Direct Conversion of Aldehydes to Amides,
Tetrazoles, and Triazines in Aqueous
Media by One-Pot Tandem Reactions
Jiun-Jie Shie and Jim-Min Fang*
Department of Chemistry, National Taiwan University, Taipei, Taiwan 106
jmfang@ccms.ntu.edu.tw Received September 6, 2002
Abstract: A variety of aldehydes reacted with iodine in ammonia water at room temperature to give the nitrile intermediates, which were trapped by addition of hydrogen peroxide, sodium azide, or dicyandiamide to produce their corresponding amides, tetrazoles, and 1,3,5-triazines in modest to high yields. The one-pot tandem reactions were conducted in water media, and the products were obtained simply by extraction or filtration.
In comparison with some inflammable and toxic or-ganic solvents, water may serve as a superior solvent that is safe to use in organic reactions.1The low cost of water renders the chemical processes more economical. In many cases, water can be recycled to alleviate the problem of solvent disposal. Furthermore, using water as a solvent may also have advantages of simple operation and high efficiency in many organic reactions that involve water-soluble substrates and reagents.1For example, we have recently found a direct method for transformation of aldehydes 1 to nitriles 2 by using iodine in ammonia water (eq 1)2instead of liquid ammonia or ammonia gas saturated in alcohol solvents. This transformation is completed within a short period (<1 h) at room temper-ature. A variety of aldehydes, including aromatic, het-erocyclic, aliphatic, conjugated, and polyhydroxy alde-hydes, have thus been converted to their corresponding nitriles in high yields (83-97%). This transformation utilizes iodine as an appropriate oxidant and presumably proceeds with an intermediate of N-iodo aldimine (A),3,4e which eliminates an HI molecule in ammonia solution to afford the nitrile product. When compared to the previously reported procedures4that use various oxidants and promoters in organic solvents, our method appears to be simple, efficient, and environmentally benign.
Nitrile compounds are viable precursors for prepara-tion of a variety of nitrogen-containing funcprepara-tional
com-pounds.5It would be desirable that one could start with the readily available aldehydes to carry out tandem reactions, via the intermediacy of nitriles, in aqueous media to furnish other nitrogen-containing functional compounds of biological and material importance. In this paper, we wish to demonstrate that this type of tandem reaction in a one-pot procedure can provide an expedient route to amides 3, triazoles 4, and tetrazines 5 (eqs 2-4). The results are collected in Table 1.
When benzaldehyde (5 mmol) was treated with iodine (5.5 mmol) in ammonia water (30 mL of 28% solution) and THF (5 mL) at room temperature for 1 h, the dark solution became colorless as iodine was consumed. A practically pure product of benzonitrile (96% yield) was obtained after charge with aqueous Na2S2O3and extrac-tion with ether.2 On the other hand, benzamide was produced in 98% yield if the reaction mixture was charged with aqueous H2O2(35% solution) for 2.5 h. The two-step reaction sequence is mandatory to procure amide products in high yields. If H2O2was added together with I2to benzaldehyde in ammonia water, only a 35% yield of benzamide was obtained. The decreased yield was presumably due to a partial consumption of I2by H2O2.6 The presumed generation of hypoiodic acid might also cause the side oxidations of aldehyde to other unidenti-fied compounds.4c,fBenzaldehydes bearing either electron-donating or electron-withdrawing substituents (e.g., 4-methoxybenzaldehyde (1b) and 4-nitrobenzaldehdye (1c)) gave the substituted benzamides (e.g., 3b and 3c) in high yields by the similar reaction procedures. It is known that nitrile compounds can be converted to their corresponding amides by heating (e.g., 40-50 °C) with alkaline hydrogen peroxide in organic solvents (e.g., acetone, ethanol, dioxane, THF, and DMSO).7The hydra-tion of nitrile is initiated by a nucleophilic addihydra-tion of -OOH ion to the cyano group, giving an intermediate peroxycarbaximidic acid (B), which is then reduced by H2O2 (or DMSO) to produce carboxamide along with dioxygen (or dimethyl sulfone).7We have mentioned that I-ion was generated during the reaction of aldehyde with I2/aq NH3 to form a nitrile product. Thus, a facilitated degradation of the peroxycarbaximidic acid intermediate,
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1158 J. Org. Chem. 2003, 68, 1158-1160
10.1021/jo026407z CCC: $25.00 © 2003 American Chemical Society Published on Web 12/20/2002
derived by addition of H2O2 to the transient nitrile product in basic ammonia solution, could be achieved by I-ion.
Treatments of 2-cyanobenzaldehyde sequentially with I2/aq NH3and H2O2yielded a bisamide 3d (phthalamide), whereas the similar treatments of terephthaldehyde afforded a bisamide 3e (terephthamide). Heterocyclic and aliphatic aldehdyes such as 2-furaldehyde, thiophene-2-carbaldehyde, 1-methylpyrrole-2-thiophene-2-carbaldehyde, valer-aldehyde, and pivalaldehyde were also transformed into their corresponding amides 3f-j in high yields (81-94%) by conducting the tandem reactions with I2/aq NH3and H2O2in a one-pot procedure.
Tetrazoles play important roles in coordination chem-istry, as useful ligands, and in medicinal chemchem-istry, as stable isosteres of carboxylic acids.8 Tetrazoles can be obtained by addition of azide ion to nitriles. The conven-tional methods require either drastic reaction conditions or use of unconventional reagents of alkylaluminum,
alkylsilicon, and alkyltin azides.9The formation of tet-razoles is accelerated by microwave irradiation of a mixture of NaN3, nitrile, and NH4Cl in DMF solution.10 In this operation, one should take precautions on the built-up high pressure and the sublimed ammonium azide that may explode in dry form.9b,dAs DMF is not a preferable solvent for industrial use, the reaction in aqueous media is more appealing.1 Sharpless and co-workers have recently carried out the addition reactions of nitrile compounds with sodium azide in water by the promotion of zinc salts.11The high heat capacity of water is able to mitigate the explosion hazards on using sodium azide.9b,d In our study, benzaldehyde was successfully converted to 5-phenyltetrazole (4a) by tandem reactions with I2/aq NH3at room temperature and NaN3/ZnBr2at reflux. The optimal conditions applying 1.2 equiv of NaN3 and 1.5 equiv of ZnBr2afforded an 81% yield of tetrazole 4a. ZnI2was an equally efficient promoter, but ZnCl2, Et3NHCl, or Al(OMe)3 were inferior. By the similar procedures, substituted benzaldehydes (4-methoxyben-zaldehyde and 4-nitroben(4-methoxyben-zaldehyde) and heterocyclic aromatic aldehydes (2-furaldehyde, thiophene-2-carbal-dehyde, and pyridine-2-carbaldehyde) also underwent the
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TABLE1. Reactions of Aldehydes with Iodine in Ammonia WateraFollowed by Treatments with Hydrogen Peroxide, Sodium Azide, or Dicyandiamide, Giving Amides 3, Tetrazoles 4, and Triazines 5
entry aldehydes treatments conditions product (yield, %) 1 C6H5CHO (1a) 35% H2O2 r.t., 2.5 h amide 3a (98)
2 4-MeOC6H4CHO (1b) 35% H2O2 r.t., 4 h amide 3b (95)
3 4-O2NC6H4CHO (1c) 35% H2O2 r.t., 3 h amide 3c (81)
4 2-NCC6H4CHO (1d) 35% H2O2 r.t., 2.5 h amide 3d (93)
5 4-OHCC6H4CHO (1e) 35% H2O2 r.t., 2.5 h amide 3e (95)
6 2-furaldehyde (1f) 35% H2O2 r.t., 2 h amide 3f (94)
7 thiophene-2-carbaldehyde (1g) 35% H2O2 r.t., 3.5 h amide 3g (81)
8 1-methylpyrrole-2-carbaldehyde (1h) 35% H2O2 r.t., 2 h amide 3h (93)
9 CH3(CH2)3CHO (1i) 35% H2O2 r.t., 3.5 h amide 3i (91)
10 Me3CCHO (1j) 35% H2O2 r.t., 2.5 h amide 3j (91)
11 C6H5CHO (1a) NaN3, ZnBr2 reflux, 24 h tetrazole 4a (81)
12 4-MeOC6H4CHO (1b) NaN3, ZnBr2 reflux, 48 h tetrazole 4b (72)
13 4-O2NC6H4CHO (1c) NaN3, ZnBr2 reflux, 17 h tetrazole 4c (89)
14 2-furaldehyde (1f) NaN3, ZnBr2 reflux, 24 h tetrazole 4f (79)
15 thiophene-2-carbaldehyde (1g) NaN3, ZnBr2 reflux, 14 h tetrazole 4g (87)
16 pyridine-2-carbaldehyde (1k) NaN3, ZnBr2 reflux, 12 h tetrazole 4k (82)
17 C6H5CHdCHCHO (1l) NaN3, ZnBr2 reflux, 48 h tetrazole 4l (84)
18 C6H5CHO (1a) dicyandiamide, KOH reflux, 24 h triazine 5a (78)
19 4-MeOC6H4CHO (1b) dicyandiamide, KOH reflux, 48 h triazine 5b (56)
20 4-O2NC6H4CHO (1c) dicyandiamide, KOH reflux, 24 h triazine 5c (72)
21 2-furaldehyde (1f) dicyandiamide, KOH reflux, 24 h triazine 5f (80) 22 thiophene-2-carbaldehyde (1g) dicyandiamide, KOH reflux, 24 h triazine 5g (82) 23 pyridine-2-carbaldehyde (1k) dicyandiamide, KOH reflux, 18 h triazine 5k (80) 24 C6H5CHdCHCHO (1l) dicyandiamide, KOH reflux, 18 h triazine 5l (70) aA small amount of THF was used as the cosolvent. The aldehydes were allowed to react with iodine in ammonia water at room
temperature for 1 h before the subsequent addition of H2O2, NaN3/ZnBr2, or dicyandiamide/KOH.
one-pot tandem reactions with I2/aq NH3and NaN3/ZnBr2 to give reasonable yields (72-89%) of 5-aryltetrazoles (entries 12-16). Cinnamaldehyde was also converted to the corresponding tetrazole 4l (84%) with the CdC double bond retained.
Diamino-1,3,5-triazines are a class of compounds pos-sessing diverse bioactivities such as anti-inflammation, antiallergy, and protective effect against gastric lesions.12 Diaminotriazines are also applicable to material design via assembly of the multiple hydrogen-bonded com-plexes.13Among a number of synthetic methods for 2,4-diaminotriazines,14the most convenient approach utilizes the addition reactions of nitrile compounds with dicyan-diamide (also called cyanoguanidine). The reaction is catalyzed by base. In our present study, benzonitrile resulted in situ from the reaction of benzaldehyde with I2/aq NH3was treated with dicyandiamide (1.1 equiv) and KOH (2.2 equiv) at refluxing temperature for 24 h to afford 2,6-diamino-4-phenyl-1,3,5-triazine (5a) in 78% yield. A control reaction of benzonitrile with dicyandi-amine (1.1 equiv) and KOH (2.2 equiv) in aq NH3/THF (9:1) yielded 82% of 5a. Without ammonia, the reaction of benzonitrile (1.1 equiv) and KOH (2.2 equiv) in aqueous THF at refluxing temperature for 24 h gave 5a in 69% yield. Using a smaller amount of KOH (1.1 equiv) decreased the yield of 5a (64%). Omission of KOH gave an even lower yield of 5a (42%) after refluxing for a prolonged period (48 h). It appeared that our current one-pot tandem reaction in ammonia water was the method of choice for the direct conversion of aldehyde to triazines. Thus, a series of 2,4-diaminotriazines were synthesized by the one-pot tandem reactions using appropriate alde-hydes as the starting materials (entries 18-24).
In summary, we have explored a new methodology using one-pot tandem reactions for the direct conversion of aldehydes to amides, tetrazoles, and triazines, via addition of H2O2, NaN3/ZnBr2,and dicyandiamide/KOH to the intermediate nitriles. These reactions are con-ducted smoothly in aqueous media, and the desired products are obtained simply by extraction or filtration.
The advantageous features of this method, including simple operation, high yielding, and solvent reuse, pro-vide an excellent opportunity for parallel synthesis and industrial production. This method can also circumvent the problem in prior preparation of nitrile compounds from halides and toxic cyanides.
Experimental Section
CAUTION: It is known that iodine reacts with ammonia water under certain conditions to give a black powder of nitrogen triiodide monoamine (NI3‚NH3).15 The dry powder explodes
readily by mechanical shock, heat, or irradiation. Although we did not have any incidents when handling the reactants in this study, one should avoid using excess reagent.
Representative Procedure for Transformation of Alde-hydes into Amides. A solution of appropriate aldehyde (1a-j, 5 mmol) and iodine (5.5 mmol) in ammonia water (30 mL of 28% solution) and THF (5 mL) was stirred at room temperature for 1 h. The dark solution became colorless at the end of reaction. Aqueous H2O2(3 mL of 35% solution) was then added dropwise.
The reaction mixture was stirred for 2-4 h and extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2
-SO4), and concentrated in vacuo. The residue was rinsed with
hexane/EtOAc (1:3) to give a pure amide product (3a-j, 81-98% yields). Amides 3a-j are characterized by their physical and spectral properties that are consistent with known com-pounds (see Supporting Information).
Representative Procedure for Transformation of Alde-hydes into Tetrazoles. CAUTION: Although a study has shown this protocol only releases a minute amount of hydrazoic acid (HN3),11one should still avoid using excess amounts or high
concentrations of sodium azide in the following procedure. A solution of appropriate aldehyde (1 mmol) and iodine (1.1 mmol) in ammonia water (9 mL of 28% solution) and THF (1 mL) was stirred at room temperature for 1 h. The dark solution became colorless at the end of reaction. A mixture of NaN3(1.2
mmol) and ZnBr2 (1.5 mmol) was then added. The reaction
mixture was heated at reflux for 12-48 h with vigorous stirring. HCl (10 mL of 1 M solution) and EtOAc (50 mL) were added, and vigorous stirring was continued until no solid was present and the aqueous layer had a pH of 1. The organic phase was concentrated in vacuo, and the remaining solids were rinsed with EtOAc (20 mL) to give a pure tetrazole product (4a-c, f, g, k, l, 72-89% yields). These 5-substituted tetrazoles are characterized by their physical and spectral properties that are consistent with known compounds (see Supporting Information).
Representative Procedure for Transformation of Alde-hydes into Triazines. A solution of appropriate aldehyde (1 mmol) and iodine (1.1 mmol) in ammonia water (9 mL of 28% solution) and THF (1 mL) was stirred at room temperature for 1 h. The dark solution became colorless at the end of the reaction. A mixture of dicyandiamide (1.1 mmol) and KOH (2.2 mmol) was then added. The reaction mixture was heated at reflux for 12-48 h. The suspended solid products were filtered and rinsed with Et2O to give a pure diaminotriazine (5a-c, f, g, k, l,
56-82% yields). These 6-substituted 2,4-diamino-1,3,5-triazines are characterized by their physical and spectral properties that are consistent with known compounds (see Supporting Information).
Acknowledgment. We thank the National Science
Council for financial support.
Supporting Information Available: Physical and spec-tral data and pertinent references for amides 3, tetrazoles 4, and triazines 5. These materials are available free of charge via the Internet at http://pubs.acs.org.
JO026407Z
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