C-H bond arylations and benzylations on oxazol(in)es with a palladium catalyst of a secondary phosphine oxide

Article abstract of DOI:10.1021/ol200986x

An air-stable, well-defined palladium complex derived from secondary phosphine oxide (SPO) (1-Ad)₂P(O)H enabled efficient C-H bond functionalizations with ample scope, which set the stage for direct arylations and benzylations of (benz)oxazoles, as well as unprecedented palladium-catalyzed C-H bond arylations on nonaromatic oxazolines.

Full text of DOI:10.1021/ol200986x

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3082–3085
CꢀH Bond Arylations and Benzylations
on Oxazol(in)es with a Palladium Catalyst
of a Secondary Phosphine Oxide
€
Lutz Ackermann,* Sebastian Barfusser, Christoph Kornhaass, and Anant R. Kapdi
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received April 14, 2011
ABSTRACT
An air-stable, well-defined palladium complex derived from secondary phosphine oxide (SPO) (1-Ad)2P(O)H enabled efficient CꢀH bond
functionalizations with ample scope, which set the stage for direct arylations and benzylations of (benz)oxazoles, as well as unprecedented
palladium-catalyzed CꢀH bond arylations on nonaromatic oxazolines.
Secondary phosphine oxides (SPOs) are air- and moist-
ure-stable preligands, which form in a self-assembly pro-
cess late transition metal complexes bearing hydrogen
Scheme 1. Synthesis of Complex 1 via a Self-Assembly Process
bond-stabilized bidentate ligands (Scheme 1).1 In recent
years, these complexes were shown to be remarkably active
catalysts for traditional cross-coupling reactions between
aryl (pseudo)halides and organometallic reagents.2 For
(1) Reviews: (a) Ackermann, L. Isr. J. Chem. 2010, 50, 652–663.
(b) Ackermann, L. Synthesis 2006, 1557–1571. (c) Ackermann, L.; Born,
R.; Spatz, J. H.; Althammer, A.; Gschrei, C. J. Pure Appl. Chem. 2006,
78, 209–214. (d) Dubrovina, N. V.; Borner, A. Angew. Chem., Int. Ed.
2004, 43, 5883–5886. See also: (e) Nemoto, T.; Hamada, Y. Tetrahedron
2011, 67, 667–687.
(2) For representative examples, see: (a) Hu, D.-F.; Weng, C.-M.;
Hong, F.-E. Organometallics 2011, 30, 1139–1147. (b) Ackermann, L.;
Kapdi, A. R.; Schulzke, C. Org. Lett. 2010, 12, 2298–2301. (c) Ack-
ermann, L.; Vicente, R.; Hofmann, N. Org. Lett. 2009, 11, 4274–4276.
(d) Yang, D. X.; Colletti, S. L.; Wu, K.; Song, M.; Li, G. Y.; Shen, H. C.
Org. Lett. 2009, 11, 381–384. (e) Xu, H.; Ekoue-Kovi, K.; Wolf, C.
J. Org. Chem. 2008, 73, 7638–7650. (f) Wolf, C.; Xu, H. J. Org. Chem.
2008, 73, 162–167. (g) Lerebours, R.; Camacho-Soto, A.; Wolf, C.
J. Org. Chem. 2005, 70, 8601–8604. (h) Li, G. Y. Angew. Chem., Int.
Ed. 2001, 40, 1513–1516. See also: (i) Ackermann, L.; Kapdi, A. R.;
Fenner, S.; Kornhaass, C.; Schulzke, C. Chem.;Eur. J. 2011, 17, 2965–
2971. (j) Ackermann, L.; Potukuchi, H. K. Synlett 2009, 2852–2856.
(3) Ackermann, L.; Potukuchi, H. K.; Kapdi, A. R.; Schulzke, C.
Chem.;Eur. J. 2010, 16, 3300–3303.
instance, particularly palladium(II) complex 1 allowed
for challenging arylations of 2-pyridyl Grignard reagents
with low nucleophilicities.3
€
Within our program directed toward more sustainable
syntheseswithoutprefunctionalizedstarting materials,4 we
observed that complex 1 serves as efficient catalyst for
economically and ecologically more attractive direct CꢀH
bond functionalizations.5ꢀ7 Thus, phosphinous acid com-
plex 1 allowed among others for efficient direct benzyla-
tions of azoles, as well as first palladium-catalyzed direct
arylations8 of challenging oxazolines;versatile building
blocks in organic synthesis.9
At the outset of our studies, we evaluated the efficacy
of representative palladium catalysts in the direct
(4) (a) Ackermann, L. Pure Appl. Chem. 2010, 82, 1403–1413.
(b) Ackermann, L. Synlett 2007, 507–526.
r
10.1021/ol200986x
Published on Web 05/18/2011
2011 American Chemical Society

palladium(II) complex 1 provided a significantly improved
yield of desired product 4a (entry 15).
Table 1. Optimization of Direct Benzylation of Oxazole 2aa
Subsequently, we testedair-stablecomplex1 inthe direct
benzylation of heteroarenes 2 with differently substituted
benzyl chlorides 3 (Scheme 2). Hence, we observed that
valuable electrophilic functional groups were well toler-
ated by the catalyst.
entry
[Pd]
L (mol %)
yield
Scheme 2. Scope of Direct Benzylation of Azoles 2
1
ꢀ
ꢀ
ꢀ
ꢀ
2
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
Pd(OAc)2
ꢀ
54%
75%
59%
(15%)b
16%
32%
74%
61%
62%
43%
51%
69%
97%
3
X-Phos (10)
SHIPrCl (5.0)
HIPrCl (5.0)
Xantphos (5.0)
dppf (5.0)
4
5
6
7
8
rac-BINAP (5.0)
dppe (5.0)
9
10
11
12
13
14
15
HIPrCl (10)
John-Phos (10)
Dave-Phos (10)
dppe (5.0)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[Pd(SIPr)(3-ClPy)Cl2]
1
ꢀ
ꢀ
a Reaction conditions: 2a (1.0 mmol), 3a (1.0 mmol), [Pd] (5.0 mol
%), L (5.0ꢀ10 mol %), Cs2CO3 (2.0 mmol), 1,4-dioxane (3.0 mL),
110 °C, 18 h; X-Phos = 2-dicyclohexylphosphino-20,40,60-triisopropyl-
biphenyl; (S)HIPr = N,N0-bis-(2,6-diisopropylphenyl)imidazol(in)ium;
John-Phos = 2-(dicyclohexylphosphino)biphenyl; Dave-Phos = 2-di-
cyclohexylphosphino-20-(N,N-dimethylamino)biphenyl; isolated yields.
b GC-conversion.
Moreover, complex 1 also proved applicable to the
challenging conversion of benzyl phosphate 5a as electro-
phile (Scheme 3). Importantly, the yield of product 4a
turned out to be improved as compared to a previously
reported catalytic system (dppe as the ligand: 69%).10g
benzylation10 of oxazole 2a (Table 1). Among various
palladium catalysts, promising results were accomplished
with in situ generated or preformed palladium complexes
derived from N-heterocyclic carbenes (entries 4, 5, 10, and
14) or bidentate ligand dppe (entries 9, and 13). However,
Scheme 3. Direct Benzylation with Phosphate 5a as Electrophile
(5) Select recent reviews on metal-catalyzed CꢀH bond functionali-
zations: (a) Hartwig, J. F. Chem. Soc. Rev. 2011, 40, 1992–2002.
(b) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976–
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Hartwig, J. F. Chem. Rev. 2010, 110, 890–931. (f) Willis, M. C. Chem.
Rev. 2010, 110, 725–748. (g) Ackermann, L.; Potukuchi, H. K. Org.
Biomol. Chem. 2010, 8, 4503–4513. (h) Daugulis, O. Top. Curr. Chem.
2010, 292, 57–84. (i) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun.
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O. Chem.;Eur. J. 2010, 16, 2654–2672. (m) Lei, A.; Liu, W.; Liu, C.;
Chen, M. Dalton Trans. 2010, 39, 10352–10361. (n) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169. (o) Dudnik, A. S.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2096–2098. (p) Giri, R.;
Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev 2009, 38,
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L.; Vicente, R; Kapdi, A. Angew. Chem., Int. Ed 2009, 48, 9792–9826.
(t) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009,48, 5094–5115. (u) Thansandote, P.; Lautens, M. Chem.;Eur. J. 2009,
15, 5874–5883. (v) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res.
2009, 42, 1074–1086. (w) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013–3039.
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cited therein.
It is noteworthy that subsequent direct benzylations10h
and alkylations on product 4l occurred even in the absence
(6) For (heteroatom-substituted) secondary phosphine oxides in
CꢀH bond functionalizations on indoles, see: (a) Ackermann, L.;
€
Barfusser, S. Synlett 2009, 808–812. (b) Zhang, Z.; Hu, Z.; Yu, Z.; Lei,
P.; Chi, H.; Wang, Y.; He, R. Tetrahedron Lett. 2007, 48, 2415–2419.
For the use of a palladium catalyst derived from a secondary phosphine
chloride in combination with Cu(Xantphos)I, see: (c) Huang, J.; Chan,
J.; Chen, Y.; Borths, C. J.; Baucom, K. D.; Larsen, R. D.; Faul, M. M.
J. Am. Chem. Soc. 2010, 132, 3674–3675.
(7) For SPO (1-Ad)2P(O)H as preligand in ruthenium-catalyzed
CꢀH bond functionalizations, see: (a) Ackermann, L.; Vicente, R.;
Althammer, A. Org. Lett. 2008, 10, 2299–2302. (b) Ackermann, L. Org.
Lett. 2005, 7, 3123–3125.
(8) For a very recent example of palladium-catalyzed direct alkynyla-
tion, see: Kim, S. H.; Chang, S. Org. Lett. 2010, 12, 1868–1871.
(9) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297–2360.
Org. Lett., Vol. 13, No. 12, 2011
3083

Table 2. Optimization of Direct Arylation on Oxazoline 8aa
Scheme 4. Metal-Free Direct Benzylation and Alkylation of a
C(sp3)ꢀH Bond
entry
[Pd]
L (mol %)
base (equiv)
yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
ꢀ
LiOt-Bu (2.0)
LiOt-Bu (2.0)
11
23
37
35
24
53
18
31
70
of transition metal catalysts at the activated benzhydryl-
type position (Scheme 4).
Pd(OAc)2 PCy3 (10)
Pd(OAc)2 rac-BINAP (5.0) LiOt-Bu (2.0)
The well-defined complex 1 was not limited to direct
benzylations, but allowed for efficient CꢀH bond aryla-
tions11 on oxazole 2a as well (Scheme 5). Notably, the
catalysts broad substrate scope included sterically demand-
ing ortho-substituted electrophiles as well as heteroaryl
bromides 6.
Pd(OAc)2 Xantphos (5.0)
Pd(OAc)2 dppf (5.0)
Pd(OAc)2 dppp (5.0)
LiOt-Bu (2.0)
LiOt-Bu (2.0)
LiOt-Bu (2.0)
KOt-Bu (2.5)
NaOt-Bu (2.5)
LiOt-Bu (2.5)
1
1
1
ꢀ
ꢀ
ꢀ
a Reaction conditions: 8a (0.5 mmol), 6a (1.0 mmol), [Pd] (5.0
mol %), base, DMA, 100 °C, 14ꢀ20 h; isolated yields.
Scheme 5. Scope of Direct Arylations
ligands in the direct arylation of oxazoline 8a (Table 2).
Interestingly, complex 1 outperformed palladium com-
plexes derived from representative mono- or bidentate
phosphine ligands (entries 1ꢀ6), including Xantphos
(entry 4), which was previously employed for palladium-
catalyzed direct alkynylations.8 Among a variety of bases,
LiOt-Bu provided most satisfactory results, whereas the
use of K2CO3, Cs2CO3, Rb2CO3 or K3PO4 gave no desired
product 9a.13 Webelievethatthe remarkably high catalytic
activity exerted by complex 1 is due to the bidentate,
(11) For recent progress in transition-metal-catalyzed direct aryla-
tions of heteroarenes, see: (a) Kirchberg, S.; Tani, S.; Ueda, K.;
Yamaguchi, J.; Studer, A.; Itami, K. Angew. Chem., Int. Ed. 2011, 50,
2387–2391. (b) Wagner, A. M.; Sanford, M. S. Org. Lett. 2011, 13, 288–
291. (c) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 3308–3311.
(d) Nadres, E. T.; Lazareva, A.; Daugulis, O. J. Org. Chem. 2011, 76,
471–483. (e) Ackermann, L.; Fenner, S. Chem. Commun. 2011, 47, 430–
432. (f) Ueda, K.; Yanagisawa, S.; Yamaguchi, J.; Itami, K. Angew.
Chem., Int. Ed. 2010, 49, 8946–8949. (g) Seiple, I. B.; Su, S.; Rodriguez,
R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am.
Chem. Soc. 2010, 132, 13194–13196. (h) Roy, D.; Mom, S.; Beauperin,
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H.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2010, 49,
2202–2205. (k) Ackermann, L.; Vicente, R. Org. Lett. 2009, 11, 4922–
4925. (l) Kim, M.; Kwak, J.; Chang, S. Angew. Chem., Int. Ed. 2009, 48,
8935–8939. (m) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-
Laperle, M.; Villemure, E.; Sun, H.-Y.; Lasserre, S.; Guimond, N.;
Lecavallier, M.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291–3306. (n)
Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem., Int. Ed. 2009,
48, 201–204. (o) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.;
Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1473–1476. (p) Turner, G. L.;
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12405 and references cited therein.
In recent years, significant progress was made in direct
arylations of heteroarenes.5,11 On the contrary, a palla-
dium-catalyzed12 CꢀH bond arylation of nonaromatic
oxazolines was as of yet not reported, despite of their
practical importance as key intermediates in synthetic
organic chemistry.9 Consequently, we tested different
(10) Direct benzylations under basic reaction conditions were only
ꢀ
recently developed. [Ru]: (a) Ackermann, L.; Novak, P. Org. Lett. 2009,
ꢀ
11, 4966–4969. (b) Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N.
Angew. Chem., Int. Ed. 2009, 48, 6045–6048. (c) Ackermann, L.;
Hofmann, N.; Vicente, R. Org. Lett. 2011, 13, 1875–1877. [Pd]: (d)
Lapointe, D.; Fagnou, K. Org. Lett. 2009, 11, 4160–4163. (e) Verrier, C.;
Hoarau, C.; Marsais, F. Org. Biomol. Chem. 2009, 7, 647–650. (f) Zhang,
Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 6097–6100.
(12) For an example of an elegant rhodium-catalyzed CꢀH bond
functionalization, see: (a) Lewis, J. C.; Wiedemann, S. H.; Bergman,
R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35–38. (b) Lewis, J. C.; Berman,
A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493–
2500.
€
(g) Ackermann, L.; Barfusser, S.; Pospech, J. Org. Lett. 2010, 12, 724–
726. (h) Mukai, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12,
1360–1363. (i) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Chem.;Eur. J.
2010, 16, 12307–12311. (j) Shabashov, D.; Daugulis, O. J. Am. Chem.
Soc. 2010, 132, 3965–3972. A review: (k) Ackermann, L. Chem.
Commun. 2010, 46, 4866–4877.
(13) This result is indicative of a reaction manifold involving an initial
in situ deprotonation with the base LiOt-Bu.
3084
Org. Lett., Vol. 13, No. 12, 2011

monoanionic nature of the self-assembled, sterically de-
manding ligand.
Scheme 6. Scope of Direct Arylations of Oxazolines 8
With optimized reaction conditions in hand, we probed
the scope of direct arylations of oxazolines 8 employing
aryl halides 6 (Scheme 6). Interestingly, complex 1 proved
applicable to CꢀH bond arylations with functionalized as
well as sterically congested ortho-substituted aryl bromides
or chlorides 6. Likewise, differently substituted oxazolines
8 were found to be viable substrates.
In summary, we have reported on the use of an air-stable
palladium complex derived from a sterically hindered SPO
preligand for high-yielding CꢀH bond functionalizations
of heterocycles. Thus, a phosphinous acid complex en-
abled efficient direct arylations and benzylations of
(benz)oxazoles, as well as first palladium-catalyzed direct
arylations of oxazolines with ample scope.
Acknowledgment. Support by the DFG, the CaSuS
(Catalysis for Sustainable Synthesis) PhD program
(fellowship to C.K.), and the Alexander-von-Humboldt
foundation (fellowship to A.R.K.) is gratefully acknow-
ledged.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 12, 2011
3085