A biaryl cross-coupling strategy for functionalisation of benzocrown ethers

Article abstract of DOI:10.1039/b709861h

Preparation of (di)benzocrown-substituted aryl-zinc or -boron reagents and their palladium-catalysed cross-coupling with functionalised aryl halides is described for convenient synthesis of novel crown ether systems. The Royal Society of Chemistry.

Full text of DOI:10.1039/b709861h

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A biaryl cross-coupling strategy for functionalisation of benzocrown
ethers{
Sally Dixon, Richard C. D. Brown* and Philip A. Gale*
Received (in Austin, TX, USA) 28th June 2007, Accepted 18th July 2007
First published as an Advance Article on the web 6th August 2007
DOI: 10.1039/b709861h
Table 1 Synthesis of bis-crown ethers 4
Preparation of (di)benzocrown-substituted aryl-zinc or -boron
reagents and their palladium-catalysed cross-coupling with
functionalised aryl halides is described for convenient synthesis
of novel crown ether systems.
Entry
Product
n1
n2
Yield [%]a
1
2
3
4
5
a
4a
4a
4a
4b
4c
2
2
2
1
2
2
2
2
1
1
21b
40c
79d
92
The uses of crown ethers in supramolecular chemistry have
evolved from metal cation complexation1 through transporters for
cations2,3 and chiral recognition,4 to sensors,5 and as components
of complex supramolecular assemblies6–8 and prototypical mole-
cular machines.9,10 Despite the significant effort focused on the
synthesis of functionalised crown ethers and bis-crown ether
systems, there is still a need for new, high-yielding routes to
functionalised derivatives of these useful compounds.
76
Yields refer to isolated analytically pure material, purified by
b
column chromatography. From treatment of 1 with i) tert-BuLi
(1.05 equiv.) at 278 uC; ii) ZnBr2 (1.05 equiv.) 278 uC to 250 uC;
c
iii) 3 (n2 = 2), Pd(PPh3)4 (5 mol%), 250 uC to rt. From treatment
of 1 with i) i-PrMgCl (1.05 equiv.) at 0 uC; ii) 3 (n2 = 2), Pd(PPh3)4
d
(5 mol%) at 0 uC. With 0.5 equiv. ZnBr2 4a was isolated in
46% yield.
Palladium-catalysed Negishi cross-coupling between organozinc
reagents and organohalides11,12 has become an important method
for the preparation of functionalised biphenyls13 following the
ready availability of functionalised arylzinc reagents, directly from
arylhalides by insertion of zinc14–20 or via transmetalation from
aryl-lithium21 or arylmagnesium13 species’. Whilst halogen–lithium
exchange requires low temperature reaction conditions under
which most benzocrowns display poor solubility,22 halogen–
magnesium exchange occurs at higher temperatures. Attempted
Grignard preparation of benzocrown-functionalised aryl magne-
sium reagents, using magnesium metal, has been demonstrated to
result in cleavage of the crown ether ring by radical or carbanion
species’.23 Consequently, these potentially very powerful reagents
have not, until now, been readily available for use in the synthesis
of novel crown ethers.
Highly efficient iodine–magnesium exchange was conveniently
achieved upon treatment of 1 (n1 = 1 or 2) with i-propyl
magnesium chloride at 0 uC, furnishing 2 (n1 = 1 or 2)
quantitatively as judged by 1H NMR of the protonated material.
Direct cross-coupling of arylmagnesium reagent 2 (n1 = 2) with 3
(n2 = 2) catalysed by Pd(PPh3)4 was incomplete and 4a isolated in
moderate yield (Table 1, Entry 2); gratifyingly magnesium–zinc
transmetalation of 2 facilitated efficient Neghishi cross-coupling of
the corresponding arylzinc reagent with 4-iodobenzocrowns 3,
furnishing biphenyl-linked bis-crowns 4a–c in good yield (Scheme 1
and Table 1, Entries 3–5). This one-pot preparation has the key
advantage that introduction of a group with different binding
selectivity is possible in the final step and permits synthesis of
useful, unsymmetrical products. The procedure may therefore be
applied also to the synthesis of 4-(hetero)aryl functionalised
benzocrowns and preparation of 4-[3-thiophene]benzo-18-crown-
6 ether (5) was illustrative.
Herein we report that benzocrown-substituted aryl magnesium
reagents of type 2 are conveniently prepared by iodine–magnesium
exchange from 4-iodobenzocrowns and participate in efficient
transmetalation to either zinc or boron, followed by synthetically
useful palladium-catalysed biaryl cross-couplings.
We wished also to demonstrate practical usefulness of
arylmagnesium reagent 2. Importantly, 2 (n1 = 2) displays good
solubility in THF at 278 uC. Solubility of 2 (n1 = 1) is reduced due
to presumed competing intermolecular co-ordination of magne-
sium by the crown ether;23,27 however transmetalation to boron
upon treatment of 2 (n1 = 1 or 2) with trimethyl borate at 278 uC
furnishes stable, isolable arylboronic acids 6a/b, both in reasonable
yield following acid hydrolysis of the intermediate boronic acid
methyl esters. Subsequent Suzuki coupling28 of 6a/b with
4-iodobenzocrowns 3 (n2 = 1 or 2) led once more to biphenyl
linked bis-crowns 4a/c in high yield (Scheme 2).
Iterative treatment of 4-iodobenzo-18-crown-6 ether 1 (n1
=
2)24–26 with tert-butyl lithium in THF at 278 uC, ZnBr2 and a
solution of 3 (n2 = 2)/Pd(PPh3)4 (5 mol%) resulted in a low yield of
biphenyl 4a due to the sparing solubility of 1 at low temperature
and consequent incomplete iodine–lithium exchange (Table 1,
Entry 1).
School of Chemistry, University of Southampton, Highfield,
Southampton, Hampshire, UK SO17 1BJ. E-mail: rcb1@soton.ac.uk;
philip.gale@soton.ac.uk; Fax: +44 (0)23 80596805;
Fax: +44 (0)23 80596805; Tel: +44 (0)23 80594108
Tel: +44 (0)23 80593332
{ Electronic supplementary information (ESI) available: representative
experimental methods and spectroscopic characterisation of compounds
4a–c, 5, 6a–b and 10. See DOI: 10.1039/b709861h
Dibenzo-24-crown-8 ether (DB24C8) is an important motif in
supramolecular templating6 and construction of the bis-DB24C8
moiety constitutes a useful application of the described biphenyl
cross-couplings. A bis-ethyleneoxy derivative of catechol was
prepared29 and tosylation of the diol30 then carried out to furnish
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Scheme 2 Reagents and conditions: i) i-PrMgCl (1.05 equiv.), THF, 0 uC,
2 h; ii) ZnBr2 (1.05 equiv.), 0 uC, 45 min; iii) 3-iodothiophene (1.0 equiv.),
Pd(PPh3)4 (5 mol%), 0 uC to rt then rt overnight; iv) B(OMe)3, 278 uC to
r.t 16 h; v) HCl (aq.), rt; vi) 3 (n2 = 1 or 2), Pd(PPh3)4, Na2CO3 (2 M),
toluene/MeOH, 80 uC 16 h.
Scheme 1 Reagents and conditions: i) i-PrMgCl (1.05 equiv.), THF, 0 uC,
2 h; ii) ZnBr2 (1.05 equiv.), 0 uC, 45 min; iii) 3 (1.0 equiv.), Pd(PPh3)4
(5 mol%), 0 uC to rt then rt overnight.
to zinc and palladium-catalysed coupling with a further equivalent
of 9. Bis-crown 10 was obtained in good yield.
7. Coupling of 7 with 4-bromocatechol was templated with Cs+
and 4-bromo-DB24C8 (8) was obtained in good yield (Scheme 3).31
Halogen–metal exchange of 8 with i-propyl magnesium chloride or
i-propyl magnesium chloride?LiCl at 0 uC32 did not take place and
although improved solubility of 8 (cf. 1) at 278 uC enabled us to
carry out bromine–lithium exchange of 8, subsequent transmetala-
tion to zinc was incomplete33 and emphasises the requirement for
magnesium–zinc transmetalation. However, 4-iodo-DB24C8 (9)
underwent efficient iodine–magnesium exchange, transmetalation
We have demonstrated for the first time efficient iodine–
magnesium exchange reaction of 4-iodobenzocrown ethers in THF
under mild conditions and subsequent transmetalation to either
zinc or boron. Complementary routes for biphenyl cross-coupling
of the resulting arylzinc or arylboron reagents have been applied to
the preparation of various functionalised benzocrowns. This route
gives access to a plethora of new crown ether compounds with
many potential uses in the supramolecular chemistry arena.
Scheme 3 Reagents and conditions: i) 4-bromobenzene-1,2-diol, CsCO3, MeCN; ii) n-BuLi, 278 uC then I2; iii) i-PrMgCl (1.05 equiv.), THF, 0 uC, 2 h; iv)
ZnBr2 (1.05 equiv.), 0 uC, 45 min; v) 9 (1.0 equiv.), Pd(PPh3)4 (5 mol%), 0 uC to rt then rt overnight.
3566 | Chem. Commun., 2007, 3565–3567
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16 F. F. Kneisel, M. Dochnahl and P. Knochel, Angew. Chem., Int. Ed.,
2004, 43, 1017.
17 A. Krasovskiy, V. Malakhov, A. Gavryushin and P. Knochel, Angew.
Chem., Int. Ed., 2006, 45, 6040.
We would like to thank the EPSRC for a post-doctoral
fellowship (S.D.).
18 T. N. Majid and P. Knochel, Tetrahedron Lett., 1990, 31, 4413.
19 M. Ueno, A. E. H. Wheatley and Y. Kondo, Chem. Commun., 2006,
3549.
20 L. Zhu, R. M. Wehmeyer and R. D. Rieke, J. Org. Chem., 1991, 56,
1445.
Notes and references
1 R. M. Izatt, Chem. Soc. Rev., 2007, 36, 143 and references cited therein.
2 T. M. Fyles, Chem. Soc. Rev., 2007, 36, 335.
3 G. W. Gokel and I. A. Carasel, Chem. Soc. Rev., 2007, 36, 378.
4 S. Seyhan, Y. Turgut, M. Merdivan and H. Hosgoren, Tetrahedron:
Asymmetry, 2006, 17, 1700.
21 C. E. Tucker, T. N. Majid and P. Knochel, J. Am. Chem. Soc., 1992,
114, 3983.
22 Attempted preparation of 4-lithiobenzo-18-crown-6 ether at 0 uC failed
to generate a stable aryllithium reagent, we were unable to trap the
species formed with chlorotrimethylsilane.
23 P. R. Markies, O. S. Akkerman, F. Bickelhaupt, W. J. J. Smeets and
A. L. Spek, J. Am. Chem. Soc., 1988, 110, 4284.
5 V. Souchon, I. Leray and B. Valeur, Chem. Commun., 2006, 4224.
6 S. J. Loeb, Chem. Soc. Rev., 2007, 36, 226; S. J. Loeb, J. Tiburcio and
S. J. Vella, Chem. Commun., 2006, 1598; S. J. Loeb and D. A.
Tramontozzi, Org. Biomol. Chem., 2005, 3, 1393.
7 F. H. Huang, P. Gantzel, D. S. Nagvekar, A. L. Rheingold and
H. W. Gibson, Tetrahedron Lett., 2006, 47, 7841; F. H. Huang, H. B.
Yang, N. Das, U. Maran, A. M. Arif, H. W. Gibson and P. J. Stang,
J. Org. Chem., 2006, 71, 6623.
8 J. M. Mahoney, A. M. Beatty and B. D. Smith, Inorg. Chem., 2004, 43,
7617; A. J. Evans and P. D. Beer, Dalton Trans., 2003, 4451.
9 J. D. Badjic, C. M. Ronconi, J. F. Stoddart, V. Balzani, S. Silvi and
A. Credi, J. Am. Chem. Soc., 2006, 128, 1489.
10 G. Rogez, B. F. Ribera, A. Credi, R. Ballardini, M. T. Gandolfi,
V. Balzani, Y. Liu, B. H. Northrop and J. F. Stoddart, J. Am. Chem.
Soc., 2007, 129, 4633.
24 E. M. Hyde, I. Shepherd and B. L. Shaw, J. Chem. Soc., Dalton Trans.,
1978, 1696.
25 In our hands, preparation of 4-iodobenzo-18-crown-6 or -15-crown-5
ether under the reported conditions24 resulted in trace quantities of
inseparable 4,5-substituted bisiodide. 4-Iodobenzocrowns were instead
cleanly obtained under milder aqueous iodination conditions.26.
26 D. Mujahidin and S. Doye, Eur. J. Org. Chem., 2005, 2689.
27 P. R. Markies, T. Nomoto, G. Schat, O. S. Akkerman, F. Bickelhaupt,
W. J. J. Smeets and A. L. Spek, Organometallics, 1991, 10, 3826.
28 A. O. Aliprantis and J. W. Canary, J. Am. Chem. Soc., 1994, 116,
6985.
29 T. Bogaschenko, S. Basok, C. Kulygina, A. Lyapunov and
N. Lukyanenko, Synthesis, 2002, 2266.
30 T. Lazarides, T. A. Miller, J. C. Jeffery, T. K. Ronson, H. Adams and
M. D. Ward, Dalton Trans., 2005, 528.
11 E. Negishi, L. F. Valente and M. Kobayashi, J. Am. Chem. Soc., 1980,
102, 3298.
12 E. Negishi, X. Zeng, Z. Tan, M. Qian, Q. Hu and Z. Huang, in Metal-
Catalyzed Cross-Coupling Reactions, 2004; ed. P. J. Stang and F.
Diederich, Wiley-VCH, Weinheim. p. 815.
31 J. J. Pak, J. L. Mayo and E. Shurdha, Tetrahedron Lett., 2006, 47, 233.
32 A. Krasovskiy and P. Knochel, Angew. Chem., Int. Ed., 2004, 43, 3333.
33 Preparation of 10 from 8 was made in 42% isolated yield: i) 8, n-BuLi
(1.0 equiv.), 278 uC, 40 min; ii) ZnBr2 (1.05 equiv.), 278 uC to 0 uC; iii)
9 (1.0 equiv.), Pd(PPh3)4 (5 mol%), 0 uC to rt then rt overnight.
13 I. Sapountzis, H. Dube and P. Knochel, Adv. Synth. Catal., 2004, 346,
709.
14 H. Fillon, C. Gosmini and J. Perichon, J. Am. Chem. Soc., 2003, 125,
3867.
15 L. Z. Gong and P. Knochel, Synlett, 2005, 267.
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