Focused ortho-Lithiation and Functionalization of p-Bromo- and p-Iodoanisole

Article abstract of DOI:10.1002/ejoc.201800616

By use of the strategy for ortho-lithiation (DoM) that conceptually diminishes the pK_A difference between the ortho-H of the substrate and the conjugate acid of the metalating agent, effective metalation of bromine and iodine bearing aryl substrates can be carried out. As a set of prototypes, p-bromoanisole (p-BrA) and p-iodoanisole (p-IA) have been successfully ortho-metalated in promoted hydrocarbon media using ortho-lithiodimethylbenzylamine (o-LiDMBA) as the metalating agent. No hint of exchange of either halogen was noted using these conditions. These studies add to the emerging evidence of a hitherto unidentified acidifying effect on the proton(s) ortho- to a directing metalation group (DMG) by both a p-iodo and a p-bromo substituent.

Full text of DOI:10.1002/ejoc.201800616

A Journal of
Accepted Article
Title: Focused ortho-Lithiation and Functionalization of p-Bromo- and
p-Iodoanisole
Authors: Donald Warren Slocum, John A Jennings, Thomas K
Reinscheld, and Paul E Whitley
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800616
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800616
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10.1002/ejoc.201800616
European Journal of Organic Chemistry
FULL PAPER
Focused ortho-Lithiation and Functionalization of p-Bromo- and
p-Iodoanisole
D. W. Slocum*[a], John A. Jennings[b], Thomas K. Reinscheld[b], and Paul E. Whitley[b]
Abstract: By use of the strategy for ortho-lithiation (DoM) that
conceptually diminishes the pKA difference between the ortho-H of the
substrate and the conjugate acid of the metalating agent, effective
metalation of bromine and iodine bearing aryl substrates can be
carried out. As a set of prototypes, p-bromoanisole (p-BrA) and p-
iodoanisole (p-IA) have been successfully ortho-metalated in
promoted hydrocarbon media using ortho-lithiodimethylbenzylamine
(o-LiDMBA) as the metalating agent. No hint of exchange of either
halogen was noted during these same conditions. These studies add
to the emerging evidence of a hitherto unidentified acidifying effect on
the proton(s) ortho- to a directing metalation group (DMG) by both a
p-iodo and a p-bromo substituent.
base and that of the substrate. By doing so, milder metalation
conditions are formed which are less prone to produce secondary
metalations and / or attack of substituents. Two avenues are
utilized to achieve these focused metalation conditions. One is the
use of doped hydrocarbon media to modulate the basicity /
reactivity of n-BuLi. The second is to use aryllithiums as
metalating agents.
Phenyllithium (PhLi) is less basic and less nucleophilic than
is n-BuLi (pKA’s of the conjugate acids are ~44 and ~50,
respectively). As the use of PhLi was undesirable, a “surrogate”
aryl metalating agent, one that did not produce benzene upon
extraction of a hydrogen, was needed. Such a surrogate
metalating agent could be conveniently formed either by ortho-
lithiation or by the halogen / lithium exchange.
An initial foray into surrogate metalation was published in
2009.7 In this paper ortho-lithiodimethylaniline3a was used as the
surrogate for PhLi. Reasonable yields of eight ortho-substituted
products of p-bromoanisole were isolated. This was an
achievement at the time in that for seventy years, there was a fear
of the intervention of a rapid halogen/lithium exchange followed
by a secondary ortho-lithiation (equation 1). Both George Wittig8
and Henry Gilman,9 the co-discovers of the ortho-lithiation
reaction, also elucidated the sequence shown below.
Introduction
Aryllithium chemistry has gone through numerous phases
since the initial ortho-lithiation1 and halogen/lithium(X/Li)1a,c,e,f, 2
exchange procedures were published. Through the decades,
these procedures have become mainstays in the
organic/organometallic chemist’s toolbox. Overall, a varied and
diverse set of protocols have been developed to bring about ortho
C-H bond activation of a broad spectrum of substituted aryls.
Our group’s preoccupation over the last two decades has
been the utilization of doped hydrocarbon media, in particular
cyclohexane, for both ortho-lithiations3 and the halogen/lithium
exchange.4 By use of small increments of THF and/or
tetramethylethylenediamine (TMEDA) as dopants, both reactions
have been enabled to proceed with facility in hydrocarbon media.
Incremental amounts of an ether or bis-chelating amine serve to
deoligomerize n-BuLi, by far the most utilized alkyllithium reagent,
in a controlled manner. By use of this strategy, controlled, fine-
tuning of the reactivity of a doped hydrocarbon solution of n-BuLi
has been achieved.5 In addition, such solutions are much more
stable to alkyllithium reagents than the currently utilized ether and
ether/TMEDA solutions6.
Equation 1.
Consideration of this sequence leads to an intriguing
speculation, that the ortho-H of p-BrA must be more acidic than
that of anisole. Recently, this was demonstrated by comparative
surrogate metalation studies of both p-BrA and p-IA.10 Related
low-temperature experimental metalations11 as well as
computational studies12 have afforded the insight that a bromine
substituent provides a distinct acidification of the proton(s) meta-
to it. For a p-substituted aryl such as anisole, this would translate
as a measureable acidification of the ortho-proton, i. e., the proton
that undergoes ortho-lithiation.
To further our investigations of fine-tuning of aryl metalation
reactions, the concept of focused metalations has been
developed. Focused metalations are realized by decreasing the
pKA difference between the conjugate acid of the organolithium
Some success has already been realized in the ortho-
lithiation of p-FA13 and p-ClA,3a,14 but it is known that other p-XA’s
(p-XA, p-haloanisoles), namely, p-BrA and p-IA, preferentially
undergo the X/Li exchange if an alkyllithium reagent is utilized
(equation 1). The alternative is to use a less basic, less
[a]
[b]
D. W. Slocum
Department of Chemistry
Western Kentucky University
1906 College Heights Blvd, Bowling Green, KY 42101
E-mail: donald.slocum@wku.edu
J. A. Jennings, T. K. Reinscheld, P. E. Whitley
Department of Chemistry
Western Kentucky University
1906 College Heights Blvd, Bowling Green, KY 42101
nucleophilic organolithium.
A substituted aryllithium would
generate, upon its use for a metalation, a substituted benzene
possessing a pKA of its conjugate acid less than 44. Offered
herein is a study of the effective ortho-lithiation of both p-BrA and
p-IA using such a reagent where there was no indication that the
halogens have been attacked.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800616
European Journal of Organic Chemistry
FULL PAPER
Our working hypothesis is that a focused metalation can be
achieved if there is only a 3-5 pKA unit difference between the
acidity of the substrate and that of the conjugate acid of the
metalating agent. The underlying assumption here is that such a
reagent would be less aggressive and therefore less prone to
attack substituents. Herein is presented an approach to a
“focused” metalation procedure wherein a substituted aryllithium
reagent is utilized. This approach not only gains the lower
conjugate acid pKA value of the metalating agent, but also avoids
the initiation of the X/Li exchange.
This focused metalation concept was originated as a
consequence of the many reports to be found in the literature
describing metalations that have had their yields compromised,
have generated metalations at secondary sites or have failed
altogether. Many of these problems can be generalized by use of
the term “over metalation”. Such can be the result from use of too
strong a base, too much promoter, too much base and sometimes
some combination of two of these conditions. A softer touch might
lead in many cases to more controlled, more focused metalations.
Our success in this regard was reported recently for ortho-
lithiation under the rubric “deficiency catalysis” where the
conditions involved only n-BuLi in hydrocarbon media
substituted products were realized in 32% and 55% yields,
respectively. Schlosser and coworkers performed a complete
study of the lithiation of all three fluoroanisoles ortho- to the
methoxy group.19
Lithiation ortho- to several aryl DMG’s has been
accomplished in the presence of a p-Cl substituent. These include
19, 20a
the methoxy group3a,
as well as the amide20b and
methoxymethyl (-MOM)20c directing groups.
Arenes containing a DMG where either a p-Br or p-I
substituent is present seldom have been subjected to ortho-
lithiation conditions. For the most part this has been due to
concern that the –Br or –I substituent will preferentially undergo
rapid X/Li exchange. Both Gilman8 and Wittig9 attempted ortho-
lithiation of p-bromoanisole with both eventually realizing that the
transformation illustrated in equation 1 was occurring. Wittig21
went on to investigate the use of PhLi for the ortho-lithiation of the
haloanisoles, ultimately isolating the anticipated triarylcarbinol
derived from p-BrA and benzophenone in 70% yield (equation 2).
Eaborn and Walton17 later repeated this procedure, isolating the
trimethylsilyl derivative of p-BrA in 44% yield and that of p-IA in
58% yield.
(cyclohexane)
minimally
activated
by
a
deficiency
(substoichiometric equiv.) of TMEDA or an equiv. or two of THF.3a
These modulated systems avoided several competing
metalations or other strong base reactions that might have
intervened. Such conditions and the results therefrom provide
excellent examples of the benefits provided by focused conditions
for ortho-lithiations.
Equation 2.
Sporadic reports of metalation of bromine containing aryl
systems have appeared in the literature. Hirata et al22 achieved
regioselective lithiation of anisole (1) with a product isolated in
33% yield. Majetich and coworkers23 attempted the X/Li exchange
of compound (2) achieving as the likely result the exchange/ortho-
lithiation sequence depicted in equation 1. In at least one case
The concept of focused metalations encompasses two
broad but separate categories:
•
Regiospecific metalation of designated site on an
aryl where one or more potentially competing
site(s) are present. This includes, but is not limited
to, the related concept of “optional site
selectivity”.15
concern that
a p-bromo substituent would undergo the
halogen/lithium exchange instead of the sought ortho-lithiation
caused a pharmaceutical research team to pursue an alternative
approach.24
•
Efficient metalation of aryls where a potentially
competing reaction is suppressed.
These two categories can be further subdivided, but for our
purposes, these two separate designations will suffice. Our
“deficiency catalysis” paper provides many examples of the first
category.3a In this current contribution, examples are provided
that conform to the second category, i.e., metalation ortho- to the
methoxy group of p-bromo- and p-iodo-anisole (p-BrA and p-IA)
with complete suppression of the X/Li exchange.
At ambient temperatures, halogens possess some stability
to ortho-lithiation conditions, but only if located in the p-position.
Only p-fluoro-13 and p-chloro-aryls3a,14 afford this stability. The
p-F substituent in p-fluoroanisole was found to be a weaker
director than the methoxy group using n-BuLi in ether at ambient
temperature and so lithiation took place adjacent to the methoxy
group. Earlier, both Gilman16 and Eaborn,17 each attained using
PhLi only a 13% yield of product from the metalation of p-
fluoroanisole after having run the metalation overnight. In each
study, a black product solution was formed indicative of benzyne
formation. By running the metalation over much shorter periods
with n-BuLi, 5 h in one study18 and 1 h in another,13 ortho-
Figure 1.
Results and Discussion
The concept of use of organolithium reagents less basic
than n-BuLi has led to some intriguing developments. Such
reagents increase our ability to modulate reactivity in a controlled
manner. Focused metalations using such reagents, among other
attributes, would allow more substituent tolerance. Numerous
substituents are too prone to side reactions with an organolithium
reagent to survive either ortho-lithiation or halogen/lithium
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10.1002/ejoc.201800616
European Journal of Organic Chemistry
FULL PAPER
exchange conditions. Exceptional substituents, aside from
directing metalation groups (DMG’s) themselves, which have
been shown to remain intact during the course of a lithiation or
exchange are –R, –SiR3, (–F), –Cl and –D. Additional substituents,
in particular ones that provide access to further functional
Equation 4.
elaboration, would be most desirable. Retention of
a
Reproducible extents of ortho-lithiation of DMBA itself are
95-98% whereas those for DMA are in the area of 88-92%.3a
o-LiDMBA is thus a more concentrated reagent than o-LiDMA.
Furthermore o-LiDMA is formed using the “deficiency catalysis”
procedure involving 0.1 equiv. of TMEDA in cyclohexane. The
TMEDA would carry forward into subsequent reactions which is
an undesirable feature. Its presence did not appear to be a
problem in our preliminary study, but it was felt that the presence
of TMEDA could present problems in future studies. o-LiDMBA
does not present any such problem as it is generated in
cyclohexane activated with an equiv. of MTBE. Moreover, the
DMBA generated as a result of the metalation process is
somewhat easier to extract from the reaction mixture than is the
generated DMA.
transformable aryl –Br or –I substituent from an ortho-lithiation
procedure would represent a giant step towards this goal.
Most ortho-lithiations are carried out using n-BuLi or even
more basic alkyllithiums. ortho-H’s of many aryl substrates
possess pKA’s between 37 and 41.25,26
As the
basicity/nucleophilic nature of an aryllithium is significantly lower
than that of n-BuLi (pKA of the conjugate acid, butane, is ca. 50),
a decrease in both the aryllithium’s basicity and nucleophilicity
towards substituents will result. In the past PhLi was used in this
regard, but this is no longer practical as PhLi generates, upon use
in a metalation, benzene, a carcinogen (equation 3).
Carbon-carbon and carbon-heteroatom bond formation for
ortho-products of both p-bromo and p-iodoanisole range
percentage-wise for the most part from the 60’s to the high 70’s
(Tables 1 and 2, respectively). No clear difference was discovered
between the yields of the ortho- products derived from the two
separate substrates. No halogen/lithium exchange was observed
during the ortho-lithiation of either substrate.
Most of these products can be further derivatized via the
halogen/lithium exchange. In particular, the o-TMS derivatives of
p-BrA and p-IA can be double derivatized, first by the X/Li
exchange of either the bromine or iodine substituents and second
by the ipso substitution of the -TMS group. In a sense, the
compounds 4-Br-2-TMSA and 4-I-2-TMSA comprise a set of aryl
synthons for convenient access to 2,4-disubstituted anisoles.
Dilution of the generated ortho-lithio intermediate with THF
prior to derivatization solubilizes much of the particulate matter.
Further study of this technique in general will potentially improve
the percent isolated yields.
Equation 3.
By decreasing the difference in pKA values between the
conjugate acid of the metalating agent and that of the ortho-H of
the substrate, a more focused ortho-lithiation can be achieved.
This is the mantra to be followed in all future metalation efforts
from our group. In a sense our recent publications involving ortho-
lithiations and exchanges in activated hydrocarbon media3,4
conforms to this mantra. Deficiencies of THF or TMEDA in
hydrocarbon media were shown to provide efficient lithiations, yet
the systems were much less activated than when a full equiv. of
TMEDA or bulk ether solutions of n-BuLi were utilized.5
To afford a safer, greener ortho-lithiation procedure for the
metalation of p-BrA, our initial investigations utilized ortho-
lithiodimethylaniline (o-LiDMA) as the metalating agent.7 o-LiDMA
provided a reasonable extent-of-metalation of p-bromoanisole
such that good yields of ortho- substituted products were isolated.
Moreover, as the metalating agent was o-LiDMA, the protonated
aryl generated in the reaction was dimethylaniline, not benzene.
Use of this metalating agent permitted an acid/base extraction as
part of the work-up, resulting in recovery of DMA for potential
recycle.
To further this approach we now report the efficient ortho-
lithiation of both p-BrA and p-IA (Tables 1 and 2, respectively)
utilizing ortho-lithiodimethylbenzylamine (o-LiDMBA) as the
metalating agent. DMA and DMBA each are estimated to possess
a pKA for their respective ortho-H’s of 40.3 or greater.25 Both
provide about the same extent of metalation of p-bromoanisole
but use of o-LiDMBA offers several advantages over use of o-
LiDMA. In addition, ortho-lithiation of p-IA has been achieved
using o-LiDMBA (equation 4). Use of o-LiDMA was not attempted
in this latter investigation.
Conclusions
For decades, chemists have been seeking methods to
further the effectiveness of metalation chemistry. Systems
involving superbases27 and mixed main group metals28 have been
developed for this expressed purpose. We propose a third
alternative; utilization of organolithium bases whose conjugate
acids are only 3-5 pKA units less acidic than the most acidic site
being metalated. Such bases can be formed by ortho-lithiation
and/or, possibly, using chemistry yet to be explored, by the
halogen/lithium exchange. The principal bases in our repertoire
are
ortho-lithiodimethylaniline
(o-LiDMA)7
and
ortho-
lithiodimethylbenzylamine (o-LiDMBA). Both of these bases can
be conveniently formed by “deficiency catalysis” metalation with
n-BuLi.3a By this strategy, the basicity of the n-BuLi is stepped
down, i.e., the difference between the pKA of the conjugate acid
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10.1002/ejoc.201800616
European Journal of Organic Chemistry
FULL PAPER
of the base and the pKA of the acidic site of the substrate is
reduced, ideally to a difference of 3-5 pKA units, thereby forming
a more focused metalating system.
Experimental Section
General- All research chemicals were supplied by Aldrich Chemical Co.
Solvents were order anhydrous and used as received. GC analysis was
performed on a capillary gas chromatograph equipped with a BP-10
capillary column (25m x 0.22mm, 0.25mm film and FID). Identities of
products were confirmed by GC/MS analysis (30m x 0.32mm, 0.25 mm
film) on an instrument equipped with a quadrupole mass detector and
separate FID. NMR data was attained using an ECA-500 MHz instrument.
Combustion analysis was performed on a CHN analyser. Several products
were purified by column chromatography using silica gel (60Å, 65 x 250
mesh, 500-600 m2/g) available from Sorbent Technologies. TLC analysis
was performed using identical silica plates also available from Sorbent
Technologies.
Successful ortho-lithiation of both p-IA and p-BrA has
afforded a series of ortho-substituted anisoles in modest to good
yields. The two trimethylsilyl derivatives can serve as aryl
synthons for the preparation of 2-, 4-disubstitued anisoles. An
initial halogen/lithium exchange followed by ipso-substitution of
the trimethylsilyl moiety of either synthon would afford access to
a wide array of appropriately substituted anisoles. Under these
conditions, no products from a halogen/lithium exchange were
observed.
Both dimethylbenzylamine (DMBA) and dimethylaniline
(DMA) have a measured ortho-H acidity with a pKA of >40.3.25
Anisole’s ortho-H acidity possesses a measured pKA of 39.25 Our
conjecture is that a 3-5 pKA unit difference in acidity is necessary
between the conjugate acid of the metalating agent and the acidic
site of the substrate for an effective focused metalation to be
achieved. Larger differences brings about unwanted side-
reactions. Anisole itself is not effectively ortho-lithiated using o-
LiDMBA (pKA = 40.3 vs 39). This being the case, metalation of p-
BrA and p-IA cannot be accomplished unless both of these
halogenated anisoles are more acidic than anisole by two or three
pKA units.
These observations lead to a conundrum. The strong
electronegativity of the p-halogen could explain the observed
increase in ortho-H acidity of p-chloroanisole and p-fluoroanisole
over that of anisole. Both can be metalated under milder
conditions than anisole.13,3a,14 The above results also indicate that
both p-bromo- and p-iodoanisole possess ortho-protons more
acidic than anisole. Yet electronegativity seemingly cannot
explain this last observation. Another possibility is an opposing-
pi-resonance contribution.29 By opposing the pi-donation of the
–OMe oxygen, the p-substituent in effect increases the
localization of oxygen’s electron pairs. This in turn serves to
increase the contribution of alkyllithium complexion via the
Complex-Induced Proximity Effect (CIPE)30 leading to a perceived
increase in acidity. However, it is difficult to envision how the large
orbitals on –Br or –I can provide sufficient “opposing” to make the
ortho-H’s appear as acidic as those in their –F and –Cl
counterparts.
Preparation of o-Li-p-Bromoanisole- To a clean, dry nitrogen-purged round
bottom flask was added a 1.33 M suspension in cyclohexane of o-LiDMBA
(15 mL, 20 mmol; prepared as described previously3a) via 14 gauge needle.
Next, MTBE (2.4 mL, 20 mmol) and p-bromoanisole ((2.4 mL, 19 mmol)
0.95 equiv. of p-BrA is used since the o-LiDMBA is typically 94-96% pure)
was added and the reaction mixture was allowed to stir at 60°C under a
positive nitrogen atmosphere for 20-30h. The prepared o-Li-p-BrA was
used in subsequent derivatizations without purification. The same
procedure was followed for the preparation of o-Li-p-Iodoanisole using
4.45 g (19 mmol) of p-iodoanisole.
General Derivatization of o-Li-p-Bromoanisole and o-Li-p-Iodoanisole- To
a stirred solution of o-Li-p-bromoanisole or o-Li-p-iodoanisole (as prepared
above) was slowly added 0.95 equiv. (based on p-BrA or p-IA) of the
desired derivatizing agent (electrophile) via syringe for liquids and directly
as a solid for solids. Attempts were made to maintain ambient reaction
temperature with aid of a water bath or ice bath. The reaction mixture was
allowed to stir at room temperature for at least 3 h. The reaction was slowly
quenched with water (unless otherwise stated) and transferred to a
separatory funnel with the aid of 20-30 mL of MTBE. Upon separation, the
organic layer was washed with 25 mL of 1M HCl (to remove DMBA) and
25mL brine. The organic layer was then dried over sodium sulfate and
concentrated in vacuo to provide crude product which was purified by
trituration and/or recrystallization (to >95% pure by GC) as described for
each individual product. In some cases, one or two additional
crystallizations were necessary to obtain analytically pure samples for the
combustion analysis of previously unknown compounds.
5-Bromo-2-methoxy-α-phenyl-benzenemethanol (1) - To a stirred solution
of 1.1 M o-Li-p-bromoanisole (17.1 mL) was slowly added benzaldehyde
(1.8 mL, 18.2 mmol) via syringe. The crude product was triturated with
hexanes, filtered and washed with cold hexanes to afford 4.47 g, 67%.
Melting point 76.0-77.4 °C (Lit. mp 76.4-78.4°C 7); M+ 292.0 / 294.0; Base
Peak 292.0 / 294.0; 1H NMR (500 MHz, CDCl3, 25°C): δ = 2.69 (s, 1H, OH),
3.77 (s, 3H), 6.01 (s, 1H), 6.73-6.75 (d, J = 8.6 Hz, 1H), 7.24-7.29 (m, 1H),
7.31-7.38 (complex m, 5H), 7.444-7.450 (d, J = 2.9 Hz, 1H). 13C NMR:
δ = 55.8, 71.5, 112.5, 113.4, 126.6, 127.6, 128.5, 130.4, 131.4, 134.2,
142.7, 155.7; Analysis calculated for C14H13BrO2 (293.16): C, 57.36%; H,
4.47%. Found: C, 57.36%; H, 4.56%.
So, what is the cause of the observed acidity enhancement
of the p-bromo- and p-iodoanisoles? Recent experimental11 and
computational investigations12 have indicated some generality to
the observed acidifying of the position(s) meta- to a bromine
substituent. This is exactly the relationship of the ortho-H to the
p-Br substituent in p-BrA. Separate studies, both experimental
and computation, are in progress to further our knowledge of this
electronic effect, to gain more insight into its origin and, ultimately,
its potential utility in synthesis.
5-Bromo-2-methoxy-α,α-diphenyl-benzenemethanol (2) - To a stirred
solution of 1.1 M o-Li-p-bromoanisole (17.0 mL) was slowly added
benzophenone (3.3 g, 18.1 mmol) as a solid. The crude product was
triturated with cyclohexane, filtered and washed with cyclohexane to afford
4.47 g, 67%. Melting point 121.5-123.3 °C (Lit. mp 121.5-123.3°C 21); M+
368.1 / 370.1; Base Peak 291.1; 1H NMR (500 MHz, CDCl3, 25°C):
δ = 3.63 (s, 3H), 5.12 (s, 1H, OH), 6.635-6.641 (d, J = 2.3 Hz, 1H), 6.82-
Table 1. Here
Table 2. Here
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10.1002/ejoc.201800616
European Journal of Organic Chemistry
FULL PAPER
6.84 (d, J = 9.2 Hz, 1H). 13C NMR: δ = 56.1, 81.8, 113.4, 113.9, 127.4,
127.7, 128.0, 131.8, 133.0, 137.7, 145.9, 156.6.
dried over sodium sulfate and concentrated in vacuo. The crude product
was triturated with cyclohexane, filtered and washed with cyclohexane to
afford 3.0 g, 66% of a yellow solid. Melting point 101-102°C M+ 290.0 /
292.0; Base Peak 213.0; 1H NMR (500 MHz, CDCl3, 25°C): δ = 3.70 (s,
3H), 6.87-6.89 (d, J = 9.2 Hz, 1H), 7.41-7.46 (m, 3H), 7.54-7.59 (m, 2H),
7.79-7.80 (d, J = 7.4 Hz, 2H). 13C NMR: δ = 56.0, 112.9, 113.3, 128.5,
129.9, 130.7, 132.0, 133.5, 134.5, 137.2, 156.4. Analysis calculated for
C14H11BrO2 (291.14): C, 57.76%; H, 3.81%. Found: C, 58.09%; H, 3.93%.
5-Bromo-α-cyclopentyl-2-methoxy-benzenemethanol (3) - To a stirred
solution of 1.0
M o-Li-p-bromoanisole (15 mL) was slowly added
cyclopentanone (1.2 mL, 13.7 mmol) via syringe. The crude product was
triturated with cyclohexane, filtered and washed with cyclohexane to afford
2.34 g, 63%. Melting point 67.9-69.0 °C (Lit. mp 67.5-69.1°C 7); M+ 270.1
/ 272.0; Base Peak 162.1; 1H NMR (500 MHz, CDCl3, 25°C): δ = 1.70-2.10
(complex m, 8H), 3.32 (s, 1H, OH), 3.87 (s, 3H), 6.77-6.79 (d, J = 8.6 Hz,
5-Bromo-α-(4-chlorophenyl)-2-methoxy-benzenemethanol (8)
- To a
1H), 7.32-7.35 (dd, J = 8.6, 2.3 Hz, 1H), 7.44-7.45 (d, J = 2.8 Hz, 1H). 13
C
stirred solution of 1.22M o-Li-p-bromoanisole (14.8 mL) was slowly added
4-chlorobenzaldehyde (2.36g, 16.9 mmol). The crude product was
triturated with hexanes, filtered and washed with cold hexanes to afford
3.03 g, 55%. Melting point 101.2-101.8°C, M+/Base peak envelope
centered at 328.0; 1H NMR (500 MHz, CDCl3, 25°C): δ = 2.83 (s, 1H, OH),
3.78 (s, 3H), 5.96 (s, 1H), 6.73-6.75 (d, J = 8.6 Hz, 1H), 7.25-7.41 (complex
m, 6H). 13C NMR: δ = 55.8, 70.1, 112.6, 113.4, 128.0, 128.6, 130.3, 131.6,
133.3, 133.8, 141.2, 155.6. Analysis calculated for C14H13IO2 (340.16): C,
49.43%; H, 3.85%. Found: C, 49.09%; H, 3.83%.
NMR: δ = 23.5, 39.2, 55.7, 82.4, 112.9, 113.4, 128.9, 130.7, 136.6, 156.5.
Analysis calculated for C12H15BrO2 (271.15): C, 53.15%; H, 5.58%. Found:
C, 53.37%; H, 5.53%.
1-(5-Bromo-2-methoxy-phenyl)-cyclohexanol (4) - To a stirred solution of
1.15 M o-Li-p-bromoanisole (16 mL) was slowly added cyclohexanone
(1.85 mL, 17.8 mmol) via syringe. The crude product was triturated with
cyclohexane, filtered and washed with cyclohexane to afford 2.66 g, 53%.
Melting point 98.3-98.9 °C (Lit. mp 93.9-97.6°C 7); M+ 284.1 / 286.1; Base
Peak 162.1; 1H NMR (500 MHz, CDCl3, 25°C): δ = 1.15-1.28 (m, 1H), 1.57-
1.97 (complex m, 9H), 3.76 (s, 1H, OH), 3.83 (s, 3H), 6.77-6.79 (d, J = 8.6
Hz, 1H), 7.31-7.33 (dd, J = 9.2, 2.9 Hz, 1 H), 7.435-7.440 (d, J = 2.8 Hz,
1H). 13C NMR: δ = 21.9, 25.8, 36.5, 55.7, 73.0, 113.2, 113.8, 129.1, 130.5,
138.8, 156.4; Analysis calculated for C13H17BrO2 (285.18): C, 54.75%; H,
6.01%. Found: C, 54.77%; H, 5.99%.
(5-Iodo-2-methoxy-phenyl)-phenyl-methanol (9) - To a stirred solution of
1.14 M o-Li-p-iodoanisole (15.3 mL) was slowly added benzaldehyde (1.7
mL, 16.8 mmol) via syringe. The crude product was triturated with hexanes
(5-6 mL), filtered and washed with cold hexanes to afford 3.8 g, 67%.
Melting point 79.4-80.8°C, M+/Base peak 340.1; 1H NMR (500 MHz, CDCl3,
25°C): δ = 2.75 (s, 1H, OH), 3.76 (s, 3H), 5.99 (s, 1H), 6.62-6.64 (d, J =
2.2 Hz, 1H). 13C NMR: δ = 55.7, 71.4, 83.5, 113.2, 126.6, 127.6, 128.4,
134.6, 136.2, 137.5, 142.8, 156.5. Analysis calculated for C14H13IO2
(340.16): C, 49.43%; H, 3.85%. Found: C, 49.09%; H, 3.83%.
4-Bromo-1-methoxy-2-(trimethylsilyl)-benzene (5) - To a stirred solution of
0.96
M
o-Li-p-bromoanisole (19 mL) was slowly added
chlorotrimethylsilane ((2.5 mL, 20 mmol) A slight excess (1.1 equiv.) of
ClTMS was employed since any residual can be easily hydrolyzed and
removed in the aqueous work up.) via syringe. After 1 h the reaction
mixture was quenched slowly with aqueous saturated sodium carbonate
(rather than the typical water quench). The organic layer was then washed
with 1M HCl, brine, dried over sodium sulfate and concentrated in vacuo.
The crude product was then treated with hexanes (5 mL) and allowed to
sit in the refrigerator overnight whereupon needlelike crystals formed. The
solution was filtered and washed with cold hexanes and afforded 2.47 g,
52% of (5-Bromo-2-methoxy-phenyl)-trimethyl-silane as clear needles.
Melting point 56.7-57.7 °C (Lit. mp 58-58.5°C 17); M+ 258.0 / 260.0; Base
Peak 258.0 / 260.0; 1H NMR (500 MHz, CDCl3, 25°C): δ = 0.24 (s, 9H),
3.77 (s, 3H), 6.68-6.70 (d, J = 8.0 Hz, 1H), 7.39-7.42 (m, 2H). 13C NMR: δ
= 1.1, 55.4, 111.5, 113.4, 131.3, 133.2, 137.4, 163.3.
5-Iodo-2-methoxy-α,α-diphenyl-benzenemethanol (10)
- To a stirred
solution of 1.13 M of o-Li-p-iodoanisole (10.4 mL) was slowly added
benzophenone (2.6 g, 11.3 mmol) as a solid. The crude product was
triturated with cyclohexane, filtered and washed with cyclohexane to afford
3.39 g, 72%. Melting point 136.3-137.4°C (Lit mp 136-137°C 21); M+ 416.1;
Base Peak 339.1; 1H NMR (500 MHz, CDCl3, 25°C): δ = 3.62 (s, 3H), 5.10
(s, 1H, OH), 6.71-6.72 (d, J = 9.6 Hz, 1H), 6.780-6.784 (d, J = 2.3 Hz, 1H),
7.20-7.32 (complex m, 10H), 7.57-7.60 (dd, J = 8.6, 2.3 Hz, 1H). 13C NMR:
δ = 56.0, 81.7, 83.7, 177.5, 127.4, 127.7, 137.9, 138.1, 138.7, 145.9, 157.4.
5-Iodo-α-cyclopentyl-2-methoxy-benzenemethanol (11) - To a stirred
solution of 1.0
M o-Li-p-iodoanisole (14.4 mL) was slowly added
cyclopentanone (1.77 mL, 20.02 mmol) via syringe. The crude product was
triturated with cyclohexane, filtered and washed with cyclohexane to afford
2.45 g, 40%. Melting point 92.4-94.1°C; M+ 318.1; Base Peak 289.0; 1H
NMR (500 MHz, CDCl3, 25°C): δ = 1.74-2.10 (complex m, 8H), 3.29 (s, 1H,
OH), 3.87 (s, 3H), 6.66-6.68 (d, J = 8.6 Hz), 7.51-7.53 (dd, J = 8.6, 2.3,
1H), 7.60-7.61 (d, J = 2.3 Hz, 1H). 13C NMR: δ = 23.5, 39.2, 55.6, 82.3,
83.3, 133.5, 134.7, 136.9, 137.0, 157.3. Analysis calculated for C12H15IO2
(318.15): C, 45.30%; H, 4.75%. Found: C, 45.67%; H, 4.66%.
5-Bromo-2-methoxy-benzaldehyde (6) - To a stirred solution of 1.0M o-Li-
p-bromoanisole (16.5 mL) was slowly added N,N-dimethylformamide ((2.5
mL, 32.4 mmol) An excess of DMF was used as it can be easily removed
during aqueous workup)) via syringe. The crude product was triturated with
hexane, filtered and washed with hexane to afford 2.95 g, 73.8%. Melting
point 102.0-104.0 °C (Lit. mp 107-109°C 31); M+ 214.0 / 216.0; Base Peak
214.0 / 216.0; 1H NMR (500 MHz, CDCl3, 25°C): δ = 3.91 (s, 3H), 6.88-6.9
(d, 8.6 Hz, 1H), 7.61-7.63 (dd, J = 8.6, 2.9 Hz, 1H), 7.907-7.912 (d, J = 2.8
Hz, 1H), 10.37 (s, 1H). 13C NMR: δ = 56.1, 113.6, 113.8, 126.2, 131.1,
138.4, 160.8, 188.5.
1-(5-Iodo-2-methoxy-phenyl)-cyclohexanol (12) - To a stirred solution of
1.15M o-Li-p-iodoanisole (15 mL) was slowly added cyclohexanone (1.81
mL, 17.46 mmol) via syringe. The crude product was triturated with
cyclohexane, filtered and washed with cyclohexane to afford 3.98 g, 69%.
Melting point 109.9-111.0°C; M+ 332.1; Base Peak 289.0; 1H NMR (500
MHz, CDCl3, 25°C): δ = 1.21-1.24 (m, 1H), 1.57-1.62 (complex m, 2H),
1.69-1.97 (complex m, 7H), 3.65 (s, 1H, OH), 3.86 (s, 3H), 6.66-6.68 (d, J
= 8.6 Hz, 1H), 7.50-7.52 (dd, J = 8.6, 2.3 Hz, 1H), 7.592-7.596 (d, J = 2.3
Hz, 1H). 13C NMR: δ = 21.9, 25.8, 36.5, 55.6, 72.9, 84.2, 113.8, 134.9,
136.7, 139.2, 157.2. Analysis calculated for C13H17IO2 (332.18): C,
47.00%; H, 5.16%. Found: C, 46.76%; H, 5.09%.
(5-Bromo-2-methoxy-phenyl)-phenyl-methanone (7) - To a stirred solution
of 1.0 M o-Li-p-bromoanisole (17 mL) was slowly added benzonitrile (1.6
mL, 15.5 mmol) via syringe. After stirring for 18 h, the reaction was
quenched with water and extracted with MTBE. The organic layer was
transferred to a round bottom flask and treated with 1M sulfuric acid (25
mL). Following stirring vigorously for 2 h, the reaction mixture was
transferred to a sepratory funnel and the organic layer was separated. The
aqueous layer was back extracted with MTBE and the combined organic
layers were washed with aqueous saturated sodium bicarbonate and brine,
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4-Iodo-1-methoxy-2-(trimethylsilyl)-benzene (13) - To a stirred solution of
Analysis calculated for C7H6ClIO (268.47): C, 31.31%; H, 2.25%. Found:
C, 31.0%; H, 2.25.
1.21
M
o-Li-p-Iodoanisole (15.5 mL) was slowly added
chlorotrimethylsilane ((4.8 mL, 37.6 mmol) An excess (2.0 equiv.) of
ClTMS was employed since any residual can be easily hydrolyzed and
removed in an aqueous work up) via syringe. After 1 h the reaction mixture
was quenched slowly with aqueous saturated sodium carbonate (rather
than the typical water quench). The organic layer was then washed with
1M HCl, brine, dried over sodium sulfate and concentrated in vacuo. The
crude product was then triturated with hexanes (5 mL) and allowed to sit
in the refrigerator overnight whereupon needlelike crystals formed. The
solution was filtered and washed with cold hexanes to afford 4.46 g, 78%.
Melting point 50.3-50.9°C (Lit. mp 50-50.5°C 17); M+ 306.0; Base Peak
289.0; 1H NMR (500 MHz, CDCl3, 25°C): δ = 0.24 (s, 9H), 3.77 (s, 3H),
6.59-6.61 (d, J = 8.6 HZ, 1H), 7.56-7.61 (m, 2H). 13C NMR: δ = 1.1, 55.3,
84.1, 112.2, 132.0, 139.2, 143.3, 164.0.
Acknowledgements
Initial aspects of this work were performed under NSF
CHE0710021. We are grateful for our current support by the WKU
Research Foundation and the WKU Department of Chemistry.
Keywords: ortho-lithiation • surrogate metalation • ortho-proton
acidity • strong base • aryl synthesis
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p-iodoanisole (14.8 mL) was slowly added N,N-dimethylformamide ((2.9
mL, 38.0 mmol) An excess of DMF was used as it can be easily removed
during aqueous work up) via syringe. The crude product was triturated with
hexane, filtered and washed with hexane to afford 3.14 g, 61%. Melting
point 142.0-143.5°C (Lit. mp 140-142 °C 32); M+ 262.0; Base Peak 262.0;
1H NMR (500 MHz, CDCl3, 25°C): δ = 3.91 (s, 3H), 6.77-6.79 (d, 8.6 Hz,
1H), 7.79-7.81 (dd, J = 8.6, 2.3 Hz, 1H), 8.075-8.079 (d, J = 2.3 Hz, 1H),
10.33 (s, 1H). 13C NMR: δ = 56.0, 83.1, 114.2, 126.6, 137.2, 144.2, 161.5,
188.4.
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(5-Iodo-2-methoxy-phenyl)-phenyl-methanone (15) - To a stirred solution
of 1.28M o-Li-p-iodoanisole (15 mL) was slowly added benzonitrile (1.88
mL, 19.2 mmol) via syringe. After stirring for 18h, the reaction was
quenched with water and extracted with MTBE. The organic layer was
transferred to a round bottom flask and treated with 1M sulfuric acid (25
mL). Following stirring vigorously for 2h, the reaction mixture was
transferred to a separatory funnel and the organic layers were washed with
aqueous saturated sodium bicarbonate and brine, dried over sodium
sulfate and concentrated in vacuo. The crude product was triturated with
cyclohexane, filtered and washed with cyclohexane to afford 5.55 g, 86%
of (5-Iodo-2-methoxy-phenyl)-phenyl-methanone as yellow solid. Melting
point 79.8-81.6 °C; M+/ Base peak 338.1; 1H NMR (500 MHz, CDCl3,
25°C): δ = 3.70 (s, 3 H), 6.76-6.78 (d, J = 8.6 Hz, 1H), 7.42-7.80 (complex
m, 7H). 13C NMR: δ = 55.9, 82.5, 113.8, 128.5, 129.9, 131.2, 133.4, 137.2,
137.7, 140.4, 157.3, 194.7. Analysis calculated for C14H11IO2 (338.14): C,
49.73%; H, 3.28%.
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5-Iodo-α-(4-chlorophenyl)-2-methoxy-benzenemethanol (16) - To a stirred
solution of 1.23 M o-Li-p-iodoanisole (14.8 mL) was slowly added 4-
chlorobenzaldehyde (2.38 g, 17.0 mmol). The crude product was triturated
with cyclohexane overnight, filtered and washed with cold cyclohexane to
afford 5.06 g, 79%. Melting point 104.7-106.4°C; M+ 374.0; Base Peak
374.0; 1H NMR (500 MHz, CDCl3, 25°C): δ = 2.76 (s, 1H, OH), 3.76 (s, 3H),
5.95 (s, 1H), 6.63-6.65 (d, J = 8.6 Hz, 1H), 7.29 (s, 4H), 7.54-7.56 (dd, J =
8.6, 2.3 Hz, 1H), 7.578-7.582 (d, J = 2.3 Hz, 1H). 13C NMR: δ = 55.7, 70.9,
83.5, 113.2, 128.0, 128.6, 133.3, 134.2, 136.0, 137.7, 141.2, 156.4.
Analysis calculated for C14H12ClIO2 (374.60): C, 44.89%; H, 3.23%. Found:
C, 45.16%; H, 3.19%.
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2-Chloro-4-iodo-1-methoxybenzene (17) - To a stirred solution of 1.64 M
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11.8 mmol) as a solid. The reaction mixture was allowed to stir overnight
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poured over an evaporating dish and allowed to evaporate at room
temperature (approximately 10 min.) whereupon white powder like crystals
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35%. Melting point 88.9-90.4°C (Lit. mp 93-95°C 33); M+/ Base peak 268.0;
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10.1002/ejoc.201800616
European Journal of Organic Chemistry
FULL PAPER
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((Insert TOC Graphic here: max.
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ortho-lithiation*
D. W. Slocum*, J. A. Jennings, T. K.
Reinscheld, P. E. Whitley
Page No. – Page No.
Focused ortho-Lithiation and
Functionalization of p-Bromo and p-
Iodoanisole
By use of the strategy for ortho-lithiation (DoM) that conceptually diminishes the pKA
difference between the ortho-H of the substrate and the conjugate acid of the metalating
agent, effective metalation of bromine and iodine bearing aryl substrates can be carried
out. As a set of prototypes, p-bromoanisole (p-BrA) and p-iodoanisole (p-IA) have been
successfully ortho-metalated in promoted hydrocarbon media using ortho-
lithiodimethylbenzylamine (o-LiDMBA) as the metalating agent. No hint of exchange of
either halogen was noted during these same conditions. These studies add to the
emerging evidence of a hitherto unidentified acidifying effect on the proton(s) ortho- to a
directing metalation group (DMG) by both a p-iodo and a p-bromo substituent.
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