Microwave-assisted intramolecular huisgen cycloaddition of azido alkynes derived from α-amino acids

Article abstract of DOI:10.1021/jo802463r

The intramolecular version of the Huisgen cycloaddition is a potentially useful reaction for the stereocontrolled preparation of 1,5-disubstituted and 1,4,5-trisubstiututed triazoles. When α-azido propargyl esters derived from α-amino acids are submitted

Full text of DOI:10.1021/jo802463r

Microwave-Assisted Intramolecular Huisgen Cycloaddition of Azido
Alkynes Derived from r-Amino Acids
Evita Balducci, Luca Bellucci, Elena Petricci, Maurizio Taddei,* and Andrea Tafi
Dipartimento Farmaco Chimico Tecnologico, UniVersita` degli Studi di Siena, Via A. Moro,
53100 Siena, Italy
taddei.m@unisi.it
ReceiVed NoVember 10, 2008
The intramolecular version of the Huisgen cycloaddition is a potentially useful reaction for the
stereocontrolled preparation of 1,5-disubstituted and 1,4,5-trisubstiututed triazoles. When R-azido propargyl
esters derived from R-amino acids are submitted to [3 + 2] cycloaddition, the expected 4H-
[1,2,3]triazolo[5,1-c][1,4]oxazin-6-ones are not formed; rather, an oligomeric cyclic polyester is obtained
via a prevailing intermolecular cycloaddition. We have discovered that propargyl R-azido amides undergo
metal-free intramolecular Huisgen cycloaddition in MeCN/H2O under microwave dielectric heating. This
reaction provides access to new condensed triazoles that can be considered as conformationally constrained
peptidomimetics. Moreover, the following microwave-assisted lactam ring opening provides 1,4-
disubstituted and 1,4,5-trisubstituted triazole amino acids. The same kind of compounds are obtained
from the ester cycloadduct by reaction with primary amines in the presence of AlMe3. In order to
interpretate this unpredictable behavior, an ab initio study of the reaction pathway was undertaken using
GAMESS(US) at the B3LYP/6-31G** level of theory. Different relaxed potential energy profiles were
obtained for esters and amides, suggesting that the cis-arrangement of the -COdN- could account for
the amide reactivity.
Introduction
possibility of using Ru catalysts to produce 1,5-disubstituted
triazoles has been described,5 although this has not been
investigated as widely as Cu.6 Regiocontrol is still an issue when
targeting 1,4,5-trisubstituted triazoles.7 Recently, the regiocon-
trolled synthesis of 5-aryl, 1,4-trisubstituted 1,2,3-triazoles via
a click reaction/direct triazole CH insertion sequence has been
reported.8
In recent times, azides have became one of the most useful
functional groups in organic chemistry.1 This is due in part to
their ability to undergo Cu-catalyzed cycloaddition with terminal
alkynes2 as well as applications in bioorganic3 and medicinal
chemistry.4 In addition to reacting in high yield and simple
product isolation, one of the main features of this reaction is
the possibility to control the regiochemistry of the addition
providing exclusively 1,4-disubstituted triazoles. Recently, the
Several authors have recently demonstrated that “click” Cu-
catalyzed reactions can be also used as assisted methods for
(4) For example, see: (a) Speers, A. E.; Adam, G. C.; Cravatt, B. F. J. Am.
Chem. Soc. 2003, 125, 4686. (b) Brik, A.; Muldoon, J.; Lin, Y.-C.; Elder, J. H.;
Goodsell, D. S.; Olson, A. J.; Fokin, V. V.; Sharpless, B.; Wong, C.-H.
ChemBioChem 2003, 4, 1246. (c) Speers, A. E.; Cravatt, B. F. Chem. Biol. 2004,
11, 535. (d) Burley, G. A.; Gierlich, J.; Mofid, M. R.; Nir, H.; Tal, S.; Eichen,
Y.; Carell, T. J. Am. Chem. Soc. 2006, 128, 1398.
(5) Zhang, L.; Chen, X.; Sun, H. H. Y.; Williams, I. D.; Sharpless, K. B.;
Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998.
(6) Rasmussen, L. K.; Boren, B. C.; Fokin, V. V. Org. Lett. 2007, 9, 5337.
For the synthesis of the catalyst see:Chinn, M. S.; Heinekey, D. M. J. Am. Chem.
Soc. 1990, 112, 5166.
(1) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596. Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann,
V. Angew. Chem., Int. Ed. 2005, 44, 5188.
(2) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001,
40, 2004. Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem.
2006, 51. Gil, M. V.; Are´valo, M. J.; Lo´pez, O. Synthesis 2007, 1589.
(3) Kolb, H.; Sharpless, K. B. Drug DiscoVery Today 2003, 8, 1128. Vocadlo,
D. J.; Bertozzi, C. R. Angew Chem. Int. Ed. 2004, 43, 5338. Sawa, M.; Hsu,
T.-L.; Itoh, T.; Sugiyama, M.; Hanson, S. R.; Vogt, P. K.; Wong, C.-H. Proc.
Natl. Acad. Sci. U.S.A. 2006, 103, 12371.
1314 J. Org. Chem. 2009, 74, 1314–1321
10.1021/jo802463r CCC: $40.75 2009 American Chemical Society
Published on Web 01/12/2009

Huisgen Cycloaddition of Azido Alkynes
SCHEME 1. Reaction of Azide Esters
SCHEME 2
ring closing of macrocyclic (pseudo)-peptides.9 However, the
regiochemical control in the Cu-mediated reaction can be a
limitation when the triazole must be inserted in a cycle
containing less than 14 atoms, as in the case of triazole
containing ꢀ-turn mimic peptides.10 The development of an
intramolecular version of the Huisgen cycloaddition (copper
free) can be an useful alternative to drive the regiochemistry of
the cycloaddition toward the complementary isomer in respect
to the product of the Cu mediated reaction. The introduction of
a labile template between the azide and the alkyl moieties would
allow the further hydrolysis with formation of the expected fully
elaborated triazole. With the idea to investigate the possibility
of forcing the regiochemistry of the Huisgen cycloaddition
through an intramolecular reaction, we decided to choose the
ester or the amide function as the labile template suitable of
postcycloaddition cleavage.11
SCHEME 3
Results and Discussion
Starting from L-phenylalanine, the corresponding R-azido acid
1 was prepared following a literature report.12 Further reaction
with propargyl alcohol in the presence of EDC and DMAP gave
compound 2, which was employed as the model to find the best
reaction conditions for cyclization (Scheme 1).
Based on classical reports on thermal Huisgen cycloaddi-
tion,13 we initially subjected 2 to conditions of refluxing toluene
for several hours which gave mainly unreacted starting material.
Using microwave dielectric heating and toluene as the solvent,
the reaction mixture did not reach a temperature suitable for
cyclization. The addition of a catalytic amount of the ionic liquid
[bmim][BF4] to the toluene increased the temperature up to 180
°C without formation of the cycloadduct. When water was
employed as the solvent, the formation of a precipitate was
observed after heating at 175 °C for 40 min (200 W power,
max internal pressure 200 psi). Unfortunately, after separation,
the precipitate could not be dissolved in any solvents. Diluted
NMR spectra in DMSO-d6 showed the resonances expected for
the cyclization product (with a large shape); however, analysis
of the ES/MS spectra suggested the formation of oligomers.
Product 3 was not formed even with the increase of the dilution
(up to 10-4 M). With the aim to improve reactivity increasing
the solubility of 2, mixtures of THF/water, acetone/water, EtOH/
water, or the corresponding organic solvents alone were tried,
but again, 3 was obtained in very low yields.14 Attempts to use
classical “click” conditions (Cu(II) salts and Na ascorbate) or
the Cp*RuCl(PPh3)2 catalyst were unsuccesful, possibly due to
the hindrance that the alkyne-metal complex exerts to the rest
of the molecule.
In order to prove the effective formation of the oligomers
proposed on the basis of the molecular weight deduced from
ESI-MS specrum, aminolysis of the ester bond was attempted.
Treatment of the presumed oligomer 4 with p-methoxybenzy-
lamine and Me3Al in refluxing toluene resulted in the isolation
of triazole 5 in 32% yield (Scheme 2). Compound 5 was the
only species containing a triazole ring present in the reaction
mixture.15 In order to ascertain the regiochemistry of 5, the 1,4
disubstituted derivative 7 was prepared following standard
“click” chemistry (Scheme 3).
(7) For an approach to regioselective intermolecular Huisgen reaction with
internal alkynes using the Ru catalyst, see: Majireck, M. M.; Weinreb, S. M. J.
Org. Chem. 2006, 71, 8680.
(8) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org. Lett.
2008, 10, 3081.
(9) Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2006, 8, 4145. Turner, R. A.;
Oliver, A. G.; Lokey, R. S. Org. Lett. 2007, 9, 5011. Looper, R. E.; Pizzirani,
D.; Schreiber, S. L. Org. Lett. 2006, 8, 2063.
(10) Angell, Y.; Burgess, K. J. Org. Chem. 2005, 70, 9595.
(11) For examples of intramolecular formation of 1,2,3-triazoles not oriented
to the regiocontrolled synthesis of substituted triazoles, see: Guerin, D. J.; Miller,
S. J. J. Am. Chem. Soc. 2002, 124, 2134. Thomas, A. W. Bioorg. Med. Chem.
Lett. 2002, 12, 1881. Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. W.
Tetrahderon Lett. 2004, 45, 8429. Hotha, S.; Anegundi, R. I.; Natu, A. A.
Tetrahedron Lett. 2005, 46, 4585. Mohapatra, D. K.; Maity, P. K.; Gonnade,
R. G.; Chorghade, M. S.; Gurjar, M. K. Synlett 2007, 1893. Oliva, A. I.;
Christmann, U.; Font, D.; Cuevas, F.; Ballester, P.; Buschmann, H.; Torrens,
A.; Yenes, S.; Pericas, M. A. Org. Lett, 2008, 10, 1617. Sudhir, V. S.; Baig,
R. B. N.; Chandresekaran, S. Eur. J. Org. Chem. 2008, 2423. For one example
of intramolecular reaction appied to the synthesis of a triazole amino acid as
peptide turn inducers, see: Pokorski, J. K.; Miller Jenkins, L. M.; Feng, H.; Durell,
S. R.; Bai, Y.; Appella, D. H. Org. Lett. 2007, 9, 2381.
1
The comparison between the H NMR spectra of 5 and 7
showed substantial differences in the resonances of several
protons, suggesting that 5 was the 1,5 isomer.
Changes in the nature of the starting amino acid were also
examined, but the corresponding azido esters never cyclized
properly to provide oligomers that could be cleaved with amine
(14) In no case did we isolate a discrete product having 1H NMR and MS
spectra fully coherent with the proposed structure.
(12) Lundquist, J. T., IV.; Pelletier, J. C. Org. Lett. 2001, 3, 781.
(13) Huisgen, R. Angew. Chem. 1963, 75, 604.
(15) Data recovered by analysis of the mass spectra of all the components
of the reaction mixture.
J. Org. Chem. Vol. 74, No. 3, 2009 1315

Balducci et al.
SCHEME 4. Reaction of Azido Amides
SCHEME 5
TABLE 1. Cyclization of Amides 13-18
R
amide, yield (%)a
triazole, yield (%)a
C6H5CH2-
CH3-
(CH3)2CH-
(CH3)2CHCH2-
CH3SCH2CH2-
BocNH(CH2)4-
13 (70)
14 (65)
15 (79)
16 (75)
17 (68)
18 (60)
19 (94)b
20 (94)c
21 (93)c
22 (94)c
23 (94)c
24 (70)c
SCHEME 6
a Yields of isolated compounds. b 70% ee. c >95% ee.
and AlMe3 to produce the 1,5-disubstituted triazoles in yields
suitable for preparative purposes.
In addition to the investigation on esters, the intramolecular
cycloadditon was also attempted on amide 13, prepared as
described in Scheme 4.16 We were surprised and gratified to
find that cycloadduct 19 was obtained in good yield when the
tively, microwave-assisted hydrolysis of the lactam bond
occurred at 85 °C for 3 h in HCl 6 M in water and produced
the 1,4-disubstituted triazole amino acid 27 in good yields.20
This reaction sequence provided an alternative way to prepare
disubstituted triazole amino acids regiocomplementary to the
isomers obtained through the Cu-mediated reaction.21
17
reaction was carried out in wet MeCN. Optimization of the
procedure (MeCN/H2O 4:1, 160 °C, maximum internal pressure
200 psi, 60 min) gave 19 in 94% isolated yields after evaporation
of the solvent and crystallization.
This reaction condition proved to be effective on other
R-azido propargylamides (14-18), prepared from the R-amino
acids 8-12 as described above. The corresponding 7-substituted-
4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones (20-24)
were obtained in good yields (Table 1) after simple crystalliza-
tion from EtOH/H2O. Compounds 20-24 were obtained in ee
>95%. Compound 19 was instead obtained with ee ) 70%,
due to partial racemization of the phenylalanine azide during
the prolonged heating.18 In order to increase the molecular
diversity around the newly formed heterocycle, the possibility
of further functionalization at the amide NH was explored
(Scheme 5). Treatment of 19 with BrCH2COOEt or BnBr in
DMF in the presence of NaH under microwave dielectric
heating, gave compounds 25 and 26 in good yields.19 Alterna-
In order to apply this procedure to the synthesis of trisub-
stituted triazoles,22 propargylamine 30 was prepared. Allylation
of N-propargylphthalimide 28 occurred rapidly and in good
yields under very mild conditions, adapting a procedure previ-
ously described for simple alkynes (Scheme 6).23 We found it
convenient to prepare 30 by treatment of 29 with an excess of
MeNH2 in EtOH under microwave dielectric heating that
provided 30 in higher yield and purity when compared to
refluxing conditions (less than 40% of product isolated after
12 h of reflux).
Coupling of amine 30 with R-azido acids 1 and 8-10 in the
presence of DMTMM17 gave R-azido amides 31-34 in good
yields. Our first attempts to apply the standard conditions to
the cyclization of 31 gave the bicyclic triazole 35 in 30% yield
after 1 h of microwave dielectric heating at 160 °C. After two
additional cycles of 1 h each, an 80% conversion of 31 into the
triazole was effected. Purification by column chromatography
gave bicyclic triazole 35 in 65% yields as a single isomer. The
(16) Zhao, H.; Sanda, F.; Matsuda, T. Macromolecules 2004, 37, 8888.
DMTMM: 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride.
See: Falchi, A.; Giacomelli, G.; Porcheddu, A.; Taddei, M. Synlett 2000, 277.
DMTMM is commercially available from Acros Organics.
(17) When MeCN alone was used as the solvent, the solution did not reach
the temperature required for cycloaddition. When ionic liquid was employed in
order to increase the internal temperature, cycoaddition did not occur.
(18) HPLC analysis with Chiral Column Chiralpack 1B 0.46 × 15 cm.
(19) The yields reported in the scheme were obtained exclusively when the
vial containing all the reagents was submitted to MW heating. When the classical
procedure of succession in reagent addition was followed, very low yields were
obtained at room temperature, whereas MW heating (after addition of benzyl
bromide) provided the dibenzyl derivative 42.
(20) Compound 27 was obtained in 70% ee, the same of the starting
compound 19. When lactam hydrolysis was attempted in oil bath at 100 °C,
more then 24 h were required to obtain 75% yields of 19.
(21) For the Cu-catalyzed synthesis of triazole-containing amino acids, see:
Angelo, N. G.; Arora, P. S. J. Am. Chem. Soc. 2005, 127, 17134.
(22) Although it is possible, no applications of intramolecular cycloaddition
to the synthesis of trisubstituted triazoles have been reported until now. For one
example of the synthesis of substituted bicyclic triazole via ring opening of
aziridine-propargylic derivatives, see: (a) Kim, M. S.; Yoon, H. J.; Lee, B. K.;
Known, J. H.; Lee, W. K.; Kim, Y.; Ha, H.-J. Synlett 2005, 2187. (b) Yanai, H.;
Taguchi, T. Tetrahedron Lett. 2005, 46, 8639.
(23) Bieber, L. W.; da Silva, M. F. Tetrahedron Lett. 2007, 48, 7088.
1316 J. Org. Chem. Vol. 74, No. 3, 2009

Huisgen Cycloaddition of Azido Alkynes
SCHEME 7
SCHEME 9. Ab Initio Study of the Reaction Pathway
TABLE 2. Cyclization of Amides 31-34
R
amide, yield (%)a
triazole, yield (%)a
PhCH2-
CH3-
(CH3)2CH-
(CH3)2CHCH2-
31 (70)
32 (70)
33 (68)
34 (70)
35 (65)b
36 (64)c
37 (64)c
38 (70)c
hydrolysis, demonstrating the possibility to access to this kind
of new triazole with complete control of the regiochemistry.
Results obtained on compounds 2 and 13-18 revealed a very
different behavior in azide-alkyne cycloaddition on changing
the template from ester to amide. With the aim to shed light on
this peculiar aspect of the reaction, an ab initio study of the
reaction pathway was undertaken, and azides 15 and 43 were
chosen as models of the experimental systems. These substrates
were chosen for computational study since they retained the
essential electronic features without the computational complex-
ity of additional substituents on the chiral carbon atom.26
The transition states (TS) of the pathways for the ester and
amide reaction (Scheme 9) were first localized and validated
by analysis of their imaginary vibrational frequencies and of
their relaxation toward reactants and products (IRC calcula-
tions)27 with the aim to interpretate the experimental outcomes
using the differences between the calculated gas-phase activation
barriers.
a Yields of isolated compounds; 5-10% of starting material recovered
after column chromatography. b 70% ee. c >95% ee.
SCHEME 8
The geometries and the energies of transition states and
ground states were calculated using GAMESS(US)28 at the
B3LYP/6-31G** level of theory. The resulting reaction profiles
with relative energy values and optimized geometries are
displayed in Figure 1, together with the TS imaginary frequency
values. Both model reactions displayed exothermic energy
profile with similar activation energy values. The calculated
barriers (17-19 kcal/mol) represented a plausible range for
cyclization reactions requiring heating to take place.
As a matter of fact, IRC calculations did not highlight any
different microscopic event, during the bond formation, that
could explain the diversity observed in reactivity of amides in
respect to esters. As the reaction studied is an intramolecular
cycloaddition, it is plausible to imagine that the correct orbital
orientation required in the TS could be reached after a
conformational arrangement and that this additional event could
account for the rate-determining step.
time required for cyclization of 31 was remarkably long if
compared with standard microwave-assisted reaction.24
The use of microwave heating was critical to the success of
the reaction. When the cyclization was attempted at the same
temperature under conventional heating, after 24 h of stirring
the reaction mixture in a sealed vial immersed in an oil bath
heated at 160 °C, the starting material was completely consumed
without formation of compound 35. Cyclisation was repeated
on amides 32-34 giving the expected triazoles 35-38 in
acceptable yields (Scheme 7 and Table 2).
Consequently, the potential energy profile generated by
scanning the C(O)dN dihedral angle of 15 was studied at the
same level of theory of the transition states but with gradient
convergence set to 10-3 hartree/bohr. The corresponding relaxed
dihedral scan was performed as well for the C-O bond of 43,
Further elaboration of 35-38 by alkylation of the nitrogen,
lactam ring opening, or functionalization of the double bond25
is possible. (Scheme 8).
For example, the N-benzyl derivative 39 was obtained by
microwave dielectric heating of 35 in the presence of BnBr and
Na in DMF. Analogously, the 1,4,5-trisubstituted amino acids
40 and 41 were obtained after microwave-assisted lactam
(26) Compound 43 was prepared but its cyclization to 44 did not occur under
the reaction conditions explored for compound 2.
(27) For DFT prediction of Cu-catalyzed synthesis of triazole, see: Himo,
F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.;
Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210.
(28) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon,
M. S.; Jensen, J. J.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.; Su, S.; Windus,
T. L.; Dupuis, M.; Montgomery, J. A. J. Comput. Chem. 1993, 1, 4–1347.
(24) Comparable yields were observed by heating in succession of 20 min
irradiation periods for 2 h overall.
(25) Although not described here, double-bond functionalization is
possible, for example, by oxidative hydroboration, cross-methathesis, or
hydroformylation.
J. Org. Chem. Vol. 74, No. 3, 2009 1317

Balducci et al.
on amide molecular models.29 The scan performed on the ester
C-O bond showed a significantly lower activation barrier
(13-14 kcal/mol). The pseudo-cis conformation of the ester,
however, was thermodynamically less stable than the cis amide
geometry, due to absence of partial double bond character of
the rotated bond.
According to the above-reported results, this study suggest
that the reactions might proceed through a two-stage mechanism
involving two sequential transition states. The first (TS1)
provides a conformational rearrangement required to orientate
the molecule and to permit the second one (TS2) corresponding
to the true cycladditions step. The main difference was found
in the TS1 with the cis conformation of the amide found more
stable than the corresponding geometry of the ester.30 The
(microwave dielectric) heating accelerates the trans-cis equili-
bration in the amide allowing a rapid replacement of the cis
isomer consumed by cyclization and decreasing the amount of
the oligomers formed by the other conformers. This phenomenon
does not occur in the ester where all the conformers have a
comparable energy and the intramolecular process may prevail.
In conclusion, we have found that intramolecular cycload-
dition of azido alkynes may occur under microwave dielectric
heating if the (temporary) template linkage is an amide. The
intramolecular arrangements control the regiochemistry of the
addition forming one of the possible isomer, that, after template
cleavage, gave 1,4-disubstituted or 1,4,5-trisubstitued 1,2,3-
triazoles. The differences found between amides and esters were
also explained on the basis of a proposed two stage mechanism
in which the bond formation is anticipated by a conformational
rearrangement (preorganization step) that correctly approaches
the reactive part of the molecule.
FIGURE 1. IRC energy profiles of the reactions reported in Scheme
9: TS, transition state; ∆E, energy value relative to the corresponding
TS; freq, imaginary frequency value (cm-1) of the TS. (a) Amide 15
as starting material. (b) Amide 43 as starting material.
Experimental Section
(S)-Prop-2-ynyl, 2-Azido-3-phenylpropanoate (2). General Pro-
cedure. Propargyl alcohol (58 mg, 1.05 mmol), DMAP (0.1 mmol),
and EDC (1.15 mmol) were added to a stirred solution of (S)-2-
azido-3-phenylpropanoic acid (1) (200 mg, 1.05 mmol) in dry
CH2Cl2 (6 mL) under nitrogen atmosphere. After 3 h, the solvent
was evaporated and the mixture purified by flash chromatography
(eluent ) CHCl3). Compound 2 was isolated as an oil, 168 mg
1
(70% yield). H NMR (400 MHz, CDCl3) δ: 7.33-7.22 (m, 5H);
4.75 (d, J ) 2 Hz, 2H); 4.09 (m, 1H); 3.19 (dd, J1 ) 5, J2 ) 14
Hz, A of an AB system, 1H); 3.02 (dd, J1 ) 8, J2 ) 14 Hz, B of
an AB system, 1H); 2.51 (t, J ) 2 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ: 169.2; 135.6; 129.2; 128.7; 127.4; 75.8; 63.0; 53.1; 37.5.
MS(ES+): m/z 252 [M + Na]+. HRMS (ES+) calcd for
C12H11N3NaO2 252.0749, found 252.0744.
(S)-2-(5-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxy-
benzyl)-3-phenylpropanamide (5). (S)-Prop-2-ynyl 2-azido-3-phe-
nylpropanoate (2) (70 mg, 0.3 mmol) was dissolved in THF/H2O
4:1 (1.5 mL) and submitted to microwave dielectric heating
(Discover synthesizer from CEM Corp.) at 150 °C (measured by
the vertically focused IR temperature sensor) for two cycles of 30
min each (max internal pressure 200 psi, max 100 W). After
cooling, a white solid (21 mg) was separated and analyzed by
HPLC/MS-ESI showing three peaks with m/z ) 230 (compound
FIGURE 2. Calculated relaxed potential energy profile for the dihedral
angle H-N-CdO of 15 (black). The geometries at each stationary
point are shown over the curve. The corresponding potential energy
profile for the equivalent conformations of 43 is also shown (red) for
comparison pourposes, superimposed to the amide profile.
even if, in that case, the partially double character of the rotated
bond was missing and consequently the ester group of 43 was
expected to be free to rotate.
The results obtained by the dihedral scans are shown in Figure
2. They point out a different energy profile for the amide bond
rotation with respect the ester. The scan around the amide bond
showed two conformational transition states at approximately
ω ) ( 90° (∆E ) 27-28 kcal/mol), while the cis (ω ) 0°)
conformer was found to be thermodynamically less stable than
the trans (ω ) 180°) geometry by about 7 kcal/mol. These data
were in agreement with the results reported in previous studies
(29) Aparicio-Martinez, S.; Hall, K. R.; Balbuena, P. B. J. Phys. Chem. A
2006, 110, 9183.
(30) The activation barrier for the amide was greater than the activation barrier
of the ester. However, the cycloaddition reaction exhibits the same magnitude
of energy; therefore, at experimental condition of both reactions, we can exclude
a discrimination through kinetic effects. It is important to point out that
calculations are performed in vacuo but that the presence of the solvent should
stabilize the cis amide conformer. See: Fisher, G. Chem. Soc. ReV. 2000, 29,
119–127.
1318 J. Org. Chem. Vol. 74, No. 3, 2009

Huisgen Cycloaddition of Azido Alkynes
3) and m/z ) 459 and 687 (compound 4 as cyclodimer and
cyclotrimer). A solution of p-methoxybenzylamine (0.36 mmol) in
dry CH2Cl2 (5 mL) was cooled to 0 °C, and Me3Al (2 M solution
in toluene, 0.6 mmol) was added. After 30 min, the mixture was
warmed to room temperature, and the solid obtained in the previous
reaction was added. The reaction was heated at reflux for 24 h and
then cooled in ice bath, and H2O (5 mL) was added. The organic
layer was separated and the aqueous phase washed with CH2Cl2 (5
mL × 3). The organic layers, collected together, were washed with
satured NaCl(aq) (5 mL), dried over anhydrous Na2SO4, filtered,
and concentrated by rotatory evaporation under vacuum. The residue
was purified by flash chromatography on silica gel (eluent ) CHCl3/
MeOH 95:5) to give 25 mg of a yellow oil (22% yield). 1H NMR
(400 MHz, CDCl3) δ: 7.64 (s, 1H); 7.19-6.98 (m, 6H); 6.88 (d, J
) 8 Hz, 2H); 6.68 (d, J ) 8 Hz, 2H); 5.27 (t, J ) 7 Hz, 1H); 4.59
(s, 2H); 4.22 (dd, J1 ) 5, J2 ) 14 Hz, A of an AB system, 1H);
4.11 (dd, J1 ) 5, J2 ) 14 Hz, B of an AB system, 1H); 3.67 (s,
3H); 3.47 (dd, J1 ) 7, J2 ) 13 Hz, A of an AB system, 1H); 3.25
(dd, J1 ) 8, J2 ) 13 Hz, B of an AB system, 1H); 2.94 (bs, 1H).
13C NMR (100 MHz, CDCl3) δ: 167.1; 159.1; 147.8; 135.3; 129.2;
128.8; 128.3; 127.4; 122.2; 114.4; 113.7; 66.0; 56.3; 55.4; 43.6;
39.4. MS(ES+): m/z 389 [M + Na]+. HRMS(ES+) calcd for
C20H22N4NaO3 389.1590, found 389.1584.
2-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyben-
zyl)-3-phenylpropanamide (7). 2-Azido-N-(4-methoxybenzyl)-3-
phenylpropanamide (6) (190 mg, 0.61 mmol) was dissolved in
t-BuOH (2 mL) and H2O (2 mL). Propargyl alcohol (36 µL, 0.61
mmol), Cu2SO4 (1 mg, 0.006 mmol), and Na ascorbate (12 mg,
0.06 mmol) were added, and the mixture was stirred at room
temperature for 12 h. The solvent was evaporated and the residue
purified by flash chromatography on silica gel (eluent ) EtOAc).
Compound 7 was obtained as an yellow oil: 212 mg (95% yield).
1H NMR (400 MHz, CDCl3) δ: 7.82 (s, 1H); 7.56 (bs, 1H); 7.12
(s, 3H); 7.01 (d, J ) 2 Hz, 2H); 6.83 (d, J ) 8 Hz, 2H); 6.65 (d,
J ) 8 Hz, 2H); 5.47 (t, J ) 7 Hz, 1H); 4.53 (s, 2H); 4.20 (dd, J1
) 6, J2 ) 14 Hz, A of an AB system, 1H); 3.99 (dd, J1 ) 4, J2 )
14 Hz, B of an AB system, 1H); 3.76 (bs, 1H); 3.65 (s, 3H); 3.46
(dd, J1 ) 8, J2 ) 13 Hz, A of an AB system, 1H); 3.25 (dd, J1 )
8, J2 ) 13 Hz, B of an AB system, 1H). 13C NMR (100 MHz,
CDCl3) δ: 167.4; 158.9; 147.9; 135.3; 129.3; 128.9; 128.5; 122.2;
114.3; 113.9; 65.4; 55.9; 55.3; 43.6; 39.5. MS(ES+): m/z 389 [M
+ Na]+. HRMS(ES+) calcd for C20H22N4NaO3 389.1590, found
389.1584.
3.94 (m, 2H); 3.66 (d, J ) 4 Hz, 1H); 2.20 (m, 1H); 2.15 (t, J )
2 Hz, 1H); 0.93 (d, J ) 6 Hz, 3H); 0.81 (d, J ) 6 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ: 169.2; 79.1; 71.5; 70.0; 31.7; 28.9;
19.4; 17.0. MS(ES+): m/z 203 [M + Na]+. HRMS(ES+): calcd for
C8H12N4NaO 203.0909, found 203.0902.
(S)-2-Azido-4-methyl-N-(prop-2-ynyl)pentanamide (16). Oil: 190
1
mg (75% yield). H NMR (400 MHz, CDCl3) δ: 6.81 (bs, 1H);
3.99 (m, 2H); 3.89 (q, J ) 4 Hz, 1H); 2.20 (t, J ) 2 Hz, 1H);
1.74-1.60 (m, 3H); 0.89 (d, J ) 6 Hz, 6H). 13C NMR (100 MHz,
CDCl3) δ: 169.9; 79.0; 71.9; 62.5; 41.0; 29.2; 24.9; 23.0; 21.5.
MS(ES+): m/z 217 [M + Na]+. HRMS(ES+): calcd for C9H14N4NaO
217.1065, found 217.1060.
(S)-2-Azido-4-(methylthio)-N-(prop-2-ynyl)butanamide (17). Oil:
189 mg (68% yield). 1H NMR (400 MHz, CDCl3) δ: 6.79 (bs, 1H);
4.12 (q, J ) 4 Hz, 2H); 4.00 (m, 1H); 2.55 (m, 2H); 2.21 (t, J )
2 Hz, 1H); 2.18-2.10 (m, 1H); 2.04 (s, 3H); 2.01-1.95 (m, 1H).
13C NMR (100 MHz, CDCl3) δ: 169.0; 79.0; 72.1; 62.6; 31.4; 29.8;
29.2; 15.3. MS(ES+): m/z 235 [M + Na]+. HRMS(ES+): calcd for
C8H12N4OS 235.0630, found 235.0626.
(S)-tert-Butyl-5-azido-6-oxo-6-(prop-2-ynylamino)hexylcarbam-
ate (18). Oil: 243 mg (60% yield). 1H NMR (400 MHz, CDCl3) δ:
6.72 (bs, 1H); 4.61 (bs, 1H); 4.00 (m, 2H); 3.93 (m, 2H); 3.06 (d,
J ) 6 Hz, 1H); 2.21 (t, J ) 2 Hz, 1H); 1.91-1.77 (m, 4H);
1.49-1.43 (m, 2H); 1.38 (s, 9H). 13C NMR (50 MHz, CDCl3) δ:
169.0; 155.9; 79.1; 78.8; 71.8; 63.8; 55.3; 31.6; 29.5; 29.0; 28.3;
22.3. MS(ES+): m/z 332 [M + Na]+. HRMS(ES+): calcd for
C14H23N5NaO3 332.1699, found 332.1695.
(S)-2-Azido-N-(hex-5-en-2-ynyl)-3-phenylpropanamide (31). Yel-
1
low oil: 246 mg (70% yield). H NMR (400 MHz, CDCl3) δ:
7.32-7.23 (m, 5H); 6.41 (bs, 1H); 5.76 (m, 1H); 5.23 (d, J ) 17
Hz, 1H); 5.10 (d, J ) 9 Hz, 1H); 4.17 (m, 1H, X of an ABX
system); 4.08-4.06 (m, 2H); 3.33 (dd, J1 ) 3, J2 ) 14 Hz, A of
an ABX system, 1H); 3.00 (dd, J1 ) 8, J2 ) 14 Hz, B of an ABX
system, 1H); 2.93 (s, 2H). 13C NMR (100 MHz, CDCl3) δ: 168.2;
136.1; 132.1; 129.5; 128.7; 127.3; 116.4; 82.9; 80.9; 65.5; 38.6;
29.7; 23.0. MS(ES+): m/z 291 [M + Na]+. HRMS(ES+): calcd
for C15H16N4NaO 291.1222, found 291.1217.
(S)-2-Azido-N-(hex-5-en-2-ynyl)propanamide (32). Yellow oil:
176 mg (70% yield). 1H NMR (400 MHz, CDCl3) δ: 6.53 (bs, 1H);
5.67 (m, 1H); 5.20-5.12 (m, 1H); 5.02-4.95 (m, 1H); 4.00-3.87
(m, 3H); 2.85-2.82 (m, 2H); 1.42 (m, 3H). 13C NMR (100 MHz,
CDCl3) δ: 169.4; 132.1; 116.3; 83.6; 80.8; 59.0; 29.7; 22.9; 17.0.
MS(ES+): m/z 215 [M + Na]+. HRMS(ES+): calcd for C9H12N4NaO
215.0909, found 215.0902.
(S)-2-Azido-N-(hex-5-en-2-ynyl)-3-methylbutanamide (33). Yel-
low oil: 196 mg (68% yield). 1H NMR (400 MHz, CDCl3) δ: 6.72
(bs, 1H); 5.70 (m, 1H); 5.20 (d, J ) 16 Hz, 1H); 5.02 (d, J ) 10
Hz, 1H); 3.98 (m, 2H); 3.71 (d, J ) 4 Hz, 1H); 2.87 (m, 2H); 2.26
(m, 1H); 0.98 (d, J ) 6 Hz, 3H); 0.83 (d, J ) 6 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ: 168.9; 132.1; 116.1; 80.3; 70.2; 53.5; 31.8;
29.4; 22.9; 19.4; 17.0. MS(ES+): m/z 243 [M + Na]+. HRMS(ES+):
calcd for C11H16N4NaO 243.1222, found 243.1217.
(S)-2-Azido-N-(hex-5-en-2-ynyl)-4-methylpentanamide (34). Yel-
low oil: 215 mg (70% yield). 1H NMR (400 MHz, CDCl3) δ: 6.50
(bs, 1H); 5.69 (m, 1H); 5.19 (d, J ) 16 Hz, 1H); 5.01 (d, J ) 10
Hz, 1H); 3.96 (m, 2H); 3.85 (q, J ) 4 Hz, 1H); 2.86 (m, 2H);
1.76-1.63 (m, 2H); 1.61-1.54 (m, 1H); 0.87 (dd, J1 ) 2, J2 ) 6
Hz, 6H). 13C NMR (100 MHz, CDCl3) δ: 169.5; 132.1; 116.3; 80.8;
62.8; 41.1; 29.7; 24.9; 23.0; 23.0; 21.5. MS(ES+): m/z 257 [M +
Na]+. HRMS(ES+): calcd for C12H18N4NaO 257.1378, found
257.1371.
(S)-2-Azido-3-phenyl-N-(prop-2-ynyl)propanamide (13). Gen-
eral Procedure. (S)-2-Azido-3-phenylpropanoic acid (1) (250 mg,
1.31 mmol) and propargylamine (90 µL, 1.31 mmol) were dissolved
in AcOEt (10 mL), and the resulting solution was stirred at room
temperature for 10 min. DMTMM (363 mg, 1.31 mmol) was added
and the reaction stirred at room temperature for 12 h. The mixture
was washed with HCl(aq) (1 M), saturated NaHCO3(aq), and
saturated NaCl(aq), dried over anhydrous Na2SO4, filtered, and
concentrated by rotatory evaporation under vacuum. The residue
was purified by flash chromatography on silica gel using CH2Cl2
1
as eluent: obtained 209 mg of an oil (70% yield). H NMR (400
MHz, CDCl3) δ: 7.30-7.21 (m, 5H); 6.83 (bs, 1H); 4.14 (m, 1H);
4.00-3.97 (m, 2H); 3.27 (dd, J1 ) 3, J2 ) 14 Hz, A of an AB
system, 1H); 2.99 (dd, J1 ) 8, J2 ) 14 Hz, B of an AB system,
1H); 2.21 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 168.7; 136.1;
129.4; 128.7; 127.3; 79.0; 71.9; 65.1; 38.4; 29.2. MS(ES+): m/z
251 [M + Na]+. HRMS(ES+): calcd for C12H12N4NaO 251.0909,
found 251.0903.
(S)-2-Azido-N-(prop-2-ynyl)propanamide (14). Oil: 129 mg (65%
(R,S)-7-Benzyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-
one (19). General Procedure. (S)-2-Azido-3-phenyl-N-(prop-2-
ynyl)propanamide (13) (50 mg, 0.22 mmol) was dissolved in
CH3CN (12 mL) and H2O (3 mL) in a 80 mL vessel and heated
under microwave conditions at 160 °C for 1 h (Discover - CEM,
Method “standard”: power max 250 W, ramp time 1 min, hold time
60 min, T 160 °C, internal pressure max 200 psi). The solvent was
evaporated, giving compound 19 as a white solid that was
1
yield). H NMR (400 MHz, CDCl3) δ: 6.69 (bs, 1H); 4.05-3.96
(m, 3H); 2.20 (t, J ) 2 Hz, 1H); 1.48 (d, J ) 6 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ: 169.6; 78.9; 71.9; 58.9; 29.2; 16.9. MS(ES+):
m/z 175 [M + Na]+. HRMS(ES+): calcd for C6H8N4NaO 175.0596,
found 175.0589.
(S)-2-Azido-3-methyl-N-(prop-2-ynyl)butanamide (15). Oil: 186
1
mg (79% yield). H NMR (400 MHz, CDCl3) δ: 7.05 (bs, 1H);
J. Org. Chem. Vol. 74, No. 3, 2009 1319

Balducci et al.
crystallized from EtOH/H2O 1:1 (47 mg, 94% yield). Mp: 165-166
4.07 (dd, J1 ) 3, J2 ) 15 Hz, 1H); 3.57 (d, J ) 3 Hz, 2H); 3.42
(dd, J1 ) 6, J2 ) 16 Hz, 1H, A of an ABX system); 3.31 (dd, J1
) 6, J2 ) 16 Hz, 1H, B of an ABX system); 3.08 (d, J ) 16 Hz,
1H).13C NMR (100 MHz, CDCl3) δ: 167.4; 139.3; 133.7; 133.6;
129.6; 128.4; 127.8; 125.6; 116.8; 60.7; 39.7; 36.3; 29.7. MS(ES+):
m/z 291 [M + Na]+. HRMS(ES+): calcd for C15H16N4NaO
291.1222, found 291.1217. HPLC (Chiral Column Chiralpack 1B
0.46 cm × 15 cm; hexane/i-PrOH: 90/10) tR: 65 min (85%); 69
min (15%).
1
°C. H NMR (400 MHz, CDCl3) δ: 7.42 (s, 1H); 7.20-7.10 (m,
3H); 6.80 (bs, 1H); 6.69 (d, J ) 7 Hz, 2H); 5.48 (s, 1H); 4.21 (d,
J ) 16 Hz, 1H); 3.59 (s, 2H); 3.21 (d, J ) 16 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ: 167.2; 133.5; 129.6; 128.7; 128.5; 128.3;
127.8; 60.8; 39.7; 36.3. MS(ES+): m/z 251 [M + Na]+. HRM-
S(ES+): calcd for C12H12N4NaO 251.0909, found 251.0903. HPLC
(Chiral Column Chiralpack 1B 0.46 cm × 15 cm; hexane/i-PrOH:
95/5) tR: 77 min (85%); 85 min (15%).
(S)-7-Methyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-
one (20). White solid: 31 mg (94% yield). Mp: 182-183 °C. H
(S)-3-Allyl-7-methyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-
6(7H)-one (36). Yellow solid: 27 mg (64% yield). Mp: 122-123
1
1
NMR (400 MHz, CDCl3) δ: 7.60 (s, 1H); 7.04 (bs, 1H); 5.14 (q,
J ) 7 Hz, 1H); 4.69 (s, 2H); 1.88 (d, J ) 7 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ: 168.4; 129.9; 126.2; 55.7; 36.9; 19.1. m/z
[ES/MS]: 175 [M + Na]+. HRMS(ES+): calcd for C6H8N4NaO
175.0596, found 175.0590. HPLC (Chiral Column Chiralpack 1B
0.46 cm × 15 cm; hexane/i-PrOH: 95/5) tR: 65 min (99%); 71 min
(1%)
°C. H NMR (400 MHz, CDCl3) δ: 7.67 (bs, 1H); 5.90 (m, 1H);
5.12-5.05 (m, 3H); 4.54 (s, 2H); 3.48 (d, J ) 6 Hz, 2H); 1.85 (d,
J ) 7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 168.8; 139.9; 133.8;
123.7; 117.2; 55.7; 36.9; 30.0; 19.2. MS(ES+): m/z 215 [M + Na]+.
HRMS(ES+): calcd for C9H12N4NaO 215.0909, found 215.0902.
HPLC (Chiral Column Chiralpack 1B 0.46 cm × 15 cm; hexane/
i-PrOH: 90/10) tR: 89 min (98%); 93 min (2%).
(S)-7-Isopropyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-
one (21). White solid: 37 mg (93% yield). Mp: 144-145 °C. H
(S)-3-Allyl-7-isopropyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-
6(7H)-one (37). Yellow solid: 31 mg (64% yield). Mp: 112-113
1
1
NMR (400 MHz, CDCl3) δ: 7.65 (bs, 1H); 7.60 (s, 1H); 5.04 (d,
J ) 3 Hz, 1H); 4.64 (s, 2H); 2.65 (m, 1H); 1.12 (d, J ) 7 Hz, 3H);
0.93 (d, J ) 7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 168.1;
129.0; 127.8; 65.5; 36.9; 34.3; 19.1; 17.4. MS(ES+): m/z 203 [M
+ Na]+. HRMS(ES+): calcd for C8H12N4NaO 203.0909, found
203.0903. HPLC (Chiral Column Chiralpack 1B 0.46 cm × 15 cm;
hexane/i-PrOH: 95/5) tR: 98 min (99%); 105 min (1%)
°C. H NMR (400 MHz, CDCl3) δ: 7.28 (bs, 1H); 5.91 (m, 1H);
5.12-5.00 (m, 3H); 4.50 (s, 2H); 3.50 (m, 2H); 2.64 (m, 1H); 1.11
(d, J ) 6 Hz, 3H); 0.94 (d, J ) 7 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ: 167.9; 139.5; 133.9; 124.9; 117.0; 65.5; 37.0; 34.4; 29.9;
19.0; 17.5. MS(ES+): m/z 243 [M + Na]+. HRMS(ES+): calcd for
C11H16N4NaO 243.1222, found 243.1216. HPLC (Chiral Column
Chiralpack 1B 0.46 cm × 15 cm; hexane/i-PrOH: 90/10) tR: 100
min (99%); 104 min (1%).
(S)-7-Isobutyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-
1
one (22). White solid: 40 mg (94% yield). Mp: 101-102 °C. H
(S)-3-Allyl-7-isobutyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-
6(7H)-one (38). Yellow oil: 36 mg (70% yield). 1H NMR (400 MHz,
CDCl3) δ: 7.39 (bs, 1H); 5.91 (m, 1H); 5.12-5.08 (m, 3H); 4.52
(m, 2H); 3.49 (d, J ) 6 Hz, 2H); 2.04-1.99 (m, 1H); 1.96-1.89
(m, 1H); 1.79 (m, 1H); 0.93 (t, J ) 6 Hz, 6H). 13C NMR (100
MHz, CDCl3) δ: 168.9; 139.8; 133.9; 124.1; 117.1; 59.0; 42.4; 36.7;
30.0; 24.4; 22.8; 21.8. MS(ES+): m/z 257 [M + Na]+. HRMS(ES+):
calcd for C12H18N4NaO 257.1378, found 257.1371. HPLC (Chiral
Column Chiralpack 1B 0.46 cm × 15 cm; hexane/i-PrOH: 95/5)
tR: 39 min (100%). HPLC (Chiral Column Chiralpack 1B 0.46 cm
× 15 cm; hexane/i-PrOH: 90/10) tR: 98 min (99%); 102 min (1%).
Ethyl 2-(7-Benzyl-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-
5(4H)-yl)acetate (25). General Procedure. 7-Benzyl-4,5-dihydro-
[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-one (19) (50 mg, 0.22 mmol)
and ethyl bromoacetate (27 µL, 0.24 mmol) were added to a
suspension of NaH (17.6 mg, 0.44 mmol) (previously washed with
petroleum ether) in dry DMF (1 mL) at room temperature. The
mixture was submitted to microwave dielectric heating at 100 °C
for 30 min. The solution was diluted with AcOEt (15 mL) and
washed with H2O (5 mL × 5). The organic phase was dried over
dry Na2SO4 and filtered and the solvent evaporated, obtaining
NMR (400 MHz, CDCl3) δ: 8.06 (bs, 1H); 7.57 (s, 1H); 5.13 (t, J
) 6 Hz, 1H); 4.63 (s, 2H); 2.11-1.98 (m, 1H); 1.97-1.87 (m,
1H); 1.76 (m, 1H); 0.91 (dd, J ) 6, 11.2 Hz, 6H). 13C NMR (100
MHz, CDCl3) δ: 169.1; 129.1; 127.3; 58.9; 42.3; 36.6; 24.4; 22.9;
21.5. MS(ES+): m/z 217 [M + Na]+. HRMS(ES+): calcd for
C9H14N4NaO 217.1065, found 217.1059. HPLC (Chiral Column
Chiralpack 1B 0.46 cm × 15 cm; hexane/i-PrOH: 95/5) tR: 105
min (100%).
(S)-7-(2-(Methylthio)ethyl)-4,5-dihydro[1,2,3]triazolo[1,5-a]py-
razin-6(7H)-one (23). White solid 44 mg (94% yield). Mp: 71-72
1
°C. H NMR (400 MHz, CDCl3) δ: 7.95 (bs, 1H); 7.58 (s, 1H);
5.22 (s, 1H); 4.67 (s, 2H); 2.62 (m, 1H); 2.50-2.42 (m, 3H); 1.99
(s, 3H). 13C NMR (100 MHz, CDCl3) δ: 167.9; 129.1; 127.6; 58.4;
36.9; 31.7; 29.0; 15.0. MS(ES+): m/z 235 [M + Na]+. HRMS(ES+):
calcd for C8H12N4NaOS 235.0630, found 235.0625. HPLC (Chiral
Column Chiralpack 1B 0.46 cm × 15 cm; hexane/i-PrOH: 95/5)
tR: 89 min (98%); 95 min (2%).
(S)-tert-Butyl 4-(6-Oxo-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]py-
razin-7-yl)butylcarbamate (24). Yellow oil: 48 mg (70% yield),
obtained after column chromatography (eluent AcOEt/MeOH 97:
1
1
compound 25 as a yellow oil (46 mg, 66% yield). H NMR (400
3). H NMR (400 MHz, CDCl3) δ: 7.97 (bs, 1H); 7.57 (s, 1H);
MHz, CDCl3) δ: 7.40 (s, 1H); 7.20-7.08 (m, 3H); 6.68 (d, J ) 7
Hz, 2H); 5.57 (t, J ) 3 Hz, 1H); 4.37 (d, J ) 7 Hz, 1H); 4.27 (d,
J ) 15 Hz, 1H); 4.17 (q, J ) 7 Hz, 2H); 3.74 (d, J ) 17 Hz, 1H);
5.11 (s, 1H); 4.64 (s, 3H); 2.99 (d, J ) 5 Hz, 2H); 2.30 (m, 1H);
2.19 (m, 1H); 1.40-1.35 (m, 11H); 1.10 (m, 2H). 13C NMR (100
MHz, CDCl3) δ: 168.1; 156.0; 129.1; 127.5; 59.8; 40.1; 36.7; 32.9;
29.5; 28.4; 21.4. MS(ES+): m/z 332 [M + Na]+. HRMS(ES+): calcd
for C14H23N5NaO3 332.1699, found 332.1694. HPLC (Chiral
Column Chiralpack 1B 0.46 cm × 15 cm; hexane/i-PrOH: 95/5)
tR: 112 min (99%); 124 min (1%)
3.60 (m, 2H); 3.37 (d, J ) 15 Hz, 1H); 1.24 (t, J ) 7 Hz, 3H). 13
C
NMR (100 MHz, CDCl3) δ: 167.6; 165.1; 133.5; 129.5; 128.6;
128.5; 128.0, 127.7; 61.7; 60.7; 48.0; 42.5; 40.0; 14.1. MS(ES+):
m/z 337 [M + Na]+. HRMS(ES+): calcd for C16H18N4NaO3
337.1277, found 337.1270.
(R,S)-3-Allyl-7-benzyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-
6(7H)-one (35). General Procedure. (S)-2-Azido-N-(hex-5-en-2-
ynyl)-3-phenylpropanamide (31) (60 mg, 0.22 mmol) was dissolved
in CH3CN (12 mL) and H2O (3 mL) in a 80 mL vessel and
submitted to microwave dielectric heating at 160 °C (method
“standard” as previously described) for three cycles of 1 h each.
The solvent was evaporated, and the crude mixture purified by flash
chromatography (eluent AcOEt): 38 mg of 35 as a light orange
5,7-Dibenzyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-
one (26). Oil: 42 mg (60% yield), after column chromatography
1
(eluent AcOEt/petroleum ether (40-60 °C) 2:1). H NMR (400
MHz, CDCl3) δ: 7.29-7.19 (m, 5H); 7.08-7.04 (m, 2H); 6.90 (t,
J ) 7 Hz, 2H); 6.53 (d, J ) 7 Hz, 2H); 5.54 (m, 1H, X of an ABX
system); 4.56 (d, J ) 14 Hz, 1H); 4.41 (d, J ) 14 Hz, 1H); 3.98
(d, J ) 15 Hz, 1H); 3.57 (m, 2H, AB of an ABX system); 2.97 (d,
J ) 16 Hz, 1H). MS(ES+): m/z 341 [M + Na]+. HRMS(ES+):
calcd for C19H18N4NaO 341.1378, found 341.1371.
1
solid was obtained (65% yield). Mp: 121-122 °C. H NMR (400
MHz, CDCl3) δ: 7.22-7.08 (m, 3H); 7.00 (bs, 1H); 6.71 (d, J )
7 Hz, 2H);.5.75 (m, 1H); 5.43 (m, 1H, X of an ABX system); 5.01
(dd, J1 ) 1, J2 ) 10 Hz, 1H); 4.93 (dd, J1 ) 1, J2 ) 17 Hz, 1H);
3-Allyl-5,7-dibenzyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-
6(7H)-one (39). Compound 39 was obtained after only 15 min of
1320 J. Org. Chem. Vol. 74, No. 3, 2009

Huisgen Cycloaddition of Azido Alkynes
microwave heating. Yellow oil: 51 mg (65% yield), obtained after
column chromatography (eluent AcOEt/petroleum ether (40-60 °C)
1:1). 1H NMR (400 MHz, CDCl3) δ: 7.29-7.26 (m, 3H); 7.12-7.08
(m, 3H); 6.93 (t, J ) 7 Hz, 2H); 6.57 (d, J ) 7 Hz, 2H); 5.69 (m,
1H); 5.52 (m, 1H, X of an ABX system); 4.94 (dd, J1 ) 1, J2 ) 10
Hz, 1H); 4.84 (dd, J1 ) 1, J2 ) 17 Hz, 1H); 4.59 (d, J ) 6 Hz,
1H); 4.43 (d, J ) 14 Hz, 1H); 3.88 (d, J ) 16 Hz, 1H); 3.62 (dd,
J1 ) 2, J2 ) 13 Hz, 1H, A of an AB system); 3.55 (dd, J1 ) 4, J2
) 13 Hz, 1H, B of an AB system); 3.34 (dd, J1 ) 6, J2 ) 16 Hz,
1H); 3.23 (dd, J1 ) 6, J2 ) 16 Hz, 1H); 2.88 (d, J ) 16 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ: 164.5; 139.1; 134.7; 133.7; 129.9;
129.6; 129.5; 129.0; 128.7; 128.4, 128.3; 128.3; 128.2; 128.0; 125.7;
116.6; 60.7; 50.5; 40.1; 40.0; 29.5. MS(ES+): m/z 381 [M + Na]+.
HRMS(ES+): calcd for C22H22N4NaO 381.1691, found 381.1687.
2-(5-(Aminomethyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoic Acid
(27). General Procedure. A 6 M solution of HCl(aq) (2.7 mL) was
added to 7-benzyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-
one (19) (50 mg, 0.22 mmol), and the mixture was heated under
microwave conditions at 85 °C for three periods of 1 h each. The
solution was extracted with CHCl3 (4 × 3 mL) and the water layer
evaporated under vacuum to give compound 27 as a light orange
2H); 7.66 (m, 2H); 5.68 (m, 1H); 5.21 (d, J ) 18 Hz, 1H); 5.00 (d,
J ) 10 Hz, 1H); 4.39 (s, 2H); 2.85 (s, 2H). 13C NMR (100 MHz,
CDCl3) δ: 167.1; 134.1; 132.0; 132.0; 123.4; 116.3; 80.1; 75.9;
27.4; 22.9. MS(ES+): m/z 248 [M + Na]+. HRMS(ES+): calcd
for C14H11NNaO2 248.0687, found 248.0681.
Hex-5-en-2-yn-1-amine (30). N-2-(Hex-5-en-2-ynyl)phthalimide
(29) (600 mg, 2.66 mmol) was dissolved in a 33% solution of
MeNH2 in absolute EtOH (5 mL). The mixture was heated under
microwave conditions at 70 °C for 10 min. The crude reaction was
filtered twice over Celite with Et2O, and the solvent was evaporated
1
to obtain compound 30 as a yellow oil (243 mg, 96% yield). H
NMR (400 MHz, CDCl3) δ: 5.79 (m, 1H); 5.27 (d, J ) 11 Hz,
1H); 5.08 (d, J ) 9 Hz, 1H); 3.42 (s, 2H); 2.93 (s, 2H); 1.49 (bs,
2H). The product was not further purified and was used at this level
of purity in the synthesis of compounds 31-34.
Computational Details. All of the structures were constructed
by Ghemical31 software package and were optimized with MPQC32
software at the HF level of theory using the 6-21G basis set. All
fine calculations were performed at the DFT level using the
B3LYP33 hybrid functional and 6-31G** basis set on vacuum
within GAMESS(US) software, and the results were visualized with
MOLDEN34 or VMD35 software packages. Within the $CONTRL
group of options, QMTOLL was set to 10-6 and ICUT was set to
11. The DIRSCF flag ($SCF group) was activated. Stationary points
characterized as transition state showed the proper number of
imaginary harmonic vibrational frequencies. Molecular geometries
were fully optimized with gradient convergence set to 10-4 hartree/
bohr. In the saddle point searches, the Hessian was updated with
the mixed Murtagh-Sargent/Powell procedure.36 Intrinsic reaction
coordinate (IRC) calculations were used to verify the adjacent local
minima. IRC were traced at the B3LYP/6-31G** level of theory
from transition states toward both reactants and product directions
using the Gonza`lez-Schlegel algorithm.37 Potential energy profile
calculations for the dihedral angles (see the Results and Discussion)
were performed with same level of theory but with gradient
convergence set to 10-3 hartree/bohr.
1
waxy material (46 mg, 85% yield). H NMR (400 MHz, MeOD)
δ: 7.95 (bs, 1H); 7.17-7.06 (m, 6H); 5.82 (1H, X of an ABX
system); 4.12 (d, J ) 16 Hz, 1H); 3.93 (d, J ) 15 Hz, 1H); 3.63
(2H, AB of an ABX system). 13C NMR (100 MHz, MeOD) δ:
168.8; 135.8; 133.1; 132.4; 128.8; 128.4; 127.0; 63.3; 36.6, 31.6.
MS(ES+): m/z 269 [M
C12H14N4NaO2 269.1014, found 269.1008.
+
Na]+. HRMS(ES+): calcd for
2-(4-Allyl-5-(aminomethyl)-1H-1,2,3-triazol-1-yl)-3-phenylpro-
1
panoic Acid (40). Orange waxy material: 53 mg (84% yield). H
NMR (400 MHz, MeOD) δ: 7.15-7.04 (m, 6H); 5.90-5.78 (m,
2H); 5.04 (d, J ) 10 Hz, 1H); 4.89 (m, 1H); 3.97 (d, J ) 15 Hz,
1H); 3.86 (d, J ) 15 Hz, 1H); 3.71 (m, 1H); 3.57-3.45 (m, 3H).
13C NMR (100 MHz, MeOD) δ: 169.2; 145.0; 135.8; 129.4; 129.0;
128.7; 128.2; 127.9; 127.6; 126.4; 116.5; 63.6; 35.9; 29.3; 28.1.
MS(ES+): m/z 309 [M
C15H18N4NaO2 309.1327, found 309.1321.
+
Na]+. HRMS(ES+): calcd for
2-(4-Allyl-5-((benzylamino)methyl)-1H-1,2,3-triazol-1-yl)-3-phe-
nylpropanoic Acid (41). HCl concd (1 mL) was added to 3-allyl-
5,7-dibenzyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-one
(39) (40 mg, 0.11 mmol), and the mixture was submitted to
microwave dielectric heating at 150 °C for three periods of 1 h
each. The solution was evaporated and the crude reaction purified
by flash chromatography (eluent AcOEt), obtaining compound 41
as a yellow waxy material (17 mg, 41% yield). 1H NMR (400 MHz,
CDCl3) δ: 7.31-7.29 (m, 2H); 7.18-7.09 (m, 4H); 6.96-6.91 (m,
2H); 6.59 (d, J ) 7 Hz, 2H); 5.55-5.48 (m, 2H); 4.63-4.46 (m,
2H); 4.02-3.93 (m, 2H); 3.67-3.55 (m, 4H); 3.00 (d, J ) 16 Hz,
2H). MS(ES+): m/z 399 [M + Na]+. HRMS(ES+) calcd for
C22H24N4NaO2 399.1797, found 399.1791.
Acknowledgment. This work was financially supported by
the University of Siena (PAR project 2006) and MIUR (Rome,
PRIN project 2006).
Supporting Information Available: Chromatographic and
spectroscopic characterization of compounds 2, 3, 5-7, 13-27,
and 29-41 and atom coordinates and energies for compounds
15 and 43. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO802463R
N-2-(Hex-5-en-2-ynyl)phthalimide (29). A mixture of propargyl
phthalimide (28) (2.9 g, 15.67 mmol), allyl bromide (2.04 mL, 23.51
mmol), Na2SO3 (988 mg, 7.84 mmol), K2CO3 (2.16 g, 15.67 mmol),
DBU (1.25 mL, 8.37 mmol), and CuI (597 mg, 3.13 mmol) was
stirred at room temperature in DMF (25 mL) for 2 h. The solution
was then diluted with Et2O (70 mL) and washed with H2O (25 mL
× 5). The organic phase was dried over dry Na2SO4, filtered, and
evaporated, obtaining compound 29 as a white solid (3.33 g, 95%
(31) Hassinen, T.; Pera¨kyla¨, M. J. Comput. Chem. 2001, 22, 1229.
(32) The Massively Parallel Quantum Chemistry Program” (MPQC), Version
2.3.1. Janssen, C. L.; Nielsen, I. B.; Leininger, M. L.; Valeev, E. F.; Kenny,
J. P.; Seidl, E. T. Sandia National Laboratories, Livermore, CA, 2008.
(33) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(34) Schaftenaar, G.; Noordik, J. H. J. Comput. Aided. Mol. Des. 2000, 14,
123.
(35) Humphrey, W.; Dalke, A.; Schulten, K. J. Molec. Graphics 1996, 14,
33.
(36) Bofill, J. M. J. Comput. Chem. 1994, 15, 1.
(37) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523.
1
yield). Mp: 82-83 °C. H NMR (400 MHz, CDCl3) δ: 7.78 (m,
J. Org. Chem. Vol. 74, No. 3, 2009 1321