Pd- and Ni-catalyzed cross-coupling reactions of functionalized organozinc reagents with unsaturated thioethers

Article abstract of DOI:10.1002/chem.201002850

A variety of unsaturated thioethers have been subjected to cross-coupling reactions with functionalized zinc reagents in the presence of a transition-metal catalyst. Three different catalytic systems based on Pd(OAc)₂ or [Ni(acac)₂] and the ligands S-Phos or DPE-Phos gave the best results. N-Heterocyclic thioethers based on a pyridine, pyrimidine, pyrazine, pyridazine, triazine, benzothiazole, benzoxazole, pyrrole, or quinazoline ring, as well as thiomethylacetylenes, serve as electrophiles in this cross-coupling reaction. Aryl-, heteroaryl-, benzylic, and alkylzinc halides with sensitive functionalities, such as ester, nitrile, or ketone groups react at ambient temperature with unsaturated thioethers using a Ni catalyst. The corresponding Pd-catalyzed reactions require slightly higher temperatures. Large-scale cross-coupling experiments (10-20 mmol) with N-heterocycles are also reported.

Full text of DOI:10.1002/chem.201002850

DOI: 10.1002/chem.201002850
Pd- and Ni-Catalyzed Cross-Coupling Reactions of Functionalized
Organozinc Reagents with Unsaturated Thioethers
Laurin Melzig, Albrecht Metzger, and Paul Knochel*[a]
Abstract: A variety of unsaturated thi-
triazine, benzothiazole, benzoxazole,
pyrrole, or quinazoline ring, as well as
thiomethylacetylenes, serve as electro-
philes in this cross-coupling reaction.
Aryl-, heteroaryl-, benzylic, and alkyl-
zinc halides with sensitive functionali-
oethers have been subjected to cross-
coupling reactions with functionalized
zinc reagents in the presence of a tran-
sition-metal catalyst. Three different
ties, such as ester, nitrile, or ketone
groups react at ambient temperature
with unsaturated thioethers using a Ni
catalyst. The corresponding Pd-cata-
lyzed reactions require slightly higher
temperatures. Large-scale cross-cou-
pling experiments (10–20 mmol) with
N-heterocycles are also reported.
catalytic systems based on PdACHTUGNRTEN(NUGN OAc)2 or
[Ni(acac)2] and the ligands S-Phos or
ACHTUNGTRENNUNG
Keywords: cross-coupling · hetero-
cycles · homogeneous catalysis ·
nickel · palladium · zinc
DPE-Phos gave the best results. N-
Heterocyclic thioethers based on a pyr-
idine, pyrimidine, pyrazine, pyridazine,
Introduction
actions of unsaturated heterocyclic[8] and alkynyl[9] thioeth-
ers with organozinc reagents under mild conditions. Herein,
we report the full scope of these novel cross-coupling reac-
tions.
The conversion of a carbon–sulfur bond into a carbon–
carbon bond under transition-metal catalysis is a useful
cross-coupling procedure, which is especially important
when the corresponding organic halides are unstable or dif-
ficult to prepare. In 1979, the groups of Wenkert and Takei
described the cross-coupling between unsaturated thioethers
or thiols and Grignard reagents under nickel catalysis.[1]
Later, Fukuyama and co-workers, and in particular Liebe-
skind and co-workers, extended the scope of this cross-cou-
pling reaction, which led to a general ketone synthesis that
involved reacting functionalized thioesters with organozinc
reagents or organoboronic acids in the presence of a palladi-
um catalyst.[2] Furthermore, organostannanes,[3] as well as or-
ganoindium reagents,[4] have also been used as nucleophilic
partners for the direct synthesis of ketones starting from the
corresponding thioesters. More recently, this Pd-catalyzed
reaction has been modified to allow the coupling of organo-
boronic acids or organostannanes with heteroaromatic or al-
kynyl thioethers.[5] All of these cross-coupling reactions re-
quire stoichiometric amounts of CuI salts to proceed. Zinc
organometallics are very useful reagents for organic synthe-
sis due to their high tolerance to a broad range of functional
groups.[6] However, they have rarely been used for cross-
coupling reactions with unsaturated thio derivatives.[7] Re-
cently, we reported Pd- and Ni-catalyzed cross-coupling re-
Results and Discussion
Preparation of unsaturated thioethers: Thioether-substituted
N-heterocycles, as well as acetylenes can be easily prepared
by several methods, as shown in Scheme 1. The thioether
moiety can be attached to N-heterocycles by the direct sub-
stitution of a halogen atom using the corresponding thiolate.
Thus, the chloro-substituted triazine 1a reacted with sodium
thiomethanolate in DMF or MeCN at 258C to provide the
corresponding
2,4-dimethoxy-6-(methylthio)-1,3,5-triazine
(2a) in 87% yield (Scheme 1a).[8a] Alternatively, heterocy-
cles may be metallated and then quenched with MeSSMe.
Thus, N-methylpyrrole (1b) was lithiated with nBuLi[10] and
the resulting lithium reagent was treated with dimethyl di-
sulfide to afford 1-methyl-2-(methylthio)pyrrole (2b) in
68% yield (Scheme 1b). The methylation of heterocyclic
thiols constitutes another method. Thus, successive treat-
ment of benzoxazole-2-thiol (1c) at 258C with sodium hy-
dride and iodomethane gave 2-(methylthio)-1,3-benzoxazole
(2c) in almost quantitative yield (Scheme 1c).[11] This meth-
ylation step could be combined with a condensation reac-
tion.[12] The reaction of 4,4,4-trifluoro-1-(2-thienyl)butane-
1,3-dione (1d) with thiourea, followed by the above steps
with sodium hydride and iodomethane, gave the functional-
ized pyrimidine 2d in 19% overall yield (Scheme 1d). In the
case of the polyfunctional alkynyl steroid 1e,[13] deprotona-
tion with iPrMgCl·LiCl[14] and subsequent treatment with S-
methyl methanethiosulfonate afforded the thiomethylated
ethynyl estradiol derivative 3a in 83% yield (Scheme 1e).[9]
[a] L. Melzig, A. Metzger, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax : (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002850.
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FULL PAPER
Scheme 2. Pd-catalyzed cross-coupling reaction of thiomethyl-substituted
N-heterocycles 2 with functionalized organozinc reagents 4; Cy=cyclo-
hexyl.
methylthio-substituted pyridazine 2e to give the functional-
ized pyridazine 5c in 76% yield (258C, 4 h, Table 1,
entry 3). Functionalized benzylic zinc reagents reacted
straightforwardly and the coupling of 3-cyanobenzylzinc
chloride (4d) and pyridazine 2e afforded the substituted di-
arylmethane 5d in 71% yield (508C, 14 h, Table 1, entry 4).
Other diaza heterocycles, such as 2-thiomethylpyrazine (2 f)
or 2-thiomethylpyrimidine (2g), also underwent smooth
cross-coupling reactions. Thus, the reactions of 1-naphthyl-
zinc iodide (4e) or 3-(trifluoromethyl)benzylzinc chloride
(4 f) with methylthio-substituted pyrazine 2 f, as well as pyri-
midine 2g led to the desired compounds 5e–5g in yields of
59–83% within 16–20 h at 258C (Table 1, entries 5–7). Fur-
thermore, thioether-substituted pyridines were also suitable
coupling partners for the described reaction protocol. Thus,
nicotinic ester 2h underwent an efficient cross-coupling with
the electron-poor arylzinc reagent 4g to afford ethyl 2-[4-
(ethoxycarbonyl)phenyl]nicotinate (5h) in 69% yield (258C,
6 h, Table 1, entry 8). Similarly, trifluoromethyl-substituted
pyridine 2i gave, after cross-coupling with 4-cyanopropylzinc
bromide (4h, 258C, 16 h), the alkylated heterocycle 5i in
84% yield (Table 1, entry 9). The reaction of 6,7-dimethoxy-
4-(methylthio)quinazoline (2j) with the same alkylzinc re-
agent 4h or with the ester-substituted benzylic zinc reagent
4i yielded the functionalized quinazolines 5j and 5k in
yields of 74 and 78%, respectively (Table 1, entries 10 and
11). Finally, this Pd-catalyzed cross-coupling reaction could
also be performed with electron-rich N-heterocycles, such as
the Boc-protected pyrrole 2k. Reaction of the latter with 4-
methoxyphenylzinc iodide (4a) smoothly afforded tert-butyl
2-(4-methoxyphenyl)-1H-pyrrole-1-carboxylate (5l) in 67%
yield (258C, 2 h, Table 1, entry 12).
Scheme 1. Various pathways for the synthesis of unsaturated thioethers;
MOM=methoxymethyl.
Bis(thiomethyl)acetylene (3b) was prepared in 55% yield
by using sodium acetylide (1 f) and methyl thiocyanate
(258C, 1 h, Scheme 1f).[15] These various synthetic methods
allowed us to prepare a variety of functionalized unsaturat-
ed thioethers, which were used in the subsequent Pd- and
Ni-catalyzed cross-coupling reactions.
Pd-catalyzed cross-coupling reactions of unsaturated N-het-
erocycles with organozinc reagents: Pd0-catalyzed cross-cou-
pling reactions of functionalized aryl-, benzylic-, and alkyl-
zinc reagents (1.5 equiv) with various thiomethyl-substituted
N-heterocycles (1.0 equiv) were best carried out using Pd-
Selective bis-functionalization of pyrimidines at their 2-
and 4-positions could be achieved. Cross-coupling occurs at
the 2- or 4-position depending on the substrate. Thus, the re-
action of 2-bromo-4-(methylthio)pyrimidine (2l) with 4-me-
thoxybenzylzinc chloride (4j, 1.02 equiv) proceeded rapidly
ACHTUNGTRENNUNG(OAc)2/S-Phos as the catalytic system. This efficient combi-
nation was originally introduced by Buchwald[16]
(Scheme 2). Most of the reactions described herein were car-
ried out at 258C within 2–20 h.
in the presence of [Pd
tone, tfp=tri(2-furyl)phosphine) within 3 h at 258C
(Scheme 3a).[17] After direct addition of a second catalyst
system (Pd(OAc)2/S-Phos) to the reaction mixture, a second
ACHTUNGRTEN(NUNG dba)2]/tfp (dba=dibenzylideneace-
Thus, 2,4-dimethoxy-6-(methylthio)-1,3,5-triazine (2a,
1.0 equiv) reacted with 4-methoxyphenylzinc iodide (4a,
1.5 equiv) in THF (258C, 5 h) to provide the triazine 5a in
83% yield (Table 1, entry 1). Furthermore, the triazine 2a
was used for a cross-coupling reaction with cyclohexylzinc
bromide (4b) in THF (258C, 20 h), which led to the func-
tionalized triazine 5b in 43% yield (Table 1, entry 2). More-
over, 4-cyanophenylzinc iodide (4c) reacted smoothly with
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
cross-coupling occurred with 4-(ethoxycarbonyl)phenylzinc
iodide (4g, 1.50 equiv) to provide the 2,4-disubstituted pyri-
midine 5m in 67% overall yield. Alternatively, 4-iodo-2-
(methylthio)pyrimidine (2m) was converted into the regioi-
someric 2,4-disubstituted pyrimidine 5n by first performing
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P. Knochel et al.
Table 1. Pd-catalyzed cross-coupling reactions of thiomethylated N-het-
erocycles.
Entry
Electrophile
Zinc reagent
Product, Conditions, Yield[a]
1
2a
2a
4a
4b
5a: 258C, 5 h, 83%
5b: 258C, 20 h, 43%
2
3
4
2e
2e
4c
4d
5c: 258C, 4 h, 76%
5d: 508C, 14 h, 71%
Scheme 3. Selective one-pot cross-coupling reactions of a) 2-bromo-4-
(methylthio)pyrimidine (2l) and b) 4-iodo-2-(methylthio)pyrimidine
(2m).
5
6
a cross-coupling with 4-methoxybenzylzinc chloride (4j,
2 f
2g
4e
4e
5e: 258C, 18 h, 83%
5 f: 258C, 20 h, 75%
1.02 equiv) using [Pd
rying out a second cross-coupling with the arylzinc reagent
4g (1.50 equiv) in the presence of Pd(OAc)2/S-Phos (258C,
ACHTUNGRTEN(NUNG dba)2]/tfp (258C, 10 min) and then car-
AHCTUNGTRENNUNG
20 h). The pyrimidine 5n was obtained in 80% overall yield
by this one-pot double cross-coupling sequence
(Scheme 3b).
7
8
Ni-catalyzed cross-coupling reactions of thiomethyl-substi-
tuted N-heterocycles with organozinc reagents: Thiomethy-
lated N-heterocycles (1.0 equiv) could also be cross-coupled
with functionalized aryl-, benzylic-, and alkylzinc reagents
(1.5 equiv) under Ni0 catalysis. By using the inexpensive and
2g
4 f
5g: 258C, 16 h, 59%
robust system of [NiACHTNUTRGNE(NUG acac)2] (2.5 mol%) and bis(2-diphenyl-
phosphinophenyl)ether (DPE-Phos, 5.0 mol%), the reac-
tions took place within 5–20 h at 258C in THF (Scheme 4).
2h
2i
4g
4h
5h: 258C, 6 h, 69%
5i: 258C, 16 h, 84%
9
10
2j
4h
5j: 258C, 5 h, 74%
11
12
Scheme 4. Ni-catalyzed cross-coupling reaction of thiomethyl-substituted
N-heterocycles 2 with functionalized organozinc reagents 4.
2j
4i
5k: 508C, 12 h, 78%
5l: 258C, 2 h, 67%
Utilizing this protocol, the triazine 2a (1.0 equiv) under-
went cross-coupling with the trifluoromethyl-substituted
benzylic zinc reagent 4 f (1.5 equiv) in 4 h at 258C, to afford
2,4-dimethoxy-6-[3-(trifluoromethyl)benzyl]-1,3,5-triazine
(5o) in 72% yield (Table 2, entry 1). Similarly, triazine 2a
reacted with 4-fluorobenzylzinc chloride (4k) or 3-penta-
2k
4a
[a] Yield of isolated, analytically pure product.
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Highly Versatile Pd- and Ni-Catalyzed Cross-Coupling Reactions
FULL PAPER
Table 2. Ni-catalyzed cross-coupling reactions of thiomethylated N-het-
erocycles.
noylbenzylzinc chloride (4l) to give the diarylmethanes 5p
and 5q in yields of 89 and 82%, respectively (Table 2, en-
tries 2 and 3). Thiomethyl-substituted pyridazine 2e under-
went a straightforward cross-coupling with 4-chlorophenyl-
zinc iodide (4m) to afford the 3,6-difunctionalized pyrida-
zine 5r in 72% yield (Table 2, entry 4). Cross-coupling of 4-
methyl-2-(methylthio)pyrimidine (2n) with the electron-de-
ficient ester-substituted arylzinc reagent 4n provided the 2-
arylpyrimidine 5s in 95% yield (Table 2, entry 5). The reac-
tion of trifluoromethylated pyrimidine 2d with 2-thienylzinc
iodide (4o) gave the trisubstituted pyrimidine 5t in 94%
yield (Table 2, entry 6). Alkylzinc reagents were also found
to be well suited to these Ni-catalyzed reactions. Thus, as ex-
pected, reactions of 2-methylthiobenzoxazole (2c) with
either the chloro-substituted benzylic zinc reagent 4p or 5-
cyano-5-methylhexylzinc bromide (4q) at 258C provided the
benzoxazole derivatives 5u and 5v in yields of 76 and 82%,
respectively (Table 2, entries 7 and 8). Similarly, the cross-
coupling reaction of 4-(N,N-dimethylamino)phenylzinc
iodide (4r) with benzo[d]thiazole 2o gave the 2-arylbenzo-
thiazole 5w in 89% yield (258C, 5 h, Table 2, entry 9). Fur-
thermore, reactions of 2-(methylthio)nicotinonitrile (2p)
with the organozinc reagents 4g and 4p led to the 2,3-disub-
stituted pyridines 5x and 5y in yields of 67 and 69%, re-
spectively (Table 2, entries 10 and 11). Finally, the electron-
rich 1-methyl-2-(methylthio)-1H-pyrrole (2b) also reacted
Entry
Electrophile
Zinc reagent
Product, Conditions, Yield[a]
1
2a
4 f
5o: 258C, 4 h, 72%
2
2a
2a
4k
4l
5p: 258C, 4 h, 89%
5q: 258C, 5 h, 82%
3
4
2e
2n
4m
4n
5r: 258C, 6 h, 72%
5s: 258C, 12 h, 95%
5
6
well with 4-fluorobenzylzinc chloride (4k) using [NiACHTUNGTRENNUNG(acac)2]/
DPE-Phos to afford the functionalized pyrrole 5z in 42%
yield (508C, 18 h, Table 2, entry 12).
2d
2c
4o
4p
5t: 258C, 16 h, 94%
5u: 258C, 18 h, 76%
Large-scale cross-coupling reactions of thiomethylated N-
heterocycles: To demonstrate that these cross-coupling pro-
tocols can be scaled-up, additional Pd- and Ni-catalyzed re-
actions were carried out on a larger scale. Thus, pyrimidine
2n (1.0 equiv) was reacted with 4-(ethoxycarbonyl)phenyl-
zinc iodide (4g, 1.5 equiv) on a 10 mmol scale under Pd cat-
alysis (258C, 3 h), which gave ethyl 4-(4-methylpyrimidin-2-
yl)benzoate (5aa) in 91% yield (Scheme 5). This arylzinc
iodide 4g also underwent a straightforward cross-coupling
reaction with 2,4-dimethoxy-6-(methylthio)-1,3,5-triazine
(2a) on a 20 mmol scale, which gave the triazine 5ab in
86% yield (258C, 18 h). 2-Methylthiopyrazine (2 f) was used
in a Ni-catalyzed cross-coupling reaction with 4-methoxy-
benzylzinc chloride (4j), which led to the functionalized dia-
rylmethane 5ac (258C, 15 h, 10 mmol scale, 84% yield). Fi-
nally, the arylzinc reagent 4r reacted smoothly with the thio-
methyl-substituted benzothiazole 2o to give 4-(benzo[d]thia-
zol-2-yl)-N,N-dimethylaniline (5w) in 85% yield (258C, 5 h,
20 mmol scale).
7
8
2c
2o
4q
4r
5v: 258C, 12 h, 82%
5w: 258C, 5 h, 89%
9
10
11
2p
2p
4g
4p
5x: 258C, 18 h, 67%
5y: 258C, 24 h, 69%
Pd-catalyzed cross-coupling reactions of ethynyl thioethers:
Pd0-catalyzed cross-coupling reactions of functionalized
aryl-, heteroaryl-, and alkylzinc reagents (1.5 equiv) with
various thiomethyl-substituted acetylenes (1.0 equiv) were
12
achieved by using PdACHTUNTRGNEUNG(OAc)2/DPE-Phos as the catalytic
system (Scheme 6). These reactions could be carried out at
2b
4k
5z: 508C, 18 h, 42%
[a] Yield of isolated, analytically pure product.
25–508C and were complete within 6–24 h.
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P. Knochel et al.
thio)ethynyl]benzene (3e) reacted smoothly with the elec-
tron-deficient zinc reagents 4m and 4g at 258C to give the
expected products 6e and 6 f in yields of 76 and 77%, re-
spectively (Table 3, entries 5 and 6). Secondary alkylzinc re-
agents could also be used. Cyclohexylzinc bromide (4b) un-
derwent a smooth cross-coupling reaction with the unsatu-
rated thioether 3e (258C, 18 h), from which the substituted
cyclohexylethylene derivative 6g was isolated in 66% yield
(Table 3, entry 7). The use of heterocyclic reagents as both
the electrophile and the organozinc species proved to be
compatible with these reaction conditions. Thus, the pyri-
dine derivative 3 f could be coupled with 2-thienylzinc
iodide (4o) to give the bis-heteroarylacetylene 6h in 72%
yield (508C, 8 h, Table 3, entry 8). Alkyl-substituted acety-
lenes have also been successfully used, and the cross-cou-
pling reactions of 1-[(methylthio)ethynyl]cyclohexene (3g)
with 2,4-dichlorophenylzinc iodide (4s) or 2-thienylzinc
iodide (4o, 258C, 10–16 h) led to the expected cyclohexeny-
lacetylenes 6i and 6j in yields of 69 and 65%, respectively
(Table 3, entries 9 and 10). Remarkably, bis(methylthio)ace-
tylene (3b, 1.0 equiv) could be easily cross-coupled using
the catalytic system and 3.0 equivalents of the organozinc
compound. This is especially useful since the corresponding
dihaloacetylenes are known to be toxic, carcinogenic, and
explosive, and consequently not practical substrates. Thus,
the thioether-substituted alkyne 3b was functionalized with
heteroarylzinc reagent 4o or 2-benzofuranylzinc iodide (4t)
to afford the symmetrically substituted acetylenes 6k and 6l
in yields of 67 and 74%, respectively (508C, 3–20 h, Table 3,
entries 11 and 12). Electron-rich arylzinc reagents 4u and
4v, as well as their electron-deficient counterparts, such as
4-(ethoxycarbonyl)phenylzinc iodide (4g) and 4-cyanophe-
nylzinc iodide (4c), each reacted smoothly with bis(meth-
ylthio)acetylene (3b) to deliver the bis-arylacetylenes 6m–
6p in yields of 64–79% (25–508C, 10–16 h, Table 3, en-
tries 13–16).
Scheme 5. Large-scale cross-couplings of thiomethyl-substituted N-het-
erocycles 2 with organozinc reagents 4 under Pd or Ni catalysis.
Scheme 6. Pd-catalyzed cross-coupling reaction of thiomethyl-substituted
Finally, the (methylthio)ethynyl-substituted steroid 3a was
prepared starting from commercially available ethynyl estra-
diol (Scheme 1e) and was easily functionalized by using 4-
(dimethylamino)phenylzinc iodide (4r, 1.5 equiv, 258C, 8 h)
to afford the protected ethynyl estradiol derivative 6q in
75% yield (Scheme 7).
acetylenes 3 with functionalized organozinc reagents 4.
Thus, [(methylthio)ethynyl]benzene (3c, 1.0 equiv) react-
ed with 4-chlorophenylzinc iodide (4m, 1.5 equiv) to afford
the bis-arylacetylene 6a in 68% yield (258C, 24 h, Table 3,
entry 1). Acetylene 3c was also used for cross-coupling reac-
tions with functionalized alkylzinc reagents. For example, 4-
cyanopropylzinc bromide (4h) underwent a smooth cross-
coupling reaction with 3c to afford alkyne 6b in 52% yield
(508C, 16 h, Table 3, entry 2). Moreover, 1-chloro-4-[(meth-
ylthio)ethynyl]benzene (3d) reacted well with 4-chlorophe-
nylzinc iodide (4m) to afford the symmetrically substituted
bis-arylacetylene 6c in 73% yield (508C, 12 h, Table 3,
entry 3). Sensitive functional groups, such as an ester group,
were also tolerated in this cross-coupling reaction. Thus, re-
action of the chloro-substituted phenylacetylene 3d with 4-
(ethoxycarbonyl)phenylzinc iodide (4g) provided the func-
tionalized bis-arylacetylene 6d in 53% yield (508C, 6 h,
Table 3, entry 4). Similarly, 1-trifluoromethyl-4-[(methyl-
Scheme 7. Pd-catalyzed cross-coupling reaction of the MOM-protected
ethynyl estradiol derivative 3a with 4-(N,N-dimethylamino)phenylzinc
iodide (4r).
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Highly Versatile Pd- and Ni-Catalyzed Cross-Coupling Reactions
Table 3. Pd-catalyzed cross-coupling reactions of thiomethylated acetylenes.
FULL PAPER
Entry
Electrophile
Zinc reagent
Product, Conditions, Yield[a]
Entry
Electrophile
Zinc reagent
Product, Conditions, Yield[a]
1
9
3c
3c
4m
4h
6a: 258C, 24 h, 68%
6b: 508C, 16 h, 52%
3g
3g
4s
6i: 258C, 10 h, 69%
6j: 258C, 16 h, 65%
2
3
10
11
4o
3d
3d
4m
6c: 508C, 12 h, 73%
3b
3b
4o
6k: 508C, 20 h, 67%[b]
4
5
6
12
13
14
4g
6d: 508C, 6 h, 53%
4t
6l: 508C, 3 h, 74 %[b]
3e
4m
6e: 258C, 12 h, 76%
3b
3b
4u
6m: 258C, 10 h, 79%[b]
3e
4g
6 f: 258C, 20 h, 77%
4v
6n: 258C, 14 h, 73%[b]
7
8
15
16
3e
3 f
4b
4o
6g: 258C, 18 h, 66%
6h: 508C, 8 h, 72%
3b
3b
4g
4c
6o: 508C, 12 h, 67%[b]
6p: 508C, 16 h, 64%[b]
[a] Yield of isolated, analytically pure product. [b] 3.0 equivalents of the zinc reagent were used.
Comparison between Pd and Ni catalysts used in cross-cou-
pling reactions of organozinc reagents with N-heterocyclic
methyl thioethers: We have compared the reactivities of the
two different catalytic systems used for the cross-coupling
reactions between various functionalized zinc reagents
(1.5 equiv) and thiomethyl-substituted N-heterocycles
(1.0 equiv). Six different compounds were prepared using
both of the described protocols. The reaction times, temper-
atures, and yields of the isolated products were compared,
and the results of these experiments are shown in Table 4.
Arylzinc reagents were investigated first. Thus, the electron-
rich organozinc reagent 4a (1.5 equiv) was treated with 2-
thiomethylbenzothiazole 2o (1.0 equiv) with Pd
ACHTUNGRTEN(NUNG OAc)2/S-
Phos or [Ni(acac)2]/DPE-Phos (2.5 mol%/5 mol%). Full
AHCTUNGTRENNUNG
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P. Knochel et al.
Table 4. Comparison of Pd- and Ni-catalyzed cross-coupling reactions of
thiomethylated N-heterocycles with organozinc reagents.
dine (2q) could only be functionalized with 4-methoxyben-
zylzinc chloride (4j) utilizing the PdACTHNUTRGENUG(N OAc)2/S-Phos system
in 8 h at 508C, whereby the diarylmethane 7d was obtained
in 94% yield. When the same reaction was performed with
Entry
Thioether
Zinc re-
agent
Product, Conditions, Yield[a]
[NiACTHUNTRGENNG(U acac)2]/DPE-Phos as the catalytic system, full conver-
sion of the pyrimidine 2q was observed after just 3 h at
258C, although the yield of 7d was lower at 85% (Table 4,
entry 5). Furthermore, alkylzinc reagents were also studied,
which showed different reactivities with the respective cata-
lysts. Thus, triazine 2a underwent a smooth cross-coupling
reaction with 4-cyanopropylzinc bromide (4h) (258C, 5 h,
1
2o
2n
4a
4c
7a: Pd: 258C, 2 h, 73%; Ni: 25 8C,
3 h, 85%
2
3
4
66% yield) in the presence of Pd
(acac)2] it took 48 h at 258C to deliver a slightly higher yield
of alkyltriazine 7e (68%, Table 4, entry 6).
Thus, the two catalytic systems used here, Pd
Phos and [Ni(acac)2]/DPE-Phos, perform equally well for
ACHTUNGRTEN(NUGN OAc)2, but by using [Ni-
AHCTUNGTRENNUNG
7b: Pd: 258C, 16 h, 74%; Ni:
258C, 18 h, 73%
AHCTUNGRTEN(GNUN OAc)2/S-
AHCTUNGTRENNUNG
most substrates. Although the Ni-catalyzed reactions usually
require longer reaction times, especially for alkylzinc re-
agents, the yields of the isolated products are very close to
those achieved under Pd catalysis. An advantage of the [Ni-
2a
2e
4g
4k
5ab: Pd: 258C, 5 h, 84%; Ni:
258C, 7 h, 81 %
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Cross-coupling reactions of thiophenylated N-heterocycles:
Despite the thiomethyl moiety being the most economic
thioester leaving group in the cross-coupling reactions, the
advantages of these methods were further stressed by em-
ploying thiophenylated N-heterocycles. These could easily
be prepared by nucleophilic attack of thiophenolate on het-
erocyclic chlorides in analogy to Scheme 1a. The reaction of
2-(phenylthio)nicotinonitrile (2r, 1.0 equiv) with 3-(ethoxy-
7c: Pd: 258C, 5 h, 73 %; Ni: 258C,
5 h, 74%
5
6
2q
2a
4j
7d: Pd: 508C, 8 h, 94 %; Ni: 258C,
3 h, 85%
carbonyl)benzylzinc chloride (4i, 1.5 equiv) using PdACHTUNGTRENNUNG(OAc)2
and S-Phos (2.5 mol%/5.0 mol%) provided the substituted
pyridine 7 f in 91% yield after 8 h at 258C (Table 5,
entry 1). The same pyridine 2r underwent a smooth cross-
coupling reaction with ortho-functionalized benzylzinc re-
agent 4p and the functionalized nicotinonitrile 5y was iso-
lated in 87% yield (258C, 14 h, entry 2). 3-Chlorobenzylzinc
4h
7e: Pd: 258C, 5 h, 66 %; Ni: 258C,
48 h, 68%
[a] Yield of isolated, analytically pure product.
conversion was achieved with the Pd catalyst after 2 h at
258C, giving the product in 73% yield, whereas by using the
Ni catalyst, the reaction took place within 3 h, delivering the
cross-coupled product 7a in 85% yield (Table 4, entry 1).
Electron-deficient 4-cyanophenylzinc iodide (4c) reacted
with pyrimidine 2n at 258C in the presence of either catalyt-
ic system in 16–18 h to give 2-arylpyrimidine 7b in compara-
ble yields (73 and 74%, Table 4, entry 2). Also, the reaction
of triazine 2a and 4-(ethoxycarbonyl)phenylzinc iodide (4g)
led to the trisubstituted triazine 5ab after similar reaction
times at 258C and in similar yields (Pd: 5 h, 84% yield; Ni:
7 h, 81% yield, Table 4, entry 3). The reaction behavior of
benzylic zinc reagents was also investigated. Whereas the
cross-coupling of electron-deficient 4-fluorobenzylzinc chlo-
ride (4k) with pyridazine 2e to afford heterocycle 7c gave
similar results using both catalytic systems (258C, 5 h, 73
and 74% yields, Table 4, entry 4), electron-rich reagents
showed different activity. 4,6-Dimethyl-2-methylthiopyrimi-
Table 5. Pd-catalyzed cross-coupling reactions of thiophenylated N-het-
erocycles.
Entry
Electrophile
Zinc reagent
Product, Conditions, Yield[a]
1
2r
2r
2s
4i
4p
4p
7 f: 258C, 8 h, 91 %
5y: 258C, 14 h, 87%
7g: 258C, 16 h, 68%
2
3
[a] Yield of isolated, analytically pure product.
2954
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Chem. Eur. J. 2011, 17, 2948 – 2956

Highly Versatile Pd- and Ni-Catalyzed Cross-Coupling Reactions
FULL PAPER
chloride (4p) could also be cross-coupled with phenyl-
thioether 2s to afford the trichloro-substituted bis-arylme-
thane 7g in 68% yield (258C, 16 h, Table 5, entry 3). These
examples demonstrate the versatility of these reaction pro-
tocols and the scope of thioethers that are compatible with
them.
Acknowledgements
We thank the Deutsche Forschungsgemeinshaft (DFG) and the Europe-
an Research Council (ERC) for financial support. We thank Chemetall
GmbH (Frankfurt) and BASF SE (Ludwigshafen) for generous gifts of
chemicals.
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Conclusion
We have developed two different, very efficient catalytic
systems, PdACHTUNGTRENNUNG(OAc)2/S-Phos and [NiACHTUNGTRNEN(GUN acac)2]/DPE-Phos, for
the cross-coupling of a range of thiomethylated N-heterocy-
cles with functionalized organozinc reagents. Aryl-, benzylic,
as well as alkylzinc halides, with sensitive functional groups,
such as ester, nitrile, or ketone, can be used, and all of the
Ni-catalyzed, as well as most of the Pd-catalyzed reactions
can be conducted at 258C. No copper(I) salts are necessary
to achieve good yields of the cross-coupling products and
these protocols are suitable for multigram reactions. A third
catalytic system (PdACHTUNTRGNEUNG(OAc)2/DPE-Phos) has been used for
thiomethylated alkynes, as well as bis(thiomethyl)acetylene.
In a series of comparison experiments, the different activi-
ties of the catalysts towards different combinations of het-
erocycles and organometallic reagents have been evaluated.
The possibility of using different classes of thioethers as
electrophiles has been demonstrated, along with the differ-
ent synthetic approaches for their preparation. Further ex-
tensions of this methodology, as well as applications in natu-
ral product synthesis and materials chemistry, are currently
underway in our laboratories.
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Experimental Section
For experimental procedures, analytical data, and NMR spectra, see the
Supporting Information.
Representative preparation of 5q: In a dry, argon-flushed Schlenk flask
equipped with a septum and a magnetic stirring bar, compound 2a
(187 mg, 1.00 mmol), [NiACTHNUTRGNEUNG(acac)2] (6.4 mg, 2.5 mol%), and DPE-Phos
(27 mg, 5.0 mol%) were dissolved in THF (1 mL). After 10 min of stir-
ring, a solution of (3-pentanoyl)benzylzinc chloride (4l) in THF (0.44m,
3.41 mL, 1.50 mmol) was added dropwise, and the reaction mixture was
stirred for 5 h at 258C until GC analysis of a hydrolyzed aliquot showed
full conversion of the electrophile. The reaction mixture was then
quenched with a saturated aqueous solution of K2CO3 (15 mL) and ex-
tracted with EtOAc (3ꢀ25 mL). The combined organic layers were dried
(Na2SO4), and the solvent was removed in vacuo. Purification by flash
chromatography (silica gel; pentane/Et2O, 1:1) afforded the triazine 5q
(258 mg, 82%) as a clear oil. 1H NMR (CDCl3, 600 MHz): d=7.96–7.95
(m, 1H), 7.83–7.79 (m, 1H), 7.58–7.54 (m, 1H), 7.50–7.35 (m, 1H), 4.06
(s, 2H), 3.99 (s, 6H), 2.93 (t, J=7.43 Hz, 2H), 1.73–1.63 (m, 2H), 1.44–
1.32 (m, 2H), 0.92 ppm (t, J=7.31 Hz, 3H); 13C NMR (CDCl3,
150 MHz): d=200.3, 180.9, 172.5, 137.3, 136.9, 133.9, 129.0, 128.7, 126.7,
55.1, 44.9, 38.4, 26.4, 22.4, 13.9 ppm; IR (ATR): n˜ =2955 (w), 1682 (m),
1546 (vs), 1500 (s), 1458 (m), 1378 (m), 1350 (vs), 1264 (m), 1231 (m),
1202 (m), 1106 (m), 1091 (m), 1069 (m), 820 (m), 731 (m), 690 cmÀ1 (m);
MS (EI, 70 eV): m/z (%): 316 (4), 315 (M+, 15), 274 (7), 273 (40), 259
(15), 258 (100), 245 (6), 231 (11), 230 (4), 158 (6); HRMS (EI): m/z:
calcd for C17H21N3O3: 315.1583; found: 315.1577.
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[17] This catalytic system proved to be the best for achieving a selective
coupling with the carbon–halogen bonds of pyrimidines 2l and 2m.
When using PdACHTNUGTRENUNG(OAc)2/S-Phos for the first step of Scheme 3, a mix-
ture of the two possible cross-coupling products was obtained.
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Received: October 4, 2010
Published online: January 30, 2011
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Chem. Eur. J. 2011, 17, 2948 – 2956