Preparation of polyfunctional zinc organometallics using an Fe- or Co-catalyzed Cl/Zn-exchange

Article abstract of DOI:10.1021/ol201100p

A new Fe- or Co-catalyzed Cl/Zn-exchange reaction allows the direct transformation of aryl, heteroaryl, and also alkyl chlorides into the corresponding zinc reagents. The method tolerates functional groups such as a nitrile or an ester. Remarkably, secondary and tertiary alkyl chlorides are suitable substrates for the Cl/Zn exchange.

Full text of DOI:10.1021/ol201100p

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3174–3177
Preparation of Polyfunctional Zinc
Organometallics Using an Fe- or Co-
Catalyzed Cl/Zn-Exchange
ꢀ
Laurin Melzig, Coura R. Diene, Christoph J. Rohbogner, and Paul Knochel*
€
€
Ludwig Maximilians Universitat Munchen, Department of Chemistry, Butenandtstrasse
5-13, Haus F, 81377 Mu€nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received April 26, 2011
ABSTRACT
A new Fe- or Co-catalyzed Cl/Zn-exchange reaction allows the direct transformation of aryl, heteroaryl, and also alkyl chlorides into the
corresponding zinc reagents. The method tolerates functional groups such as a nitrile or an ester. Remarkably, secondary and tertiary alkyl
chlorides are suitable substrates for the Cl/Zn exchange.
8
Zinc organometallics are of great importance since these
reagents tolerate the presence of many functional groups.1
Direct zinc insertion,2 base directed metalation,3 boronꢀ
zinc exchange,4 transmetalation,5 and halide/zinc-ex-
changeperformedwithiPr2Zn,6 Et2Zn,7 orzincatessuchas
Bu4ZnLi2 have been used for their preparation. The
halogen/zinc-exchange was successful mostly with aryl
iodides and in some cases with aryl bromides.6ꢀ9 Although
aryl chlorides are ideal precursors in light of their
good availability, stability, and low price in comparison
to the corresponding bromides and especially iodides,
these substrates, however, are reluctant to undergo a
(1) (a) Knochel, P.; Singer, R. Chem. Rev. 1993, 93, 2117. (b) Negishi,
E. In Organozinc Reagents; Knochel, P., Jones, P., Eds.; Oxford University
Press: Oxford, U.K., 1999; Chapter 1. (c) Knochel, P.; Millot, N.; Rodriguez,
A.; Tucker, C. E. Org. React. 2001, 58, 417. (d) Knochel, P. Handbook
of functionalized Organometallics; Knochel, P., Ed.; WILEY-VCH:
Weinheim, 2005; Vol. 1, p 7.
^
(9) (a) For a Cl/Li-exchange, see: Gillet, J. P.; Sauvetre, R.; Normant,
J. F. Tetrahedron Lett. 1985, 26, 3999. (b) For a Cl/Mg-exchange, see:
€
Abarbri, M.; Thibonnet, J.; Berillon, L.; Dehmel, F.; Rottlander, M.;
ꢁ
(2) (a) Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. A.;
Gavryushin, A.; Knochel, P. Chem.;Eur. J. 2009, 15, 7192. (b) Bluemke,
T. D.; Piller, F. M.; Knochel, P. Chem. Commun. 2010, 46, 4082.
(3) (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am.
Chem. Soc. 1999, 121, 3539. (b) Bresser, T.; Mosrin, M.; Monzon, G.;
Knochel, P. J. Org. Chem. 2010, 75, 4686. (c) Wunderlich, S. H.;
Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 7685.
(4) (a) Hupe, E.; Calaza, I. M.; Knochel, P. J. Organomet. Chem.
2003, 680, 136. (b) Paixao, M. W.; Braga, A. L.; Ludtke, D. S. J. Braz.
Chem. Soc. 2008, 19, 813. (c) Charette, A. B.; Mathieu, M. S.; Fournier,
J.-F. Synlett 2005, 1779.
(5) Metzger, A.; Piller, F. M.; Knochel, P. Chem. Commun. 2008, 44,
5824.
(6) Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem., Int. Ed.
2004, 43, 1017.
(7) Naka, H.; Ito, K.; Ueno, M.; Kobayashi, K.; Kondo, Y. New J.
Knochel, P. J. Org. Chem. 2000, 65, 4618.
(10) (a) Cahiez, G.; Moyeux, A. Chem. Rev. 2010, 10, 1435. (b) Affo,
W.; Ohmiya, H.; Fujioka, T.; Ikeda, Y.; Nakamura, T.; Yorimitsu, H.;
Oshima, K.; Inamura, Y.; Mizuta, T.; Miyoshi, K. J. Am. Chem. Soc.
2006, 128, 8068. (c) Ohmiya, H.; Yorimitu, H.; Oshima, K. Chem. Lett.
2004, 33, 1240. (d) Fillon, F.; Gosmini, C.; Perichon, J. J. Am. Chem.
Soc. 2003, 125, 3867. (e) Gosmini, C.; Moncomble, A. Isr. J. Chem. 2010,
ꢁ
ꢁ
50, 568. (f) Gosmini, C.; Amatore, M.; Claudel, S.; Perichon, J. Synlett
ꢁ
2005, 2171. (g) Kazmierski, I.; Gosmini, C.; Paris, J.-M.; Perichon, J.
Synlett 2006, 881.
(11) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004,
€
104, 6217. (b) Sherry, B. D.; Furstner, A. Acc. Chem. Res. 2008, 41, 1500.
(c) Czaplik, W. M.; Grupe, S.; Mayer, M.; von Wangelin, A. J. Chem.
Commun. 2010, 46, 6350. (d) Castagnolo, D.; Botta, M. Eur. J. Org.
Chem. 2010, 17, 3224. (e) Yoshikai, N.; Mieczkowski, A.; Matsumoto,
A.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2010, 132, 5568. (h) Hess,
W.; Treutwein, J.; Hilt, G. Synthesis 2008, 3537. (i) Driller, K. M.;
Prateeptongkum, S.; Jackstell, R.; Beller, M. Angew. Chem., Int. Ed.
Chem. 2010, 34, 1700.
(8) (a) Uchiyama, M.; Furuyama, T.; Kobayashi, M.; Matsumoto,
Y.; Tanaka, K. J. Am. Chem. Soc. 2006, 128, 8404. (b) Furuyama, T.;
Yonehara, M.; Arimoto, S.; Kobayashi, M.; Matsumoto, Y.; Uchiyama,
M. Chem.;Eur. J. 2008, 14, 10348.
€
2011, 50, 537. (j) Furstner, A.; Martin, R. Chem. Lett. 2005, 34, 624. (k)
€
Furstner, A.; Martin, R.; Majima, K. J. Am. Chem. Soc. 2005, 127,
12236.
r
10.1021/ol201100p
Published on Web 05/19/2011
2011 American Chemical Society

Cl/Zn-exchange. Interestingly, related Cl/Li- or Cl/Mg-
exchanges also proceed, but only for specific substrates.9
Various cobalt10 and iron11 salts have been used in orga-
nic synthesis as versatile catalysts for several organic trans-
formations. We also reported a Co-catalyzed sulfonate/
copper-exchange, allowing the synthesis of functionalized
arylcopper derivatives.12 This led us to investigate the Cl/
Zn-exchange reaction using transition-metal catalysis.
Herein, we report new iron(III) and cobalt(II)-catalyzed
Cl/Zn-exchange reactions on aryl, heteroaryl, and alkyl
chlorides as substrates using a triorganozincate13 as an
exchange reagent. We have selected the chloromagnesium
triorganozincate (4-Me2NC6H4)2Zn(iPr)MgCl (1), since
the hydrolyzed zincate and the resulting quenching bypro-
duct with electrophiles are readily removed by an acidic
workup. After numerous optimization reactions, we have
found that the treatment of a heterocyclic chloride such as
the 2-chlorothiophene 2a with the zincate 1 (2.0 equiv) in
the presence of 10% Fe(acac)3 and 20% 4-fluorostyrene14
provides under mild conditions (THF, 25 °C, 16 h) a zinc
organometallic species that reacts with typical electro-
philes such as pivaloyl chloride (3.0 equiv) in the presence
Table 1. Fe-Catalyzed Cl/Zn-Exchange of Aryl, Heteroaryl, and
Alkyl Chlorides and Reaction with Electrophiles
of 20% CuCN 2LiCl,15 leading to the expected acylated
3
thiophene 3a in 62% isolated yield (Scheme 1). The pre-
sence of a catalytic amount of 4-fluorostyrene14 increases
the Cl/Zn-exchange rate and improves the reaction yield.16
Interestingly, 2,5-dichlorothiophene (2d) undergoes a
selective monoexchange under these conditions, providing
the thiophene 3d in 60% yield after a Pd(0)-catalyzed
cross-coupling (Table 1, entry 3). Also electron-deficient
aromatic chlorides such as 1,3,5-trichlorobenzene (2e)
undergo a selective monoexchange, affording the aryl
iodide 3e in 56% yield after iodolysis (entry 4).
Scheme 1. Fe-Catalyzed Cl/Zn-Exchange of Organic Chlorides
2a,g,j and Reaction with Electrophiles
a Yield of isolated analytically pure product; 3 equiv of the electro-
phile were used. b 20% CuCN 2LiCl used as catalyst. c 2% Pd(PPh3)4
3
used as catalyst. d dr = 1.4:1.
a10% Fe(acac)3, 20% 4-fluorostyrene, THF, 25 °C, 16 h. bTHF, ꢀ20
°C, 30 min. cTHF, 25 °C, 30 min.
118, 8733. (d) Naka, H.; Ito, K.; Ueno, M.; Kobayashim, K.; Kondo, Y.
New J. Chem. 2010, 34, 1700.
ꢀ
(12) Rohbogner, C. J.; Diene, C. R.; Korn, T. J.; Knochel, P. Angew.
Chem., Int. Ed. 2010, 49, 1874.
€
(14) (a) Piber, M.; Jensen, A. E.; Rottlander, M.; Knochel, P. Org.
(13) For the use of zincates for performing I/Zn and Br/Zn exchange
reactions, see: (a) Nakamura, S.; Liu, C.-Y.; Muranaka, A.; Uchiyama,
M. Chem.;Eur. J. 2009, 15, 5686. (b) Chau, N. T. T.; Meyer, M.;
Komagawa, S.; Chevallier, F.; Fort, Y.; Uchiyama, M.; Mongin, F.;
Gros, P. C. Chem.;Eur. J. 2010, 16, 12425. (c) Uchiyama, M.; Koike,
M.; Kameda, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1996,
Lett. 1999, 1, 1323. (b) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67,
79. (c) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48,
9717. (d) Johnson, J. B.; Rovis, T. Angew. Chem., Int. Ed. 2008, 47, 840.
(15) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, T. J. Org. Chem.
1988, 53, 2390.
Org. Lett., Vol. 13, No. 12, 2011
3175

Performing the Cl/Zn-exchange protocol with chloropen-
tafluorobenzene (2f) leads to the ketone 3f in 65% yield after
acylation (entry 5). Remarkably, using these conditions, alkyl
chlorides could also be converted to organozincs. Therefore,
ethyl 4-chlorobutanoate (2g) reacted with zincate 1 (THF,
25 °C, 16 h) and furnished the alkyl aryl sulfide 3g in 63%
yield after quenching of the resulting alkylzinc reagent with a
thiosulfonate (Scheme 1). Other functionalized chlorides
such as the benzyl-protected 6-chlorohexanol 2h underwent
the Cl/Zn-exchange (25 °C, 18 h). The resulting organozinc
reagent could either be acylated with furoyl chloride to yield
functionalized furan 3h in 63% yield (entry 6) or be submitted
to a Pd(0)-catalyzed cross-coupling to form the benzonitrile
derivative 3i in 61% yield (entry 7). Also the nitrile-substi-
tuted alkyl chloride 2i ledtoanalkylzincspecies(25°C, 16 h),
which after acylation with 4-methoxybenzoyl chloride gave
the ketone 3j in 66% yield (entry 8).
Scheme 2. Preparation of Zincate 4 and Co-Catalyzed Cl/Zn-
Exchange of Heterocyclic Chlorides 2l,m
Preparatively useful is the performance of a Cl/Zn-
exchange on tertiary chlorides, which are generally known
to be difficult to convert into organometallic species.17
Hence, the reaction of1-chloroadamantane(2j) furnishes a
tertiary organozinc reagent 2j0 under our conditions
(25 °C, 24 h), which after quenching with S-methyl metha-
nesulfonothioate resulted in the thiomethyl adamantane
3k (66% yield, Scheme 1). Alternatively, quenching the
adamantylzinc species with iodine furnished 1-iodoada-
mantane (3l) in 61% yield (Table 1, entry 9). Finally, a
secondary chloride like cholesteryl chloride (2k) smoothly
undergoes a Cl/Zn-exchange (25 °C, 24 h). Trapping the
zinc reagent with tosyl cyanide or a thiosulfonate led to the
functionalized steroids 3 m,n in 60ꢀ66% yield as a mixture
of two diastereomers (entries 10 and 11).
a20% Co(acac)2, 50% 4-fluorostyrene, THF, 50 °C, 5 h. bTHF, ꢀ20
°C, 30 min.
species using the same conditions. Quenching with allyl
bromide furnished the trisubstituted pyridine 3p in 67%
yield. Moreover, we performed the Cl/Zn-exchange on 3,5-
dichloropyridine (2n, 50 °C, 5 h). After Cu-catalyzed allyla-
tion the desired heterocycle 3q was obtained in 64% yield
(Table 2, entry 1).
Table 2. Co-Catalyzed Cl/Zn-Exchange of Heteroaryl and Aryl
Chlorides and Reaction with Electrophiles (E)
The scope of the Fe-catalyzed Cl/Zn-exchange was
satisfactory for alkyl chlorides. However, we found some
limitationsforarylchloridesand chloro-substitutedN-het-
erocycles. This led us to investigate an alternative transi-
tion metal catalyst. Co(acac)2 was found to be the most
appropriate salt. Although zincate 1 was an efficient ex-
change reagent for Fe-catalysis, we found that the readily
available zincate 4 performed better on most aryl and
N-heterocyclic chlorides. This zincate was prepared from
4,40-oxybis(3-iodo-1-methylbenzene) (5) by an I/Mg-
exchange with iPrMgCl LiCl (2.0 equiv, THF, ꢀ78 °C, 1
3
h), followed by transmetalation with ZnCl2 and addition
of tBuLi (1.0 equiv, THF, 0 °C, 0.5 h, Scheme 2).
Thus, the pyrazolopyridine 2l underwent a Cl/Zn-ex-
change reaction using zincate 4 (4.0 equiv) and 20% Co-
(acac)2 (50% 4-fluorostyrene, THF, 50 °C, 5 h). The
resulting zinc species reacted with iodine, furnishing the
functionalized N-heterocycle 3o in 65% yield. Furthermore,
the 3-chloro-pyridine derivative 2m was converted into a zinc
(16) We assume that 4-fluorostyrene facilitates the reductive elim-
ination step during the catalytic cycle. Its presence is essential for the Cl/
Zn-exchange. Apparently, 4-fluorostyrene is not consumed during the
reaction, as shown by GC analysis using an internal standard.
(17) For the preparation of adamantyllithium and adamantylmag-
nesium reagents, see: (a) Molle, G.; Dubois, J.-E.; Bauer, P. Tetrahedron
Lett. 1978, 19, 3177. (b) Molle, G.; Bauer, P.; Dubois, J.-E. J. Org. Chem.
1983, 48, 2975.
a Yield of isolated analytically pure product; 5 equiv of electrophile
were used. b 20% CuCN 2LiCl used as catalyst.
3
Also 1-chloroisoquinoline (2o) undergoes the Cl/Zn-
exchange reaction (50 °C, 5 h). Quenching with iodine
(18) Villieras, J.; Rambaud, M. Synthesis 1982, 924.
3176
Org. Lett., Vol. 13, No. 12, 2011

suitable for aryl chlorides bearing a nitrile group. So the
benzonitrile derivative 2s was converted to a zinc reagent
(50 °C, 5 h), which after Cu-catalyzed allylation gives the
1,2,3-trisubstituted benzene 3v in 57% yield (entry 6).
A tentative catalytic cycle is proposed for this new Cl/
Zn-exchange (Scheme 3). Under the reaction conditions,
we anticipate the formation of a reduced active metal
catalyst [Met] (Met = FeLn, CoLn) 8.20 The formation
of biphenyldiamine derivative 6 and dimethylbenzofuran 7
is mostly complete by mixing the reagents. The organic
chloride 2 may initially undergo an oxidative addition to
the metal catalyst (8) resulting in the formation of the
organometallic 11. The reaction of 11 with either zinc
reagent 9 or 10 transfers the R group from the transition
metal center to zinc leading to the new zinc reagent 12 and
to the iPr- or tBu-organometallic intermediate 13 (Alk-
[Met]-Cl; Alk = iPr or tBu). After β-hydride elimination
with formation of propene or isobutylene, the active metal
catalyst (8) is regenerated and is available for a new
catalytic cycle.21
Scheme 3. Proposed Mechanism for the Cl/Zn-Exchange
In summary, we have developed a new Cl/Zn-exchange
reaction allowing the direct transformation of aryl, hetero-
aryl, and also alkyl chlorides into the corresponding zinc
reagents. The method tolerates several functional groups
such as a nitrile or an ester. Remarkably, also secondary
and even tertiary chlorides are suitable substrates for the
exchange protocol. The synthetic scope of this new method
is currently being investigated in our laboratories.
furnished the 2-iodoisoquinoline 3r (59% yield, entry 2).
The Co-catalyzed Cl/Zn-exchange protocol using zincate 4
also proceeds well with nonheteroaromatic chlorides. This
Cl/Zn-exchange protocol gives access to 1,3,5-trisubsti-
tuted arenes, which are tedious to prepare by classical
methods.19 An ester function is well tolerated in the
exchange: the dichlorobenzene 2q was converted after Cl/
Zn-exchange and subsequent allylation to ethyl 3-allyl-
5-chlorobenzoate (3t) in 62% yield (entry 4).
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the European Research Council (ERC), and
the Deutsche Forschungsgemeinschaft (DFG) for finan-
cial support. We also thank Evonik AG (Hanau), BASF
AG (Ludwigshafen), W. C. Heraeus GmbH (Hanau), and
Chemetall GmbH (Frankfurt) for the generous gift of
chemicals.
A selective monoexchange is also possible on 1,2,3-tri-
chloro-5-(trifluoromethyl)benzene (2r, 50 °C, 5 h). Quench-
ing with PhSO2ꢀSPh furnished the trisubstituted thioether
3u in 63% yield (entry 5). The Cl/Zn-exchange reaction was
Supporting Information Available. Experimental pro-
cedure and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.
org.
(19) Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2007,
129, 15434.
(21) By using the zincate (4-Me2NC6H4)2Zn(Oct)MgCl as an ex-
change reagent we have observed a constant increase of the formation of
octene during the course of the reaction. This elimination was observed
only if an organic chloride is added to the mixture of the exchange
reagent (zincate) and the catalytic system.
€
(20) (a) Furstner, A.; Krause, H.; Lehmann, C. W. Angew. Chem.,
€
Int. Ed. 2006, 45, 440. (b) Furstner, A.; Martin, R.; Krause, H.; Seidel,
G.; Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773. (c)
Nakamura, M.; Nagashima, H. J. Am. Chem. Soc. 2009, 131, 6078.
Org. Lett., Vol. 13, No. 12, 2011
3177