Use of mixed Li/K metal TMP amide (LiNK chemistry) for the synthesis of [2.2]metacyclophanes

Article abstract of DOI:10.3762/bjoc.7.145

A new two-step general approach to [2.2]metacyclophane synthesis from substituted m-xylenes is described. The strategy employs a selective benzylic metalation and oxidative C-C bond formation for both synthetic operations. Regioselective benzylic metalati

Full text of DOI:10.3762/bjoc.7.145

Use of mixed Li/K metal TMP amide (LiNK chemistry)
for the synthesis of [2.2]metacyclophanes
Marco Blangetti, Patricia Fleming and Donal F. O'Shea*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1249–1254.
Centre for Synthesis and Chemical Biology, School of Chemistry and
Chemical Biology, University College Dublin, Belfield, Dublin 4,
Ireland
doi:10.3762/bjoc.7.145
Received: 16 May 2011
Accepted: 21 July 2011
Email:
Published: 09 September 2011
Donal F. O'Shea* - donal.f.oshea@ucd.ie
This article is part of the Thematic Series "Directed aromatic
functionalization".
* Corresponding author
Keywords:
Guest Editor: V. Snieckus
benzylic metalation; LiNK chemistry; [2.2]metacyclophane; oxidative
coupling; planar chirality
© 2011 Blangetti et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A new two-step general approach to [2.2]metacyclophane synthesis from substituted m-xylenes is described. The strategy employs
a selective benzylic metalation and oxidative C–C bond formation for both synthetic operations. Regioselective benzylic metala-
tion is achieved using the BuLi, KOt-Bu, TMP(H) (2,2,6,6-tetramethylpiperidine) combination (LiNK metalation conditions) and
oxidative coupling with 1,2-dibromoethane. The synthetic ease of this approach compares favourably with previously reported
methods and allows for ready access to potentially useful planar chiral derivatives.
Introduction
While direct metalation reactions are an essential contribution conditions) is uniquely suited for the selective achievement of
to the repertoire of modern synthetic methods, an underlying challenging metalations. Specifically, the use of the reagent
and often underestimated challenge remains in the achievement triad BuLi/KOt-Bu/TMP(H) to generate a mixed Li/K metal
of predictable selective metalations of substrates that offer TMP amide in situ has proven to be an efficient and general
several potential sites of reaction. Examples of such challenges method to achieve vinyl and benzylic metalations with excel-
include the selective aryl metalation of arenes containing more lent selectivity [6,7]. We now exploit this selective benzylic
than one directing group (DG), arene metalation in positions not metalation protocol for the specific synthesis of [2.2]metacyclo-
ortho to the directing group, or the identification of reaction phanes.
conditions to achieve selective benzylic metalation of substi-
tuted toluenes 1 to provide 3 (Scheme 1) [1-5]. We recently Chemists have a long-standing fascination for the [2.2]cyclo-
reported that mixed Li/K metal TMP amide (LiNK metalation phane structures and have extensively studied their unusual
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interest (Scheme 2). Oxidative homo-coupling of benzyl anions
has previously been noted, but it has remained relatively unex-
plored as a synthetic procedure [22-24]. We speculated that if
oxidative coupling of the benzyl metalated xylenes 5 could be
achieved to form the open dimer 6, then a second metalation
and oxidative ring closure would yield the [2.2]metacyclo-
phanes 8. A stepwise approach, as shown in Scheme 2, could
allow for the introduction of different groups on each of the aryl
rings. In addition, it could facilitate the synthesis of planar
chiral derivatives without the complication of mixtures with
achiral isomers being generated, which occurs if, for example, a
1-substituted-2,4-bis(halomethyl)benzene is used as the starting
compound [15].
Scheme 1: Selective benzylic metalation with LiNK conditions. DG =
directing group.
Results and Discussion
In order to examine the scope and potential of this approach,
five differently substituted xylenes were investigated, namely
m-xylene (4a), mesitylene (4b), 1-methoxy-3,5-dimethylben-
zene (4c), (3,5-dimethylphenyl)dimethylamine (4d) and 2,4-
dimethylbenzoic acid (4e) (Figure 1). These xylenes present
interesting challenges for metalation selectivity in that for
derivatives 4a–d both methyl groups are equivalent and so the
physical and chemical properties induced by the close spatial
proximity of their aryl rings [8]. Undoubtedly the most studied
of the series (ortho, meta and para) are the [2.2]paracyclo-
phanes, which have seen a recent resurgence of interest notably
as planar chiral scaffolds for asymmetric catalysis [9-13].
Surprisingly, the [2.2]metacyclophanes, which also have the
potential to be exploited as planar chiral templates, have
received scant attention since the seminal reports of Schlögl in
the early 1970s [14-16]. One possible explanation for this
is the cumbersome methods required for their synthesis.
Typical approaches have utilised Wurtz coupling, the
oxidation and thermal (500–600 °C) extrusion of SO2 from
dithia[3.3]cyclophanes or the photochemical ring contraction of
diselena[3.3]cyclophanes [17-21].
We envisaged that our LiNK metalation conditions with in situ
oxidative coupling could offer a facile general approach to
[2.2]metacyclophanes, which would be of general synthetic
Figure 1: Xylene substrates.
Scheme 2: Iterative LiNK/oxidative coupling synthesis of [2.2]metacyclophanes.
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alternative metalation sites are in the aryl ring, whereas the quenched with CD3OD. It was anticipated that under our low
challenge is elevated for 4e as it contains two differing benzylic temperature yet thermodynamically controlled conditions the
sites and an ortho-aryl position primed for metalation by a selective site of metalation should be the more acidic 2-methyl
strong directing group.
position [26]. This was confirmed by 2H NMR, which showed
that incorporated deuterium was above 90% in the 2-methyl
Sequential treatment of 4a–d with BuLi, KOt-Bu and TMP(H) position with less than 10% in the 4-methyl group and no
at −78 °C followed by the oxidant 1,2-dibromoethane [25] gave detectable aryl deuteration (Figure 2).
good to excellent yields of the targeted homo-dimer products
6a–d (Table 1, entries 1–4). It was also possible to form a A similar experiment was carried out for the even more com-
“mixed dimer” by the reaction of 4a and 4c together, which plex hetero-dimer substrate 6f, in which a selective di-benzylic
gave 6e, containing one m-OCH3 substituted aryl ring, in a 22% metalation of the two different methyl positions was attempted.
yield (Table 1, entry 5) following chromatography to remove Treatment of 6f with three equivalents of BuLi (one to deproto-
the other homo-coupled products (6a, 6c). A similar approach nate the carboxylic acid) and two equivalents of KOt-Bu/
was used in a combined reaction of 4a and 4e, giving purified TMP(H) followed by deuteration gave the di-deuterated pro-
4-methyl-2-(3-methylphenethyl)benzoic acid (6f) (Table 1, duct D2-6f. 2H NMR analysis showed no aryl or bridging meth-
entry 6). This product is the result of oxidative hetero coupling ylene deuteration, with deuterium incorporated only into the
of benzylic metalated xylene and 2-(methyl-metalated)-4- two non-equivalent benzylic methyl positions (Figure 3).
methylbenzoate.
With the benzylic metalation confirmed, the second step to
To more clearly illustrate a site selective metalation of 4e for complete the [2.2]metacyclophane synthesis required identical
the methyl group ortho to the carboxylate, this substrate was conditions to the first to provide the di-benzylic metalated
metalated using LiNK metalation conditions (using an addition derivatives 7 (Table 2). We anticipated that an intramolecular
equivalent of BuLi to first deprotonate the carboxylic acid) and ring closing by oxidative coupling would provide the desired
Table 1: Oxidative coupling of benzylic metalated xylenes 4.
Entry
Substrate
R
Product
Yield %
1
2
3
4
5
6
4a
H
6a
6b
6c
6d
6e
6f
91
4b
CH3
72
4c
OCH3
N(CH3)2
OCH3/H
CO2H/H
92
4d
49
4a/4c
4a/4e
22a
13b
a6a and 6c also obtained in 14% and 49% yields respectively.
b6a and dimer of 4e also obtained in 11% and 62% yields respectively.
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Figure 2: Metalation selectivity for 4e (arrows indicate potential metalation sites). 2H NMR spectrum in CH2Cl2. *CD2Cl2. **2-Methyl-4-D-methylben-
zoic acid.
cyclophane product in addition to open chain oligomers or which upon oxidative coupling gave the corresponding metacy-
larger ring systems.
clophanes 8a–e. This provided unsubstituted cyclophane 8a in
40% yield and 5,13-disubstituted derivatives 8b–d, containing
Substrates 6a–e were treated with two equivalents of BuLi/ CH3, OCH3 and N(CH3)2 substituents respectively, in compa-
KOt-Bu/TMP(H) to generate the corresponding dianions 7a–e, rable yields (Table 2, entries 1–4). In addition, the mono-
Figure 3: Di-metalation selectivity for 6f. 2H NMR spectrum in CH2Cl2. *CD2Cl2.
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Beilstein J. Org. Chem. 2011, 7, 1249–1254.
Table 2: Metalation/oxidative coupling to [2.2]metacyclophanes.
Entry
Substrate
R1/R2
Position
Product
Yield %
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
H/H
—
8a
8b
8c
8d
8e
8f
40
54
33
43
42
39
CH3/CH3
OCH3/OCH3
N(CH3)2/N(CH3)2
OCH3/H
5,13
5,13
5,13
5
CO2H/H
4
methoxy substituted derivative 6e was effectively ring closed 8.9(1)° from planarity. The intra-annular distance as measured
under our reaction conditions to yield 8e in a 42% yield. In each from C(8) to C(16) is as expected for [2.2]metacyclophanes at
case, the majority of the remaining material was oligomeric in 2.66(1) Å [29].
nature, although it was not characterised. Substrate 6f offered
the potential to generate the planar chiral 4-carboxylic acid
substituted metacyclophane 8f. This was readily achieved in a
39% yield, with the characteristic NMR aromatic proton signals
for C(H)-8/16 observed at 4.21 and 4.18 ppm. The efficient two
step synthesis of a C(4)-substituted planar chiral 8f was
achieved from inexpensive substrates, under identical reagent
conditions for both steps. This compares favourably to the
previously reported elaborate seven step synthesis, which was
required due to the difficulties of incorporating substituents at
the C(4) position after metacyclophane synthesis [27,28]. The
Figure 4: X-Ray structure of 8c with thermal ellipsoids drawn at 50%
probability level.
resolution of 8f by salt formation with (+)-1-phenylethylamine
[27] has previously been accomplished.
The stepwise anti conformation of the metacyclophane 8c was Conclusion
confirmed by single crystal X-ray analysis. Cyclophane 8c crys- A new two-step general approach to [2.2]metacyclophane syn-
tallised by the slow room temperature evaporation of a diethyl thesis was described from substituted m-xylenes. Our strategy
ether solution, into the monoclinic space group P21/n as shown employs a selective benzylic metalation and oxidative C–C
in Figure 4. 8c contains an inversion centre with the co-planar bond formation for both synthetic operations under LiNK meta-
aromatic rings bent into shallow boat forms with an angle of lation conditions. The synthetic ease of this approach compares
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synthetic applications of LiNK metalation conditions are also
under development.
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Supporting Information
Supporting Information File 1
All experimental details, 1H and 13C NMR spectra for
compounds 6a–f and 8a–f and X-ray crystallographic data
for 8c.
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Acknowledgements
We thank the Science Foundation Ireland, The Irish Research
Council for Science, Engineering and Technology and ERA-
Chemistry for financial support. Thanks to Dr. J. Muldoon for
NMR analysis and Dr. Helge Müller-Bunz for X-ray structure.
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