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Gold-Catalyzed Synthesis of Tetrazoles from Alkynes by C[BOND]C Bond Cleavage

Authors

  • Morgane Gaydou,

    1. Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona (Spain)
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  • Prof. Antonio M. Echavarren

    Corresponding author
    1. Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona (Spain)
    2. Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/Marcel⋅li Domingo s/n, 43007 Tarragona (Spain)
    • Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona (Spain)===

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  • We thank the MICINN (CTQ2010-16088/BQU), the European Research Council (Advanced Grant No. 321066), the AGAUR (2009 SGR 47), and the ICIQ Foundation for financial support. We also thank the ICIQ X-Ray diffraction unit for the X-ray structures.

Abstract

original image

Goldenes Doppel: Tetrazole entstehen bei der Reaktion von Alkinen mit TMSN3 (TMS=Trimethylsilyl) in Gegenwart von iPrOH und dem Gold(I)-Katalysator [JohnPhosAu(MeCN)]SbF6. Diese Umwandlung zeigt Gold in einer Doppelrolle: Zunächst aktiviert es das Alkin, dann erzeugt es in situ eine Brønsted-Säure.

Cycloadditions of azides with alkynes to form triazoles under thermal conditions (Huisgen cycloaddition)1 or in the presence of copper [click reaction, copper-catalyzed azide–alkyne cycloaddition (CuAAC)]2, 3 are reactions of fundamental importance in organic chemistry. Triazoles can also be obtained by means of ruthenium,4 silver,5 and iridium6 catalysis, as well as by a zinc-mediated process.7 In sharp contrast, very different reactivity has been observed in the reaction of terminal alkynes with TMSN3 in the presence of group 11 metal salts and complexes.8 Thus, the group of Jiao recently made the remarkable observation that alkynes (1; R=alkyl, aryl, alkenyl) react with TMSN3 in the presence of Ag2CO3 as catalyst to form nitriles (2; Scheme 1).9 The same group has reported the cleavage of the arylalkyne C(sp2)[BOND]C(sp) bond of alkynes (1) using [Au(PPh3)Cl] and AgCO3 in the presence of H2O and trifluoroacetic acid (TFA) to form carboxamides.10

Scheme 1.

Synthesis of nitriles (2)9 and carboxamines (3)10 from alkynes (1) by arylalkyne C(sp2)[BOND]C(sp) bond cleavage. DMSO=dimethylsulfoxide, TFA=trifluoroacetic acid, TMS=trimethylsilyl.

The formation of nitriles (2)9 and carboxamides (3)10 was proposed to proceed by nucleophilic addition of azide to (η2-alkyne)metal complexes to form the intermediates 4 a,b, with subsequent protonolysis to give the alkenyl azides 5 (Scheme 2). The nitriles 2 could then be produced by a 1,3-dipolar cycloaddition and subsequent fragmentation of 6. In the presence of TFA, protonation of 5 would form 7, which could evolve by a Schmidt rearrangement1113 to give the amides 3. A somewhat related cleavage of triple bonds to form nitriles has been reported using TMSN3 and N-iodosuccinimide, and was proposed to proceed via 2-iodo-2H-azirines.14

Scheme 2.

Mechanistic proposal for the formation of 2 and 3.9, 10

We now report that by using the JohnPhos/gold(I) catalyst A,15 which allows performing reactions in the absence of AgI, the N-aryltetrazoles 8 are obtained from 1 by C[BOND]C bond cleavage with the concomitant insertion of four nitrogen atoms (Scheme 3). In this transformation gold plays a dual role, first activating the alkyne towards nucleophilic attack and then generating the Brønsted acid required for the transformation of the alkenyl azide into the final tetrazole.

Scheme 3.

Synthesis of N-aryltetrazoles (8) from alkynes (1). DCE=1,2,-dichloroethane.

We first studied the reaction of the aryl alkynes 1 ac with TMSN316 and complex A under stoichiometric conditions. Surprisingly, the reaction gave 5-methyl-1-aryl-1H-tetrazole–gold(I) complexes (9 ac) as crystalline white solids, whose structures were determined by X-ray diffraction (Scheme 4).17, 18 The complex 9 a was also obtained in 56 % yield by reaction of neutral [(JohnPhos)AuCl] with phenyl acetylene (1 a) and TMSN3 in the presence of AgSbF6.

Scheme 4.

Formation of the tetrazole–gold(I) complexes 9 ac and their X-ray crystal structures. For the ORTEP plots the thermal ellipsoids are shown at 50 %. Au yellow, F green, N blue, O red, P violet, Sb light blue.

We have provided evidence that the rate-determining step in certain catalytic reactions involving alkynes is the ligand substitution reaction between the complexes [Au(product)L]+ and the starting alkyne.19 The isolation of stable gold(I) complexes (9 ac) under stoichiometric conditions shows that in this case the development of a catalytic process for the synthesis of tetrazoles would be a challenging task, since this ligand substitution would be particularly slow. Thus, either no reaction or very poor yields of the tetrazole 8 d were obtained with complex A in MeCN, CH2Cl2, or toluene (Table 1, entries 1–4). Better results were obtained in 1,2-dichloroethane at 80 °C (Table 1, entries 5 and 6). In contrast, the related gold(I) catalysts B and C, and complexes DG with NHC (N-heterocyclic carbene), phosphite, or less-bulky phosphine ligands led to poor results (Table 1, entries 9 and 16).

Table 1. Catalyst and solvent optimization for the formation of 8 b. inline image

Entry

[Au]

Solvent

T [°C]

Yield [%][a]

  1. [a] Determined by NMR spectroscopy. [b] No reaction. [c] 10 mol % catalyst. [d] iPrOH (4–10 equiv).

    original image

1

A

MeCN

23

[b]

2

A

MeCN

80

8

3

A

CH2Cl2

40

[b]

4

A

toluene

110

9

5

A

DCE

80

40

6

A[c]

DCE

80

59

7[d]

A[c]

DCE

80

78–81

8

A

DCE

110

38

9

B

DCE

80

8

10

C

DCE

80

7

11

D

DCE

80

[b]

12

D′

DCE

80

[b]

13

E

DCE

80

[b]

14

F

DCE

80

15

15

G

DCE

80

18

16

[Au(PPh3)Cl]/ Ag2CO3

DCE

80

[b]

A further improvement was achieved by performing the reaction in the presence of iPrOH (Table 1, entry 7). Under these reaction conditions, aryl-, heteroaryl-, and alkyl-substituted alkynes react with TMSN3 to give the corresponding tetrazoles 8 (Scheme 5). Lower yields of the tetrazoles 8 g and 8 k were obtained from employing aryl alkynes substituted with electron-withdrawing groups. In the case of p-nitrophenylacetylene (1 c), no tetrazole was formed and the alkenyl azide 5 c was isolated instead (23 % yield). Diphenyl acetylene, having an internal alkyne, failed to give the corresponding tetrazole. Aliphatic alkynes also reacted to give tetrazoles (8 mo). Interestingly, whereas cyclohexylacetylene provided 8 m in good yield as the sole product, 1-pentyne gave 8 n along with 1-methyl-5-propyl-1H-tetrazole (8 n′; 10:1 ratio) and cyclopropylacetylene gave 8 o and 8 o′ (1:3 ratio).

Scheme 5.

Gold(I)-catalyzed synthesis of tetrazoles from the aryl- and alkyl-substituted alkynes 1. Yields refer to isolated compounds.

All these results can be accommodated by a mechanism proceeding by reaction between a (η2-alkyne)gold(I) complex and HN3, formed in situ from TMSN3 and iPrOH, to give 4 b, which undergoes protodeauration to give 5 (Scheme 6), and is in accordance with that proposed for the formation of nitriles and carboxamides.9, 10 Protonation of 5 would give the iminodiazonium cation 7, which could evolve to form the nitrilium cation 10 by migration of R group (path a). Competitive migration of the methyl group (path b) explains the formation of regioisomers 8 n′ and 8 o′ in the reactions of 1-pentyne and cyclopropylacetylene. It is interesting that preferential migration of the methyl group has been observed in the Schmidt reaction of methyl cyclopropyl ketone in aqueous sulfuric acid at lower acid strengths.12a Finally, a formal 1,3-dipolar cycloaddition of HN3 to 10 would lead to 8.20, 21 It is important to note that nitrilium cations 10 have been reported to give also triazolium salts by reaction of the initial azide addition product with a second nitrilium cation,21b a process that was not observed under these reaction conditions.

Scheme 6.

Mechanistic proposal for the formation of the tetrazoles 8 from 4 b.

Although formation of digold(I) intermediates (11) by reaction of 4 b with a second equivalent of a gold(I) complex cannot be entirely excluded,22 the following experiments using (1-azidovinyl)benzene (5 a, R=Ph) as the substrate strongly suggest that the transformation of 4 b into 7 is a Brønsted acid catalyzed reaction: 1) reaction of 5 a with TMSN3 and iPrOH with A under the standard reaction conditions gave 8 a (42 % yield by NMR); 2) in the absence of iPrOH, 5 a gave 8 a in only 12 % yield; 3) only traces of 8 a were obtained in the absence of gold catalyst A; 4) replacing iPrOH and A by HOAc (2 equiv) led to 8 a in 78 % yield.23 Presumably, under the gold(I)-catalyzed conditions, the Brønsted acid [JohnPhosAu(iPrOH)]SbF6 is formed, which mediates the transformation of 4 b into 7.24, 25 Protonation by this acid could also facilitate the associative displacement of the tetrazole ligands by the incoming alkyne in 9 under catalytic conditions.

Acetophenones, which could have been formed by gold(I)-catalyzed hydration, were not detected in this reaction.26, 27 The proposed mechanism was further supported by additional results, including two labeling experiments. First, reaction of [D]-1 a led to [D]-9 a, with the deuterium labeling at the methyl group (Scheme 7). Additionally, when the reaction of 1 a, TMSN3, and complex A was carried out in CH2Cl2 containing 1.1 equivalents of D2O, the deuterated complex [D2]-9 a was obtained.

Scheme 7.

Deuterium-labeling experiments.

Tetrazoles, which are important in medicinal chemistry and as energetic materials, have been obtained by 1,3-dipolar cycloaddition of azides with activated nitriles28, 29 and by cycloaddition of hydrazoic acid with the Ugi adducts generated in situ from carbonyl compounds, amines, and isonitriles.30, 31 This new reaction demonstrates that this new class of heterocyclic compounds can be prepared under relatively mild reaction conditions from readily available alkynes in a process in which gold(I) catalyzes the formation of alkenyl azides by nucleophilic attack onto the alkynes, as has been shown in the formation of carboxamides.10 In addition, gold presumably provides the Brønsted acid required for the protodeauration and final formation of tetrazoles from the intermediate alkenyl azides under anhydrous, catalytic conditions. Further work aimed at developing new catalysts for the synthesis of tetrazoles from alkynes is in progress.