Efficient Synthesis of Polycyclic γ-Lactams by Catalytic Carbonylation of Ene-Imines via Nickelacycle Intermediates

Article abstract of DOI:10.1002/anie.201703187

The nickel(0)-catalyzed carbonylative cycloaddition of 1,5- and 1,6-ene-imines with carbon monoxide (CO) is reported. Key to this reaction is the efficient regeneration of the catalytically active nickel(0) species from nickel carbonyl complexes such as [Ni(CO)₃L]. A variety of tri- and tetracyclic γ-lactams were thus prepared in excellent yields with 100 % atom efficiency. Preliminary results on asymmetric derivatives promise potential in the synthesis of enantioenriched polycyclic γ-lactams.

Full text of DOI:10.1002/anie.201703187

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201703187
German Edition: DOI: 10.1002/ange.201703187
Heterocycles
Efficient Synthesis of Polycyclic g-Lactams by Catalytic Carbonylation
of Ene-Imines via Nickelacycle Intermediates
Yoichi Hoshimoto, Keita Ashida, Yukari Sasaoka, Ravindra Kumar, Ken Kamikawa,
Xavier Verdaguer, Antoni Riera, Masato Ohashi, and Sensuke Ogoshi*
Abstract: The nickel(0)-catalyzed carbonylative cycloaddition
of 1,5- and 1,6-ene-imines with carbon monoxide (CO) is
reported. Key to this reaction is the efficient regeneration of the
catalytically active nickel(0) species from nickel carbonyl
complexes such as [Ni(CO)3L]. A variety of tri- and tetracyclic
g-lactams were thus prepared in excellent yields with 100%
atom efficiency. Preliminary results on asymmetric derivatives
promise potential in the synthesis of enantioenriched polycyclic
g-lactams.
oxidative cyclization of unsaturated compounds with nickel-
(0) species.[4,5] These hetero-nickelacycles afforded the cor-
responding lactones and lactams in the presence of an excess
amount of CO gas. However, the simultaneous formation of
nickel(0) carbonyl complexes such as [Ni(CO)3L] was inevi-
table.[5,6] The formation of a nickel(0) species from nickel(0)
carbonyl complexes, which promote the oxidative cyclization,
is generally challenging in the presence of CO gas, and the
development of a nickel(0)-catalyzed carbonylative cyclo-
addition with CO gas itself might thus be hampered.[1c,6,7] To
overcome this limitation, we employed phenyl formate as
a CO source[8] to regulate the concentration of CO, as it has to
be sufficiently high for the reaction with the nickelacycle
intermediates, yet also sufficiently low to ensure the forma-
tion of [Ni(CO)3L]. Thus, the first nickel(0)-catalyzed
[2+2+1] carbonylative cycloaddition was developed with
imines and either alkynes or norbornene.[9] However, the
direct use of CO gas remains unsuccessful because of the
rapid formation of [Ni(CO)3PCy3] (Scheme 1a).
T
he use of gaseous carbon monoxide (CO) in organic
synthesis is ideal since it offers a straightforward, cost-
economical, atom-efficient, and widely applicable synthetic
pathway to a variety of carbonyl compounds.[1] The Pauson–
Khand reaction is a representative carbonylation which is
mediated or catalyzed by transition metals and yields cyclic
ketones.[2] In contrast, the corresponding catalytic carbon-
ylation to prepare lactones and lactams, the so-called hetero-
Pauson–Khand reaction, remains limited because of difficul-
ties associated with the repeated generation of key hetero-
metalacycle intermediates under a CO atmosphere.[3] The
judicious choice of both the transition-metal catalyst and the
reaction conditions is critical for generating these heterome-
talacycle intermediates in high efficiency under the catalytic
carbonylation conditions.
We expect the desirable reactivity from nickel(0) as
a catalyst in the hetero-Pauson–Khand reaction, considering
that a variety of hetero-nickelacycles were obtained by the
[*] Dr. Y. Hoshimoto, K. Ashida, Y. Sasaoka, Dr. R. Kumar,
Prof. Dr. M. Ohashi, Prof. Dr. S. Ogoshi
Department of Applied Chemistry, Faculty of Engineering
Osaka University
Suita, Osaka 565-0871 (Japan)
E-mail: ogoshi@chem.eng.osaka-u.ac.jp
Dr. Y. Hoshimoto
Frontier Research Base for Global Young Researchers, Graduate
School of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
Scheme 1. Nickel(0)-catalyzed carbonylation with a) phenyl formate
and b) CO itself.
Prof. Dr. K. Kamikawa
Department of Chemistry, Graduate School of Science, Osaka
Prefecture University, Sakai, Osaka 599-8531 (Japan)
Direct utilization of gaseous CO leads to the development
of an ideal nickel(0)-catalyzed carbonylation system proceed-
ing via nickelacyles. Thus, the system should be constructed to
effectively regenerate an active nickel(0) species from nickel-
(0) carbonyl complexes under a CO atmosphere. Herein, we
demonstrate our strategy to utilize gaseous CO itself in
a nickel(0)-catalyzed intramolecular [2+2+1] carbonylative
cycloaddition of ene-imines, a reaction which affords poly-
cyclic g-lactams (Scheme 1b).
Prof. Dr. X. Verdaguer, Prof. Dr. A. Riera
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona
Institute of Science and Technology, Barcelona 08028 (Spain)
and
Departament de Quꢀmica Inorgꢁnica i Orgꢁnica, Secciꢂ Orgꢁnica,
Universitat de Barcelona, Barcelona 08028 (Spain)
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.201703187.
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To confirm the reactivity of [Ni(CO)3PCy3] as a nickel(0)
source in the carbonylative cycloaddition,[10] the reaction with
N-benzylidene toluenesulfonamide and diphenylacetylene
was examined. The formation of the target lactam was not
observed under the reaction conditions shown in Scheme 2a
Scheme 3. Optimization of the catalytic conditions. Yields of isolated
products are given. [a] Yield given by stirring the mixture at 1350 rpm.
cod=1,5-cyclooctadiene.
conducted under vigorous stirring (1350 rpm), the color of the
reaction mixture changed to colorless within 15 minutes, and
2a was obtained in only 12% yield. Continuing stirring did
not increase the conversion of 1a at room temperature. Even
after stopping stirring, the yield of 2a did not increase
substantially at either room temperature or 808C (ca. 5%
increase after 4 h). These results indicate that stirring of the
reaction mixture leads to a rapid CO saturation, which
hampers the progress of the catalytic carbonylation. There-
fore, the following experiments were conducted without
stirring. Heating at 608C for 4 hours gave 2a in 94% yield
(entry 2). Even in the presence of about 12.5 equivalents of
CO, 2a was obtained in greater than 99% yield at 608C
(entry 3). Moreover, upon decreasing the catalyst loading to
1 mol%, 2a was still formed in 99% yield after 6 hours at
808C (entry 4). A variety of ligands were examined to
demonstrate that a combination of [Ni(cod)2] with mono-
dentate tertiary phosphine ligands such as PCy3, PPh3, and
PtBu3 affords better results than with P(OPh)3, bidentate
phosphines (DCPE, Xantphos), and an N-heterocyclic car-
bene.[11] Based on these results, the optimized reaction
conditions used 1 mol% [Ni(cod)2/PCy3] in toluene at 808C
with 0.5 atm of CO gas.
The nickel(0)/PCy3-catalyzed carbonylative cycloaddition
of the 1,5-ene-imines 1a–g was carried out under the
optimized reaction conditions, thus resulting in the generation
of tricyclic the g-lactams 2a–g in excellent yields (Scheme 4).
Notably, the larger-scale synthesis of 2a (2.0 mmol) was
successfully achieved in greater than 99% yield by using
a 50 mL autoclave reactor. Fluorine- and chlorine-substituted
substrates successfully afforded 2b and 2c in 97 and greater
than 99% yield, respectively. Introduction of a single
methoxy group furnished 2d in 99% yield, even though the
reaction of 1e having two methoxy groups required 5 mol%
catalyst to obtain 2e in 76% yield. Because of the low
solubility of 1 f in toluene, a mixed solvent of THF/toluene
(3:2, v/v) was used, and gave the tetracyclic g-lactam 2 f in
90% yield. A substrate with the methallyl group was
efficiently converted into 2g (99% yield). Replacing the N-
Ts with a N-diphenylphosphinic group did not affect the
reaction, thus reflecting the ability of the N-diphenylphos-
phinic group to stabilize the hetero-nickelacycle intermediate
Scheme 2. Stoichiometric carbonylative cycloadditions with
[Ni(CO)3PCy3]. Ts=4-toluenesulfonyl.
(conversion of [Ni(CO)3PCy3] is less than 1 and 5% at room
temperature and 608C, respectively).[11] Thus, the 1,5-ene-
imine 1a (Scheme 2b) was examined based on our previous
report that 1,5-enals efficiently coordinate to nickel(0) in an
h2-alkene:h2-aldehyde fashion.[12] Treatment of 1a with [Ni-
(CO)3PCy3] (0.33 equiv) resulted in the formation of the
tricyclic g-lactam 2a in 85% yield as a single diastereomer
after 32 hours at room temperature. In the presence of 5.0 atm
of CO, this reaction furnished 2a in 79% yield. Notably, these
reactions were conducted in a pressure-tight NMR tube
(inner volume: 2.2 mL) without stirring the reaction mixture.
These results show that a nickel(0)-catalyzed intramolecular
carbonylative cycloaddition of an imine and an alkene with
CO gas can be achieved even after the complete trans-
formation of the nickel(0) species into [Ni(CO)3PCy3]. This
type of tricyclic g-lactam is part of the core structure of
strigolactam, which exhibited agrochemical activity during
the generation of parasitic weed seeds.[13] Strigolactam is
useful as a seed germination simulator and plant growth
regulator,[13a,b] but straightforward and efficient methods to
synthesize strigolactam derivatives remain to be developed.
The formation of the hetero-nickelacycle A was confirmed by
NMR analyses, and indicates that 2a was generated via A
(Scheme 2b). The intramolecular coordination of the tosyl
(Ts) group to the nickel(II) center is proposed based on our
previous report[5] as well as on the results that are discussed
later.
Subsequently, the nickel-catalyzed carbonylative cyclo-
addition of 1a was examined under an atmosphere of CO
(Scheme 3). A 25 mL autoclave reactor was filled with 1a
(0.4 mmol), [Ni(cod)2/PCy3] (0.04 mmol, 10 mol%), toluene
(1.0 mL), and 0.5 atm of CO gas (ca. 0.5 mmol, 1.3 equiv with
respect to 1a) at room temperature to give a red solution.
Then, the reaction mixture was allowed to stand for 18 hours
without stirring, and furnished 2a in greater than 99% yield
upon isolation (entry 1). At the end of the reaction, the
reaction mixture was colorless, thus suggesting the quantita-
tive formation of [Ni(CO)3PCy3].[11] When the reaction was
2
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of 2n–r with a tetralin core, all of which were isolated in
excellent yields. All products were obtained as a single
diastereomer. These reactions represent 100% atom effi-
ciency, and thus, generated no waste.
Derivatization of 2a and 2h by removal of the N-Ts and
the N-diphenylphosphinic groups resulted in the formation of
2s, which is a key component in the synthesis of strigolac-
tam,[13a] thus demonstrating the utility of the present catalytic
system (Scheme 5).
Scheme 5. Synthesis of 2s from either 2a or 2h. Yields of isolated
products are given. THF=tetrahydrofuran.
Given the mild reaction conditions in the present carbon-
ylative cyclization, the expansion of the present system to an
asymmetric variant was also examined, and preliminary
results for the ligand screening with 1h are shown in
Scheme 6. The chiral phosphoramidite ligand[14] L*1 worked
Scheme 6. Nickel(0)-catalyzed asymmetric [2+2+1] carbonylative
cycloaddition with 1h. General conditions: A multiple autoclave
reactor (V: 3.7 mL ꢃ 18 reactors) was used. 1h (0.20 mmol),
[Ni(cod)2]/L*1–L*4 (0.020 mmol), and toluene (0.50 mL) were mixed in
the each reactor, followed by pressurizing CO at 0.5 atm at RT, and
heating at 608C for 15 h. Yields of isolated products are given. The ee
values were determined by SFC, using a chiral stationary phase.
[a] Yield determined by NMR spectroscopy.
well to give 2h in 95% yield and 62% ee. The chiral MOP
ligand[15] L*2, P-stereogenic iminophosphorane[16] L*3, and
the planar-chiral phosphine-olefin ligand[17] L*4 were also
used, as these compounds should act as hemilabile bidentate
ligands. However, any improvements on the results were not
observed. Nevertheless, the result given by L*1 shows
promising reactivity of nickel(0)/chiral monodentate phos-
phine systems in this first example of a nickel(0)-catalyzed
asymmetric carbonylative cycloaddition of ene-imines and
CO. Further studies to attain higher enantioselectivity are
currently ongoing.
Scheme 4. Nickel(0)-catalyzed [2+2+1] carbonylative cycloaddition
with CO gas. General conditions: A multiple autoclave reactor (V:
3.7 mL ꢃ 18 reactors) was used. 1 (0.20 mmol), [Ni(cod)2]/PCy3
(1 mol%), and toluene (0.50 mL) were mixed in the each reactor,
followed by pressurizing CO at 0.5 atm at RT, and heating at 808C.
Yields of isolated products are given. [a] 5 mol% catalyst. [b] THF/
toluene (3:2, v/v). [c] THF/toluene (1:1, v/v). [d] 3 mol% catalyst.
[e] 24 h.
=
by intramolecular coordination of P O moiety to the nickel-
(II) center,[5d,e] which manifested excellent yields of 2h–k.
Neither 1l nor 1m afforded the target products (2l or 2m),
presumably because of the limited ability of the N-substituted
groups to stabilize the nickelacycle intermediates. The present
catalytic system was also successfully applied to the synthesis
As described in Scheme 2b, the nickelacycle A was
formed by the reaction of 1a with [Ni(CO)3PCy3], as well as
by the reaction with [Ni(cod)2] and PCy3 (Scheme 7a).
Similarly, the nickelacycle B was synthesized quantitatively
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“Stimuli-responsive Chemical Species (No. 2408)” (JSPS
KAKENHI Grant Number JP15H00943) and “Precisely
Designed Catalysts with Customized Scaffolding (JSPS
KAKENHI Grant Number JP15H05803)” from MEXT, and
by ACT-C (Grant Number JPMJCR12Y6) from JST. Y.H.
acknowledges support from the Frontier Research Base for
Global Young Researchers, Osaka University, on the program
of MEXT. X.V. and A.R. thank the Spanish Ministerio de
Economia y Competividad (CTQ2014-56361-P) and IRB
Barcelona for financial support. K.K. acknowledges support
from “Precisely Designed Catalysts with Customized Scaf-
folding (JSPS KAKENHI Grant Number JP16H01039)”
from MEXT. We would like to express our thanks to Prof.
Dr. N. Tohnai, Graduate School of Engineering, Osaka
University, for his assistance on X-ray analysis.
Scheme 7. a) Formation of nickelacycles, and their transformations
into 2. b) Reaction of A with 1b. [a] Yield of isolated product. [b] Yield
determined by NMR spectroscopy.
Conflict of interest
The authors declare no conflict of interest.
by the stoichiometric reaction of 1r with [Ni(cod)2] and PCy3.
The molecular structure of B was unambiguously confirmed
by X-ray crystallography (see Figure S4 in the Supporting
Keywords: carbonylation · cyclization · enantioselectivity ·
heterocycles · nickel
Information).
A distorted square-planar structure was
observed, and includes an intramolecular coordination of
the Ts group to the nickel(II) center. Treatment of either A or
B with CO gas (3 atm) resulted in the quantitative formation
of either 2a or 2r. These results support the formation of
a hetero-nickelacycle by the oxidative cyclization with an
active in situ generated nickel(0) species as the key inter-
mediate in the present catalytic reaction (Scheme 1b). Treat-
ment of A with 1b at 808C resulted in the formation of the
nickelacycle C in 21% yield with the concomitant production
of 1a (15%) and an unidentified compound (Scheme 7b).[11]
Thus, the retro-oxidative cyclization from A to [(h2:h2-1a)Ni-
(PCy3)] is possible, even though this process would be
unlikely to occur under the present catalytic conditions.
In summary, CO gas itself has been utilized in a nickel(0)-
catalyzed [2+2+1] carbonylative cycloaddition reaction with
1,5- and 1,6-ene-imine substrates. A variety of tri- and
tetracyclic g-lactams were prepared in excellent yields with
100% atom efficiency. The key to this catalytic process is
a reaction environment, in which the active nickel(0) species
can be reactivated from nickel(0) carbonyl complexes such as
[Ni(CO)3L] in the presence of CO gas. Preliminary results on
the development of an asymmetric variant showed promising
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Acknowledgements
This work was supported by Grants-in Aid for Young
Scientists (A) (JSPS KAKENHI Grant Number
JP25708018), and Scientific Research on Innovative Areas
4
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[10] [Ni(CO)3PCy3] (dP = 45.8 ppm) is stable in C6D6 at RT. An 11%
thermal decomposition was observed at 608C, after a period of
2 days, to give a single unidentified compound (dP = 46.2 ppm).
[11] See the Supporting Information for details.
Manuscript received: March 27, 2017
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126, 11802; b) Y. Hoshimoto, Y. Hayashi, H. Suzuki, M. Ohashi,
Accepted manuscript online: January 0, 0000
Version of record online: && &&, &&&&
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Communications
Heterocycles
Y. Hoshimoto, K. Ashida, Y. Sasaoka,
R. Kumar, K. Kamikawa, X. Verdaguer,
A. Riera, M. Ohashi,
S. Ogoshi*
&&&& — &&&&
CO gas is employed in a nickel(0)-cata-
lyzed [2+2+1] carbonylative cycloaddi-
tion reaction with 1,5- and 1,6-ene-imine
substrates. The method affords a variety
of tri- and tetracyclic g-lactams in excel-
lent yields with 100% atom efficiency.
Efficient Synthesis of Polycyclic g-
Lactams by Catalytic Carbonylation of
Ene-Imines via Nickelacycle
Intermediates
6
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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