Synthesis of solid 2-pyridylzinc reagents and their application in Negishi reactions

Article abstract of DOI:10.1021/ol402798z

In search of alternatives to unstable or unreliable 2-pyridylboron reagents, we have explored two new varieties of solid, moderately air-stable 2-pyridylzinc reagents. Both reagents can be manipulated in air and are competent nucleophiles in Negishi cross-coupling reactions.

Full text of DOI:10.1021/ol402798z

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5754–5757
Synthesis of Solid 2‑Pyridylzinc Reagents
and Their Application in Negishi Reactions
James R. Colombe,† Sebastian Bernhardt,‡ Christos Stathakis,‡
Stephen L. Buchwald,*,† and Paul Knochel*,‡
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts
Avenue, Cambridge, Massachusetts 02139, United States, and Department Chemie,
€
Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13, 81377 Munchen,
€
€
Germany
sbuchwal@mit.edu; Paul.Knochel@cup.uni-muenchen.de
Received September 26, 2013
ABSTRACT
In search of alternatives to unstable or unreliable 2-pyridylboron reagents, we have explored two new varieties of solid, moderately air-stable
2-pyridylzinc reagents. Both reagents can be manipulated in air and are competent nucleophiles in Negishi cross-coupling reactions.
The 2-pyridyl group is a structural component of a
variety of biologically active compounds,1 functional
materials,2 and ligands in metal-mediated reactions.3
While SuzukiꢀMiyaura coupling with heteroaryl boro-
nates is a convenient and popular method for the installa-
tion of heteroaryls,4 coupling of 2-pyridyl boronates5 is
plagued by reagent instability6 and has been slow to
develop. The best strategy for this problem has been the
employment of 2-pyridyl MIDA5d and pinacol5eꢀg boro-
nates, but a method with milder conditions and higher
generality with respect to 2-pyridyl nucleophiles and elec-
trophilic coupling partners remains highly desirable.
In contrast, 2-pyridylzinc reagents are excellent nucleo-
philes in cross-coupling processes and their reactions often
proceed at room temperature.7 Although these reagents
are more basic than the corresponding boronates, their use
avoids the troublesome protodeboronation issues com-
monly observed with 2-heteroarylboronates. We have
concurrently pursued two strategies to obtain solid, air-
stable 2-pyridylzinc reagents, with the goal of uniting the
operational simplicity of boronates and the reliability of
2-pyridylzinc halides.
(5) (a) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem.
2009, 74, 973–980. (b) Ren, W.; Li, J.; Zou, D.; Wu, Y. Tetrahedron 2012,
68, 1351–1358. (c) Billingsley, K. L.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2008, 47, 4695–4698. (d) Dick, G. R.; Woerly, E. M.; Burke, M. D.
Angew. Chem., Int. Ed. 2012, 51, 2667–2672. (e) 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. (f) Crowley,
B. M.; Potteiger, C. M.; Deng, J. Z.; Prier, C. K.; Paone, D. V.; Burgey,
C. S. Tetrahedron Lett. 2011, 52, 5055–5059. (g) Yang, D. X.; Colletti,
S. L.; Wu, K.; Song, M.; Li, G. Y.; Shen, H. C. Org. Lett. 2009, 11, 381–
384. (h) Yamamoto, Y.; Takizawa, M.; Yu, X.-Q.; Miyaura, N. Angew.
Chem., Int. Ed. 2008, 47, 928–931. (i) Sakashita, S.; Takizawa, M.; Sugai,
J.; Ito, H.; Yamamoto, Y. Org. Lett. 2013, 15, 4308–4311.
† Massachusetts Institute of Technology.
‡
€
Ludwig-Maximilians-Universitat M€unchen.
(1) (a) Ohori, M.; Kinoshita, T.; Okubo, M.; Sato, K.; Yamazaki, A.;
Arakawa, A.; Nishimura, S.; Inamura, N.; Nakajima, H.; Neya, M.;
Miyake, H.; Fujii, T. Biochem. Biophys. Res. Commun. 2005, 336, 357–
363. (b) Rao, K. V.; Cullen, W. Antibiot. Annu. 1959, 7, 950–953. (c)
Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro, M. H. G.;
Parkin, S.; Hope, H. Tetrahedron 1994, 50, 3987–3992. (d) Jakubec, P.;
Hawkins, A.; Felzmann, W.; Dixon, D. J. J. Am. Chem. Soc. 2012, 134,
17482–17485.
(2) (a) Whittell, G. R.; Manners, I. Adv. Mater. 2007, 19, 3439–3468.
€
(b) Wild, A.; Winter, A.; Schlutter, F.; Schubert, U. S. Chem. Soc. Rev.
(6) Lennox, A. J. J.; Lloyd-Jones, G. C. Isr. J. Chem. 2010, 50, 664–
674.
2011, 40, 1459–1511. (c) Glasson, C. R. K.; Lindoy, L. F.; Meehan, G. V.
Coord. Chem. Rev. 2008, 252, 940–963.
(3) (a) Lee, E.; Hooker, J. M.; Ritter, T. J. Am. Chem. Soc. 2012, 134,
17456–17458. (b) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C.
Chem. Rev. 2013, 113, 5322–5363. (c) Izawa, Y.; Zheng, C.; Stahl, S. S.
Angew. Chem., Int. Ed. 2013, 52, 3672–3675. (d) Chelucci, G.; Thummel,
R. P. Chem. Rev. 2002, 102, 3129–3170.
(7) (a) Coleridge, B. M.; Bello, C. S.; Ellenberger, D. H.; Leitner, A.
Tetrahedron Lett. 2010, 51, 357–359. (b) Walla, P.; Kappe, C. O. Chem.
Commun. 2004, 564–565. (c) Luzung, M. R.; Patel, J. S.; Yin, J. J. Org.
Chem. 2010, 75, 8330–8332 and references therein. (d) Kim, S.-H.; Rieke,
R. D. Tetrahedron Lett. 2009, 50, 5329–5331. (e) Kim, S.-H.; Rieke,
R. D. Tetrahedron 2010, 66, 3135–3146. (f) Kim, S.-H.; Rieke, R. D.
Tetrahedron Lett. 2010, 51, 2657–2659. (g) Yang, Y.; Oldenhuis, N. J.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52, 615–619.
(4) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14073–14075.
r
10.1021/ol402798z
Published on Web 10/24/2013
2013 American Chemical Society

Scheme 1. Synthesis of Solid 2-Pyridylzinc Pivalates
Scheme 2. Negishi Coupling of 2-Pyridylzinc Pivalates
a Complexed LiOPiv and MgOPivCl omitted for clarity.
Table 1. Air Stability of 2-Pyridylzinc Pivalates
entry
compound
1 ha
1
2
3
4
5
1
90%
86%
69%
70%
72%
3
4a
5a
5b
a Percentage of original titer by titration with iodine after aging for
1 h in air (see Supporting Information for details).
First, we have applied the organozinc pivalate
approach8 that provides reagents that are free-flowing
solids, indefinitely stable when stored under an inert atmo-
sphere, and comparable in reactivity to organozinc halides
in Negishi reactions. A second, newer approach is based
on the hypothesis that the use of additional ligands could
provide an air-stabilized, solid organozinc halide. This is in
many ways analogous to Burke’s MIDA boronate meth-
od. Thesetwoconceptuallydifferentapproacheshaveboth
resulted in solid reagents that are stable in air for roughly
one day and are competent nucleophiles in cross-coupling
reactions.
Minimal optimization was required for the synthesis
of 2-pyridylzinc pivalates.8a,b Lithiumꢀ or magnesiumꢀ
halogen exchange followed by transmetalation to Zn(OPiv)2
and evaporation of solvent gave compounds 1ꢀ5 in
69ꢀ97% yields (Scheme 1).9 Both metalꢀhalogen ex-
change methods gave reagents with air stability compar-
able to that of the most stable organozinc pivalates known
a Complexed LiOPiv or MgOPivCl omitted for clarity.
(see Table 1).8b,c Notably, 5a and 5b had virtually identical
air stabilities, even though 5b, synthesized by magnesiumꢀ
halogen exchange, is presumably complexed with an extra
equivalentof hygroscopic lithium chloride (Table 1, entries
4 and 5). While the reagents cannot be stored under
ambient atmosphere for long periods of time without
significant decomposition, compounds 1ꢀ5 can be easily
weighed in air with minimal loss of the active zinc reagent.
The solid 2-pyridylzinc pivalate reagents prepared as
above exhibited excellent functional group compatibility
in Negishi reactions with aryl chlorides and bromides
(Scheme 2), tolerating ketones (6b, 6c, 6g), esters (6a, 6f,
6i, 6j, 6k), and free NꢀH groups (6d, 6h, 6i, 6k). Of note,
2-chloroisonicotinonitrile was coupled to give the unsym-
metrical 2,20-bipyridyl (6l) in good yield. The pivalate
reagents are relatively stable to trace water and oxygen
under cross-coupling conditions and could be coupled
(8) (a) Bernhardt, S.; Manolikakes, G.; Kunz, T.; Knochel, P. Angew.
Chem., Int. Ed. 2011, 50, 9205–9209. (b) Stathakis, C. I.; Bernhardt, S.;
Quint, V.; Knochel, P. Angew. Chem., Int. Ed. 2012, 51, 9428–9432. (c)
Stathakis, C. I.; Manolikakes, S. M.; Knochel, P. Org. Lett. 2013, 15,
1302–1305.
(9) Yield of the reaction was determined by titration of a solution of
the solid material with iodine. See: Krasovskiy, A.; Knochel, P. Synthesis
2006, 5, 890ꢀ891.
Org. Lett., Vol. 15, No. 22, 2013
5755

Scheme 3. Negishi Coupling with Dioxanate Reagenta
Table 2. Evaluation of Potentially Stabilizing Ligands
a Complexed MgCl2 and ZnCl2 omitted for clarity. b By titration with
iodine. c By titration with iodine after aging in air. Percentage based on
yield of pyridylzinc reagent.
under air in either technical grade ethyl acetate or THF as
solvent in excellent yields (6n, 6m).
a Reaction conditions: 14 (1.3 mmol), ArꢀX (1.0 mmol), 15 (2 mol %),
THF (4 mL), temp, 16 h; isolated yields, average of two runs.
Looking for an alternative means to produce air-
stable and solid 2-pyridylzinc reagents, it was hypothesized
that the addition of a ligand for zinc could provide a
2-pyridylzinc halide complex that was protected from
ambient moisture and/or less basic or hygroscopic. There
is significant precedent for this strategy. Charette recently
prepared a series of bipyridyl-ligated zinc carbenoids that
showed improved stability toward ambient atmosphere
and were reactive for up to eight months.10 An early
example is from Sheverdina, who crystallized a variety of
alkyl- and arylorganozinc compounds as the correspond-
ing 1,4- dioxane complexes.11 Subsequently, Noltes pre-
pared a variety of ligated organozinc compounds which
“seem[ed] to be less sensitive towards hydrolysis” than the
unligated compounds.12
a sticky orange solid was obtained13 that was titrated to
give a reference point for the complexes prepared with
additives (Table 2, entry 1). All of the ligated compounds
were obtained as nondeliquescent solids and were easily
manipulated. A variety of potentially chelating ligands
were studied (Table 2, entries 2ꢀ7), but only the complexes
formed with 2.3 equiv of 1,4-dioxane (12)14 and 1,2-
dimethoxyethane (13) were markedly more stable than
the “ligandless” case (Table 2, entries 8 and 11), with the
dimethoxyethane complex roughly half as stable as the
dioxanate.
The dioxanate complex 14 was an effective nucleophile
under recently developed Negishi cross-coupling condi-
tions (see Scheme 3).7g Simple electron-poor and electron-
rich haloaromatics (Scheme 3, 16a, 16b, and 16c) as well as
the triflate of estrone (16i) could be coupled in good yields.
Moreover, the complex 14 could alsobe coupled with more
challenging, heterocycle-containing aryl (16e, 16g, 16j)
and heteroaryl (16d, 16f, 16h) bromides and chlorides in
61ꢀ95% yield.
Potential ligands were added to a solution of 2-pyridyl-
zinc chloride prepared by sequential magnesiumꢀhalogen
exchange and transmetalation with zinc chloride (see
Table 2).7c The resulting mixture was then concentrated
under reduced pressure. The material was aged and then
titrated9 to determine air stability. In the absence of ligand,
The dioxanate 14 should be titrated to determine its
concentration for use after long-term storage. However,
(10) Charette, A. B.; Marcoux, J.-F.; Molinaro, C.; Beauchemin, A.;
ꢀ
Brochu, C.; Isabel, E. J. Am. Chem. Soc. 2000, 122, 4508–4509.
(11) (a) Sheverdina, N. I.; Abramova, L. V.; Kocheskov, K. A. Dokl.
Akad. Nauk SSSR 1959, 124, 602–605. (b) Sheverdina, N. I.; Abramova,
L. V.; Kocheskov, K. A. Dokl. Akad. Nauk SSSR 1959, 128, 320–322.
(c) Sheverdina, N. I.; Abramova, L. V.; Kocheskov, K. A. Dokl. Akad.
Nauk SSSR 1960, 134, 853–855.
(12) (a) Noltes, J. G.; Van Den Hurk, J. W. G. J. Organomet. Chem.
1964, 1, 377–383. (b) Noltes, J. G.;Van Den Hurk, J. W. G. J. Organomet.
Chem. 1965, 3, 222–228.
(13) The “ligandless” example could have been the tetrahydrofuran
(solvent) complex of the 2-pyridylzinc species.
(14) The optimized procedure for the preparation of the dioxanate
reagent was performed with 30 mmol of 2-bromopyridine. No larger
scales were attempted. The average yield over seven preparations at
30 mmol scale was 58% (47%ꢀ70%).
5756
Org. Lett., Vol. 15, No. 22, 2013

We have successfully applied the organozinc pivalate
technologytothe Negishi coupling ofa new class of hetero-
cycles and developed a second, new approach to solid zinc
reagents. Both strategies should be applicable to other
nucleophiles and may be further developed as practical
surrogates for unstable or insufficiently reactive organo-
boron compounds.
Scheme 4. Reactivity of Partially Decomposed Reagents
Acknowledgment. Research reported in this publication
was supported by the National Institutes of Health under
Award Number GM46059. J.R.C. would like to thank the
National Institutes of Health for a supplement under
Awards Number 3-R01-GM046059-20S. The content is
solely the responsibility of the authors and does not
necessarily represent the official views of the National
Institutes of Health. Varian spectrometers were used in
this work and were purchased with funds from the Na-
tional Science Foundation (CHE-9808061). This material
is based upon work supported by the National Science
Foundation Graduate Research Fellowship under Grant
No. 1122374. The MIT authors would like to thank Dr.
Nathan Jui (MIT) for help in preparing this manuscript
and Nicholas C. Bruno (MIT) for preparation of metha-
nesulfonate precatalyst 15. The research performed in
Munich has received funding from the European Research
Council under the European Community’s Seventh Frame-
work Programme (FP7/2007-2013) ERC Grant Agree-
ment No. 227763.
b
a By titration with iodine. By titration with iodine after aging as
described. Isolated yield based on 1 mmol of aryl bromide (17) and
c
1.3 mmol of aged solid organozinc reagent (14); mass of solid organozinc
reagent mixtureused dependedon concentration of active zinc reagentin
mixture by titration with iodine.
decomposition products do not interfere with the reagent’s
efficacy. Three different samples;one stored in a glove-
box for 30 days, another stored in the glovebox for 30 days
and then in air for 24 h, and a third stored in a vacuum
desiccator for 40 days;all gave virtually identical yields
of cross-coupled product (see Scheme 4). While the aged
samples have lower concentrations of an active zinc nu-
cleophile and are presumably admixed with unreactive
material, these decomposition products have no effect on
the cross-coupling reaction in terms of yield.
Supporting Information Available. Experimental pro-
cedures, characterizations, and spectral data for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we have developed two methods for the
preparation of solid 2-pyridylzinc nucleophiles that are
sufficiently air stable to be handled on the bench and viable
alternatives to boronates in cross-coupling reactions.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5757