A straightforward synthesis of alkyl 1H-tetrazol-5-yl thioethers via a one-pot reaction of aldehydes and 1H-tetrazole-5-thiols mediated by N-tosylhydrazones

Abstract

A straightforward approach for the synthesis of alkyl 1H-tetrazol-5-yl thioethers from aldehydes and 1H-tetrazole-5-thiol through a one-pot procedure is presented. The aldehydes were first condensed with N-tosylhydrazine to generate the N-tosylhydrazones, which were then reductively coupled in situ with 1H-tetrazole-5-thiols under metal-free conditions to afford the thioethers in high to excellent yields.

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1H-Tetrazol-5-yl thioether skeletons are key structural motifs in many bioactive compounds and drugs.¹ Typically, such units are frequently present in a wide variety of clinically used antibiotics such as cefotiam (1),² cefminox (2),³ cefbuperazone (3),⁴ cefamandole (4),⁵ cefpiramide (5),⁶ and latamoxef (6)⁷ (Scheme 1). More importantly, the alkyl 1H-tetrazol-5-yl thioethers are useful precursors or intermediates in organic synthesis. For instance, they serve as precursors in Kocienski-modified Julia olefination which has been one of the most popularly used methods for the construction of internal olefins and shows a unique advantage for the preparation of non-conjugated alkenes in high E-selectivity.⁸ Therefore, development of efficient approaches for the synthesis of 1H-tetrazol-5-yl thioethers is of greatly attractive. Classical methods for the synthesis of alkyl 1H-tetrazol-5-yl thioethers have been relied mainly on the substitution reaction of an alkyl (pseudo)halide with a 1H-tetrazole-5-thiol under basic conditions,⁹ and the Mitsunobu condensation between an alcohol and a 1H-tetrazole-5-thiol.¹⁰ Although these protocols have been widely used due to high yield, broad functional group compatibility, and mild reaction conditions, a multistep procedure is essentially required when aldehydes or ketones are employed as starting materials.

Scheme 1 Structures of some clinically used antibiotics.

Recently, a rapidly growing interest has been observed in the area of transition-metal-catalyzed and metal-free cross-coupling of N-tosylhydrazones.¹¹ The versatility of this reagent has been well demonstrated through the creation of various C–C bonds.¹² In addition, the formation of C–O,¹³ C–N,¹⁴ C–P,¹⁵ C–S,¹⁶ and N–N bonds^14b,c has also been exemplified. Since N-tosylhydrazones are prepared through the condensation of aldehydes or ketones with N-tosylhydrazine, and moreover, aldehydes and ketones are abundant chemicals from nature and industry, these extensive contributions expand significantly the utilities of aldehyde and ketone compounds in organic synthesis.

Stimulated by these pioneering works, we became interested in investigating the metal-free cross-coupling reaction of N-tosylhydrazones with 1H-tetrazole-5-thiols because this transformation would provide a more straightforward pathway for flexibly accessing alkyl 1H-tetrazol-5-yl thioethers from aldehydes and ketones. The successful demonstration of this chemistry will be presented herein.

The evaluation on the feasibility of the transformation was carried out by using N-tosylhydrazone 7a and commercially available 1-methyl-1H-tetrazole-5-thiol 8a as the coupling partners (Table 1). Initial trial under the metal-free conditions showed that the reaction could proceed to give the desired product 9a. However, the yield was rather low (30%, entry 1). Attempted improvement of the reaction efficiency by varying the solvents (entries 2–6) and bases (entries 7–13) was futile albeit the use of LiOH base led to a slightly increased yield (36%, entry 13). A further optimization of the molar ratio of 7a to 8a and the amount of base (entries 14–16) revealed that the yield of 9a might be increased to 68% when the molar ratio of 7a to 8a was changed from 1 : 2 to 2 : 1 combined with the use of 4.0 equiv. of LiOH base (entry 16).

Table 1 Evaluation of the reaction conditions^a

Entry	Base	Solvent	Yield^b (%)
a Unless otherwise noted, the reaction conditions were: N-tosylhydrazone 7a (0.8 mmol), tetrazole thiol 8a (1.6 mmol), and base (2.4 mmol) in solvent (4 mL) at 110 °C for 2 h.b Isolated yield based on N-tosylhydrazone 7a.c No desired product was isolated due to decomposition of 7a.d 4.0 equiv. of LiOH was used.e The molar ratio of 7a/8a was 2 : 1 in the presence of 3.0 equiv. of LiOH; isolated yield based on 8a.f The molar ratio of 7a/8a was 2 : 1 in the presence of 4.0 equiv. of LiOH; isolated yield based on 8a.
1	K2CO3	Dioxane	30
2	K2CO3	Toluene	—^c
3	K2CO3	PhF	—^c
4	K2CO3	MeCN	16
5	K2CO3	DME	21
6	K2CO3	THF	—^c
7	Na2CO3	Dioxane	—^c
8	KOH	Dioxane	27
9	NaOH	Dioxane	28
10	Cs2CO3	Dioxane	23
11	^tBuOK	Dioxane	—^c
12	K3PO4	Dioxane	25
13	LiOH	Dioxane	36
14	LiOH	Dioxane	36^d
15	LiOH	Dioxane	46^e
16	LiOH	Dioxane	68^f

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By employing the conditions in entry 16 as the optimal ones, we examined the generality of the method. Unfortunately, only poor to moderate yields were obtained for a range of N-tosylhydrazones derived from different aliphatic aldehydes. These results indicate that the conditions optimized in this way are less general. In fact, a survey of literature revealed that for the metal-free cross-coupling of N-tosylhydrazones with heteroatom nucleophiles,^13–16 the N-tosylhydrazones derived from aliphatic aldehydes and ketones were much less investigated than those derived from aryl aldehydes or ketones. Moreover, it is also noted from the few available examples that the aliphatic N-tosylhydrazones usually displayed a lower reactivity to compare with the aromatic ones. These observations imply that methods for the coupling of N-tosylhydrazones derived from aliphatic aldehydes and ketones are neither general nor practical.

According to the proposed mechanism in prior literature,^11b,16c we reasoned that the sluggish reaction between aliphatic N-tosylhydrazones and 1H-tetrazole-5-thiols investigated herein should be resulted from the relatively low reactivity of both coupling partners. As shown in Scheme 2, the thioether product 9 may be produced through the substitution of a diazo ion A with a tetrazole thioanion B. However, the diazo ion A generated from an aliphatic hydrazone 7 is less electrophilic than that formed from an aromatic one. On the other hand, the thioanion B generated from 1H-tetrazole-5-thiol 8 is considered to be a weak nucleophile as a result of the electron-withdrawing nature of tetrazole moiety.¹⁷ Consequently, less effective reactions were observed.

Scheme 2 Proposed coupling of N-tosylhydrazones and 1H-tetrazole-5-thiols.

Based on the above analysis, we reasoned that the reaction efficiency might be improved by means of the addition of a halogen anion X⁻ (X = I, Br, Cl) into the reaction system. Namely, with the presence of such an anion, the diazo ion A might be converted into the halogenoalkane C. Subsequently, the substitution reaction of C with tetrazole thioanion B should proceed smoothly to deliver the thioether 9 because such a transformation has been well demonstrated for the synthesis of thioethers.⁹ Accordingly, we examined the effect of an array of halogen salts (Table 2). While the yields were somewhat decreased when several organic chloride and bromide salts were added (entries 1–3), the presence of a catalytic amount of ⁿBu₄NI resulted in a slightly increased yield of 9a (entry 4). The yield could be improved to 80% when 2.0 equiv. of ⁿBu₄NI was used (entry 5). These results suggest that the use of an appropriate iodide salt would be beneficial for the reaction. The assumption was further supported by a parallel comparison of different lithium halides. That is, LiI was much more effective than LiBr, giving 9a in 88% yield (entries 6 vs. 7). In comparison, LiCl displayed a detrimental effect to the reaction (entry 8). A brief optimization of the molar equivalent of LiI showed that the use of 1.0 equiv. of LiI was optimal, affording 9a in almost equally high yield to that of the presence of 2.0 equiv. of LiI (entries 6 vs. 9 and 10). We also evaluated the effect of the counter ions of I⁻. The results showed that LiI afforded a better outcome than NaI and KI (entries 9 vs. 11 and 12). An examination on the effect of the molar equivalent of hydrazone (entries 9 vs. 13) revealed that the use of 2.0 equiv. of 7a was important since the by-products 10 and 11 (ref. 18) generated from the homocoupling of 7a were unavoidably formed under different conditions (Fig. 1). Finally, the reaction could also be performed through a one-pot operation to afford the product 9a in 91% yield (entry 14).

Table 2 Screening of the additives^a

Entry	Halogen salts (equiv.)	Yield^b (%)
a Unless otherwise noted, the reaction conditions were: N-tosylhydrazone 7a (1.6 mmol), tetrazole thiol 8a (0.8 mmol), and LiOH (3.2 mmol) in dioxane (8 mL) at 110 °C for 4 h.b Isolated yield based on tetrazole 8a.c 1.2 mmol of 7a was used.d The reaction was performed via a one-pot operation.
1	^nBu4NCl (0.2)	56
2	^nBu3P(^nC16H33)Br (0.2)	59
3	Ph3P(Me)Br (0.2)	58
4	^nBu4NI (0.2)	73
5	^nBu4NI (2)	80
6	LiI (2)	88
7	LiBr (2)	73
8	LiCl (2)	52
9	LiI (1)	87
10	LiI (0.5)	72
11	NaI (1)	80
12	KI (1)	64
13	LiI (1)	52^c
14	LiI (1)	91^d

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Fig. 1 By-products generated in the reaction system.

Thus, an exhaustive screening of various parameters enabled us to define the high yielding conditions for a straightforward and high yielding synthesis of alkyl tetrazol-5-yl thioethers from the aldehydes and 1H-tetrazole-5-thiols, which are 2 : 2 : 1 of aldehyde to N-tosylhydrazine to 1H-tetrazole-5-thiol, 4.0 equiv. of LiOH, and 1.0 equiv. of LiI in dioxane at 110 °C. To evaluate the generality of this protocol, an array of aldehydes 12 and 1H-tetrazole-5-thiols 8 were examined through the one-pot procedure. The results showed that the method exhibited good compatibility to a wide variety of aldehydes. As summarized in Table 3, the simply substituted aliphatic aldehydes reacted smoothly with various commercially affordable 1H-tetrazole-5-thiols 8a–c to give the thioethers 9a–f in high yields. In addition, an aromatic and a heteroaromatic aldehyde were also well tolerated, giving 9g–l in high to excellent yields. Most significantly, an array of aliphatic aldehydes modified by various functional groups such as Bz (9m–o), Boc (9p and 9q), and Cbz (9r and 9s) protected amino groups, as well as TBDMS (9t) protected hydroxy group were also viable substrates under the optimized reaction conditions. The broad compatibility to a variety of functional groups would be an important advantage of the method because it provides additional opportunities for further modification of the coupled products through the orthogonal transformation of latent amino/alcohol and thioether functionalities. Finally, the method can be applied for the efficient synthesis of thioethers 9u–w, which were synthesized previously by us¹⁹ through the conventional multistep procedure and used as the key intermediates for the synthesis of aliskiren, a novel marketed drug for the treatment of hypertensive disease. It should be mentioned that while the protocol exhibits a broad generality to aldehydes, a brief examination showed that ketones were less effective substrates under the conditions.

Table 3 Substrate scope^a,b

a Reaction conditions: aldehyde 12 (1.6 mmol), TsNHNH₂ (1.6 mmol), 1H-tetrazole-5-thiols 8 (0.8 mmol), LiOH (3.2 mmol), and LiI (0.8 mmol) in dioxane (8 mL) at 110 °C for 4 h.b Isolated yield based on 8.c The yield was determined by ¹H-NMR analysis due to the contamination of a small amount of inseparable side-product.d Aldehyde 12 (1 mmol), TsNHNH₂ (1 mmol), 8 (0.5 mmol), LiOH (2 mmol), and LiI (0.5 mmol) in dioxane (5 mL) at 110 °C for 4 h.e Aldehyde 12 (0.8 mmol), TsNHNH₂ (0.8 mmol), 8 (0.4 mmol), LiOH (1.6 mmol), and LiI (0.4 mmol) in dioxane (4 mL) at 110 °C for 4 h.

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To confirm the concrete role played by LiI additive, we carried out some control experiments (Scheme 3). Treatment of aldehyde 12a under the otherwise conditions identical to the optimized conditions bust just with the absence of 1H-tetrazole-5-thiol 8a produced 1-iodo-3-phenylpropane 13 in 23% yield (46% based on LiI) and the homo-coupled by-product 11 (see Fig. 1) in 19% yield. In addition to the two major products, several other minor products were also observed by the TLC monitoring; however, their structures and contents were not determinated due to the difficulty of separation. The reaction of 13 with 1H-tetrazole-5-thiol 8a proceeded very rapidly within 15 min to give thioether 9a in quantitative yield. These results suggest that in good agreement with the proposed mechanism (Scheme 2), the addition of LiI could help to improve the synthetic efficiency of alkyl tetrazol-5-yl thioethers through the formation of a more reactive iodoalkane intermediate.

Scheme 3 Control experiments.

Conclusions

As a summary, we have established a straightforward method that allows for a one-pot synthesis of alkyl 1H-tetrazol-5-yl thioethers from aldehydes through the metal-free reductive coupling of in situ generated N-tosylhydrazones with 1H-tetrazole-5-thiols. In addition, the method exhibits a broad generality for a wide variety of aldehydes and various 1H-tetrazole-5-thiols. Most significantly, various aliphatic aldehydes including those decorated by N- and O-containing functionalities were viable substrates under the reaction conditions. As a result, the methodology would find practical applications owing to the great importance of alkyl 1H-tetrazol-5-yl thioethers either as key structural motif in pharmaceuticals or as important precursors in synthetic organic chemistry. The use of this method for an improved synthesis of aliskiren is currently underway in our lab.

Experimental section

General procedure for the one-pot synthesis of 9

A mixture of aldehyde 12 (1.6 mmol, 2.0 equiv.) and TsNHNH₂ (1.6 mmol, 2.0 equiv.) in dioxane (5.0 mL) was stirred at rt for 0.5 h under argon atmosphere. Then, LiOH (3.2 mmol, 4.0 equiv.), 8 (0.8 mmol, 1.0 equiv.), LiI (0.8 mmol, 1.0 equiv.), and dioxane (3.0 mL) were recharged in situ to the reaction vessel. The resulting mixture was then stirred vigorously at 110 °C for 4 h under argon atmosphere. After the completion of the reaction as monitored by TLC, the mixture was cooled to room temperature and diluted with CH₂Cl₂ (20 mL). The mixture was filtered through a celite pad to remove the insoluble materials, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel by using a mixed solvent of EtOAc and petroleum ether as eluent to afford product 9.

Acknowledgements

Financial support from NSFC (21272225), and State Key Laboratory of Fine Chemicals (KF 1201) is acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Details of experimental procedures, characterization data, and copies of NMR spectra. See DOI: 10.1039/c5ra04050g

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