Co(I) catalyzed yne-ene-yne [2+2+2] cycloaddition: Synthesis of highly strained pentacyclic bis-lactones. A new access to tetraaryl N-hydroxyphthalimides

Article abstract of DOI:10.1016/j.tetlet.2014.03.081

Highly strained pentacyclic bis-lactones can be obtained by an unusual Co(I) catalyzed [2+2+2] cycloaddition of an yne-ene-yne diester substrate. These bis-lactones can be further transformed into tetraaryl N-hydroxyphthalimides which are potential aerobic oxidation organocatalysts.

Full text of DOI:10.1016/j.tetlet.2014.03.081

Tetrahedron Letters 55 (2014) 2849–2852
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Co(I) catalyzed yne–ene–yne [2+2+2] cycloaddition: synthesis
of highly strained pentacyclic bis-lactones. A new access to tetraaryl
N-hydroxyphthalimides
⇑
Jérôme Michaux, Rémi Poirot, Jacques Einhorn, Bernard Bessières
Département de Chimie Moléculaire (SERCO), UMR-5250, ICMG FR-2607, Université Joseph Fourier, 301 Rue de la Chimie, BP 53, 38041 Grenoble, Cedex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly strained pentacyclic bis-lactones can be obtained by an unusual Co(I) catalyzed [2+2+2]
cycloaddition of an yne–ene–yne diester substrate. These bis-lactones can be further transformed into
tetraaryl N-hydroxyphthalimides which are potential aerobic oxidation organocatalysts.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 14 February 2014
Revised 12 March 2014
Accepted 18 March 2014
Available online 26 March 2014
Keywords:
[2+2+2] Cycloaddition
Enediyne
NHPI
Cobalt
N-Hydroxyphthalimide (NHPI, Fig. 1) has been recognized as a
valuable organocatalyst for the aerobic oxidation of various organic
compounds under mild conditions.1 However, the major drawback
of this system is the rather low turnover number of NHPI, requiring
typically 10 mol % of catalyst to obtain good conversions (thus lim-
iting its use on a large scale). Our group, among others, has been
engaged in the synthesis of NHPI analogs having improved or
new catalytic properties.2 The best catalyst we have obtained so
far is the simple tetraphenyl analog (NHTPPI, Fig. 1) with which
Figure 1. Structure of NHPI and NHTPPI.
a
10-fold decrease in catalyst loading (i.e., 1 mol %) can be
achieved.2a Consequently, we have further developed methods giv-
ing access to other polyarylated phthalimides,3 and we wish to re-
port in this Letter a new route to such compounds via the [2+2+2]
cycloaddition of yne–ene–yne linear substrates.
The [2+2+2] cycloaddition of three alkynes is a very powerful
and elegant method for the formation of highly substituted ben-
zene rings4 and among the many transition metal catalysts used,
cobalt occupies a prominent place.5 This led us to devise a route
to substituted analogs of NHTTPI, based on the cobalt catalyzed
intramolecular cycloaddition of a triyne (Scheme 1).
Scheme 1. Retrosynthetic analysis of tetraaryl N-hydroxyphthalimides.
The obvious substrate for the planned cycloaddition is triyne
ester 1 (Fig. 2). However, although simple acetylene dicarboxylic
esters like methyl, ethyl, or butyl are commercially available,
esterification of acetylene dicarboxylic acid (ADA) is noteworthily
⇑
Corresponding author. Tel.: +33 476 514 840; fax: +33 476 635 983.
E-mail address: bernard.bessieres@ujf-grenoble.fr (B. Bessières).
Figure 2. Structure of triyne ester 1.
http://dx.doi.org/10.1016/j.tetlet.2014.03.081
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

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J. Michaux et al. / Tetrahedron Letters 55 (2014) 2849–2852
difficult as the triple bond is very electrophilic, thus leading to con-
jugate addition products rather than the expected esters.6 Indeed,
all our attempts to synthesize ADA esters of suitably functionalized
phenols failed.
We then imagined installing the carboxyl functions after the
cycloaddition. We thus readily prepared triyne ether
2 by
condensation of ortho-ethynylphenol7 with 1,4-dichlorobutyne
and submitted it to the cobalt catalyzed cycloaddition under clas-
sical reaction conditions5 (light irradiation in refluxing toluene) to
access the expected pentacyclic bis-benzochromene 3 in 62% yield
(Scheme 2). This first result was very interesting as it gave an easy
access to the highly substituted aromatic nucleus needed.
Unfortunately, all our attempts to fully oxidize 3 to the bis-chro-
mene-6-one 5 failed. In the best case, using conditions reported
for the oxidation of parent mono-benzochromene8 only traces of
bis-lactone 5 were obtained, in 36% yield of the mono-oxidized
product 4.
As our first two strategies failed, we envisaged to prepare fuma-
royl esters of type 6 and engage them in the [2+2+2] cycloaddition
(Scheme 3). But although the total intramolecular cycloaddition of
acyclic triynes9 and ene–diynes10 is rather well known, the use of
the linear yne–ene–yne sequence is much less common.11
We have thus prepared yne–ene–yne 6a by condensation of
ortho-ethynylphenol with fumaroyl chloride (Scheme 3). This lin-
ear substrate was then subjected to the classical Co(I) cycloaddi-
tion in refluxing toluene, under visible light irradiation.12 In this
case, a stoichiometric amount of cobalt catalyst is necessary, as
the intermediate cyclohexadiene is a very good ligand of Co(I).
After the oxidative decomplexation/aromatization of the cyclo-
hexadienyl–cobalt(I) intermediate, we were pleased to obtain
bis-lactone 5a in an encouraging 25% yield for two steps and the
formation of three CAC bonds. After many attempts, a maximum
of 30% yield could be obtained.13 This yield can seem low but it ap-
pears that bis-lactone 5a is rather unstable during chromato-
graphic purification and thus, part of the product is lost during
purification.14 The X-ray diagram of 5a15 shows a very strained
structure: as the two lactone carbonyl groups are pointing toward
each other, steric and electronic repulsion implies an out of plane
deformation of the central aromatic nucleus. The dihedral angle
of the planes containing the two C@O is 40° and their OAO
Scheme 3. Synthesis and [2+2+2] cycloaddition of yne–ene–yne 6a.
distance is 2.78 Å, indicating a trans conformation of the two lac-
tones as expected.
After this first successful reaction, we wanted to explore the
scope of this new methodology, and started with variation of the
R substitution at the alkynes (Table 1). Replacement of the phenyl
terminal group by a TMS or iodine (entry 2 and 3) does not lead to
any cyclized product but to extensive decomposition. A first possi-
ble explanation based on the steric hindrance was ruled out by the
fact that the terminal alkyne (R = H) does not give any cyclized
product either (entry 4), whereas a butyl chain led to 5% of the cor-
responding dilactone 5e.
These first results indicating the need for a terminal aromatic
group, we then prepared enediynes 6f and 6g, whose terminal aro-
matic is substituted respectively by a para-methoxy and a para-tri-
fluoromethyl group. In the case of the electronically enriched 6f,
the cylotrimerization proceeds in a better 40% yield (entry 6)
compared to the nonsubstituted case, and in only 5% yield for
electron poor 6g (entry 7).
Our next questioning was whether the geometry of the central
double bond plays an important role in the outcome of the
Table 1
Cyclization of yne–ene–yne 6
Entry
R
Isolated yield
1
2
3
4
5
6
7
6a, Ph
6b, TMS
6c, I
6d, H
6e, Bu
5a, 30%
—
—
—
5e, 5%
5f, 40%
5g, 5%
6f, p-MeOPh
6g, p-CF3Ph
Scheme 2. Synthesis and [2+2+2] cycloaddition of triyne ether 2.

J. Michaux et al. / Tetrahedron Letters 55 (2014) 2849–2852
2851
reaction. Indeed, when enediyne 6a is reacted with cobalt(I), either
metalacyclopentene A or metalacyclopentadiene B can be formed
but both pathways lead to the same trans configuration of the
cyclohexadienyl cobalt complex C (Scheme 4).16 In the first case
the trans configuration is set during the alkyne–alkene oxidative
coupling, whereas in the second case it comes from the insertion
of the E double bond in the metalacyclopentadiene formed by al-
kyne–alkyne oxidative coupling.
If the same reasoning is applied to the Z analog of 6a, then a
very crowded cis-cyclohexadienyl cobalt complex D would be
formed, in which the two carbonyl groups would be facing each
other on the same side of the cycle. Although aromatization of D
will lead to the same lactone 5a, going through this intermediate
would be a highly energetic, hence unfavorable pathway. Indeed,
when 7 is reacted with Co(I), the trans bis-lactone 5a is obtained
in a very low 4% yield (Scheme 5). The hypothesis of an E to Z
isomerization of the central double bond by light irradiation can
be ruled out as, after refluxing yne–ene–yne 7 alone in toluene
under light irradiation, the product is recovered unchanged.
Scheme 6. Synthesis of N-hydroxyimide 8.
Scheme 7. Catalytic evaluation of N-hydroxyimide 8.
Finally, lactone 5a was converted to hydroxyimide by reaction
with hydroxylamine, affording the first substituted NHTPPI 8 in
40% yield (Scheme 6). Unfortunately, the first oxidation tests per-
formed with this compound have shown a very low catalytic activ-
ity (Scheme 7), probably due to the presence of the free phenols
which can inhibit the radical mechanism associated with NHPI1a
through the formation of phenoxyl radicals.17
In conclusion, we have explored the synthesis of highly strained
pentacyclic bis-lactones by an unusual cobalt(I) catalyzed [2+2+2]
cyclization of an yne–ene–yne linear fragment. Although the scope
of the reaction is rather narrow, we have been able to prepare 8,
the first substituted analog of NHTPPI. The presence of two
ortho-OH substituents on the apical phenyl rings also induces the
presence of two chirality axes and thus allows a new access to chi-
ral NHPI analogs.2b Further derivatization of these phenol function-
alities is under way in our laboratory for the study of the catalytic
properties of these derivatives.
Acknowledgements
Financial support from the CNRS and the Université Joseph Fou-
rier (UMR 5250, FR-2607) and a fellowship award (to J.M.) from the
Département de Chimie Moléculaire are gratefully acknowledged.
Dr. Christian Philouze is thanked for the cristallographic study.
Supplementary data
Supplementary data (experimental procedure as well as charac-
terization of new compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2014.03.081.
Scheme 4. Possible [2+2+2] cycloaddition routes of yne–ene–yne 6a.
References and notes
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Scheme 5. [2+2+2] Cycloaddition of yne–ene–yne 7.

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