Functionalization of Csp3-H and Csp 2-H bonds: Synthesis of spiroindenes by enolate-directed ruthenium-catalyzed oxidative annulation of alkynes with 2-aryl-1,3-dicarbonyl compounds

Article abstract of DOI:10.1002/anie.201207170

Ru(de) awakening: The synthesis of carbocycles by the ruthenium-catalyzed oxidative annulation of alkynes with 2-aryl cyclic 1,3-dicarbonyl substrates is described. Proceeding by the functionalization of C sp 3-H and C sp 2-H bonds, and the formation of an all-carbon quaternary center, the reaction provides a diverse range of spiroindenes in good yields with high levels of regioselectivity. Copyright

Full text of DOI:10.1002/anie.201207170

Angewandte
Chemie
DOI: 10.1002/anie.201207170
À
C H Functionalization
À
À
Functionalization of Csp3 H and Csp2 H Bonds: Synthesis of
Spiroindenes by Enolate-Directed Ruthenium-Catalyzed Oxidative
Annulation of Alkynes with 2-Aryl-1,3-dicarbonyl Compounds**
Suresh Reddy Chidipudi, Imtiaz Khan, and Hon Wai Lam*
The metal-catalyzed oxidative annulation of alkynes with aryl
or alkenyl substrates bearing various heteroatom-containing
functional groups has proven to be a versatile, efficient, and
atom-economic strategy to access a range of valuable
heterocyclic products.[1–7] These processes generally rely
upon coordination of the metal center to the heteroatom-
À
containing functional group, which directs site selective Csp2
H bond cleavage[8] to form the metallacycle A (Scheme 1a).
Coordination and migratory insertion of the alkyne and
À
subsequent C X (X = heteroatom) reductive elimination
then forms the heterocyclic product.
These alkyne oxidative annulations have been comple-
mented by variants that result in the functionalization of two
[9]
Csp2 H bonds, with or without[10] the assistance of directing
À
groups (Scheme 1b).[11,12] While these reactions are effective
in forming aromatic carbo- and azacycles, the scope and utility
of the general process would be considerably enhanced if
[3j,13]
À
variants involving the functionalization of Csp3 H bonds
could be developed, thus resulting in partially saturated cyclic
products. However, progress in this area has been limited. To
our knowledge, the only existing report comes from Nakao,
Hiyama and co-workers, who recently described the oxidative
annulation of formamides with alkynes, in which an extra
equivalent of alkyne acts as the stoichiometric oxidant
(Scheme 1c).[14]
Herein, we report a new mode of catalytic alkyne
oxidative annulation involving the (formal) functionalization
Scheme 1. a)–d) Metal-catalyzed oxidative annulation of alkynes.
À
À
of one Csp3 H bond and one Csp2 H bond (Scheme 1d). This
ruthenium-catalyzed process[15] results in the formation of
indenes, which are important structures in various biologically
active compounds[16] and functional materials.[17] A notable
feature of this process is the formation of an all-carbon
quaternary center, which has not been described previously in
alkyne oxidative annulations.
At the outset of this work, we hypothesized that a-
arylcarbonyl compounds might be suitable substrates for
alkyne oxidative annulations by virtue of the acidic nature of
the a protons, that is, deprotonation would generate an
enolate which could serve as an efficient directing group for
[*] Dr. S. Reddy Chidipudi, I. Khan, Dr. H. W. Lam
EaStCHEM, School of Chemistry, University of Edinburgh
Joseph Black Building, The King’s Buildings, West Mains Road
Edinburgh EH9 3JJ (UK)
E-mail: h.lam@ed.ac.uk
À
Csp2 H bond cleavage. 2-Aryl cyclic 1,3-dicarbonyl com-
Homepage: http://homepages.ed.ac.uk/hlam/index.html
pounds were selected for investigation on the basis of their
high acidity and the permanent close proximity of the aryl and
carbonyl groups. This latter feature renders these substrates
conformationally predisposed for cyclometallation, thus
forming a six-membered metallacycle in readiness for migra-
tory insertion of the alkyne and spiroindene formation.
2-Aryl-1,3-diketones, which exist predominantly in the
enol tautomer, were investigated first, and we began with
a study of the reaction of 3-hydroxy-2-phenyl-2-cyclohexe-
none (1a) with 1-phenyl-1-propyne (2a; Table 1). The
[**] We thank the European Commission (Marie Curie International
Incoming Fellowship to S.R.C., Project No. PIIF-GA-2009-252561)
and the University of Edinburgh for financial support. We are
grateful to the EPSRC for a Leadership Fellowship to H.W.L. We
thank Martin D. Wieczysty (University of Edinburgh) for assistance
in the preparation of substrates, and Gary S. Nichol (University of
Edinburgh) for X-ray crystallography. The EPSRC National Mass
Spectrometry Service Centre is gratefully acknowledged for provid-
ing high-resolution mass spectra.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207170.
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Table 1: Optimization of reaction conditions for the synthesis of 3a.[a]
Table 2: Ruthenium-catalyzed oxidative annulation of various alkynes
with a range of 2-aryl-3-hydroxy-2-cyclohexenones.[a]
Entry [M]
mol% Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
[{RuCl2(p-cymene)}2] 2.5
K2CO3 tAmOH
K2CO3 THF
K2CO3 1,4-dioxane
60
55
62
80
15
[{RuCl2(p-cymene)}2] 2.5
[{RuCl2(p-cymene)}2] 2.5
[{RuCl2(p-cymene)}2] 2.5
[{RuCl2(p-cymene)}2] 2.5
–
–
–
1,4-dioxane
DMF
1,4-dioxane <5
3a: R=Me, 80%
3b: R=Ph, 50%[b]
3c: Ar=4-MeOC6H4,
70%
3d: Ar=4-
3e: 77%
Pd(OAc)2
5
Pd(OAc)2
5
K2CO3 1,4-dioxane <5
K2CO3 1,4-dioxane 74
1,4-dioxane 88
[{RhCp*Cl2}2]
[{RhCp*Cl2}2]
2.5
2.5
MeO2CC6H4, 81%
–
[a] Reactions were conducted using 0.25 mmol of 1a. [b] Yield of isolated
compounds. Cp*=C5Me5, DMF=N,N’-dimethylformamide, tAm=tert-
amyl, THF=tetrahydrofuran.
reactions were conducted at 908C and Cu(OAc)2 (2.2 equiv)
was employed as the stoichiometric oxidant. Although
rhodium, ruthenium, and palladium precatalysts have
proven to be highly effective in a range of oxidative
annulations of alkynes,[1–5,9,10] the ruthenium complex
[{RuCl2(p-cymene)}2] (2.5 mol%) was examined first on the
basis of its much lower cost compared with rhodium and
palladium complexes. In the presence of K2CO3 (2.5 equiv),
we were pleased to find that successful formation of the
spiroindene 3a occurred in a variety of solvents, (Table 1,
entries 1–3). Consistent with literature precedent,[4] the
3 f: Ar=3,5-
(CF3)2C6H3, 71%
3g: Ar=2-thienyl, 70%
3h: 67%
3i: R=CF3, 66%
3j: R=OMe, 64%
À
reactions were highly regioselective, with initial C C bond
formation occurring exclusively at the methyl-substituted
carbon atom of the alkyne.[18] Subsequently, K2CO3 was found
to be unnecessary. In 1,4-dioxane as the solvent, the yield of
3a increased to 80% in the absence of K2CO3 (Table 1,
entry 4) whereas DMF provided inferior results (Table 1,
entry 5). Although Pd(OAc)2 proved to be totally ineffective
(Table 1, entries 6 and 7), the RhIII complex [{RhCp*Cl2}2]
provided an 88% yield of 3a in the absence of K2CO3
(Table 1, entry 9). Although [{RhCp*Cl2}2] provided the
highest yield of 2a, [{RuCl2(p-cymene)}2] was selected for
further experimentation on the basis of its lower cost.
3k: 74%[b]
3l: 66%[b]
3m: 72%
[a] Reactions were conducted using 0.50 mmol of 1a–f. Cited yields are
of the isolated material. [b] Reactions conducted with the addition of
K2CO3 (2.5 equiv).
Heteroarenes on the alkyne, such as 2-thienyl (product 3g)
or indoles (products 3h and 3l) were also tolerated. However,
terminal alkynes were unsuitable substrates, and gave com-
plex mixtures of products.
An assessment of the reaction scope was conducted by
varying the alkyne, and the aryl group of the 3-hydroxy-2-
cyclohexenone (Table 2). These experiments revealed that
the process demonstrates good generality. In certain cases, the
inclusion of K2CO3 (2.5 equivalents) provided higher yields
(products 3b, 3k, and 3l).[19] Oxidative annulation occurred
smoothly with various alkyl/(hetero)aryl-substituted alkynes.
Again, regioselectivity was high with unsymmetrical alkynes,
Regarding the phenyl group of the 3-hydroxy-2-cyclo-
hexenone, substrates containing p-methoxy, p-methyl, or p-
carbomethoxy groups underwent efficient reaction (products
À
3k–m). With m-substituted phenyl groups, Csp2 H function-
alization occurred exclusively at the least sterically encum-
bered site (products 3i and 3j).[20] The high site selectivity
observed in the formation of 3j is notable, given that mixtures
of isomers were formed when substrates containing m-
methoxyphenyl groups were employed in related re-
actions.[4a,c,d] We found substrates containing o-substituted
phenyl groups were unreactive.
À
with initial C C bond formation occurring at the alkyne
carbon atom bearing the alkyl substituent.[18] With respect to
the alkyne substituents, phenyl rings containing methoxy,
ester, or trifluoromethyl groups were tolerated (products 3c,
3d, and 3 f), as was a 2-naphthyl group (product 3m).
Table 3 presents the results of experiments where the 2-
aryl cyclic 1,3-dicarbonyl substrate was varied. Again, a wide
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Table 3: Ruthenium-catalyzed oxidative annulation of various alkynes
with a range of 2-aryl cyclic 1,3-dicarbonyl compounds.[a]
5a: 76%
5b: R1, R2 =Me, Ph,
54%[b]
5d: 59%[b]
5c: R1 =R2 =Et, 48%[b]
ation was also observed at the more sterically hindered site,
albeit to a lower extent (ca. 24%). This experiment suggests
that in the presence of D2O and the absence of an alkyne,
cycloruthenation is rapid, reversible, and faster at the more
sterically accessible site. The recovery was relatively modest
(68% yield) because of competitive substrate decomposition.
Repeating this experiment in the presence of the alkyne
2a gave the spiroindene [Dn]-3j (45% yield) that contained
minimal (ca. 5%) deuteration at the indene, but was partially
deuterated in the cyclohexane [Eq. (2)].[21] In addition, the
recovered starting material was partially deuterated. These
observations are consistent with cycloruthenation being
partially reversible in the presence of an alkyne. Slightly
higher deuterium incorporation was observed at the more
hindered site of [Dn]-1c obtained from the reaction in
Equation (2), which is in contrast with [Dn]-1c obtained
from the reaction in Equation (1). This outcome is consistent
with migratory insertion of the alkyne being more rapid with
the ruthenacycle derived from functionalization at the least
hindered site of 1c, thus depleting deuterium at this site
preferentially.
Finally, cycloruthenation was found to be largely irrever-
sible in the reaction of 1a with 2e, as evidenced by a reaction
run to partial completion in the presence of D2O, in which no
deuteration was detected at the indene of the annulation
product, and only minimal deuteration (ca. 5% at each site)
was observed in recovered [Dn]-1a [Eq. (3)].
In line with catalytic cycles put forth for related process-
es,[4] a possible mechanism for these oxidative annulations is
illustrated in Scheme 2.[22] Under the reaction conditions,
deprotonation of the cyclic 1,3-dicarbonyl substrate generates
an enolate, which is then able to direct cycloruthenation with
complex 6 to form the six-membered ruthenacycle 7. It should
5e: R1, R2 =Me, Ph,
76%
5g: 84%
5h: R=H, 80%
5i: R=OMe, 73%
5 f: R1 =R2 =Et, 75%
[a] Reactions were conducted using 0.50 mmol of 4a–e. Cited yields are
of the isolated material. [b] Reactions conducted with the addition of
K2CO3 (2.5 equiv).
range of unsymmetrical alkynes were tolerated, and the
reactions were highly regioselective. While successful forma-
tion of the product 5a was not surprising given the results
presented in Table 2, we were pleased to find that a range of
Meldrumꢀs acid derivatives containing various 2-aryl sub-
stituents (which exist predominantly in their b-dicarbonyl
form rather than the enol form) also underwent annulation
(products 5b–d). In these cases, the presence of K2CO3
(2.5 equiv) was required to obtain the products in acceptable
yields (48–59%).[19] Barbituric acid derivatives, which also
exist in the b-dicarbonyl form, were also found to be effective
in this process (products 5e–i formed in 73–80% yield).
Interestingly, substrates containing only one carbonyl group,
such as 2-phenylcyclohexanone, do not undergo oxidative
annulation under these conditions. Also, acyclic substrates
such as diethyl phenylmalonate were unreactive.
To gain insight into the mechanism and regioselectivity of
these reactions, deuteration experiments were carried out.
First, the substrate 1c was subjected to the standard reaction
conditions with the inclusion of D2O, but in the absence of
alkyne [Eq. (1)]. After only 15 minutes, the recovered 1c
contained a significant amount of deuterium (ca. 79%) at the
eventual site of spiroindene formation, as expected. Deuter-
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alkyne oxidative annulations reported to date involve initial
cyclometallation to form five-membered ruthenacycles. Coor-
dination and migratory insertion of the alkyne 2 with 7 then
À
occurs with preference for C C bond formation at the alkyne
carbon atom bearing the alkyl substituent to form the second
ruthenacycle 8, which although depicted as an oxa-p-allylru-
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À
Finally, C C reductive elimination of 8, with concomitant
CuII-promoted oxidation of Ru0 back to the RuII species 6,
À
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In conclusion, we have developed metal-catalyzed oxida-
tive annulations of alkynes involving (formal) functionaliza-
À
À
tion of Csp3 H and Csp2 H bonds, thus resulting in products
containing all-carbon quaternary centers. Under the action of
ruthenium catalysis, the process provides a diverse range of
spiroindenes with high levels of regioselectivity. The develop-
ment of further metal-catalyzed oxidative annulations, includ-
ing asymmetric variants, is continuing in our group.
Received: September 4, 2012
Published online: October 24, 2012
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À
Keywords: annulation · C H functionalization · oxidation ·
ruthenium · synthetic methods
.
[11] The formation of benzene rings from metal-catalyzed function-
À
alization of multiple Csp2 H bonds with two or four alkynes has
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À
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[18] The origin of this regioselectivity is not clear at the present time.
[19] This process generates two equivalents of AcOH (see
Scheme 2), and some of the 2-aryl cyclic 1,3-dicarbonyl sub-
strates are sensitive towards acid-catalyzed decomposition under
the reaction conditions. Presumably, the presence of K2CO3
reduces the rate of this decomposition, thus leading to, in
certain cases, higher yields of the spiroindene products.
[20] The structures of the spiroindenes 3i and 3j were confirmed by
X-ray crystallography. See the Supporting Information for
details. CCDC 894550 (3i) and CCDC 897478 (3j) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[21] Deuteration at the cyclohexane ring most likely occurs by
reversible enolization after the formation of the spiroindene 3j,
as evidenced by the following experiment:
[13] For the synthesis of pyrroles by oxidative annulation of enamines
À
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[22] For an alternative mechanism, see the Supporting Information.
[23] An intermediate similar to ruthenacycle 8 has been proposed
previously in the palladium-catalyzed synthesis of phenanthrone
À
derivatives by dual C H activation: P. Gandeepan, K. Partha-
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Angew. Chem. Int. Ed. 2012, 51, 12115 –12119
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