COMMUNICATION
The cross-coupling conditions are mild enough that chiral
amides such as bromobenzamide 6 or amino acid derivatives
such as 7a and 7b undergo Negishi cross-coupling with aryl
and benzylic zinc regents 1j–1l, leading to the products 8a–
8c in 85–94% yield (Scheme 2).
As mentioned above, numerous pharmaceuticals bear an
amide function with an acidic proton. To demonstrate the
broad applicability of our method, we have prepared several
biologically active compounds. Thus, the antiarrythmic
agents 10a and 10b (Bristol–Myers Squibb)[13] were pre-
pared in 92–97% yield by the direct cross-coupling of the
zinc reagents 1m[14] and 1e under the standard conditions
from the bromoamide 9 (Scheme 3). The reaction of the het-
erocyclic zinc reagent 1n, prepared by direct zinc inser-
tion,[9,13] with the secondary amides 11 and 2e led to the
kinase inhibitors 12a and 12b (GlaxoSmithKine)[15] in 91–
96% yield (Scheme 3). Finally, the sodium channel blockers
15a–15c (Merck)[16] were synthesized from the primary
amide 14 and the zinc reagents 1o–1q[14,17] in 94–97% yield
(Scheme 3).
Figure 2. Reactivity of organozinc reagents with N-benzylbenzamide.
[a] Yields are determined by quenching with CuCN/allyl bromide in THF
followed by GC analysis with tetradecane as internal standard.
In summary, we have reported reaction conditions, using
Buchwaldꢃs S-PHOS, which allow a general Pd-catalyzed
Negishi cross-coupling of functionalized alkyl, aryl, heteroar-
yl, and benzylic zinc reagents with aryl halides bearing
amide or sulfonamide functions with acidic hydrogens. The
mild reaction conditions considerably increase the applica-
This ligand has already been successfully applied for Negishi
cross-couplings in the presence of free alcohols and
amines.[5]
As shown in Table 1, we have found that by using Pd-
ACHTUNGTRENNUNG(OAc)2 (1 mol%) and S-PHOS (2 mol%) and adding the
zinc reagent within 90 min to the aryl bromide at 258C, it
was possible to perform efficient cross-couplings between
various aryl bromides bearing amide groups (1.0 equiv) and
functionalized zinc reagents (1.2 equiv, Scheme 1 and
Table 1). This procedure has a remarkably broad scope and
affords high yields (75–96%). Importantly no large excess of
the zinc reagent is needed and no extra base was added to
deprotonate the amide function prior to the cross-coupling.
As shown in Table 1, the cross-coupling proceeds well with
arylzinc reagents, prepared by the direct zinc insertion in
the presence of LiCl (such as 1a and 1b; entries 1 and 2).[9]
Zinc reagents derived from electron-poor heteroarenes, such
as 3-pyridylzinc iodide (1c) and electron-rich heterocycles,
such as 2-thienylzinc chloride (1d)[10] or the uracil-derived
zinc reagent 1e,[11] react smoothly, providing the cross-cou-
pling products 4c–4 f in 81–89% yield (entries 3–6). Ester-
and nitrile-substituted alkylzinc reagents 1 f and 1g, respec-
tively, react at the same rate. After addition of the zinc re-
agent and stirring for 30 min at 258C, the cross-coupling of
the primary or secondary amides are complete, furnishing
the polyfunctional molecules 3g–3i in 83–96% yield (en-
tries 7–9).[12] Finally, the polyfunctional benzylic zinc re-
agents 1h and 1i lead to the cross-coupling products 4j and
4k in 90–91% yield (entries 10 and 11). Interestingly, also
iodosulfonamides such as 3a and 3b are excellent substrates,
requiring no protection of the acidic N–H and cross-cou-
pling with the alkylzinc reagents 1 f and 1g, and the benzylic
zinc chloride 1h affords the desired polyfunctional sulfona-
mides (5a–5c) in 75–95% yield (entries 12–14).
Scheme 2. Cross-coupling of optically active aryl halides.
Chem. Eur. J. 2009, 15, 1324 – 1328
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1325