A cobalt-catalyzed sulfonate/copper exchange for the preparation of highly functionalized electron-deficient aryl copper reagents

Article abstract of DOI:10.1002/anie.200905379

(Chemical Equation Presentation) Organocopper reagents from phenols: A new cobalt-catalyzed aryl sulfonate/ copper exchange reaction allows the synthesis of highly functionalized aryl copper reagents from sulfonates bearing elec-tron-deficient substituents under mild conditions (25-45 °C, 1-6 h; see example). Sensitive functional groups, such as aldehydes, esters, and nitriles, are welltolerated.

Full text of DOI:10.1002/anie.200905379

Communications
DOI: 10.1002/anie.200905379
Organocopper Reagents
A Cobalt-Catalyzed Sulfonate/Copper Exchange for the Preparation of
Highly Functionalized Electron-Deficient Aryl Copper Reagents**
Christoph J. Rohbogner, Coura R. Diꢀne, Tobias J. Korn, and Paul Knochel*
Dedicated to Dr. Klaus Rꢁmer on the occasion of his 70th birthday
The preparation of highly functional aryl organometallics is of
great importance for the synthesis of drugs, agrochemicals
and materials.[1] Recently, copper-catalyzed reactions[2] and
highly chemoselective functionalized copper reagents[3–5]
have attracted great attention.[6] A direct copper insertion,[3]
an iodine–copper exchange[4] or a directed cupration[5] have
been used to prepare functionalized aryl copper reagents
from the corresponding aryl bromides or iodides. Alterna-
tively, phenol derivatives, such as sulfonates, have been
seldomly used for the preparation of aryl organometallics
owing to the strength of the carbon–oxygen bond.[7,8]
A
transition-metal-catalyzed activation of the aryl group–
oxygen bond has been envisioned to achieve this goal;
cobalt has been the metal of choice because of to its high
reactivity and moderate price.[9,10]
Scheme 1. The cobalt(II)-catalyzed aryl sulfonate/copper exchange
reaction.
Herein, we report a novel preparation of highly function-
alized aryl copper reagents 1 bearing a range of sensitive
functional groups (esters, nitriles, or aldehydes) starting from
aryl sulfonates 2 using a cobalt-catalyzed sulfonate/copper
exchange reaction mediated by phenylcopper (PhCu)
(Scheme 1).[11]
In the course of our studies on cobalt-catalyzed cross-
couplings,[12] we observed that the reaction of electron-
deficient aryl p-tolylsulfonates (ArOTs) with PhCu produced,
together with the cross-coupling product 3, an aryl copper
compound 1, which is the result of a OTs/Cu exchange.
Although this was a minor product under standard cross-
coupling conditions,[12] we were able to optimize its formation.
By replacing the tosyl group by an aryl sulfonate bearing a
donor substituent in the para position (OMe, NMe2), using a
higher catalyst loading (from 7.5 mol% to 20 mol%), and
performing the reaction in a 5:2 THF:DMPU mixture
(DMPU = N,N’-dimethyl-N,N’-propylene urea), the sulfo-
nate/copper exchange became the major reaction pathway
(ratio of 1:3 up to 10:1; Scheme 1). Thus, the reaction of 1,3-
dicarbethoxy benzenesulfonate (2a, 1 equiv) with PhCu
(3 equiv)[11] in the presence of [Co(acac)2] (20 mol%), 4-
fluorostyrene (50 mol%),[13,14] and Bu4NI[14] (1.0 equiv) in a
THF/DMPU mixture (5:2) furnishes the aryl copper reagent
1a within 2 h at 258C, and provides the aryl iodide (4a) after
iodolysis in 72% yield (Scheme 2).
Similarly, trapping the aryl copper species 1b obtained by
the reaction of 2b with PhCu (3.0 equiv after 3 h at 258C)
with iodine furnishes ethyl 3-cyano-5-iodobenzoate 4b in
65% yield (Scheme 2b). The copper reagent 1a could also be
trapped by various other electrophiles. Allylation with 3-
bromopropene affords the allylated product 4c in 78% yield
(Scheme 2c), and acylation using pivaloyl chloride furnishes
the benzophenone 4d in 61% yield (Scheme 2d). The
organocopper reagent derived from 2a undergoes a smooth
substitution reaction with 3-iodocyclohexen-1-one, yielding
the cyclohexenone 4e in 64% yield (Scheme 2e). A carbo-
cupration[15] of ethyl propiolate with 1a furnishes the alkene
4 f in 61% yield (Scheme 2 f). The related copper reagent 1b
undergoes a 1,4-addition with cyclohexenone, yielding the
corresponding Michael adduct 4g in 66% yield. The reaction
of 1b with S-methyl thiomethyl sulfonate MeSSO2Me fur-
nished the thioether 4h in 73% yield (Scheme 2h).
[*] Dipl.-Chem. C. J. Rohbogner, Dr. C. R. Diꢀne, Dr. T. J. Korn,
Prof. Dr. P. Knochel
Ludwig Maximilians Universitꢁt Mꢂnchen,
Department Chemie & Biochemie
Butenandtstrasse 5–13, Haus F, 81377 Mꢂnchen (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
Homepage: http://www.knochel.cup.uni-muenchen.de
Further trapping reactions of aryl copper reagents pre-
pared from the aryl sulfonates 2a–g are summarized in
Table 1. 1,3,5-trisubstituted arenes, which are usually difficult
to prepare, can also be easily accessed by this method.[16] Thus,
3,5-dicyanophenyl-4-methoxybenzenesulfonate 2c reacts
under standard conditions within 6 h at 458C, leading to the
corresponding copper reagent that was quenched with iodine
to yield 5-iodo isophthalonitrile 4i (Table 1, entry 1). Other
[**] We thank the Fonds der Chemischen Industrie, the European
Research Council (ERC), and the Deutsche Forschungsgemein-
schaft (DFG) for financial 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.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905379.
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Chemie
Table 1: Synthesis of products 4 obtained by the reaction of aryl
sulfonates with PhCu subsequent quenching with an electrophile.
Entry
Substrate[a]
E+
Product
Yield
[%][b]
1
2
2c
I2
4i
4j
64
71
2d PhCOCl
3
4
2d
4k
4l
71
69
2e
Scheme 2. Aryl sulfonate/copper exchange of the sulfonates 2a,b and
trapping with various electrophiles. Reagents and conditions: a) PhCu
(3.0 equiv) [Co(acac)2] (20 mol%), 4-fluorostyrene (50 mol%), Bu4NI
(1.0 equiv), THF/DMPU=5:2, 258C, 2–3 h; b) I2 (2.0 equiv), ꢀ208C,
30 min, 258C, 2 h; c) 3-bromopropene (2.0 equiv), ꢀ208C, 30 min,
258C, 2 h; d) tBuCOCl (2.0 equiv), ꢀ208C, 30 min, 258C, 2 h, e) 3-
iodocyclohexen-1-one (2.0 equiv), ꢀ208C, 30 min, 258C, 2 h; f) ethyl
propiolate (2.0 equiv), ꢀ408C, 30 min, 258C, 2 h; g) cyclohexenone
(2.0 equiv), TMSCl (2.0 equiv), ꢀ208C, 30 min, 258C, 2 h; h) MeS-
SO2Me (2.0 equiv), ꢀ208C, 30 min, 258C, 2 h.
5
6
2e
I2
4m 69
2e PhCOCl
4n
4o
4p
70
62
61
7
8
2 f
aryl sulfonates bearing electron-withdrawing groups are
readily converted into the corresponding copper species.
Thus, 3,5-bis(trifluoromethyl)phenyl-4-(dimethylamino)ben-
zenesulfonate 2d gave the aryl copper reagent 1d within 4 h
at 258C. Benzoylation yielded the benzophenone 4j in 71%
yield; alternatively, allylation with ethyl 2-(bromomethyl)-
acrylate[17] gave the 1,3,5-trisubstituted arene 4k in 71% yield
(Table 1, entries 2 and 3). The ortho-substituted sulfonate 2e
also reacted well, providing the aryl copper reagent 1e, which
was then allylated with 3-bromo-2-methylpropene to yield the
ethyl benzoate 4l in 69% yield (Table 1, entry 4). Reaction
with iodine or benzoyl chloride gave the iodo derivative 4m
and ketone 4n in 69% and 70% yields, respectively (Table 1,
entries 5 and 6). Monosubstituted aryl sulfonates, such as 2 f,
readily led to aryl sulfonate/copper exchange (5 h at 508C).
The resulting aryl copper 1 f was trapped with ethyl
2-(bromomethyl)acrylate[17] or benzoyl chloride, furnishing
the para-disubstituted arenes 4o and 4p in up to 62% yield
(Table 1, entries 7 and 8).
1,2,3,5-tetrasubstituted arenes are also accessible. Triester
2g affords the expected aryl copper reagent 1g within 1 h at
258C. Allylation with 3-bromo-2-methylpropene furnished
the 1,2,3-triester 4q in 72% yield (Table 1, entry 9). The
compatibility of our method with N heterocycles is also
shown: the substituted quinoline 2h reacts with PhCu in the
presence of [Co(acac)2] at 258C within 3 h to give copper
reagent (1h), which was allylated with methallyl bromide,
leading to the functionalized quinoline 4r in 53% yield
(Table 1, entry 10).
2 f PhCOCl
9
2g
2h
4q
4r
72
53
10
[a] An=4-MeOC6H4, Dma=4-Me2NC6H4. [b] Yield of isolated analytically
pure product.
Remarkably, an aldehyde function was also tolerated
during the exchange reaction. For example, 3-cyano-5-for-
mylphenyl 4-methoxybenzenesulfonate (2i) afforded 1i
under standard conditions, which was then trapped with
S-methyl thiomethylsulfonate to give thioether 4s in 68%
yield. Acylation of 1i furnished the ketone 4t in 60% yield
(Scheme 3).
A catalytic cycle is proposed for the reaction mechanism
(Scheme 4). PhCu initially undergoes a transmetalation to the
corresponding cobalt derivative Ph2Co (5). Nucleophilic
addition of 5 to an electron-deficient aryl sulfonate 2 would
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Communications
synthetic scope of this new reaction is currently being
investigated in our laboratories.
Received: September 25, 2009
Revised: November 13, 2009
Published online: February 5, 2010
Keywords: aryl sulfonates · cobalt · cuprates · exchange reaction ·
.
organometallic reagents
Scheme 3. Aryl sulfonate/copper exchange on substituted benzalde-
hydes. Reagents and conditions: a) PhCu (3.0 equiv) [Co(acac)2]
(20 mol%), 4-fluorostyrene (50 mol%), Bu4NI (1.0 equiv), THF/
DMPU=5:2, 258C, 1 h; a) MeSSO2Me (2.0 equiv), ꢀ208C, 30 min,
258C, 2 h, b) tBuCOCl (2.0 equiv), ꢀ208C, 30 min, 258C, 2 h.
[1] a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed. (Eds.: A.
de Meijere, F. Diederich), Wiley-VCH, Weinheim, 2004;
b) Transition Metals for Organic Synthesis, 2nd ed. (Eds.: M.
Beller, C. Bolm), Wiley-VCH, Weinheim, 2004; c) Handbook of
Functionalized Organometallics (Ed.: P. Knochel), Wiley-VCH,
Weinheim, 2005; d) Modern Arylation Methods (Ed.: L. Acker-
mann), Wiley-VCH, Weinheim, 2009.
[2] a) P.-F. Larsson, A. Correa, M. Carril, P.-O. Norrby, C. Bolm,
Angew. Chem. 2009, 121, 5801; Angew. Chem. Int. Ed. 2009, 48,
5691; b) S. L. Buchwald, C. Bolm, Angew. Chem. 2009, 121, 5694;
Angew. Chem. Int. Ed. 2009, 48, 5586; c) F. Shi, M. K. Tse, X.
Cui, D. Gꢀrdes, D. Michalik, K. Thurow, Y. Deng, M. Beller,
Angew. Chem. 2009, 121, 6026; Angew. Chem. Int. Ed. 2009, 48,
5912; d) A. Alexakis, J. E. Bꢁckvall, N. Krause, O. Pamies, M.
Diꢂguez, Chem. Rev. 2008, 108, 2796; e) J. P. Das, H. Chechik, I.
Marek, Nat. Chem. 2009, 1, 128.
[3] a) G. W. Ebert, R. D. Rieke, J. Org. Chem. 1984, 49, 5280;
b) R. D. Rieke, R. H. Wehmeyer, T. C. Wu, G. W. Ebert,
Tetrahedron 1989, 45, 443; c) G. W. Ebert, J. W. Cheasty, S. S.
Tehrani, E. Aouad, Organometallics 1992, 11, 1560; d) G. W.
Ebert, D. R. Pfenning, S. D. Suchan, T. A. Donovan, Tetrahedron
Lett. 1993, 34, 2279.
[4] a) C. Piazza, P. Knochel, Angew. Chem. 2002, 114, 3397; Angew.
Chem. Int. Ed. 2002, 41, 3263; b) X. Yang, T. Rotter, C. Piazza, P.
Knochel, Org. Lett. 2003, 5, 1229; c) M. I. Calaza, X. Yang, D.
Soorukram, P. Knochel, Org. Lett. 2004, 6, 529; d) X. Yang, A.
Althammer, P. Knochel, Org. Lett. 2004, 6, 1665; e) X. Yang, P.
Knochel, Org. Lett. 2006, 8, 1941.
Scheme 4. Proposed mechanism for the sulfonate/copper exchange
reaction.
[5] a) S. Usui, Y. Hashimoto, J. V. Morey, A. E. H. Wheatly, M.
Uchiyama, J. Am. Chem. Soc. 2007, 129, 15102; b) J. Haywood,
J. V. Morey, A. E. H. Wheatley, C.-Y. Liu, S. Yasuike, J. Kurita,
P. R. Raithby, M. Uchiyama, Organometallics 2009, 28, 38.
[6] a) R. J. K. Taylor, Organocopper Reagents, Oxford University
Press, Oxford, 1994; b) Modern Organocopper Chemistry (Ed.:
N. Krause), Wiley-VCH, Weinheim, 2002; c) A. Hoffmann-
Rꢀder, N. Krause, Synthesis 2001, 171.
[7] a) M. Yus, Recent Res. Dev. Org. Chem. 1997, 1, 397; b) D.
Guijarro, M. Yus, Recent Res. Dev. Org. Chem. 1998, 2, 713;
c) D. J. Ramꢃn, M. Yus, Eur. J. Org. Chem. 2000, 225; d) C. G.
Screttas, M. Micha-Screttas, J. Org. Chem. 1978, 43, 1064.
[8] In a multistep sequence, the conversion of a phenol into a
reactive organometallic species may be achieved (for example,
OH!OTf!SnR3), but with moderate atom economy; see:
R. C. Winstead, T. H. Simpson, G. A. Lock, M. D. Schiavelli,
D. W. Thompson, J. Org. Chem. 1986, 51, 275; ArOH!ArOTf/
ArOMs!ArZnX: I. Kazmiersi, C. Gosmini, J.-M. Paris, J.
Perichon, Synlett 2006, 881; for a Review, see: J. K. Stille, Angew.
Chem. 1986, 98, 504; Angew. Chem. Int. Ed. Engl. 1986, 25, 508.
[9] a) H. Avedissian, L. Bꢂrillon, G. Cahiez, P. Knochel, Tetrahedron
Lett. 1998, 39, 6163; b) C. Gosmini, Y. Rollin, J.-Y. Nꢂdꢂlec, J.
Pꢂrichon, J. Org. Chem. 2000, 65, 6024; c) H. Fillon, E. Le Gall,
C. Gosmini, J. Pꢂrichon, Tetrahedron Lett. 2002, 43, 5941; d) T.
Tsuji, H. Yorimitsu, K. Oshima, Angew. Chem. 2002, 114, 4311;
Angew. Chem. Int. Ed. 2002, 41, 4137; e) H. Fillon, C. Gosmini, J.
Pꢂrichon, J. Am. Chem. Soc. 2003, 125, 3867; f) H. Ohmiya, H.
then lead to a cobalt(IV) intermediate 6 that is stabilized by a
h5-complexation. This type of complexation may explain why
electron-poor aromatic systems react faster. After re-aroma-
tization, this cobalt complex produces a cobalt(IV) inter-
mediate[16] 7. Reductive elimination of the cobalt reagent 7
would then affords biphenyl[18,19] and the aryl cobalt(II)
reagent 8. The reaction of this intermediate with PhCu results
in the formation of compound 9, which only slowly undergoes
a reductive elimination to ArPh (3). A subsequent trans-
metalation with PhCu leads to the aryl copper reagent 1 and
regenerates Ph2Co[19] (5). This pathway is preferred over the
formation of 3, as ratios of 10:1 are obtained (Scheme 1).
Alternatively, a reduction of [Co(acac)2] to a reactive
cobalt(I) intermediate[9e] may be envisioned, leading to a
similar sequence as shown in Scheme 4.
In summary, we have developed a novel sulfonate/copper-
exchange that allows phenol derivatives (aryl sulfonates) to
be converted into the corresponding copper reagents. This
cobalt-catalyzed reaction tolerates sensitive functional
groups, such as an aldehyde, a nitrile, or an ester. The
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Yorimitsu, K. Oshima, Chem. Lett. 2004, 33, 1240; g) I.
Kazmierski, M. Bastienne, C. Gosmini, J.-M. Paris, J. Pꢂrichon,
J. Org. Chem. 2004, 69, 936; h) T. J. Korn, P. Knochel, Angew.
Chem. 2005, 117, 3007; Angew. Chem. Int. Ed. 2005, 44, 2947;
i) J.-M. Bꢂgouin, C. Gosmini, J. Org. Chem. 2009, 74, 3221.
[10] H. Shinokubo, K. Oshima, Eur. J. Org. Chem. 2004, 2081.
[11] For experimental details, see the Supporting Information.
[12] a) T. J. Korn, M. A. Schade, S. Wirth, P. Knochel, Org. Lett. 2006,
8, 725; b) T. J. Korn, M. A. Schade, M. N. Cheemala, S. Wirth,
S. A. Guevara, G. Cahiez, P. Knochel, Synthesis 2006, 3547.
[13] 4-Fluorostyrene facilitates the reductive elimination step during
the catalytic cycle, and its presence is essential for performing
the sulfonate/copper exchange reaction. Apparently, 4-fluoros-
tyrene is not consumed during the reaction, as shown by GC
analysis using an internal standard: See: a) M. Piber, A. E.
Jensen, M. Rottlꢁnder, P. Knochel, Org. Lett. 1999, 1, 1323;
b) A. E. Jensen, P. Knochel, J. Org. Chem. 2002, 67, 79.
Org. Chem. 1994, 59, 6095; b) M. T. Reetz, R. Breinbauer, K.
Wanninger, Tetrahedron Lett. 1996, 37, 4499; c) K. Nakamura,
H. Okubo, M. Yamaguchi, Synlett 1999, 549; d) W. J. Scott, J. K.
Stille, J. Am. Chem. Soc. 1986, 108, 3033; e) A. H. Roy, J. F.
Hartwig, J. Am. Chem. Soc. 2003, 125, 8704.
[15] J.-F. Normant, A. Alexakis, Synthesis 1981, 841.
[16] J. M. Murphy, X. Liao, J. F. Hartwig, J. Am. Chem. Soc. 2007,
129, 15434.
[17] J. Villiꢂras, M. Rambaud, Org. Synth. 1988, 66, 220.
[18] We have tested whether a cobalt(0) species (generated by a pre-
reduction of [Co(acac)2] with PhCu) is not a catalytically active
species. The use of [Co(acac)3] as a catalyst did not lead to any
conversion. For a report of a cobalt(IV) species, see: Z. Nagy-
Magos, L. Markꢃ, G. Bor, J. Organomet. Chem. 1968, 14, 205.
[19] [Co(acac)2] promotes the decomposition of PhCu to biphenyl.
The additional presence of 4-fluorostyrene and Bu4NI even
accelerates this homocoupling process, thus explaining the need
of an excess of PhCu.
[14] The role of Bu4NI may be to de-aggregate organometallic
reagents. See: a) S. W. Wright, D. L. Hageman, L. D. McClure, J.
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