A new enantioselective synthesis of β-amino acids

Article abstract of DOI:10.1016/S0957-4166(01)00097-0

Enantioselective hydrogenation of some α,β-unsaturated nitriles and their corresponding methyl esters bearing a phthalimidomethyl substituent at the α-carbon using Rh-DuPHOS catalysts afforded β-amino acid precursors with modest e.e.s of up to 48%. Hydrogenation of the α,β-unsaturated methyl esters using a Ru-BINAP catalyst gave higher e.e.s of up to 84%. Method development for the determination of the enantiomeric excesses of these derivatives using chiral HPLC is also reported.

Full text of DOI:10.1016/S0957-4166(01)00097-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 657–667
A new enantioselective synthesis of b-amino acids
Dilek Saylik,a Eva M. Campi,a Andrew C. Donohue,a W. Roy Jacksona,b,* and Andrea J. Robinsona
aSchool of Chemistry, PO Box 23, Monash University, Victoria 3800, Australia
bCentre for Green Chemistry, PO Box 23, Monash University, Victoria 3800, Australia
Received 5 February 2001; accepted 26 February 2001
Abstract—Enantioselective hydrogenation of some a,b-unsaturated nitriles and their corresponding methyl esters bearing a
phthalimidomethyl substituent at the a-carbon using Rh-DuPHOS catalysts afforded b-amino acid precursors with modest e.e.s
of up to 48%. Hydrogenation of the a,b-unsaturated methyl esters using a Ru-BINAP catalyst gave higher e.e.s of up to 84%.
Method development for the determination of the enantiomeric excesses of these derivatives using chiral HPLC is also reported.
© 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
double bond hydrogenations using both Rh and Ru
catalysts has been established and extensively dis-
cussed.2–4 It has been established that enantioselective
Rh-catalysed reactions of a-N-acylacrylates are facili-
tated by secondary binding of the amide carbonyl
group with Rh in the alkyl–Rh(III) intermediate
Unsaturated nitriles bearing an a-phthalimidomethyl
substituent 1 can be prepared by the nickel-catalysed
addition of hydrogen cyanide (CAUTION)† to appro-
priate alkynes 2 and hydrogenated over Pd/CaCO3 to
give b-amino acid precursors 31 (Scheme 1).
through
a five-membered chelate 4
(Fig. 1).5 It
appeared to us that the phthalimido derivatives 1 could
possibly also stabilise Rh(III) intermediates through the
formation of a six-membered chelate 5. Similar six-ring
chelates could be formed via N-acetyl or N-Boc-
In this paper, attempts to carry out enantioselective
conversions of 1 to 3 are described. The importance of
amide substituents in promoting enantioselectivity in
R
H
Ft
Ft
R
Ft
H2
HCN
[Ni]
R
Pd/CaCO3 or Rh/L*
CN
CN
2
1
3
+
O
R
Ft
N
Ft =
NC
H
O
6
Scheme 1. R=a, H; b, Me; c, Ph; d, TBDMS; e, TMS; L*=(R,R)-Et-DuPHOS or (R,R)-Me-BPE.
* Corresponding author. Tel.: +61-03-9905-4552; fax: +61-03-9905-4597; e-mail: w.r.jackson@sci.monash.edu.au
†
Use of HCN is hazardous and suitable precautions for use and disposal must be taken.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00097-0

658
D. Saylik et al. / Tetrahedron: Asymmetry 12 (2001) 657–667
2. Results and discussion
2.1. Preparation of substrates
R
CN
N
C
C
LnRh(III)
R
O
CO2Me
C
O
LnRh(III)
Substrates 1 were prepared by Ni[P(OPh)3]4-catalysed
addition of hydrogen cyanide to the alkynes 2. Com-
pounds 1a–1c have been prepared previously and simi-
lar yields of 1 together with similar percentages of the
undesired isomers 6 were obtained.1 Hydrocyanation of
the TBDMS and the TMS analogues 2d and 2e gave
the desired isomers 1d and 1e together with 6d and 6e in
ratios of 85:15 and 73:27, respectively. The N-acetyl 7
and N-Boc 8 analogues (Fig. 2) of the phthalimido
nitriles 1a were prepared by similar hydrocyanation of
the N-acetyl and N-Boc 3-amino-1-propynes.
NH
C
O
C
4
5
Figure 1.
Methanolysis of the phthalimido nitriles 1a and 1b gave
the corresponding methyl esters 9a and 9b (Scheme 2).
Several attempts to prepare N-acyl derivatives of the
unsaturated amino acid 10a were unsuccessful and led
to uncharacterisable insoluble products.
H
NHAc
H
NHBoc
H
CN
H
CN
8
7
2.2. Hydrogenations of phthalimido nitriles
Figure 2.
The phthalimido nitriles 1a–1e were hydrogenated
using (R,R)-Et-DuPHOS-Rh(I) and (R,R)-Me-BPE-
Rh(I) (Scheme 1) and the results are summarised in
Table 1. Reactions of the methylene compound 1a
using the DuPHOS-Rh catalyst gave high yields of the
saturated compound 3a when MeOH or MeCN were
used as solvent but no reaction occurred in THF at
ambient temperature and 70 psi H2 (entries 1–3). Simi-
larly, a high yield was obtained when the BPE-Rh
catalyst was used in MeOH (entry 4).
propargylamino derivatives but none of these systems
appear to have been evaluated in enantioselective
routes to b-amino acid precursors.
Three catalysts were chosen for evaluation in this study,
the Ru-BINAP6 and the Rh-DuPHOS7 and the closely
related Rh-BPE system.7 The Rh-DuPHOS and Rh-
BPE catalysts are known to produce excellent enan-
tioselectivities for the hydrogenation of a-amino acid
precursors and the Ru-BINAP system has previously
been used to give b-amino acids with high enantioselec-
tivity in the hydrogenation of (E)-b-(acylamino)acrylic
acids, these methodologies are different from the study
reported herein.8
The specific rotation of the product 3a from the (R,R)-
DuPHOS-Rh catalysed reaction in MeOH (+8.3) was
significantly higher than the value obtained from the
same reaction in MeCN (cf. entries 1 and 2). Hydro-
genation using the (R,R)-BPE-Rh system in MeOH
gave a similar e.e. (by HPLC). The specific rotation was
lower and also of opposite sign to the product obtained
from reactions using the (R,R)-DuPHOS-Rh catalyst.
R
H
Ft
R
H
Ft
R
H
NH3 Cl
conc. HCl
100oC
MeOH/H2SO4
80oC
CO2Me
CN
CO2H
9
1
10
AcCl, py
or PhCOCl, NaOH
or Boc-ON, Et3N
H
R
R'
N
O
CO2H
H
Scheme 2. R=a, H; b, Me.

D. Saylik et al. / Tetrahedron: Asymmetry 12 (2001) 657–667
659
Table 1. Enantioselective hydrogenation of a,b-unsaturated phthalimido nitriles 1 using Rh catalystsa
Entry
Substrate 1,
R=
Catalyst
Solvent
Temp. (°C)
Pressure (psi)
[h]D
e.e.b (%)
Product yield (%)c
1
2
3
4
5
6
7
8
1a, H
1a, H
1a, H
1a, H
1b, Me
1c, Ph
1d, TBDMS
1e, TMS
DuPHOS-Rhd
DuPHOS-Rh
DuPHOS-Rh
BPE-Rhe
DuPHOS-Rh
DuPHOS-Rh
DuPHOS-Rh
DuPHOS-Rh
MeOH
MeCN
THF
MeOH
MeOH
MeOH
C6H6
20
20
20
20
40
40
40
40
70
70
70
+8.3
+1.0
–
−6.8
+1.0
0.0
14
4
–
12
33
3
48
14
86
81
–
78
88
78
84
93
60
100
100
100
100
−8.3
+2.5
MeOH
a Reductions for 24 h.
b Enantiomeric excess determined by HPLC (see below).
c Isolated yield after chromatography.
d (R,R)-Et-DuPHOS-Rh(I).
e (R,R)-Me-BPE-Rh(I).
A sample of the product 3a with [h]D +8.3 was
hydrolysed using conc. HCl to give a sample of the
hydrochloride salt of a-methyl-b-alanine 11 which was
converted to the free amino acid 12 by passing through
an Amberlite column (Scheme 3).
phosphine ligand, for example from Me, Et and n-Pr to
i-Pr in the case of DuPHOS, can lead to a change in
the absolute configuration of the product.7c
The inconsistencies in using the specific rotation values
of free amino acids as measures of enantioselectivity are
well known11 and thus the amino acid was converted
into its Fmoc-derivative 13 (Scheme 3). The sample was
then compared with an authentic sample of the (S)-
Fmoc derivative prepared by Seebach et al.12 Unfortu-
nately, the sample prepared by us showed variable
solubility and [h]D values in contrast to the material
prepared by Seebach. An alternative method for deter-
mining the reaction enantioselectivity was therefore
sought. The amino acid 12 was converted into the
N-benzoyl ethyl ester 14 (Scheme 3), which was success-
fully resolved by chiral HPLC using a Chiralcel OJ
column. The enantioselectivity was shown to be a dis-
The specific rotation of the free amino acid 12, [h]D +19
was at the higher end of the range of values reported in
the literature, where [h]D values of −14 and −219,10 have
been recorded under identical conditions, i.e. c=0.42 in
H2O, for the (R)-enantiomer. Preferential formation of
the (S)-enantiomer using a (R,R)-Et-DuPHOS-Rh cat-
alyst is also opposite to that shown for hydrogenations
of a-N-acylacrylates where the (R,R)-catalyst leads to a
preference for (R)-configured a-amino acids.7c Surpris-
ingly, the (R,R)-Me-BPE-Rh system led to a preference
for the opposite (R)-enantiomer. It should be noted
that small changes in the substitution pattern of the
Cl
NH3
Ft
conc. HCl
CO2H
CN
3a
11
Amberlite
NHCOPh
i) NaOH, PhCOCl
CO Et
2
ii) DBU, EtI or
NH3
Et3SiCl
14
CO2
NHFmoc
12
Fmoc-OSu, Na2CO3
CO2H
13
Scheme 3.

660
D. Saylik et al. / Tetrahedron: Asymmetry 12 (2001) 657–667
CN
The possibility that these hydrogenations involved an
initial isomerisation of 1 merited investigation since the
resultant a,b-unsaturated amide 15 (Scheme 4) would
also be expected to hydrogenate smoothly in line with
the many literature examples.2 Reactions of the nitriles
1a and 1b with deuterium using (R,R)-Et-DuPHOS-
Rh(I) gave no evidence for deuterium incorporation
into the CH2 adjacent to the phthalimido group
R
Ft
R
Ft
DuPHOS-Rh
D2
H
CN
D
D
1
16
1
2
(Scheme 4). The H, H and 13C NMR spectra of the
products were consistent with deuterium incorporation
as shown in the phthalimido nitrile 16.
R
Ft
CN
2.3. Hydrogenations of phthalimido esters
15
The phthalimido nitriles 1 were converted into the
phthalimido methyl esters 9 which were hydrogenated
using the BINAP-Ru and DuPHOS-Rh catalysts
(Scheme 5). Excellent enantioselectivities have been
reported for enantioselective hydrogenations of a,b-
unsaturated esters with a-7,13 and b-amido8,14 sub-
stituents or an a-CH2CO2Me substituent.15
Scheme 4. R=a, H; b, Me.
DuPHOS-Rh
or BINAP-Ru
R
Ft
R
Ft
H2
H
CO2Me
CO2Me
Hydrogenation of 9a using BINAP-Ru at ambient tem-
perature with a H2 pressure of either 100 or 50 psi gave
excellent yields of the phthalimido ester 17a with good
enantioselectivity, 80 and 84% e.e., respectively (entries
9 and 10, Table 2). A hydrogenation using the
DuPHOS-Rh catalyst gave a low e.e., 12% (entry 11),
similar to that obtained in the hydrogenation of the
phthalimido nitrile 1a using this catalyst (entry 1, Table
1). Disappointingly, reaction of the homologue 9b also
gave poor enantioselectivity, with an e.e. of 10% (entry
12, Table 2), using the BINAP-Ru catalyst.
17
9
Scheme 5. R=a, H; b, Me
appointing 11% and the possibility of racemisation
during the hydrolysis of the phthalimido nitrile 3a or
the formation of the N-benzoyl ethyl ester 14 was
considered. Extensive experimentation finally led to
conditions which allowed HPLC resolution of the
phthalimido nitrile 3a using a Chiralcel OB column. An
e.e. value of 14% was obtained showing that no signifi-
cant racemisation had occurred and that only low
enantioselectivity had been obtained in the hydrogena-
tion reaction.
Hydrolysis of the phthalimido ester 17a gave a-methyl-
b-alanine 12 with [h]D −8.2 (c 0.31, H2O), again within
the range of values previously reported.9–11 The a-
methyl-b-alanine obtained using (S)-BINAP-Ru had
(R)-absolute configuration, opposite to that obtained
using (R,R)-Et-DuPHOS-Rh, which was consistent
with related hydrogenations of acetamido acrylates.16
The saturated ester obtained using (R,R)-Et-DuPHOS-
Rh showed a small positive rotation, consistent with a
preference for formation of the (S)-enantiomer of 17a.
Attempted hydrogenation of 1a using (S)-BINAP-
Ru(II) in MeOH under similar conditions (20°C, 50 psi)
failed to give any saturated product.
Similar hydrogenations of the substituted phthalimido
nitriles 1b–1e (Scheme 1) were carried out and the
enantioselectivities measured by HPLC using Chiralcel
OB or OD columns (Table 1, entries 5–8). Modest e.e.s
of 33% for the methyl (entry 5) and 48% for the
TBDMS (entry 7) derivatives 3b and 3d were obtained.
The phenyl derivative 3c was obtained in only 3% e.e.,
a surprising result in view of the successful hydrogena-
tion of cinnamate derivatives.2
2.4. Hydrogenations of NHAc and NHBoc nitriles
Hydrogenation of the acetamido nitrile 7 using (R,R)-
Et-DuPHOS-Rh(I) gave the saturated compound 18 in
high yield (89%) (Fig. 3). The e.e. was shown to be 64%
Table 2. Enantioselective hydrogenation of a,b-unsaturated phthalimido esters 9a
Entry
Substrate 9, R=
Catalystb
Temp. (°C)
Pressure (psi)
[h]D
e.e.c (%)
Yieldd (%)
9
9a, H
9a, H
9a, H
9b, Me
BINAP-Ru
BINAP-Ru
DuPHOS-Rh
BINAP-Ru
20
20
20
100
50
50
−16.9
−17.2
+6.3
0.0
80
84
12
10
92
91
93
91
10
11
12
100
90
a Reactions in MeOH for 40 h.
b (S)-BINAP-Ru(II); (R,R)-Et-DuPHOS-Rh(I).
c Enantiomeric excess determined by HPLC (see below).
d Isolated yield after chromatography.

D. Saylik et al. / Tetrahedron: Asymmetry 12 (2001) 657–667
661
no. 9385). Analytical thin-layer chromatography (TLC)
was performed on Polygram Sil G/UV254 plates. Optical
rotations were measured with a Perkin–Elmer 141
polarimeter (in a cell length of 1 dm) at a wavelength of
589 nm (sodium D line) at a temperature of 20°C.
High-performance liquid chromatography (HPLC) was
performed on two instruments. One system involved a
NHBoc
NHAc
H
CN
H
CN
18
Figure 3.
19
,
Waters Model 6000A (Column: Deltapak C18—100 A,
3.9 mm×30 cm, 10 mL), Waters gradient programme
model 660 and Waters model 481 detector. Product
distributions were obtained from peak areas from a
peak printout using HP Chemstation 3365 Series II
software. Alternatively, HPLC was performed on a
Varian LC model 5000 with a Varian UV-50 detector.
Product distributions were obtained from peak areas in
a peak printout using Class LC 10 software. The
columns used were Chiralcel OB (column no. OB00CE-
1H013), Chiralcel OD (column no. OD00CE-HL011)
and Chiralcel OJ (column no. OJ00CE-JJ028). Both the
Chiralcel OB and OJ columns have a cellulose ester
derivative coated on silica gel adsorbent while the Chi-
ralcel OD has a cellulose carbamate derivative on silica
gel adsorbent. All columns were 0.46 cm ID×25 cm
with a particle size of 10 mm. Retention times (tR) are
an average of two runs.
by HPLC using a Chiralcel OB column and the product
was shown to have an excess of the (S)-enantiomer by
hydrolysis to a sample of a-methyl-b-alanine 12 with an
[h]D +7.6. In contrast, hydrogenation of the NHBoc
derivative 8 using similar conditions gave only racemic
product 19 (Fig. 3).
3. Conclusion
Enantioselective hydrogenation of acyl derivatives of
a-aminomethyl substituted a,b-unsaturated nitriles and
esters give b-amino acid precursors in good yield and
with e.e. values ranging from 0% to 84%. The highest
e.e.s were obtained in the hydrogenation of the phthal-
imido ester 9a with the BINAP-Ru catalyst. Introduc-
tion of a b-substituent, as in 9b, led to a significant
decrease in e.e. In contrast, the highest e.e.s from
hydrogenation of the phthalimido nitriles 1 were
obtained from b-Me or b-TBDMS substituted com-
pounds with DuPHOS-Rh as catalyst, substantiating
the theory that this enantioselective hydrogenation is
substrate specific.
Solvents were purified according to standard proce-
dures. Chloroform used for optical rotations was of
analytical purity. (−)-1,2-Bis[(2R,5R)-2,5-diethylphos-
pholano]benzene(1,5-cyclooctadiene)rhodium(I)
trifl-
uoromethanesulfonate [(R,R)-EtDuPHOS-Rh(I)] and
(R,R) - (−) - 1,2 - bis[(o - methoxyphenyl)(phenyl)phosph-
ino]ethane(1,5-cyclooctadiene)rhodium(I) tetrafluoro-
borate [(R,R)-MeBPE-Rh(I)] were used as supplied
from Strem Chemicals. [(S)-(−)-2,2%-Bis(diphenyl-
phosphino)-1,1%-binaphthyl]chloro(p-cymene)ruthenium
chloride [(S)-BINAP-Ru(II)] was used as supplied from
Fluka. Palladium on calcium carbonate (5%, Pd/
CaCO3) was obtained from Aldrich. Starting materials
and reagents were purchased from Sigma–Aldrich and
were used without further purification. Nitrogen and
hydrogen (supplied by BOC Gases) and deuterium
(99.5%) (supplied by CIG Gases) gases, used in the
hydrogenation reactions to purge and fill the system,
were of high purity (<10 ppm oxygen) and additional
purification was achieved by passage of the gases
through water, oxygen and hydrocarbon traps. Solvents
used for metal-catalysed reactions were degassed by
bubbling high purity nitrogen through for 60 min prior
to use.
HPLC conditions were established for determination of
the enantiomeric excess of these b-amino acid
precursors.
4. Experimental
4.1. General
Melting points were determined using a Gallenkamp
MFB-595 melting point apparatus and are uncorrected.
Microanalyses were performed either by Chemical and
Micro Analytical Services Pty Ltd, Melbourne or by
the University of Otago, Chemistry Department,
Dunedin, New Zealand. NMR spectra were recorded
on a Bruker AC-200 spectrometer operating at 200 (1H)
and 50 (13C) MHz, on a Bruker DPX-300 spectrometer
operating at 300 (1H) and 75 (13C) MHz, or on a
Bruker DRX-400 spectrometer operating at 400 (1H),
100 (13C) and 61.4 (2H) MHz using either Me4Si (1H) or
the solvent peak (13C, 2H) as the reference. Infrared
(IR) spectra were recorded on a Perkin–Elmer 1600
FT-IR spectrophotometer. Low resolution electron
impact mass spectra (EI) were obtained on a Fisons
TR10-1000 mass spectrometer. Accurate mass measure-
ments were obtained at high resolution with a Bruker
BioApex 47e FTMS and a 4.7 T superconducting mag-
net. The instrument was externally calibrated with
FC5311. Flash column chromatography was carried
out using 40–63 mm (230–400 mesh) silica gel 60 (Merck
4.2. Preparation of alkynes
The phthalimido alkynes 2a–2c, N-(prop-2-ynyl)-
acetamide and tert-butyl N-(prop-2-ynyl)carbamate
were prepared as described in the literature.1a
4.2.1. N - [3% - (t - Butyldimethylsilyl)prop - 2% - ynyl]pht-
halimide 2d. Compound 2d was prepared from the
corresponding alcohol as described by Landini17 and
recrystallised from ethanol as colourless crystals (yield:

662
D. Saylik et al. / Tetrahedron: Asymmetry 12 (2001) 657–667
89%); mp 136.5–137.5°C; IR: w=2926, 2855, 2181,
4.3.3. (E)-2-(2%-Cyano-3%-phenylprop-2%-enyl)phthalimide
1c1a. Yield: 58%; 13C NMR (100 MHz, CDCl3) l 36.1
(C-1%), 111.1 (C-2%), 117.9 (CN), 123.7 (C-4/7), 128.9,
129.4, 130.0 (ArCH), 131.8 (C-3a/7a), 133.1 (ArC),
134.3 (C-5/6), 146.5 (C-3%), 167.3 (CO).
1774, 1714, 1612, 1464, 1419, 1393, 1319, 1252, 1117,
1
1037, 939, 835, 775, 724, 713, 680 cm−1; H NMR (200
MHz, CDCl3) l 0.06 (s, 6H, Si(CH3)2), 0.89 (s, 9H,
C(CH3)3), 4.46 (s, 2H, 1%-CH2), 7.71–7.77 (m, 2H,
ArH), 7.85–7.90 (m, 2H, ArH); 13C NMR (50 MHz,
CDCl3)
l −4.7 (Si(CH3)2), 16.6 (C(CH3)3), 26.1
4.3.4. (E)-2-[3%-(t-Butyldimethylsilyl)-2%-cyanoprop-2%-
enyl]phthalimide 1d. Yield: 75%; mp 125–128°C; IR:
w=2923, 2854, 2206, 1771, 1722, 1463, 1378, 1341,
1309, 1252, 950, 852, 826, 711 cm−1; 1H NMR (300
MHz, CDCl3) l 0.32 (s, 6H, Si(CH3)2), 0.98 (s, 9H,
(CH3)3C), 4.52 (d, 2H, J=1.6 Hz, 1%-CH2), 6.81 (t, 1H,
J=1.5 Hz, 3%-CH), 7.75 (m, 2H, ArH), 7.88 (m, 2H,
ArH); 13C NMR (75 MHz, CDCl3) l −4.9 (Si(CH3)2),
17.1 ((CH3)3C), 26.2 ((CH3)3C), 39.2 (C-1%), 117.5
(CN), 123.7 (C-4/7), 125.2 (C-2%), 131.8 (C-3a/7a), 134.3
(C-5/6), 150.8 (C-3%), 167.3 (CO); MS (EI): m/z 326
(M+, 1%), 311 (3), 270 (19), 269 (100), 242 (4), 130 (70),
102 (27), 75 (27), 57 (23); C18H19N2O2Si (323.45) calcd:
C, 66.2; H, 6.8; N, 8.6; found: C, 66.6; H, 7.1; N, 8.5%.
(C(CH3)3), 28.1 (C-1%), 85.5 (C-3%), 99.3 (C-2%), 123.6
(C-4/7), 132.1 (C-3a/7a), 134.2 (C-5/6), 167.0 (CO); MS
(EI): m/z (no M+), 284 (M−15, 1%), 242 (100), 130 (50),
102 (22); C17H21NO2Si (299.45) calcd: C, 68.2; H, 7.1;
N, 4.7; found: C, 68.4; H, 7.2; N, 4.4%.
4.2.2. N-[3%-(Trimethylsilyl)prop-2%-ynyl]phthalimide 2e.
Compound 2e was prepared as above and recrystallised
from ethanol as colourless crystals (yield: 74%); mp
125–126.2°C; IR: w=2924, 2854, 2181, 1770, 1465,
1429, 1393, 1379, 1353, 1328, 1252, 1122, 1028, 950,
848, 732, 652 cm−1; H NMR (200 MHz, CDCl3) l 0.12
1
(s, 9H, Si(CH3)3), 4.45 (s, 2H, 1%-CH2), 7.71 (m, 2H,
ArH), 7.87 (m, 2H, ArH); 13C NMR (50 MHz, CDCl3)
l −0.1 (Si(CH3)3), 28.1 (C-1%), 88.3 (C-3%), 98.6 (C-2%),
123.3 (C-4/7), 132.2 (C-3a/7a), 134.3 (C-5/6), 167.1
(CO); MS (EI): m/z 257 (M+, 5%), 243 (20), 242 (100),
163 (11), 130 (74), 104 (14), 102 (50), 77 (17), 76 (36), 73
(23), 50 (11); C14H15NO2Si (257.37) calcd: C, 65.4; H,
5.9; N, 5.4; found: C, 65.4; H, 6.1; N, 5.5%.
4.3.5. (E)-2-[2%-Cyano-3%-(trimethylsilyl)prop-2%-enyl]-
phthalimide 1e. Yield: 70%; mp 82–84.5°C; IR: w=2925,
2854, 2211, 1771, 1719, 1465, 1430, 1390, 1343, 1311,
1253, 1190, 1122, 948, 865, 848, 737, 711 cm−1; 1H
NMR (300 MHz, CDCl3) l 0.32 (s, 9H, Si(CH3)3), 4.50
(d, 2H, J=1.4 Hz, 1H, 1%-CH2), 6.77 (t, J=1.3 Hz, 1H,
3%-CH), 7.74 (m, 2H, ArH), 7.86 (m, 2H, ArH); 13C
NMR (75 MHz, CDCl3) l −0.7 (Si(CH3)3), 39.1 (C-1%),
117.5 (CN), 123.7 (C-4/7), 123.8 (C-2%), 131.8 (C-3a/7a),
134.3 (C-5/6), 153.1 (C-3%), 167.3 (CO); MS (EI): m/z
284 (M+, 3%), 283 (4), 270 (18), 269 (76), 205 (18), 204
(82), 160 (35), 130 (100), 105 (10), 104 (16), 102 (42), 77
(30), 73 (40), 58 (14); C15H16N2O2Si (284.39) calcd: C,
63.4; H, 5.7; N, 9.8; found: C, 63.4; H, 5.7; N, 9.5%.
4.3. General procedure for hydrocyanation reactions
All hydrocyanation reactions were carried out in a 75
mL stainless steel autoclave as described previously.1,18
The substrate (5 mmol), catalyst (Ni[P(OPh)3]4 (100
mmol)), ligand (P(OPh)3 (1 mmol)) and dry degassed
benzene (10 mL) were placed, in order, in the autoclave
under a nitrogen atmosphere. Hydrogen cyanide (5
mmol) was added using a gas-tight syringe. In some
cases, when ambient temperature exceeded 20°C, a
larger volume of HCN was used. The reactor was
sealed and heated at 120°C for the required time. The
autoclave was cooled, the excess hydrogen cyanide was
vented and the benzene removed. The catalyst was
precipitated with chloroform and removed by filtration
and the solvent removed in vacuo to give the crude
product. Flash chromatography (silica, ethyl acetate/
light petroleum) gave the product nitriles.
4.3.6. N-(2%-Cyanoprop-2%-enyl)acetamide 7. Distillation
of the hexane insoluble fraction gave compound 7 as a
colourless oil (yield: 29%); bp (oven) 150°C/0.20 mm;
IR: w=3295, 3076, 2936, 2227, 1662, 1548, 1428, 1374,
1
1289, 1033, 953 cm−1; H NMR (400 MHz, CDCl3) l
2.04 (s, 3H, CH3), 4.01 (dt, 2H, J=6.2, 1.3 Hz, 1%-CH2),
5.95 (t, 1H, J=1.5 Hz, 3%-CH(E)), 5.99 (t, 1H, J=1.2
Hz, 3%-CH(Z)), 6.46 (bs, 1H, NH); 13C NMR (100
MHz, CDCl3) l 22.9 (CH3), 41.8 (C-1%), 117.3 (CN),
120.2 (C-2%), 131.6 (C-3%), 170.5 (CO); MS (EI): m/z 124
(M+, 12%), 109 (8), 82 (100), 81 (57), 66 (42), 55 (30),
54 (40), 52 (43), 51 (36); HRMS (EI): m/z calcd for
C6H8N2O: 124.0637; found: 124.0636.
4.3.1. 2-(2%-Cyanoprop-2%-enyl)phthalimide 1a1a. Obta-
ined from 2a as a mixture with (E)-2-(3%-cyanoprop-2%-
enyl)phthalimide 6a in the ratio 85:15, respectively, as a
white solid. Yield: 68%; mp 71–72°C; 13C NMR (100
MHz, CDCl3) l 39.6 (C-1%), 116.6 (C-2%), 118.0 (CN),
123.8 (C-4/7), 131.7 (C-3%), 132.9 (C-3a/7a), 134.5 (C-5/
4.3.7. t-Butyl N-(2%-cyanoprop-2%-enyl)carbamate 8. Com-
pound 8 was isolated by chromatography (ethyl ace-
tate:light petroleum:ammonia solution, 2:8:1) as a
colourless oil (yield: 42%); bp (oven) 140°C/0.12 mm;
IR: w=3350, 2979, 2930, 2227, 1699, 1516, 1368, 1252,
1170, 1053, 949, 862 cm−1; 1H NMR (300 MHz, CDCl3)
l 1.46 (s, 9H, C(CH3)3), 3.89 (bd, 2H, J=6.3 Hz,
1%-CH2), 4.90 (bs, 1H, NH), 5.92 (bt, 1H, J=1.5 Hz,
3%-CH(E)), 5.98 (t, 1H, J=1.3 Hz, 3%-CH(Z)); 13C
NMR (75 MHz, CDCl3) l 28.3 (C(CH3)3), 43.1 (C-1%),
80.4 (C(CH3)3), 117.3 (CN), 121.0 (C-2%), 130.7 (C-3%),
155.3 (CO); MS (EI): m/z 167 (M+−CH3, 9%), 149 (12),
1
6), 167.1 (CO). H NMR spectral data were consistent
with the literature.1a
4.3.2. (E)-2-(2%-Cyanobut-2%-enyl)phthalimide 1b1a. Yie-
ld: 44%; 13C NMR (100 MHz, CDCl3) l 14.8 (C-4%),
34.6 (C-1%), 111.2 (C-2%), 118.0 (CN), 123.6 (C-4/7),
131.8 (C-3a/7a), 134.3 (C-5/6), 147.0 (C-3%), 167.3
(CO).

D. Saylik et al. / Tetrahedron: Asymmetry 12 (2001) 657–667
663
127 (80), 126 (100), 123 (20), 109 (26); C9H14N2O2
(182.22) calcd: C, 59.32; H, 7.74; N, 15.37; found: C,
59.27; H, 7.68; N, 15.36%.
mg) and dry, degassed solvent (4–10 mL). The vessel
was evacuated and flushed with hydrogen gas three
times before the autoclave was filled with hydrogen gas
to a pressure that exceeded the desired reaction pres-
sure. The autoclave was tested for leaks, the hydrogen
gas was then vented until the desired reaction pressure
of 145 psi was achieved and the vessel was heated at
70°C for 16 h. The autoclave was cooled to ambient
temperature, the gas was slowly vented, the mixture
filtered through a Celite pad and the solvent removed in
vacuo. The crude product was purified by flash chro-
matography (silica, ethyl acetate:light petroleum, 20:80
unless otherwise noted).
4.4. 2-(Phthalimidomethyl)alkenoates 9
Concentrated sulfuric acid (11.0 g, 112.2 mmol) was
added slowly with frequent shaking to an ice-cold solu-
tion of the cyanophthalimide 1a or 1b (1.37 mmol) in
methanol (12.0 g).19 The mixture was stirred under
reflux for 6.3 h (for 1a) or heated at 80°C for 24 h (for
1b). The solution was cooled and added to an ice-water
slurry. Extraction with dichloromethane (3×20 mL) fol-
lowed by drying (MgSO4), filtration and evaporation of
the solvent in vacuo gave the alkenoates 9a and 9b
which were purified by flash chromatography (ethyl
acetate:light petroleum, 20:80).
Method 2: Reactions involving the asymmetric homoge-
neous catalysts (Rh and Ru complexes of DuPHOS,
BPE and BINAP) were performed using a drybox. In
the drybox, a Fisher–Porter shielded aerosol pressure
reactor was charged with catalyst (1–2 mg), substrate
(60–250 mg) and dry, deoxygenated solvent (ca. 5 mL).
The reaction vessel was assembled and tightly sealed
within the drybox. The apparatus was connected to the
manifold and the line was purged three times using a
vacuum and nitrogen flushing cycle before the pressure
vessel was opened to the manifold and purged three
times using a vacuum and hydrogen flushing cycle. The
reactor was filled with hydrogen to a pressure of 70 psi
unless otherwise stated and the reaction was stirred at
ambient temperature (20°C) for 24 h unless noted oth-
erwise. The hydrogen gas was vented and the contents
were transferred to a flask and the solvent removed in
vacuo. Purification was achieved by flash chromatogra-
phy as described above.
4.4.1. Methyl 2-(phthalimidomethyl)prop-2-enoate 9a.
White solid, mp 93–96°C; yield: 54%; IR: w=2923,
2854, 1774, 1730, 1709, 1463, 1426, 1394, 1376, 1265,
1
1196, 1157, 1114, 961, 733, 714 cm−1; H NMR (300
MHz, CDCl3) l 3.80 (s, 3H, OCH3), 4.56 (t, 2H, J=1.5
Hz, NCH2), 5.59 (t, 1H, J=1.5 Hz, 3-CH(E)), 6.32 (t,
1H, J=1.1 Hz, 3-CH(Z)), 7.74 (m, 2H, ArH), 7.87 (m,
2H, ArH); 13C NMR (75 MHz, CDCl3) l 38.3 (NCH2),
52.1 (OCH3), 123.5 (C-4%/7%), 126.1 (C-3), 132.0 (C-3a%/
7a%), 134.1 (C-5%/6%), 134.5 (C-2), 165.7, 167.7 (CO); MS
(EI): m/z 214 (M+−OCH3, 37%), 213 (100), 186 (22),
185 (64), 160 (28), 157 (19), 130 (17), 104 (25), 77 (13),
76 (23), 44 (16); C13H11NO4 (245.24) calcd: C, 63.67; H,
4.52; N, 5.71; found: C, 63.40; H, 4.39; N, 5.66%.
4.4.2. (E)-Methyl 2-(phthalimidomethyl)but-2-enoate 9b.
Compound 9b was obtained as a pale yellow oil that
solidified on standing, mp 80–83°C; yield: 41%; IR:
w=3056, 2988, 2954, 1774, 1720, 1469, 1438, 1397,
1363, 1332, 1202, 1145, 1058 cm−1; 1H NMR (300
MHz, CDCl3) l 2.05 (d, 3H, J=7.3 Hz, 4-CH3), 3.71
(s, 3H, OCH3), 4.58 (s, 2H, NCH2), 7.13 (q, 1H, J=7.3
Hz, 3-CH), 7.69 (m, 2H, ArH), 7.82 (m, 2H, ArH); 13C
NMR (75 MHz, CDCl3) l 14.6 (C-4), 33.9 (NCH2),
51.8 (OCH3), 123.2 (C-4%/7%), 127.1 (C-2), 132.1 (C-3a%/
7a%), 133.8 (C-5%/6%), 143.3 (C-3), 166.8, 167.8 (CO);
C14H13NO4 (259.26) calcd: C, 64.86; H, 5.05; N, 5.40;
found: C, 64.84; H, 5.25; N, 5.26%.
Hydrogenation experiments are described in the follow-
ing format: substrate, solvent, catalyst, hydrogen pres-
sure, reaction temperature, reaction time, isolated yield,
retention time (HPLC conditions), enantiomeric excess
(assigned configuration) and optical rotation.
The assigned configuration of amino acid derivatives of
a-methyl-b-alanine is based on the configuration of the
hydrolysed amino acid compared with the absolute
configuration of a-methyl-b-alanine 12. Retention time
(tR) is quoted for the major enantiomer.
4.6.1. 2-(2%-Cyanopropyl)phthalimide 3a. (a) 2-(2%-
Cyano-2%-prop-2%-enyl)phthalimide 1a (30.5 mg), ethyl
acetate (4 mL), Pd/CaCO3 (10.0 mg) using Method 1
gave 3a, yield 95%, HPLC: tR=36 and 43 min (Chiral-
cel OB, flow rate=1 mL/min, detection at 254 nm,
eluent=90% hexane:10% 2-propanol. (b) A mixture of
2-(2%-cyanoprop-2%-enyl)phthalimide 1a and (E)-2-(3%-
cyanoprop-2%-enyl)phthalimide 6a (isomer ratio 85:15)
(930 mg), methanol (15 mL), (R,R)-EtDuPHOS-Rh(I)
(10 mg), 70 psi H2 using Method 2 gave 3a, yield 86%
(and 6a, yield 13%), HPLC (for 3a): tR=36 min, 14%
e.e. (S), [h]D +8.3 (c 2.0, CHCl3). (c) Nitriles 1a and 6a
(ratio 85:15) (101 mg), acetonitrile (5 mL), (R,R)-
EtDuPHOS-Rh(I) (1 mg), 70 psi H2 using Method 2,
gave 3a, yield 81% (and 6a, yield 12%), HPLC (for 3a):
tR=36 min, 4% e.e. (S), [h]D +1.0 (c 2.0, CHCl3). (d)
Nitriles 1a and 6a (ratio 85:15) (114 mg) methanol (5
4.5. 2-(Aminomethyl)prop-2-enoic acid hydrochloride
10a
2-(Aminomethyl)prop-2-enoic acid hydrochloride 10a
1
was prepared as described in the literature.1a The H
NMR spectral data were consistent with that previously
reported.1a
4.6. Hydrogenation reactions
Method 1: Reactions employing Pd/CaCO3 were per-
formed in a 100 mL stainless steel Parr autoclave, lined
with a glass sleeve, equipped with a magnetic Teflon-
coated stirrer bead and heated in a thermostat con-
trolled Eurotherm heating block. The reactor was
charged with the catalyst (10–50 mg), substrate (30–160

664
D. Saylik et al. / Tetrahedron: Asymmetry 12 (2001) 657–667
mL), (R,R)-MeBPE-Rh(I) (1 mg), 60 psi H2 using
Method 2 gave 3a, yield 78% (and 6a, yield 17%), HPLC
(for 3a): tR=43 min, 12% e.e. (R), [h]D −6.8 (c 2.0,
CHCl3).
93%, HPLC: tR=10 and 12 min (Chiralcel OD, flow
rate=1 mL/min, detection at 254 nm, eluent=95%
hexane:5% 2-propanol). (b) Compound 1d (110 mg),
benzene (5 mL), (R,R)-EtDuPHOS-Rh(I) (1 mg,), 100
psi H2, 40°C using Method 2 gave 3d, yield 84%, HPLC:
tR=10 min, 48% e.e., [h]D −8.3 (c 2.0, CHCl3).
Compound 3a: White solid, mp 94–96°C (lit.1a 95–97°C);
1H NMR (400 MHz, CDCl3) l 1.39 (d, 3H, J=7.1 Hz,
3%-CH3), 3.24 (m, 1H, 2%-CH), 3.77 (dd, 1H, J=13.7, 7.0
Hz, NCH(H)), 4.01 (dd, 1H, J=13.7, 8.3 Hz, NCH(H)),
7.76 (m, 2H, ArH), 7.88 (m, 2H, ArH); 13C NMR (100
MHz, CDCl3) l 15.6 (C-3%), 25.2 (C-2%), 40.1 (C-1%), 120.4
(CN), 123.7 (C-4/7), 131.6 (C-3a/7a), 134.4 (C-5/6), 167.7
Compound 3d: White solid, mp 83.5–86°C; IR: w=2926,
2854, 2220, 1768, 1708, 1464, 1398, 1377, 1366, 776, 716
cm−1; 1H NMR (400 MHz, CDCl3) l 0.10 (s, 3H, SiCH3),
0.16 (s, 3H, SiCH3), 0.88 (dd, 1H, J=14.7, 4.9 Hz,
SiCH(H)), 0.89 (s, 9H, (CH3)3C), 1.01 (dd, 1H, J=14.7,
10.7 Hz, SiC(H)H), 3.19 (m, 1H, 2%-CH), 3.71 (dd, 1H,
J=13.6, 6.1 Hz, NCH(H)), 4.05 (dd, 1H, J=13.6, 9.6 Hz,
NC(H)H), 7.75 (m, 2H, ArH), 7.89 (m, 2H, ArH); 13C
NMR (100 MHz, CDCl3) l −6.2, −5.7 (Si(CH3)2), 13.7
(C-3%), 16.5 ((CH3)3C), 26.3 ((CH3)3C), 27.1 (C-2%), 42.2
(C-1%), 120.9 (CN), 123.7 (C-4/7), 131.8 (C-3a/7a), 134.4
(C-5/6), 167.8 (CO); MS (EI): m/z 328 (M+, 2%), 327 (5),
281 (20), 272 (21), (29), 160 (10), 130 (10), 73 (16), 44 (10).
1
(CO). H NMR spectral data were consistent with that
previously reported.1a
4.6.2. 2-(2%-Cyanobutyl)phthalimide 3b. (a) (E)-2-(2%-
Cyanobut-2%-enyl)phthalimide 1b (32 mg), ethyl acetate
(4 mL), Pd/CaCO3 (10 mg) using Method 1 gave 3b, yield
88% (after recrystallisation from methanol), HPLC:
tR=33 and 39 min (Chiralcel OB, flow rate=1 mL/min,
detection at 254 nm, eluent=90% hexane:10% 2-
propanol). (b) Compound 1b (140 mg), methanol (5 mL),
(R,R)-EtDuPHOS-Rh(I) (2 mg), 100 psi H2, 40°C using
Method 2 gave 3b, yield 88%, HPLC: tR=39 min, 33%
e.e., [h]D +1.0 (c 2.0, CHCl3).
4.6.5. 2-(2%-Cyano-3%-trimethylsilylpropyl)phthalimide 3e.
(a) (E)-2-(2%-Cyano-3%-trimethylsilyl-2%-propenyl)phthal-
imide 1e (88 mg), ethyl acetate (7 mL), Pd/CaCO3 (37 mg)
using Method 1 gave 3e, yield 92% (after chromatogra-
phy, ethyl acetate:light petroleum, 10:90), HPLC: tR=7
and 8 min (Chiralcel OD, flow rate=1 mL/min, detection
at 254 nm, eluent=80% hexane:20% 2-propanol). (b)
Compound 1e (100 mg), methanol (4 mL), (R,R)-
EtDuPHOS-Rh(I) (1 mg), 100 psi H2, 40°C using
Method 2 gave 3e, yield 93%, HPLC: tR=7 min, 10% e.e.,
[h]D +2.5 (c 2.0, CHCl3).
Compound 3b: White solid, mp 66–70°C (lit.1a 65–70°C);
1H NMR (400 MHz, CDCl3) l 1.16 (t, 3H, J=7.4 Hz,
4%-CH3), 1.71 (m, 2H, 3%-CH2), 3.13 (m, 1H, 2%-CH), 3.79
(dd, 1H, J=13.7, 7.0 Hz, NCH(H), 4.03 (dd, 1H,
J=13.7, 8.4 Hz, NC(H)H), 7.76 (m, 2H, ArH), 7.89 (m,
2H, ArH); 13C NMR (75 MHz, CDCl3) l 11.2 (C-4%), 23.2
(C-3%), 32.8 (C-2%), 38.7 (C-1%), 119.5 (CN), 123.7 (C-4/7),
1
131.7 (C-3a/7a), 134.4 (C-5/6), 167.7 (CO). H NMR
Compound 3e: Colourless oil; IR: w=2954, 2241, 1775,
spectral data were consistent with the literature.1a
1720, 1468, 1434, 1396, 1356, 1302, 1252, 1191, 1088, 963,
1
845, 716, 700 cm−1; H NMR (400 MHz, CDCl3) l 0.15
4.6.3. 2-(2%-Cyano-3%-phenylpropyl)phthalimide 3c. (a)
(E)-2-(2%-Cyano-3%-phenylprop-2%-enyl)phthalimide 1c
(84 mg), ethyl acetate (7 mL), Pd/CaCO3 (31 mg) using
Method 1 gave 3c, yield 70% (after chromatography and
recrystallisation from ethanol), HPLC: tR=33 and 49
min (Chiralcel OB, flow rate=1.5 mL/min, detection at
254 nm, eluent=80% hexane:20% 2-propanol). (b) Com-
pound 1c (130 mg), methanol (4 mL), (R,R)-EtDuPHOS-
Rh(I) (2 mg), 100 psi H2, 40°C using Method 2 gave 3c,
yield 78%, HPLC: tR=49 min, 3% e.e., [h]D 0.0 (c 2.0,
CHCl3).
(s, 9H, (SiCH3)3), 0.86 (dd, 1H, J=14.7, 5.1 Hz,
SiCH(H)), 1.02 (dd, 1H, J=14.6, 10.7 Hz, SiCH(H)),
3.18 (m, 1H, 2%-CH), 3.71 (dd, 1H, J=13.6, 6.3 Hz,
NC(H)H), 4.03 (dd, 1H, J=13.6, 9.2 Hz, NCH(H)), 7.75
(m, 2H, ArH), 7.89 (m, 2H, ArH); 13C NMR (100 MHz,
CDCl3) l −1.4 (Si(CH3)3), 17.7 (C-3%), 26.9 (C-2%), 41.9
(C-3%), 120.8 (CN), 123.7 (C-4/7), 131.7 (C-3a/7a), 134.3
(C-5/6), 167.7 (CO); MS (EI): m/z 286 (M+, 2%), 272 (5),
271 (27), 160 (100), 130 (13), 126 (11), 104 (13), 76 (18),
73 (23), 72 (27), 58 (23), 50 (14); C15H18N2O2Si (286.41)
calcd: C, 62.90; H, 6.33; N, 9.78; found: C, 62.71; H, 6.44;
N, 9.71%.
Compound 3c: White solid, mp 114–116°C (lit.1a 114–
1
116°C); H NMR (400 MHz, CDCl3) l 2.99 (m, 2H,
4.6.6. N-(2%-Cyanopropyl)acetamide 18. (a) N-(2%-
Cyanoprop-2%-enyl)acetamide 7 (106 mg), ethyl acetate (7
mL), Pd/CaCO3 (22 mg) using Method 1 gave 18, yield
92% (after distillation), HPLC: tR=14 and 29 min
(Chiralcel OB, flow rate=1 mL/min, detection at 220 nm,
eluent=90% hexane:10% 2-propanol). (b) Compound 7
(250 mg), methanol (6 mL), (R,R)-EtDuPHOS-Rh(I) (2
mg), 60 psi H2 using Method 2 gave 18, yield 89% (after
chromatography using ethyl acetate:light petrol-
eum:ammonia solution, 2:8:1), HPLC: tR=29 min, 64%
e.e. (S), [h]D +77.8 (c 2.0, CHCl3).
3%-CH2), 3.48 (m, 1H, 2%-CH), 3.84 (dd, 1H, J=13.8, 6.7
Hz, NC(H)H), 4.06 (dd, 1H, J=13.8, 8.6 Hz, NCH(H)),
7.29 (m, 5H, ArH), 7.73 (m, 2H, ArH(Ft)), 7.85 (m, 2H,
ArH(Ft)); 13C NMR (100 MHz, CDCl3) l 32.9 (C-2%),
36.2 (C-3%), 38.9 (C-1%), 119.2 (CN), 123.7 (C-4/7), 127.5,
128.86, 128.89 (ArCH), 131.7 (C-3a/7a), 134.4 (C-5/6),
1
135.7 (ArC), 167.7 (CO). H NMR spectral data were
consistent with reported data.1a
4.6.4. 2 - [3% - (t - Butyldimethylsilyl) - 2% - cyanopropyl]-
phthalimide 3d. (a) (E)-2-[3%-(t-Butyldimethylsilyl)-2%-
cyanoprop-2%-enyl]phthalimide 1d (100 mg), ethyl acetate
(7 mL), Pd/CaCO3 (30 mg) using Method 1 gave 3d, yield
Compound 18: Clear, colourless oil, bp (oven) 114°C/0.5
mm; IR: w=3293, 3083, 2987, 2942, 2244, 1660,

D. Saylik et al. / Tetrahedron: Asymmetry 12 (2001) 657–667
665
1556, 1456, 1440, 1376, 1293, 1144, 1115 cm−1; 1H
NMR (400 MHz, CDCl3) l 1.31 (d, 3H, J=7.1 Hz,
3%-CH3), 2.02 (s, 3H, OCH3), 2.98 (m, 1H, 2%-CH),
3.25 (m, 1H, NCH(H)), 3.52 (m, 1H, NC(H)H), 6.78
(s, 1H, NH); 13C NMR (100 MHz, CDCl3) l 15.2
(C-3%), 22.8 (OCH3), 26.4 (C-2%), 42.2 (C-1%), 121.7
(CN), 170.9 (CO); MS (EI): m/z 126 (M+, 5%), 125
(1), 111 (11), 72 (100), 43 (99), 42 (12), 41 (11);
HRMS (EI): m/z calcd for C6H10N2O+H: 127.0871;
found: 127.0872.
(OCH3), 123.4 (C-4%/7%), 132.0 (C-3a%/7a%), 134.1 (C-5%/
6%), 168.1, 174.3 (CO); MS (EI): m/z 247 (M+, 3%),
217 (1), 188 (13), 187 (40), 161 (11), 160 (100);
C13H13NO4 (247.25) calcd: C, 63.15; H, 5.30; N, 5.67;
found: C, 63.28; H, 5.44; N, 5.65%.
4.6.9. (E)-Methyl 2-(phthalimidomethyl)butanoate 17b.
(a) (E)-Methyl 2-(phthalimidomethyl)but-2-enoate 9b
(20 mg), ethyl acetate (3 mL), Pd/CaCO3 (5 mg)
using Method 1 gave 17b, yield 89%, HPLC: tR=50
and 59 min (Chiralcel OJ, flow rate=1.5 mL/min,
detection at 254 nm, eluent=100% hexane). (b) Com-
pound 9b (30 mg), methanol (4 mL), (S)-BINAP-
Ru(II) (1 mg), 90 psi H2, 100°C, 40 h using Method
2 gave 17b, yield 91%, HPLC: tR=50 min, 10% e.e.,
[h]D 0.0 (c 1.0, CHCl3).
4.6.7. t-Butyl N-(2%-cyanopropyl)carbamate 19. (a) t-
Butyl N-(2%-cyanoprop-2%-enyl)carbamate 8 (160 mg),
ethyl acetate (7 mL), Pd/CaCO3 (54 mg) using
Method 1 gave 19, yield 81% (after chromatography
using ethyl acetate:light petroleum:ammonia solution,
2:8:1). The enantiomers could not be resolved by
HPLC using Chiracel OD and OB columns. (b) Com-
Compound 17b: White solid, mp 81–83°C, IR: w=2926,
pound
8
(140 mg), methanol (6 mL), (R,R)-
2856, 1772, 1724, 1463, 1396, 1377, 1356, 1176,
1
1045, 722 cm−1; H NMR (300 MHz, CDCl3) l 0.96
EtDuPHOS-Rh(I) (1 mg), 60 psi H2 using Method 2
gave 19, yield 91% (after chromatography as above),
HPLC, racemic material, [h]D 0.0 (c 2.0, CHCl3).
(t, 3H, J=7.4 Hz, 4-CH3), 1.64 (m, 2H, 3-CH2), 2.82
(m, 1H, 2-CH), 3.66 (s, 3H, OCH3), 3.81 (dd, 1H,
J=13.8, 6.2 Hz, NC(H)H), 3.95 (dd, 1H, J=13.8, 8.0
Hz, NCH(H)), 7.71 (m, 2H, ArH), 7.84 (m, 2H,
ArH); 13C NMR (100 MHz, CDCl3) l 11.4 (C-4),
22.9 (C-3), 39.3 (NCH2), 46.0 (C-2), 51.9 (OCH3),
123.4 (C-4%/7%), 132.0 (C-3a%/7a%), 134.0 (C-5%/6%), 168.1,
173.9 (CO); MS (EI): m/z 261 (M+, <1%), 230 (4),
201 (50), 186 (11), 160 (100), 133 (10). HRMS (EI):
m/z calcd for C14H15NO4: 261.1001; found: 261.1002.
Compound 19: White solid, mp 79.5–80°C; IR: w=
3342, 2925, 2854, 2243, 1682, 1521, 1460, 1377, 1368,
1282, 1248, 1162, 1146, 984 cm−1; 1H NMR (400
MHz, CDCl3) l 1.29 (d, 3H, J=7.1 Hz, 3%-CH3), 1.44
(s, 9H, (CH3)3C), 2.91 (m, 1H, 2%-CH), 3.19 (m, 1H,
NCH(H)), 3.37 (m, 1H, NC(H)H), 4.98 (bs, 1H, NH);
13C NMR (100 MHz, CDCl3) l 15.2 (C-3%), 27.1 (C-
2%), 28.3 ((CH3)3C), 43.6 (C-1%), 80.2 ((CH3)3C), 121.7
(CN), 155.7 (CO); MS (EI): m/z 185 (M+, 1%), 169
(13), 130 (100), 129 (47), 128 (15), 111 (42);
C9H16N2O2 (184.24) calcd: C, 58.67; H, 8.75; N,
15.21; found: C, 58.49; H, 8.62; N, 15.09%.
4.7. Hydrolysis to a-methyl-b-alanine 12 (3-amino-2-
methylpropanoic acid)
Using
a similar procedure to that described by
Galat,20 3a, 18 or 17a (ca. 60 mg) and 6 M HCl (3
mL) were stirred under reflux for 15–24 h. The solu-
tion was cooled and the precipitated phthalic acid
was filtered off. The filtrate was evaporated to dry-
ness and the resultant solid was dissolved in hot 2-
propanol and the NH4Cl removed by filtration.
Removal of the 2-propanol gave the amino acid
hydrochloride 11 which was dissolved in water and
passed through an ion exchange column (IR-4B
Amberlite resin). Removal of the water gave the free
amino acid 12 together with some phthalic acid as a
pale yellow hygroscopic solid.
4.6.8. Methyl 2-methyl-3-phthalimidopropanoate 17a.
(a) Methyl 2-(phthalimidomethyl)prop-2-enoate 9a (72
mg), ethyl acetate (7 mL), Pd/CaCO3 (32 mg) using
Method 1 gave 17a, yield 91%; HPLC: tR=51 and 59
min (Chiralcel OJ, flow rate=1 mL/min, detection at
254 nm, eluent=99% hexane:1% 2-propanol). (b)
Compound 9a (70 mg), methanol (4 mL), (R,R)-
EtDuPHOS-Rh(I) (1 mg), 50 psi H2, 40 h using
Method 2 gave 17a, yield 93%, HPLC: tR=59 min,
12% e.e. (S), [h]D +6.3 (c 1.0, CHCl3). (c) Compound
9a (52 mg), methanol (4 mL), (S)-BINAP-Ru(II) (1
mg), 100 psi H2, 40 h using Method 2 gave 17a, yield
92%, HPLC: tR=51 min, 80% e.e. (R), [h]D −16.9 (c
1.0, CHCl3). (d) Compound 9a (10 mg), methanol (2
mL), (S)-BINAP-Ru(II) (1 mg), 50 psi H2, 40 h gave
17a, yield 91%, HPLC: tR=51 min, 84% e.e. (R), [h]D
−17.2 (c 0.95, CHCl3).
4.7.1. (S)-a-Methyl-b-alanine 12. (a) 2-(2%-Cyano-
propyl)phthalimide 3a (sample having [h]D+8.3,
14% e.e, see Section 4.6.1.b) (60 mg) gave 12, yield
58%; [h]D (corrected for chemical conversion) +19.0
(c 0.42, D2O), (S)-enantiomer. (b) N-(2%-Cyano-2%-pro-
penyl)acetamide 18 (sample having [h]D +77.8, 64%
e.e., see Section 4.6.6) (63 mg) gave 12, yield 88%,
[h]D +7.6 (c 0.42, H2O), (S)-enantiomer.
Compound 17a: White solid, mp 86–87°C; IR: w=
2921, 2853, 1775, 1731, 1707, 1463, 1398, 1376, 1358,
1322, 1212, 1190, 1065, 1033, 911, 791 cm−1; 1H
NMR (300 MHz, CDCl3) l 1.21 (d, 3H, J=7.1 Hz,
CH3), 2.98 (sept., 1H, J=7.1 Hz, 2%-CH), 3.66 (s, 3H,
OCH3), 3.78 (dd, 1H, J=13.8, 6.8 Hz, NC(H)H),
3.97 (dd, 1H, J=13.8, 7.6 Hz, NCH(H)), 7.72 (m,
2H, ArH), 7.85 (m, 2H, ArH); 13C NMR (75 MHz,
CDCl3) l 14.7 (CH3), 38.5 (C-2), 40.6 (C-3), 52.0
4.7.2. (R)-a-Methyl-b-alanine 12. Methyl 2-methyl-3-
phthalimidopropanoate 17a (sample having [h]D
−16.9, 80% e.e., see Section 4.6.8) (49 mg) gave 12,
yield 90%, [h]D (corrected for chemical conversion)
−8.2 (c 0.42, D2O), (R)-enantiomer.

666
D. Saylik et al. / Tetrahedron: Asymmetry 12 (2001) 657–667
1
Compound 12: H NMR (400 MHz, D2O) l 1.18 (d,
3H, J=7.3 Hz, CH3), 2.64 (m, 1H, 2-CH), 3.03 (dd,
1H, J=12.9, 5.3 Hz, NCH(H)), 3.11 (dd, 1H, J=12.9,
8.4 Hz, NC(H)H); 13C NMR (100 MHz, D2O) l 15.0
(CH3), 38.8 (C-2), 42.3 (C-3), 180.8 (CO); MS (EI): m/z
103 (M+, 8%), 89 (86), 87 (100), 85 (11), 83 (17), 78
(11), 55 (30), 44 (12), 43 (40) (lit.9 [h]D −14.0 (c 0.42,
D2O) for the (R)-enantiomer).
HPLC: tR=59 min, 11% e.e., (S)-enantiomer, [h]D +3.1
(c 1.0, CHCl3). (b) (S)-a-Methyl-b-alanine 12 (prepared
as described in Section 4.7.1 from a sample of nitrile 3a
having an [h]D +8.3) (50 mg) using Method B gave 14,
yield 100%, [h]D +3.4 (c 1.0, CHCl3).
Compound 14: Yellow viscous oil; IR: w=3331, 2981,
2938, 1732, 1644, 1603, 1580, 1538, 1490, 1463, 1380,
1310, 1258, 1190, 1135, 1096, 1076, 1024, 713, 695
cm−1; 1H NMR (200 MHz, CDCl3) l 1.24 (d, 3H,
J=7.3 Hz, CH3), 1.27 (t, 3H, J=7.2 Hz, CH2CH3),
2.81 (m, 1H, 2-CH), 3.51 (m, 1H, NCH(H)), 3.71 (m,
1H, NC(H)H), 4.17 (q, 2H, J=7.1 Hz, 2H, CH2CH3),
6.91 (bs, 1H, NH), 7.46 (m, 3H, ArH), 7.77 (m, 2H,
ArH); 13C NMR (50 MHz, CDCl3) l 14.3, 15.0 (CH3,
CH2CH3), 39.6 (C-2), 42.1 (C-3), 60.9 (CH2CH3),
127.0, 128.6, 131.5 (ArCH), 134.5 (ArC), 167.5 (COPh),
175.9 (CO2); MS (EI): m/z 235 (M+, 10%), 190 (17), 134
(10), 105 (100), 75 (10), 76 (13); HRMS (EI): m/z calcd
for C13H17NO3: 235.1208; found: 235.1205.
4.8. Preparation of N-benzoyl derivatives of 12
4.8.1. 3-(Benzoylamino)-2-methylpropanoic acid. A solu-
tion of a-methyl-b-alanine hydrochloride 11 (240 mg,
2.35 mmol) in aqueous NaOH (2 M, 4 mL) was treated
with benzoyl chloride (0.38 mL, 3.29 mmol) and
allowed to stir at ambient temperature overnight. The
solution was extracted with dichloromethane (10 mL)
to remove base soluble material, acidified with HCl (2
M) and the aqueous solution extracted with ethyl ace-
tate (3×15 mL). The organic extracts were washed with
brine (15 mL), dried (MgSO4), filtered and evaporated
to dryness. The crude was purified by flash chromatog-
raphy (ethyl acetate:light petroleum:acetic acid, 4:6:1)
to give the benzoyl derivative as a clear, colourless oil
which solidified on standing, yield 27%; IR: w=3448,
3054, 2986, 1708, 1663, 1604, 1579, 1522, 1488, 1465,
4.9. 3-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-2-
methylpropanoic acid 13
a-Methyl-b-alanine hydrochloride 11 (0.92 g, 8.96
mmol) and sodium carbonate (1.66 g, 15.68 mmol) were
suspended in water (25 mL) and acetone (20 mL) and
the mixture cooled in ice with stirring. A solution of
N-(9-fluorenylmethoxycarbonyloxy)succinimide (Fmoc-
OSu) (3.02 g, 8.96 mmol) in acetone (15 mL) was added
dropwise. The mixture was stirred at 4°C for 20 min
and at ambient temperature for 4 h, diluted with water
(80 mL) and washed with ethyl acetate (30 mL). The
aqueous layer was acidified to pH 3–4 with concen-
trated HCl and extracted with ethyl acetate (3×30 mL).
The organic extracts were combined, washed with water
(2×30 mL), brine (20 mL), dried over MgSO4, filtered
and evaporated to dryness to give a white solid (1.80 g).
Purification by flash chromatography (ethyl ace-
tate:light petroleum:acetic acid, 2:8:1) gave 13, yield
35%.
1422, 1154 cm−1; H NMR (200 MHz, CDCl3) l 1.27
1
(d, 3H, J=7.2 Hz, CH3), 2.85 (m, 1H, 2-CH), 3.51 (m,
1H, NCH(H)), 3.74 (m, 1H, NC(H)H), 6.95 (bs, 1H,
NH), 7.45 (m, 3H, ArH), 7.75 (m, 2H, ArH); 13C NMR
(50 MHz, CDCl3) l 14.9 (CH3), 39.6 (C-2), 42.1 (C-3),
127.1, 128.7, 131.8 (ArCH), 134.2 (ArC), 168.2 (COAr),
180.6 (CO2H); MS (EI): m/z 207 (M+, 3%), 189 (2), 161
(15), 122 (30), 105 (62). HRMS (EI): m/z calcd for
C11H13NO3: 207.0895; found: 207.0901.
4.8.2. Ethyl 3-(Benzoylamino)-2-methylpropanoate 14.
Method A: Ethyl iodide (28 mL, 0.35 mmol) was added
to a solution of racemic 3-(benzoylamino)-2-methyl-
propanoic acid (prepared from racemic a-methyl-b-ala-
nine) (50 mg, 0.29 mmol) and freshly distilled
1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) (52 mL, 0.35
mmol) in benzene (5 mL) and the solution was heated
at reflux for 15 h. Water (10 mL) was added and the
mixture extracted with diethyl ether (3×10 mL), dried
over MgSO4, filtered and the solvent removed in vacuo
to give a yellow oil. Flash chromatography (ethyl ace-
tate:light petroleum, 30:70) gave the ester 14, yield 72%,
HPLC: tR=59 and 68 min (Chiralcel OJ, flow rate=1
mL/min, detection at 254 nm, eluent=99.5% hex-
ane:0.5% 2-propanol).
(a) Reaction of a-methyl-b-alanine 12 (sample having
an [h]D +19.0, see Section 4.7.1.a) (100 mg) with Fmoc-
Osu (330 mg) as described above gave 13, yield 35%;
[h]D +25.5 (c 1.0, CH2Cl2) (S)-enantiomer (lit.12 [h]D +9
(c 1.0, CH2Cl2) (S)-enantiomer. (b) An identical reac-
tion of a freshly prepared sample of 12 gave 13, yield
33%; [h]D +2.5 (c 1.0, CH2Cl2).
Compound 13: White solid; mp 165.5–168°C (lit.12
165.5–168°C); IR: w=3337, 2924, 2854, 1692, 1544,
1460, 1377, 1273, 1221, 1159, 1006, 758, 742, 734 cm−1;
1H NMR (300 MHz, CD3OD) l 0.99 (m, 3H, CH3),
2.60 (sept., 1H, J=7.0 Hz, 2-CH), 3.16 (dd, 1H, J=
13.5, 6.4 Hz, NCH(H)), 3.33 (dd, 1H, J=13.6, 6.5 Hz,
NC(H)H), 4.16 (m, 1H, 9%-CH), 4.30 (m, 2H, OCH2),
4.47 (bs, 1H, NH); 13C NMR (75 MHz, CD3OD) l 12.7
(CH3), 38.6 (C-9%), 42.2 (C-3), 46.1 (C-2), 65.3 (OCH2),
118.5, 123.7, 125.7, 126.3 (C-1%/8%), 140.2 (C-4a%/4b%),
142.9 (C-8a%/9a%), 156.5 (CO-Fmoc), 176.2 (CO2H); MS
(EI): m/z 325 (M+, <1%), 237 (1), 178 (100), 166 (61),
163 (31), 70 (25).
Method B: 3-(Benzoylamino)-2-methylpropanoic acid
(50 mg, 0.24 mmol) was dissolved in dry ethanol (3 mL)
and the solution cooled to 0°C before the slow addition
of chlorotriethylsilane (61 mL, 0.36 mmol). The result-
ing solution was stirred at 0°C for 1.5 h and at ambient
temperature for a further 6 h. Evaporation afforded the
ester 14 which was purified as above (yield 100%).
(a) (S)-a-Methyl-b-alanine 12 (prepared as described in
Section 4.7.1 from a sample of nitrile 3a having an [h]D
+8.3) (120 mg) using Method A gave 14, yield 78%,

D. Saylik et al. / Tetrahedron: Asymmetry 12 (2001) 657–667
667
4.10. Reactions with deuterium
mutter, P.; Smallridge, A. J. Tetrahedron Lett. 1988, 29,
1983–1984.
Reactions of the nitriles 1a and 1b with deuterium were
carried out as described for hydrogenation reactions in
Section 4.6, Method 2.
2. Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley-Interscience: New York, 1994; pp. 16–94.
3. Takaya, H.; Ohta, T.; Noyori, R. In Catalytic Asymmet-
ric Synthesis; Ojima, I., Ed. Asymmetric hydrogenation.
VCH: New York, 1993; pp. 1–39.
4. Brown, J. M. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N.; Pfaltz, A. K.; Yamamoto, H., Eds.
Hydrogenation of functionalised carbon–carbon double
bonds. Springer-Verlag: Berlin, 1999; Vol. 1, pp. 121–195.
5. (a) Brown, J. M.; Chaloner, P. A.; Morris, G. A. J.
Chem. Soc., Perkin Trans. 2 1987, 1583–1588; (b) Brown,
J. M.; Chaloner, P. A. J. Am. Chem. Soc. 1980, 102,
3040–3048; (c) Brown, J. M.; Parker, D. Organometallics
1982, 1, 950–956.
4.10.1. (2% - 2H1,3% - 2H1) - 2 - (2% - Cyanopropyl)phthalimide
16a. Reaction of 2-(2%-cyano-2%-propenyl)phthalimide
1a (260 mg, 1.24 mmol), methanol (10 mL) and (R,R)-
EtDuPHOS-Rh(I) (5 mg) with deuterium (70 psi) at
20°C gave 16a as a white solid after chromatography,
yield 81%; IR: w=2923, 2854, 2243, 1777, 1715, 1464,
1
1435, 1394, 1378, 1354, 973, 720 cm−1. H NMR (400
MHz, CDCl3) l 1.37 (bs, 2H, CH2D), 3.75 (d, 1H,
J=13.7 Hz, NCH(H)), 4.00 (d, 1H, J=13.7 Hz,
2
NC(H)H), 7.76 (m, 2H, ArH), 7.88 (m, 2H, ArH); H
NMR (61.4 MHz, CDCl3) l 1.29 (bs, 1D, 3%-D), 3.11
(bs, 1D, 2%-D); 13C NMR (100 MHz, CDCl3) l 15.2 (t,
J=20.0 Hz, C-3%), 24.9 (t, J=21.1 Hz, C-2%), 40.1
(C-1%), 120.4 (CN), 123.7 (C-4/7), 131.7 (C-3a/7a), 134.4
(C-5/6), 167.7 (CO); HRMS (EI) m/z calcd for
C12H8D2N2O2: 216.0866; found: 216.0870; [h]D +8.5 (c
2.0, CHCl3).
6. (a) Mashima, K.; Kusano, K.; Ohta, T.; Noyori, R.;
Takaya, H. J. Chem. Soc., Chem. Commun. 1989, 1208–
1210; (b) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm,
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Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem.
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7. (a) Burk, N. J.; Bedingfield, K. M.; Kiesman, W. F.;
Allen, J. G. Tetrahedron Lett. 1999, 40, 3093–3096; (b)
Burk, M. J.; Gross, M. F.; Harper, G. P.; Kalberg, C. S.;
Lee, J. R.; Martinez, J. P. Pure Appl. Chem. 1996, 68,
37–44; (c) Burk, M. J.; Feaster, J. E.; Nugent, W. A.;
Harlow, R. L. J. Am. Chem. Soc. 1993, 115, 10125–
10138.
8. Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron:
Asymmetry. 1991, 2, 543–554.
9. Balenovic, K.; Bregant, N. Tetrahedron 1959, 5, 44–47.
10. Asen, S.; Thompson, J. F.; Morris, C. J.; Irreverre, F. J.
Biol. Chem. 1959, 234, 343–346.
11. (a) Juaristi, E.; Quintana, D.; Balderas, M.; Garcia-Pe´rez,
E. Tetrahedron: Asymmetry 1996, 7, 2233–2246; (b) Juar-
isti, E.; Escalante, J.; Lamatsch, B.; Seebach, D. J. Org.
Chem. 1992, 57, 2396–2398.
12. Guichard, G.; Abele, S.; Seebach, D. Helv. Chim. Acta
1998, 81, 187–206.
4.10.2. (2%-2H1,3%-2H1)-2-(2%-Cyanobutyl)phthalimide 16b.
Reaction of 2-(2%-cyano-2%-butenyl)phthalimide 1b (100
mg, 0.43 mmol), methanol (5 mL) and (R,R)-
EtDuPHOS-Rh(I) (1 mg) with deuterium (100 psi) at
40°C gave 16b as a white solid after chromatography,
yield 81%; IR: w=2923, 2854, 2243, 1773, 1721, 1463,
1
1438, 1396, 1376, 1352, 989, 722 cm−1; H NMR (300
MHz, CDCl3) l 1.15 (d, 3H, J=7.4 Hz, 4%-CH3), 1.70
(m, 1H, 3%-CH), 3.79 (d, 1H, J=13.7 Hz, NCH(H)),
4.02 (d, 1H, J=13.7 Hz, NC(H)H), 7.76 (m, 2H, ArH),
2
7.88 (m, 2H, ArH); H NMR (61.4 MHz, CDCl3) l
1.59 (bs, 1D, 3%-D), 3.02 (bs, 1D, 2%-D); 13C NMR (75
MHz, CDCl3) l 11.1 (C-4%), 22.7 (t, J=20.1 Hz, C-3%),
32.4 (t, J=21.0 Hz, C-2%), 38.6 (C-1%), 119.5 (CN), 123.7
(C-4/7), 131.7 (C-3a/7a), 134.4 (C-5/6), 167.7 (CO);
HRMS (EI): m/z calcd for C13H10D2N2O2: 230.1022;
found: 230.1026; [h]D +1.2 (c 2.0, CHCl3).
13. Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito,
K.; Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102,
7932–7934.
14. Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64,
6907–6910.
Acknowledgements
15. (a) Chan, A. S. C.; Chen, C. C.; Yang, T. K.; Huang, J.
H.; Lin, Y. C. Inorg. Chim. Acta 1995, 234, 95–100; (b)
Kawano, H.; Ikariya, T.; Ishii, Y.; Saburi, M.;
Yoshikawa, S.; Uchida, Y.; Kumobayashi, H. J. Chem.
Soc., Perkin Trans. 1 1989, 1571–1575.
The authors would like to thank the Australian
Research Council for support and provision of an
Australian Postgraduate Research Award (to D.S.),
Johnson Matthey Pty Ltd for a loan of precious metals
and Professor Dieter Seebach, ETH, for his helpful
comments and Dr. Stefan Abele, ETH, for comparison
of the properties of the Fmoc derivative 13 with an
authentic sample.
16. Reference 3, p. 8.
17. Landini, D.; Rollo, F. Synthesis 1976, 389–391.
18. (a) Fitzmaurice, N. J.; Jackson, W. R.; Perlmutter, P. J.
Organomet. Chem. 1985, 285, 375–381; (b) Jackson, W.
R.; Lovel, C. G. Aust. J. Chem. 1983, 36, 1975–1982.
19. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.;
Tatchell, A. R. Vogel’s Textbook of Practical Organic
Chemistry, 5th ed.; Longman: Singapore, 1989; p. 706.
20. Galat, A. J. Am. Chem. Soc. 1945, 67, 1414–1415.
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