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Chimica Oggi - Chemistry Today - vol. 31 n. 1 January/February 2013

Gerald L. Larson

ORGANIC CHEMISTRY

1,1,3,3-tetramethyldisiloxane:a versatile reducing agent

GERALD L LARSONGelest Inc., 11 East Steel Road, Morrisville, PA 19067, USA

KEYWORDS

Reductions, organosilane reductions, tetramethyldisiloxane, TMDS.

ABSTRACT

Some recent applications of several highly useful reducing capabilities of tetramethyldisiloxane, TMDS, are reviewed.

hexachloroplatinate as the catalyst. Here again the yields are excellent and in this case the reaction conditions are quite moderate. The employed platinum catalyst, though expensive, is only required in low amount (3). It was found that a synergistic effect of the two Si-H groups in the TMDS formed an intermediate Pt(IV) species 1 leading to the full reduction of the amide carbonyl moiety.Whereas the indium(III) bromide-triethylsilane reduction of N,N-

dibenzylacetamide gave a 90% yield of the corresponding dibenzylethylamine, TMDS, under these conditions, gave only a 51% yield of the amine (4). The reduction of secondary amides to secondary amines employing the ruthenium catalyst 2 has been reported (5).

The facile, copper (II)-triflate-catalyzed TMDS reduction of secondary amides to secondary amines in good to excellent yields is possible when a diamine ligand is employed (6). Under similar conditions using other silane reducing agents including PMHS, and triethylsilane resulted in poor yields.

INTRODUCTION

The hydride of organosilanes has been employed in the reductions of a vast array of organic substrates oftentimes with excellent chemoselectivity. This high degree of

chemoselectivity can be credited to the weakly hydridic character of the Si-H bond along with the large variation in catalytic protocols available to carry out the reductions. A comprehensive review of the ionic and transition metal-catalyzed silane reductions has been published (1). In addition to the potential for high selectivity via the weakly hydridic silanes the organosilane reducing agents are available in a variety of forms including the popular and easily handled triethylsilane, the more sterically demanding triisopropylsilane, the specialty phenylsilane, and, finally, the more economical polymethylhydrogen siloxanes, PMHS. Sym-tetramethyldisiloxane, TMDS, has recently been shown to bring about several interesting and highly useful reductions, some of which are presented herein.

THE REDUCTION OF AMIDES TO AMINES

The reduction of amides to amines, a transformation traditionally carried out with borane or a borane derivative, can be nicely done with TMDS in the presence of the inexpensive triirondodecacarbonyl catalyst. Although the conditions are somewhat harsh, the yields for this transformation are good (2). The reduction of tertiary and secondary amides proceeds very well, but a single primary amide studied gave only a 3 percent yield. Similar reductions are possible with dihydrogen

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scheme 3.

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scheme 5.

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Chimica Oggi - Chemistry Today - vol. 31 n. 1 January/February 2013

ORGANIC CHEMISTRY

REDUCTION OF NITRO GROUPS

The TMDS/Fe3(CO)12 combination that works well for the reduction of amides to amines was also shown to reduce nitro groups to primary amines in good yields (2).

The iron (III) pentanedionate-catalyzed reduction of aryl nitro compounds provides a high-yield, economical process for this important reduction (10, 11). The process was shown to tolerate aryl bromide, ester, carboxylic acid, cyano, and m-nitro groups. PMHS was shown to be a viable alternative to the TMDS in these reductions as well.

REDUCTION OF AMIDES TO ENAMINES

In another illustration of the effect of different catalysts on the reactivity of the TMDS, an iridium catalyst takes amides that contain an α-hydrogen to the enamine (12) These conditions provide the (E)-enamine in excellent yields. This transformation is also possible with PMHS as the reducing agent and an impressively low loading of the iridium catalyst.

PREPARATION OF SILYL ETHERS

It was recently shown that TMDS is an excellent reagent for the formation of various silyl ethers from ethers, alcohols or carbonyl precursors (13). The catalyst of choice for these transformations is the simple palladium on charcoal, Pd/C. Of particular interest is the reaction of cyclic ethers. For example, the reductive

ring opening of styrene oxide gives a single product with the resulting silyloxy unit located exclusively on the b-carbon, whereas the reductive ring opening of 1,2-epoxyhexane gives a mixture of the regioisomeric disiloxanes. Similar non-regioselectivity is found with the reductive ring opening of 2-methyl- and 3-methyltetrahydrofuran.

REDUCTIVE AMINATION OF ESTERS

In a very useful transformation it was found that the reaction of esters with tosylamides in the presence of TMDS as a reducing agent and catalyzed by the ruthenium catalyst 2 results in the formation of the tosylamide of primary or secondary amines (7). The tosyl group can be readily removed to give the desired amine. The yields in these reactions are excellent and the reaction conditions are mild. It was further shown that ethyldimethylsilane was an effective reducing component in the reaction. Interestingly, it was shown that when the alcohol portion of the ester is that of a primary or secondary alcohol the alkyl group to form the amine comes from the acid half of the ester.However, when the alcohol portion of the ester is a tertiary alcohol it is this alcohol portion that alkylates the amine, thus providing an excellent entry into tertiary alkyl-substituted amines. The reaction was extended with equal success to cyclic amines and spirocyclic amines. These conversions take advantage of both modes of reaction incorporating either the acid (cyclic amines) or the alcohol (spirocyclic amines) portion of the ester.

REDUCTION OF AMIDES TO ALDEHYDES

Buchwald and coworkers showed that it was possible to reduce a tertiary amide to an aldehyde using phenylsilane as the reducing agent. (8) More recently it has been shown that TMDS converts tertiary and secondary aromatic or aliphatic amides to aldehydes in high yields using the inexpensive tetraisopropoxy titanium as the catalyst. (9)

scheme 6.

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scheme 12.

scheme 13.

scheme 14.

scheme 15.

scheme 16.

scheme 17.

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Chimica Oggi - Chemistry Today - vol. 31 n. 1 January/February 2013

ORGANIC CHEMISTRY

The reductive bromination of carboxylic acids is possible with the use of the TMDS as the reducing agent and bromotrimethylsilane as the bromide source. The yields of this transformation are good to excellent (17). Remarkably, the reaction conditions are tolerant of a variety of functional groups.

ENANTIOSELECTIVE REDUCTIVE MICHAEL CYCLIZATION REACTIONS

The silane reduction of α,β-unsaturated esters can occur in a Michael fashion to provide an intermediate silyl ketene acetal, which can react with an electrophile to give the α-subsituted ester. This has been carried out with bis-α,β--unsaturated ester systems wherein one of the functional groups is reduced by the silane forming the silyl ketene acetal (or enolate) and the second serves as the electrophile producing the cyclized diester. In the presence of a chiral ligand and a copper catalyst this process has been shown to be both high yielding and highly enantioselective. The SEGPHOS ligand proved to be the most effective (18).

REDUCTIVE CLEAVAGE OF ANISOLES

The methoxy group has long been exploited in the regioselective substitution of aromatic systems both by its strong ortho/para directing effect and its ability to direct metalation to an ortho position. In certain circumstances it would be desirable to remove the methoxy group from anisoles after it has carried out its directing function. A nickel-catalyzed TMDS reductive cleavage of anisoles accomplishes this feat in an admirable fashion and with the demonstrated tolerance of aryl pyrrole, aryl morpholino, carboxylic ester, 1,2-diazole, methoxymethyl, dimethylacetal, and TIPS ether groups (19).

SELECTIVE REDUCTION OF ACETALS

TMDS has been shown to regioselectively cleave the acetal group of hexopyranosyl acetals to produce either the ether of C6 from the reductive cleavage of O-C4 or the ether of C4 from the reductive cleavage of O-C6. With the 4,6-O-benzylidene glycosyl acetals the cleavage was regioselective with either the combination of TMDS/Cu(OTf)2 or of TMDS/AlCl3, however,

When provided with the option of ring opening or reaction with an alcohol the reaction occurs at the alcohol. In a similar fashion the reduction of aldehydes or ketones with TMDS results in the formation of 1,3-dialkoxytetramethyldisiloxanes as does the dehydrogenative coupling of TMDS with primary or secondary alcohols.

REDUCTION OF CARBOXYLIC ACIDS

The indium tribromide-catalyzed organosilane reduction of 4-bromophenylacetic acid showed low yields and product mixtures of the primary alcohol and its silyl ether with triethylsilane and phenylsilane. TMDS, on the other hand, gives a 99% yield of the 2-(4-bromophenyl)ethanol (14). Other acids are converted to the primary alcohol under these conditions with tolerance for hydroxy, nitro, olefin, cyclopropane, aryl iodide, and thiol ether groups being demonstrated. Due to the strong carbocationic character generated during the reaction, the reduction of benzoic acid in toluene solvent results in the benzylation of toluene to form a mixture of ortho and para benzyltoluene. No reduction takes place with benzoic acid in chloroform.

TMDS in the presence of a catalytic amount of copper (II) triflate carries out the reduction of carboxylic acids to the corresponding alcohols in moderate to good yields (15). This reagent combination was also found to reductively couple aldehydes and ketones to symmetrical ethers.

The direct thioetherification of aromatic carboxylic acids has proven to be possible with the combination of TMDS and InBr3. For the direct thioetherification of aliphatic carboxylic acids the TMDS/InI3 system proved best (16). TMDS proved to be significantly better than triethylsilane or phenylsilane in these transformations.

scheme 18.

scheme 19.

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scheme 26.

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Chimica Oggi - Chemistry Today - vol. 31 n. 1 January/February 2013

ORGANIC CHEMISTRY

REFERENCES

1. G. L. Larson, J. L. Fry, Ionic and Organometallic-Catalyzed Organosilane Reductions, S. E. Denmark, Ed., John Wiley and Sons, Organic Reactions, 71, pp. 1-737 (2008).

2. Y. Sunada, H. Kawakami, et al., Angew. Chem. Int. Ed. Engl., 48, pp. 9511-9514 (2009).

3. S. Hanada, E. Tsutsumi, et al., J. Am. Chem. Soc., 131, pp. 15032-15040 (2009).

4. N. Sakai, K. Fujii, et al., Tetrahedron Lett., 49, pp. 6873-6875 (2008).5. S. Hanada, T. Ishida, et al., J. Org. Chem., 72, pp. 7551-7559 (2007).6. S. Das, B. Join, Ket al., Chem. Commun., 48, pp. 2683-2685 (2012).7. T. Nishikata, H. Nagashima, Angew. Chem. Int. Ed., 51, pp. 5363-5366

(2012).8. S. Bower, K. A. Kreutzer, et al., Angew. Chem. Int. Ed. Engl., 35, pp.

1515-1516 (1996).9. S. Laval, W. Dayoub, et al.,Tetrahedron Lett., 51, pp. 2092-2094

(2010).10. L. Pehlivan, E. Métay, et al., Tetrahedron Lett., 51, pp. 1939-1941

(2010).11. L. Pehlivan, E. Métay, et al., Tetrahedron, 67, pp. 1971-1976 (2011).12. Y. Motoyama, M. Aoki, et al., Chem. Commun., 48, pp. 1574-1576

(2009).13. L. Pehlivan, E. Métay, et al., Eur. J. Org. Chem., pp. 4687-4692 (2011).14. N. Sakai, K. Kawana, et al., Eur. J. Org. Chem., pp. 3178-3183 (2011).15. Y.-J. Zhang, W. Dayoub, et al, Tetrahedron, 68, pp. 7400-7407 (2012).16. N. Sakai, T. Miyazaki, et al., Org. Lett., 14, pp. 4366-4369 (2012).17. T. Moriya, S. Yoneda, et al., Org. Lett., 14, pp. 4842-4845 (2012).18. C. L. Oswald, J. A. Peterson, et al., Org. Lett., 11, pp. 4504-4507

(2009).19. P. Alvarez, R. Martin, J. Am. Chem. Soc., 132, pp. 17352-17353 (2010).20. Y.-J. Zhang, W. Dayoub, G.-R. Chen, M. Lemaire, Eur. J. Org. Chem.

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Demonchaux, G. Mignani, M. Lemaire, Tetrahedron Lett., 50, 7005-7007 (2009).

22. K. Naumann, G. Zoun, K. Mislow, J. Am. Chem. Soc., 91, 7012-7023 (1969).

23. L. Pehlivan, E. Métay, D. Delbrayayelle, G. Mignani, M. Lemaire, Tetrahedron, 68, 3151-3155 (2012).

24. M. Berthod, A. Favre-Réguillon, J. Mohamad, G. Mignani, G. Docherty, M. Lemaire, Synlett, 1545-1548 (2007).

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the regiochemistry varies depending on the mode of protection on the hydroxyl groups (20). The 4,6-O-alkylidene glycosyl acetals are selectively cleaved at the O-C6 bond in all cases. These reductions are possible when the other hydroxyls are protected or are free.

REDUCTION OF NITRILES

TMDS has been shown to reduce nitriles to primary amines in high yields under mild conditions with a stoichiometric amount of isopropyl titanate. (21) The reaction work-up involves washing the reaction mixture with aqueous hydrochloric acid and isolation of the product as the hydrochloride salt. The by-products are a silicone gel from the TMDS and titanium dioxide from the Ti(Oi-Pr)4. The reaction was shown to be tolerant of aryl bromides and nitro groups.

REDUCTION OF PHOSPHINE OXIDES

The reduction of phosphine oxides to the parent tri-substituted phosphine is an important transformation in the formation of numerous phosphine ligands. Although this reduction is possible with other reagents, including hexachlorodisilane, they are typically difficult to handle and give undesirable by-products (22). It has now been found that the InBr3/TMDS combination reduces phosphine oxides to phosphines in excellent yields under rather mild conditions.The isolation of those phosphines that are readily oxidized back to the phosphine oxide were isolated as their borane adducts in this study (23).

The less expensive and more easily handled Ti(O1Pr)4/TMDS system reduces phosphine oxides to the phosphines in very good yields and compares very well with the InBr3/TMDS combination. In one glaring example the reduction of 1,4-bis(diphenyloxophosphino)butane is reduced with the Ti(O1Pr)4/TMDS system in 95% yield and not at all under the indium bromide-catalyzed conditions (24, 25). The mechanism of this reaction was studied and the evidence supports a single electron transfer (SET) mechanism (26).

CONCLUSIONS

Recent work has shown the synthetic versatility of the readily available tetramethyldisiloxane, TMDS, in several previously difficult and important organic reductions. These findings illustrate the potential to provide cleaner, safer and, in many cases, more economical routes to functional groups important in the field of organic synthesis.

scheme 27.

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scheme 29.