Amine-catalyzed [3+2] Huisgen cycloaddition strategy for the efficient assembly of highly substituted 1,2,3-triazoles

Article abstract of DOI:10.1002/chem.201103393

An enamine-catalyzed strategy has been utilized to fully promote the Huisgen [3+2] cycloaddition with a broad spectrum of carbonyl compounds and azides, thereby permitting the efficient assembly of a vast pool of highly substituted 1,2,3-triazoles. In par

Full text of DOI:10.1002/chem.201103393

DOI: 10.1002/chem.201103393
Amine-Catalyzed [3+2] Huisgen Cycloaddition Strategy for the Efficient
Assembly of Highly Substituted 1,2,3-Triazoles
Lei Wang, Shiyong Peng, Lee Jin Tu Danence, Yaojun Gao, and Jian Wang*[a]
Abstract: An enamine-catalyzed strat-
egy has been utilized to fully promote
the Huisgen [3+2] cycloaddition with
a broad spectrum of carbonyl com-
pounds and azides, thereby permitting
the efficient assembly of a vast pool of
highly substituted 1,2,3-triazoles. In
particular, the employment of com-
monly used and commercially available
carbonyl compounds has resulted in
the introduction of a diverse set of
functional groups, such as alkyl, aryl,
nitrile, ester, and ketone groups, at the
1-, 4-, or 5-positions of the 1,2,3-tria-
zole scaffold. This approach might be
manipulated to access more useful and
sophisticated heterocyclic compounds.
Most significantly, the reaction process
exhibits complete regioselectivity, with
the formation of only one regioisomer.
Keywords:
enamines
cycloaddition
organocatalysis
·
·
·
regiospecificity · triazoles
Introduction
Organocatalytic activation of readily available substrates
has led to the rapid development of many reactions in the
last decade.[1] Enamine catalysis, as one of the most power-
ful tools, has been extensively investigated, and has been re-
ported to facilitate a diverse set of transformations based on
the enamine intermediates generated in situ.[2] Although
many transformations have been reported, the enamine–
azide [3+2] Huisgen cycloaddition still remains a challenging
topic. Recently, we discovered the first examples of organo-
catalytic regiospecific enamide–azide [3+2] cycloadditions
of a-functionalized ketones to azides [Eq. (1)].[3] However,
we recognized that the substituents at the 4-position on the
1,2,3-triazole skeleton were essentially limited to electron-
withdrawing groups. This limitation may potentially restrict
the wider application of this synthetic methodology. Herein,
we wish to report our further endeavors in examples of
amine-catalyzed [3+2] cycloadditions of a broad spectrum
of carbonyl compounds and azides with a view to achieving
the efficient assembly of a vast pool of highly substituted
1,2,3-triazoles [Eq. (2)].[4]
1,2,3-triazole unit does not occur in Nature, it has biological
activity.[7] Thereby, the significance of triazole compounds in
medicinal chemistry is indubitable. In view of their occur-
rence in a broad spectrum of important pharmaceutically
active compounds, such as those examples outlined in Fig-
ure 1,[5u–w] highly substituted 1,2,3-triazoles continue to at-
tract ever increasing attention in the synthetic chemistry
community. Although elegant preparative methods for such
motifs have been reported, synthetic methodologies allowing
the rapid and regiospecific construction of 1,4,5-trisubstitut-
ed 1,2,3-triazoles tend to be extremely demanding.[8]
While some direct protocols leading to 1,2,3-triazoles
have been described, including tradition thermal[9] or metal-
free[8c,d,f] [3+2] cycloadditions of linear alkynes or highly
strained alkynes with azides, these reactions are often slow
because of high activation energies (ca. 16–24 kcalmolꢀ1),[10]
and also produce a mixture of regioisomers (Scheme 1). The
CuI-catalyzed azide–alkyne cycloaddition (CuAAC) has
been developed as a powerful tool to access 1,2,3-triazole
molecules, but is usually restricted to terminal alkynes and
The 1,2,3-triazole core is a prominent scaffold that is fea-
tured in a large number of bioactive molecules.[5] Addition-
ally, 1,2,3-triazole moieties are attractive connections in bio-
logical systems because they are stable to metabolic degra-
dation and capable of hydrogen bonding to biomolecular
targets, which can also improve solubility.[6] Although the
[a] L. Wang, S. Peng, L. J. T. Danence, Y. Gao, Prof. Dr. J. Wang
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax : (+65)6516-1691
E-mail: chmwangj@nus.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103393.
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FULL PAPER
Figure 1. Representative examples of bioactive 1,2,3-triazoles.
Figure 2. Evaluation of organocatalysts.
became apparent that the ring size is not crucial for reaction
yield and rate (Figure 2, 33% and 44% yield, respectively).
Moreover, a diverse set of acyclic secondary amines was
tested (V, VI, VII), but these exhibited inferior catalytic per-
formances (24%, <5%, and <5%, respectively). Besides
secondary amines, primary amine IX and tertiary amine
VIII were also evaluated in this model reaction system. As
shown in Figure 2, tertiary amine VIII displayed no catalytic
activity in the process (<5% yield). Primary amine IX af-
forded only a 26% yield in 24 h. Finally, an unsubstituted,
less bulky secondary amine, pyrrolidine II, displayed
a higher activity (84%, 24 h). After identifying the suitable
catalyst II, we attempted to optimize the reaction by system-
atically varying several other parameters. Initially, various
solvents including N-methylpyrrolidine> (NMP), DMF, di-
methylacetamide (DMA), MeOH, 1,4-dioxane, 1,2-dichloro-
ethane (DCE), toluene, and CH3CN were screened (see the
Supporting Information), and we eventually concluded that
higher yields in polar solvents were most likely due to
strengthened polar interactions between substrate and cata-
lyst. Screening showed that no obvious improvement in re-
action rate or yield could be achieved in other solvents. We
also investigated the effects of temperature and catalyst
loading (see the Supporting Information). As expected,
a lower temperature (508C) or lower catalyst loading
(5 mol%) incurred a significant decrease in yield. Conse-
quently, the use of pyrrolidine II in DMSO was found to
lead to satisfactory results in the organocatalytic enamine–
azide [3+2] cycloaddition process.
Scheme 1. Methods for the synthesis of highly substituted 1,2,3-triazoles.
only facilitates 1,4-disubstituted 1,2,3-triazole formation
(Scheme 1).[11] In addition, in spite of its vast success in in-
dustry, this strategy is not ideal for biological applications.
Recent studies have indicated that CuI can cause oxidative
DNA degradation,[12] although careful selection of CuI-stabi-
lizing ligands can avoid DNA degradation and even facili-
tate this cycloaddition process in living organisms.[13] Howev-
er, Cu is intrinsically cytotoxic and this may remain an issue
when pharmaceutical therapeutics are desired. Therefore, in
the search for an ideal strategy to replace known methods,
we believe that a metal-free, enamine-catalyzed, and broad
substrate-tolerant method may offer a preferred solution.
Results and Discussion
Once the optimized conditions had been identified
(Figure 2), various substrates were examined. The scope of
the amine-catalyzed [3+2] Huisgen cycloaddition of azides
is indicated by the examples listed in Table 1. It was found
that the pyrrolidine II-catalyzed cycloaddition was applica-
ble to a variety of azides 1a–l to afford 1,2,3-triazoles in
moderate to high yields (Table 1, 45–88%). The reactions
proceeded smoothly and were little affected by the electron-
ic nature of the substituents on the aromatic ring. Electron-
withdrawing (Table 1, entries 5, 6, and 8), electron-donating
Optimization studies of organocatalytic enamine–azide
[3+2] cycloaddition were initiated by an investigation of
phenyl azide 1a and cyclohexanone 2a in the presence of
a catalytic amount of the secondary a-amino acid l-proline
(I; Figure 2). The initial experimental result showed that
only 40% yield was obtained in 24 h. With a view to im-
proving the catalytic activity, we then examined six-mem-
bered-ring-based secondary amine catalysts III and IV. It
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J. Wang et al.
Table 1. Substrate scope of azides.[a]
bered-ring ketones, we reduced the catalyst loading from
20 mol% to 10 mol%. The reaction still afforded an 89%
yield in 30 h (Table 2, entry 7). It is noteworthy that acyclic
ketones also gave appreciable reaction yields (Table 2, en-
tries 9 and 10). For example, the asymmetric acyclic ketone
2-butanone 2j gave a 75% yield of 3aj in 24 h (Table 2,
entry 9), and no other regioisomers were observed. We
deduce that the thermodynamically controlled enamine for-
mation of 2-butanone 2j affects the regioselectivity of this
reaction. The symmetric acyclic ketone 3-pentanone 2k
gave a 65% yield of 3ak in 20 h. Additionally, a phenyl-
ring-fused cyclohexanone 2l also reacted at room tempera-
ture (Table 2, entry 11) to afford 3al, albeit in a slightly
lower yield (57%, 10 h) due to some decomposition of this
product under the reaction conditions. Besides the above
types of ketones 2a–l, we also examined some a-functional-
ized ketones (Table 2, entries 12–16). Gratifyingly, b-ketoni-
trile 2m, 1,3-diketone 2n, and a-ester ketone 2o reacted ef-
ficiently, giving high product yields (Table 2, entries 12–14,
90–95%). Moreover, alkyl azide 1m could be reacted with
active b-ketonitrile 2m to afford an appreciable synthetic
yield of 3mm (Table 2, entry 16, 80%, 24 h). In contrast to
our previously reported results for reactions catalyzed by an
acyclic secondary amine catalyst (diethylamine V),[3] we
found that the cyclic secondary amine (pyrrolidine II) could
also efficiently catalyze such transformations under the opti-
mized reaction conditions. The regioselectivities of products
3aa[14] and 3ac[15] were determined by single-crystal X-ray
diffraction analysis.
To further extend the scope in terms of azides, we pro-
ceeded to examine tosyl azide 1n. As shown in Equa-
tion (3), the reaction with this substrate was completely dif-
ferent. In this case, pyrrolidine II served as a starting materi-
al, providing easy access to the biologically interesting N-
tosyl amidine 3na[16] in 85% yield. We deduce that when the
triazoline ring bears an electron-withdrawing group at the
N1-position, it is very labile. Thus, the initially formed tria-
zoline intermediate decomposes immediately to produce
amidine 3na through rearrangement with the loss of N2. Sur-
prisingly, l-proline showed no activity in this reaction. How-
ever, b-tetralone 2l reacted with tosyl azide 1n in the pres-
ence of l-proline to efficiently produce the desired triazole
compound 3nl (Equation (4), 85%, 5 h, RT). In this case, no
amidine product was formed. This may possibly be attribut-
ed to the steric hindrance of the carboxylic group, which
would inhibit the potential rearrangement and prohibit the
formation of the crowded amidine. Subsequent attempts to
subject two linear aldehydes (propionaldehyde 2r and 2-
phenylacetaldehyde 2s) to the reaction were unsuccessful.
The failure to obtain the desired triazoles might be attribut-
ed to a competitive self-aldol reaction.
Entry
1
R
Product[b]
Entry
7
R
Product[b]
3aa; 84%
24 h
3ga; 75%
12 h
3ba; 88%; 16 h
3ha; 62%
24 h
2
3
8
9
(78%; 30 h)[c]
3ca; 85%
14 h
3ia; 45%
18 h
3da; 72%
12 h
3ja; 80%
20 h
4
10
3ea; 72%
16 h
3ka; 67%
10 h
5
6
11
12
3 fa; 68%
18 h
3la; 60%
16 h
[a] Reaction conditions: 1a–i (0.25 mmol, 1.0 equiv), 2a (0.5 mmol,
2.0 equiv), DMSO (0.5 mL), 20 mol% catalyst II at 808C. [b] Yield of
isolated product. [c] 10 mol% of catalyst.
(Table 1, entries 2–4 and 10), or electron-neutral (Table 1,
entry 1) groups on the phenyl ring of the azide did not
affect the reaction. In some cases, a steric interaction ap-
peared to have a negative effect on the reaction yield. For
example, the presence of an ester group at the o-position of
the phenyl ring led to a lower yield (Table 1, entry 9, 45%).
Notably, a naphthalene ring was also tolerated in this reac-
tem (Table 1, entry 12, 60%). If a lower catalyst loading
(10 mol%) was employed, the reaction still afforded a good
yield in a reasonable time (Table 1, 78%, 30 h). However,
the reaction dramatically slowed down (<5% yield, 24 h)
when an alkyl (ethyl group) azide was applied to replace the
phenyl azide. Slow conversion of starting material was de-
tected by 1H NMR analysis.
Having investigated the reactivity of azides, we then eval-
uated carbonyls (Table 2). To our delight, this method can
tolerate a broad range of unmodified, commercially avail-
able carbonyl compounds. Cyclic six-member ring based ke-
tones gave good to high yields (Table 2, entries 1–6). This
six-member ring can bear alkyl, ester, dialkyl, or ketal
groups at the b- or g-positions with respect to the ketone
function (Table 2, entries 1–5). Furthermore, the six-mem-
bered ring can also incorporate a heteroatom (Table 2,
entry 6). Interestingly, seven- or eight-membered-ring cyclic
ketones also efficiently provided high yields under the stan-
dard conditions, thus demonstrating that the ring size of the
ketone had little effect on this cycloaddition (Table 2, en-
tries 7 and 8, 94% and 85%, respectively). To verify the
high reaction efficiency seen with seven- or eight-mem-
To demonstrate the synthetic utility of this methodology,
we applied it to the synthesis of a CB1 cannabinoid receptor
antagonist (Scheme 2). The pyrrolidine II-catalyzed Huisgen
[3+2] cycloaddition between azide 1o and b-keto ester 2q
under optimized conditions (see Figure 2 and the Supporting
Information) furnished the intermediate 3oq in 98% yield
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Triazole Synthesis by Enamine–Azide Cycloaddition
FULL PAPER
Scheme 3. Plausible reaction mechanism.
intermediate 5. The results of the catalyst screening suggest-
ed that the process catalyzed by an organic base, such as ter-
tiary amine VIII (Figure 2, <5% yield), will not be the
main contribution for 1,2,3-triazole synthesis. Thereafter,
a plausible 1,3-hydride shift might assist the formation of
a zwitterion. Finally, an elimination step regioselectively
generated the final product, 1,2,3-triazole 3aa. Meanwhile,
the catalyst II was released and could partake in the next
catalytic cycle. According to our experimental evidence, we
predict that the rate-determining step is probably the 1,3-di-
polar cycloaddition process. The observation of enamine for-
mation by LC-MS suggests that the catalytic cycle accumu-
lates at this stage. In addition, no further evidence indicates
the presence of the triazoline intermediate 5. Finally, we are
aware that the identification of an active catalytic enamine
species will provide a more reliable validation of this reac-
tion mechanism.
Scheme 2. Synthesis of CB1 cannabinoid receptor antagonist.[17]
in 0.5 h. Compound 3oq is a key intermediate that can be
converted into the target CB1 cannabinoid receptor antago-
nist by a known method.
Conclusion
Driven by the lack of an efficient synthesis of highly substi-
tuted 1,2,3-triazoles, we have developed an enamine-cata-
lyzed strategy, using a small organic molecule as organocata-
lyst, to fully promote Huisgen [3+2] cycloaddition reactions.
This strategy has been applied to a broad spectrum of car-
bonyl compounds and azides, thereby providing efficient
access to a vast pool of highly substituted 1,2,3-triazoles. In
particular, the employment of commonly used and commer-
cially available carbonyl compounds has allowed the intro-
duction of a diverse set of functional groups, such as alkyl,
aryl, nitrile, ester, and ketone groups, at the 1-, 4-, or 5-posi-
tions of the 1,2,3-triazole scaffold. This approach might be
further manipulated to access more useful and sophisticated
heterocyclic compounds. Most significantly, the reaction pro-
cess exhibits complete regioselectivity, with no regioisomer
As shown in Scheme 3, we propose a plausible catalytic
cycle to explain the reaction pathway. While the reaction
mechanism is still unclear at this stage, it is believed that the
sequence is triggered by the generation of enamine 4 by the
condensation of ketone 2a and pyrrolidine catalyst II. En-
amine 4 acts as the electron-rich olefinic partner, and reacts
with phenyl azide 1a in a Huisgen 1,3-dipolar cycloaddition
process to afford the intermediate, triazoline 5. Most impor-
tantly, this process demonstrates a complete and unique re-
giospecificity, which allowed us to readily introduce a diverse
set of functional substituents at the desired 1-, 4-, and 5-po-
sitions. In fact, besides an enamine-triggered cycloaddition
process, an enolate-triggered cycloaddition process catalyzed
by an organic base may also potentially afford the desired
Chem. Eur. J. 2012, 18, 6088 – 6093
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J. Wang et al.
Table 2. Substrate scope of carbonyl compounds.[a]
Experimental Section
General procedure for amine-catalyzed Huisgen [3+2] cyclo-
addition: The catalyst pyrrolidine II (4.1 mL, 0.05 mmol,
0.2 equiv) was added to
a solution of phenyl azide 1a
(0.25 mmol, 1 equiv) and cyclohexanone 2a (0.5 mmol,
2.0 equiv) in DMSO (0.5 mL), and the reaction mixture was
stirred at 808C for 24 h. The crude product was purified by
column chromatography on silica gel, eluting with hexane/
EtOAc (10:1 ! 4:1), to afford the desired product 3aa (42 mg,
84% yield) as a pale-yellow oil. 1H NMR (500 MHz, CDCl3):
d=7.57–7.50 (m, 4H), 7.47–7.43 (m, 1H), 2.85 (t, J=4.9 Hz,
2H), 2.75 (t, J=5.0 Hz, 2H), 1.93–1.84 ppm (m, 4H);
13C NMR (125 MHz, CDCl3): d=144.43, 137.37, 132.47, 129.89,
129.02, 123.56, 23.20, 22.92, 22.39, 22.27 ppm; HRMS (ESI):
calcd for C12H14N3 [M+H]+ 200.1182, found 200.1186.
Entry 2b–i
Product[b]
Entry 2j–p
Product[b]
1
9
2
3
10
11[d]
Acknowledgements
We gratefully acknowledge the National University of Singa-
pore and Ministry of Education (Singapore) for financial sup-
4
5
6
12
port
(Academic
Research
Grants
R143000408133,
R143000408733, R143000443112, and R143000480112). We
also thank Dr. Tan Geok Kheng for performing X-ray crystal
structure analysis.
13[e]
[1] For reviews and books, see: a) P. I. Dalko, L. Moisan,
Angew. Chem. 2001, 113, 3840; Angew. Chem. Int. Ed.
2001, 40, 3726; b) M. Benaglia, A. Puglisi, F. Cozzi, Chem.
Rev. 2003, 103, 3401; c) A. Berkessel, H. Grçger, in
Metal-Free Organic Catalysts in Asymmetric Synthesis,
Wiley-VCH, Weinheim, 2004; d) “Special Issue: Asym-
metric Organocatalysis”, Acc. Chem. Res. 2004, 37, 487;
e) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116, 5248; .
Chem. Int. Ed. 2004, 43, 5138; f) J. T. Mohr, M. R. Krout,
B. M. Stoltz, Nature 2008, 455, 323; g) D. W. C. MacMil-
lan, Nature 2008, 455, 304; h) A. Berkessel, H. Grçger, in
Asymmetric Organocatalysis, Wiley-VCH, Weinheim,
2005; i) P. I. Dalko, in Enantioselective Organocatalysis,
Wiley-VCH, Weinheim, 2007; j) M. T. Reetz, B. List, S.
Jaroch, H. Weinmann, in Organocatalysis, Springer,
Berlin, 2007; k) B. List, in Asymmetric Organocatalysis,
Springer, Heidelberg, 2009.
14[e]
7
8
15[e]
16[e]
[2] For selected reports and reviews, see: a) B. List, R. A.
Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000, 122,
2395; b) B. List, J. Am. Chem. Soc. 2000, 122, 9336;
c) K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J.
Am. Chem. Soc. 2000, 122, 4243; d) S. Mukherjee, J. W.
Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471.
[3] L. J. T. Danence, Y. J. Gao, M. G. Li, Y. Huang, J. Wang,
Chem. Eur. J. 2011, 17, 3584.
[a] Reaction conditions: 1a–i (0.25 mmol, 1.0 equiv), 2a (0.5 mmol, 2.0 equiv), DMSO
(0.5 mL), 20 mol% II at 808C. [b] Yield of isolated product. [c] 10 mol% of II.
[d] Room temperature. [e] 708C.
formation. The versatility of amine-catalyzed Huisgen cyclo-
addition seems endless, yet we are still in the early develop-
[4] In the process of submitting this manuscript, Bressy’s group pub-
lished similar work (Chem. Eur. J. 2011, 17, 12927–12931). Our
group has previously reported enamine–azide [3+2] methodology
(ref. [3]).
ment stages of this concept-driven research. In addition, we
believe that the presented methodology will open access to
more interesting compounds for potential biological evalua-
tion. Further extension of this synthetic strategy to other
types of reactions is under way in our laboratory and our re-
sults will be presented in due course.
[5] For selected reports and reviews, see: a) R. Kharb, P. C. Sharma,
M. S. Yar, J. Enzyme Inhib. Med. Chem. 2011, 26, 1; b) R. S. Boha-
cek, C. McMartin, W. C. Guida, Med. Res. Rev. 1996, 16, 3; c) M.
Meldal, C. W. Tornoe, Chem. Rev. 2008, 108, 2952; d) Y. L. Angell,
K. Burgess, Chem. Soc. Rev. 2007, 36, 1674; e) F. Pagliai, T. Pirali,
E. D. Grosso, R. D. Brisco, G. C. Tron, G. Sorba, A. A. Genazzani,
J. Med. Chem. 2006, 49, 467; f) T. Lee, M. Cho, S.-Y. Ko, H.-J. Youn,
D. J. Baek, W.-J. Cho, C.-Y. Kang, S. Kim, J. Med. Chem. 2007, 50,
585; g) G. Smith, M. Glaser, M. Perumal, Q.-D. Nguyen, B. Shan, E.
Arstad, E. O. Aboagye, J. Med. Chem. 2008, 51, 8057; h) C.-B. Yim,
6092
www.chemeurj.org
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Triazole Synthesis by Enamine–Azide Cycloaddition
FULL PAPER
I. Dijkgraaf, R. Merkx, C. Versluis, A. Eek, G. E. Mulder, D. T. S.
Rijkers, O. C. Boerman, R. M. J. Liskamp, J. Med. Chem. 2010, 53,
3944; i) F. Pisaneschi, Q.-D. Nguyen, E. Shamsaei, M. Glaser, E.
Robins, M. Kaliszczak, G. Smith, A. C. Spivey, E. O. Aboagye,
Bioorg. Med. Chem. 2010, 18, 6634; j) D. Imperio, T. Pirali, U. Galli,
F. Pagliai, L. Cafici, P. L. Canonico, G. Sorba, A. A. Genazzani,
G. C. Tron, Bioorg. Med. Chem. 2007, 15, 6748; k) I. Carvalho, P.
Andrade, V. L. Campo, P. M. M. Guedes, R. Si-Costa, J. S. Silva, S.
Schenkman, S. Dedola, L. Hill, M. Rejzek, S. A. Nepogodiev, R. A.
Field, Bioorg. Med. Chem. 2010, 18, 2412; l) Y. Saito, V. Escuret, D.
Durantel, F. Zoulim, R. F. Schinazic, L. A. Agrofoglio, Bioorg. Med.
Chem. 2003, 11, 3633; m) R. V. Somu, H. Boshoff, C. Qiao, E. M.
Bennett, C. E. Barry III, C. C. Aldrich, J. Med. Chem. 2006, 49, 31;
n) R. P. Tripathi, A. K. Yadav, A. Ajay, S. S. Bisht, V. Chaturvedi,
S. K. Sinha, Eur. J. Med. Chem. 2010, 45, 142; o) N. S. Vatmurge,
B. G. Hazra, V. S. Pore, F. Shirazi, P. S. Chavan, M. V. Deshpande,
Bioorg. Med. Chem. Lett. 2008, 18, 2043; p) O. A. Phillips, E. E.
Udo, M. E. Abdel-Hamid, R. Varghese, Eur. J. Med. Chem. 2009,
44, 3217; q) T. B. Stensbøl, P. Uhlmann, S. Morel, B. L. Eriksen, J.
Felding, H. Kromann, M. B. Hermit, J. R. Greenwood, H. Brauner-
Osborne, U. Madsen, F. Junager, P. Krogsgaard-Larsen, M. Begtrup,
P. Vedso, J. Med. Chem. 2002, 45, 19; r) T. Harrison, A. P. Owens,
B. J. Williams, C. J. Swain, A. Williams, E. J. Carlson, W. Rycroft,
F. D. Tattersall, M. A. Cascieri, G. G. Chicchi, S. Sadowski, N. M. J.
Rupniak, R. J. Hargreaves, J. Med. Chem. 2001, 44, 4296; s) T. Balle,
J. Perregaard, M. T. Ramirez, A. K. Larsen, K. K. Søby, T. Liljefors,
K. Andersen, J. Med. Chem. 2003, 46, 265; t) J. Roppe, N. D. Smith,
D. Huang, L. Tehrani, B. Wang, J. Anderson, J. Brodkin, J. Chung,
X. Jiang, C. King, B. Munoz, M. A. Varney, P. Prasit, N. D. P. Cos-
ford, J. Med. Chem. 2004, 47, 4645; u) M. J. Fray, D. J. Bull, C. L.
Carr, E. C. L. Gautier, C. E. Mowbray, A. Stobie, J. Med. Chem.
2001, 44, 1951; v) D. K. Mohapatra, P. K. Maity, M. Shabab, M. I.
Khan, Bioorg. Med. Chem. Lett. 2009, 19, 5241; w) C. Gill, G.
Jadhav, M. Shaikh, R. Kale, A. Ghawalkar, D. Nagargoje, M. Shirad-
kar, Bioorg. Med. Chem. Lett. 2008, 18, 6244.
49, 2607; c) J. M. Baskin, J. A. Prescher, S. T. Laughlin, N. J. Agard,
P. V. Chang, I. A. Miller, A. Lo, J. A. Codelli, C. R. Bertozzi, Proc.
Natl. Acad. Sci. USA 2007, 104, 16793; d) N. J. Agard, J. A. Prescher,
C. R. Bertozzi, J. Am. Chem. Soc. 2004, 126, 15046; e) D. B. Ram-
achary, K. Ramakumar, V. V. Narayana, Chem. Eur. J. 2008, 14,
9143; f) T. Plass, S. Milles, C. Koehler, C. Schultz, E. A. Lemke,
Angew. Chem. 2011, 123, 3964; Angew. Chem. Int. Ed. 2011, 50,
3878.
[9] a) A. Michael, J. Prakt. Chem. 1893, 48, 94; b) R. Huisgen, Angew.
Chem. 1963, 75, 604; Angew. Chem. Int. Ed. Engl. 1963, 2, 565; c) R.
Huisgen, Angew. Chem. 1963, 75, 742; Angew. Chem. Int. Ed. Engl.
1963, 2, 633.
[10] a) V. O. Rodionov, V. V. Fokin, M. G. Finn, Angew. Chem. 2005, 117,
2250; Angew. Chem. Int. Ed. 2005, 44, 2210; b) F. Himo, T. Lovell,
R. Hilgraf, V. V. Rostovtesv, L. Noodleman, K. B. Sharpless, V. V.
Fokin, J. Am. Chem. Soc. 2005, 127, 210.
[11] a) V. V. Rostovtesv, L. G. Green, V. V. Fokin, K. B. Sharpless, J. Am.
Chem. Soc. 2002, 114, 2708; b) C. W. Tornøe, C. Christensen, M.
Meldal, J. Org. Chem. 2002, 67, 3057.
[12] a) J. Gierlich, G. A. Burley, P. M. E. Gramlich, D. M. Hammond, T.
Carell, Org. Lett. 2006, 8, 3639; b) L. M. Gaetke, C. K. Chow, Toxi-
cology 2003, 189, 147; c) A. J. Link, D. A. Tirrell, J. Am. Chem. Soc.
2003, 125, 11164.
[13] a) D. Soriano del Amo, W. Wan, H. Jiang, C. Besanceney, A. C. Yan,
M. Levy, Y. Liu, F. L. Marlow, P. Wu, J. Am. Chem. Soc. 2010, 132,
16893; b) T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org.
Lett. 2004, 6, 2853.
[14] CCDC-837111 (3aa) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
[15] CCDC-846218 (3ac) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
[6] a) D. K. Dalvie, A. S. Kalgutkar, S. C. Khojasteh-Bakht, R. S.
Obach, J. P. O’Donnell, Chem. Res. Toxicol. 2002, 15, 269; b) W. S.
Horne, M. K. Yadav, C. D. Stout, M. R. Ghadiri, J. Am. Chem. Soc.
2004, 126, 15366.
[16] CCDC-846217 (3na) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
[7] M. I. Garcꢁa-Moreno, D. Rodriguez-Lucena, C. O. Mellet, J. M. G.
Fernandez, J. Org. Chem. 2004, 69, 3578.
[17] H. Shu, S. Izenwasser, D. Wade, E. D. Stevens, M. L. Trudell,
Bioorg. Med. Chem. Lett. 2009, 19, 891.
[8] For selected examples of the synthesis of 1,4,5-trisubstituted 1,2,3-
triazoles, see: a) C. Spiteri, J. E. Moses, Angew. Chem. 2010, 122, 33;
Angew. Chem. Int. Ed. 2010, 49, 31; b) Y. Zhou, T. Lecourt, L. Mi-
couin, Angew. Chem. 2010, 122, 2661; Angew. Chem. Int. Ed. 2010,
Received: October 28, 2011
Revised: February 14, 2012
Published online: March 29, 2012
Chem. Eur. J. 2012, 18, 6088 – 6093
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6093