C-H alkenylation of azoles with enols and esters by nickel catalysis

Article abstract of DOI:10.1002/anie.201304492

Rather u(Ni)que: Two new C-H alkenylation reactions, that is C-H/Ci￡O alkenylation and decarbonylative C-H alkenylation, of azoles are uniquely catalyzed by Ni/dcype. These azole alkenylation reactions are successfully applied to the convergent formal synthesis of siphonazoleB.

Full text of DOI:10.1002/anie.201304492

Angewandte
Chemie
Communications
À
C H Activation
L. Meng, Y. Kamada, K. Muto,
J. Yamaguchi,* K. Itami*
&&&& — &&&&
À
C H Alkenylation of Azoles with Enols
and Esters by Nickel Catalysis
À
Rather u(Ni)que: Two new C H alkenyla-
Ni/dcype. These azole alkenylation reac-
À
À
tion reactions, that is C H/C O alkeny-
tions are successfully applied to the
convergent formal synthesis siphonazo-
le B.
À
lation and decarbonylative C H alkeny-
lation, of azoles are uniquely catalyzed by
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DOI: 10.1002/anie.201304492
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C H Activation
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C H Alkenylation of Azoles with Enols and Esters by Nickel
Catalysis**
Lingkui Meng, Yuko Kamada, Kei Muto, Junichiro Yamaguchi,* and Kenichiro Itami*
Transition metal catalyzed alkenylation is one of the most
reliable methods for making alkenyl-substituted arenes as
exemplified by the Mizoroki–Heck reaction.[1] Recently,
[2]
À
direct C H alkenylation has received growing interest as
an emerging tool for constructing alkenylated arenes and
particularly alkenylated heteroarenes, since they are predom-
inant motifs in biologically active natural products, pharma-
ceuticals and organic materials (Scheme 1a).[3] Representa-
À
tive reaction types of C H alkenylation include (Scheme 1b):
À
À
1) C H/C X alkenylation (X = halogens including triflates)
of heteroarenes with alkenyl halides by using palladium and
copper catalysts,[4] 2) C H/C H alkenylation (oxidative
Mizoroki–Heck reaction) of heteroarenes with simple
alkenes by using palladium and rhodium catalysts,[5] and
À
À
À
3) C H addition of heteroarenes to alkynes by transition-
metal catalysts.[6] There also exist other C H couplings which
À
are outside the realm of the above-mentioned category.[7]
Meanwhile, our group has developed a number of unique
À
C H arylation reactions of heteroarenes catalyzed by tran-
sition-metal complexes.[8–10] For example, we recently discov-
À
À
ered the first nickel-catalyzed C H/C O coupling of hetero-
arenes and phenol derivatives[10a] as well as a decarbonylative
[10b]
À
C H coupling between heteroarenes and aryl esters.
These catalytic processes are unique among other C H
arylation methods not only because they allow incorporation
À
À
of unconventional aryl electrophiles in C H arylation (phenol
derivatives and arenecarboxylates), but also because these
reactions are uniquely promoted by an enabling supporting
[*] L. Meng, Y. Kamada, K. Muto, Prof. Dr. J. Yamaguchi,
Prof. Dr. K. Itami
Department of Chemistry, Graduate School of Science
Nagoya University
Chikusa, Nagoya 464-8602 (Japan)
E-mail: junichiro@chem.nagoya-u.ac.jp
itami.kenichiro@a.mbox.nagoya-u.ac.jp
L. Meng
College of Chemistry and Molecular Sciences, Wuhan University
Wuhan, Hubei, 430072 (P.R. China)
Scheme 1. a) Useful alkenyl-substituted heteroarenes. b) A classifica-
À
tion of the type of direct C H alkenylation of heteroarenes.
Prof. Dr. K. Itami
Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya
University, Chikusa, Nagoya 464-8602 (Japan)
ligand, 1,2-bis(dicyclohexylphosphino)ethane (dcype), on
a nickel(0) catalyst (other closely related ligands display
extremely low or no promoting effect in these catalyses).
Based on these auspicious discoveries, we questioned
[**] This work was supported by the Funding Program for the Next
Generation World-Leading Researchers from the JSPS (220GR049 to
K.I.), a Grant-in-Aid for Scientific Research on Innovative Areas
“Molecular Activation Directed toward Straightforward Synthesis”
(25105720 to J.Y.) from the MEXT. L.M. acknowledges the support
from the Funding Program for Ph.D. Short-time Mobility of Wuhan
University. Prof. Aiwen Lei (Wuhan Univ) is acknowledged for
supporting L.M.
À
whether unprecedented C H alkenylations of heteroarenes
would become possible with a Ni/dcype catalyst by using enol
derivatives [Scheme 1b, 4)] and a,b-unsaturated esters [Sche-
À
À
me 1b, 5)] as alkenylation agents. The C H/C O alkenyla-
tion of heteroarenes is rare,[11] and the decarbonylative C H
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304492.
À
alkenylation is thus far unknown. Herein, we report the C H
2
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alkenylation of azoles with enol derivatives and unsaturated
esters catalyzed by Ni/dcype, which is advantageous because
of the low cost of the catalyst as well as the expansion of the
scope of the alkenyl substrate. The application to the
convergent formal synthesis of siphonazole B is also de-
scribed.
We began by investigating the coupling of benzoxazole
(1A) with styryl pivalate (2a), carbamate (2a’), and phenyl
cinnamate (3a) as alkenylating agents (Scheme 2). Gratify-
À
À
Scheme 3. Substrate scope of C H/C O alkenylation. cod=cyclo-1,5-
octadiene.
À
À
The success of this C H/C O alkenylation using enol
derivatives offers the opportunity to assume carbonyl com-
pounds, in particular ketones, as a source of alkenyl groups in
synthesis. Indeed, the enol carbamate 2b, which can be
readily prepared from b-tetralone in one step, smoothly
coupled with azoles 1A and 1E to furnish the alkenylated-
azoles 4Ab (61%) and 4Eb (80%), respectively (Scheme 4).
À
À
Scheme 2. Nickel-catalyzed C H/C O alkenylation and decarbonyla-
À
tive C H alkenylation of azoles. Reaction conditions: 1A (0.4 mmol),
2a, 2a’, or 3a (0.6 mmol), [Ni(cod)2] (0.04 mmol), dcype (0.08 mmol),
K3PO4 (0.8 mmol), 1,4-dioxane, 1308C (for 2a and 2a’) or 1508C (for
3a).
ingly, by slightly modifying our original reaction conditions
À
À
À
for C H/C O arylation and decarbonylative C H aryla-
tion,[12] the Ni/dcype catalyst displayed activity for the target
reactions to afford the alkenylazole 4Aa. For example, 1A
was coupled with 2a (1.5 equiv) in the presence of [Ni(cod)2]
(10 mol%), dcype (20 mol%), and K3PO4 (2.0 equiv) in 1,4-
dioxane at 1308C for 12 hours to produce 4Aa in 47% yield
À
À
(C H/C O alkenylation). When styryl carbamate (2a’) was
used instead of pivalate 2a, 4Aa was obtained in 77% yield.
À
The decarbonylative C H alkenylation also took place very
smoothly. Phenyl cinnamate (3a) served as an alkenylating
agent in the coupling with 1A under the influence of
[Ni(cod)2]/dcype/K3PO4 at 1508C to give 4Aa in 92% yield.
Notably, it was again found that dcype is the only enabling
À
À
Scheme 4. C H/C O alkenylation using the ketone-derived enol carba-
mate 2b.
ligand for these nickel catalyses. Other ligands displayed
It should be noted that the aromatization of 2b and the
products 4Ab and 4Eb, a reaction which could be a serious
side reaction for these compounds, did not take place under
[12]
À
essentially no activity for these C H alkenylations.
With the optimized reaction conditions in hand, the
À
À
À
À
substrate scope of the C H/C O alkenylation using various
azoles with styryl pivalate (2a) and carbamate (2a’) was
investigated (Scheme 3).[13] Benzoxazoles with substituents at
the C5 position (methyl, methoxy, and tert-butyl) nicely
reacted with either 2a or 2a’ to afford the corresponding
styrylated products 4Ba, 4Ca, and 4Da in moderate to good
yields. Oxazole derivatives were also found to react with 2a
and 2aꢀ to give the corresponding product 4Ea in 51% and
56% yields, respectively. Unfortunately, however, benzothia-
zole did not react with 2a and 2a’ under the present reaction
conditions.
the C H/C O alkenylation conditions. These results under-
score the synthetic utility of the present coupling using enol
derivatives.
À
Scheme 5 shows the scope of decarbonylative C H
alkenylation catalyzed by the [Ni(cod)2]/dcype/K3PO4
system. The scope with regard to azole substrates was
examined using phenyl cinnamate (3a) as the alkenylating
agent. Benzoxazoles bearing 5-methyl, 5-methoxy, and 5-tert-
butyl groups reacted with 3a to give the products 4Ba, 4Ca,
and 4Da, respectively, in high yields. The 5-aryloxazoles 1G–I
underwent coupling with 3a in moderate yields. The scope of
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Scheme 6. Convergent synthesis of siphonazole B intermediates by
Scheme 5. Substrate scope of decarboxylative C H alkenylation.
À
nickel-catalyzed C H alkenylation. DDQ=2,3-dichloro-5,6-dicyano-p-
benzoquinone, PMB=p-methoxybenzyl.
a,b-unsaturated esters (alkenylating agents) was examined
using 1A as the azole component, and was found to be broad.
A range of aromatic and heteroaromatic substituents at the
b position of the phenyl acrylates 3c–g was tolerated and
furnished the corresponding decarbonylative coupling prod-
ucts 4Ac–Ag in high yields. Coupling proceeded well with
substrates having a sterically demanding ortho-substituent
(3e) and 3,3-diphenylacrylate (3h). The coupling of sub-
strates having aliphatic substituents at the b position of the
phenyl acrylate structure 3i and 3j also took place to give 4Ai
and 4Aj, respectively, albeit in somewhat lower yields. Thus,
this coupling reaction shows a broader scope for a,b-
unsaturated esters over enol derivatives. However, unsubsti-
tuted a,b-unsaturated esters as the alkenylating agent as well
as other heteroarenes such as thiazoles and imidazoles did not
react under the present reaction conditions.
Finally, as a showcase of these new azole alkenylation
methods, we applied them to the synthesis of siphonazole B,
a natural product isolated from a metabolite from Herpeto-
siphon sp.[3a] Although siphonazole B has already been
synthesized by Moody and co-workers[14a,b] and Zhang and
Ciufolini,[14c] their syntheses took many steps because of
a parallel repetition of linear synthetic sequences. To address
this problem, we attempted the convergent synthesis of
and alkenyl precursors (2c and 3d), and coupled them using
À
À
the [Ni(cod)2]/dcype/K3PO4 system. The C H/C O alkeny-
lation of 1E with (E)-2c furnished the coupling product 5Ec
À
over four linear steps. The decarbonylative C H alkenylation
of 1J with 3d occurred as well under similar reaction
conditions at 1708C. The follow-up deprotection and oxida-
tion afforded the aldehyde 5Jd over five linear steps
(including the preparation of 1J). Thus, the total synthesis
of siphonazole B is be shorter than previous reports. Addi-
À
tionally, the nickel-catalyzed C H alkenylations have an
advantage that both alkenylating agents (enol derivative and
unsaturated ester) are easily prepared by a Wittig reaction,
and can be directly coupled without producing halogen waste.
À
In summary, we have developed two new C H alkenyla-
À
À
tions of azoles, that is C H/C O alkenylation and decarbon-
À
ylative C H alkenylation, which are uniquely catalyzed by Ni/
dcype. These newly developed azole alkenylation reactions
were successfully applied to the convergent formal synthesis
of siphonazole B. Determining the role of dcype in the
catalysis and the expansion of substrate scope, particularly
with respect to heteroarenes, are ongoing.
Received: May 24, 2013
Published online: && &&, &&&&
À
siphonazole B by using our nickel-catalyzed C H alkenyla-
tion reactions (Scheme 6). Although 5Ec and 5Jd are the
intermediates in the previous synthesis, each fragment needs
to be synthesized in seven linear steps. Thus, we retrosyntheti-
cally break up both intermediates into oxazoles (1E and 1J)
À
Keywords: alkenes · C H activation · heterocycles ·
natural products · nickel
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[12] See the Supporting Information for details and further screening
of reaction conditions.
À
[13] Although the C H alkenylation reactions were performed by
using a mixture of isomers of 2a (E/Z = 1:1) or 2aꢀ (E/Z = 1:3),
the resulting coupling products 4 were obtained as the E isomer.
After careful monitoring of the reaction, we found that the
Z isomers were not consumed under our standard reaction
conditions. Additionally, when (E)-2a (E/Z = 20:1), which is
prepared by other procedures (see the Supporting Information),
was used, the yield of 4 was nearly identical. Therefore, 1.5 equiv
of enol derivative, based on the amount of (E)-2 present was
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À
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