Practical and efficient iridium catalysis for benzannulation: An entry to isoindolines

Article abstract of DOI:10.1002/cssc.201200443

Iridium(III) catalysis provides a convenient and general method for the synthesis of isoindolines via [2+2+2] cycloaddition reactions of diynes and alkynes. The reaction proceeds smoothly in environmentally benign and non-distilled isopropyl alcohol, providing highly functionalized aromatic compounds in moderate to excellent yields.

Full text of DOI:10.1002/cssc.201200443

DOI: 10.1002/cssc.201200443
Practical and Efficient Iridium Catalysis for Benzannulation: An Entry To
Isoindolines
Anne-Laure Auvinet,[a] Mehdi Ez-Zoubir,[a] Maxime R. Vitale,[a] Jack A. Brown,[b] Vꢀronique Michelet,*[a] and
Virginie Ratovelomanana-Vidal*[a]
Benzannulation reactions are among the most efficient and
direct methods to assemble highly substituted aromatic com-
pounds.[1] Transition metals have proven their synthetic utility
in the construction of complex and heavily substituted ben-
zene-derived systems from relatively simple starting materials.
The most useful cobalt, nickel, rhodium, and ruthenium cata-
lysts offer the possibility to catalyze [2+2+2] cycloadditions
leading to aromatic compounds.[2] However, only a few exam-
ples in the literature have demonstrated the use of iridium
catalysis.[3] Takeuchi described an iridium-catalyzed (i.e.,
[Ir(cod)Cl]2/dppe) [2+2+2] cycloaddition of diynes and alkynes
to synthesize dihydro-indene and dihydro-isobenzofuran deriv-
atives in benzene or dioxane.[3a] Surprisingly, the iridium-cata-
lyzed [2+2+2] cycloaddition of nitrogen-based diynes and al-
kynes to access isoindoline scaffolds has been less studied.
To the best of our knowledge, synthesis of the isoindoline scaf-
fold via a [2+2+2] iridium-catalyzed cycloaddition has only
been described by Shibata et al. in the context of the prepara-
tion of atropoenantioenriched complex polyaromatic biaryl
structures,[3g–k] or on solid supported systems by Martinez
et al.[3b] In the latter report, the role of Takeuchi’s catalyst
system was explored and the use of microwave irradiation
proved essential for access to isoindoline derivatives.
reoselective dimerization of enynes.[5e] We wish to report
herein the synthesis of isoindoline scaffolds via a [2+2+2] cy-
cloaddition of diynes and alkynes employing the stable and
practical ionic triply iodo-bridged iridium-catalyzed [{Ir(H)[rac-
binap]}2(m-I)3]I with a focus on benign solvent system such as
isopropyl alcohol[6] toward a greener [2+2+2] cycloaddition
process.
We started our investigations by studying the cycloaddition
of diyne 1 with propargyl alcohol in refluxing toluene (Table 1,
entries 1 and 2). The reaction proceeded with good conver-
sion. Nonetheless, the iridium-catalyzed cycloaddition provided
Table 1. Optimization table.[a]
Entry
Solvent
T
[8C]
t
[h]
Conv.
[%]
Yield 2:3[d]
[%]
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene/acetone
toluene/isopropyl alcohol
acetone
isopropyl alcohol
acetone
reflux
reflux
80[b]
17
12
17
17
17
48
17
17
17
17
17
17
>90
>90
60
>90
>90
>98
>90
>90
<5
32:49
38:44
n.d[c]
34:24
n.d[c]
71:8
56:27
71:15
n.d[c]
n.d[c]
78:5
110[b]
130[b]
130[b]
130[b]
130[b]
RT[b]
Considering that isoindolines are highly interesting and
useful building blocks for the synthesis of biologically active
compounds,[4] and owing to the limitation of Takeuchi’s cata-
lyst system to access isoindolines, we decided to embark upon
the investigation of an efficient iridium-catalyzed benzannula-
tion approach to isoindoline systems. One key point of our
study was to use a simple, easy to handle, and air-stable cata-
lyst that would operate in an environmentally and industrially
friendly solvent. The second issue was the possibility to intro-
duce functional groups allowing further cross-coupling reac-
tions. In our previous reports we demonstrated the versatility
and the efficiency of triply halogen-bridged iridium(III) com-
plexes in the asymmetric hydrogenation of cyclic imines,[5a]
quinolines,[5b] quinolinium salts,[5c] and quinoxalines.[5d] We also
reported that this class of catalysts is able to catalyze the ste-
9
10
11
12
RT[b]
<5
>98
>98
80[b]
isopropyl alcohol
80[b]
80:5
[a] Reaction conditions: 0.2 mmol of diyne 1 and 3 equivalents of prop-
argyl alcohol, 4 mol% [{Ir(H)[rac-binap]}2(m-I)3]I in 1 mL of solvent. [b] Re-
action run in sealed tube. [c] Yield not determined. [d] Isolated yield, de-
1
termined by H NMR.
a mixture of two different products, the desired alcohol 2 and
its oxidized version, an aldehyde 3, as the major product. Vary-
ing the reaction time did not show significant improvement in
this ratio (entries 1 and 2). We next performed the reaction in
a sealed tube. The temperature had to be kept close to the
boiling point of toluene to provide a good conversion (en-
tries 3–5). To our delight, when running the reaction for
a longer period of time (entry 6), the desired compound 2 was
obtained in good yield.
[a] Dr. A.-L. Auvinet, Dr. M. Ez-Zoubir, Dr. M. R. Vitale, Dr. V. Michelet,
Dr. V. Ratovelomanana-Vidal
Chimie ParisTech, Laboratoire Charles Friedel, UMR 7223
11 rue Pierre et Marie Curie, 75231 Paris Cedex 05 (France)
Fax: (+33)1-44071062
E-mail: veronique-michelet@chimie-paristech.fr
virginie-vidal@chimie-paristech.fr
[b] Dr. J. A. Brown
Next, we tried to reduce the reaction time by adding a co-
solvent to the reaction mixture. Toluene/acetone gave promis-
ing results (Table 1, entry 7) toward the generation of alcohol
2.
GlaxoSmithKline, Epinova DPU, II TAU, Medicines Research Centre
Gunnels Wood Road, Stevenage, SG1 2NY (UK)
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201200443.
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We then turned our attention to a system composed of tolu-
ene/isopropyl alcohol. Pleasingly, we were able to access the
desired compound 2 in 71% yield (Table 1, entry 8). Consider-
ing the importance of acetone and isopropyl alcohol in the sol-
vent mixture we decided to perform the reaction in either iso-
propyl alcohol or acetone as sole solvent. The reactions carried
out at room temperature were not successful (entries 9 and
10). Delightfully, we observed full conversion by increasing the
temperature to 808C, and excellent isolated yields of 2 were
obtained (entries 11 and 12). We found that isopropyl alcohol
was well suited for this transformation and used Normapur
quality without any further purification (see the Experimental
Section).
Table 2. Substrate scope.[a]
Entry
1
R1
Ts
Alkyne
Product
Yield [%]
69
5
2
3
4
Ts
Ts
Ts
6
7
8
70
62[b]
61[b]
With this catalytic system in hand, we explored the scope of
this iridium-catalyzed process, and our results are highlighted
in Table 2. We carried out the cycloaddition of diyne 1 with ter-
minal alkynes bearing a selection of substituents. A number of
functional groups were tolerated, including alcohol (entry 1),
ether (entry 2), alkyl (entry 3), and cycloalkyl (entry 4). Unfortu-
nately, the reaction showed poor conversion with aromatic
substituted alkynes. Therefore, due to the lack of reactivity of
diyne 1, we turned our attention to Boc-protected amine
diyne partner 4. The same trend was observed, alcohols (en-
tries 5 and 6), ether (entry 7), alkyl (entry 10), and cyclopropyl
(entry 11) were also tolerated, and diyne 4 proved to be more
efficient than diyne 1 in most cases. Specifically, we found that
Boc-protected diyne 4 also underwent smooth cycloaddition
with chloropentyne to give the corresponding isoindoline 14
in reasonable yield (entry 10). Pleasingly, the cycloaddition of 4
performed under the same reaction conditions was also suc-
cessful with aromatic substituted alkynes providing the desired
isoindoline derivatives 15–17 in reasonable yield (entries 11–
13). With these exciting observations in hand, we decided to
extend this chemistry to include more heavily substituted
diynes to target highly functionalized aromatic systems. When
we applied the method on diyne 19 with propargyl alcohol,
we were delighted to observe the desired compound 20 in
73% yield (Scheme 1).
5
6
Boc
Boc
9
85
90
10
7
8
9
Boc
Boc
Boc
11
12
13
64
63[b]
66[b]
10
11
Boc
Boc
14
15
61[b]
47
12
13
Boc
Boc
16
17
59
52
The cycloaddition of unsymmetrical diyne 19 with cyclopro-
pylacetylene or propargyl alcohol gave a regioisomeric mixture
of the corresponding isoindolines, always favoring the ortho
isomer: 21 (72:28) and 22 (67:63) were obtained in respectable
yields given the challenging nature of the diyne substrate
(Scheme 1). In an effort to employ more synthetically versatile
functionalities, we decided to incorporate a boronate moiety
within the system. Indeed, aromatic boronic acid derivatives
represent an important target as they are widely acknowl-
edged as being amongst the most versatile intermediates in
synthetic chemistry.[7] Alkynyl boronates have been used previ-
ously as partners in transition metal-catalyzed cycloaddition re-
actions, allowing direct access to functionalized aromatic bor-
onic ester derivatives.[8] To our delight, diyne 18 and n-butyl al-
kynyl boronate 23 underwent [2+2+2] cycloaddition to furnish
the corresponding isoindoline 25 in useful yield. With this
promising result in hand, we decided to use terminal alkyne
24 in the cycloaddition. Interestingly, the reaction of diyne 18
with alkyne 24 proved to be more efficient, resulting in a signif-
[a] Reaction conditions: 1 equivalent of diyne and 3 equivalents of alkyne
in 1 mL of isopropyl alcohol. [b] 10 equivalents of alkyne.
Scheme 1. Reaction conditions: 1 equivalent of diyne and 3 equivalents of
alkyne in 1 mL of isopropyl alcohol. [a] 48 h at 1308C. [b] 10 equivalents of
alkyne.
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icant yield improvement (26, 69%) (Scheme 2). Moreover, di-
phenyl-substituted diyne 27 was also tolerated and led to iso-
indoline 28 in high yield (78%; Scheme 3). The reaction per-
isoindolines, the versatility of this class of compound repre-
sents great potential for further synthetic elaboration. To the
best of our knowledge, the Ir-catalyzed [2+2+2] cycloaddition
with alkynyl boronates is unprecedented and leads to com-
pounds of significant interest to the synthetic community.
Finally, the present methodology provides a powerful means
for the generation of heavily substituted aromatic products
which can be used as key intermediates in drug syntheses.
Experimental Section
Experimental details are provided in the Supporting Information.
Acknowledgements
This work was supported by the Ministꢀre de l’Education et de la
Recherche and the Centre National de la Recherche Scientifique
(CNRS), M.E.-Z thanks GSK and CNRS, and A.-L.A. is grateful to
the Fondation Pierre Gilles de Gennes pour la Recherche for
a grant. Johnson Matthey Inc. is acknowledged for a generous
loan of IrCl3.
Scheme 2. Reaction conditions: 1 equivalent of diyne and 1.1 equivalents of
alkynyl boronate in 1 mL of toluene.
Keywords: alkynes · cycloaddition · homogeneous catalysis ·
iridium · isoindolines
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functionalized isoindoline derivatives and provides a compara-
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the reaction gave similar results when carried out with or with-
out an inert atmosphere, and does not require microwave as-
sistance. With regard to the synthesis of boronate-substituted
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Received: June 27, 2012
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COMMUNICATIONS
Iridium(III) catalysis provides a conven-
ient and general method for the synthe-
sis of isoindolines via [2+2+2] cycload-
dition reactions of diynes and alkynes.
The reaction proceeds smoothly in envi-
ronmentally benign and non-distilled
isopropyl alcohol, providing highly func-
tionalized aromatic compounds in mod-
erate to excellent yields.
A.-L. Auvinet, M. Ez-Zoubir, M. R. Vitale,
J. A. Brown, V. Michelet,*
V. Ratovelomanana-Vidal*
&& – &&
Practical and Efficient Iridium
Catalysis for Benzannulation: An Entry
To Isoindolines
ChemSusChem 0000, 00, 1 – 4
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
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These are not the final page numbers!