MICROREVIEW

DOI: 10.1002/ejoc.201101018

Ritter Reaction: Recent Catalytic Developments

Amandine Gurinot,[a] Sbastien Reymond,*[a] and Janine Cossy*[a]
Keywords: Synthetic methods / Multicomponent reactions / Atom economy / Homogeneous catalysis / Amides / Nitriles / Ritter reaction
The Ritter reaction is a method of choice for the production of amides, which are versatile intermediates in organic synthesis and compounds of interest in natural product synthesis. Recent efforts have been directed towards the development of catalytic versions for the development of more ecofriendly synthetic routes to amides. This review summarizes the recent progress in this area and covers new applications in the field of Ritter-type and multicomponent reactions.

1. Introduction 2. Classical Ritter Reaction 2.1. Brnsted Acid Catalysis 2.2. Lewis Acid and Metal Catalysis 3. Ritter-Type Reactions 3.1. Brnsted Acid Catalysis 3.2. Lewis Acid and Metal Catalysis
[a] Laboratoire de Chimie Organique, associ au CNRS, ESPCI ParisTech, 10 rue Vauquelin, 75231 Paris Cedex 05, France Fax: +33-1-40794660 E-mail: sebastien.reymond@espci.fr janine.cossy@espci.fr

4. Miscellaneous 5. Conclusion

1. Introduction
The Ritter reaction, first reported in 1948, allows the formation of amides, which are ubiquitous motifs in natural products and in various synthetic materials.[1,2] This reaction is particularly useful for the preparation of bulky amides, which can be precursors of hindered amines. In this reaction (Scheme 1), a carbocation generated in situ from an alcohol, an alcohol derivative, or an olefin is trapped by a nitrile to produce a nitrilium species, which

Amandine Gurinot was born in 1983 in Troyes, France. She studied chemistry at ESPCI ParisTech, where she received her engineers diploma. In 2007 she joined the organic chemistry laboratory at ESPCI to prepare her Ph.D. under the supervision of Dr. Sbastien Reymond and Prof. Janine Cossy in the field of iron catalysis applied to organic synthesis (20072010). She is currently a postdoctoral associate in the group of Prof. Sylvain Canesi at UQAM (Universit du Qubec Montral, Canada).

Sbastien Reymond was born in Valence, France, in 1975. He received his engineers diploma in 1999 from ENSSPICAM, now Ecole Centrale de Marseille, and his Ph.D. in 2003 from the University of Aix-Marseille III in the group of Prof. Grard Buono. After a one-year postdoctoral stay with Prof. Jean-Pierre Gent at ENSCP in Paris, he was appointed associate professor in 2004 at ESPCI (Ecole Suprieure de Physique et de Chimie Industrielles de la Ville de Paris) in the group of Prof. Janine Cossy. His research interests include the development of eco-friendly synthetic organic methods, iron catalysis, and the synthesis of biologically active compounds.

Janine Cossy was born in Reims (Champagne area), France and did her undergraduate and graduate studies at the University of Reims working on the photochemistry of ketones and enamino ketones under the supervision of Prof. JeanPierre Pete. After a two-year postdoctoral appointment with Prof. Barry M. Trost at the University of Wisconsin (USA), she returned to Reims in 1990 where she became a director of research for CNRS. The same year she moved to Paris to become professor of organic chemistry at ESPCI. She was President of the Organic Division of the French Chemical Society (from 2002 to Feb. 2007), since 2005 she has been Organic Letters associate editor, and from 2001 to 2010 she was a member of the advisory board of the European Journal of Organic Chemistry. Her research interests are photochemistry, radicals, rearrangements, enantioselectivity, organometallics, and multistep synthesis of biologically active compounds.

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MICROREVIEW
after hydrolysis delivers an amide. When olefins are used, the addition of water is required, whereas in the case of alcohols, the substrate itself generates H2O and the process becomes atom-economical. Other reactions in which a carbocation generated in situ is trapped by a nitrile are referred to as Ritter-type reactions. 2.1. Brnsted Acid Catalysis

A. Gurinot, S. Reymond J. Cossy

2. Classical Ritter Reaction

The first example of the Ritter reaction in the presence of a substoichiometric amount of a Brnsted acid was reported by Reddy in 2002 for the preparation of the N-tertbutyl amides 3 (Scheme 3).[3] tert-Butyl acetate was shown to be one of the best sources of tert-butyl carbocation when treated with concentrated sulfuric acid. However, 0.94 equivalents of H2SO4 were still required to achieve fast conversion of the nitriles. Only p-methoxybenzonitrile, an electron-rich nitrile, allows the use of lower amounts of H2SO4 (0.47 equiv.). Aromatic and heteroaromatic nitriles bearing either electron-donating or electron-withdrawing groups, as well as aliphatic nitriles, were converted into the corresponding amides in high yields after 1 h to 6 h (Scheme 3). This method is efficient and easy to perform, but it is limited to the formation of N-tert-butyl amides and suffers from the need for quasi-stoichiometric amounts of H2SO4.

Scheme 1. Classical examples of the Ritter reaction.

The Ritter reaction typically requires stoichiometric amounts of strong acids (usually sulfuric acid), thus limiting its application to compounds containing acid-stable functional groups. However, according to the commonly assumed mechanism, the acid is regenerated, thus making the development of catalytic versions of the reaction possible; see, for example, the mechanism of the Ritter reaction involving phenylethanol and acetonitrile in the presence of a Brnsted acid catalyst (Scheme 2).

Scheme 3. H2SO4-catalyzed Ritter reactions between nitriles and tert-butyl acetate.

In 2007, Sanz et al. reported a general method for Brnsted-acid-catalyzed Ritter reactions between secondary benzylic alcohols and acetonitrile.[4] After screening of various acids (10 mol-%), PPTS, 2,4-dinitrobenzenesulfonic acid (DNBSA), triflic acid (TfOH), and H2SO4 were shown to catalyze the Ritter reaction between 1-phenylethanol and acetonitrile efficiently, with 82 % to 85 % yields of 2a being obtained after 12 h to 48 h (Table 1). When the catalytic loading of DNBSA was decreased to 5 mol-%, the reaction
Table 1. Catalyst screening in the Ritter reaction between phenylethanol and acetonitrile. Scheme 2. Proposed mechanistic process for the H+-mediated Ritter reaction of phenylethanol 1a.

In the last twenty years, remarkable progress has been made in the field of catalytic Ritter reactions in the presence of Brnsted or Lewis acids. Recent developments are highlighted in this work, which provides a concise overview of the scope of this reaction under homogeneous conditions. The Ritter reaction under heterogeneous conditions is also mentioned.
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Entry 1 2 3 4 5

Acid PPTS (10 mol-%) TfOH (10 mol-%) H2SO4 (10 mol-%) DNBSA (10 mol-%) DNBSA (5 mol-%)

Yield of 2a (time) 84 % 85 % 82 % 85 % 75 % (48 h) (12 h) (15 h) (12 h) (24 h)

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Ritter Reaction: Recent Catalytic Developments

time was increased (24 h instead of 12 h) and the yield decreased to 75 %. Because of its high activity and its easy handling, DNBSA was used to evaluate the scope of the reaction. A wide range of 1-arylethanol derivatives 1 (Scheme 4) was successfully transformed into the corresponding amides 2 in the presence of DNBSA (10 mol-%) in acetonitrile as the solvent. Various substituents on the aromatic ring of the benzylic alcohol were tolerated, including halides or methoxy groups. The reactions are not sensitive to air and moisture and can be achieved on a multigram scale. The benzhydrol derivatives 4 also proved to be excellent substrates, delivering the N-benzhydryl-acetamides 5 in high yields (Scheme 4). These compounds are particularly interesting because they are ubiquitous in biologically active products.

Scheme 5. DNBSA-catalyzed diastereoselective Ritter reactions of -substituted benzylic alcohols.

derivatives 4, which were treated with aromatic and aliphatic nitriles in the presence of 8 (10 mol-%). The expected amides 5 were isolated in moderate to good yields after 3 h to 84 h in the nitrile at reflux (Scheme 6). When aromatic nitriles were used, no electronic effects were observed whatever the nature of the aromatic substituents. In contrast, steric effects were decisive, with the presence of a methyl group ortho to the nitrile considerably reducing the yield (5d, 30 %). The reactions tolerate both electron-withdrawing and electron-donating groups on the benzhydrol partners, but when two electron-donating groups were present the expected amides were not isolated.

Scheme 4. DNBSA-catalyzed Ritter reactions between benzylic alcohols and nitriles.

Recently, Bach et al. developed diastereoselective DNBSA-catalyzed Ritter reactions involving the chiral secondary benzylic alcohols 6 and a set of nitriles (Scheme 5).[5] The amides 7 were isolated in good yields and good diastereomeric ratios in favor of the syn compounds. These reactions were also mediated by triflic acid at 0 C in CH2Cl2, although 1.25 equivalents of this acid were required. To explain the excellent diastereoselectivity, the authors suggest that under kinetic control, the less hindered face of the carbocation intermediate is preferentially attacked by the nitrile, thus giving rise to the syn product. As a result of hyperconjugation of the carbocation with the -tert-butyl group, this group might shield one of the faces of the carbocation in the more reactive conformation (Scheme 5). In 2009, Ritter reactions between benzylic alcohols and nitriles were successfully carried out in the presence of catalytic amounts of commercially available o-benzenedisulfonimide (8) (Scheme 6).[6] The nitriles were generally employed as the solvents, but it is worth noting that the reactions could also be carried out without solvent, by use of stoichiometric amounts of nitriles, without the yields being affected. When benzhydrol (4a) was used in acetonitrile at reflux, the corresponding amide 5a was isolated in 87 % yield. In addition, the catalyst was easily recovered from the reaction mixture and could be reused twice without loss of activity. The method was first extended to the benzhydrol
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Scheme 6. Ritter reactions between benzhydrol derivatives and nitriles catalyzed by o-benzenedisulfonimide (8).

These conditions were then applied to Ritter reactions between the phenylethanol derivatives 1 and acetonitrile. Dramatic effects of both the nature and the positions of the substituent on the aromatic groups were observed. (Scheme 7). The desired amides could not be isolated in the presence either of a strongly electron-withdrawing group (NO2) or of an electron-donating group (OMe) in the para position. Primary benzylic alcohols were much less reactive than secondary benzylic alcohols, and an increase in the catalyst loading (20 to 40 mol-%) was necessary to obtain the corresponding amides in moderate yields. When phenylwww.eurjoc.org

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MICROREVIEW
ethanol was used, the substitution product of 8 compound 9 was isolated along with 2g, although 8 is known to be a poor nucleophile (Scheme 7).

A. Gurinot, S. Reymond J. Cossy

Scheme 9. TfOH-catalyzed synthesis of the N-[3-(arylmethylidene)cyclobutyl]acetamides 11.

Phosphotungstic acid (PTA, H3PW12O40) was evaluated as a catalyst in Ritter reactions between alcohols and aromatic nitriles or acetonitrile in water at reflux (Scheme 10).[8,9] Silyl ethers, tetrahydropyranyl ethers (THP ethers) and methyl tert-butyl ether (MTBE) were also shown to be valuable substrates. Isolated yields ranging from 50 % to 99 % were obtained after 10 h to 30 h; some examples are shown in Scheme 10. In cases of solid nitriles it was necessary to use sodium dodecyl sulfate (SDS) as an additive (10 mol-%).

Scheme 7. Ritter reactions between phenylethanol derivatives and acetonitrile catalyzed by 8.

o-Benzenedisulfonimide (8) was also evaluated as a catalyst for reactions between tert-butyl alcohol as the carbocation source and nitriles (Scheme 8). With the use of 8 (10 mol-%) in tert-butanol as the solvent, the N-tert-butylamides 3 were isolated in good yields, except when the bulky 2-methylbenzonitrile was used.

Scheme 10. Ritter reactions of alcohols, ethers and nitriles catalyzed by PTA (H3PW12O40).

Scheme 8. Synthesis of tert-butyl amides from nitriles and tBuOH catalyzed by 8.

TfOH-catalyzed Ritter reactions allow access to complex amides. In 2006, Tian et al. showed that the 2-(arylmethylene)cyclopropylcarbinols 10 (Scheme 9) reacted with acetonitrile in the presence of substoichiometric amounts of triflic acid (0.7 equiv.) to afford the ring-enlarged N-[3-(arylmethylidene)cyclobutyl]acetamides 11 in moderate to good yields.[7] From a mechanistic point of view, the authors suggested the formation of cyclobutonium intermediates during the course of the reactions.
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The use of another heteropolyacid phosphomolybdic acid (PMA, H3PW12O40), heterogenized on silica was reported by Yadav et al.[10] Various benzylic or tertiary alcohols, and even cyclohexanol reacted with nitriles, providing the expected amides in 8095 % yield. Further to Reddys report (Scheme 3),[3] it was shown that H2SO4 supported on silica was able to induce the Ritter reaction between benzyl alcohol and acetonitrile, but the acidic material was not recycled.[11] In order to allow a reuse of the acid reagent, NafionNR50, a perfluorinated sulfonic acid resin, was used as the catalyst in microwaveassisted Ritter reactions between benzylic alcohols or adamantanol and aromatic nitriles; in this case the catalyst could be reused up to six times without any change in the activity.[12] Worthy of note is the very recent use of a sulfonic acid ionic liquid to catalyze Ritter reactions involving alcohols.[13] Some other heterogeneous catalysts that have been evaluated in Ritter reactions of alcohols include P2O5/SiO2,[11] zeolites,[14] and, very recently, HClO4-functionalized silicacoated magnetic nanoparticles (-Fe2O3/SiO2/HClO4),[15]
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Ritter Reaction: Recent Catalytic Developments

which can be easily recovered from the reaction medium with the aid of a magnetic device and reused at least six times.

2.2. Lewis Acid and Metal Catalysis Catalysis of Ritter reactions by a Lewis acid was first reported in 1994 by Badparva et al., who developed the amidation of benzylic alcohols induced by catalytic amounts of boron trifluoride.[16] A variety of primary and secondary benzylic alcohols was treated with aromatic or aliphatic nitriles to produce the expected amides in good to excellent yields (Scheme 11). The electron-deficient p-nitrobenzyl alcohol was unreactive under these conditions, as well as were secondary and tertiary aliphatic alcohols. From a mechanistic point of view, the authors suggest that the treatment of a benzylic alcohol with BF3OEt2 leads to the formation of an intimate ion pair (Scheme 12), which would be immediately attacked by a nitrile to give a nitrilium cation. A hydroxy group transfer from the boron trifluorohydroxide species to the nitrilium cation would afford the amide and the Lewis acid would in turn be regenerated.

of acetic anhydride to the reaction medium appeared to be essential to obtain full conversion of the substrate in MeCN as the solvent. To explain this observation the authors suggest that the allylic alcohol first undergoes CoCl2-catalyzed acylation with acetic anhydride to give an allylic acetate, which would generate a cobalt -allyl complex. This would then be attacked by the nitrile and, after hydrolysis, an amide would be released. Some examples are depicted in Scheme 13. When the benzylic allylic alcohol 13 was used, isomerization of the double bond took place at first, and the conjugated amide 14 was formed as the sole product. On the other hand, a 1:1.5 mixture of the regioisomers 16 and 17 was obtained from the alcohol 15. Finally, the amide 19, resulting from initial isomerization of the double bond, was isolated from the tertiary alcohol 18.

Scheme 11. BF3OEt2-catalyzed Ritter reactions between benzylic alcohols and nitriles.

Scheme 13. CoCl2-catalyzed Ritter reactions between allylic alcohols and acetonitrile.

Scheme 12. Proposed mechanism for BF3OEt2-catalyzed Ritter reactions between benzylic alcohols and nitriles.

Cobalt(II)-catalyzed conversions of secondary and tertiary allylic alcohols into their corresponding allylic amides and/or regioisomers were reported in 1995.[17] The addition
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As an alternative, cobalt(III)-catalyzed Ritter reactions were developed by the same group.[18] The scope and the regioselectivity of these reaction are similar to those observed in the CoCl2-catalyzed reactions, but unlike to the cobalt(II)-catalyzed process, these amidations do not require the prior formation of allylic acetates and can be carried out without acetic anhydride (Scheme 14). This observation clearly indicates that cobalt(II)- and cobalt(III)-catalyzed amidation reactions proceed by two different pathways. In the case of the latter process a cationic intermediate was believed to be formed. A general procedure allowing the conversion of nitriles and tBuOH into N-tert-butylamides with catalysis by bismuth triflate was developed by Barrett et al.[19] Of the different metal triflates evaluated in the reaction between tBuOH and benzonitrile, bismuth triflate [Bi(OTf)3] (20 mol-%) was found to give the best results (Table 2, Entries 14). When the amount of Bi(OTf)3 was decreased (5 mol-%), a lower yield of 3a was obtained (Table 2, Enwww.eurjoc.org

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MICROREVIEW

A. Gurinot, S. Reymond J. Cossy

Scheme 14. CoIII-catalyzed Ritter reactions of allylic alcohols.

try 5). It is worth noting that the use of 20 mol-% of TfOH or Bi(OTf)3 resulted in similar yields of 3a. This suggests that Bi(OTf)3 generates TfOH under the reaction conditions and that this is the effective catalyst involved in this Ritter reaction (Table 2, Entry 6). A wide range of nitriles was screened under the previously optimized conditions (Scheme 15): aliphatic nitriles, including the bulky pivalonitrile, were converted into the corresponding N-tert-butyl amides in excellent yields. When aromatic nitriles were used, both electron-withdrawing and electron-donating groups on the aromatic ring were tolerated. A variety of tertiary alcohols were also induced to react with benzonitrile, giving rise to the expected amides in very good yields. In addition, it was also possible to apply these reactions to MTBE (Scheme 15).
Table 2. Screening of various metal triflate catalysts.

Scheme 15. Bi(OTf)3-catalyzed Ritter reactions between tertiary alcohols/ethers and nitriles: synthesis of tert-amides. Entry 1 2 3 4 5 6 Cat. [mol-%] Yb(OTf)3 (20 mol-%) Sc(OTf)3 (20 mol-%) Hf(OTf)3 (20 mol-%) Bi(OTf)3 (20 mol-%) Bi(OTf)3 (5 mol-%) TfOH (20 mol-%) 3a [%] no reaction 56 % 67 % 87 % 68 % 93 %

In 2009, our group reported that the inexpensive, safe, and eco-friendly FeCl36 H2O complex (10 mol-%) is able to catalyze Ritter reactions involving benzylic alcohols (Scheme 16).[20] The addition of two equivalents of water to the reaction medium was essential to achieve fast conversions of the alcohols, usually in 0.5 h to 4.5 h. The reactions are general, with various benzylic amides 2 or 5 being obtained from the different benzylic alcohols 1 or benzhydrol derivatives 4 and nitriles. Benzhydrol (4a) was shown to be an excellent substrate, reacting smoothly with acetonitrile,
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Scheme 16. FeCl36 H2O-catalyzed Ritter reactions between benzylic alcohols and nitriles.
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Ritter Reaction: Recent Catalytic Developments

benzonitrile, or acrylonitrile to produce the corresponding amides in good yields. The reactions were generally carried out in the nitriles as solvents, except when acrylonitrile was used. In this case, cumene was added as a co-solvent in order to reduce the amount of acrylonitrile in the reaction medium, thus avoiding polymerization. FeCl36 H2O was also used to catalyze the formation of the N-tert-butyl amides 3 by using tert-butyl acetate as the carbocation source (Scheme 17). Both aromatic and benzylic nitriles were converted into their corresponding amides in moderate to good yields. Interestingly, the poorly reactive 2-methylbenzonitrile afforded the expected amide 3h in 49 % yield.

ter the PMA-mediated Prins reaction between the aldehydes and the homoallylic alcohols, are trapped by MeCN. TfOH-catalyzed condensations of phenols with aromatic aldehydes and nitriles, in a Ritter-type process, were studied by Das et al.[25] The benzaldehyde derivatives 24 (Scheme 19), bearing various substituents on their aromatic rings (Cl, Br, NO2, OMe, OH), were treated with phenols or 2-naphthol (27) in acetonitrile or acrylonitrile in the presence of TfOH (10 mol-%) to afford the corresponding amides 28 in good yields. These Ritter-type reactions provide convenient access to a wide range of (amidoalkyl)-phenol derivatives 28. For these three-component reactions, the authors suggest that the reaction of a phenol with an aldehyde first generates an ortho-quinone methide intermediate. This would then undergo a H+-mediated addition of the nitrile, giving rise to a nitrilium intermediate, which would be quenched by water to produce the final amide.

Scheme 17. FeCl36 H2O-catalyzed Ritter reactions. Synthesis of tert-butyl amides.

Like Brnsted acid catalysts, Lewis acid catalysts have been heterogenized in order to make the catalytic systems reusable. Catalytic systems consisting, for example, of ZnCl2/SiO2,[21] Montmorillonites,[22] or a polymer-supported BF3[23] were used in Ritter reactions involving alcohols, ethers, and tert-butyl acetate with nitriles.

Scheme 19. TfOH-catalyzed three-component synthesis of amidoalkyl phenols 28.

3. Ritter-Type Reactions
3.1. Brnsted Acid Catalysis A three-component, one-pot PrinsRitter sequence producing cis-4-aminotetrahydropyrans catalyzed by phosphomolybdic acid (PMA, H3PMo12O40) was reported by Yadav et al. in 2008.[24] On treatment of the homoallylic alcohols 25 (Scheme 18) and the aldehydes 23 or 24 in acetonitrile in the presence of PMA (20 mol-%), the cis-4-aminotetrahydropyrans 26 were isolated in good yields (80 92 %) and with high diastereoselectivities. In this Ritter-type process, the carbocation intermediates, generated in situ af-

Very recently, Togni et al. described the Ritter-type synthesis of N-(trifluoromethyl)imines from nitriles, azoles, and the hypervalent trifluoromethylating agent 30 (Scheme 20).[26] These reactions, catalyzed by bis(trifluoromethanesulfonyl)imide (Tf2NH), allow the formation of NCF3 derivatives for which few synthetic methods exist in moderate to good yields (3863 %). In the case of benzotriazole (29), the adduct 31 was isolated in 63 % yield.

Scheme 20. Tf2NH-catalyzed Ritter-type synthesis of N-CF3 benzotriazole derivative.

3.2. Lewis Acid and Metal Catalysis In 2007, Yadav et al. reported that CeCl37 H2O is able to promote a PrinsRitter tandem reaction in the presence of acetyl chloride (1.5 equiv.) as an additive.[27] A variety of aldehydes was treated with homoallylic alcohols in various
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Scheme 18. PMA-catalyzed PrinsRitter sequence. Synthesis of the cis-4-aminotetrahydropyrans 26.

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MICROREVIEW
nitriles to afford the corresponding cis-tetrahydropyrans in 6 h to 8.5 h. When cyclic ketones were used instead of aldehydes, spirocyclic adducts were isolated (Scheme 21). In the presence of acetyl chloride alone, 20 % to 45 % conversions were observed, but the combination of CeCl37 H2O (10 mol-%) and AcCl (1.5 equiv.) ensured high yields and fast reactions. However, the authors did not discuss the role of the additive.

A. Gurinot, S. Reymond J. Cossy

Scheme 23. Bi(OTf)34 H2O-catalyzed SakuraiPrinsRitter sequence of reactions.

Scheme 21. CeCl37 H2O-catalyzed PrinsRitter reactions.

Scheme 24. BiBr3-catalyzed Ritter-type reactions of epoxides.

After Barretts work showing the catalytic activity of Bi(OTf)3 in the Ritter reaction, Yadav et al. reported efficient Bi(OTf)3-catalyzed, one-pot, three-component PrinsRitter reactions involving homoallylic alcohols, aldehydes or ketones, and nitriles.[28] After reaction times of 4 h to 9 h in nitriles as the solvents, the diastereoselective formation of a wide array of 4-amidotetrahydropyrans in 80 % to 93 % yields was achieved. Some examples are depicted in Scheme 22.

Very recently, Cu(OAc)2-catalyzed Ritter-type reactions between unactivated olefins and dichloramine-T (37) (Scheme 25) were reported by Ishikura et al.[31] In the case of cyclohexene, the reaction afforded the 2-chlorocyclohexylamidine derivative 38, which can easily be transformed into the imidazole derivative 39.

Scheme 22. Bi(OTf)3-catalyzed PrinsRitter reactions.

Scheme 25. Cu(OAc)2-catalyzed Ritter-type reaction between cyclohexene and dichloramine-T (37).

In parallel, the same group also reported that Bi(OTf)3 4 H2O was able to catalyze a SakuraiPrinsRitter sequence of reactions giving rise to meso cis-2,4,6-amidotetrahydropyrans.[29] Various aldehydes (2 equiv.) were treated with allyltrimethylsilane (Scheme 23) in acetonitrile, benzonitrile, or isobutyronitrile in the presence of Bi(OTf)3 4 H2O (10 mol-%). Epoxides can be useful precursors in Ritter-type reactions. In 2006 Le Roux et al. reported that bismuth salts were able to promote the conversion of epoxides into vicacylamino-hydroxy compounds through an epoxide-opening/Ritter reaction sequence (Scheme 24).[30] This highyielding method was applied to a steroid synthesis.
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4. Miscellaneous
In 2002, Ishii et al. reported that N-hydroxyphthalimide (40) (Scheme 26), in combination with ammonium hexanitratocerate(IV) (CAN), acts as an efficient catalyst in Ritter-type reactions between nitriles and alkylbenzene or adamantane derivatives.[32] When alkylbenzene derivatives were used, the amidation took place selectively at the benzylic position (Scheme 26). From a mechanistic point of view, the authors suggested that 40 first reacts with CAN in order to form the phthalimide N-oxyl radical species. This would abstract a hydrogen atom from the substrate to generate the benzylic radical 41, which could undergo a
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Ritter Reaction: Recent Catalytic Developments

one-electron oxidation by CeIV to afford a benzylic carbocation. This would be finally trapped by the nitrile and, after hydrolysis, the amide 42 would be liberated.

tractive. Furthermore, some heterogeneous catalysts are very promising in terms of catalyst recycling. Thanks to the development of smart and promising catalysts, the Ritter reaction should in the future find use for the induction of chemoselective and diastereoselective transformations to produce complex biologically relevant molecules without the worry of contamination of these with toxic residues. However, the reported catalytic systems still require high doses of catalysts (510 mol-%) at high temperatures, and are applied to nonfunctionalized nitriles. Future challenges are the use of low catalytic loadings ( 1 mol-%) and of functionalized nitriles in Ritter reactions. Furthermore, the use of chiral catalysts remains unexplored; an enantioselective catalytic Ritter reaction to access highly valuable enantioenriched amine derivatives would undoubtedly be another worthy goal.

Acknowledgments
The Centre National de la Recherche Scientifique (CNRS) (grant to A. G.) is gratefully acknowledged. [1] a) J. J. Ritter, P. P. Minieri, J. Am. Chem. Soc. 1948, 70, 4045 4048; b) J. J. Ritter, J. Kalish, J. Am. Chem. Soc. 1948, 70, 40484050. [2] a) R. Bishop, in Comprehensive Organic Synthesis, vol. 6 (Eds.: B. M. Trost, I. Fleming, E. Winterfeldt), Pergamon, Oxford, 1991, pp. 261300; b) L. I. Krimen, D. J. Cota, in Organic Reactions, vol. 17 (Eds.: R. Adams, A. H. Blatt, V. Boekelheide, T. L. Cairns, D. J. Cram, H. O. House), John Wiley & Sons, New York, 1969, p. 213325. [3] K. L. Reddy, Tetrahedron Lett. 2003, 44, 14531455. [4] R. Sanz, A. Martnez, V. Guilarte, J. M. lvarez-Guitirrez, F. Rodrguez, Eur. J. Org. Chem. 2007, 46424645. [5] P. Rubenbauer, T. Bach, Chem. Commun. 2009, 21302132. [6] M. Barbero, S. Bazzi, S. Cadamuro, S. Dughera, Eur. J. Org. Chem. 2009, 430436. [7] M. Shi, G.-Q. Tian, Tetrahedron Lett. 2006, 47, 80598062. [8] H. Firouzabadi, R. Iranpoor, A. Khoshnood, Catal. Commun. 2008, 9, 529531. [9] For two other examples of the use of heteropolyacids as catalysts for the Ritter reaction of camphene, see: a) V. R. Kartashov, A. V. Arkhipova, K. V. Malkova, T. N. Sokolova, Russ. Chem. Bull. 2006, 55, 387389; b) V. R. Kartashov, K. V. Malkova, A. V. Arkhipova, T. N. Sokolova, Russ. J. Org. Chem. 2006, 42, 966968. [10] J. S. Yadav, B. V. Subba Reddy, T. Pandurangam, Y. J. Reddy, M. K. Gupta, Catal. Commun. 2008, 9, 12971301. [11] F. Tamaddon, M. Khoobi, E. Keshavarz, Tetrahedron Lett. 2007, 48, 36433646. [12] a) V. Polshettiwar, R. S. Varma, Tetrahedron Lett. 2008, 49, 26612664; b) See also: T. Yamato, J.-Y. Hu, N. Shinoda, J. Chem. Res. Synop. 2007, 11, 641643; c) G. A. Olah, T. Yamato, P. S. Iyer, N. J. Trivedi, B. P. Singh, G. K. Surya Prakash, Mater. Chem. Phys. 1987, 17, 2130. [13] a) R. G. Kalkhambar, S. N. Waters, K. N. Laali, Tetrahedron Lett. 2011, 52, 867871; b) See also: F. Jiang, Y. J. Lin, H. F. Duan, Z. H. Li, J. G. Cao, D. P. Liang, Chem. Res. Chin. Univ. 2010, 26, 384388. [14] For examples, see: a) X. Chen, H. Matsuda, T. Okuhara, Chem. Lett. 1999, 799800; b) X. Chen, T. Okuhara, J. Catal. 2002, 207, 194201; c) T. Okuhara, X. Chen, Microporous Mesoporous Mater. 2001, 48, 293299. [15] L. Mamani, A. Heydari, M. Sheykhan, Appl. Catal. A 2010, 384, 122127.
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Scheme 26. Ritter-type reactions of alkylbenzenes.

More recently, Ritter reactions based on iodine catalysis were achieved.[33] The scope of the reactions is broad: benzylic alcohols as well as tert-butanol and tert-butyl acetate were treated with a wide array of nitriles to generate the corresponding amides (Scheme 27). The authors hypothesize that the polarization of iodine in the nitrile, a polar solvent, might allow the activation of an alcohol to induce the formation of a carbocation intermediate.

Scheme 27. Ritter reactions of benzylic alcohols and nitriles catalyzed by I2.

5. Conclusion
The Ritter reaction is of great interest in organic synthesis because it allows the preparation of highly valuable amide derivatives from cheap, simple, and commercially available starting materials. We are now far away from the original harsh conditions described by Ritter himself, with significant efforts having been made to optimize Ritter and Ritter-type reactions through the use of catalytic amounts of Brnsted or Lewis acids. These reactions are also very interesting in view of their high levels of atom-economy. Safe catalysts usable under mild conditions have been developed; among them, the inexpensive FeCl36 H2O is atEur. J. Org. Chem. 2012, 1928

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MICROREVIEW
[16] H. Firouzabadi, A. R. Sardarian, H. Badparva, Synth. Commun. 1994, 24, 601607. [17] M. Mukhopadhyay, M. M. Reddy, G. C. Maikap, J. Iqbal, J. Org. Chem. 1995, 60, 26702676. [18] M. Mukhopadhyay, J. Iqbal, J. Org. Chem. 1997, 62, 1843 1845. [19] E. Callens, A. J. Burton, A. G. M. Barrett, Tetrahedron Lett. 2006, 47, 86998701. [20] B. Anxionnat, A. Gurinot, S. Reymond, J. Cossy, Tetrahedron Lett. 2009, 50, 34703473. [21] F. Tamaddon, F. Tavakoli, J. Mol. Catal. A 2011, 337, 5255. [22] a) Montmorillonite KSF: H. M. Sampath Kumar, B. V. Subba Reddy, S. Anjaneyulu, E. J. Reddy, J. S. Yadav, New J. Chem. 1999, 23, 955956; b) Fe-Montmorillonite K10: M. M. Lakouraj, B. Movassagh, J. Fasihi, Synth. Commun. 2000, 30, 821827. [23] M. M. Lakouraj, M. Mokhtary, Monatsh. Chem. 2009, 140, 5356. [24] J. S. Yadav, B. V. Subba Reddy, S. Aravind, G. G. K. S. Narayana Kumar, C. Madhavi, A. C. Kunwar, Tetrahedron 2008, 64, 30253031.

A. Gurinot, S. Reymond J. Cossy [25] B. Das, K. Laxminarayana, P. Thirupathi, B. Ramarao, Synlett 2007, 31033106. [26] K. Niedermann, N. Frh, E. Vinogradova, M. S. Wiehn, A. Moreno, A. Togni, Angew. Chem. 2011, 123, 10911095; Angew. Chem. Int. Ed. 2011, 50, 10591063. [27] J. S. Yadav, B. V. Subba Reddy, S. Aravind, G. G. K. S. Narayana Kumar, G. Madhusudhan Reddy, Tetrahedron Lett. 2007, 48, 49034906. [28] J. S. Yadav, B. V. Subba Reddy, D. N. Chaya, G. G. K. S. Narayana Kumar, Can. J. Chem. 2008, 86, 769773. [29] G. Sabitha, M. Bhikshapathi, S. Nayak, J. S. Yadav, R. Ravi, A. C. Kunwar, Tetrahedron Lett. 2008, 49, 57275731. [30] R. M. A. Pinto, J. A. R. Salvador, C. Le Roux, Synlett 2006, 20472050. [31] T. Abe, H. Takeda, Y. Miwa, K. Yamada, R. Yanada, M. Ishikura, Helv. Chim. Acta 2010, 93, 233241. [32] S. Sakagushi, T. Hirabayashi, Y. Ishii, Chem. Commun. 2002, 516517. [33] P. Theerthagiri, A. Lalitha, P. N. Arunachalam, Tetrahedron Lett. 2010, 51, 28132819. Received: July 13, 2011 Published Online: October 10, 2011

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