Reductions with metal alkoxyaluminium hydrides

Last updated

Reductions with metal alkoxyaluminium hydrides are chemical reactions that involve either the net hydrogenation of an unsaturated compound or the replacement of a reducible functional group with hydrogen by metal alkoxyaluminium hydride reagents. [1] [2]

Contents

Introduction

Sodium borohydride and lithium aluminium hydride are commonly used for the reduction of organic compounds. [3] [4] These two reagents are on the extremes of reactivity—whereas lithium aluminium hydride reacts with nearly all reducible functional groups, sodium borohydride reacts with a much more limited range of functional groups. Diminished or enhanced reactivity may be realized by the replacement of one or more of the hydrogens in these reagents with alkoxy groups.

Additionally, substitution of hydrogen for chiral alkoxy groups in these reagents enables asymmetric reductions. [5] Although methods involving stoichiometric amounts of chiral metal hydrides have been supplanted in modern times by enantioselective catalytic reductions, they are of historical interest as early examples of stereoselective reactions.

The table below summarizes the reductions that may be carried out with a variety of metal aluminium hydrides and borohydrides. The symbol "+" indicates that reduction does occur, "-" indicates that reduction does not occur, "±" indicates that reduction depends on the structure of the substrate, and "0" indicates a lack of literature information.

Mechanism and stereochemistry

Prevailing mechanism

Reduction by alkoxyaluminium hydrides is thought in most cases to proceed by a polar mechanism. [6] Hydride transfer to the organic substrate generates an organic anion, which is neutralized either by protic solvent or upon acidic workup.

Reductions of α,β-unsaturated carbonyl compounds may occur in a 1,2 sense (direct addition) or a 1,4 sense (conjugate addition). The tendency to add in a 1,4 sense is correlated with the softness of the hydride reagent according to Pearson's hard-soft acid-base theory. [7] Experimental results agree with the theory—softer hydride reagents afford higher yields of the conjugate reduction product. [8]

A few substrates, including diaryl ketones, [9] diarylalkenes, [10] and anthracene, [11] are known to undergo reduction by single-electron transfer pathways with lithium aluminium hydride.

Metal alkoxylaluminium hydride reagents are well characterized in a limited number of cases. [12] Precise characterization is complicated in some cases by disproportionation, which converts alkyoxyaluminium hydrides into alkoxyaluminates and metal aluminium hydride: [13]

Stereochemistry

The origin of diastereoselectivity in reductions of chiral ketones has been extensively analyzed and modeled. [14] [15] According to a model advanced by Felkin, [16] diastereoselectivity is controlled by the relative energy of the three transition states I, II, and III. Transition state I is favored in the absence of polar groups on the α carbon, and stereoselectivity increases as the size of the achiral ketone substituent (R) increases. Transition state III is favored for reductions of alkyl ketones in which RM is an electron-withdrawing group, because the nucleophile and electron-withdrawing substituent prefer to be as far away from one another as possible.

Diastereoselectivity in reductions of cyclic ketones has also been studied. Conformationally flexible ketones undergo axial attack by the hydride reagent, leading to the equatorial alcohol. Rigid cyclic ketones, on the other hand, undergo primarily equatorial attack to afford the axial alcohol. Preferential equatorial attack on rigid ketones has been rationalized by invoking "steric approach control"—an equatorial approach of the hydride reagent is less sterically hindered than an axial approach. [17] The preference for axial attack on conformationally flexible cyclic ketones has been addressed by a model put forth by Felkin and Anh. [18] [19] The transition state for axial attack (IV) suffers from steric strain between any axial substituents and the incoming hydride reagent. The transition state for equatorial attack (V) suffers from torsional strain between the incoming hydride reagent and adjacent equatorial hydrogens. The difference between these two strain energies determines which direction of attack is favored, and when R is small, torsional strain in V dominates and the equatorial alcohol product is favored.

Scope and limitations

Alkoxyaluminium and closely related hydride reagents reduce a wide variety of functional groups, often with good selectivity. This section, organized by functional group, covers the most common or synthetically useful methods for alkoxyaluminium hydride reduction of organic compounds.

Many selective reductions of carbonyl compounds can be effected by taking advantage of the unique reactivity profiles of metal alkoxylaluminium hydrides. For instance, lithium tri-tert-butoxy)aluminium hydride (LTBA) reduces aldehydes and ketones selectively in the presence of esters, with which it reacts extremely slowly. [20]

α,β-Unsaturated ketones may be reduced selectively in a 1,2 or 1,4 sense by a judicious choice of reducing agent. Use of relatively unhindered lithium trimethoxyaluminium hydride results in nearly quantitative direct addition to the carbonyl group (Eq. ( 9 )). [21] On the other hand, use of the bulky reagent LTBA leads to a high yield of the conjugate addition product (Eq. ( 10 )). [22]

Ether cleavage is difficult to accomplish with most hydride reagents. However, debenzylation of benzyl aryl ethers may be accomplished with SMEAH. [23] This protocol is a useful alternative to methods requiring acid or hydrogenolysis (e.g., Pd/C and hydrogen gas).

Epoxides are generally attacked by alkoxyaluminium hydrides at the less substituted position. A nearby hydroxyl group may facilitate intramolecular delivery of the hydride reagent, allowing for selective opening of 1,2-disubstituted epoxides at the position closer to the hydroxyl group. [24] The configuration at the untouched epoxide carbon is preserved.

Unsaturated carbonyl compounds may be reduced either to saturated or unsaturated alcohols by alkoxyaluminium hydride reagents. Addition of an unsaturated aldehyde to a solution of Red-Al afforded the saturated alcohol; inverse addition yielded the unsaturated alcohol product. [25]

Alkenes undergo hydroalumination in the presence of some alkoxyaluminium hydrides. [26] In a related application, NaAlH2(OCH2CH2OCH3)2 (sodium bis(methoxyethoxy) aluminium dihydride, SMEAH or Red-Al) reacts with zirconocene dichloride to afford zirconocene chloride hydride (Schwartz's reagent). Alkenes undergo hydrozirconation in the presence of this reagent, affording functionalized products after quenching with an electrophile. [27]

Functional groups containing heteroatoms other than oxygen may also be reduced to the corresponding hydrocarbons in the presence of an alkoxyaluminium hydride reagent. Primary alkyl halides undergo reduction to the corresponding alkanes in the presence of NaAlH(OH)(OCH2CH2OCH3)2. Secondary halides are less reactive, but afford alkanes in reasonable yield. [28]

Sulfoxides are reduced to the corresponding sulfides in good yield in the presence of SMEAH. [29]

Imines are reduced by metal alkoxyaluminium hydrides to the corresponding amines. In the example below, use of the exo amine forms with high diastereoselectivity. The selectivity of hydride reduction in this case is higher than that of catalytic hydrogenation. [30]

Experimental conditions and procedure

Preparation of hydride reagents

Alkoxyaluminium hydrides are typically prepared by treatment of lithium aluminium hydride with the corresponding alcohol. [31] Hydrogen evolution indicates the formation of alkoxyaluminium hydride products. Hindered hydrides such as lithium tri-(tert-butoxy)aluminium hydride (LTBA) are stable for long periods of time under inert atmosphere, but lithium trimethoxyaluminium hydride (LTMA) undergoes disproportionation and should be used immediately after preparation. Pure, solid Red-Al is stable for several hours under inert atmosphere and is available commercially as a 70%-solution in toluene under the trade name Vitride or Synhydrid.

Reduction conditions

Reduction may typically be carried out in a round-bottom flask equipped with a drying-tube-capped reflux condenser, a mercury-sealed mechanical stirrer, a thermometer, a nitrogen inlet, and an additional funnel with a pressure-equalizing side arm. The most common solvents used are tetrahydrofuran and diethyl ether. Whatever solvent is used should be anhydrous and pure. Alkoxyaluminium hydrides should be kept as dry as possible and represent a significant fire hazard, particularly when an excess of hydride is used (hydrogen evolves during workup).

Example procedure [32]

To a solution of 1,3-dihydro-1,3-bis(chloromethyl)benzo[c] thiophene 2,2-dioxide (0.584 g, 2.2 mmol) in 50 ml of dry benzene was added 0.80 mL (2.8 mmol) of a 70% benzene solution of NaAlH2(OCH2CH2OCH2)2 via syringe, and the solution was refluxed for 12 hours. The mixture was cooled to 0° and decomposed with 20% sulfuric acid. The benzene layer was separated, washed with 10 mL of water, dried over potassium carbonate, and concentrated to give the product as a yellow oil in 91% yield (0.480 g); IR (film) 770, 1140, and 1320 cm–1; NMR (CDCl3) δ 4.22 (q, 2 H), 1.61 and 1.59 (2 d, 6 H, J = 7 Hz), 7.3 (s, 4 H); m/e (rel. intensity) 196 (M+) (14), 132 (M-SO2) (100); MS analysis 196.055796 (calc.), 196.057587 (obs.).

Related Research Articles

<span class="mw-page-title-main">Lithium aluminium hydride</span> Chemical compound

Lithium aluminium hydride, commonly abbreviated to LAH, is an inorganic compound with the chemical formula Li[AlH4] or LiAlH4. It is a white solid, discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic synthesis, especially for the reduction of esters, carboxylic acids, and amides. The solid is dangerously reactive toward water, releasing gaseous hydrogen (H2). Some related derivatives have been discussed for hydrogen storage.

<span class="mw-page-title-main">Organolithium reagent</span> Chemical compounds containing C–Li bonds

In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C−Li bond is highly ionic. Owing to the polar nature of the C−Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.

<span class="mw-page-title-main">Sodium borohydride</span> Chemical compound

Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula NaBH4. It is a white crystalline solid, usually encountered as an aqueous basic solution. Sodium borohydride is a reducing agent that finds application in papermaking and dye industries. It is also used as a reagent in organic synthesis.

<span class="mw-page-title-main">Organic redox reaction</span> Redox reaction that takes place with organic compounds

Organic reductions or organic oxidations or organic redox reactions are redox reactions that take place with organic compounds. In organic chemistry oxidations and reductions are different from ordinary redox reactions, because many reactions carry the name but do not actually involve electron transfer. Instead the relevant criterion for organic oxidation is gain of oxygen and/or loss of hydrogen. Simple functional groups can be arranged in order of increasing oxidation state. The oxidation numbers are only an approximation:

<span class="mw-page-title-main">Chiral auxiliary</span> Stereogenic group placed on a molecule to encourage stereoselectivity in reactions

In stereochemistry, a chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. The auxiliary can then be typically recovered for future use.

<span class="mw-page-title-main">Asymmetric induction</span> Preferential formation of one chiral isomer over another in a chemical reaction

Asymmetric induction describes the preferential formation in a chemical reaction of one enantiomer or diastereoisomer over the other as a result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment. Asymmetric induction is a key element in asymmetric synthesis.

<span class="mw-page-title-main">Aluminium hydride</span> Chemical compound

Aluminium hydride is an inorganic compound with the formula AlH3. Alane and its derivatives are part of a family of common reducing reagents in organic synthesis based around group 13 hydrides. In solution—typically in ethereal solvents such tetrahydrofuran or diethyl ether—aluminium hydride forms complexes with Lewis bases, and reacts selectively with particular organic functional groups, and although it is not a reagent of choice, it can react with carbon-carbon multiple bonds. Given its density, and with hydrogen content on the order of 10% by weight, some forms of alane are, as of 2016, active candidates for storing hydrogen and so for power generation in fuel cell applications, including electric vehicles. As of 2006 it was noted that further research was required to identify an efficient, economical way to reverse the process, regenerating alane from spent aluminium product.

The reduction of nitro compounds are chemical reactions of wide interest in organic chemistry. The conversion can be effected by many reagents. The nitro group was one of the first functional groups to be reduced. Alkyl and aryl nitro compounds behave differently. Most useful is the reduction of aryl nitro compounds.

<span class="mw-page-title-main">Lithium triethylborohydride</span> Chemical compound

Lithium triethylborohydride is the organoboron compound with the formula LiEt3BH. Commonly referred to as LiTEBH or Superhydride, it is a powerful reducing agent used in organometallic and organic chemistry. It is a colorless or white liquid but is typically marketed and used as a THF solution. The related reducing agent sodium triethylborohydride is commercially available as toluene solutions.

<span class="mw-page-title-main">Shvo catalyst</span> Chemical compound

The Shvo catalyst is an organoruthenium compound that catalyzes the hydrogenation of polar functional groups including aldehydes, ketones and imines. The compound is of academic interest as an early example of a catalyst for transfer hydrogenation that operates by an "outer sphere mechanism". Related derivatives are known where p-tolyl replaces some of the phenyl groups. Shvo's catalyst represents a subset of homogeneous hydrogenation catalysts that involves both metal and ligand in its mechanism.

Carbonyl oxidation with hypervalent iodine reagents involves the functionalization of the α position of carbonyl compounds through the intermediacy of a hypervalent iodine(III) enolate species. This electrophilic intermediate may be attacked by a variety of nucleophiles or undergo rearrangement or elimination.

Oxidation with dioxiranes refers to the introduction of oxygen into organic molecules through the action of a dioxirane. Dioxiranes are well known for their oxidation of alkenes to epoxides; however, they are also able to oxidize other unsaturated functionality, heteroatoms, and alkane C-H bonds.

<span class="mw-page-title-main">Carbonyl reduction</span> Organic reduction of any carbonyl group by a reducing agent

In organic chemistry, carbonyl reduction is the conversion of any carbonyl group, usually to an alcohol. It is a common transformation that is practiced in many ways. Ketones, aldehydes, carboxylic acids, esters, amides, and acid halides - some of the most pervasive functional groups, -comprise carbonyl compounds. Carboxylic acids, esters, and acid halides can be reduced to either aldehydes or a step further to primary alcohols, depending on the strength of the reducing agent. Aldehydes and ketones can be reduced respectively to primary and secondary alcohols. In deoxygenation, the alcohol group can be further reduced and removed altogether by replacement with H.

Enantioselective ketone reductions convert prochiral ketones into chiral, non-racemic alcohols and are used heavily for the synthesis of stereodefined alcohols.

<span class="mw-page-title-main">Reductions with samarium(II) iodide</span>

Reductions with samarium(II) iodide involve the conversion of various classes of organic compounds into reduced products through the action of samarium(II) iodide, a mild one-electron reducing agent.

Reductions with hydrosilanes are methods used for hydrogenation and hydrogenolysis of organic compounds. The approach is a subset of ionic hydrogenation. In this particular method, the substrate is treated with a hydrosilane and auxiliary reagent, often a strong acid, resulting in formal transfer of hydride from silicon to carbon. This style of reduction with hydrosilanes enjoys diverse if specialized applications.

In organic chemistry, α-halo ketones can be reduced with loss of the halogen atom to form enolates. The α-halo ketones are readily prepared from ketones by various ketone halogenation reactions, and the products are reactive intermediates that can be used for a variety of other chemical reactions.

Intramolecular reactions of diazocarbonyl compounds include addition to carbon–carbon double bonds to form fused cyclopropanes and insertion into carbon–hydrogen bonds or carbon–carbon bonds.

Benzylic activation and stereocontrol in tricarbonyl(arene)chromium complexes refers to the enhanced rates and stereoselectivities of reactions at the benzylic position of aromatic rings complexed to chromium(0) relative to uncomplexed arenes. Complexation of an aromatic ring to chromium stabilizes both anions and cations at the benzylic position and provides a steric blocking element for diastereoselective functionalization of the benzylic position. A large number of stereoselective methods for benzylic and homobenzylic functionalization have been developed based on this property.

Reactions of alkenyl- and alkynylaluminium compounds involve the transfer of a nucleophilic alkenyl or alkynyl group attached to aluminium to an electrophilic atom. Stereospecific hydroalumination, carboalumination, and terminal alkyne metalation are useful methods for generation of the necessary alkenyl- and alkynylalanes.

References

  1. ↑ Málek, J. Org. React. 1985, 34, 1. doi : 10.1002/0471264180.or034.01
  2. ↑ Málek, J. Org. React.1988, 36, 249. doi : 10.1002/0471264180.or036.03
  3. ↑ Brown, G. Org. React.1951, 6, 469.
  4. ↑ Schenker, E. in Newer Methods of Preparative Organic Chemistry, Vol. IV., W. Foerst, Ed., Academic Press, New York, 1968, pp. 163–335.
  5. ↑ Itsuno, S. Org. React.1998, 52, 395.
  6. ↑ House, O. Modern Synthetic Reactions, 2nd ed., W. A. Benjamin, Menlo Park, Calif., 1972.
  7. ↑ Pearson, G. J. Chem. Educ.1968, 45, 581.
  8. ↑ Bottin, J.; Eisenstein, O.; Minot, C.; Anh, T. Tetrahedron Lett., 1972, 3015.
  9. ↑ Cerný, M.; Málek, J. Collect. Czech. Chem. Commun.. 41, 119 (1976).
  10. ↑ Málek, J.; Cerný, M. J. Organomet. Chem.1975, 84, 139.
  11. ↑ Málek, J.; Cerný, M.; Rericha, R. Collect. Czech. Chem. Commun.1974, 39, 2656.
  12. ↑ Bec, M.; Huet, J. Bull. Soc. Chim. Fr., 1972, 1636.
  13. ↑ Brown, C.; Shoaf, J. J. Am. Chem. Soc.1964, 86, 1079.
  14. ↑ Cram, J.; Abd Elhafez, A. J. Am. Chem. Soc.1952, 74, 5828.
  15. ↑ Chérest, M.; Prudent, N. Tetrahedron1980, 36, 1599.
  16. ↑ Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett., 1968, 2199.
  17. ↑ Dauben, W. G.; Fonken, G. J.; Noyce, D. S. J. Am. Chem. Soc.1956, 78, 2579.
  18. ↑ Chérest, M.; Felkin, H. Tetrahedron Lett., 1971, 383.
  19. ↑ Huet, J.; Maroni-Barnaud, Y.; Anh, N. T.; Seyden-Penne, J. Tetrahedron Lett., 1976, 159.
  20. ↑ Torii, S.; Tanaka, H.; Inokuchi, T.; Tomozane, K. Bull. Chem. Soc. Jpn.1982, 55, 3947.
  21. ↑ Danh, N. C.; Arnaud, C.; Huet, J. Bull. Soc. Chim. Fr.1974, 1071.
  22. ↑ Durand, J.; Anh, N. T.; Huet, J. Tetrahedron Lett.1974, 2397.
  23. ↑ Kametani, T.; Huang, S. P.; Ihara, M.; Fukumoto, K. J. Org. Chem.1976, 41, 2545.
  24. ↑ Finan, M.; Kishi, Y. Tetrahedron Lett.1982, 23, 2719.
  25. ↑ Bazant, V.; Capka, M.; Cerny, M.; Chvalovský, V.; Kochloefl, K.; Kraus, M.; Málek, J. Tetrahedron Lett., 1968, 3303.
  26. ↑ Ashby, C.; Noding, A. J. Org. Chem.1980, 45, 1035.
  27. ↑ Hart, W.; Schwartz, J. J. Am. Chem. Soc.1974, 96, 8115.
  28. ↑ Capka, M.; Chvalovský, V. Collect. Czech. Chem. Commun.1969, 34, 3110.
  29. ↑ Weber, L. Chem. Ber.1983, 116, 2022.
  30. ↑ Law, J.; Lewis, H.; Borne, F. J. Heterocycl. Chem.1978, 15, 273.
  31. ↑ Véle, I.; Fusek, J.; Štrouf, O. Collect. Czech. Chem. Commun.1972, 37, 3063.
  32. ↑ Barton, T. J.; Kippenhan, R. C. J. Org. Chem. 1972, 37, 4194.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.