Letter pubs.acs.org/journal/ascecg
Rutile Promoted Synthesis of Sulfonylamidonitriles from Simple Aldehydes and Sulfonamides Nicholas V. Costantini,‡ Alex D. Bates,† Graham J. Haun,† Natasha M. Chang,† and Gustavo Moura-Letts*,† †
Department of Chemistry and Biochemistry, Rowan University, 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States Department of Chemical Engineering, Rowan University, 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States
‡
S Supporting Information *
ABSTRACT: We report the first rutile-promoted synthesis of sulfonylamidonitriles from aldehydes and sulfonamides with NaCN in water. This transformation has proven to work for a variety of aliphatic and aromatic aldehydes with excellent yields. The scope also extends to a variety of substituted sulfonamides. Rutile can be easily recycled and reused without significant reaction erosion. The benign nature of rutile and its natural abundance highlights this transformation as a model green reaction. KEYWORDS: Strecker reaction, Rutile, Heterogeneous catalysis, Green reaction, Sulfonylamidonitriles
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INTRODUCTION Aminonitrile-containing scaffolds are of significant interest in organic chemistry1,2 and are usually prepared by the nucleophilic addition of cyanide to an imine; also known as the Strecker reaction.3−5 This reaction is an important process in organic synthesis and provides access to a wide range of key precursors that act as building blocks in the pharmaceutical industry.6−8 Standard catalytic processes using homogeneous catalysts are efficient;9−12 however, they require expensive or toxic catalytic systems.13 The use of these catalysts presents difficulties in separation, scalability, tedious workup, and waste production.14 Heterogeneous catalysis in the presence of molecular sieves,15 polymeric sulfuric acid,16 nanosize materials,17 supported complexes, and heteropolyacids have proven to increase the efficiencies (separation, recovery, cost) of this reaction.18−20 However, the toxicity and waste management of these reactions still present a concern at the academic and industrial level.21 The nucleophilic addition of cyanide to sulfonylimines for the synthesis of sulfonylamidonitriles is one of the most important Strecker-type reactions.22−24 Several methods for the synthesis of these scaffolds, some enantioselective, have relied on combinations of organic sources of cyanide and transition metals to achieve high levels of efficiencies and selectivities.25−27 However, issues with toxicity, volatility, and high cost associated with these reagents have shifted attention to the development of cyanide sources that are cheaper, less toxic, and easier to dispose.28−30 Titanium dioxide is the largest natural source of titanium, and rutile is its most abundant mineral form.31,32 The nontoxicity, optical and electronic properties, high physical and chemical stability, and high refractive index of this material have made it widely researched in various scientific fields.33 © XXXX American Chemical Society
Recently, it has been demonstrated that TiO2 can be used as catalyst support.34 Reports have shown that this material allows the modulation of catalytic activities for many reactions, including dehydrogenation, hydrodesulphurization, water gas shift, and thermal catalytic decomposition.35−37 Moreover, TiO2 nanoparticles have been recently used as a catalyst for the synthesis of quinolinones via a domino hydrolysis/aldol condensation/Michael addition reaction.38 However, to our knowledge, TiO2 in its natural form (rutile) has never been used to efficiently promote organic transformations. Our laboratory is focused on developing green and efficient methods for the synthesis of N-containing heterocycles.39 Thus, in this paper we report the reaction of aldehydes and sulfonamides for the efficient synthesis of substituted sulfonylamidonitriles with rutile as a recyclable catalyst. We began this study with the reaction of p-tolualdehyde and p-toluenesulfonamide in the presence of a variety of cyanide sources. We sought to find the simplest combination of reagents and solvents to obtain the desired sulfonylamidonitrile with complete conversion (Table 1). We quickly found that in H2O with an excess of sulfonamide we achieved high conversion to imine 1, but with low yield for the formation of sulfonylamidonitrile 2 (entry 1). The reaction with organic sources of cyanide (TMSCN and acetone cyanohydrin, entries 2 and 3) in CHCl3 proved to be considerably less efficient at providing the desired sulfonylamidonitrile. Methods that successfully introduce cyanide groups from organic sources across imines most often rely on previously isolated imines.40,41 Thus, we sought to improve the efficiency using THF/H2O and Received: February 2, 2016 Revised: February 21, 2016
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DOI: 10.1021/acssuschemeng.6b00241 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Letter
ACS Sustainable Chemistry & Engineering Table 1. Reaction Discovery and Optimization
entry
solvent
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
H2O CHCl3 CHCl3 THF/H2O THF THF/H2O THF THF THF THF THF H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O
promoter
molar ratioa
CN
conversion (%)b
yield 2 (%)c
TBAI TBAI TiCl4 Ti(EtO)4 Ti(EtO)4/TBAI TiO2c TiO2/TBAIc TiO2d ZrO2 Fe2O3 ZnO MgO TiO2e TiO2d TiO2d TiO2d TiO2d
1:2:1:2 1:2:1:2 1:2:1:2 1:2:1:2 1:2:1:2 1:1:1:2 1:1:1:2 1:1:1:2 1:1:1:2 1:1:1:2 1:1:1:2 1:1:1:2 1:1:1:2 1:1:1:2 1:1:1:2 1:1:1:2 1:1:1:2f 1:1:0.5:2 1:1:0.2:2 1:1:0.1:2 1:1:0.2:1f
NaCN cyanohydrin TMSCN NaCN NaCN NaCN cyanohydrin cyanohydrin NaCN NaCN NaCN NaCN NaCN NaCN NaCN NaCN NaCN NaCN NaCN NaCN NaCN
90 88 84 95 93 71 78 89 95 90 95 99 88 82 80 88 95 99 99 80 80
64 50 55 68 66 59 40 62 75 90 89 97 75 55 71 64 82 92 93 71 62
Reaction conditions: tolualdehyde (0.1 mmol), toluenesulfonamide (0.1 mmol), and rutile (0.02 mmol) were mixed in H2O, and then NaCN (0.2 mmol) was added as a 4 M H2O solution. aMolar ratio: aldehyde:sulfonamide:rutile:NaCN. bReaction conversion measured by 1H NMR. cIsolated yield. dTiO2 as rutile. eTiO2 as anatase. fReaction with 1 equiv of NaHCO3.
and then quickly recovered by filtration. Other metal oxides (ZrO2, Fe2O3, ZnO, and MgO) proved to be much less successful at efficiently promoting this transformation (entries 13, 14, 15, and 16). We were also interested in assessing other crystalline forms of TiO2. We found that anatase (entry 17) provided high conversion but lower yield for the desired sulfonylamidonitrile. We were also interested in assessing the reaction’s efficiency under substoichiometric amounts of rutile. We found that high conversions and yields were successfully obtained using 50 and 20 mol % of rutile (entries 18 and 19). Unfortunately, lower catalyst loading failed to promote this transformation efficiently (entry 20). We were also interested in reducing the excess of NaCN in the reaction and we found that in the presence of an exogenous base (NaHCO3, entry 21) conversion and yield dropped significantly. The optimized reaction conditions allowed for the isolation of 2 with complete conversion and 93% yield without silica gel purification (entry 19). All of the nonorganic waste was filtered off the crude mixture and the small amount of organic waste produced was easily disposed. These initial results encouraged us to assess the generality of this transformation for a variety of aromatic and aliphatic aldehydes (Table 2). We found that under the optimized reaction conditions aliphatic aldehydes reacted with p-toluenesulfonamide with very high yields (entries 1, 2, and 3 with 95, 98, and 99% yield, respectively). Aliphatic aldehydes with a chromophore (hydrocinnamaldehyde, entry 4, 92% yield), also proved to be highly successful for this transformation. We then turned our attention to aromatic aldehdyes with a variety of substitution patterns. We found that benzaldehyde and tolualdehyde (entries 5 and 6)
we found higher conversion but similar yield (entry 4, 95% conversion, 68% yield). Phase transfer catalysts have often been used in Strecker-like reactions to achieve high levels of conversion and efficiencies.42 We found that TBAI in THF enhanced the reaction environment to achieve 93% conversion and 66% isolated yield for the desired sulfonylamidonitrile. Although these reaction conditions provided 2 in acceptable yields, purification and waste management were still unsatisfactory. Further optimization showed that equal molar amounts of sulfonamide and aldehyde with TBAI in THF/H2O (entry 6) provided good conversion but low reaction yield. Titanium based Lewis acids (LAs) have been shown to efficiently promote carbonyl reactions. Thus, we then turned our attention to TiCl4 as a promoter for this transformation and we found that 2 was obtained in good yield (entry 7). A milder LA (Ti(OEt)4) displayed improved conversion and yield (entries 9 and 10 with 62 and 75% yield). Thus, we envisioned an even milder LA would be a better promoter. Surfactants with LA properties have the potential to efficiently promote stepwise reaction processes. Rutile (3.3−6.1 m2/g BTE, 0.9−1.6 μm) could maximize the amount of LA interactions with the substrate, thereby producing higher conversions and yields under mild reaction conditions. We found that rutile as a stoichiometric promoter provided high conversions and a significant improvement in yields (entries 10 and 11 with 90 and 89% yield). We then found that in H2O the conversion and yield were optimal (entry 12, 99% conversion and 97% yield). Moreover, because of the heterogeneous nature of the reaction conditions, rutile was easily separated from the excess NaCN B
DOI: 10.1021/acssuschemeng.6b00241 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Letter
ACS Sustainable Chemistry & Engineering Table 2. Reaction Scope for Aromatic and Aliphatic Aldehydes
a
Reaction conversion measured by 1H NMR. bIsolated yield. cIsolated through automated silica gel chromatography.
ically relevant thiophenesulfonamide and p-nitrophenylsulfonamide and also found that the reaction proceeded with high conversions and yields (entries 2 and 3 with 90 and 97% yield, respectively). We also found that trifluoromethanesulfonamide provided the expected sulfonylamidonitrile with excellent yield (entry 4, 91%). The structural nature of the sulfonamide proved to not affect the outcome of the reaction. Given the success with sulfonamides, we were interested in assessing if similar results could be achieved using sulfinamides. The significance of using sulfinamides rests on the potential for high level chirality transfer from commercially available enantiopure t-butylsulfinylamides.44 Unfortunately, we found that when reacting hydrocinnamaldehyde with (R)-t-butylsulfinylamide under the reaction conditions, we were only able to recover traces of the sulfinylamidonitrile (entry 5,
