Accelerated zincations for an efficient and mild functionalization of aromatics and heterocycles

Article abstract of DOI:10.1002/adsc.201300049

An improved process for the preparation of aromatic and heteroaromatic diorganozinc reagents and their subsequent reaction with electrophiles is presented. The new method, featuring the use of a 2,2,6,6-tetramethylpiperidyl (TMP) magnesium base in the presence of zinc chloride (ZnCl₂), is superior to the previous methods, which require the preparation of zinc bases. Specifically, the shorter reaction times under mild conditions provide an easier and more practical process, while the use of only a slight excess of the amide allows the isolation of products in high yields. These improvements are particularly significant for the large-scale preparation of organozincs and their subsequent reactions. Remarkably, beside the high kinetic activity, a wide range of functional groups is tolerated and sensitive heteroaromatics can easily be converted into the corresponding organometallic reagents and reacted with various electrophiles. Copyright

Full text of DOI:10.1002/adsc.201300049

UPDATES
DOI: 10.1002/adsc.201300049
Accelerated Zincations for an Efficient and Mild
Functionalization of Aromatics and Heterocycles
Andreas Unsinn,a Stefan H. Wunderlich,a and Paul Knochela,*
a
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen, Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen,
Germany
Fax : (+49)-89-2180-77680; e-mail: paul.knochel@cup.uni-muenchen.de
Received: January 19, 2013; Published online: March 15, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300049.
Abstract: An improved process for the preparation
of aromatic and heteroaromatic diorganozinc re-
agents and their subsequent reaction with electro-
philes is presented. The new method, featuring the
use of a 2,2,6,6-tetramethylpiperidyl (TMP) magne-
sium base in the presence of zinc chloride (ZnCl2),
is superior to the previous methods, which require
the preparation of zinc bases. Specifically, the short-
er reaction times under mild conditions provide an
easier and more practical process, while the use of
only a slight excess of the amide allows the isolation
of products in high yields. These improvements are
particularly significant for the large-scale prepara-
tion of organozincs and their subsequent reactions.
Remarkably, beside the high kinetic activity, a wide
range of functional groups is tolerated and sensitive
heteroaromatics can easily be converted into the
corresponding organometallic reagents and reacted
with various electrophiles.
ized aromatics and heteroaromatics. We have de-
scribed an additional procedure involving a complexa-
tion of some organic substrates with ZnCl2 prior to
the addition of TMP2Mg·2LiCl (2) which led to im-
proved metalation yields.[8] However, this last method
had several drawbacks: (i) the stability of
TMP2Mg·2LiCl (2) is limited due to its high kinetic
basicity;[9] (ii) the tolerance of functional groups and
sensitive heterocycles is also moderate.
Since we noticed that zincations may be performed
at elevated temperatures,[10] we have envisioned to
use the transmetalation energy to perform fast and ef-
ficient zincations at moderately elevated temperatures
(reaction temperature up to 408C). Herein, we wish
to report that this moderate increase of temperature
leads to a dramatic decrease in the reaction time. Re-
markably, this small temperature increase (10–158C)
is sufficient to provide a rate acceleration of up to 50
times.
Thus, whereas the zincation of coumarin (5) with
TMP2Zn·2MgCl2·2LiCl (4) requires 4 h at 258C to
reach >95% conversion, the sequential treatment of
5 with ZnCl2 (0.5 equiv.) followed by the addition of
TMPMgCl·LiCl (1; 1.1 equiv.) leads to the zincated
species 6 within 2 h. If ZnCl2·LiCl[11] (0.5 equiv.) is
used followed by the addition of TMPMgCl·LiCl (1;
Keywords: cross-coupling; Grignard reaction; het-
erocycles; metalation; synthetic methods; zinc
The directed ortho-metalation of aromatic and heter- 1.1 equiv.) 6 is obtained in 5 min (Figure 1, Scheme 1).
ocyclic compounds is an efficient method for the func-
After a Pd-catalyzed Negishi cross-coupling[12] with
tionalization of these scaffolds.[1] Besides conventional 4-iodoanisole, the expected coumarin derivative 7 is
lithium bases a range of new bimetallic ate-bases has obtained in 82% yield (Scheme 1). A similar behav-
been introduced by Kondo, Mulvey, Mongin and iour is found for quinoxaline (8). The addition of
Uchiyama.[2] These bases allow a smooth metalation TMP2Zn·2MgCl2·2LiCl (4, 0.55 equiv.) provides the
of a number of unsaturated systems due to synergetic diheteroaryl zinc reagent 9 after 5 h at 258C. Whereas
effects between the two metals. Recently, we have the sequential treatment of the substrate with ZnCl2
also reported highly soluble metal amides complexed (0.5 equiv.)
followed
by
the
addition
of
by LiCl such as TMPMgCl·LiCl (1),[3] (TMP=2,2,6,6- TMPMgCl·LiCl (1; 1.1 equiv.) leads to the zincated
tetramethylpiperidyl),
TMP2Mg·2LiCl
(2),[4] species 9 in >95% within 2 h. In this case also the
TMPZnCl·LiCl (3),[5] TMP2Zn·2MgCl2·2LiCl (4)[6] usage of ZnCl2·LiCl (0.5 equiv.) followed by
and TMP3Al·3LiCl[7] which allowed a chemo- and re- TMPMgCl·LiCl (1; 1.1 equiv.) accelerates the metala-
gioselective metalation of a broad range of functional- tion and leads to complete conversion within 1 h. The
Adv. Synth. Catal. 2013, 355, 989 – 995
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
989

Andreas Unsinn et al.
UPDATES
Figure 1. Progress of the metalation of coumarin (5) using
different metalation procedures.
Figure 2. Progress of the metalation of quinoxaline (8) using
different metalation procedures.
reaction can be further accelerated by addition of one
extra equivalent of LiCl. Thus, if the monomeric com- the addition of TMPMgCl·LiCl (1) to the substrate/
plex ZnCl2·2LiCl[13] (0.5 equiv.) is used instead, fol- ZnCl2 solution is complete. Whereas the temperature
lowed by the addition of TMPMgCl·LiCl (1; rises to 388C in the case of substrate/ZnCl2·2LiCl so-
1.1 equiv.) 9 is obtained within 15 min (Figure 2).
lution. This high rate increase in the metalation for
Careful monitoring of the reaction temperature a comparatively small temperature increase may be
(20-mmol scale experiments) indicates that the tem- rationalized by an alternative reaction pathway,
perature increases moderately to reach 348C when where the organic substrate is activated by forming
Scheme 1. Dramatic acceleration of the metalation of coumarin (5) and quinoxaline (8) with TMP2Zn·2MgCl2·2LiCl (4) and
the new sequential procedure.
990
asc.wiley-vch.de
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 989 – 995

Accelerated Zincations for an Efficient and Mild Functionalization of Aromatics and Heterocycles
a Lewis acid adduct with ZnCl2·2LiCl and then reacts and a Pd(0)-catalyzed cross-coupling with 4-iodoani-
with kinetically enhanced TMPMgCl·LiCl (1), to gen- sole furnishes the doubly functionalized quinoxaline
erate in situ an organomagnesium intermediate which 13l in 57% yield (entry 12). This method allows the
can then easily transmetalate with carbophilic ZnCl2 zincation of N-Boc-protected 5-bromoindazole (12e)
already present in the solution. On the other hand in position 3. Such a metalation is hard to achieve
these results may be an indication for a species differ- since usually a ring fragmentation occurs.[16] The mild
ent from TMP2Zn·2MgCl2·2LiCl (4) being present in conditions of the zincation procedure [(i) ZnCl2·LiCl
the metalation. The alternative species TMP3Zn has (0.5 equiv.), 258C, 10 min; (ii) TMPMgCl·LiCl (1,
been proven to be unstable.[14]
1.1 equiv.), 258C, 0.1 h] lead to the 3-zincated inda-
Pd(0)-catalyzed cross-coupling of 9 with ethyl 4-io- zole. Copper(I)-catalyzed acylation with 4-chloroben-
dobenzoate (258C, 3 h) furnishes the expected prod- zoyl chloride provides the product 13m in 74% yield.
uct 10 in 79% yield (Scheme 1).
Remarkably, this method also allows a smooth zin-
The new procedure is quite general and by treating cation of ethyl N-Boc-indole-2-carboxylate (14) in po-
a variety of aromatics of type 11 and heterocycles of sition 3. The fast and efficient zincation procedure [(i)
type 12 with ZnCl2·2LiCl (0.5 equiv.), ZnCl2·LiCl ZnCl2·2LiCl
(0.5 equiv.),
258C,
10 min;
(ii)
(0.5 equiv.) or ZnCl2 (0.5 equiv.) followed by TMPMgCl·LiCl (1, 1.1 equiv.), 258C, 0.5 h] leads
TMPMgCl·LiCl (1, 1.1 equiv., 258C), a range of poly- smoothly to the 3-zincated indole 15 within 30 min.
functional diorganozincs was prepared at slightly ele- Pd-catalyzed cross-coupling using 2% [1,3-bis(2,6-di-
vated temperature, leading after a quenching with
ACHTUNGTRENiNUNG sopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)-
electrophiles to the expected products of type 13 in palladium(II) dichloride (PEPPSI-i-Pr)[17] as catalyst
57–94% yield (Table 1). Thus, methyl esters like and gentle heating to 508C for 2 h allows the coupling
methyl 4-bromo- and 4-chlorobenzoate (11a and 11b) with an electron-deficient aryl bromide (1.1 equiv.),
are readily zincated within 20 h providing after a cop- providing smoothly the 3-arylated indole 16 in 81%
per(I)-mediated
benzoylation[15]
[CuCN·2LiCl yield. Applying our new procedure to ethyl 5-
benzofuran-2-carboxylate (17) gives the ex-
(1.1 equiv.), PhCOCl (1.2 equiv.), À40 to 258C, 20 h] methoxy
AHCTUNGTRENNUNG
the corresponding keto esters 13a and 13b in 85–86% pected zinc reagent 18 within 30 min at only moder-
yield (entries 1 and 2). Interestingly, the zincation of ately elevated temperature. Using the already known
11a and 11b with TMP2Zn·2MgCl2·2LiCl (4, conditions (PEPPSI-i-Pr, 508C) the cross-coupling
0.55 equiv.) requires a considerably longer reaction with 4-bromobenzonitrile is successful within 1 h pro-
time (110 h instead of 20 h for the new procedure). viding the desired polyfunctional benzofuran 19 in
Similarly, the methyl ester 11c is zincated within 5 h 75% yield. Similarly ethyl 5-methoxybenzothiophene-
and furnishes after acylation with 2-thiophenecarbox- 2-carboxylate 20 is metalated readily under the same
ylic acid chloride the polyfunctional ketone 13c in conditions, providing the 3-metalated benzothiophene
82% yield (entry 3). Substituted ethyl benzoates like derivative 21 after 30 min. Once more cross-coupling
11d–f are zincated similarly. After copper(I)-mediated is achieved within 1 h at 508C, yielding the desired
acylations, the ketones 13d and 13e are obtained in highly functionalized benzothiophene derivative 22 in
91–94% yield (entries 4 and 5). Negishi cross-coupling 87% yield (Scheme 2).
of metalated 11f with 3-iodoanisole using Pd
G
In summary, we have reported a new zincation pro-
(2%) and P(o-fur)3 (4%) gave the biphenyl 13f in cedure involving the sequential addition of ZnCl2 and
ACHTUNGTRENNUNG
87% yield (entry 6). The zincation of 1,3-difluoroben- TMPMgCl·LiCl. This practical method combines fast
zene (11g) is completed within 6 h using the new pro- metalations with an excellent functional group toler-
cedure (a reaction time of 90 h is required with ance (compatibility with a methyl ester, an aldehyde
TMP2Zn·2MgCl2·2LiCl (4)). Copper(I)-mediated acy- and various electron-deficient heterocycles). With this
lation with 4-chlorobenzoyl chloride furnishes the method, an N1-protected indazole scaffold can be
benzophenone 13g in 80% yield (entry 7). Further- metalated without fragmentation and undergoes read-
more, various heterocycles undergo this accelerated ily a subsequent Cu-catalyzed acylation. This new
zincation. Thus, 3,6-dimethoxypyridazine (12a) is procedure involves a metalation rate increase up to
metalated within 5 h. Negishi cross-coupling with 50 times for only 10–158C temperature increase, indi-
ethyl 4-iodobenzoate provides the substituted pyrida- cating either a reaction pathway including a Lewis
zine 13h in 65% yield (entry 8). Interestingly, the het- acid activation of the organic substrate, followed by
erocycles 12b and 12c are zincated regioselectively af- a magnesiation and a fast transmetalation with ZnCl2
fording after the reactions with typical electrophiles or that a more reactive species could be generated at
the products 13i and 13j in 57–82% yield (entries 9 this moderately elevated temperature. Further studies
and 10). The metalation of the aldehyde 12d proceeds along these lines are underway in our laboratories.
smoothly within 2 h and iodolysis leads to the 2-io-
doindole 13k in 78% yield (entry 11). The quinoxaline
10 (see Scheme 1) can be further zincated within 2 h
Adv. Synth. Catal. 2013, 355, 989 – 995
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
991

Andreas Unsinn et al.
UPDATES
Table 1. Products obtained by using the stepwise metalation procedure with ZnCl2·nLiCl (n=0, 1, 2) and TMPMgCl·LiCl
(1).[a]
Substrate; Time [h][b]
E+
Product; Yield[c]
PhCOCl
1
2
11a: X=Br, n=0; 20 (110)
11b: X=Cl, n=0; 20 (110)
13a: X=Br; 85%[d]
13b: X=Cl; 86%[d]
3
11c: n=0; 5 (36)
13c; 82%[d]
4
5
11d: X=Br, n=0; 4 (72)
11e: X=F, n=0; 2 (12)
13d: X=Br; R=H; 91%[d]
13e: X=F; R=Cl; 94%[d]
6
7
8
9
11f: n=0; 3 (25)
11g: n=0; 6 (90)
12a: n=0; 5
13f; 87%[e]
13g; 80%[d]
13h; 65%[e]
13i; 82%[d]
PhCOCl
12b: n=1; 0.1
10
11
12c: n=1; 1
12d: n=1; 2
13j; 57%[e]
13k; 78%
I2
992
asc.wiley-vch.de
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 989 – 995

Accelerated Zincations for an Efficient and Mild Functionalization of Aromatics and Heterocycles
Table 1. (Continued)
Substrate; Time [h][b]
E+
Product; Yield[c]
12
13
10: n=2; 2
13l; 57%[e]
12e: n=2; 0.1
13m; 74%[d]
[a]
[b]
[c]
[d]
[e]
Reactions conditions: 2 mmol substrate, 2 mL THF, 1 mL 1M ZnCl2·nLiCl solution, 2 mL 1.2M TMPMgCl·LiCl solution.
In parentheses are given the metalation times using TMP2Zn·2MgCl2·2LiCl (4) (0.55 equiv.).
Isolated yield of analytically pure product.
A transmetalation with CuCN·2LiCl (1.1 equiv.) was performed.
Obtained by palladium-catalyzed cross-coupling using PdACTHNUTRGNEN(UG dba)2 (2%) and PACHUTNGTERN(NUGN o-fur)3 (4%).
Scheme 2. Expeditive zincation at position 3 of indole, benzofuran and benzothiophene derivatives.
methyl 4-bromobenzoate (11a; 428 mg, 2.0 mmol) in dry
Experimental Section
THF (1 mL) and treated with ZnCl2 (1M solution in THF,
1.0 mL, 1.0 mmol). TMPMgCl·LiCl (1.2M in THF, 1.85 mL,
2.2 mmol) was added dropwise and the reaction mixture was
stirred at 258C for 20 h. The reaction mixture was cooled to
À408C, then CuCN·2LiCl (1M in THF, 2.2 mL, 2.2 mmol)
and benzoyl chloride (0.28 mL, 2.4 mmol) were added. The
Synthesis of 2-Benzoyl-4-bromobenzoic Acid Methyl
Ester (13a)
A dry and argon-flushed 25-mL Schlenk tube, equipped
with a magnetic stirring bar was charged with a solution of
Adv. Synth. Catal. 2013, 355, 989 – 995
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
993

Andreas Unsinn et al.
UPDATES
mixture was allowed to warm to 258C and stirred overnight.
The reaction mixture was quenched with a saturated aque-
ous NH4Cl solution (10 mL), extracted with diethyl ether
(3ꢃ20 mL) and dried over MgSO4. After filtration, the sol-
vent was evaporated under vacuum. The crude product was
purified by column chromatography (pentane:ether=6:1) to
give 13a as a yellow solid; yield: 542 mg (85%).
2958; b) S. H Wunderlich, C. J. Rohbogner, A. Unsinn,
P. Knochel, Org. Process Res. Dev. 2010, 14, 339; c) T.
Kunz, P. Knochel, Angew. Chem. 2012, 124, 1994;
Angew. Chem. Int. Ed. 2012, 51, 1958;.
[4] a) G. C. Clososki, C. J. Rohbogner, P. Knochel, Angew.
Chem. 2007, 119, 7825; Angew. Chem. Int. Ed. 2007, 46,
7681; b) C. J. Rohbogner, G. C. Clososki, P. Knochel,
Angew. Chem. 2008, 120, 1526; Angew. Chem. Int. Ed.
2008, 47, 1503.
[5] a) L. Klier, T. Bresser, T. A. Nigst, K. Karaghiosoff, P.
Knochel, J. Am. Chem. Soc. 2012, 134, 13584; b) T.
Bresser, P. Knochel, Angew. Chem. 2011, 123, 1954;
Angew. Chem. Int. Ed. 2011, 50, 1914; c) M. Mosrin, P.
Knochel, Org. Lett. 2009, 11, 1837.
[6] a) A. Unsinn, P. Knochel, Chem. Commun. 2012, 48,
2680; b) M. Jaric, B. A. Haag, A. Unsinn, K. Karaghios-
off, P. Knochel, Angew. Chem. 2010, 122, 5582; Angew.
Chem. Int. Ed. 2010, 49, 5451; c) S. H. Wunderlich, P.
Knochel, Angew. Chem. 2007, 119, 7829; Angew. Chem.
Int. Ed. 2007, 46, 7685.
Acknowledgements
The research leading to these results has received funding
from the European Research Council under the European
Communityꢀs Seventh Framework Programme (FP7/2007-
2013) ERC grant agreement No. 227763. We thank the Fonds
der Chemischen Industrie for financial support. We also
thank BASF SE (Ludwigshafen), Heraeus Holding GmbH
(Hanau) and Rockwood Lithium GmbH (Frankfurt) for the
generous gift of chemicals.
[7] a) S. H. Wunderlich, P. Knochel, Angew. Chem. 2009,
121, 1530; Angew. Chem. Int. Ed. 2009, 48, 1501; b) M.
Kienle, A. Unsinn, P. Knochel, Angew. Chem. 2010,
122, 4860; Angew. Chem. Int. Ed. 2010, 49, 4751.
[8] Z. Dong, G. C. Clososki, S. H. Wunderlich, A. Unsinn,
J. Li, P. Knochel, Chem. Eur. J. 2009, 15, 457.
References
[1] a) N. Chatani, Directed Metallation, in: Topics in Or-
ganometallic Chemistry, Springer Verlag, Berlin, 2007;
[9] C. J. Rohbogner, S. H. Wunderlich, G. C. Clososki, P.
À
b) G. Dyker, Handbook of C H Transformations,
Knochel, Eur. J. Org. Chem. 2009, 1781.
Wiley-VCH, Weinheim, 2005; c) M. Yus, F. Foubelo, in:
Handbook of Functionalized Organometallics, (Ed.: P.
Knochel), Wiley-VCH, Weinheim, 2005, Vol. 1; d) V.
Snieckus, Chem. Rev. 1990, 90, 879; e) M. Schlosser,
Angew. Chem. 2005, 117, 380; Angew. Chem. Int. Ed.
2005, 44, 376; f) M. C. Whisler, S. MacNeil, P. Beak, V.
Snieckus, Angew. Chem. 2004, 116, 2256; Angew.
Chem. Int. Ed. 2004, 43, 2206.
[10] S. H. Wunderlich, P. Knochel, Org. Lett. 2008, 10, 4705.
[11] for the effects of LiCl see: E. Hevia, R. E. Mulvey,
Angew. Chem. 2011, 123, 6576; Angew. Chem. Int. Ed.
2011, 50, 6448.
[12] a) E. Negishi, S. Baba, J. Chem. Soc. Chem. Commun.
1976, 596; b) S. Baba, E. Negishi, J. Am. Chem. Soc.
1976, 98, 6729; c) E. Negishi, A. O. King, N. Okukado,
J. Org. Chem. 1977, 42, 1821; d) E. Negishi, N. Okuka-
do, A. O. King, D. E. Van Horn, B. I. Spiegel, J. Am.
Chem. Soc. 1978, 100, 2254; e) E. Negishi, T. Takahashi,
S. Baba, D. E. Van Horn, N. Okukado, J. Am. Chem.
Soc. 1987, 109, 2393; f) E. Negishi, Acc. Chem. Res.
1982, 15, 340; g) E. Negishi, Angew. Chem. 2011, 123,
6870; Angew. Chem. Int. Ed. 2011, 50, 6738.
[13] a) B. Brehler, H. Jacobi, Naturwissenschaften 1964, 51,
11; b) I. Solinas, H. D. Lutz, J. Solid State Chem. 1995,
117, 34.
[14] a) J-M. L’Helgoual’ch, A. Seggio, F. Chevallier, M. Yo-
nehara, E. Jeanneau, M. Uchiyama, F. Mongin, J. Org.
Chem. 2008, 73, 177; b) R. E. Mulvey, Chem. Commun.
2001, 1049; c) P. Garcꢅa-ꢆlvarez, R. E. Mulvey, J. A.
Parkinson, Angew. Chem. 2011, 123, 9842; Angew.
Chem. Int. Ed. 2011, 50, 9668.
[2] a) Y. Kondo, M. Shilai, M. Uchiyama, T. Sakamoto, J.
Am. Chem. Soc. 1999, 121, 3539; b) M. Uchiyama, T.
Miyoshi, Y. Kajihara, T. Sakamoto, Y. Otani, T.
Ohwada, Y. Kondo, J. Am. Chem. Soc. 2002, 124, 8514;
c) M. Uchiyama, H. Naka, Y. Matsumoto, T. Ohwada,
J. Am. Chem. Soc. 2004, 126, 10526; d) H. Naka, M.
Uchiyama, Y. Matsumoto, A. E. H. Wheatley, M.
McPartlin, J. V. Morey, Y. Kondo, J. Am. Chem. Soc.
2007, 129, 1921; e) R. E. Mulvey, F. Mongin, M.
Uchiyama, Y. Kondo, Angew. Chem. 2007, 119, 3876;
Angew. Chem. Int. Ed. 2007, 46, 3802; f) F. Chevallier,
F. Mongin, Chem. Soc. Rev. 2008, 37, 595; g) T.
Nguyen, N. Marquise, F. Chevallier, F. Mongin, Chem.
Eur. J. 2011, 17, 10405; h) K. Snꢄgaroff, S. Komagawa,
F. Chevallier, P. C. Gros, S. Golhen, T. Roisnel, M.
Uchiyama, F. Mongin, Chem. Eur. J. 2010, 16, 8191;
i) L. Balloch, J. A. Garden, A. R. Kennedy, R. E.
Mulvey, T. Rantanen, S. D. Robertson, V. Snieckus,
Angew. Chem. 2012, 124, 7040; Angew. Chem. Int. Ed.
2012, 51, 6934; j) R. E. Mulvey, V. L. Blair, W. Clegg,
A. R. Kennedy, J. Klett, L. Russo, Nat. Chem. 2010, 2,
588; k) D. R. Armstrong, V. L. Blair, W. Clegg, S. H.
Dale, J. Garcꢅa-ꢆlvarez, G. W. Honeyman, E. Hevia,
R. E. Mulvey, L. Russo, J. Am. Chem. Soc. 2010, 132,
9480.
[15] a) P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert, J.
Org. Chem. 1988, 53, 2390; b) P. Knochel, S. A. Rao, J.
Am. Chem. Soc. 1990, 112, 6146.
[16] W. M. Welch, C. E. Hanau, W. M. Whalen, Synthesis
1992, 937.
[17] a) C. J. OꢇBrien, E. A. B. Kantchev, C. Valente, N.
Hadei, G. A. Chass, A. Lough, A. C. Hopkinson, M. G.
Organ, Chem. Eur. J. 2006, 12, 4743; b) M. G. Organ, S.
Avola, I. Dubovyk, N. Hadei, E. A. B. Kantchev, C. J.
OꢇBrien, C. Valente, Chem. Eur. J. 2006, 12, 4749; c) J.
Nasielski, N. Hadei, G. Achonduh, E. A. B. Kantchev,
[3] a) A. Krasovskiy, V. Krasovskaya, P. Knochel, Angew.
Chem. 2006, 118, 3024; Angew. Chem. Int. Ed. 2006, 45,
994
asc.wiley-vch.de
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 989 – 995

Accelerated Zincations for an Efficient and Mild Functionalization of Aromatics and Heterocycles
C. J. OꢇBrien, A. Lough, M. G. Organ, Chem. Eur. J.
2010, 16, 10844; d) H. N. Hunter, N. Hadei, V. Blago-
jevic, P. Patschinski, G. T. Achonduh, S. Avola, D. K.
Bohme, M. G. Organ, Chem. Eur. J. 2011, 17, 7845;
e) S. Bernhardt, G. Manolikakes, T. Kunz, P. Knochel,
Angew. Chem. 2011, 123, 9372; Angew. Chem. Int. Ed.
2011, 50, 9205.
Adv. Synth. Catal. 2013, 355, 989 – 995
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
995