Ln[N(SiMe3)2]3-catalyzed cycloaddition of terminal alkynes to azides leading to 1,5-disubstituted 1,2,3-triazoles: New mechanistic features

Article abstract of DOI:10.1039/c3cc42534g

The first example of rare earth metal-catalyzed cycloaddition of terminal alkynes to azides resulting in the formation of 1,5-disubstituted 1,2,3-triazoles is described. Preliminary studies revealed that the present cycloaddition shows unprecedented mecha

Full text of DOI:10.1039/c3cc42534g

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Ln[N(SiMe3)2]3-catalyzed cycloaddition of terminal
alkynes to azides leading to 1,5-disubstituted
1,2,3-triazoles: new mechanistic features†‡
Cite this: DOI: 10.1039/c3cc42534g
Received 8th April 2013,
Accepted 29th April 2013
Longcheng Hong,a Weijia Lin,a Fangjun Zhang,a Ruiting Liua and Xigeng Zhou*ab
DOI: 10.1039/c3cc42534g
www.rsc.org/chemcomm
The first example of rare earth metal-catalyzed cycloaddition of use of stoichiometric or even large excess amounts of strong bases
terminal alkynes to azides resulting in the formation of 1,5-disub- and the problem of generating waste. Although a few reports of the
stituted 1,2,3-triazoles is described. Preliminary studies revealed metal-catalyzed version that forms regioselectively 1,5-disubstituted
that the present cycloaddition shows unprecedented mechanistic 1,2,3-triazoles have appeared recently, all the reactions require the
features involving a tandem anionic cascade cyclization and anti- use of expensive ruthenium complexes as catalysts.2a,12 Very recently,
R
addition across the C C triple bond.
Fokin et al. reported the first base-catalyzed cycloaddition of terminal
alkynes and azides, which provides access to 1,5-diaryl-substituted
The development of synthetic methods for the construction of triazoles.13 Nevertheless, the reaction is limited to aryl acetylenes and
substituted 1,2,3-triazoles has been of longstanding importance in aryl azides. Therefore, there still exists a need for the development of
organic chemistry1,2 because of the frequent existence of such new and mild methods for obtaining 1,5-disubstituted 1,2,3-triazoles
structures in biologically active molecules,3 natural products4 and under conditions tolerated by sensitive functional groups.
designed materials1d,5 as well as their role as synthetic intermediates6
Despite significant advances in activation of C–H bonds,14 there
and ligands.7 Among them the cycloaddition of alkynes with azides is has been no precedent for the formation of heterocycles by organo-
an exceedingly attractive method for the construction of 1,2,3-triazole lanthanide-catalyzed tandem insertion of unsaturated C–C and
derivatives in a highly atom economical manner.1 Furthermore, the heteroatom-containing functional groups into the C–H bond.
reaction also provides a simple method for labeling oligonucleotides Heteroatoms often coordinate more strongly to rare earth metals
with fluorescent dyes, sugars, peptides and other reporter groups, than alkenes (alkynes) and inhibit such catalytic turnover. On the
probing the binding landscapes of biological molecules, and modi- other hand, an important challenge during organolanthanide-cata-
fying DNA.8 Much attention has been paid to the development of the lyzed intramolecular addition–cyclization reaction of unsaturated
catalytic systems for such cycloadditions in the last decade. The substrates remains the versatile control of the regioselectivity, in
pioneering studies show that copper6a,9 and silver10 can effect the which exocyclic products resulting from syn-addition are generally
catalytic cycloaddition of terminal alkynes to azides in the presence obtained.15 Our continuous interest in organolanthanide-catalyzed
of a base or acid, forming 1,4-disubstituted 1,2,3-triazoles regioselec- transformations of alkynes16 prompted us to explore the possibility
tively. In contrast, there are as yet few satisfactory catalytic systems for of using a combination of tandem inter- and intramolecular inser-
the regioselective formation of 1,5-disubstituted 1,2,3-triazoles. tion into the lanthanide–ligand bond and the C–H bond activation
Typical synthetic routes to the corresponding 1,5-disubstituted as key steps for the catalytic cycloaddition of alkynes with azides.
regioisomers employ the reaction of azides with the in situ generated Herein, we report the results.
sodium, lithium, or magnesium acetylides.1e,11 However, these syn-
We initiated our research on the model reaction of benzyl
thetic approaches suffer some disadvantages, such as the required azide with phenylacetylene under different reaction conditions
(Table 1). 1,5-Disubstituted 1,2,3-triazole (3aa) was obtained in
75% isolated yield upon treatment of a 1 : 1 mixture of 1a and
2a with 5 mol% Sm[N(SiMe3)2]3 in toluene at 50 1C (entry 2).
a Department of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and
Innovative Materials, Fudan University, Shanghai 200433, People’s Republic of
The structure of 3aa was confirmed by X-ray diffraction
analysis.12a Screening of the solvents gave toluene as the
solvent of choice (entries 2 and 5–10). Examination of different
rare earth metal catalysts revealed Sm[N(SiMe3)2]3 as the best
catalyst (entries 2 and 11–13). As observed in the previous
China. E-mail: xgzhou@fudan.edu.cn; Fax: +86-21-65643769;
Tel: +86-21-65643769
b State Key Laboratory of Organometallic Chemistry, Shanghai 200032,
People’s Republic of China
† Dedicated to Professor Xiaozeng You on the occasion of his 80th birthday.
‡ Electronic supplementary information (ESI) available: Detailed description of
experimental procedures, characterization of all compounds. See DOI: 10.1039/
c3cc42534g
n
reports,16b,17 the presence of 10 mol% BuNH2 could improve
the yield (entry 14).
c
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Table 1 Optimization of the reaction conditionsa
Table 2 Sm[N(SiMe3)2]3-catalyzed cycloaddition of terminal alkynes with azidesa
Entry
Ln
Solvent
T/1C
Additive
Yieldb (%)
1
2
3
4
5
6
7
8
Sm
Sm
Sm
Sm
Sm
Sm
Sm
Sm
Sm
Sm
Nd
Y
Gd
Sm
Sm
Sm
Sm
Sm
Toluene
Toluene
Toluene
Toluene
THF
DMF
DMSO
25
50
75
Reflux
50
50
50
50
50
50
50
50
50
50
50
50
50
50
64 (59)
80 (75)c
74 (66)
63
54
34
35
35
37
42
73 (65)
67 (61)
68 (60)
88 (82)c
47 (40)
73 (65)
48 (40)
91 (85)
CH3CN
DCE
9
10
11
12
13
14
15
16
17
18d
Hexane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
nBuNH2
PhNH2
iPr2NH
Et3N
nBuNH2
a
1a (0.2 mmol), 2a (0.2 mmol), catalyst (0.01 mmol), additive (10 mol%),
solvent (1 mL) for 24 h under N2. b Yield determined using GC-MS with
isopropylbenzene as an internal standard, and isolated yields in parentheses.
c Average of three runs. d 0.24 mmol of 2a was used.
a
1 (0.4 mmol), 2 (0.48 mmol), Sm[N(SiMe3)2]3 (0.02 mmol), nBuNH2
(10 mol%), toluene (2 mL) for 24 h at 50 1C under N2, isolated yield of 3.
b
2.4 equiv. of 2a was used.
Different azides and alkynes were then applied to evaluate the
reaction substrate scope. As shown in Table 2, the protocol is
effective for the transformation of a number of different substrate
combinations. Aryl azides (1e–1j) are more reactive than alkyl azides
(1a–1d), which might be attributed to the fact that the aryl ring is
favorable to the delocalization of negative charge to its neighboring
N atom by conjugation, leading to the strengthening nucleophilicity
of the N atom in the cyclization process. The reaction was hardly
affected by non-coordinated substituents at the para position of
aromatic azides (1f–1h). However, o-methoxyphenyl azide (1i) pro-
duced 3ia in moderate yield, which might be a consequence of the
chelating coordination capable of increasing the kinetic inertness
and thermodynamical stability of the Ln–N bond. In addition, the
competing coordination of nitro to the metal led to the decrease in
yield (3ka) too. Similarly, the strong chelating coordination of the
pyridyl group reduces the reactivity of alkyne (2j).
Scheme 1 The role of lanthanide acetylides as a reaction trigger.
attempts to catalyze cycloaddition of 1e to 2a using Yb(OTf)3 were
unsuccessful (Scheme 1). However, (PhCRC)Y[N(SiMe3)2]2 could
undergo the cyclization with 1e, giving the hydrolysis product 3ea
in 48% yield (Scheme 2). These results suggest that the formation
of the acetylide complex intermediate should be involved in the
reaction and play an important role in both determining the
reactivity trend of alkynes and controlling selectivity.
Based on the results described above, a plausible reaction path-
way for Ln[N(SiMe3)2]3-catalyzed cycloaddition of terminal alkynes to
azides is shown in Scheme 3. Terminal alkyne C–H bond activation
leads to the formation of lanthanide acetylide (A) together with
liberation of HN(SiMe3)2. Coordination and subsequent 1,1-insertion
of azide into the Ln–C bond of A gives the key intermediates
(C and D).18 Subsequently, the intramolecular anti-nucleophilic
attack of the far N atom to the p-coordinated alkyne moiety would
lead to the formation of triazolate complex (E). Finally, protonation
of E with another alkyne affords 3 and regenerates A (Path a).
Alternatively, the catalytic cycle might be carried out via Path b.
In contrast to the observation in the base-catalytic system,13
aliphatic azides (1a–1d) and aliphatic alkynes (2b, 2c, 2g, 2k) worked
well under the current conditions, affording the corresponding
triazoles (3aa–3af, 3ba–3da, 3eb, 3ec, 3eg and 3ek) in moderate to
excellent yields. 1-Azido-4-(azidomethyl)benzene gave the mono- and
dicyclization products 3la and 4la, respectively, depending on the
stoichiometric ratio. However, reaction of hexa-1,5-diyne (2k) with 1e
afforded only the monocyclization product 3ek as the main product.
All the previously reported metal-catalyzed cycloadditions of
azides with alkynes proceeded through a sequential oxidative-
coupling–reductive-cyclization pathway.9,12 Obviously, the present
cycloaddition is likely to operate through another mechanistic
pathway. To gain a better understanding of how the cyclization
occurs under these conditions, we examined the reaction of
PhCRCPh with PhN3 in the presence of Sm[N(SiMe3)2]3, indi-
cating that no cycloaddition product was formed. In addition, Scheme 2 Cyclization of yttrium acetylide with phenyl azide.
c
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Rev., 2010, 39, 1233; (e) L. Casarrubios, M. C. de la Torre and
M. A. Sierra, Chem.–Eur. J., 2013, 19, 3534.
´
2 (a) J. R. Johansson, P. Lincoln, B. Norden and N. Kann, J. Org. Chem.,
´
´
2011, 76, 2355; (b) S. Lal and S. Dıez-Gonzalez, J. Org. Chem., 2011,
76, 2367; (c) J. H. Li, D. Wang, Y. Q. Zhang, J. T. Li and B. H. Chen, Org.
Lett., 2009, 11, 3024; (d) B. Chattopadhyay, C. I. R. Vera, S. Chuprakov
and V. Gevorgyan, Org. Lett., 2010, 12, 2166; (e) J. R. Donald and
S. F. Martin, Org. Lett., 2011, 13, 852; ( f ) S. Sengupta, H. F. Duan,
W. B. Lu, J. L. Petersen and X. D. Shi, Org. Lett., 2008, 10, 1493;
(g) R. Kumar, P. Pradhan and B. Zajc, Chem. Commun., 2011, 47, 3891.
3 (a) J. S. Tullis, J. C. VanRens, M. G. Natchus, M. P. Clark, B. De, L. C.
Hsieh and M. J. Janusz, Bioorg. Med. Chem. Lett., 2003, 13, 1665; (b) M. S.
Alam, J. Huang, F. Ozoe, F. Matsumura and Y. Ozoe, Bioorg. Med. Chem.
Lett., 2007, 17, 5086; (c) Carbocyclic 7-Deazaguanosine Nucleoside as
Antiviral Agents, ed. C. K. Chu and D. C. Baker, Plenum Press,
New York, 1993; (d) S. Miura and S. Izuta, Curr. Drug Targets, 2004, 5, 191.
4 T. Pathak, Chem. Rev., 2002, 102, 1623.
5 (a) J. F. Lutz, Angew. Chem., Int. Ed., 2007, 46, 1018; (b) Y. R. Hua and
A. H. Flood, Chem. Soc. Rev., 2010, 39, 1262; (c) P. L. Golas and
¨
K. Matyjaszewski, Chem. Soc. Rev., 2010, 39, 1338; (d) K. D. Hanni
´ˇ
and D. A. Leigh, Chem. Soc. Rev., 2010, 39, 1240; (e) M. Jurıcek, P. H. J.
Kouwer and A. E. Rowan, Chem. Commun., 2011, 47, 8740; ( f ) D. Kumar,
B. A. Mishra, K. P. C. Shekar, A. Kumar, K. Akamatsu, E. Kusaka and
T. Ito, Chem. Commun., 2013, 49, 683; (g) J. E. M. Lewis, C. J. McAdam,
M. G. Gardinerb and J. D. Crowley, Chem. Commun., 2013, 49, 3398.
6 (a) J. E. Hein and V. V. Fokin, Chem. Soc. Rev., 2010, 39, 1302;
(b) L. Y. Liang and D. Astruc, Coord. Chem. Rev., 2011, 255, 2933;
(c) Z. Y. Chen, D. Q. Zheng and J. Wu, Org. Lett., 2011, 13, 848.
Scheme 3 Proposed mechanism.
´
7 G. Aromı, L. A. Barrios, O. Rubeau and P. Gamez, Coord. Chem. Rev.,
2011, 255, 485.
8 (a) S. K. Mamidyala and M. G. Finn, Chem. Soc. Rev., 2010, 39, 1252;
(b) A. H. El-Sagheer and T. Brown, Chem. Soc. Rev., 2010, 39, 1388;
(c) E. M. Sletten and C. R. Bertozzi, Acc. Chem. Res., 2011, 44, 666;
(d) M. D. Best, M. M. Rowland and H. E. Bostic, Acc. Chem. Res.,
2011, 44, 686; (e) J. M. Holub and K. Kirshenbaum, Chem. Soc. Rev.,
2010, 39, 1325.
9 (a) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless, Angew.
Chem., Int. Ed., 2002, 41, 2596; (b) C. W. Tornøe, C. Christensen and
M. Meldal, J. Org. Chem., 2002, 67, 3057; (c) Q. Wang, T. R. Chan,
R. Hilgraf, V. V. Fokin, K. B. Sharpless and M. G. Finn, J. Am. Chem.
Soc., 2003, 125, 3192; (d) A. E. Speers, G. C. Adam and B. F. Cravatt,
J. Am. Chem. Soc., 2003, 125, 4686; (e) J. C. Anderson and P. G. Schultz,
J. Am. Chem. Soc., 2003, 125, 11782; ( f ) A. J. Link and D. A. Tirrell, J. Am.
Chem. Soc., 2003, 125, 11164; (g) P. Wu, A. K. Feldman, A. K. Nugent,
Scheme 4 Trapping of the triazolate samarium intermediate by MeI.
Since amines can act as proton sources to abstract the resulting
triazolate ligand and as suitable ligands to activate the catalyst
in the catalytic cycle,16b,17 the presence of amine additives
would be favorable to the cycloaddition.
Consistent with this, the treatment of a 1 : 1 mixture of 1a and
2a with one equivalent of Sm[N(SiMe3)2]3 followed by reacting
with MeI gave the expected product 5 in 23% yield (Scheme 4).
In conclusion, the Ln[N(SiMe3)2]3-catalyzed cycloaddition of
terminal alkynes with azides is an ideal addition to the family of
click reactions. The process exhibits broad scope, readily avail-
able catalyst and mild conditions, and provides 1,5-disubstituted
1,2,3-triazoles in moderate to excellent yields. Furthermore, the
present catalytic system not only differentiates between internal
and terminal alkynes but also shows unprecedented mechanistic
features involving a tandem anionic cascade cyclization reaction
and anti-addition across the CRC triple bond. Quite generally,
organolanthanide-catalyzed intramolecular hydroelementation
reactions produce exclusively the exocyclic hydroamination pro-
ducts resulting from syn-addition.15 We believe that the present
5-endo cyclization pattern seems to indicate the untapped
potential of organolanthanide catalysis, and would have a great
impact on the regioselectivity control of lanthanide-mediated
intramolecular additions. Further investigations regarding the
mechanism and synthetic applications are in progress.
´
C. J. Hawker, A. Scheel, B. Voit, J. Pyun, J. M. J. Frechet, K. B. Sharpless
and V. V. Fokin, Angew. Chem., Int. Ed., 2004, 43, 3928; (h) F. Himo,
T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B. Sharpless
and V. V. Fokin, J. Am. Chem. Soc., 2005, 127, 210; (i) Y. Angell and
K. Burgess, Angew. Chem., Int. Ed., 2007, 46, 3649.
10 J. McNulty, K. Keskar and R. Vemula, Chem.–Eur. J., 2011, 17, 14727.
´
11 A. Krasinski, V. V. Fokin and K. B. Sharpless, Org. Lett., 2004, 6, 1237
and references therein.
12 (a) L. Zhang, X. G. Chen, P. Xue, H. H. Y. Sun, I. D. Williams,
K. B. Sharpless, V. V. Fokin and G. C. Jia, J. Am. Chem. Soc., 2005,
127, 15998; (b) B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang,
H. T. Zhao, Z. Y. Lin, G. C. Jia and V. V. Fokin, J. Am. Chem. Soc.,
2008, 130, 8923; (c) L. K. Rasmussen, B. C. Boren and V. V. Fokin,
Org. Lett., 2007, 9, 5337.
13 S. W. Kwok, J. R. Fotsing, R. J. Fraser, V. O. Rodionov and
V. V. Fokin, Org. Lett., 2010, 12, 4217.
14 (a) H. Kaneko, H. Nagae, H. Tsurugi and K. Mashima, J. Am. Chem.
Soc., 2011, 133, 19626; (b) B. Guan and Z. Hou, J. Am. Chem. Soc.,
2011, 133, 18086; (c) B. Deelman, W. M. Stevels, J. H. Teuben,
M. T. Lakin and A. L. Spek, Organometallics, 1994, 13, 3881.
15 (a) S. Hong and T. J. Marks, Acc. Chem. Res., 2004, 37, 673;
(b) J. Scott, F. Basuli, A. R. Fout, J. C. Huffman and D. J. Mindiola,
Angew. Chem., Int. Ed., 2008, 47, 8502; (c) C. J. Weiss and T. J. Marks,
Dalton Trans., 2012, 41, 6576; (d) M. R. Douglass, C. L. Stern and
T. J. Marks, J. Am. Chem. Soc., 2001, 123, 10221.
We thank the National Natural Science Foundation of China,
973 program (2009CB825300).
16 (a) X. L. Bu, Z. X. Zhang and X. G. Zhou, Organometallics, 2010,
29, 3530; (b) Q. S. Shen, W. Huang, J. L. Wang and X. G. Zhou,
Organometallics, 2008, 27, 301.
Notes and references
1 (a) M. Meldal and C. W. Tornøe, Chem. Rev., 2008, 108, 2952;
(b) C. O. Kappe and E. V. der Eycken, Chem. Soc. Rev., 2010, 17 K. Komeyama, K. Takehira and K. Takaki, Synthesis, 2004, 1062.
39, 1280; (c) J. C. Jewett and C. R. Bertozzi, Chem. Soc. Rev., 2010, 18 W. J. Evans, T. J. Mueller and J. W. Ziller, J. Am. Chem. Soc., 2009,
39, 1272; (d) C. L. Droumaguet, C. Wang and Q. Wang, Chem. Soc.
131, 2678.
c
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Chem. Commun.