Peptidoyl benzotriazolide-mediated acylation of nitrile-activated methylene groups

Article abstract of DOI:10.1055/s-0033-1338473

Peptidoyl benzotriazoles permit the acylation of active methylene groups of nitriles to provide CH-acylated nitrile enols from α-amino acids or from di- or tripeptides with no loss of chirality. Georg Thieme Verlag Stuttgart.New York.

Full text of DOI:10.1055/s-0033-1338473

1256▌
PAPER
paper
Peptidoyl Benzotriazolide-Mediated Acylation of Nitrile-Activated Methylene
Groups
Acylation of Nitrile-Activated Methylene Groups
Sandhyamayee Sahu,a Iryna O. Lebedyeva,a Siva S. Panda,a Alan R. Katritzky*a,b
a
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Fax +1(352)3929199; E-mail: katritzky@chem.ufl.edu
b
Chemistry Department, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Received: 18.12.2012; Accepted after revision: 05.03.2013
no acids or small peptides to acylate the active methylene
Abstract: Peptidoyl benzotriazoles permit the acylation of active
group of Meldrum’s acid,15 various diketones,13 peptidyl-
methylene groups of nitriles to provide CH-acylated nitrile enols
substituted α-keto methylenetriphenylphosphoranes,16 or
from α-amino acids or from di- or tripeptides with no loss of chiral-
cyano esters. We recently used the benzotriazole method-
ology to achieve C-acylations of dimedone and cyclohex-
ane-1,3-dione with N-protected tri- and tetrapeptidoyl-
benzotriazoles14 and C-acylations of malononitrile,
Meldrum’s acid, and cyclohexane-1,3-dione with azido
acids.17 Here, we present an extension of this methodolo-
gy to provide a convenient and efficient technique for pre-
paring N-protected amino acids and di- and tripeptide
conjugates with nitriles.
ity.
Key words: acylations, cyclizations, peptides, nitriles, drugs, het-
erocycles
β-Keto nitriles are precursors for the synthesis of many
heterocyclic compounds, such as dihydropyrans, dihydro-
thiopyrans, pyrazoles, pyridones, or imidazoles, and for
the synthesis of specific ketones upon decyanation.1 Re-
ported methods for the synthesis of β-keto nitriles2 include
the base-mediated acylation of nitriles with nonactivated
esters in the presence of sodium amide/liquid ammonia,3
sodium alkoxide,4 lithium diisopropylamide, or sodium
hydride,5 or with activated N-acylbenzotriazoles in the
presence of butyllithium or potassium tert-butoxide.6 Ad-
ditionally, sterically hindered nitriles react with enoliz-
able or nonenolizable esters in the presence of three
equivalents of potassium 2,2-dimethylbutan-1-olate to
give the corresponding β-keto nitriles in high yields.7
Benzotriazole derivatives 1a–e, 4a, 4b, 6a, and 6b, syn-
thesized by our previously reported method,14 reacted
with various nitriles as C-nucleophiles in the presence of
1.5 equivalents of N,N-diisopropylethylamine with micro-
wave irradiation at 50 °C and 30 W to give good yields of
the corresponding peptide conjugates 3a–f (Scheme 1),
5a, 5b (Scheme 2), 7a, and 7b (Scheme 3). Microwave ir-
radiation of benzotriazoles 1, 4, and 6 in presence of ni-
triles 2 provided higher yields (45–90%; Table 1) than did
the corresponding reactions when performed overnight at
room temperature (yields ≤32%)
Elaboration of small peptides at both their N- and C-ter-
mini has been an area of interest over the past five de-
cades.8 Diverse functional groups and potentially
bioactive residues have been introduced into native9 or
synthetic peptides10 and into peptidomimetics11 in efforts
to expand their biological activities. Elaboration at the C-
terminus has frequently been accomplished by using acti-
vated intermediates of the form COX where X is an
imidazole residue,12a,b a succinimide residue,13 or, advan-
tageously, a benzotriazole (Bt) residue. 1-Peptidoyl-1H-
1,2,3-benzotriazoles have advantages as coupling re-
agents in that they are sufficiently reactive to form amide
bonds at ambient temperatures, they are stable enough to
resist side reactions and to permit storage in the crystalline
state at room temperature, and they provide good yields
without detectable racemization. Thus, benzotriazole-
activated N-protected amino acids and peptides have been
extensively used, especially in N-, O-, and S-acylations,14
and less frequently in C-acylations.6,14 Several reports
have demonstrated the ability of carbonyl-activated ami-
O
OH
R2
H
H
N
N
CN
THF, DIPEA
+
PG
Bt
PG
CN
MW (50 °C, 30 W)
30 min
R1
R1
R2
1a R1 = i-Pr
1b R1 = Bn
2a R2 = CN
3a R1 = i-Pr, R2 = CN
3b R1 = Bn, R2 = CN
3c R1 = CH2(3-indolyl),
2b R2 = COPh
1c R1 = CH2(3-indolyl) 2c R2 = COOEt
1d R1 = H
R
2 = CN
1e R1 = Me
3d R1 = H, R2 = CN
3e R1 = Me, R2 = COPh
3f R1 = H, R2 = COOEt
Bt = 1H-1,2,3-benzotriazol-1-yl
Scheme 1 Reactions of benzotriazolyl-activated N-protected amino
acids with nitriles 2a–c
Cyclization of the amino acid and peptide conjugates 3b,
3d (Scheme 4), and 5b (Scheme 5) in 10% aqueous hydro-
chloric acid at room temperature gave the corresponding
2-amino-4-oxo-4,5-dihydropyrrole-3-carbonitriles 8a–c,
respectively, in good yields (Table 2).
SYNTHESIS 2013, 45, 1256–1260
Advanced online publication: 09.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338473; Art ID: SS-2012-M0978-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Acylation of Nitrile-Activated Methylene Groups
1257
R2
CN
R1
O
O
H
H
CN
N
THF, DIPEA
PG
N
PG
N
CN
+
N
Bt
H
MW (50 °C, 30 W)
30 min
H
R1
OH
CN
O
R2
4a R1 = Me, R2 = Bn
5a R1 = Me, R2 = Bn
5b R1 = Bn, R2 = H
2a
4b R1 = Bn, R2 = H
Scheme 2 Reactions of carbonyl-activated N-protected dipeptides 4a,b with malononitrile 2a
O
O
O
OH
H
H
H
H
N
CN
R2
R2
CN
THF, DIPEA
N
N
N
+
PG
N
Bt
PG
N
H
MW (50 °C, 30 W)
30 min
H
R1
O
R1
O
6a R1 = H
6b R1 = Bn
7a R1 = H, R2 = CN
7b R1 = Bn, R2 = COPh
2a R2 = CN
2b R2 = COPh
Scheme 3 Reactions of tripeptidoylbenzotriazoles 6a and 6b with methylenenitriles 2a and 2b
Table 2 2-Amino-4-oxo-4,5-dihydropyrrole-3-carbonitriles 8a–c
Table 1 C-Acylation of N-Protected Aminoacyl, Dipeptidoyl, and
Tripeptidoylbenzotriazoles
Reactant
Product
Yield (%)
Mp (°C)
Reactant
Nitrile Product Yield Mp (°C)
(%)
3b
3d
5b
8a
8b
8c
87
73
87
171–173
157–15915
161–163
Boc-Val-Bta (1a)
Cbz-Phe-Bt (1b)
Cbz-Trp-Bt (1c)
Cbz-Gly-Bt (1d)
Cbz-Ala-Bt (1e)
Cbz-Gly-Bt (1d)
Boc-Ala-Phe-Bt (4a)
Cbz-Phe-Gly-Bt (4b)
2a
2a
2a
2a
2b
2d
2a
2a
3a
3b
3c
3d
3e
3f
68
60
85
83
45
88
78
90
62
64
sticky solid
74-80
133–137
sticky solid
69–71
In conclusion, N-protected aminoacyl, dipeptidoyl, and
tripeptidoyl benzotriazoles are sufficiently reactive to
couple with the active methylene group of nitriles under
microwave irradiation at 50 °C. This offers a convenient
and efficient method for the preparation of chirally pure
N-protected peptide conjugates in synthetically useful
yields by C-acylation. The chirality of the starting materi-
als was preserved in the products, as demonstrated by 1H
and 13C NMR spectroscopy and by high-performance liq-
uid chromatographic analysis (see Supporting Informa-
tion).
210–213
147–152
69–74
5a
5b
7a
7b
Boc-Gly-Gly-Gly-Bt (6a) 2a
Cbz-Phe-Gly-Gly-Bt (6b) 2b
a Bt = 1H-1,2,3-benzotriazol-1-yl.
135–143
115–117
All the reagents were purchased from commercial sources and were
used as received unless otherwise indicated. The products were pu-
rified by column chromatography on silica gel (300–400 mesh).
Melting points were determined on a capillary melting-point appa-
ratus equipped with a digital thermometer. NMR spectra were re-
corded in CDCl3, DMSO-d6, or CD3OD on Mercury or Gemini
NMR spectrometers operated at 300 MHz for 1H (with TMS as an
internal standard) or 75 MHz for 13C. High-resolution mass spectra
were recorded on an Agilent Technologies 6210 Time of Flight
LC/MS instrument operating in the ESI mode. Elemental analyses
were performed on a Carlo-Erba EA1108 instrument. All micro-
wave-assisted reactions were carried out with a single-mode-cavity
Discover Microwave Synthesizer (CEM Corporation, NC, USA).
The reaction mixtures were transferred into a 10-mL glass pressure
microwave tube equipped with a magnetic stirrer bar. The tube was
closed with a silicon septum and the reaction mixture was subjected
to microwave irradiation (Discover mode: run time: 60 s; Power-
Max-cooling mode).
O
R
OH
H
10% HCl
20 °C, 15 min
N
CN
CN
Cbz
N
Cbz
R
CN
NH2
3b R = Bn
3d R = H
8a R = Bn
8b R = H
Scheme 4 Intramolecular cyclization of enols to give 2-amino-4-
oxo-4,5-dihydropyrrole-3-carbonitriles 8a and 8b
O
Ph
Ph
OH
H
10% HCl
Cbz
N
CN
CN
Cbz
N
N
N
20 °C, 1 h
H
H
O
CN
NH2
O
5b
8c
Scheme 5 Synthesis of 2-amino-4-oxo-4,5-dihydropyrrole-3-carbo-
nitrile 8c
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1256–1260

1258
S. Sahu et al.
PAPER
Benzyl [(1S)-3,3-Dicyano-2-hydroxy-1-(1H-indol-3-ylmeth-
yl)prop-2-en-1-yl]carbamate (3c)
Yield: 187 mg (0.48 mmol, 85%); light-orange solid; mp 133–
137 °C.
N-(Aminoacyl )benzotriazoles 1a–e, 4a, 4b, 6a, and 6b; General
Procedure
All the amino acid– and peptide–benzotriazole conjugates were pre-
pared as reported previously.18
1H NMR (DMSO-d6): δ = 10.75 (s, 1 H), 7.72 (d, J = 8.1 Hz, 1 H),
7.33–6.90 (m, 10 H), 4.93 (d, J = 13.2 Hz, 1 H), 4.86 (d, J = 12.6
Hz, 1 H), 4.60–4.42 (m, 1 H), 3.05 (dd, J = 14.3 Hz, 3.5 Hz, 1 H),
2.78 (dd, J = 14.4 Hz, 10.2 Hz, 1 H).
13C NMR (DMSO-d6): δ = 191.8, 155.6, 137.2, 136.1, 128.3, 127.6,
127.5, 124.0, 122.4, 120.7, 118.7, 118.2, 111.2, 110.7, 65.0, 59.2,
56.0, 28.2.
tert-Butyl ((1S)-2-{[(1S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-ben-
zyl-2-oxoethyl]amino}-1-methyl-2-oxoethyl)carbamate (4a)
Yield: 220 mg (0.49 mmol, 67%); white solid; mp 115–117 °C.
1H NMR (DMSO-d6): δ = 8.14 (dd, J = 8.4, 0.9 Hz, 1 H), 8.06 (dd,
J = 8.1, 0.9 Hz, 1 H), 7.80–7.70 (m, 1 H), 7.62–7.56 (m, 1 H), 7.49–
7.43 (m, 1 H), 7.35–7.30 (m, 1 H), 7.20–6.98 (m, 4 H), 6.21–6.11
(m, 1 H), 5.20 (br s, 1 H), 4.28 (br s, 1 H), 3.44–3.38 (m, 1 H), 3.24–
3.14 (m, 1 H), 1.38 (s, 9 H), 1.28 (d, J = 6.9 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C22H18N4NaO3: 409.1271;
found: 409.1268.
13C NMR (DMSO-d6): δ = 173.1, 170.5, 155.7, 146.0, 135.3, 131.1,
130.9, 129.3, 128.7, 127.4, 126.6, 120.4, 114.4, 80.5, 60.5, 54.2,
38.6, 28.4, 18.3.
Benzyl (3,3-Dicyano-2-hydroxyprop-2-en-1-yl)carbamate (3d)
Yield: 170 mg (0.67 mmol, 83%); light-yellow sticky solid.
1H NMR (DMSO-d6): δ = 7.43–7.29 (s, 5 H), 7.05 (br s, 1 H), 5.01
(s, 2 H), 3.74 (d, J = 5.7 Hz, 2 H).
Anal. Calcd for C23H27N5O4: C, 63.14; H, 6.22; N, 16.01. Found: C,
63.38; H, 7.01; N, 15.22.
tert-Butyl {2-[(2-{[2-(1H-1,2,3-Benzotriazol-1-yl)-2-oxoeth-
yl]amino}-2-oxoethyl)amino]-2-oxoethyl}carbamate (6a)
Yield: 430 mg (1.10 mmol, 64%); white solid; mp 123–124 °C.
1H NMR (DMSO-d6): δ = 8.61 (br s, 1 H), 8.27 (d, J = 6.6 Hz, 1 H),
8.24–8.15 (m, 2 H), 7.79 (br s, 1 H), 7.65–7.58 (m, 1 H), 7.06–6.98
(m, 1 H), 4.97 (d, J = 5.4 Hz, 2 H), 3.87 (d, J = 5.4 Hz, 2 H), 3.61
(d, J = 5.7 Hz, 2 H), 1.37 (s, 9 H).
13C NMR (DMSO-d6): δ = 187.5, 156.3, 137.2, 128.3, 127.7, 127.7,
127.1, 121.9, 120.5, 65.3, 59.8, 45.4.
HRMS (ESI): m/z [M + H]+ calcd for C13H12N3O3: 258.0873; found:
258.0861.
Benzyl [(1S,2E)-3-Cyano-2-hydroxy-1-methyl-4-oxo-4-phenyl-
but-2-en-1-yl]carbamate (3e)
Yield: 121 mg, (0.34 mmol, 45%); orange solid; mp 69–71 °C.
1H NMR (DMSO-d6): δ = 7.69–7.66 (m, 1 H), 7.51–7.31 (m, 9 H),
13C NMR (DMSO-d6): δ = 169.9, 168.5, 155.8, 145.2, 131.0, 130.5,
126.6, 120.2, 113.7, 78.1, 43.3, 42.5, 41.7, 28.2.
5.02 (s, 2 H), 5.02–4.88 (m, 1 H), 1.29–1.24 (m, 3 H).
13C NMR (DMSO-d6): δ = 194.3, 187.8, 155.1, 142.6, 137.2, 129.2,
Anal. Calcd for C17H22N6O5: C, 52.30; H, 5.68; N, 21.53. Found: C,
51.84; H, 5.55; N, 22.08.
128.3, 127.6, 127.4, 124.5, 83.1, 65.1, 52.3, 19.0.
HRMS (ESI): m/z [M + Na]+ calcd for C20H18N2NaO4: 373.1159;
Nitriles 3a–f, 5a, 5b, 7a, and 7b; General Procedure
A dry, heavy-walled, Pyrex tube equipped with a small stirrer bar
was charged with a solution of the appropriate benzotriazole inter-
mediate (1 equiv), C-nucleophile (1 equiv), and DIPEA (1.5 equiv)
in THF (5 mL). The mixture was exposed to microwave irradiation
(50 °C, 30 W) for the appropriate time with simultaneous cooling.
When the reaction was complete (TLC), the THF was evaporated
and the reside was acidified with 2 M HCl, then extracted with
EtOAc (3 × 20 mL). The solvent was evaporated under reduced
pressure, and the residue was purified by crystallization (EtOAc).
found: 373.1161.
Ethyl 4-{[(Benzyloxy)carbonyl]amino}-2-cyano-3-oxobutano-
ate (3f)
Yield: 215 mg, (0.33 mmol, 88%); white solid; mp 210–213 °C.
1H NMR (DMSO-d6): δ = 7.35 (s, 5 H), 6.66 (s, 1 H), 5.00 (s, 2 H),
4.04–3.91 (m, 4 H), 1.12 (t, J = 6.0 Hz, 3 H).
13C NMR (DMSO-d6): δ = 188.2, 168.7, 156.7, 138.0, 129.0, 128.3,
123.3, 71.0, 65.8, 57.8, 48.6, 15.6.
HRMS (ESI): m/z [M – H]– calcd for C15H15N2O5: 303.0986; found:
303.0987.
tert-Butyl [(1S)-3,3-Dicyano-1-isopropyl-2-oxopropyl]carba-
mate (3a)
Yield: 141 mg (0.53 mmol, 68%); sticky light-orange solid.
1H NMR (DMSO-d6): δ = 6.00 (d, J = 8.1 Hz, 1 H), 4.11 (br s, 1 H),
1.85 (br s, 1 H), 1.36 (s, 9 H), 0.84 (d, J = 6.3 Hz, 3 H), 0.74 (d,
J = 5.7 Hz, 3 H).
13C NMR (DMSO-d6): δ = 191.0, 155.1, 121.9, 120.5, 77.7, 58.8,
46.4, 31.1, 28.2, 19.5, 17.6.
tert-Butyl ((1S)-2-{[(1S)-1-Benzyl-3,3-dicyano-2-hydroxyprop-
2-en-1-yl]amino}-1-methyl-2-oxoethyl)carbamate (5a)
Yield: 172 mg (0.45 mmol, 78%); white solid; mp 147–152 °C.
1H NMR (DMSO-d6): δ = 7.54 (d, J = 8.1 Hz, 1 H), 7.19–7.16 (m,
5 H), 6.95 (br s, 1 H), 4.72 (br s, 1 H), 3.92–3.82 (m, 1 H), 2.93–
2.68 (m, 2 H), 1.37 (s, 9 H), 1.07 (d, J = 7.5 Hz, 3 H).
HRMS (ESI): m/z [M – H]– calcd for C13H18N3O3: 264.1356; found:
13C NMR (DMSO-d6): δ = 192.6, 174.0, 156.6, 137.7, 129.8, 128.4,
264.1354.
126.7, 121.3, 119.6, 80.0, 60.8, 55.3, 51.0, 39.4, 28.0, 17.7.
HRMS (ESI): m/z [M + Na]+ calcd for C20H24N4NaO4: 407.1690;
found: 407.1689.
Benzyl [(1S)-1-Benzyl-3,3-dicyano-2-hydroxyprop-2-en-1-
yl]carbamate (3b)
Yield: 130 mg (0.37 mmol, 60%); white solid; mp 74–80 °C.
1H NMR (DMSO-d6): δ = 7.33–7.20 (m, 10 H), 4.90 (s, 2 H), 4.48–
4.44 (m, 1 H), 2.92–2.63 (m, 2 H).
Benzyl {(1S)-1-Benzyl-2-[(3,3-dicyano-2-hydroxyprop-2-en-1-
yl)amino]-2-oxoethyl}carbamate (5b)
13C NMR (DMSO-d6): δ = 190.9, 155.6, 138.7, 137.2, 129.1, 128.2,
127.9, 127.6, 127.4, 126.1, 122.1, 120.6, 65.0, 57.1, 44.9, 40.4,
38.0.
Yield: 200 mg (0.50 mmol, 90%); light-orange solid; mp 69–74 °C.
1H NMR (DMSO-d6): δ = 7.91 (br s, 1 H), 7.55 (d, J = 8.7 Hz, 1 H),
7.32–7.19 (m, 10 H), 4.93 (s, 2 H), 4.39–4.20 (m, 1 H), 3.84 (d,
J = 4.8 Hz, 2 H), 3.04–3.02 (m, 1 H), 2.79–2.62 (m, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C20H17N3NaO3: 370.1162;
found: 370.1160.
Synthesis 2013, 45, 1256–1260
© Georg Thieme Verlag Stuttgart · New York

PAPER
Acylation of Nitrile-Activated Methylene Groups
1259
13C NMR (DMSO-d6): δ = 186.9, 171.5, 155.9, 138.3, 137.1, 129.3,
128.4, 128.1, 127.7, 127.4, 126.3, 121.7, 120.3, 65.3, 56.4, 44.9,
44.1, 37.6.
Benzyl [(1S)-2-(5-Amino-4-cyano-3-oxo-2,3-dihydro-1H-pyr-
rol-1-yl)-1-benzyl-2-oxoethyl]carbamate (8c)
Yield: 217 mg (0.54 mmol, 87%); white solid; mp 161–163 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C22H20N4NaO4: 427.1377;
found: 427.1366.
1H NMR (DMSO-d6): δ = 7.96 (br s, 1 H), 7.56 (d, J = 9.0 Hz, 1 H),
7.40–7.18 (m, 10 H), 4.93 (br s, 2 H), 4.3 (br s, 1 H), 3.89–3.80 (m,
2 H), 3.12–2.92 (m, 1 H), 2.80–2.70 (m, 1 H).
tert-Butyl [2-({2-[(3,3-Dicyano-2-hydroxyprop-2-en-1-yl)ami-
no]-2-oxoethyl}amino)-2-oxoethyl]carbamate (7a)
Yield: 134 mg (0.39 mmol, 62%); dark-orange solid; mp 135–
143 °C.
1H NMR (DMSO-d6): δ = 8.02 (br s, 1 H), 7.78 (br s, 1 H), 7.00 (br
s, 1 H), 3.80 (d, J = 5.1 Hz, 2 H), 3.72 (d, J = 5.4 Hz, 2 H), 3.57 (d,
J = 5.7 Hz, 2 H), 1.38 (s, 9 H).
13C NMR (DMSO-d6): δ = 186.8, 169.6, 168.5, 155.8, 121.7, 120.3,
78.1, 59.8, 43.9, 43.3, 41.9, 28.2.
HRMS (ESI): m/z [M + Na]+ calcd for C14H19N5NaO5: 360.1278;
found: 360.1268.
13C NMR (DMSO-d6): δ = 186.9, 171.4, 155.9, 138.3, 137.0, 129.2,
128.3, 128.0, 127.6, 127.4, 126.2, 65.2, 56.2, 46.7, 43.9, 37.5.
HRMS (ESI): m/z [M + Na]+calcd for C22H20N4NaO4: 427.1377;
found: 427.1371.
Acknowledgment
We thank the University of Florida, The Kenan Foundation, and
King Abdulaziz University, Jeddah, Saudi Arabia, for financial sup-
port. We also thank to Dr. C. D. Hall, Mrs. G. Vakulenko, and Mr.
Z. Wang for reading the manuscript.
Benzyl {(1S)-1-Benzyl-2-[(2-{[(2Z)-3-cyano-2-hydroxy-4-oxo-4-
phenylbut-2-en-1-yl]amino}-2-oxoethyl)amino]-2-oxoeth-
yl}carbamate (7b)
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
Yield: 170 mg, (0.31 mmol, 64%); orange solid; mp 115–117 °C.
1H NMR (DMSO-d6): δ = 8.38 (br s, 1 H), 8.13 (br s, 1 H), 7.77 (d,
J = 7.2 Hz, 2 H), 7.62–7.45 (m, 3 H), 7.39–7.02 (m, 12 H), 4.94 (s,
2 H), 4.42–4.21 (m, 3 H), 3.87–3.67 (m, 2 H), 3.15–2.98 (m, 1 H),
2.83–2.65 (m, 1 H).
References
(1) Laufer, S. A.; Zimmermann, W.; Ruff, K. J. J. Med. Chem.
2004, 47, 6311.
13C NMR (DMSO-d6): δ = 194.6, 185.9, 171.9, 169.0, 155.9, 138.2,
137.0, 135.4, 132.0, 129.2, 128.4, 128.3, 128.1, 127.6, 127.4, 126.3,
126.2, 119.1, 86.9, 65.2, 56.2, 46.8, 41.9, 37.5.
HRMS (ESI): m/z [M + Na]+ calcd for C30H28N4NaO6: 563.1901;
found: 563.1902.
(2) (a) Goasdoue, N.; Gaudemar, M. J. Organomet. Chem.
1974, 71, 325. (b) Kobler, H.; Schuster, K.; Simchen, G.
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Elmoghayar, M. R. H.; Elgemeie, G. E. H. Synthesis 1984, 1.
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Chem. 2003, 68, 4932.
2-Amino-4-oxo-4,5-dihydropyrrole-3-carbonitriles 8a–c;
General Procedure
10% aq HCl (1 mL) was added to a solution of 3b, 3d or 5b (1
equiv) in EtOAc (5 mL). The mixture was stirred vigorously for 15
min to 1 h at 25 °C and then the organic layer was separated and
concentrated under vacuum.
(7) (a) Ji, Y.; Trenkle, W. C.; Vowles, J. V. Org. Lett. 2006, 8,
1161. (b) Liu, H. D.; Li, L.; Sheng, H. T.; Zhu, X. H.; Xu,
Fan.; Shen, Qi. Chin. Sci. Bull. 2011, 56, 1357.
(8) (a) Benoiton, N. L. Chemistry of Peptide Synthesis; Taylor
& Francis: Boca Raton, 2005. (b) Eade, C. R.; Wood, M. P.;
Cole, A. M. Curr. HIV Res. 2012, 10, 61. (c) Majmudar, J.
D.; Gibbs, R. A. ChemBioChem 2011, 12, 2723.
(9) Chen, X.; Muthoosamy, K.; Pfisterer, A.; Neumann, B.;
Weil, T. Bioconjugate Chem. 2012, 23, 500.
Benzyl (2S)-5-Amino-2-benzyl-4-cyano-3-oxo-2,3-dihydro-1H-
pyrrole-1-carboxylate (8a)
Yield: 217 mg (0.62 mmol, 87%); white solid; mp 171–173 °C.
1H NMR (DMSO-d6): δ = 9.21 (br s, 1 H), 8.51 (s, 1 H), 7.56–7.39
(m, 5 H), 7.16 (m, 3 H), 6.78 (s, 2 H), 5.44 (d, J = 12.0 Hz, 1 H),
5.32 (d, J = 11.4 Hz, 1 H), 4.45 (d, J = 3.0 Hz, 1 H).
13C NMR (DMSO-d6): δ = 188.6, 166.2, 150.9, 134.9, 134.2, 129.2,
129.1, 128.7, 128.6, 128.0, 126.8, 113.5, 72.0, 68.5, 64.5, 34.9.
(10) (a) Rijkers, D. T. S.; De Prada López, F.; Liskamp, R. M. J.;
Diederich, F. Tetrahedron Lett. 2011, 52, 6963.
HRMS (ESI): m/z [M + Na]+ calcd for C20H17N3NaO3: 370.1162;
found: 370.1173.
(b) Bol’shakov, O.; Lebedyeva, I.; Katritzky, A. R.
Synthesis 2012, 44, 2926. (c) Pawar, S. A.; Jabgunde, A. M.;
Govender, P.; Maguire, G. E. M.; Kruger, H. G.; Parboosing,
R.; Soliman, M. E. S.; Sayed, Y.; Dhavale, D. D. Eur. J.
Med. Chem. 2012, 53, 13. (d) Hu, X.; Gao, C.; Tan, C.;
Zhang, C.; Zhang, H.; Li, S.; Liu, H.; Jiang, Y. Protein Pept.
Lett. 2011, 18, 1258. (e) Geng, Q.; Sun, X.; Gong, T.; Zhang,
Zh. Bioconjugate Chem. 2012, 23, 1200.
Benzyl 5-Amino-4-cyano-3-oxo-2,3-dihydro-1H-pyrrole-1-car-
boxylate (8b)
Yield: 182 mg (0.76 mmol, 73%); white solid; mp 157–159 °C.
1H NMR (DMSO-d6): δ = 9.47 (br s, 1 H), 8.65 (br s, 1 H), 7.45–
7.33 (m, 5 H), 5.27 (s, 2 H), 4.11 (s, 2 H).
13C NMR (DMSO-d6): δ = 186.7, 166.5, 150.8, 135.0, 128.4, 128.2,
(11) (a) Fowler, S. A.; Blackwell, H. E. Org. Biomol. Chem.
2009, 7, 1508. (b) Levine, P. M.; Imberg, K.; Garabedian,
M. J.; Kirshenbaum, K. J. Am. Chem. Soc. 2012, 134, 6912.
127.7, 113.8, 72.0, 67.9, 53.8.
HRMS (ESI): m/z [M + Na]+calcd for C13H11N3NaO3: 280.0693;
found: 280.0697.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1256–1260

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© Georg Thieme Verlag Stuttgart · New York