Metalation of o-methylanisole (o-MA); An optional-site selectivity reassessment

Article abstract of DOI:10.1016/j.tet.2010.05.036

'Deficiency catalysis' is the concept applied to metalation chemistry that increments of TMEDA or an equivalent or two of an ether activate alkyllithiums in hydrocarbon media. Amplification of this concept to conflicting reports of α- and ortho-metalation

Full text of DOI:10.1016/j.tet.2010.05.036

Tetrahedron 66 (2010) 4939e4942
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Metalation of o-methylanisole (o-MA); an optional-site selectivity reassessment
*
*
D.W. Slocum , Sophia Wang, Christopher B. White, Paul E. Whitley
Department of Chemistry, Western Kentucky University, 1906 College Heights Blvd. Bowling Green, KY 42101-1079, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
‘Deficiency catalysis’ is the concept applied to metalation chemistry that increments of TMEDA or an
equivalent or two of an ether activate alkyllithiums in hydrocarbon media. Amplification of this concept
Received 6 May 2010
Accepted 10 May 2010
Available online 1 June 2010
to conflicting reports of
a- and ortho-metalation of ortho-methylanisole (o-MA) is explored. Both re-
gioselective metalations were realized in selectivity ratios of >7:1 for the desired isomers. Some rationale
is provided for the various selectivities. These results are at variance with prior results and in-
terpretations thereof found in the literature.
Keywords:
a
-Metalation
Ó 2010 Elsevier Ltd. All rights reserved.
ortho-Metalation
Optional-site selectivity
ortho-Methylanisole
1. Introduction
Directed ortho-metalation (DoM)1 is a useful alternative to
electrophilic aromatic substitution (EAS) for the preparation of
specifically oriented multi-substituent aromatic compounds. A re-
lated reaction, directed
ation at a benzylic position ortho- to a directing metalation group
(DMG) situated on an aromatic nucleus. Directed -metalation is
a-metalation, affords regiospecific metal-
Figure 1. Optional-site selectivity: (a) two p-oriented DMG’s on a benzene ring illus-
trating metalation at position A under conditions that allow eDMG1 to control the site
of metalation; a dissimilar set of metalating conditions will allow DMG2 to control the
site of metalation at position B. (b) Similarly, a-metalation is effected at position A
under one set of conditions while under a dissimilar set of conditions ortho-lithiation is
a
the set of lateral metalations2 at the benzylic positions of an arene
ring that possesses the greater utility. Arene lateral metalations
that are not directed, i.e., those where there is no ortho-DMG, are
often a hindrance to regiospecific metalation in that they afford
a secondary site for metalation and thereby provide mixtures of
isomeric products upon addition of an electrophile.
effected at position B.
conflicting factors involving
iation, and directed ortho-metalation (DoM). The goal was to find
conditions to achieve regiospecific ortho- and, separately, -met-
a-lithiation, undirected lateral lith-
Recently, a study of the optional-site selectivity of an oxazoline
derivative of o-toluic acid revealed that careful manipulation of
metalation conditions allowed optional site selective metalation at
a
alation in all cases. Our intent was and still is to demonstrate the
effectiveness of the concept of ‘deficiency catalysis’ in hydrocarbon
media to bring about atom-economical metalations.5a As uncata-
lyzed hydrocarbon media do not normally provide sufficient
either the a-methyl group or the ortho-position of 4,4-dimethyl-2-
(o-tolyl)oxazoline.3 ‘Optional-site selectivity’ is a term attributable
to Schlosser and co-workers,4 which has primarily been used to
indicate regiospecific metalation at a particular ortho-position of
a benzene ring possessing p-oriented DMG’s (Fig. 1). Its extension
alkyllithium activation5b to afford either ortho- or
a-metalation,
addition of increments of THF, TMEDA, etc., can be used to provide
the necessary activation. That excellent metalation activation can
be achieved by addition of modest amounts of these reagents is
documented below.
to ortho- versus a-metalation is useful and will be used throughout
our discussion.
Investigation of the atom-economical, hydrocarbon media
supported regiospecific metalations of o-, m-, and p-methylanisoles
was undertaken to understand the interplay among several
The paper by Iwao and co-workers describes3 two sets of met-
alation conditions that provide separately ortho-lithiation or
a
-lithiation. The dimethyloxazoline group is a relatively strong
DMG1b with a reported pKa of an ortho-H in 4,4-dimethyl-2-phe-
nyloxazoline of 38.1.6 Estimates of the pKa of the methyl group in
toluene ranges from 39 to 45.2 using a variety of media and
* Corresponding authors. Tel.: þ1 270 7455239; fax: þ1 270 7455 361; e-mail
addresses: donald.slocum@wku.edu (D.W. Slocum), paul.whitley@wku.edu
(P.E. Whitley).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.036

4940
D.W. Slocum et al. / Tetrahedron 66 (2010) 4939e4942
measurement procedures.7 If under metalation conditions the pKa
of the methyl group of 4,4-dimethyl-2-(o-tolyl)oxazoline is ꢀ40.1,
then there is at least two orders of magnitude difference in the
acidities of the two positions suggesting the possibility that selec-
tive ortho-lithiation can be achieved. Regioselective ortho-lithiation
was realized under extraordinary aggressive conditions (10 equiv
TMEDA, ꢁ78 ꢂC), which the authors ascribe to being kinetic. Met-
metalation cannot be achieved at either the a- or the ortho-position
of o-MA and therefore possesses no synthetic utility.2 Furthermore,
a computational treatment of the o-MA system concludes that ‘in
line with the experimental observations’ optional site selective
metalation of o-MA with alkyllithium reagents cannot be
achieved.14
Our initial examination of the metalation of o-MA was with
various n-BuLi/catalytic TMEDA (0.1 equiv, etc.,) systems in cyclo-
hexane at 25 ꢂC and at 60 ꢂC followed by quenching with CISiMe3
(Table 1). An array of products was conjectured to be formed from
these reactions (Fig. 2).
alation of the putative less acidic a-methyl was achieved under less
stringent conditions (ether, ꢁ78 ꢂC).3
As the measured pKa of the ortho-H in anisole is 39.0,6 it was
anticipated that greater difficulty would be encountered in dis-
covering regioselective conditions for a- and, separately, for ortho-
metalation of o-MA than for 4,4-dimethyl-2-(o-tolyl)oxazoline.3
This preliminary analysis was based on the conjecture that the
eOMe DMG would be at least as acidifying as the oxazoline DMG of
their respective ortho-methyl groups. Hence the difference in the
Table 1
Various conditions utilized in attempted regioselective metalation of o-MAa
Run
Time (h)
T (ꢂC)
Equiv additive
% o-
%
a-
% o-/a- Ratio
1
1
1
18
1
4
28
3
25
60
25
60
25
25
60
25
25
25
25
0
1.0 TMEDA
1.0 TMEDA
0.1 TMEDA
0.1 TMEDA
75.9
82.5
66.2
71.8
73.0
78.1
69.6
36.4
50.7
23.3
19.8
75.9
71.7
10.1
11.3
20.3
13.2
11.2
12.7
16.6
43.8
8.8
61.2
62.9
10.7
10.1
7.5
7.3
3.3
5.4
6.5
6.1
4.2
1/1.2
5.7
1/2.6
1/3.2
7.1
relative pKa values of the ortho- versus a-protons would be less in o-
2b
3
MA than in the ortho-methyloxazoline thus making regioselective
metalation conditions more difficult to discover. Moreover, we
wished to provide less restrictive metalation conditions than those
published by Iwao and co-workers.3 Lastly, we wished to demon-
strate the power of ‘deficiency catalysis’ in hydrocarbon solvents to
bring about safe, relatively green, and atom-economical
metalations.
Some success has already been achieved for p-methylanisole
(p-MA). Use of a catalytic amount of TMEDA (0.2 equiv) and
2.0 equiv of n-BuLi afforded over a 90% extent of ortho-lithiation
accompanied by 2e3% of the isomeric lateral metalated product as
revealed by CITMS quench followed by GC/MS analysis.8 Although
this represented a considerable improvement in both regiospeci-
ficity and efficiency over previous reports, the metalation was not
4
5
6
7
8
9
10
11
12
13
0.5 TMEDA
1.0 THF/0.1 TMEDA
1.0 THF/0.1 TMEDA
3.0 THF/0.1 TMEDA
1.0 THF
2.0 THF
3.0 THF
4
48
24
24
24
3
1.0 THF/1.0 TMEDA
1.0 THF/0.1 TMEDA
25
7.1
a
Conditions: 1:1 o-MA, n-BuLi in cyclohexane; analysis: GC of benzophenone
quench product.
b
Me2S2 quench afforded the eSMe derivatives in a mixture EoM of 75.4% o- and
10.4% a- for an o-/a- ratio of 7.2.
Figure 2. Possible TMS-derivatized products from the lithiation of o-MA: 1, a-; 2, o-; 3, a-, o-; 4, a-, a
-; 5, and 6, Bates rearrangement products.13
effected in hydrocarbon media and moreover was not atom-
economical. An improved system was subsequently published
using catalytic amounts of THF in n-hexane with a 1:1 ratio of
substrate to n-BuLi.9 This system allowed realization of about an
80% extent of metalation (EoM) at the ortho-position in 6 h with no
detection of the laterally metalated product. Schlosser and co-
workers4 report a somewhat similar regiospecific ortho-lithiation
of p-MA using more stringent conditions (n-BuLi/KOt-Bu, THF, 15 h,
ꢁ50 ꢂC, 78%) again with no evidence of the product of lateral
metalation being found.10 Earlier studies had reported low yields11
and mixtures of products.11b
It became apparent that both 1 and 2 were being generated but
that they could not be satisfactorily resolved on our capillary GC
column. Occasionally, a small amount of a bis-TMS product was
detected by GC/MS, but the choice between the possible structures,
3 and 4, could not be made. There is some literature precedent for
the enhanced acidity of a methylene group attached to a eTMS
moiety, which suggested to us the possibility of the structure 4.15
No evidence for Bates rearrangement products13 were discerned,
but cannot be ruled out.
Further attempts to successfully discover optional site selective
conditions for the metalation of o-MA at either the a- or o- posi-
tions were made along with modification of our GC regimen. De-
rivatization of the lithio-intermediates with benzophenone
produced readily resolvable derivatives for GC and GC/MS exami-
nation (Table 1). Use of our customary ‘deficiency catalysis’ systems,
i.e., 1e3 equiv of THF or 0.1 or so equivalents of TMEDA at ambient
temperature or 60 ꢂC in hydrocarbon solvent, preferably cyclo-
2. Results and discussion
In this article we report our detailed reinvestigation of the op-
tional site selective metalations of o-MA. We were particularly in-
terested in this project because of some conflicting past studies
involving attempted optional site selective metalation of o-MA.
hexane, afforded mixtures of a- and ortho-metalated products with
Two early studies reported a mixture of
a- and ortho-products
most sets of conditions affording mixtures that favored the ortho-
ranging from a 1:1 ratio to one containing about a 3:1 mixture
favoring the ortho-product.11a,12 Further complicating these find-
ings was the observation that anisoles, among them alkylanisoles,
in refluxing superbase solution undergo a methyl migration from
the oxygen atom to an adjacent ring position.13 An authoritative
review of lateral metalation, which examines this reaction in light
of these earlier studies concludes that optional site selective
isomer. Only equivalents of THF (runs 10 and 11) produced product
ratios favoring the
Ultimately, extension of our concept of ‘deficiency catalysis’
provided a regioselective system for successful -metalation of o-
MA. It was reasoned that t-BuLi, because of its steric bulk, would
be more selective in lithiating the -position than the ortho-po-
sition. Likewise only mild activation of the t-BuLi was deemed
a-product.
a
a

D.W. Slocum et al. / Tetrahedron 66 (2010) 4939e4942
4941
necessary. Use of THF, even only 2 or 3 equiv, was not desirable
due to THF’s instability in the presence of t-BuLi.16 Hence, activa-
tion was not attained with THF but rather with equivalents of
MTBE. After repetitive studies of the metalation wherein only the
equivalents of MTBE were varied, a maximized EoM of o-MA was
realized using 1.5 equiv MTBE (Table 2). This t-BuLi effected met-
alation study was performed with analysis using ClSiMe3 de-
rivatization. The study only revealed the overall EoM, but
The question remained regarding the feasibility of a regiose-
lective ortho-metalation of o-MA. This question was unexpectedly
answered by a repetition of Shirley’s original 1974 conditions12a
(1 equiv TMEDA, 25 ꢂC) (Runs 1 and 2, Table 1). After several at-
temptstoimpose ourprotocols(fractional equivalents TMEDA, 25 ꢂC
and, separately, at 60 ꢂC) (Runs 3e8, 12, Table 1), as well as several
involving equivalents of THF, (Runs 9e11, Table 1), a second pro-
cedure was found that provided enrichment similar to thatof Shirley
for regioselective production of the ortho-isomer (Run 13, Table 1).
Interestingly, 2 and 3 equiv of THF provided enhanced metalation at
sufficient GC separation of the
a- and ortho-benzophenone de-
rivatives could be achieved for determination that the product
mixture was overwhelmingly a-.
Table 2
% Combined TMS products from the metalation of o-MA using various equivalents of
MTBE
Equiv MTBEa
Metalationb (%)
the
a-position (Runs 10 and 11, Table 1). Clearly an enhanced ratio of
0.5
0.75
1.0
1.5
2.0
3.0
58
71
76
81
74
63
ortho- to
a
-product is produced over that reported by the original
authors.12a More detail regarding the run (Run 1, Table 1) providing
ortho-lithiation of o-MA is recorded in Table 4.
Table 4
a
1:1 o-MA, t-BuLi in cyclohexane at 0 ꢂC containing various equivalents of MTBE.
CISiMe3 quench followed by uncorrected GC analysis.
Generation of the o-diphenylcarbinol derivative of o-MAa,b
b
Time (h)
o-Metalation (%)
a
-Metalation(%)
o-/a- Ratio
Use of the maximizing equivalents of MTBE (1.5) at 0 ꢂC and
quenching with benzophenone brought about a satisfactory a-se-
lectivity for the metalation of o-MA (Table 3).
1
2
3
4
75.9
69.5
75.3
74.5
68.4
10.1
9.8
11.4
11.2
9.3
7.5
7.1
6.6
6.6
7.3
18
Table 3
a
1:1:1 o-MA, n-BuLi, TMEDA (each 1.0 M) in cyclohexane at 25 ꢂC.
Benzophenone quench followed by uncorrected GC analysis.
% Disposition of diphenylcarbinol derived products from the treatment of the a-
b
metalated intermediates of o-MA with benzophenonea,b
Time (h)
% o-Product
%
a
-Product
a-/o- Ratio
Isolation of this benzophenone product, 8, in 60% yield provided
a new compound possessing a 1H NMR spectrum containing
a three-proton singlet at 2.28 ppm and a separate three-proton
singlet at 3.04 ppm. This result, combined with the absence of
a benzyl two-proton peak at 3.71 ppm, firmly supports the con-
clusion that ortho-derivatization of o-MA has been achieved.
1
2
3
8.7
9.9
10.9
66.9
74.0
76.1
7.7
7.5
7.0
a
1:1 o-MA, t-BuLi (each 1.1 M) and 1.5 equiv MTBE in cyclohexane at ꢂ0 C.
b
Quenched with benzophenone after various times followed by uncorrected GC
analysis.
That the metalation had been successfully achieved at the
a-po-
We conjecture that the way optional-site selectivity is manifested
sition of o-MA was proven by isolation of the benzophenone de-
rivative 7 in 61% yield. A 1H NMR spectrum of this compound clearly
exhibited a three-proton singlet at 3.79 ppm (eOCH3) and a two-
proton singlet at 3.71 ppm (eCH2e). This is what one would antici-
in o-MA is as follows. For
effect of using t-BuLi plus the mildest of activation allows reasonable
focus on the less hindered -methyl group. ortho-Metalation, on the
other hand, is accelerated by the complex-induced proximity effect
(ClPE). An undetermined contribution to this acceleration must be an
increase in acidity of the ortho-H. Thus the momentary pKa of the
ortho-Hmustbelowerthantheequilibriumvalueof39determinedby
Fraser and Monsour.6 We speculate that this brings about a momen-
tary twotothree orders of magnitude loweringof the pKa of the ortho-
position of o-MA, which facilitates discriminating ortho-metalation.
a-metalation the combination of the steric
a
pate for the product of
of o-MA has been previously reported, no spectral data have been
provided. The unknown -benzophenone derivative is surprisingly
stable with no dehydration to the alkene detected upon work up.
To further amplify proof of structure of the -product, 7 was
a-substitution. Although the a-TMS derivative
a
a
subjected to dehydration conditions (equation below). Loss of
water from 7 produced a triaryl substituted alkene, 9, which has
been reported in the literature.17 The 1H spectrum revealed the loss
of the 2H benzylic protons at 3.71 ppm in the starting material with
retention of the 3H methoxy group signal at 3.80 ppm. A broad
unresolved envelope of signals integrating to 15H represents the
total of 14 aromatic protons plus the single vinyl proton.
3. Conclusion
In summary, separate conditions have been affirmed, which
provide reasonable (>7:1 enhancement) yield of the product of
either a- or ortho-metalation of o-MA. Although ortho-metalation

4942
D.W. Slocum et al. / Tetrahedron 66 (2010) 4939e4942
of o-MA was accomplished using the conventional 1.0 equiv of
TMEDA, the -lithiation procedure elaborates our already articu-
lated protocols for ‘deficiency catalyzed’ metalation. Some litera-
ture conjectures and conclusions have been modified by the
observations contained herein. Furthermore, the protocols pre-
sented demonstrate that safe, relative green, and atom-economical
(dd, J¼7.5, 1.2 Hz, 1H), 6.83e6.86 (t, J¼7.5 Hz, 1H), 7.11e7.13 (d,
a
J¼6.9 Hz, 1H), 7.25e7.34 (complex m, 10H). 13C NMR
d 16.6, 60.0,
82.3, 123.1, 127.2, 127.9, 128.0, 128.1, 131.5, 141.0, 147.0, 156.9. The
above carbon spectrum is short one carbon peak. It was observed
that the 127.9 peak is much larger than the other aromatic peaks.
Anal. Calcd for C21H20O2 (304.38): C, 82.86; H, 6.62. Found: C, 82.76;
H, 6.85.
conditions sufficient for scale up can be found to afford
ortho-optional-site selectivity in suitable arene substrates.
a- and
4.1.3. (2-(2-Methoxyphenyl)ethene-1,1-diyl)dibenzene
(9). To
4. Experimental
4.1. General
a clean dry 100 mL two neck round-bottom flask equipped with
a DeaneStark tube was added 2-(2-methoxyphenyl)-1,1-dipheny-
lethanol (1.7 g; 5.59 mmol), toluene (50 mL), and p-toluenesulfonic
acid (spatula tip). Following reflux for 4 h the reaction mixture was
washed with aqueous saturated sodium carbonate and brine, dried
over sodium sulfate, and concentrated in vacuo to afford 1.1 g (69%)
and analyzed crude. Rf¼0.48 (9:1 hexanes/ethyl acetate) (GC purity
All research chemicals were supplied by Aldrich Chemical Co.
Solvents were ordered dry and used as received. GC analysis was
performed on a Agilent 6850 equipped with a FID detector and GC/
MS analysis was performed on an Agilent 5973 MSD instrument
with 6890 N network system equipped with an FID detector. NMR’s
were performed on a JEOL Eclipse ECA 500 instrument.
>99%). 1H NMR (CDCl3)
d 3.80 (s, 3H), 6.61e7.31 (br m, 15H).
Acknowledgements
4.1.1. 2-(2-Methoxyphenyl)-1,1-diphenylethanol (7). To a clean, dry
round-bottom flask was added 2-methylanisole (2.5 mL; 20 mmol).
Next tert-butyllithium (1.7 M in pentane) (11.8 mL; 20 mmol) was
added slowly at 0 ꢂC followed by slowly adding anhydrous MTBE
(3.6 mL; 30 mmol). The reaction mixture was allowed to continue
stirring at 0 ꢂC for 3 h followed by the addition of benzophenone
(3.04 g; 16.7 mmol, an amount estimated to only consume the
metalated substrate) as a solid. After stirring overnight, the reaction
was quenched with water and transferred to a separatory funnel
with the aid of 30e40 mL MTBE. After the aqueous layer was sep-
arated and back extracted with an additional 30 mL MTBE, the
combined organic layers were washed with brine, dried over so-
dium sulfate, and concentrated in vacuo to provide a crude white
solid product, which was recrystallized with MTBE to afford (3.05 g;
60%), melting point 103.6e105.4 ꢂC; Rf¼0.60 (8:2, hexanes/ethyl
Early studies of these metalations were performed by Dustin
Smith and Adam Watson. Support of this research is under the
auspices of NSF, CHE 070021. Support of our preliminary studies
was provided by the Research Corporation, grant CC5027.
References and notes
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acetate). 1H NMR (CDCl3)
d 3.71 (s, benzylic 2H), 3.79 (s, 3H), 3.99 (s,
OH), 6.47e6.48, (d, J¼7.5 Hz, 1H), 6.66e6.69 (t, J¼7.5 Hz, 1H),
6.85e6.87 (d, J¼8 Hz, 1H), 7.13e7.21 (m, 3H), 7.23e7.28 (m, 4H),
7.41e7.42 (m, 4H). 13C NMR
d 42.4, 55.5, 78.8, 110.3, 120.6, 125.0,
126.5, 126.6, 127.8, 128.0, 132.7, 147.4, 157.7. Anal. Calcd for C21H20O2
(304.38): C, 82.86; H, 6.62. Found: C, 83.25; H, 6.94.
4.1.2. (2-Methoxy-3-methylphenyl)diphenylmethanol (8). To a clean,
dry round-bottom flask was added 2-methylanisole (1.87 mL;
15 mmol), anhydrous cyclohexane (3.4 mL), and TMEDA
(2.25 mL; 15 mmol). Next n-butyllithium (2.0 M in cyclohexane)
(7.5 mL; 15 mmol) was added slowly via syringe and the reaction
was allowed to stir at room temperature for 1.5 h. The reaction was
then cooled to 0 ꢂC and benzophenone (2.5 g; 13.8 mmol, an amount
estimated to only consume the metalated substrate) was added as
a solid. After stirring overnight the reaction was quenched with
water and transferred to a separatory funnel with the aid of
30e40 mL MTBE. After the aqueous layer was separated and back
extracted with an additional 30 mL MTBE, the combined organic
layers were washed with brine, dried over sodium sulfate, and
concentrated in vacuo to provide a crude white solid product, which
was recrystallized with MTBE to afford 2.55 g; 61% (three crops).
Melting point 151.3e152.1 ꢂC; Rf¼0.69 (8:2, hexanes/ethyl acetate).
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Tetrahedron Lett. 1985, 26, 1969.
16. Stanetty, P.; Mihavilovic, M. D. J. Org. Chem. 1997, 62, 1514.
17. In our hands the product remained an oil which could not be induced to
crystallize (reported mp, 80e82 ꢂC17b). (a) Shen, W.; Wang, L. J. Org. Chem. 1999,
64, 8873; (b) Pendersen, C. T. Acta Chem. Scand. 1968, 22, 247.
1H NMR (CDCl3)
d 2.28 (s, 3H), 3.04 (s, 3H), 5.80 (s, OH), 6.39e6.41