Nickel-catalyzed synthesis of stereochemically defined enamides via Bi- and tricomponent coupling reaction

Article abstract of DOI:10.1021/acs.orglett.7b02166

The stereoselective synthesis of (E)-trisubstituted tertiary enamides is documented via site-selective Ni-catalyzed β-arylation of allenamides with boronic acids in high yields (up to 89%). The nucleophilic character of the "organo-Ni" intermediates is further exploited to implement a one-pot tricomponent procedure involving the final allylation of aldehydes (yields up to 93%). Mechanistic insights and efficiency on a gram scale process were also documented.

Full text of DOI:10.1021/acs.orglett.7b02166

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Synthesis of Stereochemically Defined Enamides
via Bi- and Tricomponent Coupling Reaction
Y. Liu, A. De Nisi, A. Cerveri, M. Monari, and M. Bandini*
Department of Chemistry “G. Ciamician”, Alma Mater Studiorum, University of Bologna, via Selmi 2, 40126 Bologna, Italy
S
* Supporting Information
ABSTRACT: The stereoselective synthesis of (E)-trisubstituted tertiary enamides is documented via site-selective Ni-catalyzed
β-arylation of allenamides with boronic acids in high yields (up to 89%). The nucleophilic character of the “organo-Ni”
intermediates is further exploited to implement a one-pot tricomponent procedure involving the final allylation of aldehydes
(yields up to 93%). Mechanistic insights and efficiency on a gram scale process were also documented.
perturbation performed by the “amidyl” group onto the allenyl
tereochemically defined enamides are common molecular
Smotifs in numerous naturally occurring compounds and unit could guarantee an initial site-selective insertion of
pivotal chemical partners in countless organic transformations.1
In this direction, growing attention toward the realization of
synthetic protocols for enamides with increased chemical
efficiency and cost effectiveness/environmental sustainability
has been recorded in recent years.2 Acid catalyzed regio- and
stereoselective nucleophilic addition to allenamides (also
referred as N-allenyl amides)3 represents an unparalleled
approach to access enamides in a straightforward manner,
with some limitations related to stereochemical issues and to
the employment of second- and third-row soft noble metals as
promoters.3−5
In order to further expand the synthetic applicability of N-
allenyl amide derivatives, we envisioned the possibility to create
a new reaction channel for the manipulation of allenamides
based on a formal inversion of their classic reactivity (Figure 1
upper). In particular, we thought that the overall electronic
nucleophilic organometallic reagents (M−R′ in Figure 1
lower) into the cumulene core (vide infra), followed by
electrophilic trapping of the resulting allylic organometallic
intermediate at the γ-position. In addition, sustainability issues
are targeted by replacing conventional noble 4d and 5d
transition metals with earth-abundant first-row analogues in the
present investigation.6 At the outset of our study, we
considered nickel catalysis being a desirable low-cost first-row
transition metal element,7 which is known to efficiently
promote cross-coupling reactions based on nucleophilic
organometallic intermediates.
It is worth mentioning that 3d-metal based activation of
allenamides is sporadic8 and nickel has not been associated with
this class of transformations to date.9
In order to ascertain the feasibility of the working hypothesis,
allenamide 1a and PhB(OH)2 (2a) were elected as model
substrates and a range of reaction conditions, such as nickel
complexes, bases, solvents, reaction temperatures, and
stoichiometry, were assessed (see Supporting Information
(SI)).5,10
From this survey, parameters reported in Scheme 1 were
elected as optimal, namely [NiCl2(L)] (5 mol %), K2CO3 (3
equiv), 1,4-dioxane, 1 h, 90 °C, providing (E)-3aa in a
stereochemically defined manner (X-ray analysis) in 82%
isolated yield. It is worth mentioning that every deviation
from the listed conditions caused a marked drop in catalytic
performance.
Figure 1. Classic reaction profile of N-EWG-allenes (upper). Working
plan for the present study (lower).
Received: July 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02166
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Organic Letters
Letter
a
Scheme 1. Optimal Reaction Conditions
Scheme 3. Reaction Scope on Allenamides
a
Compounds 3 were isolated in a E/Z ratio >20:1 (reaction crude by
Having established the optimal catalytic system, we verified
the potential of the present cross-coupling protocol with a
range of boronic acids (2b−q), and the results obtained are
summarized in Scheme 2. The methodology turned out to be
1H NMR).
previously reported11 and it excludes the existence of [Ni(0)]
intermediates that would promote the deiodination of the
allenyl precursor or perhaps the Suzuki coupling on the aryl
unit.
With the aim of gaining preliminary information on the
possible activation modes of the nickel complexes, a single-
crystal X-ray analysis was carried out on [NiCl2(L3)]. The X-
ray structure depicted in Figure 2 shows that the Ni(II)-species
Scheme 2. Scope of the Reaction Focusing on Boronic
a
Acids
Figure 2. ORTEP drawing of [Ni(H2O)2Cl2(L3)] (thermal ellipsoids
are at 30% of the probability level).
was isolated as an aquo-complex (e.g., [NiCl2(H2O)2(L3)]) in
which the Ni atom adopts a distorted octahedral geometry
being coordinated by two N atoms of a disubstituted bis-pyridyl
ligand, two chlorides, and two oxygen atoms belonging to water
molecules. The Ni−N distances are slightly different [2.049(7)
and 2.058(6) Å] being the longer one in trans position with
respect to Cl1. Interestingly both the two water molecules and
the two chloro ligands are in mutual cis position, an unusual
geometry that has not been found in crystal structures of
analogous mononuclear nickel(II) complexes in the CSD
(Cambridge Structural database).12 The absence of coordinat-
ing water in the native [NiCl2L] complexes was ascertained via
solid ATR-FTIR spectroscopy.
Mechanistically, although a conclusive picture is not
available, the tentative catalytic cycle depicted in Scheme 4 is
proposed. The initial transmetalation step between the [Ni(II)]
complex and the ArB(OH)2 would lead to the [Ni]−Ar
intermediate A. Complexation of A with the allenamide would
trigger the regioselective insertion of the Ni−Ar bond into the
CC of the allenyl unit (B) providing the allylic-Ni
intermediate C with concomitant transfer of the aryl unit at
the central carbon atom of the π-system.13
a
Compounds 3 were isolated with an E/Z ratio >20:1 (reaction crude
1
by H NMR).
highly robust (yields: 62−89%) concerning aromatic boronic
acids with remarkable tolerance toward electron-withdrawing
(e.g., F, Br, COMe, CO2Me, NO2) and electron-donating
substituents (Me, OMe, OBn, OH, NMe2) in different
positions (ortho, meta and para) of the phenyl ring.
Additionally, the 2-naphthyl boronic acid 2q performed
satisfyingly, providing the corresponding enamide 3aq in 82%
yield. It is noteworthy that high stereospecificity toward the
formation of the E-isomer was always recorded. However, the
process faced some limitations in the inertness of the
ortho,ortho-dimethylphenyl boronic acid and 3-pyridyl analogue
that could be rationalized in terms of steric hindrance and
poisoning of the Ni-catalyst, respectively.
Interestingly, the protocol did not appear limited to cyclic
allenamides. In fact, N-Boc, N-Bz, N-Ac and N-Piv based
compounds (3d−i) took part in the coupling processes to a
moderate to good extent (yields: 63−81%, Scheme 3) always
guaranteeing high stereospecificity toward the trans-adduct.
Notably, the methodology proved tolerant toward the iodo-
substituted benzene derivative 1f. This evidence emphasizes the
complementarity of our method with that of the Pd-catalysis
Finally, proto-demetalation of the resulting allyl organo-
nickel C by one molecule of boronic acid would result in the
release of product 3 with concomitant restoring of the
precatalytic nickel species A. The recorded inertness of
B
DOI: 10.1021/acs.orglett.7b02166
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Organic Letters
Letter
Scheme 4. (a) Hypothetical Mechanistic Cycle; (b) Labeling
Experiment; (c) Attempted Two-Component Cross-
Coupling with Allene 1a'
Scheme 5. Three-Component Ni-Catalyzed Cross-Coupling
a
Reaction performed on 5 mmol scale of 1a (70 min reaction time, 1
b
mol % [NiCl2(L3)]). The product was isolated as TMS-ether.
ortho, meta, para) of the arene. Additionally, also the
heterocyclic aromatic aldehyde 4m proved competent in the
methodology providing the corresponding enamidyl-alcohol
5m in 73% yield. Finally, both aliphatic and α,β-unsaturated
aldehydes coupled effectively with the organo-nickel inter-
mediate providing the expected compounds in moderate to
good yields (39−68%). Structural confirmation as well as
configuration assignment of the CC in the three-component
products 5 was performed via X-ray analysis of compound 5c
(see SI).
Interestingly, the present multicomponent reaction did not
require external additives (e.g., hard Lewis acids, organometallic
reagents, or reducing agents) and attempts to perform the
protocol by using the two-component product 3aa as the
staring material failed in providing 5a with benzaldehyde. This
evidence supports the direct involvement of the in situ formed
organo-nickel intermediate C in the final allylating event.
Finally, the synthetic potential of the methodology was further
supported by running the three-component Suzuki-type
coupling/allylation sequence on gram-scale (5 mmol of 1a)
by employing 1 mol % of [NiCl2(L3)], 1.39 g of stereochemi-
cally defined (E)-5a (84% yield) were obtained in 70 min
reaction time.
In conclusion, the reactivity profile of synthetically relevant
allenamides has been revisited by exploiting the nucleophilic
character of allyl-Ni species obtained in situ through the site-
selective stereoselective condensation of boronic acids on
allenamides (β-arylation of allenamides). A range of stereo-
chemically defined trisubstituted enamides were obtained in
excellent yields via two- and three-component reaction
methodologies. Attempts to extend the present protocol to
other nucleophilic as well as electrophilic reaction partners are
currently ongoing in our laboratories and will be presented in
due course.
phenylboronic acid pinacol ester in the present approach could
account for the role played by boronic acid in the conclusive
events of the catalytic cycle.14
The presence of an organo-nickel intermediate C was proven
by a labeling experiment in which allenamide 1a was coupled
with triphenylboroxin (0.5 equiv) and D2O (4 equiv).
Compound d-3aa was isolated in 44% yield with deuterium
incorporation of 73% at the γ-position, exclusively. This
outcome could be tentatively rationalized in terms of the
more extended conjugate π-system as well as lower steric
congestion of σ-C with respect to σ-C′. Finally, indirect
evidence for the pivotal role played by the conjugate amidyl
unit on the overall reaction profile was gained by subjecting
allene 1a′ (Scheme 4c) to optimal conditions that failed in
promoting the two-component cross-coupling. In fact, a
complex mixture of regio- and stereoisomers was isolated
from the reaction crude in low yield.
This evidence prompted us to further expand the synthetic
utility of the protocol in order to realize a three-component
process in which a suitable electrophilic partner could intercept
the transient organo-nickel intermediate C.
As a proof of concept, we tested PhCHO (4a, 2 equiv) as a
third component in the one-pot protocol. To our delight, the
corresponding homoallylic alcohol 5a was obtained in 84%
yield after 1 h of reaction with a trans-stereochemically defined
carbon−carbon double bond. The generality of the multi-
component Suzuki-type cross-coupling/allylation reaction
sequence was then assessed15 by screening a range of aldehydes
(Scheme 5). Also encouraging was the fact that the scope of
aromatic aldehydes proved to be significantly broad with
tolerance toward electron-withdrawing (5b−d,j) as well as
electron-donating (5e−i,k) groups at different positions (e.g.,
C
DOI: 10.1021/acs.orglett.7b02166
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2015, 5, 3911−3915. (g) De Nisi, A.; Sierra, S.; Ferrara, M.; Monari,
M.; Bandini, M. Org. Chem. Front. 2017, 4, 1849−1853.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02166.
■
S
(6) Zweig, J. E.; Kim, D. E.; Newhouse, T. R. DOI: 10.1021/
acs.chemrev.6b00833.
(7) For general reviews on Ni catalysis, see: (a) Netherton, M. R.; Fu,
G. C. Adv. Synth. Catal. 2004, 346, 1525−1532. (b) Tasker, S. Z.;
Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299−309. (c) Li, Z.;
Liu, L. Chin. J. Catal. 2015, 36, 3−14. (d) Standley, E. A.; Tasker, S. Z.;
Jensen, K. L.; Jamison, T. F. Acc. Chem. Res. 2015, 48, 1503−1514. (e)
Modern Organonickel Chemistry; Tamaru, Y., Ed.; Wiley-VCH: 2015.
(f) Wang, D.; Astruc, D. Chem. Soc. Rev. 2017, 46, 816−854.
(8) (a) Gholap, S. S.; Takimoto, M.; Hou, Z. Chem. - Eur. J. 2016, 22,
Synthetic procedures (PDF)
NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: marco.bandini@unibo.it.
ORCID
́
8547−8552. (b) Perego, L. A.; Blieck, R.; Groue, A.; Monnier, F.;
Taillefer, M.; Ciofini, I.; Grimaud, L. ACS Catal. 2017, 7, 4253−4264.
(9) In a recent paper Ni-based Lewis acid catalysis was applied in a
formal [2 + 2]-cycloaddition: Liu, R. R.; Hu, J. P.; Hong, J.-J.; Lu, C.-J.;
Gao, J.-R.; Jia, Y.-X. Chem. Sci. 2017, 8, 2811−2815.
M. Bandini: 0000-0001-9586-3295
Notes
(10) For a selection of very recent examples of Ni-catalyzed cross-
coupling reactions with boronic acids, see: (a) Wang, J.; Qin, T.; Chen,
T.-G.; Wimmer, L.; Edwards, J. T.; Cornella, J.; Vokits, B.; Shaw, S. A.;
Baran, P. S. Angew. Chem., Int. Ed. 2016, 55, 9676−9679. (b) Guo, L.;
Rueping, M. Chem. - Eur. J. 2016, 22, 16787−16790. (m) Xiao, Y.-L.;
Min, Q.-Q.; Xu, C.; Wang, R.-W.; Zhang, X. Angew. Chem., Int. Ed.
2016, 55, 5837−5841. (c) Gu, J.-W.; Min, Q.-Q.; Yu, L.-C.; Zhang, X.
Angew. Chem., Int. Ed. 2016, 55, 12270−12274. (d) Guo, L.; Liu, X.;
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2017, 56, 3679−3683.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Acknowledgement is made to University of Bologna for
financial support. Y.L. thanks Chinese Scholarship Council
No. 201609120008 for funding support.
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