Ortho-lithiations reassessed: The advantages of deficiency catalysis in hydrocarbon media

Article abstract of DOI:10.1021/om301120e

Hydrocarbon media based metalation procedures involving "deficiency catalysis" are described for the ortho-lithiation of anisole (A), p-chloroanisole (p-ClA), o-, m-, p-methylanisoles (o-, m-, p-MA), the three dimethoxybenzenes (DMB's), dimethylaniline (DMA), dimethybenzylamine (DMBA), m-methoxydimethylaniline (m-MeODMA), and tetramethyl-p-phenylenediamine (p-TMPDA). These procedures involve certain mechanistic considerations, which must be fine-tuned to maximize the extent of metalation (EoM). Our working hypothesis is that a controlled deoligomerization of the n-BuLi hexamer found in hydrocarbon media will afford a "sweet spot" of deoligomerization such that a maximally efficient metalation medium can be formed. In many cases, a substoichiometric ratio of equivalent TMEDA to n-BuLi is 0.1-0.2:1.0, but certain substrates suffer multiple sites of metalation under these conditions, so different promoted hydrocarbon media systems incorporating measured equivalents of an ether have been formulated. This paper represents the summary of our successful efforts to render ortho-lithiations safer, greener, and more atom-economical by use of hydrocarbon solvent media. EoM's of 11 of the 12 substrates under these atom-economical conditions range from 87 to 97%.

Full text of DOI:10.1021/om301120e

Article
pubs.acs.org/Organometallics
ortho-Lithiations Reassessed: the Advantages of Deficiency Catalysis
in Hydrocarbon Media
D. W. Slocum,* Thomas K. Reinscheld, Christopher B. White, Michael D. Timmons, Philip A. Shelton,
Matthew G. Slocum, Rebecca D. Sandlin, Erica G. Holland, Damir Kusmic, John A. Jennings,
Kristen C. Tekin, Quang Nguyen, Steven J. Bush, Julia M. Keller, and Paul E. Whitley*
Department of Chemistry, Western Kentucky University, 1906 College Heights Boulevard, Bowling Green, Kentucky 42101, United
States
ABSTRACT: Hydrocarbon media based metalation proce-
dures involving “deficiency catalysis” are described for the
ortho-lithiation of anisole (A), p-chloroanisole (p-ClA), o-, m-,
p-methylanisoles (o-, m-, p-MA), the three dimethoxybenzenes
(DMB’s), dimethylaniline (DMA), dimethybenzylamine
(DMBA), m-methoxydimethylaniline (m-MeODMA), and
tetramethyl-p-phenylenediamine (p-TMPDA). These proce-
dures involve certain mechanistic considerations, which must be fine-tuned to maximize the extent of metalation (EoM). Our
working hypothesis is that a controlled deoligomerization of the n-BuLi hexamer found in hydrocarbon media will afford a “sweet
spot” of deoligomerization such that a maximally efficient metalation medium can be formed. In many cases, a substoichiometric
ratio of equivalent TMEDA to n-BuLi is 0.1−0.2:1.0, but certain substrates suffer multiple sites of metalation under these
conditions, so different promoted hydrocarbon media systems incorporating measured equivalents of an ether have been
formulated. This paper represents the summary of our successful efforts to render ortho-lithiations safer, greener, and more
atom-economical by use of hydrocarbon solvent media. EoM’s of 11 of the 12 substrates under these atom-economical
conditions range from 87 to 97%.
reagents in such media by the addition of measured amounts of
ethers, notably THF, or bis-chelating amines such as
tetramethylethylenediamine (TMEDA). Both types of agents
have long been known to activate alkyllithium reagents by
facilitating their disassociation to lower oligomeric forms. These
reagents sufficiently activate alkyllithium reagents for DoM
chemistry to be realized, ethers from the beginning of ortho-
lithiation chemistry and TMEDA, the principal bis-chelating
amine utilized, from the late 1960s.5 Indeed, our group was
among the first to maintain that DoM could be catalyzed by use
of TMEDA.6 Up to the time of our current investigations, it
was customary to use ethers as bulk solvents and TMEDA in
ratios amounting to full equiv. relative to the alkyllithium
reagent. That fractional equiv. of TMEDA could be effective in
catalyzing ortho-lithiations was first demonstrated by our group
in 19942a and the effectiveness of measured equiv. of THF in
bulk hydrocarbon solvent was illustrated two years later.2b The
promise of all these discoveries was that not only could DoM
chemistry be made safer and greener, but also the potential
existed that atom-economy could be achieved upon further
parameter and condition refinements. This paper represents the
summary of these successful efforts.
INTRODUCTION
■
Over the past two decades, our research program has focused
on making strong base chemistry, and in particular the directed
ortho-metalation (DoM) reaction,1 safer, more efficient, atom-
economical and, for want of a better notation, “greener.”2 Our
approach has been to incorporate the use of bulk hydrocarbon
media for these reactions. In so doing, we minimize the
principal problem of strong base chemistry, the dependence on
ethers as solvents. Ethers offer a greater breadth of solubility of
substrates for such reactions, but suffer from several
pronounced drawbacks (1) their hydroscopic nature and
overall water solubility, (2) their tendency to form explosive
peroxides, and (3) their reactivity with strong base reagents,3 in
particular alkyllithium reagents, the strong base reagent of
choice for ortho-lithiations.
Use of hydrocarbon solvents has its own set of drawbacks for
use with alkyllithium reagents. The most pronounced of these
is that alkyllithium reagents in hydrocarbon solvents are highly
associated, that is, are in their least reactive state.4 Hydrocarbon
solvents possess a lower ability to dissolve many substrates so
preparatory metalations tend to be more dilute than those run
in ether. An advantage of hydrocarbon solvents, in addition to
their not suffering from the general drawbacks of ethers, is that
they require relatively little maintenance or treatments for use
in metalation chemistry.
Our reasoning began with the fundamental insight provided
by W. Bauer and P.v.R. Schleyer7 that a coordinately
unsaturated n-BuLi dimer was involved in the transition state
How then to get around the lack of solubility and the lack of
the necessary reactivity of alkyllithium reagents in hydrocarbon
solvents? The answer is to promote the disassociation of these
Received: November 21, 2012
© XXXX American Chemical Society
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for ortho-lithiation (eq 1).In their view, the n-BuLi hexamer
was converted by the bis-chelating amine to a fully saturated n-
These considerations led to the concept of a “sweet spot” for
our hydrocarbon media promoted solutions. Manifestation of
this “sweet spot” was to be found by plotting extents-of-
metalation (EoM’s) vs a range of equiv. of ether or TMEDA
additive to the hydrocarbon media and observation of a
maximum. Moreover, it was realized that the maximum EoM
for any system should be temperature dependent with the
maximum EoM at higher temperatures requiring fewer equiv. of
additive. Evidence for the truth of this statement is contained
herein.
BuLi dimer stabilized by two amine ligands. Disassociation of
one of these amine ligands afforded a coordinately unsaturated
n-BuLi dimer 1, to which an unshared pair of electrons of
anisole (A), N,N-dimethylaniline (DMA), etc. could initially
coordinate leaving one vacant orbital on lithium to interact and
eventually insert into the aryl-H bond at the ortho-position.
Subsequent analyses for the transition state of ortho-lithiation
have been published by Schleyer and by others,8 but none
afford the clear predictive potential as the series of
intermediates put forward in 1989 by Bauer and Schleyer.7
In our view, the unsaturated mono TMEDA dimer in 1 is a
seminal proposal. Additional insight suggests that in ether
media (e) (DEE, THF, MTBE, etc.), coordinately deficient
dimers 2 and 3 would be formed. Complex 3 can exist in three
forms. The ability of substoichiometric amounts of TMEDA to
catalyze the ortho-lithiation of various aryl substrates we have
termed “deficiency catalysis”. We are unsure that equiv. of THF
or other ethers in bulk hydrocarbon media can be called
catalysis in the same regard, but the effect of 1.0, 2.0, and 3.0
equiv. of THF in bulk hydrocarbon media is certainly profound
as we will later demonstrate.
The proposed unsaturated TMEDA dimer possessed the bis-
coordinated structure 1. Additional insight by our group
suggested that a similar bis-coordinated intermediate 2
contributed to metalations in an ether as well. However, the
prevailing bis-coordinated n-BuLi dimer ether(e) media
intermediate would be 3. It is likely that 2, the THF version
of the Bauer and Schleyer intermediate,7 would be present in
relatively minor amounts. This may, at least in part, explain n-
BuLi’s much greater reactivity enhancement when complexed
by TMEDA compared to THF. It occurred to us that if 1 were
an intermediate in the course of a TMEDA-catalyzed
metalation reaction, addition of increasing increments of
TMEDA would deoligomerize the n-BuLi hexamer and move
the known equilibrium toward the coordinately deficient dimer
1 to an increasing extent. A similar statement can be made
regarding THF except that to generate intermediate 2,
stoichiometric quantities of THF would be required to reach
effective concentrations of intermediate 2. It was further
realized that too much TMEDA or THF would increase the
population of saturated forms of the dimer which would be
counterproductive! It is the generation of the coordinately
unsaturated intermediates 1 and 2 that must be maximized in
our doped hydrocarbon media to achieve the greatest
metalation efficiency.
Measured doping of hydrocarbon solvents, that is, the
addition of increments of THF, TMEDA, etc. to bulk
hydrocarbon solvents containing an alkyllithium, in particular
n-BuLi, has revealed maximally effective metalating solutions
for a variety of substrates (vide infra). Such solutions drive the
oligomer equilibrium to favor the unsaturated dimers
(structures 1 and 2), the putative reactive intermediate in
alkyllithium metalation chemistry. Just as would bulk ether
solvents or media containing a full equiv. of TMEDA,
hydrocarbon media promoted metalation solutions will contain
some concentration of a coordinately unsaturated dimer. This
unsaturated dimer must exist so that the more weakly
coordinating DMG (directing metalation group) of the aryl
substrate can associate with the dimer. The association to be
sure also takes place in bulk ether solvents and in the presence
of a full equiv. of TMEDA, but the dimer concentration,
presumably larger than in our doped media, is either
coordinatively saturated or nearly so. This makes it more
difficult for the ArDMG reacting substrate to achieve the prior
coordination necessary to proceed through the transition state.
Only by supplying a measured amount of deoligomerizing
agent(s) to the hydrocarbon solution can the balance between
dimer formation and ArDMG coordination be made most
efficient. This equilibrium is illustrated in eq 2 for TMEDA
complexation. We are uncertain of the number of TMEDA’s in
the n-BuLi tetramer, but we hypothesize that among the dimer
complex population, some percentage would possess structure
1. A similar set of “deficiency catalysis” equilibria applies to
metalations in THF/hydrocarbon media.
RESULTS AND DISCUSSION
■
Anisole (A). ortho-Lithiation chemistry began with the
seminal observations of Gilman9 and Wittig10 that anisole,
upon treatment with n-BuLi in ether and subsequently
derivatized, afforded ortho-substituted products. Since that
time countless papers have appeared detailing efforts to
determine the mechanism of the ortho-lithiation process.8
Anisole has served as the benchmark for virtually all of these
studies. Numerous other reports of the utilization of ortho-
lithioanisole (o-LiA) in synthesis have also been published with
modest to good product yields being reported in most cases.11
We attribute most of these modest yields to initial incomplete
ortho-lithiation of anisole. Yields approaching 100% have been
realized by the expedient of using the halogen/lithium exchange
on o-bromoanisole at −78 °C.12
Utilizing this benchmark substrate, we have studied EoM’s in
three time-honored media: (1) DEE, (2) DEE/TMEDA, and
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(3) THF. Over the course of these reactions, it is clear that high
EoM’s can be achieved in TMEDA/ether and in THF (Table
1). Our studies emphasize a 1:1 ratio of anisole to n-BuLi
are not normally associated with ortho-lithiations, these results
provided initial impetus for our further study of the effect of
elevated temperatures on metalation procedures. Under these
same conditions and over the same period, but without the
presence of THF, that is, in pure hydrocarbon media,
metalation of anisole could be effected in only about an 8−
10% EoM at 22 °C and about a 40% EoM at 60 °C.
Further investigation involved the use of TMEDA instead of
THF to enhance EoM in cyclohexane. Varying the equiv. of
TMEDA vs equiv. of anisole and n-BuLi from 0.05:1:1 to 2:1:1
provided significantly different EoM’s, but data points exhibited
unacceptable scatter for plotting. The solutions over all equiv.
ratios of TMEDA were heterogeneous with copious amounts of
a white flocculant precipitate being produced. This situation
made reproducible repeated sampling difficult. Nevertheless, it
became apparent that a maximum EoM was possible for this
system with a catalyst: reactant equiv. ratio of 0.1−0.2:1.0:1.0.
Larger ratios of TMEDA than 0.2 equiv. were counter-
productive in that the EoM was observed to decrease. Study
of the effect of temperature for the 0.1:1:1 system exhibited a
significant variation (Figure 2). This study was performed on
more dilute systems (0.67 M vs the usual 1.0 or 1.3 M), which
allowed reproducible samples to be obtained, but with slightly
lower EoM’s.
Subsequent investigation maintaining the 0.1:1:1 ratio of
TMEDA and the two reactants each 2 M in cyclohexane
afforded reproducible 93−95% EoM’s (Figure 3). Further
enhancement of the purity of this solution was possible by
centrifugation, syringing off the supernate and replacing same
with an equal volume of cyclohexane. This procedure was
sufficient to remove the few remaining percent of anisole such
that the residual o-LiA approached a purity of 99%. As o-LiA is
insoluble in hydrocarbon solvents, minimal loss of intermediate
was experienced and so the remaining amount of o-LiA could
be determined by simply allowing for the 2−4% loss of
unmetalated anisole upon washing and transfer. This is a
defining example since all the other ortho-lithio intermediates
possess greater solubility in hydrocarbon media.
Interestingly, both PMDTA and (−)-sparteine were found to
catalyze the ortho-lithiation of anisole at 22 °C (Table 1). Both
studies were performed in a 1.0 M cyclohexane solution of the
reactants with 0.2 equiv. of catalyst and must be regarded as
preliminary at the present time. The (−)-sparteine studies
afforded no increase in EoM with an increase in temperature.
Table 1. Summary of Preliminary Anisole Metalation Studies
a
medium
equiv. amine/ether
T (°C) time (h)
EoM (%)
b
DEE
0
22
22
22
22
22
22
45
45
45
22
22
6
4
3
8
6
6
8
6
6
6
6
57
83
89
62
78
84
85
86
90
94
92
b
DEE
1.0 TMEDA
0
b
THF
c
c
c
c
c
c
c
c
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
1.0 THF
2.0 THF
3.0 THF
1.0 THF
2.0 THF
3.0 THF
d
0.2 PMDTA
0.2 (−)-sparteine
a
b
Period at which a maximum EoM was observed. Reactants 1.3 M.
Reactants 1.0 M. Pentamethyldiethylenetriamine.
c
d
whereas many of the examples found in the literature employ
an excess of the alkyllithium reagent. All of the EoM vs time
plots recorded herein involve derivatization of the generated
ortho-lithio intermediate with chlorotrimethylsilane (ClTMS)
and subsequent GC analysis as a measure of EoM. EoM is a GC
percentage defined simply as the areas of TMSAr / (TMSAr +
ArH) × 100. In that the efficient reactions afforded EoM’s
>87%, no correction factor was applied. These transformations
are very clean for the anisole metalation with no other material
besides the unreacted starting material and the product being
detected under all conditions.
Our earliest study of metalation in hydrocarbon solvents
revealed that a maximum EoM of anisole at room temperature
could be achieved by the addition of 3 equiv. of THF to the
bulk hexane solvent.2b A repeat of this study using cyclohexane
as solvent instead of hexane (Table 1) illustrates that in 8 h an
85% EoM of anisole is obtained at ambient temperature using 3
equiv. of THF. Lesser EoM’s are obtained using 1.0 or 2.0
equiv. of THF. We since have observed that higher EoM’s for
this system can be obtained at elevated temperatures, explicitly
45 °C (Table 1) and 60 °C (Figure 1) with about a 95% EoM
being realized at 60 °C. Moreover, at 60 °C, the system
containing just 2.0 equiv. of THF afforded nearly the same
EoM when comparing the 4 h points. As elevated temperatures
Figure 1. EoM vs time utilizing a 1.0 M solution of anisole/n-BuLi at 60 °C in cyclohexane containing (green) 1.0 equiv. THF, (blue) 2.0 equiv.
THF, and (red) 3.0 equiv. THF.
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Figure 2. EoM vs time for a 0.67 M solution of anisole/n-BuLi in cyclohexane containing 0.1 equiv. TMEDA at various temperatures: (purple) 0 °C,
(green) 22 °C, (blue) 45 °C, and (red) 60 °C.
simultaneously bis-chelates a lithium in the oligomer or first
becomes monodentate and then conformational interconverts
to become bis-chelated.
p-Chloroanisole (p−ClA). The EoM enhancement with
increase of temperature of anisole prompted us to reexamine
the ortho-lithiation of p-chloroanisole (p-ClA).2e,13 The initial
hydrocarbon media based studies were carried out in hexanes
media at ambient temperature. Using the same conditions as
were employed in the high yield ortho-lithiation of anisole (1.0
M substrate and n-BuLi, cyclohexane, equiv. THF, 60 °C),
enhanced EoM’s compared to the original results were realized
(Figure 4).
Metalation experiments utilizing TMEDA were attempted. p-
ClA in the presence of TMEDA brought immediate formation
of a benzyne intermediate due to a competing lithiation ortho
to the −Cl substituent.2h For p-ClA, as little as 0.5 equiv. of
THF in cyclohexane at 60 °C after 6 h afforded EoM’s >95%.
o-, m- and p- Methylanisole (o-, m-, p-MA). The
continuing interest in calixarenes, cavitands, carcarands and
similar constructs suggests that synthetic routes to specifically
substituted alkylanisoles and alkylphenols will be useful. Our
program has long been involved with the study of metalation of
the methylanisoles. Already reported are our results for p-
methylanisole (p-MA)2b,c and o-methylanisole (o-MA).2i Here-
in we document our results for improved ortho-metalation of o-
MA and p-MA. Successful ortho-metalation of m-MA in
hydrocarbon media is reported for the first time.
Figure 3. Typical product solution from the treatment of anisole (2
M) with n-BuLi (2 M) with the addition of 0.15 equiv. of TMEDA.
The top layer is the supernate and the bottom layer is associated o-LiA
precipitate.
This is a provocative observation suggesting that TMEDA
experiences conformational benefit from bis-chelation with
increasing temperature (eq 3).With increasing temperature the
Several previous studies of the methylanisoles have appeared
in the literature with some contentious results having been
reported. Early studies by Shirley and co-workers of the
metalation and carboxylation of the o-MA system resulted in
isolation of a benzoic acid, which was the product of ortho-
lithiation and an acetic acid, the product of lateral lithiation.14a
These products were obtained in modest yields and in various
ratios. An earlier work had provided the same mixture of
products in low yields.14b The papers by Shirley and co-workers
first agreed with and then disputed the concept that the ortho-
methyl group caused a conformational steric bias of the
methoxy group that would retard the ortho-lithiation process in
this system. This was in response to the significant retardation
observed for the metalation of o-t-butylanisole observed under
various conditions.11j Further intrigue relative to the course of
this metalation is to be found in assessments of these
observations in the literature. Anisoles, among them
alkylanisoles, have been observed in superbase solution at
staggered/eclipsed Newman projection form on the right
would increase in population causing enhanced complexing
ability with n-BuLi and as a consequence enhanced ortho-
metalation. (−)-Sparteine possesses a locked conformation,
which is essentially eclipsed. Therefore it significantly outper-
forms TMEDA at 22 °C, but with no bis-chelating enhance-
ment with increasing temperature, trails TMEDA at 60 °C in
EoM. These arguments obviate whether or not TMEDA
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Figure 4. EoM vs time for a 1.0 M solution of p-ClA/n-BuLi in cyclohexane at 60 °C containing (green) 0.5 equiv. THF, (blue) 1.0 equiv. THF, and
(red) 2.0 equiv. THF.
Figure 5. EoM vs time for a 3-MeA/n-BuLi in cyclohexane containing 0.1 equiv. of TMEDA and 1.0 equiv. of THF at 60 °C; (red) 6-TMS-3-MA
and (blue) 2-TMS-3-MA.
reflux to undergo a methyl migration from the oxygen atom to
adjacent positions.15 An authoritative review, which has
examined these metalations in light of the previous studies,
concludes that metalation of o-MA cannot be regiospecifically
accomplished.16 Likewise, a computational treatment of the o-
MA systems concludes in line with the experimental
observations that regiospecific lithiation at either position
cannot be achieved.17
In 1974, studies of the metalation of m-MA afforded mixtures
of products from metalation at both ortho positions.14
Schlosser et al were later able to efficiently provide lateral
metalation of m-MA in 71% GC yield (carbonation, diazo-
methane) using n-BuLi/NaOt-Bu.18 Utilizing a different
metalating mixture, t-BuLi/pentamethyldiethylenetriamine
(PMDTA), nearly regiospecific ortho-lithiation at the un-
hindered ortho-position was achieved.18
In an early study, Letsinger and Schnizer found that ortho-
lithiation and carbonation of p-MA using n-BuLi/KOt-Bu and
subsequent carbonation afforded 59% of the ortho-product
along with 10% of the product from metalation of the p-methyl
group.19 A few years later, Schlosser utilized the same
metalating system in THF followed by carbonation, treatment
with diazomethane and GC analysis to attain a 78% GC yield of
the ortho-lithiation product of p-MA.20 An attempt by
Schlosser to selectively laterally metalate the p-methyl group
of p-MA resulted in a mixture of ortho- and lateral metalation
products. Our own group’s previous contribution to these
studies was the realization by GC analysis of >90% EoM using
2 equiv. of n-BuLi/0.2 equiv. TMEDA in DEE contaminated
with 2−3% of the laterally metalated product2c and essentially
regiospecific ortho-lithiation using increments of THF/n-
hexane in a GC analyzed 80% EoM.2b
All these earlier background observations have been
contradicted by the results of the thorough examination of
the metalation of all the MA’s by Schlosser and co-workers. For
ortho-lithiation of o-MA a 52% yield was attained using the
base combination of n-BuLi/NaOt-Bu.18 Lateral metalation was
regiospecifically accomplished in 67% yield using a different
base combination, that is, LDA/KOt-Bu. Other base combina-
tions, t-BuLi/PMDTA and t-BuLi/KOt-Bu were utilized to
regiospecificially metalate m-MA (64%) and p-MA (78%). All
of the results recorded by Schlosser et al. are based on
carboxylation, treatment with diazomethane followed by CG
analysis.
Satisfactory discrimination between the ortho-metalated
intermediated and lateral (α-) metalated intermediate was
observed by our group.2i ortho-Lithiation was achieved using
the original procedure of Harmon and Shirley,13 which utilized
a full equiv. of TMEDA. These authors reported about a 4:1
bias toward ortho-metalation at ambient temperature after 10 h.
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Repeating these conditions, we achieved a 7.5:1 preponderance
of the ortho-metalation intermediate in 1h.2i Further tweaking
of these conditions has resulted in a significant improvement in
the selectivity to a realized ortho-product preponderance of
11:1. These new conditions involved merely reducing the
TMEDA/n-BuLi ratio to 0.92:1 and heating the solution to 60
°C. Alternatively, DEE can be used to effect ortho-lithiation of
o-MA.21
The results is that e-density is more localized on the oxygens of
1,4-DMB than that in A, making the coordinating ability of the
oxygens in 1,4-DMB greater than the oxygen in A. Stated
differently, this would result in an enhanced complex-induced-
proximity-effect (CIPE).8a,b This activation toward ortho-
lithiation takes precedent in spite of the fact that the overall
e-density of the aromatic ring is higher in 1,4-DMB than it is in
A.
A completely different metalation profile was realized for m-
MA. After metalation for at least 48 h at 60 °C, 6-position EoM
reached 70% (Figure 5). Further equilibration for another 24 h
brought a maximized EoM of 80%. Nearly negligible amounts
of the 2-lithio intermediate were detected after 48 h, the
remaining contaminant being starting material. In unpublished
work, a number of derivatives of the 6-metalated intermediate
have been prepared and isolated in yields from 41 to 84%.
p-MA was efficiently ortho-metalated using the same
conditions as those used for 95% EoM of anisole, 3 equiv.
THF/cyclohexane, 60 °C. An EoM comparable to that for
anisole was realized. A slightly retarding effect of the p-methyl
substituent on the rate and EoM was noted.22
Dimethoxybenzenes (o-, m-, p-DMB). Utilization of the
“deficiency catalysis” concept with the dimethoxybenzenes
(DMB’s) brought quick reward with little fine-tuning of the
equiv. of TMEDA. Only 0.1 and 0.3 equiv. of TMEDA were
investigated with 1,2-DMB requiring 0.3 equiv. and the other
two isomers requiring only 0.1 equiv. For 1,2- and 1,4-DMB,
the principal compromising effect for a high EoM of
monometalation of these two aryl substrates was the tendency
to afford the dimetalated intermediate. In the case of 1,2-DMB,
this was the 3,6-dilithio intermediate and for the 1,4-DMB, the
2,5-dilithio intermediate. High EoM’s (88−90%) of these
substrates were attained in short periods of time at ambient
temperature. Each was contaminated with a small quantity of
the respective dilithiated intermediate. For 1,2-DMB, trituration
with pentane afforded 95% pure 3-lithio 1,2-DMB free of the
dilithio intermediate. This procedure proved impractical for the
1,4-isomer as the lithio intermediate was too soluble in pentane.
The EoM of 1,3-DMB was so high (97%) that no attempt was
made to further upgrade its purity.
There are questions regarding the relative reactivity of the
DMB’s in comparison to that of anisole. Certainly, 1,3-DMB is
more reactive than anisole in all cases. The origin of this
increased reactivity has had some varying insights ranging from
the “tweezer effect” articulated by Saa and co-workers23 to the
monocoordinated, second methoxy group acidifying effect
described by Collum et al.24 A hydrocarbon medium only
ortho-lithiation has been described for each of the DMB’s.2g
However, none of these procedures are what we would
consider to approach atom-economy(≥90% ortho-lithiation).
In hydrocarbon media, all three DMB’s are more reactive than
anisole with the order of reactivity being 1,2- > 1,3- > 1,4- > A.2f
This is not the order found in ether media. The hydrocarbon
media activation has been attributed to the substrate itself
providing the necessary deoligomerizative activation of n-BuLi
to effect ortho-lithiation. Thus the order observed reflects the
relative bis-chelating ability of the substrate with 1,2- being
greater than 1,3-. That 1,4-DMB is less reactive than either of
the other two DMB’s reflects its inability to bis-chelate, but its
greater reactivity compared to anisole to a different effect, the
opposing-π-resonance effect.25 Here the normal delocalization
of the unshared pairs on the methoxy group’s oxygens is
opposed by the delocalization of the p-oriented methoxy group.
However, our goal here is to activate the already described
regiospecific metalations in hydrocarbon media sufficient to
render these metalations atom-economical. Numbers of
procedures for the metalation of all the DMB’s have been
described in the literature.26−28 Most utilize either ether or
THF as the reaction medium and a few use a combination of
both ethers. Only for 1,4-DMB were several instances described
where the 2-Li-1,4-DMB intermediate was accessed via the
halogen/lithium exchange of 2-Br-1,4-DMB.29 Room temper-
ature metalations are the norm, with a significant number of
such metalations having been effected at lower temperatures.
Virtually all of these metalations have been accomplished with
n-BuLi with other organolithiums being utilized only rarely.
Extents of metalation (EoM’s) have in general been modest as
judged by isolated yields. In certain cases, metalation yields
have been quite high, but these yields are based on use of an
excess of metalating agent.
Dimethylaniline (DMA). ortho-Lithiation of DMA to
produce o-LiDMA has proven to be somewhat problematical
over the years. First described by Art Lepley and co-workers in
the 1960s,30 subsequent papers describe varying success with
this ortho-lithiation. Notable among these, although not atom-
economical, is the procedure recorded by Brandsma and
Verkruijse.1h This procedure relied on significant excess of
DMA. Other papers report product yields from the metalation
of DMA that are extremely varied.31 As with anisole and 1,4-
DMB, some researchers preferred to prepare o-LiDMA through
the ortho-bromo derivative via the halogen/metal exchange.32
Surprisingly, several of the systems found successful for
promoting high yields of ortho-lithiation in anisole failed when
applied to DMA. A study of equiv. of THF in cyclohexane at 25
°C afforded no better than a 15% EoM of DMA. Similar results
were achieved with fractional equiv. of (−)-sparteine. One is
tempted to ascribe steric congestion to the (−)-sparteine•n-
BuLi complex’s interaction with the dimethylamino group of
DMA as the cause for the failure of the (−)-sparteine
metalation system. A rationale for the failure of the THF-
promoted hydrocarbon media system is puzzling and requires,
in all likelihood, a more subtle explanation.
Further exploration turned to the system of fractional equiv.
of TMEDA in cyclohexane, the system so successful for the
ortho-lithiation of anisole. For this system reproducible
sampling data was attainable such that a plot of EoM vs
equiv. of TMEDA at various temperatures could be achieved
(Figure 6). The data supports our contention that there is a
competition between the dimer complexed with two TMEDA’s
and that with just one TMEDA and the substrate. Clearly, at 45
and 60 °C a deficiency of TMEDA provides superior results.
This system exhibited somewhat greater component
solubility than that of anisole allowing more reproducible
sampling data points to be obtained. It is clear from the plot
that ca. 90% o-LiDMA can be obtained at 60 °C using 0.1−0.2
equiv. (we have settled on 0.15 equiv.) of TMEDA with the
same 2 M concentration of reactants as was so successful for
the metalation of anisole. As with o-LiA, metalation slurry’s of
F
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−CH2NMe2 group was a relatively strong director, it was
reasoned that a more weakly activating promoter might provide
a more selective metalation, and avoid α-metalation. A series of
cyclohexane solutions were doped with MTBE with the
gratifying results plotted in Figure 8. Not only was 1.0 equiv.
of MTBE found to provide enhanced and accelerated ortho-
lithiation, but also significant regioselectivity. At 60 °C
reproducible atom-economical yields of o-LiDMBA in the
95−97% range could be attained. At 60 °C, ca. 2% of the α-
intermediate is generated which essentially disappears after 6 h
resulting in a two-phase system of the ortho-lithio intermediate
(Figure 9) similar in appearance to that obtained for o-LiA
(Figure 3).
m-Methoxydimethylaniline(m-MeODMA) and p-Tet-
ramethylphenylenediamine (p-TMPDA). Few metalations
of these substrates are to be found in the literature. Our earlier
work denoting the metalation of m-MeODMA in ether at
ambient temperature achieved an EoM of 80%.6c That
procedure utilized a 1:1 n-BuLi/TMEDA ratio each about 0.5
M with results determined by NMR analysis. In the present
study, our GC determined EoM of 88% using deficiency
catalysis at 60 °C surpasses this. Interestingly, the maximum
EoM is realized after 3 h which is much more rapid than those
noted for A and DMA (vide supra). However, 0.5 equiv. of
TMEDA was found necessary to achieve this EoM. In contrast,
1,3-DMB is metalated to an EoM of 97% in 1.5 h at ambient
temperature using a deficiency catalyzing TMEDA concen-
tration of only 0.1 equiv.
Figure 6. EoM vs Equiv. TMEDA for 1.3 M DMA/1.3 M n-BuLi in
cyclohexane at various temperatures: (blue) 60 °C, (red) 45 °C, and
(green) 22 °C.
this system could be upgraded by centrifugation, removal and
replacement of the supernate with pure hydrocarbon solvent.
However, for the DMA system to achieve purities of 95% or
greater two such washings were needed. Unfortunately, the o-
LiDMA is somewhat more soluble than o-LiA in cyclohexane/
hexanes and so more intermediate is lost in the washings. It is
estimated that ca. 15% of the DMA (as DMA and o-LiDMA) is
lost during such washings. Therefore working titers of this
reactive intermediate are assessed to be 85% of the original 2 M
solutions, that is, 1.7 M.
Dimethylbenzylamine (DMBA). Initial examination of
THF-doped and TMEDA-doped hydrocarbon solutions for the
metalation of DMBA were a disappointment. All additive
increments examined afforded percentages of the well-known
α-(lateral) metalation product (Figure 7).
A cooperative effect of the 1,3-oriented DMG’s appears
likely. Originally, this effect was called the “tweezer effect” by
Saa,23 but has more recently been attributed to an additional
acidifying effect of the second methoxy group by Collum.24
A
relevant observation made during our studies is that
derivatization with ClTMS must gestate at least 6 h in order
for an accurate EoM to be observed. This suggests that the 1,3-
DMG dimer proposed by Saa et al.23 might not only possess
some generality, but also some stability (eq 4). Only one of the
several possible bridged dimers is depicted. It is likely that a
mixture of these dimers exists as they do for o-LiDMBA as
determined by Reich and co-workers.35t,u
Figure 7. EoM vs time for the system 1.3 M DMBA/1.3 M n-BuLi at
22 °C containing 0.3 equiv. of TMEDA: (1) ortho-lithio intermediate
in (red) hexanes, (blue) cyclohexane and (2) α-intermediate in
(purple) hexanes, (green) cyclohexane.
C. R. Hauser, who discovered the directing properties of the
−CH2NMe2 group,33 also identified the α-lithio intermediate.
In an elegant study, he and his students demonstrated the
rearrangement of the α- to the o-lithio intermediate over time.34
Numbers of papers over the years have utilized the various
potentials of metalation of the DMBA system.35
With the failure of our standby regimens to affect
regiospecific ortho-lithiation, a working observation that
MTBE was useful in promoting efficient EoM’s was put to
the test. Earlier studies had shown that increments of MTBE,
usually about 1.0 equiv, promoted the ortho-lithiation of several
substrates, but that it was not as effective as THF. Since the
In contrast, metalation of p-TMPDA using deficiency
catalysis achieved results (ca. 95% EoM) slightly better than
that for DMA. A higher ratio of n-BuLi to TMEDA (1: 0.25)
was utilized but the reaction was run at ambient temperature.
Most importantly, barely detectable amounts (ca. 0.1%) of a
product from dimetalation (presumably the 2-,5-product) was
observed. This is much more of a problem with the metalation
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Figure 8. EoM vs time for the system 1.3 M DMBA/1.3 M n-BuLi in cyclohexane containing (blue) 0.7 equiv. and (red) 1.0 equiv. MTBE in
hexanes at 60 °C.
possess a 2-,5-orientation. The EoM for p-TMPDA recorded
here is much higher than from any other reported metalation of
this substrate.36
CONCLUSIONS
■
These hydrocarbon media metalations emphasize atom-
economy. For the most part, the Li/H exchange (ortho-
lithiation) of n-BuLi and an activated aryl’s ortho-position is
effected in a 1:1 ratio of the reactants. Moreover, minimum
quantities of catalyst/promoter are utilized resulting in
heterogeneous product solutions of nearly pure ortho-lithio
intermediates. No other alkyl-/aryl-lithium or other metal-
containing reagents are utilized. The fact that these trans-
formations can be efficiently accomplished in promoted
hydrocarbon media provides safety, sustainability, green and
control factors to these procedures, which are advantageous
compared to those for ether media.
Table 2 summarizes the details of the 12 procedures. Seven
of the 12 substrates were successfully metalated using a
deficiency of TMEDA between 0.1 and 0.5 equiv. For three of
the remaining substrates, p-ClA, p-MA and DMBA, increments
of TMEDA proved too aggressive and so promotion of the
Figure 9. Product solution from treatment of 1.3 M DMBA/1.3 M n-
metalation utilized equiv. of an ether. Uniquely, for 3-MA, a
combination of TMEDA and THF provided the maximum
EoM. Lastly, 2-MA, the only substrate containing a sterically
impacted directing group, required a more aggressive metal-
ating system, which was found using 0.92 equiv. of TMEDA.
BuLi in cyclohexane containing 1.0 equiv. of MTBE. The top layer is
the supernate and the bottom layer is associated o-LiDMBA.
of p-DMB where 2−3% of a product from dimetalation was
routinely found. This product from several studies is known to
Table 2. Summary of Hydrocarbon Media ortho-Lithiations
substrate
analyzed ortho-deriv.
-TMS
equiv. amine/ether
time (h)
EoM%
purified
A
0.15 TMEDA
0.5 THF
18−24
4
93−96
96
96−98
N/A
a
p-ClA
-TMS (4)
2-MA
-CPh2OH
0.92 TMEDA
0.1 TMEDA/1.0 THF
3.0 THF
1
86−88
78−83
94−96
89−90
96−97
87−88
85−91
91−96
86−88
93−95
N/A
a
3-MA
-CPh2OH (5)
36
N/A
4-MA
-TMS
-TMS
-TMS
-TMS
-TMS
-TMS
24
N/A
1,2-DMB
1,3-DMB
1,4-DMB
DMA
0.3 TMEDA
0.1 TMEDA
0.1 TMEDA
0.15 TMEDA
1.5 MTBE
0.63
1.5
94−95
N/A
0.33
18−24
18−24
3
N/A
98−99
97−98
N/A
DMBA
a
3-MeODMA
1,4-TMPDA
-CPh2OH (6)
0.5 TMEDA
0.25 TMEDA
a
-TMS (7)
19
N/A
a
New compound.
H
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Sorbent Technologies. TLC analysis was performed using identical
silica plates also available from Sorbent Technologies.
Consideration of the reactivity of these ArLi’s generated in
hydrocarbon media has caused us to begin dilution/dissolution
studies. At present we have focused on these studies using THF
and MTBE. Some scattered but significant alterations/
improvements in nucleophilic reactions have been noted
which are highly dependent on the ArLi being studied. There
is literature evidence that these ortho-lithio aryl intermediates
exhibit some of the same equilibria as n-BuLi, that is, dimer,
tetramer, etc.11e,35t,u As our deficiency catalysis approach and
subsequent purification procedures (when applicable) allow
relatively unadulterated ortho-lithio intermediates to be
prepared, the study of additives/promoters on derivatization
of these intermediates is anticipated to be both insightful and
fruitful.
Much progress has been made in ortho-metalations using
other metalation agents which incorporate a variety of metal/
base combinations. In this current study, we have shown that
highly selective, efficient ortho-lithiation can be achieved by
deficiency catalysis using n-BuLi as the only base. We believe
that media manipulation can complement metal manipulation
in the enhancement of ortho-metalations. It is a logical
extrapolation that investigation of additive/promoters will
enhance derivatization procedures as it has for the metalation
protocols described herein. Our preliminary studies indicate
that this is so; the literature has already provided a few
provocative examples.8i,11u,37
o-Lithioanisole (o-LiA) Method 1 (Standard Procedure). To a
clean, dry round-bottom flask equipped with a large stir bar was added
anisole (4.35 mL, 40.0 mmol) and cyclohexane (4.74 mL) via syringe.
Next, n-BuLi (2 M in cyclohexane) (20.0 mL, 40.0 mmol) followed by
TMEDA (0.91 mL, 6.0 mmol) (0.15 equiv.) were added slowly via
syringe to attain an overall reaction molarity of 1.33 M. The reaction
mixture was stirred at 60 °C for 18−24 h under nitrogen atmosphere.
At this point the EoM of o-LiA was found to be 93−96% by ClTMS
derivatization followed by GC analysis. If TMEDA removal and further
purification is desired, the reaction, now containing a copious amount
of precipitate, was allowed to cool and the stirred slurry was
transferred via syringe fitted with a 14 gauge needle to clean, dry
nitrogen-purged, graduated centrifuge tubes, which were each sealed
with a septum and centrifuged for 2 min. The resulting supernate was
removed via syringe and discarded. The settled solid was agitated with
a volume of anhydrous cyclohexane equal to the amount previously
removed in order to retain the approximate molarity of 1.33 M (i.e.,
total volume remained 30 mL). The tube was centrifuged again and
the supernate removed to afford 96−98% pure o-LiA, as demonstrated
by ClTMS treatment and GC analysis. The supernate contained no o-
LiA using the same analytical procedure as above, only minute
amounts of anisole. If desired, the generated pure o-LiA precipitate can
be dissolved in THF or other ether media for subsequent
homogeneous derivatization. At this scale minute losses are incurred
during transfer and purification providing a routinely overall
recoverable yield of solid o-LiA of ca. 85%.
o-LiA Method 2 (Additive Experiments). To a clean, dry round-
bottom flask equipped with a large stir bar was added anisole (1.1 mL,
10 mmol) and cyclohexane (1.8 mL) via syringe. Next, n-BuLi (2 M in
cyclohexane) (5 mL, 10.0 mmol) immediately followed by the desired
ether additive (THF, MTBE, DEE, 2-methyl THF, dibutyl ether,
glyme, diglyme, dioxane, or dioxolane) (10 or 20 mmol) (1 or 2 equiv,
respectively) were added via syringe to attain an overall reaction
molarity of 1.0M. The reaction mixture was stirred at the desired
temperature (22, 45, or 65 °C) under nitrogen atmosphere. Aliquots
were analyzed by first quenching with a modest excess of a 2 M
cyclohexane solution of ClTMS and allowing to sit for >30 min. After
aqueous Na2CO3 work up, each sample was analyzed by GC and GC/
MS to obtain EoM. Some comparative results are shown in Table 1
with the best results, those for THF, plotted in Figure 1.
2-Lithio-4-chloroanisole (2-Li-4-ClA). To a clean, dry round-
bottom flask equipped with a large stir bar was added anhydrous
cyclohexane (5.1 mL), 4-chloroanisole (1.8 mL, 15 mmol), and THF
(0.61 mL, 7.5 mmol) (0.5 equiv.) under a nitrogen atmosphere. Next
n-BuLi (2 M in hexanes) (7.5 mL, 15 mmol) was carefully added with
stirring. The overall reaction concentration was 1.0 M. The reaction
mixture was stirred at 60 °C. The EoM was determined to be 96% in 4
h. There was ca. 1.0% of what appeared to be a biphenyl product
detected after ClTMS derivatization. The EoM was observed to slowly
decline after 24 h.
Isolation of (5-Chloro-2-methoxyphenyl)trimethylsilane (4).
The entire 2-Li-4-ClA reaction above was slowly quenched with
ClTMS (2.85 mL, 22.5 mmol) after 4 h and allowed to stir overnight.
Following quenching with aqueous saturated Na2CO3 carbonate, the
reaction mixture was transferred to a separatory funnel with the aid of
25−30 mL MTBE. The organic layer was separated, washed with
brine, dried over sodium sulfate and concentrated in vacuo. The crude
product was recrystallized with hexanes (3 mL) and filtered to provide
2.83 g, 88% of pure product 4 as clear needles. mp = 43.9−46.0 °C. 1H
NMR (CDCl3) δ 0.25 (s, 9H), 3.78 (s, 3H), 6.73−6.75 (dd, J = 9.2,
3.5 Hz, 1H), 7.25−7.27 (m, 2H). 13C NMR δ −1.1, 55.5, 110.9, 125.7,
130.2, 130.6, 134.6, 162.8. Anal. Calcd for C10H15ClOSi (214.06): C,
55.93; H, 7.04. Found: C, 55.69; H, 7.13.
EXPERIMENTAL SECTION
■
General. All reagents including anhydrous reaction solvents were
purchased from Aldrich Chemical Co. and used without further
purification unless otherwise noted. Usually, reactions were run with a
1:1 ratio of substrate and n-BuLi (2 M in cyclohexane or 10 M in
hexanes) at concentrations ranging from 1.0 to 2.0 M in cyclohexane
at the temperature indicated. Lower concentration runs were
occasionally utilized to provide smoother reaction sampling/profiling.
Reactions were conducted in 25, 50, or 100 mL one-neck septum
sealed flasks (fitted with a condenser if heated) that was purged and
maintained at a slight positive pressure with N2 or Ar. Typically, the
substrate was introduced into the flask, followed by hydrocarbon
solvent, and an additive [N,N,N′,N′-tetramethylethylenediamine
(TMEDA), THF, etc.]. n-BuLi was then introduced to the septum-
fitted flask via syringe, the syringe having been filled to the requisite
volume under a slight positive pressure of N2 or Ar. Exotherms were
controlled with a water bath or ice bath. The plots of extents-of-
metalation (EoM) vs time were made by extracting via syringe ca. 0.4
mL samples from the reaction mixture. Many of these reacting
solutions form flocculent precipitates. From such heterogeneous
mixtures, representative samples could be extracted utilizing a syringe
fitted with a 14 gauge needle, which allowed both particulate matter
and solution to be taken up. The sample aliquots were injected into a
modest excess of a 2 M chlorotrimethylsilane (ClTMS) solution in
cyclohexane and allowed to sit for >30 min unless otherwise indicated.
After dilution with 2−3 mL of MTBE and aqueous Na2CO3 (2−3 mL)
work up, each sample was analyzed by GC equipped with a BP-10
capillary column (25 m × 0.22 mm, 0.25 μm film and FID). Identities
of products were confirmed by GC/MS analysis (30 m × 0.32 mm,
0.25 μm film) on an instrument equipped with a quadrupole mass
detector and separate FID. GC yields were not corrected since TMS-
derivative GC yields were, with one exception, 87% or greater resulting
in minimal change upon correction. Each plot represents the average
of at least three runs. In several cases where the o-lithio intermediate
had some solubility in cyclohexane, hexane or pentane was used for the
wash. NMR data was attained using an ECA-500 MHz instrument.
Combustion analysis was performed on a CHN analyzer. Previously
unknown compounds 4−7 were purified by column chromatography
6-Lithio-2-methylanisole (6-Li-2-MeA). To a clean, dry, round-
bottom flask equipped with a large stir bar was added 2-methylanisole
(0.62 mL, 5 mmol), anhydrous cyclohexane (1.2 mL), and TMEDA
(0.69 mL, 4.6 mmol) (0.92 equiv.) under nitrogen atmosphere. Next,
the flask was carefully charged with n-BuLi (2 M in cyclohexane) (2.5
2
́
using silica gel (60 Å, 65 × 250 mesh, 500−600 m /g) available from
I
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mL, 5 mmol). The overall reaction concentration was 1 M. A very
slight exotherm was observed and the reaction was allowed to stir at 60
°C for 1 h. The resulting solution was analyzed by quenching a sample
with a slight excess of a cyclohexane solution of benzophenone. After
work up with brine and MTBE, an 86% yield of the benzophenone
derivative of 2-lithio-5-methylanisole was found by GC analysis. There
was 8.2% of α-metalated product observed with the remainder being
starting material. Benzophenone was used as the GC derivatizing agent
because excellent resolution of the ortho- and lateral derivatives was
achieved. The comparable -TMS derivatives could not be resolved by
GC.2i Isolation of the benzophenone derivative has already been
reported.2i
6-Lithio-3-methylanisole (6-Li-3-MeA). To a clean, dry, round-
bottom flask equipped with a large stir bar was added 3-methylanisole
(1.9 mL, 15 mmol), anhydrous cyclohexane (4.2 mL), THF (1.21 mL,
15 mmol) (1.0 equiv.) and TMEDA (0.23 mL, 1.5 mmol) (0.1 equiv.)
under a nitrogen atmosphere. Next, the flask was carefully charged
with n-BuLi (2 M in cyclohexane) (7.5 mL, 15 mmol). The overall
reaction concentration was 1 M. A very slight exotherm was observed
and the reaction was allowed to stir at 60 °C. The reaction provided a
50:50 mixture of the two possible ortho-lithio intermediates (i.e., the 2-
lithio-3-methyl anisole and the 6-lithio-3-methyl anisole) within the
first several hours as determined by ClTMS derivatization. This
mixture equilibrated over 36 h to 83% of the 6-lithio-3-methyl anisole
with <1% of the 2-lithio-3-methyl anisole being detected. The only
other contaminant was starting material.
2-Lithio-1,4-dimethoxybenzene (2-Li-1,4-DMB). To a clean,
dry, round-bottom flask equipped with a large stir bar was added 1,4-
dimethoxybenzene (1,4-DMB) (2.69 g, 19.5 mmol), anhydrous
cyclohexane (9 mL), TMEDA (0.3 mL, 1.95 mmol) (0.1 equiv.)
and anhydrous pentane (10 mL) under a nitrogen atmosphere. The
mixture was gently heated until all the 1,4-DMB was dissolved. Next n-
BuLi (10 M in hexanes) (1.95 mL, 19.5 mmol) was carefully added
with vigorous stirring. The overall reaction concentration was 0.81 M.
After 2−3 min stirring at room temperature an additional amount of
anhydrous pentane (2 mL) was added in order to maintain a smoothly
stirring mixture. After 5−10 min, the reaction solution became a white
suspension. The EoM reached 88% in 20 min. There was 2%
dimetalated product by ClTMS derivatization, that is, 2,5-bis-TMS-
1,4-DMB. The o-lithio intermediate began to degrade after 1 h. It is
not recommended to attempt purification of this intermediate.
2-Lithio-1,3-dimethoxybenzene (2-Li-1,3-DMB). To a clean,
dry, round-bottom flask equipped with a large stir bar was added
anhydrous hexanes (6 mL), n-BuLi (2 M in cyclohexane) (7.88 mL,
15.8 mmol) and TMEDA (0.23 mL, 1.52 mmol) (0.1 equiv.) under a
nitrogen atmosphere. After vigorous stirring for several minutes, 1,3-
dimethoxybenzene (1,3-DMB) (1.96 mL, 15.0 mmol) was added. The
overall reaction concentration was 1.1 M. The reaction reached
maximum EoM (97%) in 1.5 h, slowly declining in yield when left for
longer periods. There was 0.6% dimetalation (2,4-bis-TMS-1,3-DMB)
and 0.3% of the desired product that had been demethylated. With
such a high initial EoM, there was no attempt to further purify this
lithio intermediate.
Isolation of (2-methoxy-4-methylphenyl)diphenylmethanol
(5). The TMS derivative, 6-TMS-3-methylanisole proved difficult to
separate from starting material and so the benzophenone derivative
was isolated. The entire 6-Li-3-MeA reaction above was slowly
quenched with benzophenone (2.54 g, 13.9 mmol) and allowed to stir
overnight. Following quenching with water, the reaction mixture was
transferred to a separatory funnel with the aid of 25−30 mL MTBE.
The aqueous layer was back-extracted with 25 mL MTBE and the
combined organic layers were washed with brine, dried over sodium
sulfate and concentrated in vacuo. Following trituration with
cyclohexane (8 mL), the slurry was filtered to provide 2.93 g, 70%
of pure 5 as a white powder. mp = 134.8−135.8 °C. 1H NMR
(CDCl3) δ 2.35 (s, 3H), 3.64 (s, 3H), 5.27 (s, OH), 6.36−6.37 (d, J =
7.4 Hz, 1H), 6.61−6.63 (d, J = 7.4 Hz, 1H), 6.76 (s, 1H), 7.22−7.29
(complex m, 10H). 13C NMR δ 21.5, 55.7, 82.0, 113.1, 121.1, 127.0,
127.7, 127.9, 130.2, 132.5, 139.1, 146.9, 157.3. Anal. Calcd for
C21H20O2 (304.15): C, 82.86; H, 6.62. Found: C, 82.80; H, 6.55.
2-Lithio-4-methylanisole (2-Li-4-MeA). To a clean, dry round-
bottom flask equipped with a large stir bar was added anhydrous
cyclohexane (1.6 mL), 4-methylanisole (1.9 mL, 15.0 mmol), and
THF (3.65 mL, 45.0 mmol) (3 equiv.) under nitrogen atmosphere.
Next n-BuLi (2 M in hexanes) (7.9 mL, 15.0 mmol) was carefully
added with vigorous stirring. The reaction was allowed to stir at room
temperature. The overall reaction concentration was 1.0 M. The EoM
was determined to be 94% after 24 h. The only other component
observed in the GC spectrum was starting material.
3-Lithio-1,2-dimethoxybenzene (3-Li-1,2-DMB). To a clean,
dry round-bottom flask equipped with a large stir bar was added
anhydrous cyclohexane (5.59 mL), 1,2-dimethoxybenzene (1,2-DMB)
(1.61g, 12.6 mmol), and TMEDA (0.57 mL, 3.78 mmol) (0.3 equiv.)
under a nitrogen atmosphere. Next n-BuLi (10 M in hexanes) (1.26
mL, 12.6 mmol) was carefully added with vigorous stirring followed
immediately by anhydrous pentane (6.5 mL). The overall reaction
concentration was 0.81 M. The reaction was highly exothermic during
this period so the flask was cooled in a water bath as the reaction
mixture went from clumpy to a tractable white suspension. The EoM
was determined to be 90% in 40 min; the EoM began to decline after
1−1.5 h. There was 1.2% dimetalated product detected by TMS
derivatization, that is, 3,6-bis-TMS-1,2-DMB. To remove TMEDA and
purify the lithio intermediate, the reaction mixture was centrifuged and
washed with pentane twice and hexane once, removing the supernate
each time. Very little lithiated intermediate was lost in these washes
(≤1% as evidenced by TMS derivatization/GC analysis); the overall
yield of 95% pure 3-lithio-1,2-DMB was 85%.
o-Lithiodimethylaniline (o-LiDMA). To a clean, dry round-
bottom flask equipped with a large stir bar was added N,N-
dimethylaniline (DMA) (7.6 mL, 60.0 mmol), anhydrous cyclohexane
(15.0 mL), TMEDA (1.36 mL, 9.0 mmol) (0.15 equiv.) and n-BuLi
(10 M in hexanes) (6 mL, 60.0 mmol) under nitrogen atmosphere.
The overall reaction concentration was 2 M. The solution was allowed
to stir at 60 °C for 18−22 h, whereupon after cooling, a copious
precipitate of o-LiDMA formed. At this point, the EoM of o-LiDMA
was 85−91% by ClTMS derivatization/GC analysis and can be used as
is if desired. If TMEDA removal and further purification is desired, the
reaction, now containing a copious amount of precipitate, was allowed
to cool and the stirred slurry was transferred via syringe fitted with a
14 gauge needle to clean, dry nitrogen-purged centrifuge tubes, which
were each sealed with a septum and centrifuged for 2 min. The
supernate was removed and replaced with an equal volume of
anhydrous hexanes. Following centrifugation, removal of the hexane
supernate and repeating the hexane washing process, the now 98−99%
pure o-LiDMA was diluted for subsequent reaction(s). The overall
yield was ca. 70% of nearly pure solid o-LiDMA. These procedures
have been performed on a 15, 30, and 60 mL scale with identical
profiles.
o-Lithiodimethylbenzylamine (o-Li-DMBA). To a clean, dry,
round-bottom flask equipped with a large stir bar was added N,N-
dimethylbenzylamine (DMBA) (3.0 mL, 20 mmol), anhydrous
cyclohexane (6.4 mL), MTBE (3.6 mL, 30 mmol) (1.5 equiv.)
under a nitrogen atmosphere. Next the flask was carefully charged with
n-BuLi (10 M in hexanes) (2.0 mL, 20 mmol) with an exotherm being
observed. The overall reaction concentration was 1.33 M. The reaction
was allowed to continue stirring at room temperature for 18 h. The
reaction can be allowed to stir at room temperature for as long as 48 h
with minimal product decomposition. A 93−96% EoM as determined
by ClTMS quench and GC analysis was found after 18 h. Over the first
6 h, 1−2% of a second intermediate, the product of α-lithiation, was
noted. A slightly lower EoM for the o-LiDMBA (91−95%) was
observed when the reaction was stirred at 60 °C for 6 h. To effect
purification, the o-lithio intermediate was centrifuged and washed with
anhydrous hexanes as described previously to remove MTBE and to
obtain product with purity as high as 98%. An estimated 10−15%
overall loss of o-LiDMBA was incurred using this procedure. Reactions
have been performed on a 15, 30, and 60 mL scale with identical EoM
profiles.
2-Lithio-3-methoxy-N,N-dimethylaniline (2-Li-3-MeODMA).
To a clean, dry, round-bottom flask equipped with a large stir bar
J
dx.doi.org/10.1021/om301120e | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
was added anhydrous cyclohexane (0.86 mL), TMEDA (0.51 mL, 3.4
mmol) (0.5 equiv.) and 3-methoxy-N,N-dimethylaniline (3-MeOD-
MA) (purchased from Alfa Aeasar) (1.0 mL, 6.8 mmol) under
nitrogen atmosphere. Next, the flask was carefully charged with n-BuLi
(2 M in cyclohexane) (4.43 mL, 8.85 mmol), a 1.3 equiv. excess. The
overall reaction concentration was 1 M. An external exotherm was
initially observed, after which the reaction was allowed to stir at 60 °C
for 3 h. The reaction proceeded to an 88% EoM as determined by
ClTMS quench. It was found that the quench solution must be left for
at least 6 h to ensure complete ClTMS derivatization.
Jennifer Cooper, Marty Jo Watson, Jason Rosenberger, Laura
Leeper, Adam Watson, Travis Wilson, Ryan Sullivan, Megan
Jackson, Ben McClure, Sam Warnell, Allison Spencer, Courtney
Phillips, Melody Taylor, Jamie Rucker, Lori Daniel, Richard
Granese, Jackie Granese, Karen Lalonde, Troy Reece, Jared
Bolton, Kathryn Dudley, Brian Jones, and Maria Diloreto.
Valuable discussions were held with Prof. Rob Holman, Idaho
State University, and early on with Prof. Alan Siegel, Indiana
State University.
Isolation of (2-(Dimethylamino)-6-methoxyphenyl)-
diphenylmethanol (6). The 2-Li-3-MeODMA procedure was
repeated as described above, and was slowly quenched with
benzophenone (1.24 g, 6.8 mmol) and allowed to stir overnight.
Following quenching with water, the reaction mixture was transferred
to a separatory funnel with the aid of 25−30 mL MTBE. The aqueous
layer was back-extracted with 25 mL MTBE and the combined organic
layers were washed with brine, dried over sodium sulfate and
concentrated in vacuo. Following trituration with cyclohexane (8
mL), the slurry was filtered to provide 1.39 g, 60% of pure 6 as a white
powder. mp = 144.0−146.1 °C (lit.6c 142−143 °C). 1H NMR
(CDCl3) δ 2.56 (s, 6H), 3.05 (s, 3H), 6.73−6.75 (d, J = 8 Hz, 1H),
7.02−7.04 (d, J = 8 Hz, 1H), 7.16−7.34 (complex m, 11H), 11.2 (s,
OH) . 13C NMR δ 45.7, 55.6, 82.2, 111.7, 115.4, 126.2, 127.3, 127.7,
128.9, 132.4, 148.9, 153.5, 157.7.
2-Lithio-N,N,N′,N′-tetramethyl-1,4-phenylenediamine (2-Li-
1,4-TMPDA). To a clean, dry round-bottom flask equipped with a
large stir bar was added N,N,N′,N′-tetramethyl-1,4-phenylenediamine
(1,4TMPDA) (1.5 g, 9.1 mmol), anhydrous cyclohexane (4.6 mL) and
TMEDA (0.35 mL, 2.3 mmol) (0.25 equiv.) and n-BuLi (10 M in
hexanes) (0.91 mL, 9.1 mmol) under nitrogen atmosphere. The
overall reaction concentration was 1.24 M. After 15 min the solution
became milky as a copious precipitate of the 2-Li-1,4-TMPDA formed.
The solution was allowed to stir at room temperature for 19 h. At this
point the EoM of 2-Li-1,4-TMPDA was 95% by ClTMS
derivatization/GC analysis with 0.1% product from dimetalation
being observed, presumably 2,5-bis-TMS-1,4-TMPDA.
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AUTHOR INFORMATION
Corresponding Author
*donald.slocum@wku.edu; whitley.paul@gmail.com
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Investigation of these procedures were begun under Research
Corporation Award (CC5027), Petroleum Research Grant
(PRF 42090-B1), and National Science Foundation Awards
(CHE 0101435 and CHE 0710021). Internal support was used
to complete the investigation. In addition to the coauthors
listed on this paper and our previous publications, the following
students were instrumental in assisting in the development of
these procedures: Dustin Smith, Melinda Crawford, Shorena
Nadaria-Hoke, Danny Woosley, Seth Parmley, Stephanie Bragg,
K
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Organometallics
Article
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dx.doi.org/10.1021/om301120e | Organometallics XXXX, XXX, XXX−XXX