A mild negishi cross-coupling of 2-heterocyclic organozinc reagents and aryl chlorides

Article abstract of DOI:10.1021/jo1018798

A mild Negishi cross-coupling of 2-heterocyclic organozinc reagents and aryl chlorides is described. The use of Pd₂(dba)₃ and X-Phos as a ligand provides high yields for many examples. An efficient method to generate the organozinc reagents at room temperature is also demonstrated.

Full text of DOI:10.1021/jo1018798

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SCHEME 1. Cross-Coupling Reactions of 2-Heterocyclic
Organometallic Reagents with Aryl Halides
A Mild Negishi Cross-Coupling of 2-Heterocyclic
Organozinc Reagents and Aryl Chlorides
Michael R. Luzung,* Jigar S. Patel, and Jingjun Yin*
Department of Process Research,
Merck Research Laboratories, P.O. Box 2000 Rahway,
New Jersey 07065, United States
michael_luzung@merck.com; jingjun_yin@merck.com
Received September 23, 2010
on aryl bromides, iodides, or activated chlorides. 2-Pyridyl
borates can be synthesized, but they often require a cryogenic
lithium-halogen exchange before subsequent trapping with
a boron source, which is followed by alcohol metathesis at
refluxing temperatures for isolation.2f,3
An attractive alternative to the Suzuki reaction for this
transformation is the Negishi cross-coupling, for which numer-
ous reports have recently described using aryl bromides or
iodides.4 This note addresses the Negishi cross-coupling of
2-heterocyclic organozinc reagents with aryl and heteroaryl
chlorides (Scheme 1). Aryl chlorides5 may be more useful
due to their low cost and higher availability relative to
the corresponding bromides and iodides. Organozinc re-
agents have typically been synthesized using either lithium-
halogen exchange6a or highly reactive Rieke zinc.7 This note
also addresses the synthesis of 2-heterocyclic organozinc
reagents using Knochel conditions8 at ambient temperature.
A mild Negishi cross-coupling of 2-heterocyclic organozinc
reagents and aryl chlorides is described. The use of Pd2(dba)3
and X-Phos as a ligand provides high yields for many
examples. An efficient method to generate the organozinc
reagents at room temperature is also demonstrated.
The coupling of 2-heterocyclic organometallic reagents
with aryl halides is a transformation used by many in the
chemical community to produce coupled products prevalent
in pharmaceuticals, ligands, and materials. Extensive re-
search has focused on a variety of ways to form this C-C
bond using Pd catalysis.1 The Suzuki reaction has been the
focus of many groups for this transformation (Scheme 1).2
2-Pyridyl couplings have been of particular interest to our
drug discovery efforts.2b,c Commercially available 2-pyridyl-
boronic esters can couple with aryl bromides and iodides
using palladium phosphine oxide or chloride catalysts2b or
utilizing CuCl2c,d to facilitate the transmetalation of these
electron-deficient nucleophiles. While these methods show
versatility in substrate scope, the reactions are performed at
high temperatures in moderate yields, require stoichiometric
Cu, or require substitution at the 6-position of the pyridyl
reagent. Unactivated aryl chlorides have been relatively
difficult to couple,2g as such research has mainly focused
(3) (a) Yamamoto, Y; Takizawa, M.; Yu, X. Q.; Miuaura, N. Angew.
Chem., Int. Ed. 2008, 47, 928–931. (b) Dick, G. R.; Knapp, D. M.; Gillis,
E. P.; Burke, M. D. Org. Lett. 2010, 12, 2314–2317.
(4) For selected 2-pyridylzinc Negishi cross-couplings, see: (a) Kim,
S.-H.; Rieke, R. D. Tetrahedron 2010, 66, 3135–3146. (b) Kim, S.-H.; Rieke,
R. D. Tetrahedron Lett. 2010, 51, 2657–2659. (c) Coleridge, B. M.; Bello,
C. S.; Ellenberger, D. H.; Leitner, A. Tetrahedron Lett. 2010, 51, 357–359.
€
(d) Kiehne, U.; Bunzen, J.; Staats, H.; Lutzen, A. Synthesis 2007, 7, 1061–
1069. (e) Lutzen, A.; Hapke, M.; Staats, H.; Bunzen, J. Eur. J. Org. Chem.
€
2003, 20, 3948–3957. (f) Fang, Y.-Q.; Hanan, G. S. Synlett 2003, 6, 852–854.
(g) Savage, S. A.; Smith, A. P.; Fraser, C. L. J. Org. Chem. 1998, 63, 10048–
10051. For selected 2-furyl and 2-thienyl zinc Negishi reactions, see:
(h) Mignani, G.; Leising, F.; Meyrueix, R.; Samson, H. Tetrahedron Lett.
1990, 31, 4743–4746. (i) Pelter, A.; Rowlands, M.; Jenkins, I. H. Tetrahedron
Lett. 1987, 28, 5213–5216. (j) Pelter, A.; Rowlands, M.; Clements, G.
Synthesis 1987, 1, 51–53.
(5) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176–
4211. (b) For two examples of microwave-assisted Ni-catalyzed Negishi
cross-coupling of 2-pyridylzinc chloride, see: Walla, P.; Kappe, C. O. Chem.
Commun. 2004, 564–565.
(1) For a review on 2-pyridyl cross-couplings, see: Campeau, L.-C.;
Fagnou, K. Chem. Soc. Rev. 2007, 36, 1058–1068.
(2) For selected heterocyclic Suzuki reactions, see: (a) Guetz, G.; Luetzen,
A. Synthesis 2010, 1, 85–90. (b) Yang, D. X.; Colletti, S. L.; Wu, K.; Song, M.;
Li, G. Y.;Shen, H. C.Org.Lett. 2009, 11, 381–384.(c) Deng,J. Z.;Paone, D.V.;
Ginnetti, A. T.; Kurihara, H.; Dreher, S. D.; Weissman, S. A.; Stauffer, S. R.;
Burgey, C. S. Org. Lett. 2009, 11, 345–347. (d) Knapp, D. M.; Gillis, E. P.;
Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961–6963. (e) Ackermann, L.;
Potukuchi, H. K. Synlett 2009, 17, 2852–2856. (f) Billingsley, K. L.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2008, 47, 4695–4698. (g) Billingsley, K.; Buchwald,
S. L. J. Am. Chem. Soc. 2007, 129, 3358–3366. (h) Hodgson, P. B.; Salingue,
F. H. Tetrahedron Lett. 2004, 45, 685–687. (i) Bouillon, A.; Lancelot, J.-C.;
Sopkova de Oliveira Santos, J.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron
2003, 59, 10043–10049. (j) Deshayes, K.; Broene, R. D.; Chao, I.; Knobler,
C. B.; Diederich, F. J. Org. Chem. 1991, 56, 6787–6795.
(6) (a) For organozinc synthesis and RuPhos, see: Milne, J. E.; Buchwald,
S. L. J. Am. Chem. Soc. 2004, 126, 13028–13032. (b) S-Phos: Walker, S. D.;
Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004,
43, 1871–1876. (c) For S-Phos and Negishi, see: Manoliakakes, G.; Schade,
M. A.; Hernandez, C. M.; Mayr, H.; Knochel, P. Org. Lett. 2008, 10, 2765–
2768. (d) JohnPhos: Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158–1174.
(7) (a) Wu, X.; Rieke, R. D. J. Org. Chem. 1995, 60, 6658–6659. (b) Rieke,
R. D. Science 1989, 246, 1260–1264.
(8) (a) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Vu, V. A.;
Knochel, P. Synthesis 2002, 4, 565–569. (b) For synthesis of 2-pyridylboronic
acids using Knochel conditions, see: Matondo, H.; Souirti, S.; Baboulene,
M. Synth. Commun. 2003, 33, 795–800.
8330 J. Org. Chem. 2010, 75, 8330–8332
Published on Web 11/03/2010
DOI: 10.1021/jo1018798
r
2010 American Chemical Society

Luzung et al.
JOCNote
TABLE 1. Ligand Screen.a
TABLE 2. Pd-Catalyzed Negishi Cross-Coupling of 2-Pyridylorgano-
zinc Reagents and Aryl Chlorides with X-Phosa
ligand (conversion, %)
ligand (conversion, %)
dppe (<3%)
dppf (<3%)
1,10-(tBu2P)-ferrocene (<3%)
Cy3P-HBF4 (<3%)
tBu3P-HBF4 (10%)
S-Phos (∼20%)
tBu-X-Phos (∼30%)
JohnPhos (∼50%)
RuPhos (∼50%)
X-Phos (100%)
aConversion monitored by HPLC with an internal standard (biphenyl).
The coupling of 2-pyridylzinc bromide with 2-chloroani-
sole was attempted for the ligand screen using Pd2(dba)3 as
the Pd source in THF at 65 °C (Table 1). While bidentate
ligands9 were unsuccessful for the Negishi cross-coupling, it
was found that more electron-rich Buchwald-type ligands6,10
were the key to higher conversion. Surprisingly, RuPhos,6a
which was previously reported to give excellent yields for
Ar-Ar Negishi cross-couplings with aryl chlorides, gave
only ∼50% conversion to the desired coupled product. An
extensive ligand survey revealed that X-Phos10 gave com-
plete conversion for this transformation.
With these conditions in hand, 2 mol % of Pd2(dba)3 and 8
mol % of X-Phos in THF at 65 °C, we attempted to under-
stand the scope of this reaction using several aryl and hetero-
aryl chlorides and commercially available 2-pyridyl- and
2-thienylzinc reagents (Table 2). Aryl chlorides with varying
substituents on the phenyl ring ranging from electron rich to
electron poor were successfully coupled (3a-i,o,q,t). Func-
tional handles such as nitrile, ketone, ester, and nitro (3d-g,o,q)
were well tolerated under the reaction conditions. Fluo-
rinated substrates (3h-i,n-o) also gave excellent yields.
Heteroaryl chlorides such as indole, benzothiazole, pyrrole,
thiophene, and quinoline survived these conditions with no
major side reactions observed (3j-n,p,r-s).
While there are very useful methods of organozinc genera-
tion for 2-heterocyclic substrates, we wanted to apply condi-
tions that would not require cryogenic temperatures or highly
reactive metals which may be a safety issue on large scale. In
order to generate these reagents on large scale in a safe and easy
manner, we applied Knochel conditions (Table 3).8 2-Pyridyl
and 2-thienyl bromides were treated with isopropylmagnesium
chloride for metal-halogen exchange at room temperature.
The organozinc reagent was then synthesized in situ by treating
the Grignard with a solution of zinc chloride at ambient
temperature to undergo transmetalation. These mixtures were
then further utilized for subsequent Negishi cross-coupling with
heteroaryl chlorides.
aReaction conditions: 1.5 equiv of 1, 1 equiv of ArCl 2(1 mmol), 2 mol %
of Pd2(dba)3, 8 mol % of X-Phos, THF (0.3-0.4M), 65 °C, 2-12 h.
All isolated yields. b3.5 equiv of RZnX used.
tial for late-stage coupling. The parent compound to entry
6f is hydroquinine 4-chlorobenzoate, which is a well-known
ligand used in asymmetric catalysis.11 It contains a tertiary
amine, an ester, and a quinoline, all of which can potentially
undergo side reactions. Under the optimized two-step sequence,
compound 6f is obtained in 97% yield.
In conclusion, we have described a mild Negishi cross-
coupling of 2-heterocyclic organozinc reagents with aryl and
heteroaryl chlorides, demonstrated with 26 examples total.
This method complements current reactions for the coupling
of 2-heterocyclic organometallic reagents and is expected to
show utility in future drug discovery and development efforts.
The organozinc reagents can be generated in situ using
Knochel conditions at room temperature. These combined
Table 3 shows coupling with a variety of heterocycles in
excellent yields. In particular, compound 6c, which contains
a hydroxyl group as an additional functional handle, can be
formed in good yield. The Negishi cross-coupling can also be
applied to more complicated molecules, showing the poten-
(9) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158–163.
(10) X-Phos=2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl:
Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 6653–6655.
(11) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroeder, G.; Sharpless,
K. B. J. Am. Chem. Soc. 1988, 110, 1968–1970.
J. Org. Chem. Vol. 75, No. 23, 2010 8331

Luzung et al.
JOCNote
TABLE 3. Sequential Organozinc Synthesis and Negishi Cross-Couplinga
the temperature not exceeding 30 °C. After 3-4 h, zinc chloride
(0.5 M, 12 mL, 6.0 mmol, 1.2 equiv) was added dropwise with the
temperature not exceeding 30 °C. After 1 h at room temperature,
the mixture was used as is for subsequent cross-coupling.
Representative Procedure for the Negishi Cross-Coupling.
A solution of Pd2(dba)3 (18.3 mg, 0.02 mmol, 2 mol %) and
X-Phos (38.1 mg, 0.08 mmol, 8 mol %) in 2.7 mL of THF under
nitrogen was stirred and heated at 65 °C for 10 min. To this
solution was added an aryl chloride substrate (1 mmol). After
the mixture was stirred for 15 min, an organozinc reagent (1.5
mmol) was added dropwise. The reaction was monitored by
HPLC and/or TLC and upon completion was cooled to room
temperature. The reaction was then quenched with 3 mL of
NaHCO3 and 3 mL of H2O. After separation, the aqueous layer
was extracted three times with EtOAc. The combined organic
layers were washed with H2O, dried over MgSO4, filtered, and
concentrated by rotary evaporation. The crude product was
purified by column chromatography on silica gel with a
gradient of EtOAc in hexanes. Experimental data for 3a: reaction
time 2 h; yellow oil, purified by column chromatography on silica
gel (182.6 mg, 97% yield); 1H NMR (CDCl3, 400 MHz) δ 8.71 (d,
1H, J= 4.6 Hz), 7.82 (d, 1H, J= 8.0 Hz), 7.78 (dd, 1H, J= 7.6, 1.6
Hz), 7.71 (td, 1 H, J=7.8, 1.7 Hz), 7.40-7.36 (m, 1H), 7.27-7.19
(m, 1H), 7.09 (t, 1H, J=7.5 Hz), 7.01 (d, 1H, J=8.3 Hz), 3.87 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 157.0, 156.2, 149.4, 135.6,
131.2, 129.9, 129.2, 125.1, 121.7, 121.1, 111.4, 55.6; HRMS calcd for
C12H11NOHþ 186.0913, found 186.0919.
aReaction conditions: 1.5 equivof5, 1 equifofArCl (1mmol), 2 mol %
of Pd2(dba)3, 8 mol % of X-Phos, THF (0.3-0.4 M), 65 °C, 2-12 h. All
isolated yields. b3.5 equiv of RZnX used. c2-Bromo-6-(hydroxymethyl)-
pyridine was used.
transformations can be applied to large-scale synthesis with-
out further temperature or safety precautions. This method
is currently being examined on more complex 2-heterocyclic
organozinc reagents and the results will be reported in due
course.
Acknowledgment. We thank Chaoxian Cai for prelimi-
nary results and Dr. Shane Krska for helpful discussions.
This work was supported by the Merck Future Talent
Program (J.S.P.).
Experimental Section
Representative Procedure for the Synthesis of 2-Pyridyl and
2-Thienylzinc Chloride. A three-neck round-bottom flask with a
stirbar was charged with isopropylmagnesium chloride (2.0 M,
2.75 mL, 5.5 mmol, 1.1 equiv). To this mixture was added neat
2-bromopyridine (0.476 mL, 5.0 mmol, 1.0 equiv) or 2-bro-
mothiophene (0.479 mL, 5.0 mmol, 1.0 equiv) dropwise with
Supporting Information Available: Experimental proce-
1
dures, full characterization, and copies of H and 13C NMR
spectra of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
8332 J. Org. Chem. Vol. 75, No. 23, 2010