Pd-catalyzed cross-coupling of functionalized organozinc reagents with thiomethyl-substituted heterocycles

Article abstract of DOI:10.1021/ol9017003

Various thiomethyl-substituted N-heterocycles (pyridines, pyrimidines, pyrazines, pyridazines, triazines, benzothiazoles, benzoxazoles, pyrazoles, benzindazoles, quinazolines, etc.) undergo smooth Pd-catalyzed cross-coupling reactions with functionalized

Full text of DOI:10.1021/ol9017003

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4228-4231
Pd-Catalyzed Cross-Coupling of
Functionalized Organozinc Reagents
with Thiomethyl-Substituted
Heterocycles
Albrecht Metzger, Laurin Melzig, Christina Despotopoulou, and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersity,
Butenandtstr. 5-13, 81377, Munich, Germany
paul.knochel@cup.uni-muenchen.de
Received July 24, 2009
ABSTRACT
Various thiomethyl-substituted N-heterocycles (pyridines, pyrimidines, pyrazines, pyridazines, triazines, benzothiazoles, benzoxazoles, pyrazoles,
benzindazoles, quinazolines, etc.) undergo smooth Pd-catalyzed cross-coupling reactions with functionalized aryl-, heteroaryl-, benzylic-, and
alkylzinc reagents using Pd(OAc)2/S-Phos as the catalytic system mostly at 25 °C. No copper salt is required to perform these reactions.
The transition-metal catalyzed cross-coupling reaction of
unsaturated thioethers with Grignard reagents has been
pioneered by Wenkert in 1979.1 It represents an attractive
method for converting a C-S bond into a C-C bond. More
recently, Liebeskind and Srogl have shown that various
boronic acids2 as well as organotin,3 organozinc,4 and
organoindium reagents5 undergo efficient cross-couplings
with thioethers or -esters using a Pd- or Ni-catalysis.
Casalnuovo showed also that benzylzinc bromide reacts with
heterocyclic thioethers in the presence of Pd(PPh3)4 at ele-
vated temperatures.6 Strambuli used such Ni- and Pd-catalyzed
cross-couplings for the functionalization of oxazoles.7 A mild
iron-catalyzed cross-coupling of alkenyl sulfides with Grignard
reagents has also been described by Yoshida.8 Functionalized
organozinc reagents are now readily available.9 Herein, we
report an efficient Pd(0)-catalyzed cross-coupling reaction
of functionalized aryl-, benzylic-, and alkylzinc reagents
with various thiomethyl-substituted N-heterocycles using
Pd(OAc)2/S-Phos as the catalytic system which has been
introduced by Buchwald (Scheme 1).10,11
(1) (a) Wenkert, E.; Ferreira, T. W.; Michelotti, E. L. J. Chem. Soc.,
Chem. Commun. 1979, 637. (b) Wenkert, E.; Ferreira, T. W. J. Chem. Soc.,
Chem. Commun. 1982, 840. (c) Wenkert, E.; Shepard, M. E.; McPhail, A. T.
J. Chem. Soc., Chem. Commun. 1986, 1390.
Scheme 1. Pd-Catalyzed Cross-Coupling Reaction of
Thiomethyl-Substituted N-Heterocycles with Various Organozinc
(2) (a) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2000, 2, 3229.
(b) Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4, 979. (c) Kusturin, C. L.;
Liebeskind, L. S.; Neumann, W. L. Org. Lett. 2002, 4, 983. (d) Kusturin,
C.; Liebeskind, L. S.; Rahman, H.; Sample, K.; Schweitzer, B.; Srogl, J.;
Neumann, W. L. Org. Lett. 2003, 5, 4349. (e) Lengar, A.; Kappe, C. O.
Org. Lett. 2004, 6, 771.
Reagents
(3) (a) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801. (b) Wittenberg,
R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 3033.
(4) (a) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S. J. Am. Chem.
Soc. 1999, 121, 9449. (b) For Pd-catalyzed reaction of organozinc reagents
with thioimidates see: (i) Ghosh, I.; Jacobi, P. A. J. Org. Chem. 2002, 67,
9304. (ii) Roberts, W. P.; Ghosh, I.; Jacobi, P. A. Can. J. Chem. 2004, 82,
279.
Thus, the reaction of 4-methoxyphenylzinc iodide (1a)
with 2-(methylthio)-5-(trifluoromethyl)pyridine (2a) provided
(5) Fausett, B. W.; Liebeskind, L. S. J. Org. Chem. 2005, 70, 4851.
10.1021/ol9017003 CCC: $40.75
Published on Web 08/19/2009
 2009 American Chemical Society

substituted triazine 2d reacted with 3-ethoxycarbonylphe-
nylzinc iodide (1d) furnishing the triazine 3e in 84% yield
(entry 5). Five-membered heterocycles such as pyrazole 2e
and condensed rings such as benzothiazole 2f led to the
expected products 3f,g in 52-73% yield (entries 6 and 7).
Moreover, heterocyclic zinc reagents readily participate to
the cross-coupling under these conditions. Thus, 2-thienylzinc
iodide (1e) reacted with the substituted pyridine 2g and the
quinazoline 2h leading to the heterocyclic biphenyls 3h,i in
93-95% yields (entries 8 and 9).
Table 1. Reaction of Aromatic and Heteroaromatic Zinc
Reagents (1) with Thiomethyl-Substituted Heterocycles (2)
Using this method, it was possible to prepare the anti-
inflammatory agent12 3j in 84% yield by treating the 2,4,6-
substituted triazine 2d with the arylzinc reagent 1c (Scheme
2). Furthermore, this Pd-catalyzed cross-coupling reaction
Scheme 2. Preparation of the Anti-Inflammatory Agent 3j
proceeds also well with benzylic zinc reagents of type 4.
Thus, the reaction of 4-fluorobenzylzinc chloride (4a) with
the cyano-substituted pyridine 2g provided the pyridine 5a
in 83% yield (entry 1 of Table 2). Ester-substituted pyrimi-
dine 2i underwent smooth cross-coupling with the 3,4,5-
trimethoxy-substituted benzylic zinc reagent 4b affording the
2-benzylated pyridine 5b in 88% yield (entry 2). Function-
alized pyrimidine 2j, pyridazine 2b, and quinazoline 2h
undergo also an efficient cross-coupling with various benzylic
zinc reagents bearing an ester or a nitrile group furnishing
the heterocyclic diarylmethanes 5c-e in 71-78% yields
(entries 3-5). Similarly, triazine 2d reacted with 3-(trifluo-
romethyl)benzylzinc chloride (4e) leading to the triazine 5f
in 70% yield (entry 6). Moreover, thiomethyl-substituted
five-membered rings 2e-k underwent cross-couplings with
benzylic zinc reagents 4a,b furnishing the heterocycles 5g-i
in 62-80% yield (entries 7-9).
A selective bis-functionalization of pyrimidines in posi-
tions 2 and 4 can be achieved. Cross-coupling occurs first
(6) Angiolelli, M. E.; Casalnuovo, A. L.; Selby, T. P. Synlett 2000, 905.
(7) Lee, K.; Counceller, C. M.; Stambuli, J. P. Org. Lett. 2009, 11, 1457.
(8) Itami, K.; Higashi, S.; Mineno, M.; Yoshida, J.-i. Org. Lett. 2005,
7, 1219.
a Yield of analytically pure product. b Reaction performed at 50 °C.
(9) (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 6040. (b) Metzger, A.; Schade, M. A.;
Knochel, P. Org. Lett. 2008, 10, 1107.
(10) (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.
(11) Pd(OAc)2/S-Phos was superior related to iPr-PEPPSI,
Pd(dba)2/tfp, and Pd(dppe)Cl2. In the absence of the Pd catalyst, no
reaction occurs.
(12) (a) Menicagli, R.; Samaritani, S.; Signore, G.; Vaglini, F.; Dalla
Via, L. J. Med. Chem. 2004, 47, 4649. (b) Dianzani, C.; Collino, M.;
Gallicchio, M.; Samaritani, S.; Signore, G.; Menicagli, R.; Fantozzi, R.
J. Pharm. Pharmacol. 2006, 58, 219. (c) Samaritani, S.; Signore, G.;
Malanga, C.; Menicagli, R. Tetrahedron 2005, 61, 4475.
the cross-coupling product 3a in 95% yield (entry 1 of Table
1). Electron-poor zinc reagents 1b,c bearing a nitrile or an
ester function readily reacted with 3-methoxy-(6-methyl-
thio)pyridazine (2b) leading to the functionalized pyridazines
3b,c in 76-77% yield (entries 2 and 3). Cyano-substituted
pyrazine 2c is smoothly converted to the substituted pyrazine
3d in 57% yield (entry 4). Furthermore, electron-rich triazines
undergo the cross-coupling as well. Thus, dimethoxy-
Org. Lett., Vol. 11, No. 18, 2009
4229

Table 2. Reaction of Benzylic Zinc Chlorides (4) with
Thiomethyl-Substituted Heterocycles (2)
Scheme 3. Selective One-Pot Cross-Coupling Reactions of
2-Bromo-4-(methylthio)pyrimidine (2l) or
4-Iodo-2-(methylthio)pyrimidine (2m) Using Pd(dba)2/tfp and in
Situ Pd(OAc)2/S-Phos
of a second catalyst system (Pd(OAc)2/S-Phos) to the reaction
mixture, a second cross-coupling occurs with (4-ethoxycar-
bonyl)phenylzinc iodide (1c) providing the 2,4-disubstituted
pyrimidine 5j in 68% overall yield (Scheme 3).
Alternatively, 4-iodo-2-(methylthio)pyrimidine14 (2m) can
be converted into the regiomeric 2,4-disubstituted pyrimidine
5k by performing first a cross-coupling with 4-methoxyben-
Table 3. Reaction of Alkylzinc Reagents (6) with
Thiomethyl-Substituted Heterocycles (2)
a Yield of analytically pure product. b Reaction performed at 50 °C.
in position 2 or 4 depending on the substrate. Thus, the
reaction of 2-bromo-4-(methylthio)pyrimidine13 (2l) with
4-methoxybenzylzinc chloride (4f) proceeds rapidly in the
presence of Pd(dba)2/tfp (25 °C, 3 h). After a direct addition
a Yield of analytically pure product. b Reaction performed at 50 °C.
Org. Lett., Vol. 11, No. 18, 2009
(13) Mosrin, M.; Knochel, P. Org. Lett. 2008, 10, 2497.
4230

zylzinc chloride (4f) using Pd(dba)2/tfp (25 °C, 10 min)
followed by a second cross-coupling with the arylzinc reagent
1c in the presence of Pd(OAc)2/S-Phos (25 °C, 20 h). The
pyrimidine 5k is obtained in 80% overall yield in this one-
pot double cross-coupling sequence. The scope of this Pd-
catalyzed cross-coupling reaction was extended to alkylzinc
reagents. Thus, 4-cyanopropylzinc bromide (6a) reacted with
trifluoromethyl-substituted pyridine 2a providing the pyridine
7a in 84% yield (entry 1 of Table 3).15 Smooth cross-
coupling occurred between alkylzinc reagent 6a and pyridine
2n providing the pyridine 7b in 54% yield (entry 2).
Moreover, thiomethyl-substituted quinazoline 2h and triazine
2d were converted to the desired products 7c,d under
standard conditions (66-74% yield; entries 3 and 4).
Acknowledgment. We thank the DFG and the European
Research Council (ERC) for financial support. We thank
Chemetall GmbH (Frankfurt), Evonik Industries AG (Hanau),
and BASF SE (Ludwigshafen) for the generous gift of
chemicals.
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9017003
(15) Typical procedure: Preparation of 4-[5-(trifluorometh-
yl)pyridin-2-yl]butanenitrile (7a): In a dry and argon flushed
Schlenk flask, equipped with a magnetic stirring bar and a
rubber septum, 2-(methylthio)-5-(trifluoromethyl)pyridine (2a,
193 mg, 1.0 mmol), Pd(OAc)2 (5.6 mg, 25 µmol), and S-Phos
(20.5 mg, 50 µmol) were dissolved in dry THF (1 mL). After
10 min of stirring at 25 °C, (3-cyanopropyl)zinc bromide (6a,
3.66 mL, 1.5 mmol, 0.41 M in THF) was added dropwise. After
16 h at 25 °C, GC analysis of a hydrolyzed aliquot showed
full conversion. The reaction mixture was quenched with sat.
Na2CO3 solution (25 mL) and extracted with EtOAc (3 × 25
mL). The combined organic layers were dried over Na2SO4,
and after filtration the solvents were removed in vacuo. Flash
column chromatography (pentane/Et2O ) 1:1 + 2-Vol% NEt3)
furnished the pyridine 7a as a yellow oil (180 mg, 0.84 mmol,
84%).
Finally, the pyrazole 2e was reacted with 4-ethoxy-4-
oxybutylzinc bromide (6b)leading to the functionalized
pyrazole 7e in 69% yield (entry 5).
In summary, we have reported a new Pd-catalyzed cross-
coupling reaction using Pd(OAc)2/S-Phos which proceeds
mostly at room temperature. A broad range of functional
groups are tolerated in this cross-coupling in which alkyl-,
aryl-, heteroaryl, and benzylic zinc reagents can be used.
Further extensions of this cross-coupling are currently
underway in our laboratories.
(14) Majeed, A. J.; Antonsen, O.; Benneche, T.; Undheim, K. Tetra-
hedron 1989, 45, 993.
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