A nickel-based, tandem catalytic approach to isoindolinones from imines, aryl iodides, and CO

Article abstract of DOI:10.1021/acs.organomet.5b00215

We describe herein a modular nickel-catalyzed synthesis of isoindolinones from imines, aryl iodides, and CO. This reaction is catalyzed by Ni(1,5-cyclooctadiene)₂ in concert with chloride salts and postulated to proceed via a tandem nickel-cata

Full text of DOI:10.1021/acs.organomet.5b00215

Communication
pubs.acs.org/Organometallics
A Nickel-Based, Tandem Catalytic Approach to Isoindolinones from
Imines, Aryl Iodides, and CO
Jevgenijs Tjutrins,† Jia Lun Shao,† Veeranna Yempally,‡ Ashfaq A. Bengali,*,‡ and Bruce A. Arndtsen*,†
†Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
‡Department of Chemistry, Texas A&M University at Qatar, Doha, Qatar
S
* Supporting Information
ABSTRACT: We describe herein a modular nickel-catalyzed
synthesis of isoindolinones from imines, aryl iodides, and CO.
This reaction is catalyzed by Ni(1,5-cyclooctadiene)2 in concert
with chloride salts and postulated to proceed via a tandem nickel-
catalyzed carbonylation to form N-acyl iminium chloride salts,
followed by a spontaneous nickel-catalyzed cyclization. A range of aryl iodides and imines have been found to be viable substrates
in this reaction, providing a modular route to generate substituted isoindolinones with high atom economy.
Scheme 1. Catalytic Synthesis to Isoindolinones
ransition-metal-catalyzed carbonylation reactions have
1
Tseen growing use in synthetic chemistry. In addition to
simple esters, amides, ketones, and related carboxylic acid
derivatives, there has been significant recent application of
carbonylations to the assembly of more elaborate carbocyclic
and heterocyclic products. Examples of these can range from
carbonylative cyclizations2 to ring expansions,3 Pauson−Khand
type reactions,4 and others.5 One important class of
heterocyclic products toward which carbonylations have been
applied are isoindolinones. These heterocycles represent the
core unit in a variety of natural products and other
pharmaceutically relevant compounds, including antitumor,
anesthetic, anti-inflammatory, and antidiabetic agents and
others.6 A number of approaches have been reported for the
carbonylative synthesis of isoindolinones with ortho-function-
alized aryl halides, including those with o-imino- and o-vinyl-
substituted arenes (Scheme 1a).7 However, similar to other
approaches to isoindolinones, these often require the initial
assembly of the appropriate aryl-tethered precursors for
cyclization.
In considering the structure of isoindolinones, we postulated
that a more modular approach to these products might be via
the carbonylative coupling of aryl halides and imines. Watson
and co-workers demonstrated that nickel catalysts can mediate
the cyclization of synthetic N-benzoylaminals to isoindolinones
(Scheme 1b).8 An alternative would be to generate the N-acyl
iminium salt intermediates via carbonylation. We have recently
reported that palladium catalysts can be employed to generate
acid chlorides from aryl iodides, which are reactive with even
weak nucleophiles such as imines.9 However, these palladium
systems are potent carbonylation catalysts and mediate a
second, spontaneous carbonylation of the N-acyl iminium salt
rather than the double-carbonylative formation of 1. We
describe herein the successful realization of this goal and an
efficient, tandem catalytic approach to isoindolinones.
Our initial studies of this transformation examined the
carbonylative coupling of 4-iodotoluene and imine (Table 1).
The use of the catalyst nickel(0) bis(cyclooctadiene) (Ni-
(COD)2) led to only trace amounts of isoindolinone 2a and
to form mesoionic 1,3-oxazolium-5-oxides 1 (i.e., Munchnones,
̈
Scheme 1c).10 Relative to palladium, nickel catalysts often show
diminished reactivity in carbonylations.11 This suggests that
nickel catalysts may be better suited to mediate a tandem
carbonylation/C−H functionalization reaction (Scheme 1d),
Received: March 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.5b00215
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Communication
a
Table 1. Catalyst Design for Carbonylative Isoindolinone
Synthesis
Table 2. Aryl Iodide Diversity in Isoindolinone Synthesis
a
a
Conditions: Ar-I (1.00 mmol), imine (105 mg, 0.50 mmol), EtiPr2N
(77 mg, 0.60 mmol), Bu4NCl (134 mg, 0.50 mmol), Ni(COD)2 (14
mg, 0.05 mmol), CO (1 atm), MeCN (2 mL), 120 °C for 24 h.
Isolated yields.
The compatibility of this reaction with imines was also
examined (Table 3). A number of N-alkyl (2k,l)- and N-benzyl-
a
Conditions unless specified otherwise: p-tolyl-I (44 mg, 0.20 mmol),
imine (21 mg, 0.10 mmol), EtiPr2N (16 mg, 0.12 mmol), additive
(0.10 mmol), Ni(COD)2 (3 mg, 0.01 mmol), CO (4 atm), CD3CN
(0.7 mL), 120 °C for 24 h. NMR yields. CO (1 atm). Isolated yield
given in parentheses.
a
Table 3. Imine Diversity in Isoindolinone Synthesis
b
c
instead generated amide 3a in low yield. The addition of
various ligands to this reaction also did not afford significant
amounts of 2a. We have previously noted in our studies of
palladium-catalyzed carbonylation that chloride sources can
facilitate coupling with weakly nucleophilic substrates by
allowing the in situ generation of acid chlorides.9a As was
hoped, the addition of tetrabutylammonium chloride to the
catalytic reaction with simple Ni(COD)2 catalyst resulted in the
high-yield formation of isoindolinone 2a as the major reaction
product. Most added ligands retard the formation of 2a, with
only the bulky and weak donor P(o-tolyl)3 leading to yields
approaching that of simple Ni(COD)2. These results suggest
that the active catalyst for this system is unligated nickel(0).12
Decreasing the reaction pressure to 1 atm does not appear to
influence the product yield (entry 16).
With the optimized reaction conditions in hand, we explored
the substrate diversity of the aryl halide reaction partner (Table
2). Both electron-rich (2e) and electron-deficient (2b,c,f−h)
aryl iodides can participate in this reaction and lead to products
in good yields. In addition to simple para-substituted aryl
iodides, symmetrically disubstituted aryl iodides are viable
substrates in this chemistry (2i). On the other hand, ortho-
substituted aryl iodides such as 2-iodotoluene and 2-iodoanisole
failed to produce any of the corresponding isoindolinone
products under these conditions. Simple meta-substituted aryl
iodides lead to a mixture of isomeric products (2j).
a
Conditions: p-tolyl-I (218 mg, 1.00 mmol), imine (0.50 mmol),
EtiPr2N (77 mg, 0.60 mmol), Bu4NCl (134 mg, 1.0 mmol),
Ni(COD)2 (14 mg, 0.05 mmol), CO (1 atm), MeCN (2 mL), 120
°C for 24 h. Isolated yields. Reaction performed on a 4 mmol scale.
b
B
DOI: 10.1021/acs.organomet.5b00215
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substituted (2n,o) imines can undergo carbonylative cyclization
to form isoindolinones. However, N-aryl-substituted imines
yield only starting material under these conditions, presumably
due to their decreased nucleophilicity for N-acyl iminium salt
formation (vide infra). The imine carbon can tolerate a range of
aromatic units, including those with electron-withdrawing (2o)
and electron-donating (2m,n) arenes, or heteroaryl units (2q).
direct role in facilitating C−H bond functionalization.8 While
we at present cannot distinguish between these mechanisms,
the conversion of N-acyl iminium chloride to the more
electrophilic iodide or triflate salt also leads to cyclization,
consistent with a Lewis acidic role of the nickel catalyst.
In conclusion, we have developed a nickel-catalyzed process
for the synthesis of highly substituted isoindolinones from aryl
iodides, imines, and carbon monoxide. This reaction is believed
to proceed via the in situ generation of an N-acyl iminium
chloride, which can further undergo a nickel-mediated
annulation. Overall, this process provides a modular synthesis
of isoindolinones from available substrates and is directly
amenable to structural diversification.
t
As shown with isoindolinone 2p, Bu-substituted imines can
also be employed in this chemistry. This reaction can be
applied to a gram-scale synthesis of isoindolinones (e.g., 2o).
While the mechanism of this transformation is still under
investigation, on the basis of preliminary studies we postulate a
dual role of the nickel catalyst in this reaction (Scheme 2a).
ASSOCIATED CONTENT
* Supporting Information
Scheme 2. Mechanism of Isoindolinone Synthesis
■
S
Text and figures giving experimental procedures, character-
ization data, and NMR spectra for new compounds. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.organomet.5b00215.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for A.A.B.: ashfaq.bengali@qatar.tamu.edu.
*E-mail for B.A.A.: bruce.arndtsen@mcgill.ca.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This publication was made possible by funding through an
NPRP award (5-156-1-037) from the Qatar National Research
Fund (member of Qatar Foundation). The statements made
herein are solely the responsibility of the authors.
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