The Stereoselective Reductions of Ketones to the Most Thermodynamically Stable Alcohols Using Lithium and Hydrated Salts of Common Transition Metals

Article abstract of DOI:10.1021/acs.joc.5b01232

A simple method is presented for the highly stereoselective reductions of ketones to the most thermodynamically stable alcohols. In this procedure, the ketone is treated with lithium dispersion and either FeCl₂·4H₂O or CuCl₂·2H₂O in THF at room temperature. This protocol is applied to a large number and variety of ketones and is both more convenient and efficient than those commonly reported for the diastereoselective reduction of five- and six-membered cyclic ketones.

Full text of DOI:10.1021/acs.joc.5b01232

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The Stereoselective Reductions of Ketones to the Most Thermodynamically
Stable Alcohols Using Lithium and Hydrated Salts of Common Transition
Metals.
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Nicole Kennedy* and Theodore Cohen*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
nmk28@pitt.edu and cohen@pitt.edu
TABLE OF CONTENTS/ABSTRACT GRAPHIC
45 Examples, Up to 99% Yield,
Excellent Stereoselectivity,
Most Thermodynamically Stable Alcohol
ABSTRACT
A simple method is presented for the highly stereoselective reductions of ketones to the most
thermodynamically stable alcohols. In this procedure, the ketone is treated with lithium
dispersion and either FeCl2ꢀ4H2O or CuCl2ꢀ2H2O in THF at room temperature. This protocol is
applied to a large number and variety of ketones and is both more convenient and efficient than
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those commonly reported for the diastereoselective reduction of 5ꢀ and 6ꢀ membered cyclic
ketones.
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INTRODUCTION
One of the most widely used and valuable functional group transformations in synthetic organic
chemistry is the reduction of unsaturated substrates, specifically ketones in order to obtain the
corresponding alcohols. Interesting alternatives to the catalytic hydrogenation of ketones, which
employs high hydrogen pressure or hazardous reducing agents, include metalꢀmediated
reductions by electronꢀ or hydrideꢀtransfer.1 Most of the published results for the stereoselective
reduction of cyclic ketones consist of using metal hydrides or complex reducing agents.2 In
general, for 6ꢀmembered rings, bulky reducing agents favor the approach to the carbonyl group
via an equatorial trajectory, giving the thermodynamically less stable axial alcohol.3 Several
valuable protocols have been devised for the synthesis of the more stable equatorial alcohols;4
however, a simple, consistently high yielding method is unavailable.
We now present a new, simple and effective methodology to accomplish the
diastereoselective reduction of monoꢀ and polyꢀcyclic ketones under very mild conditions to
afford the thermodynamically more stable alcohol product. This method was developed during
our investigation of the remarkable protocol that was recently discovered by Yus and coꢀ
workers5 for the reduction of unsaturated groups. Their procedure makes use of the hydrates of
transition metal salts FeCl2ꢀ4H2O, NiCl2ꢀ2H2O, or CuCl2ꢀ2H2O in the presence of lithium metal
and catalytic amounts of p,p´ꢀdiꢀtertꢀbutyl biphenyl (DBB) (Scheme 1). The role of the latter
additive is thought to be that it picks up an electron from the Li to form an aromatic radicalꢀ
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anion, which then transfers the electron to another component of the solution, thus acting as an
electron transfer agent.
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Scheme 1. Yus’s reduction of carbonyl compounds. M = Cu, Ni or Fe, X = 2 or 4.
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50ꢀ93%
In a publication that will soon appear in The Journal of Organic Chemistry, we reveal
that the reductive lithiation of alkyl phenyl thioethers and chlorides, previously done only in the
presence of such aromatic electron transfer agents, surprisingly does not actually require the use
of such reagents when the Li is supplied in the form of a dispersion in mineral oil. This led us to
investigate whether or not the same is true of the ketone reductions performed by Yus1,6,7 in the
presence of the hydrates of transition metal salts. We restricted our studies to the commercially
available copper and iron salts, and did not examine the commercially unavailable8 and toxic
nickel salts. It turns out that in the reduction of ketones by this procedure, the aromatic electron
transfer agent is indeed not required. Furthermore, most surprisingly, in some important cases,
the reported diastereoselectivity is just the opposite in the presence of such agents.1 We have not
been able to reproduce some of these reported stereoselectivity results.
RESULTS AND DISCUSSION
Yus and coꢀworkers employ an 8:1 molar ratio of lithium sand to CuCl2ꢀ2H2O7 and an 8:1 molar
ratio of lithium powder to FeCl2ꢀ4H2O.1 There is no mention as to why they use different types
of lithium or what their lithium sources are. We were able to use a 4:1 molar ratio of lithium
dispersion, (25 wt% in mineral oil) containing 0.1% sodium, to CuCl2ꢀ2H2O and in the case of
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the more highly hydrated FeCl2ꢀ4H2O, a 6:1 molar ratio to achieve the diastereoselective
reduction of cyclic ketones in moderate to excellent yields. An important advantage of this
dispersion is that it can be weighed and transferred to the designated flask open to the air without
the lithium reacting. The mineral oil that coats the lithium metal can then be removed under
argon by rinsing with hexanes so that the lithium remains unreacted under argon until the solvent
and the substrate are added.
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In the reduction of 4ꢀtertꢀbutylcyclohexanone, 1, (Table 1, entries 1 and 3), in which the
bulky tertꢀbutyl group is locked in the equatorial position and is remote from the carbonyl
reaction center, the resulting product was the thermodynamically more stable equatorial alcohol,
transꢀ4ꢀtertꢀbutylcyclohexanol, 8.9 This result resembles those obtained with the most common
metal hydrides (LiAlH4, NaBH4, or LiBH4)10 or the complex reducing agents of Caubére’s
group.11 Lithium metal in liquid ammonia afforded only the trans isomer, although in a much
lower yield (57%).12 More recently, Cha and coꢀworkers performed the reduction of 1 with 1.1
equivalents of Alꢀmethanesulfonyldiisobutylalane (DIBAO3SCH3) at room temperature to obtain
99% (as determined by GC after 72 h.) of the more stable transꢀalcohol in a ratio of 94:6 eq/ax.4g
Their procedure not only requires the preparation of the DIBAO3SCH3 reagent but also a
significantly longer reaction time in order to achieve a diastereoselectivity that is similar to that
obtained in our present work. In our work, using the deuterated salt CuCl2ꢀ2D2O, prepared from
anhydrous CuCl2 and D2O, instead of the hydrated one, furnished the corresponding alcohol, 9,
deuterated at the 1ꢀposition (entry 2).
In the case of the more hindered ketone, 2ꢀmethylcyclohexanone, 2, (Table 1, entries 4
and 5), the thermodynamically more stable equatorial alcohol, transꢀ2ꢀmethylcyclohexanol, 10,
was produced after only 10 minutes. The crude alcohol was protected as a benzyl ether,13 11, in
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order to ease the isolation and purification of the product. The diastereoselectivity of 10
surpasses that observed with common reducing systems, such as LiAlH4, NaBH4, 9ꢀBBN,14 or
BH3ꢀTHF.1 The metalꢀammonia reduction of 2 affords nearly exclusive formation of the
equatorial alcohol; however, a significantly lower yield (63%) was collected after 100 min.4a In
the work by Cha et al., a longer reaction time, when compared to our procedure, was employed
in their reduction of 2 with Alꢀtrifluoromethanesulfonyldiisobutylalane (DIBAO3SCF3) to
produce 94% (as determined by GC after 1 h.) of the more stable transꢀalcohol in a ratio of 91:9
eq/ax.4h
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Interestingly, the reduction of (±)ꢀcamphor, 3, (Table 1, entries 6 and 7) required 2
equivalents of the metal (II) salts and a longer reaction time (24 h) leading to ratios of 96:4 and
95:5 of the more stable endoꢀborneol, 12, to exo. Yus reported that, for the same reaction time
and equivalents, the reduction of 3 yielded 55% of 12 (endo/exo 85:15) with CuCl2ꢀ2H2O and
62% of 12 (endo/exo 90:10) with FeCl2ꢀ4H2O.1 Thus, a higher yield and diastereoselectivity was
obtained under our conditions, that is, in the absence of an aromatic electron transfer reagent.
In the reduction of (ꢀ)ꢀmenthone, 4, (Table 1, entries 8 and 9) the alcohol that is so
favorably produced, (ꢀ)ꢀmenthol, 13, is capable of an allꢀequatorial configuration. Solodar and
coꢀworkers obtained less of 13, 74% (ꢀ)ꢀmenthol to 26% mixture of neoꢀ, isoꢀ, and neoisoꢀ
menthol, in their stereoselective reduction of 4 with 3 equivalents of lithium metal and 1
equivalent of water in ether at ambient temperature.15
When our methodology was applied to a mixture of cisꢀ and transꢀ1ꢀdecalone, 5, (Table
1, entries 10 and 11), the major diastereomeric product, (±)ꢀtrans,cisꢀdecahydroꢀ1ꢀnaphthol, 14a,
was that which would result from the reduction of pure transꢀ1ꢀdecalone, despite the starting
material containing a mixture of isomers. Presumably, the transꢀisomer of 5 reacts faster than the
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cisꢀisomer. The (±)ꢀcis,cisꢀdecahydroꢀ1ꢀnaphthol was not produced in either reduction reaction.
Houk and coꢀworkers observed only 60% of 14a after 24 h. by NaBH4 reduction of transꢀ1ꢀ
decalone.16 Alternatively, Yus et al. isolated the less thermodynamically stable axial alcohol, (±)ꢀ
trans, transꢀdecahydroꢀ1ꢀnaphthol, 14b, with their M(II)Cl2ꢀXH2OꢀLiꢀDBB reduction of transꢀ
1ꢀdecalone.1
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In the case of 3,3,5ꢀtrimethylcyclohexanone, 6, (Table 1, entries 12 and 13), a
significantly higher yield of the thermodynamically stable equatorial alcohol, cisꢀ3,3,5ꢀ
trimethylcyclohexanol, 15, was isolated with the FeCl2ꢀ4H2O in comparison to the CuCl2ꢀ2H2O.
Furthermore, 2 equiv of CuCl2ꢀ2H2O were required to reduce 6 to an isolable amount. More
recently, Cha and coꢀworkers performed the reduction of 6 with their DIBAO3SCF3 to obtain the
more stable cisꢀalcohol in a ratio of 98:2 eq/ax after 72 h,4h that is with less diastereoselectivity
than in our reduction after only 1 h.
Examination of the conformation of 3ꢀmethylcyclopentanone shows that the 3ꢀmethyl
group prefers to occupy a pseudoꢀequatorial position17 of an envelope conformation.18 Under our
conditions, the reduction of 3ꢀmethylcyclopentanone, 7, (Table 1, entries 14 and 15) led to 3ꢀ
methylcyclopentanol, in only 5 min., with an excess of the cisꢀisomer, 16a. The LiAlH4
reduction of 7 also provides a 60:40 cis to trans ratio of 3ꢀmethylcyclopentanol.19 Similar to the
case of 2, the reduction product was protected as a benzyl ether to afford 17.
TABLE 1. Stereoselective Reduction of Cyclic Ketones with either CuCl2ꢀ2H2O-Li(disp.) or FeCl2ꢀ4H2O-
Li(disp.).
Rxn.
Equiv Time
(h.)
Metal
(II)
Ketonea
Productb
%Yieldc
d.r.d
Entry
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1
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Cu
Cu
Fe
1.5
1.5
1.5
4
4
4
83
78e
77
99:1
1
1
8
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ꢀ
100:0
1
2
8
11
11
4
5
Cu
Fe
1.5
1.5
10 min.
10 min.
80f
99f
92:8g
95:5g
2
3
6
7
Cu
Fe
2
2
24
24
65
78
96:4
95:5
12
3
4
12
13
13
8
9
Cu
Fe
1.5
1.5
4
4
86
99
94:6
95:5
4
10
Cu
1.5
2
82
92:5:3i
5h
14a
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Fe
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94:4:2i
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5h
14a
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12
13
14
Cu
Fe
2
1.5
1j
1
1
26
70
63f
100:0
100:0
60:40k
6
6
7
15
Cu
5 min.
17
17
15
Fe
1l
5 min.
70f
60:40k
7
a
b
c
1.0 mmol scale. The structure of the major diastereoisomer is shown. Isolated yield after chromatography
d
1
e
purification. Diastereomeric ratio determined by HNMR. CuCl2ꢀ2D2O was used instead of CuCl2ꢀ2H2O,
Deuterium incorporation ≥ 85% (1HNMR). Isolated yields of benzylꢀether product. Diastereomeric ratio of transꢀ
f
g
h
2ꢀmethylcyclohexanol to cis. Commercially available unknown mixture of cis and trans from SigmaꢀAldrich.
iDiastereomeric ratio of (±)ꢀtrans, cisꢀ to (±)ꢀtrans, transꢀ20 to (±)ꢀcis, transꢀ21 decahydroꢀ1ꢀnaphthol determined by
1HNMR. 3:1 ratio of lithium dispersion to CuCl2ꢀ2H2O. Diastereomeric ratio of cisꢀ3ꢀmethylcyclopentanol to
j
k
trans. l5:1 ratio of lithium dispersion to FeCl2ꢀ4H2O.
In order to further assess the reduction capability of our method in the presence of
various functional groups, other than alkyl substituents, we have successfully reduced ketones
containing a trifluoromethyl group, a hydroxyl group, a methoxy group, and a tertiary amine
(Table 2). 3ꢀ(Trifluoromethyl)cyclohexanone, 18, was reduced to the more thermodynamically
stable cisꢀ3ꢀ(trifluoromethyl)cyclohexanol, 22, in excellent diastereoselectivity (Table 2, entries
1 and 2). The crude alcohol was protected as a benzyl ether, 23, in order to ease the isolation and
purification of the product. To the best of our knowledge, the only other reduction of 18 occurred
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with microorganisms, in which 18 was reduced with Streptomyces C53 in 94% in a ratio of 55:45
cisꢀ3ꢀ(trifluoromethyl)cyclohexanol to trans after 24 h.22
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The hindered steroidal ketone, 3αꢀhydroxyꢀ5αꢀandrostanꢀ17ꢀone, 19, was
diastereoselectively reduced to 5αꢀandrostaneꢀ3α,17βꢀdiol, 24 (Table 2, entries 3 and 4). The free
3αꢀhydroxy group did not affect the ketone reduction. Satoh and coꢀworkers23 indicated that the
reduction of 19 with NaBH4 alone is difficult; therefore, they employed a large excess of NaBH4
(10 equiv) and PdCl2 in their reduction of 19 to obtain 24 in 96% yield.
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The reduction of 4,4´ꢀdimethoxybenzophenone, 20, (Table 2, entries 5 and 6) yielded
bis(4ꢀmethoxyphenyl)methanol, 25, in moderate or good yield depending on whether the iron or
copper salt was employed. There have been many reports of biological reductions 24 and
asymmetric hydrogenations25 of 3ꢀquinuclidinone, 21, and/or the hydrochloride salt of 21. As
shown in Table 2 (entries 7 and 8), 21 was reduced to 3ꢀquininuclidinol, 26, in moderate yield
under our mild reduction conditions.
TABLE 2. Reduction of Ketones Containing Various Functional Groups with either CuCl2ꢀ2H2O-Li(disp.) or
FeCl2ꢀ4H2O-Li(disp.).
Rxn.
Time
(h.)
Metal
Ketonea
Productc
%Yieldd
d.r.e
Entry
(II)b
1
Cu
1
1
70f
95:5g
18
18
23
23
2
Fe
85f
97:3g
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3
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Cu
Fe
4
4
75
96
100:0
100:0
19
24
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19
20
24
25
5
6
Cu
Fe
2
2
83
60
ꢀ
ꢀ
20
21
21
25
26
26
7
8
Cu
Fe
24
24
65
65
ꢀ
ꢀ
a 1.0 mmol scale in THF at room temperature. 1.5 equiv CuCl2ꢀ2H2O or FeCl2ꢀ4H2O. The structure of the major
b
c
d
e
diastereoisomer is shown. Isolated yield after chromatography purification. Diastereomeric ratio determined by
1HNMR. f Isolated yields of benzylꢀether product. gDiastereomeric ratio of cisꢀ3ꢀ(trifluoromethyl)cyclohexanol to
trans.
Further experiments were performed on the reduction of 4ꢀtertꢀbutylcyclohexanone, 1, in
order to determine the effect of variables such as solvent, the presence or absence of the copper
salt, and the state of hydration (Table 3). When the solvent was changed from THF to hexanes,
the reduction of 1 with CuCl2ꢀ2H2O produced approximately a 30% lower yield of 8 (Table 3,
entry 2) presumably because, unlike THF, hexanes cannot complex the lithium metal or the
intermediate carbonyl radicalꢀanion. In the absence of a proton donor source from the hydrate of
the Cu (II) salt, as in entries 3 and 4, a considerably lower yield of 8 was isolated. Because some
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of the reduction product was observed in these cases, the carbonyl radicalꢀanion intermediate
most likely reacts with atmospheric moisture to form the alkoxy radical, which would then be
further reduced to an alkoxide ion.9 This is evident when both 1.1 equiv and a stoichiometric
amount of water were introduced into the reaction mixture and the yields of 8 increases (entries 5
and 6); however, these yields remain significantly lower than those achieved in the presence of
the metal (II) hydrate salts. When the reaction mixture was quenched with D2O, rather than
water, there was no change in the amount of 8. This further supports the fact that the hydrogen at
the 1ꢀposition of the reduction product alcohol indeed comes from the hydrate of the metal (II)
salt and not from the THF solvent.
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TABLE 3. Effects of Some Reaction Variables on the Stereoselective Reduction of 4-tert-Butylcyclohexanone.
Solventa % Yieldb
d.r.c
99:1
100:0
Entry
1
2
Additive
CuCl2ꢀ2H2O
CuCl2ꢀ2H2O
CuCl2
(anhydrous)
ꢀ
Water
(1.1 equiv)
Water
THF
Hexanes
83
54
3
4
5
THF
THF
THF
28
26
42
98:2
95:5
99:1
6
48
94:6
(2.2 equiv)
THF
a1.0 mmol scale. b Isolated yield after chromatography purification. c Diastereomeric ratio determined by 1HNMR.
In order to determine if commercially available granular lithium behaved in a manner
similar to that of lithium dispersion, the Li source was changed to granular lithium (0.5%
sodium), which presumably has less surface area due to the large chunks of granular metal. A
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slight excess of the granular lithium, in comparison to the amount of lithium dispersion, was
employed because the granular Li metal is not stored in mineral oil, therefore, can react with
moisture in the air upon transferring to the desired flask. Furthermore, a longer reaction time (24
h) was necessary to achieve the diastereoselective reduction of cyclic ketones in moderate to
excellent yields (Table 4). Thus, the increase in the surface area of the Li metal, from the
granular to the dispersion, apparently somewhat enhances the rate of electron transfer for the
reduction of ketones, despite the granular lithium having five times the amount of sodium
compared to the lithium dispersion.26 The diastereoselectivities remained the same as, or very
similar to, those observed with the lithium dispersion reduction conditions shown in Table 1. The
only major discrepancy in going from the dispersion to the granular was in the case of 6 (Table
4, entry 8), in which a significantly lower yield of 15 was isolated with the FeCl2ꢀ4H2O,
regardless of whether the equivalents of the Fe (II) salt employed was increased or decreased.
This result remains puzzling and perhaps a better understanding of the reduction mechanism
would provide an explanation.
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TABLE 4. Stereoselective Reduction of Cyclic Ketones with Granular Lithium and either CuCl2ꢀ2H2O or
FeCl2ꢀ4H2O.
Metal
Ketonea
Productb %Yieldc
d.r.d
Entry
Equiv
(II)
Cu
Fe
Cu
Fe
Cu
Fe
Cu
Fe
1
2
3
4
5
6
7
8
1.5
1.5
2
86
85
44
64
99
99
56
31
96:4
100:0
100:0
90:10
93:7
94:6
100:0
100:0
1
1
3
3
4
4
6
6
8
8
12
12
13
13
15
15
1
1.5
1.5
1.5
1.5
b
c
a1.0 mmol scale. The structure of the major diastereoisomer is shown. Isolated yield after chromatography
purification. d Diastereomeric ratio determined by 1HNMR.
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In a blank reaction, Yus and coꢀworkers attempted to reduce an alkyne, 1ꢀ
ethynylcyclohexanol, to the corresponding alkane in the absence of an arene electron carrier
catalyst and the yield of 1ꢀethylcyclohexanol decreased from 70% to less than 5%.27 It was thus
determined that the role of the arene was crucial for the reaction to proceed, and therefore, an
arene electron transfer catalyst, either naphthalene or DBB, has been included in Yus’s metal
reduction reaction conditions.1,5ꢀ7 In order to determine the significance of an arene electron
transfer catalyst in our work, 10 mol% of DBB was added to the CuCl2ꢀ2H2Oꢀgranular lithium
reduction of various substrates (Table 5). The ratio of the starting material (SM) to the product
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1
was determined by HNMR and compared to the ratio obtained from the reduction of the same
substrates in the absence of the DBB (Table 5). The reduction conditions were repeated with the
Fe (II) salt. As shown in Table 5, DBB did not affect the rate of the reduction or the
diastereoselectivity observed under either the CuCl2ꢀ2H2O or the FeCl2ꢀ4H2O reaction
conditions. Surprisingly, Yus et al. isolated the less thermodynamically stable alcohol, cisꢀ2ꢀ
methylcyclohexanol, with their M(II)Cl2ꢀXH2OꢀLiꢀDBB reduction of 2,1 which is the opposite
of what we observed in our reduction of 2 in the presence of a catalytic amount of DBB (Table 5,
entries 5 and 6). We are unable to explain this discrepancy.
TABLE 5. Stereoselective Reduction of Cyclic Ketones with Granular Lithium and either CuCl2ꢀ2H2O or
FeCl2ꢀ4H2O in Presence or Absence of DBB after 4 h.
Metal
(II)
Cu
Cu
Fe
Fe
Cu
Fe
Ratio SM/
Ketonea
Productb
d.rd
Entry
DBB
Productc
2:1
1
2
3
4
5
6
Yes
No
Yes
No
Yes
Yes
90:10
95:5
100:0
100:0
91:9
1
1
1
1
2
2
8
8
8
8
10
10
2:1
17:1
19:1
ꢀe
ꢀe
98:2
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Cu
Cu
Fe
Fe
Cu
Cu
Fe
Fe
Yes
No
Yes
No
Yes
No
Yes
No
12:1
8:1
9:1
14:1
4:1
1.5:1
7:1
100:0
100:0
100:0
100:0
96:4
94:6
97:3
97:3
4
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6
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2:1
b
c
a1.0 mmol scale in THF at room temperature. The structure of the major diastereoisomer is shown. Ratio
determined by 1HNMR. d Diastereomeric ratio determined by 1HNMR. d Ratio not provided because the reduction of
2 was not performed with granular lithium in the absence of DBB, therefore, the ratio would be ambiguous.
CONCLUSION
It was found that the reductions of monocyclic and bicyclic sixꢀmembered ring ketones using
lithium and either FeCl2ꢀ4H2O or CuCl2ꢀ2H2O in the presence of DBB, the system promulgated
by Yus and collaborators,1,7 is just as effective in the absence of the latter electron transfer agent
provided that the lithium is a dispersion in mineral oil or the commercially available granular
form. Under our very mild conditions, the reduction is highly stereoselective, affording the most
thermodynamically stable alcohol in moderate to excellent yields, even in the presence of various
functional groups. The procedure presented here is more efficient than the most commonly
reported reduction protocols due to the use of only commercially available reagents at room
temperature and a shorter reaction time in most cases. The source of the carbinol proton is the
hydrate of the transition metal salts. It is most surprising and inexplicable that in two important
cases, that of 2ꢀmethylcyclohexanone and transꢀ1ꢀdecalone, Yus et al. obtained the opposite
diastereoselectivity, that is the least thermodynamically stable alcohol products, under their
reduction conditions;1 although we have not been able to reproduce their results. The
FeCl2ꢀ4H2OꢀLi and CuCl2ꢀ2H2OꢀLi reducing systems developed here should become the default
protocol for the kind of ketone reductions studied here and should have significant mechanistic
implications.
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Since our laboratory will soon shut down, we hope that others will study the scope and
mechanism of this new fascinating reduction procedure.
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EXPERIMENTAL SECTION
General Information. All reactions were carried out under a positive pressure of dry argon gas
o
in ovenꢀdried (120 C) flasks and standard precautions against moisture were taken. An ice bath
was used to obtain 0 oC. Flash chromatography was performed with silica gel (32ꢀ63 µm). Thinꢀ
layer chromatography was performed on glass supported (0.25 mm) silica plates. Visualization
of TLC plates was accomplished with one or more of the following: 254 nm UV light; aqueous
solution of KMnO4; solution of pꢀanisaldehyde (PAA); iodine (I2). Commercial solvents and
reagents were used as received with the following exceptions: 3ꢀquinuclidinone was used after
neutralization of 3ꢀquinuclidinone hydrochloride, tetrahydrofuran (THF) was distilled over
sodium metal in the presence of benzophenone as indicator, and hexanes was freshly distilled
over CaH2. Lithium dispersion (25 wt% in mineral oil) was commercially available from Sigmaꢀ
Aldrich. Toward the end of the work described here, SigmaꢀAldrich discontinued offering
lithium dispersion; however, recipes for its preparation are available.28 Furthermore, granular
lithium, commercially available from SigmaꢀAldrich, is only slightly less effective than the
1
13
1
dispersion. H and C NMR spectra operating at 300 MHz or 400 MHz for H and 75 MHz for
13C at 22 oC unless otherwise noted. Chemical shift data are reported in units of δ (ppm) relative
to internal standard TMS (set to 0 ppm). Chemical shifts for 13C are referenced to the central
peak of CHCl3 triplet (set to 77.0 ppm). Multiplicities are given as s (singlet), d (doublet), t
(triplet), q (quartet), pent (pentet), m (multiplet), and br (broad). Coupling constants, J, are
reported in Hz.
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CuCl2ꢀ
2H2O and Lithium Dispersion Reduction (Table 1 and Table 2)
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A 25 mL roundꢀbottom flask was charged with 25 wt% lithium dispersion in mineral oil (82 mg,
3.0 mmol; 0.17 g, 6.0 mmol; or 0.22 g, 8.0 mmol). The lithium was washed three times with
hexanes (3 mL) and once with THF (3 mL). THF (3.5 mL) was added to the lithium and the
mixture was stirred at room temperature. Copper (II) chloride dihydrate (0.17 g, 1.0 mmol; 0.26
g, 1.5 mmol; or 0.34 g, 2.0 mmol) was added at once followed by the dropwise addition of a
solution of the ketone substrate (1.0 mmol) in THF (0.5 mL). The reaction mixture was stirred at
room temperature for the allotted amount of time (see Table) and then was cooled in an iceꢀwater
bath and quenched with water. The mixture was filtered through a celite pad and washed with
diethyl ether. The filtrate was further extracted with diethyl ether; the combined organic extracts
were dried over MgSO4 and concentrated in vacuo. Flash chromatography on silica gel
(EtOAc/hexanes) afforded pure product.
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FeCl2ꢀ4H2O and Lithium Dispersion Reduction (Table 1 and Table 2)
A 25 mL roundꢀbottom flask was charged with 25 wt% lithium dispersion in mineral oil (0.14 g,
5.0 mmol; 0.25 g, 9.0 mmol; or 0.33 g, 12 mmol). The lithium was washed three times with
hexanes (3 mL) and once with THF (3 mL). THF (3.5 mL) was added to the lithium and the
mixture was stirred at room temperature. Iron (II) chloride tetrahydrate (0.20 g, 1.0 mmol; 0.30
g, 1.5 mmol; or 0.40 g, 2.0 mmol) was added at once followed by the dropwise addition of a
solution of the ketone substrate (1.0 mmol) in THF (0.5 mL). The reaction mixture was stirred at
room temperature for the allotted amount of time (see Table) and then was cooled in an iceꢀwater
bath and quenched with water. The mixture was filtered through a celite pad and washed with
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diethyl ether. The filtrate was further extracted with diethyl ether; the combined organic extracts
were dried over MgSO4 and concentrated in vacuo. Flash chromatography on silica gel
(EtOAc/hexanes) afforded pure product.
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CuCl2ꢀ2H2O and Lithium Dispersion Reduction of 1 in Hexanes (Table 3, entry 2)
A 25 mL roundꢀbottom flask was charged with 25 wt% lithium dispersion in mineral oil (0.17 g,
6.0 mmol). The lithium was washed four times with hexanes (3 mL). Hexanes (3.5 mL) was
added to the lithium and the mixture was stirred at room temperature. Copper (II) chloride
dihydrate (0.20 g, 1.5 mmol) was added at once followed by the dropwise addition of a solution
of 4ꢀtertꢀbutylcyclohexanone, 1 (0.15 g, 1.0 mmol) in hexanes (0.5 mL). The reaction mixture
was stirred at room temperature for 4 h. and then was cooled in an iceꢀwater bath and quenched
with water. The mixture was filtered through a celite pad and washed with diethyl ether. The
filtrate was further extracted with diethyl ether; the combined organic extracts were dried over
MgSO4 and concentrated in vacuo. Flash chromatography on silica gel (EtOAc/hexanes)
afforded transꢀ4ꢀtertꢀbutylcyclohexanol, 8 (83 mg, 54% yield).
CuCl2 (anhydrous) and Lithium Dispersion Reduction of 1 in THF (Table 3, entry 3)
A 25 mL roundꢀbottom flask was charged with 25 wt% lithium dispersion in mineral oil (0.17 g,
6.0 mmol). The lithium was washed three times with hexanes (3 mL) and once with THF (3 mL).
THF (3.5 mL) was added to the lithium and the mixture was stirred at room temperature. Copper
(II) chloride anhydrous (0.20 g, 1.5 mmol) was added at once followed by the dropwise addition
of a solution of 4ꢀtertꢀbutylcyclohexanone, 1 (0.15 g, 1.0 mmol) in THF (0.5 mL). The reaction
mixture was stirred at room temperature for 4 h. and then was cooled in an iceꢀwater bath and
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quenched with water. The mixture was filtered through a celite pad and washed with diethyl
ether. The filtrate was further extracted with diethyl ether; the combined organic extracts were
dried over MgSO4 and concentrated in vacuo. Flash chromatography on silica gel
(EtOAc/hexanes) afforded 4ꢀtertꢀbutylcyclohexanol, 8 (44 mg, 28% yield) with a trans to cis
ratio of 98:2.
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Lithium Dispersion Reduction of 1 in THF (Table 3, entry 4)
A 25 mL roundꢀbottom flask was charged with 25 wt% lithium dispersion in mineral oil (67 mg,
2.4 mmol). The lithium was washed three times with hexanes (2 mL) and once with THF (2 mL).
THF (3.5 mL) was added to the lithium and the mixture was stirred at room temperature. A
solution of 4ꢀtertꢀbutylcyclohexanone, 1 (0.15 g, 1.0 mmol) in THF (0.5 mL) was added
dropwise and the reaction mixture was stirred at room temperature for 4 h. and then was cooled
in an iceꢀwater bath and was quenched with water. The mixture was extracted with diethyl ether;
the combined organic extracts were dried over MgSO4 and concentrated in vacuo. Flash
chromatography on silica gel (EtOAc/hexanes) afforded 4ꢀtertꢀbutylcyclohexanol, 8 (40 mg,
26% yield) with a trans to cis ratio of 95:5.
Lithium Dispersion Reduction of 1 in Wet THF (Table 3, entry 5)
A 25 mL roundꢀbottom flask was charged with 25 wt% lithium dispersion in mineral oil (0.11 g,
4.0 mmol). The lithium was washed three times with hexanes (3 mL) and once with nonꢀ
anhydrous THF (3 mL). Nonꢀanhydrous THF (3.5 mL) was added to the lithium and water (0.02
mL, 1.1 mmol) were added to the lithium and the mixture was stirred at room temperature. A
solution of 4ꢀtertꢀbutylcyclohexanone, 1 (0.15 g, 1.0 mmol) in nonꢀanhydrous THF (0.5 mL) was
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added dropwise and the reaction mixture was stirred at room temperature for 4 h. and then was
cooled in an iceꢀwater bath and quenched with water. The mixture was extracted with diethyl
ether; the combined organic extracts were dried over MgSO4 and concentrated in vacuo. Flash
chromatography on silica gel (EtOAc/hexanes) afforded 4ꢀtertꢀbutylcyclohexanol, 8 (65 mg,
42% yield) with a trans to cis ratio of 99:1.
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Lithium Dispersion Reduction of 1 in Wet THF (Table 3, entry 6)
A 25 mL roundꢀbottom flask was charged with 25 wt% lithium dispersion in mineral oil (0.14 g,
5.0 mmol). The lithium was washed three times with hexanes (3 mL) and once with nonꢀ
anhydrous THF (3 mL). Nonꢀanhydrous THF (3.5 mL) was added to the lithium and water (0.04
mL, 2.2 mmol) were added to the lithium and the mixture was stirred at room temperature. A
solution of 4ꢀtertꢀbutylcyclohexanone, 1 (0.15 g, 1.0 mmol) in nonꢀanhydrous THF (0.5 mL) was
added dropwise and the reaction mixture was stirred at room temperature for 4 h. and then was
cooled in an iceꢀwater bath and quenched with water. The mixture was extracted with diethyl
ether; the combined organic extracts were dried over MgSO4 and concentrated in vacuo. Flash
chromatography on silica gel (EtOAc/hexanes) afforded 4ꢀtertꢀbutylcyclohexanol, 8 (75 mg,
48% yield) with a trans to cis ratio of 94:6.
CuCl2ꢀ2H2O and Granular Lithium Reduction (Table 4)
A 25 mL roundꢀbottom flask was charged with granular lithium (63 mg, 9.0 mmol or 83 mg, 12
mmol). THF (3.5 mL) was added to the lithium and the mixture was stirred at room temperature.
Copper (II) chloride dihydrate (0.26 g, 1.5 mmol or 0.34 g, 2.0 mmol) was added at once
followed by the dropwise addition of a solution of the ketone substrate (1.0 mmol) in THF (0.5
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mL). The reaction mixture was stirred at room temperature for 24 h. and then was cooled in an
iceꢀwater bath and quenched with water. The mixture was filtered through a celite pad and
washed with diethyl ether. The filtrate was further extracted with diethyl ether; the combined
organic extracts were dried over MgSO4 and concentrated in vacuo. Flash chromatography on
silica gel (EtOAc/hexanes) afforded pure product.
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FeCl2ꢀ4H2O and Granular Lithium Reduction (Table 4)
A 25 mL roundꢀbottom flask was charged with granular lithium (56 mg, 8.0 mmol or 83 mg, 12
mmol). THF (3.5 mL) was added to the lithium and the mixture was stirred at room temperature.
Iron (II) chloride tetrahydrate (0.20 g, 1.0 mmol or 0.30 g, 1.5 mmol) was added at once
followed by the dropwise addition of a solution of the ketone substrate (1.0 mmol) in THF (0.5
mL). The reaction mixture was stirred at room temperature for 24 h. and then was cooled in an
iceꢀwater bath and quenched with water. The mixture was filtered through a celite pad and
washed with diethyl ether. The filtrate was further extracted with diethyl ether; the combined
organic extracts were dried over MgSO4 and concentrated in vacuo. Flash chromatography on
silica gel (EtOAc/hexanes) afforded pure product.
CuCl2ꢀ2H2O, DBB, and Granular Lithium Reduction (Table 5)
A 25 mL roundꢀbottom flask was charged with granular lithium (63 mg, 9.0 mmol). THF (3 mL)
was added to the lithium and the mixture was stirred at room temperature. Copper (II) chloride
dihydrate (0.26 g, 1.5 mmol) was added at once followed by a solution of DBB (27 mg, 0.10
mmol) in THF (0.5 mL). A solution of the ketone substrate (1.0 mmol) in THF (0.5 mL) was
added dropwise and the reaction mixture was stirred at room temperature for 4 h. and then was
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cooled in an iceꢀwater bath and quenched with water. The mixture was filtered through a celite
pad and washed with diethyl ether. The filtrate was further extracted with diethyl ether; the
combined organic extracts were dried over MgSO4 and concentrated in vacuo.
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FeCl2ꢀ4H2O, DBB, and Granular Lithium Reduction (Table 5)
A 25 mL roundꢀbottom flask was charged with granular lithium (83 mg, 12 mmol). THF (3 mL)
was added to the lithium and the mixture was stirred at room temperature. Iron (II) chloride
tetrahydrate (0.30 g, 1.5 mmol) was added at once followed by a solution of DBB (27 mg, 0.10
mmol) in THF (0.5 mL). A solution of the ketone substrate (1.0 mmol) in THF (0.5 mL) was
added dropwise and the reaction mixture was stirred at room temperature for 4 h. and then was
cooled in an iceꢀwater bath and quenched with water. The mixture was filtered through a celite
pad and washed with diethyl ether. The filtrate was further extracted with diethyl ether; the
combined organic extracts were dried over MgSO4 and concentrated in vacuo.
transꢀ4ꢀtertꢀbutylcyclohexanol 8.21
1
White solid (0.13 g, 83% yield). HNMR (CDCl3) δ (ppm): 3.52 (ddt, J = 6.3, 4.5, 4.2 Hz, 1H),
2.00 (d, J = 10.5 Hz, 2H), 1.78 (d, J = 10.2 Hz, 2H), 1.57 (br, 1H), 1.26ꢀ1.10 (m, 2H), 1.06ꢀ0.96
(m, 3H), 0.85 (s, 9H); 13CNMR (CDCl3) δ (ppm): 71.1, 47.1, 35.9, 32.2, 27.6, 25.5.
1ꢀdeuteroꢀ4ꢀtertꢀbutylcyclohexanꢀ1ꢀol 9.
A 25 mL roundꢀbottom flask was charged with 25 wt % lithium dispersion in mineral oil (0.17 g,
6.0 mmol). The lithium was washed three times with hexanes (3 mL) and once with THF (3 mL).
THF (3.5 mL) was added to the lithium and the mixture was stirred at room temperature.
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CuCl2ꢀ2D2O (prepared from anhydrous CuCl2 and D2O; 0.26 g, 1.5 mmol) was added at once
followed by the dropwise addition of a solution of 4ꢀtertꢀbutylcyclohexanone, 1 (0.15 g, 1.0
mmol) in THF (0.5 mL). The reaction mixture was stirred at room temperature for 4 h. and then
was cooled in an iceꢀwater bath and the reaction was quenched with water. The mixture was
filtered through a celite pad and washed with diethyl ether. The filtrate was further extracted with
diethyl ether; the extract was dried over MgSO4 and concentrated in vacuo. Flash
chromatography on silica gel (EtOAc/hexanes) afforded pure product 9 (0.12 g, 78% yield) as a
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1
white residue in a D to H ratio of 85:15. HNMR (CDCl3) δ (ppm): 2.15 (br, 1H), 1.96 (d, J =
12.0 Hz, 2H), 1.74 (d, J = 9.6 Hz, 2H), 1.22ꢀ1.14 (m, 2H), 1.06ꢀ0.92 (m, 3H), 0.81 (s, 9H);
13CNMR (CDCl3) δ (ppm): 71.0, 70.8, 70.6, 70.3, 47.1, 35.9 (d, J = 8.2 Hz), 32.2, 27.6, 25.5 (d,
2
J = 7.5 Hz); FTMS (+p ESI) Calcd for C10H20 HO 158.16497; Found 158.16455.
transꢀ2ꢀmethylcyclohexanol 10.21
1
Crude oil. HNMR (CDCl3) δ (ppm): 3.10 (dd, J = 5.6, 4.0 Hz, 1H), 1.95ꢀ1.91 (m, 1H), 1.74ꢀ
1.57 (m, 4H), 1.30ꢀ1.16 (m, 4H), 0.99 (d, J = 6.4 Hz, 3H); 13CNMR (CDCl3) δ (ppm): 76.6,
40.4, 35.6, 33.8, 25.8, 25.3, 18.7.
benzyl transꢀ2ꢀmethylcyclohexyl ether 11.29
A 10 mL roundꢀbottom flask was charged with 60 wt% sodium hydride in mineral oil (80 mg,
2.0 mmol). The sodium hydride was washed three times with hexanes (2 mL) and once with THF
(2 mL). THF (4 mL) was added to the flask and the mixture was cooled to 0 oC. A solution of the
crude alcohol, 10 (~0.19 g) in THF (0.25 mL) was added dropwise. Tetrabutylammonium iodide
(60 mg, 0.16 mmol) was added to the reaction mixture at once followed by the dropwise addition
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of benzyl bromide (0.20 mL, 1.7 mmol). The iceꢀwater bath was removed and reaction mixture
was stirred at room temperature for 24 h. and then the reaction was quenched with water. The
product was extracted with diethyl ether; the combined organic extracts were dried over MgSO4
and concentrated in vacuo. Flash chromatography on silica gel (hexanes) afforded pure product
11 as a colorless oil (0.16 g, 80% yield). 1HNMR (CDCl3) δ (ppm): 7.34ꢀ7.21 (m, 5H), 4.63 (d, J
= 11.7 Hz, 1H), 4.43 (d, J = 11.7 Hz, 1H), 2.89 (ddd, J = 5.1, 4.5, 4.2 Hz, 1H), 2.14ꢀ2.11 (m,
1H), 1.75ꢀ1.69 (m, 2H), 1.61ꢀ1.44 (m, 2H), 1.26ꢀ1.21 (m, 4H), 1.01 (d, J = 6.3 Hz, 3H);
13CNMR (CDCl3) δ (ppm): 139.3, 128.2, 127.6, 127.3, 83.6, 70.6, 38.4, 33.9, 31.1, 25.6, 25.0,
18.9; TOF MS (EI+) Calcd for C14H20O 204.1514; Found 204.1551; IR (film) 697, 735, 926, 986,
1028, 1072, 1096, 1160, 1205, 1250, 1303, 1355, 1453, 1496, 2856, 2927, 3031, 3064 cmꢀ1.
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endoꢀborneol 12.30
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White solid (0.10 g, 65% yield). HNMR (CDCl3) δ (ppm): 4.00 (dd, J = 8.4, 1.6 Hz, 1H), 2.27
(dddd, J = 4.4, 3.6, 1.8, 0.8 Hz, 1H), 1.92ꢀ1.85 (m, 1H), 1.77ꢀ1.69 (m, 1H), 1.63ꢀ1.61 (m, 2H),
1.28ꢀ1.21 (m, 2H), 0.94 (dd, J = 10.0, 3.4 Hz, 1H), 0.87 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H);
13CNMR (CDCl3) δ (ppm): 77.3, 49.4, 48.0, 45.1, 39.0, 28.2, 25.9, 20.2, 18.6, 13.3.
(ꢀ)ꢀmenthol 13.31
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White solid (0.13 g, 86% yield). HNMR (CDCl3) δ (ppm): 3.41 (td, J = 6.4, 3.6 Hz, 1H), 2.17
(pent, J = 5.7 Hz, 1H), 1.96 (d, J = 11.4 Hz, 1H), 1.64 (t, J = 13.2 Hz, 2H), 1.45 (m, 2H), 1.15ꢀ
1.08 (m, 1H), 0.94ꢀ0.90 (m, 9H), 0.81 (d, J = 6.9 Hz, 3H); 13CNMR (CDCl3) δ (ppm): 71.4,
50.0, 45.0, 34.5, 31.6, 25.7, 23.0, 22.1, 21.0, 16.0.
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(±)ꢀtrans,cisꢀdecahydroꢀ1ꢀnaphthol 14a.32
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White solid (0.13 g, 82% yield). 1HNMR (CDCl3) δ (ppm): 3.18 (ddd, J = 6.0, 4.4, 3.2 Hz, 1H),
2.12 (d, J = 7.6 Hz, 1H), 1.98ꢀ1.94 (m, 1H), 1.88 (br, 1H), 1.78ꢀ1.62 (m, 4H), 1.51 (d, J = 10.0
Hz, 1H), 1.34ꢀ1.19 (m, 4H), 0.97ꢀ0.87 (m, 5H); 13CNMR (CDCl3) δ (ppm): 74.9, 50.4, 41.1,
35.7, 33.5, 33.4, 28.9, 26.3, 26.1, 24.0. The 3 isomers could not be separated; therefore, the
following data concern the mixture of these 3 compounds: TOF MS (ES+) Calcd for C10H17O
153.1279; Found 153.1284; IR (film) 823, 839, 915, 953, 1020, 1040, 1059, 1141, 1238, 1358,
1448, 1641, 2853, 2919, 3369 cmꢀ1.
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cisꢀ3,3,5ꢀtrimethylcyclohexanol 15.
White solid (37 mg, 26% yield). 1HNMR (CDCl3) δ (ppm): 3.72 (ddd, J = 4.5, 4.2, 2.6 Hz, 1H),
2.21 (br, 1H), 1.91 (d sextet, J = 2.4, 1.8 Hz, 2H), 1.67ꢀ1.51 (m, 2H), 1.26 (d pent, J = 6.0, 1.8
Hz, 1H), 0.90 (s, 3H), 0.88 (s, 3H), 0.86 (s, 3H), 0.73 (q, J = 10.0 Hz, 2H); 13CNMR (CDCl3) δ
(ppm): 67.8, 48.2, 47.6, 44.6, 33.1, 32.2, 27.2, 25.7, 22.3; TOF MS (ES+) Calcd for C9H17O
141.1279; Found 141.1265; IR (film) 1026, 1080, 1365, 1460, 1641, 2922, 2925, 2951, 3412 cmꢀ
1
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cisꢀ3ꢀmethylcyclopentanol 16a.18
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Crude oil. HNMR (CDCl3) δ (ppm): 4.32ꢀ4.27 (m, 1H), 2.27ꢀ2.13 (m, 1H), 2.04ꢀ1.09 (m, 6H),
1.06 (d, J = 6.4 Hz, 3H); 13CNMR (CDCl3) δ (ppm): 73.7, 44.1, 35.4, 32.9, 32.2, 21.0.
transꢀ3ꢀmethylcyclopentanol 16b.18
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Crude oil. HNMR (CDCl3) δ (ppm): 4.36 (pent, J = 2.8 Hz, 1H), 2.27ꢀ2.13 (m, 1H), 2.04ꢀ1.09
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6
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(m, 6H), 0.99 (d, J = 6.4 Hz, 3H); 13CNMR (CDCl3) δ (ppm): 73.7, 44.3, 35.2, 32.4, 31.8, 20.6.
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benzyl cisꢀ3ꢀmethylcyclopentyl ether 17.
A 10 mL roundꢀbottom flask was charged with 60 wt % sodium hydride in mineral oil (40 mg,
1.0 mmol). The sodium hydride was washed three times with hexanes (2 mL) and once with THF
o
(2 mL). THF (1.8 mL) was added to the flask and the mixture was cooled to 0 C. A solution of
the crude alcohol, 16 (~90 mg) in THF (0.5 mL) was added dropwise. Tetrabutylammonium
iodide (40 mg, 0.10 mmol) was added to the reaction mixture at once followed by the dropwise
addition of benzyl bromide (0.13 mL, 1.1 mmol). The iceꢀwater bath was removed and reaction
mixture was stirred at room temperature for 24 h. and then the reaction was quenched with water.
The product was extracted with diethyl ether; the combined organic extracts were dried over
MgSO4 and concentrated in vacuo. Flash chromatography on silica gel (Et2O/hexanes) afforded
1
pure product 17 as a colorless oil (0.12g, 63% yield). HNMR (CDCl3) δ (ppm): 7.33ꢀ7.26 (m,
5H), 4.45 (d, J = 4.2 Hz, 2H), 3.98 (q, J = 5.7 Hz, 1H), 2.19ꢀ2.08 (m, 1H), 1.94ꢀ1.68 (m, 4H),
1.36ꢀ1.20 (m, 2H), 1.04 (d, J = 6.6 Hz, 3H); 13CNMR (CDCl3) δ (ppm): 139.0, 128.2, 127.5,
127.3, 80.9, 70.8, 41.3, 32.9, 32.4, 32.2, 20.9; TOF MS (AP+) Calcd for C13H19O 191.1436;
Found 191.1434; IR (film) 649, 699, 733, 908, 1028, 1068, 1095, 1205, 1376, 1496, 2868, 2955,
3032, 3066, 3089 cmꢀ1.
cisꢀ3ꢀ(trifluoromethyl)cyclohexanol 22.22
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Crude oil. 1HNMR (CDCl3) δ (ppm): 3.61 (tt, J = 4.2, 2.4 Hz, 1H), 2.20ꢀ2.15 (m, 1H), 2.11ꢀ1.86
(m, 4H), 1.43ꢀ1.12 (m, 4H); 13CNMR (CDCl3) δ (ppm): 132.7, 129.0, 125.3, 121.6, 69.3, 40.9 (q,
J = 27.0 Hz), 34.7, 34.0 (q, J = 2.2 Hz), 24.0 (q, J = 2.2 Hz), 22.7.
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benzyl cisꢀ3ꢀ(trifluoromethyl)cyclohexyl ether 23.
A 10 mL roundꢀbottom flask was charged with 60 wt % sodium hydride in mineral oil (57 mg,
1.4 mmol). The sodium hydride was washed three times with hexanes (2 mL) and once with THF
o
(2 mL). THF (1.7 mL) was added to the flask and the mixture was cooled to 0 C. A solution of
the crude alcohol, 22 (~0.16 g) in THF (0.5 mL) was added dropwise. Tetrabutylammonium
iodide (35 mg, 0.095 mmol) was added to the reaction mixture at once followed by the dropwise
addition of benzyl bromide (0.14 mL, 1.2 mmol). The iceꢀwater bath was removed and reaction
mixture was stirred at room temperature for 24 h. and then the reaction was quenched with water.
The product was extracted with diethyl ether; the combined organic extracts were dried over
MgSO4 and concentrated in vacuo. Flash chromatography on silica gel (Et2O/hexanes) afforded
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pure product 23 as a colorless oil (0.18g, 70% yield). HNMR (CDCl3) δ (ppm): 7.36ꢀ7.27 (m,
5H), 4.57 (s, 2H), 3.34ꢀ3.33 (m, 1H), 2.31 (d, J = 11.5 Hz, 1H), 2.13ꢀ2.02 (m, 2H), 1.88 (m, 2H),
1.33ꢀ1.23 (m, 4H); 13CNMR (CDCl3) δ (ppm): 138.6, 128.4, 127.8, 127.5, 127.5, 76.0, 70.0, 41.0
(q, J = 26.2 Hz), 31.8, 31.1 (d, J = 1.2 Hz), 24.4 (d, J = 2.5 Hz), 22.8; 19FNMR (CDCl3) δ
(ppm): ꢀ73.6 (d, J = 5.0 Hz); TOF MS (AP+) Calcd for C14H17OF3 258.1232; Found 258.1251;
IR (film) 698, 736, 1028, 1089, 1122, 1173, 1213, 1253, 1278, 1320, 1360, 1454, 1496, 2867,
2945, 3031, 3065 cmꢀ1.
5αꢀandrostaneꢀ3α,17βꢀdiol 24.33
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White solid (0.22g, 75% yield). HNMR (CDCl3) δ (ppm): 4.04 (m, 1H), 3.63 (t, J = 8.4 Hz,
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1H), 2.11ꢀ1.99 (m, 1H), 1.79 (d, J = 12.3 Hz, 1H), 1.69ꢀ0.89 (m, 22H), 0.79 (s, 3H), 0.73 (s,
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13
8
3H); CNMR (CDCl3) δ (ppm): 82.0, 66.5, 54.5, 51.1, 43.0, 39.2, 36.8, 36.2, 35.9, 35.6, 32.2,
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31.6, 30.5, 29.0, 28.4, 23.4, 20.4, 11.2, 11.1; TOF MS (EI+) Calcd for C19H31O2 291.2324; Found
291.2347.
bis(4ꢀmethoxyphenyl)methanol 25.34
White solid (0.20 g, 83% yield). 1HNMR (CDCl3) δ (ppm): 7.24 (d, J = 8.4 Hz, 4H), 6.83 (d, J =
13
8.4 Hz, 4H), 5.70 (s, 1H), 3.75 (s, 6H), 2.44 (br, 1H); CNMR (CDCl3) δ (ppm): 158.8, 136.4,
127.7, 113.7, 75.2, 55.2.
3ꢀquinuclidinol 26.25a
1
White solid (83 mg, 65% yield). HNMR (CDCl3) δ (ppm): 3.81 (t, J = 4.0 Hz, 1H), 3.31 (br,
1H), 3.10 (dddd, J = 6.3, 3.6, 2.1, 1.8 Hz, 1H), 2.94ꢀ2.84 (m, 1H), 2.76ꢀ2.55 (m, 4H), 1.98ꢀ1.87
13
(m, 1H), 1.78 (q, J = 3.0 Hz, 1H), 1.71ꢀ1.61 (m, 1H), 1.50ꢀ1.29 (m, 2H); CNMR (CDCl3) δ
(ppm): 67.4, 58.0, 47.4, 46.3, 28.4, 24.8, 18.9.
ACKNOWLEDGEMENTS
We are grateful to Dr. Damodaran Krishnan Achary for the NMR facilities and Dr. Bhaskar
Godugu for help with the mass spectra. We also thank Dr. Guoquing Wei for his insightful
discussions.
SUPPORTING INFORMATION
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Copies of H and C NMR spectra. This material is available free of charge via the Internet at
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