Preparation and Application of Solid, Salt-Stabilized Zinc Amide Enolates with Enhanced Air and Moisture Stability

Article abstract of DOI:10.1002/anie.201700216

The treatment of various N-morpholino amides with TMPZnCl?LiCl (TMP=2,2,6,6-tetramethylpiperidyl) and Mg(OPiv)₂ in THF at 25 °C provides solid zinc enolates with enhanced air and moisture stability (t_1/2 in air: 1–3 h) after solvent evaporation. These enolates undergo Pd- and Cu-catalyzed cross-couplings with (hetero)aryl bromides as well as allylic and benzylic halides. The arylated N-morpholino amides were converted into various ketones by LaCl₃?2 LiCl mediated acylation with Grignard reagents. The new, solid enolates were used to prepare a potent anti-breast-cancer drug candidate in six steps and 23 % overall yield.

Full text of DOI:10.1002/anie.201700216

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201700216
German Edition: DOI: 10.1002/ange.201700216
Synthetic Methods
Preparation and Application of Solid, Salt-Stabilized Zinc Amide
Enolates with Enhanced Air and Moisture Stability
Yi-Hung Chen+, Mario Ellwart+, Georgios Toupalas, Yusuke Ebe, and Paul Knochel*
Abstract: The treatment of various N-morpholino amides with
TMPZnCl·LiCl (TMP = 2,2,6,6-tetramethylpiperidyl) and
Mg(OPiv)2 in THF at 258C provides solid zinc enolates with
enhanced air and moisture stability (t1/2 in air: 1–3 h) after
solvent evaporation. These enolates undergo Pd- and Cu-
catalyzed cross-couplings with (hetero)aryl bromides as well as
allylic and benzylic halides. The arylated N-morpholino
amides were converted into various ketones by LaCl3·2LiCl
mediated acylation with Grignard reagents. The new, solid
enolates were used to prepare a potent anti-breast-cancer drug
candidate in six steps and 23% overall yield.
ides.[11] Owing to the high synthetic potential of Reformatsky
reagents, we envisioned the preparation of solid zinc enolates
using our previously developed method.[9] Preliminary experi-
ments showed that solid zinc pivalate ketone or ester enolates
have moderate air and thermal stability and do not qualify for
practical usage in organic synthesis. However, we found that
amides are much better precursors for the preparation of solid
enolate reagents. Herein, we report a new class of solid zinc
amide enolates with greatly enhanced air and moisture
stability and excellent reactivity in Pd-catalyzed arylations.
We also demonstrate their utility through the synthesis of
a potent anti-breast-cancer drug candidate.
M
etal enolates are key intermediates in organic synthesis.[1]
Treatment of tert-butyl acetate with TMPZnCl·LiCl[12]
(TMP = 2,2,6,6-tetramethylpiperidyl; 258C, 1 h) followed by
the addition of Mg(OPiv)2 produced the corresponding zinc
enolate in about 90% yield. After solvent removal and
storage under argon, we noticed a considerable loss of
activity, which was due to the decomposition of this solid
zinc ester enolate, and an iodometric titration performed after
two weeks of storage at 258C showed that only 11% of the
zinc enolate were still present. In contrast, the zinc amide
enolate derived from N,N-dimethylacetamide (1a,
Scheme 1), which was prepared analogously by treatment
with TMPZnCl·LiCl and Mg(OPiv)2, showed improved
thermal stability. Iodometric titration indicated that 54% of
the active enolate 2a remained after two weeks at 258C under
argon atmosphere.
In recent years, enolates of Li,[2] Mg,[3] B,[4] and Si[5] have
found extensive applications for the stereoselective elabo-
ration of aldol products. Furthermore, the arylation of
enolates is an important transformation in which alkali-
metal and silicon enolates have been used.[6] Ester zinc
enolates generated in situ, which are known as Reformatsky
reagents,[7] have also proven their utility in organic synthesis,
including in Pd-catalyzed arylations.[8] However, the extensive
application of Reformatsky reagents in synthesis has been
hampered by the moderate air and moisture stability of these
zinc enolates. We recently reported that the presence of
Mg(OPiv)2 (OPiv = OCOtBu) strongly enhanced the thermal,
air, and moisture stability of solid aryl, benzyl, heteroaryl, and
allyl zinc reagents.[9] These organometallic reagents contain-
ing magnesium and lithium salts were abbreviated for the
sake of simplicity as RZnOPiv and referred to as organozinc
pivalates, keeping in mind that the pivalate anion may also be
coordinated to magnesium and/or lithium.[10] After solvent
removal, these organozinc pivalates gave powders that are
usually stable for several hours in air and several years under
argon. Furthermore, these solid zinc pivalates proved to be
versatile reagents for the high-throughput screening of
palladium-catalyzed Negishi cross-couplings and generally
display the same reactivity as the regular organozinc hal-
After some screening experiments, we found that the best
results were obtained with N-morpholino acetamide (1b).
After solvent evaporation, the solid zinc enolate 2b resulted,
which was perfectly stable at 258C under argon atmosphere
for four weeks (97% remaining activity). After storing this
solid zinc enolate in air for two hours, 85% of the original
[*] Dr. Y.-H. Chen,[+] Dr. M. Ellwart,[+] G. Toupalas, Prof. Dr. P. Knochel
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Department Chemie
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Y. Ebe
Department of Chemistry
Graduate School of Science, Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
Scheme 1. Preparation of pivaloxy zinc amide enolates. Values in
parentheses indicate the percentage of active enolate species after
2–4 weeks under argon atmosphere and after 2 h in air determined by
iodometric titration. Complexed Mg(OPiv)Cl and LiCl were omitted for
clarity.
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201700216.
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 1: a-Arylation of solid zinc amide enolates 2 with aryl bromides
and iodides with Pd(dba)2 (2 mol%) and DavePhos (4 mol%) at 25–
508C in THF.
enolate concentration remained. We attribute the higher
stability of the zinc N-morpholino amide enolates to addi-
tional stabilization through the formation of chelate struc-
tures (3 or 4; Scheme 1). Interestingly, 13C NMR analysis
Entry
Zinc enolate[a]
Electrophile[b]
Product[c]
clearly showed that the zinc amide enolate 2b features a
[13]
À
À
Zn C bond such as that in 3 and not a Zn O bond as in 4.
Similarly, we prepared a-substituted zinc N-morpholino
amide enolates (2c–e) as well as the zincated glycine
derivative 2 f in 65–96% yield (Scheme 2). Remarkably, all
1
2b
2b
5a
5b
6a: 86%
6b: 93%
2
3
2b
2b
5c
5d
6c: 70%
6d: 87%
4
5
6
7
2c
2c
5e
5 f
6e: 92%
6 f: 81%
2c
2c
5g
5h
6g: 90%
6h: 99%
Scheme 2. Synthesis of solid zinc amide enolates of type 2 from the
corresponding morpholino amides of type 1 by using TMPZnCl and
Mg(OPiv)2. [a] Complexed Mg(OPiv)Cl and LiCl were omitted for
clarity.
8
9
of these zinc enolates provided white to yellow powders after
solvent evaporation, which displayed excellent stability under
argon atmosphere and could be handled in air for a short
period of time without significant loss of activity. We
determined the half-lives in air of all of these solid zinc
enolates (t1/2 = 1–3 h). They displayed very similar reactivity
to regular zinc amide enolates[14] and reacted with a range of
different electrophiles, including aryl and alkenyl bromides
and iodides (5a–i), in the presence of Buchwaldꢀs Pd catalyst
systems.[15] Thus zinc enolates of type 2 can be readily arylated
with various aryl halides, providing the corresponding
N-morpholino amides 6a–j in 70–99% yield.
2d
5b
6i: 76%
10
11
2e
2b
5i
5j
6j: 93%
6k: 84%
[a] Complexed Mg(OPiv)Cl and LiCl were omitted for clarity. [b] Electro-
phile (0.8 equiv). [c] Yields refer to isolated, analytically pure products.
In the presence of Pd(dba)2 (2 mol%) and DavePhos[15]
(4 mol%), the solid zinc enolate 2b reacted smoothly with
various aryl bromides (5a–d) producing the expected cou-
pling products (6a–d) in 70–93% yield (Table 1, entries 1–4).
Similarly, the zincated N-morpholino amide 2c reacted with
the heterocyclic bromides 5e and 5 f, providing the a-arylated
products 6e and 6 f in 92 and 81% yield, respectively, after 4 h
at 508C (entries 5 and 6). This arylation procedure is typical,
and the related solid zinc enolates 2c–e were arylated with
aromatic bromides and iodides (5b, 5g–i) to give the
corresponding N-morpholino amides (6g–j) in 76–99%
yield (entries 7–10). Interestingly, a stereospecific alkenyla-
tion was realized with (Z)-iodohexene (5j) as the reaction of
2b with 5j provided the Z-configured N-morpholino amide
6k in 84% yield in isomerically pure form (entry 11), showing
that the coupling proceeds with complete retention of the
double-bond configuration.
In addition, these solid zinc enolates of type 2 can readily
undergo benzylation in the presence of the same catalytic
system (Scheme 3). The glycine-derived zinc enolate 2 f
reacted with various benzylic chlorides (7a–d) to give the
benzylated amides 8a–d in 88–93% yield. A copper catalyst
2
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 2: Further transformations of arylated N-morpholino amides 6 into
aldehydes or ketones (11a–e).
Entry
Substrate
Reagent/
catalyst
Product
Cp2Zr(H)Cl
1
2
3
6a
11a: 90%
nBuMgCl·LiCl
LaCl3·2LiCl
6d
6e
11b: 76%
11c: 96%
PhMgCl·LiCl
LaCl3·2LiCl
p-MeC6H4MgCl·LiCl
4
5
LaCl3·2LiCl
Scheme 3. Palladium-catalyzed benzylation of the zincated glycine
derivative 2 f and copper-catalyzed allylation reactions of pivaloxy zinc
enolates 2b and 2c to morpholino amides 10a and 10b. Complexed
Mg(OPiv)Cl and LiCl were omitted for clarity.
6h
6b
11d: 60%
11e: 84%
BnMgCl·LiCl
LaCl3·2LiCl
(10 mol% CuCN·2LiCl,[16] À208C, 2 h) enabled smooth
allylation reactions of the zinc enolates (2b,c) with the
ester-substituted allylic bromides 9a and 9b, providing
amides 10a and 10b in 91 and 97% yield, respectively.
The resulting arylated N-morpholino amides of type 6 can
be readily converted into aldehydes such as 11a by using
a method developed by Georg[17] and co-workers using
Schwartzꢀs reagent (Cp2Zr(H)Cl; Table 2, entry 1).[18] Fur-
thermore, the morpholino group readily undergoes various
functional group interconversions,[19] and the reaction of
amides of type 6 with Grignard reagents (alkyl, aryl, and
benzyl magnesium derivatives) in the presence of the THF-
soluble Lewis acid LaCl3·2LiCl[20] (1.5 equiv, 08C, 4–6 h)
provided the corresponding ketones (11b–e) in 60–96% yield
(entries 2–5).
stituted N-morpholino amide 14 in 56% yield. Treatment of
14 with benzoquinone in the presence of ZnCl2 (10 mol%)
provided the expected indole 15 in 78% yield in a Nenitzescu
reaction.[22] The structure of 15 was confirmed by X-ray
analysis.[23] Methylation of the phenolic hydroxy group of 15
with MeI in the presence of K2CO3 afforded the methylated
indole derivative 16 in 94% yield. Reduction of the
N-morpholino amide moiety to the corresponding aldehyde
was realized using Cp2Zr(H)Cl. Finally, oxidative deprotec-
tion of the indolic N-benzyl group using tBuOK and O2 in
DMSO[24] provided the desired target molecule in 63% yield
(Scheme 4).
In conclusion, we have reported the first solid Reformat-
sky-type reagents with enhanced air and moisture stability,
and examined their reactivity towards standard electrophiles.
Palladium-catalyzed arylation proceeded particularly well
with DavePhos as the ligand in combination with 2 mol%
To demonstrate the applicability of the new solid zinc
enolates, we prepared the very potent anti-breast-cancer drug
candidate 12[21] starting from N-morpholino amide 2b.
Addition of 2b to 4-methoxybenzonitrile (13) gave an
intermediate that reacted with benzylamine in an addition–
elimination process, providing the unsaturated 3-amino-sub-
Scheme 4. Synthesis of the potent anti-breast-cancer drug candidate 12 starting from solid zinc enolate 2b.
Angew. Chem. Int. Ed. 2017, 56, 1 – 6 ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
[8] a) J. F. Fauvarque, A. Jutand, J. Organomet. Chem. 1977, 132,
C17 – C19; b) J. F. Fauvarque, A. Jutand, J. Organomet. Chem.
1979, 177, 273 – 281; c) F. Orsini, F. Pelizzoni, Synth. Commun.
1987, 17, 1389 – 1402; d) F. Orsini, F. Pelizzoni, L. M. Vallarino, J.
Organomet. Chem. 1989, 367, 375 – 382; e) M. L. Hlavinka, J. R.
Hagadorn, Tetrahedron Lett. 2006, 47, 5049 – 5053; f) S. Duez, S.
Bernhardt, J. Heppekausen, F. F. Fleming, P. Knochel, Org. Lett.
2011, 13, 1690 – 1693; g) T. Hama, S. Ge, J. F. Hartwig, J. Org.
Chem. 2013, 78, 8250 – 8266; h) N. M. Barl, V. Malakhov, C.
Mathes, P. Lustenberger, P. Knochel, Synthesis 2015, 692 – 700.
[9] a) S. Bernhardt, G. Manolikakes, T. Kunz, P. Knochel, Angew.
Chem. Int. Ed. 2011, 50, 9205 – 9209; Angew. Chem. 2011, 123,
9372 – 9376; b) C. I. Stathakis, S. Bernhardt, V. Quint, P.
Knochel, Angew. Chem. Int. Ed. 2012, 51, 9428 – 9432; Angew.
Chem. 2012, 124, 9563 – 9567; c) C. I. Stathakis, S. M. Manoli-
kakes, P. Knochel, Org. Lett. 2013, 15, 1302 – 1305; d) J. R.
Colombe, S. Bernhardt, C. Stathakis, S. L. Buchwald, P. Knochel,
Org. Lett. 2013, 15, 5754 – 5757; e) S. M. Manolikakes, M.
Ellwart, C. I. Stathakis, P. Knochel, Chem. Eur. J. 2014, 20,
12289 – 12297; f) M. Ellwart, P. Knochel, Angew. Chem. Int. Ed.
2015, 54, 10662 – 10665; Angew. Chem. 2015, 127, 10808 – 10811.
[10] A. Hernꢁn-Gꢂmez, E. Herd, E. Hevia, A. R. Kennedy, P.
Knochel, K. Koszinowski, S. M. Manolikakes, R. E. Mulvey, C.
Schnegelsberg, Angew. Chem. Int. Ed. 2014, 53, 2706 – 2710;
Angew. Chem. 2014, 126, 2744 – 2748.
Pd(dba)2. Furthermore, the reactive N-morpholino amides
were readily converted into aldehydes using Schwartzꢀs
reagent or various ketones by a reaction with Grignard
reagents in the presence of LaCl3·2LiCl. Finally, we demon-
strated the utility of these new enolates by preparing the
important drug candidate 12 in six steps and 23% overall
yield. Further investigations of the synthesis and reactivity of
this new class of zinc enolates are underway in our labora-
tories.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (SFB 749,
B2) for financial support, Simon Graßl for preliminary
experiments, and Prof. Rasmus Linser and Dr. David
Stephenson for helpful discussions.
Conflict of interest
The authors declare no conflict of interest.
[11] T. J. Greshock, K. P. Moore, R. T. McClain, A. Bellomo, C. K.
Chung, S. D. Dreher, P. S. Kutchukian, Z. Peng, I. W. Davies, P.
Vachal, M. Ellwart, S. M. Manolikakes, P. Knochel, P. G.
Nantermet, Angew. Chem. Int. Ed. 2016, 55, 13714 – 13718;
Angew. Chem. 2016, 128, 13918 – 13922.
Keywords: a-arylation · cross-coupling · solid zinc reagents ·
synthetic methods · zinc amide enolates
[12] a) M. Mosrin, P. Knochel, Org. Lett. 2009, 11, 1837 – 1840; b) M.
Mosrin, G. Monzon, T. Bresser, P. Knochel, Chem. Commun.
2009, 5615 – 5617; c) T. Bresser, M. Mosrin, G. Monzon, P.
Knochel, J. Org. Chem. 2010, 75, 4686 – 4695.
[13] Efforts to crystallize these zinc amides have been unsuccessful
thus far. For their 13C NMR spectra, see the Supporting
Information.
[14] a) J. Cossy, A. de Filippis, D. G. Pardo, Org. Lett. 2003, 5, 3037 –
3039; b) J. Cossy, A. de Filippis, D. G. Pardo, Synlett 2003, 2171 –
2174; c) T. Hama, X. Liu, D. A. Culkin, J. F. Hartwig, J. Am.
Chem. Soc. 2003, 125, 11176 – 11177; d) A. de Filippis, D. G.
Pardo, J. Cossy, Tetrahedron 2004, 60, 9757 – 9767; e) E. Bentz,
M. G. Moloney, S. M. Westaway, Tetrahedron Lett. 2004, 45,
7395 – 7397; f) T. Hama, D. A. Culkin, J. F. Hartwig, J. Am.
Chem. Soc. 2006, 128, 4976 – 4985; g) G. Satyanarayana, M. E.
Maier, Tetrahedron 2008, 64, 356 – 363; h) S. L. McDonald, Q.
Wang, Chem. Commun. 2014, 50, 2535 – 2538; i) B. Wong, X.
Linghu, J. J. Crawford, J. Drobnick, W. Lee, H. Zhang, Tetrahe-
dron 2014, 70, 1508 – 1515.
[1] a) T. Mukaiyama, Pure Appl. Chem. 1983, 55, 1749; b) B.
Schetter, R. Mahrwald, Angew. Chem. Int. Ed. 2006, 45, 7506 –
7525; Angew. Chem. 2006, 118, 7668 – 7687.
[2] D. Seebach, Angew. Chem. Int. Ed. Engl. 1988, 27, 1624 – 1654;
Angew. Chem. 1988, 100, 1685 – 1715.
[3] E. R. Hurley, X. He, S. N. Brown, K. W. Henderson, J. Am.
Chem. Soc. 2009, 131, 6056 – 6057.
[4] a) S. Masamune, W. Choy, B. Imperiali, J. Am. Chem. Soc. 1981,
103, 1566 – 1568; b) D. A. Evans, J. V. Nelson, E. Vogel, T. R.
Taber, J. Am. Chem. Soc. 1981, 103, 3099 – 3111; c) D. A. Evans,
J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981, 103, 2127 – 2129.
[5] a) G. Stork, P. F. Hudrlik, J. Am. Chem. Soc. 1968, 90, 4462 –
4464; b) E. M. Carreira, R. A. Singer, W. Lee, J. Am. Chem. Soc.
1994, 116, 8837 – 8838; c) T. Akiyama, J. Itoh, K. Yokota, K.
Fuchibe, Angew. Chem. Int. Ed. 2004, 43, 1566 – 1568; Angew.
Chem. 2004, 116, 1592 – 1594.
[6] a-Arylations of aldehydes, ketones, and carboxylic acid deriv-
atives were pioneered by the groups of Miura, Buchwald, and
Hartwig; for representative publications, see: a) T. Satoh, Y.
Kawamura, M. Miura, M. Nomura, Angew. Chem. Int. Ed. Engl.
1997, 36, 1740 – 1742; Angew. Chem. 1997, 109, 1820 – 1822;
b) M. Palucki, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119,
11108 – 11109; c) B. C. Hamann, J. F. Hartwig, J. Am. Chem. Soc.
1997, 119, 12382 – 12383; for relevant reviews, see: d) G. C.
Lloyd-Jones, Angew. Chem. Int. Ed. 2002, 41, 953 – 956; Angew.
Chem. 2002, 114, 995 – 998; e) M. Miura, M. Nomura, Top. Curr.
Chem. 2002, 219, 212 – 237; f) D. A. Culkin, J. F. Hartwig, Acc.
Chem. Res. 2003, 36, 234 – 245; g) A. C. B. Burtoloso, Synlett
2009, 320 – 327; h) C. C. C. Johansson, T. J. Colacot, Angew.
Chem. Int. Ed. 2010, 49, 676 – 707; Angew. Chem. 2010, 122, 686 –
718; i) F. Bellina, R. Rossi, Chem. Rev. 2010, 110, 1082 – 1146.
[7] For recent reviews, see: a) P. G. Cozzi, Angew. Chem. Int. Ed.
2007, 46, 2568 – 2571; Angew. Chem. 2007, 119, 2620 – 2623; b) R.
Haraguchi, S. Matsubara, Synthesis 2014, 2272 – 2282.
[15] a) R. Martin, S. L. Buchwald, Acc. Chem. Res. 2008, 41, 1461 –
1473; b) D. S. Surry, S. L. Buchwald, Chem. Sci. 2011, 2, 27 – 50.
[16] P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert, J. Org. Chem.
1988, 53, 2390 – 2392.
[17] J. T. Spletstoser, J. M. White, A. R. Tunoori, G. I. Georg, J. Am.
Chem. Soc. 2007, 129, 3408 – 3419.
[18] J. Schwartz, J. A. Labinger, Angew. Chem. Int. Ed. Engl. 1976,
15, 333 – 340; Angew. Chem. 1976, 88, 402 – 409.
[19] a) M. Kurosu, Y. Kishi, Tetrahedron Lett. 1998, 39, 4793 – 4796;
b) C. Douat, A. Heitz, J. Martinez, J.-A. Fehrentz, Tetrahedron
Lett. 2000, 41, 37 – 40; c) M. Badioli, R. Ballini, M. Bartolacci, G.
Bosica, E. Torregiani, E. Marcantoni, J. Org. Chem. 2002, 67,
8938 – 8942; d) A. R. Jeon, M. E. Kim, J. K. Park, W. K. Shin,
D. K. An, Tetrahedron 2014, 70, 4420 – 4424.
[20] A. Krasovskiy, F. Kopp, P. Knochel, Angew. Chem. Int. Ed. 2006,
45, 497 – 500; Angew. Chem. 2006, 118, 511 – 515.
[21] a) D. Kaufmann, M. Pojarovꢁ, S. Vogel, R. Liebl, R. Gastpar, D.
Gross, T. Nishino, T. Pfaller, E. von Angerer, Bioorg. Med.
4
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
Chem. 2007, 15, 5122 – 5136; b) N. K. Kaushik, N. Kaushik, P.
[24] A. A. Haddach, A. Kelleman, M. V. Deaton-Rewolinski, Tetra-
Attri, N. Kumar, C. H. Kim, A. K. Verma, E. H. Choi, Molecules
2013, 18, 6620 – 6662.
hedron Lett. 2002, 43, 399 – 402.
[22] V. S. Velezheva, A. G. Kornienko, S. V. Topilin, A. D. Turashev,
A. S. Peregudov, P. J. Brennan, J. Heterocycl. Chem. 2006, 43,
873 – 879.
[23] CCDC 1523335 contains the supplementary crystallographic
data for this paper. These data are provided free of charge by
The Cambridge Crystallographic Data Centre.
Manuscript received: January 9, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Synthetic Methods
Y.-H. Chen, M. Ellwart, G. Toupalas,
Y. Ebe, P. Knochel*
&&&& — &&&&
Preparation and Application of Solid, Salt-
Stabilized Zinc Amide Enolates with
Enhanced Air and Moisture Stability
Solid chemistry: A convenient method for
the preparation of solid zinc enolates with
enhanced air and moisture stability is
described. These enolates undergo Pd-
and Cu-catalyzed cross-couplings. The
reactive N-morpholino amides can be
readily converted into aldehydes or vari-
ous ketones. These new zinc enolates
were employed in the short synthesis of
a 3-formylindole derivative that is
a potent inhibitor of tubulin polymeri-
zation.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!