Metalations utilizing aryllithiums; ortho-functionalization of p-bromoanisole (pBrA)

Article abstract of DOI:10.1016/j.tetlet.2009.01.104

An ortho-metalation protocol has been developed, which permits the survival of a bromine substituent in p-bromoanisole. Eight derivatives of the generated ortho-lithiated intermediate have been prepared. A neglected metalation concept is being explored here; one which proposes that minimizing the pK_a difference between the aryl substrate and the conjugate acid of the metalating agent will lead to a regiospecific and selective metalation process.

Full text of DOI:10.1016/j.tetlet.2009.01.104

Tetrahedron Letters 50 (2009) 1593–1595
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metalations utilizing aryllithiums; ortho-functionalization
of p-bromoanisole (pBrA)
*
D. W. Slocum , Troy L. Reece, Rebecca D. Sandlin, Thomas K. Reinscheld, Paul E. Whitley
Department of Chemistry, Western Kentucky University, Bowling Green, KY 42101, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An ortho-metalation protocol has been developed, which permits the survival of a bromine substituent in
p-bromoanisole. Eight derivatives of the generated ortho-lithiated intermediate have been prepared. A
neglected metalation concept is being explored here; one which proposes that minimizing the pKa differ-
ence between the aryl substrate and the conjugate acid of the metalating agent will lead to a regiospecific
and selective metalation process.
Received 15 January 2009
Accepted 16 January 2009
Available online 23 January 2009
Published by Elsevier Ltd.
1. Introduction
bridges the gap between the nucleophilicity and the basicity of a
particular metalating agent. Additionally, we wish to design a sys-
Metalation reactions are rendered safer and greener by running
them in hydrocarbon solvents. Initially, we had anticipated that
‘activated’ hydrocarbon solvents, those containing equivalents of
THF or fractional equivalents of TMEDA, would support ortho-lith-
iations in yields approaching those attained in the conventional
ether solvents.1 Actually, far more efficient and atom-economical
ortho-lithiations of several common aryl substrates can be realized
utilizing this approach.2 Also discovered was the realization that
activated hydrocarbon media made possible more focused
ortho-lithiations. These include prevention of lateral metalation
in p-methylanisole,3 preservation of the p-Cl substituent in p-
chloro-anisole4 and avoidance of a contaminating dimetalation in
the metalation of 1,2- and 1,4-dimethoxybenzene.5 All of the above
were accomplished using the common metalating agent, n-BuLi.
In this Letter, we describe a strategy for preservation of an aryl-
Br substituent while simultaneously maintaining our hydrocarbon
media atom-economy preoccupation. Metalation of p-BrA in acti-
vated hydrocarbon solvent with n-BuLi afforded significant
amounts of the undesired halogen/metal exchange. Taking a clue
from the literature,6 we metalated p-BrA with phenyllithium, not
in ether solvent but in hydrocarbon media.7 We eventually found
conditions that allowed 50–60% yields of the o-TMS derivatized
product to be realized as determined by uncorrected GC analysis.
What might a chemist do to expand the utility of ortho-lithia-
tion reactions? One answer to this question is to devise reaction
systems where substituents normally sensitive to metalation con-
ditions can survive the process. Our approach has been to design
metalating reagents that will be minimally aggressive towards
such substituents while still providing the necessary hydrogen/
lithium exchanges. A tightrope needs to be walked here, one that
tem that will address current environmental concerns.
A successful approach to walking the tightrope was put forward
at an early stage by both Gilman et al.6a and Wittig et al.6b for the
ortho-lithiation of p-BrA. For this aryl substrate, the bromine sub-
stituent is readily susceptible to halogen/metal exchange and so
experiences ortho-lithiation conditions at great risk. Their ap-
proach was to use a metalating agent, phenyllithium, somewhat
weaker in basicity than alkyllithium reagents, but much less nucle-
ophilic than these reagents (Eq. 1). As stated above, examination of
this process in our laboratories but utilizing hydrocarbon media
indicated that yields approaching 60% ortho-lithiation could be
achieved. There is the caveat, of course, that metalations involving
PhLi generate benzene, a listed carcinogen. It would be difficult to
implement this process on a large scale by utilizing PhLi, given
safety and green chemistry concerns:
OCH3
OCH3
+
PhLi
+
PhH
Br
Br
Li
ð1Þ
If an aryl metalating agent is the key, the reason likely lies in the
realm of aryllithiums being less basic and even less nucleophilic
than alkyllithiums. If the production of benzene is undesirable,
then let us use an aryllithium reagent of similar basicity, but one
with even less nucleophilicity than PhLi. This reagent must be
readily accessible. We herein propose use of ortho-lithiodimethy-
laniline (o-LiDMA).8
o-LiDMA has been difficult to prepare in the past. Recently, we
have developed a reproducible preparation of this intermediate
with yields P90%.2 Once this intermediate has been generated in
hydrocarbon media, the o-LiDMA evidently forms a complex, pre-
sumably an aryllithium dimer, and settles from solution. From this
* Corresponding author. Tel.: +1 270 745 3457; fax: +1 270 745 6471.
E-mail address: donald.slocum@wku.edu (D.W. Slocum).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.01.104

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D. W. Slocum et al. / Tetrahedron Letters 50 (2009) 1593–1595
Table 1
ortho-Substituted p-bromoanisoles
Reactant
o-Derivative
% Isolated Yield
Mp (°C) (uncorrected)
Lit.
Observed
Benzaldehyde
Benzophenone
Cyclopentanone
–CHPhOH
–CPh2OH
58
65
69
76.4–78.412
98.6–9912
127–128
67.5–69.112
HO
Cyclohexanone
74
93.9–97.612
HO
CH2=N+Me2Iꢀ
TMS-Cl
Hexachloroethane
Diphenyl diselenide
–CH2NMe2
–TMS
–Cl
28
60
67
73
oil
58–58.510
65.8–67
92–9313
56.7–57.7
66.5–68.212
59.7–61.1
–SePh
two-phase system the supernate is syringed off and replaced with
an equal volume of hexanes. In this manner, most unreacted n-BuLi
and DMA are removed. The remaining suspension, considered as
being 75% of the original DMA molarity,9 is then used as the meta-
lating agent for p-BrA (Eq. 2):
for 18–22 h, where upon cooling, a copious precipitate of the o-
LiDMA formed. At this point, the o-LiDMA was 85–91% pure by
TMSCl derivatization and GC analysis. The suspension was trans-
ferred via a syringe equipped with a 14 gauge needle to graduated
centrifuge tubes and was centrifuged for ca. 2 m. The supernate
was removed and replaced with an equal volume of cold anhy-
drous hexanes. Following centrifugation, removal of the hexane
supernate and repetition of the hexane washing process, the now
96 % pure o-LiDMA9,11 was diluted to 0.65 M with anhydrous
cyclohexane and was placed in a clean, dry round-bottomed flask
under nitrogen atmosphere. To increase homogeneity and to speed
up the reaction,2 1.0 equiv of anhydrous methyl tert-butyl ether
(based on the 0.75 equiv DMA being carried forward primarily as
o-LiDMA) and 0.75 equiv of p-bromoanisole were added, and the
reaction mixture was allowed to stir at 55–60 °C for 24 h. The
resulting 85–90% o-lithio-p-bromoanisole solution was treated
with the various electrophiles (0.95 equiv with respect to p-BrA)
without dissolution. Use of THF to dissolve the various carbonyl com-
pounds led to products resulting from benzyne formation. The yields
were calculated based on the amount of electrophile.
Continuing our attempts to provide synthetic methods useful to
the industrial community, we made effort to isolate the com-
pounds with convenient and potentially scalable procedures. Thus,
most derivatives were isolated by crystallization and/or trituration
from hexanes. The exceptions were the benzophenone derivative
that was isolated by crystallization from MTBE/hexanes, the phe-
nylselenide derivative that was isolated by column chromatogra-
phy (hexanes/ethyl acetate) and the dimethylaminomethyl
derivative that was isolated by a novel extraction method. This
extraction method employed 0.24 M acetic acid which selectively
protonates the more basic tertiary aliphatic amine but not the ter-
tiary arylamine.
OCH3
OCH3
N(CH3)2
+
DMA
+
Br
Li
Br
Li
ð2Þ
A sustainability component of this approach is that DMA is
recoverable and potentially recyclable from this process by acid
extraction of the product solution.
Treatment of p-BrA in cyclohexane with a slurry of o-LiDMA in
cyclohexane afforded a reaction solution from which small aliquots
were taken over various periods. Each sample was quenched with
chlorotrimethylsilane (CITMS) and analyzed by GC. These studies
revealed that maximum extents of ortho-lithiation of p-BrA were
realized by allowing the metalation to run overnight. Using puri-
fied o-LiDMA solutions (96 2%),9 an equal quantity of p-BrA could
be from 85% to 90% ortho-lithiated.
The literature reveals that our methodology has synthetic
advantage over the use of PhLi in ether. Wittig et al.6b reported a
70% yield of the benzophenone addition product, but this was con-
taminated with a 10% yield of Ph3COH, that is, the product of the
reaction of PhLi with benzophenone. Little (<2%) to no metalating
reagent derived products were noted in our product mixtures. Ea-
born and Walton10 prepared the trimethylsilyl derivative in 44%
yield using the procedure reported by Wittig et al.6b
The use of o-LiDMA, prepared in hydrocarbon solvents, in con-
junction with addition of the derivatizing agent to the generated
o-Li-p-BrA without dissolution, fulfills our preoccupation with
making DoM a greener and safer protocol. The use of ethers is
thereby minimalized. Synthetic results from this protocol are sum-
marized in Table 1.
Acknowledgements
Support of this research by both PRF, 42090-B1 and NSF
0710021 is greatly appreciated. We thank Mr. Greg Hayes and
Mr. Phillip Shelton for performing the preliminary metalation of
p-BrA with PhLi.
2. Experimental
2.1. Preparation of o-lithio-p-bromoanisole and subsequent
derivatization
References and notes
1. For recent reviews of ortho-lithiation chemistry, cf: (a) Gschwend, H. W.;
Rodriguez, H. R. Org. React. 1979, 26; (b) Snieckus, V. Chem. Rev. 1990, 90,
879; (c) Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon Press:
Oxford, 2002; (d) Clayden, J. In The Chemistry of Organolithium Compounds;
Rappoport, Z., Marek, I., Eds.; John Wiley & Sons, Ltd: West Sussex, 2004; p
495.
To a clean, dry round-bottomed flask under nitrogen atmo-
sphere were added 1.0 equiv of N,N-dimethylaniline (DMA),
0.15 equiv of TMEDA, 1.0 equiv of n-butyllithium (10 M in hex-
anes) and sufficient anhydrous cyclohexane to bring the reaction
concentration to 2 M. The solution was allowed to stir at 60 °C

D. W. Slocum et al. / Tetrahedron Letters 50 (2009) 1593–1595
1595
2. Slocum, D. W.; Reece, T.;White, C.B.;Sandlin, R. D.;Lalonde, K.;Bolton, J.;Warnell,
S.; Bragg, S.A.; Whitley, P.E. Abstracts, 235th National Meeting of the American
Chemical Society, New Orleans, LA, April 2008, section ORGN, paper 594.
3. Slocum, D. W.; Reed, D.; Jackson, F., III; Friesen, C. J. J. Organomet. Chem. 1996,
512, 265.
11. If the washing purification procedure is omitted, biphenyl formation via
benzyne intermediate production is increased. Even with these washings about
2% of biphenyl contaminants can be detected. This is likely due to the lingering
amounts of TMEDA bringing about an increase in the basicity of the remaining
o-LiDMA.
4. Slocum, D. W.; Dietzel, P. Tetrahedron Lett. 1999, 42, 1823.
12. The benzophenone and chloro derivatives are commercially available (Sigma–
Aldrich and Capot Chemical Co., respectively). NMR’s for the benzaldehyde, the
cyclopentanone and the cyclohexanone derivatives are shown below in
respective order:1H NMR (CDCl3) d 2.69 (br s, OH), 3.77 (s, 3H), 6.01 (s, 1H),
6.72–6.74 (d, 1H), 7.25–7.29 (t, 1H), 7.31–7.37 (m, 5H), 7.44–7.45 (d, 1H). 13C
5. Slocum, D. W.; Ray, J.; Shelton, P. Tetrahedron Lett. 2002, 43, 6071.
6. (a) (1) Gilman, H.; Langham, W.; Moore, W. J. Am. Chem. Soc. 1940, 62, 2327; (2)
Gilman, H.; Langham, W.; Willis, H. B. J. Am. Chem. Soc., 1940, 62, 346; (3)
Gilman, H.; Swiss, J.; Cheney, C. J. Am. Chem. Soc., 1940, 62, 1963.; (b) Wittig, G.;
Pockels, U.; Droge, H. Chem. Ber. 1938, 71, 1903.
7. 1.0 M p-BrA, 1.8 M PhLi diluted with hexanes to 1.0 M (commercial grade, that
is, dissolved in n-Bu2O) in n-hexane with no catalyst, heated at 60 °C for 4–6 h.
8. o-LiDMA is less basic than PhLi. The pKa of the o-hydrogen of DMA has been
estimated as P40.3 (Fraser, R. R.; Bresse, M.; Mansour, T. S. J. Am. Chem. Soc.,
1983, 105, 7790) Most textbooks assign a pKa value of 43 to benzene.
NMR
d 55.8, 71.5, 112.5, 113.4, 126.6, 127.6, 128.5, 130.4, 131.4, 142.7,
155.7.1H NMR (CDCl3) d 1.65–1.74 (m, 2H), 1.93-2.02 (m, 6H), 3.32 (s, OH), 3.88
(s, 3H), 6.76–6.79 (m, 1H), 7.31–7.35 (m, 1H), 7.43–7.46 (m, 1H). 13C NMR d
23.5, 39.2, 55.7, 82.4, 112.9, 113.4, 129.0, 130.7, 136.6, 156.5.1H NMR (CDCl3) d
1.22–1.97 (m, 10H), 3.67 (s, OH), 3.87 (s, 3H), 6.77–6.79 (d,1H), 7.31–7.33 (d,
1H), 7.43–7.44 (d, 1H). 13C NMR d 21.9, 25.8, 36.5, 55.7, 73.0, 113.2, 113.8,
129.1, 130.5, 138.8, 156.4..
9.
A reproducible 25% loss of DMA accrues from the combined effects of
incomplete metalation, o-LiDMA solubility in hydrocarbon solvent and the
two transfers necessary for the two washings with cold hexanes.
10. Eaborn, C.; Walton, D. R. M. J. Organomet. Chem. 1964, 3, 169.
13. Oddershede, J.; Henriksen, L.; Larsen, S. Org. Biomol. Chem. 2003, 1, 1053. We
have no explanation for the discrepancy in mp’s of the two samples. The
published NMR and the NMR we have obtained appear identical.