.2, 113.7, 117.3,
128.1, 129.0, 129.6, 139.2, 147.6, 173.7; ee% (the methyl ester): 1
(HPLC: Chiralcel OJ-H column, hexane/iPrOH 90/10, 0.8 mL/min,
254 nm, t1¼46.5 min, t2¼50.0 min).
4.1.18. 4-(Phenylamino)benzoic acid (3ar)53
.
1H NMR (400 MHz,
CDCl3):
d
6.09 (br, 1H), 7.00 (d, J¼8.0 Hz, 2H), 7.09 (t, J¼7.6 Hz, 1H),
7.19 (d, J¼8.4 Hz, 2H), 7.36 (t, J¼7.6 Hz, 3H), 7.99 (d, J¼8.0 Hz, 2H);
4.1.10. (S)-N-Phenyl methionine (3aj)9. 1H NMR (400 MHz, CDCl3):
13C NMR (100 MHz, DMSO):
141.5, 148.2, 167.2.
d 114.0, 119.2, 120.3, 121.7, 129.4, 131.3,
d
1.99e2.10 (m, 1H), 2.11 (s, 3H), 2.17e2.25 (m, 1H), 2.65e2.69 (m,
2H), 4.25e4.28 (m, 1H), 6.67 (d, J¼7.6 Hz, 2H), 6.79 (t, J¼8.4 Hz, 1H),
7.19 (t, J¼7.6 Hz, 2H); 13C NMR (100 MHz, DMSO):
d
14.7, 30.0, 31.7,
4.1.19. 2-Amino-3-(1-phenyl-1H-indol-3-yl)propanoic acid (3as)54
.
1H
54.7, 112.5, 116.5, 129.0, 148.1, 175.3. ½a D25
ꢂ
ꢃ3.4 (c 0.41, CH3OH); ee%
NMR (400 MHz, DMSO): 3.11e3.17 (m, 2H), 3.52e3.61 (m, 1H), 7.13
d
(the methyl ester): 29 (HPLC: Chiralcel OJ-H column, hexane/iPrOH
(t, J¼7.6 Hz, 1H), 7.18 (t, J¼7.6 Hz, 1H), 7.36e7.40 (m, 1H), 7.54e7.58
90/10, 0.8 mL/min, 254 nm, t1¼29.7 min, t2¼39.3 min).
(m, 5H), 7.71 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, DMSO)
d 26.9,
54.3, 110.2, 112.1, 119.0, 119.9, 122.4, 123.6, 126.1, 127.4, 129.2, 129.7,
135.3, 139.2.
.
4.1.11. (S)-3-(Phenylamino)butanoic acid (3ak)22 1H NMR (400 MHz,
CDCl3):
d
1.30 (d, J¼6.8 Hz, 3H), 2.46e2.69 (m, 2H), 3.91e3.96 (m,
1H), 5.70 (br, 2H), 6.90 (d, J¼8.0 Hz, 2H), 6.78 (t, J¼7.6 Hz,1H), 720 (d,
4.1.20. N-(4-Trifluoromethylphenyl)-alanine (3ba)55. White solid.
J¼6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d
20.5, 40.5, 46.5, 114.4,
Mp: 197e198 ꢀC. 1H NMR (400 MHz, CDCl3):
d
1.56 (d, J¼7.2 Hz, 3H),
4.21 (q, J¼7.2 Hz, 1H), 6.62 (d, J¼7.6 Hz, 2H), 7.43 (d, J¼8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3):
16.6, 51.3, 112.8, 126.7e126.8 (m),
1118.7, 129.5, 146.0, 177.0. ½a D25
þ19.6 (c 1.18, CHCl3); ee% (the methyl
ꢂ
ester): 97 (Original ee of substrate: 97%. HPLC: Chiralcel OD-H
d

F. Ma et al. / Tetrahedron 67 (2011) 9405e9410
9409
148.7, 179.5. IR (cmꢃ1): 3352, 3254, 2362, 2338, 1715, 1618, 1533,
1319, 1225, 1108, 1069, 829, 754. HRMS: calcd for C10H10NO2F3:
233.0664; found: 233.0663.
(m, 3H); 13C NMR (100 MHz, CDCl3)
d
18.7, 51.8, 55.4, 109.8, 110.6,
118.1, 121.1, 136.0, 147.0, 180.0. IR (cmꢃ1): 3408, 3249, 2361, 2333,
1715, 1516, 1456, 1223, 1183, 1023, 907, 743. HRMS: calcd for
C10H13NO3: 195.0895; found: 195.0896.
4.1.21. N-(4-Carboxylphenyl)alanine (3ca)56. White solid. Mp:
128e131 ꢀC. 1H NMR (400 MHz, DMSO)
d
1.39 (d, J¼7.2 Hz, 3H),
4.2. General procedure for the Palladium-catalyzed coupling
reaction of amino esters with aryl halides
4.02e4.05 (m, 1H), 6.56 (d, J¼8.8 Hz, 2H), 6.70 (br, 1H), 7.67 (d,
J¼8.4 Hz 2H), 12.3 (br, 2H); 13C NMR (100 MHz, DMSO)
d 19.7, 52.4,
113.1, 119.4, 132.9, 153.5, 169.3, 177.0. IR (cmꢃ1): 3404, 2973, 2360,
2337, 1671, 1602, 1522, 1420, 1289, 1177, 1118, 929, 835, 766. HRMS:
calcd for C10H11NO4: 209.0688; found: 209.0685.
An oven-dried Schlenk flask was charged with Pd(dba)2
(11.4 mg, 0.02 mmol), L1 (13.6 mg, 0.03 mmol), Cs2CO3 (3.0 mmol),
2-aminopropanoate hydrochloride (1.2 mmol). Dioxane (2.5 mL)
and aryl halides (1.00 mmol) were added in sequence via a syringe.
The flask was sealed and the mixture was heated at 100 ꢀC for 20 h.
After cooling to room temperature, the mixture was neutralized
with saturated NH4Cl. The aqueous layer was extracted with diethyl
ether; the combined organic phase was dried over anhydrous
Na2SO4, and concentrated. The residue was purified by column
chromatography on silica gel (ethyl acetate/hexane) to afford the
coupling product.
4.1.22. N-(3-Carboxylphenyl)alanine (3da). White solid. Mp:
202e204 ꢀC. 1H NMR (400 MHz, DMSO)
d
1.36 (d, J¼7.2 Hz, 3H),
3.93 (q, J¼6.8 Hz, 1H), 6.22 (br, 1H), 6.75 (d, J¼6.8 Hz, 1H), 7.11e7.20
(m, 3H), 12.65 (br, 2H); 13C NMR (100 MHz, DMSO)
d 19.1, 52.0,
113.8, 117.7, 118.3, 130.0, 132.4, 149.0, 168.9, 176.8. IR (cmꢃ1): 3243,
2360, 2337, 1697, 1437, 1291, 1229, 946, 812, 751. HRMS: calcd for
C10H11NO4: 209.0688; found: 209.0687.
4.1.23. N-(4-Methylphenyl)alanine (3ea)57 1H NMR (400 MHz,
.
4.2.1. Methyl
(400 MHz, CDCl3):
2-(phenylamino)propanoate
(5aa)61. 1H
NMR
CDCl3):
d
1.53 (d, J¼7.2 Hz, 3H), 2.25 (s, 3H), 4.05 (q, J¼6.8 Hz, 1H),
d
1.47 (d, J¼6.4 Hz, 3H), 3.73 (s, 3H), 4.14e4.15
6.57 (d, J¼7.6 Hz, 2H), 7.02 (d, J¼7.6 Hz, 2H); 13C NMR (100 MHz,
(m, 2H), 6.59e6.61 (m, 1H), 6.72e6.76 (m, 1H), 7.16e7.20 (m, 2H);
13C NMR (100 MHz, CDCl3):
129.59, 146.7, 175.4.
d
19.2, 52.1, 52.5, 113.5, 118.6, 129.56,
DMSO):
d 19.3, 21.1, 52.2, 113.5, 125.6, 130.3, 146.6, 177.1.
4.1.24. N-(2-Methylphenyl)alanine (3fa)58 1H NMR (400 MHz,
.
CDCl3):
d
1.57 (d, J¼6.8 Hz, 3H), 2.20 (s, 3H), 4.18 (q, J¼7.2 Hz, 1H),
4.2.2. Methyl 4-(1-methoxy-1-oxopropan-2-ylamino)benzoate (5la)
. Red solid. Mp: 59e60 ꢀC. 1H NMR (400 MHz, CDCl3):
1.50 (d,
6.55 (d, J¼8.4 Hz, 1H), 6.72 (t, J¼6.8 Hz, 1H), 7.08e7.14 (m, 2H); 13C
d
NMR (100 MHz, CDCl3):
130.4, 144.0, 180.5.
d 17.3, 18.8, 51.9, 110.6, 118.4, 122.8, 127.1,
J¼6.8 Hz, 3H), 3.76 (s, 3H), 3.85 (s, 3H), 4.21 (d, J¼7.2, 1H), 4.61 (s, 1H),
6.54e6.57 (m, 2H), 7.86e7.88 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
18.8, 51.4, 51.7, 52.6, 112.1, 115.3, 119.4, 131.7, 131.9, 150.3, 167.3, 174.4.
IR (cmꢃ1): 3379, 2952, 2356, 1732, 1687, 1603, 1530, 1437, 1338, 1279,
1171, 1117, 1055, 840, 735. HRMS: calcd for C12H15NO4: 237.1001;
found: 237.1003.
4.1.25. N-(3,5-Dimethylphenyl)alanine (3ga). White solid. Mp:
122e124 ꢀC. 1H NMR (400 MHz, CDCl3)
1.52 (d, J¼7.2 Hz, 3H), 2.24
(s, 6H), 4.05e4.10 (m, 1H), 6.28 (s, 2H), 6.48 (s, 1H); 13C NMR
d
(100 MHz, CDCl3) d 18.7, 21.4, 52.6, 111.9, 121.2, 139.1, 145.8, 179.7. IR
(cmꢃ1): 3186, 2973, 2361, 2338, 1584, 1520, 1456, 1396, 1359, 856.
HRMS: calcd for C11H15NO2: 193.1107; found: 193.1103.
4.2.3. Di-tert-butyl 2-(phenylamino)pentanedioate (5ab). 1H NMR
(400 MHz, CDCl3):
d 1.43 (s, 9H), 1.44 (s, 9H), 2.00e2.11 (m, 2H),
2.35e2.41 (m, 2H), 3.98e3.99 (m, 1H), 4.18 (br, 1H), 6.62 (d,
J¼6.8 Hz, 1H), 6.72 (t, J¼6.8 Hz, 1H), 7.16 (t, J¼7.2 Hz, 2H); 13C NMR
4.1.26. N-(4-tert-Butylphenyl)alanine (3ha). White solid. Mp:
118e120 ꢀC. 1H NMR (400 MHz, CDCl3):
d 1.27 (s, 9H), 1.52 (d,
(100 MHz, CDCl3):
d 28.2, 28.3, 31.9, 56.9, 80.8, 82.0, 113.8, 118.4,
J¼7.2 Hz, 3H), 4.08 (q, J¼7.6 Hz, 1H), 6.59 (d, J¼8.4 Hz, 2H), 7.23 (d,
129.5, 147.3, 172.6, 173.1.
J¼8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 18.5, 31.4, 33.9, 53.1,
114.1, 126.2, 142.4, 142.9, 179.2. IR (cmꢃ1): 3384, 3062, 2960, 2899,
2780, 2682, 2501, 2360, 2337,1699,1616,1521,1362,1233,1041, 817.
HRMS: calcd for C13H19NO2: 221.1416; found: 221.1415.
Acknowledgements
We thank the National Natural Science Foundation of China for
financial support.
4.1.27. N-(4-Methoxylphenyl)alanine (3ia)59. White solid. Mp:
148e150 ꢀC. 1H NMR (400 MHz, DMSO):
d
1.31 (d, J¼6.8 Hz, 3H),
Supplementary data
3.60 (s, 3H), 3.84 (q, J¼7.2 Hz, 1H), 6.49 (d, J¼9.2 Hz, 2H), 6.68 (dd,
J¼9.2, J¼2.4 Hz, 2H); 13C NMR (100 MHz, DMSO):
d 18.4, 51.9, 55.4,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.09.109.
113.7, 114.6, 142.1, 151.2, 176.4. IR (cmꢃ1): 3081, 2999, 2362, 2339,
1567, 1513, 1486, 1408, 1360, 1266, 1030, 853, 820, 750. HRMS: calcd
for C10H13NO3: 195.0895; found: 195.0900.
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1.53 (d, J¼7.2 Hz, 3H), 3.76 (s,
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