Cerium-free Luche reduction directed by rehydrated alumina

Article abstract of DOI:10.1016/j.tet.2016.03.017

A 1,2-regioselective reduction of α,β-unsaturated ketones to their corresponding allylic alcohols is accomplished with NaBH₄ in the presence of acidic activated alumina rehydrated to the Brockmann II grade by adding 3 % w/w water. The substrate scope includes eight ketones reduced in high regio- and diastereoselectivity to their corresponding allylic alcohols. This is the first example of the strategy of systematically tuning the surface chemistry of alumina via partial rehydration in order to modulate selectivity in a reaction. Alumina is an appealing alternative to the common Luche reduction additive, CeCl₃, from the perspective of cost and procedural simplicity.

Full text of DOI:10.1016/j.tet.2016.03.017

Accepted Manuscript
Cerium-Free Luche Reduction Directed by Rehydrated Alumina
Ebenezer Jones-Mensah, Leslie A. Nickerson, Jackson L. Deobald, Hailey J. Knox,
Alyssa B. Ertel, Jakob Magolan
PII:
S0040-4020(16)30149-1
10.1016/j.tet.2016.03.017
TET 27557
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 January 2016
Revised Date: 2 March 2016
Accepted Date: 3 March 2016
Please cite this article as: Jones-Mensah E, Nickerson LA, Deobald JL, Knox HJ, Ertel AB, Magolan
J, Cerium-Free Luche Reduction Directed by Rehydrated Alumina, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.03.017.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Cerium-Free Luche Reduction Directed by Rehydrated Alumina
Ebenezer Jones-Mensah,‡ Leslie A. Nickerson,‡ Jackson L. Deobald, Hailey J. Knox, Alyssa B.
Ertel, Jakob Magolan*
Department of Chemistry, University of Idaho, Moscow, ID 83844-2343
Abstract: A 1,2-regioselective reduction of α,β-unsaturated ketones to their corresponding
allylic alcohols is accomplished with NaBH4 in the presence of acidic activated alumina
rehydrated to the Brockmann II grade by adding 3% w/w water. The substrate scope includes
eight ketones reduced in high regio- and diastereoselectivity to their corresponding allylic
alcohols. This is the first example of the strategy of systematically tuning the surface chemistry
of alumina via partial rehydration in order to modulate selectivity in a reaction. Alumina is an
appealing alternative to the common Luche reduction additive, CeCl3, from the perspective of
cost and procedural simplicity.
Key Words:
Alumina, Brockmann, Hydration, Selective Reduction, Unsaturated Ketones, Sodium
Borohydride
Graphical Abstract:
Page 1 of 14

ACCEPTED MANUSCRIPT
1. Introduction
Transition aluminas (γ-, δ-, κ-, χ-, and η-Al2O3), often broadly termed ‘activated’ aluminas, are
the products of thermal dehydration of various polymorphs of aluminum hydroxide Al(OH)3.1, 2
The structural and surface characteristics of transition aluminas have been extensively studied.3-6
With high-surface areas, Lewis acidic, Brønsted acidic, and basic surface sites, activated
aluminas have found use as catalysts and catalyst supports for both industrial processes1 and
laboratory-scale organic chemistry.7-13
In 1941 Brockmann and Schodder altered the chromatographic behavior of activated alumina by
adding water and equilibrating in a closed vessel at room temperature.14 The resulting
‘Brockmann Scale’ (numbered I-V and corresponding to approximately 0, 3, 6, 10, and 15 %
w/w water added to activated alumina) now serves as general terminology used to crudely
quantify and standardize the degree of dehydration/rehydration (or activation/deactivation) of
some activated aluminas.15 Activated aluminas are typically sold at the Brockmann I grade
which corresponds to a water content of 1-1.5 % as determined by Karl Fisher titration (or
Al2O3ꢀnH2O where n = 0.06 - 0.08).15
The apparent simplicity of Brockmann’s hydration scale is starkly contrasted by the complex and
multi-faceted relationships that exists between degree of hydration and the surface properties,
particularly Lewis acidity, of aluminas which continue to be elucidated.16 While a number of
chemo-, regio-, and stereoselective reactions at alumina surfaces have been reported,17-21 the
degree of hydration of aluminas has not been generally considered as a variable with a potential
impact on reaction selectivity.
Schuchardt and co-workers have published a series of reports describing the use of aqueous H2O2
in the presence of alumina to epoxidize olefins.22-25 The authors investigated the role of water in
the context of catalytic activity of alumina surfaces. They correlated the amount of water per
unit of surface area of alumina to the hydrophilicity of the alumina surfaces and concluded that
the epoxidations proceeded best with an optimal level of hydrophilicity that was high enough to
promote rapid interaction of the alumina surface with hydrogen peroxide but also low enough to
avoid impeding the approach of olefin substrates to the active sites.23
The concept of “wet alumina” (water added to commercially available alumina), has appeared
several times in synthetic literature primarily in the context oxidations of a variety of substrates
using chromium (VI) oxide,26-28 potassium peroxymonosulfate (Oxone®),29-32 and other
oxidants,33, 34 supported on wet alumina. As part of our broader efforts to develop heterogeneous
tools that reduce the environmental footprint, cost, and procedural complexity of synthesis,35, 36
we recently began looking closer at the rehydration of activated aluminas as practical strategy for
modulating reactivity and selectivity.
Wet alumina was first used to effect a synthetic transformation by Morinoto and co-workers in
1991.32 The authors described a Baeyer-Villiger Oxidation of several ketones in the presence of
Oxone and wet alumina in dichloromethane. The alumina was prepared by adding 20 % w/w
water to a commercial alumina followed by vigorous shaking. The word ‘wet’ did not imply the
presence of a slurry as the alumina remains a free-flowing powder after addition of water. As
Page 2 of 14

ACCEPTED MANUSCRIPT
the authors did not report whether studies were conducted that led them to choose 20 % as a
suitable amount of water, we decided to conduct a brief experiment of our own to investigate this
issue. The results of our study are illustrated in Figure 1. We used commercially available
acidic, activated alumina, Brockmann I grade, with water added in eight sequential increments
from 0 to 28 % w/w. These rehydrated aluminas were combined with Oxone, and 4-tert-
butylcyclohexanone in ethyl acetate and the mixtures stirred for eight hours at room temperature
followed by filtration and analysis of the crude reaction mixtures by 1H NMR. We found the
yield of the Baeyer-Villiger Oxidation product, γ-tert-butyl-ε-caprolactone, to be dependent on
the amount of water that been added to the alumina. The maximum NMR yield of 68 % was
observed with 16% w/w water. At 8 % water and below, we observed less than 5 % of the
lactone.
Figure 1. Effect of water content of alumina on the yield of the Bayer-Villiger Oxidation of 4-
tert-butylcyclohexanone with Oxone and wet alumina. (Product yields were determined via 1H
NMR with anisole used as an internal standard.)
We considered the above result to be a clear demonstration that the degree of rehydration of
alumina is a significant and potentially valuable variable in the context of new reaction
development whenever alumina is a support or catalyst. Consequently, we have begun an effort
to investigate new potential applications of rehydrated aluminas. As our first original
contribution in this area, herein we describe a simple and inexpensive process that employs
partially rehydrated activated acidic alumina (3% w/w water added; Brockmann II) to promote
the regioselective 1,2-reduction of α,β-unsaturated ketones with sodium borohydride (NaBH4) in
ethyl acetate (EtOAc).
Page 3 of 14

ACCEPTED MANUSCRIPT
Scheme 1. History of 1,2-Reductions of α,β-Unsaturated Ketones.
The Luche reduction of α,β-unsaturated ketones to allylic alcohols with NaBH4 in the presence
of stoichiometric CeCl3 in methanol was reported in 1978 (Scheme 1).37, 38 This mild protocol
was preferable to previous approaches with AlH3,39 DIBAL,40 or 9-BBN,41, 42 and has remained
the primary method of choice for more than thirty-five years with few others reported.43 In 2012,
Fuchter and co-workers, seeking alternatives to lanthanides and expanding upon work by
45
Utimoto,44 found that Ca(OTf)2 was a suitable substitute for CeCl3. In 2015, Nardi used
catalytic Er(OTf)3 to achieve selective reductions in 2-MeTHF (Scheme 1).46
Gemal and Luche attributed the 1,2-selectivity of their NaBH4/CeCl3/MeOH system to two
factors: 1) Brønsted acid coordination of MeOH (enhanced by CeCl3) to the enone, and 2) the
conversion of NaBH4 to NaB(OMe)nH4-n species more selective for 1,2-hydride delivery.38
Nardi’s recent protocol used an aprotic solvent (2-MeTHF) which could neither react with
NaBH4 nor engage in Brønsted-type coordination to the substrate, leaving Lewis Acid
coordination by Er(OTf)3 to the enone as the sole rationale for selectivity.46 One might consider
Er(OTf)3 to be ideally suited to predispose α,β-enones toward reaction with NaBH4 in a 1,2-
fashion. With these studies in mind we decided to investigate the strategy of ‘tuning’ alumina
acidity via rehydration in the context of NaBH4-mediated reduction of enones. Relative to all of
the previous strategies described above, we considered the use of NaBH4 paired with alumina to
be preferable in terms of cost, procedural simplicity, and environmental impact.
2. Results and discussion
We began by treating 2-cyclohexenone (1) with NaBH4 in the presence of a series of aluminas
(Table 1). A control reaction with NaBH4 in methanol in the absence of an additive resulted in a
1:1 mixture of alcohols 2 and 3 (entry 1) while Luche conditions gave exclusively the allylic
alcohol (2, entry 2). Treatment of 1 with NaBH4 (1 equiv.) in the presence of activated neutral
alumina Brockmann Grade I (Al2O3-neutral-B1, 1 g/mmol) in MeOH yielded primarily the
dimethylacetal of 1 (entry 3) in accordance with previous reports of alumina-mediated carbonyl
acetylations.47, 48 When a series of non-alcoholic solvents were evaluated, most were found to
yield an unfavorable ratio of 2 to 3. Ethyl acetate, which offered a 54:46 ratio in favor of the
allylic alcohol 2, was selected as a suitable solvent for further optimization of the alumina
additive (entry 4).
Table 1. Optimization of Alumina Additive for the Reduction of 2-Cyclohexenone.a
Page 4 of 14

ACCEPTED MANUSCRIPT
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
Additive
Solvent
MeOH
MeOH
2 : 3 b
50 : 50
> 20 : 1
n/a e
54 : 46
75 : 25
68 : 32
65 : 35
46 : 54
70 : 30
69 : 31
57 : 43
79 : 21
71 : 29
None
CeCl3
c
Al2O3-neutral-B1 d MeOH
Al2O3-neutral-B1 EtOAc
Al2O3-neutral-B2 EtOAc
Al2O3-neutral-B3 EtOAc
Al2O3-neutral-B4 EtOAc
Al2O3-basic-B1 EtOAc
Al2O3-basic-B2 EtOAc
Al2O3-basic-B3 EtOAc
Al2O3-acidic-B1 EtOAc
Al2O3-acidic-B2 EtOAc
Al2O3-acidic-B3 EtOAc
a. Reaction conditions for entries 3-13: 2-
cyclohexenone (1 mmol), NaBH4 (1 mmol),
alumina (1 g), solvent (5 mL), rt, 24 h. b. Ratio
determined using 1H NMR after filtration.
c. Luche conditions were employed (see ref. 38).
d.
Neutral, basic, and acidic Brockmann I
activated aluminas (Aldrich) were used as
purchased (B1) or pre-modified by addition of
water (B2-B4, see Experimental section). e. The
dimethyl acetal of 1 was the major reaction
product.
Brockmann II neutral activated alumina (Al2O3-neutral-B2) was prepared by adding 3% w/w
water to commercially available neutral activated alumina, briefly shaking, and allowing the
mixture to equilibrate at room temperature in a sealed vial overnight. The effect of this altered
alumina on the selectivity of the reduction was considerable yielding a product ratio 75:25 in
favor of 1,2-reduction (entry 4). When the alumina was further rehydrated to Brockmann III (6
% water added) and IV (10 % water added) the selectivity dropped to 68:32 and 65:35
respectively (entries 5 and 6). Commercial suppliers typically offer neutral, basic, acidic
versions of activated alumina. This terminology corresponds to the pH of a 5% aqueous
suspensions of the aluminas which is approximately 9.5, 7.5, and 4.5 for basic, neutral and acidic
aluminas respectively.15 Aluminas initially obtained by thermal activation of aluminum
hydroxide are ‘basic’ and are subsequently neutralized and acidified by acid treatment under
conditions which are proprietary with the degree of hydration remaining at Brockmann I for all
Page 5 of 14

ACCEPTED MANUSCRIPT
three commercially available acidities. We evaluated basic and acidic activated aluminas at the
Brockmann I, II, and III water content levels (entries 8-13). In all cases Brockmann II aluminas
(3% w/w water) gave a higher selectivity for 1,2-reduction than Brockmann I and III aluminas.
Overall, acidic activated Brockmann II alumina (Al2O3-acidic-B2, entry 12) gave the most
favorable 2 to 3 ratio of 79:21. Reaction workup in this study consisted of filtration, washing
with EtOAc, and removal of solvent. Analysis of the crude filtrate residues by 1H NMR showed
primarily compounds 2 and 3 with no major impurities evident. No evidence of boron
byproducts was observed via 11B NMR of the crude reaction mixture after filtration.
Furthermore, the mass of alumina recovered after filtration and drying was higher than the initial
mass suggesting presence of adsorbed boron species. Two other common amorphous solids,
silica gel (SiO2) and titania (TiO2), also resulted in inferior 1,2-selectivity relative to the
aluminas evaluated above.
Using the most effective alumina, Al2O3-acidic-B2, additional variables were optimized (Table
2). Increasing the amount of alumina from 1 to 3 grams per mmol of substrate corresponded to
enhancement of selectivity to 84:16 with no further improvement observed at 4 g/mmol (entries
1-4). The reaction rate increased substantially with the substrate consumed in 1 hour and a
small drop in selectivity when the amount of NaBH4 was doubled to 2 equiv. (entry 5). All of
the above reactions were performed as follows: a slurry of NaBH4 and alumina in ethyl acetate
was stirred for 10 minutes before addition of the cyclohexenone. When the NaBH4/alumina pre-
stirring time was increased from 10 minutes to 4 hours the reaction rate slowed and selectivity
fell to 59:41 (entry 6) while 8 hours of pre-stirring inhibited the reaction entirely (entry 7).
These two experiments were interpreted to indicate that under these reaction conditions, in the
absence of a substrate, NaBH4 is converted to species that are both less reactive and less 1,2-
selective toward the reduction of enones. Consequently, we altered the order of addition by
combining the substrate and alumina in EtOAc for ten minutes prior to addition of NaBH4. This
resulted in an increase of selectivity to 90:10 (entry 8). A sixty minute delay offered no
additional benefit (entry 9). Two acidic aluminas purchased from different suppliers (see
Supplementary Information) and rehydrated to Brockmann II offered comparable results to those
of our original activated alumina (entries 10-11). Finally, replacement of NaBH4 with
NaCNBH3 as the hydride source corresponded to a decrease in reaction rate and selectivity (entry
12) while NaBH(OAc)3 did not react with 2-cyclohexenone under these conditions resulting only
in recovery of unreacted substrate (entry 13).
Page 6 of 14

ACCEPTED MANUSCRIPT
Table 2. Optimization of Reduction in the presence of Al2O3-Acidic-B2.a
b
Entry
Al2O3
NaBH4
Order of Addition
Time (h) Ratio (A:B)c
(g/mmol) (equiv.)
1
2
3
4
5
6
7
8
1
2
3
4
3
3
3
3
1
1
1
1
2
2
2
2
2
2
2
2
2
Al2O3+ NaBH4 (10 min) then 1
Al2O3 + NaBH4 (10 min) then 1
Al2O3 + NaBH4 (10 min) then 1
Al2O3 + NaBH4 (10 min) then 1
Al2O3 + NaBH4 (10 min) then 1
Al2O3 + NaBH4 (4 h) then 1
24
24
24
24
1
18
24
1
79 : 21
77 : 23
84 : 16
84 : 16
80 : 20
59 :41
NRd
90 : 10
90 : 10
88 : 12
90 : 10
34 : 66
NR
Al2O3 + NaBH4 (8 h) then 1
Al2O3 + 1 (10 min) then NaBH4
Al2O3 + 1 (60 min) then NaBH4
Al2O3 + 1 (10 min) then NaBH4
Al2O3 + 1 (10 min) then NaBH4
Al2O3 + 1 (10 min) then NaCNBH3 24
Al2O3 + 1 (10 min) then
9
3
1
1
1
10
11
12
13
3 e
3 f
3
3
24
NaBH(OAc)3
a. Reaction conditions: cyclohexenone (1 mmol), alumina, NaBH4, EtOAc (10 mL), r.t. Workup:
filtration, washing with EtOAc, and removal of solvent; b. Al2O3-acidic-B2 prepared from:
aluminum oxide, activated, acidic, Brockmann I (Sigma-Aldrich #199966); c. Ratio determined via
1H NMR after filtration; d. No reaction observed.; e. Al2O3-acidic-B2 prepared from: aluminum
oxide, activated, acidic, Brockmann I (Alfa Aesar #11501); f. Al2O3-acidic-B2 prepared from:
aluminum oxide, activated, acidic, gamma (Strem Chemicals #93-1329);
The most favorable ratio of 1,2-reduction to 1,4-reduction of cyclohexenone was 90:10 (Table 2,
entry 8). Although this procedure constitutes a practically simple and inexpensive approach to
1,2-selective reduction of unsaturated ketones, it is inferior to the Luche conditions in terms of
selectivity in the case of 2-cyclohexenone (Table 1, entries 2).
The protocol was applied to seven additional α,β-unsaturated ketones as summarized in Table 3.
We were pleased to observe that in all cases the selectivity was higher than that of our initial
substrate with 4 of 8 enones reduced to their corresponding allylic alcohols with no 1,2-reduction
observed (i.e., >20:1 based on analysis of crude 1H NMR spectra prior to purification). The
reductions of 2-cyclohexenone, 3-octene-2-one, isophorone, and 3,5-dimethylcyclohexenone to
their corresponding allylic alcohols 2, 5, 8 and 13 yielded mixtures with saturated alcohols in
ratios of 90:10, 93:7, 97:3 and 95:5 respectively. In these cases the yields reported in Table 3
correspond to mixtures of alcohols. We found that acetone was preferable to EtOAc for washing
the alumina residue during filtration resulting in higher isolated yields which ranged from 64 to
Page 7 of 14

ACCEPTED MANUSCRIPT
93 %. Most of the reductions were complete in 1 or 2 hours with the exception of isophorone
which failed to react completely after 48 h. Alcohol 8 was obtained in just 64 % in addition to
some unreacted isophorone recovered. Allylic alcohols 9 and 10 were prepared in high
diastereomeric ratios.
Table 3. Substrate Scope for NaBH4/Al2O3-acidic-B2 Reduction of Enones.a
a. Reaction conditions: substrate (2 mmol), Al2O3-acidic-B2 (6.0 g), EtOAc (10 mL), r.t. 10 min,
then NaBH4 (4 mmol), r.t.; Workup via filtration with acetone wash; Ratios of A:B and
diastereomeric products were determined via 1H NMR prior to chromatography (see
Supplementary Information).
Regarding the mechanistic rationale for 1,2-selectivity in this reaction, based our observed
optimal order of addition of the reagents (see Table 2), we believe that the likely hydride source
in this process is NaBH4 rather than a hydroxyborohydride species analogous to the
methoxyborohydrides of the Luche reduction. The Al3+ surface sites of Al2O3 act as a Lewis
Acid to modulate the nature of electrophilicity of the substrate via coordination to the carbonyl
moiety. The surface electronic environment of Al2O3, and consequently degree of Lewis
Acidity, are strongly influenced by degree of hydration.16 The issue of why this particular level
of hydration of acidic alumina is optimal for 1,2-selectivity in this reaction remains an open
question. Indeed, delineating a mechanistic rationale for the observed selectivity under these
reaction conditions presents a daunting challenge that is complicated not only by the
heterogeneity of alumina but also by the low solubility of NaBH4 in ethyl acetate.
Page 8 of 14

ACCEPTED MANUSCRIPT
A few additional practical considerations are as follows. Spent alumina, which contains
adsorbed boron byproducts, could not be re-used effectively. The selectivity in the reduction of
2-cyclohexanone decreased from 90:10 to 64:36 (2:3) upon reuse of spent alumina and the ratio
continued to decrease with repeated use. The 1,2-reduction of 2-cyclopentenone, which is
acknowledged to be especially prone to undergo 1,4-additions,9 does not occur under these
conditions with only cyclopentanol formed. In the interest of familiarity to readers, we chose to
employ the Brockmann numbering system throughout this initial study, however, there is no
inherent reason for hydration corresponding to the arbitrary Brockmann I-V scale to be
distinguished from any other intermediate values. In this reaction, Brockmann 1.5 and 2.5
aluminas (corresponding to 1.5 and 4.5 % w/w water) did not offer any improvement in
selectivity over Brockmann II. Nonetheless, as we continue our work in this area we have
transitioned to a more systematic nomenclature that explicitly states the % water added, acidity
level, and alumina polymorph where available; for example γ-Al2O3-acidic+3%H2O.
From a practical perspective, given the ubiquity of activated aluminas in chemistry laboratories,
it is surprising that their ‘rehydration’ has remained unexplored in the context of reactivity and
selectivity in laboratory-scale organic synthesis. Interest is perhaps hampered by the proprietary
and opaque nature of the industrial production of aluminas. In addition, adsorbed substrates do
not interact with surface sites via consistent and well-defined transition states which would aid in
the rationalization and prediction of selectivity.
Furthermore, a methodology that relies on a well-defined degree of hydration of alumina must
address the fact that activated aluminas can adsorb water upon long term storage. This concern
can be resolved by adoption of a standard dehydration protocol such as heating under vacuum at
350-400 °C,49, 50 prior to re-hydrating. Future work from our lab will address this issue in depth.
Notably, the water content of alumina can be accurately measured via Karl Fischer titration.51
3. Summary and conclusions
In summary, we have demonstrated the selective reduction of α,β-unsaturated ketones in a 1,2-
fashion by NaBH4 in EtOAc in the presence of activated acidic Brockmann II aluminas (Al2O3-
acidic-B2) prepared simply by adding 3% water to the corresponding commercially available
Brockmann I alumina. Alumina is a potentially desirable replacement for CeCl3 and other
homogeneous Lewis Acids which are more expensive and more difficult to separate from
reaction products. In this case, eight substrates were reduced with selectivity for 1,2- over 1,4-
reduction ranging from 90:10 to >20:1.
More generally, with our disclosure of this reaction we hope to draw attention to rehydration of
activated alumina as a variable that may have a significant impact on reactivity and selectivity in
synthetic chemistry. Activated aluminas are already present in many organic laboratories where
they are used as chromatographic media and catalyst supports. They should also now be
considered surfaces with acid/base properties that can be finely tuned by simple addition of water
to impact reactivity and selectivity.
Page 9 of 14

ACCEPTED MANUSCRIPT
4. Experimental section
General experimental details
Infrared spectra were obtained on a Thermo Scientific Nicolet 380 FT-IR spectrometer as thin
films on ZnSe disks and peaks are reported in cm-1. 1H and 13C NMR experiments were
performed on a Bruker AVANCE 500 MHz instrument and samples were obtained in CDCl3
(referenced to 7.26 ppm for 1H and 77.16 ppm for 13C). Coupling constants (J) are in Hz. The
multiplicities of the signals are described using the following abbreviations: s = singlet, br s =
broad singlet, d = doublet, t = triplet, dd = doublet of doublets, dq = doublet of quartets, dsep =
doublet of septets; tt = triplet of triplets, m = multiplet, app = apparent. MALDI-HRMS of
compounds were recorded on a Q-TOF mass spectrometer. Reaction progress was monitored by
thin-layer chromatography on silica gel plates (60-F254), observed under UV light and plates
were stained using p-anisaldehyde. Column chromatography was performed using silica gel
(particle size 40-63µm). Ketone substrates were purchased from commercial suppliers
AKScientific, VWR, Aldrich, and used without further purification. Activated aluminas
(Brockmann I) were purchased from Sigma-Aldrich, Alfa-Aesar, and Strem Chemicals and were
rehydrated to Brockmann II, III, and IV levels as described below.
Procedure for rehydration of activated aluminas to Brockmann II, III, & IV grade.
Example: Activated acidic alumina Brockmann II (acidic-Al2O3-B2): To a 100 mL round
bottomed flask was added activated acidic alumina Brockmann I (10.0 g) and deionized H2O
(0.30 mL, 3.0 % w/w). The flask was capped tightly and shaken until visible clumps were
broken apart. The capped flask was allowed to sit at room temperature for a minimum of 12
hours before use. Analogous procedures were used to make Brockmann III aluminas using 0.60
mL (6.0 % w/w) of water and Brockmann IV aluminas using 1.0 mL (10 % w/w) of water. Note:
Note: The choice of 12 hours of equilibration time was based on directions reported in a
technical bulletin from Sigma Aldrich.15 Brockmann II-IV aluminas were generally prepared on
multi-gram scale and stored in a sealed vessels without any notable change in reactivity observed
over the course of several weeks of storage.
General procedure for 1,2-reduction of α,β-unsaturated ketones to allylic alcohols. To a
reaction vial equipped with a stir bar were added: activated acidic alumina Brockmann II (acidic-
Al2O3-B2, 6 g), EtOAc (10 ml), and the α,β-unsaturated ketone substrate (2 mmol). The vial was
capped and the mixture was stirred at room temperature for 10 minutes before NaBH4 (152 mg,
2.0 mmol) was added in one portion. The reaction vial was capped and the mixture was stirred at
room temperature and monitored by TLC and/or 1H NMR until complete disappearance of
starting material was observed. The reaction mixture was filtered through filter paper
(Whatman, 42 Ashless) and the solids washed with acetone (approximately 3 x 20 mL). The
filtrate was concentrated in vacuo and the residue purified via flash column chromatography on
silica gel (EtOAc/hexanes with gradient elution).
Characterization of allylic alcohols 2, 4-10
2-cyclohexenol (2): The general procedure was used with 2-cyclohexen-1-one (193.6 µL, 2.0
mmol). After 1 hour the reaction mixture was filtered and purified as described above to yield a
Page 10 of 14

ACCEPTED MANUSCRIPT
mixture of 2-cyclohexenol and cyclohexanol (90:10 ratio, 159 mg, 81% yield corresponding to
both alcohols); pale yellow oil; Rf = 0.36 (hexanes/EtOAc 70:30 v/v); 1H NMR (500 MHz,
CDCl3) δ 5.81 – 5.77 (m, 1H), 5.73 – 5.69 (m, 1H), 4.18 – 4.13 (m, 1H), 2.09 – 1.48 (m, 7H); 13C
NMR (125 MHz, CDCl3) δ 130.5, 130.1, 65.6, 32.1, 25.2, 19.1. This NMR data is consistent
with an authentic sample from Sigma Aldrich. cyclohexanol: 1H NMR δ 3.60 – 3.53 (m, 1H,
CHOH); this resonance was consistent with an authentic sample and was used to determine
product ratio.
1-(cyclohexen-1-yl) ethanol (4): The general procedure was used with 2-cyclohexen-1-one
(258.7 µL, 2.0 mmol). After 1 hour the reaction mixture was filtered and purified as described
above to yield 1-(cyclohexen-1-yl) ethanol (234 mg, 93% yield); colorless oil; Rf = 0.51
1
(hexanes/EtOAc 70:30 v/v); H NMR (500 MHz, CDCl3) δ 5.65 – 5.62 (m, 1H), 4.13 (q, J = 6.5
Hz, 1H), 2.03 – 1.92 (m, 4H), 1.77 (s, 1H), 1.66 – 1.50 (m, 4H), 1.22 (d, J = 6.5 Hz, 3H). 13C
NMR (125 MHz, CDCl3) δ 141.4, 121.5, 72.2, 25.0, 24.8, 22.8, 22.7, 21.6. This NMR data is
consistent with previously reported values.52
Oct-3-en-2-ol (5): The general procedure was used with 3-octen-2-one (296.9 µL, 2.0 mmol).
After 1 hour the reaction mixture was filtered and purified as described above to yield a mixture
of oct-3-en-2-ol and 2-octanol (93:7 ratio, 205 mg, 80% yield corresponding to both alcohols);
colorless oil; Rf = 0.66 (Hexanes/EtOAc 70:30 v/v); 1H NMR (500 MHz, CDCl3) δ 5.63 (dt, J =
15.4, 6.7 Hz, 1H), 5.54 – 5.48 (m, 1H), 4.28 – 4.22 (m, 1H), 2.02 (q, J = 7.4 Hz, 2H), 1.47 (br s,
1H), 1.37 – 1.28 (m, 4H), 1.21 (d, J = 6.3 Hz, 3H), 0.93 – 0.86 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 134.3, 131.3, 69.2, 31.9, 31.5, 23.6, 22.3, 14.0. This NMR data is consistent with
previously reported values.53 2-octanol: 1H NMR δ 3.82 – 3.75 (m, 1H, CHOH); this resonance
was consistent with an authentic sample and was used to determine product ratio.
4-methylpent-3-en-ol (6): The general procedure was used with mesityl oxide (228.79 µL, 2.0
mmol). After 1 hour the reaction mixture was filtered and purified as described above to yield 4-
methylpent-3-en-ol (144 mg, 72% yield); colorless liquid; Rf = 0.42 (Hexanes/EtOAc 70:30
v/v); 1H NMR (500 MHz, CDCl3) δ 5.21 (app dsep, J = 8.4, 1.4 Hz, 1H), 4.56 (dq, J = 8.5, 6.2
Hz, 1H), 1.71 (d, J = 1.4 Hz, 3H), 1.69 (d, J = 1.4 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H);13C NMR
(125 MHz, CDCl3) δ 134.4, 129.5, 65.0, 29.8, 25.8, 23.8, 18.2. This NMR data is consistent
with previously reported values.54
4-Phenyl-3-buten-2-ol (7): The general procedure was used with 4-phenyl-3-buten-2-one (292
mg, 2.0 mmol). After 48 hours, the reaction mixture was filtered and purified as described above
to yield 4-Phenyl-3-buten-2-ol (276 mg, 93% yield); colorless oil; Rf = 0.59 (Hexanes/EtOAc
1
70:30 v/v); H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 7.1 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.24
(t, J = 7.3 Hz, 1H), 6.57 (d, J = 15.9 Hz, 1H), 6.27 (dd, J = 15.9, 6.4 Hz, 1H), 4.50 (app pd, J =
6.3, 1.2 Hz, 1H), 1.56 (br s, 1H), 1.38 (d, J = 6.4 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 136.9,
133.7, 129.6, 128.7, 127.8, 126.6, 69.1, 23.6. This NMR data is consistent with previously
reported values.54
3,5,5-trimethylcyclohex-2-en-1-ol (8): The general procedure was used with isophorone (299
µL, 2.0 mmol). After 48 hours, the reaction mixture was filtered and purified as described above
Page 11 of 14

ACCEPTED MANUSCRIPT
to yield mixture of 3,5,5-trimethylcyclohex-2-en-1-ol and cis-3,3,5-trimethylcyclohexanol
(97:3 ratio; 179 mg, 64% yield corresponding to both alcohols); colorless oil; Rf = 0.45
(Hexanes/EtOAc 70:30 v/v); 1H NMR (500 MHz, CDCl3) δ 5.41 (dq, J = 2.5, 1.2 Hz, 1H), 4.24
– 4.18 (m, 1H), 1.87 – 1.79 (m, 1H), 1.78 – 1.71 (m, 1H), 1.66 (s, 3H), 1.62 – 1.56 (m, 1H), 1.21
(dd, J = 12.4, 9.0 Hz, 1H), 0.98 (s, 3H), 0.87 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 136.1,
123.8, 67.0, 45.4, 44.3, 31.3, 31.2, 26.4, 23.6. This NMR data is consistent with previously
1
reported values.52 cis-3,3,5-trimethylcyclohexanol: H NMR δ 3.78 – 3.71 (m, 1H, CHOH);
this resonance was consistent previously reported data and was used to determine product ratio.55
cis-3,5-dimethylcyclohex-2-enol (9): The general procedure was used with 3,5-
dimethylcyclohexenone (248 mg, 2.0 mmol). After 1 hour, the reaction mixture was filtered and
purified as described above to yield a mixture of cis-3,5-dimethylcyclohex-2-enol and three
minor byproducts: trans-3,5-dimethylcyclohex-2-enol (9A), 3,5-cis-dimethyl-1-cis-cyclohexanol
(9B), and 3,5-cis-dimethyl-1-trans-cyclohexanol (9C). (9 : 9A : 9B : 9C ratio of 100 : 5 : 4 : 1
see below; 214 mg, 85% yield corresponding to all four alcohols); colorless oil; Rf = 0.56
(Hexanes/EtOAc 70:30 v/v); cis-3,5-dimethylcyclohex-2-enol (11): 1H NMR (500 MHz,
CDCl3) δ 5.38 (dq, J = 2.3, 1.2 Hz, 1H), 4.30 – 4.23 (m, 1H), 2.04 – 1.99 (m, 1H), 1.90 (dd, J =
17.2, 4.7 Hz, 1H), 1.77 – 1.68 (m, 1H), 1.67 (d, J = 1.3 Hz, 3H), 1.64 – 1.56 (m, 1H), 1.08 – 0.99
(m, 1H), 0.98 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3,) δ 137.0, 125.6, 68.7, 41.6, 39.0,
28.4, 23.3, 22.0. trans-3,5-dimethylcyclohex-2-enol (9A): 1H NMR δ 4.18 (br s, 1H, CHOH);
3,5-cis-dimethyl-1-cis-cyclohexanol (9B): 1H NMR δ 3.60 (tt, J = 11.1, 4.3 Hz, 1H, CHOH);
3,5-cis-dimethyl-1-trans-cyclohexanol (9C): 1H NMR δ 4.13 – 4.10 (m, 1H, CHOH); The ratio
of unsaturated to saturated alcohols = 95:5 and the ratio of cis:trans allylic alcohol diastereomers
(9:9A) = 95:5. (See Supporting Information) The above NMR resonances are consistent with
previously reported data.56
Compound 10: The general procedure was used with spironolactone (209 mg, 0.5 mmol),
acidic-Al2O3-B2 (1.5 g), EtOAc (5 ml) and NaBH4 (38 mg, 1.0 mmol). After 2 hours the
reaction mixture was filtered and purified as described above to yield compound 10 (137 mg, 66
1
% yield); colorless oil; Rf = 0.7 (Hexanes/EtOAc 70:30 v/v); H NMR (500 MHz, CDCl3) δ 5.30
– 5.28 (m, 1H), 4.20 (dddd, J = 10.0, 6.0, 2.1, 2.1 Hz, 1H), 3.90 (app q, J = 3.7 Hz, 1H), 2.67
(dddd, J = 14.3, 4.0, 2.0 Hz, 1H), 2.57 – 2.41 (m, 2H), 2.39 – 2.30 (m, 1H), 2.32 (s, 3H), 2.23 –
2.16 (m, 1H), 2.09 (dd, J = 14.3, 2.7 Hz, 1H), 1.99 – 1.86 (m, 3H), 1.82 – 1.69 (m, 2H), 1.64 (br
s, 1H), 1.61 – 1.31 (m, 8H), 1.28 – 1.20 (m, 2H), 1.08 (s, 3H), 1.03 – 0.94 (m, 1H), 0.94 (s, 3H),
0.80 (td, J = 11.8, 4.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 194.9, 176.8, 142.1, 127.9, 95.9,
67.6, 50.0, 46.2, 46.1, 45.6, 39.4, 39.3, 37.5, 35.4, 35.3, 31.4, 31.4, 31.3, 29.4, 29.2, 22.5, 20.5,
19.2, 14.7; IR (cm-1): 3435, 2938, 1767, 1683, 1177; HRMS calculated for C24H34O4S (M+H)+
419.22506; found 419.2249. Stereochemistry at C-3 (β-epimer) was inferred via comparison of
1H NMR resonance C3-H to a similar compound.57 (See Supporting Information)
Acknowledgements
This work was made possible by support from the National Science Foundation (Grant #
1301506). L.N. received research support from an IDeA award from the NIGMS (Grant
Page 12 of 14

ACCEPTED MANUSCRIPT
#P20GM103408). We thank Dr. Alex Blumenfeld and Dr. Lee Deobald for NMR and HRMS
analyses respectively.
Supplementary Data
NMR spectra of 2, 4-10.
Corresponding Author
*jmagolan@uidaho.edu
Author Contributions
‡These authors contributed equally.
Notes: The authors declare no competing financial interests.
References and notes
1.
Hudson, K. L.; Misra, C.; Perrotta, A. J.; Wefers, K.; Williams, F. S., In Ullmann's
Encyclopedia of Industrial Chemistry, Wiley-VCH: Hoboken, NJ, 2003; pp 339-378.
Misra, C., Industrial Alumina Chemicals. American Chemical Society: Washington, DC, 1986.
Busca, G. Catal. Today 2014, 226,
2.
3.
4.
Levin, I.; Brandon, D. J. Am. Ceram. Soc. 1998, 81,
5.
Knözinger, H.; Ratnasamy, P. Cat. Rev. - Sci. Eng. 1978, 17,
Coster, D.; Blumenfeld, A.; Fripiat, J. J. Phys. Chem. 1994, 98,
Kabalka, G. W.; Pagni, R. M. Tetrahedron 1997, 53,
6.
7.
8.
Varma, R. S. Green Chem. 1999, 1,
9.
Posner, G. H. Angew. Chem. Int. Ed. 1978, 17,
10.
11.
12.
Posner, G. H.; Rogers, D. J. Am. Chem. Soc. 1977, 99,
Ballini, R.; Clemente, R. R.; Palmieri, A.; Petrini, M. Adv. Synth. Catal. 2006, 348,
Bartoli, G.; Bartolacci, M.; Giuliani, A.; Marcantoni, E.; Massaccesi, M.; Torregiani, E.
J. Org. Chem 2005, 70,
13.
14.
15.
Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A. Green Chem. 2005, 7,
Brockmann, H.; Schodder, H. Ber. 1941, 74,
Mineral Adsorbents, Filter Agents and Drying Agents (Aldrich Technical Information Bulletin AL-
143); Aldrich Chemical Co., Milwaukee, WI.
16.
Wischert, R.; Laurent, P.; Copéret, C.; Delbecq, F. o.; Sautet, P. J. Am. Chem. Soc. 2012,
134,
17.
18.
19.
20.
Sartori, G.; Ballini, R.; Bigi, F.; Bosica, G.; Maggi, R.; Righi, P. Chem. Rev. 2004, 104,
Maggi, R.; Ballini, R.; Sartori, G.; Sartorio, R. Tetrahedron Lett. 2004, 45,
Rosini, G.; Galarini, R.; Marotta, E.; Righi, P. J. Org. Chem 1990, 55,
Koreeda, M.; Ricca, D. J.; Luengo, J. I. J. Org. Chem 1988, 53,
Page 13 of 14

ACCEPTED MANUSCRIPT
21.
22.
Hudrlik, P. F.; Hudrlik, A. M.; Kulkarni, A. K. Tetrahedron Lett. 1985, 26,
van Vliet, M. C.; Mandelli, D.; Arends, I. W.; Schuchardt, U.; Sheldon, R. A. Green
Chem. 2001, 3,
23.
24.
25.
26.
Rinaldi, R.; Schuchardt, U. J. Catal. 2004, 227,
Rinaldi, R.; Sepulveda, J.; Schuchardt, U. Adv. Synth. Catal. 2004, 346,
Rinaldi, R.; Schuchardt, U. J. Catal. 2005, 236,
Heravi, M. M.; Ajami, D.; Shoar, R. H.; Sarmad, N.; Faridbod, F. Phosphorus Sulfur
Silicon Relat. Elem. 2004, 179,
27.
28.
29.
30.
Heravi, M. M.; Ajami, D.; Ghassemzadeh, M. Synth. Commun. 1999, 29,
Varma, R. S.; Saini, R. K. Tetrahedron Lett. 1998, 39,
Alavi Nikje, M. M.; Bigdeli, M. A. Phosphorus Sulfur Silicon Relat. Elem. 2004, 179,
Bigdeli, M. A.; Nikje, M. M. A.; Heravi, M. M. Phosphorus Sulfur Silicon Relat. Elem.
2002, 177,
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
Greenhalgh, R. P. Synlett 1992,
Hirano, M.; Oose, M.; Morimoto, T. Chem. Lett. 1991,
Ganguly, N. C.; De, P.; Sukai, A. K.; De, S. Synth. Commun. 2002, 32,
Caddick, S.; Murtagh, L.; Weaving, R. Tetrahedron 2000, 56,
Weires, N. A.; Boster, J.; Magolan, J. Eur. J. Org. Chem. 2012, 2012,
Karki, M.; Araujo, H. C.; Magolan, J. Synlett 2013, 24,
Luche, J. L. J. Am. Chem. Soc. 1978, 100,
Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103,
Brown, H. C.; Hess, H. M. J. Org. Chem. 1969, 34,
Wilson, K.; Seidner, R.; Masamune, S. J. Chem. Soc. D., Chem. Commun. 1970,
Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1975, 40,
Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1977, 42,
Cha, J. S.; Kwon, O. O.; Kwon, S. Y. Org Prep Proced Int 1996, 28,
Fujii, H.; Oshima, K.; Utimoto, K. Chem. Lett. 1991,
Forkel, N. V.; Henderson, D. A.; Fuchter, M. J. Green Chem. 2012, 14,
Nardi, M.; Sindona, G.; Costanzo, P.; Oliverio, M.; Procopio, A. Tetrahedron 2015, 71,
Moghaddam, F. M.; Sharifi, A. Synth. Commun. 1995, 25,
Kamitori, Y.; Hojo, M.; Masuda, R.; Yoshida, T. Tetrahedron Lett. 1985, 26,
Gaetano, K.; Pagni, R. M.; Kabalka, G. W.; Bridwell, P.; Walsh, E.; True, J.;
Underwood, M. J. Org. Chem. 1985, 50,
50.
51.
52.
53.
54.
Posner, G. H.; Rogers, D. Z.; Kinzig, C. M.; Gurria, G. M. Tetrahedron Lett. 1975, 16,
Bryant, W.; Mitchell Jr, J.; Smith, D. M.; Ashby, E. J. Am. Chem. Soc. 1941, 63,
Cho, B. T.; Kang, S. K.; Kim, M. S.; Ryu, S. R.; An, D. K. Tetrahedron 2006, 62,
Lu, Z.; Ma, S. J. Org. Chem. 2006, 71,
Hall, J. F.; Bourne, R. A.; Han, X.; Earley, J. H.; Poliakoff, M.; George, M. W. Green
Chem. 2013, 15,
55.
56.
57.
Alonso, F.; Riente, P.; Yus, M. Tetrahedron 2008, 64,
Chen, J.-X.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M. Tetrahedron 2000, 56,
Parr, M. K.; Zapp, J.; Becker, M.; Opfermann, G.; Bartz, U.; Schänzer, W. Steroids 2007,
72,
Page 14 of 14