Direct introduction of glycine/mercaptoacetic acid units into electron-poor alkenes: a novel route to functionally rich α-amino/α-mercapto acids

Article abstract of DOI:10.1016/j.tetlet.2008.07.103

The first example of an operationally simple direct introduction of glycine/mercaptoacetic acid units into electron-poor alkenes is reported. In this protocol, Lewis acid-catalyzed Michael addition of activated glycine or mercaptoacetic acid, that is 2-phenyl-1,3-oxazol-5-one or 2-methyl-2-phenyl-1,3-oxathiolan-5-one, to various electron-poor alkenes in water/1,4-dioxane (1:2, v/v) solvent system diastereoselectively affords the corresponding functionally rich α-amino acids or α-mercapto acids, respectively, in high yields at ambient temperature.

Full text of DOI:10.1016/j.tetlet.2008.07.103

Tetrahedron Letters 49 (2008) 5751–5754
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct introduction of glycine/mercaptoacetic acid units into electron-poor
alkenes: a novel route to functionally rich
a-amino/a-mercapto acids
*
Lal Dhar S. Yadav , Ankita Rai
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first example of an operationally simple direct introduction of glycine/mercaptoacetic acid units into
electron-poor alkenes is reported. In this protocol, Lewis acid-catalyzed Michael addition of activated
glycine or mercaptoacetic acid, that is 2-phenyl-1,3-oxazol-5-one or 2-methyl-2-phenyl-1,3-oxathio-
lan-5-one, to various electron-poor alkenes in water/1,4-dioxane (1:2, v/v) solvent system diastereoselec-
Received 10 June 2008
Revised 14 July 2008
Accepted 18 July 2008
Available online 24 July 2008
tively affords the corresponding functionally rich
high yields at ambient temperature.
a-amino acids or
a-mercapto acids, respectively, in
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
a-Amino acids
a-Mercapto acids
Michael addition
Lewis acid
Stereoselective synthesis
Activated alkenes
The Michael addition of various nucleophiles to highly electron
deficient olefins has proven to be an atom-economical and
versatile transformation.1 Although there are numerous reports
on the Michael addition of various aldehydes and ketones to
activated alkenes, there is no report on the addition of glycine/
mercaptoacetic acid to activated alkenes, which is the target reac-
tion of the present investigation.2 The products of this reaction
α-amination
Strecker
reaction
α-
thio
latio
n
HS/H2N
R
CO2H
Present disconnection approach
CO2Me/CN/NO2
electrophilic
substitution
are multifunctionalized
a-amino/a-mercapto acids, which are of
various functional group
transformations
significant chemical and pharmacological interest.3 For example,
b-substituted
products, and
for a convenient synthesis of
a
c
-amino acids are present in several peptidic natural
-nitro- -amino acids act as open chain precursors
-lactam analogues of b-lactam anti-
Figure 1. Various functionalities installed in the target molecule.
a
c
biotics.4,5 Furthermore, these amino acids themselves are a useful
source of chiral substrates, auxiliaries and catalysts in various
fields of organic chemistry.6 As a consequence, a great deal of effort
has been dedicated to the development of efficient and practical
Table 1
Optimization of the Lewis acid catalyst
synthetic methods for both natural and non-natural a-amino acids,
which are of considerable importance in a variety of fields includ-
Entry
Catalyst (mol %)
Time (h)
Yielda (%)
Syn/antib
ing chemistry and biology.7
1
2
3
4
5
6
7
8
CuCl2Á2H2O (20)
15
14
12
12
10
8
30
42
51
66
60
67
85
85
66:34
71:29
73:27
78:22
76:24
80:20
94:6
Mercaptoacetic acid derivatives have been found to be oxytocin
inhibitors in the avian vasodepressor (AVD) assay.8 From a chemical
FeCl3Á7H2O (20)
Ce2(SO4)3 (20)
Ce2(SO4)3/NaI (1:1) (20)
CeCl3Á7H2O (20)
viewpoint,
a-mercapto acids have been utilized as substrates for
the synthesis of bioactive molecules and medicines, and are also
CeCl3Á7H2O/NaI (1:1) (10)
CeCl3Á7H2O/NaI (1:1) (20)
CeCl3Á7H2O/NaI (1:1) (25)
used as reagents for the identification of carbonyl compounds.9
8
8
94:6
a
Yield of isolated and purified products.
* Corresponding author. Tel.: +91 5322500652; fax: +91 5322460533.
E-mail address: ldsyadav@hotmail.com (L. D. S. Yadav).
b
As determined by 1H NMR of the crude products.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.103

5752
L. D. S. Yadav, A. Rai / Tetrahedron Letters 49 (2008) 5751–5754
Table 2
Diastereoselective synthesis of
a
-amino acids 4 and
a
-mercapto acids 5 from electron-poor alkenes 1
Entry
1
Lactone 2 or 3
Alkene 1
Product 4 or 5
Yield (%)a,b (Time, h)c
83 (10)
Syn/antid
COOH
H
N
H2N
NO2
2
93:7
O
4a
4b
4c
4d
4e
4f
O
C6H5
H
Ph
NO2
COOH
H
H2N
NO2
2
3
4
5
6
2
2
2
2
2
87 (9)
86 (10)
90 (8)
82 (10)
83 (9)
94:6
95:5
94:6
93:7
—
H
Cl
4-ClC6H4
NO2
COOH
NO2
H2N
H
H
3-NO2C6H4
O2N
O2N
NO2
COOH
H
H2N
NO2
H
4-NO2C6H4
NO2
COOH
H2N
H
H
NO2
4-MeOC6H4
MeO
NO2
COOH
H2N
H
H
H
COOMe
COOH
COOH
H
H
S
HS
C6H5
Ph
NO2
O
7
8
3
3
5a
5b
85 (8)
89 (7)
94:6
95:5
O
Me
NO2
COOH
HS
4-ClC6H4
H
H
NO2
Cl
NO2
COOH
H
H
NO2
HS
9
3
3
5c
92 (9)
93 (7)
96:4
95:5
3-NO2C6H4
O2N
O2N
NO2
COOH
H
H
HS
4-NO2C6H4
NO2
10
5d
NO2
COOH
H
H
HS
4-MeOC6H4
NO2
11
12
3
3
3
5e
5f
84 (9)
88 (8)
85 (8)
94:6
—
MeO
NO2
COOH
HS
H
H
H
CN
CN
COOH
H
HS
H
13
COOMe
5g
—
H
COOMe
a
Yield of isolated and purified products.
b
c
All compounds gave C, H and N analyses within 0.38% and satisfactory spectral (IR, 1H NMR, 13C NMR and EIMS) data.
Stirring time at rt (excluding the time required for debenzoylation of 7 to give 4, Scheme 2).
As determined by 1H NMR of the crude products.
d

L. D. S. Yadav, A. Rai / Tetrahedron Letters 49 (2008) 5751–5754
5753
COOH
CeCl3 7H2O/NaI
H2O/1,4-dioxane (1:2, v/v)
rt; 7-10 h
(i)
N
H2N
R
H
H
O
O
Ph
Ph
H3O+, 45 min
2
EWG
(ii)
EWG
4, 82-90% yield
or
+
R
1
or
COOH
CeCl3 7H2O/NaI
H2O/1,4-dioxane (1:2, v/v)
rt; 7-10 h
S
O
R = H, C6H5, 3-NO2C6H4,
4-NO2C6H4, 4-ClC6H4,
4-MeOC6H4
O
HS
H
H
Me
R
3
EWG = NO2, COOMe, CN
EWG
5, 84-93% yield
Scheme 1. Synthesis of a-amino acids 4 and a-mercapto acids 5 from electron-poor alkenes 1.
Therefore, the medicinal and synthetic utility of
a
-amino and
oxathiolan-5-one 3 and activated alkene 1 with the Lewis acid cat-
alyst CeCl3Á7H2O/NaI in water/1,4-dioxane at rt for 7–10 h (Scheme
1). Isolation and purification by recrystallization from EtOAc–hex-
ane (1:20) afforded compounds 4 and 5 in 82–93% yields (Table 2).
The formation of 4 and 5 was highly diastereoselective in favour of
the syn isomer.
a-mercapto acids is the major driving force for attracting organic
and medicinal chemists to devise their diverse syntheses.
In this Letter, we report a convenient installation of versatile
functional groups such as amino, mercapto, carboxylic acid, nitro,
ester, cyano and aryl on the activated olefinic double bond of
methyl acrylate, acrylonitrile and nitrostyrenes (Fig. 1) via a C–C
bond forming Michael reaction.
The diastereomeric ratios in the crude isolates were determined
by 1H NMR spectroscopy to note any alteration of these ratios dur-
ing subsequent purification. The crude isolates of 4 and 5 were
found to be diastereomeric mixtures containing 93–96% of the
syn isomer. On the basis of 1H NMR spectroscopy and literature
precedent,14 the syn configuration was conclusively assigned to 4,
5 and 7, as their coupling constant (J2H,3H = 3.9–4.1 Hz) was smaller
than that for the minor anti isomer (J2H,3H = 8.3–9.4 Hz). The
coupling constant for vicinal protons of the analogous syn isomer
is reported to be J2H,3H = 4.8 Hz and that of the anti isomer
J2H,3H = 9.6 Hz.14a Similarly, the coupling constants reported by
The present synthesis of the target functionalized
a-amino/a-
mercapto carboxylic acids is an outcome of our continuous interest
in Michael type reactions for developing new routes to chemically
and pharmacologically relevant compounds.10
Initially, we investigated the Michael addition of glycine/mer-
captoacetic acid to electron-poor alkenes but did not obtain the
desired products 4 or 5, probably due to the presence of free
–COOH and –NH2 or –SH groups. Instead, we turned our attention
to activate the glycine and mercaptoacetic acid units by converting
them into 2-phenyl-1,3-oxazol-5-one 2 and 2-methyl-2-phenyl-
1,3-oxathiolan-5-one 3, respectively.11,12 This worked well as the
–COOH and –NH2 or –SH groups of glycine/mercaptoacetic acid
were blocked, and their methylene group was activated to act as
the Michael donor.15
Kamimura et al.14b for the syn (J2H,3H = 4.3 Hz) and anti (J2H,3H
=
7.9 Hz) isomers are comparable to that of compounds 4, 5 and 7.
Furthermore, 3-H signals for syn isomers of compounds 4, 5 and
7 always appeared in the lower field (d = 3.18–3.50) than the
corresponding signals for anti isomers (d = 2.85–3.08), which is in
conformity with the earlier observation.14b
As regards the choice of catalyst, we tested several Lewis acids
for the synthesis of the representative compound 5 (R = Ph;
EWG = NO2) using a water/1,4-dioxane (1:2, v/v) solvent system.
The best result was obtained in the case of the CeCl3Á7H2O/NaI
(1:1) catalyst system (Table 1, entry 7). This is in conformity with
the earlier observation that the catalytic activity of CeCl3Á7H2O in-
creases dramatically in the presence of an iodide source, such as
NaI, owing to the formation of a complex, which exhibits stronger
Lewis acid character than CeCl3Á7H2O.13 The optimum catalyst
loading for the CeCl3Á7H2O/NaI (1:1) system was found to be
20 mol %. A decrease in the amount of catalyst decreased both
the yield and diastereoselectivity considerably (Table 1, entry 6).
However, a higher catalyst loading did not appreciably increase
the yield and diastereoselectivity (Table 1, entry 8). Next, optimiza-
tion of the solvent for the synthesis of representative compound 5
(R = Ph; EWG = NO2) was undertaken. It was found that amongst
H2O, MeOH, EtOH, 1,4-dioxane, MeOH/H2O (2:1), EtOH/H2O (2:1)
and 1,4-dioxane/H2O (2:1), the best solvent system in terms of
the yield and diastereoselectivity was 1,4-dioxane/H2O (2:1). In or-
der to investigate the substrate scope of the reaction, various elec-
tron–poor alkenes such as [E]-b-nitrostyrenes, methyl acrylate and
acrylonitrile were reacted under the optimized reaction conditions.
The yields and diastereoselectivities were consistently good (Table
2), the highest yield being 93% (Table 2, entry 10) and the best syn
stereoselectivity being 96% (Table 2, entry 9). The strategy followed
The formation of compounds 4 and 5 may be explained by inter-
molecular nucleophilic attack of C-4 of 2-phenyl-1,3-oxazol-5-one
2 or 2-methyl-2-phenyl-1,3-oxathiolan-5-one 3 at the double bond
of alkene 1 (e.g., at the
a-carbon of b-nitrostyrene) to afford the
Michael adducts 6 and 8 (Schemes 2 and 3). The adduct 6 upon
hydrolysis gave 7,15 which on debenzoylation afforded the target
a
8
-amino acid 416 as depicted in Scheme 2. Similarly, the adduct
afforded
a
-mercaptoacetic acid 517 following removal of
EWG
Ph
Ph
O
R
O
1
O
O
N
N
H
O
2'
2
:OH2
H
Ph
H
O
O
O
N
PhCON
EWG
EWG
R
R
6
H3O+
COOH
EWG
COOH
H
PhCONH
H2N
R
45 min
H
R
for the envisaged diastereoselective synthesis of
and -mercapto acids 5 was successfully realized by stirring a mix-
ture of 2-phenyl-1,3-oxazol-5-one 2 or 2-methyl-2-phenyl-1,3-
a-amino acids 4
4
7
EWG
Scheme 2. A plausible mechanism for the formation of -amino acids 4.
a
a

5754
L. D. S. Yadav, A. Rai / Tetrahedron Letters 49 (2008) 5751–5754
Kim, R. M.; Kahne, D. E.; Chapman, K. T. Preparation of Glycopeptides as
EWG
Antibacterial Agents. PCT Int. Appl. WO 2000069893, 2000; Chem. Abstr. 2000,
134, 5162. For leading references on the asymmetric synthesis of arylglycines,
see: (d) Shang, G.; Yang, Q.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 6360; (e)
Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889; (f) Stammer, C. H.
Tetrahedron 1990, 46, 2231; (g) Heimgartner, H. Angew. Chem., Int. Ed. Engl.
1991, 30, 238.
Ph
Me
Ph
Me
O
O
R
1
O
O
S
S
H
3
3'
H
S
:OH2
Ph
H
O
O
8. Dyckes, D. F.; Smith, C. W.; Ferger, M. F.; Vigneaud, V. D. J. Am. Chem. Soc. 1974,
72, 7549.
Me
O
O
S
EWG
EWG
9. (a) Koeing, N. H.; Swern, D. J. Am. Chem. Soc. 1957, 79, 362; (b) Soper, Q. F.;
Whitehead, C. W.; Behrens, O. K.; Corse, J. J.; Jones, R. G. J. Am. Chem. Soc. 1948,
70, 2849; (c) Ritter, J. J.; Lover, M. J. J. Am. Chem. Soc. 1952, 74, 5576.
10. (a) Yadav, L. D. S.; Rai, A.; Rai, V. K.; Awasthi, C. Synlett 2007, 12, 1905; (b)
Yadav, L. D. S.; Awasthi, C.; Rai, V. K.; Rai, A. Tetrahedron Lett. 2007, 48, 4899; (c)
Yadav, L. D. S.; Rai, A.; Rai, V. K.; Awasthi, C. Tetrahedron 2008, 64, 1420.
11. Vandenberg, G. E.; Harrison, J. B.; Carter, H. E.; Magerlein, B. J. Org. Synth. Coll.
1973, 5, 946.
-PhCOMe
R
R
8
COOH
HS
H
H
R
EWG
5
12. Yadav, L. D. S.; Yadav, S.; Rai, V. K. Tetrahedron 2005, 61, 10013.
13. Bartoli, G.; Bartolacci, M.; Bosco, M.; Foglia, G.; Giulani, A.; Marcantoni, E.;
Sambri, L.; Torregiani, E. J. Org. Chem. 2003, 68, 4594.
Scheme 3. A plausible mechanism for the formation of a-mercapto acids 5.
14. (a) Albertshofer, K.; Thayumanavan, R.; Utsumi, N.; Tanaka, F.; Barbas, C. F.
Tetrahedron Lett. 2007, 48, 693; (b) Kamimura, A.; Mitsudera, H.; Asano, S.;
Kidera, S.; Kakehi, A. J. Org. Chem. 1999, 64, 6353.
15. General procedure for the synthesis of N-benzoyl-
a
-amino acids 7: A mixture of
(1 mmol),
acetophenone during the course of reaction, without requiring any
additional deprotection step (Scheme 3).
In conclusion, we have developed a novel method for direct
introduction of glycine/mercaptoacetic acid units into electron-
poor alkenes via Lewis acid-catalyzed Michael reaction to afford
activated alkene (1 mmol), 2-phenyl-1,3-oxazol-5-one
1
2
CeCl3Á7H2O (0.2 mmol) and NaI (0.2 mmol) in 15 mL of water/1,4-dioxane
(1:2 v/v) was stirred at room temperature for 7–10 h (Table 2). After
completion of the reaction (monitored by TLC), water (10 mL) was added
and the product was extracted with CH2Cl2 (3 Â 15 mL). The combined extract
was dried over Na2SO4, filtered, concentrated under reduced pressure and the
crude product thus obtained was recrystallized from ethyl acetate to afford an
analytically pure 7. Physical data of representative compound 7a (R = Ph,
EWG = NO2: yellowish solid, yield 91%, mp 205–207 °C. IR (KBr) mmax 3310,
functionally rich a-amino acids and a-mercapto acids. The present
synthetic protocol involves simple operations at ambient-temper-
ature to give high yields and diastereoselectivities of the products
in a one-pot procedure and which may find application in organic
synthesis.
3000, 2985, 2845, 1725, 1657, 1602, 1588, 1451, 753, 705 cmÀ1 1H NMR
.
(400 MHz; DMSO-d6 + D2O/TMS) d: 3.50 (ddd, 1H, J = 8.1, 4.1, 5.2 Hz, 3-H), 3.86
(d, 1H, J = 4.1 Hz, 2-H), 4.60 (dd, 1H, J = 12.9, 5.2 Hz, 4-Ha), 4.79 (dd, 1H, J = 12.9,
8.1 Hz, 4-Hb), 7.15–7.95 (m, 10Harom). 13C NMR (100 MHz, DMSO-d6/TMS) d:
31.9, 58.8, 76.2, 125.4, 126.3, 127.6, 128.5, 129.7, 132.4, 133.9, 148.8, 167.3,
174.2. EIMS (m/z) 328 (M+). Anal. calcd for C17H16N2O5: C, 62.19; H, 4.91; N,
8.53. Found: C, 62.44; H, 4.58; N, 8.29.
Acknowledgement
16. General procedure for the synthesis of a-amino acids 4: Compound 7 (1 mmol)
We sincerely thank SAIF, CDRI, Lucknow, for providing microa-
nalyses and spectra.
was refluxed in H2SO4/H2O (8 mL, 4:3, v/v) for 45 min in an oil-bath. The
reaction mixture was cooled, precipitated benzoic acid was filtered off and the
filtrate was neutralized by adding concentrated NH4OH (specific gravity 0.88)
under ice cooling. The crude product thus precipitated was recrystallized from
aqueous methanol to afford an analytically pure sample of 4. Physical data of
representative compound 4a: yellowish solid, yield 83%, mp 180–183 °C. IR
References and notes
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Trans. 1 1998, 1113.
(KBr) mmax 3340, 3005, 2988, 2852, 1720, 1600, 1585, 1450, 748, 708 cmÀ1 1H
.
NMR (400 MHz; DMSO-d6 + D2O/TMS) d: 3.21 (ddd, 1H, J = 7.9, 4.0, 4.8 Hz,
3-H), 3.86 (d, 1H, J = 4.0 Hz, 2-H), 4.57 (dd, 1H, J = 12.5, 4.8 Hz, 4-Ha), 4.81 (dd,
1H, J = 12.5, 7.9 Hz, 4-Ha), 7.10–7.19 (m, 5Harom). 13C NMR (100 MHz, DMSO-d6/
TMS)) d: 35.3, 62.1, 76.9, 125.0, 126.4, 128.7, 148.2, 173.9. EIMS (m/z) 224 (M+).
Anal. calcd for C10H12N2O4: C, 53.57; H, 5.39; N, 12.49. Found: C, 53.91; H, 5.68;
N, 12.11.
17. General procedure for the synthesis of
followed was the same as described for the synthesis of 7 (Ref. 15) except that
1,3-oxathiolan-5-one (1 mmol) was used instead of 1,3-oxazol-5-one
a-mercapto acids 5: The procedure
2
1
(1 mmol). The crude product was recrystallized from aqueous methanol to
afford an analytically pure sample of 5. Physical data of representative
compound 5a: yellowish solid, yield 85%, mp 110–112 °C. IR (KBr) mmax 3008,
5. Heydari, A.; Khaksar, S.; Pourayoubi, M.; Mahjoub, A. R. Tetrahedron Lett. 2007,
48, 4059.
2982, 2845, 2580, 1718, 1598, 1583, 1445, 745, 704 cmÀ1 1H NMR (400 MHz;
.
DMSO-d6 + D2O/TMS) d: 3.18 (ddd, 1H, J = 7.7, 3.9, 4.8 Hz, 3-H), 3.89 (d, 1H,
J = 3.9 Hz, 2-H), 4.64 (dd, 1H, J = 12.7, 4.8 Hz, 4-Ha), 4.79 (dd, 1H, J = 12.7,
7.7 Hz, 4-Hb), 7.12–7.21 (m, 5Harom.), 13C NMR (100 MHz, DMSO-d6/TMS)): d
36.2, 46.5, 78.5, 125.2, 126.4, 128.7, 148.2, 173.9. EIMS (m/z) 241 (M+). Anal.
calcd for C10H11NO4S: C, 49.78; H, 4.60; N, 5.81. Found: C, 49.47; H, 4.93; N,
6.04.
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Molecules Using Amino Acids; John Wiley & Sons: New York, NY, 1987.
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