Reductive Lithiation in the Absence of Aromatic Electron Carriers. A Steric Effect Manifested on the Surface of Lithium Metal Leads to a Difference in Relative Reactivity Depending on Whether the Aromatic Electron Carrier Is Present or Absent

Article abstract of DOI:10.1021/acs.joc.5b01136

One of the most widely used methods of preparation of organolithium compounds is by the reductive lithiation of alkyl phenyl thioethers or, usually less conveniently, alkyl halides with either aromatic radical-anions of lithium or lithium metal in the presence of an aromatic electron-transfer catalyst. Here we present results showing that lithium dispersion can achieve reductive lithiation in the absence of the electron-transfer agent. This procedure is more efficient, and surprisingly, the order of reactivity of substrates is reversed depending on whether the electron-transfer agent is present or absent. For example, in the presence of a preformed radical-anion, tert-butyl phenyl sulfide cleaves significantly faster than methyl phenyl sulfide, whereas in the absence of the radical-anion, it is just the opposite. Density functional theory calculations reveal that the exothermicity of the cleavage of the C-S bond in alkyl phenyl thioethers on the lithium surface is dependent on the size of the alkyl group, the smaller the alkyl group the greater the exothermicity. The increased reactivity is attributed to the smaller steric repulsion between the alkyl group and the lithium surface. The methodology includes, but may not be limited to, the lithium dispersion reductive lithiation of phenyl thioethers, alkyl chlorides, acrolein diethyl acetal, and isochroman.

Full text of DOI:10.1021/acs.joc.5b01136

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Reductive Lithiation in the Absence of Aromatic Electron Carriers. A Steric
Effect Manifested on the Surface of Lithium Metal Leads to a Difference in
Relative Reactivity Depending on Whether the Aromatic Electron Carrier is
Present or Absent.
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Nicole Kennedy,* Gang Lu, Peng Liu* and Theodore Cohen*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
nmk28@pitt.edu, pengliu@pitt.edu, and cohen@pitt.edu
TABLE OF CONTENTS/ABSTRACT GRAPHIC
84ꢀ95% Yield
∆ELi R = Me < iꢀPr < 2ꢀButyl < 3ꢀHexyl ≈ tꢀBu
ABSTRACT
One of the most widely used methods of preparation of organolithium compounds is by the
reductive lithiation of alkyl phenyl thioethers or, usually less conveniently, alkyl halides, with
either aromatic radicalꢀanions of lithium or lithium metal in the presence of an aromatic electron
transfer catalyst. Here we present results, which show that lithium dispersion can achieve
reductive lithiation in the absence of the electron transfer agent. This procedure is more efficient
and, surprisingly, the order of reactivity of substrates is reversed depending on whether the
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electron transfer agent is present or absent. For example, in the presence of such an agent, tertꢀ
butyl phenyl sulfide cleaves significantly faster than methyl phenyl sulfide, whereas in the
absence of the agent, it is just the opposite. DFT calculations reveal that the exothermicity of the
cleavage of the CꢀS bond in alkyl phenyl thioethers on the lithium surface is dependent on the
size of the alkyl group, the smaller the alkyl group the greater the exothermicity. The increased
reactivity is attributed to the smaller steric repulsion between the alkyl group and the lithium
surface. The methodology includes, but may not be limited to, the lithium dispersion reductive
lithiation of phenyl thioethers, alkyl chlorides, acrolein diethyl acetal, and isochroman.
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INTRODUCTION
One of the most versatile methods known for generating organolithiums is by the reductive
lithiation of phenyl thioethers, the replacement of a CꢀS bond with a CꢀLi bond, using aromatic
radicalꢀanions, as the source of the electron (Scheme 1).1ꢀ4 Aromatic radicalꢀanions including:
lithium naphthalenide (LN), lithium 1ꢀ(N,Nꢀdimethylamino)naphthalenide (LDMAN), and
lithium p,p’ꢀdiꢀtertꢀbutylbiphenylide (LDBB) are currently in use. The superiority of alkyl
phenyl thioethers as substrates for reductive lithiation arises from their almost unique ease of
construction as well as the ability of the phenylthio group to enter a molecule as a nucleophile,
electrophile, or radical.5
Scheme 1. Reductive Lithiation of Phenyl Thioethers with Aromatic RadicalꢀAnions.
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Because LDMAN decomposes to 1ꢀlithionaphthalene above ꢀ45 oC,6 a ‘catalytic method,’
which employs a catalytic amount rather than a stoichiometric amount of the aromatic
hydrocarbon, was devised in this laboratory.7 This allowed higher temperatures to be used
without destroying the LDMAN intermediate. More recently, Yus and coꢀworkers performed the
catalytic reductive lithiation of some alkyl chlorides and alkyl phenyl sulfides,8 in which a
solution of the substrate to be reduced is mixed with 1ꢀ5 mol% of the aromatic hydrocarbon,
usually p,p´ꢀdiꢀtertꢀbutyl biphenyl (DBB)9ꢀ11 and a large excess of specially prepared lithium
powder.12 Furthermore, Yus has claimed, in a number of his papers, that the catalytic aromatic
method, in which the radicalꢀanion is continually generated and rapidly destroyed by electron
transfer to the substrate,5 is far more powerful than the use of a stoichiometric amount of
preformed aromatic radicalꢀanion.9 This claim was tested in a number of cases and in all but one
case the opposite was found, namely that the preformed radicalꢀanion method was superior to the
catalytic method.5
The one case in which Yus’s contention proved to be correct was the reductive cleavage
of Nꢀphenylaziridine (1). He reported that the threeꢀmembered ring can be opened by excess Li
metal with a catalytic amount of naphthalene in 93% yield at ꢀ78 oC.13 The Cohen lab found that
the reductive lithiation of 1 with LN did not cause the desired cleavage at the temperature and
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time reported.5 A possible explanation of this result, shown in Scheme 2, is that the transfer of an
electron from the lithium to naphthalene (Np) occurs more slowly than the transfer of an electron
to 1. However, in the presence of Np, the resulting radicalꢀanion (2) of Nꢀphenylaziridine can
transfer an electron to the Np to generate the more thermodynamically stable radicalꢀanion, LN.5
Thus, 2 is the kinetic product of electron transfer from lithium, but LN is the thermodynamic
radicalꢀanion and Np acts as an inhibitor rather than a catalyst. Experimentally, it was
demonstrated that naphthalene is indeed an inhibitor in this case.5
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Scheme 2. Proposed Mechanistic Explanation for the Catalytic Method of Reductive
Lithiation of N-phenylaziridine.
The reason that 1 accepts an electron from lithium more rapidly than Np is unknown;
however, this finding is consistent with 1ꢀ(N,Nꢀdimethylamino)ꢀnaphthalene (DMAN) forming
LDMAN at ꢀ45 oC, faster than the formation of LN at room temperature.5 The amino group may
complex with a lithium cation, which increases the electrophilicity of the ring as well as the
electron donating power of the metal surface. Therefore, an electron would be transferred more
rapidly to the pi system of the aromatic.5 Because Nꢀphenylaziridine acquires an electron from Li
metal faster than Np does and the resulting radicalꢀanion can transfer the electron rapidly to Np,
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1 “catalyzes” the formation of LN; however, 2 is unstable and easily undergoes ring opening at ꢀ
78 oC.14
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Thus, the commercially available and more stable analogue, N,Nꢀdimethylaniline (DMA),
was tested as an electron transfer reagent on the reasonable assumption that its radicalꢀanion
would also form very rapidly but would not readily decompose. While we were disappointed to
find that DMA did not behave as a catalyst for reductive lithiation, when lithium dispersion is the
source of Li metal,15 it was unexpectedly discovered that many compounds commonly used to
generate organolithiums could actually be reductively lithiated in the absence of an aromatic
electron transfer reagent under the right conditions and the selectivity is just the opposite of that
of the preformed radicalꢀanion method. Phenyl thioethers with smaller alkyl groups were found
to react significantly faster with lithium dispersion. DFT calculations were performed to
investigate the origin of the steric effect.
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RESULTS AND DISCUSSION
Attempted DMA Catalyzed Reductive Lithiation.
In order to properly assess its ability to promote the transfer of an electron from lithium to a
substrate, DMA was compared to the wellꢀknown reductive lithiation catalyst, DBB, as well as,
the preformed radicalꢀanion method with LDBB. Lithium dispersion (25 wt% in mineral oil)
containing 0.1% sodium was used as the lithium metal source in the following reductive
lithiations. 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. Lithium dispersion
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alone, without an aromatic electron carrier, was used as the control. The reductive lithiation of
methyl phenyl sulfide (3) was studied and the methyllithium intermediate (4) was trapped with
benzaldehyde to form the isolable alcohol product, 1ꢀphenylethanol (5, Table 1). Surprisingly,
the lithium dispersion reductive lithiation of 3 (Table 1, entry 4) produced 5 in a yield
comparable to those achieved via the preformed radicalꢀanion (Table 1, entry 1) and catalytic
(Table 1, entries 2 and 3) reductive lithiation methods.
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Table 1. Catalytic, Preformed RadicalꢀAnion, and Lithium Dispersion Methods of
Reductive Lithiation of Methyl Phenyl Sulfide.
Yield (%)a
Entry
Conditions
LDBB
Li (disp., 2.4 equiv), DMA (10 mol%)
Li (disp., 2.4 equiv), DBB (10 mol%)
Li (disp., 2.4 equiv)
1
2
3
4
79
77
74
73
a Isolated yield of 5 after chromatography purification.
Since 3 reacted with lithium dispersion both in the presence and absence of an aromatic
electron carrier, the role of DMA could not be determined. There were two factors to be
measured occurring in one reaction pot, the nonꢀcatalyzed and catalyzed reductive lithiation,
which may be happening simultaneously or affecting one another. Therefore, the DMA catalyzed
reductive lithiation of anisole (6), which does not readily undergo reductive lithiation in the
absence of an aromatic electron carrier,5 was investigated (Table 2). DBB and DMAN
successfully catalyzed the reductive lithiation of 6 at 0 oC (Table 2, entries 1 and 2); however, in
the presence of DMA, no cleavage product was formed, even after 24 h. at room temperature
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(Table 2, entries 3 and 4). With these results, it was concluded that DMA does not catalyze the
reductive lithiation of either 3 or 6, and therefore, may not be an effective electron transfer
promoter when lithium dispersion is the source of Li metal.
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Table 2. Catalytic Method of Reductive Lithiation of Anisole.
Aromatic
Electron Carrier
DBB
Yield (%)a
Entry Temp. (oC)
1
2
3
4
0
0
0
rt
59
66
0b
DMAN
DMA
DMA
0b,c
b
1
a Isolated yield of 5 after chromatography purification. Trace amounts of phenol detected in crude HNMR. c After
24 h.
Reductive Lithiation of Phenyl Thioethers.
In order to gain a preliminary understanding of the scope of the lithium dispersion reductive
lithiation of phenyl thioethers and to optimize conditions, four substrates, which had previously
undergone either catalytic or preformed radicalꢀanion reductive lithiation, were surveyed. The
phenyl thioethers, including: isopropyl phenyl sulfide (7),16 5ꢀ(phenylthio)ꢀ1ꢀpentene (8),17 1ꢀ
(phenylthio)ꢀ1ꢀcyclohexene (9),18 tertꢀbutyl phenyl sulfide (10),19 2ꢀ(phenylthio)ꢀbutane (11),20
3ꢀ(phenylthio)ꢀhexane (12),20 and cyclooctyl phenyl sulfide (13),20 were synthesized following
the literature protocols. Unlike Yus’s procedure, which generally uses a large excess of lithium,
prepared in a special apparatus12 not generally available in synthetic labs, the procedure
developed here uses a slight stoichiometric excess (2.4 equivalents) of the lithium dispersion.
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Excellent yields of the corresponding benzyl alcohol products were obtained after the
organolithium intermediates were captured with benzaldehyde (80ꢀ95% yield) (Table 3). With
optimum conditions developed, the significance of DBB in the reductive lithiation of phenyl
thioethers was determined. As shown in Table 3 (entries 4, 6, and 16), DBB did not affect the
isolated yield under identical reaction conditions. Furthermore, less time was required for the
lithium dispersion reductive lithiation of 3 and 9 in comparison to the catalytic and preformed
radicalꢀanion reductive lithiations of these substrates at the same temperature (Table 3, entries 2,
3, 12, and 13).8,21 Lastly, similar amounts of unreacted starting material 8 were recovered, in
both the presence and absence of DBB (Table 3, entries 10 and 11), after the organolithium
intermediate was quenched with water. Thus, it was determined that DBB does not catalyze the
reductive lithiation of phenyl thioethers when lithium dispersion is the Li metal source.
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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. The
granular lithium reductive lithiation of 8 and 9 produced a slightly lower isolated yield (Table 3,
entries 9 and 17), despite the granular lithium having five times the amount of sodium compared
to the lithium dispersion.22 Thus, the increase in the surface area of the Li metal, from the
granular to the dispersion, apparently somewhat enhances the rate of reductive lithiation.
Table 3. Reductive Lithiation of Phenyl Thioethers Using Lithium Dispersion and Some
Comparisons with the Use of Granular Lithium and DBB Catalysis.
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Temp. Time
Methoda
Product
(%)b
Entry SM
R
E
(oC)
(min.)
7
8
9
1
2
CH3
CH3
0
15
A
A
C6H5CHOH
5 (95)
3
3
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
0
60
150
60
90
90
15
60
60
10
10
15
30
60
60
60
60
5 (95)
(92)c
C6H5CHOH
(CH2)5COH
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11
12
13
14
15
16
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19
20
21
22
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3
4
CH3
B
C
A
C
A
A
D
E
3
3
7
7
8
8
8
8
8
9
9
9
9
9
9
CH3
5 (88)
C6H5CHOH
C6H5CHOH
C6H5CHOH
C6H5CHOH
C6H5CHOH
C6H5CHOH
H
5
CH(CH3)2
14 (87)
14 (87)
15 (80)
15 (83)
15 (77)
8 (11)
6
CH(CH3)2
7
(CH2)3CH=CH2
(CH2)3CH=CH2
(CH2)3CH=CH2
(CH2)3CH=CH2
(CH2)3CH=CH2
C=CH(CH2)3CH2
C=CH(CH2)3CH2
C=CH(CH2)3CH2
C=CH(CH2)3CH2
C=CH(CH2)3CH2
C=CH(CH2)3CH2
8
ꢀ78
ꢀ78
ꢀ78
ꢀ78
0
9
10
11
12
13
14
15
16
17
F
8 (10)
H
A
G
A
A
C
D
16 (88)
(63)d
C6H5CHOH
0
cꢀC6H11CHOH
ꢀ45
ꢀ78
ꢀ78
ꢀ78
16 (88)
16 (84)
16 (86)
16 (64)
C6H5CHOH
C6H5CHOH
C6H5CHOH
C6H5CHOH
Method A: Li (disp.); Benzaldehyde. Method B: Li powder, Np (1 mol%); Cyclohexanone.8 Method C: Li
(disp.), DBB (10 mol%); Benzaldehyde. Method D: Li granular; Benzaldehyde. Method E: Li (disp.); H2O.
Method F: Li (disp.), DBB (10 mol%); H2O. Method G: LN; Cyclohexanecarboxaldehyde.21 b Product and isolated
yield after chromatography purification. c Ref. 8. d Ref. 21.
a
The finding that phenyl thioethers were reductively lithiated by lithium metal with no
aromatic catalyst present was surprising. In the past, with very few exceptions, the overwhelming
number of reductive lithiations of phenyl thioethers have been performed in the presence of
either preformed aromatic radicalꢀanions or an aromatic catalyst that was thought to act as an
electron carrier. The only exceptions of which we are aware of are the findings of Screttas et. al.
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that a few phenyl thioethers can be reductively lithiated by a substantial excess of specially
prepared lithium dispersion alone1 and that allylic phenyl thioethers can be reductively lithiated
under highly unusual conditions, that is with an excess of lithium chips in solutions of diethyl
ether, rather than the standard THF, at ice bath temperature.23
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In Table 3, overall yields were used to compare the efficacy of the procedures for
different substrates. In order to gain an understanding of the relative rates of cleavage of two
different substrates, 3 and 10, the yields of the unreacted starting materials after a 5ꢀminute
reductive lithiation were determined. As shown in Scheme 3, 3 cleaves significantly faster than
10 rather than slower, as would be predicted for the preformed radicalꢀanion method.3a,g The
relative reactivity is reversed in going from the preformed radicalꢀanion method (Scheme 4) to
the lithium dispersion method (Scheme 3). Thus, the preformed radicalꢀanion method of
reductive lithiation must be fundamentally different from the lithium dispersion method.
Scheme 3. Lithium Dispersion Reductive Lithiation of 3 and 10.a
a % of recovered starting material after chromatography purification.
Under the preformed radicalꢀanion method with LDBB (Scheme 4), the unreacted
starting material was oxidized to a sulfone24 in order to facilitate separation from DBB via
column chromatography. Thus, as expected, 10 cleaved more rapidly than 3.
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Scheme 4. Preformed RadicalꢀAnion Reductive Lithiation of 3 and 10.a
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4
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a % of isolated sulfone after chromatography purification.
Further evidence includes the lithium dispersion reductive lithiation of a 1:1 mixture of 3
and 10 being selective for methyl phenyl sulfide, resulting in a 1:150 ratio of recovered starting
material (Scheme 5). The reversal in reactivity in the presence and absence of the electron
transfer agent is truly remarkable.
Scheme 5. Selective Reductive Lithiation of 3.a
a Ratio of recovered starting material determined from 1HNMR.
In order to determine if this unique finding results from an electronic effect or a steric
effect, the relative rates of reductive lithiation of secondary alkyl phenyl sulfides, increasing in
bulkiness, were compared. Four substrates were individually reductively lithiated with lithium
dispersion and the lithium thiophenoxide products were oxidized to diphenyl disulfide (19)
(Table 4). The ratio of the starting material (SM) to 19 was determined by comparing the ratio of
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the ortho aromatic protons of each product in the crude HNMR spectrum. The result is that the
5
6
7
8
rate is very sensitive to steric effects; an increase in bulkiness of the alkyl group led to a sharp
increase in unreacted starting material. This thus is a steric effect rather than an electronic effect.
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Table 4. Lithium Dispersion Reductive Lithiation of Secondary Alkyl Phenyl Sulfides.
SM (H) : 19 (H)a
Entry SM
R1
CH3
CH3
R2
CH3
CH2CH3
CH2CH2CH3
1
2
3
4
3:1
8:1
34:1
36:1
7
11
12
13
CH2CH3
ꢀcꢀC8C15ꢀ
a Ratio determined from crude 1HNMR.
The preformed radicalꢀanion reductive lithiation of some of these substrates was
performed in order to determine whether there are similar or different steric effects on the rate of
reductive lithiation when compared to the lithium dispersion method. The ratio of the starting
1
material to 19 could not be determined by HNMR due to overlap of the aromatic protons with
Np; therefore, the unreacted starting material was isolated. As shown in Scheme 6, compounds 7,
12, and 13 have similar rates of cleavage under the preformed radicalꢀanion reaction conditions.
There was little to no discrepancy observed in the percentages of the unreacted SM (Scheme 6)
in comparison to the considerable difference observed in the ratios of the SM to 19 in Table 4.
Scheme 6. Preformed RadicalꢀAnion Reductive Lithiation of Secondary Alkyl Phenyl
Sulfides.a
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a % of recovered starting material after chromatography purification.
Computational Studies of CꢀS Bond Cleavage of Alkyl Phenyl Sulfides on the Lithium
Surface.
This is one of those rare circumstances in which one discovers completely unexpected chemical
results that, without theoretical calculations, are quite inexplicable. The reductive lithiation of
alkyl phenyl sulfides with lithium dispersion is expected to occur through the dissociative
adsorption mechanism on the lithium surface. This process involves molecular adsorption of the
alkyl phenyl sulfide on the lithium surface, followed by CꢀS bond cleavage to form a
thiophenoxyl radical and an alkyl radical adsorbed on the lithium surface. The carbonꢀhalogen
bond dissociative adsorption of alkyl halides on magnesium, aluminum, and various transition
metal surfaces have been investigated in detail experimentally and computationally.25,26
Interestingly, the carbonꢀhalogen bond cleavage is generally promoted by substrates with longer
or bulkier alkyl chains,27 which is opposite to the reactivity trend observed in the reductive
lithiation of alkyl phenyl sulfides with lithium dispersion. The increased reactivity of bulky alkyl
halides on metal surface was attributed to the greater molecular adsorption energy of the longerꢀ
chain alkyl halides, while the rate of the subsequent CꢀX bond cleavage step was found to be
independent of alkyl chain length.28 To investigate the steric effects of alkyl substituents on the
reactivity of alkyl phenyl sulfide CꢀS bond cleavage on lithium surface, density functional theory
(DFT) calculations were performed to evaluate the dissociative adsorption of substrates with
different alkyl groups (3, 7, 10, 11, and 12).
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We first computed the molecular adsorption energies (ꢁEad) of alkyl phenyl sulfides on
the lithium surface (Table 5). The adsorption energies of the sulfides are surprisingly similar
regardless of the very different size of the alkyl groups. The small effects of the alkyl group on
the adsorption energies are attributed to the adsorbed geometry of the substrate on the surface. In
all complexes, the substrate binds with the phenyl group and the sulfur atom parallel to the
surface, while the alkyl group stands upright, pointing away from the surface (Figure 1). In
contrast, based on previous reports,27b the alkyl chain in adsorbed alkyl halide complexes binds
to the metal surface, and thus has much more significant effects on the adsorption energies. The
lack of correlation between the computed adsorption energy and reactivity suggests the cleavage
rate does not depend on the substrate adsorption step. As a result, the reaction energies of the Cꢀ
S bond cleavage on the surface of lithium were computed to investigate the reactivity trend in
this step. Previous studies have demonstrated the reactivity of carbonꢀheteroatom bond cleavage
on metal surface follows the BrønstedꢀEvansꢀPolanyi relationship, i.e. the reactivity depends
linearly on the reaction energy of bond cleavage.29
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Table 5. Substrate Adsorption Energy on Li Surface.
R
PhS–R
∆Ead
S
+
(Li surface)
(Li surface)
Substrate on Li (110)
Surface (*)a
ꢁEad
(kcal/mol)
ꢀ12.0
Entry Substrate
1
2
3
4
5
6
PhSꢀMe +
PhSꢀiꢀPr +
*
ꢀ PhSꢀMe
ꢀ PhSꢀ iꢀPr
ꢀ PhSꢀ2ꢀbutyl
ꢀ PhSꢀ3ꢀhexyl
ꢀ PhSꢀtꢀBu
ꢀ PhOꢀMe
*
3
7
11
12
10
6
*
*
ꢀ15.5
ꢀ14.4
ꢀ15.1
ꢀ15.1
PhSꢀ2ꢀbutyl +
PhSꢀ3ꢀhexyl +
PhSꢀtꢀBu +
*
*
*
*
*
*
*
PhOꢀMe +
*
ꢀ6.3
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a All calculations were performed with the PBE functional in CP2K/Quickstep.30 Li (110) surface was modeled
using five atomic layers with a p(5x5) supercell. See the Supporting Information for Computational Details.
6
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Figure 1. Adsorption geometries of methyl phenyl sulfide (3) and tertꢀbutyl phenyl sulfide (10)
on Li(110) surface.
The computed CꢀS bond dissociation energies in the gas phase (ꢁEgas) and on the Li
surface (ꢁELi, i.e. the reaction energy of the adsorbed alkyl phenyl sulfide on the Li surface to
form a thiophenoxyl radical and an alkyl radical bound to the Li surface) are shown in Table 6.
The CꢀS bond cleavage on the Li surface is found to be exothermic and the exothermicity
parallels the reactivity trend. The reaction with 3 is the most favorable thermodynamically,
although the PhSꢀMe bond is the strongest in terms of gas phase bond dissociation energies
(Table 6, entry 1). The bulkier alkyl groups, 10 and 12, result in much less exothermic CꢀS bond
cleavage on the Li surface (Table 6, entries 4 and 5). The unfavorable steric interaction between
the bulky alkyl groups and the surface is evident from the elongation of the LiꢀC distance of the
adsorbed RꢀLi complexes in going from the methyl group to the larger tertꢀbutyl group (Figure
2).
Table 6. Calculated SꢀC Bond Dissociation Energies.a
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(a) bond dissociation energy in gas phase
∆Egas
5
6
+
PhS–R
PhS
R
S
7
8
9
(b) bond dissociation energy on Li surface
10
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R
∆ELi
R
S
+
(Li surface)
(Li surface)
d(LiꢀC)c
(Å)
ꢁEgas
(kcal/mol)
68.1
ꢁELi
Entry Substrate
R
(kcal/mol)b
ꢀ38.0
1
2
3
4
5
Me
iꢀPr
2.17
2.24
2.26
2.28
3
7
60.2
ꢀ27.1
ꢀ26.4
ꢀ24.5
ꢀ24.8
2ꢀbutyl
3ꢀhexyl
tꢀBu
60.7
60.7
57.1
11
12
10
2.31
a All calculations were performed with the PBE functional in CP2K/Quickstep.30 Li (110) surface was modeled
using five atomic layers with a p(5x5) supercell. See the Supporting Information for Computational Details. b The
dissociative adsorption energy is the energy difference between adsorbed PhS and R groups on the Li surface and
the adsorbed substrate and Li surface. See equation (b). c Average distance of three shortest LiꢀC bonds in adsorbed
alkyl radical complex.
Figure 2. Adsorption geometries of Me and tꢀBu radicals on Li(110) surface.
The origin of the more favorable CꢀS bond dissociation with smaller alkyl groups is
attributed to the stronger binding of the sterically less hindered alkyl radical to the Li surface.31
According to Table 7, the adsorption of the methyl radical on Li is the most exothermic and the
adsorption energy decreases as the bulkiness of the alkyl group increases. Again, an electronic
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explanation, rather than a steric one, is quite unlikely since there is a noticeable difference in the
adsorption energies between the secondary radicals (Table 7, entries 2ꢀ4). Although experimental
studies on lithium surfaces are rare, calorimetry and DFT studies about alkyl adsorption on Pt
reveal that, similar to the reaction with Li, the methyl radical was found to adsorb much more
strongly than the tertꢀbutyl radical on the Pt surface.32
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Table 7. Calculated Radical Adsorption Energies.
Radical Adsorption on Li
Surface (*)a
ꢁEad
(kcal/mol)
ꢀ45.4
Entry Substrate
1
2
3
4
5
Meꢁ + * ꢀ Me*
iꢀPrꢁ + * ꢀ iꢀPr*
2ꢀbutylꢁ + * ꢀ 2ꢀbutyl*
3ꢀhexylꢁ + * ꢀ 3ꢀhexyl*
tꢀBuꢁ + * ꢀ tꢀBu*
3
7
11
12
10
ꢀ30.2
ꢀ28.9
ꢀ27.7
ꢀ24.3
a Li (110) surface modeled by five atomic layers with a p(5x5) supercell.
In summary, the DFT calculations indicate that the relative rates of cleavage of the
phenyl thioethers are controlled by the steric repulsions between the alkyl group and the lithium
surface in the adsorbed alkyl radical complex.
Reductive Lithiation of Additional Substrates.
In order to determine if other functional groups behaved in a manner similar to that of the phenyl
thioether, that is accept an electron from lithium metal in the absence of an aromatic electron
transfer reagent, the lithium dispersion method of reductive lithiation of some diverse substrates,
which have previously undergone either catalytic or preformed radicalꢀanion reductive lithiation,
was investigated. The importance of the lithium dispersion methodology is currently
demonstrated in the industrial production of commercially available organolithium reagents. This
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procedure involves the exothermic reaction of the alkyl chloride with lithium dispersion (0.5ꢀ2%
Na) in the desired hydrocarbon solvent.22
7
8
9
Yus and coꢀworkers have performed a large number of catalyzed lithiation reactions of
alkyl chlorides.8,33 In two of their blank reactions, in the absence of an aromatic electron carrier,
the lithiation of different alkyl chlorides resulted in one failed reaction, with 2ꢀ(3ꢀchloropropyl)ꢀ
2ꢀmethylꢀ1,3ꢀdioxolane (20) (Table 8, entry 1),8 and one successful reaction, with 6ꢀchloroꢀ1ꢀ
hexene (21) (Table 8, entry 3).33d In order to determine if 20 could be lithiated under our lithium
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dispersion conditions, we treated this substrate with lithium dispersion, also at ꢀ78 C. As a
result, the corresponding alcohol product 24 was successfully obtained, in half the amount of
time, after capturing the organolithium intermediate with benzaldehyde (entry 2).
Unlike the cyclopentyl product that Yus isolated (entry 3), our reductive lithiation of 21
gave no rearranged product (entry 4). In the process of CꢀS bond cleavage on the Li surface, no
free alkyl radical is formed. The large adsorption energies (Table 7) suggest the alkyl group
remains strongly adsorbed on the surface. Furthermore, the short CꢀLi distance in the adsorbed
complexes (Figure 2) indicates bonding interaction with the radical carbon, which will likely
prevent the radical cyclization to form the cyclopentylmethyl radical. The lithium dispersion
method of reductive lithiation of isopropyl chloride (22) and neopentyl chloride (23) provided
excellent yields of the corresponding alcohol products, 14 and 26, after the organolithium
intermediates were trapped with benzaldehyde (Table 8, entries 5 and 6). It is probably safe to
assume that the reductive lithiation of alkyl chlorides, like that of phenyl thioethers, is general in
the absence of added aromatic electron carriers under our very mild conditions.
Table 8. Reductive Lithiation of Alkyl Chlorides.
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Temp. Time
%
Entry
Alkyl Chloride
Product
Yielda
(oC)
(min.)
6
7
8
9
1
ꢀ78
240
0b
20
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2
ꢀ78
120
85
20
21
24
3
4
ꢀ30
ꢀ45
50
60
83c
78
21
25
14
26
5
ꢀ45
30
79
99
22
23
6
ꢀ45
30
a Isolated yield after chromatography purification. b Ref 8. c Ref 33d.
o
A 2006 report of the reductive cleavage of anisole (6) at the alkyl CꢀO bond, at 0 C
indicated that using 14 equivalents of Li but no DBB gave no product.5 When this result was
repeated with our lithium dispersion method, no cleavage product was formed. This result was
puzzling because the bond dissociation energy values for the homolytic cleavage of the methylꢀ
heteroatom bond of anisole (65.7 kcal/mol) and of methyl phenyl sulfide (66.7 kcal/mol) are
close in energy.34 Therefore, under the same reductive lithiation conditions, the rate at which the
methyl radical is formed from each compound should be similar.
Calculations reveal that the adsorption energy of 6 onto the surface of lithium is
significantly less exothermic than the adsorption energies of alkyl phenyl sulfides (Table 5, entry
6). The more favorable adsorption energies of the alkyl phenyl sulfides compared to anisole are
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presumably due to the greater polarizability of sulfur compared to oxygen. Since previous studies
indicated stronger substrate adsorption promotes carbonꢀhalogen bond cleavage,27 the much
greater moleculer adsorption energies of phenyl thioethers compared to anisole are expected to
contribute to their reactivity on the lithium surface in the absence of an aromatic electron carrier.
In that same 2006 report, Cohen and coꢀworkers performed the PAR reductive cleavage
of acrolein diethyl acetal (27).5,35 When 27 was subjected to the lithium dispersion method
conditions developed in our work, the reductive cleavage occurred smoothly at ꢀ45 oC to provide
a 68% yield of 29 in a Z/E ratio of 7:1 (Scheme 7). This yield closely matches that obtained from
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the LDBB reductive cleavage of 27 after 90 min. at ꢀ50 C.5 Our yield of 29 surpasses the 34%
yield obtained with Yus’s CA method in which a 4ꢀfold excess of lithium and Barbier conditions
were employed.36
Scheme 7. Reductive Lithiation of Acrolein Diethyl Acetal.
In 1995, Yus and coꢀworkers reported that isochroman (30) can be converted into lithium
2ꢀ(2ꢀlithiomethylphenyl)ethanolate (31) via the reductive ringꢀopening by an excess of lithium
powder (20 molar) and a catalytic amount of DBB (Table 9, entries 1 and 3).37 Furthermore, the
claim is made that in the absence of the DBB, lithiation times were longer (ca. 3 h) and yields
were considerably lower.37 When 30 was subjected to our lithium dispersion conditions, 2ꢀ(2ꢀ
o
o
methylphenyl)ethanol (32) was isolated in excellent yields at both 0 C and ꢀ78 C (Table 9,
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entries 2 and 5). The formation of 31 was confirmed by quenching the reaction mixture with D2O
(entry 4) to obtain 2ꢀ(2ꢀdeuteriomethylphenyl)ethanol (33). Thus, only 2.4 molar equivalents of
lithium dispersion were necessary to achieve similar yields as Yus et. al., even at lower
temperatures.
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Table 9. Reductive Lithiation of Isochroman.
Temp. Time
% Yielda
Entry
Product
(oC)
20
0
(min.)
45
1
2
3
4
5
H (32)
H (32)
D (33)
D (33)
H (32)
89b
78
30
20
0
45
30
86b
70
ꢀ78
120
99
aIsolated yield after chromatography purification. b Ref 37.
CONCLUSION
Many reductive lithiations, previously thought to be possible only in the presence of aromatic
electron transfer reagents, can be performed by the use of lithium metal alone with no electron
transfer reagent present when lithium dispersion is the Li metal source. Furthermore, the absence
of the transfer reagents can completely change and even reverse the selectivity of ease of
reduction of different but very similar substrates. Phenyl thioethers with smaller alkyl groups are
much more reactive than those with bulkier substituents. This is highly unusual and probably
unprecedented.
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DFT calculations reveal that the key step of alkyl phenyl sulfide cleavage on the lithium
surface involves the formation of a thiophenoxyl and an alkyl radical adsorbed on the surface.
Sterically less hindered alkyl radicals bind the surface more strongly, and thus lead to more
exothermic cleavage of the alkyl phenyl sulfide. To the best of our knowledge, the work
presented here is the first example where this steric effect controls the selectivity in reductive
lithiation reactions. The methodology developed in this work includes, but may not be limited to,
the reductive lithiation of phenyl thioethers, alkyl chlorides, acrolein diethyl acetal, and
isochroman.
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EXPERIMENTAL SECTION
General Methods.
o
All reactions were carried out under a positive pressure of dry argon gas in ovenꢀdried (120 C)
flasks and standard precautions against moisture were taken. A dry ice/acetone bath was used to
obtain ꢀ78 oC, an iceꢀwater bath was used to obtain 0 oC, and a dry ice/acetonitrile bath was used
o
to obtain ꢀ45 C. Flash chromatography (low pressure) was performed with either silica gel (32ꢀ
63 µm) or aluminum oxide, activated basic or neutral. Thinꢀlayer 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.
Commercial solvents and reagents were used as received with the following exceptions:
tetrahydrofuran (THF) was distilled over sodium metal in the presence of benzophenone as
indicator, hexanes was freshly distilled over CaH2, and benzaldehyde was washed with saturated
NaHCO3(aq), extracted with diethyl ether, and vacuum distilled (~20 mm Hg).38 Lithium
dispersion (25 wt% in mineral oil) was commercially available from SigmaꢀAldrich. Toward the
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end of the work described here, SigmaꢀAldrich discontinued offering lithium dispersion;
however, recipes for its preparation are available.39 Furthermore, as described here, granular
lithium, commercially available from SigmaꢀAldrich, is only slightly less effective than the
dispersion. 1H and 13C NMR operated at 300 MHz or 400 MHz for 1H and 75 MHz for 13C at 22
oC unless otherwise noted. Chemical shift data are reported in units of δ (ppm) relative to
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internal standard TMS (set to 0 ppm). Chemical shifts for C are referenced to the central peak
of the 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.
Phenyl Thioethers.
Isopropyl Phenyl Sulfide (7). A roundꢀbottom flask was charged with water (45 mL) and NaOH
(1.75 g, 43.8 mmol). Thiophenol (4.0 mL, 39 mmol) was added dropwise to the solution. The
reaction mixture was stirred for 30 min. to insure the complete formation of sodium
thiophenoxide. Isopropyl iodide (4.0 mL, 40 mmol) in ethanol (7 mL) was added slowly at room
temperature. The resulting reaction mixture was stirred at the same temperature for 24 h. The
product was extracted with dichloromethane and the combined organic extracts were washed
with 1 M NaOH(aq) followed by water. The organic layer was dried over MgSO4 and
concentrated in vacuo. The crude colorless oil 7 was used without purification (4.91 g, 80%
yield). 1HNMR (CDCl3) δ (ppm): 7.39 (d, J = 8.0 Hz, 2H), 7.28, (t, J = 7.6 Hz, 2H), 7.21 (t, J =
7.4 Hz, 1H), 3.36 (septet, J = 6.7 Hz, 1H), 1.29 (d, J = 6.4 Hz, 6H); 13CNMR (CDCl3) δ (ppm):
135.5, 131.9, 128.7, 126.6, 38.2, 23.1. These NMR data compare well with the literature
values.16
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5ꢀ(Phenylthio)ꢀ1ꢀpentene (8). A 100 mL roundꢀbottom flask was charged with water (45 mL)
and NaOH (1.7 g, 45 mmol). Thiophenol (4.3 g, 39 mmol) was added dropwise to the solution.
The reaction mixture was stirred for 30 min. to insure the complete formation of sodium
thiophenoxide. 5ꢀBromoꢀ1ꢀpentene (3.7 mL, 31 mmol) in ethanol (6 mL) was added slowly at
room temperature. The resulting reaction mixture was stirred at the same temperature for 24 h.
The product was extracted with dichloromethane and the combined organic extracts were washed
twice with 1 M NaOH(aq) followed by water. The organic layer was dried over MgSO4 and
concentrated in vacuo. The crude colorless oil 8 was used without purification (6.0 g, 99%
9
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yield). HNMR (CDCl3) δ (ppm): 7.32 (d, J = 8.0 Hz, 2H), 7.27 (t, J = 7.6 Hz, 2H), 7.16 (t, J =
7.2 Hz, 1H), 5.78 (ddt, J = 6.8, 3.6, 3.4 Hz, 1H), 5.05ꢀ4.97 (m, 2H), 2.92 (t, J = 7.2 Hz, 2H), 2.19
(q, J = 7.2 Hz, 2H), 1.74 (pentet, J = 7.2 Hz, 2H); 13CNMR (CDCl3) δ (ppm): 137.6, 136.7,
129.1, 128.9, 125.8, 115.4, 33.0, 32.7, 28.3. These NMR data compare well with the literature
values.17
1ꢀ(Phenylthio)ꢀ1ꢀcyclohexene (9). Thiophenol (2.0 mL, 20 mmol), cyclohexanone (2.1 mL, 20
mmol), Montmorillonite K10 (4.0 g) and toluene (200 mL) were added under argon to a 250 mL
three neck roundꢀbottom flask equipped with a Dean Stark trap and condenser. The light beige
slurry was heated at reflux for a 6 h. period and then was cooled to ambient temperature and was
filtered. The filter pad was washed with toluene and the filtrate was washed twice with 1 M
NaOH(aq) followed by water. The organic layer was dried over MgSO4 and concentrated in
vacuo. Flash chromatography on silica gel (100% hexanes) afforded pure product 9 (2.8 g, 72%
1
yield) as a colorless oil. HNMR (CDCl3) δ (ppm): 7.31ꢀ7.23 (m, 4H), 7.17ꢀ7.14 (m, 1H), 6.06
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(s, 1H), 2.13(m, 4H), 1.62 (dd, J = 20.4, 3.8 Hz, 4H); CNMR (CDCl3) δ (ppm): 135.2, 132.7,
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131.3, 130.0, 128.8, 126.2, 29.9, 26.7, 23.6, 21.6. These NMR data compare well with the
literature values.18
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Tertꢀbutyl phenyl sulfide (10). A mixture of indium powder (1.0 g, 8.7 mmol), diphenyl disulfide
(1.9 g, 8.7 mmol), and tertꢀbutyl bromide (2.0 mL, 18 mmol) in dichloromethane (50 mL) was
heated at reflux for 2 h. under argon. The reaction mixture was cooled to room temperature and
then was then quenched with 1 M HCl(aq). The product was extracted with dichloromethane and
the combined organic extracts were washed twice with 1 M NaOH(aq) followed by water. The
organic layer was dried over MgSO4 and concentrated in vacuo to afford 10 (2.1 g, 72% yield) as
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a colorless oil. HNMR (CDCl3) δ (ppm): 7.53ꢀ7.52 (m, 2H), 7.36ꢀ7.29 (m, 3H), 1.29 (s, 9H);
13CNMR (CDCl3) δ (ppm): 137.4, 132.7, 128.6, 128.4, 45.8, 31.0. These NMR data compare
well with the literature values.19
2ꢀ(Phenylthio)ꢀbutane (11). Sodium hydride (60 wt% in mineral oil, 0.60 g, 15 mmol) was
charged to a 3ꢀneck 25 mL roundꢀbottom flask equipped with a condenser. The sodium hydride
was washed with hexanes. DMF (5 mL) was added and the reaction mixture was stirred at room
temperature. Thiophenol (1.0 mL, 9.8 mmol) was added dropwise to the reaction mixture
followed by 2ꢀbromobutane (0.70 mL, 6.4 mmol). The reaction mixture was stirred at
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approximately 80 C for 2 h. under argon and then was cooled to room temperature and
quenched with water. The product was extracted with hexanes and the combined organic extracts
were washed twice with 1 M NaOH(aq) followed by H2O. The organic layer was dried over
MgSO4 and concentrated in vacuo. Flash chromatography on basic alumina (100% hexanes)
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afforded pure product 11 (0.95 g, 89% yield) as a colorless oil. HNMR (CDCl3) δ (ppm): 7.36
(dd, J = 5.1, 2.2 Hz, 2H), 7.28 (t, J = 7.2 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 3.13 (sextet, J = 6.6
Hz, 1H), 1.71ꢀ1.42 (m, 2H), 1.25 (d, J = 6.9 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H); 13CNMR (CDCl3)
δ (ppm): 135.6, 131.9, 128.7, 126.6, 44.9, 29.5, 20.5, 11.4. These NMR data compare well with
the literature values.20
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3ꢀ(Phenylthio)ꢀhexane (12). Sodium hydride (60 wt% in mineral oil, 1.2 g, 30 mmol) was
charged to a 3ꢀneck 25 mL roundꢀbottom flask equipped with a condenser. The sodium hydride
was washed with hexanes. DMF (10 mL) was added and the reaction mixture was stirred at room
temperature. Thiophenol (2.0 mL, 19.6 mmol) was added dropwise to the reaction mixture
followed by 3ꢀbromohexane (1.8 mL, 12.8 mmol). The reaction mixture was stirred at 100 oC for
2 h. under argon and then was cooled to room temperature and quenched with water. The product
was extracted with hexanes and the combined organic extracts were washed twice with 1 M
NaOH(aq) followed by H2O. The organic layer was dried over MgSO4 and concentrated in vacuo.
Flash chromatography on basic alumina (100% hexanes) afforded pure product 12 (2.4 g, 99%
yield) as a colorless oil. 1HNMR (CDCl3) δ (ppm): 7.36 (d, J = 7.5 Hz, 2H), 7.20 (t, J = 7.4 Hz,
2H), 7.14ꢀ7.09 (m, 1H), 3.01 (pent, J = 6.2 Hz, 1H), 1.63ꢀ1.41 (m, 6H), 0.98 (t, J = 7.4 Hz, 3H),
0.88 (t, J = 6.9 Hz); 13CNMR (CDCl3) δ (ppm): 136.0, 131.8, 128.7, 126.4, 50.4, 36.2, 27.3,
20.1, 14.0, 11.1; IR (thin film) 3073 (s); 2959 (m); 2930 (m); 2872 (m); 1584 (s); 1477 (s); 1459
(s); 1439 (s); 1378 (s); 1091 (s); 1025 (s); 740 (m); 692 (m) cmꢀ1; TOF MS (ES+) Calcd for
C12H18S 194.1129; Found 194.1126.
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Cyclooctyl phenyl sulfide (13). Sodium hydride (60 wt% in mineral oil, 0.7 g, 15 mmol) was
charged to a 3ꢀneck 25 mL roundꢀbottom flask equipped with a condenser. The sodium hydride
was washed with hexanes. DMF (5 mL) was added and the reaction mixture was stirred at room
temperature. Thiophenol (1.10 mL, 10.8 mmol) was added dropwise to the reaction mixture
followed by cyclooctyl bromide (1.0 g, 5.2 mmol). The reaction mixture was stirred at 100 oC for
3 h. under argon and then was cooled to room temperature and quenched with water. The product
was extracted with hexanes and the combined organic extracts were washed twice with 1 M
NaOH(aq) followed by H2O. The organic layer was dried over MgSO4 and concentrated in vacuo.
Flash chromatography on basic alumina (100% hexanes) afforded pure product 13 (0.81 g, 52%
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yield) as a colorless oil. HNMR (CDCl3) δ (ppm): 7.37 (dd, J = 7.2, 0.8 Hz, 2H), 7.27 (dd, J =
5.6, 1.6 Hz, 2H), 7.19 (td, J = 5.2, 1.2 Hz, 1H), 3.43ꢀ3.36 (m, 1H), 2.00ꢀ1.93 (m, 2H), 1.79ꢀ1.50
(m, 12H); 13CNMR (CDCl3) δ (ppm): 136.3, 131.5, 128.9, 126.5, 47.8, 32.1, 27.3 26.0, 25.3.
These NMR data compare well with the literature values.20
Catalytic and Lithium Dispersion Reductive Lithiation of Methyl Phenyl Sulfide (3):
(Table 1)
A 10 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)
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under argon. The lithium was then cooled to ꢀ78 C and THF (1 mL) was added. A solution of
the electron transfer catalyst (DBB or DMA, 0.10 mmol) in THF (0.5 mL) was added dropwise
to the flask. Immediately following, was the dropwise addition of a solution of methyl phenyl
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sulfide, 3 (0.11 mL, 1.0 mmol) in THF (0.5 mL). The reaction mixture was stirred at ꢀ78 C for
30 min. Benzaldehyde (0.12 mL, 1.2 mmol) was added dropwise and the reaction mixture was
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stirred at ꢀ78 C for 30 min. The reaction was then quenched with water and the product was
extracted with diethyl ether. For the DMA catalyst, the combined organic extracts were washed
with 1% HCl(aq) (5 mL); the organic layer was dried over MgSO4 and concentrated in vacuo.
Flash chromatography on silica gel (EtOAc/hexanes) afforded 1ꢀphenylethanol (5) as a light
yellow oil. 1HNMR (CDCl3) δ (ppm): 7.33ꢀ7.27 (m, 4H), 7.26ꢀ7.22 (m, 1H), 4.82 (q, J = 6.4 Hz,
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1 H), 2.37 (br, 1H), 1.44 (d, J = 6.4 Hz, 3H); CNMR (CDCl3) δ (ppm): 146.0, 128.4, 127.3,
125.5, 70.2, 25.2. These NMR data compare well with the literature values.5
LDBB Reductive Lithiation of Methyl Phenyl Sulfide (3): (Table 1)
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)
under argon. THF (3 mL) was added and the mixture was stirred at room temperature. A solution
of DBB (0.64 g, 2.7 mmol) in THF (2 mL) was added to the flask and the reaction mixture was
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stirred at room temperature for 5 min. and then was cooled to 0 C. The reaction mixture was
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stirred at 0 C for 5 h. and then was cooled to ꢀ78 C. A solution of methyl phenyl sulfide, 3
(0.11 mL, 1.0 mmol) in THF (0.5 mL) was added dropwise and the reaction mixture was stirred
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at ꢀ78 C for 30 min. Benzaldehyde (0.12 mL, 1.2 mmol) was added dropwise and the reaction
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mixture was stirred at ꢀ78 C for 30 min. The reaction was then quenched with water and the
product 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 5 (96
mg, 79% yield).
Catalytic Method of Reductive Lithiation of Anisole (6): (Table 2)
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An ovenꢀdried 25 mL roundꢀbottom flask was charged with 25 wt% lithium dispersion in
mineral oil (220 mg, 7.9 mmol). The lithium was washed three times with hexanes (3 mL) and
once with THF (3 mL) under argon. The lithium was then cooled to 0 oC and THF (2.5 mL) was
added followed by a solution of DBB (98 mg, 0.37 mmol) in THF (0.5 mL). Anisole, 6 (0.40
mL, 3.7 mmol) was added dropwise and the reaction proceeded for 30 min. at 0 oC and then was
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cooled to ꢀ45 C. Benzaldehyde (0.46 mL, 4.5 mmol) was added dropwise and the mixture was
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stirred for an additional 15 min. at ꢀ45 C and then 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 (EtOAc/hexanes) afforded 5 (0.26 g,
59% yield).
Under the same conditions but with 10 mol% of DMAN (63 mg, 0.37 mmol), afforded the title
compound 5 (0.30 g, 66% yield).
Under the same conditions but with 10 mol% of DMA (45 mg, 0.37 mmol), afforded no product.
Under the same conditions but with 10 mol% of DMA (45 mg, 0.37 mmol) at room temperature
for 24 h., afforded no product.
Reductive Lithiation of (3), (7), (8), and (9) with Lithium Dispersion: (Table 3, Method A)
A 10 mL roundꢀbottom flask was charged with 25 wt% lithium dispersion in mineral oil (0.13 g,
4.8 mmol). The lithium was washed three times with hexanes (3 mL) and once with THF (3 mL)
under argon. The lithium was cooled (see Table 3, Method A) and THF (3.5 mL) was added. A
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solution of methyl phenyl sulfide, 3 (0.25 g, 2.0 mmol) in THF (0.5 mL) was then added
dropwise. The reaction mixture was stirred for the allotted amount of time and then
benzaldehyde (0.24 mL, 2.4 mmol) was added dropwise. The reaction mixture was warmed to
room temperature and then was quenched with water in an iceꢀwater bath. The product 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 5.
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2ꢀMethylꢀ1ꢀphenylpropanꢀ1ꢀol (14): The same procedure as that for 3 with isopropyl phenyl
sulfide, 7 (0.30 g, 2.0 mmol) in place of methyl phenyl sulfide, afforded the title compound 14 as
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a light yellow oil. HNMR (CDCl3) δ (ppm): 7.33ꢀ7.23 (m, 5H), 4.31 (d, J = 6.8 Hz, 1H), 2.08
(br, 1H), 1.93 (sextet, J = 6.8 Hz, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 7.2 Hz, 3H);
13CNMR (CDCl3) δ (ppm): 143.6, 128.0, 127.2, 126.5, 79.8, 35.1, 18.9, 18.2. These NMR data
compare well with the literature values.40
1ꢀPhenylhexꢀ5ꢀenꢀ1ꢀol (15): The same procedure as that for 3 with 5ꢀ(phenylthio)ꢀ1ꢀpentene, 8
(0.36 g, 2.0 mmol) in place of methyl phenyl sulfide, afforded the title compound 15 as a light
1
yellow oil. TOF MS (ES+) Calcd for C12H15O 175.1123; Found 175.1114; HNMR (CDCl3) δ
(ppm): 7.34ꢀ7.23 (m, 5H), 5.77 (ddd, J = 6.5, 3.6, 3.2 Hz, 1H), 5.00ꢀ4.92 (m, 2H), 4.64ꢀ4.61 (m,
13
1H), 2.08 (br, 1H), 2.06, (q, J = 7.2 Hz, 2H), 1.82ꢀ1.65 (m, 2H), 1.54ꢀ1.32 (m, 2H); CNMR
(CDCl3) δ (ppm): 145.0, 138.7, 128.5, 127.5, 126.0, 114.8, 74.5, 38.5, 33.7, 25.2. These NMR
data compare well with the literature values.41
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