Rhenium-Catalyzed Synthesis of 1,3-Diiminoisoindolines via Insertion of Carbodiimides into a C-H Bond of Aromatic and Heteroaromatic Imidates

Article abstract of DOI:10.1021/acs.orglett.6b01012

The rhenium-catalyzed synthesis of 1,3-diiminoisoindolines and their related compounds from aromatic or heteroaromatic imidates and carbodiimides are reported via C-H bond activation. This reaction is the first example of a transition-metal-catalyzed inse

Full text of DOI:10.1021/acs.orglett.6b01012

Letter
pubs.acs.org/OrgLett
Rhenium-Catalyzed Synthesis of 1,3-Diiminoisoindolines via
Insertion of Carbodiimides into a C−H Bond of Aromatic and
Heteroaromatic Imidates
Zijia Wang,† Shunsuke Sueki,†,‡,§ Motomu Kanai,† and Yoichiro Kuninobu*,†,‡
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡CREST, Japan Science and Technology Agency (JST), 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: The rhenium-catalyzed synthesis of 1,3-diiminoisoindolines and
their related compounds from aromatic or heteroaromatic imidates and
carbodiimides are reported via C−H bond activation. This reaction is the first
example of a transition-metal-catalyzed insertion of carbodiimides into an aromatic
or heteroaromatic C−H bond and a novel method for synthesizing 1,3-
diiminoisoindolines and their related compounds. Unsymmetrical 1,3-diiminoi-
soindolines were easily obtained using this method. The reaction proceeded in
good to excellent yield using a variety of substrates.
1,3-Diiminoisoindolines are diimidated phthalimides and partial
structures of phthalocyanines and their metal complexes.
Phthalocyanines and their metal complexes are useful as
organic functional materials, such as pigments, organic
electroluminescence, and organic field effect transistors.1 In
addition, 1,3-diiminoisoindolines and their derivatives exhibit
several biological activities as a complement component 3a
antagonist and antimalarial candidates.2 Synthetic reactions of
1,3-diiminoisoindolines, however, are still rare.3 In addition,
synthesis of unsymmetrical 1,3-diiminoisoindolines using
previously reported synthetic methods remains difficult.
metal catalysts have been developed.4 To the best of our
knowledge, however, there are no examples of transition-metal-
catalyzed insertion of carbodiimides into an aromatic C−H
bond. We reported new synthetic reactions of cyclic
compounds by the insertion of unsaturated molecules into a
C−H bond of various substrates and successive intramolecular
nucleophilic cyclization under rhenium catalysis.5−7 We then
considered that synthesis of 1,3-diiminoisoindolines, shown in
Scheme 1, could be achieved using a rhenium catalyst. Herein
we report the rhenium-catalyzed synthesis of 1,3-diiminoisoin-
dolines from aromatic imidates and carbodiimides.
We began our studies with several transition metal complexes
and salts using aromatic imidate 1a and N,N′-diisopropyl-
carbodiimide (2a) as model substrates. A rhenium complex,
Re2(CO)10, exhibited high catalytic activity. Treatment of 1a
with 2a in the presence of the Re2(CO)10 catalyst in
chlorobenzene at 170 °C for 24 h gave 1,3-diiminoisoindoline
3a in 99% yield (Scheme 2). Several other transition metal
complexes promoted the annulation reaction, but the yields of
3a were low.8 The stereochemistry of the imino groups was
We considered a new synthetic method of 1,3-diiminoisoin-
dolines via C−H bond activation (Scheme 1): (1) a 1,3-
Scheme 1. Retrosynthetic Route of 1,3-Diiminoisoindolines
Scheme 2. Rhenium-Catalyzed Synthesis of 1,3-
Diiminoisoindoline from Aromatic Imidate and
Carbodiimide
diiminoisoindoline is obtained by intramolecular nucleophilic
cyclization of intermediate A and elimination of methanol; (2)
intermediate A is formed by the insertion of a carbodiimide
into a rhenium−carbon bond of intermediate B; and (3)
intermediate B is generated by oxidative addition of an
aromatic imidate to a rhenium catalyst (C−H bond activation).
Transition-metal-catalyzed C−H insertion reactions of
unsaturated molecules have recently received considerable
attention, and many reactions using several types of transition
Received: April 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01012
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Letter
determined by nuclear Overhauser effect experiments using
(E)-N-((E)-5-bromo-2-isopropyl-3-(isopropylimino)-1-isoin-
dolinylidene)-1-propanamine 3A (see Supporting Information
for details). Interestingly, the desired reaction proceeded in
advance of the consumption of 2a by the addition of methanol
(byproduct) to 2a.9 This reaction is the first example of
transition-metal-catalyzed insertion of a carbodiimide into a C−
H bond of aromatic and heteroaromatic compounds and a
novel example of the synthesis of an unsymmetric 1,3-
diiminoisoindoline derivative.
naphthyl imidate 1i and heteroaromatic imidates 1j and 1k
were used as substrates.
Next, we examined the substrate scope of carbodiimides
(Scheme 4). Dicyclohexylcarbodiimide (2b) afforded the
Scheme 4. Reactions between Aromatic Imidate 1a and
a
Several Carbodiimides 2
We then investigated the substrate scope of aromatic and
heteroaromatic imidates (Scheme 3). The desired reaction
Scheme 3. Reactions between Several Aromatic or
Heteroaromatic Imidates 1 and N,N′-
a
Diisopropylcarbodiimide 2a
a
b
c
2 (1.0 equiv). dr = 2:1. E/Z = 5:1.
corresponding 1,3-diiminoisoindoline 3l in 90% yield. Carbo-
diimides bearing primary alkyl groups, 2c−2e, also produced
1,3-diiminoisoindolines 3m−3o in 82%−94% yield without loss
of the functional groups. The corresponding 1,3-diiminoisoin-
dolines 3p and 3q were obtained in good yield using dibenzylic
carbodiimides as substrates. Interestingly, the regioselectivity
was completely controlled in the reaction between 1a and
unsymmetric carbodiimide 2h, and a single product 3r was
produced. A diaryl carbodiimide 2i also gave the corresponding
1,3-diiminoisoindoline 3s in 83% yield.
a
2a (1.0 equiv).
A proposed mechanism for the formation of 1,3-
diiminoisoindolines 3 is shown in Scheme 5: (1) oxidative
addition of aromatic imidate 1 to a rhenium catalyst (C−H
bond activation); (2) insertion of carbodiimide 2 into the
formed rhenium−carbon bond; (3) stereoinversion of a CN
double bond to avoid the steric repulsion between substituents
R3 and R4, and intramolecular nucleophilic cyclization; and (4)
reductive elimination and elimination of methanol to give 1,3-
diiminoisoindoline 3 and regenerate the rhenium catalyst. As
described above, the stereochemistry of product 3 was
determined by nuclear Overhauser effect experiments. In
addition, the formation of methanol was detected by 1H
NMR of the crude mixture.
proceeded, and 1,3-diiminoisoindoline 3b was obtained in 85%
yield when an aromatic imidate with a phenyl group on the
nitrogen, 1b, was used as a substrate. In the case of N-octyl
aromatic imidates bearing an electron-donating or -withdrawing
group, 1c−1g, the corresponding 1,3-diiminoisoindolines 3c−
3g were afforded in 96%−99% yield. In these substrates, the
functional groups remained unchanged during the reactions. A
mixture of two regioisomers, 3h and 3h′, was formed when an
aromatic imidate with a methyl group at the meta-position, 1h,
was used as a substrate. In this reaction, the major product 3h
was produced by the reaction at the sterically less hindered site.
The desired reaction also proceeded regioselectively when
B
DOI: 10.1021/acs.orglett.6b01012
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Letter
their related compounds. Introduction of different substituents
on the imino groups of 1,3-diiminoisoindolines by previously
reported synthetic methods remains difficult. From this point of
view, the present method is useful for synthesizing unsym-
metrical 1,3-diiminoisoindolines. The reaction proceeded in
good to excellent yield using a variety of substrates, even in
gram scale. Double annulation also proceeded in excellent yield
to give the desired product as a single product. We hope that
the present reaction will become a useful method to synthesize
1,3-diiminoisoindolines and their related compounds.
Scheme 5. Proposed Mechanism for the Formation of 1,3-
Diiminoisoindolines 3
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.6b01012.
Experimental procedures and compound characterization
data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
The annulation reaction proceeded in excellent yield, even in
gram scale (Scheme 6). An annulation reaction of 1.09 g of
aromatic imidate 1a with carbodiimide 2a gave 1.28 g of the
desired product 3a in 85% yield.
*E-mail: kuninobu@mol.f.u-tokyo.ac.jp.
Present Address
§Department of Chemistry, Graduate School of Science and
Engineering, Tokyo Metropolitan University, 1-1 Minami
Osawa, Hachioji, Tokyo, 192-0397, Japan.
Scheme 6. Gram-Scale Synthesis of 1,3-Diiminoisoindoline
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by CREST from JST and
Grant-in-Aid for Scientific Research (B) from the Ministry of
Education, Culture, Sports, Science, and Technology of Japan.
A double annulation reaction also proceeded in excellent
yield (Scheme 7). Treatment of aromatic diimidate 4 with N,N-
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