Synthesis of new chiral 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines from α-amino acid derivatives under mild conditions

Article abstract of DOI:10.1055/s-2007-984537

A practical and efficient regioselective synthesis of several new chiral 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines is described from α-amino acid derivatives following intramolecular 'click' reaction as the key step. The method obviates product pu

Full text of DOI:10.1055/s-2007-984537

LETTER
1893
Synthesis of New Chiral 4,5,6,7-Tetrahydro[1,2,3]triazolo[1,5-a]pyrazines
from a-Amino Acid Derivatives under Mild Conditions
Synthesis of
N
ew C
e
hiral 4, 5,6
b
, 7-Tetrahydr
e
o[1, 2,3]tria
n
zolo[1,5-
a
]
p
d
yrazines ra K. Mohapatra,* Pradip K. Maity, Rajesh G. Gonnade, Mukund S. Chorghade, Mukund K. Gurjar
Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India
E-mail: dk.mohapatra@ncl.res.in
Received 3 April 2007
the synthesis of 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-
Abstract: A practical and efficient regioselective synthesis of sev-
eral new chiral 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines is
described from a-amino acid derivatives following intramolecular
‘click’ reaction as the key step. The method obviates product
purification; to obtain the pure triazole products, only the solvent
needs to be evaporated.
a]pyrazines,17 stimulated our interest.
Several different methods, such as the intramolecular
cyclization of bishydrazones or mixed hydrazones, mis-
cellaneous oxidations, 1,3-dipolar cycloaddition between
azides and alkynes, have been described for synthesis of
1,2,3-triazoles.18 The 1,3-dipolar cycloaddition reaction is
typically carried out in refluxing toluene, but labile groups
may not survive these conditions. Our group has been in-
volved in the synthesis of natural products and crucial
synthetic intermediates19 from amino acids. We wished to
develop a synthetic protocol that would enable the synthe-
sis of chiral-fused polycyclic 1,2,3-triazoles in solution/
solid phase. Towards this end, we considered performing
intramolecular 1,3-dipolar cycloaddition reactions on a-
amino acid derived azido-alkynes. In this communication,
we report an effective integration of ‘click’ chemistry
onto a-amino acid derivatives for the synthesis of 1,2,3-
triazole-fused pyrazines.
Key words: pyrazine, 1,2,3-triazole, a-amino acid, click chemistry,
1,3-dipolar cycloaddition
N-Heterocyclic compounds are broadly distributed in
Nature, and constitute an integral component of several
amino acids, purines, pyrimidines, tetrahydropyrazines,
and other natural products. Such functionalized hetero-
cycles exhibit ability to mimic peptides, as well as their
ability to reversibly bind proteins. They, therefore, pro-
vide interesting scaffolds for the preparation of diversity-
oriented compound libraries for medicinal and pharma-
ceutical applications.1–8 Devising simple and efficient
solution- and solid-phase methods for the generation of
libraries is an attractive proposition.
We devoted our initial efforts toward the synthesis of
compound 2a (Scheme 1) from L-valine. Boc-protected
amino alcohol was prepared by following a standard liter-
ature procedure.20 Activation of the hydroxyl group by
formation of a tosylate was next achieved, in good yield,
by treatment of 1a with p-toluenesulfonyl chloride in
pyridine at ambient temperature.
Among the large variety of novel nitrogen-containing
molecules, tetrahydropyrazine derivatives are of particu-
lar interest because of their diverse biological activities
and potential therapeutic applications. This core ring
structure, is present in many natural products that elicit a
wide array of biological effects including antitumor,9a,b
cytotoxic,9a,b antidepressant,9c HIV protease inhibitor
(crixivan),9d,e and drug under development.9f Additional-
ly, piperazinyl-linked ciprofloxacin have been reported as
potent antibacterial agents against resistant strains,9g dual
calcium antagonists,9h antimalarial agents,9i and potent
antipsychotic agents.9j
Azido compound was obtained in 92% yield by SN2 dis-
placement of the corresponding tosylate with sodium
azide in DMF at 60 °C (Scheme 1). The alkyne function-
ality was then introduced by treatment with NaH and
O
NH2
a–c
OH
ref. 20
O
NH
Similarly, the 1,2,3-triazole structural motif found in a
large number of compounds possessing anti-HIV activi-
ty,10 selective b3-adrenergic receptor inhibition,11 antibac-
terial activity,12 potent antihistamine activity,13 and
more.14,15 These compounds are also commercially em-
ployed as anticorrosive agents, agrochemicals, photosta-
bilizer photographic materials, and dyes.16 The frequent
occurrence of triazoles and pyrazines in biologically ac-
tive compounds, as well as the paucity of the literature for
OH
O
O
1a
O
d
O
N
O
N
N
N
N
N3
2a
3a
Scheme 1 Reagents and conditions: (a) TsCl, pyridine, CH2Cl2,
0 °C to r.t., 8 h, 91%; (b) NaN3, DMF, 60 °C, 5 h, 92%; (c) propargyl
bromide, NaH, DMF, 0 °C to r.t., 4 h, 87%; (d) CHCl3 or CH2Cl2,
reflux, 4 h, 95%.
SYNLETT 2007, No. 12, pp 1893–1896
Advanced online publication: 27.06.2007
DOI: 10.1055/s-2007-984537; Art ID: G12307ST
© Georg Thieme Verlag Stuttgart · New York
2
4
.0
7
.2
0
0
7

1894
D. K. Mohapatra et al.
LETTER
propargyl bromide in DMF. The structure of 2a was con- 3a was established by NMR spectroscopy. The character-
firmed by NMR. Compound 2a was heated under reflux istic resonances observed at d = 128.9, 128.6, and 46.3
in toluene without any catalyst to convert it to 1,2,3-triaz- ppm were attributed to double bond carbon and methylene
ole-fused 4,5,6,7-tetrahydropyrazine moiety 3a. Purifica- carbon adjacent to the double bond and the resonance at
tion by silica gel column chromatography afforded the d = 7.53 ppm was attributed to H-8. The structure was also
desired product 3a in 52% yield. The low yield was attrib- confirmed by a characteristic ion at m/z = 267, attributable
utable to the harsh conditions that led to the deprotection to [M + H]+ in its mass spectrum (EI).22
of the Boc group (≥110 °C).21 We then chose CHCl3 or
This result encouraged us to verify the feasibility of using
CH2Cl2 as the solvent for the 1,3-dipolar cycloaddition re-
other azido-alkynes obtained from different amino acids
action and were surprised to see complete consumption of
azido-alkyne 2a in four hours under reflux conditions.
The pure product was obtained in 95% yield by simple
under identical reaction conditions. As exemplified in
Table 1, the reaction proceeded smoothly to completion,
and the corresponding 1,2,3-triazole-fused 4,5,6,7-tetra-
evaporation of the solvent. At room temperature, the reac-
hydropyrazine products were obtained in three to four
tion took 72 hours for complete conversion and proceeded
hours with excellent yields and high purity.
with the same yield. The structure of bicyclic compound
Table 1 Intramolecular 1,3-Dipolar Cycloaddition Reaction under Catalyst-Free Conditions in Chloroform
Azido-alkyne 2
Product 3
Time (h)
Yield (%)
95
O
O
2b
2c
3b
3c
3
O
N
N
N
O
N
N
N
N
Ph
N
N
N
Ph
N3
N
N
N
O
O
O
O
3
4
94
96
O
O
O
N
N3
2d
3d
O
N
N3
O
O
O
O
O
O
N
N
2e
2f
3e
3f
3
4
92
94
O
O
N
N
N
N
N
N
N
N
N3
N3
OTBS
OTBS
O
N
O
N
2g
2h
3g
3h
4
3
95
93
O
O
N
TBSO
N
N
TBSO
N3
O
N
O
N
O
O
N
N
N
N3
MeS
MeS
Synlett 2007, No. 12, 1893–1896 © Thieme Stuttgart · New York

LETTER
Synthesis of New Chiral 4,5,6,7-Tetrahydro[1,2,3]triazolo[1,5-a]pyrazines
1895
We then decided to extend these reaction conditions to a
proline derivative in order to obtain tricyclic compound
3i. The azido-alkyne obtained from L-proline was heated
under reflux in CHCl3 or CH2Cl2 to afford the correspond-
ing 1,2,3-triazole-4,5,6,7-tetrahydropyrazine in 94% yield
as a single product (Scheme 2). The NMR and mass spec-
trometry were used to establish the structure. In addition,
X-ray crystallographic analysis23–25 unambiguously con-
firmed the structure of 3i (Figure 1).
References and Notes
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O
H
N
ref. 20
a–c
O
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OH
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N
N
d
N
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3i
2i
Scheme 2 Reagents and conditions: (a) TsCl, pyridine, CH2Cl2,
0 °C to r.t., 8 h, 89%; (b) NaN3, DMF, 60 °C, 5 h, 90%; (c) (i) TFA,
CH2Cl2, 0 °C to r.t., 2 h; (ii) propargyl bromide, NaH, DMF, 0 °C to
r.t., 4 h, 84% (over two steps); (d) CHCl3 or CH2Cl2, reflux, 4 h, 94%.
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Figure 1 ORTEP diagram of compound 3i
In conclusion, we have achieved the regioselective syn-
thesis of several new chiral 1,2,3-triazole-fused 4,5,6,7-
tetrahydropyrazine bicyclic and tricyclic compounds with
excellent yield and high purity under mild reaction condi-
tions. The method obviates product purification; one only
needs evaporation of solvent to provide the pure triazole
products thereby rendering the process an ideal intramo-
lecular ‘click’ reaction. Further studies on the synthesis of
other triazole-fused heterocylic compounds are under way
and will be reported in due course.
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Acknowledgment
P.K.M. thanks CSIR, New Delhi for the financial assistance in the
form of a research fellowship. We thank also Dr. Mohan M. Bhad-
bhade and Dr. P. R. Rajmohanan for the X-ray crystallographic
assistance and NMR data, respectively
Synlett 2007, No. 12, 1893–1896 © Thieme Stuttgart · New York

1896
D. K. Mohapatra et al.
LETTER
(14) (a) Tullis, J. S.; VanRens, J. C.; Natchus, M. G.; Clark, M.
P.; De, B.; Hsieh, L. C.; Janusz, M. J. Bioorg. Med. Chem.
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4.33 (m, 2 H), 4.76 (d, 1 H, J = 12.5 Hz), 5.13 (m, 1 H), 7.53
(s, 1 H). 13C NMR (50 MHz, CDCl3): d = 18.7, 19.5, 26.6,
27.8, 36.1, 46.3, 54.3, 55.6, 80.6, 128.6, 128.9, 153.8. ESI-
MS: m/z = 267 [M + H]+. Anal. Calcd (%) for C13H22N4O2:
C, 58.62; H, 8.33; N, 21.04. Found: C, 58.51; H, 8.47; N,
20.88.
Compound 3c: [a]D25 –40.21 (c 1.1, CHCl3). IR (CHCl3):
2980, 1697, 1395, 1218, 1167 cm–1. 1H NMR (400 MHz,
CDCl3): d = 1.16 (d, 3 H, J = 7.3 Hz), 1.51 (s, 9 H), 4.32–
4.37 (m, 2 H), 4.47 (d, 1 H, J = 13.2 Hz), 4.92 (m, 1 H), 5.07
(d, 1 H, J = 17.4 Hz), 7.56 (s, 1 H). 13C NMR (100 MHz,
CDCl3): d = 15.7, 28.1, 36.1, 45.0, 50.1, 81.0, 128.9, 129.1,
153.7. ESI-MS: m/z = 239 [M + H]+, 261 [M + Na]+. Anal.
Calcd (%) for C11H18N4O2: C, 55.45; H, 7.61; N, 23.51.
Found: C, 55.67; H, 7.69; N, 23.42.
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Compound 3d: [a]D25 –30.74 (c 0.95, CHCl3). IR (CHCl3):
3020, 1703, 1508, 1407, 1215 cm–1. 1H NMR (500 MHz,
CDCl3): d = 0.84 (d, 3 H, J = 6.5 Hz), 0.87 (d, 3 H, J = 6.4
Hz), 1.06–1.12 (m, 1 H), 1.25–1.31 (m, 1 H), 1.40 (s, 9 H),
1.43–1.48 (m, 1 H), 4.12 (d, 1 H, J = 17.6 Hz), 4.21 (dd, 1 H,
J = 12.8, 4.8 Hz), 4.36 (d, 1 H, J = 12.8 Hz), 4.72 (m, 1 H),
5.04 (d, 1 H, J = 17.6 Hz), 7.41 (s, 1 H). 13C NMR (125
MHz, CDCl3): d = 21.9, 22.6, 24.7, 28.1, 35.9, 38.6, 47.3,
49.1, 80.9, 128.7, 128.9, 153.7. ESI-MS: m/z = 281 [M +
H]+, 303 [M + Na]+. Anal. Calcd (%) for C14H24N4O2: C,
59.98; H, 8.63; N, 19.98. Found: C, 59.87; H, 8.71; N, 19.76.
Compound 3i: [a]D25 +98.54 (c 1.1, CHCl3). IR (CHCl3):
3020, 1508, 1409, 1215 cm–1. 1H NMR (500 MHz, CDCl3):
d = 1.61–1.69 (m, 1 H), 1.92–2.05 (m, 2 H), 2.10–2.17 (m, 1
H), 2.36 (q, 1 H, J = 8.8 Hz), 2.68 (m, 1 H), 3.24–3.27 (ddd,
1 H, J = 8.81, 7.5, 2.8 Hz), 3.38 (d, 1 H, J = 14.6 Hz), 3.95
(dd, 1 H, J = 12.5, 10.6 Hz), 4.29 (d, 1 H, J = 14.6 Hz), 4.68
(dd, 1 H, J = 12.5, 3.9 Hz), 7.42 (s, 1 H). 13C NMR (125
MHz, CDCl3): d = 22.2, 27.5, 46.8, 51.2, 53.3, 59.6, 128.4,
131.8. ESI-MS: m/z = 165 [M + H]+, 187 [M + Na]+. Anal.
Calcd (%) for C8H12N4: C, 58.52; H, 7.37; N, 34.12. Found:
C, 58.37; H, 7.11; N, 33.98.
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(23) X-ray intensity data was collected on Bruker SMART APEX
CCD diffractometer with graphite-monochromated
(MoKa = 0.71073 Å) radiation at r.t. All the data were
corrected for Lorentzian, polarization and absorption effects
using Bruker’s SAINT and SADABS programs. SHELX-97
(ShelxTL)25 was used for structure solution and full matrix
least squares refinement on F2. Hydrogen atoms were
included in the refinement as per the riding model.
(24) Sheldrick, G. M. SHELX-97 Program for Crystal Structure
Solution and Refinement; University of Göttingen:
Germany, 1997.
(20) McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58,
3568.
(25) Crystallographic data for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC 633496
for 3i. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge, CB2
1EZ, UK [fax: +44(1223)336033; or e-mail:
(21) Rawal, V. H.; Cava, M. P. Tetrahedron Lett. 1985, 26, 6141.
(22) Analytical and Spectral Data
Compound 3a: [a]D25 –47.76 (c 1.2, CHCl3). IR (CHCl3):
3023, 1696, 1497, 1223 cm–1. 1H NMR (200 MHz, CDCl3):
d = 0.92 (d, 3 H, J = 6.6 Hz), 0.99 (d, 3 H, J = 6.5 Hz), 1.50
(s, 9 H), 1.53–1.65 (m, 1 H), 4.22 (dd, 1 H, J = 14.0, 4.5 Hz),
deposit@ccdc.cam.ac.uk].
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