Practical Ni-Catalyzed Cross-Coupling of Unsaturated Zinc Pivalates with Unsaturated Nonaflates and Triflates

Article abstract of DOI:10.1021/acs.orglett.8b03417

A practical nickel-catalyzed cross-coupling of (hetero)aryl or alkynylzinc pivalates with various unsaturated nonaflates or triflates is described. Organozinc pivalates allow these cross-couplings to take place with high yields and a low catalyst loading (0.5 mol %). Couplings with (E)- and (Z)-alkenyl triflates proceed with retention of configuration.

Full text of DOI:10.1021/acs.orglett.8b03417

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Practical Ni-Catalyzed Cross-Coupling of Unsaturated Zinc Pivalates
with Unsaturated Nonaflates and Triflates
Maximilian S. Hofmayer, Ferdinand H. Lutter, Lucie Grokenberger, Jeffrey M. Hammann,
and Paul Knochel*
̈
̈
Department of Chemistry, Ludwig-Maximilians-Universitat, Butenandtstrasse 5-13, 81377 Munchen, Germany
S
* Supporting Information
ABSTRACT: A practical nickel-catalyzed cross-coupling of (hetero)aryl or alkynylzinc pivalates with various unsaturated
nonaflates or triflates is described. Organozinc pivalates allow these cross-couplings to take place with high yields and a low
catalyst loading (0.5 mol %). Couplings with (E)- and (Z)-alkenyl triflates proceed with retention of configuration.
pivalate (1a) was coupled with various unsaturated triflates
and nonaflates (Table 2).4a,9 The reaction with 1-naphthyl
triflate (2b) afforded biphenyl 3b in 87% yield (entry 1). In
addition, para- and meta-cyano-substituted aryl triflates 2c and
2d underwent this cross-coupling with zinc pivalate 1a, giving
3c and 3d in 84% and 71% yield (entry 2). Similarly, the
benzonitrile derivative 3e was obtained in 66% yield (entry 3).
Interestingly, ester and ketone moieties were tolerated in this
cross-coupling. Thus, the reaction of triflate 2f and nonaflate
2g with organozinc reagent 1a led to products 3f and 3a in
81−87% yield (entries 4 and 5). Using p-anisylzinc chloride
instead of the corresponding arylzinc pivalate 1a gave 3f in
only 68% yield (entry 4). The p-benzophenone triflate 2h was
successfully coupled with arylzinc pivalate 1a, leading to 3g in
66% yield (entry 6). Coumarin derivative 3h was readily
obtained by the reaction of 1a with the heterocyclic triflate 2i
in 95% yield (entry 7). Moreover, pyridyl and quinolyl triflates
and nonaflates 2j and 2k proved to be good substrates for this
cross-coupling. Pyridyl triflate 2j led to the 2,3-disubstituted
pyridine 3i in 87% yield, and quinolyl nonaflate 2k furnished
the quinoline derivative 3j in 84% yield (entries 8 and 9).
Additionally, alkenyl nonaflates were employed in this reaction.
Therefore, nonaflate 2l and zinc pivalate 1a were cross-
coupled, leading to 3k in 73% yield (entry 10).
rganozinc reagents are key intermediates in organic
1
Osynthesis.
Their main features are a high functional
group tolerance, low toxicity, and moderate price.1e Recently,
we have reported the preparation of organozinc pivalates with
enhanced air and moisture stability.2 These zinc species can be
handled in air for several hours without appreciable
decomposition.2 Previously, we have demonstrated that
organozinc pivalates are superior reagents for various cross-
couplings.2,3 Functionalized nonaflates and triflates are
excellent coupling partners with numerous organometallic
reagents, and a broad variety of these sulfonates can easily be
obtained from the corresponding alcohols and enolates.4
However, the nickel-catalyzed reactions of arylzinc reagents
with unsaturated triflates and nonaflates lack generality.5
Thus, the reaction of p-anisylzinc pivalate6 (1a) with triflate
2a was further optimized (Table 1). In the absence of a
transition-metal catalyst, no product formation was observed.
CuCl2, CrCl2, MnCl2, FeCl2, and CoCl2 resulted in only poor
yields, in contrast to NiCl2, which afforded 3a in 47% yield
(entries 1−7, Table 1). To increase the amount of the coupling
product, various ligands were added (L1−9, entries 8−16,
Table 1).7 To our delight, the cheap and commercially
available NiCl2(PPh3)2 catalyst led to 3a in 86% isolated yield.
Remarkably, using p-anisylzinc chloride instead of p-anisylzinc
pivalate (1a) resulted in only 52% of product 3a, showing the
superior ability of organozinc pivalates to promote cross-
couplings (entry 16, Table 1).3a Varying the solvent system
and reaction temperature did not further improve the reaction
outcome.8
Next, we examined the organozinc pivalate scope (Table 3).
The coupling of electron-rich 3,4,5-trimethoxyphenylzinc
pivalate (1b) with an electron-poor benzonitrile 2e and ester
derivative 2a led to the biaryl compounds 3l and 3m in 81−
With these optimized conditions in hand, we further
Received: October 25, 2018
examined the electrophile scope. Therefore, p-anisylzinc
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03417
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reaction Conditions Optimization of the Cross-
Coupling of Arylzinc Pivalate 1a with Aryl Triflate 2a
Table 2. Nickel-Catalyzed Cross-Coupling between p-
Anisylzinc Pivalate (1a) and Various (Hetero)aryl and
Alkenyl Triflates and Nonaflates of Type 2
a
entry
catalyst
ligand
yield (%)
1
2
3
4
5
6
7
8
0
0
0
0
3
CuCl2
CrCl2
MnCl2
FeCl2
CoCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
8
47
20
59
4
L1
L2
L3
L4
L5
L6
L7
L8
L9
9
10
11
12
13
14
15
16
54
35
79
36
8
b
c
90 (52), (86)
a
b
Using 1a stored as a solid under argon for 8 d. Using p-anisylzinc
chloride.
a
b
Calibrated GC yield using undecane as internal standard. Using p-
c
anisylzinc chloride. Isolated yield of analytically pure product.
with p-anisylzinc pivalate (1a), affording only E-alkene 3w in
89% yield (E/Z > 99:1).11 Similarly, the corresponding (Z)-
triflate10 2r reacted with arylzinc pivalate 1a in 86% yield to
give the (Z)-acrylate 3x in high diastereoselectivity (Z/E >
99:1).11 Remarkably, by using the corresponding organozinc
chloride instead of the corresponding arylzinc pivalate 1a, the
reaction proceeds without retention of configuration, leading
to the (E)-isomer 3w in only 67% yield (Z/E = 11:89).
Remarkably, alkynylzinc pivalates of type 4 underwent this
cross-coupling (Table 4). The reaction of TIPS-ethinylzinc
pivalate (4a) with triflate 2i led to 5a in 97% yield (entry 1).
Using the phenyl-substituted alkynylzinc pivalate 4b, the
corresponding alkyne 5b was obtained in 73% yield (entry 2).
In addition, alkynylzinc pivalate 4c was cross-coupled with 2i,
providing 5c in 87% yield (entry 3). Finally, the reaction of (3-
chlorophenyl)ethynylzinc pivalate (4d) with 2i gave the
desired product 5d in 93% yield (entry 4).
In summary, we have reported a practical Ni-catalyzed cross-
coupling of unsaturated zinc pivalates with unsaturated triflates
and nonaflates. Using (hetero)aryl and alkynylzinc pivalates as
organometallic reagents provided the coupling products in
high yields. Furthermore, the beneficial effect of organozinc
pivalates in comparison to organozinc chlorides was demon-
strated. Thus, the coupling products were obtained in
significantly higher yields and a better diastereomeric ratio.
In addition, the catalyst loading was only 0.5 mol %. Further
extensions of this method are underway.
85% yield (entries 1 and 2). Furthermore, benzodioxol-5-ylzinc
pivalate (1c) reacts with the triflates 2c and 2j, furnishing the
biphenyls 3n and 3o in 85−89% yield (entries 3 and 4).
In addition, fluorinated arylzinc pivalates can readily be
employed in this cross-coupling. Thus, 4-(trifluoromethoxy)-
phenylzinc pivalate (1d) and 4-cyano-substituted aryl triflate
2d were successfully cross-coupled, leading to biaryl 3p in 83%
yield (entry 5). Similarly, 4-(trifluoromethyl)phenylzinc
pivalate (1e) reacted with 4-methylquinoline-2-yl nonaflate
(2m) and 3-cyano-substituted aryl nonaflate 2n, affording the
desired products 3q and 3r in 83−91% yield (entries 6 and 7).
Using 4-(trifluoromethyl)phenylzinc chloride instead of the
corresponding arylzinc pivalate 1e gave 3r in only 75% yield
(entry 7). In addition, the use of electron-poor arylzinc
reagents was possible. Thus, 4-cyano-3-fluorophenylzinc
pivalate 1f and (E)-4-styrylphenyl triflate (2o) led to 3s in
71% yield (entry 8). Interestingly, couplings between
heterocyclic zinc pivalates and heterocyclic triflates could be
performed. The coumarin derivative 3t was obtained in 84%
yield by coupling 3-thienylzinc pivalate 1g and triflate 2i (entry
9). Furthermore, N-methyl 5-indolylzinc pivalate (1h) reacted
with triflates 2j and 2p, leading to the bis-heterocyclic products
3u and 3v in 85−86% yield (entries 10 and 11).
Additionally, this nickel-catalyzed cross-coupling retained
the double-bond configuration and used alkenyl triflates as
electrophiles (Scheme 1). Thus, the (E)-alkenyl triflate10 of
ethyl acetoacetate 2q underwent a stereoretentive reaction
B
DOI: 10.1021/acs.orglett.8b03417
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Nickel-Catalyzed Cross-Coupling of
(Hetero)arylzinc Pivalates 1b−h with (Hetero)aryl Triflates
and Nonaflates of Type 2
Scheme 1. Stereoretentive Coupling of p-Anisylzinc Pivalate
(1a) and the Alkenyl Triflates of Ethyl Acetoacetate 2q and
2r
a
Using p-anisylzinc chloride.
Table 4. Nickel-Catalyzed Cross-Coupling of Alkynylzinc
Pivalates of Type 4 with Triflate 2i
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03417.
1
Full experimental details and H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: paul.knochel@cup.uni-muenchen.de.
ORCID
Paul Knochel: 0000-0001-7913-4332
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the DFG and the LMU Munich for financial support.
We also thank Albemarle (Hoechst, Germany) for the
generous gift of chemicals. We thank Emanuel Joseph, Pavlos
Pelagias, and Arne Stolpmann for the preparation of starting
materials.
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Letter
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DOI: 10.1021/acs.orglett.8b03417
Org. Lett. XXXX, XXX, XXX−XXX