A rapid and facile method for the general synthesis of 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues

Article abstract of DOI:10.1039/c1ob05255a

We report a general and facile method that provides rapid entry into 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues in one-pot under palladium-copper catalysis. The methodology utilises simple and easily available substrates of broad range. The applicability of this reaction for the synthesis of optically active products has been demonstrated. A plausible reaction mechanism has also been proposed.

Full text of DOI:10.1039/c1ob05255a

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Organic &
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PAPER
A rapid and facile method for the general synthesis of 3-aryl substituted
4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused
analogues†
Chinmay Chowdhury,* Sanjukta Mukherjee, Biswajit Chakraborty and Basudeb Achari
Received 17th February 2011, Accepted 23rd May 2011
DOI: 10.1039/c1ob05255a
We report a general and facile method that provides rapid entry into 3-aryl substituted
4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues in one-pot under
palladium–copper catalysis. The methodology utilises simple and easily available substrates of broad
range. The applicability of this reaction for the synthesis of optically active products has been
demonstrated. A plausible reaction mechanism has also been proposed.
the development of elegant methods for the synthesis of fused
Introduction
triazoles4 remains a real challenge in organic synthesis.
The thermal cycloaddition between azides and acetylenes studied
It may be pointed out that 1,2,3-triazoles are of particular
by Huisgen1a–c during the 1960’s led to the development of
a straightforward synthesis of 1,4- and 1,5-substituted 1,2,3-
triazoles as regioisomeric mixtures. This classical reaction gained
enormous importance after its discovery.1d The regio-selective
synthesis of 1,4-substituted 1,2,3-triazoles through the use of a
copper catalyst was pioneered independently by Sharpless2a and
Meldal2b which ensured dramatic acceleration of the reaction
rate and lowering of the reaction temperature. Subsequently,
exclusive formation of 1,5-substituted 1,2,3-triazoles, the other
regio-isomer, was also achieved by Fokin and co-workers2c–e
through judicious employment of a Ru(II) catalyst.2c,d In addition,
the synthesis of fully decorated (1,4,5-substituted) triazoles has
also been achieved.2f
Metal catalysed cycloaddition reactions, popularly known as
‘click reactions’, have found numerous applications in various
fields ranging from medicinal chemistry3a–d to materials science.3e–h
Despite such advancements, most of the applications for these
have been reported for intermolecular reactions, while examples
involving intramolecular versions are relatively limited possibly
due to the constraint of structural requirements. In principle,
intramolecular reactions should constitute powerful methods for
the synthesis of diverse analogues including fused triazoles difficult
to obtain through intermolecular reactions. In actual practice,
most of such substrates require high temperature and long reaction
times to undergo thermal cycloaddition; survival of the labile
protecting group(s) also becomes difficult. With this background,
interest due to their wide array of biological effects5 includ-
ing anti-HIV,5a anticancer,5b antibacterial,5c antiallergic,5d and
antihaemagglutination5e among others.5f–h Fused 1,2,3-triazoles
have also been equally important due to their broad spectrum of
activities including antitumor,6a anticancer,6b antiviral,6c glycosi-
dase inhibitory,6d and 5-HT1A/B/D receptor antagonistic activity.6e
On the other hand piperazines fused with specific nitrogen
heterocycles (e.g. pyrrole, triazole etc.) are found in a number of
biologically active natural products, synthetic agents, and drugs.
Notable among the pyrrolo-piperazines are phakellstatins (anti-
neoplastic and anticancer alkaloids),7 longamide and longamide B
(antibacterial compounds isolated from marine organisms),8 and
antileishmanial agents.9 Besides, 1,2,3-triazolo[1,5-a]quinoxaline10
1 (Fig. 1) has also been shown to elicit good affinity toward
benzodiazepine and adenosine receptors.10a,b
Fig. 1 Some important triazolo-piperazine derivatives.
Chemistry Division, Indian Institute of Chemical Biology (CSIR), 4, Raja
S. C. Mullick Road, Kolkata-7000032, India. E-mail: chinmay@iicb.res.in;
Fax: +91 33 2473 5197; Tel: +91 33 2499 5862
† Electronic supplementary information (ESI) available: Experimental
procedures, characterization data and copies of spectra. CCDC reference
numbers 804536 and 804692. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1ob05255a
In view of the frequent occurrence of 1,2,3-triazoles and
piperazines in various biologically active compounds, we en-
visioned that 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines 2
and/or their fused analogues 3 (Fig. 1) could be novel phar-
macophores or important building blocks. Only a few methods
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Table 1 Synthesis of the fused analogues
3
of 4,5,6,7-tetrahydro-
are available in the literature for the synthesis of compounds
of type 211 (R4 = H/alkyl) and of its 6-keto derivatives.12 The
majority of the syntheses used the conventional intramolecular
cycloaddition between azide and terminal alkyne, limiting the
diversity of substitutions at C-3 of the product. Regarding fused
analogues 3, only a few specific examples (n = 4, R4 = H/alkyl) of
this class have been prepared,11b employing classical cycloaddition
reactions.
[1,2,3]triazolo[1,5-a]pyrazines under palladium-copper catalysisa
In continuation of our interest in the development of palladium
catalysed synthetic methods,13 we felt it desirable to develop a
facile and general means for rapid access to 3-substituted 4,5,6,7-
tetrahydro[1,2,3]triazolo[1,5-a]pyrazines 2 and of their ring fused
analogues 3 through palladium–copper catalysis. We report herein
the results obtained in this direction (Scheme 1).
Timec (h)
Entry Azide-alkyneb Aryl iodide 5 (rt + heating) Product Yieldd (%)
1
4a
1.25 + 1.0
3aa
68
2
4a
1.5 + 4.0
3ab
47
3
4
4a
4a
1.5 + 3.0
3ac
3ad
71
50
1.5 + 0.75
Scheme
1
Synthesis of the fused analogues
3
of 4,5,6,7-
tetrahydro[1,2,3]triazolo[1,5-a]pyrazines.
5
6
7
4a
4a
4b
1.5 + 4.0
1.5 + 3.0
1.0 +2.5
3ae
3af
3bg
61
44
47
Results and discussion
At the outset, we were keen to find out the optimised reaction
conditions using 4a and 5a as substrates. Thus, a variety of
reaction conditions were screened, varying palladium catalyst,
base, solvent, temperature etc. (see electronic supplementary
information for details about optimisation studies). In each case, a
competing self cycloaddition of substrate 4a took place; however,
employment of Pd(OAc)2/PPh3 as catalyst and CuI as cocatalyst
along with K2CO3 as base allowed the reaction to proceed to
completion within a few hours, affording exclusively the desired
product 3aa with good yield (68%; Table 1, entry 1).
With the optimised reaction conditions in hand, we became
interested to explore the scope and generality of the reaction. This
was tested with different trans-azido-alkynes 3a–d and a range of
aryl/heteroaryl iodides 5a–m (Table 1). As can be seen from Table
1, various substitutions (e.g. methyl, methoxy, carbomethoxy,
fluoro, trifluoromethyl, nitro etc.) in the aryl iodide 5 were well
tolerated under the reaction conditions. We also employed aryl di-
iodides (5f, 5l) in this reaction with a view to testing the feasibility
of bis-heteroannulation in one pot. To our delight, reactions
using 1,4-diiodobenzene (5f) and 4,4¢-diiodobiphenyl (5l) led to
the isolation of bis-heteroannulated products 3af (44%) and 3cl
(71%), respectively (Table 1, entry 6 and 15). Thus, this method
is amenable to the synthesis of polyheteroannulated frameworks
also. It is noteworthy that immediate heating without stirring at
room temperature for the requisite time resulted in lower yields
of the desired products. Interestingly, the time period of heating
to effect the cycloaddition was found to be relatively shorter in
the cases of seven-/eight-membered substrates 4c–d compared to
those of five-/six-membered compounds 4a–b (Table 1, entries
11–17 vs. entries 1–10).
8
4b
4b
4b
1.5 + 2.5
1.5 + 4.0
1.0 + 2.0
3bc
3bh
3bi
77
60
53
9
10
11
12
4c
4c
0.75 + 0.75
2.0 + 0.75
3cd
3cg
55
52
13
14
4c
4c
0.75 + 1.25
3.0 + 0.75
3cj
51
48
3ck
Some of the synthesised compounds (3aa, 3ae and 3bc) were
examined to assess the viability of the deprotection of the N-tosyl
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Table 2 Synthesis of optically active productsa,b 2¢ and 2¢¢
Table 1 (Contd.)
Time (h)c
(rt + heating)
Product 2¢
Product 2¢¢
Entry
1
Aryl iodide 5
(yield %)d
(yield %)d
0.75 + 1.0
2¢a (43)
2¢¢a (98)
2
3
4
0.75 + 1.0
0.75 + 1.0
0.75 + 1.5
2¢c (74)
2¢i (57)
2¢j (55)
2¢¢c (89)
2¢¢i (81)
2¢¢j (88)
Timec (h)
Entry Azide-alkyneb Aryl iodide 5 (rt + heating) Product Yieldd (%)
15
4c
0.75 + 1.0
3cl
71
16
17
4d
4d
0.75 + 0.75
0.75 + 0.75
3da
46
54
5
6
0.75 + 1.0
2¢m (60)
2¢n (50)
2¢¢m (96)
2¢¢n (91)
3dm
0.75 + 0.75
a Azido-alkyne 4 (1.1 equiv), iodide 5 (1.0 equiv), Pd(OAc)2 (0.05 equiv),
PPh3 (0.2 equiv), CuI (0.1 equiv), K2CO3 (2.0 equiv), Bu4NBr (0.05
equiv◦) in dry DMF stirred at rt for requisite time followed by heating
at 95 C. b Substrates 4a–d are all racemic mixture. c Time required for the
consumption of starting materials/intermediate based on TLC. d Yields of
the products isolated after column chromatographic purification.
a Compound 7 (0.55 mmol), iodide 5 (0.5 mmol), Pd(OAc)2 (0.025 mmol),
PPh3 (0.1 mmol), CuI (0.05 mmol) in dry DMF (3.0 mL) stirred at rt
for requisite time followed by heating at 95 ◦C. b Product 2¢ (0.25 mmol),
TFA (0.5 mL) in dry DCM (3 mL) stirred at 0 ◦C to rt during 1–1.5 h.
c Time required for the synthesis of product 2¢ as determined through TLC.
d Yields of the purified products.
group; indeed, treatment with sodium/naphthalene afforded the
corresponding detosylated amines with good yields (61–72%) (see
electronic supplementary information for details).
The structures of the products were determined based on
spectral (NMR, IR, mass) and analytical data. The trans stere-
ochemistry of the tricyclic scaffolds 3 was deduced from the large
(~9–12 Hz) coupling constant (J) between the methine protons
We next applied this method for the synthesis of optically
active 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines 2. Toward
this objective, we prepared azido-alkyne 7 from R-styrene oxide
via (S)-amino alcohol 6,11b using a reaction sequence involving
mesylation and azide addition followed by N-propargylation
(Scheme 2). When substrate 7 was allowed to react with aryl iodide
5 under the optimised reaction conditions, the expected 4,5,6,7-
tetrahydro[1,2,3]triazolo[1,5-a]pyrazine 2¢ was formed with mod-
erate to good yields (Scheme 2 and Table 2). Finally, the
removal of the Boc group could easily be carried out by the
treatment of trifluoroacetic acid, resulting in the formation of the
corresponding amines 2¢¢ (81–98%). The free amine functionality
of product 2¢¢ may serve as a diversification site in combinatorial
synthesis.
1
observed in the H-NMR spectra. The structural deduction was
further supported by a single crystal X-ray analysis of product 3cj
(Fig. 2).14a Careful examination of the 1H-NMR spectra of amines
2¢¢ revealed an interesting feature of their structures. The vicinal
H–H coupling constants (J) in the piperazine ring of products 2¢¢
appeared to be large (~10–12 Hz), suggesting the orientation of
the phenyl ring as equatorial. Single crystal X-ray study of 2¢¢i was
in conformity with this conclusion (Fig. 2).14b
A plausible reaction mechanism can be envisaged (Scheme 3)
through control experiments and known features of palladium
chemistry. Based on the evidence,15 we believe that the intermediate
internal alkyne D is formed through the conventional copper-
assisted Sonogashira pathway. Thus the oxidative addition of
aryl iodide 5 to Pd(0), formed in situ through the interaction
of palladium acetate and triphenyl phosphine,16 affords s-aryl-
palladium(II) complex A which undergoes transmetalation with
copper-acetylide B to generate arylalkynylpalladium complex
C.17 This on reductive elimination of palladium(0) affords the
intermediate C-arylated internal alkyne D. Palladium(0) may
then activate the triple bond of intermediate D through a p-
complex E, in which palladium is stabilised by the nitrogen in
proximity.18 Next, insertion of palladium into the triple bond
possibly leads to the vinylidene like transition state F. Presumably,
the increase of electron density in the dipolarophile due to
the palladium insertion accelerates the cycloaddition through a
Scheme
2
Synthesis
of
the
optically
active
4,5,6,7-
tetrahydro[1,2,3]triazolo[1,5-a]pyrazines 2¢ and 2¢¢.
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significance. It thus promises to be of interest to practitioners of
both organic and medicinal chemistry.
Experimental section
General procedure for the synthesis of product 3
A mixture of Pd(OAc)2 (9.6 mg, 0.043 mmol, 5 mol%) and
PPh3 (44.8 mg, 0.171 mmol, 20 mol%) in dry DMF (1 mL) was
stirred at room temperature for 10 min under argon atmosphere.
Aryl iodide 5 (0.855 mmol), K2CO3 (236 mg, 1.709 mmol) and
tetrabutylammonium bromide (13.8 mg, 0.043 mmol, 5 mol%)
were then added successively and the whole reaction mixture was
allowed to stir at room temperature for another 10 min. A solution
of azido-acetylene 4 (0.940 mmol) in dry DMF (2 mL) was added
dropwise, followed by the addition of CuI (16.3 mg, 0.085 mmol,
10 mol%). The resulting mixture was flushed with argon carefully
and stirred for the specified time (Table 1) at room temperature.
After disappearance of starting materials (monitored by TLC),
the reaction mixture was allowed to heat at 95 ◦C for the requisite
time period (Table 1). Upon completion of the reaction (TLC), the
solvent was removed in vacuo; the residue was mixed with water
(10 mL) and then extracted with ethyl acetate (3 ¥ 15 mL). The
combined organic extracts were washed with brine (10 mL), dried
(anhydrous Na2SO4), filtered, and concentrated under reduced
pressure. The resulting residue was purified through silica gel
(100–200 mesh) column chromatography (ethyl acetate–petroleum
ether).
Fig. 2 X-ray crystal structure of products 3cj and 2¢¢i.
( )-trans-(5a,8a)-3-(4-Methyl-phenyl)-5-(toluene-4-sulfonyl)-
5,5a,6,7,8,8a-hexahydro-4H -cyclopenta[e][1,2,3]triazolo[1,5-a]-
[1,4]pyrazine (3aa). Yield: 68%; white solid, m.p.: 231–233 ◦C;
IR (KBr): nmax 3434, 2960, 1614, 1505, 1327, 1303, 1251, 1157,
1
1089, 1030 cm-1; H NMR (CDCl3, 600 MHz): d 1.93–1.98 (m,
2H), 2.09–2.12 (m, 1H), 2.22–2.25 (m, 1H), 2.39–2.42 (m, 1H),
2.42 (s, 3H), 2.67–2.72 (m, 1H), 2.84 (ddd, J = 6.4, 9.7, 11.5 Hz,
1H), 3.87 (s, 3H), 4.19 (ddd, J = 7.4, 10.2, 10.2 Hz, 1H), 4.36 (d,
J = 15.6 Hz, 1H), 5.18 (d, J = 15.6 Hz, 1H), 7.01 (d, J = 9.0 Hz,
2H), 7.31 (d, J = 7.8 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.70 (d,
J = 8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d 19.6, 21.5, 23.9,
27.4, 45.1, 55.3, 62.3, 62.4, 114.3, 123.0, 125.3, 127.5, 127.6, 130.1,
133.1, 142.0, 144.6, 159.4; ESI-MS: m/z 424.98 [M + H]+, 446.98
[M + Na]+, 460.07 [M + K]+; HRMS Calcd. for C22H25N4O3S [M
+ H]+ 425.1647, found 425.1666.
Scheme 3 Plausible reaction mechanism.
HOMO(dipolarophile)–LUMO(dipole) interaction19 leading to the for-
mation of the desired cycloadduct 3 (or 2) with concurrent
regeneration of palladium(0). Further evidence in favour of the
proposed mechanism for the conversion of D to the final product
3 (or 2) was clinched by control experiments.20
( )-trans-(5a,8a)-5-(Toluene-4-sulfonyl)-3-p-tolyl-5,5a,6,7,8,8a-
hexahydro-4H -cyclopenta[e][1,2,3]triazolo[1,5-a][1,4]pyrazine
(3ae). Yield: 61%; off-white solid, m.p.: 239–241 ◦C; IR (KBr):
nmax 3434, 2968, 1597, 1507, 1452, 1383, 1349, 1303, 1166, 1115,
1090, 1036, 1005 cm-1; 1H NMR (CDCl3, 600 MHz): d 1.95–2.00
(m, 2H), 2.08–2.12 (m, 1H), 2.20–2.26 (m, 1H), 2.38–2.40 (m, 1H),
2.41 (s, 3H), 2.42 (s, 3H), 2.67–2.72 (m, 1H), 2.84 (ddd, J = 6.1,
10.0, 11.5 Hz, 1H), 4.19 (ddd, J = 7.6, 10.2, 10.2 Hz, 1H), 4.38
(d, J = 15.6 Hz, 1H), 5.20 (d, J = 15.6 Hz, 1H), 7.28 (d, J = 7.8
Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.70
(d, J = 8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d 19.5, 21.2,
21.4, 23.8, 27.3, 45.1, 62.1, 62.2, 125.6, 126.0, 127.5, 129.5, 130.0,
133.0, 137.8, 142.0, 144.5; MS (FAB+): m/z 409 [M + H]+; HRMS
Calcd. for C22H25N4O2S [M + H]+ 409.1698, Found 409.1679.
Conclusions
In conclusion we have developed an efficient and general method
that provides rapid access to 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-
a]pyrazines and their fused analogues with moderate to excellent
yields. The methodology utilises easily accessible substrates of
broad range. A variety of functional groups can easily be
accommodated without affecting the outcome. This protocol is
successfully utilised for the formation of one C–C and two C–N
bonds in one pot. The method is also suitable for synthesising
optically active compounds which may be of possible biological
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( )-trans-(5a,9a)-3-(4-Trifluoromethyl-phenyl)-5-(toluene-4-sul-
fonyl)-4,5,5a,6,7,8,9,9a-octahydro[1,2,3]triazolo[1,5-a]quinoxaline
(3bi). Yield: 53%; white solid, m.p.: 196–198 ◦C; IR (KBr): nmax
135.6, 141.2, 144.1, 166.7; MS (FAB+): m/z 495 [M + H]+, 517
[M + Na]+; HRMS Calcd. for C26H31N4O4S [M + H]+ 495.2066,
found 495.2091.
1
2938, 2864, 1621, 1452, 1325, 1161, 1117, 1068, 1006 cm-1; H
General procedure for preparation of optically active 4,5,6,7-
tetrahydro[1,2,3]triazolo[1,5-a]pyrazines 2¢
NMR (CDCl3, 300 MHz): d 1.34–1.67 (m, 3H), 1.93–2.04 (m,
3H), 2.36 (s, 3H), 2.36–2.44 (m, 1H), 2.98–3.02 (m, 1H), 3.28
(ddd, J = 2.4, 10.9, 10.9 Hz, 1H), 3.96 (ddd, J = 3.3, 10.3, 10.3
Hz, 1H), 4.74 (d, J = 17.1 Hz, 1H), 5.33 (d, J = 16.8 Hz, 1H), 7.11
(d, J = 7.8 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.75–7.77 (m, 4H);
13C NMR (CDCl3, 75 MHz): d 21.5, 23.6, 25.2, 29.9, 30.3, 43.8,
59.2, 62.3, 125.8, 125.9, 126.4, 126.8, 127.4, 127.5, 129.8, 134.1,
136.8, 140.4, 144.3; ESI-MS: m/z 477.22 [M + H]+, 499.19 [M
+ Na]+; HRMS Calcd. for C23H24F3N4O2S [M + H]+ 477.1572,
found 477.1579.
A mixture of Pd(OAc)2 (5.6 mg, 0.025 mmol, 5 mol%) and
PPh3 (26.2 mg, 0.1 mmol, 20 mol%) in dry DMF (3 mL) was
stirred at room temperature for 10 min under argon atmosphere.
Iodo-compound 5 (0.5 mmol), K2CO3 (138 mg, 1.0 mmol) and
tetrabutylammonium bromide (8.0 mg, 0.025 mmol, 5 mol%)
were then added successively. The whole reaction mixture was
allowed to stir at room temperature for another 10 min under
argon atmosphere. A solution of azido-acetylene 7 (165.0 mg,
0.55 mmol) in dry DMF (2 mL) was added dropwise, followed by
the addition of CuI (9.5 mg, 0.05 mmol). The resulting mixture
was flushed with argon carefully and stirred at room temperature
for specified time (as shown in Table 2). After disappearance of
starting materials (TLC), the whole mixture was allowed to heat
at 95 ◦C for the requisite time period (as shown in Table 2).
Upon completion of the reaction (TLC), the solvent was removed
in vacuo; the residue was mixed with water (10 mL) and then
extracted with ethyl acetate (3 ¥ 15 mL). The combined organic
extracts were washed with brine (10 mL), dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The
resulting residue was purified through silica gel (100–200 mesh)
column chromatography (ethyl acetate-petroleum ether) to afford
the desired product.
( )-trans-(5a,9a)-3-(3-Methoxy-phenyl)-5-(toluene-4-sulfonyl)-
4,5,5a,6,7,8,9,9a-octahydro[1,2,3]triazolo[1,5-a]quinoxaline (3bh).
Yield: 60%; off-white solid, m.p.: 192–194 ◦C; IR (KBr): nmax 2944,
1
2867, 1580, 1495, 1449, 1349, 1292, 1158, 880 cm-1; H NMR
(CDCl3, 600 MHz): d 1.36–1.39 (m, 1H), 1.45–1.48 (m, 1H), 1.57–
1.61 (m, 1H), 1.92–1.98 (m, 3H), 2.35 (s, 3H), 2.43–2.46 (m, 1H),
2.96–2.98 (m, 1H), 3.25 (ddd, J = 3.2, 11.1, 11.1 Hz, 1H), 3.88
(ddd, J = 4.2, 10.8, 10.8 Hz, 1H), 3.90 (s, 3H), 4.75 (d, J = 16.8
Hz, 1H), 5.29 (d, J = 16.8 Hz, 1H), 6.94 (ddd, J = 0.6, 2.5, 8.2 Hz,
1H), 7.09 (d, J = 7.8 Hz, 2H), 7.13 (dt, J = 1.2, 7.2 Hz, 1H), 7.29
(dd, J = 1.2, 2.4 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.47 (d, J =
8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d 21.5, 23.6, 25.3, 29.9,
30.6, 43.9, 55.4, 59.0, 62.3, 111.8, 113.9, 118.6, 126.7, 126.8, 129.8,
129.9, 131.9, 136.7, 141.6, 144.2, 160.0; ESI-MS: m/z 439.13 [M
+ H]+, 461.12 [M + Na]+; Anal. Calcd. for C23H26N4O3S: C, 62.99;
H, 5.98; N, 12.78. Found: C, 62.95; H, 6.02; N, 12.74%.
(6S)-tert-Butyl-6-phenyl-3-(4-trifluoromethyl-phenyl)-6,7-dihy-
dro-4H-[1,2,3]triazolo[1,5-a]pyrazine-5-carboxylate (2¢i). Yield:
57%; white solid, m.p.: 179–180 ◦C; [a]D20 +6.03 (c 0.24, CHCl3); IR
(KBr): nmax 2978, 1696, 1620, 1454, 1405, 1323, 1245, 1171, 1122,
1071, 1007 cm-1; 1H NMR (CDCl3, 300 MHz): d 1.56 (s, 9H), 4.20
(d, J = 17.1 Hz, 1H), 4.69 (dd, J = 4.6, 13.3 Hz, 1H), 5.26 (d, J =
13.8 Hz, 1H), 5.35 (d, J = 17.1 Hz, 1H), 5.99 (br, 1H), 7.11 (d,
J = 5.4 Hz, 2H), 7.28 (br, 3H), 7.66 (d, J = 7.8 Hz, 2H), 7.80 (d,
J = 7.8 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d 28.3, 37.9, 47.9,
51.1, 82.2, 122.2, 125.7, 125.8, 126.0, 126.3, 127.3, 128.4, 129.2,
129.8, 134.2, 135.8, 140.3, 154.1; MS (FAB+): m/z 445 [M + H]+;
HRMS Calcd. for C23H23F3N4O2Na [M + Na]+ 467.1671, found
467.1645.
( )-trans-(5a,10a)-3-(2,4-Dimethoxy-pyrimidin-5-yl)-5-(toluene-
4-sulfonyl)-5,5a,6,7,8,9,10,10a-octahydro-4H-cyclohepta[e][1,2,3]-
triazolo[1,5-a][1,4]pyrazine (3cd). Yield: 55%; light yellow solid,
m.p.: 134–135 ◦C; IR (KBr): nmax 3428, 2931, 2865, 1611, 1560,
1
1477, 1386, 1342, 1280, 1161, 1083 cm-1; H NMR (CDCl3, 600
MHz): d 1.70–1.79 (m, 4H), 1.91–1.94 (m, 2H), 2.02–2.08 (m, 2H),
2.34 (s, 3H), 2.41–2.45 (m, 1H), 3.11–3.14 (m, 1H), 3.84 (ddd, J =
3.4, 9.7, 9.7 Hz, 1H), 3.96 (ddd, J = 3.0, 9.7, 9.7 Hz, 1H), 4.09 (s,
3H), 4.10 (s, 3H), 4.60 (d, J = 17.4 Hz, 1H), 4.92 (d, J = 17.4 Hz,
1H), 7.03 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 8.62 (s,
1H); 13C NMR (CDCl3, 150 MHz): d 21.5, 24.4, 24.7, 24.9, 29.7,
33.1, 41.1, 54.2, 55.2, 59.9, 61.6, 106.0, 126.5, 129.5, 129.6, 135.0,
135.9, 144.1, 158.2, 165.2, 166.9; MS (FAB+): m/z 485 [M + H]+;
Anal. Calcd. for C23H28N6O4S: C, 57.01; H, 5.82; N, 17.34. Found:
C, 56.97; H, 5.88; N, 17.31%.
(6S)-tert-Butyl-3-(4-fluoro-phenyl)-6-phenyl-6,7-dihydro-4H-
[1,2,3]triazolo[1,5-a]pyrazine-5-carboxylate (2¢j). Yield: 55%;
◦
white solid, m.p.: 202–204 C; [a]2D0 +10.52 (c 0.13, CHCl3); IR
(KBr): nmax 2983, 1700, 1516, 1452, 1397, 1372, 1300, 1238, 1161,
1
1095, 1004 cm-1; H NMR (CDCl3, 300 MHz): d 1.56 (s, 9H),
( )-trans-(5a,11a)-3-(4-Methoxycarbonyl-phenyl)-5-(toluene-4-
sulfonyl)-4,5,5a,6,7,8,9,10,11,11a-decahydrocycloocta[e][1,2,3]-
triazolo[1,5-a][1,4]pyrazine (3dm). Yield: 54%; white solid, m.p.:
222–224 ◦C; IR (KBr): nmax 3415, 2930, 2860, 1718, 1614 cm-1;
1H NMR (CDCl3, 600 MHz): d 1.55–1.57 (m, 1H),1.61–1.75 (m,
5H), 1.81–1.88 (m, 3H), 2.04–2.12 (m, 2H), 2.33 (s, 3H), 2.85–2.89
(m, 1H), 3.97 (s, 3H), 4.23 (ddd, J = 5.1, 10.5, 5.1 Hz, 1H), 4.40
(ddd, J = 5.2, 5.2, 10.9 Hz, 1H), 4.54 (d, J = 17.4 Hz, 1H), 5.22
(d, J = 16.8 Hz, 1H), 7.00 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 8.4 Hz,
2H), 7.70 (d, J = 8.4 Hz, 2H), 8.16 (d, J = 8.4 Hz, 2H); 13C NMR
(CDCl3, 150 MHz): d 21.5, 22.6, 23.1, 26.5, 26.7, 31.7, 33.8, 38.1,
52.3, 55.0, 56.8, 126.1, 126.6, 128.3, 129.6, 129.7, 130.4, 134.8,
4.17 (d, J = 17.1 Hz, 1H), 4.67 (dd, J = 2.4, 13.5 Hz, 1H), 5.23
(d, J = 13.8 Hz, 1H), 5.29 (d, J = 18.6 Hz, 1H), 5.98 (br, 1H),
7.11 (br, 4H), 7.28 (br, 3H), 7.64 (br, 2H); 13C NMR (CDCl3, 75
MHz): d 28.3, 37.8, 47.8, 51.1, 82.1, 115.7, 115.9, 126.0, 126.3,
126.9, 127.6, 127.7, 128.3, 129.1, 135.9, 140.8, 154.1, 160.6, 163.9;
ESI-MS: m/z 395.04 [M + H]+, 417.01 [M + Na]+; HRMS Calcd.
for C22H24FN4O2 [M + H]+ 395.1883, found 395.1861.
(6S)-tert-Butyl-3-(4-methoxycarbonyl-phenyl)-6-phenyl-6,7-
dihydro-4H-[1,2,3]triazolo[1,5-a]pyrazine◦-5-carboxylate
(2¢m).
Yield: 60%; white solid, m.p.: 259–261 C; [a]2D0 +17.04 (c 0.15,
CHCl3); IR (KBr): nmax 2976, 1718, 1690, 1614, 1442, 1403, 1363,
5860 | Org. Biomol. Chem., 2011, 9, 5856–5862
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1281, 1243, 1174, 1114, 1003 cm-1; 1H NMR (CDCl3, 300 MHz):
d 1.56 (s, 9H), 3.92 (s, 3H), 4.21 (d, J = 17.1 Hz, 1H), 4.69 (dd,
J = 4.6, 13.3 Hz, 1H), 5.26 (d, J = 13.8 Hz, 1H), 5.36 (d, J = 17.1
Hz, 1H), 5.99 (br, 1H), 7.11 (d, J = 5.1 Hz, 2H), 7.26–7.28 (m,
3H), 7.76 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.1 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): d 28.3, 37.9, 47.9, 51.1, 52.2, 82.2, 125.7, 126.7,
127.3, 128.4, 129.2, 130.2, 135.1, 135.8, 137.7, 140.7, 154.2, 166.7;
MS (FAB+): m/z 435 [M + H]+; HRMS Calcd. for C24H27N4O4
[M + H]+ 435.2032, found 435.1997.
(d, J = 8.4 Hz, 2H); 13C NMR (CDCl3, 150 MHz): d 42.5, 52.8,
57.0, 121.6, 126.8, 127.5, 128.1, 128.8, 129.1, 130.2, 132.0, 138.6,
140.4; MS (FAB+): m/z 355 and 357 [M + H]+, 377 and 379
[M + Na]+; HRMS Calcd. for C17H15BrN4 [M+] 354.0480, found
354.0502.
Acknowledgements
Financial support from CSIR net-work projects (NWP-0009, IAP-
0001) is gratefully acknowledged. B.A. thanks CSIR, India for an
EMS grant.
General procedure for Boc-deprotection
To a solution of Boc-protected product 2¢¢ (0.135 mmol) in dry
DCM (2 mL) was added trifluoroacetic acid (0.1 mL, 1.35 mmol)
at 0 ◦C under argon atmosphere. The reaction mixture was allowed
to reach to room temperature during 1–1.5 h. After completion
of the reaction (TLC), the solvent was evaporated to dryness. The
residue was treated with saturated NaHCO3 solution followed by
extraction with ethyl acetate (3 ¥ 10 mL). The combined organic
extracts were washed with water (10 mL) and brine (10 mL),
then dried over anhydrous Na2SO4. After evaporation of the
solvent, the residue was purified through silica gel (100–200 mesh)
column chromatography (ethyl acetate–petroleum ether) to afford
the purified product 2¢¢.
Notes and references
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(6S)-3-(4-Methoxy-phenyl)-6-phenyl-4,5,6,7-tetrahydro[1,2,3]-
triazolo[1,5-a]pyrazine (2¢¢a). Yield: 98%; yellow solid, m.p.: 127–
◦
129 C; [a]2D0 +111.68 (c 0.2, CHCl3); IR (KBr): nmax 3289, 2929,
2102, 1680, 1611, 1556, 1501, 1457, 1296, 1247, 1177, 1113, 1030
cm-1; 1H NMR (pyridine-d5, 600 MHz): d 3.74 (s, 3H), 4.18 (dd,
J = 3.9, 10.5 Hz, 1H), 4.29 (t, J = 11.4 Hz, 1H), 4.39 (d, J = 15.6
Hz, 1H), 4.65 (d, J = 15.6 Hz, 1H), 4.79 (dd, J = 3.9, 12.3 Hz,
1H), 7.14 (d, J = 8.4 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.44 (t,
J = 7.5 Hz, 2H), 7.64 (d, J = 7.2 Hz, 2H), 8.01 (d, J = 9.0 Hz,
2H); 13C NMR (CDCl3, 75 MHz): d 42.5, 52.7, 55.3, 57.1, 114.3,
123.9, 126.8, 127.1, 127.4, 128.7, 129.1, 138.8, 141.3, 159.2; ESI-
MS: m/z 307.18 [M + H]+, 329.15 [M + Na]+; HRMS Calcd. for
C18H18N4ONa [M + Na]+ 329.1378, found 329.1380.
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(6S)-3-(4-Methoxycarbonyl-phenyl)-6-phenyl-4,5,6,7-tetrahy-
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◦
solid, m.p.: 193–195 C; [a]2D0 +190.56 (c 0.2, CHCl3); IR (KBr):
nmax 3318, 2945, 1718, 1680, 1442, 1277, 1184, 1105, 1006 cm-1;
1H NMR (pyridine-d5, 600 MHz): d 3.86 (s, 3H), 4.23 (dd, J =
3.6, 10.8 Hz, 1H), 4.33 (t, J = 11.4 Hz, 1H), 4.42 (d, J = 16.2
Hz, 1H), 4.70 (d, J = 16.2 Hz, 1H), 4.82 (dd, J = 3.9, 12.3 Hz,
1H), 7.39 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.65 (d,
J = 7.8 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H), 8.28 (d, J = 8.4 Hz,
2H); 13C NMR (CDCl3, 75 MHz): d 42.6, 52.1, 52.8, 57.0, 125.7,
126.8, 128.8, 128.9, 129.0, 129.1, 130.2, 135.7, 138.6, 140.4, 166.8;
ESI-MS: m/z 335.16 [M + H]+, 357.14 [M + Na]+; HRMS Calcd.
for C19H18N4O2Na [M + Na]+ 357.1327, found 357.1351.
(6S)-3-(4-Bromo-phenyl)-6-phenyl-4,5,6,7-tetrahydro[1,2,3]tria-
zolo[1,5-a]pyrazine (2¢¢n). Yield: 91%; white solid, m.p.: 195–
◦
197 C; [a]2D0 +88.05 (c 0.5, CHCl3); IR (KBr): nmax 3298, 3036,
1
2878, 1478, 1322, 1233, 1073, 1001 cm-1; H NMR (pyridine-d5,
600 MHz): d 4.19 (dd, J = 3.9, 10.5 Hz, 1H), 4.30 (t, J = 11.4 Hz,
1H), 4.36 (d, J = 16.2 Hz, 1H), 4.63 (d, J = 16.2 Hz, 1H), 4.80
(dd, J = 3.6, 12.0 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5
Hz, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.90
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20 Heating of acyclic intermediate
D [R1+R2 = -(CH2)3-, PG =
-SO2C6H4Me-p, Ar = -C6H4OMe-p] at 95 ◦C in DMF without any
catalyst yielded the cycloadduct 3aa only in 21% yield even after 13 h,
along with recovery of the starting material (78%). However, the desired
cycloaddition affording the product 3aa occurred when intermediate D
was heated at 95 ◦C in DMF in the presence of 5 mol% Pd(OAc)2 and 20
mol% PPh3 for 1.5 h (91% yield) or in the presence of 5 mol% Pd(OAc)2
alone for 3 h (93% yield). In the latter case with phosphine free system,
preactvation of Pd(II) to Pd(0) might occur while heating Pd(OAc)2
in presence of trace amount of dimethylamine (see: I. P. Beletskaya,
and A. V. Cheprakov, Chem. Rev., 2000, 100, 3009) which is being
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5862 | Org. Biomol. Chem., 2011, 9, 5856–5862
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The Royal Society of Chemistry 2011
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