Synthesis of new optically active and racemic phenylsuccinamic acids

Article abstract of DOI:10.1055/s-2002-19294

The synthesis, isolation, and characterization of new (S)-(+)- and racemic phenylsuccinamic acids, obtained from the reaction of (S)-(+)-phenylsuccinic anhydride (1) with five different primary amines (2a-e) is described. Ring opening of anhydride 1 led t

Full text of DOI:10.1055/s-2002-19294

PAPER
47
Synthesis of New Optically Active and Racemic Phenylsuccinamic Acids
Synthesis of
N
ew
.
Optically
A
S
ctive and
R
ac
t
emic
P
e
henylsuccin
p
amic
A
cids hani,* V. Cesare, I. Sadarangani, I. Lengyel
Department of Chemistry, St. John’s University , Jamaica, New York, 11439, USA
Fax +1(718)9901876; E-mail: stephanr@stjohns.edu
Received 15 April 2001; revised 13 September 2001
In 1940, Naps and Johns7 synthesized optically active (+)-
-phenylsuccinamic acid and (+)- -phenylsuccinanilic
acid. No mention was made of the -isomers and in the
case of the (+)- -phenylsuccinamic acid, the authors re-
Abstract: The synthesis, isolation, and characterization of new (S)-
(+)- and racemic phenylsuccinamic acids, obtained from the reac-
tion of (S)-(+)-phenylsuccinic anhydride (1) with five different pri-
mary amines (2a–e) is described. Ring opening of anhydride 1 led
to the formation of two isomeric phenylsuccinamic acid products ported that some racemization occurred during purifica-
with the phenyl substituent to the amide function being the pre-
tion.
ferred product. Complete racemization occurred with all of the
-
Eleven years later, Miller and Long8 synthesized a num-
ber of N-substituted phenylsuccinamic acids by reacting
racemic phenylsuccinic anhydride with various amines,
(methylamine, ethylamine, n-propylamine, isopropy-
lamine, allylamine, n-butylamine, isobutylamine, and sec-
butylamine). Although they reported that a mixture of -
and -phenylsuccinamic acid isomers formed, only the -
isomers were isolated and their melting points reported.
Neither the ratio of - to -isomer nor the isolation and
characterization of the -isomers for any of these reac-
tions were given.
André Foucaud9, was the first to report how varying the
substituents on one of the methylene carbons of succinic
anhydride affected the ratio of - to -isomer formation.
A phenyl group was one of the substituents studied. Fou-
caud reported, on the basis of column chromatography,
that the ratio of - to -phenylsuccinamic acid was 46.5%
to 53.5% when phenylsuccinic anhydride was reacted
with ammonia and 23% ( ) to 77% ( ) when phenylsuc-
cinic anhydride was reacted with dimethylamine. Howev-
er, neither of the isomers was isolated.
phenylsuccinamic acids (3a–e) and -phenylsuccinamic acids 4b
and 4c. However, -phenylsuccinamic acids 4a, 4d, and 4e were
found to be optically active.
Key words: anhydride, chirality, nucleophilic addition, racemiza-
tion, ring opening
Recently, we reported1 the auto-resolution of nonracemic
antihistamines under achiral conditions. During our initial
attempts to improve upon existing methods2–5 of antihis-
tamine resolution by HPLC, we prepared several n-propy-
lamino silica gel columns modified by various (S)-(+)-
phenylsuccinamic acids. Although these modified col-
umns did not prove successful, several interesting results
were observed when (S)-(+)-phenylsuccinic anhydride (1)
was reacted with different amines (2) to obtain the desired
phenylsuccinamic acids. Therefore, the reaction of anhy-
dride 1 with various primary amines (2a–e) was further
investigated and the results are reported here.
Succinamic acids (4-amino-4-oxobutanoic acids) contain
both the carboxylic acid and amide functionalities. When
one of the methylene hydrogens is replaced by a different
substituent (i.e. phenyl), two regioisomers are possible.
The substituent will either be alpha ( -succinamic acid) or
beta ( -succinamic acid) to the amide.
Richard Anschütz6, in 1907, was the first to report the syn-
thesis of a phenylsuccinamic acid by reacting racemic
phenylsuccinic anhydride with ammonia. He reported that
the -isomer of phenylsuccinamic acid (mp 144–145 °C)
was the major product. He also reacted phenylsuccinic
anhydride with aniline and reported that the -phenylsuc-
cinanilic acid (mp 169–170 °C) was the only product
formed. From these results, Anschütz concluded that the
carbonyl carbon to the phenyl substituent of the anhy-
dride is more susceptible to attack by the amine and that
ring opening will result in the formation of the -phenyl-
succinamic acid as the major product.
To our knowledge, no -phenylsuccinamic acids have
ever been isolated or characterized and only two optically
active -phenylsuccinamic acids have been reported.7 In
addition, although the ratio of - to -succinamic acid for-
mation has been investigated when varying the substituent
on one of the methylene carbons,9 no study has been re-
ported concerning the effects that varying the amine
would have on the - to -phenylsuccinamic acid ratio.
Given these facts, we report the isolation and character-
ization of several new - and -phenylsuccinamic acids
and their percent composition when (S)-(+)-phenylsuccin-
ic anhydride (1) is reacted with five primary amines (2a–
e).
The racemic phenylsuccinic acid was resolved10,11 and the
(S)-(+)-phenylsuccinic anhydride (1) was synthesized7
from (S)-(+)-phenylsuccinic acid using published meth-
25
ods. The optical activity, [ ]D +97.8° (c 0.3, benzene),
melting point, 83–85 °C, and the infrared carbonyl
stretching bands, 1860 and 1788 cm–1 of anhydride 1 are
in agreement with the literature7 reported values. The
amines chosen for this study were n-propylamine (2a),
Synthesis 2002, No. 1, 28 12 2001. Article Identifier:
1437-210X,E;2002,0,01,0047,0052,ftx,en;M01801SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

48
R. Stephani et al.
PAPER
Table 1 Yields and Percent Composition of - and -Phenyl-
succinamic Acid Isomers
R-Group
Product
Yield (%)c
Yield (%)d
Ratioa
3a
4a
3b
4b
3c
4c
3d
4d
3e
4e
n-C3H7
n-C3H7
i-C3H7
i-C3H7
t-C4H9
t-C4H9
C6H5
45
97
85
55
38
89
80
93
96
73
62
74
-
Scheme 1 Reaction between (S)-(+)-phenylsuccinic anhydride (1)
and amines 2a–e
62
39
61
isopropylamine (2b), tert-butylamine (2c), aniline (2d),
and benzylamine (2e).
29b
71b
41
The general reaction of (S)-(+)-phenylsuccinic anhydride
(1) with amines 2a–e in ether is shown in Scheme 1. Using
2.2 equivalents of amine 2 ensured ring opening of anhy-
dride 1 and complete salt formation of the - and -phe-
nylsuccinamic acids 3 and 4. The isomeric products 3 and
4 were isolated by cooling the reaction mixture to 0°C and
dissolving their amine salts in distilled water. After the
ether was removed, the resulting solution was acidified to
approximately pH 1 using 1 M HCl and the -, -isomer
mixture was collected by filtration.
C6H5
C6H5-CH2
C6H5-CH2
59
aDetermined by HPLC, mobile phase: n-hexane–THF–HOAc,
70:25:5, flow rate: 0.25 mL/min.
bMobile phase: n-hexane–THF–HOAc, 80:17:3, flow rate:
0.25 mL/min.
c Total yield of both isomer at r.t.
d Total yield of both isomers at –60 °C.
The ratio of - to -isomer for these reactions was deter-
mined by HPLC and is shown in Table 1, along with the
overall yields.
71%). However, for each reaction there was also a signif-
icant formation of -isomer 3 (29–45%). The reaction of
anhydride 1 with amines 2a–d at lower temperatures
(0 °C or –60 °C) had no effect on the ratio of product for-
mation, however, the overall yields decreased. For exam-
ple, when anhydride 1 was reacted with n-propylamine
(2a), there was no change ( 2%) in the ratio of product
formation (3 and 4), but the overall yield decreased form
97% at 25 °C to 85% at –60 °C.
From Table 1 it can be seen that the overall yield of iso-
meric products 3 and 4 decreases as the bulkiness of the
R-group of the amine increases. For example, the yields
decreased as anhydride 1 was reacted with n-propylamine
(97%), isopropylamine (89%), or tert-butylamine (80%).
In addition, no matter which amine was reacted with an-
hydride 1, -isomer 4 was always the major product (55–
Scheme 2 A possible mechanism for the racemization of the -phenylsuccinamic acids 3
Synthesis 2002, No. 1, 47–52 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis of New Optically Active and Racemic Phenylsuccinamic Acids
49
The - and -phenylsuccinamic acids 3 and 4 were sepa- resulting enol tautomer is stabilized by conjugation with
rated by cooling the initial reaction mixture to 0 °C, dis- the phenyl ring, thus facilitating racemization. With -at-
solving their amine salts in distilled water and then tack, formation of the carboxylate anion occurs at the -
removing the ether. Dropwise acidification12 of the aque- position, therefore abstraction of the -hydrogen is less
ous solution to approximately pH 4 using 1 M HCl and likely to occur due to the fact that this would place two
stirring the resulting mixture for 30 minutes, led to the se- negative charges in close proximity to each other, hence
lective precipitation of the -product. Further acidifica- impeding racemization.
tion of the filtrate to about pH 1 caused the precipitation
of the -isomer. However, complete separation of the two
A more interesting observation was that racemization also
occurred in formation of -phenylsuccinamic acids 4b
regioisomers of phenylsuccinanilic acids 3d and 4d could
and 4c, when anhydride 1 was reacted with isopropy-
not be achieved by the above procedure. Thus, 98% pure
lamine (2b) and tert-butylamine (2c), respectively. How-
-isomer 4d was isolated as determined by HPLC (it con-
ever, -phenylsuccinamic acids 4a, 4d, and 4e resulting
tained 2% of the -isomer), while -isomer 3d was found
from the reaction of anhydride 1 with n-propylamine (2a),
to contain 15% of -isomer 4d. Other attempts to isolate
aniline (2d), and benzylamine (2e), respectively, re-
mained optically active. A possible mechanism explain-
ing the racemization of only the -phenylsuccinamic acid
products 4b and 4c is shown in Scheme 3.
pure 3d were not successful. The melting points, specific
rotations, and IR properties of phenylsuccinamic acids 3
and 4 are listed in Table 2.
The specific rotations presented in Table 2 show that ra-
cemization occurred in all of the -phenylsuccinamic ac-
Isopropylamine (2b) and tert-butylamine (2c) are stronger
in base strength, yet are weaker nucleophiles than n-pro-
ids isolated 3a–c, 3e. A rationale for the racemization of
pylamine (2a) or benzylamine (2e). Therefore, amines 2b
the -products is shown in Scheme 2.
and 2c act more as a base (pathway A) and racemization
When the -carbonyl of the anhydride ring 1 is attacked of anhydride 1 can occur via intermediate 5 before nucleo-
( -attack) by the basic nitrogen of the amine, the anhy- philic attack of the carbonyl carbon (pathway B). With the
dride ring opens to obtain a carboxylate anion in the -po- less hindered amines, n-propylamine (2a) and benzyl-
sition and an amide in the -position. The -hydrogen, amine (2e), or with the less basic amine, aniline (2d), nu-
which is benzylic and therefore somewhat acidic, can be cleophilic attack (pathway B) can occur before racemiza-
abstracted by a base, such as another amine molecule. The tion takes place (pathway A). An alternative possibility is
Table 2 Physical Data for Amic Acids 3 and 4
a
R-Group
n-C3H7
n-C3H7
i-C3H7
i-C3H7
t-C4H9
t-C4H9
mp °C
[ ]D
IR: N–H cm–1
3290
IR: amide C=O cm–1
3a
4a
3b
4b
3c
4c
4d
3e
4e
166–167
124–125
175–177
122–125
197–200
143–146
138–139
162–165
136–138
rac.
1640
1615
1638
1641
1641
1612
1662
1638
1648
+122.7
rac.
3360
3276
rac.
3341
rac.
3307
rac.
3356
b
C6H5
+148.7
rac.
3352
C6H5CH2
C6H5CH2
3289
+85.6
3341
aFor conditions, see experimental.
bPure 3d was not isolated.
Scheme 3 A possible mechanism for racemization of -phenylsuccinamic acids 4b and 4c
Synthesis 2002, No. 1, 47–52 ISSN 0039-7881 © Thieme Stuttgart · New York

50
R. Stephani et al.
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(S)-(+)-3-Phenyldihydrofuran-2,5-dione (1)
that acid catalyzed racemization occurred during the HCl
work up. If this were the case, then racemization would
have occurred in all -phenylsuccinamic acid products
(4a–e). This was not observed, and products 4a, 4d, and
4e are all optically active.
The procedure of Naps and Johns7 was followed. The yield of pure
(+)-1 was 96.5%.
Mp 83–85 °C, lit.7 mp 82 °C.
[ ]D25 +97.8° (c 0.3, benzene), lit7 [ ]D29 +99.8° (c 0.751, benzene).
IR (KBr): 1860 (C=O), 1788 cm–1 (C=O).
1H NMR (CDCl3): = 3.15 (dd, J = 19 Hz, C*HCHH, 1 H), 3.45
(dd, J = 7 Hz, C*HCHH, 1 H), 4.33 (dd, C*H, 1 H), 7.27–7.41 (m,
Ph, 5 H).
As expected, due to the presence of the chiral center, the
adjacent methylene protons of phenylsuccinic anhydride
(1) and all of the phenylsuccinamic acid products (3 and
4) are diastereotopic and therefore exhibit an ABX system
1
13C NMR (CDCl3): = 37.08 (CH2), 46.94 (C*H), 127.69 (Phpara),
in the H NMR; that is, the methylene protons split each
other and are split by the adjacent methine proton. This 129.12 (Phmeta, 2 C), 129.92 (Phortho, 2 C), 135.03 (Ph), 169.88
( CO), 171.96 ( CO).
splitting results in the formation of a symmetrical multip-
let of eight lines (two doublets of doublets). However, sur-
-Amic acids (3) and -Amic acids (4); General Procedure
prisingly, a second ABX system was also observed in the
A solution of amine 2 (56.3 mmol) in Et2O (50 mL) was added drop-
wise to a solution of (S)-(+)-phenylsuccinic anhydride (1) (4.50 g,
1H NMR spectra of the N-benzylphenylsuccinamic acids
3e and 4e. Even though the benzylic methylene group is
separated from the chiral center by as many as five bonds,
the splitting of the two diastereotopic benzylic protons by
each other and the N–H proton results in a total of eleven
lines. Other examples13 of methylene protons which are
not adjacent to a chiral center, yet are diastereotopic, have
been reported. The geminal coupling between the benzyl-
ic methylene protons prevails even after the N–H has been
exchanged for N–D (by DMSO-d6/CF3COOD), resulting
in a pair of doublets (an AB-quartet). This indicates that
the diastereotopic benzylic methylene protons are caused
by the chiral center, not by the adjacent N–H.
25.6 mmol) in Et2O (250 mL) at 0 °C. The reaction mixture was
stirred for 30 min, distilled water (100 mL) was added, and the re-
action mixture stirred for an additional 30 min. The 2 phases were
separated and the organic layer was washed with distilled water
(100 mL). The aqueous layers were combined and 1 M HCl (ca 15
mL) was added dropwise, until a turbid mixture was observed, (ca
pH 4). The mixture was stirred for 30 minutes at 0 °C, the solid was
filtered, and washed twice with distilled water (25 mL) to yield a
crude sample of -amic acid 3. After recrystallization from distilled
water, an analytical sample of 3 was obtained. The filtrate, of 3, was
treated with 1 M HCl until the pH was ca 1. After stirring the mix-
ture for 30 minutes at 0 °C, the solid was filtered and washed twice
with distilled water (25 mL) to yield a crude sample of -amic acid
4. After recrystallization from distilled water, an analytical sample
of 4 was obtained.
In summary the reaction of (S)-(+)-phenylsuccinic anhy-
dride (1) with various primary amines (2a–e) led to the
formation of two isomeric products and the percentage of
each isomer was determined. In each case, the -phenyl-
succinamic acid (4a–e) was the major product. The isola-
tion and characterization of the first -phenylsuccinamic
acids (3a–c, 3e) are also reported. In addition, several new
-phenylsuccinamic acids (4a–e) were also synthesized
and characterized. It was determined that racemization oc-
curs during -product (3a–e) formation and in -products
(4b, 4c), where the attacking amine is a somewhat stron-
ger base, but a poor nucleophile.
( )-4-Oxo-3-phenyl-4-(propylamino)butanoic Acid (3a)
Mp 166–167 °C.
IR (KBr): 3290 (N–H), 1700 (C=O, acid), 1640 cm–1 (C=O, amide).
1H NMR (DMSO): = 0.74 (t, J = 7 Hz, CH3, 3 H), 1.33 (sextet,
J = 8 Hz, CH3CH2, 2 H), 2.50 (dd, J = 17 Hz, C*HCHH, 1 H), 2.97
(m, C*HCHH, NCH2, 3 H), 3.88 (dd, J = 10 Hz, C*H, 1 H), 7.19–
7.52 (m, Ph, 5 H), 7.99 (t, J = 6 Hz, NH, 1 H), 12.11 (br s, OH, 1 H).
13C NMR (DMSO): = 11.11 (CH3), 22.18 (CH3CH2), 37.27
(C*HCH2), 40.26 (NCH2), 47.02 (C*H), 126.62 (Phpara), 127.39
(Phmeta, 2 C) 128.19 (Phortho, 2 C), 140.23 (Ph), 171.59 (NCO),
172.62 (COOH).
Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C,
66.10; H, 7.21; N, 5.93.
Elemental analyses were performed by Atlantic Laboratory, Inc.
1
(Norcross, GA). Nuclear magnetic resonance spectra (13C and H
NMR) were recorded by NuMega Resonance Labs, Inc. (San Di-
ego, CA) on a 500 MHz Bruker instrument or a 400 MHz Bruker
NMR spectrophotometer. All chemical shifts ( ) are quoted in ppm
downfield from TMS and coupling constants (J) in Hz. All NH and
OH protons undergo deuterium exchange in DMSO-d6 values given
are for NMR carried out in D2O–TFD. The infrared spectra were ob-
tained as a KBr pellet on a Perkin Elmer Fourier Transform (FTIR)
Spectrophotometer Spectrum 1000. Optical rotations were obtained
using a Perkin Elmer 241 Polarimeter. HPLC analyses were per-
formed on a WatersTM 600 Controller equipped with a WatersTM
996 Photodiode Array Detector. A 15-cm WatersTM Resolve Silica
Gel (5 m) column was used for all separations. Melting points
were obtained using a Thomas-Hoover capillary melting point ap-
paratus.
(+)-(2S)- 4-Oxo-2-phenyl-4-(propylamino)butanoic Acid (4a)
Mp 124–125 °C. [ ]D25 +122.7° (c 0.3, acetone).
IR (KBr): 3360 (N–H), 1710 (C=O, acid), 1615 cm–1 (C=O, amide).
1H NMR (DMSO): = 0.76 (t, J = 7 Hz, CH3, 3 H), 1.33 (sextet, J
= 8 Hz, CH2CH3, 2 H), 2.42 (dd, J = 17 Hz, C*HCHH, 1 H), 2.81
(dd, J = 17 Hz, C*HCHH, 1 H), 2.94 (m, NCH2, 2 H); 3.93 (dd, J =
10 Hz, C*H, 1 H), 7.24–7.34 (m, Ph, 5 H), 7.81 (t, J = 6 Hz, NH, 1
H), 12.29 (br s, OH proton, 1 H).
13C NMR (DMSO): = 11.19 (CH3), 22.24 (CH3CH2), 39.62
(C*HCH2), 41.07 (NCH2), 47.96 (C*H), 126.89 (Phpara), 127.62
(Phmeta, 2 C), 128.37 (Phortho, 2 C), 139.05 (Ph), 169.61 (NCO),
174.08 (COOH).
Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C,
66.25; H, 7.22; N, 5.93.
Commercially available reagents and solvents were used without
further purification except aniline and benzylamine, which were
distilled before use.
Synthesis 2002, No. 1, 47–52 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis of New Optically Active and Racemic Phenylsuccinamic Acids
51
( )-4-Oxo-3-phenyl-4-(isopropylamino)butanoic Acid (3b)
IR (KBr): 3350 (N–H), 1718 (C=O, acid), 1662 cm–1 (C=O, amide).
Mp 175–177 °C.
IR (KBr): 3276 (N–H), 1700 (C=O, acid), 1638 cm–1 (C=O, amide).
1H NMR (DMSO): = 0.98 (dd, J = 7 Hz, 2 CH3, 6 H), 2.50 (dd,
J = 16 Hz, C*HCHH, 1 H), 2.93 (dd, J = 14 Hz, C*HCHH, 1 H),
3.76 (septet, J = 7 Hz, NCH, 1 H), 3.85 (dd, C*H, 1 H), 7.20–7.29
(m, Ph, 5 H), 7.89 (d, J = 8 Hz, NH, 1 H), 12.10 (br s, OH, 1 H).
1H NMR (DMSO): = 2.70 (dd, J = 16 Hz, C*HCHH, 1 H), 3.11
(dd, J = 16 Hz, C*HCHH, 1 H), 4.05 (dd, J = 10 Hz, C*H, 1 H),
7.01–7.57 (m, 2 Ph, 10 H), 9.97 (s, NH, 1 H), 12.38 (br s, OH, 1H).
13C NMR (DMSO): = 39.74 (CH2), 46.80 (C*Ph), 118.93
(C*HPhortho, 2 C), 123.11 (C*HPhpara), 127.13 (Phpara), 127.73
(Phortho, 2 C), 128.60 (Phmeta, 2 C), 128.68 (C*HPhmeta, 2 C),
138.98 (Ph), 139.29 (C*HPh), 169.07 (NCO), 174.16 (COOH).
13C NMR (DMSO): = 22.20 (2
CH3), 37.53 (CH2), 40.40
(NCH), 47.02 (C*H), 126.67 (Phpara), 127.46 (Phmeta, 2 C), 128.28
(Phortho, 2 C), 140.35 (Ph), 170.85 (NCO), 172.76 (COOH).
Anal. Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C,
71.38; H, 5.60; N, 5.23.
Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N 5.95. Found: C,
66.20; H, 7.28; N, 6.06.
( )-4-Benzylamino-4-oxo-3-phenylbutanoic Acid (3e)
Mp 163–165 °C.
( )-4-Oxo-2-phenyl-4-(isopropylamino)butanoic Acid (4b)
IR (KBr): 3289 (N–H), 1702 (C=O, acid), 1638 cm–1 (C=O, amide).
Mp 122–125 °C, lit.8 mp 117–119 °C.
1H NMR (DMSO): = 2.55 (dd, J = 17 Hz, C*HCHH, 1 H), 3.05
(dd, J = 17 Hz, C*HCHH, 1 H), 3.98 (dd, J = 10 Hz, C*H, 1 H), 4.18
(dd, J = 15 Hz, CHHPh, 1 H), 4.32 (dd, J = 15 Hz, CHHPh, 1 H),
7.13–7.54, (m, 2 Ph, 10 H), 8.57 (t, J = 16 Hz, NH, 1 H), 12.21 (br
s, OH, 1 H).
13C NMR (DMSO): = 38.13 (CH2), 42.84 (CH2Ph), 47.96 (C*H),
127.45 (Phpara), 127.74 (CH2Phpara), 128.45 (Phmeta, CH2Phmeta, 4
IR (KBr): 3341 (N–H), 1717 (C=O, acid), 1641 cm–1 (C=O, amide).
1H NMR (DMSO): = 0.96 (dd, J = 7 Hz, 2 CH3, 6 H), 2.39 (dd,
J = 15 Hz, C*HCHH, 1 H), 2.79 (dd, J = 15 Hz, C*HCHH, 1 H),
3.76 (septet, NCH, 1 H), 3.92 (dd, J = 9 Hz, C*H, 1 H), 7.25–7.31
(m, phenyl protons, 5 H), 7.67 (d, J = 8 Hz, NH, 1 H), 12.29 (br s,
OH, 1 H).
C), 128.96 (CH2Phortho, 2 C), 129.21 (Phortho, 2
(CH2Ph), 140.94 (Ph), 172.80 (NCO), 173.67 (COOH).
C), 140.33
13C NMR (DMSO): = 22.34 (2
(NCH), 47.11 (C*H), 126.96 (Phpara), 127.73 (Phmeta, 2 C), 128.43
(Phortho, 2 C), 139.12 (Ph), 168.86 (NCO), 174.19 (COOH).
CH3), 38.82 (CH2), 40.16
Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C,
72.09; H, 6.12; N, 5.07.
Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C,
66.34; H, 7.23; N, 5.95.
(+)-(2S)-Benzylamino-4-oxo-2-phenylbutanoic Acid (4e)
Mp 138–140 °C. [ ]D25+85.6° (c 0.305, MeOH).
( )-4-tert-Butylamino-4-oxo-3-phenylbutanoic Acid (3c)
Mp 197–200 °C.
IR (KBr): 3341 (N–H), 1716 (C=O, acid),1648 cm–1 (C=O, amide).
IR (KBr): 3307 (N–H), 1701 (C=O, acid),1641 cm–1 (C=O, amide).
1H NMR (DMSO): = 2.56 (dd, J = 15 Hz, C*HCHH, 1 H), 2.92
(dd, J = 15 Hz, C*HCHH, 1 H), 4.00 (dd, J = 9 Hz, C*H, 1 H), 4.21
(dd, J = 15 Hz, CHHPh, 1 H), 4.27 (dd, J = 15 Hz, CHHPh, 1 H),
7.09–7.34, (m, Ph, 10 H), 8.37 (t, J = 6 Hz, NH, 1 H), 12.38 (br s,
OH, 1 H).
13C NMR (DMSO): = 39.62 (CH2), 42.72 (CH2Ph), 48.01 (C*H),
127.45 (Phpara), 127.80 (CH2Phpara), 127.92 (Phmeta, 2 C), 128.71
(CH2Phmeta, 2 C), 129.02 (CH2Phortho, 2 C), 129.38 (Phortho, 2
C), 139.91 (CH2Ph), 140.26 (Ph), 170.84 (NCO), 175.07 (COOH).
1H NMR (DMSO): = 1.18 (s, 3 CH3, 9 H), 2.45 (dd, J = 16 Hz,
C*HCHH, 1 H), 2.89 (dd, J = 16 Hz, C*HCHH, 1 H), 3.90 (dd, J =
10 Hz, C*H, 1 H), 7.18–7.33 (m, Ph, 5 H), 7.60 (s, NH, 1 H), 12.10
(br s, OH, 1 H).
13C NMR (DMSO): = 28.39 (3 CH3), 37.68 (CH2), 47.20 (C*H),
49.94 (NC), 126.48 (Phpara), 127.37 (Phmeta, 2 C), 128.16 (Phortho
C), 140.59 (Ph), 171.32 (NCO), 172.75 (COOH).
,
2
Anal. Calcd for C14H19NO3: C, 67.45; H, 7.68; N, 5.62. Found: C,
67.67; H, 7.77; N, 5.54.
Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C,
72.00; H, 6.09; N, 4.98.
( )-4-tert-Butylamino-4-oxo-2-phenylbutanoic Acid (4c)
Mp 143–146 °C.
IR (KBr): 3356 (N–H), 1704 (C=O, acid),1612 cm–1 (C=O amide).
1H NMR (DMSO): = 1.17 (s, 3 CH3, 9 H), 2.39 (dd, J = 15 Hz,
C*HCHH, 1 H), 2.80 (dd, J = 15 Hz, C*HCHH, 1 H), 3.90 (dd, J =
9 Hz, C*H, 1 H), 7.28 (s, Ph, 5 H), 7.41 (s, NH, 1 H), 12.20 (s, OH,
1 H).
To Determine the Percentage Composition and Total Yield of
Amic Acids (3 and 4); General Procedure
A solution of amine 2 (2.2 mmol) in Et2O (10 mL) was added drop-
wise to a solution of (S)-(+)-phenylsuccinic anhydride (1) (176 mg,
1.0 mmol) in Et2O (10 mL) at r.t. (or –60 °C). The reaction mixture
stirred for 30 min, distilled water (20 mL) was added and the reac-
tion mixture stirred for an additional 5 min. HCl (6 M, 2 mL) was
added and the mixture stirred for 10 min. The pH of the aqueous lay-
er was approximately 1. The two layers were then separated and the
aqueous layer was washed with Et2O (20 mL). The two ether layers
were combined and dried over anhyd Na2SO4. The ether was re-
moved under reduced pressure to afford a mixture of 3 and 4. The
percent composition of these mixtures was determined by HPLC on
a mixture of 3a–e and 4a–e, dissolved in a solution of n-hexane–
MeOH (50:50) (Table 1).
13C NMR (DMSO): = 28.51 (3 CH3), 39.48 (CH2), 47.24 (C*H),
49.90 (NC), 126.95 (Phpara), 127.82 (Phmeta, 2 C), 128.43 (Phortho
C), 139.23 (Ph), 169.52 (NCO), 174.32 (COOH).
,
2
Anal. Calcd for C14H19NO3: C, 67.45; H, 7.68; N, 5.62. Found: C,
67.72; H, 7.80; N, 5.49.
( )-4-Anilino-4-oxo-3-phenylbutanoic Acid (3d)
Crude 3d was isolated and consisted of 85% 3d and 15% 4d, as de-
termined by HPLC. Further attempts to separate this mixture not
successful.
References
(1) Stephani, R.; Cesare, V. J. Chromatogr. A 1998, 813, 79.
(2) Guide to HPLC; Phenomenex: California, 1995, 1035.
(+)-(2S)- 4-Anilino-4-oxo-2-phenylbutanoic Acid (4d)
25
Mp 138–139 °C, lit.7 mp 125–127 °C. [ ]D +148.7° (c 0.300,
MeOH), lit.7 [ ]D33+151.8° (c 0.876, EtOH).
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52
R. Stephani et al.
PAPER
(3) Cyclobond Handbook: A Guide to using Cyclodextrin
Bonded Phases, Advanced Separation Technologies;
Whippany: New Jersey, 1987.
(4) Okamoto, Y.; Aburatani, R.; Hatano, K.; Hatada, K. J. Liq.
Chromatogr. 1988, 11, 2147.
(5) Schell, G.; Wainer, I. W.; Barkan, S. A. J. Liq. Chromatogr.
1986, 9, 641.
(6) Anschütz, R. Ann. 1907, 354, 117.
(9) Foucaud, A. Bull. Soc. Chim. Fr. 1963, 159, 873.
(10) Stephani, R.; Cesare, V. J. Chem. Educ. 1997, 74, 1226.
(11) Shiraima, T.; Sado, Y.; Fugu, S.; Nakamura, M.; Kurokawa,
H. Bull. Chem. Soc. Jpn. 1987, 60, 824.
(12) This method for the separation of - and -phenyl-
succinamic acid was first reported in ref.8
(13) Mislow, K.; Raban, M. In Topics in Stereochemistry;
Allinger, N. L.; Eliel, E. L., Eds.; John Wiley & Sons Inc.:
New York, 1967, 26.
(7) Naps, M.; Johns, I. B. J. Am. Chem. Soc. 1940, 62, 2450.
(8) Miller, C. A.; Long, L. M. J. Am. Chem. Soc. 1951, 73, 4895.
Synthesis 2002, No. 1, 47–52 ISSN 0039-7881 © Thieme Stuttgart · New York