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ALUMINUM AMALGAM 23

Aluminum Amalgam1

[ l 1 4-30-81 A1 (M W 26.98)

(reducing agent for many functional groups,' effects re-ductive dimerization of unsaturated compounds, can cleave

carbon-element and element-element bonds.)

Physical Data: shiny solid.

Preparative M ethods: Aluminum turnings (oil-free) are etchedwith dilute Sodium Hydroxide to a point of strong hydrogenevolution and the solution is decanted. The metal is washedonce with water so that it retains som e alkali, then treated with

0.5%Mercury(ZZ) Chlor ide solution for 1-2 min, and the entire

procedure is repeated. The shiny amalgamated metal is washedrapidly in sequence with water, ethanol, and ether and usedat once.2 Aluminum amalgam (1 ) reacts vigorously with wa-

ter with liberation of hydroge n in the amount equivalent to theamou nt of alum inum present and can be used to dry organic sol-vents (ether, ethanol).2a Aluminum amalgam can be also pre-

pared from aluminum foil, which is cut into strips -10 cm x

1 cm and immersed, all at once, into a 2% aqueous solution

of HgCl2 for 15 s. The strips are rinsed with absolute alco-hol and then with ether and cut immediately with scissors

into pieces -1 cm square, directly into the reaction vessel.2bBefore immersion, each strip may be rolled into a cylinder-1 cm in diameter. Each cylinder is amalgamated, rinsed suc-cessively with ethanol and ether and then placed in the reaction

Handling, Storage, and Precautions: moisture-sensitive. Precau-tions shou ld be taken as it readily reacts with w ater with hydro-gen evolution. Can be stored under dry ether. Toxic.

C=C Bond Reduction. Alkenic substrates are transformed

into saturated compo unds upon reaction with Al-Hg. Sub-strates with carbon-carbon double bonds activated by electron-withdrawing substituents are most easily re d ~ c e d . ~he reactionmay proceed with asymmetric induction and high chemoselectiv-

ity, leaving other functionalities unchanged (eq l ) .4Reduction of1 3-dienes5' an d a-nitroalkenesSb results in 1,4-addition of hy-

drogen to the v-system. Aluminum amalgam can also promote

reductive dimerization of a,P-unsaturated acid esters.6a*b

C=O Bond Reduction. Cycloalkanones and aldehydes arereduced to the corresponding alcohols (eq 2). Acyclic ketones

remain alm ost inert.'

In spite of the ability of carboxylic acid esters to be reducedto alcohols,8 in oxosuccinic acid esters only the ketone carbonylgroup is reduced?

Ultrasound-promoted reduction of the C=O group of N -

substituted phthalimides leads to hydroxylactams. Th e ultrasonicirradiation provides rapid fragmentation of the amalgam, giv-ing a reactive dispersion and accelerates the reaction owing tothe increase of mass transport between the solution and the

A W g surface where reduction occurs. The reaction is highly

sensitive to substrate structure and N-benzylglutarimide and N-

benzylsuccinimide are not reduced.'O

OM e$7I'o*o

A1-HgDME-H*O ( 7 S : l )

0 "C, h,61%

H2N\jlC02Hl )

HCI-reflux, 6 h ~ 0 . g

74%

17%ee

10equiv AI-HgTHF-H20 (9 :1)

Reductive dimerization of carbonyl compounds to pinacolsdoes not always effectively compete with reduction to alcohols,but in certain cases it becomes the main process (eq 3).'.'' Fac-

tors which determine reduction-dim erization ratios include steric

inhibition, torsion strain, and angle strain.'

A1-Hg

Q-x,- S H O 3)

CHZC12. reflux, 1-4 h, 21-38%C&-EtOH (1:1), reflux, 4 , 95%THF-HzO (9:), -10 "C -+ rt,94%

A special case of reduction involves removal of the carbonyloxygens from anthraquinones12a3bnd related compound^'^ withrearomatization (eq 4).'2b

A1-Hg, EtOH-H20 (4:9)

sat aq NHhOH

\ 60-65 OC, 2 h

*

78 %O

0

HO =OH (4)

C=N Bond Reduction. Aluminum amalgam reduces Schiffbases to the corresponding ar ni ne ~. '~ mong these reactions

of great importance is the reduction of A*-thiazolines tothia~o lidine s,'~-'' widely used in the synthesis of aldehydes

(e q 5),15 P-hydroxy aldehydes, and homoallylic alcohols.16Aluminum amalgam also induces reductive dimerization of

Schiff base^'^^,^* to produce 1,2-diamin es. This process has been

used in macro cyclic ring closure.18a n respect to reductive dimer-ization of A'-pyrrolines, aluminum amalgam is much more ef-fective than Zinc in aq ueous NH4C1.'8b Similar to Schiff bases,

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24 ALUMINUM AMALGAM

oximes are also readily reduced to corresponding amines," whilereduction of hydrazides provides hydrazines?O

10-12 equiv A1-HgEtZO-HzO

b

reflux, 1 h or n, 4

("-,?? 1. BuLi, THF, -78 "C

N 2.RI, THF, -78 "C N74% 90%

R = Ph(CH2)zCHz

'N' - n, 2 hH 71%

NO2 and N3 Group Reduction. Aluminum am algam reduc-tion is an excellent method for deoxygenation of aliphatic and

aromatic nitro groups to produce aminesZ1 eq Q 2 1 d Nitro alkenescan be chemo selectively reduced, retaining the C =C bond.21a Inmoist ether the reduction can be stopped at the stage of hyd roxy-

lamine formation."

02KoHther-MeOH1-Hg *

100%

Ph Ph

Organic azides are also readily reduced to the corresponding

amines. The procedure has been used in a general synthesis ofa$-unsaturated a-amino acids.23

Reactions of Carbon-Halogen Bonds. Organic halides ex-hibit diverse behavior in reactions with Al-Hg. Thus atrichloromethyl group has been reduced to a dichloromethyl

group.24At the sam e time, A1 inserts into the C-Br bond of sily-lated propargyl bromide affording the allenylaluminum reagent,

whereas only direct metalation without rearrangement has beenobserved in metalation with Zinc Amalgam (eq 7).25

1.A1-Hg, dry THFreflux, 3 h.. yclohexanone, 0 C, 1 h LJI 70% Me3Si

Me3Si = \

Br(7 )

1.Zn-HgC12, dry TH F0-25 OC, -8 h

2. cyclohexanone, 0 " C , 1 h75%

Mild reductive deacetoxybrominationof glycosyl bromides of-fers an approach to glucals bearing acid-sensitive substituents

(e q 8) .26

Aco7 Aco7A1-Hg

r t . 6 hI

OA c 85%

C-0 Bond Cleavage. Ether linkages of various substrates,for e xa mple g l yc os i d e ~ , ~ ~,3-dioxolanes$ tetra hydro fur an^,^^^^

and oxiranes?l undergo reductive cleavage with formation of al-

cohols. Among thereactions listed, the reductive cleavage of epox-ides (eq 9p Za s presumably of the most importance. It has been

widely used in the sy nthesis of prostaglandin^,^'^,^^^^ steroids:l''derythronolide B,33and vitamin precursors.%

A1-HgEtOH-HzO-THF-sat aqNaHC03

dM ' (87:48:303), C, 3 h . -R 99% H& 3

Deoxygenation of certain terpene oxid es with A1 foil activated

by HgC12 has been reported instead of reduction to the desiredalcohols.35

N - O and N-N Bond Cleavage. On exposure to excess A1-Hgin aqueous THF at 0 "C for several hours, N-O bonds in b icyclicDiels-Alder adducts are readily cleaved.36 Mild cond itions pro-

vide a highly chemoselective process and carbon-carbon double

bonds and acid labile functional group s survive, in contrast to thealternative method s employed such as catalytic hydrogen olysisorreduction withzinc-A cetic The reaction occurs with high

stereoselectivity and the product is formed with a cis dispositionof N- and 0-con taini ng substituents (eq lo).%

MeS,

1.A1-Hg (excess)THF-H20 (1 O : l ) . 0 "C

*

2 . Ac ~ O , y-DM AP41 %

0

b A c

Aluminum analgam is also highly effective in reductive cleav-age of N-N b onds to produce a m i n e ~ . ~ ~

Reductive Desulfurization. Th e abilit y of A1-Hg to reduce

C-S bonds is widely used in organic synthesis in conjunction with

method ology involving reactions of highly reactive a-sulfinyl- anda-sulfonylalkyl car bani on^^^,^^ as well as (a-sulfoximidoy1)alkylcar bani on^.^^ Removal of the activating sulfur substituent is fre-quently accomplished using Al-Hg. The methodology offers

facile synthetic approaches to ketone^?^^^*^^^ enones! di- an dtrike tone^,^^^^^ hydroxy ketones (eq 11),"3 unsaturated acids,44and y-0x0-a-amino acids.45

1 .2 BuLi, dry THF, -90 C

c

0hS02CgH17

2. g , O 0C

3. aq NH&O "C61 8

0 0PhS02+0H A1-Hg

THF-H2O (9:l)

reflux, 3-6 h99%

C7H1S

Readily removed on treatment with A1-Hg asymm etric sulfinyl

and sulfonim idoyl groups may serv e as chiral auxiliaries in enan-tiocontrolled synthesis of 3-substi tu te d c yc l ~ a l ka no ne s~ ~nd 3-

hydroxy4' and 3-arylcarboxylic acid esters.@

Lists ofAbbreviation s and Journal Codes on Endpapers

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ALUMINUM AMALGAM 25

Alum inum amalgam mediated cleavage of C-S bonds playsan important role in sulfoximine-based alkenation of carbonyl

compounds via p-hydroxysulfoximines49 (eq 12).49b

9r S - P h

F N M e

9 LDAt

Phd THF, 85 “C

under N l91%

Aluminum amalgam can also be em ployed in reductive elimina-tion of phenylthio groups from 2-phenylthioalkanone~,~~tereo-

specific reduction of sulfoximines,51 selective cleavage of thesulfinyl sulfur-methy lene carbon bond in the presence of a disul-

fide moiety?’ and reductive scissio n of S-S and S-N bond^.^^,^^

For some reactions mediated by aluminu m activated with mer-cury(11) chloride, also see Aluminum.

Related Reagents. See Classes R-1, R-2, R-3, R-5, R-6, R-9, R-10, R-15, R-16, R-21, R-22, R-23, R-24, R-25, R-27, R-30,

R-31, and R-3 2, pages 1-10,

1 .

2.

3.

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13.

14.

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16.

\I18.

Smith, M. Reduction Techniques and Applications in Organic Synthesis;

Augustine, R. L., Ed.; Dekker: New York, 1968; pp 95-170.

(a) Wislecenus, H.; Kaufmann, L. CB 1895, 28, 1323. (b) Corey, E. J.;

Chaykovsky, M. JACS 1 96 5,8 7, 1345. (c) Calder, A,; Forrester, A. R.;

Hepburn, S. P. OS 1972,52 ,77 .

(a) Ghatak, U .; Saha, N. N.; Dutta, P. C. JACS 1957, 79, 4487. (b)

Tankard, M. H.; Whitehurst, J. S. JCS(P1) 1973, 615. (c) Stahly, G.

P.; Jackson, A. JO C 1991,56 ,5472.

Tamura, M.; Harada, K. BCJ 1980,53,561.

(a) Miller, R. E.; Nord F. F. JO C 1951, 16, 1380. (b) Mladenov, I. ;

Boeva, R. ; Aleksiev, D.; Lyubcheva, M. God. Vissh. Khim.-Tekhnol. Inst.,

Burgas, Bulg. 1977/1978,2,25; CA 1979.90, 137 409t.

(a) Crombie, L.; Hancock, J. E. H.; Linstead, R. P. JC S 1953, 3496. (b)

Leraux, Y. CR(C) 1971 ,273, 178.

Hulce, M.; LaVaute, T. TL 1988,29, 525.

Ray, J. N.; Mukherji, A .; Gupta, N. D. JI C 1961,38, 705.

Nguyen, D. A ,; Cerutti, E. BSF(2) 1976,596

Luzzio, F. A.; O’Hara, L. C. SC 1990,20 ,3223.

(a) Schreibmann, A. A. P. TL 1970, 4271. (b) Stocker, J. H.; Walsh, D.

J. JO C 1979,44 ,3589.

(a) Bilger, C.; Demerseman, P.; Royer, R. JH C 1985,22 ,735. (b) P etti,

M. A .; She padd, T. J.; Barrans, Jr., R. E.; Dougherty, D. A. JACS 1988 ,

110,6825.

Atwell, G. J.; Re wcastle, G . W., Baguley, B. C.; Den ny, W. A. J M C 1987,

30, 664.

(a) Thies, H.; Schonenberger, H.; Bauer, K. H . AP 1960, 293, 67. (b )

Takeshima, T.; Murao ka, M.; Asaba, H.; Yokoyama, M. BCJ 1968,41 ,

506.

Meyers, A. I.; Durandetta, J. L. JO C 1975,40 ,2021.

Meyers, A. I.; Durandetta, J. L.; Munavu, R. JOC 1975,40 ,2025.

C q e [ , R . D , G.; Jose, F. L. ACS 1972,94 ,1021.

(a)Bastian, J.-M.; Jaunin,R . HCA 1963,46,1248.b)Bapat,J.B.;B\ack,D. St. C. AJ C 1968,21 ,2497.

19.

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(a) Berlin, K. D.; Clau nch, R. T.; Gaudy, E. T. JO C 1968,33, 3090. (b)

Hosmane, R. S . ;Lim, B. B. TL 1985,26,1915.(c) Muratake, H. ; Okabe,K.; Natsume, M. T 1991,40, 8545.

Gilchrist, T. L. ; Hughes, D. ; Wasson, R. TL 1987, 28, 1537.

(a)Boyer,J.H.;Alul,H. JACS1959,81,2136. b)Corey,E. J.;Andersen.N. H.; Carlson R. M.; Paust, J. ; Vedejs, E.; Vlattas, I. ; Winter, R. E. K.

JACS 1968, 90, 3 247. (c) Kraus, G. A,; Fraizer, K. TL 1978, 3195. (d )

Trost, B. M.; King, S . A.; Schm idt, T. JACS 1989,111,5902.Healey, K.; Calder, I. C. AJC 1979, 32, 1307.

(a) Shin, C.; Yonezawa, Y.; oshimura, J. CL 1976, 1095. (b) SmodiS,

J.; Zupet, R.; P etnc, A .; Stanovnik, B.; TiSler, M. H 1990, 30,393.

Inoi, T.; Gericke, P.; Horton, W. J. JO C 1962, 27,459 7.

Daniels, R. G.; Paquette, L. TL 1981,22, 1579.

Jain, S.; Suryawanshi, S. N.; Bhakuni, D. S. IJC(B) 1987,26,866.

Kennedy, R. M.; Abiko , A.; Masamune, S . TL 1988,29 ,447 .

Johnson, C. R. ; Penning, T. D. JACS 1986,108,5655.

Vandew alle, M.; Van der Eycken, J.; Opp olzer, W.; Vullioud, C. T1986,

42 ,4035.

Arai, Y.; Kawanami, S.; Koizumi, T. CL 1990, 1585.

(a) Schne ider, W. P.; Bundy, G.L., Lincoln, F.H. CC1973,254. (b) Corey,

E. J.; Ensley, H. E. JOC 1973, 38, 3187. (c) Narwid, T. A,; Blount, J.F.; Iacobelli, J. A.; Uskokovic, M. R. HC A 1974, 57, 781. (d) Hossain,A. M. M., Kirk, D. N .; Mitra, G. Steroids 1976, 27, 603. (e) Brough, P.

A.; Gallagher, T.; Thomas, P.; Wonnacott, S. ; Baker, R .; Abdul Malik,

K. M.; Hursthouse, M. B. CC 1992, 1087.

(a) Greene, A. E.; Teixeira, M. A.; Barreiro, E.; Cruz, A,; Crabbe. P.

JO C 1982,47 ,2553. b) Schneider, W. P.; Bundy, G. L., Linc oln, F. H. ;Daniels, E. G.; Pike, J. E. JACS 1977,99, 1222. (c) Danieli, R.; Martelli,

G.; Sp unta, G.; Rossini, S . ; Cainelli, G.; Panunzio, M. JO C 1983, 48,

123.

Corey, E. J.; Trybulski, E. J.; Melvin, L. S . ; Nicolaou, K. C.; Secrist. J.

A.; Lett, R.; Sheldrake, P. W.; Falck, J. R.; Brunelle, D. J.; Haslanger,

M. F.; Kim, S.; Yoo, S. JACS 1978,100,4618.

Solladie,G.; Hutt, J. JO C 1987, 52, 3560.

Mitchell, P. W. D. OPP 1990, 22, 534.

(a) Keck, G. .; Fleming, S . ;Nickell, D .; Weider, P. SC 1979,9 ,281 ,(b)

King, S. B.; Ganem, B. JACS 1991,113,5089.

(a) Mellor, J. M.; Sm ith, N . M . JCS(P1) 1984,2927. (b) Athnson, R. S . ;

Edwards, P. J.; Tho mson, G. A. CC 1992, 1256.

Corey, E. J.; Chaykovsky, M. JACS 19 64 ,86 , 1639.

Johnson, C. R. ACR 19 73, 6, 341.

(a) Stetter, H.; Hesse, R. M 1967,98 ,755 .(b) Fulmer, T. D.; Bryson, T.

A. JO C 1989,54 ,3496. c) He, X . S . ; Eliel, E. L.; T 1987,43 ,4979.

Ohtsuka, Y.; Sasahara, T.; Oishi, T. CPB 1982,30, 1106.

Cannon, J. R.; Chow , P. W.; Fuller, M. W.; Hamilton, B. H.; Metcalf, B.

W.; Power, A. J. AJC 1973,26 ,2257.

Cavicchioli, S . ;Savoia, D.; Trombini, C.; Umani-Ronchi, A. JO C 1984,

49, 1246.

Ohnuma, T.; Hata, N.; Fujiwara, H.; Ban, Y. JO C 1982,47, 4713.

Baldwin, J. E.; Adlington, R. M.; Codfrey, C. R. A,; Gollins, D. W.;

Smith, M. L.; Russel, A. T. SL 1993,51.

(a) Posner, G. H .; Mallam o, J. P.; Hulce, M.; Frye, L. L. JACS 1982,104,

4180. (b) Posner, G. H.; Hulce, M. TL 1984,25 ,379 . (c) Posner, G . H.;

Weitzberg, M.; Ha mill, T. G.; Asirvatham, E.; Cun -heng, H.; Clardy, J.

T 1986,42 ,2919.

(a) Mioskowski, C.; Solladie, G. T 1980, 36, 227. (b) Fujisawn, T.;

Fujimura, A,; Sato, T. BCJ 1988,61, 1273.

Pyne, S . G. JO C 1986,51 ,81 .

(a) Johnson,C. R.; Shan klin, J. R.; Kirchhoff, R. A. JACS 1973,95 ,646 2.

(b) Boys, M. L.; Collington, E. W.; Finch, H.; Swanson, S.; Whitehead,

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26 ALUMINUM HYDRIDE

52. Block, E.; 'Connor, J. JACS 1974,96, 929.

53. Komblum, N.; idmer, J. JACS 1978, 00,7086.

54. Arzeno, H. .; Kemp, D. S . S 1988,32.

Emmanuil I. Troyansky

Institute of Organic Chem istry, Russian Academ y of Sciences,

Moscow, Russia

Aluminum Hydridel

[ 784 2I-61 (M W 29.99)

(reducing agent for many functional groups; used in hydroalumi-nation of alkynes; allylic rearrangements)

Alternate Name: alane.Physical Data: colorless, nonvolatile solid in a highly poly-

merized state; mp 110°C (dec). X-ray data have also beenobtainede2

Solubility: sol TH F and ether; precipitates from ether after stand-

ing for approximately 30min depending upon method of prepa-ration.

Analysis o Reagent Purity: hydride concentration can be deter-mined by hydrolyzing aliquots and measuring the hydrogene v ~ l v e d . ~

Preparative Methods: can be prepared by treating an ether solu-tion of Lithium Aluminum Hydride with Aluminum Chloride(eq l ).4 This affords an ether solution of AlH3 after precipita-

tion of LiC1. Solutions have to be used im mediately otherw iseAlH3 precipitates as a white solid which consists of a poly-meric material with ether. The solvent can be removed and thesolid redissolved in T HE 5 Alternatively, TH F solutions can beprepared directly according to one of the reactions shown in

eqs 2-4.596

3 LiAlH4 + AIC13- A1H3 + 3 LiCl (1)

2 LiAlH4 + BeClz - AIH3 + LiBeH2C12 (2)

2 L i A I K + - AIH3 + Li2SO4 + 2 Hz (3)

2 LiAlH4 + ZnC12 - A1H3 + 2 LiCl + ZnHz (4)

Handling, Storage, and Precautions: solutions of AlH3 are not

spontaneously i ~~ f lam ma ble .~owever, since A1H3 has reac-tivity comparable to LiAlH4, one should follow similar han-dling and precautions as tho se exercised for LiAIH4. Solutions

of AIH3 are prepared in situ but are known to degrade after 3days, and long term storag e of solutions is not possible. Use in

a fume hood.

Functional Group Reductions. Reductions by alane takeplace primarily by a two-electron However, evi-

dence for a SET pathway exists.' AIH3 will reduce a wide va-riety of functional group^.^ These include aldehydes, ketones,

quinon es, carboxylic acids, anhydrides, acid chlorides, esters, and

~ ~~

lactones, from which the corresponding alcohol is the isolatedproduct. Amides, nitriles, oximes, and isocyanates are reducedto amines. Nitro compounds are inert to AlHs. Sulfides and sul-

fones are unreactive, but disulfides and sulfoxides can be reduced.Tosylates are also not reduced by AlH3.

The reduction of ketones with AlH3 has selectivity different

from other hydride reagents (eqs 5 and 6).'O The hydroxymethy-lation of ketones via a two-step procedure has also been accom-

plished (eq 7)." The conversion of a,P-unsaturated ketones toallylic alcohols can be carried out with very good selectivity us-

ing A1H3 (eq 8);" however, DIBAL is the reagent of choice for

this transformation (see Diisobutylaluminum Hydride).lZc

L i A l h trans:& = 1.9:1AIH3 7.3:l

LiA1H(O-t-Bu)3 0 : l O O

A I H ~ 91:9

1. NaH, EtOzCH

2. NaH, A1H3

t-Bu t-Bu

Carboxylic acids and esters are reduced more rapidly by A1H3

than by LiAlH4, whereas the converse is true for alkyl halides.As a result, acids and esters can be reduced in the presence ofhalides (eq 9). In addition, esters can be reduced in the presence

of nitro groups (eq 10).This stands in contrast to LiAlH4 in whichnitro groups are reduced. Acetals can also be reduced to the half

protected diol as illustrated in eq 11 I 3

Lists of Abbreviations and Journal Codes on Endpapers

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ALUMINUMHYDRIDE 27

In reductions of amides to amines there is a competition be-tween C-0 and C-N bond cleavage which depends upon the re-

action conditions. This complication do es not occu r with AIH3. Aquantitative yield of amine is ob tained with short reaction times.

Conjugated amides can be cleanly reduced to the allylic amine

(eq 121 .~

0

P h d Mq - h-NMeZ (12)

LiAlH4 0%

AlH3 94 %

Th e less basic AIH3 appears to be better than LiAlH4 for re-

ducing nitriles with relatively acidic a-hydrogens to amines, and

enolizable keto esters to diols (eq 13).6

Ph98%Ph

Th e reduction of p-lactams to azetidines can be accomplished

with A1H3 (eq 14),14while ring opening was observed with

LiAlH4. AlH3 can also convert enamines to the corresponding

alkenes (eq 15).15

R4 R3 R4 R3R4*R3 A ~ H ~ R 4 - 4 4 . R 3 '-

R'&Ao 63-81% R'

While alkyl halides are usually inert to AIH3, the reduction

of cyclopropyl halides to cyclopropanes (eq 16)16 and glycosylfluorides to tetrahydropyrans (eq 17)" are known.

Ph

Ph Ph

"'"T,IBnBnoq ,17)

OBn OBn

BnO'"' 90% BnO'"' "'OBn

Desulfurization of sultones is rapid and proceeds in good yieldwith AlH3 while LiAlH4 affords poor yields with long reaction

times (eq 18).18

Epoxide Ring Opening. With most epoxides, hydride attackoccurs at the least sterically hindered site to give the correspond-

ing alcohol (eq 19).19However, due to the electrophilic nature of

AlH3 compared to L i A l a , it is possible for ring opening to oc-

cur at the more hindered site. With phenyl substituted epoxides,

mechanistic studies have shown that attack at a benzylic carbe-nium ion or a 1,Zhydride shift followed by hydride attack gives

products with the same regiochemistry but with different stere-

ochemistry (eq 20).6320 he stereoselectivity of AlH3 mediatedepoxide openings has been studied in depth.21

Ph H

AlD3

1

A ~ D ~

(20)

Hydroalumination. Th e addition of AIH3 across a triple bondhas been show n to occur in propargylic systems.22When the reac-

tions are quenched with Zodine, A1H3 gives the 2-io do- (a-a lke ne

while LiAIH4 giv es the 3-iodo-(E)-alken e (eq 21 ). A1H3 can also

be used in conjunction w ith Titanium(ZV)Chloride to carry out a

react ion similar to a hy d r~ bo ra t i on .~ ~hus 1-hexene is converted

to hexane upon aqueous work-up or to the corresponding alco-hol upon exposure of the reaction intermediate to oxygen (eq 22).

Similar results w ere obtained with nonconjugated dienes.

1. AlH3

2. 12

fOH I *

1. LiAIH4

NaOMe2 . 12 -

60-75%

-

90%

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28 ALUMINUM ISOPROPOXIDE~

Allylic Rearrangements (SN~'). he S N ~ 'isplacement of agood leaving group to give the rearranged allylic system can becarried out with A1H3.24This reaction appears not to be sterically

demand ing as a variety of displacements are possible (eq 23).

P h T " h 3 *IH3 ~ p h a

P h p ; P h l php23)

E:Z = 2:31%

Ph 98 % Ph

Preparation of allenes from propargylic systems can also beaccomplished." Mo st systems show a preference for syn elim-ination; however, mesylates prefer an anti mode of elimination

(eq 24). This same procedure has been used to prepare fluoroal-lenes (eq 25).25

X A1H3 H H H) e P h - *=( >*=(ph (24)

H Ph

X = OH, OMS,Br syn anti

Dialkylaluminum hydrides also behave as hydroaluminationreagents (see Diisobutykduminum Hydride) and are more com-

monly used than AlH3.

Related Reagents. See Classes R-1, R-4, R-5, R-12, R-13,R-20, R-23, R-27, R-30 , and R-32, pages 1-10.

1.

2.

3.

4.

5.

6.

7.

8.

9.

(a) Gaylord, N. G. Reduction With Complex Metal Hydrides;

Interscienc e: New Y ork, 1956. (b) Semen enko, K. N.; Bulychev, B. M.;

Shevlyagina, E. A , RCR 1966, 35, 649. (c) Rerick, M. N. Reduction

TechniquesandApplica tions in Organic Synthesis,Augustine, R. L., Ed.;

Dekker: New York, 196 8. (d) Cucinella, S.;Mazzei, A .; Marconi, W.IC A

Rev. 1970.51 . (e) Walker, E. R. H. CSR 1976, 5, 23. (f)Brown, H. C.;Krishnarnurthy, S. T1 979, 35,56 7. (g) Hajos, A. Complex Hydn des and

Related Reducing Agents in Organic Synthesis; Elsevier: Amsterdam,1979. (h) Seyden-Penne, J. Reduction by the Alumino- and Borohydrides

in Organic Synthesis; VCH: New York, 1991.

Turley, J. W.; Ri m, H. W. ZC 1969, 8, 18.

Yoon, N. M.; B rown, H. C. JACS 1968,90 ,2927.

Finholt, A. E.; Bond, A. C .; Schlesinger,H. I. JACS 1947,69, 1199.

(a) Brown, H. C .; Yoon, N. M. JACS 1966 ,88, 1464. (b) Browner, E M.;

Matzek, N. E.; R eigler, P. E; Ri m, H. W.; Roberts, C. B.; Schmidt, D.L.; Snover, J. A.; Terada, K. JACS 1976,98,2450.

Ashby, E. C.; Sanders, J. R.; Claudy, P,; Sch warts, P. JACS 1973, 95,6485.

Laszlo, P.; Teston, M. JACS 1990, 112, 8751.

(a) Park, S.-U.;Chung, S.-K.; Newcornb, M. JO C 1987, 52, 3275. (b)Yarnataka, H.; H anafusa, T. JOC 1988,53 ,773 .

(a) Ashby, E. C.; Goel, A. B. TL 1981, 22, 4783. (b) Ashby, E. C.;

DePriest, R. N.; Pharn, T. N. 2" 1983, 24, 2825. (c) Ashby, E. C.;

10.

11 .12 .

13.

14 .

15.

16.

17 .

18 .

19 .

20.

21.

22.

23.

24 .

25 .

DePriest, R. N.; Goel, A. B.; Wenderoth, B.; Pharn, T. N. JOC 1984.49,3 545. (d) Ashby, E. C.; Pham, T. N. JOC 1986,51,3598. (e) Ashby.

E. C.; Pharn, T. N. TL 1987,28 ,3197.

(a) Ayres, D. C.; Sawdaye, R. JCS(P2)1967,58 1. (b) Ayres,D. C.; Kirk,D. N. ; Sawdaye, R. JCS(P2) 1970, 505. (c) Guyon, R.; Villa, P. BSF

1977, 145. (d) Guyon, R.; Villa, P. BS F 1977, 152. (e) Martinez, E. ;

Muchowski, J. M.; V elarde, E. JOC 1977,42, 1087.

Corey, E. J. ; Cane, D. JOC 1971,36,3070.(a) Jorgenson, M. J. TL 1962, 559. (b) Brown, H. C.; Hess, H. M. JOC1969,34 ,2206. (c) Wilson, K. E.; Seidner, R. T.; Masamune, S . CC1970,

213. (d) Dilling, W. L.; Plepys, R. A. JOC 1970,35,2971. (e ) Ashby, E.C.; Lin, J. J. TL 1976, 3865.

(a ) Danishefsky, S. ; Regan, J. TL 1981, 22, 3919. (b) Takano, S. ;

Akiyarna, M.; Sato, S.; Ogasawara, K. CL 1983, 1593. (c) Richter, W. J.JO C 1981,46 ,5119.

Jackson, M. B.; Mander, L. N. ; Spotsw ood, T. M. AJC 1983,36 ,779 .

Coulter, J. M. ; Lewis, J. W.; Lynch, P. P.T 1968,24,4489.

Muller, P. HCA 1974, 57 , 704.

Nicolaou, K. C. ; Dolle, R. E.; Chucholowski, A.; Ra ndal, J. L. CC1984,1153.

(a) Wolinsky, J.; Marhenke, R. L.; Eustace, E. J. JO C 1973, 38, 1428.

(b) Smith, M. B.; Wolinsky, J. JOC 1981,46, 101.Maruoka, K.; Saito, S.; Ooi, T.; Yarnarnoto, H. S L 1991, 255.

Lansbury, P. T.; Scharf, D. J.; Pattison, V.A. JO C 1967, 32, 1748.

Elsenbaumer, R. L .; Mosher, H. S.; Momson, J. D .; Tornaszewski, J. E.

JOC 1981,46 ,4034.

Corey, E. J.; Katzenellenbogen, J. A .; Posner, G. H . JACS 1967,89,4245.

Sato, F.; ato, S.; Kodama, H.; Sato, M. JOM 1977, 142, 71.

Claesson, A.; Olsson, L.4 . JACS 1979,101, 7302.

Castelhano, A.; Krantz, A. JACS 1987,109,3491.

Paul GalatsisUniversity of Guelph, Ontario, Canada

Aluminum Isopropoxide'

[555-31-71 C 9 H 2 1A103 (M W 204.25)

(mild reagent for Meenvein-Po nndorf-Verley reduction;' Oppe-

nauer oxidation;13hydroly sis of oximes;16 earrang ement of epox-ides to allylic alcohol^;'^ regio- and chemoselective ring opening

of epoxides;20preparation of ethers21)

Alternate Name: triisopropoxyaluminum.Physical Data: mp 138-142 "C (99.99+%), 118 "C (98+%); bp

Solubility: sol benzene; less sol alcohols.Form Supplied in: white solid (99.99+% or 98+% p urity based on

Preparative Methods: see example below.

Handling, Storage, and Precautions: the dry solid is corrosive,moisture sensitive, flammable, and an irritant. Use in a fumehood.

140.5"C;d 1.035 g ~ m - ~ .

metals analysis).

NMR Analysis of Aluminum Isopropoxide. Evidence from

molecular weight determinations indicating that aluminum iso-

propox ide aged in benzene solution consists largely of the tetramer

Lists ofAbbreviations and Journal Codes on Endpapers

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ALUMINUM ISOPROPOXIDE 29

( l ) ,whereas freshly distilled molten material is trimeric (2),2 is

fully confirmed by NMR spe ctr o~ co py .~

RO I

Meerwein-Ponndorf-Verley Reduction. One use of the

reagent is for the reduction of carbonyl compounds, particularlyof unsaturated aldehyd es and ketones, for the reagent attacks only

carbonyl compoun ds. An example is the reduction of crotonalde-hyde to crotyl alcohol (eq l).' A mixture of 27 g of cleaned Alu- ,

minum foil, 300 mL of isopropan ol, and 0.5 g of Mercury(ZZ)Chloride is heated to boiling, 2mL of carbon tetrachloride isadded as catalyst, and heating is continued. The mixture turnsgray, and vigorous evolution of hydrogen begins. Refluxing is

continued until gas evolution has largely subsided (6-12 h). Thesolution, which is black from the presence of suspended solid,can be concentrated and the aluminum isopropoxide distilled invacuum (colorless liquid) or used as such. Thus the undistilled

solution prepared as described from 1.74 mol of aluminu m and

500mL of isopropano l is treated with 3 mol of croto naldehyd e

and 1L of isopropanol. On reflux at a bath temp erature of 110"C,

acetone slowly distills at 60-70 'C. After 8-9 h, when the distil-late no longer gives a test for acetone, most of the remaining iso-

propano l is distilled at reduced pressure and the residue is cooledand hydrolyzed with 6 N sulfuric acid to liberate crotyl alcoholfrom its aluminum derivative.

The Meerwein-Ponndorf-Verley reduction of the ketone (3)

involves formation of a cyclic coordination complex (4) which,

by hydro gen transfer, affords the mixed alkoxide (5 ) ,hydrolyzedto the alcohol (6) (eq 2).4 Further reflection suggests that underforcing conditions it might be possible to effect repetition of thehydrogen transfer and produce the hydrocarbon (7). Trial indeed

shows that reduction of diary1 ketones can be effected efficientlyby heating w ith excess reagent at 25 0 "C (eq 3).'

A study6of this reduction of mono- and bicyclic ketones shows

that, contrary to commonly held views, the reduction proceedsat a relatively high rate. The reduction of cyclohexanone and of

2-methylcyclohexanone is imm easurably rapid. Even menthoneis reduced alm ost completely in 2 h. The stereochem istry of thereduction of 3-isothujone (8) and of 3-thujone (11) has been ex-amined (eqs 4 and 5). The ketone (8) produces a preponderanceof the cis-alcohol (9).The stereoselectivity is less pronounced in

the case of 3-thujone ( l l ) , lthough again the cis-alcohol (12)predominates. The preponderance of the cis-alcohols can be in-creased by decreasing the concentration of ketone and alkoxide.

L -I

& l(O-l-Pr)3,250 OC

95 %

75 %

92%

anthraquinone * anthracene

anthrone - anthracene

This reducing agent is the reagent of choice for reductionof enones of type (14) to the qj3-unsaturated alcohols (15)

(eq 6). Usual reducing agen ts favor 1,4-reductio n to the saturatedalcohol.'

& Al(O-i-R) j* &5Hll6 )

%HI1BPCO BPCO

0 OH

(14)BP C = biphenylcarbonyl

(15)20%, each isomel

The Meerwein-Ponndorf-Verley reduction of pyrimid in-2( lH)-ones using Zirconium Tetraisopropoxide or aluminum iso-propoxide leads to exclusive formation of the 3,4-dihydro iso-

mer (eq 7).* The former reducing agent is found to be more

effective.

Zr(O-i-Pr)4 or Al(O-i-Pr)s

i-PrOH, 90 OC 2 days20-9 1%

17Bn

*

BnO I

R = H, halide

Reductions with Chiral Aluminum Alkoxides. The re-duction of cyclohexyl methyl ketone with catalytic amounts

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30 ALUMINUM ISOPROPOXIDE

of aluminum alkoxide and excess chiral alcohol gives (S)-1-

cyclohexylethanol in 22% ee (eq 8).9

I 22%ee

Isobornyloxyaluminum dichloride is a good reagent for reduc-ing ketones to alcohols. The reduction is irreversible and subject

to marked steric approach control (eq 9).1°

Diastereoselective Reductions of Chiral Acetals. Recently,it has been reported that Pentufluorophenol is an effective accel-

erator for Meenvein-Ponndorf-Verley reduction." Reduction of4-t-butylcyclohexanone with aluminum isopropoxide(3 equiv) in

dichlorom ethane, for example, is very slow at 0 "C(4%ield for5 h), but in the presence of pentafluorophen ol(1 equiv), the reduc-

tion is cleanly completed within 4 h at 0 "C (eq 10).The questionof why th is reagent retains sufficient nucleophilicity is still open.

It is possible that the o-halo substituents of the phenoxide lig-and may coordinate with the aluminum atom, thus increasing thenucleophilicity of the reagent.

Al(O-i-Pr)3 (3 equiv)C6F50H (1 equiv)

CH2C12,O 'C

t-Bu t-BU

Chiral acetals derived from (-)-(2R,4R)-2,4-Pentanediolndketone are reductively cleaved with high diastereoselectivity by a1 :2mixture of diethylaluminum fluoride and pentafluorophenol."Furthermore, aluminum pentafluorophenoxide is a very power-ful Lewis acid catalyst for the present reaction.12 The reduc-

tive cleavage in the presence of 5mol % of Al(OC6F5)3 af-fords stereoselectively retentive reduced p-alkoxy ketones. Thereaction is an intramolecu lar Meenvein-Ponndorf-Verley reduc-

tive and Oppenauer oxidative reaction on an acetal template

(eq 11).

EtzAlF-2C6FsOH(1.2 equiv)

R1>R2

The direct formation of a,P-alkoxy ketones is quite useful.

Removal of the chiral auxiliary, followed by base-catalyzed p-

elimination of the resulting p-alko xy ketone, easily gives an opti-

cally pure alcoho l in good yield. Several examples of the reactionare summarized in Table 1,

Table 1 Reductive Cleavages of Acetals Using Al(OC6F& Catalyst

"'"'fll(OC6F5)3 02

( 5 mol %)

O x 0' R2 CH2C12 * R ' X R 2

R' R2 Yield (% ) Ratio(S :R)

C5Hii Mei-Bu Mei-Pr MePh MePh Etc-Hex Me

CH2 CH2

U

83 82:18

61 73:2790 94:671 >99:178 92:8

8 9 9 5 5

67 81:19(trans: is)

I

GBU

Althou gh the detailed mechanism is not yet clear, it is assumedthat an energetically stable tight ion-paired intermediate is gener-

ated by stereoselective coordination of Al(OC &)3 to one of theoxygens of the acetal; the hydrogen atom of the alkoxide is then

transferred as a hydride from the retentive direction to this depart-ing oxygen, which leads to the (S) onfiguration at the resulting

ether carbon, as described (eq 12).

R i Y o O FR*

I , ' L I

Oppenauer O xidation13. Cholestenone is prepared by oxida-

tion of cholesterol in toluene solution with aluminum isopropox-ide as catalyst and cyclohexanone as hydrogen acceptor (eq 13).14

AI(O-i-Pr)s

cyclohexanone

toluene

72-74%

0O

A formate, unlike an acetate, is easily oxidized and gives the

same product as the free alco h01 .l~ or oxidation of (16) o (17) he

Lists of Abbreviations and Journal C odes on Endpapers

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ALUMINUM ISOPROPOXIDE 31

combination of cyclohexanone and aluminum isopropoxide and a

hydrocarbon solvent isused: xylene (bp 14 0 "C at 760 mmHg) or

toluene (bp 1 1 1 "C at 76 0 mmHg) (eq 14).

Al(O-i-Pr)3

I cyclohexanone -xylene or toluene

86%

%,\OCOMe

(14)&16)

0

(17)

Hydrolysisof Oximes.16 Oximes can be converted into parentcarbonyl compounds by aluminum isopropoxide followed by acid

hydrolysis (2N HC l) (eq 15). Yields are generally high in the caseof ketones, but are lower for regeneration of aldehydes.

Rearrangement of Epoxides to Allylic Alcohols. The keystep in the synthesis of the sesquiterpene lactone sau ssurea lactone

(21) involved fragmentation of the epoxymesylate (U), btainedfrom a-santonin by several steps (eq 16)." When treated withaluminum isopropoxide in boiling toluene (N2.72 h), (18) s con-

verted mainly into (20). The minor product (19) is the only productwhen the fragmentation is quenched after 12 h. Other bases such

as potassium t-butoxide, LDA, and lithium diethylamide cannotbe used. Aluminum isopropoxide is effective probably because

aluminum has a marked affinity for oxygen and effects cleav-

age of the epoxide ring.Meenvein-Ponndorf-Verley reduction isprobably involved in one step.

MsO

5 steps

(19) 9% (20) 68%

a-Pi nen e oxide (22) rearranges to pinocarvenol(23) in the pres-

ence of 1mol % of aluminum isopropoxide at 100-120°C fo r1h.'* The ox ide (22) rearranges to pinanone (24) in the presenceof 5 mol % of the alkoxide at 140-170 "C for 2 h. Aluminum iso-

propoxide has been used to rearrange (23) to (24)2OO0C, 3 h ,

80%yield) (eq 17).19

8-22)

Al(O-i-h)s, 100 "C OH

(17)

Al(O-i-Pr)3, 150 "C 0

69%

(24)

Regio- and Chemoselective Ring Opening of Epo-xides. Functionalized epoxides are regioselectively opened us-ing trimethylsilyl azidelaluminum isopropoxide, giving 2-tri-

methylsiloxy azides by attack on the less substituted carbon

(eq 18)."

Me3SiN3 (1.5 equiv)

. "918)R g l(O-i-Pr)3 (0.1 equiv)

CHzC12 TMSO R259-93%

H O H

Preparation of Ethers. Ethers ROR' are prepared from alu-minum alkoxides, Al(OR)3, and alkyl halides, R'X. Thus EtCH-

MeO H is treated w ith Al, HgBr2, and Me1 in DM F to give EtCH-

MeOMe (eq 19).'l

DMF, reflux, 2 days

AI(OR)3 + R' X * RORI (19)

20-806

R, R' = alkyl; X = halide

Related Reagents. See Classes R-1, R-10, and R-12, pages1-10.

1 .

2.

3.

4.

5 .

6.

7.

8.

9.

10.

1 1 .

12.

Wilds, A. L. OR 1944,2 , 178.

Shiner, V. J.; Whittaker, D. ; Fernandez, V. P. JACS 1963,85,2318.

Worrall, I. J. J. Chern. Educ. 1969,46, 510.

Woodward, R. B.; Wendler, N. L.; Brutschy, F. J. JACS 1945, 67,

1425.

Hoffsommer, R. D .; Taub, D.; Wendler,N. L. C2(L) 1964,482.

Hach, V. JOC 1973,38,293.

Picker, D. H. ; Andersen, N. H.; Leovey, E. M. K. SC 1975,5, 451.

Hoseggen, T.; Rise, F.; Undheim, K. J CS ( P I ) 1986,849.

Doering, W. von E.; Young, R. W. JACS 1950,72,631.

Nasipuri, D.; Sarker,G. JZC 1967,44, 165.

Ishihara, K. ; Hanaki, N.; Yamarnoto, H. JACS 1991,123,7074.

Ishihara,K.; Hanaki,N .; Yarnamoto, H. SL 1993, 127;JACS, 1993,115,

10695.

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32 ALUMINUM ISOPROPOXIDE

13. Djerassi, C. OR 1951, 6,207 . 19. Schmidt,H. CB 1929,6 2, 104.

14. Eastham, J. F.;Teranishi, R. OSC 1963,4 , 192.

15. Ringold, H. J.; Loken, B.; Rosenkran z, G.; Sondheimer, F. JACS 1956,78, 816.

16. Sugden, J. K. CI(L)1972,680.

17. Ando, M.; Tajima, K.; Takase, K. CL 1978, 617.

18. Scheidl,F. S 1982, 728.

20. Emziane, M.; Lhoste, P.; Sinou, D. S 1988,541.

21. Lompa-Krzymien,L.; Leitch, L. C. Pol. J. Chem. 1 9 8 3 ,5 7 ,6 2 9 .

Kazuaki Ishihara & Hisashi YamamotoNagoya University, Japan

Lists ofAbbreviations and Journal Codeson Endpapers

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