One-pot Negishi cross-coupling reactions of in situ generated zinc reagents with aryl chlorides, bromides, and triflates

Article abstract of DOI:10.1021/jo801063c

(Chemical Equation Presented) In situ generated aryl, heteroaryl, alkyl, or benzylic poly-functional zinc reagents obtained by the addition of zinc and LiCl to the corresponding organic iodides undergo smooth Pd(0)-catalyzed cross-coupling reactions with

Full text of DOI:10.1021/jo801063c

SCHEME 1. Preliminary Experiments of One-Pot Negishi
Cross-Coupling Reaction
One-Pot Negishi Cross-Coupling Reactions of In
Situ Generated Zinc Reagents with Aryl
Chlorides, Bromides, and Triflates
Shohei Sase, Milica Jaric, Albrecht Metzger,
Vladimir Malakhov, and Paul Knochel*
Department Chemie & Biochemie,
Ludwig-Maximilians-UniVersita¨t Mu¨nchen, Butenandtstr.
5-13, Haus F, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
ReceiVed May 21, 2008
organometallics have, however, the drawback of being air- and
moisture-sensitive. Recently, we have developed a very efficient
LiCl-mediated direct insertion of zinc into unsaturated halides.5
Using this method, we wish to report a one-pot protocol avoiding
the handling of sensitive organozinc intermediates.
In preliminary experiments, we have treated ethyl 4-iodo-
benzoate (1a, 1.0 equiv) with zinc dust (3.0 equiv) and LiCl
(3.0 equiv) in THF, resulting in the formation of the zinc reagent
2a at 50 °C within 3 h (>98% conversion, Scheme 1). To this
mixture, we have added 3-bromobenzonitrile (3a, 0.8 equiv) as
well as Pd(PPh3)4 (0.3 mol %). After 15 h reaction time at 25
°C, we have obtained the desired cross-coupling product 4a in
79% isolated yield. There was no need to remove the excess of
zinc powder for performing the cross-coupling. We have
improved these initial reaction conditions by reducing the zinc
dust and LiCl amount (1.5 equiv) and by optimizing the Pd
catalyst. In our hands, PEPPSI, introduced by Organ, displays
the broader applicability.6 Shorter reaction times and higher
yields are generally obtained (Scheme 1 and Table 1).
Thus, we have prepared in situ a variety of arylzinc reagents
bearing an ester group (derived from 1a or 1b; entries 1 and 2)
or a nitrile (derived from 1c or 1d; entries 3-5). In all cases,
the Negishi cross-coupling reaction occurs smoothly using 0.8
equiv of an aromatic bromide or chloride, affording the desired
cross-coupling products 4b-f in 80-91% yields. An ortho-
substituted aryl iodide such as 2-trifluoromethyl-1-iodobenzene
(1e) is readily converted to the intermediate zinc reagent and
undergoes the expected cross-coupling reaction with 4-cyano-
1-bromobenzene (3g) at 25 °C within 15 h, providing the biaryl
4g in 97% yield (entry 6). Aromatic iodides bearing electron-
donating groups are also good substrates, although the zinc
insertion is slower (48-180 h; entries 7 and 8). The subsequent
cross-coupling with an unsaturated halide furnishes the desired
products 4h (92%; entry 7) and 4i (67%; entry 8). In addition,
In situ generated aryl, heteroaryl, alkyl, or benzylic poly-
functional zinc reagents obtained by the addition of zinc and
LiCl to the corresponding organic iodides undergo smooth
Pd(0)-catalyzed cross-coupling reactions with aryl bromides,
chlorides, and triflates in the presence of PEPPSI as a
catalyst. This procedure avoids the manipulation of water
and air-sensitive organozinc reagents and produces cross-
coupling products in high yields.
Pd-catalyzed cross-coupling reactions have found numerous
applications in research as well as in industry.1 The Suzuki
cross-coupling reaction especially has been used extensively due
to the air and moisture stability of boronic acids and their
derivatives.2 Although this cross-coupling has a broad synthetic
scope, it suffers from some limitations. Thus, the boronic
derivatives often have to be prepared from the corresponding
magnesium or lithium species, which limits the presence of
functional groups.3 Alternatively, organozinc reagents display
in Pd-catalyzed cross-couplings (Negishi cross-coupling) much
higher reactivity4 and can readily be prepared in the presence
of various functional groups. These environmentally friendly
(1) (a) Tsuji, J. Palladium Reagents and Catalysts, InnoVations in Organic
Synthesis; Wiley: New York, 1995. (b) Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998.
(2) (a) Song, Q. B.; Lin, R. X.; Teng, M. Y.; Zhang, J.; Ma, C. A. Synthesis
2006, 123. (b) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419. (c) Kotha,
S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633. (d) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147. (e) Miyaura, N. AdVances in Metal-Organic
Chemistry; Liebeskind, L. S., Ed.; JAI: London, 1998; Vol. 6, p 187. (f) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(3) (a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2001, 40, 4544. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002,
41, 4176. (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
(d) Knochel, P. Handbook of Functionalized Organometallics; Wiley-VCH:
Weinheim, Germany, 2005.
(4) (a) Negishi, E.-i. In Metal-Catalyzed Cross-Coupling Reactions: Dieder-
ich, F.; Stang, P. J., Eds.; Wiley: New York, 1998; Chapter 1. (b) Erdik, E.
Tetrahedron 1992, 48, 9577.
(5) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 6040.
(6) (a) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass,
G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem.sEur. J. 2006, 12,
4743. (b) Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.;
O’Brien, C. J.; Valente, C. Eur. J. Chem. 2006, 12, 4749.
7380 J. Org. Chem. 2008, 73, 7380–7382
10.1021/jo801063c CCC: $40.75 2008 American Chemical Society
Published on Web 08/12/2008

TABLE 1. One-Pot Negishi Reaction for Functionalized Aryl
Compound Synthesis
TABLE 2. One-Pot Negishi Reactions Using Alkyl and Benzylic
Zinc Intermediates
a Isolated yields of analytical pure product. b One-pot cross-coupling
reaction had been done in THF/DMI ) 2/1. c Reaction conditions for
the zinc insertion. d 0.8 equiv of the reagent was used. e Reaction
conditions for the Pd-catalyzed cross-coupling reaction. f 0.5 equiv of
the reagent was used. g 0.25 mol % of PEPPSI was used.
9-12). The cross-coupling could be further extended to other
organic electrophiles such as aryl and vinyl triflates (3k and
3l) in 75-78% yield (entries 13 and 14). In the case of
3-iodopyridine (1i), the amount of zinc and LiCl should be
increased to 3.0 equiv to achieve full conversion to the
corresponding organozinc intermediate.
a Isolated yields of analytical pure product. b Reaction conditions for
the zinc insertion reaction. c Reaction conditions for the Pd catalyzed
cross-coupling reaction. d 3.0 equiv of Zn and LiCl was used for the
zinc insertion.
Alkylzinc halides bearing an ester or a nitrile (5a and 5b)
were generated in situ in a similar way. After the addition of
an unsaturated bromide or chloride in the presence of PEPPSI,
the desired cross-coupling products 7a-e are obtained in
70-87% yield (entries 1-5 of Table 2). The addition of 1,3-
dimethyl-2-imidazolidinone (DMI) as cosolvent facilitates the
reaction.
we have applied this one-pot protocol to heteroaromatic
compounds, such as 2-iodothiophene (1h), 3-iodopyridine (1i),
and 2-bromo-5-(carbethoxy)furan (1j), affording the expected
cross-coupling products 4j-m in 75-91% yields (entries
J. Org. Chem. Vol. 73, No. 18, 2008 7381

and Me3SiCl (1 mol %, heating to ebullition for 15 s). The aryl
iodide (1.0 mmol) was added at 25 °C, and the resulting reaction
mixture was stirred at the indicated temperature. When capillary
GC analysis of a hydrolyzed aliquot containing an internal standard
showed a conversion of >98%, the aryl halide (3, 0.5-0.8 equiv)
in THF (0.5-0.8 mL) was added at the indicated temperature
followed by the addition of PEPPSI (0.20 mL of 20 mmol/L solution
in THF, 0.004 mmol). After completion of the cross-coupling
reaction (as determined by GC analysis), the reaction mixture was
quenched with saturated aqueous NH4Cl solution (5 mL) and
extracted with ether (3 × 5 mL), and the combined organic phase
was washed with brine and dried over MgSO4. Evaporation of the
solvent in vacuo and purification by column chromatography
afforded the expected cross-coupling products.
Remarkably, polyfunctional benzylic zinc reagents bearing
a keto group can be generated in situ starting from the
corresponding benzylic chlorides 5c-e.7 A smooth cross-
coupling occurs with 0.5 equiv of various aromatic bromides,
furnishing polyfunctional diarylmethanes 7f-j in 60-94% yield
(entries 6-10 of Table 2).
In summary, we have reported a practical in situ generation
of polyfunctional zinc reagents using commercially available
zinc dust in the presence of LiCl and found general reaction
conditions using PEPPSI for a subsequent cross-coupling with
various aryl and heteroaryl bromides, chlorides, or triflates. This
procedure avoids the handling of air- and water-sensitive zinc
reagents and would be suited for large-scale industrial applications.
Acknowledgment. We thank the 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.
Experimental Section
General Procedure. Anhydrous LiCl (1.5-3.0 equiv) was
placed in an argon-flushed flask and dried using a heat gun under
high vacuum. Zinc dust (<10 µm, Aldrich, 98+%, 1.5-3.0 equiv)
was added under argon, and the heterogeneous mixture of Zn and
LiCl was dried again on high vacuum. The reaction flask was
flushed with argon, and then THF (ca. 0.8 M) was added. Zn was
activated by BrCH2CH2Br (5 mol %; heating to ebullition for 15 s)
Supporting Information Available: Experimental proce-
dures and full characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(7) Metzger, A.; Schade, M. A.; Knochel, P. Org. Lett. 2008, 10, 1107.
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