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Microwave-Assisted One-Pot Tandem Reactions

for Direct Conversion of Primary Alcohols and

Aldehydes to Triazines and Tetrazoles in

Aqueous Media

Jiun-Jie Shie and Jim-Min Fang*

Department of Chemistry, National Taiwan UniVersity, Taipei 106, Taiwan, and The Genomics Research Center,

Academia Sinica, Taipei 115, Taiwan jmfang@ntu.edu.tw ReceiVed December 12, 2006

A series of primary alcohols and aldehydes were treated with iodine in ammonia water under microwave irradiation to give the intermediate nitriles, which without isolation underwent [2 + 3] cycloadditions with dicyandiamide and sodium azide to afford high yields of the corresponding triazines and tetrazoles, including the R-amino- and dipeptidyl tetrazoles in high optical purity.

Using water as a safe medium for various organic reactions

has been reviewed.1We have previously shown that a variety

of aldehydes are converted to their corresponding nitriles using

iodine as an appropriate oxidant in ammonia water.2 In

comparison with similar reactions using liquid ammonia or

ammonia gas saturated in alcohol solvents,3 operation in

ammonia water is simpler and more efficient, giving the nitriles in high yields at room temperature within a short reaction time (<1 h). Nitrile compounds are viable precursors for preparation

of nitrogen-containing functional compounds.4We have

previ-ously demonstrated the tandem reactions of various aldehydes in aqueous media to furnish the corresponding amides, triazines,

and tetrazoles via the intermediate nitriles by additions of H2O2,

dicyandiamide/KOH, and NaN3/ZnBr2in one-pot procedures.5

Though the reaction of the intermediate nitriles with H2O2was

carried out smoothly at room temperature, the formation of

triazines and tetrazoles still required refluxing (e.g., g100°C)

for a prolonged period (12-48 h). In order to improve these preparation protocols, we considered using microwave irradia-tion, which has become a powerful technique to accelerate

thermally driven chemical reactions.6It has been shown that

aryl halides are converted to the aryl nitriles and further to the aryl tetrazoles in a tandem reaction with sodium azide under

microwave irradiation in DMF solution or on solid support.7

We anticipated that the similar cycloaddition reactions of nitriles would be enhanced by microwave irradiation, especially in the above-mentioned salt-containing aqueous media that may take microwave energy effectively.

Our study began with the direct conversion of an aldehyde with iodine in ammonia water to a nitrile intermediate, which without isolation was heated with dicyandiamide, using a focused microwave reactor (power of 80-100 W), to furnish the [2 + 3] cycloaddition product 2,6-diamino-1,3,5-triazine in a one-pot operation (Scheme 1 and Table 1). The 1,3-dipolar cycloaddition of nitrile compounds 2a-e (generated in situ from aldehydes 1a-e) with dicyandiamide proceeded smoothly at

80 °C under microwave irradiation.8 The reaction time was

shortened to 15-30 min, even without using KOH as an external base, which is often utilized as a promoter in conventional

heating methods.5,9Diamino-1,3,5-triazines such as 3a-e are

a class of compounds possessing diverse bioactivities10 and

widely used in material design via assembly of the multiple

hydrogen-bonded complexes.11

* To whom correspondence should be addressed. Tel: (886-2)-33661663. Fax: (886-2)-23637812.

(1) (a) Reichardt, C. In SolVents and SolVent Effects in Organic Chemistry; VCH: Weinheim, Germany, 2003. (b) Li, C. J. Chem. ReV. 1993, 93, 2023-2035. (c) Li, C. J. In Organic Reactions in Aqueous Media;

Wiley: New York, 1997. (d) Lindstro¨m, U. M. Chem. ReV. 2002, 102, 2751-2772. (e) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275-3279.

(2) Talukdar, S.; Hsu, J.-L.; Chou, T.-K.; Fang, J.-M. Tetrahedron Lett.

2001, 42, 1103-1105.

(3) Misono, A.; Osa, T.; Koda, S. Bull. Chem. Soc. Jpn. 1967, 40, 2875-2884.

(4) (a) Mowry, D. T. Chem. ReV. 1948, 42, 189-283. (b) Friedrich, K.; Wallensfels, K. In The Chemistry of Cyano Group; Rappoport, Z., Ed.; Wiley-Interscience: New York, 1970. (c) North, M. In ComprehensiVe Organic Functional Group Transformations; Katritzky, A. R., Meth-Conn, O., Rees, C. W., Eds.; Pergamon: Oxford 1995; pp 617-618.

(5) (a) Shie, J.-J.; Fang, J.-M. J. Org. Chem. 2003, 68, 1158-1160. (b) Taber, D. F. Org. Chem. Highlights: Best Synthetic Methods; March 8, 2004; www.organic-chemistry.org.

(6) (a) Mingos, D. M. P.; Baghurst, D. R. MicrowaVe-Enhanced Chemistry: Fundamentals, Sample Preparation, and Applications; Kingston, H. M., Haswell, S. J., Eds.; American Chemical Society: Washington, DC, 1997. (b) Hayes, B. L. MicrowaVe Syntheses: Chemistry at the Speed of Light; CEM Publishing: Mattews, NC, 2002. (c) De la Hoz, A.; Diaz-Ortiz, A.; Langa, F. MicrowaVes Org. Syn. 2002, 295-343. (d) Nuechter, M.; Ondruschka, B.; Bonrath, W.; Gum, A. Green Chem. 2004, 6, 128-141. (e) Kuznetsov, D. V.; Raev, V. A.; Kuranov, G. L.; Arapov, O. V.; Kostikov, R. R. Russ. J. Org. Chem. 2005, 41, 1719-1749. (f) Wolkenberg, S. E.; Shipe, W. D.; Lindsley, C. W.; Guare, J. P.; Pawluczyk, J. M. Curr. Opin. Drug DiscoVery DeV. 2005, 8, 701-708. (g) Westman, J. MicrowaVe Assisted Org. Synth. 2005, 102-132. (h) Leadbeater, N. E. Chem. Commun. 2005, 23, 2881-2902. (i) Kaval, N.; Ermolat’ev, D.; Appukkuttan, P.;

Dehaen, W.; Kappe, C. O.; Van der Eycken, E. J. Comb. Chem. 2005, 7, 490-502.

(7) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984-7989. (8) The cycloadditions of nitriles with dicyandiamide are usually conducted by heating methods; however, an example using microwave irradiation in ionic liquid has been reported. See: Peng, Y.; Song, G. Tetrahedron Lett. 2004, 45, 5313-5316.

10.1021/jo0625352 CCC: $37.00 © 2007 American Chemical Society

J. Org. Chem. 2007, 72, 3141-3144 3141

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The microwave-assisted cycloadditions of nitriles with NaN3

and cyanoarylboronate esters with trimethylsilyl azide have been carried out at high temperature (150-220°C) in DMF or DME solutions.7,12As the drastic reaction conditions and the organic

solvents are not preferable, the microwave-assisted reaction in aqueous media is more appealing.1In particular, the high heat

capacity of water is able to mitigate the explosion hazards on using sodium azide. In this study, a one-pot procedure for the direct conversion of aldehydes to tetrazoles was carried out by

the microwave-assisted method. Thus, aldehydes 1a-e were subjected to oxidation with I2in ammonia water and in situ

cycloadditions with NaN3/ZnBr2 by microwave irradiation at

80°C for 10 min to give the 5-aryl-1,2,3,4-tetrazoles 4a-e in 70-83% overall yields (Table 1). In comparison with the conventional heating method using prolonged reflux (17-48 h) at a high temperature (>100°C),5,13the current

microwave-accelerated reaction in aqueous media is safer and more efficient.

We also prepared the N-Cbz-R-aminonitriles 6a-c and dipeptidyl nitrile 6f by a similar approach,5i.e., treatment of

appropriate aldehydes 5a-c with I2in ammonia water at room

temperature.16 Furthermore, the N-Cbz-R-aminonitriles 6a-c

generated in situ were treated with NaN3 and ZnBr2 under

microwave irradiation for 30 min to furnish the N-Cbz-R-aminotetrazoles 7a-c in high yields (84-88%).14The

microwave-assisted direct conversion of dipeptidyl aldehyde 5f to dipeptidyl tetrazole 7f (78% yield) was similarly carried out. The1H NMR

analysis (600 MHz) indicated that no apparent existence of the diastereomers of 7f (see Supporting Information).

The scope of this method was further broadened by combina-tion with the direct oxidative conversion of primary alcohols to nitriles in iodine-ammonia water.15Thus, the

microwave-promoted reactions of benzyl alcohol (8a), N-Cbz-prolinol (8c), and the tyrosine-derived primary alcohol (8d) with iodine (4 equiv) in ammonia water gave the corresponding nitriles, which underwent cycloadditions with sodium azide in one pot to

(9) (a) Smolin, E. M.; Rapoport, I. In The Chemistry of Heterocyclic

Compounds; Weissberg, A., Ed.; Wiley: New York, 1959; Vol. 13, s-triazines. (b) Quirke, J. M. E. In ComprehensiVe Heterocyclic Chemistry;

Katritzky, A. R., Rees, C. W., Boulton, A. J., McKillop, A., Eds.; Pergamon: Oxford, 1984; Vol. 3, Chapter 2.20, 1,3,5-Triazines. (c) Cooke, G.; Augier de Cremiers, H.; Rotello, V. M.; Tarbit, B.; Vanderstraeten, P. E. Tetrahedron 2001, 57, 2787-2789.

(10) (a) Hasegawa, Y.; Yanagisawa, T.; Okui, Y.; Sato, T.; Hosaka, K.; Chin, M.; Mitsuhashi, H. Chem. Pharm. Bull. 1991, 39, 3180-3182. (b) Brzozowski, Z.; Saczewski, F.; Gdaniec, M. Eur. J. Med. Chem. 2000, 35, 1053-1064. (c) Jensen, N. P.; Ager, A. L.; Bliss, R. A.; Canfield, C. J.; Kotecka, B. M.; Rieckmann, K. H.; Terpinski, J.; Jacobus, D. P. J. Med.

Chem. 2001, 44, 3925-3931. (d) Baindur, N.; Chadha, N.; Brandt, B. M.;

Asgari, D.; Patch, R. J.; Schalk-HiHi, C.; Carver, T. E.; Petrounia, I. P.; Baumann, C. A.; Ott, H.; Manthey, C.; Springer, B. A.; Player, M. R.

J. Med. Chem. 2005, 48, 1717-1720. (e) Saczewski, F.; Bulakowska, A.;

Bednarski, P.; Grunert, R. Eur. J. Med. Chem. 2006, 41, 219-225. (11) (a) Beijer, F. H.; Sijbesma, R. P.; Vekemans, J. A. J. M.; Meijer, E. W.; Kooijman, H.; Spek, A. L. J. Org. Chem. 1996, 61, 6371-6380. (b) Deans, R.; Rotello, V. M. J. Org. Chem. 1997, 62, 4528-4529. (c) Balogh, D. T.; Dhanabalan, A.; Dynarowicz-Latka, P.; Schenning, A. P. H. J.; Oliveira, O. N., Jr.; Meijer, E. W.; Janssen, R. A. J. Langmuir 2001, 17, 3281-3285. (d) Frankamp, B. L.; Uzun, O.; Ilhan, F.; Boal, A. K.; Rotello, V. M. J. Am. Chem. Soc. 2002, 124, 892-893.

(12) (a) Koldobskii, G. I. Russ. J. Org. Chem. 2006, 42, 469-486. (b) Duncia, J. V.; Pierce, M. E.; Santella, J. B., III. J. Org. Chem. 1991, 56, 2395-2400. (c) Huff, B. E.; Staszak, M. A. Tetrahedron Lett. 1993, 34, 8011-8014. (d) Koguro, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis 1998, 910-914. (e) Curran, D. P.; Hadida, S.; Kim, S.-Y. Tetrahedron 1999, 55, 8997-9006. (f) Schulz, M. J.; Coats, S. J.; Hlasta, D. J. Org. Lett. 2004, 6, 3265-3268.

(13) (a) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2001, 3, 4091-4094. (b) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945-7950. (c) Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2110-2113. (d) Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2113-2116. (e) Himo, F.; Demko, Z. P.; Noodleman, L.; Sharpless, K. B.

J. Am. Chem. Soc. 2002, 124, 12210-12216. (f) Himo, F.; Demko, Z. P.;

Noodleman, L.; Sharpless, K. B. J. Am. Chem. Soc. 2003, 125, 9983-9987.

(14) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4, 2525-2527. (15) Mori, N.; Togo, H. Synlett 2005, 1456-1458.

SCHEME1. Microwave-Assisted One-Pot Tandem Reactions for Direct Conversion of Alcohols and Aldehydes to Triazines and Tetrazoles in Aqueous Media

TABLE1. Direct Conversion of Aldehydes to Triazines and Tetrazoles via Cycloadditions of Intermediate Nitriles with Dicyandiamide and Sodium Azide by Microwave-Assisted Methods

products (yield, %)a

aldehyde R ) triazineb tetrazolec

1a C6H5 3a (71) 4a (79)

1b 4-MeOC6H4 3b (69) 4b (77) 1c 4-O2NC6H4 3c (76) 4c (76) 1d 2-furyl 3d (77) 4d (70) 1e 2-thienyl 3e (83) 4e (83) aOverall yield of two steps.bThe aldehyde was stirred with I

2 in ammonia water for 1 h, followed by addition of dicyandiamide, and the mixture was exposed to microwave irradiation at 80°C for 15-30 min.

cThe aldehyde was stirred with I

2in ammonia water for 1 h, followed by addition of NaN3and ZnBr2, and the mixture was exposed to microwave irradiation at 80°C for 10 min.

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furnish the desired tetrazole products 4a, 7c, and 7d in 80%, 77%, and 82% yields, respectively. The direct conversion of the tryptophan-derived primary alcohol 8e was similarly per-formed, albeit by using a larger quantity of NaN3(18 equiv)

and ZnBr2(9 equiv) for a longer period (45 min), to obtain a

70% yield of the tryptophan tetrazole 7e with concomitant removal of the Boc group. The cycloaddition of the tryptophan nitrile generated from 8e was more sluggish presumably as a result of its low solubility in the reaction conditions. The R-aminotetrazoles 7a-e prepared as such showed only minimal racemerization (3.5-6%) during the microwave-assisted one-pot tandem reactions according to the HPLC analyses on a chiral column (see Supporting Information).

We have demonstrated an expedient microwave-assisted method for the direct transformation of primary alcohols and aldehydes into triazines and tetrazoles in aqueous media. The alcohols and aldehydes reacted with iodine in ammonia water to provide the corresponding nitrile intermediates (e.g., 2a-e,

6a-c, and 6f), which readily underwent [2 + 3] cycloadditions

with dicyandiamide and sodium azide on exposure to microwave irradiation to give the corresponding 4-aryl-2,6-diamino-1,3,5-triazines (3a-e), 5-aryl-1,2,3,4-tetrazoles (4a-e), N-Cbz-R-aminotetrazoles (7a-c), and dipeptidyl tetrazole (7f) in a one-pot operation. This method circumvents the problem in prior preparation of nitrile compounds from halides and toxic cyanides. The one-pot tandem reactions were conducted in aqueous media, and the products (triazines and tetrazoles) were obtained simply by extraction or filtration. In comparison with the previously reported heating methods, microwave irradiation has an advantage in the acceleration of reactions. No caustic KOH was required in the microwave-accelerated synthesis of triazines.

The optically active R-aminotetrazoles, e.g., 7c derivative of L-proline, have been employed as versatile chiral catalysts in organic reactions.16 Because the tetrazole products have a

striking structural resemblance to their triazole analogues, our method for an easy access to optically active R-aminotetrazoles in aqueous media may have a growing impact on drug discovery similar to that demonstrated by the click chemistry of alkynes with azides.17

Experimental Section

CAUTION: Iodine may react with ammonia water under certain conditions to give the explosive powder nitrogen triiodide monoam-ine (NI3‚NH3),18and the reaction of sodium azide may release a minute amount of hazardous hydrazoic acid (HN3). Although we

did not encounter any incidents in this study, one should avoid using excess reagents or high concentrations of iodine-ammonia water and sodium azide in the following procedures.

General Procedure for Direct Conversion of Aldehydes to Triazines Using Microwave Irradiation. A solution of aromatic aldehyde (1a-e, 1 mmol) and iodine (1.1 mmol) in ammonia water (9 mL of 28% solution) and THF (1 mL) was placed in a round-bottomed flask equipped with a condenser. The dark solution was stirred for 1 h at room temperature and became colorless at the end of the reaction. After addition of dicyandiamide (1.1 mmol), the mixture was irradiated in a single mode microwave reactor (100 W power) at approximately 80°C (as indication of the reactor’s temperature setting) for 15-30 min. The reaction mixture was cooled; the precipitates were filtered and rinsed with Et2O to give the desired pure product 6-aryl-2,4-diamino-1,3,5-triazine (3a-e) in 69-83% yields (Table 1). The physical and spectroscopic properties of 3a-e were in agreement with those data previously reported (see Supporting Information).

General Procedure for Direct Conversion of Aldehydes to Tetrazoles Using Microwave Irradiation. A solution of R-ami-noaldehyde (5a, 1 mmol) and iodine (1.1 mmol) in ammonia water (8 mL of 28% solution) and THF (2 mL) was stirred at room temperature for 1-2 h. The dark solution became colorless at the end of reaction. NaN3 (4 mmol) and ZnBr2(2 mmol) were then added sequentially. The reaction mixture was exposed to microwave irradiation (80 W) at 80°C for 30 min. The reaction mixture was cooled, aqueous HCl (1 M solution) and EtOAc were added, and the mixture was vigorously stirred until no solid was present. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The desired (S)-N-Cbz-R-aminotetrazole 7a was obtained in 88% yield by crystallization from EtOAc/Et2O solution.

Conversion of aldehydes 1a-e, 5b, 5c, and 5f to the corre-sponding tetrazoles 4a-e, 7b, 7c, and 7f using microwave irradiation was carried out by the procedure described for 7a. The physical and spectroscopic properties of tetrazoles 4a-e and 7a-c were in agreement with the previously reported data.5,14

General Procedure for Direct Conversion of R-Amino Alco-hols to R-Aminotetrazoles Using Microwave Irradiation. A solution of (S)-(benzyloxycarbonyl)prolinol 8c (3 mmol) and iodine (12 mmol) in ammonia water (12 mL of 28% solution) and THF (3 mL) was placed in a round-bottomed flask equipped with a condenser. The mixture was stirred for 5 min at room temperature and exposed to microwave irradiation in a single mode microwave reactor (100 W) at 60°C (as indication of the reactor’s temperature setting) for 15-30 min. The mixture was cooled to room temper-ature, NaN3(12 mmol) and ZnBr2(6 mmol) were added sequen-tially, and the mixture was again subjected to microwave irradiation at 80 °C for 30 min. The reaction mixture was cooled, aqueous HCl (1 M solution) and EtOAc were added, and the mixture was vigorously stirred until no solid was present. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, concentrated, and chromatographed on a silica gel column to give the desired (S)-tetrazole product 7c (77% yield, 93% ee).

Conversion of benzyl alcohol (8a) and the tyrosine- and tryptophan-derived primary alcohols 8d and 8e using microwave irradiation was carried out by the procedure described for 8c, giving the tetrazoles 4a (80% yield), 7d (82% yield, 92% ee), and 7e (70% yield, 88% ee), respectively. The physical and spectroscopic properties of 7c and 7e are listed in Supporting Information.

HPLC Analysis. The enantiomeric purity of tetrazoles 7a-e was determined by HPLC analysis on a Chiralcel OD-H column (0.46 cm i.d.× 25 cm) at 30 °C. The tetrazole sample (5.0 mg/mL in 2-propanol) was prepared, and 20µL was loaded for each analysis. The mobile phase of hexane/2-propanol (85:15, v/v) with a flow rate of 0.5 mL/min was applied, and the signals of the sample were

(16) Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831-1834.

(17) (a) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8, 1128-1137. (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.,

Int. Ed. 2001, 40, 2004-2021. (c) Prescher, J. A.; Bertozzi, C. R. Nat. Chem. Biol. 2005, 1, 13-21. (d) Van Swieten, P. F.; Leeuwenburgh,

M. A.; Kessler, B. M.; Overkleeft, H. S. Org. Biomol. Chem. 2005, 3, 20-27. (e) Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.; Carlier, P. R.; Taylor, P.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.

2002, 41, 1053-1057. (f) Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Fokin,

V. V.; Sharpless, K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125, 9588-9589. (g) Krasinski, A.; Radic, Z.; Manetsch, R.; Raushel, J.; Taylor, P.; Sharpless, K. B.; Kolb, H. C. J. Am. Chem. Soc. 2005, 127, 6686-6692. (h) Whiting, M.; Muldoon, J.; Lin, Y.-C.; Silverman, S. M.; Lindstrom, W.; Olson, A. J.; Kolb, H. C.; Finn, M. G.; Sharpless, K. B.; Elder, J. H.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 1435-1439.

(18) (a) Southwick, P. L.; Christman, D. R. J. Am. Chem. Soc. 1952,

74, 1886-1891. (b) Roesky, H. W.; Mo¨ckel, K. In Chemical Curiosities;

VCH: Weinheim, Germany 1996; pp 292-293.

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recorded by a UV detector at 206 nm wavelength. The ratio of enantiomers was calculated from the areas of each enantiomer signals.

Acknowledgment. We thank the National Science Council

for financial support.

Supporting Information Available: General experimental section, characterization of compounds,1H and13C NMR spectra of new compounds, and HPLC analyses of tetrazoles 7a-e. This material is available free of charge via the Internet at http://pubs.acs.org. JO0625352

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