Tetra-ortho-substituted biaryls through palladium-catalyzed suzuki miyaura couplings with a diaminochlorophosphine ligand

Article abstract of DOI:10.1021/ol1000186

Chemical Equetion Presentation A palladium complex derived from a sterically hindered diaminochlorophosphine allowed for Suzuki-Miyaura cross-couplings of chloroarenes with ample scope and provided access to tetra-ortho-substituted bi(hetero)aryls.

Full text of DOI:10.1021/ol1000186

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1004-1007
Tetra-ortho-Substituted Biaryls through
Palladium-Catalyzed Suzuki-Miyaura
Couplings with a
Diaminochlorophosphine Ligand
Lutz Ackermann,*,† Harish K. Potukuchi,† Andreas Althammer,† Robert Born,†
and Peter Mayer‡
Institut fuer Organische und Biomolekulare Chemie, Georg-August-UniVersitaet,
Tammannstrasse 2, 37077 Goettingen, Germany, and Department Chemie,
Ludwig-Maximilians-UniVersitaet, Butenandtstrasse 5-13, 81377 Muenchen, Germany
lutz.ackermann@chemie.uni-goettingen.de
Received January 4, 2010
ABSTRACT
A palladium complex derived from a sterically hindered diaminochlorophosphine allowed for Suzuki-Miyaura cross-couplings of chloroarenes
with ample scope and provided access to tetra-ortho-substituted bi(hetero)aryls.
Transition-metal-catalyzed cross-coupling reactions are in-
dispensable tools for regioselective C(sp2)-C(sp2) bond
formations, which have found valuable applications in
numerous research areas.1 Particularly, Suzuki-Miyaura
couplings have proven useful because of their remarkable
tolerance of functional groups, along with the low toxicities
and ready availability of organoboron nucleophiles.2 While
considerable progress in Suzuki-Miyaura coupling chemistry
has been accomplished in recent years through the develop-
ment of stabilizing ligands,2 syntheses of highly ortho-
substituted biaryls continue to constitute a significant chal-
lenge. Thus, high-yielding3 preparations of tetra-ortho-
substituted biaryls have thus far only been accomplished with
palladium complexes derived from biphenyl monophosphines
1,4,5 tertiary phosphine 2,6 or N-heterocyclic carbenes (salt
3 or complex 4)7 as sterically demanding, electron-rich
† Georg-August-Universitaet.
(3) For a low-yielding early example, see: Johnson, M. G.; Foglesong,
R. J. Tetrahedron Lett. 1997, 38, 7001–7002.
‡ Ludwig-Maximilians-Universitaet.
(1) (a) Ackermann, L., Ed. Modern Arylation Methods; Wiley-VCH:
Weinheim, Germany, 2009. (b) Beller, M., Bolm, C., Eds. Transition Metals
for Organic Synthesis, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004.
(2) Select reviews: (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147–
168. (b) Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta 2008, 41, 59–72.
(c) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2008, 64, 3047–
3101. (d) Littke, A. F. In Modern Arylation Methods; Ackermann, L., Ed.;
Wiley-VCH: Weinheim, Germany, 2009; pp 25-68.
(4) (a) Demchuk, O. M.; Yoruk, B.; Blackburn, T.; Snieckus, V. Synlett
2006, 2908–2913. (b) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685–4696. (c) Walker,
S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2004, 43, 1871–1876. (d) Yin, J.; Rainka, M. P.; Zhang, X.-X.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1162–1163
(5) A review: Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed.
2008, 47, 6338–6361
.
.
10.1021/ol1000186  2010 American Chemical Society
Published on Web 02/04/2010

stabilizing ligands (Figure 1). Contrarily, heteroatom-
substituted phosphines were, to the best of our knowledge,
as of yet not employed as ligands for these challenging
transformations.
couplings, noteworthy limitations were represented by
unsatisfactory low conversions with sterically hindered
substrates, as well as the need for KOt-Bu as a strong base.
Given that more effective arylations of amines or R-C-H
acidic compounds could be achieved with sterically hindered
ligand 5c,10 we became interested in exploring its application
to challenging Suzuki-Miyaura couplings with sterically
congested substrates. Herein, we wish to report on these
studies, which resulted in the development of a catalytic
system for coupling reactions of aryl bromides as well as
aryl or alkenyl chlorides with CsF as a milder base.
Furthermore, these findings include the first use of a
heteroatom-substituted phosphine as ligand for syntheses of
tetra-ortho-substituted biaryls through Suzuki-Miyaura cou-
plings.
At the outset of our studies, we probed representative
chlorophosphines in the palladium-catalyzed synthesis of
tetra-ortho-substituted biaryl 8aa through Suzuki-Miyaura
coupling (Table 1). Preliminary experiments with diami-
Table 1. Chlorophosphines as Ligands in the Synthesis of
Tetra-ortho-Substituted Biaryl 8aaa
Figure 1. Ligands 1-3 and complex 4 for syntheses of tetra-ortho-
substituted biaryls.
Previously, we reported on applications of diaminochlo-
rophosphine 5a (Figure 2) as a ligand for palladium-catalyzed
Figure 2. Diaminochlorophosphine ligands 5a-c.
cross-coupling reactions of aryl halides.8,9 While this catalytic
system enabled the use of chloroarenes in Suzuki-Miyaura
(6) (a) Hoshi, T.; Saitoh, I.; Nakazawa, T.; Suzuki, T.; Sakai, J.-i.;
Hagiwara, H. J. Org. Chem. 2009, 74, 4013–4016. (b) Hoshi, T.; Nakazawa,
T.; Saitoh, I.; Mori, A.; Suzuki, T.; Sakai, J.-i.; Hagiwara, H. Org. Lett.
2008, 10, 2063–2066
.
(7) (a) Organ, M. G.; Calimsiz, S.; Sayah, M.; Hoi, K. H.; Lough, A. J.
Angew. Chem., Int. Ed. 2009, 48, 2383–2387. (b) Song, C.; Ma, Y.; Chai,
Q.; Ma, C.; Jiang, W.; Andrus, M. B. Tetrahedron 2005, 61, 7438–7446.
(c) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am. Chem.
Soc. 2004, 126, 15195–15201
.
(8) (a) Ackermann, L.; Born, R. Angew. Chem., Int. Ed. 2005, 44, 2444–
2447. For reviews, see: (b) Ackermann, L.; Born, R.; Spatz, J. H.;
Althammer, A.; Gschrei, C. J. Pure Appl. Chem. 2006, 78, 209–214. (c)
Ackermann, L. Synthesis 2006, 1557–1571. (d) Ackermann, L. Synlett 2007,
507–526. (e) Ackermann, L.; Althammer, A. Chem. Unserer Zeit. 2009,
a Reaction conditions: 1a (0.50 mmol), 2a (0.75 mmol), [Pd2(dba)3]
(2.0 mol %), L (8.0 mol %), base (1.50 mmol), 1,4-dioxane (2.0 mL), 20 h,
GC conversion. b Yield of isolated product.
43, 74–83
.
(9) For select related subsequent reports on heteroatom-substituted
secondary phosphine chlorides or oxides in catalyzed coupling reactions,
see: (a) Ackermann, L.; Gschrei, C. J.; Althammer, A.; Riederer, M. Chem.
Commun. 2006, 1419–1421. (b) Ackermann, L.; Althammer, A. Org. Lett.
2006, 8, 3457–3460. (c) Mai, W.; Lu, G.; Gao, L. Synlett 2007, 2247–
2251. (d) Ackermann, L.; Potukuchi, H. K. Synlett 2009, 2852–2856, and
nochlorophosphines 5 revealed 1,4-dioxane to be the solvent
of choice. While a variety of bases provided unsatisfactory
references cited therein
.
Org. Lett., Vol. 12, No. 5, 2010
1005

results (entries 1-8), cesium salts were found to be more
effective (entries 9 and 10), with CsF being optimal (entry
10). Unfortunately, diaminochlorophosphine 5a or 5b only
gave rise to significantly less efficient catalysis (entries 11
and 12), as was also observed for alkyl-substituted phosphine
chloride 911 (entry 13).
Scheme 2. Cross-Couplings with Chloroarenes 10
With an optimized catalytic system in hand, we explored
its scope for the preparation of various tetra-ortho-substituted
biaryls 8 (Scheme 1).
Scheme 1. Synthesis of Tetra-ortho-Substituted Biaryls 8
substituted biaryls 8av-8ax and 8ay-8az, respectively, were
obtained in high yields. Interestingly, the palladium catalyst
derived from diaminochlorophosphine 5c could be used for
the challenging synthesis of tetra-ortho-substituted products
8ag-8bc, as well.
We believe that the catalyst’s high efficacy in the
formation of tri- or tetra-ortho-substituted biaryls 8 is due
to the considerable steric bulk exerted by the substituents
on chlorophosphine 5c. Thereby, highly active monophos-
phine-coordinated palladium species12 are generated, a
feature that is reflected by the selective formation of
palladium(II) complex 11,13 the molecular structure of
a [Pd] (8.0 mol %).
Thus, diversely substituted products 8ab-8ai with valu-
able functional groups, such as esters, amides, or heteroare-
nes, could be prepared in good yields.
Moreover, the optimized palladium complex generated
from ligand 5c was not limited to bromoarenes 6 as
electrophiles but proved also applicable to the conversion
of less expensive chloroarenes 10 (Scheme 2). Contrary to
the previously reported catalytic system,8a CsF could be
employed as a mild base, thereby enabling the synthesis of
biaryls 8aj-8ao with various important functionalities.
Additionally, N-heteroaryl chlorides served as viable sub-
strates to yield biaryls 8ap-8ar. An intramolecular competi-
tion experiment highlighted an excellent chemoselectivity,
which resulted in the selective formation of biaryl 8as.
Further, ortho-substituted boronic acids also could be
employed to provide access to arylated arene 8at and alkene
8au.
(11) For representative examples of alkyl-substituted secondary phos-
phine chlorides or oxides in transition-metal-catalyzed arylation reactions,
see: (a) Ackermann, L.; Vicente, R.; Hofmann, N. Org. Lett. 2009, 11,
4274–4276. (b) Yang, D. X.; Colletti, S. L.; Wu, K.; Song, M.; Li, G. Y.;
Shen, H. C. Org. Lett. 2009, 11, 381–384. (c) Xu, H.; Ekoue-Kovi, K.;
Wolf, C. J. Org. Chem. 2008, 73, 7638–7650. (d) Wolf, C.; Xu, H. J. Org.
Chem. 2008, 73, 162–167. (e) Billingsley, K. L.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2008, 47, 4695–4698. (f) Zhang, Z.; Hu, Z.; Yu, Z.; Lei,
P.; Chi, H.; Wang, Y.; He, R. Tetrahedron Lett. 2007, 48, 2415–2419. (g)
Lerebours, R.; Wolf, C. Org. Lett. 2007, 9, 2737–2740. (h) Lerebours, R.;
Wolf, C. J. Am. Chem. Soc. 2006, 128, 13052–13053. (i) Lerebours, R.;
Camacho-Soto, A.; Wolf, C. J. Org. Chem. 2005, 70, 8601–8604. (j)
Ackermann, L. Org. Lett. 2005, 7, 3123–3125. (k) Wolf, C.; Lerebours, R.
Org. Lett. 2004, 6, 1147–1150. (l) Li, G. Y. J. Org. Chem. 2002, 67, 3643–
3650. (m) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513–1516.
(12) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366–
374.
(13) Palladium(II) complex 11 (1.0 mol %) provided biaryl 8an in 93%
with KOt-Bu as base, under otherwise identical reaction conditions, as
described in Scheme 2.
Importantly, ortho-substituted chloroarenes 10 were also
efficiently converted (Scheme 3). Hence, di- and tri-ortho-
(14) CCDC-757573 contains the supplementary crystallographic data
for complex 11. The 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 CB21EZ, UK; fax: (+44)1223-
336-033; or deposit@ccdc.cam.ac.uk).
(10) Ackermann, L.; Spatz, J. H.; Gschrei, C. J.; Born, R.; Althammer,
A. Angew. Chem., Int. Ed. 2006, 45, 7627–7630.
1006
Org. Lett., Vol. 12, No. 5, 2010

Scheme 3
.
Cross-Couplings with ortho-Substituted Aryl
Chlorides 10
Scheme 4. Synthesis and Molecular Structure of Complex 11
coupling reactions with sterically hindered substrates. Hence,
a palladium complex derived from a diaminochlorophosphine
enabled inter alia the synthesis of tetra-ortho-substituted
biaryls.
Acknowledgment. Support by the DFG and the DAAD
(fellowship to H.K.P.) is gratefully acknowledged.
a [Pd] (8.0 mol %), 110 °C, 24 h.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
which was confirmed by X-ray crystal structure analysis
(Scheme 4).14
In summary, we have reported on the use of a heteroatom-
substituted phosphine for challenging Suzuki-Miyaura cross-
OL1000186
Org. Lett., Vol. 12, No. 5, 2010
1007