Nucleophilic catalysis of the iodine-zinc exchange reaction: Preparation of highly functionalized diaryl zinc compounds

Article abstract of DOI:10.1002/anie.200353316

Sensitive functional groups are tolerated in an iodine-zinc exchange reaction catalyzed by Li(acac). Aryl and heteroaryl diorganozinc compounds with keto, aldehyde, or isothiocyanate substituents can be prepared by this method (see example in scheme; acac = acetylacetone, NMP=1-methyl-2-pyrrolidinone). Such zinc reagents serve as substrates for a wide variety of coupling reactions.

Full text of DOI:10.1002/anie.200353316

Angewandte
Chemie
Organometallic Reagents
Nucleophilic Catalysis of the Iodine–Zinc
Exchange Reaction: Preparation of Highly
Functionalized Diaryl Zinc Compounds**
Florian F. Kneisel, Maximilian Dochnahl, and
Paul Knochel*
Halogen–metal exchange reactions are among the most
powerful methods for preparing organometallic reagents.
Pioneered by Wittig et al.[1] and Gilman et al.,[2] the halo-
gen–lithium exchange has become an important method for
the preparation of functionalized aryl and heteroaryl lithium
compounds.[3] The halogen–magnesium[4] and the halogen–
[*] Dipl.-Chem. F. F. Kneisel, M. Dochnahl, Prof. Dr. P. Knochel
Ludwig-Maximilians-Universität München
Department Chemie
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)89-218-077-680
E-mail: knoch@cup.uni-muenchen.de
[**] We thank the Deutsche Forschungsgemeinschaft for a fellowship to
F.F.K. (KN 347/6-1) and the Fonds der Chemischen Industrie for
generous financial support. We thank BASF AG (Ludwigshafen) and
Chemetall GmbH (Frankfurt) for generous gifts of chemicals and
Florence Darbour for preliminary experiments.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200353316
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copper[5] exchange reactions were recently investigated
iodobenzoate (2a) with iPr2Zn[12] in Et2O/NMP (1:10) at 258C
in the presence of various salts (Table 1). Mg(acac)2 and
MgCl2 were found to be the most active magnesium additives
(Table 1, entries 1–3 and 9), and Li(acac) to be by far the most
extensively, as they allow convenient access to polyfunctional
organometallic compounds.[6] However, the exchange rate of
these reactions is considerably slower than that of the
halogen–lithium exchange. Similary, the halogen–zinc
exchange reaction can only be used for the preparation of
primary and secondary dialkyl zinc compounds[7] and fails in
the case of aromatic iodides.[8,9] During the course of our
investigations into iodine–zinc exchange reactions of alkyl
iodides, we found that magnesium salts accelerate the
reaction by a factor of ꢀ 200.[7a] However, this effect was
not sufficient for the preparation of diaryl zinc compounds.
We therefore studied the reaction parameters (solvent,
additives) of this exchange reaction in detail and report
herein the first catalyzed iodine–zinc exchange reaction.
The iodine–zinc exchange provides access to functional-
ized diaryl zinc compounds of type 1 from the corresponding
aryl iodides of type 2 (Schemes 1 and 2). Preliminary experi-
Table 1: The influence of metallic salts on the rate of the iodine–zinc
exchange of 2a with iPr2Zn in Et2O/NMP (1:10) at 258C.
Entry
Additive[a]
Conversion [%][b]
1
2
3
MgCl2
MgBr2
MgI2
30
15
2
4
5
Bu4NI
LiCl
10
0
6
LiBF4
2
7
8
9
10
11
LiClO4
Li(acac)
Mg(acac)2
Cs(acac)
Zn(acac)2
2
87
33
84
2
[a] Metal salt: 10 mol%. [b] The conversion was determined after a
reaction time of 15 min by analysis of reaction aliquots by GC with
tetradecane as an internal standard; accuracy: ꢂ2%.
active lithium additive (Table 1, entries 5–8). Interestingly,
Cs(acac) was as active as Li(acac), but Zn(acac)2 did not
display any catalytic activity (Table 1, entries 10 and 11).
These results support the nucleophilic catalysis proposed
above (Scheme 1). iPr2Zn[12] proved to be a better organozinc
reagent than Et2Zn or Me2Zn for the exchange reaction. As
iPr2Zn is highly inflammable, we developed an alternative
procedure in which sBu2Zn is prepared in situ by the reaction
of sBuLi with ZnCl2 (0.5 equiv, ꢁ 788C!RT, Et2O, reaction
overnight), followed by filtration (see experimental section).
Thus, the treatment of 2a (1 equiv) with iPr2Zn (0.55 equiv) in
the presence of Li(acac) (10 mol%) in Et2O/NMP (1:10)
furnished the desired diaryl zinc 1a in 12h at 25 8C
(Scheme 2). Acylation of 1a with benzoyl chloride
(1.5 equiv) in the presence of CuCN·2LiCl[13] (10 mol%) at
508C for 5 h provided 4-carbomethoxybenzophenone (5a) in
82% yield when the reaction was performed on a 2-mmol
scale and in 75% yield when the reaction was performed on a
25-mmol scale (Table 2, entry 1). Palladium-catalyzed Negishi
cross-coupling reactions[14] of the zinc reagents prepared by
this method proceeded very well. The reaction of di(2-
carboethoxyphenyl)zinc (1b) with 1-iodo-4-nitrobenzene in
the presence of a catalytic amount of [Pd(dba)2] (2.5 mol%)
and tri(2-furyl)phosphane (tfp, 5.0 mol%) for 10 h at room
temperature provided the functionalized biphenyl 5b in 71%
yield (Table 2, entry 2).[15] The presence of an additional
methoxy group on the aryl ring of the zinc substrate enhances
its reactivity. Thus, the diaryl zinc compound 1c reacted to
give the biphenyl 5c in 83% yield (Table 2, entry 3).
Scheme 1. Catalytic cycle of the iodine–zinc exchange reaction.
Scheme 2. Nucleophilic catalysis of the iodine–zinc exchange with
Li(acac) as the catalyst (acac=acetylacetone, NMP=1-methyl-2-pyrro-
lidinone).
ments showed that no exchange reaction occurs when an aryl
iodide is treated with Et2Zn or iPr2Zn in Et2O or THF.
However, when mixtures of Et2O and N-methylpyrrolidinone
(1:10) are used at 258C, an exchange reaction occurs to
furnish the mixed diorganozinc reagent FG-ArZnR (3, R =
Et or iPr, FG = functional group).[10] To promote the transfer
of the second alkyl group R we envisaged that it might be
necessary to activate the intermediate zinc species 3 through
the formation of an ate complex of type 4, in analogy with the
Suzuki reaction in which the boronic acid is converted into a
boronate through the addition of a base.[11]
Organozinc reagents with a wide range of functional
groups can be prepared by this method. Thus, it was possible
to prepare the isothiocyanate-substituted zinc compound 1d.
The treatment of 1d with Me3SnCl (4 h, 258C) provided the
aryl tin derivative 5d in 66% yield. Both electron-donor
substituents (e.g. methoxy groups) and electron-acceptor
substituents (e.g. cyano groups) can be present in the diaryl
After transfer of the first R group, with formation of RI
and FG-ArZnR, the nucleophilic catalyst NuꢁMet+ is regen-
erated, thus, in principle, making it possible to use this
activator in catalytic amounts. We therefore treated methyl 4-
1018
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Table 2: The reaction of the polyfunctional diaryl zinc compounds 1 with electrophiles in the presence of a copper or palladium catalyst.
Entry
1
Electrophile Product 5
Yield [%][a] Entry
1
Electrophile Product 5
Yield [%][a]
82[c,f]
1
PhCOCl
9
81[d,e]
75[b,c,f]
2
3
71[d,e]
10
11
52[d,e]
83[d,e]
84[c,e]
4
5
6
7
Me3SnCl
66[f]
12
13
14
15
75[d,e]
77[c,f]
60[d,e]
86[d,e]
84[d,e]
77[d,e]
60[c,e]
54[c,f]
8
MeCOCl
87[d,e]
[a] Yields of analytically pure products. [b] Yield of the reaction on a 25-mmol scale. [c] In the presence of CuCN·2LiCl (20 mol%). [d] In the presence of
[Pd(dba)2] (2.5 mol%) and tfp (5.0 mol%). [e] With iPr2Zn as the reagent for the exchange. [f] With sBu2Zn, generated in situ by transmetalation of sBuLi, as the
reagent for the exchange.
zinc compounds (1e–g; Table 2, entries 5–8). Interestingly, a
keto group is also compatible with the mild reaction
conditions for the I–Zn exchange. The diaryl zinc compounds
1h and 1i underwent Negishi cross-coupling with methyl 4-
iodobenzoate (2a) under palladium catalysis. The reaction
proceeded in good yield for 1h (81%, Table 2, entry 9) and in
moderate yield for the dithienylzinc derivative 1i (52%,
Table 2, entry 10), which suggests that competitive deproto-
nation of the acetyl group may occur in the latter case. We
also prepared the heterocyclic zinc species 1j, which under-
went copper(i)-catalyzed allylation to give the expected
product 5k in 84% yield (Table 2, entry 11). To our surprise,
it was even possible to prepare diaryl zinc compounds with an
aldehyde functional group under our standard conditions
(1k–m, Table 2, entries 12–15).[16] Subsequent acylation or
allylation led to the polyfunctional products 5l, 5m, and 5o in
yields of 75, 77, and 60%, respectively (Table 2, entries 12, 13,
and 15). Negishi cross-coupling of 1l with 2a provided the
expected biphenyl 5n in 60% yield (Table 2, entry 14).
Finally, we examined an intramolecular carbometalation
reaction[17] starting from the readily available alkynyl iodide 6
(Scheme 3).[18] The treatment of 6 with iPr2Zn (0.55 equiv) in
the presence of Li(acac) (10 mol%) in NMP at 258C for 12h
provided the desired diaryl zinc reagent, which underwent a
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evaporated, and the product was then purified by column chroma-
tography (SiO2, pentane/Et2O 80:20). The aldehyde 5m (317 mg,
77%) was obtained as a colorless oil).
Received: November 13, 2003 [Z53316]
Published Online: January 27, 2004
Keywords: copper · cross-coupling · iodine–zinc exchange ·
.
nucleophilic catalysis · palladium
[1] a) G. Wittig, U. Pockels, H. Dröge, Ber. Dtsch. Chem. Ges. A
1938, 71, 1903; b) G. Wittig, U. Schöllkopf, Tetrahedron 1958, 91;
c) W. F. Bailey, J. J. Patricia, J. Organomet. Chem. 1988, 352, 1.
[2] a) H. Gilman, W. Langham, A. L. Jacoby, J. Am. Chem. Soc.
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[4] a) L. Boymond, M. Rottländer, G. Cahiez, P. Knochel, Angew.
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Scheme 3. Carbocupration preceded by an iodine–zinc exchange.
smooth carbocupration in the presence of CuCN·2LiCl[13]
(1.1 equiv) to give the copper reagent 7 stereoselectively.
This intermediate was trapped with ethyl (2-bromomethyl)-
acrylate[19] to provide the tetrasubstituted E alkene 8 (E/Z >
99:1) in 54% overall yield (THF/NMP, 258C, 12h).
In summary, we have reported the first example of
nucleophilic catalysis of the iodine–zinc exchange reaction.
Under the mild reaction conditions a range of sensitive
functionalities (ketones, isothiocyanates, aldehydes) are tol-
erated, thus facilitating the synthesis of a wide range of
polyfunctional diaryl zinc reagents. We are currently studying
the scope of this reaction as well as the extension of this
catalytic approach to other systems.
[5] 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.
[6] A. Boudier, L. O. Bromm, M. Lotz, P. Knochel, Angew. Chem.
2000, 112, 4584; Angew. Chem. Int. Ed. 2000, 39, 4415.
[7] a) L. Micouin, P. Knochel, Synlett 1997, 327; b) for an iodine–
magnesium exchange catalyzed by Mg(OTf)2, see: R. W. Hoff-
mann, M. Brönstrup, M. Mꢀller, Org. Lett. 2003, 5, 313.
[8] For a cobalt-catalyzed synthesis of organozinc reagents with zinc
metal, see: a) H. Fillon, C. Gosmini, J. Perichon, J. Am. Chem.
Soc. 2003, 125, 3867; for the use of activated zinc, see: b) R. D.
Rieke, Science 1989, 246, 1260; c) L. Zhu, R. M. Wehmeyer,
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[9] For the use of lithium zincates as transmetalation agents, see: M.
Uchiyama, M. Koike, M. Kameda, Y. Kondo, T. Sakamoto, J.
Am. Chem. Soc. 1996, 118, 8733.
[10] For the enantioselective addition of mixed ArZn(alkyl) com-
pounds, see: C. Bolm, J. P. Hildebrand, K. Muniz, N. Hermanns,
Angew. Chem. 2001, 113, 3382; Angew. Chem. Int. Ed. 2001, 40,
3284.
[11] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.
[12] A. Boudier, C. Darcel, F. Flachsmann, L. Micouin, M. Oestreich,
P. Knochel, Chem. Eur. J. 2000, 6, 2748.
[13] P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert, J. Org. Chem.
1988, 53, 2390.
[14] a) E. Negishi, L. F. Valente, M. Kobayashi, J. Am. Chem. Soc.
1980, 102, 3298; b) M. Kobayashi, E. Negishi, J. Org. Chem.
1980, 45, 5223; c) E. Negishi, Acc. Chem. Res. 1982, 15, 340.
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Knochel, P. Venegas, G. Cahiez, Tetrahedron 1996, 52, 7201;
b) A. Staubitz, W. Dohle, P. Knochel, Synthesis 2003, 233.
[16] No clear results were obtained with 2-iodobenzaldehyde.
Dimeric products could be detected by gas chromatography
Experimental Section
In situ preparation of sBu2Zn: A solution of sec-butyllithium in
cyclohexane (ca. 1.4m) was filtered through celite. The concentration
of the alkyl lithium reagent was determined according to a literature
procedure.[20] The solution was cooled to 08C, then concentrated in
vacuo to about 10% of its initial volume to give an orange, highly
viscous mixture, which was then cooled to ꢁ 788C. A solution of zinc
chloride in Et2O (1.0m, 0.5 equiv) was added slowly. The resulting
solution was allowed to warm up slowly to room temperature and was
stirred overnight under light exclusion. The lithium chloride that
precipitated was removed from the solution by decantation, filtration,
or centrifugation. The resulting light-sensitive solution of sBu2Zn in
Et2O had a concentration of 0.6–0.8m (determined by iodolytic
titration, see also Supporting Information).
Typical procedure for the I–Zn exchange reaction and subsequent
copper-catalyzed allylation: A dried 10-mL round-bottomed flask
was charged with 3-iodo-4,5-dimethoxybenzaldehyde (584 mg,
2.0 mmol, 1.0 equiv) and Li(acac) (21 mg, 0.2 mmol, 0.1 equiv) in
dry NMP (1.5 mL) under an argon atmosphere and cooled to 08C.
The previously prepared sBu2Zn solution (1.4 mL of a 0.8m solution,
1.1 mmol, 0.55 equiv) was added and the reaction mixture was stirred
at room temperature for 3 h. The formation of the zinc reagent 1l was
monitored by gas chromatography with tetradecane as an internal
standard. The zinc reagent 1l was treated with allyl bromide (363 mg,
3.0 mmol, 1.5 equiv) in the presence of CuCN·2LiCl (0.2mL,
0.2mmol, 0.1 equiv). The reaction was complete after 5 h. (The
consumption of the zinc reagent was monitored by gas chromatog-
raphy). A saturated solution of NH4Cl was added to the mixture, the
aqueous phase was extracted with Et2O (3 ” 30 mL), the solvent was
1020
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during the preparation of the corresponding diaryl zinc reagent,
which suggests that this species has moderate stability.
[17] The alkynyl iodide 6 was prepared in two steps from 1-
bromomethyl-2-iodobenzene according to a literature proce-
dure: D. Bouyssi, G. Balme, Synlett 2001, 1191.
[18] S. A. Rao, P. Knochel, J. Am. Chem. Soc. 1991, 113, 5735.
[19] J. Viliꢁras, M. Rambaud, Synthesis 1982, 924.
[20] H.-S. Lin, L. Paquette, Synth. Commun. 1994, 24, 2503.
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