Application of the 'resin-capture-release' methodology to macrocyclisation via intramolecular Suzuki-Miyaura coupling

Article abstract of DOI:10.1039/b101156l

Aryl boronic acids can be trapped by an ammonium hydroxide-form Dowex Ion Exchangers resin (D-OH^-) leading to polymer-ionically bound borates and cyclized, when properly designed, into macroheterocycles under Suzuki-Miyaura coupling conditions.

Full text of DOI:10.1039/b101156l

Application of the ‘resin-capture–release’ methodology to
macrocyclisation via intramolecular Suzuki–Miyaura coupling
Virginie Lobrégat,a Gilles Alcaraz,*a Hugues Bienayméb and Michel Vaultier*b
a S.E.S.O. UMR-CNRS 6510, Université de Rennes 1-Beaulieu, F-35042 Rennes, France.
E-mail: michel.vaultier@univ-rennes1.fr
b Rhône-Poulenc Industrialisation BP 62, F-69192, Saint-Fons, France.
E-mail: hugues.bienaymé@crit.rhone-poulenc.com
Received (in Cambridge, UK) 5th February 2001, Accepted 19th March 2001
First published as an Advance Article on the web 9th April 2001
Table 1 11B NMR chemical shifts for 1 and 2
Aryl boronic acids can be trapped by an ammonium
hydroxide-form Dowex® Ion Exchangers resin (D-OH2)
d11B/ppm
leading to polymer-ionically bound borates and cyclized,
when properly designed, into macroheterocycles under
1a: 28.7 (THF–C6D6)
1b: 28.5 (d6-DMSO)
1c: 28.8 (d6-DMSO)
1d: 29.3 (d6-acetone)
2a: 2.9 (D2O)-n1/2 = 339 Hz
Suzuki–Miyaura coupling conditions.
2b: 1.8 (D2O)-n1/2 = 225 Hz
2c: 2.0 (D2O)-n1/2 = 345 Hz
2d: 2.0 (D2O)-n1/2 = 270 Hz
Biarylcyclopeptides are important targets1 since such com-
pounds are potentially promising therapeutic agents.2 The solid
phase synthesis of macrocyclic systems involving a transition
metal catalysed C–C bond formation is a current challenge
investigated with polymer-covalently bound precursors.3 How-
ever, such synthetic strategies involving an aryl–aryl coupling
at a final stage are scarse. To the best of our knowledge, only
one example describing the synthesis of a b-turn mimic via a
Suzuki–Miyaura ring-closing reaction has been reported.4
These approaches generally required sophisticated multistep
synthesis on the solid support prior the crucial C–C bond
formation.
suspensions of resins 2 in D2O for example are well-resolved
(n1/2 < 500 Hz) with 11B chemical shifts observed in the
expected region (typically d ~ 2 ppm Table 1). Efficient
Suzuki–Miyaura coupling reactions could be achieved with
these immobilized arylhydroxyborates (Scheme 2). The reac-
In this context, we thought that the application of the ‘resin-
capture–release’ hybrid technique5 to the generation of polymer
supported borate species bearing a remote aryl halide moiety
followed by a releasing cyclisation under Suzuki–Miyaura’s
conditions could bring an efficient and easy solution to the
synthesis of biarylic macrocyles. In order to check this idea, we
developed a simple resin-capture method to immobilize aryl-
boronic acids species by reaction with macroporous ammonium
hydroxide-form Dowex® Ion Exchangers resin (D-OH2) as
BIV-arylborates. The simple addition of a dilute THF solution of
boronic acids 1 onto D-OH2 resin resulted in the quaternization
of the boron atom, leading to the formation of the corresponding
immobilized hydroxyborate adduct 2 (Scheme 1).
Loading of the resin was easily achieved and controlled with
1a–d featuring various functionalities. In all cases, about 75%
of the given theoretical capacity (ca. 1.6 mmol g21 of dry resin)
can be reached.6 The strength of this ionic linkage was
evaluated by submitting the phenylhydroxyborate resin 2a (as a
representative example) to continuous extraction with Soxhlet
apparatus. With water as solvent, only 10% leaching of 1a from
2a was observed after 72 h while no leaching could be detected
after 18 h using THF. Another interesting feature is that despite
their total insolubility, resins 2 can be readily analysed by
standard 11B NMR spectroscopic methods as a heterogeneous
suspension in classical solvents. The NMR spectra of such
Scheme 2 Reagents and conditions: loading of 0.8 mmol g21, D-Br2 (1
eq.), cat. Pd(OAc)2 (2 mol%), H2O, rt, 17 h.
tions leading to 4 were performed in water7 in the presence of
two bromoarenes bearing respectively an activating electron-
withdrawing group (3a; Z = 3-COMe) and an electron-
donating-group (3b; Z = 3-OMe) selected for their different
reactivity towards the rate-determining oxidative addition step
in the catalytic cycle.8 The results reported in Table 2 verify this
trend. In the case of 2c (entries 5 and 6), the expected
protodeboronation side-reaction occurs at the expense of the
formation of 4.
Table 2 Releasing Suzuki–Miyaura cross-coupling reaction
Entry
2
3
4a
1
2
3
4
5
6
2a
2a
2b
2b
2c
2c
3a
3b
3a
3b
3a
3b
86%
60%
75%
61%
38%(65%)b
22%
a Isolated yield respect to 3. b Reaction carried out at 56 °C
We then developed an original route to build up precursors 5
(Scheme 3) containing both the arylboronic and bromoaryl
moieties necessary to perform the macrocyclisation reaction
using an expedient multicomponent one pot synthesis.9 Com-
pounds 5 were obtained in good yields by mixing 3-propa-
nalbenzeneboronic acid, morpholine and the selected iso-
cyanoacetamide10 in MeOH. As described (vide supra), 5 was
efficiently anchored and in addition purified as 6 at an
optimized loading of ca. 0.15 mmol g21 of dry resin. In the
absence of added base, by mixing 6 (1 eq.) with quaternary
Scheme 1 Resin-capture of arylboronic acids.
DOI: 10.1039/b101156l
Chem. Commun., 2001, 817–818
This journal is © The Royal Society of Chemistry 2001
817

HRMS and collected NMR data are in agreement with the
proposed structures which have been confirmed by an X-ray
diffraction study performed on 7b11 Under acidic conditions the
oxazole 7b could be ring-expanded into the corresponding
biarylcyclopeptide 8b11 in 92% yield, thus opening the way to
a general and efficient synthesis of this class of macrohetero-
cycles.
Notes and references
1 For a review, see: A. V. Rama Rao, M. K. Gurjar, K. L. Reddy and A. S.
Rao, Chem. Rev., 1995, 95, 2135.
2 (a) R. Kannan and D. H. Williams, J. Org. Chem., 1987, 52, 5435; (b)
U. Schmidt, R. Meyer, V. Leitenberger, A. Lieberknecht and H.
Griesser, J. Chem. Soc., Chem. Commun., 1991, 275; (c) U. Schmidt, R.
Meyer, V. Leitenberger, A. Lieberknecht and H. Griesser, J. Chem.
Soc., Chem. Commun., 1992, 951; (d) A. G. Brown, M. J. Crimmin and
P. D. Edwards, J. Chem. Soc., Perkin Trans. 1, 1992, 123.
3 (a) M. Hiroshige, J. R. Hauske and P. Zhou, J. Am. Chem. Soc., 1995,
117, 11590; (b) K. C. Nicolaou, N. Winssinger, J. Pastor, S. Ninkovic,
F. Sarabia, Y. He, D. Vourloumis, Z. Yang, T. Li, P. Glannakakou and
E. Hamel, Nature, 1997, 387, 268; (c) K. C. Nicolaou, N. Winssinger,
J. Pastor and F. Murphy, Angew. Chem., Int. Ed., 1998, 37, 2534.
4 (a) W. Li and K. Burgess, Tetrahedron Lett., 1999, 40, 6527; (b) N.
Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
5 (a) A. Kirschning, H. Monenschein and R. Wittenberg, Chem. Eur. J.,
2000, 6, 4445; (b) J. G. Keay and E. F. V. Scriven, Chem. Ind., 1994, 53,
339; (c) S. Khound and P. J. Das, Tetrahedron, 1997, 53, 9749.
6 The loading is determined by differential weighing between the quantity
of 1 initially introduced and recovered after several washings of the
resin.
7 D. Badone, M. Baroni, R. Cardamone, A. Ielmini and U. Guzzi, J. Org.
Chem., 1997, 62, 7170.
8 A. Suzuki, in Metal-catalyzed Cross-coupling Reactions, eds. F.
Diederich and P. J. Stang, Wiley-VCH, Weinheim, 1998, p.55.
9 For recent references on multicomponent reactions see: (a) A. Dömling
and I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168; (b) H. Bienaymé, C.
Hulme, G. Oddon and P. Schmitt, Chem. Eur. J., 2000, 6, 3321.
10 Efficient synthesis of these compounds have been developed in our
laboratory: V. Lobrégat, Ph.D thesis, University of Rennes, 2000.
11 Selected physical data: 7b mp (Et2O) 176 °C, 1H NMR (200 MHz,
CDCl3) d 5.91 (s, oxazolic-CH); 13C NMR (50.33 MHz, CDCl3) d 98.8
(oxazolic-CH), 123.7, 124.1, 127.2, 127.3, 127.8, 128.5, 128.9, 130.4 (8
3 aryl-CH), 138.8, 140.8, 141.5, 141.7 (4 3 aryl-CIV), 151.4, 156.6 (2
3 oxazolic-CIV), HRMS [M+·] calcd. for C25H28N3O2: m/z 403.2260.
Found: 403.2275. 8b 13C NMR (50.33 MHz, CDCl3) d 41.5 (NH-CH2-
CO), 70.2 (N-CH-CO), 139.0, 140.7, 141.1, 142.4 (4 3 aryl-CIV), 168.3
(NH-CH2-CO), 172.0 (NH-CO), HRMS [M+·] calcd. for C25H31N3O3:
m/z 421.2365. Found: 421.2380.
Scheme 3: Reagents and conditions: (a) D-Br2 (1 eq.), cat. Pd(OAc)2 (5
mol%), TPPDS (20 mol%), THF–H2O (4+1), 40 °C, 40 h; (b) TFA (120
eq.), H2O (30 eq.), rt, 2 h.
ammonium bromide-form Dowex® Ion Exchangers resin (D-
Br2), Pd(OAc)2 (5 mol%) and triphenylphosphine disulfonic
acid disodium salt (TPPDS, 20 mol%) in a THF–H2O mixture
at 40 °C, fourteen- to sixteen-membered macrocycles 7 were
released and successfully isolated pure after a simple filtration–
extraction sequence followed by a filtration through a pad of
silica gel in 16–22% yield. For comparison, when compounds 5
were submitted to identical conditions in THF solution,
macroheterocycles 7 were not obtained (Scheme 2).
818
Chem. Commun., 2001, 817–818