Preparation of Solid Polyfunctional Alkynylzinc Pivalates with Enhanced Air and Moisture Stability for Organic Synthesis

Article abstract of DOI:10.1002/anie.201704400

We report the preparation of solid and air-stable polyfunctionalized alkynylzinc pivalates from the corresponding alkynes using TMPZnOPiv (TMP=2,2,6,6-tetramethylpiperidyl) as base. These organozinc pivalates are obtained as powders under mild conditions

Full text of DOI:10.1002/anie.201704400

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201704400
German Edition: DOI: 10.1002/ange.201704400
Synthetic Methods
Preparation of Solid Polyfunctional Alkynylzinc Pivalates with
Enhanced Air and Moisture Stability for Organic Synthesis
Yi-Hung Chen, Carl Phillip Tꢀllmann, Mario Ellwart, and Paul Knochel*
Abstract: We report the preparation of solid and air-stable
polyfunctionalized alkynylzinc pivalates from the correspond-
ing alkynes using TMPZnOPiv (TMP = 2,2,6,6-tetramethylpi-
peridyl) as base. These organozinc pivalates are obtained as
powders under mild conditions in excellent yields and can be
manipulated in air for several hours without significant
decomposition. These zinc reagents show an excellent reac-
tivity in various carbon–carbon bond- forming reactions and
1,3-dipolar cycloadditions. An alkynylzinc pivalate has been
used to prepare a carboxyamidotriazole with potential antineo-
plastic activity in eight steps and 38% overall yield.
(1a) with moderate air stability (44% activity after 4 h in air).
We speculated that this problematic air and moisture
sensitivity was due to the presence of LiCl and designed
therefore a new synthesis of TMPZnOPiv (3) which did not
contain LiCl. Thus, the treatment of TMP-H (4) with
benzylmagnesium chloride in THF[9] (408C, 12 h) followed
by the addition of Zn(OPiv)2 provided TMPZnOPiv (3) in
quantitative yield. The deprotonation of 2a with TMPZnO-
Piv (3, 1.2 equiv) afforded after solvent evaporation the
corresponding alkynylzinc pivalate (1a) with highly improved
air stability (90% yield, determined after 4 h exposure to air)
as shown in Scheme 1. This reactivity proved to be general
and a range of polyfunctional alkynylzinc pivalates (1a–1m)
were obtained with 43–90% activity after 4 h of air exposure
at 258C. Remarkably, a range of important functional groups
such as a ketone, a nitrile, and an ester are tolerated in the
zinc reagents of type 1.
Furthermore, we examined the reactivity of these new
solid alkynylzinc pivalates (1) in Negishi cross-coupling
reactions[10] with various aryl halides. The screening of several
palladium catalytic systems showed that the Buchwald ligand,
DavePhos,[11] gave the best results in combination with
Pd(dba)2 (2 mol%; dba = dibenzylideneacetone).[12] Under
these conditions, a range of (hetero)aryl iodides, bromides,
Polyfunctional alkynes are important target molecules in
material and medicinal chemistry.[1] They are also key
intermediates for the synthesis of other common functional
groups such as E- and Z-alkenes.[2] Alkynyl organometallics
are privileged reagents for the synthesis of various function-
alized alkynes.[3] Recently, we have reported several methods
for preparing organozinc reagents with enhanced air and
moisture stability starting either from (hetero)aryl, allylic,
and benzylic halides or from (hetero)arenes.[4] These zinc
organometallics were found to be valuable reagents for the
high-throughput screening of biomolecules.[5] Related solid
Reformatsky enolates have been used for organic synthesis.[6]
(Hetero)arylzinc pivalates proved to be unique bench-stable
solid reagents for cobalt-catalyzed cross-couplings.[7] Herein,
we describe the preparation of a new class of alkynylzinc
pivalates of type 1 bearing various functional groups and
displaying an enhanced air and moisture stability. They are
obtained in high yields from the corresponding alkynes of
type 2 by deprotonation using the mixed zinc–magnesium
base TMPZnCl·Mg(OPiv)2 (3; TMP = 2,2,6,6-tetramethylpi-
peridyl; abbreviated as TMPZnOPiv).[8] Further, we have
demonstrated the utility of alkynylzinc reagents (1) for the
formation of new carbon–carbon bonds including their
participation in 1,3-dipolar cycloadditions without the cleav-
age of the carbon–zinc bond. An application to the prepara-
tion of a carboxyamidotriazole with significant anticancer
activity completes our study.
Preliminary studies have shown that the deprotonation of
trimethylsilylacetylene (2a) with TMPZnOPiv·LiCl[4c] pro-
ceeded smoothly, but produced a solid alkynylzinc reagent
[*] Dr. Y.-H. Chen, C. P. Tꢀllmann, Dr. M. Ellwart, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universitꢁt Mꢀnchen
Butenandtstrasse 5-13, Haus F, 81377 Mꢀnchen (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Scheme 1. Preparation of alkynylzinc pivalates of type 1 from the
corresponding alkynes of type 2 using TMPZnCl·Mg(OPiv)2 (abbrevi-
ated as TMPZnOPiv 3). [a] Alkynylzinc chlorides and Mg(OPiv)2 com-
plexes are abbreviated as alkynylzinc pivalates for clarity. [b] The
indicated yields are obtained after 4 h of exposure to air. [c] Preparation
with TMPZnOPiv in the presence of LiCl (1 equiv).
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201704400.
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and chlorides of type 5 underwent smooth Negishi cross-
couplings producing arylated alkynes of type 6 (Table 1).
Remarkably, a variety of sensitive functional groups were
tolerated in these cross-couplings such as a ketone (entry 1 of
Table 1), an aldehyde (entry 3), an unprotected indole
(entry 4), and an amide (entry 7). The use of ethyl 6-
chloronicotinate (5b) provided alkyne 6b in 74% yield
(entry 2), which was a key intermediate for the synthesis of
tazarotene.[13]
We also found that the alkynylzinc pivalates (1) undergo
a smooth Pd-catalyzed acylation using thioesters as acylation
reagents, a reaction pioneered by Fukuyama.[14]
The use of 4% DavePhos in combination with 2%
Pd(dba)2 proved to be an excellent catalytic system. Thus, the
alkynylzinc pivalate 1e reacted with the thioester 7 providing
alkynyl ketone 8 in 76% yield (Scheme 2). Furthermore the
Table 1: Pd-catalyzed Negishi cross-coupling of solid alkynylzinc
reagents of type 1 with various aryl halides leading to alkynes of type 6.[a]
Entry
1
Electrophile
Product[b]
1
2
1a
1a
5a
5b
6a: 89% (258C, 6 h)
6b: 74% (608C, 16 h)
3
4
1b
1c
5c
5d
6c: 76% (408C, 12 h)
6d: 68% (508C, 2 d)
Scheme 2. Acylation, allylation, and aldehyde addition using solid
alkynylzinc pivalates of type 1.
alkynylzinc pivalate 1j underwent a copper-catalyzed allyla-
tion with allyl bromide (9) using 10% CuCN·2LiCl[15] as
catalyst to afford enyne 10 in 84% yield. Although such
alkynylzinc reagents did not react readily with ketones,
a smooth addition to aldehydes was promoted by AlMe3 as
reported by Woodward.[16] Thus, when alkynylzinc pivalate 1c
was added to benzaldehydes 11a,b at 258C, propargylic
alcohols 12a,b were obtained within 16 h in 79 and 70% yield,
respectively.
5
6
7
1e
1i
1i
5e
5 f
5g
6e: 91% (408C, 14 h)
6 f: 93% (408C, 16 h)
6g: 87% (508C, 2 d)
In 2002, Sharpless, Fokin, and Meldal reported copper-
catalyzed
regioselective
azide–alkyne
cycloaddition
(CuAAC) leading to 1,4-substituted triazoles.[17] This reaction
is widely used in organic synthesis, drug discovery, biochem-
istry, and polymer chemistry.[18] Now, we have found that the
robust zinc reagents of type 1 undergo copper-catalyzed 1,3-
dipolar cycloadditions[19] with in situ generated benzyl azide
(13) (obtained from NaN3 and benzyl bromide) or aryl azides
14a,b with complete regioselectivity.[20] Smooth deuterolysis,
allylation, amination,[21] or arylation proved the integrity of
the carbon–zinc bond in intermediate 15 and produced the
valuable 1,2,3-triazoles 16a–d in 69–91% yield (Table 2).[22]
To the best of our knowledge, copper-catalyzed 1,3-dipolar
cycloadditions with alkynylzinc derivatives have not been
reported previously.[23]
8
9
1k
1l
5h
5i
6h: 80% (408C, 12 h)
6i: 92% (408C, 12 h)
The synthetic utility of alkynylzinc pivalates is further
demonstrated in the preparation of an orally active agent
carboxyamidotrazole (18) with potential antineoplastic activ-
[a] Pd(dba)2 (2 mol%) and DavePhos (4 mol%) were used as catalyst.
[b] Yields refer to analytically pure products.
2
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Table 2: Copper-catalyzed dipolar cycloadditions with alkynylzinc piv-
alates of type 1 providing 1,2,3-triazoles of type 16 via zinc intermediates
15.
Entry
1
Electrophile
CH3CO2D
Product
16a: 91%
16b: 87%
1
2
1 f
1g
9
3
4
1h
1c
17
16c: 69%
16d: 72%
5j
Scheme 3. Synthesis of carboxyamidotriazole 18 using alkynylzinc
pivalate 1d.
ity (Scheme 3).[24] Thus, the protection of commercially
available benzylic alcohol 19 with TIPSCl produced the silyl
ether 20 which was smoothly magnesiated at position 4 with
TMP2Mg·LiCl[25] followed by copper-mediated acylation[15]
with 4-chlorobenzoyl chloride. After desilylation using
TBAF (tetra-n-butylammonium fluoride), benzylic alcohol
(21) was isolated in 82% yield. The resulting alcohol was
brominated with PBr3 at 258C to afford benzylic bromide 22
in 94% yield. Compound 22 was treated with NaN3 and the
ester-substituted alkynylzinc pivalate 1d in the presence of
10% CuI in DMF at 258C for 18 h affording the 1,2,3-
triazolylzinc pivalate 23, which was directly aminated with
benzoyloxydiallylamine (17)[21] furnishing the trisubstituted
1,2,3-triazole 24 in 84% yield (based on the amount of 17) via
a four-component one-pot synthesis.[26] After a Pd-catalyzed
deallylation[27] and an amidation using Mg3N2 as reported by
Ley,[28] the desired carboxyamidotriazole (18) was obtained in
89% yield (eight steps, 38% overall yield).
of the new zinc reagents 1. Further applications are currently
underway in our laboratories.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (SFB 749,
B2) and the DIP (German–Israeli Project Cooperation) for
financial support. We thank Albemarle (Germany) for the
generous gift of chemicals.
Conflict of interest
The authors declare no conflict of interest.
In summary, we have reported the preparation of a new
class of solid alkynylzinc reagents which display enhanced air
and moisture stability compared to standard alkynylzinc
halides. We have also demonstrated their utility for arylations,
allylations, and acylations. Finally, we have shown that the
robust zinc reagents 1 undergo 1,3-dipolar cycloadditions
without the cleavage of the C–Zn bond which could thus be
functionalized in a further step. An efficient preparation of
the potential antineoplastic agent 18 demonstrates the utility
Keywords: alkynes · alkynylzinc pivalates ·
carboxyamidotriazoles · click chemistry · zinc
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Manuscript received: April 28, 2017
Accepted manuscript online: January 0, 0000
Version of record online: && &&, &&&&
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Communications
Synthetic Methods
Y.-H. Chen, C. P. Tꢁllmann, M. Ellwart,
P. Knochel*
&&&& — &&&&
Preparation of Solid Polyfunctional
Alkynylzinc Pivalates with Enhanced Air
and Moisture Stability for Organic
Synthesis
Think positive: zinc pivalate. Functional-
ized solid alkynylzinc pivalates with
enhanced air and moisture stability is
reported undergo Pd-catalyzed Negishi
cross-couplings and Fukuyama acylations
as well as Cu-catalyzed allylations and
1,3-dipolar cycloadditions to afford tri-
substituted triazoles. A four-component
transformation leads to a potential anti-
neoplastic agent (eight steps and 38%
overall yield).
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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