Generation, Stability, and Utility of Lithium 4,4′-Di-tert-butylbiphenylide (LiDBB)

Article abstract of DOI:10.1021/acs.joc.6b01748

Several procedures were evaluated for the preparation of lithium 4,4′-di-tert-butylbiphenylide (LiDBB, Freeman's reagent) from lithium metal and 4,4′-di-tert-butylbiphenyl (DBB) in THF. Solutions with nominal concentration of 0.4 and 1.0 M were formed. The stability of LiDBB solutions was evaluated over time, and the gradual uptake of lithium metal was observed. At 0 °C the LiDBB solutions were stable for over a week in THF. At 20 °C the LiDBB solution underwent various decomposition pathways, which led to uptake of more lithium metal and the accumulation of side products. These decomposition pathways were studied, and the importance of ethene in the destruction of THF by LiDBB was observed. On a practical note, LiDBB solutions in THF were stable and effective for over a week at 0 °C or for more than 37 weeks when stored under argon at -25 °C. These observations will extend the utility of LiDBB as a reagent in organic synthesis.

Full text of DOI:10.1021/acs.joc.6b01748

Article
pubs.acs.org/joc
Generation, Stability, and Utility of Lithium 4,4′-Di-tert-
butylbiphenylide (LiDBB)
Richard R. Hill and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, University of CaliforniaIrvine, Irvine, California 92697, United States
S
* Supporting Information
ABSTRACT: Several procedures were evaluated for the
preparation of lithium 4,4′-di-tert-butylbiphenylide (LiDBB,
Freeman’s reagent) from lithium metal and 4,4′-di-tert-
butylbiphenyl (DBB) in THF. Solutions with nominal
concentration of 0.4 and 1.0 M were formed. The stability
of LiDBB solutions was evaluated over time, and the gradual
uptake of lithium metal was observed. At 0 °C the LiDBB
solutions were stable for over a week in THF. At 20 °C the
LiDBB solution underwent various decomposition pathways,
which led to uptake of more lithium metal and the accumulation of side products. These decomposition pathways were studied,
and the importance of ethene in the destruction of THF by LiDBB was observed. On a practical note, LiDBB solutions in THF
were stable and effective for over a week at 0 °C or for more than 37 weeks when stored under argon at −25 °C. These
observations will extend the utility of LiDBB as a reagent in organic synthesis.
Scheme 1. Preparation and Utility of LiDBB by Freeman’s
Protocol
INTRODUCTION
■
In 1976, Freeman and Hutchinson introduced a new radical
anion generated by reduction of Di-tert-ButylBiphenyl (DBB)
with lithium metal to produce Lithium Di-tert-ButylBiphenylide
(LiDBB). They demonstrated the superiority of this reagent for
the generation of alkyllithium reagents from alkyl chlorides
when compared with lithium naphthalide (LiN).1,2 The LiDBB
system exhibited fewer side reactions with the alkyllithium
reagent than LiN,3 and the higher reduction potential of the
DBB anion extended the substrate scope.4 Several other radical
anions have been used to generate alkyllithium reagents,5 and
methods with lithium metal and a catalytic arene have been
successfully developed.5,6 Stoichiometric LiDBB is still the
reagent of choice for the reductive generation of sensitive
alkyllithium regents from alkyl chlorides1 and alkyl phenyl
sulfides.7,8 It is also employed for many other single electron
reduction processes.9 We have used LiDBB extensively in our
research program, first to reductively remove nitriles,9a and later
to generate alkyllithium reagents.10 Subsequently we developed
reductive lithiations followed by intramolecular alkylations to
form new rings.11 Since LiDBB requires time and labor to
produce, we sought to systematically explore its generation and
stability, with the goal of improving its utility in the lab. The
results of these studies are presented herein.
the preferred preparation of an alkyllithium reagent, the alkyl
halide was added to a modest excess of the LiDBB solution.
Alkyllithium reagents are now often prepared from alkyl phenyl
sulfides rather than halides,7 although the reduction of other
functional groups such as oxiranes13 and oxetanes have proven
effective.14 Several interesting LiDBB reductions are presented
in Figure 1 to illustrate the broad utility of this reagent in
organic synthesis.
The common preparation of LiDBB is very similar to
Freeman’s protocol.16 The preferred concentration is nominally
0.4 M, and the reagent is prepared at 0 °C and used that day.
From the standpoint of a practicing chemist, this protocol is
tedious as 4 or 5 h are required to prepare fresh reagent prior to
its use. The 0.4 M concentration produces an upper limit on
Freeman’s standard preparation of LiDBB is shown in
Scheme 1, along with the preparation of a typical alkyllithium
reagent.1 The reduction is carried out using Li metal in a dry
solution of THF under argon.12 The original preparation
produced a ca. 0.17 M solution of LiDBB after 3−4 h, and the
use of freshly prepared solutions was recommended. The
LiDBB solution is deep green or blue-green, and the loss of
color can be used as an indication of reagent consumption. In
Received: July 21, 2016
© XXXX American Chemical Society
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Table 1. Maximum Concentration of LiDBB with Different
Starting Concentrations of DBB and Excess Li Metal after
2−3 h at 20 °C
[DBB]
[LiDBB]
0.4
1.0
2.0
3.1
0.37
0.82
1.26
1.0
and 0.4 M DBB solutions were the most promising to explore
in further experiments.
The generation of LiDBB solutions was explored at different
temperatures. Using 0.4 M DBB solutions (Figure 2) and an
excess of Li metal19 in THF, the concentration of LiDBB in
solution increased at essentially the same rate either at 0 °C or
at 20 °C. The terminal concentration was 0.36−0.37 M after 4
h. The 1.0 M solution of DBB (Figure 2) showed a difference
in rate at the two temperatures, with the 20 °C solution arriving
at a final concentration after about 1 h. In contrast, the 0 °C
solution reached a similar final concentration (0.82 M) only
after 7 h. The final conversion of the 0.4 M DBB solution to
LiDBB was about 90%, while the conversion of the 1.0 M
solution of DBB was 82%. At higher concentrations (Table 1)
the conversion was greatly reduced. Producing LiDBB solutions
at 20 °C presents a minor advantage at the 1.0 M
concentration, but does not provide any advantage at the
lower concentration.
Both the nominal 1.0 and 0.4 M solutions of LiDBB
maintained their concentration at 0 °C. The 0.36 M solution
led to a slight increase in concentration when cooled to −25
°C, but the concentration of the 0.82 M solution decreased by
14% when cooled to −25 °C for several hours, perhaps due to
precipitation of the reagent (Figure 3). Adding a nominal 1.0 M
LiDBB solution slowly to a low temperature reaction mixture
would not be expected to present a problem because it would
be diluted into the flask, and electron transfer reactions are
normally rapid enough to prevent a buildup of the reagent.
Both solutions could be stored at 0 °C without an observed
drop in molarity.
Stability of LiDBB Solutions in THF. The normal
preparation of LiDBB requires 5 h, and it is recommended
that the reagent be freshly prepared.20 We were interested in
ascertaining whether or not LiDBB solutions could be prepared
and stored for prolonged periods of time prior to use, which
would represent a considerable savings of time and effort in the
lab. In order to follow the decomposition of LiDBB solutions to
its unidentified products, we decided to track the uptake of Li
metal by the solution as it aged. All reactions of LiDBB should
produce an anion and 1 equiv of Li+ ion. The LiDBB was
prepared with a 10-fold excess of lithium metal, which was
available to regenerate the LiDBB from the obvious reduction
product, DBB. The solutions were generated and left to stir
under argon at the appropriate temperature. Aliquots were
taken periodically, worked up by extraction into water, and
diluted into volumetric glassware, and the resulting concen-
tration of Li+ ion was determined by atomic absorption
spectroscopy. The results of three decomposition experiments
are shown in Figure 4. All of the solutions maintained a blue-
green color of active LiDBB for the duration of the experiment.
The 0 °C solutions at 0.36 and 0.82 M LiDBB very slowly
took up Li metal. Oxidation rates of lithium in these reactions
were found to be 0.030 and 0.041 equiv of lithium per day,
Figure 1. Examples of carbon−carbon bond-forming reactions using
LiDBB that proceed through intermediate alkyllithium reagents.15
the alkyllithium concentration of less than 0.2 M, as 2 equiv of
LiDBB are needed for each mole of RLi generated. This
concentration limit is clearly undesirable from the standpoint of
large-scale work, as is the separation of excess DBB from the
reaction products. A number of alternatives have been
proposed, including the use of 1-N,N-dimethylaminonaph-
thalene (DMAN), which is used stoichiometrically or catalyti-
cally. DMAN can be separated from the desired products by an
acid extraction step, but LDMAN (Lithium 1-N,N−dimethyl-
aminonaphthalenide) is unstable above −45 °C and has not
gained wide acceptance.5 Reactive Li powder may be used with
catalytic DBB or naphthalene to generate alkyllithium
reagents.6 Cohen has recently shown that the catalytic
procedures lead to different reduction preferences than
stoichiometric radical anion reductions and conclude that
these are surface reactions.17 He demonstrated that other
aromatic catalysts such as dimethylaniline are effective in a
catalytic protocol.17c An advantage of LiDBB and the reason for
its continued popularity is LiDBB can generate sensitive
alkyllithium reagents at low temperature with higher yields than
any other reagent (Figure 1).2 We have investigated the
generation of LiDBB solutions and their stabilities to improve
upon the utility of this reagent.
RESULTS AND DISCUSSION
■
Generation of LiDBB Solutions in THF. Different
concentrations of DBB were reduced with excess Li metal in
THF under modified Freeman’s conditions, and the results are
shown in Table 1. The resulting LiDBB concentration was
determined by titration with thioanisole in THF at 0 °C.18
Most of the DBB is converted to the radical anion when
starting concentrations of DBB were 0.4 and 1.0 M. The 2.0 M
DBB solution led to lower conversion, and the 3.1 M
(saturated) DBB solution led to a very viscous solution with
only a modest concentration of LiDBB. We concluded that 1.0
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Figure 2. Generation of LiDBB solutions in THF as a function of concentration, temperature and time with an excess of Li metal. The
concentrations of the solutions were determined by titration with thioanisole.18
Figure 3. Preparation of LiDBB solutions and cooling them to −25 °C leads to apparent precipitation of LiDBB in the 0.82 M solution but not the
0.36 M solution.
Figure 4. Lithium consumption by LiDBB solutions in THF stored with excess lithium metal at 0 or 20 °C (see text for method). The starting DBB
concentration of solution A was 0.40 M, and the starting DBB concentration of solution B was 1.0 M.
respectively. As can be seen from the graph, these solutions are
stable at 0 °C for many days and can be used without any
problem. Similar tests with a nominal 1.0 M LiDBB solution at
20 °C found 1.02 equiv of lithium per day were consumed.
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LiDBB solutions stored in THF at 20 °C become unusable in
less than a day due to the buildup of many other lithium
species. It is interesting that the solution still had the deep
green-blue color of LiDBB after 7 days and only lost this color
after approximately 10 days. The loss of LiDBB color
presumably corresponds to the consumption of all Li metal,
and its complete conversion to various lithium byproducts.
Storing solutions of LiDBB over excess Li metal in THF at 0 °C
resulted in minimal decomposition over the course of a week.
Decomposition of LiDBB Solutions. The dark green
LiDBB color fades from THF solutions on storing at room
temperature for several days. What happens to the LiDBB
solution? The room temperature solutions are not a practical
source of LiDBB reagent, but aging solutions this way provides
a straightforward method of observing the byproducts formed
on decomposition. The solutions are stirred under argon, and
the only components of the mixture are DBB, lithium metal,
and THF. A plausible hypothesis for the decomposition is the
reduction of THF by LiDBB, which has precedent from the
direct reduction of THF by lithium metal at reflux21 and by the
BF3·OEt2 induced reductive opening of THF by LiDBB at low
temperature.22 Sonication of LiDBB solutions at room
temperature has also been reported to reduce THF.23 The
initial product, lithium (4-oxidobutyl)lithium (1), is an
alkyllithium reagent and will react with another equivalent of
THF to deprotonate it.24 The 2-lithiotetrahydrofuran (3)
spontaneously eliminates ethene to generate lithium ethenolate
(4).25 The net reaction, shown at the bottom of Scheme 2,
Scheme 3. Products from the Decomposition of an LiDBB
Solution after Treatment with t-BuPh2SiCl
did observe the expected silylated butanol 5 and silylated
acetaldehyde 6, but vinyl t-BuPh2Si (7) was also identified. In
addition, the amount of silylated acetaldehyde 6 was much
larger than the silylated butanol 5, but according to the
hypothesis outlined in Scheme 2, they should have been formed
in a 1:1 ratio. The significant deviation from the expected ratio
and the unexpected side product suggested that the original
hypothesis was too simplistic and that more was going on in the
decomposition of the LiDBB solution.
The complexity originates with ethene. Ethene is known to
react with lithium biphenylide to give a number of products
that include lithium hydride, vinyllithium, 1,4-dilithiobutane,
and higher homologues.26 The vinyllithium component would
react with t-BuPh2SiCl in the quenching reaction to deliver the
corresponding vinyl silane 7 that was observed in the
quenching study. In addition, aged LiDBB solution often
violently gave off gas on quenching with water, which would be
consistent with the accumulation of lithium hydride in the
mixture. These processes were probed by control experiments
shown in Schemes 4 and 5. A nominal 0.4 M solution of LiDBB
Scheme 2. Hypothesis for the Decomposition of LiDBB
Solutions in THF
Scheme 4. Reaction of 3-Methylbenzaldehyde with an Aged
a
Solution of LiDBB
a
Because of uncertainty regarding the limiting reagent, listed %’s are
conversion based on the addition of a standard quantity of 3-
methylbenzaldehyde.
was prepared and stored under argon for 14 days at 20 °C,
followed by addition of 3-methylbenzaldehyde. The vinyl-
lithium addition product (8) was observed by NMR spectros-
copy, along with the reduced product 9. Storing the LiDBB
solution under an atmosphere of ethene leads to much more
vinyllithium addition product. These experiments confirm that
would consume 2 equiv of THF and 2 equiv of LiDBB to
generate 1 equiv of ethene, 2 equiv of DBB, and 1 equiv each of
lithium species 2 and 4. The DBB would react with excess Li
metal to regenerate LiDBB, at least until all of the lithium was
consumed. This hypothesis would account for the gradual
consumption of Li metal in the LiDBB solution.
Scheme 5. Formation of Polyethene in the Presence of a
Large Excess of Ethene Using LiDBB
Scheme 3 presents an experiment designed to test this
hypothesis. A 0.4 M LiDBB solution was prepared in THF with
10 equiv of Li metal and allowed to age for 10 days at 20 °C
until a dark green color had faded to a reddish-brown color.
The mixture was quenched with ca. 5 equiv of t-BuPh2SiCl and
diluted with wet CH2Cl2. The crude products were identified
by GCMS against authentic standards prepared separately. We
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solutions of LiDBB stored at room temperature under argon
produce vinyllithium. The reaction of ethene with LiDBB to
produce vinyllithium (and LiH) explains some of the
complexity of the decomposed LiDBB mixtures.
Another reported reaction of lithium with ethene is the
formation of polyethene.26 The aged solutions of LiDBB often
contained varying amounts of an insoluble white solid. To aid
in the isolation and analysis, a solution of LiDBB was treated
with ethene under 400 psi for 15 h at 20 °C. The solution
absorbed many equivalents of ethene. Ethene oligomers were
isolated from the reaction, with a MW of about 1000 g/mol and
a PD of 1.28. Part of the ethene produced from LiDBB
solutions by the decomposition of 2-lithiotetrahydrofuran is
incorporated into ethene oligomers.
major factor in the decomposition.21,31 Schemes 2 and 6 explain
most of the products formed in the decomposition of aged
LiDBB solutions.
Another unexpected product was identified when the spent
DBB was analyzed as shown in Scheme 7. GCMS identified a
Scheme 7. Identification of 4,4′-Di-tert-butyl-2-ethyl-1,1′-
biphenyl (11) from LiDBB Solutions
A more complete picture of the decomposition of THF by
LiDBB is presented in Schemes 6 and 2. As described in
Scheme 6. Decomposition Pathways for Ethene and LiDBB
in THF
compounds with a MW of 294, 28 greater than DBB. An
ethene addition product was suspected, and an independent
synthesis of 4,4′-di-tert-butyl-2-ethyl-1,1′-biphenyl (EtDBB, 11)
led to a compound that was identical by GCMS retention time,
fragmentation pattern, and NMR characterization. Significant
amounts of the EtDBB (11) were only formed on prolonged
storing (≥14 days at 20 °C) of the LiDBB solution at room
temperature. A possible mechanism for its formation is
presented in Scheme 7. Deprotonation of DBB by one of the
many alkyllithium reagents in solution would produce
alkyllithium 12.3 Addition of ethene,27 followed by protonation
by the solvent would produce EtDBB (11). In our view, this
type of process is the one most likely to lead to EtDBB.
The decomposition of LiDBB solutions at 20 °C lead to a
variety of side products. The generation of ethene and its
subsequent reaction with LiDBB or alkyllithium reagents are
responsible for many of the decomposition products.
Utility of LiDBB Solutions. The original goal of the project
was to determine the utility of stored LiDBB solutions. They do
decompose at 20 °C, and the buildup of some of the
decomposition products, such as vinyllithium, would clearly
interfere with the desired LiDBB reactions. Figure 4 shows the
rate of consumption of lithium in the solutions. Storing LiDBB
solutions for many hours at 20 °C leads to the consumption of
large amounts of Li metal, accompanied by the buildup of
various decomposition products. At 0 °C, however, the
consumption of lithium metal is very slow. After 1 week, only
0.21 equiv of Li has been consumed by a 0.36 M solution.
Based on these experiments, stored 0.35 and 0.8 M LiDBB
solutions at 0 °C were found to reliably provide good activity.
Storing a 0.4 M LiDBB solution at −25 °C for several months
also led to good results.32 Table 2 demonstrates the utility of
Scheme 2, the process begins with the reduction of THF to
lithium 4-oxidobutyllithium (1) with 2 equiv of LiDBB. This
alkyllithium reagent deprotonates THF, and the subsequent
retro-[2 + 3] reaction generates 1 equiv of lithium ethenolate
(4) and 1 equiv of ethene. The presence of ethene leads to
several more pathways as shown in Scheme 6. Reduction of
ethene generates 1,2-dilithioethane (10a), which can add one
or more times to ethene to produce 1,4-dilithiobutane (10b) or
dilithiopolyethene (10c).27 As described in Scheme 5, ethene
under pressure will lead to polyethene. Dilithioethane can also
decompose to vinyllithium and lithium hydride.26 The
vinyllithium is expected to react only very slowly with THF
to form 2-lithiotetrahydrofuran (3),28 based on the rate of
reaction of aryllithium reagents with THF.29 All of the sp3-
lithium species (10a−c) are expected to react with THF within
hours to generate 2-lithiotetrahydrofuran (3),30 which will
decompose to produce 1 equiv of ethene. If the dominant
pathway goes to 10b rather than vinyllithium, as much ethene is
generated as is consumed and the process would be effectively
catalytic in ethene. Although lithium metal can participate in
the direct reduction of THF or ethene, the rates appear to be
much slower than the LiDBB reductions and should not be a
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1H NMR spectra were recorded at 500 MHz, and 13C NMR spectra
were recorded at 126 MHz. Chemical shifts (δ) were referenced to
either TMS or the residual solvent peak. The 1H NMR spectra data are
presented as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, app. = apparent, br. =
broad), coupling constant(s) in Hertz (Hz), and integration. Infrared
spectra were recorded on NaCl plates. High resolution mass
spectrometry was performed using ESI-TOF.
Table 2. Reductive Cyclization of Cyano Phosphate 14
Using LiDBB Solution That Has Been Stored in a −25 °C
Freezer
LiDBB Formation in THF. LiDBB was prepared by adding 4,4′-di-
tert-butylbiphenyl (DBB, 1.50 g, 5.64 mmol, 1 equiv), to a 50 mL flask,
followed by evacuating and flame-drying. Once the DBB was melted,
the flask was backfilled with argon and allowed to cool. An ice bath was
applied, and lithium wire (0.39 g, 56.4 mmol, 10 equiv) was clipped
into the flask under a stream of argon. THF (14 mL) was added, and
the solution turned green, darkening over for 5 h at 0 °C. This resulted
in a nominal 0.4 M LiDBB solution.
a
entry
LiDBB age
yield (%)
1
2
3
4
5
6
7
5 h
69
69
1 week
3 weeks
8 weeks
16 weeks
29 weeks
37 weeks
b
70
b
66
69
70
70
Nominal 1.0 M LiDBB was prepared by the above method by
increasing the amount of DBB (3.85 g, 14.5 mmol, 1 equiv) and
lithium (1.00 g, 144.5 mmol, 10 equiv) added.
a
Use of an old LiDBB solution (ca. 0.35 M) prepared with 10-fold
Nominal 2.0 M LiDBB was prepared by the above method by
increasing the amount of DBB (7.40 g, 27.8 mmol, 1 equiv) and
lithium (1.93 g, 277.8 mmol, 10 equiv) added.
Nominal 3.1 M LiDBB was prepared by the above method by
increasing the amount of DBB (11.6 g, 43.5 mmol, 1 equiv) and
lithium (3.02 g, 435.4 mmol, 10 equiv) added.
Titrations of Nominal 0.4 M LiDBB. To a 50 mL volumetric
flask, thioanisole (1.20 mL, 10.2 mmol) and THF (degassed by
freeze−pump−thaw) were added to form a 0.20 M solution. A dry 10
mL flask was evacuated and backfilled with argon 3 times and cooled
to 0 °C, and 1.00 mL of the 0.20 M thioanisole solution was added.
LiDBB was then added dropwise until a persistent dark-green color
was observed. The titrated solution was removed, and the procedure
was repeated three times. The first trial was excluded, and the average
volume added from titrations 2−4 was used to calculate the molarity of
the LiDBB.
Titrations of Nominal 1.0, 2.0, 3.1 M LiDBB. Titrations of
nominal 1.0, 2.0, and 3.1 M LiDBB followed the same procedure for
nominal 0.4 M LiDBB except the molarity of the thioanisole solution
was increased to 0.40 M.
Trapping of LiDBB Decomposition Products (Scheme 3). A
nominal 0.4 M LiDBB solution was prepared at 20 °C and allowed to
stir for 14 days. To a dram vial, t-BuPh2SiCl (0.2 mL, 0.77 mmol) and
LiDBB (0.2 mL) were added and stirred for 2 days. Addition of 1.00
mL of wet CH2Cl2 and removal of 4 μL of this solution for GC-HRMS
analysis led to the identification of 5, 6, and 7.
excess of lithium metal. It was stored in a −25 °C freezer in a Schlenk
flask. The solution was warmed to 0 °C and stirred for 1 h prior to use.
b
The starting phosphate used in these experiments had partially
decomposed. The yield shown is based on the isolated product mass
and the mass of starting material corrected for the loss of the Boc
group by H NMR integration.
1
stored 0.35 M LiDBB solutions in reductive cyclization
reactions. The reductive lithiation of nitrile 14 and subsequent
cyclization of the alkyllithium reagent are a reliable reaction to
produce the spiropyrrolidine 15.33 The old LiDBB solutions
stored at −25 °C in a Schlenk flask continued to be effective in
this reaction for 37 weeks.
CONCLUSION
■
The stability and utility of LiDBB solutions were evaluated.
Solutions of nominal 0.4 M LiDBB were ready for use in 4 h at
0 °C or 2 h at 20 °C, while nominal 1.0 M LiDBB solutions
were ready in 8 h at 0 °C or 2 h at 20 °C. Trapping studies
confirmed two types of THF ring-opening pathways during
decomposition, and ethene generated in the process led to
further decomposition reactions. The rate of lithium uptake was
found to be modest at 0 °C but unacceptably high at 20 °C.
Solutions of LiDBB could be used for over a week when stored
at 0 °C under argon. Nominal 0.4 M solutions of LiDBB could
be stored at −25 °C in a Schlenk flask under argon and were
still effective after 37 weeks. This project demonstrates that
LiDBB solutions can be prepared in advance and stored for
months with appropriate precautions. These observations will
extend the utility of LiDBB as a reagent in synthesis.
Trapping Study with 3-Methylbenzaldehyde (Scheme 4). A
nominal 0.4 M LiDBB solution was prepared at 20 °C and allowed to
stir for 14 days. 3-Methylbenzaldehyde (0.10 mL, 0.85 mmol) and 0.5
mL (nominal 0.20 mmol) of the LiDBB solution were added to a 5
mL flask and allowed to stir for 18 h. After quenching with NH4Cl(aq)
(2 mL), the reaction was diluted with CH2Cl2 (2 mL) and the aqueous
layer was extracted with 3 × 2 mL of CH2Cl2. The combined organic
layers were dried over MgSO4 and concentrated to give a yellow oil.
Using the added DBB as an internal standard, 1-(m-tolyl)prop-2-en-1-
ol (8) and m-tolylmethanol (9) were quantified from the reaction
1
mixture by H NMR. The analytical data matched those previously
reported.37,38
EXPERIMENTAL SECTION
■
General Information. All air- and moisture-sensitive reactions
were carried out in a flame- or oven-dried flasks equipped with a
magnetic stir bar under an argon atmosphere. All commercially
available reagents were used as received unless stated otherwise. All
reactions with LiDBB used glass stir bars. Thin layer chromatography
(TLC) was performed on 250 μm layer silica gel plates, and developed
plates were visualized by UV light, p-anisaldehyde, potassium
permanganate, or vanillin. tert-Butyldiphenyl(vinyloxy)silane (6) was
prepared from THF as described by Cohen and Stokes.34 The
analytical data matched those previously reported.35 tert-Butyl-
diphenyl(vinyl)silane (7) was prepared from tetravinyltin as described
by Gerstenberger and Konopelski, and the analytical data matched
those previously reported.36
Atomic Absorption Spectroscopy in the Determination of
Lithium. Three solutions of LiDBB were prepared: Nominal 0.4 M
LiDBB prepared at 0 °C (2.6 g DBB, 0.67 g Li metal, 24 mL THF),
nominal 0.4 M LiDBB prepared at 20 °C (2.6 g of DBB, 0.67 g of Li
metal, 24 mL of THF), and nominal 1.0 M LiDBB prepared at 0 °C
(6.6 g of DBB, 1.72 g of Li metal, 24 mL of THF). Each of these
solutions was maintained at their respective temperatures, and a 0.50
mL aliquot was removed twice daily. After quenching with 0.05 M
H2SO4(aq) (10 mL), the aliquot was diluted with CH2Cl2 (10 mL) and
the aqueous layer was added to a 100 mL volumetric flask. The organic
layer was extracted with 5 × 10 mL of 0.05 M H2SO4(aq), and the
aqueous layers were added to the volumetric flask. This was repeated
for each aliquot in a separate 100 mL volumetric flask.
F
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Using these volumetric solutions, between 2 and 5 mL were
removed and diluted in a 50 mL volumetric flask such that the
absorbance from the spectrometer was between 0.000 and 0.120. A
calibration curve was used to assign the concentration of Li+. Details of
the calibration procedure are described in the Supporting Information.
Cyclization of Nitrile 14 To Form Spirocycle 15 with Stored
LiDBB Solutions. tert-Butyl 1-Azaspiro[4.5]decane-1-carboxylate
(15). An oven-dried round−bottom flask equipped with a glass stir bar
was cooled under vacuum and backfilled with argon. The flask was
charged with 1,10-phenanthroline (1 crystal) and a 0.05 M solution of
phosphate 14 (1 equiv) in THF. The solution was cooled to −78 °C,
and n-BuLi (ca. 2 M solution in hexane) was added until a dark brown
color persisted (2 drops). To that solution at −78 °C was added
LiDBB (∼0.5 M, >2.1 equiv) via syringe to produce a solution that
remained dark green for ca. 20 s. The mixture was stirred for 1 h and
then quenched with MeOH (0.1 mL) and saturated aq. NH4Cl. The
reaction mixture was diluted with Et2O, and the aqueous layer was
separated and extracted with Et2O (3×). The combined organic layers
were washed with brine, dried over MgSO4, and concentrated in vacuo
to give a light yellow viscous solid. Purification by column
chromatography (gradient 97:3 hexane/CH2Cl2 then 98:2 hexane/
EtOAc to 95:5 hexane/EtOAc) gave the title compound. The
analytical data matched those previously reported.33
Synthesis of Authentic Standards. Butoxy(tert-butyl)diphenyl-
silane (5). To a solution of n-butanol (0.20 mL, 2.2 mmol, 1 equiv) in
THF (2.2 mL), Et3N (0.45 mL, 3.3 mmol, 1.5 equiv) and t-BuPh2SiCl
(0.63 mL, 2.4 mmol, 1.1 equiv) were added. After stirring for 18 h, the
reaction was quenched with a 10% NaHCO3 solution (4 mL), and the
solution was diluted with ethyl acetate (4 mL). The organic layer was
extracted, the aqueous layer was washed with ethyl acetate (3 × 2 mL),
and the combined organic layers were dried with MgSO4 and
concentrated in vacuo, giving a yellow oil. Flash column chromatog-
raphy (8:1 Hexanes/CH2Cl2) gave butoxy(tert-butyl)diphenylsilane in
25% yield (259 mg) as a clear oil. The analytical data matched those
previously reported.39
2-Ethyl-1,1′-biphenyl (16). A mixture of DMF (2.8 mL) and H2O
(0.56 mL) was degassed by freeze−pump−thaw, followed by addition
of phenyl boronic acid (85 mg, 0.70 mmol, 1 equiv), K2CO3 (193 mg,
1.39 mmol, 2 equiv), 1-ethyl-2-iodobenzene (0.1 mL, 0.70 mmol, 1
equiv), and PdCl2(Ph3)2 (9.8 mg, 0.014 mmol, 0.02 equiv). The
reaction was heated to 60 °C for 18 h. The solution was diluted with
H2O (5 mL) and pentane (5 mL), and the organic layer was extracted.
The aqueous layer was washed with pentane (3 × 3 mL), and the
combined organic layers were dried with MgSO4 and concentrated in
vacuo, giving a yellow oil. Flash column chromatography (100%
hexanes) gave 2-ethyl-1,1′-biphenyl (16) in 87% yield (110 mg) as a
clear oil. The analytical data matched those previously reported.40
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01748.
■
S
1H and 13C NMR spectra EtDBB (11), and calibration
data for atomic absorption determination of lithium ion
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: srychnov@uci.edu.
■
4,4′-Di-tert-butyl-2-ethyl-1,1′-biphenyl (EtDBB, 11). To a solution
of 2-ethyl-1,1′-biphenyl (16) (0.10 g, 2.2 mmol, 1 equiv) in MeNO2
(0.6 mL), tert-butyl chloride (0.133 mL, 1.21 mmol, 2.2 equiv),
followed by AlCl3 (22 mg, 0.16 mmol, 0.3 equiv), was added. After gas
evolution stopped (ca. 5 min), the reaction was poured over crushed
ice and diluted with hexanes (3 mL). The hexane layer was extracted,
the aqueous/NO2Me layers were washed with hexanes (3 × 2 mL),
and the combined organic layers were dried with MgSO4 and
concentrated in vacuo, giving a yellow oil. Preparatory plate
chromatography (100% Hexanes) gave 4,4′-di-tert-butyl-2-ethyl-1,1′-
biphenyl (11) in 2% yield (3 mg) as a white solid. The relevant
NOSEY correlations are shown below. Melting point = 109−111 °C;
1H NMR (CD2Cl2, 500 MHz) δ 7.49−7.40 (m, 2H), 7.34−7.31 (m,
1H), 7.27−7.22 (m, 3H), 7.13−7.09 (m, 1H), 2.61 (q, J = 7.5 Hz,
2H), 1.36 (s, 9H), 1.35 (s, 9H), 1.11 (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 150.1, 149.4, 141.3, 139.0, 138.8, 129.9, 129.1,
125.6, 125.0, 122.7, 34.7, 31.6, 26.5, 16.1; IR (thin film) 3025, 2961,
2887, 1608, 1491 cm−1; HRMS (ESI) calcd for C22H30NH4 [M +
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support was provided by University of California at Irvine. This
manuscript is based upon work conducted while SDR was
supported by and serving at the National Science Foundation.
We acknowledge Dr. John Greaves at UC Irvine for assistance
with the GCMS analyses and Dr. Ahmad A. Alshawa for
assistance with the atomic absorption spectroscopy.
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G
DOI: 10.1021/acs.joc.6b01748
J. Org. Chem. XXXX, XXX, XXX−XXX

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H
DOI: 10.1021/acs.joc.6b01748
J. Org. Chem. XXXX, XXX, XXX−XXX