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PAPER

2631

Direct Oxidative Conversion of Alcohols, Amines, Aldehydes, and Benzyl
Halides into the Corresponding Nitriles with Trichloroisocyanuric Acid in
Aqueous Ammonia
NitrlesbyDirectOxidativeConversion Veisi*
Hojat
Department of Chemistry, Payame Noor University (PNU), Songhor, Kermanshah, Iran
Fax +98(838)4227463; E-mail: hojatveisi@yahoo.com
Received 18 February 2010; revised 6 April 2010

Key words: trichloroisocyanuric acid, nitriles, alcohols, amines,
aldehydes, alkyl halides

Nitriles are very important intermediates in synthetic organic chemistry.1 They are important synthetic precursors, particularly to esters, amides, carboxylic acids,
amines, and nitrogen-containing heterocycles, and they
have been used as synthetic intermediates for agricultural
chemicals, pharmaceuticals, and functional materials.2,3
Consequently, there is great interest in finding methods
for their synthesis under mild conditions. A typical method is the reaction of alkyl halides with toxic cyanide via a
nucleophilic pathway; the length of the carbon chain is increased by one during this process. Due to the toxicity of
cyanide, nitriles are generally prepared by the dehydration
of amides with SOCl2, TsCl/pyridine, P2O5, COCl2,
(EtO)3P/I2, or Ph3P/CCl4.4 It has been reported that nitriles
can be prepared from carboxylic acids or their derivatives,5 amides,6,7 aldehydes,8,9 oximes,10 and nitro compounds.11 Nitrile synthesis from amines is a classical
route. Numerous metal-based oxidants, such as nickel
peroxide,12 silver reagents,13 copper reagents,14 OsO4,15
NaOCl,16 PhIO,17 trichloroisocyanuric acid (TCCA) with
TEMPO18 or triethylamine,19 IBX/I2,20 I2/NH3,21 1,3-diiodo-5,5-dimethylhydantoin (DIH) in aqueous ammonia,22,23 and ruthenium reagents24 have been used to
perform this transformation. However, there are only a
few reports on the direct oxidative conversion of alcohols
as starting materials into nitriles in a one-pot procedure,
i.e. using NH4HCO3/(Bu4N)2S2O8/Cu(O2CH)2 (cat.)/
Ni(O2CH)2 (cat.)/aq KOH–i-PrOH,25 MnO2/NH3/MgSO4/
THF–i-PrOH (for benzylic and cinnamic alcohols),25 I2/aq
NH3,26 and DIH/aq NH3,22 and KI/I2/TBHP.27 Recently,
the direct oxidative conversion of alkyl halides into ni-

SYNTHESIS 2010, No. 15, pp 2631–2635xx. 201
Advanced online publication: 18.06.2010
DOI: 10.1055/s-0029-1218827; Art ID: Z04110SS
© Georg Thieme Verlag Stuttgart · New York

triles with molecular iodine and 1,3-diiodo-5,5-dimethylhydantoin in aqueous ammonia was reported by Togo and
et al.28
Trichloroisocyanuric acid [1,3,5-trichloro-1,3,5-triazine2,4,6-(1H,3H,5H)-trione or TCCA] is a stable, homogeneous, neutral, nonvolatile, inexpensive, safe, commercially available reagent (used primarily as a disinfectant
and deodorant) that has been used as efficient catalyst, reagent, and oxidant in organic synthesis.29–34
Recently, we reported the direct, efficient, practical, and
less toxic oxidative conversion of primary alcohols and
amines into the corresponding nitriles using poly(N,N¢dichloro-N-ethylbenzene-1,3-disulfonamide) (PCBS) and
N,N,N¢,N¢-tetrachlorobenzene-1,3-disulfonamide (TCBDA)
in aqueous ammonia.35 Herein, as part of our ongoing
study on the application of N-halo reagents in organic
synthesis,36–39 we would like to present the direct oxidative conversion of alcohols, primary amines, aldehydes,
and alkyl halides into the corresponding nitriles using
trichloroisocyanuric acid as a reagent and oxidant under
mild conditions (Scheme 1).
For our initial optimization studies, benzyl alcohol (2a)
was chosen as the model substrate. A mixture of benzyl
alcohol (2a) and aqueous ammonia solution was stirred

Scheme 1

Downloaded by: A.E.Favorsky Irkutsk Institute of Chemistry SB RAS. Copyrighted material.

Abstract: A new and efficient procedure for the one-pot conversion
of various alcohols, aldehydes and primary amines into the corresponding nitriles in excellent yields was easily achieved by trichloroisocyanuric acid (TCCA) as an oxidant and reagent in aqueous
ammonia. Also, various benzylic halides were smoothly and directly converted into the corresponding aromatic nitriles in high yields
under the same conditions.

Under similar reaction conditions.E. Adding the trichloroisocyanuric acid in one portion would result in an explosive reaction. Thus. 60 °C TCCA Table 1 Conversion of Primary Amines. entries 9–11).5 5b27 90 27 92 18 3c 4-MeOC6H4 – 1.2 5d27 92 5 1e 4-ClC6H4 – 2 5e27 88 6 1f 4-H2NCH2C6H4 – 2 5f27 90b 7 1g Bn – 1. Typically. No.h which contain an electronwithdrawing group gave slightly lower yields (Table 1. entries 12. Synthesis 2010. We obtained a very good conversion irrespective of the electronic nature of the aldehyde. 2631–2635 © Thieme Stuttgart · New York Downloaded by: A. 15. these reactions were found to be faster compared to the alcohols.5 5a28 85 28 4b 4-Tol Br 3.5 5c28 95 – HCl H R I O – HCl Cl NH3 RCHO – H2O II R-CH=NH III TCCA Cl R-C=N H IV Scheme 2 The present system was further examined for the direct conversion of aldehydes 3 into nitriles.5 5c 19 3e 4-ClC6H4 – 2. benzyl alcohol (2a) in aqueous ammonia (3 mL) in a round-bottomed flask was treated with trichloroisocyanuric acid (0.26 R OH 2 TCCA R CN 5 NH3. 2632 . It should be noted that during all reactions care must be taken when adding trichloroisocyanuric acid to the substrate/ammonia solution. Then. entry 8).5 mmol to 0. but increasing the amount of trichloroisocyanuric acid from 0. 13). Alcohols. The results showed that reactions at room temperature provided low yields of benzonitrile (5a). Moreover. This aldehyde reacts with ammonia to form an aldimine III. aq NH3 60 °C Y R CN 1 Y = CH2NH2 2 Y = CH2OH 3 Y = CHO 4 Y = CH2X 5 Amine R X Time (h) Producta Yield (%) 1 1a Ph – 1 5a27 96 2 1b 4-Tol – 1 5b27 98 3 1c 4-MeOC6H4 – 1 5c27 96 4 1d 4-HOC6H4 – 1.5 5b28 85 29 4b¢ 4-Tol Cl 3.75 mmol and increasing the temperature from room temperature to 60 °C gave a moderate improvement in the conversion. there was no product formation in the absence of trichloroisocyanuric acid. entries 8–15). To avoid this problem trichloroisocyanuric acid was added very careful in several small portions. Veisi under different conditions.PAPER H.5 5g27 85 8 2a Ph – 2 5a27 90 9 2b 4-Tol – 2. Copyrighted material.5 5h 13 2e 4-ClC6H4 – 4 5e27 82 27 80 14 2g Bn – 4 5g 15 2i Pr – 5 5i27 75 27 90 16 3a Ph – 2 5a 17 3b 4-Tol – 1. and Alkyl Halides into Nitriles Catalyzed by Trichloroisocyanuric Acid in Aqueous Ammonia R TCCA. The general applicability of this method was further evaluated for various primary and benzylic alcohols under optimized reaction conditions using trichloroisocyanuric acid as an oxidant and reagent (Table 1.5 5b27 96 27 98 Entry 10 2c 4-MeOC6H4 – 2. The reactivity depends on the nature of alcohol used. According to this pathway. the aldimine III reacts with trichloroisocyanuric acid in the presence of ammonia to form an N-chloroaldimine IV. and the results are summarized in Table 1 (entries 16–24). while benzylic alcohols 2e.5 5e27 88 27 75 20 3j 4-O2NC6H4 – 3 5j 21 3k 1-naphthyl – 2 5k27 85 27 90 22 3l 2-thienyl – 2 5l 23 3m (E)-CH=CHPh – 5 5m27 75 24 3n (CH2)6Me – 5 5n27 70 25 4a Ph Br 4 5a28 80 26 4a¢ Ph Cl 3 5a28 85 27 4a¢¢ Ph I 2. followed by b-elimination of HCl by ammonia to form the aldehyde II.75 equiv) at room temperature and then stirred at 60 °C for two hours to provide benzonitrile (5a) in high yield (Table 1.5 5b28 90 30 4c 4-MeOC6H4 Br 3 5c28 92 31 4c¢ 4-MeOC6H4 Cl 3. the initial O-chlorination of the alcohol 2 with trichloroisocyanuric acid occurs to form the O-chloro compound I. followed by belimination of HCl by ammonia to generate the corresponding nitrile 5. Aldehydes. benzylic alcohols 2b–d which contain an electron-donating group were smoothly converted into the corresponding nitriles 5b–d in good yields (Table 1.5 5c 11 2d 4-HOC6H4 – 3 5d27 96 27 80 12 2h 4-BrC6H4 – 4. A plausible reaction pathway for the conversion of primary alcohols into nitriles is shown in Scheme 2.Favorsky Irkutsk Institute of Chemistry SB RAS.

E. and the results are summarized in Table 1.PAPER Table 1 Conversion of Primary Amines. TCCA 3 RCH2NH2 1 NH3. Then. No. 3 mL) at 60 °C. a plausible reaction pathway for the conversion of dibenzylamine (6) into nitrile 5a is shown in Scheme 5. This is followed by b-elimination of HCl by ammonia. followed by n-elimination of HCl to generate imine III. b Product was benzene-1. the aldimine III reacts with trichloroisocyanuric acid in the presence of ammonia to form an N-chloroaldimine IV.75 mmol) in aqueous ammonia (30%. leading to the aldimine III. entries 28–33). benzylamine (1a) afforded benzonitrile (5a) within one hour in 96% yield (Table 1. Practically. 4-methoxybenzyl. Once imino compound VII is formed. The primary amine IX reacts with trichloroisocyanuric acid to form the N-chloroamine V. 90% 6 5a TCCA (– HCl) H Cl R N R R-C=N Cl VI H (– HCl) N IV Cl V R H R-CH-NH R TCCA (– HCl) VII NH3 TCCA NH2 R VIII N H R R-CH2-NH2 IX + R-CH=NH III Scheme 5 Based on the results of above study. we used this reaction to prepare nitriles in a one-pot procedure from amines 1. and Alkyl Halides into Nitriles Catalyzed by Trichloroisocyanuric Acid in Aqueous Ammonia (continued) R CN 1 Y = CH2NH2 2 Y = CH2OH 3 Y = CHO 4 Y = CH2X R X Time (h) Producta Yield (%) 32 4e 4-ClC6H4 Br 8 5e28 80 28 80 80 33 4e¢ 4-ClC6H4 Cl 7 5e 34 4k 1-naphthyl Br 4 5k28 a The products were characterized by comparison of their spectroscopic and physical data with those of samples synthesized by reported procedures. followed by b-elimination of HCl to form the imino compound VII. we examined the feasibility of this reaction for various substrates. Thus. Primary alkyl halides should react with ammonia via an SN2 nucleophilic pathway to form the corresponding primary amines that can be smoothly oxidized to corresponding nitriles by trichloroisocyanuric acid in one-pot. the reaction was carried out by treating benzyl bromide (4a. 3 mL) with trichloroisocyanuric acid (1 mmol) at 60 °C in roundbottomed flask to provide benzonitrile (5a) in good yield (Table 1. 4 h. and finally elimination of HCl by ammonia occurs to provide the nitrile 5a. entries 1–7.Favorsky Irkutsk Institute of Chemistry SB RAS. 2631–2635 © Thieme Stuttgart · New York Downloaded by: A. 15.c. 1-Naphthylmethyl bromide (4k) could also be converted into correSynthesis 2010. dibenzylamine (6) reacted with trichloroisocyanuric acid in aqueous ammonia to provide benzonitrile (5a) in good yields (Scheme 4). Aldehydes. the reaction can be carried out in a single step.1-diamino compound VIII. Alcohols.4-dicarbonitrile. 1 mmol) in aqueous ammonia (28–30%.e could be also converted into the corresponding nitriles 5b. it reacts with aqueous ammonia to form the 1. entry 25). A plausible mechanism for the conversion of a primary amine 1 into nitrile 5 is shown in Scheme 3. 90% 5 Entry O aq NH3 (3 mL) 2 6 TCCA. aq NH3 60 °C Y CN TCCA N H NH Cl – HX 3 R-CH=NH III Based on these results.c. Furthermore. initial N-chlorination of the amine occurs to give the N-chloro secondary amine VI. 4-Methylbenzyl. R 2633 Nitriles by Direct Oxidative Conversion . entry 1). According to this mechanism. 60 °C 3 R CN 5 O O Cl NH N H – HX Cl N N Cl O O N O 3 R-C=N Cl V IV H TCCA H 3 R Scheme 3 5a Scheme 4 Amine HN 60 °C. Imine III also reacts with trichloroisocyanuric acid to form the N-chloroimine IV.21 CN TCCA N H 2 aq NH3 (3 mL) 60 °C. In this case. the initial N-chlorination of the amine with trichloroisocyanuric acid occurs to form the N-chloroamines V. Further.e in good yields under the same conditions (Table 1. Copyrighted material. and 4-chlorobenzyl halides 4b. followed by belimination of HCl by ammonia to generate the corresponding nitrile 5. 4 h. under the same conditions with trichloroisocyanuric acid (0. reference given for known compounds.26 We found that under these conditions. which smoothly decomposes to the primary amine IX and imine III. we planned to perform the direct oxidative conversion of primary alkyl halides 4 into the corresponding nitriles using trichloroisocyanuric acid in aqueous ammonia.

Wallensfels. (2) Friedrick. J. Synthesis 2003. 407. Rappoport. (9) Bose. C. Org.. (23) Iida.. K. Chem. R. 38. (22) Iida. 2634 . Lee. Huo. J. 9. 1999. D. Lett. Reddy. M. Tetrahedron 1998. (3) Fabiani. 45 mmol) in a round-bottomed flask was added TCCA (0.. M.. 2099.. and used without further purification unless otherwise stated. N-Chlorination of amine IX with trichloroisocyanuric acid take place to provide N-chloro compound V. M. 6:1). Morley.. S. 8274. S. A. J. S. Wang. Duncan. A. aldimine III reacts with trichloroisocyanuric acid to generate N-chloro compound IV. Alcohols 2. primary amines. it was quenched at this temperature with H2O (10 mL). N. hexane–EtOAc. 2629. (13) Clarke. V. T. Pohmakotr. 64. M. Scanlon. Meth-Cohn. 6:1)... it was quenched at this temperature with H2O (10 mL) and it was then was extracted with Et2O (3 × 15 mL). 15. S. 1480. (14) Yamaguchi. (6) Nakajima.....Favorsky Irkutsk Institute of Chemistry SB RAS. and this is followed by b-elimination of HCl with ammonia to give the corresponding nitrile 5. Synthesis 2001. 39. (24) Yamagguchi.. N. M. a simple and convenient method has been developed for the direct conversion of alcohols. Larock. Acknowledgment We are thankful to Payame Noor University of Songhor. 6913. Lu. Yadav. Tetrahedron Lett. Nagao. alcohol or aldehyde (1 mmol) and aq NH3 (3. 586. J. A possible reaction pathway for the conversion of benzylic halides into corresponding aromatic nitriles. General Procedure To a mixture of amine. 1999.. Synlett 2007. 63. Commun. H. R. If necessary. Downloaded by: A. K. K. Mizuno. 976–993. 45 mmol) in round bottomed flask was added TCCA (1 mmol) slowly and very carefully in several small portions at r. Yadav. If necessary.. Reddy. S. 544. B... V. 1970. (7) Bose. Synth. 1988. H. 2003. 2633. We have also examined the preparation of aliphatic nitriles under the same reaction conditions.. Z. Togo. H. 2631–2635 © Thieme Stuttgart · New York Nitriles from Amines 1.. S.. Gacon.. (1) North. Int.75 mmol) slowly and very carefully in several small portions at r. T. T. Drug News Perspect. and alkyl halides to their corresponding nitriles in good to high yields in aqueous ammonia catalyzed by trichloroisocyanuric acid as the oxidant and reagent.. Synlett 2004. 2045. The combined organic layers were washed with brine and dried (MgSO4) to give 5 in good yield. S. 1963. M. S.. Jaipetch. 1H NMR spectra were recorded on a Jeol 90 MHz FT NMR spectrometer using TMS as internal standard. S. Ubukata. but we did not observe any notable conversions.. C. V. R. T. 1997. D. 12. M. Pergamon: Oxford.. 6533. S. The obtained mixture was stirred at 60 °C. (21) Iida.. 27. operational simplicity. M. Clearly. Wiley-Interscience: New York. R. B. 60 °C mixture was stirred at 60 °C. Angew. P. with trichloroisocyanuric acid in aqueous ammonia is shown in Scheme 6. VCH: Weinheim. (4) Comprehensive Organic Transformations. R. the present reaction is a good method for the direct preparation of aromatic nitriles from benzylic halides. IR spectra were measured on a Perkin Elmer GX FT-IR spectrophotometer. P. The Chemistry of the Cyano Group. 4:1). Ed. 2180. Synthesis 2008. K. G.. 1327. (8) Kumar. TCCA 3 RCH2X 4 NH3 – HX – HX 3 RCH2NH2 Cl IX 3 R-C=N O Cl O HN NH O H Cl N O N H IV N N O TCCA Cl O H 3 R NH V Cl 3 R-CH=NH – HX III Scheme 6 In conclusion.. Bartsch. (11) Kaim. 29. The combined organic layers were washed with brine and dried (MgSO4) to give 5 in good yield. M. O. 11. Kuhakakarn. B. 1995. M. Jayalakshmi. 1997. 3391. aldehydes. Synlett 2006. 3559. Commun. P. B. (12) Nakagawa. M. Pharm. Vaid. Chem. Tsuji. 1992. A. D. 1998. entry 34). R. S. Bull... (16) Yamazaki. B. Hampson. Veisi sponding naphthalene-1-carbonitrile (5k) in good yield under the same conditions (Table 1. When the reaction was complete (TLC hexane–acetone. V.. J. Tetrahedron Lett. S. Y. D. 296. The initial nucleophilic reaction of ammonia with the benzylic halide 4 occurs to generate corresponding primary amine IX. 27. H. 5685. the product was purified by column chromatography (silica gel. 1989. Tetrahedron 2007. Nitriles 5 from Benzyl Halides 4. H. hexane–EtOAc.t. 1997.. Dai. Reutrakul. Kuang. (19) Luca. E. Herzig. Togo. N. When the reaction was complete (TLC hexane–acetone. T.0 mL.t.. Takeda.0 mL. the product was purified by column chromatography (silica gel.. 9281.. Ochiai.. K. S. easy reaction work-up. (5) Huber. Copyrighted material.. S. Mass spectra and CHN.. (20) Chiampanichayakul. Chem. Rees.. Inenaga. H.. and Aldehydes 3. Narsaiah. Synthesis 1999.. All commercially available chemicals were obtained from Merck and Fluka companies. Chem. F.PAPER H. Katritzky. 207. 1933. Ed. 1997. 42. Then. Mohanty. and it was then was extracted with Et2O (3 × 15 mL). All yields refer to isolated products.. Giacomelli. Tetrahedron Lett. Togo.E.. Eds. and generality of the reactions. Ed. L. 1713. K. A. (18) Chen. L. A. Prominent advantages of these new methods are their mild reaction conditions.. G. W. 38. No. (15) Gao. Kumar. M. 54.. The obtained Synthesis 2010.. C. J. References 3 R CN 5 NH3. (10) Kumar. J. That means that the use of the Sandmeyer reaction (diazonium with CuCN) or the dehydration of aromatic amides with dehydrating agents is not required. and the University of Sheffield for NMR. (17) Moriarty. Y. Tetrahedron Lett. L. followed by b-elimination of HCl with ammonia to provide aldimine III. Synth. 4:1). E. Comprehensive Organic Functional Group Transformations. Tetrahedron Lett.. 1968. General Procedure To a mixture of alkyl halide (1 mmol) and aq NH3 (3. Istanbul Technical University.

. F.E. 249. (28) Iida. Hemmati. 346. (33) Zolfigol. J. Liang. 2003. (31) Ye.. Maheswari.. R. H. Mendeleev Commun. Veisi. 56. (37) Ghorbani-Vaghei.. J.Favorsky Irkutsk Institute of Chemistry SB RAS. 2005. N. N. (26) Mori. Chen. Process Res.. Mol. Y. Hazarkhani. J. J. U. H. R. Kantam. Togo.. 384.. Adv.. 2010. (36) Ghorbani-Vaghei. R. 1456.. Li. E. Q... (34) Synlett Spotlight 132: Barros. M. 4. C. Chem. Dev. Mallakpour. X. (29) For a recent review on the use of trichloroisocyanuric acid.. Veisi. M. Madrakian... Weinmann. R... M. Xu. 15. Y. Liu. H. Y. Liang. (27) Reddy. Tetrahedron Lett. Synlett 2001. Downloaded by: A. see: Tilstam. H. 65. Commun. Venkateshwar. No.. M. (38) Veisi. S.(25) Chen.. U. H. S. Tetrahedron Lett. Synlett 2002. Nitriles by Direct Oxidative Conversion 2635 (32) Firouzabadi. 1804. J.. 4505. H. Veisi.. 2009. Prashanthi. L. Synthesis 2002. H. Ghaemi. X. Ohmura. 2631–2635 © Thieme Stuttgart · New York .. H. S. S. Copyrighted material. PAPER Synthesis 2010.. H. Soc. Chem. H. (35) Ghorbani-Vaghei. 6257. 207. Chegeny... R. Iranpoor. E. (39) Ghorbani-Vaghei. Org. R. Veisi. 2004. M. 1633. R. Wang.. Synthesis 2009. Zhang. 1641. Synlett 2005. A. Divers. M. 2714. Togo. H. Chin. 2115. A. (30) Ye.. 50.. H... Catal. 2002. G. Zolfigol.. Jia. 240. 945. Shahbazee. Wang.. J. Synth. Synlett 2005. 2009. C. 2006. 2050. Tetrahedron 2009.. 14. Zhang. Chen. K. Veisi... E. 47.