Facile entry to 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-ones from amines and amino acids

Article abstract of DOI:10.1002/ejoc.200800036

A practical and high-yielding regioselective synthesis of several enantiopure 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]-pyrazin-6-ones is described starting from primary amines and α-amino acid derivatives in a three-step reaction sequence by employing a constrained intramolecular "click" reaction as the key step. The method obviates chromatographic purification of products. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800036

FULL PAPER
DOI: 10.1002/ejoc.200800036
Facile Entry to 4,5,6,7-Tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-ones from
Amines and Amino Acids
V. Sai Sudhir,[a] R. B. Nasir Baig,[a] and Srinivasan Chandrasekaran*[a][‡]
Dedicated to Professor E. J. Corey on the occasion of his 80th birthday
Keywords: Triazoles / Alkynes / Cycloaddition / Nitrogen heterocycles / Amino acids
A practical and high-yielding regioselective synthesis of
several enantiopure 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]-
pyrazin-6-ones is described starting from primary amines
and α-amino acid derivatives in a three-step reaction se-
quence by employing a constrained intramolecular “click”
reaction as the key step. The method obviates chromato-
graphic purification of products.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
the emergence of combinatorial chemistry and high-speed
parallel synthesis, the development of synthetic procedures
that can be used to generate a library of compounds, espe-
cially the synthesis of target heterocycles in an enantiomer-
ically pure form, is challenging. Ring-constrained intra-
molecular Huisgen cycloaddition has been used by many
research groups to synthesize several bicyclic, as well as
polycyclic, triazole-fused nitrogen-containing heterocycles,
especially triazole-fused piperazine, pyrazine, and pyraz-
inone[7] derivatives and also in the synthesis of triazole-
fused oxygen-rich heterocycles.[8]
Literature reports on 4,5,6,7-tetrahydro[1,2,3]triazolo-
[1,5-a]pyrazin-6-ones are scarce[7a–7e] and these scaffolds re-
main relatively under-explored. Rohr et al. studied the her-
bicidal activity of a few triazole-fused pyrazinones.[7d] Re-
cently, Pokorski et al. synthesized a 1,5-triazole-substituted
amino acid (Tzl) by hydrolysis of triazole-fused tetra-
hydropyrazinone derived from bromoacetamide of propar-
gylamine.[7e] Their focus was to study its effects upon the
secondary structure of short peptoids. The significant bio-
logical profiles of 1,2,3-triazoles coupled with our interest
in the development of short and versatile routes to a variety
of novel heterocyclic structures, as well as the paucity of the
literature for the synthesis of 4,5,6,7-tetrahydro[1,2,3]-
triazolo[1,5-a]pyrazin-6-ones, stimulated us to develop a
synthetic protocol that would generate a library of enantio-
pure, triazole-fused bicyclic compounds from easily avail-
able starting materials. Herein, we report a simple synthesis
method involving a three-step protocol starting from pri-
mary amines, that is, sequential alkylation, acylation and
one-pot substitution/cycloaddition (Scheme 1) for the prep-
aration of triazole-fused tetrahydropyrazinones.
Introduction
Huisgen 1,3-dipolar cycloaddition of an azide and an al-
kyne to afford the 1,2,3-triazole ring system has been widely
used in organic synthesis.[1] Several compounds containing
the 1,2,3-triazole structural motif possess a broad spectrum
of biological properties like anti-HIV,[2a] antibacterial,[2b]
antiallergic,[2c] herbicidal, fungicidal,[2d] and antihistamine
activity.[3] With careful choice of appropriate building
blocks, “click chemistry” can provide derivatives or mimics
of traditional drugs, pharmacophores, and natural prod-
ucts.[4] Its ability lies in the generation of novel structures
that might not necessarily resemble known pharmaco-
phores. The CuI-catalyzed formation of 1,2,3-triazoles from
azides and terminal acetylenes is a particularly powerful
linking reaction because of its high degree of dependability
and complete specificity, which generates regioselectively
the 1,4-substituted ring system; this system is extensively
used in an intermolecular[5] fashion for the synthesis of
various conjugates[6a–6h] and in an intramolecular fashion
for the synthesis of triazole-containing small peptides.[6i–6k]
Ideally, an intramolecular reaction should provide a power-
ful method for the synthesis of structurally diversified ana-
logs difficult to obtain by an intermolecular version, par-
ticularly to generate fused polycyclic triazole derivatives
that should be of interest to medicinal chemists. Because of
[a] Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560012, India
Fax: +91-80-2360-2423
E-mail: scn@orgchem.iisc.ernet.in
[‡] Honorary Professor, Jawaharlal Nehru Centre for Advanced
Scientific Research, Bangalore, India
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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V. Sai Sudhir, R. B. Nasir Baig, S. Chandrasekaran
FULL PAPER
Scheme 1. Synthesis of bicyclic triazole 3a from benzylamine.
Table 1. Ring-constrained cycloaddition of chloroacetylated al-
Results and Discussion
kynes 2b–e derived from alkylamines.[a]
Our initial efforts were devoted to the synthesis of com-
pound 3a from benzylamine. N-benzyl propargylamine (1a)
was synthesized from benzylamine and propargyl bromide
in DMF by employing LiOH·H2O as the base. This was
then treated with chloroacetyl chloride in the presence of
triethylamine to give chloroacetylated alkyne 2a in excellent
yield (Scheme 1). The reaction of 2a with an excess amount
of sodium azide (5 equiv.) in DMF at 100 °C for 1 h re-
sulted in the formation of azide 2aЈ. Without isolating azide
2aЈ, the reaction mixture was further heated for 4 h, where
the latter underwent constrained intramolecular cycload-
dition with the alkyne moiety to furnish regioselectively the
desired bicyclic compound 3a in 97% yield as the only
product. This result encouraged us to synthesize other chlo-
roacetylated alkynes derived from primary amines by em-
ploying the same set of reaction conditions as those de-
scribed for the synthesis of 2a. Accordingly, compounds 2b–
e were synthesized from 1-phenylethylamine, 2-phenylethyl-
amine, (S)-α-naphthylethylamine, and 2-furfurylamine,
respectively. These compounds existed as rotameric mix-
1
tures,[9] as exemplified by their H and 13C NMR spectra.
Compounds 2b–e were then treated with sodium azide un-
der identical conditions as those described earlier, and the
results are summarized in Table 1. The reactions proceeded
smoothly (3–6 h) to afford 1,2,3-triazole-fused 4,5,6,7-tetra-
[a] Conditions: NaN3 (5 equiv.), DMF, 100 °C.
Characteristic resonances were observed around δ = 127
hydropyrazin-6-ones 3b–e as the only product in excellent and 129 ppm in the 13C NMR spectra for compounds 3a–
yields.
e, which correspond to the olefinic carbon atoms of the tri-
Scheme 2. General scheme for the synthesis of enantiopure fused triazoles from -amino acids.
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Facile Entry to 4,5,6,7-Tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-ones
azole ring. We felt that this methodology could then be ex- americ mixtures, and the rotamer ratio varied with each
tended to synthesize enantiopure 4,5,6,7-tetrahydro[1,2,3]- substrate. Enantiopure chloroacetylated alkynes 5a–g were
triazolo[1,5-a]pyrazin-6-ones from chloroacetylated alkynes then heated in the presence with an excess amount of so-
derived from α-amino acids.
dium azide (5 equiv.) in DMF at 100 °C. At this tempera-
In this context, we synthesized chloroacetylated alkynes ture, the azides formed in situ underwent constrained intra-
5a–g from the naturally abundant -amino acids alanine, molecular cycloaddition in a facile manner (3–6 h) to fur-
phenylalanine, valine, methionine, leucine, phenylglycine nish optically pure triazole-fused bicyclic compounds 6a–g
and tryptophan, respectively, according to the general as the sole products in excellent yield (92–97%) (Table 2).
scheme (Scheme 2). LiOH·H2O mediated N-alkylation of The methodology was then extended to suitably protected
amino acid esters with propargyl bromide in DMF was per- -lysine-derived chloroacetylated alkynes 7a and 7b synthe-
formed by using a literature procedure[10] to furnish N-pro- sized from H-Lys(Z)-OMe·HCl and Z-Lys-OEt, respec-
pargylated amino acids 4a–g in good yield (70–80%). These tively. They underwent facile cycloaddition to furnish 8a
N-propargyl amino acid esters were then treated with chlo- and 8b, respectively, in excellent yield (Table 3). These two
roacetyl chloride (1.2 equiv.) and triethylamine (2 equiv.) at compounds can be viewed as novel, protected amino acids
0 °C in CH2Cl2 to afford compounds 5a–g in excellent yield incorporating a heterocyclic backbone. In general, cycload-
(80–90%). All chloroacetylated alkynes 5a–g existed as rot- dition of chloroacetylated alkynes containing a bulkier side
chain (2d and 5g) was faster than the less bulky substrates.
Table 2. Intramolecular cycloaddition of chloroacetylated alkynes
5a–g derived from amino acids.[a]
Table 3. Novel protected amino acids derived from -lysine.[a]
[a] Conditions: NaN3 (5 equiv.), DMF, 100 °C.
This may be attributed to the spatial proximity of the
azide and alkyne substituents enforced by the bulky side
chain. After successfully synthesizing amino acid derived
fused triazoles 6a–g, 8a, and 8b, we decided to extend the
scope of this methodology by varying the alkyl, as well as
the acyl components, which may furnish other triazole-
fused heterocycles. Accordingly, compound 1a was treated
with chloromethane sulfonyl chloride in the presence of tri-
ethylamine to furnish chlorosulfonamide derivative 7c in
moderate yield (60%). Compound 7c was then treated with
an excess amount of sodium azide in DMF at 100 °C.
Because the cycloaddition was sluggish under these con-
ditions, the temperature was increased to 120 °C and the
cycloaddition took place to furnish 8c in moderate yield
(35%) in 9 h. It is worth noting that 8c has a substructure
hitherto unknown in the literature. Similarly, alkylating -
tryptophan methyl ester with 1-bromo-2-butyne followed
by chloroacetylation in CH2Cl2 furnished compound 7d in
good yield (70% over 2 steps). When 7d was treated with
NaN3 (DMF, 100 °C, 9 h) compound 8d could be isolated
in moderate yield (50%) (Table 4).
[a] Conditions: NaN3 (5 equiv.), DMF, 100 °C.
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V. Sai Sudhir, R. B. Nasir Baig, S. Chandrasekaran
FULL PAPER
Table 4. Cycloaddition of a few other substrates.[a]
N-Benzyl-N-(2-propynyl)-2-chloroacetamide (2a): Rf = 0.5 (hexane/
EtOAc, 7:3). Yield: 229 mg (94%). Pale-yellow oil. IR (neat): ν =
˜
3292, 2120, 1661, 1448, 1212, 956, 795, 699 cm–1. 1H NMR
(300 MHz, CDCl3, mixture of rotamers): δ = 7.38–7.24 (m, 5 H),
4.73, 4.71 (2 s, 2 H), 4.25–4.0 (m, 4 H), 2.37, 2.26 (2 t, J = 2.4 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3, major rotamer): δ = 166.3,
135.7, 128.8, 128, 126.7, 77.4, 73.3, 50.3, 41.1, 36.3 ppm. HRMS:
calcd. for C12H12ClNO [M + Na]+ 244.0505; found 244.0501.
N-(1-Phenylethyl)-N-(2-propynyl)-2-chloroacetamide (2b): Rf = 0.40
(hexane/EtOAc, 7:3). Yield: 232 mg (90%). Pale-yellow oil. IR
1
(neat): ν = 3293, 2980, 2119, 1658, 1448, 1413, 1173, 699 cm–1. H
˜
NMR (300 MHz, CDCl3, mixture of rotamers): δ = 7.36–7.27 (m,
5 H), 6.0, 5.24 (2 br. s, 1 H), 4.36–4.21 (m, 2 H), 3.93 (d, J =
18.9 Hz, 1 H), 3.69–3.49 (m, 1 H), 2.28–2.15 (m, 1 H), 1.89–1.42
(m, 3 H) ppm. 13C NMR (100 MHz, CDCl3, major rotamer): δ =
166.7, 139.2, 128.6, 127.8, 127.3, 79.4, 72.8, 52.1, 41.7, 32.4,
16.1 ppm. HRMS: calcd. for C13H14ClNO [M + Na]+ 258.0662;
found 258.0662.
[a] Conditions: NaN3 (5 equiv.), DMF, 100 °C.
N-Phenylethyl-N-(2-propynyl)-2-chloroacetamide (2c): Rf = 0.40
(hexanes/EtOAc, 7:3). Yield: 219 mg (85%). Pale-yellow oil. IR
1
(neat): ν = 3292, 2944, 2120, 1659, 1454, 1426, 1137, 701 cm–1. H
˜
Conclusions
NMR (300 MHz, CDCl3, mixture of rotamers): δ = 7.36–7.12 (m,
5 H), 4.26, 3.93 (2 d, J = 2.1 Hz, 2 H), 4.14 (s, 1 H), 3.73–3.65
(m, 3 H), 2.98–2.89 (m, 2 H), 2.35–2.30 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3, major rotamer): δ = 166.2, 137.7, 128.9, 128.7,
126.9, 78.2, 72.6, 49.3, 40.5, 34.7, 33.6 ppm. HRMS: calcd. for
C13H14ClNO [M + Na]+258.0662; found 258.0659.
We disclosed an access to achiral, as well as enantiopure,
1,2,3-triazole-fused 4,5,6,7-tetrahydropyrazin-6-ones in ex-
cellent yields from several primary amines and amino acids
in a three-step protocol (alkylation, acylation, one-pot sub-
stitution/cycloaddition) involving constrained intramolecu-
lar cycloaddition as the key step. The methodology in gene-
ral obviates chromatographic purification of products.
N-[(1S)-1-(1-Naphthyl)ethyl]-N-(2-propynyl)-2-chloroacetamide (2d):
Rf = 0.40 (hexanes/EtOAc, 6:4). Yield: 265 mg (86%). Pale-yellow
solid. M.p. 101 °C. IR (neat): ν = 3292, 2979, 2119, 1654, 1446,
˜
1414, 1177, 805, 782 cm–1. 1H NMR (300 MHz, CDCl3, mixture
of rotamers): δ = 7.90–7.83 (m, 3 H), 7.62–7.46 (m, 4 H), 6.58 (q,
J = 6.3 Hz, 1 H), 4.29 (d, J = 12.6 Hz, 1 H), 4.23 (d, J = 12.9 Hz,
Experimental Section
Physical Properties and Spectral Measurements: All glassware was
oven dried before starting a reaction. Propargyl bromide was pur-
chased from Sigma–Aldrich and used as such. Solvents like DMF,
CH2Cl2, and MeOH were purified as mentioned in “Purification
of Laboratory Chemicals” by Perrin & Armarego, Pergamon Press,
Third Edition, 1988. Analytical TLC was performed on commer-
cial plates coated with silica gel GF254 (0.25 mm). Silica gel (230–
400 mesh) was used for column chromatography. Melting points
are uncorrected. 1H and 13C NMR spectra were recorded with
300 MHz (300 MHz, 1H and 75 MHz, 13C) or 400 MHz (400 MHz,
1H and 100 MHz, 13C) spectrometers. Chemical shifts are reported
in parts per million downfield from the internal reference tetra-
1 H), 3.71 (dd, J1 = 19.5 Hz, J2 = 2.1 Hz, 1 H), 3.56 (dd, J1
=
19.2 Hz, J2 = 2.1 Hz, 1 H), 2.11 (t, J = 2.4 Hz, 1 H), 1.75 (d, J =
6.9 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, major rotamer):
δ = 166.2, 134.5, 133.8, 131.9, 129.3, 128.6, 126.9, 126.1, 125.2,
124.8, 123.6, 79.4, 72.5, 49.8, 41.9, 31.9, 16.6 ppm. [α]2D3 = –88.3 (c
= 1.0, CHCl3). HRMS: calcd. for C17H16ClNO [M + Na]+
308.0818; found 308.0832.
N-(2-Furylmethyl)-N-(2-propynyl)-2-chloroacetamide (2e): Rf = 0.40
(hexanes/EtOAc, 7:3). Yield: 196 mg (84%). Pale-yellow oil. IR
1
(neat): ν = 3292, 2121, 1662, 1451, 1353, 1198, 1012, 748 cm–1. H
˜
NMR (300 MHz, CDCl3, mixture of rotamers): δ = 7.4 (s, 1 H),
6.33 (s, 2 H), 4.67 (s, 2 H), 4.28–4.12 (m, 4 H), 2.34, 2.27 (2 br. s,
1 H) ppm. 13C NMR (75 MHz, CDCl3, major rotamer): δ = 166.0,
148.6, 143.0, 110.4, 109.2, 77.8, 72.6, 43.4, 41.1, 34.5 ppm. HRMS:
calcd. for C10H10ClNO2 [M + Na]+ 234.0298; found 234.0294.
1
methylsilane for H and CDCl3 for 13C NMR. The following ab-
breviations explain the multiplicity: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br. s = broad singlet, and dd
= doublet of doublets. IR spectra were recorded with an FTIR
spectrometer. High-resolution mass spectra (HRMS) were recorded
with a Micromass Q-TOF mass spectrometer. All propargylamines
were synthesized according to a literature procedure.[10]
Methyl (2S)-2-[(2-Chloroacetyl)(2-propynyl)amino]propanoate (5a):
Rf = 0.30 (hexanes/EtOAc, 7:3). Yield: 204 mg (85%). Pale-yellow
oil. IR (neat): ν = 3287, 2953, 2120, 1742, 1666, 1454, 1222, 1197,
˜
1
801, 676 cm–1. H NMR (300 MHz, CDCl3, mixture of rotamers):
General Procedure for the Synthesis of Chloroacetylated Alkynes:
To a solution of propargylamine (1 mmol) in CH2Cl2 (10 mL) at
0 °C was added triethylamine (2 mmol) followed by chloroacetyl
chloride (1.2 mmol) under an atmosphere of nitrogen. After 0.5 h,
the reaction mixture was washed with water (2ϫ10 mL) followed
by brine (10 mL) and dried with anhydrous Na2SO4. The filtrate
was concentrated, and the crude product was purified by flash
chromatography on silica gel (230–400 mesh) by using ethyl acetate
and petroleum ether to obtain the corresponding chloroacetylated
alkynes.
δ = 5.04 (q, J = 7.2 Hz, 1 H), 4.34–4.08 (m, 4 H), 3.76, 3.72 (2 s,
3 H), 2.43 (t, J = 2.7 Hz, 1 H), 1.65, 1.54 (2 d, J = 7.5 Hz, 3 H)
ppm. 13C NMR (75 MHz, CDCl3, major rotamer): δ = 171.4,
166.4, 78.3, 73.4, 53.4, 52.2, 41.3, 35.2, 14.6 ppm. [α]2D3 = –57.1 (c
= 1.0, CHCl3). HRMS: calcd. for C9H12ClNO3 [M + Na]+
240.0403; found 240.0406.
Methyl (2S)-2-[(2-Chloroacetyl)(2-propynyl)amino]-3phenylpropano-
ate: (5b): Rf = 0.40 (hexanes/EtOAc, 7:3). Yield: 272 mg (86%).
Pale-yellow oil. IR (neat): ν = 3286, 2952, 2122, 1742, 1666, 1450,
˜
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Facile Entry to 4,5,6,7-Tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-ones
1222, 700 cm–1. 1H NMR (300 MHz, CDCl3, mixture of rotamers):
δ = 7.29–7.21 (m, 5 H), 4.90 (dd, J1 = 6.0 Hz, J2 = 9.6 Hz, 1 H),
4.23–4.05 (m, 3 H), 3.85–3.80 (m, 1 H), 3.74–3.72 (m, 3 H), 3.4
Methyl
propynyl)amino]hexanoate (7a): Rf = 0.40 (hexanes/EtOAc, 6:4).
Yield: 345 mg (80%). Colorless oil. IR (neat): ν = 3292, 2951, 2120,
(2S)-6-[(Benzyloxy)carbonyl]amino-2-[(2-chloroacetyl)(2-
˜
(dd, J1 = 5.7 Hz, J2 = 14.4 Hz, 1 H), 3.19 (dd, J1 = 9.6 Hz, J2 = 1714, 1667, 1531, 1454, 1248, 1018, 698 cm–1. 1H NMR (300 MHz,
14.4 Hz, 1 H), 2.3 (t, J = 2.1 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3, mixture of rotamers): δ = 7.36–7.32 (m, 5 H), 5.14–5.08
CDCl3, major rotamer): δ = 170.3, 166.5, 136.7, 129.0, 128.5, 126.8, (m, 3 H), 4.87 (br. s, 1 H), 4.41–4.10 (m, 4 H), 3.74–3.68 (m, 3 H),
77.4, 73.7, 60.1, 52.3, 41.1, 36.9, 34.7 ppm. [α]2D3 = –111.3 (c = 1.0,
3.21–3.15 (m, 2 H), 2.38 (t, J = 2.4 Hz, 1 H), 2.09–1.77 (m, 2 H),
CHCl3) HRMS: calcd. for C15H16ClNO3 [M + Na]+ 316.0716; 1.58–1.34 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3, major rot-
found 316.0708.
amer): δ = 171.1, 167.4, 156.3, 136.6, 128.5, 128.4, 128.0, 78.3, 73.7,
66.5, 57.0, 52.3, 41.3, 40.6, 34.8, 29.3, 28.5, 23.2 ppm. [α]2D2 = –27.3
(c = 1.0, CHCl3). HRMS: calcd. for C20H25ClN2O5 [M + Na]+
431.1350; found 431.1352.
Methyl (2S)-2-[(2-Chloroacetyl)(2-propynyl)amino]-3-methylbutano-
ate: (5c): Rf = 0.70 (hexanes/EtOAc, 7:3). Yield: 241 mg (90%).
Pale-yellow oil. IR (neat): ν = 3288, 2967, 2122, 1740, 1670, 1445,
˜
1212, 1170, 1008, 668 cm–1. H NMR (300 MHz, CDCl3, mixture
1
Ethyl (2S)-2-[(Benzyloxy)carbonyl]amino-6-[(2-chloroacetyl)(2-pro-
pynyl)amino]hexanoate (7b): Rf = 0.30 (hexanes/EtOAc, 6:4). Yield:
of rotamers): δ = 4.91 (d, J = 10.2 Hz, 1 H), 4.44–3.98 (m, 4 H),
3.75, 3.72 (2 s, 3 H), 2.49–2.19 (m, 2 H), 1.07–0.95 (m, 6 H) ppm.
13C NMR (100 MHz, CDCl3, major rotamer): δ = 170.9, 167.4,
78.5, 73.4, 61.6, 51.9, 41.4, 33.9, 28.0, 19.4, 18.9 ppm. [α]2D2 = –141.4
(c = 1.0, CHCl3). HRMS: calcd. for C11H16ClNO3 [M + Na]+
268.0716; found 268.0713.
356 mg (80%). Colorless oil. IR (neat): ν = 3297, 2943, 2120, 1719,
˜
1659, 1533, 1454, 1251, 1026, 698 cm–1. 1H NMR (300 MHz,
CDCl3, mixture of rotamers): δ = 7.36 (br. s, 5 H), 5.38 (d, J =
7.8 Hz, 1 H), 5.11 (s, 2 H), 4.38–4.08 (m, 7 H), 3.42 (br. s, 2 H),
2.34, 2.23 (2 br. s, 1 H), 1.86–1.58 (m, 4 H), 1.41–1.34 (m, 2 H),
1.27 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3, major
rotamer): δ = 172.1, 166.4, 155.8, 136.3, 128.5, 128.1 (2 C), 78.0,
66.9, 61.4, 53.7, 47.4, 41.2, 37.6, 34.7, 32.5, 27.9, 22.2, 14.1 ppm.
[α]2D2 = +11.3 (c = 2.0, CHCl3). HRMS: calcd. for C21H27ClN2O5
[M + Na]+ 445.1506; found 445.1505.
Methyl
(2S)-2-[(2-Chloroacetyl)(2-propynyl)amino]-4-(methylsul-
fanyl)butanoate (5d): Rf = 0.40 (hexanes/EtOAc, 7:3). Yield: 246 mg
(82%). Pale-yellow oil. IR (neat): ν = 3276, 2953, 2120, 1739, 1666,
˜
1436, 1220, 1198, 798 cm–1. H NMR (300 MHz, CDCl3, mixture
1
of rotamers): δ = 5.08, 4.79 (2 dd, J1 = 9.3 Hz, J2 = 4.8 Hz, 1 H),
4.40–4.07 (m, 4 H), 3.79–3.73 (m, 3 H), 2.76–2.12 (m, 8 H) ppm.
13C NMR (100 MHz, CDCl3, major rotamer): δ = 170.7, 167.1,
78.1, 73.9, 57.4, 52.4, 41.3, 36.3, 30.7, 28.5, 15.3 ppm. [α]2D3 = 63.4
(c = 1.0, CHCl3). HRMS: calcd. for C11H16ClNO3S [M + Na]+
300.0437; found 300.0431.
N-Benzyl-N-(2-propynyl)chloromethanesulfonamide (7c): Rf = 0.50
(hexanes/EtOAc, 6:4). Yield: 168 mg (60%). Colorless oil. IR
(neat): ν = 3285, 3017, 2121, 1495, 1356, 1244, 1161, 1064,
˜
899 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.38–7.34 (m, 5 H),
4.67 (s, 2 H), 4.66 (s, 2 H), 3.94 (d, J = 2.7 Hz, 2 H), 2.45 (t, J =
2.7 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 134.7, 128.8,
128.5, 128.3, 76.6, 74.4, 55.7, 51.6, 35.7 ppm. HRMS: calcd. for
C11H12ClNO2S [M + Na]+ 280.0175; found 280.0164.
Methyl (2S)-2-[(2-Chloroacetyl)(2-propynyl)amino]-4-methylpenta-
noate: (5e): Rf = 0.40 (hexanes/EtOAc, 7:3). Yield: 234 mg (83%).
Pale-yellow oil. IR (neat): ν = 3372, 2958, 2872, 2120, 1741, 1668,
˜
Methyl (2S)-2-[2-Butynyl(2-chloroacetyl)amino]-3-(1H-3-indolyl)-
propanoate (7d): Rf = 0.40 (hexanes/EtOAc, 6:4). Yield: 295 mg
1446, 1178, 672 cm–1. 1H NMR (300 MHz, CDCl3, mixture of rota-
mers): δ = 5.3 (dd, J1 = 9.9 Hz, J2 = 4.8 Hz, 1 H), 4.38–4.07 (m, 4
H), 3.71 (s, 3 H), 2.40 (t, J = 2.7 Hz, 1 H), 1.86–1.65 (m, 3 H), 1.01–
0.93 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3, major rotamer): δ
= 171.8, 167.2, 78.5, 73.4, 55.3, 52.2, 41.4, 37.8, 34.4, 24.8, 22.8,
21.5 ppm. [α]2D3 = –40.6 (c = 2.0, CHCl3). HRMS: calcd. for
C12H18ClNO3 [M + Na]+ 282.0873; found 282.0865.
(80%). Light-brown oil. IR (neat): ν = 3404, 2231, 1735, 1652,
˜
1457, 1433, 1346, 1215, 1170, 744 cm–1. 1H NMR (300 MHz,
CDCl3, mixture of rotamers): δ = 8.19 (s, 1 H), 7.63 (d, J = 7.5 Hz,
1 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.20–7.05 (m, 3 H), 5.14 (dd, J1 =
9.3 Hz, J2 = 5.7 Hz, 1 H), 4.24–3.59 (m, 7 H), 3.52 (dd, J1
=
15.3 Hz, J2 = 6 Hz, 1 H), 3.38 (dd, J1 = 15.3 Hz, J2 = 9.6 Hz, 1
H), 1.80, 1.72 (2 br. s, 1 H), 1.57 (t, J = 2.4 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3, major rotamer): δ = 170.9, 166.8, 136.2,
127.4, 122.8, 122, 119.5, 118.5, 111.1 (2 C), 81.6, 73.0, 58.6, 52.2,
41.6, 37.0, 24.7, 3.23 ppm. [α]2D3 = –56.7 (c = 1.0, CHCl3). HRMS:
calcd. for C18H19ClN2O3 [M + Na]+ 369.0982; found 369.0992.
Methyl (2S)-2-[(2-Chloroacetyl)(2-propynyl)amino]-2-phenylethano-
ate: (5f): Rf = 0.40 (hexanes/EtOAc, 7:3). Yield: 241 mg (80%).
Pale-yellow oil. IR (neat): ν = 3289, 2954, 2122, 1747, 1668, 1446,
˜
1173, 1003, 698 cm–1. 1H NMR (300 MHz, CDCl3, mixture of rota-
mers): δ = 7.40–7.30 (m, 5 H), 6.28 (s, 1 H), 4.36 (s, 2 H), 4.14–
3.97 (m, 2 H), 3.78 (s, 3 H), 2.15 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3, major rotamer): δ = 170.3, 167.5, 132.9, 129.3,
129.1 129.0, 78.3, 72.6, 60.9, 52.5, 41.6, 34.7 ppm. [α]2D3 = 140.3 (c
= 1.0, CHCl3). HRMS: calcd. for C15H18ClNO3 [M + Na]+
302.0560; found 302.0561.
General Procedure for the Synthesis of Triazole-Fused Tetrahydropyr-
azin-6-ones: To a solution of chloroacetylated alkyne (1 mmol) in
DMF (5 mL) was added NaN3 (5 mmol). The mixture was heated
to 100 °C for appropriate time. After the reaction was complete
(monitored by TLC) DMF was evaporated under vacuum, and the
compound was extracted from the reaction mixture with CH2Cl2
(25 mL). The combined organic layer was then dried with anhy-
drous Na2SO4, filtered, and concentrated to obtain the correspond-
ing triazole-fused tetrahydropyrazin-6-ones.
Methyl (2S)-2-[(2-Chloroacetyl)(2-propynyl)amino]-3-(1H-3-indol-
yl)propanoate (5g): Rf = 0.30 (hexanes/EtOAc, 6:4). Yield: 291 mg
(82%). Light-brown oil. IR (neat): ν = 3292, 2952, 2122, 1738,
˜
1731, 1660, 1456, 1342, 1246, 1045, 746 cm–1. 1H NMR (300 MHz,
CDCl3, mixture of rotamers): δ = 8.30, 8.19 (2 br. s, 1 H), 7.62 (d,
J = 7.2 Hz, 1 H), 7.40–7.45 (m, 4 H), 5.06, 4.72 (2 dd, J1 = 9.6 Hz,
5-Benzyl-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-one (3a):
Rf = 0.30 (hexanes/EtOAc, 4:6). Yield: 222 mg (97%). White solid.
J2 = 6 Hz, 1 H), 4.34–3.35 (m, 9 H), 2.20 (t, J = 2.4 Hz, 1 H) ppm. M.p. 147 °C. IR (neat): ν = 2936, 1659, 1489, 1349, 1255, 991,
˜
13C NMR (100 MHz, CDCl3, major rotamer): δ = 170.7, 166.7,
136.2, 127.3, 122.9, 122.1, 119.6, 118.4, 111.2, 110.8, 77.3, 73.5,
59.1, 52.4, 41.4, 36.8, 24.7 ppm. [α]2D3 = –162 (c = 1.0, CHCl3).
HRMS: calcd. for C17H17ClN2O3 [M + Na]+ 355.0825; found
355.0818.
836 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.51 (s, 1 H), 7.37–
7.28 (m, 5 H), 5.11 (s, 2 H), 4.77 (s, 2 H), 4.57 (s, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 161.7, 134.8, 129.1, 129, 128.4,
128.3, 127.2, 50.2, 48.6, 41.4 ppm. HRMS: calcd. for C12H12N4O
[M + H]+ 229.1089; found 229.1085.
Eur. J. Org. Chem. 2008, 2423–2429
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2427

V. Sai Sudhir, R. B. Nasir Baig, S. Chandrasekaran
FULL PAPER
5-(1-Phenylethyl)-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-
one: (3b): Rf = 0.30 (hexanes/EtOAc, 4:6). Yield: 254 mg (96%).
Methyl (2S)-3-Methyl-2-(6-oxo-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-
a]pyrazin-5-yl)butanoate (6c): Rf = 0.50 (hexanes/EtOAc, 4:6).
Colorless viscous oil. IR (neat): ν = 2980, 1656, 1472, 1346, 990,
Yield: 240 mg (95%). Colorless gummy liquid. IR (neat): ν = 2966,
˜
˜
701 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.48 (s, 1 H), 7.37– 1740, 1691, 1555, 1210, 992, 767 cm–1 1H NMR (300 MHz,
.
7.31 (m, 5 H), 6.21 (q, J = 6.9 Hz, 1 H), 5.12 (s, 1 H), 5.11 (s, 1
H), 4.51 (d, J = 16.2 Hz, 1 H), 4.14 (d, J = 16.2 Hz, 1 H), 1.64 (d,
J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.6,
137.9, 129.1, 128.7, 128.1, 127.5, 127.3, 50.8, 48.7, 36.3, 14.9 ppm.
HRMS: calcd. for C13H14N4O [M + Na]+ 265.1065; found
265.1066.
CDCl3): δ = 7.65 (s, 1 H), 5.16 (s, 2 H), 5.03 (d, J = 10.8 Hz, 1 H),
4.97 (d, J = 16.2 Hz, 1 H), 4.66 (d, J = 16.2 Hz, 1 H), 3.75 (s, 3
H), 2.39–2.27 (m, 1 H), 1.07 (d, J = 6.6 Hz, 3 H), 0.91 (d, J =
6.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.6, 162.9,
129.3, 127.7, 61.2, 52.3, 48.9, 38.3, 27.2, 19.5, 18.9 ppm. [α]2D2
=
–17.8 (c = 1.0, CHCl3). HRMS: calcd. for C11H16N4O3 [M + H]+
253.1300; found 253.1301.
5-Phenethyl-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-one
(3c): Rf = 0.40 (hexanes/EtOAc, 4:6). Yield: 252 mg (95%). White
Methyl (2S)-4-(Methylsulfanyl)-2-(6-oxo-4,5,6,7-tetrahydro-
[1,2,3]triazolo[1,5-a]pyrazin-5-yl)butanoate (6d): Rf = 0.30 (hexanes/
solid. M.p. 158 °C. IR (neat): ν = 2925, 1652, 1489, 1347, 1169,
˜
1
991, 836, 750, 701 cm–1. H NMR (300 MHz, CDCl3): δ = 7.52 (s,
EtOAc, 1:1). Yield: 288 mg (94 %). Colorless gummy liquid. IR
(neat): ν = 3474, 2921, 1740, 1665, 1475, 1430, 1199, 991 cm–1. H
1
˜
1 H), 7.33–7.20 (m, 5 H), 5.08 (s, 2 H), 4.43 (s, 2 H), 3.8 (t, J =
7.2 Hz, 2 H), 2.98 (t, J = 7.5 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 161.7, 137.9, 129.0, 128.9, 128.7, 127.2, 126.9, 49.4,
48.7, 43.1, 33.4 ppm. HRMS: calcd. for C13H14N4O [M + Na]+
265.1065; found 265.1059.
NMR (300 MHz, CDCl3): δ = 7.65 (s, 1 H), 5.18–5.14 (m, 3 H),
4.84 (d, J = 15.6 Hz, 1 H), 4.72 (d, J = 15.9 Hz, 1 H), 3.77 (s, 3 H),
2.60–2.40 (m, 3 H), 2.27–2.10 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.0, 162.9, 129.2, 127.4, 56.5, 52.6, 48.7, 40.2, 30.5,
27.3, 15.3 ppm. [α]2D3 = –2 (c = 1.0, CHCl3). HRMS: calcd. for
C11H16N4O3S [M + Na]+ 307.0841; found 307.0836.
5-[(1S)-1-(1-Naphthyl)ethyl]-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]-
pyrazin-6-one (3d): Rf = 0.30 (hexanes/EtOAc, 5:5). Yield: 311 mg
Methyl (2S)-4-Methyl-2-(6-oxo-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-
a]pyrazin-5-yl)pentanoate (6e): Rf = 0.40 (hexanes/EtOAc, 4:6).
(99%). White solid. M.p. 94 °C. IR (neat): ν = 3052, 2980, 1651,
˜
1
144, 1346, 784 cm–1. H NMR (300 MHz, CDCl3): δ = 7.96–7.85
Yield: 253 mg (95%). Colorless gummy liquid. IR (neat): ν = 3475,
˜
(m, 3 H), 7.66–7.46 (m, 4 H), 7.37 (s, 1 H), 6.79 (q, J = 6.9 Hz, 1
H), 5.19 (d, J = 17.7 Hz, 1 H), 5.09 (d, J = 18 Hz, 1 H), 4.39 (d, J
= 16.2 Hz, 1 H), 3.67 (d, J = 16.5 Hz, 1 H), 1.75 (d, J = 6.9 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.1, 133.7, 133,
131.4, 129.4, 129.1, 128.8, 127.4, 127.1, 126.1, 125.2, 124.7, 122.7,
48.5, 48.2, 36.6, 15.3 ppm. [α]2D2 = –121.8 (c = 2.0, CHCl3). HRMS:
calcd. for C17H16N4O [M + Na]+ 315.1220; found 315.1230.
2957, 2875, 1740, 1667, 1471, 1349, 1185, 990 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 7.64 (s, 1 H), 5.42 (dd, J1 = 10.2 Hz, J2 =
5.7 Hz, 1 H), 5.15 (s, 2 H), 4.81 (d, J = 15.6 Hz, 1 H), 4.6 (d, J =
15.6 Hz, 1 H), 3.75 (s, 3 H), 1.94–1.77 (m, 2 H), 1.51–1.40 (m, 1
H), 0.96 (t, J = 6.9 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 171.1, 163, 129.3, 127.5, 54.1, 52.5, 48.8, 38.3, 36.6, 24.9, 23,
21.2 ppm. [α]2D2 = –9.2 (c = 1.0, CHCl3). HRMS: calcd. for
C12H18N4O3 [M + H]+ 267.1457; found 267.1456.
5-(2-Furylmethyl)-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-
one (3e): Rf = 0.40 (hexanes/EtOAc, 5:5). Yield: 229 mg (95%).
Methyl (2S)-2-(6-Oxo-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyr-
azin-5-yl)-2-phenylethanoate (6f): Rf = 0.30 (hexanes/EtOAc, 5:5).
Colorless oil. IR (neat): ν = 3511, 2986, 1665, 1485, 1424, 1347,
˜
1011, 751 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.91 (s, 1 H),
7.59 (s, 1 H), 6.40 (d, J = 3.3 Hz, 1 H), 6.36 (t, J = 2.1 Hz, 1 H),
5.1 (s, 2 H), 4.77 (s, 2 H), 4.72 (s, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 161.4, 148.4, 142.8, 128.9, 127.2, 110.4, 109.8, 48.3,
42.5, 41.7 ppm. HRMS: calcd. for C10H10N4O2 [M + Na]+
241.0701; found 241.0706.
Yield: 284 mg (92%). Pale-yellow gummy liquid. IR (neat): ν =
˜
2926, 1740, 1647, 1441, 1347, 1201, 986, 698 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 7.45 (s, 1 H), 7.46–7.44 (m, 3 H), 7.30–
7.26 (m, 2 H), 6.53 (s, 1 H), 5.18 (s, 2 H), 4.84 (d, J = 15 Hz, 1 H),
4.12 (d, J = 15 Hz, 1 H), 3.82 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.9, 162.9, 131.8, 129.4, 129.3 (2 C), 129.2, 127.6,
59.9, 52.7, 48.7, 38.9 ppm. [α]2D3 = 9.5 (c = 1.0, CHCl3). HRMS:
calcd. for C14H14N4O3 [M + H]+ 309.0964; found 309.0964.
Methyl (2S)-2-(6-Oxo-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyr-
azin-5-yl)propanoate (6a): Rf = 0.30 (hexanes/EtOAc, 4:6). Yield:
216 mg (96%). Colorless gummy liquid. IR (neat): ν = 2953, 1742,
˜
Methyl (2S)-3-(1H-3-Indolyl)-2-(6-oxo-4,5,6,7-tetrahydro[1,2,3]tri-
azolo[1,5-a]pyrazin-5-yl)propanoate (6g): Rf = 0.30 (hexanes/EtOAc,
1
1692, 1666, 1556, 1350, 1201, 991, 735 cm–1. H NMR (300 MHz,
CDCl3): δ = 7.65 (s, 1 H), 5.31 (q, J = 7.5 Hz, 1 H), 5.15 (s, 2 H),
4.79 (d, J = 15.3 Hz, 1 H), 4.71 (d, J = 15.6 Hz, 1 H), 3.76 (s, 3
H), 1.57 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 170.9, 162.5, 129.3, 127.4, 52.6, 52.0, 48.7, 38.6, 14.1 ppm. [α]2D2
= –4 (c = 1.0, CHCl3). HRMS: calcd. for C9H12N4O3 [M + Na]+
225.0988; found 225.0981.
5:5). Yield: 351 mg (97%). Pale-yellow gummy liquid. IR (neat): ν
˜
= 3397, 2950, 1740, 1664, 1432, 1349, 1099, 833, 744 cm–1 1H
.
NMR (300 MHz, CDCl3): δ = 8.56 (s, 1 H), 7.55 (d, J = 7.8 Hz, 1
H), 7.37 (s, 1 H), 7.33–7.06 (m, 4 H), 6.95 (d, J = 2.1 Hz, 1 H),
5.31 (dd, J1 = 11.1 Hz, J2 = 5.1 Hz, 1 H), 5.04 (d, J = 17.7 Hz, 1
H), 4.92 (d, J = 18 Hz, 1 H), 4.52 (d, J = 15.6 Hz, 1 H), 4.43 (d, J
= 15.9 Hz, 1 H), 3.78 (s, 3 H), 3.57 (dd, J1 = 15.9 Hz, J2 = 5.1 Hz,
1 H), 3.42 (dd, J1 = 15.3 Hz, J2 = 10.8 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.4, 162.8, 136.3, 129.1, 127.6, 126.9,
122.5 (2 C), 119.8, 117.9, 111.7, 109.9, 58.1, 52.8, 48.8, 40.5,
24.2 ppm. [α]2D3 = –29.4 (c = 1.0, CHCl3). HRMS: calcd. for
C17H17N5O3 [M + Na]+ 362.1229; found 362.1223.
Methyl (2S)-2-(6-Oxo-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyr-
azin-5-yl)-3-phenylpropanoate (6b): Rf = 0.30 (hexanes/EtOAc, 4:6).
Yield: 286 mg (95%). Colorless gummy liquid. IR (neat): ν = 2953,
˜
1741, 1666, 1474, 1435, 1200, 703 cm–1
CDCl3): δ = 7.51 (s, 1 H), 7.27–7.14 (m, 5 H), 5.28 (dd, J1
10.8 Hz, J2 = 5.7 Hz, 1 H), 5.05 (d, J = 18 Hz, 1 H), 4.91 (d, J =
.
1H NMR (300 MHz,
=
18 Hz, 1 H), 4.59 (d, J = 16 Hz, 1 H), 4.49 (d, J = 16 Hz, 1 H), Methyl (2S)-6-[(Benzyloxy)carbonyl]amino-2-(6-oxo-4,5,6,7-tetra-
3.76 (s, 3 H), 3.49 (dd, J1 = 14.7 Hz, J2 = 5.4 Hz, 1 H), 3.2 (dd, J1
= 14.7 Hz, J2 = 11.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 169.8, 162.5, 135.6, 128.9, 128.7, 128.5, 128.3, 127.2, 58.3, 52.6,
48.5, 40.3, 34.0 ppm. [α]2D3 = –5.8 (c = 1.0, CHCl3). HRMS: calcd.
for C15H16N4O3 [M + H]+ 301.1300; found 301.1302.
hydro[1,2,3]triazolo[1,5-a]pyrazin-5-yl)hexanoate (8a): Rf = 0.40
(hexanes/EtOAc, 4:6). Yield: 420 mg (96%). Colorless gummy li-
quid. IR (neat): ν = 3338, 2938, 2867, 1715, 1666, 1534, 1457, 1251,
˜
743, 699 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.63 (s, 1 H),
7.34–7.32 (m, 5 H), 5.27 (dd, J1 = 10.5 Hz, J2 = 5.1 Hz, 1 H), 5.13
2428
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2423–2429

Facile Entry to 4,5,6,7-Tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-ones
[2]
a) R. Alvarez, S. Velazquez, A. San-Felix, S. Aquaro, E.
De Clercq, C.-F. Perno, A. Karlsson, J. Balzarini, M. J. Camar-
asa, J. Med. Chem. 1994, 37, 4185–4194; b) M. J. Genin, D. A.
Allwine, D. J. Anderson, M. R. Barbachyn, D. E. Emmert,
S. A. Garmon, D. R. Graber, K. C. Grega, J. B. Hester, D. K.
Hutchinson, J. Morris, R. J. Reischer, C. W. Ford, G. E. Zur-
enko, J. C. Hamel, R. D. Schaadt, D. Stapert, B. H. Yagi, J.
Med. Chem. 2000, 43, 953–970; c) D. R. Buckle, C. J. M. Rock-
ell, H. Smith, B. A. Spicer, J. Med. Chem. 1986, 29, 2269–2277;
d) H.Wamhoff, in Comprehensive Heterocyclic Chemistry (Ed.:
A. R. Katritzky, C. W. Rees), Pergamon, Oxford, 1984, vol. 5,
pp. 669–732.
D. R. Buckle, C. J. M. Rockell, H. Smith, B. A. Spicer, J. Med.
Chem. 1986, 29, 2262–2267.
a) H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. Int.
Ed. 2001, 40, 2004–2021; b) G. W. Bemis, M. A. Murcko, J.
Med. Chem. 1996, 39, 2887–2893.
(br. s, 2 H), 5.05 (s, 2 H), 4.84 (br. s, 1 H), 4.75 (d, J = 15.9 Hz, 1
H), 4.59 (d, J = 16.2 Hz, 1 H), 3.74 (s, 3 H), 3.23–3.15 (m, 2 H),
2.21–2.05 (m, 1 H), 1.96–1.25 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.6, 163.2, 156.5, 136.5, 129.4, 128.5, 128.1, 128,
127.5, 66.7, 55.9, 52.6, 48.8, 40.3, 38.6, 29.4, 27.5, 23.0 ppm.
[α]2D2 = 2.8 (c = 1.0, CHCl3). HRMS: calcd. for C20H25N5O5 [M +
Na]+ 438.1753; found 438.1752.
Ethyl (2S)-2-[(Benzyloxy)carbonyl]amino-6-(6-oxo-4,5,6,7-tetra-
hydro[1,2,3]triazolo[1,5-a]pyrazin-5-yl)hexanoate (8b): Rf = 0.40
(hexanes/EtOAc, 4:6). Yield: 425 mg (94%). Colorless gummy li-
quid. IR (neat): ν = 3313, 2939, 1720, 1661, 1532, 1346, 1256, 1213,
˜
[3]
[4]
1026, 737 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.61 (s, 1 H),
7.30 (br. s, 5 H), 5.51 (d, J = 8.1 Hz, 1 H), 5.07 (s, 2 H), 5.04 (s, 2
H), 4.63 (s, 2 H), 4.34 (dd, J1 = 12.6 Hz, J2 = 7.5 Hz, 1 H), 4.19
(q, J = 6.9 Hz, 2 H), 3.55 (t, J = 6.3 Hz, 2 H), 2.04–1.56 (m, 4 H),
1.42–1.39 (m, 2 H), 1.26 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.1, 161.7, 155.9, 136.2, 129.1, 128.4,
128.1, 127.9, 127.2, 66.9, 61.5, 53.5, 48.5, 46.8, 42.1, 32.1, 26.0,
22.2, 14.1 ppm. [α]2D3 = 6.3 (c = 1.0, CHCl3). HRMS: calcd. for
C21H27N5O3 [M + Na]+ 452.1910; found 452.1905.
[5]
a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. Int. Ed. 2002, 41, 2596–2599; b) S. Kamijo, T.
Jin, Z. Huo, Y. Yamamoto, J. Org. Chem. 2004, 69, 2386–2393;
c) T. Jin, S. Kamijo, Y. Yamamoto, Eur. J. Org. Chem. 2004,
3789–3791; d) S. Kamijo, T. Jin, Y. Yamamoto, Tetrahedron
Lett. 2004, 45, 689–691.
5-Benzyl-4,5,6,7-tetrahydro-6λ6-[1,2,3]triazolo[5,1-d][1,2,5]thiadi-
azine-6,6-dione (8c): Rf = 0.40 (hexanes/EtOAc, 5:5). Yield: 100 mg
[6]
a) Q. Wang, T. R. Chan, R. Hilgraf, V. V. Fokin, K. B.
Sharpless, M. G. Finn, J. Am. Chem. Soc. 2003, 125, 3192–
3193; b) A. J. Link, D. A. Tirrell, J. Am. Chem. Soc. 2003, 125,
11164–11165; c) A. E. Speers, B. F. Cravatt, Chem. Biol. 2004,
11, 535–546; d) A. E. Speers, G. C. Adam, B. F. Cravatt, J. Am.
Chem. Soc. 2003, 125, 4686–4687; e) L. V. Lee, M. L. Mitchell,
S.-J. Huang, V. V. Fokin, K. B. Sharpless, C.-H. Wong, J. Am.
Chem. Soc. 2003, 125, 9588–9589; f) J. M. Casas-Solvas, A.
Vargas-Berenguel, L. F. Capitan-Vallvey, S.-G. Francisco, Org.
Lett. 2004, 6, 3687–3690; g) B. H. M. Kuijpers, S. Groothuys,
A. R. Keereweer, P. J. L. M. Quaedflieg, R. H. Blaauw, F. L.
Van Delft, F. P. J. T. Rutjes, Org. Lett. 2004, 6, 3123–3126; h)
S. Hotha, S. Kashyap, J. Org. Chem. 2006, 71, 364–367; i) Y.
Angell, K. Burgess, J. Org. Chem. 2005, 70, 9595–9598; j) R. A.
Turner, A. G. Oliver, R. S. Lokey, Org. Lett. 2007, 9, 5011–
5014; k) T. S. Hu, R. Tannert, H. D. Arndt, H. Waldmann,
Chem. Commun. 2007, 3942–3944.
a) I. Arkitopoulou-Zanze, V. Gracias, S. W. Djuric, Tetrahedron
Lett. 2004, 45, 8439–8441; b) F. Couty, F. Durrat, D. Prim,
Tetrahedron Lett. 2004, 45, 3725–3728; c) D. K. Mohapatra,
P. K. Maity, R. G. Gonnade, M. S. Chorgade, M. K. Gurjar,
Synlett 2007, 12, 1893–1896; d) W. Rohr, A. Fischer, A. Bad,
A.-G. Sodafabr, Pesticide Chemistry: Proceedings of the Second
International IUPAC Congress (Ed.: A. S. Tahori), Gordon and
Breach, New York, 1972, vol. 5, pp. 177–188; e) J. K. Pokorski,
L. M. Miller Jenkins, H. Feng, S. R. Durell, Y. Bal, D. H. Ap-
pella, Org. Lett. 2007, 9, 2381–2383; f) I. Kumar, C. V. Rode,
Chem. Lett. 2007, 36, 592–593; g) H. Yanai, T. Taguchi, Tetra-
hedron Lett. 2005, 46, 8639–8643.
(35%). White solid. M.p. 110 °C. IR (neat): ν = 2993, 2941, 1455,
˜
1371, 1302, 1188, 1161, 903, 736 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.56 (s, 1 H), 7.55–7.27 (m, 5 H), 5.53 (s, 2 H), 4.54
(s, 2 H), 4.38 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
133.2, 130.2, 129.2, 128.9, 128.6, 126.8, 61.6, 52.8, 42.6 ppm.
HRMS: calcd. for C11H12N4O2S [M + Na]+ 287.0579; found
287.0754.
Methyl (2S)-3-(1H-3-Indolyl)-2-(3-methyl-6-oxo-4,5,6,7-tetra-
hydro[1,2,3]triazolo[1,5-a]pyrazin-5-yl)propanoate (8d): Rf = 0.40
(hexanes/EtOAc, 5:5). Yield: 188 mg (50%). Pale-yellow gummy li-
quid. IR (neat): ν = 3336, 2928, 1741, 1665, 1435, 1344, 1234,
˜
1
745 cm–1. H NMR (300 MHz, CDCl3): δ = 8.23 (s, 1 H), 7.56 (d,
J = 7.8 Hz, 1 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.26 (s, 1 H), 7.22–7.09
(m, 2 H), 6.97 (d, J = 2.1 Hz, 1 H), 5.34 (dd, J1 = 10.8 Hz, J2 =
5.4 Hz, 1 H), 5.04 (d, J = 17.7 Hz, 1 H), 4.93 (d, J = 18 Hz, 1 H),
4.41 (d, J = 15.9 Hz, 1 H), 4.32 (d, J = 15.3 Hz, 1 H), 3.81 (s, 3 H),
3.58 (dd, J1 = 15.9 Hz, J2 = 5.7 Hz, 1 H), 3.46 (dd, J1 = 15.3 Hz, J2
= 10.5 Hz, 1 H), 2.09 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 170.3, 162.9, 138.0, 136.2, 126.9, 124.1, 122.6, 122.2, 119.9,
117.9, 111.5, 110.1, 58.1, 52.7, 48.9, 40.2, 24.2, 9.8 ppm. [α]2D3 = 4.4
(c = 1.0, CHCl3). HRMS: calcd. for C18H19N5O3 [M + Na]+
376.1386; found 376.1381.
[7]
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra for all new compounds.
[8]
a) S. Hotha, R. I. Anegundi, A. A. Natu, Tetrahedron Lett.
2005, 46, 4585–4588; b) S. Chandrasekhar, C. L. Rao, C. Na-
gesh, C. R. Reddy, B. Sridhar, Tetrahedron Lett. 2007, 48,
5869–5872; c) H. Yanai, T. Taguchi, Tetrahedron Lett. 2005,
46, 8639–8643.
Acknowledgments
V. S. S. thanks the Council of Scientific and Industrial Research,
New Delhi for a senior research fellowship and S. C. N. thanks De-
partment of Science and Technology, New Delhi for the JC Bose
National Fellowship.
[9]
G. Gerona-Navvoro, M. A. Bonache, R. Herranz, M. T. Gar-
cia-Lopez, R. Gonzalez-Muniz, J. Org. Chem. 2001, 66, 3538–
3547.
[10]
J. H. Cho, B. M. Kim, Tetrahedron Lett. 2002, 43, 1273–1276.
Received: January 12, 2008
[1] R. Huisgen in 1,3-Dipolar Cycloaddition Chemistry (Ed.: A.
Padwa), Wiley, New York, 1984, pp. 1–176.
Published Online: March 26, 2008
Eur. J. Org. Chem. 2008, 2423–2429
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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