Negishi cross-couplings of unsaturated halides bearing relatively acidic hydrogen atoms with organozinc reagents

Article abstract of DOI:10.1021/ol8009013

(Chemical Equation Presented) A wide range of polyfunctional aryl, heteroaryl, alkyl, and benzylic zinc reagents were coupled with unsaturated halides bearing an acidic NH or OH function, using Pd(OAc)₂ (1 mol %) and S-Phos (2 mol %) as catalyst without the need of protecting groups.

Full text of DOI:10.1021/ol8009013

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2765-2768
Negishi Cross-Couplings of Unsaturated
Halides Bearing Relatively Acidic
Hydrogen Atoms with Organozinc
Reagents
Georg Manolikakes, Matthias A. Schade, Carmen Mun˜oz Hernandez,
Herbert Mayr, and Paul Knochel*
Department Chemie and Biochemie, Ludwig-Maximilians-UniVersita¨t,
Butenandtstrasse 5-13, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received April 18, 2008
ABSTRACT
A wide range of polyfunctional aryl, heteroaryl, alkyl, and benzylic zinc reagents were coupled with unsaturated halides bearing an acidic NH
or OH function, using Pd(OAc)2 (1 mol %) and S-Phos (2 mol %) as catalyst without the need of protecting groups.
Pd-catalyzed cross-couplings that allow linking of unsatur-
ated molecular fragments are of central importance in
synthetic organic chemistry. The resulting products are highly
relevant for applications in the pharmaceutical or agrochemi-
cal industry, as well as for the preparation of new materials.1
The most popular Pd-catalyzed cross-coupling, the Suzuki
cross-coupling, uses as substrates boronic acids or deriva-
tives2 and is compatible with many functional groups,
especially with functional groups bearing relatively acidic
hydrogens such as amines,3 anilines,4 alcohols,5 or hetero-
cyclic NH groups.6 Due to the covalent nature of the C-B
bond of boronic acids, these cross-couplings proceed as a
rule under harsher conditions as the corresponding cross-
couplings using organozincs (Negishi cross-couplings).7
Although organozinc reagents are reactive toward acidic
hydrogens, herein we report reaction conditions and a
catalytic system allowing an efficient cross-coupling between
various organozinc reagents (1) and a broad range of aryl
halides bearing relatively acidic NH or OH groups of type
2, leading to polyfunctional products of type 3 (Scheme 1).
Scheme 1. Pd-Catalyzed Cross-Couplings between
Functionalized Zinc Reagents and Aromatic Substrates Bearing
an Acidic NH or OH Function
(1) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere,
A., Diederich, F., Eds., Wiley-VCH: Weinheim, 2004. (b) Tsuji, J. Transition
Metal Reagents and Catalysts: InnoVations in Organic Synthesis; Wiley:
Chichester, 1995. (c) Transition Metal Reagents and Catalysts: InnoVations
in Organic Synthesis; Beller, M., Bolm, M., Eds.; Wiley-VCH: Weinheim,
1998. (d) Miyaura, N., Ed. Cross-Coupling Reactions. A Practical Guide
Top. Curr. Chem. 2002, 219.
(2) (a) Miyaura, N.; Suzuki, A. Chem. Rec. 1995, 95, 2457. (b) Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387. (c) Wolfe, J. P.;
Buchwald, S. P. Angew. Chem., Int. Ed. 1999, 38, 2413. (d) Zapf, A.;
Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000, 39, 4153. (e)
Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
(3) Villard, A.-L.; Warrington, B. R.; Ladlow, M J. Comb. Chem. 2004,
6, 611.
Preliminary experiments show that a range of active catalyst
systems8 allow the cross-coupling of arylzinc halides with
various bromoanilines. However, we have found that S-Phos
(4) Miura, Y.; Oka, H.; Momoki, M. Synthesis 1995, 11, 1419.
10.1021/ol8009013 CCC: $40.75
Published on Web 06/05/2008
2008 American Chemical Society

(4), introduced by Buchwald,9 affords reproducible results
for a broad range of substrates under mild conditions. Thus,
the reaction of 4-cyanophenylzinc iodide (1a, 1.2 equiv) with
2-amino-5-bromobenzoic acid methyl ester (2a, 1.0 equiv)
in the presence of Pd(OAc)2 (1 mol %) and S-Phos (4, 2
mol %) provides the desired cross-coupling product 3a within
2 h at 25 °C in 98% isolated yield (entry 1 of Table 1). The
relatively acidic NH2 protons10 of 2a do not disturb the cross-
coupling reaction, which obviously occurs faster than the
competitive deprotonation of the aniline 2a with the zinc
reagent 1a. The use of S-Phos (4) as ligand is crucial and
allows a generalization of these results to various zinc
reagents. Thus, the arylzinc iodide 1b prepared by the direct
insertion of zinc in the presence of LiCl11 reacts smoothly
with the bromoanilines 2b within 2 h at 25 °C, leading to
the biphenyl aniline 3b in 87% yield (entry 2). Interestingly,
this behavior can be extended to functionalized alkylzinc
bromides prepared similarly by direct zinc insertion.11 Thus,
the cyano- and ester-substituted alkylzinc bromides 1c and
1d (1.2 equiv) react with the bromoanilines 2a and 2c (1.0
equiv), affording the substituted anilines 3c and 3d in 98%
and 73% yield (2 h, 25 °C, entries 3 and 4). In addition, the
functionalized benzylic zinc reagent 1e, prepared by direct
zinc insertion into benzylic chlorides,12 reacts with the
bromide 2c in 1 h at 25 °C, leading to the diarylmethane 3e
in 88% yield (entry 5). In the case of the secondary amine
2d, the cross-coupling occurs also satisfactorily. The depro-
tonation of these less acidic amines (pKa ∼ 40)10 is not a
concern; however, we have observed a palladium catalyst
desactivation due to the high donor ability of these amines.
The reaction temperature has therefore to be increased to
65 °C (16 h), providing the polyfunctional amine 3f in 78%
yield (entry 6). 5-Bromoindole (2e) was also suitable for the
cross-coupling procedure, leading to the arylated indoles 3g
and 3h in 85% and 94% yield (25 °C, 1 h, entries 7 and
8).13 Encouraged by these results, we have investigated
various unsaturated bromides bearing an alcohol function.
To evaluate the kinetic basicity of various types of zinc
reagents with alcohols, we have treated an equimolar mixture
of PhZnI·LiCl (1j), PhCH2ZnCl·LiCl (1k), and OctZnBr·LiCl
(1 L) with various amounts of 2-propanol (Scheme 2).
Scheme 2.
Selective Protonation of Organozinc Reagentsa
aYields are determined by quenching with CuCN/allyl bromide in THF
and GC analysis with n-tetradecane as internal standard.
Interestingly, we have observed that a chemoselective
protonation occurs. Thus, after the addition of 1 equiv of
i-PrOH at -10 °C, 80% of PhZnI·LiCl (1j) and 20% of
OctZnBr·LiCl (1 L) were protonated, whereas almost no
protonation of PhCH2ZnCl·LiCl (1k) was observed. After
the addition of the second equivalent of i-PrOH, the
protonation of more than 97% of PhZnI·LiCl (1j) and 90%
of OctZnBr·LiCl (1l) was observed. These results indicate
the relative kinetic basicity of zinc reagents: arylzinc halide
> alkylzinc halide > benzylzinc halide.14
Thus, adding 2-chlorobenzylzinc chloride (1f, 1.2 equiv)
slowly over 90 min (via syringe pump) to a solution of
4-bromobenzyl alcohol (2f, 1.0 equiv), Pd(OAc)2 (1 mol %),
and S-Phos (4, 2 mol %) led to the cross-coupling product
3i in 98% yield (entry 9 of Table 1). The slow addition of
the zinc reagent was crucial for obtaining a high yield. Also,
the aniline derivative 2g and the substituted indole 2h,
bearing relatively acidic NH and OH protons, react with the
benzylzinc chlorides 1g and 1h, leading to the coupling
products 3j and 3k in 64% and 72% yield (entries 10 and
11). To our delight, even more acidic phenolic protons were
tolerated by our protocol. Adding 2-chlorobenzylzinc chlo-
ride (1f, 1.3 equiv) slowly (over 90 min) to a solution of
4-bromophenol (2i, 1 equiv), Pd(OAc)2 (1 mol %), and
S-Phos (4, 2 mol %) provided the phenol 3l in 98% yield
(entry 12). Similarly, the benzylzinc chlorides 1f and 1i react
smoothly with 5-bromosalicylaldehyde (2j), leading to the
polyfunctional phenols 3m and 3n in 81% and 73% yield
(entries 13 and 14). The more basic arylzinc reagents 1a and
1b reacted only with the sterically hindered tertiary iodo-
benzyl alcohol 2k, furnishing the biaryls 3o and 3p in 78%
and 87% yield (entries 15 and 16). The less basic alkylzinc
bromide 1c could be coupled with the less hindered second-
ary iodobenzyl alcohol 2i, leading to the benzylic alcohol
(5) Baxendale, I. R.; Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. C.
Chem. Eur. J. 2006, 12, 4407.
(6) Prieto, M.; Zurita, E.; Rosa, E.; Munoz, L.; Lloyd-Williams, P.;
Giralt, E. J. Org. Chem. 2004, 69, 6812.
(7) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (b) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (c) Zeng,
X.; Quian, M.; Hu, Q.; Negishi, E. Angew. Chem., Int. Ed. 2004, 43, 2259.
(8) Using Ni(acac)2 (2 mol %)/bipyridine (3 mol %), some substrates
could be coupled at elevated temperature with similar yields.
(9) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871. (b) Martin, R.; Buchwald, S. L.
J. Am. Chem. Soc. 2007, 129, 3844. (c) Barder, T. E.; Buchwald, S. L.
J. Am. Chem. Soc. 2007, 129, 5096. (d) Biscoe, M. R.; Barder, T. E.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7232. (e) Other ligands
tested gave lower yields.
(10) Typical pKa values (in DMSO) for anilines range between 20-30;
for a comprehensive compilation of pKa data, see http://www.chem.wisc.edu/
areas/reich/pkatable/index.htmand references cited therein.
(11) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 6040.
(12) Metzger, A.; Schade, M. A.; Knochel, P. Org. Lett. 2008, 10, 1107.
(13) However, for the coupling of 5-bromoindole (2j), the zinc reagents
1a and 1b had to be prepared by transmetalation from the corresponding
magnesium reagents. Control experiments have revealed accelerated cross-
coupling reactions in the presence of magnesium salts. For the preparation
of organomagnesium reagents, see:(a) Knochel, P.; Gommermann, N.;
Kneisel, F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem.,
Int. Ed. 2003, 42, 4302. (b) Krasovskiy, A.; Knochel, P. Angew. Chem.,
Int. Ed. 2004, 43, 3333.
(14) (a) For the reactivity of 1,1-bimetallic species toward protonation,
see also: Knochel, P.; Normant, J. F. Tetrahedron Lett. 1986, 27, 1043.
2766
Org. Lett., Vol. 10, No. 13, 2008

Table 1. Pd-Catalyzed Cross-Couplings between Functionalized Zinc Reagents and Aromatic Substrates Bearing an Acidic NH or OH
Function
a Reaction time at 25 °C. b Isolated yield of analytically pure product. c Reaction temperature 65 °C.
Org. Lett., Vol. 10, No. 13, 2008
2767

functionalized unsaturated alcohol 6 in 91% yield (Scheme
3).
Scheme 3. Pd-Catalyzed Cross-Couplings between the
Functionalized Benzylic Zinc Reagent (1m) and the Cyclopentyl
Iodide 5 Bearing an Acidic OH Function
Acknowledgment. We thank the SFB 749 (DFG) for a
financial support. We thank Umicore AG (Angleur, Belgium)
for the generous gift of zinc powder. We also thank
Chemetall GmbH (Frankfurt), Evonik Industries AG (Hanau),
and BASF AG (Ludwigshafen) for the generous gift of
chemicals.
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
information is available free of charge via Internet at
http://pubs.acs.org.
3q in 88% yield (entry 17). In addition, 2-iodocyclopent-2-
enol (5) could be coupled with 2-chlorobenzylzinc chloride
(1f, 1.2 equiv, slow addition over 90 min) to afford the
OL8009013
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Org. Lett., Vol. 10, No. 13, 2008