Palladium- and nickel-catalyzed cross-couplings of unsaturated halides bearing relatively acidic protons with organozinc reagents

Article abstract of DOI:10.1021/jo8015852

(Chemical Equation Presented) A wide range of polyfunctional aryl, heteroaryl, alkyl, and benzylic zinc reagents were coupled with unsaturated aryl halides bearing an acidic NH or OH proton, using Pd(OAc)₂ (1 mol %) and S-Phos (2 mol %) as catalyst without the need of protecting groups. A similar nickel-catalyzed reaction is described. The relative kinetic basicity of organozinc compounds as well as their stability toward acidic protons is also described.

Full text of DOI:10.1021/jo8015852

Palladium- and Nickel-Catalyzed Cross-Couplings of Unsaturated
Halides Bearing Relatively Acidic Protons with Organozinc
Reagents
Georg Manolikakes,† Carmen Mun˜oz Hernandez,‡ Matthias A. Schade,† Albrecht Metzger,†
and Paul Knochel*,†
Department Chemie and Biochemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstr. 5-13,
81377 Munich, Germany, and Facultad de Ciencias, UniVersidad de Ma´laga, Campus de Teatinos s/n,
29071 Ma´laga, Spain
knoch@cup.uni-muenchen.de
ReceiVed July 17, 2008
A wide range of polyfunctional aryl, heteroaryl, alkyl, and benzylic zinc reagents were coupled with unsaturated
aryl halides bearing an acidic NH or OH proton, using Pd(OAc)2 (1 mol %) and S-Phos (2 mol %) as catalyst
without the need of protecting groups. A similar nickel-catalyzed reaction is described. The relative kinetic
basicity of organozinc compounds as well as their stability toward acidic protons is also described.
1. Introduction
bond of boronic acids, these cross-couplings proceed as a rule
under harsher conditions compared to the corresponding Negishi
cross-couplings using organozinc compounds.5 Recently, we
have found reaction conditions and a catalytic system allowing
the cross-coupling of organozinc reagents with unsaturated
halides bearing relatively acidic hydrogens, without the use of
protecting groups.6 No excess of the organozinc reagent and
no additional base for deprotonation of the acidic proton prior
to the coupling were necessary. Herein, we wish to report the
scope and limitations of this cross-coupling reaction as well as
the corresponding nickel-catalyzed version of this reaction.
Palladium- or nickel-catalyzed carbon-carbon bond forming
reactions between organometallic reagents and unsaturated
halides are important methods in modern synthetic organic
chemistry. The resulting products are highly relevant for
applications in the pharmaceutical and agrochemical industry,
as well as for the preparation of new materials or natural
products.1 Among the possible nucleophilic substrates, orga-
noboronic acids and derivatives are used most widely.2 Despite
the widespread use of organoboron reagents for Suzuki-Miyaura
couplings and the advantages associated with these reagents,
such as commercial availability, air stablility, and especially
their tolerance of relatively acidic protons,3 difficulties concern-
ing their tendency to form boroxines and competitive protode-
boronation remain.4 Also, due to the covalent nature of the C-B
2. Results and Discussion
Palladium-Catalyzed Cross-Coupling Reaction. First, we
have examined the palladium-catalyzed cross-coupling of or-
* Address correspondence to this author. Fax: (+49) 89-2180-77680.
† Ludwig-Maximilians-Universita¨t.
(3) (a) Villard, A.-L.; Warrington, B. R.; Ladlow, M. J. Comb. Chem. 2004,
6, 611. (b) Miura, Y.; Oka, H.; Momoki, M. Synthesis 1995, 11, 1419. (c)
Baxendale, I. R.; Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. C. Chem.sEur.
J. 2006, 12, 4407. (d) Prieto, M.; Zurita, E.; Rosa, E.; Munoz, L.; Lloyd-Williams,
P.; Giralt, E. J. Org. Chem. 2004, 69, 6812.
(4) For selected examples highlighting the problems with the use of
organoboron reagents, see: (a) Handy, S. T.; Zhang, Y.; Bregman, H. J. Org.
Chem. 2004, 69, 2362. (b) Chaumeil, H.; Signorella, S.; Le Drian, C. Tetrahedron
2000, 56, 9655. (c) Wanatabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
(5) (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.
‡ Universidad de Ma´laga.
(1) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 1998. (b) Transition Metal
Reagents and Catalysts: InnoVations in Organic Synthesis; Tsuji, J., Ed.; Wiley:
Chichester, UK, 1995. (c) Transition Metals for Organic Synthesis; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany, 1998. (d) Miyaura, N. Top.
Curr. Chem. 2002, 219.
(2) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Littke, A. F.;
Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387. (c) Wolfe, J. P.; Buchwald,
S. L. 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.
(6) Manolikakes, G.; Schade, M. A.; Mun˜oz Hernandez, C.; Mayr, H.;
Knochel, P. Org. Lett. 2008, 10, 2765.
8422 J. Org. Chem. 2008, 73, 8422–8436
10.1021/jo8015852 CCC: $40.75 2008 American Chemical Society
Published on Web 10/04/2008

TABLE 1. Screening of Various Palladium-Ligand Systems for
the Cross-Coupling of Unprotected Aniline 2a
3a in only 17% yield, indicating a quantitative deprotonation
of the aniline prior to the coupling reaction.
Using Pd(OAc)2/L3 as catalytic system, a broad range of
functionalized arylzinc reagents reacted with various bromoa-
nilines within 1-3 h at 25 °C in good to excellent yields (Table
2, entries 1-15). Zinc compounds bearing ester, cyano, or
trifluoromethyl groups were suitable for the palladium catalysis
and afforded the corresponding polyfunctional anilines in
72-98% yield (Table 2, entries 5-12). Also, 3-pyridylzinc
iodide (1f) reacted with the bromoanilines 2c, 2i, and 2j, leading
to the products 3n, 3o, and 3p (70-98% yield, entries 13-15).
In the case of primary or secondary amines, such as the
benzylamines 4a and 4b, the cross-coupling occurred satisfac-
torily. The deprotonation of these less acidic amines (pKa ∼
4011) was not a concern; however, we have observed a palladium
catalyst deactivation, due to the high donor ability of these
amines. The reaction temperature has therefore to be increased
to 65 °C (3-16 h), providing the polyfunctional amines 5a-5f
in 61-97% yield (entries 16-21). Interestingly, alkylzinc
bromides, prepared by direct zinc insertion in alkyl bromides,7
were suitable for the palladium-catalyzed cross-coupling. Thus,
octylzinc bromide (1g) and the functionalized alkylzinc com-
pounds 1h and 1i reacted with various bromoanilines within
1-3 h at 25 °C, leading to the polyfuctional anilines 3q-3w
in 71-98% yield (entries 22-28). Also, functionalized benzylic
zinc reagents, prepared by the direct zinc insertion into benzylic
chlorides,12 undergo a cross-coupling with various aryl bromides
in 1-3 h at 25 °C, leading to the diarylmethanes 3x-3ae in
73-98% yield (entries 29-36). The polyfunctional pyridine 3ae,
a useful intermediate for the synthesis of HIV integrase
inhibitors,13 was obtained in 92% yield (entry 36) by the reaction
of 4-fluorobenzylzinc chloride (1n) with bromopyridine 2l.
Unprotected indoles are also suitable electrophiles under the
reaction conditions described above. Thus, the reaction of
5-bromoindole (6) with the benzylzinc reagent 1m gave the
expected product 7a in 71% yield (Scheme 1). Similarly, alkyl-
or arylzinc14 halides react with the unprotected indole 6,
furnishing the functionalized indoles 7b-7e in 85-98% yield
(Scheme 1).
Interestingly, more acidic OH protons were tolerated as well
by our protocol. Thus, slowly adding phenylzinc iodide (1a,
1.2 equiv) over 90 min (via syringe pump) to a solution of the
sterically hindered tertiary iodobenzyl alcohol 8a (1.0 equiv),
Pd(OAc)2 (1 mol %) and L3 (2 mol %) led to the cross-coupling
product 10a in 95% yield (Table 3, entry 1). The slow addition
of the zinc reagent was crucial for obtaining a high yield. The
functionalized arylzinc reagents 1b and 1c also react with the
iodide 8a and gave the biaryls 10b and 10c in 78 and 87%
yield (entries 2 and 3). By using bromobenzyl alcohol 8b as
electrophile, the cross-coupling product 10c was obtained in
a Yields were determined by GC analysis with tetradecane as internal
standard. b Isolated yield of analytically pure product. c 4-Chloroaniline
was used as electrophile.
ganozinc reagents with aryl bromides in the presence of acidic
hydrogens. The reaction of phenylzinc iodide (1a, 1.2 equiv),
prepared by direct zinc insertion in the presence of LiCl,7 with
4-bromoaniline (2a, 1.0 equiv) was chosen as model system.
Various ligands were tested (Table 1). Several phosphines, such
as PPh3, tri-(2-furyl)-phosphine (tfp) or PCy3, gave low yields
of aniline 3a (<20%, entries 1-3). Similar yields were obtained
with N-heterocyclic carbene ligands, for example, PEPPSI (entry
4).8 Electron-rich biaryl phosphines L1-L3, introduced by
Buchwald,9 displayed the highest activity for this reaction, and
biphenyl 3a was obtained in moderate to high yields (57-96%
yield, entries 4-6). In this class of ligands, S-Phos10 (L3) was
identified as the most promising, leading to 3a in 96% yield
(entry 6). Even with the most active catalyst system (Pd(OAc)2/
L3), aryl chlorides were not suitable. The reaction of phenylzinc
iodide (1a, 1.2 equiv) with 4-chloroaniline furnished biphenyl
(11) Typical pKa values (in DMSO) for anilines range between 20 and 30,
for amines ∼40; for a comprehensive compilation of pKa data see: http://
www.chem.wisc.edu/areas/reich/pkatable/index.htm and references cited therein.
(12) Metzger, A.; Schade, M. A.; Knochel, P. Org. Lett. 2008, 10, 1107.
(13) Boros, E. E.; Burova, S. A.; Erickson, G. A.; Johns, B. A.; Koble, C. S.;
Kurose, N.; Sharp, M. J.; Tabet, E. A.; Thompson, J. B.; Toczko, M. A. Org.
Process Res. DeV. 2007, 11, 899.
(7) The preparation of the zinc reagent by transmetalation from the
corresponding organomagnesium or organolithium compound led to similar
results. For the preperation via direct zinc insertion, see: Krasovskiy, A.;
Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45,
6040.
(8) Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.;
O’Brien, C. J.; Valente, C. Chem.sEur. J. 2006, 12, 4749.
(9) (a) Altman, R. A.; Buchwald, S. L. Nat. Protoc. 2007, 2, 3115. (b) Barder,
T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 5096. (c) Milne, J. E.;
Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.
(10) S-Phos (L3) was purchased from Strem or prepared according to: Barder,
T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005,
127, 4685.
(14) However, for the coupling of 5-bromoindole (7), the zinc reagents 1a,
1g, and 1h 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) Krasovskiy, A.; Knochel, P. Angew. Chem.,
Int. Ed. 2004, 43, 3333. (b) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel,
F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003,
42, 4302.
J. Org. Chem. Vol. 73, No. 21, 2008 8423

Manolikakes et al.
TABLE 2. Palladium-Catalyzed Cross-Coupling of Anilines of Type 2 and Amines of Type 4a
8424 J. Org. Chem. Vol. 73, No. 21, 2008

TABLE 2. Continued
J. Org. Chem. Vol. 73, No. 21, 2008 8425

Manolikakes et al.
TABLE 2. Continued
8426 J. Org. Chem. Vol. 73, No. 21, 2008

TABLE 2. Continued
a Reaction conditions: 3.0 mmol of aryl bromide, 3.6 mmol of zinc reagent, Pd(OAc)2 (1 mol %), L3 (2 mol %). b Isolated yield of analytically pure
product. c 7.2 mmol of the zinc reagent was used. d The zinc reagent was added slowly over 90 min via syringe pump.
SCHEME 1. Palladium-Catalyzed Cross-Coupling of Unprotected Indole 6a
a Reaction conditions: 3.0 mmol of indole 6, 3.6 mmol of zinc reagent, Pd(OAc)2 (1 mol %), L3 (2 mol %).
73% yield (entry 4). Similarly, the sterically hindered diphe-
nylmethanol 8c reacted with the arylzinc iodides 1b and 1c,
leading to the products 10d and 10e in 91 and 81% yield (entries
5 and 6). In the case of the less reactive aryl bromide 8d, the
biphenyl 10e was obtained in only 40% yield (entry 7). The
alkylzinc bromides 1h and 1i reacted with the less hindered
secondary alcohols 8e and 8f and with the primary iodobenzyl
alcohol 8g, furnishing the functionalized benzylic alcohols in
59-88% yield (entries 8-11). Interestingly, various function-
alized benzylzinc chlorides could be coupled with 4-bromoben-
J. Org. Chem. Vol. 73, No. 21, 2008 8427

Manolikakes et al.
TABLE 3. Palladium-Catalyzed Cross-Coupling of Alcohols of Type 8 and Phenols of Type 9a
8428 J. Org. Chem. Vol. 73, No. 21, 2008

TABLE 3. Continued
J. Org. Chem. Vol. 73, No. 21, 2008 8429

Manolikakes et al.
TABLE 3. Continued
a Reaction conditions: 2.0 mmol of aryl halide, 2.4-2.6 mmol of zinc reagent, Pd(OAc)2 (1 mol %), L3 (2 mol %). b Isolated yield of analytically
pure product. c 5.2 mmol of the zinc reagent was used.
zyl alcohol 8h or the aryl bromides 8j and 8k, bearing relatively
acidic NH and OH protons, leading to the products 10j-10o in
64-98% yield (entries 12, 14-17). However, with 2-bro-
mobenzyl alcohol, no coupling product was observed, probably
due to an intramolecular coordination of the OH function. To
our delight, benzylzinc reagents tolerated even more acidic
phenolic protons. When we added 2-chlorobenzylzinc chloride
(1o, 1.3 equiv) slowly (over 90 min) to a solution of 4-bro-
mophenol (9a, 1.0 equiv), Pd(OAc)2 (1 mol %) and L3 (2 mol
%) provided the phenol 11a in 98% yield (entry 18). Similarly,
various functionalized benzylic zinc chlorides react smoothly
with various bromophenols and bromonaphthol (9a-9e), result-
ing in the formation of the corresponding diarylmethanes
11b-11h in 73-96% yield (entries 19-26). Remarkably, 5,5′-
dibromobinaphthol 9f, a common intermediate for various
BINOL-based ligands,15 is compatible with the cross-coupling
conditions, and the reaction with the benzylic zinc reagent 1m
(2.6 equiv) furnished binol 11i in 76% yield (entry 26).
Alkenyl halides, bearing relatively acidic protons, could be
coupled using the standard protocol. Thus, the reaction of
phenylzinc iodide (1a) with the alkenyl bromide 12a, bearing
an acidic NH proton, provided the aniline 13a in 61% yield
(Table 4, entry 1). Also, the functionalized arylzinc iodide 1b,
alkylzinc bromide 1h, and benzylzinc chlorides 1j and 1m react
with the 2-bromoallylic amine 12a, leading to the allylic amines
13b-13d in 75-81% yield (entries 2-4). More acidic OH
functions were only tolerated if benzylic zinc reagents were
used. Thus, when benzylzinc chloride (1q, 1.2 equiv) was added
slowly over 90 min (via syringe pump) to a solution containing
Pd(OAc)2 (1 mol %), L3 (2 mol %) and 3-bromoallyl alcohol
12b (1.0 equiv) afforded the allylic alcohol 13e in 65% yield
(entry 5). Similarly, the cross-coupling reactions of the cy-
cloalkenyl iodide 12c with benzylic zinc compounds 1o
furnished the unsaturated alcohols 13f (91% yield, entry 6).
Since the pKa of terminal alkynes is similar to the pKa of
anilines,11 we have examined their behavior toward zinc reagents
in the cross-coupling reaction. Competitive deprotonation was
not a concern, and the palladium-catalyzed reaction [1 mol %
of Pd(OAc)2 and 2 mol % of L3) of phenylzinc iodide (1.2
equiv of 1a) with the aryl bromide 14a (1.0 equiv), bearing an
ethynyl function, furnished the biphenyl 15a in 74% yield
(Scheme 2). Other aryl- or heteroarylzinc iodides, such as 1c
and 1f, provided the corresponding alkynes 15b and 15d in 70
and 76% yield. Also the 3-cyanopropylzinc bromide (1h) reacted
(15) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999.
8430 J. Org. Chem. Vol. 73, No. 21, 2008

TABLE 4. Palladium-Catalyzed Cross-Coupling of Alkenyl Halides of Type 12a
a Reaction conditions: 2.0 mmol of aryl halide, 2.4 mmol of zinc reagent, Pd(OAc)2 (1 mol %), L3 (2 mol %). b Isolated yield of analytically pure
product. c The zinc reagent was slowly added over 90 min via syringe pump.
with 2-bromophenylacetylene (14a), leading to the phenylacety-
lene derivative 15c in 77% yield.
phenanthroline, N-heterocyclic carbene (IPr·HCl ) N,N′-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene hydrochloride), or
diethyl phosphite.17
Nickel-Catalyzed Cross-Coupling Reaction. We have also
examined the use of nickel, which is cheaper and intrinsically
more active than palladium in cross-couplings.16 The reaction
of phenylzinc iodide, prepared by the direct zinc insertion7 (1a,
1.2 equiv), with 4-bromoaniline (2a, 1.0 equiv) was chosen as
the test reaction (Table 5). Preliminary studies showed that the
slow addition of the zinc reagent 1a (via syringe pump over 90
min) was crucial for obtaining high yields of the aniline 3a.
The best results together with complete consumption of the aryl
bromide 2a were obtained by using either PPh3 or 2,2′-
bipyridine, furnishing the biphenyl 3a in 62 and 77% yield
(Table 5, entries 1 and 2). Other phosphines, such as 1,2-
bis(diphenylphosphino)ethane (dppe) or tris(2-furyl)phosphine
(tfp), gave only yields of <20% (entries 3 and 4), presumably
due to competitive deprotonation of the aniline 2a prior to the
cross-coupling reaction. Similar results were obtained with
Using the optimized conditions (2 mol % of Ni(acac)2, 3 mol
% of 2,2′-bipyridine, slow addition of the zinc reagent),
bromoaniline 2a reacted with phenylzinc iodide (1a) leading
to the biphenyl 3a in 75% isolated yield (2 h, 25 °C, Table 6,
entry 1). Similarly, the functionalized bromoanilines 2b-2d
reacted with 1a within 2-3 h at 25 °C, leading to the biphenyl
amines 3b-3d in 75-85% yield (entries 2-4). In the case of
the secondary amine 2e, which is less acidic than anilines,11
the reaction temperature had to be increased to 60 °C, and the
amine 3e was obtained in 71% yield after 2 h (entry 5). Also,
functionalized benzylic zinc reagents, prepared by direct zinc
insertion in the presence of LiCl,12 could be used in this cross-
coupling reaction, although the procedure had to be modified.
A combination of Ni(acac)2 (2.5 mol %) and PPh3 (10 mol %)
as catalyst system, together with an elevated reaction temper-
ature (60 °C) and a slow addition of the zinc reagent, turned
(16) (a) Melzig, L.; Gavryushin, A.; Knochel, P. Org. Lett. 2007, 9, 5529.
(b) Giovannini, R.; Stu¨demann, T.; Dussin, G.; Knochel, P. J. Org. Chem. 1999,
64, 3544. (c) Giovannini, R.; Stu¨demann, T.; Dussin, G.; Knochel, P. Angew.
Chem., Int. Ed. 1998, 37, 2387.
(17) Gavryushin, A.; Kofink, C.; Manolikakes, G.; Knochel, P. Org. Lett.
2005, 7, 4871.
J. Org. Chem. Vol. 73, No. 21, 2008 8431

Manolikakes et al.
SCHEME 2. Cross-Coupling of Bromoethynylbenzene 14a and 14ba
a Reaction conditions: 2.0 mmol of aryl bromide, 2.4 mmol of zinc reagent, Pd(OAc)2 (1 mol %), L3 (2 mol %).
TABLE 5. Screening of Various Nickel-Ligand Systems for the
at -10 °C, 80% of PhZnI ·LiCl (1a) and 20% of OctZnBr ·LiCl
(1g) were protonated, whereas almost no protonation of
PhCH2ZnCl·LiCl (1q) was observed. After the addition of the
second equivalent of iPrOH, the protonation of more than 97%
of PhZnI·LiCl (1a) and 90% of OctZnBr·LiCl (1g) was
observed. These results indicate the relative kinetic basicity of
zinc reagents: arylzinc halide > alkylzinc halide > benzylzinc
halide.19
Negishi Cross-Coupling of Unprotected Aniline (2a)
yield [%]a b
,
entry
ligand
In order to investigate the reactivity of organozinc compounds
with acidic protons, these organometallics were treated with an
equimolar amount of an amine or an alcohol.20 Thus, n-
butylamine was added to a solution of PhZnI ·LiCl (1a),
OctZnBr·LiCl (1g), or PhCH2ZnCl·LiCl (1q) in THF (Figure
1). In the case of this comparatively weak acid, all three zinc
reagents are quite unreactive. After 24 h, only 25% of
PhZnI·LiCl (1a) is protonated. The less basic alkylzinc bromide
1g led to only 8% of protonation, and almost no protonation of
benzylzinc chloride (1q) occurred (98% of active zinc reagent).
These stabilities are in accordance with the results obtained in
the cross-coupling reactions with primary and secondary amines
(Table 1, entries 16-20), where long reaction times still led to
full conversion of the aryl bromides prior to the protonation of
the zinc reagents.
In a second experiment, PhZnI ·LiCl (1a), OctZnBr ·LiCl (1g),
or PhCH2ZnCl·LiCl (1q) was treated with an equimolar amount
of aniline (Figure 1). The addition of aniline to phenylzinc iodide
(1a) resulted in a relatively fast protonation. After 15 min,
already more than 50% of the corresponding zinc reagent was
protonated. In comparison, only 33% of alkylzinc bromide 1g
and 6% of benzylzinc chloride 1q were protonated after 4 h.
Noteworthy is also the long-term stability of the benzylic zinc
reagent 1q. After 1 day of stirring at 25 °C, there is still 73%
of the active zinc reagent present, as confirmed by quenching
with CuCN/allyl bromide (0% for 1a, 14% for 1g).
1
2
3
4
5
6
7
PPh3 (8 mol %)
62
77
17
12
18
16
15
2,2′-bipyridine (3 mol %)c
tfp (8 mol %)
dppe (6 mol %)
1,10-phenanthroline (6 mol %)
IPr ·HCl (4 mol %)
(EtO)2P(O)H (8 mol %)
a Yields were determined by GC analysis with tetradecane as internal
standard. b Slow addition of the zinc reagent over 90 min with a syringe
pump. c Ni(acac)2 (2 mol %) was used instead.
out to be superior compared to the conditions used for arylzinc
halides. Thus, the benzylic zinc chlorides 1j-1q reacted with
the aryl bromides 2a-2h within 2 h, affording the functionalized
diarylmethanes 3af-3am in 60-90% yield (entries 6-13).
Although the nickel-catalyzed reaction afforded high yields
combined with the use of cheap nickel and ligands,18 it displayed
several disadvantages. Functionalized arylzinc compounds were
not suitable and led to low yields (typically <20%). Also it
was difficult to predict if a chosen combination of zinc reagent
and aryl bromide would afford the desired product in satisfactory
yields.
Basicity of Organozinc Reagents. In order to understand
the chemoselectivity of the different zinc reagents toward aryl
halides, bearing acidic OH protons, we next examined their
relative basicity and also their stability in the presence of
relatively acidic hydrogens. To evaluate the relative basicity of
various types of organozinc compounds, we have treated an
equimolar mixture of PhZnI ·LiCl (1a), OctZnBr ·LiCl (1g), and
PhCH2ZnCl·LiCl (1q) with various amounts of iPrOH (Scheme
3). Interestingly, we have observed that a chemoselectiVe
protonation occurs. Thus, after the addition of 1 equiv of iPrOH
The same experiment with iPrOH as proton source led to a
rapid protonation of all three organozinc compounds (Figure
3). PhZnI·LiCl (1a) was protonated immediately (0% of active
zinc reagent after 30 s) and 73% of OctZnBr ·LiCl (1g) was
(19) For the reactivity of 1,1-bimetallic species towards protonation, see
also: Knochel, P.; Normant, J. F. Tetrahedron Lett. 1986, 27, 1043.
(20) For the preparation of zinc and copper organometallics bearing acidic
hydrogens, see: Knoess, H. P.; Rozema, M. J.; Knochel, P. J. Org. Chem. 1991,
56, 5974.
(18) Ni(acac)2 (0.48 euro/g), Pd(OAc)2 (29.40 euro/g), 2,2′-bipyridine (0.83
euro/g), and PPh3 (0.07 euro/g) were purchased from Alfa Aesar, L3 (139.50
euro/g) from Strem.
8432 J. Org. Chem. Vol. 73, No. 21, 2008

TABLE 6. Nickel-Catalyzed Cross-Coupling of Anilines of Type 2 and Amines of Type 4a
J. Org. Chem. Vol. 73, No. 21, 2008 8433

Manolikakes et al.
TABLE 6. Continued
a Reaction conditions: 3.0 mmol of aryl bromide, 3.6 mmol of zinc reagent, catalyst as mentioned, slow addition of the zinc reagent over 90 min via
syringe pump and stirred for an additional time. b Isolated yield of analytically pure product. c Ni(acac)2 (2 mol %), 2,2′-bipyridine (3 mol %).
d Ni(acac)2 (2.5 mol %), PPh3 (10 mol %).
SCHEME 3. Selective Protonation of Organozinc Reagentsa
a Yields are determined by quenching with CuCN/allyl bromide in THF and GC analysis with tetradecane as internal standard.
protonated after 5 min; PhCH2ZnCl·LiCl (1q) was slightly more
stable and after 15 min still 55% of the active zinc reagent was
detected. These results can explain the quite different reactivity
of the three zinc reagents with various aryl halides, bearing
acidic OH functions (Table 3). The strongly basic arylzinc
reagents can only be coupled with sterically hindered alcohols,
and better yields can be obtained with more reactive aryl iodides,
whereas alkylzinc bromides also tolerate less hindered alcohol
functions. The least basic benzylic zinc reagents even tolerate
more acidic phenolic protons. Using phenol as protons source
led to an instant hydrolysis of phenylzinc iodide (1a) and
octylzinc bromide (1g, 0% of the active zinc reagent was
observed after 30 s). Although ca. 70% of PhCH2ZnCl·LiCl
(1q) was protonated with phenol after 30 s, the stability seems
to be sufficient to undergo cross-coupling reaction prior to the
capture of a proton if the concentration of the reactive palladium
species is high enough to react with the benzylic zinc compound.
These results indicate the same relative kinetic basicity:
arylzinc halide > alkylzinc halide > benzylzinc halide.21 The
reason for this different relative basicity of organozinc reagents
(21) Using OctZnI · LiCl or PhCH2ZnCl · LiCl led to similar results.
8434 J. Org. Chem. Vol. 73, No. 21, 2008

FIGURE 1. Relative reaction rates of organozinc reagents with n-butylamine. Yields are determined by quenching with CuCN/allyl bromide in
THF and GC analysis with tetradecane as internal standard.
FIGURE 2. Stability of organozinc reagents toward aniline. Yields are determined by quenching with CuCN/allyl bromide in THF and GC analysis
with tetradecane as internal standard.
compared to those of carbanions or organolithium compounds
(alkyl > aryl > benzyl)22 may result from different aggregation
of zinc and lithium reagents.
reported a nickel-catalyzed version of this reaction with a smaller
substrate scope, but more economical. We have also investigated
the relative basicity of the used zinc reagents and their stability
toward acidic protons. The relative kinetic basicity of the
organozinc compounds was found to be arylzinc halide >
alkylzinc halide > benzylic zinc halide.
3. Conclusion
In summary, we have developed a general and efficient
palladium-catalyzed protocol for the cross-coupling of orga-
nozinc reagents with unsaturated aryl halides in the presence
of relatively acidic protons. No protection or deprotonation by
an additional base prior to the coupling reaction of these acidic
protons is required. The reaction has a broad substrate scope
and could be even applied to bromophenols. Additionally, we
4. Experimental Section
General Considerations. All reactions were carried out under
nitrogen using standard Schlenk techniques. Reactions were
monitored by gas chromatography (GC and GC-MS) or thin layer
chromatography. Yields refer to the isolated yields of compounds
1
estimated to be >97% pure, as determined by H NMR. Melting
points are uncorrected. Solvents were dried according to the
commonly used procedures. All ligands were prepared according
(22) Organometallics in Synthesis: A Manual, 2nd ed.; Schlosser, M., Ed.;
Wiley: Chichester, UK, 2002.
J. Org. Chem. Vol. 73, No. 21, 2008 8435

Manolikakes et al.
FIGURE 3. Reactivity of organozinc reagents with iPrOH. Yields are determined by quenching with CuCN/allyl bromide in THF and GC analysis
with tetradecane as internal standard.
to literature procedures mentioned above. All the starting materials
were purchased from commercial sources and used without further
purification.
(1o, 2.6 mL, 0.92 M in THF, 2.4 mmol) was added slowly over 90
min with a syringe pump. The reaction mixture was stirred for 1 h
at 25 °C. Then, the reaction mixture was quenched with a saturated
aq NH4Cl solution and extracted with ether (3 × 25 mL). The
combined organic phases are washed with an aq thiourea solution
and dried over Na2SO4. Purification of the crude residue obtained
after evaporation of the solvents by flash chromatography (pentane/
ether 9:1) yielded [4-(2-chlorobenzyl)phenyl]methanol (10j) as a
Typical Procedure 1 (Cross-Coupling with a Bromoaniline):
Preparation of 4′-Aminobiphenyl-4-carbonitrile (3f): A dry and
argon flushed 20 mL Schlenk tube was charged with 4-bromoaniline
(2a, 516 mg, 3 mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol), S-Phos
(L3, 24.6 mg, 0.06 mmol), and THF (2 mL). After stirring the
reaction mixture for 5 min, 4-cyanophenylzinc iodide (1g, 3.8 mL,
0.95 M in THF, 3.6 mmol) was added. The reaction mixture was
stirred for 2 h at 25 °C. Then, the reaction mixture was quenched
with a saturated aq NH4Cl solution and extracted with ether (3 ×
25 mL). The combined organic phases are washed with an aq
thiourea solution and dried (Na2SO4). Purification of the crude
residue obtained after evaporation of the solvents by flash chro-
matography (pentane/ether 7:3) yielded 4′-aminobiphenyl-4-car-
bonitrile (3f) as a light yellow solid (559 mg, 96% yield): mp
181.0-183.0 °C; 1H NMR (CDCl3, 300 MHz, 25 °C) δ )
7.67-7.58 (m, 4H), 7.41 (ddd, J ) 8.2, 1.5, 0.4 Hz, 2H), 6.76
(ddd, J ) 8.2, 1.5, 0.4 Hz, 2H), 3.87 (s, 2H); 13C NMR (CDCl3,
75 MHz, 25 °C) δ ) 147.2, 145.5, 132.5, 129.0, 128.2, 126.6, 119.3,
115.3, 109.5; MS (EI, 70 eV) m/z (%) 194 (34) [M+], 166 (44),
140 (29), 97 (14), 77 (11).
1
colorless solid (456 mg, 98% yield): mp 78.1-80.1 °C; H NMR
(CDCl3, 300 MHz, 25 °C) δ ) 7.39-7.34 (m, 1H), 7.30-7.27 (m,
2H), 7.22-7.10 (m, 5H), 4.65 (s, 2H), 4.10 (s, 2H), 1.67 (s, 1H);
13C NMR (CDCl3, 75 MHz, 25 °C) δ ) 139.0, 138.8, 138.5, 134.2,
131.0, 129.5, 129.1, 127.7, 127.2, 126.8, 65.2, 38.9; HRMS m/z
calcd for C14H13ClO 232.0655, found 232.0647; MS (EI, 70 eV)
m/z (%) 232 (87) [M+], 201 (44), 179(24), 165 (100), 107 (94); IR
(cm-1) 3301 (m), 3049 (w), 3012 (w), 2914 (w), 2865 (w), 1514
(m), 1469 (m), 1443 (m), 1421 (m), 1344 (w), 1292 (w), 1210 (w),
1048 (m), 1033 (s), 1018 (s), 995 (m), 911 (m).
Acknowledgment. We thank the Fonds der Chemischen
Industrie, SFB 749, and the DFG for financial support, and
Saltigo (Leverkusen), Chemetall (Hanau), and BASF (Ludwig-
shafen) for the generous gift of chemicals.
Typical Procedure 2 (Cross-Coupling with a Bromoalcohol):
Preparation of [4-(2-Chlorobenzyl)phenyl]methanol (10j): A dry
and argon flushed 20 mL Schlenk-tube was charged with 4-bro-
mobenzyl alcohol (8h, 374 mg, 2 mmol), Pd(OAc)2 (4.5 mg, 0.02
mmol), S-Phos (L3, 16.4 mg, 0.04 mmol), and THF (2 mL). After
stirring the reaction mixture for 5 min, 2-chlorobenzylzinc chloride
Supporting Information Available: Experimental proce-
dures and characterization of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8015852
8436 J. Org. Chem. Vol. 73, No. 21, 2008