A new approach to the synthesis of β-amino acids

Article abstract of DOI:10.1055/s-2006-950181

A detailed study of the addition of the dianions of carboxylic acids to isocyanates is presented. The use of sub-stoichiometric amounts of the amine in the generation of the dianion leads to an optimized process, which prevents the formation of urea deriv

Full text of DOI:10.1055/s-2006-950181

3092
PAPER
A New Approach to the Synthesis of b-Amino Acids
A
N
ew Approach
l
to the
a
Synthesis
o
u
f
b
-AminoA
d
c
ids ia Della Rosa, Salvador Gil, Pablo Rodríguez, Margarita Parra*
Department de Organic Chemistry, Universitat de València, C/Dr. Moliner 50, 46100 Burjassot, Spain
Fax +34(9)639083152; E-mail: Margarita.Parra@uv.es
Received 23 March 2006; revised 1 June 2006
of dianions from carboxylic acids15,16 leads to a complex
mixture in the reaction medium with several nucleophiles
in equilibrium that can react with the isocyanate. Thus, us-
ing lithium diisopropylamide as the base, only the corre-
Abstract: A detailed study of the addition of the dianions of car-
boxylic acids to isocyanates is presented. The use of sub-stoichio-
metric amounts of the amine in the generation of the dianion leads
to an optimized process, which prevents the formation of urea de-
rivatives due to the secondary reaction of isocyanates with the sponding urea was isolated.
amine. This methodology is a new approach to the synthesis of b-
Previous studies by our group on the reaction of ene-
amino acids with better control of a-substitution than previously de-
diolates with several electrophiles led us to develop new
conditions for the generation of the dianions of carboxylic
acids which, in some cases, improve the yield and selec-
tivity of the reaction. We have completely optimized the
generation of dianions of carboxylic acids by using an
equimolecular amount of butyllithium combined with a
less than stoichiometric amount of amine. A catalytic cy-
cle is possible because a carboxylate and the correspond-
ing dianion can be held together without self
condensation;17,18 this is an advantage of enediolate chem-
istry over simple enolates. The amount and nature of the
amine can be changed, a process that is usually necessary
in order to optimize the reaction for each electrophile.
scribed.
Key words: amino acids, catalysis, isocyanates, regioselectivity,
dianions
b-Amino acids are important building blocks for the syn-
thesis of natural products and pharmaceutical agents.1 In
addition, the conformational stability of b-peptides in
aqueous solution (higher than that exhibited by a-pep-
tides) is important with regard to biological activity.2–4
Therefore, the application of b-peptides as antibiotics or
enzyme inhibitors has received considerable attention in
recent years.5–7
The reaction of enediolates, generated using lithium cy-
clohexylisopropylamide as the base, with isocyanates is
complete in one hour at –78 °C; the most efficient condi-
tions use 0.5 equivalent of amine leading to the minimum
amount of the corresponding urea (5–10%). The use of
less hindered amines, such as diisopropylamine, leads to
higher proportions of urea. The formation is the urea is not
a serious drawback because it can be easily filtered out as
it precipitates out from the crude reaction mixture after the
addition of water and stirring for 16 hours. The amido acid
product is isolated with high purity after a work up that in-
volves separation of neutral and acid fractions.
Most methods, described for the synthesis of b-amino ac-
ids,1,8 have been successfully applied to the synthesis of b-
substituted or a,b-disubstituted2 b-amino acid derivatives.
a-Monosubstituted b-amino acids are less common be-
cause the monoalkylation of enolate derivatives is diffi-
cult to control and dialkylation is likely to occur under the
strong reaction conditions required.9 An additional prob-
lem arises in the synthesis of b-amino acids from enolates,
as aryl and alkenyl halides do not react with enolate an-
ions under ordinary conditions.10
Our experience with the reactivity of dianions from car-
boxylic acids led us to devise a simple method to b-amido
acids where the amide moiety can be reduced by standard
procedures.11,12 We describe here the methodology for the
addition of enediolates of carboxylic acids to isocyanates
yielding, in one step, a-monosubstituted b-amido acids
(Scheme 1) as an alternative to the ester enolate method-
ology.
OLi
R1
i-PrCyNH, BuLi
R1
1–3
CO2H
OLi
1) R2-N=C=O
2) H3O+
The addition of enediolates of saturated carboxylic acids
to commercially available isocyanates required an optimi-
zation study. It is well known that isocyanates react effi-
ciently with nucleophilic compounds such as the amine
group of amide derivatives13 and organolithium re-
agents.14 The use of standard conditions for the generation
R1
CO2H
R2
[red]
CO2H
N
R2
H
R
N
H
O
SYNTHESIS 2006, No. 18, pp 3092–3098
x
x.
x
x
.
2
0
0
6
4–6
Advanced online publication: 15.08.2006
DOI: 10.1055/s-2006-950181; Art ID: P04006SS
Scheme 1 Reagents: 1) (R3)2N=C=O; 2) H3O+.
© Georg Thieme Verlag Stuttgart · New York

PAPER
A New Approach to the Synthesis of b-Amino Acids
3093
Results obtained under optimized reaction conditions are
summarized in Table 2. We have used differently substi-
tuted unsaturated acids: (E)-but-2-enoic acid (7), (E)-2-
methylbut-2-enoic acid (8), and 3-methylbut-2-enoic acid
(9) and the same electrophiles as in Scheme 1, Table 1.
The g-adducts 13–15 are obtained regioselectively ac-
cording to the high stability of these conjugated systems.
The a-regioisomer is only observed in the reaction of 3-
methylbut-2-enoic acid with cyclohexyl isocyanate (prod-
uct 12b). As expected15,16 pure (E)-g-adducts are obtained
for (E)-but-2-enoic acid (7) and (E)-2-methylbut-2-enoic
acid (8) and (Z)-g-adducts for 3-methylbut-2-enoic acid
(9) except 15a where a mixture of Z/E isomers are ob-
tained for 15a. Isolation of 12b and 13a was not possible
because polymerization occurs on purification.
Table 1 Addition of Enediolates of Carboxylic Acids to Isocyanates
Entry
Acid
Isocyanate Product
R2
Yield (%)
R1
Pr
1
2
3
4
5
6
1
2
3
1
2
3
4-ClC6H4
4-ClC6H4
4-ClC6H4
Cy
4a
5a
6a
4b
5b
6b
37
59
58
38
70
28
Ph
Bn
Pr
Ph
Bn
Cy
Cy
The method can be extended to dianions from o-methyl-
substituted aromatic or heteroaromatic acids25 (Table 3).
The known competition between a-lithiation versus
ortho-lithiation26 has not been a problem, probably due to
the lower p-electronic density in pyridine rings,20 except
for acid 20 where a 1:1 mixture of 25b and 26 is obtained.
The results with different acids 1–3 and isocyanates under
these optimized conditions are summarized in Table 1.
The 1H NMR spectra of products 4, 5, and 6 showed that
they exhibit tautomerism. Only the amido–acid tautomer
is observed in dimethyl sulfoxide-d6 solution, whereas
only the corresponding enolic–acid tautomer is observed
in acetone-d6.
In conclusion, a general procedure for the addition of di-
anions of carboxylic acids to isocyanates is described.
From saturated carboxylic acids, this methodology is a
new approach to the synthesis of b-amino acids with a bet-
ter control of the a-substitution than previously described.
The method can be extended to unsaturated and o-methyl-
arenecarboxylic and o-methylhetarenecarboxylic acids.
On work up, a single product is usually obtained in highly
pure form.
We have extended this methodology to a,b-unsaturated
carboxylic acids (Table 2) whose double deprotonation by
lithium amides leads to lithium dienediolates that react
with electrophiles at their a- or g-carbon atoms, depend-
ing on the conditions.15,16,19,20 Thus, a-attack predomi-
nates for irreversible reactions21,22 whereas highly
stereoselective g-adducts are obtained when reversible ad-
dition to carbonyl compounds is carried out under equilib-
rium conditions.23,24
Table 2 Addition of Dienediolates of Carboxylic Acids to Isocyanates
1) i-PrCyNH, BuLi
2) R3-N=C=O
3) H3O+
R1
R2
CO2H
O
R2
R2
CO2H
O
R3
CO2H
+
R1
7–9
N
H
R1
HN
R3
10–12
13–15
Entry
Acid
Isocyanate
Product
Yield (%)
Rate a/g
R1
R2
R3
1
2
3
4
5
6
7
8
9
7
8
9
H
H
4-ClC6H4
4-ClC6H4
4-ClC6H4
Cy
13aa
14a
54
26
87
–
0:100
0:100
0:100b
–
Me
H
H
Me
H
15a
H
–
Me
H
H
Cy
14b
57
84
0:100
50:50c
Me
Cy
12ba/15b
a Polymerization occurs on purification.
b As a mixture Z/E (55:45).
c Product 15b as pure Z-isomer.
Synthesis 2006, No. 18, 3092–3098 © Thieme Stuttgart · New York

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C. Della Rosa et al.
PAPER
Table 3 Addition of Dianions of Methylacrylic Acids to Isocyanatesa
Entry
1
Acid
Product
R
Yield (%)
CO2H
O
CO2H
CO2H
16
21a
4-ClC6H4
48
18
21
53
R
N
H
CO2H
O
2
3
4
17
18
19
22a
23a
24a
4-ClC6H4
4-ClC6H4
4-ClC6H4
R
R
N
N
N
H
N
N
H
N
O
CO2H
CO2H
CO2H
CO2H
O
R
R
N
O
O
H
H
N
5
6
7
20
16
19
25a
21b
23b
4-ClC6H4
57
36
63
O
CO2H
CO2H
CO2H
S
S
CO2H
O
Cy
R
N
H
CO2H
CO2H
O
Cy
R
N
O
O
H
H
N
R
O
CO2H
S
8
20
25b + 26
Cy
69b
H
N
CO2H
R
S
H
N
O
R
CO2H
S
O
a Conditions: 1. i-PrCyNH; 2. RNCO; 3. H3O+.
b As a 1:1 mixture.
Melting points were determined with a Cambridge Instruments Hot
Plate Microscope and are uncorrected. IR spectral data were ob-
tained as liquid film or KBr discs, the measurements were carried
out by the SCSIE (Servei Central de Suport a la Investigació Exper-
imental de la Universitat de Valencia) on a Matteson Satellite FTIR
3000 model spectrophotometer. NMR spectra were recorded as so-
lutions in the stated solvent with a Bruker Avance 300, 400 or 500
spectrometers. HRMS were determined with a Fison VG Autospec
spectrometer. Flash column chromatography used silica gel (Schar-
lau, 230–400 mesh) eluting with hexane/EtOAc mixtures.
0 °C achieved by an ice/water bath. Organic extracts were dried
over anhyd MgSO4, and solutions were evaporated under reduced
pressure with a rotatory evaporator and a bath at 40 °C.
Carbamoyl-Substituted Acids; General Procedure
A 1.6 M soln of BuLi in hexane (3.13 mL, 5 mmol) was introduced
into a reaction flask that been purged. Hexane was evaporated under
vacuum and THF (2 mL) was added at –78 °C, followed by the ad-
dition of the amine (1.14 mmol) also at –78 °C. The mixture was
stirred for 15 min at 0 °C. The acid (2.25 mmol) in THF (2 mL) was
added slowly at –78 °C. After 30 min at 0 °C, isocyanate (6.75
mmol) in THF (2 mL) was added slowly at –78 °C. The soln was
stirred at –78 °C for 1 h and quenched with H2O (15 mL). After 16
h, ureas had precipitated and were separated by filtration. The re-
maining mixture was extracted with Et2O (3 × 15 mL). The aqueous
phase was acidified with concd HCl to pH 1 and then extracted with
EtOAc (3 × 15 mL).
All reactions were carried out under argon atmosphere, using stan-
dard conditions for exclusion of moisture, in oven dried glassware;
THF was freshly distilled from blue benzophenone ketyl; amines
were distilled from CaH2 and stored over molecular sieves and kept
under argon. 1.6 M BuLi in hexane was used and the exact concen-
tration was periodically checked before use. The reaction tempera-
ture (–78 °C) was achieved by cooling with a CO2/acetone bath and
Synthesis 2006, No. 18, 3092–3098 © Thieme Stuttgart · New York

PAPER
A New Approach to the Synthesis of b-Amino Acids
3095
2-(4-Chlorophenylcarbamoyl)pentanoic Acid (4a)
Prepared from pentanoic acid (1; 230 mg, 2.25 mmol) and 4-chlo-
rophenyl isocyanate (1.037 g, 6.75 mmol) as a brown solid; yield:
217 mg (37%); mp 144–146 °C.
IR (KBr): 3400–2400, 3320, 1714, 1650, 1538, 1452, 1384, 1257,
1113, 893 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 0.83 (m, 3 H, CH3), 1.14–1.25
(m, 7 H, CHCy, CH3CH2), 1.59–1.78 (m, 7 H, CHCy, CHCH2), 3.14
(t, J = 7.47 Hz, 1 H, CHCOOH), 3.47 (m, 1 H, CHNH), 7.88 (d,
J = 7.80 Hz, 1 H, NHCO).
IR (KBr): 3300–2900, 1732, 1630, 1604, 1596, 1541, 1492, 1400,
1258, 1239, 1045, 829 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 0.88 (t, J = 7.40 Hz, 3 H, CH3),
1.26 (m, 2 H, CH3CH2), 1.76 (m, 2 H, CHCH2), 3.38 (t, J = 7.44 Hz,
1 H, CHCH2), 7.36 (d, J = 6.76 Hz, 2 H, CHAr), 7.62 (d, J = 6.84 Hz,
2 H, CHAr).
13C NMR (100 MHz, DMSO-d6): d = 14.2 (CH3), 20.6 (CH3CH2),
23.4 (CHCH2), 53.1 (CHCH2), 121.2 (CHCNH), 127.4 (CCl), 129.1
(CHCCl), 138.4 (CNH), 168.4 (CONH), 171.6 (COOH).
13C NMR (100 MHz, DMSO-d6): d = 14.1 (CH3), 20.4 (CH2), 24.9
(CH2), 25.6 (CH2), 30.4 (CH2), 31.1 (CH2), 31.9 (CH2), 32.8 (CH2),
50.2 (CHNH), 51.9 (CHCOOH), 167.0 (NHCO), 171.3 (COOH).
MS: m/z (%) = 227 (M+, 0.5), 225 (M+ – 2, 34.9), 207 (M+ – 2 H2O,
19.0), 181 (M+ – 2 CO2, 80.0), 100 (CyNHCO+ + 1, 89.3), 83
(C6H11+, 100).
HRMS: m/z [M+] calcd for C12H21NO3: 227.1521; found: 227.1451.
MS: m/z (%) = 257 [M+, 0.5 (37Cl)], 257 [M+, 1.4 (35Cl)], 213 [M+ –
CH3CH2CH2, 1.2 (37Cl)], 211 [M+ – CH3CH2CH2, 3.6 (35Cl)], 129
2-(Cyclohexylcarbamoyl)-2-phenylacetic Acid (5b)
Prepared from phenylacetic acid (2; 306 mg, 2.25 mmol) and cyclo-
hexyl isocyanate (0.845 mg, 6.75 mmol) as a white solid; yield: 411
mg (70%); mp 115–118 °C.
+
+
[ClC6H4NH2 , 32.1 (37Cl)], 127 [ClC6H4NH2 , 100 (35Cl)].
HRMS: m/z [M+] calcd for C12H14ClNO3: 257.0662 (37Cl),
255.0662 (35Cl); found: 257.0657 (37Cl), 255.0653 (35Cl).
IR (KBr): 3700–3100, 2933, 2856, 1732, 1636, 1543, 1453, 1194,
697 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.00–1.40 (m, 5 H, CHCy),
1.50–1.90 (m, 5 H, CHCy), 3.54 (br s, 1 H, NHCH), 4.61 (s, 1 H,
CHCOOH), 7.26–7.45 (m, 5 H, Ph H), 8.18 (d, J = 7.48 Hz, 1 H,
CONH).
13C NMR (75 MHz, DMSO-d6): d = 24.7 (CHCy), 25.4 (CHCy), 32.5
(CHCy), 48.1 (CHNH), 57.9 (CHCOOH), 127.4 (CAr), 128.3 (CHAr),
129.2 (CHAr), 135.8 (CAr), 166.8 (COOH), 170.7 (CONH).
2-(4-Chlorophenylcarbamoyl)-2-phenylacetic Acid (5a)
Prepared from phenylacetic acid (2; 306 mg, 2.25 mmol) and 4-
chlorophenyl isocyanate (1.037 g, 6.75 mmol) as a brown solid;
yield: 385 mg (59%); mp 83–85 °C.
IR (KBr): 3500–3200, 3033, 1716, 1597, 1542, 1492, 1455, 1400,
1238, 1093, 826 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 4.82 (s, 1 H, CHCOOH), 7.2–
7.4 (m, 5 H, CHAr), 7.37 (d, J = 5.5 Hz, 2 H, CHAr), 7.63 (d, J = 8.94
Hz, 2 H, CHAr).
13C NMR (100 MHz, DMSO-d6): d = 59.2 (CHCOOH), 121.2
(CAr), 127.7 (CAr), 128.0 (CAr), 128.7 (CAr), 129.1 (CAr), 129.2 (CAr),
135.4 (CAr), 138.2 (CAr), 166.9 (CONH), 170.4 (COOH).
MS: m/z (%) = 262 (M+ + 1, 4.7), 261 (M+, 0.5), 217 (M+ + 1 – CO2,
61), 92 (C7H8, 100), 91 (C7H7, 74), 83 (C6H11, 78).
HRMS: m/z [M+] calcd for C15H19NO3: 261.1365; found: 261.1347.
MS: m/z (%) = 291 [M+, 0.1 (37Cl)], 289 [M+, 0.4 (35Cl)], 274 [M+ –
2-(Cyclohexylcarbamoyl)-3-phenylpropanoic Acid (6b)
Prepared from 3-phenylpropanoic acid (3; 338 mg, 2.25 mmol) and
cyclohexyl isocyanate (0.845 mg, 6.75 mmol) as a white solid;
yield: 170 mg (28%); mp 161–164 °C.
OH, 0.1 (37Cl)], 272 [M+ – OH, 0.2 (35Cl)], 247 [M+ – CO2, 20.9
+
(37Cl)], 245 [M+ – CO2, 66.2 (35Cl)], 129 [ClC6H4NH2 , 29.2 (37Cl)],
+
+
127 [ClC6H4NH2 , 97.6 (35Cl)], 91 (C7H7 , 100).
HRMS: m/z [M+] calcd for C15H12ClNO3: 291.0506 (37Cl),
IR (KBr): 3400–2800, 3321, 1745, 1603, 1452, 1229, 1203, 1148,
889, 697 cm–1.
289.0506 (35Cl); found: 291.0561 (37Cl), 289.0458 (35Cl).
1H NMR (400 MHz, DMSO-d6): d = 0.93 (m, 1 H, CHCy), 1.14 (m,
4 H, CHCy), 1.59 (m, 5 H, CHCy), 2.48 (m, 2 H, PhCH2), 3.48 (m, 2
H, CHCOOH, NHCH), 7.18 (m, 3 H, Ph H), 7.23 (m, 2 H, PhH),
7.81 (d, J = 7.92 Hz, 1 H, CONH).
13C NMR (100 MHz, DMSO-d6): d = 24.3 (CCy), 25.2 (CCy), 32.0
(CCy), 34.3 (PhCH), 47.4 (CONHCH), 53.3 (CHCOOH), 126.0
(CAr), 127.9 (CAr), 128.8 (CAr), 139.0 (CAr), 166.9 (CONH), 171.0
(COOH).
2-(4-Chlorophenylcarbamoyl)-3-phenylpropanoic Acid (6a)
Prepared from 3-phenylpropanoic acid (3; 338 mg, 2.25 mmol) and
4-chlorophenyl isocyanate (1.037 g, 6.75 mmol) as a yellow solid;
yield: 397 mg (58%); mp 177–179 °C.
IR (KBr): 3500–3100, 3344, 1743, 1728, 1627, 1607, 1544, 1274,
1155, 821 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.11 (dd, J1 = 8.58 Hz,
J2 = 3.89 Hz, 2 H, PhCH2), 3.73 (dd, J1 = 6.66 Hz, J2 = 8.46 Hz, 1
H, CHCOOH), 7.21 (m, 5 H, PhCH2), 7.34 (d, J = 8.88 Hz, 2 H,
CHAr), 7.56 (d, J = 8.90 Hz, 2 H, CHAr), 10.24 (s, 1 H, CONH).
13C NMR (100 MHz, DMSO-d6): d = 34.6 (PhCH2), 55.0
(CHCOOH), 121.2 (CAr), 126.4 (CAr), 126.7 (CAr), 127.5 (CAr),
128.0 (CAr), 129.1 (CAr), 129.2 (CAr), 138.2 (CAr), 139.3 (CAr), 167.5
(CONH), 171.0 (COOH).
MS: m/z (%) = 275 (M+, 28.3), 231 (M+ – CO2, 64.4), 230 (M+ –
+
COOH, 64.4), 150 (C9H10O2 , 33.3), 105 (C8H8O+, 27.0), 91
+
(C7H7 , 34.6), 83 (C6H11+, 7.7).
HRMS: m/z [M+] calcd for C16H21NO3: 275.1521; found: 275.1528.
(E)-4-(4-Chlorophenylcarbamoyl)-2-methylbut-2-enoic Acid
(14a)
Prepared from (E)-2-methylbut-2-enoic acid (8; 225 mg, 2.25
mmol) and 4-chlorophenyl isocyanate (1.037 g, 6.75 mmol) as a
white solid; yield: 145 mg (26%); mp 148–149 °C.
MS: m/z (%) = 305 [M+, 1.7 (37Cl)], 303 [M+, 5.1 (35Cl)], 261 [M+ –
+
CO2, 21.8 (37Cl)], 259 [M+ – CO2, 66.6 (35Cl)], 129 [ClC6H4NH2 ,
+
+
32.4 (37Cl)], 127 [ClC6H4NH2 , 100 (35Cl)], 91 (C7H7 , 40).
HRMS: m/z [M+] calcd for C16H14ClNO3: 305.0662 (37Cl),
IR (KBr): 3291, 3200–2900, 1693, 1660, 1593, 1524, 1491, 1396,
1291 cm–1.
303.0662 (35Cl); found: 305.0625 (37Cl), 303.632 (35Cl).
1H NMR (400 MHz, CD3OD): d = 1.73 (s, 3 H, CH3), 3.25 (d,
J = 7.13 Hz, 2 H, CH2), 6.93 (t, J = 7.13 Hz, 1 H, CH=C), 7.19 (d,
J = 8.91 Hz, 2 H, CHAr), 7.55 (d, J = 8.89 Hz, 2 H, CHAr).
2-(Cyclohexylcarbamoyl)pentanoic Acid (4b)
Prepared from pentanoic acid (1; 230 mg, 2.25 mmol) and cyclo-
hexyl isocyanate (0.845 mg, 6.75 mmol) as a yellow oil; yield: 198
mg (38%).
Synthesis 2006, No. 18, 3092–3098 © Thieme Stuttgart · New York

3096
C. Della Rosa et al.
PAPER
13C NMR (100 MHz, CD3OD): d = 12.9 (CH3), 37.4 (CH2), 121.5
(CHAr), 128.5 (CH=C), 129.5 (CHAr), 130.8 (CArCl), 135.5 (CH=C),
139.1 (CArNH),, 168.8 (CONH), 168.9 (COOH).
13C NMR (100 MHz, DMSO-d6): d = 13.8 (CH3), 24.5 (CHCy), 25.3
(CHCy), 32.8 (CHCy), 37.5 (CH2), 48.5 (CHNH), 129.6 (CH=C),
136.2 (CH=C), 168.0 (CONH), 169.8 (COOH).
MS: m/z (%) = 255 [M+, 7.8 (37Cl)], 253 [M+, 23.4 (35Cl)], 237 [M+
MS: m/z (%) = 225 (M+, 11.0), 126 (CyNHCO+, 9.5), 100
+
– H2O, 1.7 (37Cl)], 235 [M+ – H2O, 4.7 (35Cl)], 209 [M+ – C(OH)2,
(C5H8O2 , 100), 83 (C6H11+, 48.9).
5.1 (37Cl)], 207 [M+ – C(OH)2, 5.0 (35Cl)], 129 [ClC6H4NH2 ,
+
HRMS: m/z [M+] calcd for C12H19NO3: 225.1365; found: 225.0718.
+
31.4
(37Cl)],
127
[ClC6H4NH2 ,
100
(35Cl)],
99
+
(CH2 CH=C(CH3)COOH, 9.2).
Reaction of 3-Methylbut-2-enoic Acid with Cyclohexyl
Isocyanate
From 3-methylbut-2-enoic acid (9; 225 mg, 2.25 mmol) and cyclo-
hexyl isocyanate (0.845 mg, 6.75 mmol) as a mixture of 12b and
15b (50:50); yield: 436 mg (84%). On purification by column chro-
matography, only 15b could be isolated.
HRMS: m/z [M+] calcd for C12H12ClNO3: 255.0506 (37Cl),
253.0506 (35Cl); found: 255.0499 (37Cl), 253.0499 (35Cl).
4-(4-Chlorophenylcarbamoyl)-3-methylbut-2-enoic Acid (15a)
Prepared from 3-methylbut-2-enoic acid (9; 225 mg, 2.25 mmol)
and 4-chlorophenyl isocyanate (1.037 g, 6.75 mmol) as a white sol-
id as an E/Z mixture (45:55) which was purified by column chroma-
tography; yield: 496 mg (87%).
(Z)-4-(Cyclohexylcarbamoyl)-3-methylbut-2-enoic Acid (15b)
White solid; mp 148–152 °C.
E-isomer: white solid; mp 165–167 °C.
IR (KBr): 3300–2500, 3291, 1703, 1635, 1550, 1451, 1337, 1199,
868, 709 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.10–1.30 (m, 5 H, CHCy),
1.50–1.83 (m, 5 H, CHCy), 1.83 (s, 3 H, CH3), 3.49 (s, 2 H, CH2),
3.51 (br s, 1 H, CHNH), 5.72 (s, 1 H, CH=C), 7.77 (d, J = 7.95 Hz,
1 H, NH).
13C NMR (75 MHz, acetone-d6): d = 25.4 (CH3), 25.5 (CHCy), 26.4
(CHCy), 33.9 (CHCy), 41.9 (CH2), 48.7 (CHCy), 119.4 (CHCOOH),
153.5 (C=CH), 168.4 (CONH), 169.1 (COOH).
IR (KBr): 3291, 3200–2900, 1694, 1662, 1535, 1525, 1494, 1269,
1187, 935 cm–1.
1H NMR (400 MHz, CD3CN): d = 1.99 (s, 3 H, CH3), 3.62 (s, 2 H,
CH2), 5.89 (s, 1 H, CH=C), 7.29 (d, J = 6.82 Hz, 2 H, CHAr), 7.51
(d, J = 6.82 Hz, 2 H, CHAr).
13C NMR (100 MHz, CD3CN): d = 24.9 (CH3), 41.8 (CH2), 117.3
(CH=C), 120.9 (CHAr), 127.9 (CArCl), 128.7 (CHAr), 137.7
(CArNH), 153.2 (CH=C), 167.9 (CONH), 168 (COOH).
MS: m/z (%) = 225 (M+, 15.2), 207 (M+ – H2O, 1.4), 180 (M+ –
MS: m/z (%) = 255 [M+, 3.9 (37Cl)], 253 [M+, 12.4 (35Cl)], 237 [M+
+
COOH, 2.5), 127 (CyNHCO+ + 1, 20.0), 100 (C5H8O2 , 100), 83
– H2O, 2.2 (37Cl)], 235 [M+ – H2O, 6.5 (35Cl)], 209 [M+ – C(OH)2,
(C6H11+, 20.6).
2.4 (37Cl)], 207 [M+ – C(OH)2, 5.4 (35Cl)], 129 [ClC6H4NH2 ,
+
+
31.8
(37Cl)],
127
[ClC6H4NH2 ,
100
(35Cl)],
99
HRMS: m/z [M+] calcd for C12H19NO3: 225.1365; found: 225.1325.
+
(CH2 C(CH3)=CHCOOH, 9.8).
2-[(4-Chlorophenylcarbamoyl)methyl]benzoic Acid (21a)
Prepared from 2-methylbenzoic acid (16; 306 mg, 2.25 mmol) and
4-chlorophenyl isocyanate (1.037 g, 6.75 mmol) as a yellow solid;
yield: 317 mg (48%); mp 216–219 °C.
HRMS: m/z [M+] calcd for C12H12ClNO3: 255.0506 (37Cl),
253.0506 (35Cl); found: 255.0441 (37Cl), 253.0441 (35Cl).
Z-isomer: white solid; mp 153–156 °C.
IR (KBr): 3291, 3200–2900, 1692, 1660, 1595, 1524, 1269, 1187,
936 cm–1.
IR (KBr): 3500–3100, 2954, 2924, 2853, 1668, 1538, 1493, 1402,
1092, 734 cm–1.
1H NMR (400 MHz, acetone-d6): d = 2.04 (s, 3 H, CH3), 3.73 (s, 2
H, CH2), 5.95 (s, 1 H, CH=C), 7.32 (d, J = 6.82 Hz, 2 H, CHAr), 7.62
(d, J = 6.84 Hz, 2 H, CHAr).
13C NMR (100 MHz, acetone-d6): d = 24.9 (CH3), 41.6 (CH2), 118.2
(CH=C), 120.5 (CHAr), 127.5 (CArCl), 128.6 (CHAr), 138.1
(CArNH), 153.4 (CH=C), 167.5 (CONH), 167.7 (COOH).
1H NMR (400 MHz, CD3OD): d = 3.93 (s, 2 H, CH2), 7.05 (d,
J = 8.8 Hz, 2 H, Ph H), 7.21 (m, 1 H, Ph H), 7.33 (d, J = 3.8 Hz, 2
H, Ph H), 7.43 (d, J = 8.8 Hz, 2 H, Ph H), 7.86 (d, J = 7.6 Hz, 1 H,
Ph H).
13C NMR (100 MHz, CD3OD): d = 42.2 (CH2), 120.9 (CHAr), 126.6
(CHAr), 128.2 (CHAr), 128.3 (CHAr), 129.9 (CCl), 130.1(CHAr),
130.2 (CHAr), 130.3(CAr), 134.3 (2CAr), 138.3 (CAr), 171.6 (COOH,
CONH).
MS: m/z (%) = 255 [M+, 11.7 (37Cl)], 253 [M+, 35.2 (35Cl)], 237 [M+
– H2O, 8.8 (37Cl)], 235 [M+ – H2O, 24.0 (35Cl)], 209 [M+ – C(OH)2,
+
7.8 (37Cl)], 207 [M+ – C(OH)2, 13.9 (35Cl)], 129 [ClC6H4NH2 ,
MS: m/z (%) = 289 [M+, 1.3 (35Cl)], 271 [M+ – H2O, 8 (35Cl)], 153
(37Cl)],
127
[ClC6H4NH2 ,
100
(35Cl)],
99
+
+
[ClC6H4NHC=O+, 1.1 (35Cl)], 129 [ClC6H4NH2 , 3.3 (37Cl)], 127
30.4
+
+
[ClC6H4NH2 , 25.4 (35Cl)].
(CH2 C(CH3)=CHCOOH, 6.4).
HRMS: m/z [M+] calcd for C12H12ClNO3: 255.0506 (37Cl),
HRMS: m/z [M+] calcd for C15H12ClNO3: 289.0506 (35Cl); found:
253.0506 (35Cl); found: 255.0526 (37Cl), 253.0526 (35Cl).
289.0520 (35Cl).
(E)-4-(Cyclohexylcarbamoyl)-2-methylbut-2-enoic Acid (14b)
Prepared from (E)-2-methylbut-2-enoic acid (8; 225 mg, 2.25
mmol) and cyclohexyl isocyanate (0.845 mg, 6.75 mmol) as a yel-
low oil; yield: 288 mg (57%).
2-[(4-Chlorophenylcarbamoyl)methyl]pyridine-3-carboxylic
Acid (22a)
Prepared from 2-methylpyridine-3-carboxylic acid (17; 309 mg,
2.25 mmol) and 4-chlorophenyl isocyanate (1.037 g, 6.75 mmol) as
a yellow solid; yield: 117 mg (18%).
1H NMR (300 MHz, acetone-d6): d = 4.67 (s, 2 H, CH2), 7.45 (d,
J = 8.7 Hz, 2 H, CHAr), 7.74 (m, 1 H, CHAr), 7.86 (d, J = 8.7 Hz, 2
H, CHAr), 8.62 (d, J = 7.9 Hz, 1 H, CHAr), 8.89 (d, J = 4.9 Hz, 1 H,
CHAr).
13C NMR (100 MHz, acetone-d6): d = 40.9 (CH2), 120.7 (CAr),
122.7 (CAr), 128.0 (CAr), 128.4 (CAr), 128.6 (CAr), 138.4 (CAr), 139.6
(CAr), 150.4 (CAr), 155.9 (CAr), 167.1 (COOH), 168.1 (CONH).
IR (KBr): 3400–2500, 3282, 1697, 1541, 1451, 1388, 1234, 1131,
1077, 892 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.10–1.40 (m, 5 H, CHCy),
1.60–2.00 (m, 5 H, CHCy), 1.73 (s, 3 H, CH3), 3.01 (d, J = 7.89 Hz,
2 H, CH2), 3.64 (m, 1 H, NHCH), 6.77 (dt, J1 = 5.64 Hz, J2 = 7.14
Hz, 1 H, CH=C), 7.84 (d, J = 7.89 Hz, 1 H, NH).
Synthesis 2006, No. 18, 3092–3098 © Thieme Stuttgart · New York

PAPER
A New Approach to the Synthesis of b-Amino Acids
3097
3-[(4-Chlorophenylcarbamoyl)methyl]pyridine-2-carboxylic
Acid (23a)
Prepared from 3-methylpyridine-2-carboxylic acid (18; 309 mg,
2.25 mmol) and 4-chlorophenyl isocyanate (1.037 g, 6.75 mmol) as
a yellow solid; yield: 137 mg (21%).
1H NMR (300 MHz, CD3OD): d = 4.19 (s, 2 H, CH2), 7.16 (d,
J = 8.7 Hz, 2 H, CHAr), 7.45 (d, J = 8.7 Hz, 2 H, CHAr), 7.55 (m, 1
H, CHAr), 7.85 (m, 1 H, CHAr), 8.5 (s, 1 H, NH).
13C NMR (100 MHz, CD3OD): d = 35.7 (CH2), 123.4 (CAr), 127.4
(CAr), 128.1 (CAr), 129.4 (CAr), 132.0 (CAr), 136.5 (CAr), 139.7 (CAr),
147.4 (CAr), 151.9 (CAr), 163.8 (CONH), 175.5 (COOH).
13C NMR (100 MHz, DMSO-d6): d = 24.4 (CCy), 25.2 (CCy), 32.4
(CCy), 41.7 (CH2CONH), 47.5 (CONHCH), 126.5 (CAr), 130.0
(2CAr), 131.4 (2CAr), 137.1 (CAr), 168.6 (COOH), 169.1 (CONH).
+
MS: m/z (%) = 261 (M+, 22.4), 243 (M+ – H2O, 4.7), 136 (C8H8O2 ,
100), 105 (C8H6O+, 48.5), 83 (C6H11+, 13.0).
HRMS: m/z [M+] calcd for C15H19NO3: 261.1365; found: 265.1354.
2-[(Cyclohexylcarbamoyl)methyl]-5-methylfuran-3-carboxylic
Acid (24b)
Prepared from 2,5-dimethylfuran-3-carboxylic acid (19; 315 mg,
2.25 mmol) and cyclohexyl isocyanate (0.845 mg, 6.75 mmol) as a
white solid; yield: 372 mg (63%); mp 229–231 °C.
2-[(4-Chlorophenylcarbamoyl)methyl]-5-methylfuran-3-car-
boxylic Acid (24a)
Prepared from 2,5-dimethylfuran-3-carboxylic acid (19; 315 mg,
2.25 mmol) and 4-chlorophenyl isocyanate (1.037 g, 6.75 mmol) as
a yellow solid; yield: 348 mg (53%); mp 207–209 °C.
IR (KBr): 3200–2400, 3292, 1687, 1645, 1587, 1551, 1439, 1243,
1070, 942, 783 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.29 (m, 5 H, CHCy), 1.55 (m,
1 H, CHCy), 1.74 (m, 4 H, CHCy), 2.23 (s, 3 H, CH3), 3.51 (m, 1 H,
NHCH), 3.80 (s, 2 H, CH2CONH), 6.27 (s, 1 H, CHAr), 7.91 (d,
J = 7.90 Hz, 1 H, CONH).
13C NMR (100 MHz, DMSO-d6): d = 12.9 (CH3), 24.4 (CCy), 25.1
(CCy), 32.3 (CCy), 34.5 (CH2CONH), 47.6 (CONHCH), 106.6
(CArH), 115.9 (CCOOH), 150.3 (CCH3), 154.3 (CCH2CONH),
164.7 (COOH), 166.1 (CONH).
IR (KBr): 3500–2900, 3250, 3189, 1696, 1597, 1541, 1492, 1401,
1242, 1091, 831 cm–1.
1H NMR (400 MHz, CD3OD): d = 2.29 (s, 3 H, CH3), 4.08 (s, 2 H,
CH2), 6.32 (s, 1 H, CHCCH3), 7.29 (d, J = 8.9 Hz, 2 H, Ph H), 7.55
(d, J = 8.9 Hz, 2 H, Ph H).
13C NMR (100 MHz, CD3OD): d = 11.7 (CH3), 35.5 (CH2), 106.4
(CHCCH3), 115.6 (CCOOH), 121.0 (CHCNH), 128.4 (CHCCl),
128.8 (CCl), 137.2 (CArNH), 153.4 (CCH3), 158.1 (CCH2CONH),
165.6 (COOH), 167.7 (CONH).
+
+
MS: m/z (%) = 265 (M+, 1.5), 140 (C7H8O3 , 100), 122 (C7H6O2 ,
6.4), 83 (C6H11+, 6.8).
HRMS: m/z [M+] calcd for C14H19NO4: 265.1314; found: 265.1313.
MS: m/z (%) = 293 [M+, 5.2 (35Cl)], 140 (C7H8O3, 100), 139
Reaction of 3-Methylthiophene-2-carboxylic Acid with Cyclo-
hexyl Isocyanate
From 3-methylthiophene-2-carboxylic acid (20; 320 mg, 2.25
mmol) and cyclohexyl isocyanate (0.845 mg, 6.75 mmol) as a mix-
ture of 25b/26 (50:50); yield: 591 mg (69%). Column chromatogra-
phy allowed separation:
+
+
+
(C7H7O3 , 40), 129 [ClC6H4NH2 , 4.7 (37Cl)], 127 [ClC6H4NH2 ,
18.8 (35Cl)].
HRMS: m/z [M+] calcd for C14H12ClNO4: 293.0455 (35Cl); found:
293.0459 (35Cl).
3-[(4-Chlorophenylcarbamoyl)methyl]thiophene-2-carboxylic
Acid (25a)
Prepared from 3-methylthiophene-2-carboxylic acid (20; 320 mg,
2.25 mmol) and 4-chlorophenyl isocyanate (1.037 g, 6.75 mmol) as
a white solid; yield: 378 mg (57%); mp 214–215 °C.
3-[(Cyclohexylcarbamoyl)methyl]thiophene-2-carboxylic Acid
(25b)
White solid; mp 224–226 °C.
IR (KBr): 3100–2200, 3290, 3080, 1932, 1693, 1623, 1442, 1266,
1151, 880 cm–1.
1H NMR (400 MHz, CD3OD): d = 1.22–1.40 (m, 5 H, CHCy), 1.60–
2.00 (m, 5 H, CHCy), 3.65 (br d, 1 H, NHCH), 3.91 (s, 2 H,
CH2CONH), 7.08 (d, J = 4.98 Hz, 1 H, CHCCH2), 7.62 (d, J = 5.57
Hz, 1 H, CH=CHS).
IR (KBr): 3500–2900, 1698, 1621, 1504, 1401, 1391, 1264, 1092,
827, 739 cm–1.
1H NMR (400 MHz, CD3OD): d = 4.03 (s, 2 H, CH2), 7.05 (d,
J = 5.09 Hz, 1 H, CHCHS), 7.11 (d, J = 8.8 Hz, 2 H, Ph H), 7.42 (d,
J = 5.07 Hz, 1 H, CHCHS), 7.47 (d, J = 8.9 Hz, 2 H, Ph H).
13C NMR (100 MHz, CD3OD): d = 39.3 (CH2), 122.3 (CHCNH),
129.5 (CAr), 129.6 (CCl), 129.7 (CHCCl), 131.7 (CHS), 137.7
(CArNH), 138.6 (CCH2CONH), 139.2 (CCOOH), 172.2 (CONH,
COOH).
13C NMR (100 MHz, CD3OD ): d = 24.6 (CHCy), 25.2 (CHCy), 32.2
(CHCy), 36.3 (CH2), 49.3 (CHNH), 130.3 (CH=CHS), 141.8
(CCOOH), 164.0 (CCOOH), 170.3 (CH2CO).
MS: m/z (%) = 267 (M+, 100), 223 (M+ – CO2, 36.5), 142
MS: m/z (%) = 296 [M+, 21.3 (35Cl)], 154 [ClC6H4NHC=O+, 100
(C6H6O2S+, 42.0), 83 (C6H11+, 22.1).
+
(35Cl)], 127 [ClC6H4NH2 , 20.7 (35Cl)].
HRMS: m/z [M+] calcd for C13H17NO3S: 267.0929; found:
267.0923.
HRMS: m/z [M+ – H] calcd for C13H10ClNO3S: 296.007 (35Cl);
found: 296.1114 (35Cl).
5-(Cyclohexylcarbamoyl)-3-[(cyclohexylcarbamoyl)meth-
yl]thiophene-2-carboxylic Acid (26)
2-[(Cyclohexylcarbamoyl)methyl]benzoic Acid (21b)
Prepared from 2-methylbenzoic acid (16; 306 mg, 2.25 mmol) and
cyclohexyl isocyanate (0.845 mg, 6.75 mmol) as a white solid;
yield: 210 mg (36%); mp 194–195 °C.
IR (KBr): 3100–2200, 3290, 3080, 1932, 1693, 1623, 1442, 1266,
1151, 880 cm–1.
1H NMR (400 MHz, CD3OD): d = 1.22–1.40 (m, 10 H, CHCy),
1.60–2.00 (m, 10 H, CHCy), 3.64 (br s, 1 H, CH2CONHCH), 3.85
(br s, 1 H, CCONHCH), 3.91 (s, 2 H, CH2CONH), 7.58 (s, 1 H,
CHAr).
13C NMR (100 MHz, CD3OD): d = 24.5 (CHCy), 25.0 (CHCy), 25.2
(CHCy), 32.2 (CHCy), 36.3 (CH2), 49.3 (CHNH), 130.7 (CCH2CO),
130.9 (CCO), 133.1 (C=CH), 142.0 (CCOOH), 161.2 (CCONH),
164.0 (CCOOH), 170.3 (CH2CO).
IR (KBr): 3300–2400, 3310, 1703, 1641, 1540, 1406, 1269, 1082,
760, 658 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.25 (m, 5 H, CHCy), 1.56 (m,
1 H, CHCy), 1.69 (m, 4 H, CHCy), 3.62 (m, 1 H, NHCH), 3.80 (s, 2
H, CH2COOH), 7.36 (m, 2 H, Ph H), 7.45 (m, 1 H, Ph H), 7.84 (m,
2 H, Ph H, CONH).
Synthesis 2006, No. 18, 3092–3098 © Thieme Stuttgart · New York

3098
C. Della Rosa et al.
PAPER
(9) McLaren, A. B.; Sweeney, J. B. Synlett 2000, 1625.
(10) Carruthers, W.; Coldham, I. Modern Methods of Organic
Chemistry, 4th ed.; Cambridge University Press: Cambridge
U.K., 2004.
MS: m/z (%) = 392 (M+, 1.5), 374 (M+ – H2O, 2.1), 348 (M+ – CO2,
6.4), 267 (C13H17NO3S, 100), 223 (C13H17NO3S – CO2, 36.5), 142
(C6H6O2S+, 42.0), 83 (C6H11+, 22.1).
HRMS: m/z [M+] calcd for C20H28N2O4S: 392.1769; found:
392.1759.
(11) Kuwano, R.; Takahashi, M.; Ito, Y. Tetrahedron Lett. 1998,
39, 1017.
(12) Igarashi, M.; Fuchikami, T. Tetrahedron Lett. 2001, 42,
1945.
Acknowledgment
(13) Vandenabeele-Trambouze, L.; Mion, L.; Garrelly, L.;
Commeyras, A. Adv. Environ. Res. 2001, 6, 45.
(14) Wang, C.; Song, Q.; Xi, Z. Tetrahedron 2004, 60, 5207.
(15) Gil, S.; Parra, M. Curr. Org. Chem. 2002, 6, 283.
(16) Gil, S.; Parra, M. Recent Res. Dev. Org. Chem. 2002, 6, 449.
(17) Brun, E. M.; Casades, I.; Gil, S.; Mestres, R.; Parra, M.
Tetrahedron Lett. 1998, 39, 5443.
The present research has been financed by DGCYT (PPQ2002-
00986) and by the Agencia Valenciana de Ciencia y Tecnología
(Grupos 03/206). C.D.R. acknowledges the University of Valencia
for a fellowship.
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Synthesis 2006, No. 18, 3092–3098 © Thieme Stuttgart · New York