Air-stable secondary phosphine oxide or chloride (Pre)ligands for cross-couplings of unactivated alkyl chlorides

Article abstract of DOI:10.1021/ol100658y

In situ generated and crystallographically well-defined, isolated palladium complexes derived from seven novel air-stable secondary phosphine oxides or chlorides enabled challenging Kumada-Corriu cross-couplings of unactivated alkyl chlorides bearing β-hy

Full text of DOI:10.1021/ol100658y

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2298-2301
Air-Stable Secondary Phosphine Oxide or
Chloride (Pre)Ligands for Cross-Couplings
of Unactivated Alkyl Chlorides
Lutz Ackermann,*,† Anant R. Kapdi,† and Carola Schulzke‡
Institut fu¨r Organische und Biomolekulare Chemie and Institut fu¨r Anorganische
Chemie, Georg-August-UniVersitaet, Tammannstrasse 2, 37077 Goettingen, Germany
lutz.ackermann@chemie.uni-goettingen.de
Received March 19, 2010
ABSTRACT
In situ generated and crystallographically well-defined, isolated palladium complexes derived from seven novel air-stable secondary phosphine
oxides or chlorides enabled challenging Kumada-Corriu cross-couplings of unactivated alkyl chlorides bearing ꢀ-hydrogens and proved
applicable to transformations of alkyl-substituted organometallics.
Transition-metal-catalyzed cross-coupling reactions represent
indispensable tools for the regioselective preparation of
substituted (hetero)arenes.1 Generally, organomagnesium
reagents are more readily available than alternative organo-
metallic nucleophiles.2 Therefore, catalytic cross-couplings
of Grignard reagents constitute valuable tools for streamlining
arene syntheses. Particularly, the development of stabilizing
ligands resulted in broadly applicable protocols for metal-
catalyzed transformations of aryl or alkenyl halides as
electrophiles.1 However, couplings of unactivated alkyl
halides, particularly when bearing ꢀ-hydrogens, continue to
be challenging, since facile ꢀ-hydride elimination leads to
undesired byproduct formation.3,4 Alkyl chlorides are argu-
ably the most useful class of alkyl halides due to their lower
costs, yet they are more difficult to activate because of the
inherently high C-Cl bond strength.5 As a consequence,
efficient palladium-catalyzed6 Kumada-Corriu cross-cou-
plings with unactivated alkyl chlorides7 were, to the best of
our knowledge, only accomplished with complexes derived
from either electron-rich tertiary phosphines8 or N-hetero-
cyclic carbenes9 as phosphine mimetics. Contrarily, sec-
(3) Reviews: (a) Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009,
48, 2656–2670. (b) Nakamura, M.; Ito, S. Modern Arylation Methods;
Ackermann, L., Ed.; Wiley-VCH: Weinheim, 2009; pp 155-181. (c) Terao,
J.; Kambe, N. Acc. Chem. Res. 2008, 41, 1545–1554. (d) Frisch, A. C.;
Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674–688. (e) Netherton, M. R.;
Fu, G. C. AdV. Synth. Catal. 2004, 346, 1525–1532. (f) Ca´rdenas, D. J.
Angew. Chem., Int. Ed. 2003, 42, 384–387.
(4) For pioneering early examples, see. (a) Ishiyama, T.; Abe, S.;
Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 691–694. (b) Devasagayaraj,
A.; Stuedemann, T.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1996, 34,
2723–2725.
(5) For select examples of pioneering studies on metal-catalyzed cross-
couplings with unactivated alkyl chlorides, see: (a) Kirchhoff, J.; Dai, C.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 1945–1947. (b) Netherton, M. R.;
Dai, C.; Neuschtz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099–
10100.
(6) For representative examples of the use of transition metals other than
palladium for couplings with unactivated alkyl chlorides, see: [Ni]. (a) Vechorkin,
O.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 9756–9766. (b) Terao,
J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc.
2002, 124, 4222–4223. [Fe] (c) Bedford, R. B.; Bruce, D. W.; Frost, R. M.;
Hird, M. Chem. Commun. 2005, 4161–4163. (d) Martin, R.; Fu¨rstner, A.
Angew. Chem., Int. Ed. 2004, 43, 3955–3957. (e) Nagano, T.; Hayashi, T.
Org. Lett. 2004, 6, 1297–1299. (f) Nakamura, M.; Matsuo, K.; Ito, S.;
Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686–3687. [Cu] (g) Cahiez,
G.; Gager, O.; Buendia, J. Synlett 2010, 299–303. (h) Terao, J.; Todo, H.;
Begum, S. A.; Kuniyasu, H.; Kambe, N. Angew. Chem., Int. Ed. 2007, 46,
2086–2089. [Co] (i) Ohmiya, H.; Yorimitsu, H.; Oshima, K. J. Am. Chem.
Soc. 2006, 128, 1886–1889, and references cited therein. See also, ref 2.
† Institut fu¨r Organische and Biomolekulare Chemie.
‡ Institut fu¨r Anorganische Chemie.
(1) (a) Ackermann, L., Ed. Modern Arylation Methods; Wiley-VCH:
Weinheim, 2009. (b) de Meijere, A.; Diederich, F., Eds. Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004.
(2) (a) Knochel, P., Ed. Handbook of Functionalized Organometallics;
Wiley-VCH: Weinheim, 2005. (b) Ila, H.; Baron, O.; Wagner, A. J.;
Knochel, P. Chem. Commun. 2006, 583–593.
10.1021/ol100658y  2010 American Chemical Society
Published on Web 04/20/2010

ondary phosphine oxides (SPO) or chlorides were thus
far not used for cross-couplings of unactivated alkyl
halides.10 Accordingly, we became interested in develop-
ing novel air-stable (pre)ligands for catalytic transforma-
tions of inexpensive alkyl chlorides, on which we wish
to report herein.
tory results (entries 1-5), as did biphenyl monophosphine
oxides 4e-4g (entries 6-8). Thus, we set out to prepare
new sterically hindered SPO preligands (Supporting Infor-
mation). Interestingly, air- and moisture-stable preligands 4h
(Figure 1) and 4i bearing either N-arylpyrrole or N-arylindole
At the outset of our studies, we tested representative
known11 secondary phosphine oxides 4 in the cross-coupling
of unactivated alkyl chloride 2a (Table 1). Unfortunately,
previously used preligands 4a-4d provided only unsatisfac-
Table 1. Ligand Optimization Studiesa
Figure 1.
Molecular structures of (pre)ligands 4h and 5b.13
substituents,12 respectively, outperformed the corresponding
biphenyl-based preligands 4e-4g (entries 6-10). Likewise,
air-stable secondary phosphine chloride 5a-5c (Figure 1)
allowed for high-yielding cross-couplings of alkyl chloride
(7) For select examples of palladium-catalyzed cross-couplings with
other alkyl (pseudo)halides, see: (a) Terao, J.; Naitoh, Y.; Kuniyasu, H.;
Kambe, N. Chem. Commun. 2007, 825–827. (b) Yang, L.-M.; Huang, L.-
F.; Luh, T.-Y. Org. Lett. 2004, 6, 1461–1463. (c) Terao, J.; Naitoh, Y.;
Kuniyasu, H.; Kambe, N. Chem. Lett. 2003, 32, 890–891, and references
cited therein.
(8) Frisch, A. C.; Shaikh, N.; Zapf, A.; Beller, M. Angew. Chem., Int.
Ed. 2002, 41, 4056–4059.
(9) Frisch, A. C.; Rataboul, F.; Zapf, A.; Beller, M. J. Organomet. Chem.
2003, 687, 403–409.
(10) Reviews: (a) Ackermann, L. Synlett 2007, 507–526. (b) Nemoto,
T.; Hamada, Y. Chem. Rec. 2007, 7, 150–158. (c) Ackermann, L. Synthesis
2006, 1557–1571. (d) Ackermann, L.; Born, R.; Spatz, J. H.; Althammer,
A.; Gschrei, C. J. Pure Appl. Chem. 2006, 78, 209–214. (e) Dubrovina,
N. V.; Bo¨rner, A. Angew. Chem., Int. Ed. 2004, 43, 5883–5886.
(11) For representative examples of alkyl-substituted secondary phos-
phine chlorides or oxides in transition-metal-catalyzed arylation reactions,
see: (a) Ackermann, L.; Potukuchi, H. K.; Kapdi, A. R.; Schulzke, C.
Chem.sEur. J. 2010, 16, 3300–3303. (b) Ackermann, L.; Vicente, R.;
Hofmann, N. Org. Lett. 2009, 11, 4274–4276. (c) Yang, D. X.; Colletti,
S. L.; Wu, K.; Song, M.; Li, G. Y.; Shen, H. C. Org. Lett. 2009, 11, 381–
384. (d) Xu, H.; Ekoue-Kovi, K.; Wolf, C. J. Org. Chem. 2008, 73, 7638–
7650. (e) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10,
2299–2302. (f) Wolf, C.; Xu, H. J. Org. Chem. 2008, 73, 162–167. (g)
Billingsley, K. L.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 4695–
4698. (h) Zhang, Z.; Hu, Z.; Yu, Z.; Lei, P.; Chi, H.; Wang, Y.; He, R.
Tetrahedron Lett. 2007, 48, 2415–2419. (i) Lerebours, R.; Wolf, C. Org.
´
Lett. 2007, 9, 2737–2740. (j) Ackermann, L.; Born, R.; Alvarez-Bercedo,
P. Angew. Chem., Int. Ed. 2007, 46, 6364–6367. (k) Lerebours, R.; Wolf,
C. J. Am. Chem. Soc. 2006, 128, 13052–13053. (l) Lerebours, R.; Camacho-
Soto, A.; Wolf, C. J. Org. Chem. 2005, 70, 8601–8604. (m) Ackermann,
L. Org. Lett. 2005, 7, 3123–3125. (n) Wolf, C.; Lerebours, R. Org. Lett.
2004, 6, 1147–1150. (o) Li, G. Y. J. Org. Chem. 2002, 67, 3643–3650. (p)
Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513–1516, and references cited
therein.
(12) For tertiary phosphines bearing 2-substituted N-heteroarenes, see:
(a) Sergeev, A. G.; Schulz, T.; Torborg, C.; Spannenberg, A.; Neumann,
H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 7595–7599. (b) Harkal,
S.; Rataboul, F.; Zapf, A.; Fuhrmann, C.; Riermeier, T.; Monsees, A.; Beller,
M. AdV. Synth. Catal. 2004, 346, 1742–1748. (c) Rataboul, F.; Zapf, A.;
Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees, A.; Dingerdissen, U.;
Beller, M. Chem.sEur. J. 2004, 10, 2983–2990. (d) Zapf, A.; Jackstell,
R.; Rataboul, F.; Riermeier, T.; Monsees, A.; Fuhrmann, C.; Shaikh, N.;
Dingerdissen, U.; Beller, M. Chem. Commun. 2004, 38–39. (e) Zapf, A.;
Beller, M. Chem. Commun. 2005, 431–440, and references cited therein.
a Reaction conditions: 1a (3.0 mmol), 2a (2.0 mmol), Pd(OAc)2 (4.0
mol %), L (4.0 mol %), NMP (5.0 mL); yields of isolated products. b Ar )
4-MeOC6H4.
Org. Lett., Vol. 12, No. 10, 2010
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2a (entries 11-13). Importantly, this remarkable catalytic
efficacy was not due to a potential formation of tertiary
phosphines 6a or 6b, as was illustrated through their indepen-
dent synthesis and use in catalysis (entries 14 and 15).
Subsequently, we probed the most active catalytic systems
in Kumada-Corriu cross-couplings of further unactivated
alkyl chlorides 2 (Table 2). Here, the catalyst derived from
Notably, the catalytic system exhibited a useful chemose-
lectivity, thereby tolerating valuable functional groups, such
as an ester (entry 14), a ketone (entries 15 and 16), or a
nitrile (entries 17 and 18). Thus, only minor amounts (<10%)
of products stemming from nucleophilic addition reactions
were observed.
A side reaction was represented by homocouplings of
alkyl chlorides 2, which was addressed through the use
of alkyl bromides as electrophiles, among others, with a
catalyst derived from preligand 4d (entries 5, 8, 11, and
13).
Table 2. Kumada-Corriu Cross-Couplings of Alkyl Chlorides
2a
Given the remarkable activity of palladium complexes
derived from ligands 5b and 5c, we explored their coordina-
tion chemistry. As a result, structurally well-defined com-
plexes 7a and 7b were prepared in high yields (Scheme 1).14
Scheme 1. Synthesis and Molecular Structure of Complexes 7
Notably, homobimetallic complex 7a highlighted a mono-
phosphine-coordinated palladium, a general15 feature of
relevance for achieving high efficacy in challenging cross-
coupling reactions.
a Reaction conditions: 1 (3.0 mmol), 2 (2.0 mmol), Pd(OAc)2 (4.0 mol
%), L (4.0 mol %), NMP (5.0 mL), 25 °C, 20 h. b Using n-AlkBr (2.0
mmol) instead of 2. c 60 °C.
Importantly, preformed palladium complexes 7a and 7b
showed an improved catalytic performance toward cross-
coupling of unactivated alkyl chloride 2a, which allowed the
use of a lower catalyst loading (Scheme 2).
Finally, isolated palladium catalysts 7a and 7b were
evaluated for cross-coupling reactions of alkyl-substituted
ligand 5b proved superior (entries 1-4), enabling the
synthesis of various regioselectively alkylated arenes 3.
(14) CCDC-731586 contains the supplementary crystallographic data
for palladium(II) complex 7a. The data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax
(+44)1223-336-033; or deposit@ccdc.cam.ac.uk).
(13) CCDC-713169 and CCDC-715042 contain the supplementary
crystallographic data for (pre)ligands 4h and 5b, respectively. 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).
(15) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366–
374.
2300
Org. Lett., Vol. 12, No. 10, 2010

organometallic nucleophiles (Table 3). Here, complex 7a
provided optimal results in Kumada-Corriu reactions of
aromatic11 electrophiles 2 (entries 1-4). Notably, catalyst
7a was not restricted to the use of basic Grignard reagents
as nucleophilic substrates but also proved applicable to the
synthesis of functionalized arenes 3t-3y through Negishi16
cross-coupling technology (entries 9-14).17
Table 3. Kumada-Corriu and Negishi Cross-Couplings with
Alkyl-Substituted Nucelophiles 1a
Scheme 2. Cross-Couplings with Isolated Complexes 7
In summary, we have reported on the synthesis of seven
novel air-stable secondary phosphine oxide or chloride
(pre)ligands and their unprecedented use in challenging cross-
couplings of unactivated alkyl halides. Specifically, in situ
generated as well as isolated well-defined complexes of
secondary phosphine chlorides enabled Kumada-Corriu
cross-coupling of alkyl chlorides bearing ꢀ-hydrogens and
could be employed for C(sp2)-C(sp3) bond formations
through cross-couplings with alkyl magnesium or alkyl zinc
reagents.
Acknowledgment. Support by the DFG and the Alex-
ander-von-Humboldt foundation (fellowship to A.K.) is
gratefully acknowledged.
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.
OL100658Y
(16) For representative examples of Negishi cross-coupling reactions,
see: (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980,
102, 3298–3299. (b) Thaler, T.; Haag, B.; Gavryushin, A.; Schober, K.;
Hartmann, E.; Gschwind, R. M.; Zipse, H.; Mayer, P.; Knochel, P. Nat.
Chem. 2010, 2, 125–130, and references cited therein.
a Reaction conditions. Kumada-Corriu: ArBr (1.0 mmol), ArMgX (1.5
mmol), 7 (2.0 mol %), THF (2.0 mL), 60 °C, 24 h. Negishi: ArI (1.0 mmol),
ArZnCl (1.5 mmol), 7a (2.0 mol %), THF (2.0 mL), 60 °C, 24 h.
(17) As of yet, couplings of aryl chlorides as well as C(sp3)-C(sp3)
bond-forming reactions proceeded with lower efficacies.
Org. Lett., Vol. 12, No. 10, 2010
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