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An N-Heterocyclic Carbene Ligand with Flexible Steric Bulk Allows Suzuki Cross-Coupling of Sterically Hindered Aryl Chlorides at Room Temperature.

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Communications
Sterically Flexible Carbene Ligands
An N-Heterocyclic Carbene Ligand with Flexible
Steric Bulk Allows Suzuki Cross-Coupling of
Sterically Hindered Aryl Chlorides at Room
Temperature **
Gereon Altenhoff, Richard Goddard,
Christian W. Lehmann, and Frank Glorius*
However, despite considerable efforts, the coupling of aryl
chlorides to give biaryl compounds with more than one ortho
substituent at room temperature has not been realized to
date.[7]
To overcome this problem, an
electron-rich ligand is required that
is small enough to accept sterically
hindered substrates yet sufficiently
bulky to support monoligation and
promote reductive elimination. We
rationalized that these stringent
requirements could be met by new
NHC 1, which exhibits flexible steric
bulk. Imidazolium salt 4 (Scheme 1)
and the corresponding NHC 1
derived thereof are expected to
exist in the form of three different
conformers a, b and c. Conformation a should allow the coordinated
Pd0 to undergo oxidative addition, even with sterically
hindered substrates, and facilitate transmetallation, whereas
the sterically more demanding conformations b or c should
enhance reductive elimination and favor a monocarbene Pd
species.[8]
Dedicated to Professor Manfred T. Reetz
on the occasion of his 60th birthday
The Suzuki cross-coupling reaction has become a standard
method for biaryl synthesis in both academia and industry.[1]
Its popularity is based on its wide functional-group tolerance
and the ready availability and low toxicity of the required
boronic acids. Although aryl iodides or bromides usually
serve as the substrates, the development of new catalyst
systems has recently enabled the efficient coupling of aryl
chlorides, which are cheaper and more readily available.[2]
Most successful have been applications of palladium complexes of electron-rich, sterically demanding phosphane[3] or
N-heterocyclic carbene (NHC)[4, 5] ligands. Several factors are
thought to be responsible for the success of the ligands used in
these systems: 1) their electron-rich nature enhances the rate
of oxidative addition, 2) the ligands coordinate tightly to the
Pd, thus disfavoring the formation of Pd black, and 3) their
steric bulk favors a monophosphane? or monocarbene?Pd
species[6] and increases the rate of reductive elimination.[3b, 4d]
[*] Dr. F. Glorius, Dipl.-Chem. G. Altenhoff, Dr. R. Goddard,
Dr. C. W. Lehmann
Max-Planck-Institut f;r Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 M;lheim an der Ruhr (Germany)
Fax: (+ 49) 208-306-2994
E-mail: glorius@mpi-muelheim.mpg.de
[**] We thank Prof. A. F;rstner for generous support and constant
encouragement and the Fonds der Chemischen Industrie as well as
the Deutsche Forschungsgemeinschaft for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
3690
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 1. Synthesis of imidazolium salt 4. a) Diethyl oxalate,(ClCH2)2,
toluene, 80 8C, 84 %; b) SOCl2, toluene, 90 8C, 93 %; c) THF, EtOH,
NaOH, 80 8C, 96 %; d) AgOTf, chloromethyl pivalate, CH2Cl2, 40 8C,
85 %.
The synthesis of imidazolium salt 4 was based on our
recent finding that bioxazolines can be converted into
imidazolium salts with AgOTf and chloromethyl pivalate.[9]
The desired salt 4 was obtained in 64 % overall yield from
diethyl oxalate and amino alcohol 2 (Scheme 1). The conformational flexibility of imidazolium salt 4 was confirmed by
crystal structure and NMR spectroscopic analysis. The unit
cell of 4 contains two independent cations, with conformations corresponding to that of a and b (Figure 1).[10] NMR
spectroscopic analysis of 4 in CD2Cl2 revealed that 4 a and 4 b
exist in a ratio of 2.4:1 at 80 8C,
whereas only one set of signals is
observed at room temperature, thus
indicating rapid interconversion of
4 a and 4 b on the NMR timescale.
Pd(NHC)2
complex
5[11]
(Figure 2) was synthesized from 4,
[{(h3-C3H5)PdCl}2], and sodium
malonate.[12] Interestingly, 5 proved
to be catalytically inactive in the
Suzuki coupling under the conditions employed (Table 1) and
only became active at higher temperatures. However, a
catalyst prepared from Pd(OAc)2 and 1 equivalent of imida-
DOI: 10.1002/anie.200351325
Angew. Chem. Int. Ed. 2003, 42, 3690 ?3693
Angewandte
Chemie
Figure 1. Structures of the two independent cations of 2 in the crystal.
Figure 2. Structure of 5 in 5иTHF. Selected distances [G] and angles [8]:
Pd1-C1 2.001(2), C1-N1 1.367(3), C1-N2 1.373(3), C5иииC13* 4.197(4),
C6иииC14* 4.293(4), C7иииC15* 4.220(4); C1-N1-C2 135.0(2), C1-N2-C12
134.0(2), mean plane (C1, C9, C10, N1, N2, Pd1)/mean plane (C1*,
C9*, C10*, N1*, N2*, Pd1) 62(1)8.
zolium salt 4 showed excellent catalytic activity at room
temperature, thus indicating that a Pd0(NHC) species may be
the active catalyst.[6] To demonstrate the efficacy of this
system, we prepared several biaryl derivatives from aryl
chlorides and aryl boronic acids.[13] As shown in Table 1,
unsubstituted, mono-ortho-, and di-ortho-substituted aryl
chlorides can be coupled in good to excellent yields with a
variety of aryl boronic acids in the presence of 3 mol % Pd.
High turnover numbers of 1730 at room temperature and
3130 at 60 8C were obtained in the coupling of a sterically
hindered aryl chloride (Table 1, entries 7 and 8).
For sterically hindered boronic acids the use of a THF/
H2O mixture as solvent and KOtBu
as base was found to be optimal
Table 1: Suzuki coupling of sterically hindered aryl chlorides.[a]
(Table 2). Remarkably, these reacEntry
Aryl chloride
Boronic acid
Product
Yield [%][b]
tion conditions allow the coupling
of highly hindered 2,6-dimethyl[c]
1
82
benzeneboronic acid with unsubstituted, ortho-substituted, elec2
83
tron-deficient, and electron-rich
aryl chlorides (Table 2, entries 1?
5). To the best of our knowledge,
these results represent the first
3
94
room-temperature Suzuki crosscoupling of aryl chlorides with
aryl boronic acids to give di- and
79[c]
4
tri-ortho-substituted biaryl compounds. Furthermore, the reaction
of 2,6-dimethylchlorobenzene with
2-methylbenzeneboronic
acid,
5
85
which results mainly in homocoupling of the aryl boronic acid under
standard conditions, was achieved by
increasing the NHC/Pd ratio from 1
6
87
to 2 and heating at 60 8C (Table 2,
entry 6).[14]
[d]
52
7
Flexible steric bulk might be
8
94[e]
the key to success. Although Herrmann and co-workers showed that
[Pd(6)2] is an efficient catalyst for
[a] Standard conditions: Pd(OAc)2 (3 mol %), 1 (prepared from 4 (3.1 mol %), KH (6.25 mol %), KOtBu
the Suzuki cross-coupling reaction
(0.67 mol %) in THF), aryl chloride (1 mmol, 1.0 equiv), boronic acid (1.1 equiv), CsF (2.0 equiv), THF
of unhindered aryl chlorides at
(0.3 m), room temperature, 24 h (reaction times were optimized). [b] Yields of isolated products.
room temperature, ortho substitu[c] When 5 was used as catalyst, < 5 % of product was obtained. [d] Catalyst: 0.03 mol %. [e] Catalyst:
tion is less well tolerated.[4a] A
0.03 mol %, at 60 8C.
Angew. Chem. Int. Ed. 2003, 42, 3690 ?3693
www.angewandte.org
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3691
Communications
Table 2: Suzuki coupling of sterically hindered boronic acids.[a]
Entry
Aryl chloride
Boronic acid
Product
Yield [%][b]
1
70
2
69
3
95
4
72
5
76
6
66[c]
[a] Standard conditions: Pd(OAc)2 (3 mol %), 1 (prepared from 2 (3.1 mol %), KH (6.25 mol %), KOtBu
(0.67 mol %) in THF), aryl chloride (1 mmol, 1.0 equiv), boronic acid (1.1 equiv), KOtBu (2.0 equiv),
THF/H2O (10:1, 0.3 m), room temperature, 24 h (reaction times were not optimized). [b] Yields of
isolated products. [c] 60 8C.
comparison of the crystal structures of the Pd(NHC)2 complexes of 1 and 6 indicates that 6 is bulkier than 1 a.[15]
Although bulk aids reductive elimination, it impedes oxidative addition and transmetallation of sterically hindered substrates allowed
by the more flexible 1.
In conclusion, we have developed a general, highly efficient catalyst system for the roomtemperature Suzuki coupling of hindered and unhindered,
activated and deactivated aryl chlorides and aryl boronic
acids. For the first time di- and tri-ortho-substituted biaryl
compounds were formed under these conditions and high
turnover numbers were obtained. We anticipate that other
metal-catalyzed reactions will benefit from the application of
the concept of flexible steric bulk.
Experimental Section
4: Chloromethyl pivalate (1.25 mL, 8.4 mmol) was added to a
suspension of AgOTf (2.16 g, 8.4 mmol) in CH2Cl2 (30 mL), and the
resulting suspension was stirred in the absence of light for 45 min.
After filtration, the filtrate was added to bioxazoline 3 (1.60 g,
5.8 mmol), and the solution was stirred in a sealed tube in the absence
of light at 40 8C for 20 h. After the solution was cooled to room
temperature, the solvent was evaporated in vacuo and the resulting
oil was purified by column chromatography (silica gel, 2.5 B 10 cm,
CH2Cl2/MeOH 20:1!10:1). Subsequent crystallization from a sol-
3692
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
vent mixture of THF (10 mL), toluene
(40 mL), and pentane (40 mL) gave
imidazolium triflate 4 (2.15 g, 85 %) as
colorless crystals. Rf = 0.58 (CH2Cl2/
MeOH 10:1); IR (KBr): n? = 3113,
2945, 2862, 1727, 1516, 1459, 1266,
1224, 1151, 1031, 957, 913, 825, 754,
637 cm1; 1H NMR (400 MHz, CDCl3):
d = 9.12 (s, 1 H; NCHN), 4.80 (s, 4 H;
OCH2), 2.32 (td, J = 3.8, 12.5 Hz, 4 H;
CH2), 2.10?1.98 (m, 8 H; CH2), 1.74?
1.58 (m, 4 H; CH2), 1.46?1.37 ppm (m,
4 H; CH2); 13C NMR (100 MHz,
CDCl3): d = 124.6 (NCO), 120.8 (q,
J = 319 Hz, CF3), 113.9 (NCHN), 85.6
(OCH2), 67.5 (CCH2), 34.7 (CH2), 23.5
(CH2), 23.1 ppm (CH2); 19F NMR
(300 MHz, CDCl3): d = 78.5 ppm
(CF3); MS (EI): m/z (%): 289 (100),
261 (5), 194 (5), 166 (5), 122 (12), 95
(20); HRMS (EI): calcd for C17H25N2O2
(cation): 289.1916; found: 289.1918;
elemental
analysis:
calcd
for
C18H25F3N2O5S: C 49.31, H 5.75, N
6.39; found: C 49.52, H 5.75, N 6.31.
Received: March 4, 2003 [Z51325]
.
Keywords: biaryls и carbene ligands и
C?C coupling и cross-coupling и
palladium
[1] a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457; b) A.
Suzuki, J. Organomet. Chem. 1999, 576, 147; c) N. Miyaura, Top.
Curr. Chem. 2002, 219, 11; d) S. Kotha, K. Lahiri, D. Kashinath,
Tetrahedron 2002, 58, 9633.
[2] For a review, see:A. F. Littke, G. C. Fu, Angew. Chem. 2002, 114,
4350; Angew. Chem. Int. Ed. 2002, 41, 4176.
[3] For example, see: a) R. B. Bedford, C. S. J. Cazin, S. L. Hazelwood, Angew. Chem. 2002, 114, 4294; Angew. Chem. Int. Ed.
2002, 41, 4120; b) J. P. Wolfe, R. A. Singer, B. H. Yang, S. L.
Buchwald, J. Am. Chem. Soc. 1999, 121, 9550; c) A. F. Littke, C.
Dai, G. C. Fu, J. Am. Chem. Soc. 2000, 122, 4020; d) J. P.
Stambuli, R. Kuwano, J. F. Hartwig, Angew. Chem. 2002, 114,
4940; Angew. Chem. Int. Ed. 2002, 41, 4746; e) A. Zapf, A.
Ehrentraut, M. Beller, Angew. Chem. 2000, 112, 4315; Angew.
Chem. Int. Ed. 2000, 39, 4153.
[4] a) C. W. K. GstIttmayr, V. P. W. BIhm, E. Herdtweck, M.
Grosche, W. A. Herrmann, Angew. Chem. 2002, 114, 1421;
Angew. Chem. Int. Ed. 2002, 41, 1363; b) W. A. Herrmann, C.-P.
Reisinger, M. Spiegler, J. Organomet. Chem. 1998, 557, 93; c) T.
Weskamp, V. P. W. BIhm, W. A. Herrmann, J. Organomet.
Chem. 1999, 585, 348; d) G. A. Grasa, M. S. Viciu, J. Huang, C.
Zhang, M. L. Trudell, S. P. Nolan, Organometallics 2002, 21,
2866; e) C. Zhang, J. Huang, M. L. Trudell, S. P. Nolan, J. Org.
Chem. 1999, 64, 3804; f) A. FKrstner, A. Leitner, Synlett 2001,
290.
[5] For an excellent review on the use of NHC ligands in catalysis,
see: a) W. A. Herrmann, Angew. Chem. 2002, 114, 1342; Angew.
Chem. Int. Ed. 2002, 41, 1291; see also: b) A. J. Arduengo III, R.
Krafczyk, Chem. Unserer Zeit 1998, 32, 6; c) D. Bourissou, O.
Guerret, F. P. GabbaL, G. Bertrand, Chem. Rev. 2000, 100, 39.
[6] The importance of monoligated Pd0 complexes as catalytically
active species in Suzuki cross-coupling has been proposed; for
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 3690 ?3693
Angewandte
Chemie
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
example, see: a) reference [3c]; b) reference [3d]; c) Q.-S. Hu, Y.
Lu, Z.-Y. Tang, H.-B. Yu, J. Am. Chem. Soc. 2003, 125, 2856.
For the synthesis of sterically hindered biaryl compounds by
Suzuki cross-coupling at elevated temperatures, see: a) reference [3b]; b) reference [3c]; c) J. Yin, M. P. Rainka, X.-X. Zhang,
S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 1162.
For a mechanistic discussion of Pd/NHC catalyst systems in
Suzuki cross-coupling reactions, see reference [4d].
F. Glorius, G. Altenhoff, R. Goddard, C. Lehmann, Chem.
Commun. 2002, 2704.
a) Crystal data for 4:[11] [C17H25N2O2]+[CF3O3S] , from THF/
hexane, Mr = 438.46, crystal size: 0.18 B 0.18 B 0.18 mm3, monoclinic, space group P21/n (No. 14), a = 12.6250(1), b = 14.4420(1),
c = 22.1470(2) O, b = 98.289(1)8, V = 3995.88(6) O3, Z = 8,
1calcd = 1.458 g cm3, F(000) = 1840, 99 914 measured and 12 665
independent reflections (Rint = 0.068), 9933 with I > 2s(I), qmax =
30.968, Tmin = 0.958, Tmax = 0.987, 548 parameters, imidazolium H
atoms were refined isotropically, otherwise riding, one anion
slightly disordered (0.93:0.07), Chebychev weights, R1 = 0.0451,
wR2 = 0.1102 (all data), D1max/min = 0.454/0.443 e O3 ; b) Crystal data for 5иTHF:[11] [C34H48N4O4Pd]и[C4H8O], from THF/
hexane, Mr = 755.27, crystal size: 0.24 B 0.11 B 0.10 mm3, tetragonal, space group I
4 (No. 82), a = 23.7110(2), c = 12.6712(1) O,
V = 7123.9(1) O3, Z = 8, 1calcd = 1.408 g cm3, F(000) = 3184,
57 202 measured and 11 290 independent reflections (Rint =
0.053), 9227 with I > 2s(I), qmax = 30.998, Tmin = 0.899, Tmax =
0.950, 434 parameters, absolute structure not determined (Pd
atoms on Wyckhoff positions e and f), H atoms riding,
Chebychev weights, R1 = 0.037, wR2 = 0.085 (all data), D1max/
3
min = 1.820/0.673 eO .
General information for crystal-structure analysis: Data capture
on a Nonius KappaCCD diffractometer at T = 100 8C, l(MoKa) =
0.71073 O, m = 0.22 (4), 0.57 mm1 (5иTHF); structure determination by direct methods (SHELXS-97), least-squares refinement (SHELXL-97) on F20 (SHELXL-97); both programs from:
G. Sheldrick, University of GIttingen, 1997; CCDC-204549 (4)
and CCDC-204550 (5иTHF) contain the crystallographic data
(excluding structure factors) for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: (+ 44) 1223-336033; or e-mail: deposit@ccdc.cam.ac.uk).
S. Caddick, F. G. N. Cloke, G. K. B. Clentsmith, P. B. Hitchcock,
D. McKerrecher, L. R. Titcomb, M. R. V. Williams, J. Organomet. Chem. 2001, 617?618, 635.
All new compounds were fully characterized.
A beneficial effect of increasing the ligand/Pd ratio was also
observed by Buchwald and co-workers for Pd?phosphanecatalyzed cross-coupling reactions of sterically hindered substrates.[3b]
Whereas the Ccarbene-N-Csubstituent angle is 1358 in 5иTHF, in
[Pd(6)2] it is 1248. Moreover, the favorable conformation of the
spirocyclohexyl groups allows 5 to adopt an arrangement in
which the two imidazolylidene ligands are more nearly coplanar.
Thus, in [Pd(6)2] the angle between the imidazolylidene ligands
is 84.4(2)8, whereas in 5 it is 62(1)8 (mean), despite a significantly
shorter Pd?C distance (2.001(2) relative to 2.076(5) O).[4a]
Angew. Chem. Int. Ed. 2003, 42, 3690 ?3693
www.angewandte.org
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3693
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suzuki, flexible, carbene, couplings, room, cross, chloride, aryl, ligand, allows, sterin, temperature, sterically, heterocyclic, hindered, bulka
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