p-Tolylsulfonylmethyl Isocyanide1

[36635-61-7]  · C9H9NO2S  · p-Tolylsulfonylmethyl Isocyanide  · (MW 195.26)

(reductive cyanation of ketones2a and aldehydes;2b synthesis of azoles (pyrroles, oxazoles, imidazoles, thiazoles, etc.) by delivering a C-N-C fragment to polarized double bonds;3 connective reagent for coupling of alkyl halides (or carbonyl compounds) by a CO4a or a CH2 bridge;4b preparation of (formal) Knoevenagel condensation products from aldehydes and ketones5)

Alternate Name: tosylmethyl isocyanide; TosMIC.

Physical Data: mp 116-117 °C (dec).

Solubility: sol THF, CH2Cl2, CHCl3, DME, AcOEt, benzene; slightly sol Et2O, EtOH, MeOH.

Form Supplied in: white to near-white, odorless, commercially available solid.

Analysis of Reagent Purity: IR (Nujol) 2150 (N=C), 1320, 1155 cm-1 (SO2); 1H NMR (CDCl3) d 2.5 (s, CH3), 4.6 (s, CH2); 13C NMR (CDCl3) d 61.1 (CH2), 165.7 (N=C).

Preparative Method: by dehydration of N-(p-tolylsulfonylmethyl)formamide.6

Handling, Storage, and Precautions: shelf stable.

Introduction.

p-Tolylsulfonylmethyl isocyanide is the best known compound of a series of (hetero-)substituted derivatives of methyl isocyanide, which includes Diethyl Isocyanomethylphosphonate, p-Tolylthiomethyl Isocyanide, Methyl N-(p-Tolylsulfonylmethyl)thiobenzimidate (a TosMIC derivative), and Ethyl Isocyanoacetate. TosMIC is a multipurpose synthesis reagent, and by far the most versatile and most widely applicable reagent of the above series.

Typical Applications.

One characteristic example of each category of TosMIC applications will be given first (to be followed by further illustrative examples below).

Reductive Cyanations.

Most ketones are converted with TosMIC in one operation into cyanides (introduction of a one-carbon unit) using Potassium t-Butoxide (1-7 equiv) in nonprotic solvents (e.g. DME, DMSO) (eq 1).2a The reductive cyanation of aldehydes is carried out at lower temperatures and needs addition of MeOH in the final stage of the process (eq 2).2b,7 In eqs 1 and 2, the carbonyl oxygen is removed (unlike the well known addition of HCN); hence the name of this process: reductive cyanation.

Synthesis of Azoles.

Reaction of TosMIC with aldehydes in protic solvents, e.g. MeOH at 20 °C, leads to oxazolines (eq 3),8a whereas oxazoles are formed in refluxing MeOH by elimination of p-toluenesulfinic acid (salt) (eq 4).5c,8a Reaction of TosMIC with acid chlorides, anhydrides, or esters leads to oxazoles in which the tosyl group is retained.8

Imidazoles are obtained analogously from imines,3b thiazoles from dithioesters or CS2,9 and 1,2,4-triazoles from diazonium salts.10 More widely applied, however, is the synthesis of pyrroles from TosMIC and Michael acceptors (eq 5).11 The pyrroles are formed in one operation; dihydropyrrole derivatives (compare eqs 3 and 4) are not usually observed. The pyrrole ring positions 1, 2, and 5 remain intrinsically unsubstituted, which is one of the virtues of this method, since such pyrroles otherwise have to be prepared by temporarily using protective groups at these positions.11

Connective Reagent.

The two methylene hydrogens of TosMIC have been replaced consecutively by base-induced alkylations (eqs 6 and 7).12 Reactions as in eq 6 are carried out under phase-transfer catalysis (PTC) conditions to prevent twofold alkylation. In the product of eq 7, two alkyl halides (MeI and octyl iodide) are connected by the TosMIC methylene group; hence the name: connective reagent. This application of TosMIC is complementary to other reagents with activated methylenes, such as 1,3-Dithiane13 and Methylthiomethyl p-Tolyl Sulfone. Acid hydrolysis of the geminal Tos and N=C groups produces ketones (i.e. a CO bridge, eq 7), whereas reduction with Lithium in liquid ammonia provides a methylene bridge (eq 8).4b Monosubstituted TosMIC derivatives, as obtained by eq 6, may replace TosMIC in eqs 3-5 to provide azoles with an additional substituent, e.g. an additional Me at position 2 of the pyrrole ring in eq 5.3c

Knoevenagel Condensation Products.

Reactions of TosMIC with aldehydes or ketones have been directed such that formal Knoevenagel condensation products are formed by overall elimination of H2O (as contrasted to the reductive cyanation in eqs 1 and 2). In fact, this process requires two steps (eqs 9 and 10).5b,d Knoevenagel products have also been obtained by applying Peterson alkenation conditions to TosMIC (eq 11).14

The isocyano carbon of TosMIC is directly involved in the initial stages of the reductive cyanations, the azole syntheses, and the (formal) Knoevenagel condensations, but not in the application of TosMIC as a connective reagent. In fact, the first three types of reaction are based on a common reaction scheme;2a,15 different products are obtained by using different reaction conditions. To emphasize this point, eq 12 describes the three different products that have been obtained separately from TosMIC and benzaldehyde.2b,5d,8a

Fundamental Aspects of TosMIC Chemistry.

In this section, the interrelation of TosMIC reactions is discussed briefly. TosMIC is prepared in two steps: a Mannich reaction of p-Toluenesulfinic Acid (TosH), formaldehyde, and formamide gives N-(p-tolylsulfonylmethyl)formamide (TosMIC precursor), which is dehydrated (POCl3/Et3N or i-Pr2NH) to TosMIC.6 The Mannich reaction is reversible, but after dehydration to TosMIC the reverse reaction (of the TosMIC precursor) is blocked. Both TosMIC and the TosMIC precursor are N,S-acetals of formaldehyde. The methylene group of TosMIC is highly activated (estimated pKa = 14) by the two electron-withdrawing substituents. Deprotonation of TosMIC has been achieved with an array of bases, ranging from Potassium Carbonate in MeOH to n-Butyllithium in THF. Even dilithio-TosMIC has been reported.8b Thus TosMIC is a formaldehyde derivative of reversed polarity (umpolung);13 eqs 6-8 are based on this principle. Acid-catalyzed hydration of dialkylated TosMIC derivatives provides formamides, which upon hydrolysis (reversed Mannich) lead to the product ketones (eqs 7 and 35-38). In other applications of TosMIC, attack of the TosMIC anion on a carbonyl carbon is followed (or accompanied) by ring closure of the carbonyl oxygen to the electrophilic isocyano carbon to form an oxazoline (eq 3). Base-induced ring opening of these oxazolines gives a,b-unsaturated tosylformamides (eq 9), which have been dehydrated subsequently (eqs 10 and 12). Base-induced elimination of TosH from these unsaturated tosyl formamides gives N-formylketenimines (R2C=C=NCH=O; not identified), which through nucleophilic removal of the formyl group eventually produce cyanides (eqs 1, 2, and 13-16). Details of these reactions have been described.2a,15

Reductive Cyanation.

Few examples have been described of the reaction of TosMIC with aldehydes. Examples are given in eqs 2 and 13.2b,16 The reaction with ketones, however, is very general (eqs 1 and 14-16).2a,15,16 Only severely sterically hindered ketones (e.g. di-t-butyl ketone) and readily enolizable ketones (e.g. benzyl phenyl ketone) will not undergo the reductive cyanation reaction.2a

Synthesis of Azoles (Pyrroles in Particular).

The reaction of TosMIC, or monosubstituted TosMIC derivatives (see eq 6), with Michael acceptors has been used frequently for the synthesis of 1,2,5-unsubstituted pyrroles and 1,5-unsubstituted pyrroles, respectively (eqs 5 and 21-24; compare eqs 25-29, 31, and 32). Over 50 papers and patents refer to this type of application of TosMIC.17 Fewer papers deal with the use of TosMIC in the synthesis of other azoles, such as oxazoles from aldehydes (eq 4), imidazoles from imines (eq 17),3b thiazoles from dithioesters or CS2 (eq 18),9 and 1,2,4-triazoles from diazonium salts (eq 19).10 Eqs 20 and 21 show that monosubstituted TosMIC molecules react similarly to give azoles with an additional substituent.3c

The usual electron-withdrawing groups (EWG) in Michael acceptors are operative in the TosMIC based pyrrole synthesis (COR, CO2R, CN, NO2; eqs 5, 21-25, 27, and 28). Only for EWG = CHO, will the TosMIC anion react preferentially with the aldehyde group to form oxazoles,5c,11 as is also the case with aromatic aldehydes (cf. eqs 4 and 20). Several base/solvent systems have been used in the TosMIC pyrrole syntheses; the trend is to use an excess of base (up to 3 equiv) when less reactive Michael acceptors are used, whereas lower temperatures (to -70 °C) are recommended for the more reactive Michael acceptors. TosMIC has been used for the synthesis of antibiotically active pyrroles such as verrucarine E (eq 22)18a and 3-cyano-4-(2,3-dichlorophenyl)pyrrole (Fenpiclonil®) (see eq 31). Three separate reactions have been reported between TosMIC and methyl sorbate (a dienyl Michael acceptor): depending on the conditions of the reaction, one of the two monopyrroles or an oxazole is formed (eq 23).8b A bipyrrole has been synthesized from ethyl sorbate using 2 equiv of TosMIC. However, this process requires three steps. After the introduction of the first pyrrole ring, the remaining a,b-double bond needs to be activated (by N-sulfonylation of the first-formed pyrrole ring) before the second pyrrole ring can be realized (eq 24).19a Recently, a heptapyrrole has been developed along related lines.19b Other pyrrole syntheses based on TosMIC will be discussed in the next section.

Knoevenagel-Type Condensation Products; Synthesis of (Di)Vinylpyrroles, Indoles, 3-Nitropyrroles, 3-Cyanopyrroles, and 3,4-Dialkylpyrroles.

Two different types of reactions are possible with the (formal) Knoevenagel condensation products (eqs 9-12) of TosMIC. They can act as Michael acceptors (eqs 29-32) or as monosubstituted TosMIC derivatives. Eqs 25-28 provide examples of the latter type of reaction. g-Deprotonation of the condensation product of TosMIC and cyclopentanone (eq 25)5b produces an allylic anion, which reacts exclusively via its a-carbon with Michael acceptors to form pyrroles, in much the same way as in eq 21. The difference, clearly, is that in eq 25 a 2-(alk-1-enyl)pyrrole is formed. These 2-vinylpyrroles are efficient precursors for an alternate synthesis of indoles, provided that they bear a second vinyl substituent at position 3. Thermal or photochemical electrocyclic ring closure of the 6p-electron system, followed by dehydrogenation, leads to indoles (eqs 26-28). When the 3-vinyl substituent is part of an aromatic ring, electrocyclization is achieved photochemically (eq 26) but not thermally.5b Thermal ring closure is effective with normal 3-vinyl substituents, obtained via dienic and trienic Michael acceptors (eqs 27 and 28, respectively).5b,20 The main product of eq 28 is formed by an intramolecular Diels-Alder reaction of the initially formed dihydroindole (not shown).20

In yet another synthesis of pyrroles, the Knoevenagel condensation products of TosMIC and aldehydes (eqs 11 and 12) are used as Michael acceptors (eqs 29-32). Eq 29 shows a highly efficient, one-step synthesis of 3-nitropyrroles (difficult to access otherwise),21b in which the Nitromethane carbon links the isocyano- and b-carbons of the Michael acceptor into a pyrrole ring.21a The same product of eq 29 has been obtained in the reaction of TosMIC and b-nitrostyrene in only 27% yield.22 No reaction takes place when the nitromethane in eq 29 is replaced by acetonitrile. 3-Cyanopyrroles, however, are obtained effectively when cyanoacetate is used instead. Eq 313a gives an example in the form of an alternate synthesis of a commercially employed seed-protecting agent, which is produced from TosMIC and ethyl a-cyano-2,3-dichlorocinnamate.21c This approach even applies to the synthesis of 3,4-dialkylpyrroles (eq 32),3a which obviously cannot be prepared from TosMIC and alkenes (compare eq 5).

TosMIC as a Connective Reagent.

The principle of using TosMIC as a connective reagent to form CO or CH2 bridges has been exploited in several different ways (eqs 6-8 and 33-38). Eq 33 describes the synthesis of muscalure, a pheromone of the common house fly.4b The isocyano group is retained at the bridging carbon when electroreduction is applied (eq 34).23 A practical synthesis of cyclobutanone is based on the use of TosMIC as an intramolecular connective reagent (eq 35),24a a method which has been extended to the (first) synthesis of (R)- and (S)-2-methylcyclobutanone from rac-1,3-dibromobutane and a chiral analog of TosMIC, (+)-neomenthylsulfonylmethyl isocyanide.24b Eq 36 gives another recent example of the synthesis of cyclic ketones.24c Several symmetrical and unsymmetrical acyclic diketones have been prepared by using TosMIC twice (eq 37).4a TosMIC has been used extensively in the construction of hydroxyacetyl side chains of corticosteroids and acetyl side chains as in progesterone (eq 38),5e starting from 17-oxo steroids.

TosMIC Analogs and Derivatives.

Three labeled TosMIC compounds have been reported: Tos14CH2N=C,2a TosCH2N=13C,18a and TosCH215N=C.18b Derivatives of TosMIC, of which one or both methylene hydrogens are replaced by alkyl, aryl, silyl, or alkylidene groups, have been included in the above discussion. Furthermore, the p-tolyl group of TosMIC has been replaced by various other aryl or alkyl groups,1a,b among which are several chiral groups.24b,25a The TosMIC sulfur has been made a stereogenic center by replacing one oxygen for a TosN= group.25b Also, both oxygens of the sulfonyl group have been formally removed, providing the reagent p-Tolylthiomethyl Isocyanide. Finally, the isocyano carbon of TosMIC has been equipped with two substituents, for example Ph and MeS groups,26a two MeO groups,26a or a Ph3C-N= group.26b All analogs and derivatives of TosMIC show TosMIC-like ch emistry, but they have been applied much less frequently than TosMIC itself.

Related Reagents.

N,N-Diethylaminoacetonitrile; Diethyl Isocyanomethylphosphonate; Ethyl Isocyanoacetate; Isocyanomethyllithium; 2-Lithio-1,3-dithiane; Methoxyacetonitrile; Methyl Isocyanide; Methylthiomethyl p-Tolyl Sulfone; Methyl N-(p-Tolylsulfonylmethyl)thiobenzimidate; 1,1,3,3-Tetramethylbutyl Isocyanide; p-Tolylthiomethyl Isocyanide.


1. (a) van Leusen, A. M. In Perspectives in the Organic Chemistry of Sulfur; Zwanenburg, B.; Klunder, A. J. H., Eds.; Elsevier: Amsterdam, 1987; pp 119-144. (b) van Leusen, A. M. Lect. Heterocycl. Chem. 1980, 5, S111. (c) FF 1974, 4, 514; 1975, 5, 684; 1977, 6, 600; 1979, 7, 377; 1980, 8, 493; 1982, 10, 409; 1984, 11, 539; 1986, 12, 511; 1988, 13, 313.
2. (a) Oldenziel, O. H.; van Leusen, D.; van Leusen, A. M. JOC 1977, 42, 3114. (b) van Leusen, A. M.; Oomkes, P. G. SC 1980, 10, 399.
3. (a) van Leusen, D.; van Echten, E.; van Leusen, A. M. JOC 1992, 57, 2245, and footnote 3 therein. (b) van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. JOC 1977, 42, 1153. (c) Possel, O.; van Leusen, A. M. H 1977, 7, 77.
4. (a) van Leusen, A. M.; Oosterwijk, R.; van Echten, E.; van Leusen, D. RTC 1985, 104, 50. (b) Yadav, J. S.; Reddy, P. S.; Joshi, B. V. T 1988, 44, 7243.
5. (a) van Leusen, D.; van Echten, E.; van Leusen, A. M. RTC 1992, 111, 469. (b) Moskal, J.; van Leusen, A. M. JOC 1986, 51, 4131. (c) Moskal, J.; van Stralen, R.; Postma, D.; van Leusen, A. M. TL 1986, 27, 2173. (d) van Leusen, A. M.; Schaart, F. J.; van Leusen, D. RTC 1979, 98, 258. (e) van Leusen, D.; van Leusen, A. M. S 1991, 531.
6. (a) Hoogenboom, B. E.; Oldenziel, O. H.; van Leusen, A. M. OSC 1988, 6, 987; meanwhile the yield of the first reaction step has been improved from 42-47% to 86-90%, see: Tezaki, K.; Nakayama, S.; Miyazaki, Y., Sugita, Y. Jpn. Patent 61 186 359 (CA 1987, 106, 13 138t); Barendse, N. C. M. Eur. Patent 242 001 (CA 1988, 109, 24 508s). (b) Obrecht, R.; Herrmann, R.; Ugi, I. S 1985, 400.
7. Oldenziel, O. H.; Wildeman, J.; van Leusen, A. M. OSC 1988, 6, 41.
8. (a) van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. TL 1972, 2369. (b) van Nispen, S. P. J. M.; Mensink, C.; van Leusen, A. M. TL 1980, 21, 3723.
9. van Leusen, A. M.; Wildeman, J. S 1977, 501.
10. van Leusen, A. M.; Hoogenboom, B. E.; Houwing, H. A. JOC 1976, 41, 711.
11. van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen, D. TL 1972, 5337.
12. (a) van Leusen, A. M.; Bouma, R. J.; Possel, O. TL 1975, 3487. (b) van Leusen, A. M.; Possel, O. TL 1977, 4229.
13. Gröbel, B.-T.; Seebach, D. S 1977, 357.
14. van Leusen, A. M.; Wildeman, J. RTC 1982, 101, 202.
15. van Leusen, D.; van Leusen, A. M. RTC 1991, 110, 402.
16. (a) Merour, J. Y.; Buzar, A. SC 1988, 18, 2331. (b) Bull, J. R.; Tuinman, A. T 1975, 31, 2151. (c) Becker, D. P.; Flynn, D. L. S 1992, 1080.
17. See footnote 3 in Ref. 3a.
18. (a) Gossauer, A.; Suhl, K. HCA 1976, 59, 1698. (b) Cappon, J. J.; Witters, K. D.; Verdegem, P. J. E.; Hoek, A. C.; Luiten, R. J. H.; Raap, J.; Lugtenburg, J. RTC 1994, 113, 318.
19. (a) Magnus, P.; Gallagher, T.; Schultz, J.; Or, Y.-S.; Ananthanarayan, T. P. JACS 1987, 109, 2706. (b) Magnus, P.; Danikiewicz, W.; Katoh, T.; Huffman, J. C.; Folting, K. JACS 1990, 112, 2465.
20. Leusink, F. R.; ten Have, R.; van den Berg, K. J.; van Leusen, A. M. CC 1992, 1401.
21. (a) van Leusen, D.; Flentge, E.; van Leusen, A. M. T 1991, 47, 4639. (b) Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. T 1990, 46, 7587. (c) See footnotes 8 and 9 in Ref. 3a.
22. Ref. 21a; meanwhile the yield of that reaction has been improved to 70% by using NaH in DME at -40 °C at lower concentrations (ten Have, R., unpublished results).
23. Hesz, U.; Brosig, H.; Fehlhammer, W. P. TL 1991, 32, 5539.
24. (a) van Leusen, D.; van Leusen, A. M. S 1980, 325. (b) van Leusen, D.; Rouwette, P. H. F. M.; van Leusen, A. M. JOC 1981, 46, 5159 ((R)- and (S)-2-methylcyclobutanone were not obtained enantiomerically pure). (c) Breitenbach, J.; Vögtle, F. S 1992, 41.
25. (a) Hundscheid, F. J. A.; Tandon, V. K.; Rouwette, P. H. F. M.; van Leusen, A. M. T 1987, 43, 5073. (b) van Leusen, D.; van Leusen, A. M. RTC 1984, 103, 41.
26. (a) Houwing, H. A.; Wildeman, J.; van Leusen, A. M. JHC 1981, 18, 1133. (b) van Leusen, A. M.; Jeuring, H. J.; Wildeman, J.; van Nispen, S. P. J. M. JOC 1981, 46, 2069.

Albert M. van Leusen & Daan van Leusen

Groningen University, The Netherlands



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