C O M M U N I C A T I O N S
Table 3. Pd-Catalyzed Kumada-Corriu Reactions of Aryl Iodides
3), an acetal (entry 4), or a silyl ether (entry 5) in high yield. In
particular, the utilization of 2,6-difluoroaryl metal derivatives in
cross-coupling methodology has been quite difficult; with the
present method, a variety of heretofore inaccessible 2,6-difluoro-
biaryls are now readily available.
a
with Heteroaryl Grignard Reagents
1
6
In summary, a highly efficient process for the Pd-catalyzed
Kumada-Corriu reaction that proceeds at temperatures ranging
from -20 to -65 °C has been developed. The stability and
reactivity of polyfunctionalized Grignard reagents at such temper-
atures along with the tolerance of our protocol toward a wide variety
of functional groups allow for the synthesis of a broad spectrum
of valuable compounds, including heterocyclic biaryls and poly-
fluoro biaryls. Further investigations into this and related methods
are ongoing in our laboratories.
Acknowledgment. We thank the National Institutes of Health
(
GM 58160) for financial support of this work. Amgen, Merck,
a
Reaction conditions: as in Table 2, using L2 as ligand. b Isolated yields
and Boehringer Ingelheim provided additional support. R.M. thanks
the Spanish MEC for a postdoctoral fellowship.
are an average of two runs.
Table 4. Pd-Catalyzed Kumada-Corriu Reactions of Aryl Iodides
Supporting Information Available: Experimental procedures and
spectral data for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
a
with 2,n-Difluorophenylmagnesium Grignard Reagents
References
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5) For recent reviews, see: (a) Hiriyakkanavar, I.; Baron, O.; Wagner, A.
J.; Knochel, P. Chem. Commun. 2006, 583. (b) Knochel, P.; Dohle, W.;
Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu,
V. A. Angew. Chem., Int. Ed. 2003, 42, 4302.
(
6) For some exceptions, see: (a) Bonnet, V.; Mongin, F.; Tr e´ court, F.;
Qu e´ guiner, G.; Knochel, P. Tetrahedron 2002, 58, 4429. (b) Bonnet, V.;
Mongin, F.; Tr e´ court, F.; Breton, G.; Marsais, F.; Knochel, P.; Qu e´ guiner,
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G.; Knochel, P. Tetrahedron Lett. 2001, 42, 5717.
a
b
Reaction conditions: as in Table 2, using L2 as ligand. Isolated yields
c
are an average of two runs. L3 (3 mol %) was used.
(
7) For recent selected publications on Kumada-Corriu reactions, see: (a)
Organ, M. G.; Abdel-Hadi, M.; Avola, S.; Hadei, N.; Nasielski, J.; O’Brien,
C. J.; Valente, C. Chem.sEur. J. 2007, 13, 150. (b) Limmert, M. E.;
Roy, A. H.; Hartwig, J. F. J. Org. Chem. 2005, 70, 9364. (c) Ackermann,
L.; Born, R.; Spatz, J. H.; Meyer, D. Angew. Chem., Int. Ed. 2005, 44,
instances, for further functionalization via conventional cross-
coupling techniques.
Table 3 shows representative examples of the Pd-catalyzed
7216. (d) Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889.
Kumada-Corriu reaction with functionalized heteroaryl Grignard
(8) Kaye, S.; Fox, J. M.; Hicks, F. A.; Buchwald, S. L. AdV. Synth. Catal.
reagents.5a While the reaction conditions were essentially identical
2001, 343, 789.
(
9) For experimental details and the use of other ligands, see Supporting
to those in Table 2, the use of L2 gave better results than did L3;
at present, we have no explanation for this behavior. In this manner,
cross-coupling products bearing pyrazole (entry 1), furan (entry 2),
thiophene (entries 3 and 4), or pyridine (entry 5)14 moieties were
all isolated in moderate to good yields. Again, high levels of
chemoselectivity were observed, leaving esters, N-Boc amides,
acetals, and heteroaryl chlorides intact.
Information.
(10) (a) For a mechanistic study of the oxidative addition of aryl iodides and
aryl triflates to palladium catalysts, see: Alcazar-Roman, L. M.; Hartwig,
J. F. Organometallics 2002, 21, 491. (b) As oxidative addition appears to
be rate limiting, reactions with aryl bromides and aryl chlorides are slower.
Further work to allow the use of these substrates is currently in progress.
i
i
(
11) I/Mg exchange was performed using PrMgCl-LiCl. The use of PrMgBr
resulted in similar yields of the final biaryl compounds. Thus, we do not
believe, as suggested by one reviewer, that LiCl is important in our
Pd-catalyzed chemistry.
Electron-deficient arylboronic acids such as ortho-fluoro deriva-
tives are often poor substrates in Suzuki-Miyaura reactions because
of their low reactivity in the transmetalation process and higher
tendency to homocouple.15 Although we anticipated that the higher
reactivity of Grignard reagents would overcome the difficulty of
the transmetalation step, these organometallic species are unstable
at ambient temperatures, decomposing via benzyne and other
pathways. We were pleased to find using our conditions this did
not occur. Table 4 shows the results for several ortho-fluoro-
substituted Grignard reagents that were successfully combined with
aryl iodides bearing an ester (entry 2), heteroaryl substituents (entry
(
12) While this paper was in preparation, a report describing a single example
of a Pd-catalyzed Kumada-Corriu reaction with an unactivated aryl halide
at -20 °C was reported; see ref 7a.
13) For some examples of Pd-catalyzed Kumada-Corriu reactions with
activated heteroaryl halides at -40 °C, see refs 6a and 6c.
14) The reaction using 2- and 3-pyridylmagnesium reagents resulted in lower
conversion of the aryl iodides (0-30% in most cases).
15) (a) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001, 42, 4087. (b)
Thiemann, T.; Umeno, K.; Ohira, D.; Inohae, E.; Sawada, T.; Mataka, S.
New J. Chem. 1999, 23, 1067.
(
(
(
(
16) For an example of cross-coupling reaction of potassium 2,6-difluorophen-
yltrifluoroborate with 4-bromobenzonitrile, see: Molander, G. A.; Biolatto,
B. J. Org. Chem. 2003, 68, 4302.
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