ALUMINUM ISOPROPOXIDE 1
OR
Aluminum Isopropoxide1
OR
Al
RO
R
Al(O-i-Pr)3
RO
O OR
RO OR
Al
Al
RO
Al
O OR
RO OR
[555-31-7] C9H21AlO3 (MW 204.25)
R
RO
InChI = 1/3C3H7O.Al/c3*1-3(2)4;/h3*3H,1-2H3;/q3*-1;+3/ Al
RO Al Al OR
OR
O
rC9H21AlO3/c1-7(2)11-10(12-8(3)4)13-9(5)6/h7-9H,
RO OR
OR R
1-6H3
(1) (2)
InChIKey = SMZOGRDCAXLAAR-UYRFGFQLAJ
(mild reagent for Meerwein Ponndorf Verley reduction;1
Al(O-i-Pr)3
Oppenauer oxidation;13 hydrolysis of oximes;16 rearrangement
CHO + + O
OH
OH
60%
of epoxides to allylic alcohols;17 regio- and chemoselective ring
(1)
opening of epoxides;20 preparation of ethers21)
The Meerwein Ponndorf Verley reduction of the ketone (3)
Alternate Name: triisopropoxyaluminum.
ć% ć%
involves formation of a cyclic coordination complex (4) which,
Physical Data: mp 138 142 C (99.99+%), 118 C (98+%); bp
ć%
by hydrogen transfer, affords the mixed alkoxide (5), hydrolyzed
140.5 C; d 1.035 g cm-3.
to the alcohol (6) (eq 2).4 Further reflection suggests that under
Solubility: sol benzene; less sol alcohols.
forcing conditions it might be possible to effect repetition of the
Form Supplied in: white solid (99.99+% or 98+% purity based
hydrogen transfer and produce the hydrocarbon (7). Trial indeed
on metals analysis).
shows that reduction of diaryl ketones can be effected efficiently
Preparative Methods: see example below.
ć%
by heating with excess reagent at 250 C (eq 3).5
Handling, Storage, and Precautions: the dry solid is corrosive,
moisture sensitive, flammable, and an irritant. Use in a fume
hood.
O-i-Pr
O + 
O O
Al(O-i-Pr)3
Al
Ar
H
Ar Ar
Ar
Original Commentary
O-i-Pr
Kazuaki Ishihara & Hisashi Yamamoto (3)
(4)
Nagoya University, Nagoya, Japan
OH
O-i-Pr H+
NMR Analysis of Aluminum Isopropoxide. Evidence from Ar Ar
O O-i-Pr
Al
molecular weight determinations indicating that aluminum iso- (6)
Ar
H
(2)
250 °C
propoxide aged in benzene solution consists largely of the tetramer
Ar
(1), whereas freshly distilled molten material is trimeric (2),2 is
Ar Ar
fully confirmed by NMR spectroscopy.3
(5) (7)
Meerwein Ponndorf Verley Reduction. One use of the
reagent is for the reduction of carbonyl compounds, particularly
O
of unsaturated aldehydes and ketones, for the reagent attacks only
Al(O-i-Pr)3, 250 °C
carbonyl compounds. An example is the reduction of crotonalde-
(3)
95%
hyde to crotyl alcohol (eq 1).1 A mixture of 27 g of cleaned Alu-
minum foil, 300 mL of isopropanol, and 0.5 g of Mercury(II)
anthraquinone anthracene
75%
Chloride is heated to boiling, 2 mL of carbon tetrachloride is
added as catalyst, and heating is continued. The mixture turns anthrone anthracene
92%
gray, and vigorous evolution of hydrogen begins. Refluxing is
continued until gas evolution has largely subsided (6 12 h). The
solution, which is black from the presence of suspended solid,
A study6 of this reduction of mono- and bicyclic ketones shows
can be concentrated and the aluminum isopropoxide distilled in
that, contrary to commonly held views, the reduction proceeds
vacuum (colorless liquid) or used as such. Thus the undistilled
at a relatively high rate. The reduction of cyclohexanone and of
solution prepared as described from 1.74 mol of aluminum and
2-methylcyclohexanone is immeasurably rapid. Even menthone
500 mL of isopropanol is treated with 3 mol of crotonaldehyde
is reduced almost completely in 2 h. The stereochemistry of the
ć%
and1Lof isopropanol. On reflux at a bath temperature of 110 C,
reduction of 3-isothujone (8) and of 3-thujone (11) has been ex-
ć%
acetone slowly distills at 60 70 C. After 8 9 h, when the distil- amined (eqs 4 and 5). The ketone (8) produces a preponderance
late no longer gives a test for acetone, most of the remaining iso- of the cis-alcohol (9). The stereoselectivity is less pronounced in
propanol is distilled at reduced pressure and the residue is cooled
the case of 3-thujone (11), although again the cis-alcohol (12)
and hydrolyzed with 6 N sulfuric acid to liberate crotyl alcohol
predominates. The preponderance of the cis-alcohols can be in-
from its aluminum derivative.
creased by decreasing the concentration of ketone and alkoxide.
Avoid Skin Contact with All Reagents
2 ALUMINUM ISOPROPOXIDE
5 h), but in the presence of pentafluorophenol (1 equiv), the reduc-
+ (4)
ć%
tion is cleanly completed within4hat 0 C (eq 10). The question
i-Pr O i-Pr OH i-Pr OH
of why this reagent retains sufficient nucleophilicity is still open.
(8) (9) (10)
It is possible that the o-halo substituents of the phenoxide lig-
7:1
and may coordinate with the aluminum atom, thus increasing the
nucleophilicity of the reagent.
+ (5)
O OH
i-Pr O i-Pr OH i-Pr OH
Al(O-i-Pr)3 (3 equiv)
(11) (12) (13)
C6F5OH (1 equiv)
(10)
3.2:1
CH2Cl2, 0 °C
This reducing agent is the reagent of choice for reduction t-Bu t-Bu
of enones of type (14) to the Ä…,²-unsaturated alcohols (15)
Chiral acetals derived from (-)-(2R,4R)-2,4-Pentanediol and
(eq 6). Usual reducing agents favor 1,4-reduction to the saturated
ketone are reductively cleaved with high diastereoselectivity by a
alcohol.7
1:2 mixture of diethylaluminum fluoride and pentafluorophenol.11
O O
Furthermore, aluminum pentafluorophenoxide is a very powerful
O O
Lewis acid catalyst for the present reaction.12 The reductive cleav-
Al(O-i-Pr)3
(6) age in the presence of 5 mol % of Al(OC6F5)3 affords stereose-
C5H11 C5H11
lectively retentive reduced ²-alkoxy ketones. The reaction is an
BPCO BPCO
intramolecular Meerwein Ponndorf Verley reductive and Oppe-
O OH
nauer oxidative reaction on an acetal template (eq 11).
(14) (15)
20%, each isomer
BPC = biphenylcarbonyl
Et2AlF 2C6F5OH
(1.2 equiv)
O
or
The Meerwein Ponndorf Verley reduction of pyrimidin-
Al(OC6F5)3
O
2(1H)-ones using Zirconium Tetraisopropoxide or aluminum iso-
(5 mol %)
K2CO3
O O
propoxide leads to exclusive formation of the 3,4-dihydro isomer
R1 R2 CH2Cl2 or toluene R1 R2
(eq 7).8 The former reducing agent is found to be more effective.
OH
R1 > R2
R R
(11)
N Zr(O-i-Pr)4 or Al(O-i-Pr)3 HN R1 R2
(7)
The direct formation of Ä…,²-alkoxy ketones is quite useful.
i-PrOH, 90 °C, 2 days
O N O N
20 91% Removal of the chiral auxiliary, followed by base-catalyzed ²-
Bn Bn
elimination of the resulting ²-alkoxy ketone, easily gives an opti-
R = H, halide
cally pure alcohol in good yield. Several examples of the reaction
are summarized in Table 1.
Reductions with Chiral Aluminum Alkoxides. The re-
duction of cyclohexyl methyl ketone with catalytic amounts of
aluminum alkoxide and excess chiral alcohol gives (S)-1-cyclo-
Table 1 Reductive cleavages of acetals using Al(OC6F5)3 catalyst
hexylethanol in 22% ee (eq 8).9
O
O OH
Al(OC6F5)3
O
Al(OR)3
O O (5 mol %)
(8)
OH CH2Cl2 R1 R2
R1 R2
22% ee
Ratio
R1 R2 Yield (%) (S:R)
Isobornyloxyaluminum dichloride is a good reagent for reduc-
C5H11 83 82:18
Me
ing ketones to alcohols. The reduction is irreversible and subject
i-Bu 61 73:27
Me
to marked steric approach control (eq 9).10 i-Pr 90 94:6
Me
Ph 71 >
99:1
Me
Ph 78 92:8
Et
c-Hex 89 95:5
Me
O OH
OAlCl2
(9)
67 81:19
Ph Ph CH2 CH2
(trans:cis)
70% ee
t-Bu
Diastereoselective Reductions of Chiral Acetals. Recently,
it has been reported that Pentafluorophenol is an effective accel- Although the detailed mechanism is not yet clear, it is assumed
erator for Meerwein Ponndorf Verley reduction.11 Reduction of that an energetically stable tight ion-paired intermediate is gener-
4-t-butylcyclohexanone with aluminum isopropoxide (3 equiv) in ated by stereoselective coordination of Al(OC6F5)3 to one of the
ć%
dichloromethane, for example, is very slow at 0 C (<5% yield for oxygens of the acetal; the hydrogen atom of the alkoxide is then
A list of General Abbreviations appears on the front Endpapers
ALUMINUM ISOPROPOXIDE 3
transferred as a hydride from the retentive direction to this depart- (21) involved fragmentation of the epoxymesylate (18), obtained
ing oxygen, which leads to the (S) configuration at the resulting from Ä…-santonin by several steps (eq 16).17 When treated with
ether carbon, as described (eq 12). aluminum isopropoxide in boiling toluene (N2, 72 h), (18) is con-
verted mainly into (20). The minor product (19) is the only product
O
when the fragmentation is quenched after 12 h. Other bases such
R1 O
as potassium t-butoxide, LDA, and lithium diethylamide cannot
R2
be used. Aluminum isopropoxide is effective probably because
Al(OC6F5)3
aluminum has a marked affinity for oxygen and effects cleav-
age of the epoxide ring. Meerwein Ponndorf Verley reduction is
L
probably involved in one step.

L O H
rotation
Al
R1 O+ R1 O+
MsO
L O L

R2 Al
R2
L Al(O-i-Pr)3
L
O H 68%
O
R1 > R2
L = OC6F5 O
H (18)
R1 O
(12)
MsO
R2 O
5 steps
+
HO
Oppenauer Oxidation.13 Cholestenone is prepared by oxida-
H H
O
HO
tion of cholesterol in toluene solution with aluminum isopropox-
HO O O-i-Pr
O
ide as catalyst and cyclohexanone as hydrogen acceptor (eq 13).14
(19) 9% (20) 68%
Al(O-i-Pr)3
(13)
(16)
cyclohexanone
HO H
O
toluene
O
72 74%
O
(21)
A formate, unlike an acetate, is easily oxidized and gives the
same product as the free alcohol.15 For oxidation of (16)to(17) the
Ä…-Pinene oxide (22) rearranges to pinocarvenol (23) in the pres-
combination of cyclohexanone and aluminum isopropoxide and a
ć%
ć%
ence of 1 mol % of aluminum isopropoxide at 100 120 C for
hydrocarbon solvent is used: xylene (bp 140 C at 760 mmHg) or
ć%
1h.18 The oxide (22) rearranges to pinanone (24) in the presence
toluene (bp 111 C at 760 mmHg) (eq 14).
ć%
of 5 mol % of the alkoxide at 140 170 C for 2 h. Aluminum iso-
COMe
ć%
propoxide has been used to rearrange (23) to (24) (200 C, 3 h,
OCOMe
Al(O-i-Pr)3
80% yield) (eq 17).19
cyclohexanone
O
xylene or toluene
86%
OH
Al(O-i-Pr)3, 100 °C
H O
COMe
~85%
(16) OCOMe
O
(14)
(23)
(17)
O
O
Al(O-i-Pr)3, 150 °C
(22)
(17)
69%
(24)
Hydrolysis of Oximes.16 Oximes can be converted into parent
carbonyl compounds by aluminum isopropoxide followed by acid
hydrolysis (2N HCl) (eq 15). Yields are generally high in the case
Regio- and Chemoselective Ring Opening of Epoxides.
of ketones, but are lower for regeneration of aldehydes.
Functionalized epoxides are regioselectively opened using
trimethylsilyl azide/aluminum isopropoxide, giving 2-trimethyl-
NOH O
1. Al(O-i-Pr)3
siloxy azides by attack on the less substituted carbon (eq 18).20
(15)
R1 R2 2. HCl, H2O R1 R2
Me3SiN3 (1.5 equiv)
R1 R2 Al(O-i-Pr)3 (0.1 equiv) R1 N3
(18)
Rearrangement of Epoxides to Allylic Alcohols. The key
CH2Cl2
H H
O TMSO R2
59 93%
step in the synthesis of the sesquiterpene lactone saussurea lactone
Avoid Skin Contact with All Reagents
4 ALUMINUM ISOPROPOXIDE
Preparation of Ethers. Ethers ROR are prepared from is more usually a trialkylaluminum than aluminum isopropoxide.
aluminum alkoxides, Al(OR)3, and alkyl halides, R X. Thus Complexes such as that derived from aluminum isopropoxide with
EtCHMeOH is treated with Al, HgBr2, and MeI in DMF to give 2 equiv of enantiomerically pure BINOL (29) catalyze the enan-
EtCHMeOMe (eq 19).21 tioselective reduction of aromatic ketones by borane-dimethyl
sulfide, through binding of both the borane and the ketone
DMF, reflux, 2 days
(eq 23).28
Al(OR)3 + R1X ROR1 (19)
20 80%
R, R1 = alkyl; X = halide H
O O
Al
O
O
OH
H
First Update
O
(29) (10 mol %)
Ph
BH3 · SMe2, CH2Cl2, 40 °C
David Crich Ph
96%, 74% ee
Wayne State University, Detroit, MI, USA
(23)
Meerwein Ponndorf Verley and Related Reductions. The
classic MPV reaction,22 for which computational support has now Aluminum BINOL complexes have also been used to promote
been advanced in support of the concerted six-membered cyclic the reduction of N-diphenylphosphinoyl ketimines to the corre-
transition state (eq 2),23 continues to be a major use of this reagent. sponding amines by isopropanol with excellent ee s. However,
For example, aluminum isopropoxide was found to be particularly again, the preferred catalyst precursor is trimethylaluminum.29
well suited to the reduction of the spirocyclic ketone 25, as no Diasteroselective reductive amination of Ä…-methylbenzylamine-
other reagents examined gave a useful amount of the ²-carbinol derived imines has also been achieved with hydrogen over a cata-
26 (eq 20).24 lyst combination of Raney nickel and aluminum isopropoxide, but
titanium tetra(isopropoxide) was the metal alkoxide of choice.30
H
O
OH
Al(O-i-Pr)3
Oppenauer Oxidation. Oppenauer oxidation of the mesy-
O O
(20)
i-PrOH, "
loxymethyl steroidal diol 30 took place with concomitant alu-
minum isopropoxide promoted dienolate alkylation, leading to
(25) (26)
the formation of a cyclopropa-derivative 31 (eq 24).31
70%, ² :Ä… = 85:15
OH
O
It was found that a complex 27, derived in situ from aluminum
isopropoxide and a chelating hydroxyl biphenylsulfonamide, was
Al(O-i-Pr)3
an effective catalyst for the reduction of acetophenone by iso-
cyclohexanone
propanol (eq 21).25
toluene, "
HO OMs
O-i-Pr O
Al
(30)(31)
(24)
O NSO2(CF2)7CF3
78%
OH
O
The Oppenauer oxidation has also been rendered catalytic
(27) (5 mol %)
through the use of electron-deficient aldehydes as hydride accep-
(21)
Ph
Ph
i-PrOH, CH2Cl2, rt
tors. Optimal yields were obtained with trimethylaluminum as
82%
catalyst, but the process also functioned in a respectable manner
with aluminum isopropoxide (eq 25).32
Reaction of aluminum isopropoxide with trifluoroacetic acid in
dichloromethane at room temperature affords a white solid for-
OH
O2N CHO
mulated as the salt 28, which is capable of reducing a wide range 10 mol % Al(O-i-Pr)3
O
+
of alkyl and aryl aldehydes and ketones at room temperature in
toluene, rt
dichloromethane (eq 22).26
(3 equiv)
73%
O
CH2OH
(25)
CF3CO2 Al(i-O-Pr)2
H
(28)
MeO
MeO
CH2Cl2, rt
OMe
Rearrangement of Epoxides to Allylic Alcohols and Open-
OMe (22)
ing of Lactones and Anhydrides. Treatment of the epoxylac-
97%
tone 32 with aluminum isopropoxide in toluene at reflux resulted
The catalytic asymmetric MPV reaction has been much exam- in cleavage to the allylic alcohol in tandem with nucleophilic open-
ined and recently reviewed,27 but the catalyst precursor of choice ing of the lactone (eq 26). The diastereomeric epoxylactone 33
A list of General Abbreviations appears on the front Endpapers
ALUMINUM ISOPROPOXIDE 5
did not suffer opening of the lactone under the same conditions 1. Wilds, A. L., Org. React. 1944, 2, 178.
(eq 27).33 2. Shiner, V. J.; Whittaker, D.; Fernandez, V. P., J. Am. Chem. Soc. 1963,
85, 2318.
3. Worrall, I. J., J. Chem. Educ. 1969, 46, 510.
OH
OH
O
O
4. Woodward, R. B.; Wendler, N. L.; Brutschy, F. J., J. Am. Chem. Soc.
Al(O-i-Pr)3
1945, 67, 1425.
CO2-i-Pr
O
toluene, "
5. Hoffsommer, R. D.; Taub, D.; Wendler, N. L., Chem. Ind. (London) 1964,
(26)
482.
(32)
66%
6. Hach, V., J. Org. Chem. 1973, 38, 293.
7. Picker, D. H.; Andersen, N. H.; Leovey, E. M. K., Synth. Commun. 1975,
5, 451.
O O 8. HÅ‚seggen, T.; Rise, F.; Undheim, K., J. Chem. Soc., Perkin Trans. 1 1986,
O
O
OH
Al(O-i-Pr)3 849.
(27)
O 9. Doering, W.; von, E.; Young, R. W., J. Am. Chem. Soc. 1950, 72,
toluene, "
631.
10. Nasipuri, D.; Sarker, G., J. Indian Chem. Soc. 1967, 44, 165.
(33)
66%
11. Ishihara, K.; Hanaki, N.; Yamamoto, H., J. Am. Chem. Soc. 1991, 113,
7074.
12. Ishihara, K.; Hanaki, N.; Yamamoto, H., Synlett 1993, 127; J. Am. Chem.
The meso-anhydride 34 undergoes highly enantioselective ring
Soc., 1993, 115, 10 695.
opening with aluminum isopropoxide and catalytic titanium TAD-
ć%
DOLate 35 at, -34 C in good yield, albeit very slowly (eq 28).34 13. Djerassi, C., Org. React. 1951, 6, 207.
14. Eastham, J. F.; Teranishi, R., Org. Synth., Coll. Vol 1963, 4, 192.
15. Ringold, H. J.; Löken, B.; Rosenkranz, G.; Sondheimer, F., J. Am. Chem.
Ar
Ar
Soc. 1956, 78, 816.
H
O
O
O-i-Pr
16. Sugden, J. K., Chem. Ind. (London) 1972, 680.
Ti
O-i-Pr 17. Ando, M.; Tajima, K.; Takase, K., Chem. Lett. 1978, 617.
O
O
H
18. Scheidl, F., Synthesis 1982, 728.
Ar Ar
O
(35) (Ar = ²-naphthyl) (20 mol %) CO2H 19. Schmidt, H., Chem. Ber. 1929, 62, 104.
CO2-i-Pr
O 20. Emziane, M.; Lhoste, P.; Sinou, D., Synthesis 1988, 541.
80 mol % Al(O-i-Pr)3, Et2O
O
 34 °C, 24 days
21. Lompa- Krzymien, L.; Leitch, L. C., Pol. J. Chem. 1983, 57, 629.
74%, 98:2 er
(34)
22. De Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J., Synthesis
(28)
1994, 1007.
23. Cohen, R.; Graves, C. R.; Nguyen, S. T.; Martin, J. M. L.; Ratner, M. A.,
J. Am. Chem. Soc. 2004, 126, 14796.
Ä…
Enantioselective Alkylation ofÄ…
Ä…-Ketoesters. The combi- 24. Paquette, L. A.; Owen, D. R.; Bibart, R. T.; Seekamp, C. K.; Kahane, A.
L.; Lanter, J. C.; Corral, M. A., J. Org. Chem. 2001, 66, 2828.
nation of a dipeptide-derived ligand and 15 mol % aluminum
25. Ooi, T.; Ichikawa, H.; Maruoka, K., Angew. Chem. Int. Ed. 2001, 40,
isopropoxide promotes the efficient enantioselective addition of
3610.
dimethyl and diethylzinc to alkyl, aryl, and Ä…,²-unsaturated Ä…-
26. (a) Akamanchi, K. G.; Varalakshmy, N. R., Tetrahedron Lett. 1995, 36,
ketoesters in good to excellent yield and ee. The ee s were gen-
3571. (b) Akamanchi, K. G.; Varalakshmy, N. R.; Chaudhari, B. A.,
erally higher in the presence of 50 mol % diethylphosphoramide,
Synlett 1997, 371.
which is thought to serve as an additional ligand to the intermedi-
ate organozinc reagent, and with aryl Ä…-ketoesters (eq 29).35 27. Graves, C. R.; Campbell, E. J.; Nguyen, S. T., Tetrahedron: Asymmetry
2005, 16, 3460.
28. Fu, I. -P.; Uang, B. -J., Tetrahedron: Asymmetry 2001, 12, 45.
MeO
29. Graves, C. R.; Scheidt, K. A.; Nguyen, S. T., Org. Lett. 2006, 8,
N-L-Thr(Trt)-L-(Thr(Trt)-NHBu
1229.
O
OH (15 mol %)
30. Nugent, T. C.; Ghosh, A. K.; Wakchaure, V. N.; Mohanty, R. R., Adv.
OMe
Et
10 equiv Me2Zn, 15 mol % Al(O-i-Pr)3 Synth. Catal. 2006, 348, 1289.
50 mol % (EtO)2P(=O)NH2, toluene,  78 °C
O 31. Deng, G.; Li, Z.; Peng, S. -Y.; Fang, L.; Li, Y. -C., Tetrahedron 2007,
63, 4630.
H
Me
32. Graves, C. R.; Zeng, B. -S.; Nguyen, S. T., J. Am. Chem. Soc. 2006, 128,
OMe
Et 12596.
33. Reizelman, A.; Zwanenburg, B., Synthesis 2000, 1952.
O
(29)
34. Jaeschke, G.; Seebach, D., J. Org. Chem. 1998, 63, 1190.
44%
35. Wieland, L. C.; Deng, H.; Snapper, M. L.; Hovedya, A. H., J. Am. Chem.
(98% conversion)
Soc. 2005, 127, 15453.
92% ee
Avoid Skin Contact with All Reagents