Synthesis of 5-Substituted 1H-Tetrazoles from Nitriles And
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Angewandte Chemie DOI: 10.1002/anie.201003733 Microreactors Synthesis of 5-Substituted 1H-Tetrazoles from Nitriles and Hydrazoic Acid by Using a Safe and Scalable High-Temperature Microreactor Approach** Bernhard Gutmann, Jean-Paul Roduit, Dominique Roberge,* and C. Oliver Kappe* Dedicated to Professor K. Barry Sharpless Interest in tetrazole chemistry over the past few years has have been introduced as comparatively safe azide sources been increasing rapidly, mainly as a result of the role played (sometimes prepared in situ), that have the added benefit of by this heterocyclic functionality in medicinal chemistry as a being soluble in organic solvents. Unfortunately, with very metabolically stable surrogate for carboxylic acid function- few exceptions, all of these methods require long reaction alities.[1] Additional important applications for tetrazoles are times (several hours to days) in combination with high found in coordination chemistry, materials science, and as reaction temperatures. intermediates in a variety of synthetic transformations.[2] Based on atom economy and environmental impact, the The most common synthetic approach to prepare conceptually most straightforward approach to the tetrazole 5-substituted 1H-tetrazole derivatives involves the addition nucleus involves the direct addition of hydrazoic acid (HN3) of azide salts to organic nitriles in a temperature range of to organic nitriles, first attempted in 1932.[15] Unfortunately, [1,2] typically 100–1508C (Scheme 1). A plethora of synthetic HN3 is extremely toxic (comparable to HCN) and owing to the explosive nature and low boiling point (378C) of this high- [16] energy material procedures involving free HN3 have not found any practical application in tetrazole synthesis so far. In recent years, the use of microreactors and continuous flow technology in general has become increasingly popular in synthetic organic chemistry.[17,18] Enhanced heat- and mass- Scheme 1. General azide–nitrile addition strategy to give tetrazole transfer characteristics and the ability to efficiently optimize derivatives. reaction conditions by control of residence time add value to the technology. In addition, process intensification can readily protocols and variations on this general theme have been be achieved by operating in a high-temperature/high-pressure reported in the literature during the past few years.[3–14] In the regime.[19] A particularly attractive feature of microreaction majority of cases, sodium azide (NaN3) has been used as an technology is the ease with which reaction conditions can be inorganic azide source in combination with an ammonium scaled through the operation of multiple systems in parallel or halide as the additive employing N,N-dimethylformamide other techniques, thereby readily achieving production scale (DMF) or N-methylpyrrolidone (NMP) as dipolar aprotic capabilities.[20] Another key advantage of using microreactors solvents.[3,4] In some instances, the use of Brønsted[5] or Lewis compared to conventional batch reactors is the ability to acids,[6] heterogeneous[7] or nanocrystalline catalysts,[8] or safely process potentially hazardous compounds or stoichiometric amounts of ZnII salts[9,10] have been reported reagents.[17,18] In a continuous flow system, synthetic inter- as suitable additives to afford the desired azide–nitrile mediates can be generated and consumed in situ, which addition process. As an alternative to inorganic azide salts, eliminates the need to store toxic, reactive, or explosive trimethylsilyl,[11] trialkyl tin,[12] and organoaluminum azides[13] intermediates and thus makes the synthetic protocol safer.[17–21] [*] B. Gutmann, Prof. Dr. C. O. Kappe Herein, we describe a general and scalable method for the Christian-Doppler-Labor fr Mikrowellenchemie (CDLMC) continuous flow synthesis of 5-substituted 1H-tetrazole deriv- and, Institut fr Chemie, Karl-Franzens-Universitt atives via addition of HN3 to organic nitriles. Key to this Heinrichstrasse 28, 8010 Graz (Austria) process is the in situ generation of HN3 from NaN3 and acetic Fax : (+ 43)316-380-9840 acid in a microreactor coupled to an intensified high-temper- E-mail: [email protected] ature/high-pressure flow addition step to the nitrile. Under Homepage: http://www.maos.net optimized conditions tetrazole compounds are formed with Dr. J.-P. Roduit, Dr. D. Roberge Microreactor Technology, Lonza AG, 3930 Visp (Switzerland) quantitative conversion in residence times of a few minutes, E-mail: [email protected] providing excellent purities and yields of isolated product. [**] This work was supported by a grant from the Christian Doppler An evaluation of existing protocols for batch tetrazole Society (CDG). syntheses following the general azide–nitrile addition strategy [3–13] Supporting information for this article is available on the WWW (Scheme 1) made the challenges of converting batch into under http://dx.doi.org/10.1002/anie.201003733. flow conditions immediately apparent. Apart from the fact Angew. Chem. Int. Ed. 2010, 49, 7101 –7105 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 7101 Communications that most of the published procedures report reaction times of generating internal pressures up to 20 bar depending on the several hours (or even days) to obtain high conversions, in solvent system. To increase screening throughput we sub- many instances the reaction mixtures were heterogeneous sequently moved to a parallel format utilizing a standard because of the presence of reagents, additives, or catalysts of hotplate/magnetic stirrer in combination with a silicon low solubility in the chosen solvent system. In continuous carbide (SiC) reaction block with a 6 4 deep-well matrix in flow/microreactor processing fully homogeneous reaction which pressure-resistant 5 mL Pyrex screw cap reaction vials media are highly desirable. In addition, reaction times were placed (Figure S1 in the Supporting Information).[22,23] (=residence times) in flow should ideally be in the order of After analyzing the results from more than 200 independ- a few minutes for allowing a high throughput. ent experiments using 2,2-diphenylacetonitrile (1a)asa With this background an optimization campaign was model compound, an optimum set of conditions that fulfilled started selecting 2,2-diphenylacetonitrile (1a) as a model both the requirement of reaction homogeneity and reaction compound for tetrazole formation (Table 1, MW). Based on speed, while at the same time providing clean and complete atom economy and for economical reasons, NaN3 was nitrile into tetrazole conversion involved the use of NMP as [24] selected as an inexpensive azide source from the start. In a solvent, AcOH as Brønsted acid, and H2O as cosolvent. first set of experiments different solvents, Brønsted acids, and Applying two equivalents of NaN3, a 7:2:1 ratio of NMP/ Lewis acids/additives were screened (see the Supporting AcOH/H2O, and 2208C as reaction temperature provided full Information for details). As it was clearly evident from the conversion into the desired tetrazole 2a at a 1m nitrile literature[3–13] that a high yielding and fast tetrazole synthesis concentration within 10 minutes and furnished a 85% yield of would have to involve a high temperature regime, controlled isolated product (Table 1, MW). sealed-vessel microwave heating was used initially as a To explore the scope and limitations of this new high- process intensification method.[4] Optimization runs were speed tetrazole synthesis a set of 16 aliphatic, aromatic, and generally performed on small scale (1 mmol of nitrile, 0.5– heteroaromatic nitriles 1a–p was subjected to the general 1.5 mL solvent) in a temperature range of 160–2208C reaction conditions, both using a single-mode microwave Table 1: Batch and continuous flow synthesis of 5-substituted 1H-tetrazole derivatives.[a] Substrate Method t [min][b] Yield [%] Work-up[c] Substrate Method t [min][b] Yield [%] Work-up[c] MW 10 85 C MW 5 92 A 1a 1i flow[d] 15 82 C flow 10 97 A MW 5 94 B MW 5 90/96 A/B 1b 1j flow 10 94 B flow 10 97 A MW 5 90 B MW 5 92 A 1c 1k flow 10 92 B flow 10 89 A MW 6 84/95 A/B MW 5 97 B 1d 1l flow 10 95 A flow 10 98 B MW 5 94/98 A/B MW 5 77 D 1e 1m flow 10 98 A flow 10 75 D MW 5 97 A MW 5 69 D 1f 1n flow 10 90 A flow 10 68 D MW 5 98 A MW[e] 30 79 C 1g 1o flow 10 96 A flow – – – MW 6 80/88 A/B MW[e] 30 86 C 1h 1p flow 10 87 A flow – – – [a] Conditions MW: 1.0 mmol of nitrile, 2.0 mmol of NaN3, 1.0 mL of solvent (NMP/AcOH/H2O =7:2:1). Single-mode microwave heating at 2208C m À1 m (Biotage Initiator). Conditions flow: feed A (1 solution of nitrile in NMP/AcOH =5:2) at a flow rate of 0.69 mLmin and feed B (5.2 NaN3 in H2O) at 0.31 mLminÀ1 at 2208C (FlowSyn, Uniqsis Ltd, Figure 1).[25] [b] Reaction times refer to hold times at 2208C in case of MW experiments (ramp time ca. 1.5 min, cooling time ca. 2.5 min), and residence times in the 10 mL heated coil for flow experiments. [c] Work-up methods: A: product n precipitation 1 HCl (pH 1); B: liquid-liquid extraction with CHCl3 followed by acidification with conc. HCl and extraction with EtOAc; C: liquid-liquid extraction with toluene followed by product precipitation with conc. HCl; D: liquid-liquid extraction with CHCl3 followed by pH adjustment with À1 À1 conc. HCl to pH 5. [d] 0.45 mLmin feed A and 0.21 mLmin feed B (residence time 15 min). [e] 4.0 equivalents of NaN3, 1.5 mL of solvent. MW = microwave. 7102 www.angewandte.org 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem.