Regioselective heterohalogenation of 4-halo-anisoles via a series of sequential ortho-aluminations and electrophilic halogenations

Article abstract of DOI:10.1039/c2cc30795b

As the aluminate base [LiAl(TMP)₂(iBu)₂] 1 displays halogen tolerance towards substituted aromatics, 4-halo-anisoles have been ortho-aluminated and electrophilically quenched to form synthetically useful multi-heterohalogenated aniso

Full text of DOI:10.1039/c2cc30795b

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COMMUNICATION
Regioselective heterohalogenation of 4-halo-anisoles via a series of
sequential ortho-aluminations and electrophilic halogenationswz
Ben Conway, Elaine Crosbie, Alan R. Kennedy, Robert E. Mulvey* and Stuart D. Robertson
Received 3rd February 2012, Accepted 15th February 2012
DOI: 10.1039/c2cc30795b
As the aluminate base [LiAl(TMP)2(iBu)2] 1 displays halogen
tolerance towards substituted aromatics, 4-halo-anisoles have
been ortho-aluminated and electrophilically quenched to form
synthetically useful multi-heterohalogenated anisoles, with the
Al intermediates along the route structurally defined.
THF,11 along with the generation and trapping of a TMP2ꢀ
(2,2,6,6-tetramethylpiperidide) dianion12 are novel examples
of alkali-metal-mediated alumination (AMMAl) reactions
involving sp3 C–H bonds (see Scheme S1 in ESIz).
Especially important in AMMAl is the realisation that
despite displaying greater reactivity, the bis-amido aluminate
base [LiAl(TMP)2(iBu)2] 113 recently introduced by us is halogen
tolerant akin to [(TMP)3Alꢁ3LiCl]14 and [LiAl(TMP)iBu3]15
documented by Knochel and Uchiyama respectively. Thus, these
heterometallic alkali-metal aluminate bases will preferentially
perform metal–hydrogen exchange of aryl halide substrates
when faced with a choice between directed ortho-metallation
or metal–halogen exchange. The ability of these bases to form aryl
aluminium species should also be noted as the conventional
procedures used to prepare these compounds, namely transmetalla-
tion of the corresponding organolithium or Grignard reagents, are
of limited use due to poor functional group tolerance. Inspired by
the importance of halogenated aromatics and the halogen tolerance
of our base 1 we report here sequential regioselective aluminations
followed by electrophilic halogenations (Scheme 1) to form the new
synthetically useful triheterohalogenated isomers 2-bromo-4-iodo-
6-chloroanisole 4a, 2-iodo-4-chloro-6-bromoanisole 4b and 2-iodo-
4-chloro-6-bromoanisole 4c from the starting materials 4-iodo 2a,
4-bromo 2b and 4-chloroanisole 2c respectively (Table 1).y16
Utilising 1 in a 1.5 : 1.5 : 1 stoichiometric reaction with THF
and 4-iodoanisole in hexane solution gave the ortho-aluminated
compound [(THF)Li(m-TMP)(m-{1-OMe-2-Al(iBu)2-4-I-C6H3}]
2-int in a good crystalline yield of 71%. The molecular structure
of 2-int (Fig. 1) features a five-element, six-atom LiNAlCCO ring
with TMP and ortho-deprotonated 4-iodoanisole (O bonded to Li;
C bonded to Al) occupying bridging sites between Li and Al. A
terminal THF (on Li) and iBu ligands (on Al) complete the
molecular structure. We can postulate that the first step in
AMMAl is coordination of the O atom of the OMe group to
the cationic Li atom resulting in the ortho C–H bond being in
close proximity to the pseudo-terminal TMP.13 The second step
Aryl halides are a fundamentally important, synthetically
useful class of organic compounds. Owing to the different
relative strengths of carbon–halogen bonds, hetero-halogen
substituted aromatics can be regioselectively functionalised in
different ways at distinct sites.1 For example, Knochel and
Mosrin have demonstrated this through the stepwise selective
functionalisation of the heterotrihalogenated substrate
2-chloro-4-bromo-6-iodo-pyrimidine to yield the fungicide
Mepanipyrim.2 Aryl halides therefore take centre stage in the
synthesis of a wide range of commercially important materials
such as natural products,3 biologically active materials4 and
pharmaceuticals.5 Participation of aryl halides in transition
metal-catalysed cross coupling reactions,6 metal–halogen
exchange reactions7 and in the synthesis and applications of
organometallic compounds such as Grignard reagents8 are just
some of their important leading roles.
Alkali-Metal-Mediated Metallation (AMMM),9 a recent
development in deprotonative chemistry, is an attractive
method for the functionalisation of aromatic compounds
due to the use of relatively cheap, non-polar solvents and
ambient temperature protocols. This methodology exploits the
reactivity of an electropositive alkali-metal and the selectivity/
functional group tolerance of a second less electropositive metal
by combining both in a co-complex. Magnesium and zinc have
often played the lead as the second metal in AMMM reactions,
which actually performs the deprotonation (C–H to C–metal
transformation), however, recently aluminium has risen to
prominence in this context. The a-deprotonation of the
neutral donors TMEDA (N,N,N0,N0-tetramethylethylenediamine),
PMDETA (N,N,N0,N00,N00-pentamethyldiethylenetriamine)10 and
WestCHEM, Department of Pure and Applied Chemistry, University
of Strathclyde, Glasgow, UK. E-mail: r.e.mulvey@strath.ac.uk
w This article is part of the ChemComm ‘Frontiers in Molecular Main
Group Chemistry’ web themed issue.
z Electronic supplementary information (ESI) available: Full experi-
mental details and NMR data. CCDC 866081–866082 (2-int and 3-int).
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2cc30795b
Scheme 1 Sequential aluminations and halogenations of 4-haloanisole
to yield the new triheterohalogenated derivative 4.
c
4674 Chem. Commun., 2012, 48, 4674–4676
This journal is The Royal Society of Chemistry 2012

Table 1 Halogenation of various halo-anisoles with N-bromosuccinimide,
iodine or sulfuryl chloride after alkali-metal-mediated alumination
the OMe group as it is a superior donor to I. As a result, Li is far
removed from I so benzyne formation is inhibited.17 Formation of
benzyne by deprotonation adjacent to a halogen has been demon-
strated using a similar zincate base [(TMEDA)Li(m-TMP)-
(m-CH2SiMe3)Zn(CH2SiMe3)]. This reaction affords a zwitterionic
compound from chlorobenzene by addition of Zn(CH2SiMe3)2
and TMEDA across the benzyne triple bond and subsequent
deprotonation of one TMEDA methyl arm.18 Knochel et al. and
Uchiyama et al. have also aluminated 4-iodoanisole;14,15 however
Uchiyama’s preparation involves 2.2 equivalents of the base
[LiAl(TMP)(iBu)3] with the substrate. Knochel and co-workers
also use sub-ambient temperatures to prepare their aluminate base
[(C12H26N)3Alꢁ3LiCl].
Aryl halide
Product
Entry
Yield (%)
1
93
2
3
91
88
Aluminium intermediate 2-int was subjected to an excess of
N-bromosuccinimide to form 2-bromo-4-iodoanisole 3a in a
93% yield after purification by column chromatography.
Dihalo compound 3a was then added to a freshly prepared
hexane solution of 1 to ascertain if a second deprotonation
was possible.
Alumination in the 6-position produced [(THF)Li(m-TMP)-
(m-{1-OMe-2-Br-4-I-6-Al(iBu)2-C6H2}] 3-int in a crystalline
yield of 33% though overall the yield is near quantitative.
The molecular structure of 3-int (Fig. 2) is analogous to 2-int
except that the ortho-deprotonated 4-iodoanisole bridge
between Li and Al carries a Br in the 2-position. As expected
alumination occurs ortho to the stronger coordinating OMe
group. As the bond lengths and angles in 2-int and 3-int
are similar to those of previously discussed deprotonated
4
90
1
substrates,10 these are detailed in the ESI.z H NMR spectra
5
6
86
89
of 2-int and 3-int suggest that both retain their structural
integrity in solution as the resonances are consistent with
those expected from the crystal structure.
To form a triheterohalo compound, 3-int was subjected to
an excess of sulfuryl chloride, forming the new multi-hetero-
halogenated 2-bromo-4-iodo-6-chloroanisole 4a in 90% yield.
GC-MS was carried out on 4a to confirm that the molecular
weight was consistent with a compound containing the three
different halogen atoms Cl, Br and I. The parent ion found at
347.86 m/z is consistent with the molecular weight of 4a
(347.38 g). The 1H NMR spectrum of 4a is also consistent
with two different halogen atoms in the 2- and 6-positions as
[a] Y+ used = N-bromosuccinimide, [b] Y+ used = iodine, [c] Z+
used = sulfuryl chloride, [d] Z+ used = N-bromosuccinimide.
Fig. 1 Molecular structure of compound 2-int with thermal ellipsoids
drawn at the 50% probability level. Hydrogen atoms and minor
disordered components of THF have been omitted for clarity.
Fig. 2 Molecular structure of one of two independent molecules of
compound 3-int with thermal ellipsoids drawn at 50% probability
level. Hydrogen atoms have been omitted for clarity.
involves an intramolecular deprotonation of the aromatic
substrate to form TMP(H). Deprotonation occurs ortho to
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4674–4676 4675

Table 2 Brominating and chlorinating agents tested for the conversion
of 2-int to 3a and 3-int to 4a respectively and yields obtained
NH4Cl, extracted with ethyl acetate, dried over MgSO4 and solvent
removed in vacuo. The residue was purified by SiO2 column
chromatography.
Brominating agent
Br2
N-Bromosuccinimide 93
Cl2BrC–CBrCl2
Yield (%) Chlorinating agent
81 SO2Cl2
Yield (%)
90
1 (a) I. Bytschkov, H. Siebeneicher and S. Doye, Eur. J. Org. Chem.,
2003, 2888–2902; (b) D. J. Michaelis and T. A. Dineen, Tetrahedron
Lett., 2009, 50, 1920–1923.
2 P. Knochel and M. Mosrin, Chem.–Eur. J., 2009, 15, 1468–1477.
3 (a) P. Ploypradith, W. Jinaglueng, C. Pavaro and S. Ruchirawat,
Tetrahedron Lett., 2003, 44, 1363–1366; (b) J. Boukouvalas and
R. P. Loach, J. Org. Chem., 2008, 73, 8109–8112.
4 (a) B. L. Eriksen, P. Vedso and M. Begtrup, J. Org. Chem., 2001,
66, 8344–8348; (b) M. Aso, T. Kaneko, M. Nakamura, N. Koga
and H. Suemune, Chem. Commun., 2003, 1094–1095.
N-Chlorosuccinimide 48
Cl3C–CCl3
0
0
the two remaining meta-protons are inequivalent and thus
exhibit w-coupling [4J(H, H) = 2.04 and 2.02 Hz].19
Brominating and chlorinating agents were also tested to
establish the best halogenation reagents (Table 2). In addition
to N-bromosuccinimide, bromine was found to be a moderately
good brominating agent producing 3a from 2-int in an 81% yield.
A small amount of the halogen exchange product 2-bromo-
5 (a) T. A. Jensen, D. Tanner, X. Liang and N. Skjaerbaek, J. Org.
Chem., 2004, 69, 4936–4947; (b) J. R. Gage, W. R. Perrault,
T.-J. Poel and R. C. Thomas, Tetrahedron Lett., 2000, 41,
4301–4305; (c) P. M. Herrinton, C. E. Owen and J. R. Gage,
Org. Process Res. Dev., 2001, 5, 80–83; (d) T. Mase, I. N. Houpis,
A. Akao, I. Dorziotis, K. Emerson, T. Hoang, T. Iida, T. Itoh,
K. Kamei, S. Kato, Y. Kato, M. Kawasaki, F. Lang, J. Lee,
J. Lynch, P. Maligres, A. Molina, T. Nemoto, S. Okada,
R. Reamer, J. Z. Song, D. Tschaen, T. Wada, D. Zewge,
R. P. Volante, P. J. Reider and K. Tomimoto, J. Org. Chem.,
2001, 66, 6775–6786; (e) N. Ikemoto, R. A. Miller, F. J. Fleitz,
J. Liu, D. E. Petrillo, J. F. Leone, J. Laquidara, B. Marcune,
S. Karady, J. D. Armstrong and R. P. Volante, Tetrahedron Lett.,
2005, 46, 1867–1871; (f) S. J. Dolman, F. Gosselin, P. D. O’Shea
and I. W. Davies, Tetrahedron, 2006, 62, 5092–5098.
6 (a) E. Negishi, Angew. Chem., Int. Ed., 2011, 50, 2–29; (b) D. Zhao,
J. You and C. Hu, Chem.–Eur. J., 2011, 17, 5466–5492;
(c) F. Bellina and R. Rossi, Chem. Rev., 2010, 110, 1082–1146;
(d) K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem., Int.
Ed., 2005, 44, 4442–4489; (e) J. Hassan, M. Sevignon, C. Gozzi,
E. Schulz and M. Lemaire, Chem. Rev., 2002, 102, 1359–1469.
7 M. Schlosser, Angew. Chem., Int. Ed., 2005, 44, 376–393.
8 P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F. Kopp,
T. Korn, I. Sapountzis and V. A. Vu, Angew. Chem., Int. Ed., 2003,
42, 4302–4320.
1
4-bromoanisole was observed in the crude H NMR spectrum
reducing the yield of product 3a. 1,2-Dibromotetrachloroethane
on the other hand was a poor brominating agent. Sulfuryl chloride
was found to be the best chlorinating agent (yield = 90%) as
N-chlorosuccinimide produced 4a in a lower 48% yield while
hexachloroethane did not react at all.
Two isomers of triheterohalogenated 4a, 2-iodo-4-bromo-
6-chloroanisole 4b and 2-iodo-4-chloro-6-bromoanisole 4c
were also synthesised via a similar route starting from 4-bromo
2b and 4-chloroanisole 2c respectively. They were synthesised
using the optimal brominating and chlorinating reagents as well as
elemental iodine. Compound 4b and the new compound 4c were
prepared in an 86% and 89% yield respectively. Though com-
pound 4b was first reported in 1927, its characterisation was
limited.20 GC-MS was also carried out on compounds 4b and 4c.
Analogous to 4a the parent ion was found at 347.86 m/z and
347.91 m/z which is consistent with the molecular weight
of compounds 4b and 4c. 1H NMR data for each multi-
heterohalogenated compound including w-coupling for isomers
4a, 4b and 4c are tabulated in the ESI.z
9 (a) R. E. Mulvey, Organometallics, 2006, 25, 1060–1075;
(b) R. E. Mulvey, Acc. Chem. Res., 2009, 42, 743–755;
(c) R. E. Mulvey, F. Mongin, M. Uchiyama and Y. Kondo,
Angew. Chem., Int. Ed., 2007, 46, 3802–3824.
´
-Alvarez, E. Hevia, A. R. Kennedy, R. E. Mulvey
10 B. Conway, J. Garcia
´
In summary we have shown that the halogen tolerant
aluminate base 1 can regioselectively functionalise 4-halogen-
substituted anisoles via a series of sequential ortho-aluminations
and electrophilic halogenations. The synthetically useful 2,4,6-
halosubstituted anisoles were made starting from 4-iodo, 4-bromo
and 4-chloroanisole. N-Bromosuccinimide and sulfuryl chloride
were the best brominating and chlorinating agents respectively.
We thank the EPSRC (Doctoral Training Award to EC)
and the Royal Society/Wolfson Foundation (research merit
award to R.E.M) for funding this work and Dr Eva Hevia for
many insightful discussions.
and S. D. Robertson, Organometallics, 2009, 28, 6462–6468.
´
11 E. Crosbie, P. Garcia-Alvarez, A. R. Kennedy, J. Klett,
´
R. E. Mulvey and S. D. Robertson, Angew. Chem., Int. Ed.,
2010, 49, 9388–9391.
12 B. Conway, A. R. Kennedy, R. E. Mulvey, S. D. Robertson and
´
J. Garcia-Alvarez, Angew. Chem., Int. Ed., 2010, 49, 3182–3184.
´
13 R. E. Mulvey, D. R. Armstrong, B. Conway, E. Crosbie,
A. R. Kennedy and S. D. Robertson, Inorg. Chem., 2011, 50,
12241–12251.
14 S. Wunderlich and P. Knochel, Angew. Chem., Int. Ed., 2009, 48,
1501–1504.
15 M. Uchiyama, H. Naka, Y. Matsumoto and T. Ohwada, J. Am.
Chem. Soc., 2004, 126, 10526–10527.
16 For an alternative route to halo-aromatics see reviews on electrophilic
aromatic substitution: (a) K. Smith and G. A. El-Hiti, Green Chem.,
2011, 13, 1579–1608; (b) G. I. Borodkin and V. G. Shubin, Russ. J.
Org. Chem. (Transl. of Zh. Org. Khim.), 2006, 42, 1745–1770;
(c) K. Smith, J. Chem. Technol. Biotechnol., 1997, 68, 432–436.
17 E. Crosbie, A. R. Kennedy, R. E. Mulvey and S. D. Robertson,
Dalton Trans., 2012, 41, 1832–1839.
Notes and references
y All reactions were carried out under a protective argon atmosphere.
General synthesis of aluminium intermediates: 1.5 equivalents of 1
were prepared in situ by stirring iBu2Al(TMP), LiTMP and THF
in hexane.13 One equivalent of the appropriate substrate was added via
a syringe and the mixture was stirred at room temperature overnight.
Cooling this solution to ꢀ30 1C yielded crystals of the desired product.
General synthesis of hetero-halogenated anisoles: crystals of the
aluminated substrate were dissolved in hexane and stirred at 0 1C.
An excess of the electrophile was added and the mixture was stirred
overnight. It was then diluted with aqueous saturated NaHS2O3 and
18 D. R. Armstrong, L. Balloch, W. Clegg, S. H. Dale, P. Garcia-
´
´
Alvarez, E. Hevia, L. M. Hogg, A. R. Kennedy, R. E. Mulvey and
C. T. O’Hara, Angew. Chem., Int. Ed., 2009, 48, 8675–8678.
19 D. H. Williams and I. Fleming, Spectroscopic Methods in Organic
Chemistry, McGraw-Hill, Maidenhead, 5th edn, 1995.
20 M. Kohn and J. J. Sussmann, Monatsh. Chem., 1927, 48, 193–202.
c
4676 Chem. Commun., 2012, 48, 4674–4676
This journal is The Royal Society of Chemistry 2012