Rhodium(III)-catalyzed [2+2+2] cyclotrimerization of diynes with maleic anhydrides as alkyne equivalents

Article abstract of DOI:10.1002/ejoc.201500252

Substituted maleic anhydrides function as synthetic equivalents of alkynes in a rhodium(III)-catalyzed reaction with 1,6-diynes to achieve a formal [2+2+2] cyclotrimerization. This approach is useful for reactions involving alkynes with low boiling points or severe ring strain. Hard-to-access [2+2+2] cycloadducts are available through this new cycloaddition strategy by employing easy-to-handle alkyne equivalents. Substituted maleic anhydrides act as alkyne equivalents in a rhodium(III)-catalyzed reaction with 1,6-diynes to achieve a formal [2+2+2] cyclotrimerization.

Full text of DOI:10.1002/ejoc.201500252

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500252
Rhodium(III)-Catalyzed [2+2+2] Cyclotrimerization of Diynes with Maleic
Anhydrides as Alkyne Equivalents
Takanori Matsuda*[a] and Kentaro Suzuki[a]
Keywords: Synthetic methods / Homogeneous catalysis / Rhodium / Cyclotrimerization / Anhydrides / Alkynes
Substituted maleic anhydrides function as synthetic equiva- boiling points or severe ring strain. Hard-to-access [2+2+2]
lents of alkynes in a rhodium(III)-catalyzed reaction with 1,6-
diynes to achieve a formal [2+2+2] cyclotrimerization. This
approach is useful for reactions involving alkynes with low
cycloadducts are available through this new cycloaddition
strategy by employing easy-to-handle alkyne equivalents.
showed that DMF was the most suitable one to afford
product 3a in 72% yield (Entry 3). The reaction tempera-
ture of 140 °C, which was eventually determined to be opti-
mal, resulted in a shorter reaction time and comparable re-
sults (Entry 4).[7]
Introduction
[2+2+2] Cyclotrimerization of alkynes is arguably one of
the most prominent and prevailing methods for synthesiz-
ing substituted and fused benzenes.[1] However, there are
some shortcomings of the reaction: Under conventional
laboratory conditions, the use of alkynes with low boiling
points is often troublesome, and cycloalkynes with ring
sizes less than eight are unstable, necessitating them to be
generated in situ. Several methods have been developed to
address these issues.[2,3]
Table 1. Optimization of reaction conditions.[a]
We recently reported the rhodium(III)-catalyzed decarb-
onylative coupling of maleic anhydrides with alkynes to
produce α-pyrones under oxidative conditions.[4] We then
initiated a study to explore the scope of reactions of maleic
anhydrides under rhodium(III)-catalyzed conditions.[5] It
was found that maleic anhydrides act as alkyne equivalents
in reactions with diynes to effect formal [2+2+2] cyclo-
trimerizations; otherwise inaccessible cycloadducts were ob-
tained by using this new cycloaddition strategy.
Entry 1a/2a
Solvent
Temp. [°C] Time [h] Yield[b] [%]
1
2
3
4
1:1.5 t-AmOH
1:1
1:1.5
1:1.5
120
120
120
140
4
5
4.5
2
58
45
72
73
t-AmOH
DMF
DMF
Results and Discussion
[a] 1a (0.100 mmol), 2a (0.150 mmol for Entries 1, 3, and 4;
0.100 mmol for Entry 2), [Cp*Rh(MeCN)3](SbF6)2 (5.0 μmol) and
Cu(OAc)2 (0.150 mmol) were heated in solvent (1.0 mL). [b] Iso-
lated yield.
The first example involved the reaction of diyne 1a with
phenylmaleic anhydride (2a; 1.5 equiv.) under the reaction
conditions that were optimized for the previously reported
decarbonylative coupling (Table 1, Entry 1). After chroma-
tographic isolation, 4,5,7-triphenylindane derivative 3a was
obtained in 58% yield. This reaction rendered the
anhydride a masked phenylacetylene through removal of
the –CO–O–CO– group from 2a.[6] Reducing the amount of
2a led to a decrease in yield (Entry 2). Screening of solvents
Careful investigation of the reaction mixture obtained
under the conditions shown in Entry 4 revealed the forma-
tion of a byproduct, which was identified as pyrone 4a
(16% yield), by decarbonylative coupling in the opposite
direction of alkyne insertion (Scheme 1). This informative
result suggested a mechanistic explanation for the present
reaction. First, the rhodium(III)-catalyzed reaction of 1a
and 2a produces an isomeric mixture of α-pyrones 4a and
5a.[4] Then, pyrone isomer 5 (i.e. the major adduct) un-
dergoes intramolecular [4+2] cycloaddition to give interme-
diate A, which is subsequently decarboxylated by a retro
[a] Department of Applied Chemistry, Tokyo University of Science
1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
E-mail: mtd@rs.tus.ac.jp
http://www.rs.tus.ac.jp/mtd/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500252.
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[2+2+2] Cyclotrimerization of Diynes with Maleic Anhydrides
[4+2] cycloaddition to furnish 3a.[8,9] The other isomer, 4a sponding cycloadducts 3b–g in yields ranging from 37 to
(i.e. the minor adduct), is unsuitable for the intramolecular 62% (Entries 1–6). We examined two unsymmetrically sub-
cycloaddition and therefore remains intact.
stituted diynes (Entries 7 and 8). Diyne 1h, which possesses
two different aryl groups gave an almost equimolar mixture
of cycloadducts 3h (Entry 7), while diyne 1i, which has one
phenyl and one methyl group, gave 3i with the 7-methyl-
4,5-diphenyl isomer predominating (Entry 8).[12] 4,4-Bis-
(methoxymethyl)-substituted diyne 1j provided 3j in a yield
analogous to that with 1a (Entry 9), whereas the reaction
of diacetyl-substituted diyne 1k resulted in a lower yield
(Entry 10). In the case of diyne 1l, which is unsubstituted
at the 4-position, the desired product 3l was obtained in
only 17% yield along with a 22% yield of a pyrone that
corresponds to 4a, indicating that the Thorpe–Ingold effect
critically affects the reaction in terms of both the efficiency
and regioselectivity (Entry 11). Ether 1m was also not a
competent substrate for the reaction (Entry 12).[13,14]
Table 2. [2+2+2] Cyclotrimerization of various diynes 1 with 2a.[a]
Scheme 1. Proposed mechanism for the formation of 3a.
In order to corroborate the mechanism mentioned above,
we prepared the putative intermediate 5a shown in
Scheme 2. The coupling of alkyne 6 with 2a in the presence
of the rhodium(III) catalyst gave two pyrone isomers, 7 and
8, in 82% yield in a ratio of 1:3.[10] The minor isomer 7 was
then treated with phenylpropargyl bromide to afford 5a,
which, upon heating at 140 °C in DMF, quantitatively con-
verted to 3a.[11] Thus, these results support our proposed
mechanism.
[a] Reaction conditions: diyne 1, anhydride 2a (1.5 equiv.), [Cp*Rh-
(MeCN)3](SbF6)2 (5 mol-%), Cu(OAc)2 (1.5 equiv.), DMF (0.1 m),
[b]
[c]
1
140 °C, 1–3 h.
troscopy. Two isomers are indistinguishable.
NMR spectroscopy. The 7-methyl-4,5-diphenyl isomer was
Isolated yield. Determined by H NMR spec-
[d]
1
Determined by H
[e]
tentatively assigned as the major isomer.
isolated in 22% yield.
Pyrone 4l was also
Next, the substrate scope of the formal [2+2+2] cyclo-
trimerization was investigated by treating diyne 1a with a
variety of maleic anhydrides (Tables 3 and 4).[15] The reac-
tion with monoaryl-substituted maleic anhydrides (2b and
2c) afforded 4,5,7-triarylindanes (3n and 3o, respectively) in
Scheme 2. Preparation and reaction of putative intermediate 5a.
Various 1,6-diynes 1 were then subjected to formal good yields (Table 3, Entries 1 and 2). The present [2+2+2]
[2+2+2] cyclotrimerization with 2a under the optimized re- cyclotrimerization exhibited its potential for reactions in-
action conditions (Table 2). The reaction of 1,7-diaryl-1,6- volving alkynes with low boiling points. Liquid citraconic
heptadiynes 1b–f and 2,7-nonadiyne 1g produced the corre- anhydride (2d) acts as a propyne (b.p. –23 °C) equivalent in
Eur. J. Org. Chem. 2015, 3032–3035
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T. Matsuda, K. Suzuki
SHORT COMMUNICATION
the reaction with 1a to afford cycloadduct 3p in 67% yield to deliver 3t in a considerably better, but still unsatisfactory
(Entry 3). Analogously, ethyl-substituted anhydride 2e yield (Entry 2).[16] In this reaction, anhydride 2h acted as a
could be used as a 1-butyne (b.p. 8 °C) surrogate to deliver masked cyclohexyne. Further, triptycene 3u was prepared
3q (Entry 4). In addition, anhydride 2f was successfully sub- by the coupling of 1a and anhydride 2i (Entry 3). Use of
stituted for methoxyethyne in the cyclotrimerization with anhydrides 2h and 2i as convenient strained alkyne
1a (Entry 5).
surrogates would be a unique advantage of this method, as
these compounds are storable as well as inert except under
the reaction conditions.
Table 3. [2+2+2] Cyclotrimerization of 1a with monosubstituted
maleic anhydrides 2b–f.[a]
Benzynes (arynes) have been employed in transition-
metal-catalyzed cyclotrimerization reactions,[17] where they
are usually generated in situ from 2-(trimethylsilyl)aryl
triflates and cesium fluoride in acetonitrile. We explored the
possibility of anhydrides as alternatives for benzyne
precursors. Although the reaction of 1a with phthalic and
benzoic anhydrides gave the naphthalenes in very poor
yields (9% and 3%, respectively) in the presence of the
rhodium(III) catalyst, 1,8-naphthoic anhydride 2j acted as
a 1,2-naphthalyne equivalent in the reaction with 1a to give
phenanthrene as cycloadduct 3v in 38% yield (Scheme 3).
The reaction would proceed via rhodacycle B.[18] The cyclo-
trimerization was more efficient when 1-naphthoic an-
hydride 2k was employed instead of 2j, providing 3v in 62%
yield.[19]
Entry
2 (R)
3
Yield[b] [%]
1
2
3
4
5
2b (4-MeC6H4)
2c (4-ClC6H4)
2d (Me)
3n
3o
3p
3q
3r
61
69
67
69
54
2e (Et)
2f (OMe)
[a] Reaction conditions: diyne 1a, anhydride
2 (1.5 equiv.),
[Cp*Rh(MeCN)3](SbF6)2 (5 mol-%), Cu(OAc)2 (1.5 equiv.), DMF
(0.1 m), 140 °C, 2–3 h. [b] Isolated yield.
Table 4. Reactions with disubstituted maleic anhydrides 2g–2i.[a]
Scheme 3. Use of anhydrides 2j and 2k as 1,2-naphthalyne surro-
gates in the reaction with 1a.
Conclusions
A rhodium(III)-catalyzed formal [2+2+2] cyclotrimeriz-
ation of 1,6-diynes with substituted maleic anhydrides was
developed. Although the yields of the cycloadducts are not
satisfactory, the expulsion of the –CO–O–CO– moiety from
maleic anhydrides to generate alkyne equivalents is rather
unprecedented and renders this reaction attractive,
especially when they are employed as precursors for the
generation of alkynes with low boiling points or severe ring
strain.
[a] Reaction conditions: diyne 1a, anhydride
2 (1.5 equiv.),
[Cp*Rh(MeCN)3](SbF6)2 (5 mol-%), Cu(OAc)2 (1.5 equiv.), DMF
[b]
(0.1 m), 140 °C, 3–8 h. Isolated yield.
Despite the fact that disubstituted maleic anhydrides are
less reactive towards the previously reported rhodium(III)-
catalyzed coupling with alkynes,[4] we studied them for use
in the present cyclotrimerization with diynes (Table 4). The
reaction of diyne 1a with dimethylmaleic anhydride (2g) led
to disappointing results, as expected, giving hexasubstituted
benzene derivative 3s in only 17% yield (Entry 1). Bicyclic
Experimental Section
General Procedure for Rhodium(III)-Catalyzed [2+2+2] Cyclo-
trimerization of Diynes 1 with Maleic Anhydrides 2: A Schlenk tube
anhydride 2h also participated in cyclotrimerization with 1a was charged with [Cp*Rh(MeCN)3](SbF6)2 (4.2 mg, 5.0 μmol),
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[2+2+2] Cyclotrimerization of Diynes with Maleic Anhydrides
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According to our previous study, the regioselectivity observed
for the reaction of 6 and 2a (Scheme 2; to give the 3,6-diphenyl
compound) is normal. The reverse regioselectivity that is ob-
served in the reaction with diynes (Scheme 1 to give the 3,5-
diphenyl compound) might be due to a chelating effect of the
diyne.
Cu(OAc)2 (27.2 mg, 0.150 mmol), diyne 1 (0.100 mmol) and maleic
anhydride 2 (0.150 mmol), and the tube was evacuated and back-
filled with nitrogen (liquid substrates were added by syringe after
DMF). DMF (1.0 mL) was added by syringe through a septum,
and the mixture was heated at 140 °C with stirring. The reaction
mixture was cooled to room temperature, then filtered through a
plug of Florisil®, washed with hexane/AcOEt (5:1), and then the
filtrate was concentrated. The residue was purified by preparative
TLC on silica gel to afford cycloadduct 3.
[10]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and copies of
1
the H and 13C NMR spectra of new compounds.
Acknowledgments
1H NMR analysis of 5a after a few days revealed that it under-
went the pyrone Diels–Alder reaction even at room tempera-
ture.
[11]
[12]
This work was supported by Japan Society for the Promotion of
Science (JSPS) [Grant-in-Aid for Scientific Research (C) No.
25410054] and the Sumitomo Foundation.
The 7-methyl-4,5-diphenyl isomer was tentatively assigned as
the major isomer on the basis of NOESY experiments on a
product formed by the reaction of 1i and 2d. See the Support-
ing Information for details.
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[13]
[14]
The reaction of a nitrogen-tethered 1,6-diyne gave a complex
mixture of products.
In the case of the reaction of enyne 9 with 2a, the correspond-
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through a similar reaction pathway involving intermediate AЈ.
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[15]
The reaction with the parent maleic anhydride was unsuccess-
ful; the anhydride was consumed, and diyne 1a remained un-
changed. For a list of unreactive anhydrides, see the Supporting
Information.
[16] The reaction of the corresponding cycloheptene and cyclo-
octene derivatives resulted in low (27% and 9%, respectively)
yields.
[17] D. Peña, D. Pérez, E. Guitián, Chem. Rec. 2007, 7, 326.
[18] The detailed mechanism for the formation of B from 2j is not
clear.
[6] For a nickel-catalyzed coupling reaction of isatonic anhydrides
with alkynes to afford indoles, see: K. Nakai, T. Kurahashi, S.
Matsubara, Chem. Lett. 2013, 42, 1238.
[19] The reaction of 1a with 9-phenenthroic anhydride afforded tri-
phenylene 3w in 10% yield.
[7] Changes from the optimal conditions: Use of [Cp*RhCl2]2 in-
stead of [Cp*Rh(MeCN)3](SbF6)2 (19 h; 38%); use of Ag2CO3
instead of Cu(OAc)2 (7 h; 7%); use of toluene instead of t-
AmOH (7 h; trace).
[8] The reaction performed at 90 °C for 3 h yielded a mixture of
1a, 3a, 4a, and 5a with a ratio of 57:19:8:14.
[9] For pyrone Diels–Alder reactions, see: a) A. Goel, V. J. Ram,
ˇ
Tetrahedron 2009, 65, 7865; b) B. Stefane, A. Perdih, A. Pevec,
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T. Solmajer, M. Kocˇevar, Eur. J. Org. Chem. 2010, 5870; c) Y.
Sato, K. Kuramochi, T. Suzuki, A. Nakazaki, S. Kobayashi,
Received: February 22, 2015
Published Online: April 7, 2015
Eur. J. Org. Chem. 2015, 3032–3035
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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