Synthesis of γ-amino acid esters by 1,4-addition of deprotonated α-aminonitriles and α-(alkylideneamino)nitriles to α,β-unsaturated esters

Article abstract of DOI:10.1055/s-2007-965937

α-Aminonitriles and α-(alkylideneamino)nitriles can serve as readily available α-aminocarbanion equivalents. Their conjugate addition to α,β-unsaturated esters followed by reduction furnishes polysubstituted γ-amino acid esters in moderate to high yield.

Full text of DOI:10.1055/s-2007-965937

918
PAPER
Synthesis of g-Amino Acid Esters by 1,4-Addition of Deprotonated
a-Aminonitriles and a-(Alkylideneamino)nitriles to a,b-Unsaturated Esters
g
-Amino
n
AcidEsters
e
from
a
-A
m
s
inonitriles Bergner, Till Opatz*
Institut für Organische Chemie, Johannes Gutenberg-Universität Mainz, Duesbergweg 10-14, 55128 Mainz, Germany
Fax +49(6131)3924786; E-mail: opatz@uni-mainz.de
Received 20 September 2006; revised 20 December 2006
namate (2a) to yield the diastereomeric products of the
Abstract: a-Aminonitriles and a-(alkylideneamino)nitriles can
serve as readily available a-aminocarbanion equivalents. Their con-
jugate addition to a,b-unsaturated esters followed by reduction fur-
nishes polysubstituted g-amino acid esters in moderate to high
yield.
1,4-addition 3 in a 1:1 ratio. Chromatographic separation
and reductive decyanation of the diastereomers with
NaCNBH3 in both cases gave the same 8:1 mixture of the
diastereomeric g-amino acid esters 4 (Scheme 1). As the
diastereoselectivity of the reduction is independent of the
relative configuration of the starting material, the reduc-
tive decyanation most likely proceeds via an elimination–
addition sequence.
Key words: Michael addition, reduction, a-aminonitriles, a-amino-
carbanions, g-amino acids
Due to their close relation to the inhibitory neurotransmit-
ter g-aminobutyric acid (GABA), g-amino acid deriva-
tives represent interesting targets for the development of
drugs for the treatment of imbalances in GABAergic sig-
nal transmission. C-Substituted GABA derivatives are for
example used for the treatment of epilepsy, spasticity or as
medication in pain therapy.1–5 Moreover, g-amino acid de-
rivatives have been employed as building blocks for the
preparation of peptidomimetics.2,6–9 Among the methods
used for their preparation, the 1,4-addition of nitronates to
a,b-unsaturated esters10 and the 1,4-addition of ester eno-
lates to nitroolefins11 are most widely applied. A tech-
nique for the preparation of N-substituted products is the
samarium-mediated reductive addition of nitrones to a,b-
unsaturated esters developed by Masson, Vallée and
Py.12,13 Unfortunately, this elegant method requires two
equivalents of samarium diiodide as well as the subse-
quent reduction of the produced hydroxylamine. Here, we
report on a two-step procedure for the synthesis of g,N-di-
and b,g,N-trisubstituted g-amino acids from deprotonated
a-aminonitriles and a-(alkylideneamino)nitriles.
CN
1) KHMDS, THF, –78 °C
NH
2)
O
Me
OtBu
1
Cl
2a
CN Me
NH
CN Me
NH
1 : 1
OtBu
Cl
O
OtBu
Cl
O
syn-3
anti-3
NaCNBH3,
EtOH, AcOH
OtBu
O
Strecker products derived from primary amines or from
ammonia can be deprotonated in a-position without using
protecting groups to prevent the retro-Strecker reaction.14–17
The vinylogous addition of their conjugate anions to a,b-
unsaturated aldehydes or ketones allows the preparation
of highly substituted pyrrolidines in a one-pot reaction se-
quence.18,19 If a,b-unsaturated esters are used as the elec-
trophiles,20 the reductive removal of the cyano group21
from the products of the 1,4-addition yields g-amino acid
esters. As an example, the Strecker product from 2-naph-
thaldehyde and methylamine (1) was deprotonated with
KHMDS in THF at –78 °C. To the resulting solution of
the potassium salt of 1 was added tert-butyl 4-chlorocin-
NH
Me
Cl
4
anti/syn = 8:1, 54% over 2 steps
(+9% trans-γ-lactam)
Scheme 1
The relative configuration of the major product could be
established to be anti by X-ray crystallography (Figure 1).
Along with compounds 4, the trans-configured g-lactam
was formed by intramolecular aminolysis of the tert-butyl
ester of syn-4 during the reduction step. The selectivity of
this side reaction can be explained by the fact that anti-4
adopts an extended conformation (Figure 1), whereas in
the syn-diastereomer, the repulsion between the b- and the
SYNTHESIS 2007, No. 6, pp 0918–0928
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Advanced online publication: 20.02.2007
DOI: 10.1055/s-2007-965937; Art ID: T14506SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
g-Amino Acid Esters from a-Aminonitriles
919
(Scheme 2, Tables 1 and 2). Presumably, the first hydride
equivalent is consumed by the reduction of the C=N bond
while the second reduction step involves elimination of
HCN and reduction of the formed imine. Interestingly, the
g- and the N-substituent play a major role in the reductive
decyanation: N-unsubstituted aminonitriles obtained by
acid hydrolysis of compounds 6 did not yield the corre-
sponding N-unsubstituted g-amino acids. Moreover, com-
pounds 6 devoid of a g-substituent were quickly reduced
to the N-alkylated aminonitriles but the decyanation pro-
ceeded sluggishly. For example, reduction of 6h furnished
only a 4.5:1-mixture of the a-(benzhydrylamino)nitrile 9
and the decyanated g-amino acid ester 7h after nine days.
Figure 1 Crystal structure of anti-4
On the other hand, the reduction of the g-substituted
Michael adducts 6b–g was usually complete overnight.
Although similar reactivity trends have been reported for
the reductive cleavage of aminonitriles during catalytic
hydrogenation,28 the origin of these effects is not yet fully
understood.
g-substituent may induce a bent conformation in which
the N-terminus is closer to the p*-orbital of the carbonyl
group (vide infra).
Whereas the non-destructive deprotonation of a-aminoni-
triles with free NH protons requires the presence of a sta-
bilizing a-substituent such as an aromatic, heteroaromatic
or olefinic group in order to prevent a retro-Strecker reac-
tion,22 a-(alkylideneamino)nitriles 5 are much more CH-
acidic and can be easily deprotonated even if no stabiliz-
ing a-substituent is present.23–25 We tested several condi-
tions for the addition reaction and found that either phase-
transfer conditions (7.9 M KOH/CH2Cl2, 10 mol%
BnNEt3Cl)26,27 or the use of metal-free bases such a DBU
or Me4NOH furnishes the desired products. In most cases,
the biphasic system gives somewhat higher yields al-
though side reactions may occur.23 However, no general
rules could yet be devised to determine the optimal base
for a given transformation. The Michael adducts 6 were
obtained in moderate to good yield. Whereas Tsuge and
Kanemasa described fast additions to a,b-unsaturated
methyl esters, the tert-butyl esters used in this work to
prevent lactam formation reacted slower.23
R2
R3
R4
OtBu
R1
N
CN
O
5
2
base
R2
R3
CN
R4
OtBu
R1
N
O
6
NaCNBH3
AcOH
EtOH
R2
R3
OtBu
R1
N
H
R4
O
We found that the complete reduction of the stable addi-
tion products 6 with NaCNBH3 under mild conditions fur-
nishes g-amino acid esters 7 in moderate to excellent yield
7
Scheme 2 General reaction course to g-aminobutyric esters
Table 1 1,4-Addition of a-(Alkylideneamino)nitriles to a,b-Unsaturated Esters
Imine R1
R2
R3
H
Ester
2b
2b
2b
2c
R4
Methoda
Product
6a
Yield (%) dr
5a
5b
5b
5b
5b
5c
5d
5e
5a
Ph
H
Ph
H
A
A
B
C
A
B
A
A
A
80
95
43
64
51
61
94
99
84
–
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
2-naphthyl
2- naphthyl
Ph
Bn
Bn
Bn
Bn
Ph
Me
Bn
H
H
6b
–
H
H
6b
–
H
Me
6c
1.2:1
1.3:1
1.5:1
–
H
2a
4-ClC6H4
4-ClC6H4
H
6d
H
2a
6e
H
2b
2b
2a
6f
H
H
6g
–
Ph
4-ClC6H4
6h
1.2:1
a Method A: BnNEt3Cl (0.1 equiv), KOH (7.9 M, 20 equiv), CH2Cl2; Method B: DBU (1.1 equiv), THF; Method C: Me4NOH (1 equiv, 25 wt%
in MeOH), THF.
Synthesis 2007, No. 6, 918–928 © Thieme Stuttgart · New York

920
I. Bergner, T. Opatz
PAPER
Table 2 g-Aminobutyric Acid Esters via Reduction with Sodium Cyanoborohydride
1,4-Adduct R1
R2
R3
H
R4
Product
7a
Yield (%)
anti/syna
6a
6b
6c
6d
6e
6f
Ph
H
Ph
H
71
81
54
58
60
94
89
–
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
2- naphthyl
2- naphthyl
Ph
Bn
Bn
Bn
Ph
Me
Bn
H
H
7b
–
H
Me
7c
1.6:1
>98:2
6.5:1
–
H
4-ClC6H4
4-ClC6H4
H
7d
H
7e
H
7f
6g
6h
H
H
7g
–
b
Ph
4-ClC6H4
7h
–
a Determined by 1H NMR spectroscopy.
b A 4.5:1-mixture of the a-(benzhydrylamino)nitrile (9) and the doubly reduced product 7h was obtained.
In the reduction of compound 6d, a seemingly complete atives from readily available starting materials. a-Amino-
selectivity in favor of anti-7d is observed. The relative nitriles are accessible via Strecker reaction of aldehydes
configuration of this material could be assigned by its and amines, whereas a-(alkylideneamino)nitriles can be
conversion to the corresponding g-lactam 8d. NMR mea- prepared by condensing Strecker products derived from
surements revealed the cis-configuration of the product.29 ammonia with aldehydes. As a,b-unsaturated esters can
As a side product, the reduction of compound 6d also fur- also be assembled in a modular fashion, the presented
nished the trans-configured g-lactam 8d in 30% yield. methodology is amenable to the combinatorial variation
Thus, the reduction of 6d presumably yields both diaste- of substituents.
reomers of 7d but only the syn-diastereomer quantitative-
ly cyclized to the corresponding g-lactam, leaving behind
pure anti-7d (Scheme 3). A similar, though less impres-
sive, observation was also made in the case of compound
4 (vide supra) as well as compound 7e, where a 2.6:1-dia-
stereomeric mixture of g-lactams 8e in favor of the ster-
ically less encumbered trans-8e was formed.
1H NMR and 13C NMR spectra were recorded on a Bruker AC-300
or AMX-400 spectrometer, chemical shifts were referenced to the
residual solvent signal (CDCl3: dH = 7.24, dC = 77.0). FD-MS spec-
tra were measured on a Finnigan MAT-95 spectrometer. ESI-
HRMS spectra were measured on a Waters Q-TOF-Ultima 3
equipped with a LockSpray interface (HCO2Na or NaI/CsI as exter-
nal reference). IR spectra were recorded on a Perkin-Elmer 1760X
FTIR spectrometer. The melting points were measured on a Dr. Tot-
In summary, we have found a short and efficient method
for the preparation of polysubstituted g-amino acid deriv- toli apparatus (Büchi) and are uncorrected. THF was freshly dis-
OtBu
Cl
O
Cl
spontaneous
NH
O
OtBu
N
O
OMe
OMe
syn-7d
not isolated
Cl
NaCNBH3
AcOH
EtOH
NC
MeO
OtBu
OMe
trans-8d
30%
N
Cl
O
1) TFA
Cl
2) pyridine,
100 °C
MeO
OMe
O
N
NH
OMe
OMe
6d
anti-7d
cis-8d
58%
MeO
OMe
Scheme 3
Synthesis 2007, No. 6, 918–928 © Thieme Stuttgart · New York

PAPER
g-Amino Acid Esters from a-Aminonitriles
921
tilled from potassium/benzophenone under argon. EtOAc and
petroleum ether (PE) were distilled from K2CO3 and CaH2, respec-
tively, before use. All other solvents and reagents were purchased
from commercial suppliers and were used without further purifica-
tion. Petroleum ether (PE) used had a boiling range of 40–70 °C.
TLC was performed on aluminum sheets coated with silica gel (60
g-Lactam [trans-4-(4-Chlorophenyl)-1-methyl-5-(2-naphth-
yl)pyrrolidin-2-one]
1H NMR (400 MHz, CDCl3): d = 7.89 (d, J = 8.5 Hz, 1 H, H4¢),
7.88–7.76 (m, 2 H, H5¢, H8¢), 7.53–7.49 (m, 3 H, H1¢, H6¢, H7¢),
7.28–7.25 (m, 3 H, H3¢, H3¢¢,5¢¢), 7.06 (BB¢ part of AA¢BB ¢ system,
2 H, H2¢¢,6¢¢), 4.54 (d, J = 6.7 Hz, 1 H, H5), 3.41 (dt, Jt = 9.0 Hz,
Jd = 6.7 Hz, 1 H, H4), 3.03 (dd, Jgem = 17.0 Hz, Jvic = 9.0 Hz, 1 H,
H3a), 2.74 (s, 3 H, NCH3), 2.70 (dd, Jgem = 17.0 Hz, Jvic = 9.0 Hz, 1
H, H3b).
F
254, E. Merck). Flash column chromatography was carried out on
silica gel (32–63 mm, 60 Å, MP Biomedicals GmbH). Imines 5a–c
were synthesized via known literature procedures.19,30,31
Irradiation (transient NOE) at 4.54 ppm (H5) enhances the signals
at 7.52 (H1¢, 4.3%), 7.26 (H3¢, 2.2%), 7.06 (H2¢¢,6¢¢, 2.6%), 3.41
(H4, 1.2%), 2.74 (NCH3, 2.1%), 2.70 (H3b, 0.8%). Irradiation at
3.41 ppm (H4) enhanced the signals at 7.52 (H1¢, 1.0%), 7.26 (H3¢,
2.6%), 7.06 (H2¢¢,6¢¢, 4.3%), 4.54 (H5, 1.3%), 3.03 (H3a, 3.2%),
2.70 (H3b, 0.9%).
13C NMR, HSQC (100.6 MHz, CDCl3): d = 174.0 (C2), 139.7,
136.3, 133.25, 133.17, 133.1 (C2¢, C4a¢,C8a¢, C1¢¢, C4¢¢), 129.3
(C4¢), 129.0 (2 C, C3¢¢,5¢¢), 128.5 (2 C, C2¢¢,6¢¢), 127.84, 127.75
(C5¢, C8¢), 126.6, 126.4, 126.2 (C1¢, C6¢, C7¢), 123.6 (C3¢), 72.8
(C5), 47.4 (C4), 38.2 (C3), 28.5 (NCH3).
tert-Butyl 3-(4-Chlorophenyl)-4-(methylamino)-4-(2-naph-
thyl)butanoate (4)
(Methylamino)-2-naphthylacetonitrile (1; 400 mg, 2.04 mmol) was
dissolved in anhyd THF (10 mL) and cooled to –78 °C under argon.
A solution of KHMDS (447 mg, 2.24 mmol) in anhyd THF (5 mL)
was added within 1 min. After 1 more min, a solution of (E)-tert-
butyl 4-chlorocinnamate34 [2a; 487 mg, 2.04 mmol, prepared from
(E)-4-chlorocinnamic acid after a protocol by Ahmad et al.35] in an-
hyd THF (5 mL) was added to the deep red solution. After 1 h, TLC
indicated no further conversion. To the mixture were added aq sat.
NH4Cl solution (5 mL) and Et2O (15 mL). The organic layer was
separated, washed with brine (30 mL) and dried (Na2SO4). Removal
of the solvent in vacuo yielded the crude product (974 mg) as a yel-
low oil. Purification by flash chromatography (n-hexane–EtOAc,
8:1 → 5:1) furnished the diastereomeric addition products P1 (315
mg, 36%) and P2 (327 mg, 37%) as colorless oils.
4 (Ratio of anti/syn = 8:1)
IR (KBr): 3423 (br, NH), 2977, 2933, 2780, 1718 (vs), 1491, 1368,
1319, 1255, 1158 (sh), 1142, 1091, 1015, 832, 748 cm–1.
ESI-MS: m/z (%) = 410.2 (100, [M + H]+), 354.2 (18, [M – C4H8 +
H]+), 323.1 (11, [M – CH3NH]+).
P1
ESI-HRMS: m/z calcd for [C25H28ClNO2 + H]+: 410.1887; found:
410.1877.
Rf = 0.43 (n-hexane–EtOAc, 3:1).
1H NMR (300 MHz, CDCl3): d = 8.11 (d, J = 1.8 Hz, 1 H, H1¢),
7.94–7.83 (m, 3 H, H4¢, H5¢, H8¢), 7.70 (dd, 1 H, J = 8.8, 1.8 Hz, 1
H, H3¢), 7.54 (mc, 2 H, H6¢, H7¢), 7.44 (AA¢-part of AA¢BB¢ sys-
tem, 2 H, ClC6H4), 7.37 (BB¢-part of AA¢BB¢ system, 2 H, ClC6H4),
3.59 (dd, J = 11.8, 4.4 Hz, 1 H, b-CH), 2.78 (dd, Jgem = 15.5,
Jvic = 11.8 Hz, 1 H, CH2-a), 2.33 (dd, Jgem = 15.5, Jvic = 4.4 Hz, 1 H,
CH2-b), 2.13 (d, J = 5.5 Hz, 3 H, NCH3), 1.50 (br q, J = 5.5 Hz, 1
H, NH), 1.06 (s, 9 H, t-C4H9).
anti-4
1H NMR (300 MHz, CDCl3): d = 7.86–7.78 (m, 3 H, H4¢, H5¢, H8¢),
7.70 (br s, 1 H, H1¢), 7.51–7.40 (m, 3 H, H3¢, H6¢, H7¢), 7.30 (AA¢
part of AA¢BB¢ system, 2 H, H3¢¢,5¢¢), 7.22 (BB¢ part of AA¢BB¢ sys-
tem, 2 H, H2¢¢,6¢¢), 3.68 (d, J = 9.2 Hz, 1 H, H4), 3.34 (ddd, J = 10.4,
9.2, 5.3 Hz, 1 H, H3), 2.37 (dd, Jgem = 15.3 Hz, Jvic = 10.4 Hz, 1 H,
H2-a), 2.28 (dd, Jgem = 15.3 Hz, Jvic = 5.3 Hz, 1 H, H2-b), 2.08 (s, 3
H, NCH3), 1.11 (s, 9 H, t-C4H9).
13C NMR, DEPT (75.5 MHz, CDCl3): d = 170.9 (C=O), 139.7,
138.6 (C1¢¢, C4¢¢), 133.19, 133.18, 132.8 (C2¢, C4a¢, C8a¢), 129.8 (2
C, Cl-C6H4), 128.7 (2 C, Cl-C6H4), 128.4, 127.75, 127.66, 127.6,
126.1, 125.8, 125.5 (C1¢, C3¢, C4¢, C5¢, C6¢, C7¢, C8¢), 80.3
[C(CH3)3], 70.3 (C4), 48.5 (C3), 39.5 (C2), 34.8 (NCH3), 27.7 [3 C,
C(CH3)3].
P2
Rf = 0.34 (n-hexane–EtOAc, 3:1).
1H NMR (300 MHz, CDCl3): d = 7.84–7.76 (m, 4 H, H1¢, H4¢, H5¢,
H8¢), 7.84–7.76 (m, 3 H, H3¢, H6¢, H7¢), 7.13 (AA¢ part of AA¢BB¢
system, 2 H, Cl-C6H4), 6.98 (BB¢ part of AA¢BB¢ system, 2 H, Cl-
C6H4), 3.66 (dd, J = 9.3, 6.4 Hz, 1 H, b-CH), 2.86–2.82 (m, 2 H a-
CH2), 2.31 (br s, 3 H, NCH3), 1.86 (br s, 1 H, NH), 1.15 (s, 9 H, t-
C4H9).
syn-4
1H NMR (300 MHz, CDCl3): d (characteristic chemical shifts) =
7.10 (AA¢ part of AA¢BB ¢ system, 2 H, H3¢¢,5¢¢), 6.91 (BB¢ part of
AA¢BB ¢ system, 2 H, H2¢¢,6¢¢), 3.76 (d, J = 7.0 Hz, 1 H, H4), 3.51
(ddd, J = 9.0, 7.0, 6.3 Hz, 1 H, H3), 2.85 (dd, Jgem = 15.4 Hz,
Jvic = 6.3 Hz, 1 H, H2-a), 2.54 (dd, Jgem = 15.4 Hz, Jvic = 9.0 Hz, 1
H, H2-b), 2.21 (s, 3 H, NCH3), 1.27 (s, 9 H, t-C4H9).
13C NMR, DEPT (75.5 MHz, CDCl3): d (characteristic chemical
shifts) = 171.8 (C=O), 139.5, 138.2 (C1¢¢, C4¢¢), 133.0, 132.7,
(naph-Cq), 129.9 (2 C, C3¢¢,5¢¢), 128.0 (2 C, C2¢¢,6¢¢), 127.7, 127.5,
127.0, 125.9, 125.6 (2 C) (naph), 80.3 [C(CH3)3], 69.7 (C4), 47.7
(C3), 38.4 (C2), 34.6 (NCH3), 27.9 [C(CH3)3].
The diastereomer P1 (305 mg) was dissolved in EtOH (7.5 mL) and
after addition of NaCNBH3 (88.1 mg, 1.40 mmol) and AcOH (120
mL, 2.10 mmol), the mixture was stirred for 24 h at r.t. The mixture
was partitioned between Et2O (30 mL) and aq 1 N NaOH (25 mL)
solution, the organic layer was separated, washed with brine (25
mL) and dried (Na2SO4). Removal of the solvent in vacuo yielded a
colorless crystalline solid (240.8 mg). Reduction of the diastere-
omer P2 (315 mg) under identical conditions furnished a colorless
crystalline solid (269.8 mg). NMR spectroscopic analysis revealed
that both samples had an identical composition and contained an 8:1
diastereomeric mixture of the g-amino acid esters 4 along with 15%
of the trans-g-lactam. Overall yield from 4: 54%, 9% g-lactam.
2-[(2-Naphthylmethylene)amino]propionitrile (5d)
An attempt to remove the cyclized product from a sample (487 mg)
of the material by column chromatography led to partial decompo-
sition. Crystallization of the resulting diastereomeric mixture of 4
(282 mg, colorless crystals) from EtOAc yielded crystals of anti-4
suitable for X-ray crystallography.
2-Naphthaldehyde (6.0 g, 38.4 mmol) was dissolved in CH2Cl2 (40
mL). To this solution were added MgSO4 (13.9 g, 115.2 mmol), 2-
aminopropionitrile hydrochloride32 (5.3 g, 50.0 mmol) and Et3N
(5.9 mL, 42.2 mmol). After stirring the mixture overnight under ar-
gon, MgSO4 was filtered off and the solvent was removed in vacuo.
Crystallization from Et2O and petroleum ether gave a crude yellow
solid (2.95 g). The solid was dissolved in CH2Cl2 (100 mL), washed
with aq sat. NaHCO3 solution (100 mL) and dried (Na2SO4). Re-
Synthesis 2007, No. 6, 918–928 © Thieme Stuttgart · New York

922
I. Bergner, T. Opatz
PAPER
moval of the solvent and crystallization from Et2O and petroleum
ether gave the pure title compound as slightly yellow crystals (1.16
g). The mother liquor was evaporated and the resulting residue
(4.44 g) was reacted once again with equivalent amounts of amino-
nitrile hydrochloride, Et3N and MgSO4 and yielded after purifica-
tion 4.12 g pure product. The combined yield amounted to 66%;
Rf = 0.48 (PE–EtOAc, 2:1); mp 86–88 °C.
solution (2 × 5–20 mL) and with H2O (5 –20 mL). The organic layer
was dried (Na2SO4), filtered and the solvent was removed in vacuo.
Method C: In an oven-dried flask, imine 5 (1 equiv) and ester 2 (1
equiv) were dissolved in anhyd THF under argon. A solution of
Me4NOH (25 wt% in MeOH, 1 equiv) in THF was added dropwise
within 30 min at –8 °C. After 1.5 h at –8 °C, aq 1 N NaOH (25 mL)
was added. After extraction with EtOAc (3 × 15 mL) and washing
with H2O (3 × 15 mL), the organic layer was dried (Na2SO4), fil-
tered and the solvent was removed in vacuo.
IR (film): 2990 (w), 2939 (w), 2869 (w), 2250 (vw, C≡N), 1635 (s),
1347 (w), 1311 (w), 1123 (m), 973 (m), 869 (m), 827 (s), 757 cm–1
(s).
tert-Butyl 4-Cyano-4-[(diphenylmethylene)amino]butyrate (6a)
Following method A, imine 5a (500 mg, 2.27 mmol) and BnNEt3Cl
(51.7 mg, 0.227 mmol) in CH2Cl2 (10 mL), ester 2b (332.8 mL,
293.8 mg, 2.29 mmol) in CH2Cl2 (10 mL), and KOH (2.55 g, 45.4
mmol) in H2O (5.05 mL) were used. Complete conversion was
achieved after 100 min. Purification of the crude product (719.5 mg,
yellow oil) by flash chromatography (PE–EtOAc, 8:1) furnished 6a
(632.3 mg, 80%) as a slightly yellow oil; Rf = 0.66 (PE–EtOAc,
1:1).
1H NMR (300 MHz, DMSO-d6): d = 8.65 (s, 1 H, CH=N), 8.30 (s,
1 H, naph-H1), 8.07–7.88 (m, 4 H, naph-H3, -H4, -H5, -H8), 7.62–
7.52 (m, 2 H, naph-H6, -H7), 4.95 (q, J = 7.1 Hz, 1 H, CNCH), 1.58
(d, J = 7.1 Hz, 3 H, CH3).
13C NMR (75.5 MHz, DMSO-d6): d = 163.6 (C=N), 134.6 (naph-
C4a), 132.7 (naph-C2), 132.6 (naph-C8a), 131.2, 128.9, 128.7,
127.9, 127.9 (partly overlapping signals), 127.0, 123.3 (naph-C3),
120.1 (CN), 52.9 (CCN), 20.9 (CH3).
FD-MS: m/z = 208.2 (100%, [M]+).
IR (film): 2978 (m), 2242 (vw, C≡N), 1728 (s, C=O), 1619 (m),
1596 (m), 1578 (m), 1447 (m), 1368 (m), 1317 (m), 1291 (m), 1257
(m), 1152 (s), 784 (w), 698 cm–1 (s).
Anal. Calcd for C14H12N2: C, 80.74; H, 5.81; N, 13.45. Found: C,
80.93; H, 5.85; N, 13.05.
1H NMR (300 MHz, CDCl3): d = 7.64–7.18 (m, 10 H, C6H5), 4.30
(t, J = 6.4 Hz, 1 H, CHCN), 2.52–2.35 (m, 2 H, CH2), 2.26–2.09 (m,
2 H, CH2CO), 1.37 (s, 9 H, t-C4H9).
13C NMR (75.5 MHz, CDCl3): d = 173.5 (C=O), 171.3 (C=N),
138.3 (ipso-C), 135.0 (ipso-C), 131.2, 129.3, 129.0 (4 C), 128.2 (2
C), 127.3 (2 C), 119.1 (CN), 80.8 (CMe3), 51.9 (CHCN), 31.1 (b-
CH2), 30.0 (CH2CO), 28.0 [3 C, C(CH3)3].
2-[(2-Naphthylmethylene)amino]-3-phenylpropionitrile (5e)
2-Naphthaldehyde (1.6 g, 10.2 mmol) was dissolved in anhyd
CH2Cl2 (10 mL). To this solution were added, MgSO4 (3.68 g, 30.6
mmol), 2-amino-3-phenylpropionitrile33 (2.04 g, 14.0 mmol) and
AcOH (3 mL, 52.4 mmol) and the mixture was refluxed for 8 h un-
der argon. After filtration of MgSO4, the filtrate was washed with aq
sat. NaHCO3 solution (10 mL) and dried (Na2SO4). Removal of the
solvent in vacuo yielded the crude product. After crystallization
from EtOAc–cyclohexane, yellow crystals (1.50 g, 52%) were ob-
tained; Rf = 0.51 (PE–EtOAc, 10:1); mp 81–83 °C.
ESI-MS: m/z (%) = 400.1 (51), 349.0 (70, [M + H]+), 292.97 (100,
[M – C4H8]+).
ESI-HRMS: m/z calcd for [C22H24N2O2 + H]+: 349.1916; found:
IR (film): 3061 (w), 3031 (w), 2885 (w), 2232 (vw, C≡N), 1646 (s,
C = N), 1498 (m), 1455 (m), 1342 (w), 1018 (w), 867 (m), 869 (m),
824 (m), 755 (s), 698 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 8.42 (s, 1 H, CH=N), 8.05 (s, 1 H,
naph-H1), 8.01–7.96 (m, 1 H, naph-H3), 7.92–7.82 (m, 3 H, naph-
H4, -H5, -H8), 7.58–7.49 (m, 2 H, naph-H6, -H7), 7.37–7.24 (m, 5
H, C6H5), 4.95–4.88 (m, 1 H, CHCN), 3.38 (dd, J = 13.6, 5.9 Hz, 1
H, PhCH2-Ha), 3.24 (dd, J = 13.6, 7.4 Hz, 1 H, PhCH2-Hb).
13C NMR (75.5 MHz, CDCl3): d = 163.3 (C=N), 135.1 (C6H5-C1),
135.1, 132.9, 132.5, 131.4, 129.9 (2 C), 128.9, 128.7, 128.6 (2 C)
(partly overlapping signals), 127.9, 127.7, 127.5, 126.7, 123.5,
117.5 (CN), 60.1 (CCN), 40.8 (PhCH2).
349.1943.
Anal. Calcd for C22H24N2O2: C, 75.83; H, 6.94; N, 8.04. Found: C,
76.09; H, 6.80; N, 8.10.
tert-Butyl 4-Cyano-4-[(3,4-dimethoxybenzylidene)amino]-5-
phenylpentanoate (6b)
Following method A, imine 5b (500 mg, 1.699 mmol) and
BnNEt3Cl (38.7 mg, 0.170 mmol) in CH2Cl2 (5 mL), ester 2b (247
mL, 218 mg, 1.70 mmol) in CH2Cl2 (5 mL), and KOH (1.91 g, 33.97
mmol) in H2O (3.78 mL) were reacted. After 2 h, 701.3 mg of a
slightly yellow oil was isolated. A portion (682.9 mg) of the crude
product was purified by flash chromatography (cyclohexane–
EtOAc, 3:1 + 1% Me2NEt) to give 6b (662.0 mg, 95%) as a color-
less oil.
FD-MS: m/z = 284.2 (100%, [C20H16N2]+).
According to method B, the crude product (76.6 mg, brown oil) was
obtained after 20 h from a solution of 5b (60 mg, 2.204 mmol), 2b
(29.6 mL, 26.1 mg, 0.204 mmol), and DBU (33.5 mL, 34.1 mg, 0.224
mmol) in anhyd THF (0.6 mL). Purification of the crude product by
flash chromatography (PE–EtOAc, 3:1) led to 6b (37 mg, 43%) as
a colorless oil; Rf = 0.23 (PE–EtOAc, 3:1).
g-(Alkylideneamino)-g-cyanoesters 6a–h; General Procedure
(Table 1)
Method A: To a stirred mixture of imine 5 (1 equiv) and BnNEt3Cl
(0.1 equiv) in CH2Cl2, were added a solution of ester 2 (1.01–1.1
equiv) in CH2Cl2 and an aq solution of KOH (33.5 wt%, 20 equiv)
simultaneously under argon. The color of the solution changed to
yellow or orange. After stirring for several hours, the mixture was
washed with sat. aq NaHCO3 solution (3 × 5–10 mL) and H2O (1 ×
5–10 mL). The organic layer was dried (Na2SO4), filtered and the
solvent was removed in vacuo.
IR (film): 2934 (m), 1729 (s, C=O), 1642 (m), 1586 (m), 1513 (s),
1456 (m), 1422 (m), 1368 (m), 1269 (s), 1242 (m) 1154 (s), 1026
(m), 705 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.97 (s, 1 H, CH=N), 7.37 [d,
J = 1.8 Hz, 1 H, 3,4-(OMe)2C6H3-H2], 7.22–7.15 [m, 6 H, C6H5,
3,4-(OMe)2C6H3], 6.87 [d, J = 8.3 Hz, 1 H, 3,4-(OMe)2C6H3-H5],
3.94 (s, 3 H, OCH3), 3.91 (s, 3 H, OCH3), 3.15 (s, 2 H, PhCH2),
2.37–2.23 (m, 4 H, b-CH2, CH2CO), 1.39 (s, 9 H, t-C4H9).
Method B: To a stirred solution of imine 5 (1 equiv) and ester 2 (1
equiv) in anhyd THF, was added DBU (1.1 equiv) under argon. The
color change of the solution was pronounced in most cases. After
stirring for several hours, EtOAc (5–20 mL) and aq NaHCO3 solu-
tion (5–20 mL) were added to the mixture. After separation of the
aqueous layer, the organic layer was washed with sat. aq NaHCO3
ESI-MS: m/z (%) = 423.1 (100, [M + H]+), 367.0 (78, [M – C4H8 +
H]+).
Synthesis 2007, No. 6, 918–928 © Thieme Stuttgart · New York

PAPER
g-Amino Acid Esters from a-Aminonitriles
923
ESI-HRMS: m/z calcd for [C25H30N2O4 + H]+: 423.2284; found:
423.2266.
(partly overlapping signals), 127.3 (4-ClC6H4-C4), 127.5 (C6H5-
C4), 123.5 [3,4-(OMe)2C6H3-C6], 117.8 (CN), 110.7 [3,4-
(OMe)2C6H3-C2], 110.0 [3,4-(OMe)2C6H3-C5], 81.0 (CMe3), 71.5
(CCN), 56.0 (OCH3), 55.9 (OCH3), 50.6 (4-ClC6H4-CH), 44.4
(PhCH2), 38.1 (CH2CO), 27.8 [3 C, C(CH3)3].
tert-Butyl 4-Cyano-4-[(3,4-dimethoxybenzylidene)amino]-3-
methyl-5-phenylpentanoate (6c)
According to method C, the crude product (601 mg, slightly yellow
oil) was obtained from a solution of 5b (414.2 mg, 1.407 mmol) and
2c (200.1 mg, 1.41 mmol) in anhyd THF (5 mL) after addition of
Me4NOH (25 wt% in MeOH, 570 mL, 1.41 mmol) in anhyd THF (5
mL) after a reaction time of 75 min. A portion (165 mg) of the crude
product was purified by flash chromatography (cyclohexane–
EtOAc, 4:1 + 1% Me2NEt) to give 6c (108.6 mg) as a colorless oil.
Ratio of isomers: 1.2:1 (based on crude product); Rf = 0.44 (PE–
EtOAc, 2:1).
ESI-MS: m/z (%) = 533.2 (100%, [M + H]+).
ESI-HRMS: m/z calcd for [C31H33ClN2O4 + H]+: 533.2207; found:
533.2212.
Anal. Calcd for C31H33ClN2O4: C, 69.85; H, 6.24; N, 5.26. Found:
C, 69.73; H, 6.13; N, 5.18.
Major Diastereomer
Rf = 0.24 (PE–EtOAc, 3:1).
IR (film): 2976 (m), 1728 (s, C=O), 1644 (m), 1601 (m), 1586 (m),
1513 (s), 1456 (m), 1421 (m), 1368 (m), 1269 (s), 1242 (m), 1162
(s), 1142 (m), 1026 (m), 706 cm–1 (m).
IR (film): 2934 (w), 1728 (s, C=O), 1641 (m), 1600 (m), 1586 (m),
1513 (s), 1495 (m), 1456 (m), 1422 (m), 1368 (m), 1269 (s), 1241
(m), 1145 (s), 1026 (m), 734 (m), 702 cm–1 (m).
1H NMR (300 MHz, CDCl3): d (ratio of isomers a/b = 1.7:1) = 7.79
(s, 1 H, CH=Nb), 7.78 (s, 1 H, CH=Na), 7.33 [s, 1 H, 3,4-(OMe)2-
C6H3-H2a + b], 7.18–7.09 [m, 6 H, C6H5a + b, 3,4-(OMe)2C6H3-H6a + b],
6.85 [d, J = 8.2 Hz, 1 H, 3,4-(OMe)2C6H3-H5a + b], 3.93 (s, 3 H,
OCH3a + b), 3.91 (s, 3 H, OCH3a + b), 3.30–3.05 (m, 2 H) [contains:
1H NMR (300 MHz, CDCl3): d = 7.68 (s, 1 H, CH=N), 7.46–7.29
(m, 5 H), 7.16–7.07 (m, 4 H), 7.00–6.93 (m, 2 H), 6.86 [d, J = 8.3
Hz, 1 H, 3,4-(OMe)2C6H3-H5], 3.96 (s, 3 H, OCH3), 3.92 (s, 3 H,
OCH3), 3.75 (t, J = 8.0 Hz, 1 H, 4-ClC6H4-CH), 3.06 (d, J = 13.3
Hz, 1 H, PhCH2-Ha), 2.85 (d, J = 13.3 Hz, 1 H, PhCH2-Hb), 2.76 (d,
J = 8.0 Hz, 2 H, CH2CO), 1.17 (s, 9 H, t-C4H9).
13C NMR, DEPT (75.5 MHz, CDCl3): d = 170.3 (C=O), 161.7
(CH=N), 152.2 [3,4-(OMe)2C6H3-C4], 149.3 [3,4-(OMe)2C6H3-
C3], 136.2, 133.9 [2 C, C6H5-C1, 4-ClC6H4-C1, 3,4-(OMe)2C6H3-
C1], 131.1 (2 C), 131.0 (2 C), 128.6 (2 C), 127.9 (2 C), 127.8 (4-
ClC6H4-C4), 127.3 (C6H5-C4), 123.8 [3,4-(OMe)2C6H3-C6], 117.3
(CN), 110.6 [3,4-(OMe)2C6H3-C2], 109.6 [3,4-(OMe)2C6H3-C5],
80.9 (CMe3), 72.3 (CCN), 56.0 (OCH3), 56.0 (OCH3), 50.4 (4-
ClC6H4-CH), 44.4 (PhCH2), 37.4 (CH2CO), 27.7 [3 C, C(CH3)3].
b
3.26 (d, J = 13.3 Hz, 1 H, PhCH2-Haa), 3.16 (s, 2 H, PhCH2 ), 3.10
a
(d, J = 13.3 Hz, 1 H, PhCH2-Hb )], 2.77 (dd, J = 15.2, 4.3 Hz, 1 H,
CH2CO-Hab), 2.64 (mc, 1 H, MeCHa + b), 2.53 (dd, J = 15.4, 3.3 Hz,
a
1 H, CH2CO-Ha ), 2.25–2.05 (m, 2 H) [contains: 2.19 (dd, J = 15.2,
b
10.3 Hz, 1 H, CH2CO-Hb ), 2.11 (dd, J = 15.4, 10.6 Hz, 1 H,
a
b
a
CH2CO-Hb )], 1.45 (s, 9 H, t-C4H9 ), 1.41 (s, 9 H, t-C4H9 ), 1.27 (d,
a
b
J = 6.7 Hz, 3 H, CH3 ), 1.14 (d, J = 6.7 Hz, 3 H, CH3 ).
ESI-MS: m/z (%) = 459.3 (14, [M + Na]+), 437.4 (100, [M + H]+),
412.4 (40, [M – CN + 2 H]+), 381.3 (57, [M – C4H8 + H]+), 356.2
(12).
ESI-MS: m/z (%) = 555.2 (51, [M + Na]+), 533.2 (100, [M + H]+).
ESI-HRMS: m/z calcd for [C31H33ClN2O4 + H]+: 533.2207; found:
Anal. Calcd for C26H32N2O4: C, 71.53; H, 7.39; N, 6.42. Found: C,
71.33; H, 7.27; N, 6.48.
533.2199.
tert-Butyl 3-(4-Chlorophenyl)-4-cyano-4-[(3,4-dimethoxyben-
zylidene)amino]-5-phenylpentanoate (6d)
tert-Butyl 3-(4-Chlorophenyl)-4-cyano-4-[(3,4-dimethoxyben-
zylidene)amino]-4-phenylbutyrate (6e)
Following method A, imine 5b (250 mg, 0.849 mmol) and
BnNEt3Cl (19.3 mg, 0.085 mmol) in CH2Cl2 (2.5 mL), ester 2a (223
mg, 0.934 mmol) in CH2Cl2 (2.5 mL), and KOH (0.95 g, 16.9
mmol) in H2O (1.89 mL) were used. After 3 h, a slightly yellow
foam (431.7 mg) was isolated. A portion (421 mg) of the crude
product was purified by flash chromatography (PE–EtOAc, 4:1).
Two diastereomerically pure fractions of 6d (60 mg,a colorless
foam, 103.5 mg,b colorless amorphous material) and a mixture of
the two diastereomers (63.4 mg,a + b) were obtained. The combined
yield of 6d amounted to 51%. Ratio of isomers: 1.3:1 (based on
crude product).
According to method B, the crude product (820 mg, yellow oil) was
obtained after 2 h 20 min from a solution of 5c (400 mg, 1.43
mmol), 2a (340.6 mg, 1.43 mmol), and DBU (234.5 mL, 239.0 mg,
1.57 mmol) in anhyd THF (4 mL). Purification of the crude product
by flash chromatography (PE–EtOAc, 3:1) afforded 6e (117.0 mg,
61%) as a slightly yellow oil. Ratio of isomers: 1.5:1 (based on
crude product); Rf = 0.32 (PE–EtOAc, 3:1).
IR (film): 2977 (w), 1709 (s, C = O), 1639 (m), 1597 (m), 1514 (m),
1493 (m), 1368 (m), 1322 (m), 1270 (m), 1152 (s), 1092 (m), 1027
(m), 823 cm–1 (m).
1H NMR (300 MHz, CDCl3): d (ratio of isomers a/b = 1.4:1) = 8.34
Minor Diastereomer
Rf = 0.29 (PE–EtOAc, 3:1).
(s, 1 H, CH=Na), 8.16 (s, 1 H, CH=Nb), 7.61–6.86 [m, 12 H, 3,4-
a
(OMe)2C6H3, 4-ClC6H4, C6H5], 3.99 (s, 3 H, OCH3 ), 3.95 (s, 3 H,
b
a
b
OCH3 ), 3.94 (s, 3 H, OCH3 ), 3.92 (s, 3 H, OCH3 ), 3.90–3.77 (m,
IR (film): 2976 (m), 1729 (s, C=O), 1643 (m), 1600 (m), 1586 (m),
1513 (s), 1456 (m), 1421 (m), 1369 (m), 1269 (s), 1241 (m), 1146
(s), 1026 (m), 705 cm–1 (m).
1 H, 4-ClC6H4-CHa + b), 2.89–2.61 (m, 2 H, CH2COa + b), 1.14 (s, 9
H, t-C4H9 ), 1.13 (s, 9 H, t-C4H9 ).
b
a
ESI-MS: m/z (%) = 519.1 (100, [M + H]+), 463.0 (30, [M – C4H8 +
1H NMR (300 MHz, CDCl3): d = 7.63 (s, 1 H, CH=N), 7.40–7.34
(m, 2 H, C6H5-H3,5), 7.29–7.26 (m, 3 H), 7.16–7.00 (m, 6 H), 6.86
[d, J = 8.3 Hz, 1 H, 3,4-(OMe)2C6H3-H5], 3.94 (s, 3 H, OCH3), 3.91
(s, 3 H, OCH3), 3.73 (dd, J = 11.5, 4.3 Hz, 1 H, 4-ClC6H4-CH), 3.08
(d, J = 13.3 Hz, 1 H, PhCH2-Ha), 2.96 (dd, J = 15.4, 4.3 Hz, 1 H,
CH2CO-Ha), 2.90 (d, J = 13.3 Hz, 1 H, PhCH2-Hb), 2.70 (dd,
J = 15.4, 11.6 Hz, 1 H, CH2CO-Hb), 1.21 (s, 9 H, t-C4H9).
13C NMR, DEPT (75.5 MHz, CDCl3): d = 169.9 (C=O), 160.9
(CH=N), 152.1 [3,4-(OMe)2C6H3-C4], 149.3 [3,4-(OMe)2C6H3-
C3], 135.9 (C6H5-C1), 134.0 (4-ClC6H4-C1), 133.6 [3,4-
(OMe)2C6H3-C1], 131.7 (2 C), 131.0 (2 C), 128.0 (2 C), 127.9 (2 C)
H]+).
Anal. Calcd for C30H31ClN2O4: C, 69.42; H, 6.02; N, 5.40. Found:
C, 69.35; H, 5.89; N, 5.46.
tert-Butyl 4-Cyano-4-methyl-4-[(2-naphthylmethylene)ami-
no]butyrate (6f)
Following method A, imine 5d (200 mg, 0.960 mmol) and
BnNEt3Cl (21.9 mg, 0.096 mmol) in CH2Cl2 (2 mL), ester 2b (123.2
mg, 0.960 mmol) in CH2Cl2 (2 mL), and KOH (1.08 g, 19.2 mmol)
in H2O (2.14 mL) were used. After 2.5 h, 6f (308.2 mg, 94%) was
Synthesis 2007, No. 6, 918–928 © Thieme Stuttgart · New York

924
I. Bergner, T. Opatz
PAPER
obtained as a yellow oil. No further purification was required;
Rf = 0.57 (PE–EtOAc, 3:1).
138.2 (C1¢a), 138.0 (C1¢b), 134.9, 134.8, 133.5, 131.5, 131.4, 129.9,
129.8, 129.5, 129.3, 129.1, 129.0, 128.6, 128.3, 128.2, 127.3, 127.0
(partly overlapping signals), 118.0 (CNa + b), 81.1 (CMe3a + b), 57.9
(CHCNa), 57.6 (CHCNb), 45.7 (ArCHb), 45.6 (ArCHa), 37.0
(CH2COa), 36.95 (CH2COb), 27.8 [3 C, C(CH3)3a + b].
ESI-MS: m/z (%) = 481.1 (14, [M + Na]+) 403.1 (41, [M – C4H8 +
H]+), 385.0 (33, [M – C4H8 – H2O + H]+) 330.0 (27), 221.0 (100,
[Ph2CNCH2CN + H]+), 192.9 (28), 182.0 (37, [Ph2C=NH2]+), 164.9
(96, [4-ClC6H4CH=CHCO]+).
IR (film): 2980 (m), 2935 (w), 2228 (vw, C≡N), 1729 (s, C=O),
1641 (m), 1393 (w), 1368 (m), 1156 (s), 1125 (m), 861 (w), 823 (m),
750 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 8.66 (s, 1 H, CH=N), 8.13 (s, 1 H,
naph-H1), 8.01–7.97 (m, 1 H, naph-H3), 7.92–7.81 (m, 3 H, naph-
H4, -H5, -H8), 7.53 (mc, 2 H, naph-H6, -H7), 2.43–2.19 (m, 4 H,
CH2CO, b-CH2), 1.68 (s, 3 H, CH3), 1.40 (s, 9 H, t-C4H9).
13C NMR, DEPT (75.5 MHz, CDCl3): d = 171.4 (C=O), 160.2
(C=N), 135.1, 132.9, 132.5, 131.4, 128.8, 128.6, 127.9, 127.7,
126.7, 123.7 (naph), 119.5 (CN), 80.8 (CMe3), 62.8 (CCN), 36.3
(CH2), 30.9 CH2CO), 28.0 [4 C, C(CH3)3, CH3].
g-Aminobutyric Acid Esters 7a–h (Table 2); General Procedure
To a stirred solution of the g-(alkylideneamino)-g-cyanoester 6 (1
equiv) in EtOH (60 equiv) was added solid NaCNBH3 (3 equiv) un-
der argon. After addition of AcOH (6 equiv), the mixture was stirred
at least for 24 h at r.t. Two different work-up procedures were ap-
plied.
ESI-MS: m/z (%) = 337.2 (81, [M + H]+), 327.2 (38), 310.3 [M –
CN]+, 281.2 (100, [M – C4H8 + H]+), 254.1 (28), 192.2 (23).
Method A: EtOAc (3–20 mL) and aq sat. NaHCO3 solution (3–20
mL) were added to the reaction mixture. The organic layer was sep-
arated; the aqueous layer was extracted with EtOAc (2 × 3–20 mL).
The combined organic layers were washed with H2O (5–10 mL),
dried (Na2SO4) and the solvent was removed in vacuo.
tert-Butyl 4-Cyano-4-[(2-naphthylemthylene)amino]-5-phenyl-
pentanoate (6g)
Following method A, imine 5e (200 mg, 0.703 mmol) and
BnNEt3Cl (16.0 mg, 0.070 mmol) in CH2Cl2 (2 mL), ester 2b (102.1
mL, 90.1 mg, 0.703 mmol) in CH2Cl2 (2 mL), and KOH (0.78 g, 13.9
mmol) in H2O (1.57 mL) were used. After 2 h, 6g (286.8 mg, 99%)
was obtained as a slightly brown and viscous oil. No further purifi-
cation was required; Rf = 0.51 (PE–EtOAc, 3:1).
Method B: After addition of ethanolamine, the mixture was stirred
at r.t. for several hours and partitioned between EtOAc (10 mL) and
H2O (10 mL). The organic layer was washed with aq sat. NaHCO3
solution (1 × 5 mL) and with H2O (3 × 5 mL), dried (Na2SO4) and
the solvent was removed in vacuo.
IR (film): 2978 (m), 2931 (w), 2229 (vw, C≡N), 1729 (s, C=O),
1640 (m), 1456 (m), 1393 (w), 1368 (m), 1288 (w) 1154 (s), 893
(w), 848 (w), 823 (m), 749 (m), 704 cm–1 (m).
tert-Butyl 4-(Benzhydrylamino)butyrate (7a)
1H NMR (300 MHz, CDCl3): d = 8.21 (s, 1 H, CH=N), 8.03–7.95
(m, 2 H, naph-H1, -H3), 7.89–7.81 (m, 3 H, naph-H4, -H5, -H8),
7.57–7.49 (m, 2 H, naph-H6, -H7), 7.20 (m, 5 H, C6H5), 3.21 (s, 2
H, PhCH2), 2.45–2.25 (m, 4 H, CH2CO, b-CH2), 1.40 (s, 9 H, t-
C4H9).
13C NMR, DEPT (75.5 MHz, CDCl3): d = 171.4 (C=O), 161.4
(CH=N), 135.1 (C6H5-C1), 134.0, 132.9, 132.4, 131.4, 130.9 (2 C),
128.8, 128.6, 128.1 (2 C), 127.9, 127.7, 127.4, 126.7, 123.7 (C6H5-
C4), 118.2 (CN), 80.8 [CMe3], 68.2 (CCN), 46.4 (PhCH2), 35.2 (b-
CH2), 30.8 (CH2CO), 28.0 [3 C, C(CH)3].
Following the general method, 6a (200 mg, 0.574 mmol),
NaCNBH3 (108.2 mg, 1.72 mmol), and AcOH (197 mL, 3.44 mmol)
in EtOH (2 mL) were used. After stirring for 4 d at r.t., the addition
of more NaCNBH3 (108.2 mg, 1.72 mmol) was necessary because
the conversion of the intermediate product [tert-butyl 4-(benzhy-
drylamino)-4-cyanobutyrate] did not proceed further. After 2 d, an-
other portion of NaCNBH3 (108.2 mg, 1.72 mmol) was added. The
work-up procedure (method A) was performed even though the in-
termediate was not converted completely. A portion (171.4 mg) of
the crude product (181.4 mg) was purified by flash chromatography
(cyclohexane–EtOAc, 3:1 + 1% Me2NEt) to give 7a (129.6 mg,
71%) as a colorless oil; Rf = 0.58 (PE–EtOAc, 1:1).
ESI-MS: m/z (%) = 413.4 (83, [M + H]+), 402.3 (18), 386.3 (100,
[M – CN]+), 357.2 (59, [M – C4H8 + H]+), 330.2 (14, [M – C4H8 –
CN]+), 192.2 (39).
IR (film): 2977 (m), 2931 (m), 1728 (s, C=O), 1493 (m), 1454 (m),
1367 (m), 1256 (m), 1151 (s), 746 (m), 703 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 7.40–7.35 (m, 4 H, C6H5-H3,5),
7.32–7.25 (m, 4 H, C6H5-H2,6), 7.20–7.16 (m, 2 H, C6H5-H4), 4.80
(s, 1 H, Ph2CH), 2.59 (t, J = 6.9 Hz, 2 H, NCH2), 2.30 (t, J = 7.4 Hz,
2 H, CH2CO), 1.79 (quint, J = 7.1 Hz, 2 H, b-CH2), 1.51 (br s, 1 H,
NH), 1.41 (s, 9 H, t-C4H9).
13C NMR (75.5 MHz, CDCl3): d = 173.0 (C=O), 144.2 (2 C, C6H5-
C1), 128.4 (4 C, C6H5-C3,5), 127.2 (4 C, C6H5-C2,6), 126.9 (2 C,
C6H5-C4), 80.1 (CMe3), 67.5 (Ph2CH), 47.4 (NCH2), 33.5
(CH2CO), 28.1 [3 C, C(CH)3], 25.7 (b-CH2).
tert-Butyl 4-(Benzhydrylidene)amino-3-(4-chlorophenyl)-4-cy-
anobutyrate (6h)
Following method A, imine 5a (1 g, 4.54 mmol) and BnNEt3Cl (103
mg, 0.454 mmol) in CH2Cl2 (20 mL), ester 2a (1.09 g, 4.59 mmol)
in CH2Cl2 (20 mL), and KOH (5.09 g, 90.8 mmol) in H2O (10.1 mL)
were used. After 3 h, the crude product (2.12 g, quant) was obtained
as a slightly brown viscous oil. Purification by flash chromatogra-
phy (PE–EtOAc, 9:1) afforded 6h (1.74 g, 84%) as a yellow solid.
Ratio of isomers: 1.2:1 (based on crude product); Rf = 0.28 (PE–
EtOAc, 9:1).
ESI-HRMS: m/z calcd for [C21H27NO2 + Na]+: 348.1940, found:
348.1947.
IR (film): 3436 (vs), 1728 (m, C=O), 1624 (s, C=N), 1493 (w), 1446
(w), 1368 (w), 1288 (w), 1150 (m), 1094 (w), 1015 (w), 829 (w),
784 (w), 698 cm–1 (w).
Anal. Calcd for C21H27NO2: C, 77.50; H, 8.36; N, 4.30. Found: C,
77.57; H, 8.26; N, 4.36.
1H NMR (300 MHz, CDCl3): d (ratio of isomers a/b = 1.4:1) =
7.61–6.86 (m, 14 H, 2 C6H5 , 4-ClC6H4), 4.35 (d, J = 5.9 Hz, 1 H,
CHCNa), 4.31 (d, J = 5.6 Hz, 1 H, CHCNb), 3.66 (td, Jt = 10.8 Hz,
Jd = 5.6 Hz, 1 H, CHArb), 3.57 (td, Jt = 11.0 Hz, Jd = 5.9 Hz, 1 H,
CHAra), 3.09 (dd, J = 15.9, 5.3 Hz, 1 H, CH2CO-Haa), 2.99 (dd,
tert-Butyl 4-(3,4-Dimethoxybenzylamino)-5-phenylpentanoate
(7b)
Following the general method, 6b (295 mg, 0.698 mmol),
NaCNBH3 (131.6 mg, 2.095 mmol) and AcOH (239.8 mL, 4.19
mmol) in EtOH (2.5 mL) were used. After stirring overnight, etha-
nolamine (1.5 mL) was added. The mixture was stirred at r.t. for 4
h. Following work-up procedure B, 7b (224.8 mg, 81%) was ob-
tained as a colorless oil; Rf = 0.12 (PE–EtOAc, 1:1).
b
J = 15.9, 5.2 Hz, 1 H, CH2CO-Ha ), 2.88–2.71 (m, 1 H, CH2CO-
a
b
Hba + b), 1.25 (s, 9 H, t-C4H9 ), 1.23 (s, 9 H, t-C4H9 ).
13C NMR, DEPT (75.5 MHz, CDCl3,): d (ratio of isomers a/b =
1.4:1) = 174.4 (C=Oa), 174.0 (C=Ob), 170.1 (C=Nb), 170.1 (C=Na),
Synthesis 2007, No. 6, 918–928 © Thieme Stuttgart · New York

PAPER
g-Amino Acid Esters from a-Aminonitriles
925
IR (film): 2933 (s), 1724 (s), 1591 (m), 1514 (s), 1454 (m), 1417
(m), 1365 (m), 1261 (s), 1149 (s), 1030 (m), 847 (m), 806 (m), 700
cm–1 (m).
ESI-HRMS: m/z calcd for [C25H35NO4 + H]+: 414.2644; found:
414.2630.
tert-Butyl 3-(4-Chlorophenyl)-4-(3,4-dimethoxybenzylamino)-
5-phenylpentanoate (7d) and
5-Benzyl-4-(4-chlorophenyl)-1-(3,4-dimethoxybenzyl)pyrroli-
1H NMR (300 MHz, CDCl3): d = 7.28–7.12 (m, 5 H, C6H5), 6.76–
6.70 [m, 3 H, 3,4-(OMe)2C6H3], 3.83 (s, 3 H, OCH3), 3.80 (s, 3 H,
OCH3), 3.68 [AB system, J = 13.1 Hz, 2 H, 3,4-(OMe)2C6H3CH2],
2.78 (mc, 1 H, BnCH), 2.74–2.67 (m, 2 H, PhCH2), 2.32 (t, J = 7.6
Hz, 2 H, CH2CO), 1.75–1.68 (m, 3 H, NH, b-CH2), 1.40 (s, 9 H, t-
C4H9).
13C NMR, DEPT (75.5 MHz, CDCl3): d = 173.3 (C=O), 148.9 [3,4-
(OMe)2C6H3-C3], 147.9 [3,4-(OMe)2C6H3-C4], 139.0 (C6H5-C1),
132.8 [3,4-(OMe)2C6H3-C1], 129.3 (2 C), 128.4 (2 C), 126.2 (C6H5-
C4), 120.1 [3,4-(OMe)2C6H3-C6], 111.2 [3,4-(OMe)2C6H3], 110.9
[3,4-(OMe)2C6H3], 80.2 (CMe3), 57.3 (BnCH), 55.9 (OCH3), 55.8
(OCH3), 50.6 [3,4-(OMe)2C6H3CH2], 40.4 (PhCH2), 32.0 (b-CH2),
28.9 (CH2CO), 28.1 [3 C, C(CH3)3)].
din-2-one (8d)
Following the general method, 6d (95 mg, 0.178 mmol, anti/syn
>98:2), NaCNBH3 (33.6 mg, 0.535 mmol) and AcOH (61.2 mL,
1.07 mmol) in a mixture of EtOH (0.6 mL) and THF (0.6 mL) were
used. The mixture was stirred overnight at r.t. Because the conver-
sion (monitored by TLC) was incomplete, an additional amount of
NaCNBH3 (10 mg, 0.159 mmol) was added. The mixture was
stirred for 24 h. Following work-up procedure A, a slightly yellow
oil (76.2 mg) was obtained. A portion (65.8 mg) of the crude prod-
uct was purified by chromatography (PE–EtOAc, 1:1) and yielded
7d (45.3 mg, 58%) and 8d (20.3 mg, 30%) as colorless viscous oils.
ESI-MS: m/z (%) = 423.1 (13, [M + Na]+), 400.2 (90, [M + H]+),
344.0 (100, [M – C4H8 + H]+).
7d
Ratio of isomers: anti/syn = >98:2 (based on crude product);
Rf = 0.41 (PE–EtOAc, 2:1).
ESI-HRMS: m/z calcd for [C24H33NO4 + H]+: 400.2488; found:
400.2469.
IR (film): 2933 (m), 1725 (s, C=O), 1515 (s), 1494 (m), 1455 (m),
1367 (m), 1262 (s), 1238 (m), 1151 (s), 1093 (m), 1031 (m), 734
(m), 702 cm–1 (m).
Anal. Calcd for C24H33NO4: C, 72.15; H, 8.33; N, 3.51. Found: C,
71.96; H, 8.18; N, 3.54.
1H NMR (300 MHz, CDCl3), HMQC (400 MHz, CDCl3): d = 7.27–
7.16 (m, 7 H, C6H5, 4-ClC6H4-H3,5), 7.06–7.03 (BB¢ part of
AA¢BB¢ system, 2 H, 4-ClC6H4-H2,6), 6.73 [d, J = 8.1 Hz, 1 H, 3,4-
(OMe)2C6H3-H5], 6.34–6.60 [m, 1 H, 3,4-(OMe)2C6H3-H6], 6.57–
6.56 [m, 1 H, 3,4-(OMe)2C6H3-H2], 3.84 (s, 3 H, OCH3), 3.77 (s, 3
tert-Butyl 4-(3,4-Dimethoxybenzylamino)-3-methyl-5-phenyl-
pentanoate (7c)
Following the general method, 6c (430.1 mg, 0.985 mmol, dr 1.2:1),
NaCNBH3 (185.7 mg, 2.96 mmol) and AcOH (338.4 mL, 5.91
mmol) in EtOH (3.5 mL) were used. The mixture was stirred over-
night at r.t. Following work-up procedure A, 356.1 mg of a slightly
yellow oil were obtained. A portion (325.0 mg) of the crude product
was purified by chromatography (cyclohexane–EtOAc, 1:1.5). Two
fractions of 7c were obtained as slightly yellow oils (125.2 mg, dr
3.2:1 and 76.3 mg, dr 1:1). The combined yield amounted 54%. Ra-
tio of isomers (based on crude product): anti/syn = 1.6:1; Rf = 0.44
(PE–EtOAc, 2:3).
H, OCH3), 3.57 [AB system, J = 13.0 Hz,
2 H, 3,4-
(OMe)2C6H3CH2], 3.31 (dt, Jt = 5.1 Hz, Jd = 9.9 Hz, 1 H, BnCH),
2.95 (mc, 1 H, 4-ClC6H4CH), 2.87 (dd, J = 15.4, 5.5 Hz, 1 H,
CH2CO-Ha), 2.68–2.40 (m, 3 H) [contains: 2.64 (dd, J = 15.4, 9.9
Hz, 1 H, CH2CO-Hb), 2.57 (dd, J = 13.7, 4.7 Hz, 1 H, PhCH2-Ha),
2.44 (dd, J = 13.7, 8.6 Hz, 1 H, PhCH2-Hb)], 1.26 (s, 9 H, t-C4H9).
13C NMR, DEPT (75.5 MHz, CDCl3), HMQC (400 MHz, CDCl3):
d = 171.9 (C=O), 148.9 [3,4-(OMe)2C6H3-C3], 147.9 [3,4-
(OMe)2C6H3-C4], 139.7 (C6H5-C1), 139.3 (4-ClC6H4-C1), 132.9
(4-ClC6H4-C4), 132.3 [3,4-(OMe)2C6H3-C1], 130.1 (2 C, 4-
ClC6H4-C2,6), 129.1 (2 C, 4-ClC6H4-C3,5), 128.5 (2 C), 128.2 (2
C), 126.3 (C6H5-C4), 120.2 [3,4-(OMe)2C6H3-C6], 111.2 [3,4-
(OMe)2C6H3-C5], 110.8 [3,4-(OMe)2C6H3-C2], 80.3 (CMe3), 61.9
(BnCH), 55.9 (OCH3), 55.7 (OCH3), 51.8 [3,4-(OMe)2C6H3CH2],
44.0 (4-ClC6H4CH), 37.9 (PhCH2), 36.8 (CH2CO), 27.9 [3 C,
C(CH3)3].
IR (film): 2966 (m), 2934 (m), 1724 (s, C=O), 1515 (s), 1456 (m),
1367 (m), 1262 (s), 1237 (m), 1155 (s), 1031 (m), 701 cm–1 (m).
1H NMR (300 MHz, CDCl3): d (ratio of isomers: anti/syn = a/b =
3.2:1) = 7.28–7.11 (m, 5 H, C6H5a + b), 6.73–6.61 [m, 3 H, (3,4-
a
(OMe)2C6H3-H2, -H5, -H6a + b], 3.82 (s, 3 H, OCH3 ), 3.82 (s, 3 H,
b
a
b
OCH3 ), 3.76 (s, 3 H, OCH3 ), 7.75 (s, 3 H, OCH3 ) (partly overlap-
ping signals), 3.69–3.48 (m, 2 H, [3,4-(OMe)2C6H3CH2], 2.79–2.65
a + b
(m, 2 H, BnCHa + b, PhCH2-Haa + b), 2.60–2.35 (m, 3 H, PhCH2
,
CH2CO-Hab) [contains: 2.57 (dd, J = 14.7, 4.7 Hz, 1 H, CH2CO-
ESI-MS: m/z (%) = 512.2 (29), 511.2 (29), 510.2 (100, [M + H]+).
ESI-HRMS: m/z calcd for [C30H36ClNO4 + Na]+: 532.2231; found:
Haa)], 2.24 (mc, 1 H, MeCHa + b), 2.13 (dd, J = 13.9, 1.8 Hz, 1 H,
b
a
CH2CO-Hb ), 2.01 (dd, J = 14.7, 9.3 Hz, 1 H, CH2CO-Hb ), 1.42 (s,
b
a
b
9 H, t-C4H9 ), 1.41 (s, 9 H, t-C4H9 ), 1.00 (d, J = 5.4 Hz, 3 H, CH3 ),
532.2206.
a
0.98 (d, J = 6.8 Hz, 3 H, CH3 ).
Anal. Calcd for C30H36ClNO4: C, 70.64; H, 7.11; N, 2.75. Found: C,
70.70; H, 6.97; N, 2.82.
13C NMR, DEPT (75.5 MHz, CDCl3): d (ratio of isomers: anti/
syn = a/b = 3.2:1) = 173.2 (C=Oa), 172.7 (C=Ob), 148.8 [3,4-
(OMe)2C6H3-C3a + b], 147.8 [3,4-(OMe)2C6H3-C4a + b], 139.8 (C6H5-
C1a), 139.7 (C6H5-C1b), 133.3 [3,4-(OMe)2C6H3-C1a + b], 129.2 (2
Cb), 129.1 (2 Ca), 128.4 (2 Ca), 128.4 (2 Cb), 126.1 (C6H5-C4a + b),
120.1 [3,4-(OMe)2C6H3-C6a], 120.0 [3,4-(OMe)2C6H3-C6b], 111.1
[3,4-(OMe)2C6H3-C5a + b], 110.8 [3,4-(OMe)2C6H3-C2a + b], 80.1
trans-8d
Ratio of isomers: trans/cis = >98:2; Rf = 0.09 (PE–EtOAc, 2:1).
IR (film): 2934 (w), 1686 (s, C=O), 1593 (w), 1516 (m), 1494 (m),
1454 (m), 1418 (m), 1263 (m), 1236 (m), 1140 (m), 1028 (m), 825
(w), 703 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 7.26–6.66 [m, 12 H, 3,4-
(OMe)2C6H3, 4-ClC6H4, C6H5], 5.11 [d, J = 14.8 Hz, 1 H, 3,4-
b
a
(CMe3 ), 79.9 (CMe3 ), 61.8 (BnCHa), 61.8 (BnCHb), 55.9
(OCH3a + b), 55.7 (OCH3a + b), 51.5 [3,4-(OMe)2C6H3CH2 ], 51.3
a
b
b
a
[3,4-(OMe)2C6H3CH2 ], 40.0 (PhCH2 ), 38.4 (PhCH2 ), 37.1
(CH2COa), 36.4 (CH2COb), 32.4 (MeCHb), 31.9 (MeCHa), 28.1 [3 C,
(OMe)2C6H3CH2-Ha], 3.90 [d, J = 14.8 Hz,
1
H, 3,4-
C(CH3)3a + b], 15.5 (CH3 ), 15.1 (CH3 ).
(OMe)2C6H3CH2-Hb], 3.85 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3),
3.52 (mc, 1 H, H5), 3.12 (td, Jd = 9.2 Hz, Jt = 2.8 Hz, 1 H, H4), 3.03
(dd, J = 13.8, 4.5 Hz, 1 H, PhCH2-Ha), 2.76–2.70 (m, 2 H, PhCH2-
Hb, H3a), 2.36 (dd, J = 17.4, 3.3 Hz, 1 H, H3b).
a
b
ESI-MS: m/z (%) = 414.4 (73, [M + H]+), 358.2 (100, [M – C4H8 +
H]+), 151.1 (38, [3,4-(OMe)2C6H3CH2]+).
Synthesis 2007, No. 6, 918–928 © Thieme Stuttgart · New York

926
I. Bergner, T. Opatz
PAPER
13C NMR, DEPT (75.5 MHz, CDCl3): d = 173.5 (C=O), 149.3 [3,4-
(OMe)2C6H3-C3], 148.7 [3,4-(OMe)2C6H3-C4], 142.5 (C6H5-C1),
136.5 (4-ClC6H4-C1), 132.5 (4-ClC6H4-C4), 129.3 (2 C, 4-ClC6H4-
C2,6), 128.7 (4 C, C6H5-C2,6, C3,5), 128.5 [3,4-(OMe)2C6H3-C1],
127.7 (2 C, 4-ClC6H4-C3,5), 127.0 (C6H5-C4), 120.8 [3,4-
(OMe)2C6H3-C6], 111.3 [3,4-(OMe)2C6H3], 110.9 [3,4-
(OMe)2C6H3], 65.7 (C5), 55.9 (OCH3), 55.8 (OCH3), 44.5 [3,4-
(OMe)2C6H3CH2], 40.4 (C4), 38.7 (C3), 37.7 (CH2Ph).
3.19 [d, J = 13.6 Hz, 1 H, 3,4-(OMe)2C6H3CH2-Hb)], 2.27 (d,
J = 7.9 Hz, 2 H, CH2CO), 1.12 (s, 9 H, t-C4H9).
13C NMR, DEPT (75.5 MHz, CDCl3), HMQC (400 MHz, CDCl3):
d = 171.0 (C=O), 148.8 [3,4-(OMe)2C6H3-C3], 147.8 (4-ClC6H4-
C1), 141.3 [3,4-(OMe)2C6H3-C4], 139.6 (C6H5-C1), 132.7 (4-
ClC6H4-C4), 132.6 [3,4-(OMe)2C6H3-C1], 129.9 (2 C), 128.4 (2 C),
128.4 (2 C), 128.3 (2 C), 127.6 (C6H5-C4), 120.1 [3,4-(OMe)2C6H3-
C6], 111.0 [3,4-(OMe)2C6H3-C5], 110.7 [3,4-(OMe)2C6H3-C2],
80.3 (CMe3), 65.8 (PhCH), 55.9 (OCH3), 55.6 (OCH3), 50.7 [3,4-
(OMe)2C6H3CH2], 48.7 (4-ClC6H4CH), 39.5 (CH2CO), 27.7 [3 C,
C(CH3)3].
ESI-MS: m/z (%) = 499.3 (17, [M + Na + MeCN]+), 477.2 (16,
[M + H + MeCN]+), 458.2 (13, [M + Na]+), 436.3 (100, [M + H]+),
298.2 (13), 236.3 (17), 151.1 (28, [3,4-(OMe)2C6H3CH2]+).
ESI-HRMS: m/z calcd for [C26H26ClNO3 + Na]+: 458.1499; found:
ESI-MS: m/z (%) = 518.2 (15, [M + Na]+), 496.2 (100, [M + H]+),
458.1513.
421.0 (12), 345.0 (30), 263.0 (28).
ESI-HRMS: m/z calcd for [C29H34ClNO4 + Na]+: 518.2074; found:
518.2059.
cis-8d
A portion of 7d (13.2 mg, 26 mmol) was dissolved in THF (100 mL).
After addition of CF3CO2H (100 mL, 1.35 mmol) and H2O (100 mL,
5.56 mmol), the mixture was stirred at 50 °C for 3.5 h. Stirring was
continued at r.t. for 12 h, the pH of the solution was adjusted to 6 by
addition of pyridine and the solution was heated to 100 °C. After
TLC had indicated complete conversion (5.5 h), the mixture was
partitioned between sat. aq citric acid solution (3 mL) and EtOAc (5
mL). The organic layer was washed with sat. aq citric acid solution
(3 mL) and H2O (5 mL), dried (Na2SO4) and the solvent was re-
moved in vacuo to furnish a greenish oil (20 mg) which still con-
tained some CF3CO2H. Comparison of the 1H NMR spectrum with
the data of trans-8d showed that the cis-isomer had been formed.
1H NMR (300 MHz, CDCl3): d = 7.27–7.16 (m, 5 H), 7.04–6.98 (m,
2 H), 6.83–6.70 (m, 3 H), 6.55–6.49 (m, 2 H), 5.03 [d, J = 14.8 Hz,
1 H, 3,4-(OMe)2C6H3CH2-Ha], 3.98 (mc, 1 H, H5), 3.86 (s, 3 H,
OCH3), 3.81 (s, 3 H, OCH3), 3.59 (mc, 1 H, H4), 3.35 [d, J = 14.8
Hz, 1 H, 3,4-(OMe)2C6H3CH2-Hb], 2.85 (dd, J = 16.6, 10.2 Hz, 1 H,
PhCH2-Ha), 2.75 (dd, J = 16.6, 8.4 Hz, 1 H, PhCH2-Hb), 2.61 (dd,
J = 14.1, 7.8 Hz, 1 H, H3a), 2.41 (dd, J = 14.1, 5.7 Hz, 1 H, H3b).
Anal. Calcd for C29H34ClNO4: C, 70.22; H, 6.91; N, 2.82. Found: C,
70.09; H, 6.93; N, 2.88.
Minor Diastereomer (syn)
Rf = 0.30 (PE–EtOAc, 2:1).
1H NMR (300 MHz, CDCl3): d (ratio of isomers: anti/syn = a/b =
1:1.5) = 7.36–6.45 [m, 12 H, C6H5, 4-ClC6H4, 3,4-(OMe)2C6H3a + b],
b
b
a
3.88 (s, 3 H, OCH3 ), 3.86 (s, 3 H, OCH3 ), 3.85 (s, 3 H, OCH3 ),
a
3.75 (s, 3 H, OCH3 ), 3.60–3.48 [m, 2 H, PhCH, 3,4-
(OMe)2C6H3CH2-Haa + b], 3.31–3.17 [m, 2 H, 4-ClC6H4CH, 3,4-
(OMe)2C6H3CH2-Hb], 2.30–2.26 (m, 2 H, CH2COa + b), 1.14 (s, 9 H,
b
a
t-C4H9 ), 1.12 (s, 9 H, t-C4H9 ).
13C NMR (75.5 MHz, CDCl3): d (ratio of isomers: anti/syn = a/b =
1:1.5) = 171.1 (C=Ob), 171.0 (C=Oa), 149.1 [3,4-(OMe)2C6H3-
C3b], 148.8 [3,4-(OMe)2C6H3-C3a], 148.4 (4-ClC6H4-C1b), 147.9
(4-ClC6H4-C1a), 141.3 [3,4-(OMe)2C6H3-C4a], 140.2 [3,4-
+
(OMe)2C6H3-C4b], 139.6 (C6H5-C1a b), 133.5 (4-ClC6H4-C4b),
132.7 [4-ClC6H4-C4a, 3,4-(OMe)2C6H3-C1b], 132.6 [3,4-
(OMe)2C6H3-C1a], 129.9 (2 Ca), 129.9 (2 Cb), 128.4 (2 Ca + b), 128.4
(2 Ca), 128.3 (2 Ca), 128.2 (2 Cb), 128.0 (2 Cb), 127.6 (C6H5-C4a),
126.8 (C6H5-C4b), 120.9 [3,4-(OMe)2C6H3-C6b], 120.1 [3,4-
(OMe)2C6H3-C6a], 111.1 [3,4-(OMe)2C6H3-C5a], 110.8 [3,4-
(OMe)2C6H3-C2a], 110.7 [3,4-(OMe)2C6H3-C5b], 110.5 [3,4-
(OMe)2C6H3-C2b], 80.3 (CMe3a + b), 65.9 (PhCHb), 65.8 (PhCHa),
tert-Butyl 3-(4-Chlorophenyl)-4-(3,4-dimethoxybenzylamino)-
4-phenylbutyrate (7e) and
4-(4-Chlorophenyl)-1-(3,4-dimethoxybenzyl)-5-phenylpyrroli-
din-2-one (8e)
Following the general method, 6e (130 mg, 0.250 mmol, dr 1.4:1),
NaCNBH3 (47.2 mg, 0.751 mmol) and AcOH (86.0 mL, 1.503
mmol) in EtOH (1.4 mL) were used. The mixture was stirred over-
night at r.t. Because the conversion (monitored by TLC) was incom-
plete, an additional amount of NaCNBH3 (49 mg, 0.780 mmol) was
added. The mixture was stirred for 3 d. Following work-up proce-
dure B, a colorless oil (93.9 mg) was obtained. A portion (84.0 mg)
of the crude product was purified by chromatography (cyclohex-
ane–EtOAc, 3:1 + 1% Me2NEt) to give anti-7e (49.1 mg), 7e as a
mixture of isomers (17.9 mg, ratio of isomers: anti/syn = 1:1.5) and
8e (24.4 mg, 26%) as colorless viscous oils. Combined yield of 7e:
67.0 mg (60%).
b
a
a
55.9 (2 C, OCH3 , 1 C OCH3 ), 55.6 (OCH3 ), 51.0 [3,4-
b
a
(OMe)2C6H3CH2 ], 50.7 [3,4-(OMe)2C6H3CH2 ], 48.7 (4-
ClC6H4CHb), 48.7 (4-ClC6H4CHa), 39.5 (CH2COa), 39.4 (CH2COb),
27.7 [3 C, C(CH3)3a + b].
8e
Ratio of isomers: trans/cis = 2.6:1 (based on crude product).
Rf = 0.09 (PE–EtOAc, 2:1).
IR (film): 1691 (s, C=O), 1516 (m), 1594 (m), 1408 (m), 1263 (m),
1239 (m), 1140 (m), 1028 (m), 732 (m), 703 cm–1 (m).
1H NMR (300 MHz, CDCl3): d (ratio of isomers: trans/cis = a/b =
2.6:1) = 7.35–6.50 [m, 12 H, 3,4-(OMe)2C6H3, 4-ClC6H4, C6H5],
5.10 [d, J = 14.3 Hz, 1 H, 3,4-(OMe)2C6H3CH2-Haa], 5.07 [d,
J = 14.4 Hz, 1 H, 3,4-(OMe)2C6H3CH2-Hab], 4.20 (d, J = 6.2 Hz, 1
7e
Ratio of isomers: anti/syn = a:b = 6.5:1 (based on crude product).
Major Diastereomer (anti)
Rf = 0.35 (PE–EtOAc, 2:1).
b
H, H5a), 4.15 (d, J = 6.8 Hz, 1 H, H5b), 3.87 (s, 3 H, OCH3 ), 3.83
a
b
a
(s, 3 H, OCH3 ), 3.77 (s, 3 H, OCH3 ), 3.75 (s, 3 H, OCH3 ), 3.56 [d,
b
IR (film): 2976 (m), 2933 (m), 1727 (s, C=O), 1515 (s), 1493 (m),
1455 (m), 1368 (m), 1261 (m), 1237 (m), 1142 (s), 1093 (m), 1030
(m), 1014 (m), 704 cm–1 (m).
1H NMR (300 MHz, CDCl3), HMQC (400 MHz, CDCl3): d = 7.37–
7.06 (m, 9 H, C6H5, 4-ClC6H4), 6.73 [d, J = 8.1 Hz, 1 H, 3,4-
(OMe)2C6H3-H2], 6.51–6.45 [m, 2 H, 3,4-(OMe)2C6H3-H5,6], 3.84
(s, 3 H, OCH3), 3.75 (s, 3 H, OCH3), 3.59 (d, J = 8.9 Hz, 1 H,
PhCH), 3.50 [d, J = 13.6 Hz, 1 H, 3,4-(OMe)2C6H3CH2-Ha], 3.28–
3.17 (m, 2 H) [contains: 3.24 (q, J = 8.2 Hz, 1 H, 4-ClC6H4CH),
J = 14.4 Hz, 1 H, 3,4-(OMe)2C6H3CH2-Hb ], 3.44 [d, J = 14.3 Hz, 1
H, 3,4-(OMe)2C6H3CH2-Hb ], 3.28 (mc, 1 H, H4a + b), 3.01 (dd,
a
J = 17.0, 9.1 Hz, 1 H, H3aa + b), 2.69–2.66 (m, 1 H) [contains: 2.65
b
(dd, J = 17.0, 8.7 Hz, 1 H, H3b ), 2.60 (dd, J = 17.0, 7.8 Hz, 1 H,
a
H3b )].
13C NMR (75.5 MHz, CDCl3): d (ratio of isomers: trans/cis = a/b =
2.6:1) = 173.7 (C=Oa + b), 149.5 [3,4-(OMe)2C6H3-C3b], 149.1 (4-
ClC6H4-C1b), 149.0 [3,4-(OMe)2C6H3-C3a], 148.5 (4-ClC6H4-C1a),
Synthesis 2007, No. 6, 918–928 © Thieme Stuttgart · New York

PAPER
g-Amino Acid Esters from a-Aminonitriles
927
139.9 [3,4-(OMe)2C6H3-C4a], 139.6 [3,4-(OMe)2C6H3-C4b], 138.9
(C6H5-C1a), 136.1 (C6H5-C1b), 133.0 (4-ClC6H4-C4a), 132.9 (4-
ClC6H4-C4b), 130.9, 129.5, 129.0, 128.9, 128.8, 128.7, 128.5,
128.4, 128.3, 128.0, 128.0, 127.6, 127.3, 127.0 (partly overlapping
signals), 121.2 [3,4-(OMe)2C6H3-C6a], 119.8 [3,4-(OMe)2C6H3-
C6b], 111.8 [3,4-(OMe)2C6H3-C5a], 111.2 [3,4-(OMe)2C6H3-C5b],
110.9 [3,4-(OMe)2C6H3-C2a], 109.5 [3,4-(OMe)2C6H3-C2b], 69.3
(CMe3), 57.4 (CHBn), 50.9 (naphCH2), 40.5 (PhCH2), 31.9 (CH2),
29.0 (CH2CO), 28.0 [3 C, C(CH3)3].
ESI-MS: m/z (%) = 421.0 (10), 390.3 (100, [M + H]+), 345.0 (24),
334.2 (18, [M – C4H8 + H]+), 263.0 (22).
ESI-HRMS: m/z calcd for [C26H31NO2 + H]+: 390.2433; found:
390.2432.
(C5b), 69.2 (C5a), 55.9 (OCH3 ), 55.9 (OCH3 ), 55.8 (OCH3 ), 55.8
b
b
a
Anal. Calcd for C26H31NO2: C, 80.17; H, 8.02; N, 3.60. Found: C,
80.18; H, 7.94; N, 3.55.
a
b
(OCH3 ) (partly overlapping signals), 47.2 [3,4-(OMe)2C6H3CH2 ],
47.1 [3,4-(OMe)2C6H3CH2 ], 44.7 (C3b), 44.4 (C3a), 38.4 (C4a),
a
38.3 (C4b).
tert-Butyl 4-(Benzhydrylamino)-3-(4-chlorophenyl)butyrate
(7h) and
tert-Butyl 4-(Benzhydrylamino)-3-(4-chlorophenyl)-4-cyanobu-
tyrate (9)
ESI-MS: m/z (%) = 563.6 (12), 444.1 (15, [M + Na]+), 422.2 (95,
[M + H]+), 282.3 (100).
ESI-HRMS: m/z calcd for [C25H24ClNO3 + Na]+: 444.1343; found:
444.1338.
Following the general method, 6h 100 mg, 0.218 mmol), NaCNBH3
(41.2 mg, 0.655 mmol) and AcOH (75 mL, 1.31 mmol) in EtOH (1
mL) were used. The mixture was stirred for 4 d at r.t. Because the
conversion (monitored by TLC) was incomplete, more NaCNBH3
(30 mg, 0.478 mmol) was added. After stirring for 2 d, an additional
portion of NaCNBH3 (108.2 mg, 1.72 mmol) was added. Following
work-up procedure A, a slightly yellow resin (60 mg) was obtained
after additional 5 d. According to the 1H NMR spectrum, a mixture
of 7h and 9 in a ratio of 1:4.5 was obtained. Product 9 contained two
diastereomers in the ratio of 1.1:1; Rf = 0.15 (PE–EtOAc, 9:1); no
separation of 7h and 9 was achieved.
tert-Butyl 4-[(2-Naphthylmethyl)amino]pentanoate (7f)
Following the general method, 6f (298.0 mg, 0.886 mmol),
NaCNBH3 (167.0 mg, 2.66 mmol) and AcOH (304.2 mL, 5.32
mmol) in EtOH (3.1 mL) were used. The mixture was stirred over-
night at r.t. Following work-up procedure A, 7f (261.4 mg, 94%)
was obtained as a yellow oil. No further purification was required;
Rf = 0.10 (PE–EtOAc, 2:1).
IR (film): 2975 (m), 2931 (m), 1728 (s, C=O), 1456 (m) 1367 (m),
1257 (m), 1154 (s), 854 (m), 819 (m), 751 cm–1 (m).
1H NMR (300 MHz, CDCl3): d [9 (a/b = 1.1:1)/7h (c) = 4.5:1] =
7.43–7.09 (m, 14 H), 5.03 (s, 1 H, Ph2CHa), 4.97 (s, 1 H, Ph2CHb),
3.62–3.43 (m, 2 H, CNCH, 4-ClC6H4CHa + b), 3.31–3.23 (m, 1 H, 4-
ClC6H4CHc), 2.97–2.86 (m, 1 H) [contains: 2.94 (dd, J = 13.6, 6.9
Hz, 1 H, CH2CO-Hab), 2.89 (dd, J = 13.1, 6.7 Hz, 1 H, CH2CO-
1H NMR (300 MHz, CDCl3): d = 7.83–7.77 (m, 3 H, naph-H4, -H5,
-H8), 7.74 (s, 1 H, naph-H1), 7.47–7.39 (m, 3 H, naph-H3, -H6,
-H7), 3.98 (d, J = 13.3 Hz, 1 H, naphCH2-Ha), 3.89 (d, J = 13.3 Hz,
1 H, naphCH2-Hb), 2.72 (mc, 1 H, MeCH), 2.31–2.26 (m, 2 H,
CH2CO), 1.85–1.58 (m, 3 H, NH, b-CH2), 1.40 (s, 9 H, t-C4H9), 1.10
(d, J = 6.3 Hz, 3 H, CH3).
13C NMR, DEPT (75.5 MHz, CDCl3): d = 173.2 (C=O), 138.3
(naph-C2), 133.4, 132.6, 128.8, 127.7, 127.6, 126.7, 126.3, 125.9,
125.4 (naph), 80.1 (CMe3), 51.8 (MeCH), 51.3 (naphCH2), 32.1,
32.0 (b-CH2, CH2CO), 28.0 [3 C, C(CH3)3], 20.2 (CH3).
c
Haa)], 2.81–2.41 (m, 5 H, CH2CO-Hba + b, NCH2 , CH2COc), 1.71 (t,
c
J = 13.0 Hz, 1 H, NHa + b + c), 1.27 (s, 9 H, t-C4H9 ), 1.26 (s, 9 H, t-
b
a
C4H9 ), 1.25 (s, 9 H, t-C4H9 ).
The assignment of some signals to the diastereomers a and b, re-
spectively, was complicated because of the similar signal intensities
in a mixture of isomers with a dr of 1.1:1. The superscript c denotes
signals of the doubly reduced product 7h.
ESI-MS: m/z (%) = 314.2 (48, [M + H]+), 258.2 (100, [M – C4H8 +
H]+).
13C NMR, DEPT (75.5 MHz, CDCl3): d (9: a/b = 1.1:1; 7h: c) =
170.1 (C=O), 169.9 (C=O), 142.8, 142.8, 140.9, 136.4, 136.1,
134.0, 133.9, 129.9, 129.7, 129.1, 129.0, 129.0, 128.9, 128.9, 128.8,
128.6, 128.5, 127.9, 127.7, 127.4, 127.2, 126.9, 126.8, 118.9
ESI-HRMS: m/z calcd for [C20H27NO2 + H]+: 314.2120; found:
314.2113.
c
(CNa/b), 118.4 (CNa/b), 81.3 (CMe3), 81.3 (CMe3), 80.7 (CMe3 ),
Anal. Calcd for C20H27NO2: C, 76.64; H, 8.68; N, 4.47. Found: C,
76.65; H, 8.58; N, 4.29.
67.2 (Ph2CHc), 65.4 (Ph2CH), 65.3 (Ph2CH), 53.4 (CNCHb), 53.2
(CNCHc), 52.1 (CNCHa), 44.2 (4-ClC6H4CHb), 43.9 (4-
ClC6H4CHa), 42.0 (4-ClC6H4CHc), 40.4 (CH2COc), 38.7 (CH2COa),
tert-Butyl 4-[(2-Naphthylmethyl)amino]-5-phenylpentanoate
(7g)
c
37.2 (CH2COb), 27.9 [3 C, C(CH3)3 ], 27.854 [3 C, C(CH3)3a + b].
Following the general method, 6g (269.1 mg, 0.652 mmol),
NaCNBH3 (123.0 mg, 1.96 mmol) and AcOH (224.1 mL, 3.91
mmol) in EtOH (2.3 mL) were used. The mixture was stirred over-
night at r.t. Following work-up procedure A, 7g (225.7 mg, 89%)
was obtained as a yellow oil. No further purification was required;
Rf = 0.08 (PE–EtOAc, 2:1).
X-ray Crystallography of anti-436
The crystal was measured on a Turbo-CAD4 diffractometer with
Cu-Ka radiation (graphite monochromator) at 193 K. Crystal struc-
ture solution and refinement were performed using the SIR-92 and
SHELXL-97 program, respectively. C25H28ClNO2, M = 409.94
g·mol–1, monoclinic, space group P21/n, Z = 4, a = 5.6612(8) Å,
b = 20.354(2) Å, c = 19.17(2) Å, b = 93.54(6)°, R1 = 0.0798,
wR2 = 0.2245.
IR (film): 2977 (m), 2931 (m), 1725 (s, C=O), 1661 (m), 1602 (m),
1455 (m), 1367 (m), 1150 (s), 819 (m), 748 (m), 701 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.80–7.73 (m 3 H, naph-H4, -H5,
-H8), 7.60 (s, 1 H, naph-H1), 7.47–7.40 (m, 2 H, naph-H6, -H7),
7.34–7.14 (m, 6 H, naph-H3, C6H5), 3.93 (AB system, J = 13.6 Hz,
2 H, naphCH2), 2.85 (mc, 1 H, BnCH), 2.75 (d, J = 6.4 Hz, 2 H,
PhCH2), 2.36 (t, J = 7.6 Hz, 2H, CH2CO), 1.85–1.70 (m, 3 H, b-
CH2, NH), 1.40 (s, 9 H, t-C4H9).
13C NMR, DEPT (75.5 MHz, CDCl3): d = 173.3 (C=O), 139.0
(C6H5-C1), 137.8 (naph-C2), 133.3, 132.6, 129.3 (2 C), 128.4 (2 C),
127.9, 127.8, 127.6, 126.5, 126.3 (2 C), 125.8, 125.4 (naph), 80.1
Acknowledgment
The help of Dr. D. Schollmeyer (X-ray crystallography) and H.
Kolshorn (NMR spectroscopy) is gratefully acknowledged. We
thank the Deutsche Forschungsgemeinschaft, the University of
Mainz and the Fonds der Chemischen Industrie for financial sup-
port.
Synthesis 2007, No. 6, 918–928 © Thieme Stuttgart · New York

928
I. Bergner, T. Opatz
PAPER
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Synthesis 2007, No. 6, 918–928 © Thieme Stuttgart · New York