Hydrogenation of β-N-substituted and β-N,N-disubstituted enamino esters in the presence of iridium(I) catalyst

Article abstract of DOI:10.1055/s-0029-1217405

Several new β-amino esters were prepared in two simple steps from β-keto ester derivatives and primary and secondary amines under mild conditions. The hydrogenation of various enamino esters was performed at 50°C in the presence of iridium catalysts. The new β-N-substituted amino esters were isolated in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217405

PAPER
2627
Hydrogenation of b-N-Substituted and b-N,N-Disubstituted Enamino Esters in
the Presence of Iridium(I) Catalyst
I
ridium(I) Catalyst
afor the Synthesis of
b
-N
i
-Subst
a
ituted
A
mino
E
ste
H
rs ebbache,a,b Zakia Hank,a Christian Bruneau,*b Jean-Luc Renaud*c
a
Laboratoire d’Électrochimie-Corrosion, Métallurgie et Chimie Minérale, Université des Sciences et Technologies Houari Boumedienne,
Faculté de Chimie, BP32 El Alia 16111 Bab-Ezzouar, Alger, Algérie
b
UMR 6226, CNRS-Université de Rennes 1, Sciences Chimiques de Rennes, Catalyse et Organométalliques, Campus de Beaulieu,
35042 Rennes Cedex, France
Fax +33(2)23236939; E-mail: christian.bruneau@univ-rennes1.fr
c
Laboratoire de Chimie Moléculaire et Thioorganique, UMR 6507, INC3M, FR 3038, ENSICAEN-Université de Caen, 14050 Caen,
France
Fax 33(2)31452877; E-mail: jean-luc.renaud@ensicaen.fr
Received 3 April 2009; revised 14 April 2009
Abstract: Several new b-amino esters were prepared in two simple
steps from b-keto ester derivatives and primary and secondary
amines under mild conditions. The hydrogenation of various enam-
ino esters was performed at 50 °C in the presence of iridium cata-
lysts. The new b-N-substituted amino esters were isolated in high
yields.
Ph
O
NH2
Me3N+
CO2
–
OH
H2N
H2N
CO2H
OH
O
cis-pentacine
emeriamine
bestatine
Key words: catalysis, hydrogenation, iridium, b-amino esters
N
H2N
OMe
Ph
b-Amino acid derivatives are building blocks of choice
for the preparation of b-peptides. These types of peptides
usually present high enzymatic stability and three-dimen-
sional structures of interest.1 Some b-amino acids them-
selves are biologically active products, for instance cis-
pentacine shows high antibiotic and antifungal activities,2
and emeriamine exhibits hypoglycemic and anticetogenic
properties (Figure 1).3 A variety of polyfunctional linear
products,4 as well as macrocycles5 incorporating b-amino
acid substructures have revealed interesting biological ac-
tivities (Figure 1).
CO2H
O
H
CO2H
N
H
adda
N
O
NH
elarobifan
O
OH
OH
O
O
O
N
H
H2N
O
O
OH
The preparation of such b-amino acid derivatives in opti-
cally pure form has become a challenge for organic chem-
ists in recent years.6 The main approaches for
stereoselective synthesis of b-amino acids are based on
homologation of a-amino acids,7 enzymatic resolution,8
enolate addition to imines,9 Curtius rearrangement,10 con-
jugate addition of nitrogen nucleophile to a,b-unsaturated
derivatives,11 aminohydroxylation,12 and b-lactam syn-
thesis.13 However, the most promising method for a large
scale preparation of optically pure b-amino acids appears
to be the catalytic asymmetric hydrogenation of b-acet-
amidoacrylates, which involves clean atom economical
reactions and offers the preparation of both R- and S-enan-
tiomers.14 Most of the current approaches required an N-
acyl or N-carbamoyl protecting groups on the b-dehy-
droamino acids to achieve high enantioselectivities, via a
chelation between the substrate and the metal. But the ma-
jor drawback of this strategy was the difficulty to protect
and remove this protecting-chelating group. To avoid
amastatine
Ph
O
O
O
O
H
O
HO
O
O
N
O
O
HN
O
N
H
Br
N
O
N
H
O
HN
jasplakinolide
MeO
Cl
crypophycine
Figure 1 Some biologically active compounds with a b-amino acid
substructure
these extra steps, one solution might be either the enan-
tioselective hydrogenation of b-N-alkyl- or b-N-aryl-
enamino esters or a direct reductive amination. After the
evidence that enamines could be hydrogenated by transi-
SYNTHESIS 2009, No. 15, pp 2627–2633
Advanced online publication: 22.06.2009
DOI: 10.1055/s-0029-1217405; Art ID: Z05709SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9

2628
H. Hebbache et al.
PAPER
tion metal complexes,15 the first enantioselective hydro- Lewis acid. We have extended this study to several substi-
genation of unprotected enamino esters was reported by tuted anilines 2e–h leading to the formation of the enami-
the Merck group in 2004.16 In 2005, Zhang reported the no esters 3o–s. Whatever the substituents on the aromatic
hydrogenation of b-N-arylenamino esters in the presence ring and the b-keto esters used, the yields are good (73–
of a catalytic amount of Rh-Tangphos in TFE at 50 °C.17 97%, see experimental section). It is worth to mention that
The first and up to date only, direct reductive amination using this procedure, only the Z-b-N-substituted enamino
was reported by the Lanxess and the Takasago groups.18 esters were isolated from the condensation of a primary
The chiral b-amino esters were obtained in a one-pot syn- amine with a b-keto ester, and only the E-b-N,N-disubsti-
thesis from b-keto esters and ammonium acetate under a tuted enamino esters resulted from the condensation of a
pressure of hydrogen in the presence of a ruthenium cata- secondary amine (Scheme 1).
lyst bearing a Josiphos type optically active ligand. From
acyclic b-keto esters, the chemoselectivity in favor of the
amino ester and the enantioselectivity were excellent,
from acyclic b-keto ester the chemoselectivity in favor of
the amino ester was still high, but the diastereo- and the
enantioselectivity were moderate.
Finally, in the literature, no general report on hydrogena- ic trifluoroethanol20 at 50 °C under 10 bar of hydrogen
tion of b-N-substituted enamino esters was described. We starting from methyl 3-N-benzylaminobut-2-enoate (3a)
report here a general procedure for the synthesis of a wide and methyl 3-pyrrolidinobut-2-enoate (3t). Even an in-
range of b-N-substituted amino esters via a catalytic hy- crease of the catalyst loading (from 1 to 5 mol%) did not
drogenation of b-N-substituted enamino esters under mild improve the reactivity. Under the same reaction condi-
The direct hydrogenation of these substrates was investi-
gated with transition-metal catalysts. As they demonstrat-
ed good efficiency in the hydrogenation of b-acet-
amidoacrylates,14 [Rh(diphosphine)(cod)]BF4 rhodium
complexes were used as precatalyst in our first attempts.
No reaction was observed in methanol or in the more acid-
conditions.
tions, ruthenium complexes, such as [Ru(p-
cymene)(diphosphine)Cl]Cl and RuClCp(diphosphine),
did not provide any hydrogenated products either.
We recently described the synthesis of various b-N-sub-
stituted enamino esters18 and b-N,N-disubstituted enami-
no esters19 based on a simple condensation of a primary or However, in the presence of the iridium complex
a secondary amine with b-keto esters in the presence of a [Ir(P(OPh)3)2(cod)]PF6, either in trifluoroethanol or in
R4
O
O
NH
O
FeCl3•6H2O (5 mol%)
R4NH2
R1
R3
+
R1
R3
CH2Cl2, r.t. or ∆
R2
R2
3a–s
73–97%
1a: R1 = Me, R2 = H, R3 = OMe
1b: R1 = Me, R2 = H, R3 = OEt
1c: R1 = Me, R2 = H, R3 = Ot-Bu
1d: R1 = Ph, R2 = H, R3 = OEt
2a: R4 = Bn
2b: R4 = Bu
2c: R4 = i-Pr
2d: R4 = Ph
2e: R4 = p-Tol
2f: R4 = o-Tol
2g: R4 = 4-BrC6H4
2h: R4 = 3,4-Me2C6H3
3a: R1 = Me, R2 = H, R3 = OMe, R4 = Bn
3b: R1 = Me, R2 = H, R3 = OEt, R4 = Bn
3c: R1 = Me, R2 = H, R3 = Ot-Bu, R4 = Bn
3d: R1 = Me, R2 = H, R3 = OMe, R4 = Bu
3e: R1 = Me, R2 = H, R3 = OEt, R4 = Bu
3f: R1 = Me, R2 = H, R3 = Ot-Bu, R4 = Bu
3g: R1 = Me, R2 = H, R3 = OMe, R4 = i-Pr
3h: R1 = Me, R2 = H, R3 = OEt, R4 = i-Pr
3i: R1 = Me, R2 = H, R3 = Ot-Bu, R4 = i-Pr
3j: R1 = Ph, R2 = H, R3 = OEt, R4 = Bn
3k: R1 = Me, R2 = H, R3 = OMe, R4 = Ph
3l: R1 = Me, R2 = H, R3 = OEt, R4 = Ph
3m: R1 = Me, R2 = H, R3 = Ot-Bu, R4 = Ph
3n: R1 = Ph, R2 = H, R3 = OEt, R4 = Ph
3o: R1 = Me, R2 = H, R3 = OMe, R4 = 4-MeC6H4
3p: R1 = Me, R2 = H, R3 = OMe, R4 = 2-MeC6H4
3q: R1 = Me, R2 = H, R3 = OMe, R4 = 4-BrC6H4
3r: R1 = Me, R2 = H, R3 = OMe, R4 = 3,4-Me2C6H3
3s: R1 = Ph, R2 = H, R3 = OMe, R4 = 4-BrC6H4
O
O
N
FeCl3•6H2O (5 mol%)
CH2Cl2, r.t., 16 h
R
+
NH
O
CO2R
3t R = Me, 88%
3u R = t-Bu, 89%
1a–c
Scheme 1
Synthesis 2009, No. 15, 2627–2633 © Thieme Stuttgart · New York

PAPER
Iridium(I) Catalyst for the Synthesis of b-N-Substituted Amino Esters
Table 1 Hydrogenation of 3-N-Alkylenamino Esters 3a–ja
2629
methanol as solvent, at 50 °C for 20 hours under 15 bar of
hydrogen, 3a was hydrogenated to methyl 3-N-benzyl-
aminobutan-2-oate (4a) in moderate yield (50%). A rapid
screening of iridium catalysts demonstrated that the sim-
ple [IrCl(cod)]2 iridium precursor at 50 °C under 15 bar of
hydrogen led to the saturated amino ester in good yield
(Scheme 2). The nature of the solvent had a strong influ-
ence on the reactivity; alcohols (such as methanol or tri-
fluoroethanol), and THF did not lead to complete
hydrogenation, whereas in CH2Cl2 full conversion was
reached. The hydrogen pressure is also crucial for this
hydrogenation; below 10 bar of hydrogen in dichloro-
methane, the reaction did not go to completion. Thus, hy-
drogenation in the presence of 1 mol% of [IrCl(cod)]2 at
50 °C in CH2Cl2 under 10 bar of hydrogen was selected as
our standard conditions for this study.
Alk
Alk
[IrCl(cod)]2 (1 mol%)
H2 (10 bar)
NH
NH
CO2R2
CO2R2
R1
R1
CH2Cl2, 50 °C
3a–j
4a–j
R2
Entry
Alkyl
Bn
Product
4a
Time (h) R1
1
2
2
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Et
Bn
4b
4c
3
Bn
1
t-Bu
4
Bu
4d
4e
3
Me
Et
5
Bu
3
6
Bu
4f
3
t-Bu
Me
Et
Bn
R1
Bn
R1
[IrCl(cod)]2 (1 mol%)
H2 (15 bar)
7
i-Pr
i-Pr
i-Pr
Bn
4g
3
NH
NH
CO2R2
CO2R2
solvent, 50 °C, 16 h
8
4h
4i
3
Scheme 2
9
2
t-Bu
Et
10b
4j
20
With these conditions, the scope of the hydrogenation re-
action was evaluated for a variety of b-N-substituted
enamino esters (Table 1). In all reactions, whatever the N-
alkyl substituent, the conversions were complete and iso-
lated yields of products were almost quantitative. Except
for enamino ester 3j, the hydrogenation occurred rapidly
(<3 h). The lower reactivity of 3j might be due to the con-
jugation of the enamine double bond with the aromatic
substituent at C-3.
a The hydrogenation reactions were carried out with 0.5 mmol of
enamino ester 3a–j and 1% of [IrCl(cod)]2 precatalyst in 5 mL of
CH2Cl2.
b Amount of catalyst used: 2 mol%.
Table 2 Hydrogenation of 3-N-Arylenamino Esters 3k–sa
Ar
Ar
[IrCl(cod)]2 (1 mol%)
H2 (10 bar)
NH
NH
CO2R2
CO2R2
CH2Cl2, 50 °C, 2–48 h
R1
R1
Starting from N-aryl-substituted enamino esters, conver-
sions were complete and isolated yields were almost
quantitative (superior to 95% after purification on silica
gel chromatography in all the following examples). As
compared to the alkyl series, the enamino esters 3k–s
were less reactive and hydrogenations took usually longer
reaction times. The nature and the position of the substit-
uent on the aromatic ring had no noticeable influence on
the reactivity (Table 2, entries 5–9).
3k–s
4k–s
Entry
Aryl
Product
4k
Time (h) R1
R2
1
Ph
18
16
16
48
4
Me
Me
Et
2
Ph
4l
Me
Me
Ph
3
Ph
4m
4n
t-Bu
Et
4b
5
Ph
With secondary enamino esters 3t,u, the hydrogenation
proceeded also efficiently. As observed with the previous
enamino esters 3a–s, in methanol or mixture of MeOH–
CH2Cl2 the reaction was slower than in CH2Cl2. Then, in
methanol after 6 or 16 hours, the reaction was not com-
pleted, whereas in CH2Cl2, the amino esters 4t,u were iso-
lated in 98 and 99% yield, respectively, within 4 hours
under 10 bar of hydrogen (Scheme 3).
4-MeC6H4
2-MeC6H4
2-BrC6H4
3,4-Me2C6H3
2-BrC6H4
4o
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
6
4p
4
7
4q
2
8
4r
2
9b
4s
2
a The hydrogenation reactions were carried out with 0.5 mmol of
enamino ester 3a–j and 1% of iridium precatalyst in 5 mL of CH2Cl2.
b Amount of catalyst used: 2 mol%.
[IrCl(cod)]2 (1 mol%)
H2 (10 bar)
N
N
CO2R
CH2Cl2, 50 °C, 4 h
CO2R
4t R = Me, 98%
4u R = t-Bu, 99%
We then investigated two phosphoramidites L1 and L2
(Figure 2), which were recently introduced as efficient
chiral ligands for a number of reactions, in the hydrogena-
tion of the enamino ester 3a. After a screening of solvent
3t,u
Scheme 3
Synthesis 2009, No. 15, 2627–2633 © Thieme Stuttgart · New York

2630
H. Hebbache et al.
PAPER
Methyl 3-(4-Bromophenylamino)but-2-enoate (3q)
Yield: 84%.
1H NMR (300.13 MHz, CDCl3): d = 2.00 (s, 3 H), 3.70 (s, 3 H), 4.74
(s, 1 H), 6.97 (d, J = 8 Hz, 2 H), 7.45 (d, J = 8 Hz, 2 H).
13C NMR (75.03 MHz, CDCl3): d = 20.7, 50.8, 87.0, 118.5, 126.2,
O
O
O
P
P
N
NMe2
O
132.6, 138.8, 158.8, 171.1.
Methyl 3-(3,4-Dimethylphenylamino)but-2-enoate (3r)
Yield: 82%.
1H NMR (300.13 MHz, CDCl3): d = 1.98 (s, 3 H), 2.27 (s, 6 H), 3.71
L2
L1
(s, 3 H), 4.68 (s, 1 H), 6.83–7.12 (m, 3 H).
Figure 2 Phosphoramidites L1 and L2
13C NMR (75.03 MHz, CDCl3): d = 19.6, 20.3, 20.7, 50.7, 85.1,
122.6, 126.5, 130.5, 134.1, 137.3, 137.8, 160.1, 171.2.
(MeOH, THF, CH2Cl2, i-PrOH, toluene, EtOAc), pressure
(10, 20, 30 bar) and temperature (40, 50, 60, 70 °C), we
found that using 1 mol% of previously prepared catalyst
[Ir(cod)L1Cl] or [Ir(cod)L2Cl] the amino ester 4a was ob-
tained quantitatively at 70 °C in THF under 10 bar of hy-
drogen, but as a racemic mixture.
Ethyl 3-(4-Bromophenylamino)-3-phenylacrylate (3s)
Yield: 73%.
1H NMR (300.13 MHz, CDCl3): d = 1.43 (t, J = 7 Hz, 3 H), 4.23 (q,
J = 7.3 Hz, 2 H), 5.06 (s, 1 H), 6.54 (d, J = 10 Hz, 2 H), 7.20 (d,
J = 8 Hz, 2 H), 7.29–7.40 (m, 5 H).
13C NMR (75.03 MHz, CDCl3): d = 15.0, 59.9, 92.5, 116.1, 124.0,
128.6, 129.1, 130.1, 132.0, 136.0, 140.0, 158.9, 170.5.
In conclusion, we have found a general procedure for the
synthesis of a wide range of new b-N-substituted and b-
N,N-disubstituted amino esters via catalytic hydrogena-
tion of b-N-substituted and b-N,N-disubstituted enamino
esters under mild conditions in the presence of
[IrCl(cod)]2 as catalyst. Further efforts are now devoted to
the asymmetric version of this transformation.
N,N-Dialkylaminoacrylates 3t,u; General Procedure
In a Schlenk tube, methyl acetylacetate or tert-butyl acetylacetate
(1 equiv), and pyrrolidine (1.5 equiv) were successively added un-
der argon. The neat reaction mixture was stirred at 25 °C. The reac-
tion was monitored by TLC analysis. The crude mixture was
recrystallized from a mixture of Et2O–pentane.
1H NMR and 13C NMR spectra were recorded on 300 MHz Bruker
AC 200 spectrometers. Chemical shifts are reported in ppm refer-
enced to the residual proton resonances of the solvents. Mass spec-
tra (MS) were obtained on GC-MS Hewlett-Packard HP 5971
apparatus. TLC was performed on Merck silica gel 60 F 254. Silica
gel Merck Geduran SI (40–63 mm) was used for column chromatog-
raphy.
Methyl 3-(Pyrrolidino)but-2-enoate (3t)
Yield: 88%.
1H NMR (300.13 MHz, CDCl3): d = 4.89 (m, 4 H), 2.41 (s, 3 H),
3.25 (m, 4 H), 3.56 (s, 1 H), 4.41 (s, 1 H).
13C NMR (75.03 MHz, CDCl3): d = 16.6, 25.1, 47.9, 49.8, 82.7,
159.6, 169.5.
N-Arylaminoacrylates 3a–s; General Procedure
tert-Butyl 3-(Pyrrolidino)but-2-enoate (3u)
Yield: 89%.
1H NMR (300.13 MHz, CDCl3): d = 1.47 (s, 9 H), 1.91 (m, 4 H),
2.43 (s, 3 H), 3.28 (m, 4 H), 4.41 (s, 1 H).
13C NMR (75.03 MHz, CDCl3): d = 16.5, 25.2, 28.8, 47.8, 77.2,
To CH2Cl2 (5 mL/mmol), were successively added under argon
FeCl3·6H2O (5 mol%), the dicarbonyl derivative 1 (1 equiv), and fi-
nally the amine 2 (1.5 equiv). The reaction mixture was stirred at r.t.
or under reflux until complete conversion of the keto ester 1 was de-
tected by TLC analysis. The solution was then directly poured at the
top of a silica gel column and eluted with a heptane–EtOAc (7:3)
mixture. All the N-substituted aminoacrylates were fully character-
ized with 1H and 13C NMR spectra. Spectroscopic data of 3a–n have
been reported previously.19,21
85.1, 158.8, 169.2.
b-Amino Esters 4a–u; General Procedure
In a 25 mL stainless steel autoclave were placed under argon, the N-
substituted b-amino acrylate (0.5 mmol, 1 equiv) and the iridium
precatalyst (0.005 mmol, 1% mol). The mixture was degassed by
three vacuum-filling with argon cycles before adding degassed and
distilled CH2Cl2 (5 mL). Then, the autoclave was purged three times
with H2 and the vessel was pressurized to 10 or 20 bar. After 1–48
h (see text) at 50 °C, the autoclave was carefully opened, and the
solvent was removed under reduced pressure. Conversion was de-
termined by 1H NMR analysis of the crude mixture. Subsequently,
the residue was purified by purification on silica gel by eluting with
a 1:1 mixture of heptane and EtOAc.
Methyl 3-(p-Tolylamino)but-2-enoate (3o)
Yield: 97%.
1H NMR (300.13 MHz, CDCl3): d = 1.98 (s, 3 H), 2.36 (s, 3 H), 3.71
(s, 3 H), 4.70 (s, 1 H), 7.00 (d, J = 10 Hz, 2 H), 7.16 (d, J = 8 Hz, 2
H).
13C NMR (75.03 MHz, CDCl3): d = 20.3, 20.9, 50.2, 84.9, 124.8,
129.6, 135.0, 136.6, 159.6, 170.8.
Methyl 3-(o-Tolylamino)but-2-enoate (3p)
Yield: 98%.
Methyl 3-(Benzylamino)butanoate (4a)
1H NMR (300.13 MHz, CDCl3): d = 1.15 (d, J = 6 Hz, 3 H), 2.44
(ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz, 2 H), 3.16 (m, 1 H),
3.66 (s, 3 H), 3.79 (AB, JAB = 12 Hz, 2 H), 7.20–7.34 (m, 5 H).
1H NMR (300.13 MHz, CDCl3): d = 1.88 (s, 3 H), 2.31 (s, 3 H), 3.72
(s, 3 H), 4.73 (s, 1 H), 7.05–7.27 (m, 4 H).
13C NMR (75.03 MHz, CDCl3): d = 18.0, 20.1, 50.2, 84.7, 126.1,
126.4, 126.5, 130.7, 133.9, 137.9, 160.0, 170.9.
13C NMR (75.03 MHz, CDCl3): d = 20.5, 41.4, 49.7, 51.2, 51.5,
126.9, 128.1, 128.4, 140.4, 172.8.
Synthesis 2009, No. 15, 2627–2633 © Thieme Stuttgart · New York

PAPER
Iridium(I) Catalyst for the Synthesis of b-N-Substituted Amino Esters
2631
HRMS: m/z calcd for C11H14NO2 [M – CH3]+: 192.1024; found:
13C NMR (75.03 MHz, CDCl3): d = 13.9, 14.2, 20.5, 20.5, 32.4,
192.1013.
41.6, 46.8, 50.2, 60.2, 172.4.
HRMS: m/z calcd for C10H21NO2: 187.1572; found: 187.1581.
Ethyl 3-(Benzylamino)butanoate (4b)
1H NMR (300.13 MHz, CDCl3): d = 1.15 (d, J = 6 Hz, 3 H), 1.24 (t,
J = 7.5 Hz, 3 H), 2.42 (ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz,
2 H), 3.16 (m, 1 H), 3.79 (AB, JAB = 12 Hz, 2 H), 4.12 (q, J = 7 Hz,
2 H), 7.20–7.35 (m, 5 H).
tert-Butyl 3-(Butylamino)butanoate (4i)
1H NMR (300.13 MHz, CDCl3): d = 0.89 (t, J = 7.5 Hz, 3 H), 1.07
(d, J = 6 Hz, 3 H), 1.23 (m, 2 H), 1.33 (m, 2 H), 1.42 (s, 9 H), 2.27
(ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz, 2 H), 2.56 (m, 2 H),
3.02 (m, 1 H).
13C NMR (75.03 MHz, CDCl3): d = 14.2, 20.5, 41.7, 49.7, 51.2,
60.3, 126.9, 128.1, 128.4, 140.4, 172.3.
HRMS: m/z calcd for C12H16NO2 [M – CH3]+: 206.1181; found:
13C NMR (75.03 MHz, CDCl3): d = 14.0, 20.5, 28.1, 32.5, 42.8,
46.8, 50.4, 80.3, 171.8.
206.1196.
HRMS: m/z calcd for C8H16NO2 [M – t-Bu]+: 158.1181; found:
158.1197.
tert-Butyl 3-(Benzylamino)butanoate (4c)
1H NMR (300.13 MHz, CDCl3): d = 1.15 (d, J = 6 Hz, 3 H), 1.44 (s,
9 H), 2.34 (ABX, JAB = 15 Hz, JAX = 9 Hz, JBX = 6 Hz, 2 H), 3.12
(m, 1 H), 3.78 (AB, JAB = 13.5 Hz, 2 H), 7.20–7.35 (m, 5 H).
Ethyl 3-(Benzylamino)-3-phenylpropanoate (4j)
1H NMR (300.13 MHz, CDCl3): d = 1.22 (t, J = 7.5 Hz, 3 H), 2.70
(ABX, JAB = 15 Hz, JAX = 9 Hz, JBX = 6 Hz, 2 H), 3.64 (AB,
JAB = 12 Hz, 2 H), 4.09–4.18 (m, 3 H), 7.24–7.40 (m, 10 H).
13C NMR (75.03 MHz, CDCl3): d = 20.4, 28.1, 42.9, 49.9, 51.2,
80.4, 126.9, 128.1, 128.4, 140.5, 171.7.
HRMS: m/z calcd for C11H14NO2 [M – t-Bu]+: 192.1024; found:
13C NMR (75.03 MHz, CDCl3): d = 14.2, 43.2, 51.4, 58.9, 60.5,
126.9, 127.2, 127.5, 128.2, 128.4, 128.6, 140.3, 142.6, 171.8.
192.1015.
HRMS: m/z calcd for C18H22NO2 [M + H]+: 284.1650; found:
284.1649.
Methyl 3-(Isopropylamino)butanoate (4d)
1H NMR (300.13 MHz, CDCl3): d = 0.98 (dd, J = 6, 12 Hz, 6 H),
1.04 (d, J = 6 Hz, 3 H), 2.32 (ABX, JAB = 15 Hz, JAX = 7.5 Hz,
JBX = 9 Hz, 2 H), 2.83 (m, 1 H), 3.12 (m, 1 H), 3.61 (s, 3 H).
Methyl 3-(Phenylamino)butanoate (4k)
1H NMR (300.13 MHz, CDCl3): d = 1.30 (d, J = 6 Hz, 3 H), 2.56
(ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz, 2 H), 3.70 (s, 3 H), 3.97
(m, 1 H), 6.64–6.76 (m, 3 H), 7.09–7.37 (m, 2 H).
13C NMR (75.03 MHz, CDCl3): d = 20.9, 22.9, 23.5, 41.7, 45.2,
47.1, 51.3, 172.7.
13C NMR (75.03 MHz, CDCl3): d = 20.7, 40.8, 46.0, 51.6, 113.6,
HRMS: m/z calcd for C8H17NO2: 159.1259; found: 159.1271.
117.7, 129.4, 146.8, 172.3.
HRMS: m/z calcd for C11H15NO2: 193.1103; found: 193.1096.
Ethyl 3-(Isopropylamino)butanoate (4e)
1H NMR (300.13 MHz, CDCl3) : d = 1.03 (dd, J = 3, 9 Hz, 6 H),
1.09 (d, J = 6 Hz, 3 H), 1.25 (t, J = 6 Hz, 3 H), 2.36 (ABX, JAB = 15
Hz, JAX = 6 Hz, JBX = 6 Hz, 2 H), 2.89 (m, 1 H), 3.18 (m, 1 H), 4.12
(q, J = 7 Hz, 2 H).
Methyl 3-(p-Tolylamino)butanoate (4l)
1H NMR (300.13 MHz, CDCl3): d = 1.29 (d, J = 6 Hz, 3 H), 2.27 (s,
3 H), 2.56 (ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 9 Hz, 2 H), 3.71
(s, 3 H), 3.94 (m, 1 H), 6.59 (d, J = 9 Hz, 2 H), 7.02 (d, J = 9 Hz, 2
H).
13C NMR (75.03 MHz, CDCl3): d = 14.2, 21.0, 23.0, 23.5, 41.9,
45.3, 47.2, 60.2, 172.4.
HRMS: m/z calcd for C8H16NO2 [M – CH3]+: 158.1181; found:
13C NMR (75.03 MHz, CDCl3): d = 20.4, 20.7, 40.8, 46.4, 51.6,
114.0, 127.0, 129.9, 114.5, 172.4.
158.1197.
HRMS: m/z calcd for C12H17NO2: 207.1259; found: 207.1256.
tert-Butyl 3-(Isopropylamino)butanoate (4f)
Methyl 3-(o-Tolylamino)butanoate (4m)
1H NMR (300.13 MHz, CDCl3): d = 1.03 (dd, J = 3 Hz, 9 Hz, 6 H),
1.08 (d, J = 6 Hz, 3 H), 1.44 (s, 9 H), 2.27 (ABX, JAB = 15 Hz,
JAX = 9 Hz, JBX = 6 Hz, 2 H), 2.89 (m, 1 H), 3.13 (m, 1 H).
1H NMR (300.13 MHz, CDCl3): d = 1.21 (d, J = 6 Hz, 3 H), 2.03 (s,
3 H), 2.47 (ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 9 Hz, 2 H), 3.58
(s, 3 H), 3.89 (m, 1 H), 6.53–6.58 (m, 2 H), 6.94–7.05 (m, 2 H).
13C NMR (75.03 MHz, CDCl3): d = 20.9, 23.0, 23.6, 28.1, 43.1,
45.2, 47.3, 80.3, 171.8.
HRMS: m/z calcd for C8H16NO2 [M – C3H7]+: 158.1181; found:
158.1197.
13C NMR (75.03 MHz, CDCl3): d = 17.6, 20.8, 40.7, 45.7, 51.6,
110.5, 117.1, 122.4, 127.2, 130.4, 144.8, 172.3.
HRMS: m/z calcd for C12H17NO2: 207.1259; found: 207.1276.
Methyl 3-(4-Bromophenylamino)butanoate (4n)
Methyl 3-(Butylamino)butanoate (4g)
1H NMR (300.13 MHz, CDCl3): d = 1.27 (d, J = 6 Hz, 3 H), 2.53
(ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz, 2 H), 3.69 (s, 3 H), 3.88
(m, 1 H), 6.50 (d, J = 9 Hz, 2 H), 7.25 (d, J = 9 Hz, 2 H).
1H NMR (300.13 MHz, CDCl3): d = 0.89 (t, J = 7,5 Hz, 3 H), 1.09
(d, J = 6 Hz, 3 H), 1.32 (m, 2 H), 1.42 (m, 2 H), 2.38 (ABX,
JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz, 2 H), 2.57 (m, 2 H), 3.07 (m,
1 H), 3.66 (s, 3 H).
13C NMR (75.03 MHz, CDCl3): d = 20.5, 40.6, 46.1, 51.7, 109.1,
115.1, 132.0, 145.9, 172.1.
13C NMR (75.03 MHz, CDCl3): d = 14.0, 20.5, 20.6, 32.4, 41.3,
46.8, 50.2, 51.4, 172.9.
HRMS: m/z calcd for C11H14BrNO2: 271.0208; found: 271.0223.
HRMS: m/z calcd for C9H19NO2: 173.1416; found: 173.1423.
Methyl 3-(3¢,4¢-Dimethylphenylamino)butanoate (4o)
1H NMR (300.13 MHz, CDCl3): d = 1.32 (d, J = 6 Hz, 3 H), 2.22 (s,
3 H), 2.26 (s, 3 H), 2.58 (ABX, JAB = 15 Hz, JAX = 3 Hz, JBX = 6
Hz, 2 H), 3.74 (s, 3 H), 3.97 (m, 1 H), 6.45–6.53 (m, 2 H), 6.71 (d,
J = 9 Hz, 1 H).
Ethyl 3-(Butylamino)butanoate (4h)
1H NMR (300.13 MHz, CDCl3): d = 0.88 (t, J = 7.5 Hz, 3 H), 1.08
(d, J = 6 Hz, 3 H), 1.23 (t, J = 6 Hz, 3 H), 1.31 (m, 2 H), 1.41 (m, 2
H), 2.35 (ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz, 2 H), 2.57 (m,
2 H), 3.06 (m, 1 H), 4.11 (q, J = 7 Hz, 2 H).
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13C NMR (75.03 MHz, CDCl3): d = 18.7, 20.1, 20.7, 40.9, 46.4,
51.6, 111.2, 115.7, 125.8, 130.4, 137.4, 145.0, 172.4.
References
(1) (a) Gademann, K.; Hintermann, T.; Schreiber, J. V. Curr.
Med. Chem. 1999, 6, 905. (b) Gellman, S. H. Acc. Chem.
Res. 1998, 31, 173. (c) Hoekstra, W. J. Curr. Med. Chem.
1999, 6, 7940. (d) Juaristi, E. Enantioselective Synthesis of
b-Amino Acids; Wiley-VCH: New York, 1997.
HRMS: m/z calcd for C13H19NO2: 221.1416; found: 221.1426.
Ethyl 3-(Phenylamino)butanoate (4p)
1H NMR (300.13 MHz, CDCl3): d = 1.26 (d, J = 6 Hz, 3 H), 1.30 (t,
J = 4.5 Hz, 3 H), 2.54 (ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz,
2 H), 3.96 (m, 1 H), 4.16 (q, J = 7 Hz, 2 H), 6.62–6.75 (m, 3 H),
7.15–7.23 (m, 2 H).
(e) Guenard, D.; Guéritte-Voegelein, R.; Potier, P. Acc.
Chem. Res. 1993, 26, 160. (f) Seebach, D.; Matthews, J. L.
Chem. Commun. 1997, 2015.
13C NMR (75.03 MHz, CDCl3): d = 14.3, 20.6, 41.1, 46.0, 60.5,
113.6, 117.6, 129.4, 146.9, 171.8.
(2) (a) Konichi, M.; Nishio, M.; Saitoh, T.; Miyaki, T.; Oki, T.;
Kawaguchi, H. J. Antibiot. 1989, 42, 1749. (b) Oki, T.;
Hirano, M.; Tomatsu, K.; Numata, K.; Kamei, H. J. Antibiot.
1989, 42, 1756.
HRMS: m/z calcd for C12H17NO2: 207.1259; found: 207.1276.
(3) Shinagawa, S.; Kanamaru, T.; Harada, S.; Asai, M.;
Okazaki, H. J. Med. Chem. 1987, 30, 1458.
tert-Butyl 3-(Phenylamino)butanoate (4q)
1H NMR (300.13 MHz, CDCl3): d = 1.29 (d, J = 6 Hz, 3 H), 1.47 (s,
9 H), 2.46 (ABX, JAB = 15 Hz, JAX = 6 Hz, JBX = 6 Hz, 2 H), 3.92
(m, 1 H), 6.61–6.75 (m, 3 H), 7.16–7.23 (m, 2 H).
(4) (a) Namikoshi, M.; Rinehart, K. L.; Dahlem, A. M.; Beasley,
V. R.; Carmichael, W. W. Tetrahedron Lett. 1989, 30, 4349.
(b) Roers, R.; Verdine, G. L. Tetrahedron Lett. 2001, 42,
3563. (c) Wehner, V.; Blum, H.; Kurz, M.; Stilz, H. U.
Synthesis 2002, 2023. (d) Bull, S. D.; Davies, S. G.; Fox, D.
J.; Gianotti, M.; Kelly, P. M.; Pierres, C.; Savory, E. D.;
Smith, A. D. J. Chem. Soc., Perkin Trans. 1 2002, 1858.
(5) (a) Crews, P.; Manes, L.; Boehler, M. Tetrahedron Lett.
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Grossman, C. S.; Andis, S. L.; Schultz, R. M.; Worzalla, J.
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(7) See for example: (a) Yuan, C.; Williams, R. M. J. Am.
Chem. Soc. 1997, 119, 11777. (b) Yang, H.; Foster, K.;
Stephenson, C. R. J.; Brown, W.; Roberts, E. Org. Lett.
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13C NMR (75.03 MHz, CDCl3): d = 20.5, 28.1, 42.3, 46.2, 80.7,
113.5, 117.5, 129.3, 147.0, 171.2.
HRMS: m/z calcd for C10H13NO2 [M – C4H8]+: 179.0946; found:
179.0958.
Ethyl 3-Phenyl-3-(phenylamino)propanoate (4r)
1H NMR (300.13 MHz, CDCl3): d = 1.24 (t, J = 7.5 Hz, 3 H), 2.86
(d, J = 6 Hz, 2 H), 4.16 (q, J = 6 Hz, 2 H), 4.90 (t, J = 6 Hz, 1 H),
6.62 (d, J = 9 Hz, 2 H), 6.73 (t, J = 7.5 Hz, 1 H), 7.16 (t, J = 7.5 Hz,
2 H), 7.27–7.46 (m, 5 H).
13C NMR (75.03 MHz, CDCl3): d = 14.2, 43.0, 55.1, 60.8, 113.7,
117.8, 126.3, 127.5, 128.8, 129.2, 142.3, 146.9, 171.2.
HRMS: m/z calcd for C17H19NO2: 269.1416; found: 269.1428.
Ethyl 3-(4-Bromophenylamino)-3-phenylpropanoate (4s)
1H NMR (300.13 MHz, CDCl3): d = 1.22 (t, J = 7.5 Hz, 3 H), 2.83
(ABX, JAB = 15 Hz, JAX = 4.5 Hz, JBX = 7.5 Hz, 2 H), 4.15 (q, J = 7
Hz, 2 H), 4.82 (t, J = 7.5 Hz, 1 H), 6.47 (d, J = 9 Hz, 2 H), 7.20 (d,
J = 9 Hz, 2 H), 7.26–7.41 (m, 5 H).
13C NMR (75.03 MHz, CDCl3): d = 14.2, 42.8, 55.0, 60.9, 109.5,
115.3, 126.3, 127.7, 128.9, 131.9, 141.7, 145.9, 171.1.
(8) Gedey, S.; Liljeblad, A.; Lázár, L.; Fülöp, F.; Kanerva, L. T.
Tetrahedron: Asymmetry 2001, 12, 105; and references cited
therein.
(9) See for example: (a) Tang, T. P.; Ellman, J. A. J. Org. Chem.
2002, 67, 7819. (b) Wenzel, A. G.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 12964. (c) Murahashi, S.-i.; Imada,
Y.; Kawakami, T.; Harada, K.; Yonemushi, Y.; Tomita, N.
J. Am. Chem. Soc. 2002, 124, 2888. (d) Miaybe, H.; Fujii,
K.; Goto, T.; Naito, T. Org. Lett. 2000, 2, 4071.
(10) See for example: (a) Sibi, M. P.; Deshpande, P. K. J. Chem.
Soc., Perkin Trans. 1 2000, 1461. (b) Evans, D. A.; Wu, L.
D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D. H. B.; Tedrow,
J. S. J. Org. Chem. 1999, 64, 6411.
(11) See for example: (a) Sibi, M. P.; Shay, J. J.; Liu, M.;
Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615. (b) Sibi,
M. P.; Asano, Y. J. Am. Chem. Soc. 2001, 123, 9708.
(c) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.-i.; Tomioka,
K. J. Am. Chem. Soc. 2003, 125, 2886. (d) Myers, J. K.;
Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959.
(e) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124,
2134.
(12) See for example: (a) Bruncko, M.; Schlingoff, G.;
Sharpless, K. B. Angew. Chem,. Int. Ed. Eng. 1997, 36,
1483. (b) O’Brien, P. Angew. Chem. Int. Ed. 1999, 38, 326.
(13) (a) For recent examples, see: For a review, see: Palomo, C.;
Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org. Chem.
1999, 3223. (b) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc.
2002, 124, 1578. (c) Lo, M. M.-C.; Fu, G. C. J. Am. Chem.
Soc. 2002, 124, 4572.
HRMS: m/z calcd for C17H18BrNO2: 347.0521; found: 347.0525.
Methyl 3-(Pyrrolidin-1-yl)butanoate (4t)
1H NMR (300.13 MHz, CDCl3): d = 1.11 (d, J = 6 Hz, 3 H), 1.73
(m, 4 H), 2.22–2.67 (m, 1 H + 4 H + 1 H), 2.84 (m, 1 H), 3.64 (s, 3
H).
13C NMR (75.03 MHz, CDCl3): d = 18.7, 23.4, 40.1, 50.7, 51.5,
55.5, 172.9.
HRMS: m/z calcd for C9H17NO2: 171.1259; found: 171.1268.
tert-Butyl 3-(Pyrrolidin-1-yl)butanoate (4u)
1H NMR (300.13 MHz, CDCl3): d = 1.12 (d, J = 6 Hz, 3 H), 1.42 (s,
9 H), 1.74 (m, 4 H), 2.11–2.59 (m, 1 H + 5 H), 2.82 (m, 1 H).
13C NMR (75.03 MHz, CDCl3): d = 18.6, 23.4, 28.1, 41.6, 50.6,
55.6, 80.2, 171.9.
HRMS: m/z calcd for C8H14O2 [M – C4H9N ]+: 142.0994; found:
142.0982.
(14) Bruneau, C.; Renaud, J.-L.; Jerphagnon, T. Coord. Chem.
Rev. 2008, 252, 532.
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Iridium(I) Catalyst for the Synthesis of b-N-Substituted Amino Esters
2633
(15) (a) Spindler, F.; Blaser, H.-U. In Handbook of Homogeneous
Hydrogenation; de Vries, J. G.; Elsevier, C. J., Eds.; Wiley-
VCH: Weinheim, 2007, 1193–1214. (b) Tararov, V. I.;
Kadyrov, R.; Riermeier, T. H.; Holz, J.; Börner, A.
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Njolito, E.; Wang, F.; Sun, Y.; Armstrong, J. D. III;
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(18) (a) Bunlaksananusorn, T.; Rampf, F. Synlett 2005, 2682.
(b) Matsumara, K.; Saito, K. World Patent WO 2005/
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(19) (a) Vohra, R. K.; Renaud, J.-L.; Bruneau, C. Collect. Czech.
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(20) It was reported that trifluoroethanol was the best solvent for
the hydrogenation of enamino esters and b-N-arylenamino
esters in the presence of rhodium catalysts; see references 15
and 16.
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Armstrong, J. D. III; Krska, S. W.; Njolito, E.; Rivera, N. R.;
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