Negishi cross-couplings compatible with unprotected amide functions

Article abstract of DOI:10.1002/chem.200802349

The reaction conditions that allow a general Pd-catalyzed Negishi cross-coupling of a functionalized alkyl, aryl, heteroaryl, and benzylic zinc reagents with aryl acidic hydrogens were investigated. A dry and argon flushed 10 mL Schlenk-tube was charged with N-benzyl-4-bromobenzamide, Pd(OAc) ₂, S-PHOS, and THF. 3-pentanoyl-benzylzinc chloride was added slowly over 90 minutes with a syringe pump. The reaction mixture was stirred for 1 hour at 25 °C. The reaction mixture was quenched with a saturated NH ₄Cl solution and extracted with diethyl ether. The combined phases were then washed with a aqueous thiourea solution and dried over Na ₂SO₄. It was observed that the mild conditions considerably increase the ability of the Negishi cross-coupling in the synthesis of complex molecules and natural products.

Full text of DOI:10.1002/chem.200802349

DOI: 10.1002/chem.200802349
Negishi Cross-Couplings Compatible with Unprotected Amide Functions
Georg Manolikakes,[a] M.Sc. Zhibing Dong,[b] Herbert Mayr,[a] Jinshan Li,[b] and
Paul Knochel*[a]
The Pd-catalyzed cross-coupling of unsaturated halides
with organometallic reagents is one of the best methods for
ed to undergo in general couplings with organic halides
bearing amide functions.[7]
making Csp2 Csp2 bonds.[1] Among many organometallic re-
Preliminary kinetic experiments revealed large differences
in the reactivity between different types of orgoanozinc re-
agents. Thus, a 0.4m solution of OctZnBr is completely pro-
tonated within 25 min at 258C when treated with one equiv-
alent of benzamide (Figure 1). From the reaction time re-
quired for 50% conversion of the zinc reagent (<1 min for
PhZnI, 2.5 min for OctZnBr, and 20 min for BnZnCl), one
can derive approximate structure–reactivity relationships.
For secondary amides, the protonation rate is somewhat
lower, but 50% of the zinc reagent is protonated within
30 min (for PhZnI), 60 min (for OctZnBr), and 2.5 h (for
BnZnCl, Figure 2). These results indicate, that the reactivity
towards NH acids increases from benzyl<alkyl<aryl and
that a very active cross-coupling catalyst will be required to
avoid competitive protonation. Recently, Buchwald reported
the high activity of S-PHOS[8] for various cross-couplings.
À
agents used in these cross-couplings, organozinc reagents
(Negishi reaction) have proven to react under very mild
conditions.[2,3] Furthermore, organozinc compounds are com-
patible with many functionalities and allow therefore the
elaboration of polyfunctional molecules without the need
for protecting groups.[4] Recently, we have demonstrated,
that acidic hydrogens of amines, alcohols, and phenols are
compatible with the Negishi cross-coupling conditions and
do not require the use of protecting groups.[5] Herein, we
report reaction conditions that are compatible with the
amide function (Scheme 1). This functional group is ubiqui-
tous in pharmaceutically active compounds and its tolerance
in cross-coupling reactions is therefore especially impor-
tant.[6] Only boronic esters or acids have so far been report-
Scheme 1. Cross-coupling of zinc reagents with unprotected amides and
sulfonamides. R1 =alkyl, aryl, heteroaryl, benzylic, R2 =H, alkyl, aryl,
benzyl. S-PHOS=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl.
[a] Dipl.-Chem. G. Manolikakes, Prof. Dr. H. Mayr, Prof. Dr. P. Knochel
Department Chemie und Biochemie
Ludwig-Maximillians-Universitꢀt Mꢁnchen
Butenandtstrasse 5-13, 81377 Mꢁnchen (Germany)
Fax : (+49)89-2180-77680
Homepage: http://www.knochel.cup.uni-muenchen.de/
E-mail: paul.knochel@cup.uni-muenchen.de
[b] M. Z. Dong, Prof. Dr. J. Li
State Key Laboratory of Elemento-Organic Chemistry
Nankai University, Tianjin 300071 (China)
Figure 1. Stability of organozinc reagents towards benzamide. [a] Yields
are determined by quenching with CuCN/allyl bromide in THF followed
by GC analysis with tetradecane as internal standard.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802349.
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Chem. Eur. J. 2009, 15, 1324 – 1328

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.
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P. Knochel et al.
Table 1. Products of type 4 and 5 obtained by the cross-coupling between functionalized zinc reagents 1 and amides 2 or sulfonamides 3.
Entry
Zinc Reagent[a]
Electrophile
Product
Yield [%][b]
1
1a
2a
4a
96
2
3
4
5
1b
1c
1c
1d
2b
2a
2c
2d
4b
4c
4d
4e
92
89
81
86
6
7
8
9
1e
1 f
1 f
1g
2e
2a
2c
2b
4 f
4g
4h
4i
87
90
83
96
10
11
1h
1i
2d
2c
4j
96
91
4k
12
13
1 f: FG=CO2Et
1g: FG=CN
3a
3a
5a: FG=CO2Et
5b: FG=CN
75
95
14
1h
3b
5c
85
[a] The zinc reagent (1.2 equiv) was slowly added over 90 min via syringe pump. [b] Isolated yield of analytically pure product.
Experimental Section
bility of the Negishi cross-coupling in the synthesis of com-
plex molecules and natural products.
Typical procedure: preparation of N-benzyl-4-(3-pentanoyl-benzyl)-ben-
zamide (4j): A dry and argon flushed 10 mL Schlenk-tube was charged
with N-benzyl-4-bromobenzamide (2d, 580 mg, 2 mmol), Pd
ACHTUNGTRENNUNG(OAc)2
(4.5 mg, 0.02 mmol), S-PHOS (16.4 mg, 0.04 mmol), and THF (2 mL).
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Chem. Eur. J. 2009, 15, 1324 – 1328

Pd-Catalyzed Cross-Couplings
COMMUNICATION
Scheme 3. Preparation of biologically active biphenylamides: a) PdACHTUNTRGNE(NUG OAc)2 (1 mol%), S-PHOS (2 mol%), slow addition of the zinc reagent over 90 min,
THF 258C; b) iPrMgCl·LiCl, THF, À308C, 45 min, then ZnCl2, À308C to 258C; c) Cl3C(O)NCO, À408C to 258C; d) K2CO3, MeOH, 258C, 16 h; e) Pd-
ACHTUNGTRENNUNG
After the mixture had been stirred for 5 min, 3-pentanoyl-benzylzinc
chloride (1h, 1.8 mL, 1.34m in THF, 2.4 mmol, prepared by the direct
zinc insertion into the benzylic chloride)[17] was added slowly over 90 min
with a syringe pump. The reaction mixture was stirred for 1 h at 258C.
Then the reaction mixture was quenched with a saturated NH4Cl solution
and extracted with diethyl ether. The combined organic phases were
washed with an aqueous thiourea solution and dried over Na2SO4. Purifi-
cation of the crude residue obtained after evaporation of the solvents by
flash chromatography (pentane/EtOAc 4:1) gave N-benzyl-4-(3-pentano-
yl-benzyl)-benzamide (4j) as a colorless solid (755 mg, 96%).
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Acknowledgements
[5] G. Manolikakes, M. A. Schade, C. Munoz Hernandez, H. Mayr, P.
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We thank the Fonds der Chemischen Industrie, the DFG and SFB 749
for financial support. We also thank Chemetall GmbH (Frankfurt), W. C.
Heraeus (Hanau), and BASF (Ludwigshafen) for the generous gift of
chemicals. Z.D. thanks the Chinese Scholarship Council for financial sup-
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À
Keywords: biphenyl amide · C C bond formation · cross-
coupling · palladium · zinc reagents
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Received: November 12, 2008
Published online: December 29, 2008
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Chem. Eur. J. 2009, 15, 1324 – 1328