Synthesis of spiroindanes by palladium-catalyzed oxidative annulation of non- or weakly activated 1,3-dienes involving C-H functionalization

Article abstract of DOI:10.1039/c4cc09496d

The synthesis of spiroindanes by the palladium-catalyzed oxidative annulation of non- or weakly activated 1,3-dienes with 2-aryl cyclic 1,3-dicarbonyl compounds is described. Examples of the dearomatizing oxidative annulation of 1,3-dienes with 1-aryl-2-naphthols are also presented. This journal is

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Synthesis of spiroindanes by palladium-catalyzed
oxidative annulation of non- or weakly activated
Cite this:DOI: 10.1039/c4cc09496d
1
,3-dienes involving C–H functionalization†
Received 27th November 2014,
Accepted 23rd December 2014
ab
ab
ab
Imtiaz Khan, Suresh Reddy Chidipudi and Hon Wai Lam*
DOI: 10.1039/c4cc09496d
www.rsc.org/chemcomm
The synthesis of spiroindanes by the palladium-catalyzed oxidative
annulation of non- or weakly activated 1,3-dienes with 2-aryl cyclic
1,3-dicarbonyl compounds is described. Examples of the dearoma-
tizing oxidative annulation of 1,3-dienes with 1-aryl-2-naphthols
are also presented.
The site-selective, metal-catalyzed oxidative C–H functionaliza-
2
tion of aromatic C(sp )–H bonds with alkynes and activated
1
alkenes, directed by a heteroatom-containing functional group,
Scheme 1 Directed, catalytic oxidative annulation of aromatic com-
pounds with unsaturated partners by C–H functionalization.
is now well-established for the preparation of diverse hetero-
2
–5
6
cycles and carbocycles (Scheme 1A). Despite the impressive
advances that have been made, 1,3-dienes have rarely been used
as annulation partners in these types of reactions (Scheme 1B).
Booker-Milburn, Lloyd-Jones, and co-workers have described the
Pd-catalyzed oxidative annulation of N-arylureas with mostly
(
Scheme 2). These reactions result in spiroindanes, which occur
1
0
in various biologically active compounds.
Given the utility of cyclic 1,3-dicarbonyls as directing groups
3
4f,5e,f,6d
activated 1,3-dienes (R = electron-withdrawing group) to form
in various catalytic oxidative annulations,
began with the reaction of 2-phenyldimedone (1a) with diene 2a
1.5 equiv.) in the presence of various metal precatalysts (5 mol%
metal) and Cu(OAc) (2.1 equiv.) in DMF at 90 1C (Table 1).
our investigations
7
indolines. Related, but non-oxidative, annulations involving
1,3-dienes have been described by the Glorius group, who
(
recently developed the redox-neutral Rh(III)-catalyzed annulation
2
8
3
2
of aromatic oxime esters with 1,3-dienes to give isoquinolines.
Ruthenium and rhodium complexes commonly employed in
C–H functionalizations were ineffective (entries 1 and 2). However, use
Nishimura, Hayashi, and co-workers have also described non-
oxidative, Ir-catalyzed annulation of cyclic ketimines with 1,3-
5f,11
of the palladium–N-heterocyclic carbene complex PEPPSI-IPr
a in 60% yield (entry 3). t-AmOH and 1,4-dioxane were inferior solvents
compared with DMF (entries 4 and 5). Conducting the reaction
gave
9
dienes via C–H functionalization. Although currently limited in
3
number, these processes demonstrate the significant potential
of 1,3-dienes as annulation partners in C–H functionalization
reactions. The development of new types of annulations involving
1
2
in degassed DMF increased the yield slightly to 66% (entry 6).
1,3-dienes therefore remains an important objective to increase the
range of products that can be accessed.
Herein, we describe the Pd-catalyzed oxidative annulation of
1,3-dienes with 2-aryl cyclic-1,3-dicarbonyls and 1-aryl-2-naphthols
a
b
EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building,
The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK
School of Chemistry, University of Nottingham, University Park, Nottingham,
NG7 2RD, UK. E-mail: hon.lam@nottingham.ac.uk; Tel: +44-115-748-4677
Electronic supplementary information (ESI) available: Experimental proce-
†
dures, spectroscopic data for new compounds, and crystallographic data. CCDC
92451–992454. For ESI and crystallographic data in CIF or other electronic
9
format see DOI: 10.1039/c4cc09496d
Scheme 2 Pd-catalyzed synthesis of spiroindanes from 1,3-dienes.
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a
Table 1 Evaluation of conditions for the synthesis of 3a
b
Entry
[M]
mol%
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
[RuCl
[Cp*RhCl
2
( p-cymene)]
2
2.5
2.5
5
5
5
DMF
DMF
DMF
t-AmOH
1,4-Dioxane
DMF
DMF
DMF
DMF
—
—
60
39
46
2
]
2
PEPPSI-IPr
PEPPSI-IPr
PEPPSI-IPr
PEPPSI-IPr
PEPPSI-IPr
PEPPSI-IPr
c
5
66
54
68
c
2.5
10
5
c
c
Pd(OAc)
PEPPSI-IPr
2
60
d
1
0
5
DMF
—
a
b
c
Using 0.25 mmol of 1a. Yield of the isolated product. Using
d
2
degassed DMF. Without Cu(OAc) . t-Am = tert-amyl.
Use of 2.5 mol% of PEPPSI-IPr gave 3a in a more modest yield of
4% (entry 7), while increasing the catalyst loading from 5 mol%
to 10 mol% led only to a minimal increase in yield (entry 8,
compare with entry 6). For comparison, use of Pd(OAc) instead
of PEPPSI-IPr gave 3a in 60% yield (entry 9). Finally, Cu(OAc)
5
2
2
was essential for the reaction to proceed (entry 10). On the basis
of these experiments, the conditions of entry 6 were selected for
further investigations.
The scope of this Pd-catalyzed oxidative annulation was then
explored, which gave spiroindanes 3 in 46–81% yield (Scheme 3).
In addition to substrates derived from dimedone (3a–3e, 3g–3n,
and 3t), those derived from 1,3-cyclohexanedione also reacted
successfully (3o, 3q–3s, and 3u). Besides a phenyl group at the
2
-position of the 1,3-diketone, aromatic moieties containing
Scheme 3 Oxidative annulation of various 2-aryl-1,3-dicarbonyl compounds
with various 1,3-dienes. Reactions were conducted with 0.50 mmol of 1 in
degassed DMF. A complex mixture was obtained. The 1,3-diene was returned
substituents at the para- (3k–3n and 3q–3s), meta- (3t), or ortho-
positions (3u) were also tolerated. The successful formation of 3u is
notable as ortho-substitution was not tolerated in Ru-catalyzed
a
b
largely unchanged while decomposition of 2-phenyl 1,3-cyclohexanedione
oxidative annulation of 2-aryl cyclic 1,3-dicarbonyl compounds was observed.
5e,6d
reported previously.
In the case of a substrate containing a
meta-methoxyphenyl group, a complex mixture of products was
1
6
obtained, from which only spiroindane 3t could be isolated for these observations are currently not clear. A 1,1-diphenyl-
cleanly (46% yield). In 3t, C–H functionalization occurred at the substituted diene smoothly underwent the reaction (3g), as
least sterically hindered position, para- to the substituent, which is did dienes containing methyl or chloro substituents at the
5e,6d
2
consistent with previous observations,
out the formation of alternative isomers.
though we cannot rule internal position R (3h–3j and 3n). Where relevant, the stereo-
chemistry of the internal alkene of the 1,3-diene was preserved
17
The reaction is tolerant to 1,3-dienes with various substitu- in the products. 1,3-Dienes that do not contain a terminal alkene,
tion patterns. For example, 1,3-dienes 2 containing an aryl (3a, such as 1,4-disubstituted-1,3-dienes, were unreactive in this process.
3
b, 3k, 3o, 3q, 3s–3u) or alkyl (3c–3e, 3i, 3l, 3m, 3r) substituent However, isoprene (2m) reacted with 1e to provide a 2.8 : 1
3
2
4
18
at R (R = R = H) were effective substrates. The ability inseparable mixture of two isomers 3va and 3vb (eqn (1)).
to employ alkyl-substituted 1,3-dienes sets this process apart The unsymmetrical 2-aryl cyclic 1,3-dicarbonyl compound 4
from related annulations, where highly activated 1,3-dienes reacted with 1,3-diene 2a to provide a mixture of diastereomeric
containing strong electron-withdrawing groups were required spiroindanes 5a and 5b in 58% and 19% yield, respectively
7
,8,13,14
for optimal results.
This point is reinforced by the fact (eqn (2)). Phenol and naphthol-derived substrates have recently
that the use of highly activated 1,3-dienes in our reactions was been found to be viable substrates for carbocycle-forming
1
5
6g,j,k
unsuccessful (none of 3f or 3p could be isolated ). The reasons oxidative annulations with alkynes,
and we were pleased
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Migratory insertion of the 1,3-diene 2a with 9 can then occur to
give a new palladacycle 10, containing a p-allylpalladium species.
19
An inner sphere C–C bond-forming reductive elimination of 10
then provides the spiroindane 3a and the palladium(0) species 11,
which then undergoes oxidation by Cu(OAc)2 to regenerate 8.
Computational studies on the enantioselective Tsuji allylation of
enolates, which proceed via intermediates similar to 10, suggest
0
20
that in those reactions, reductive elimination by a 3,3 pathway
19
is the lowest in energy. However, in the reactions presented
herein, where the palladium enolate and allylpalladium compo-
nents are tethered to each other, the mechanism of reductive
elimination may well be different. Alternatively, it is possible that
the product could be formed by outer sphere nucleophilic attack
21
of an enol onto a p-allylpalladium species such as in 12, which
in turn could be formed by protonolysis of 10 by AcOH. Further
studies will be required to shed more light on the mechanism.
In summary, the synthesis of spiroindanes by the palladium-
catalyzed oxidative annulation of 2-aryl cyclic 1,3-dicarbonyl
compounds or 1-aryl-2-naphthols with non- or weakly activated
1,3-dienes has been reported. This work demonstrates the
broad utility of palladium catalysis in oxidative annulations
involving C–H functionalization, and increases the scope of
carbocyclic products that can be prepared using these reactions.
The development of diastereo- and enantioselective variants of
these processes along with investigations into other types of
carbocycle-forming oxidative annulations are topics for further
study in our group.
Scheme 4 Possible catalytic cycle.
to observe that 1-aryl-2-naphthol 6a reacted smoothly with 1,3-diene
2
a to provide a diastereomeric mixture of dearomatized products
17
7aa and 7ab (eqn (3)). Similar results were obtained using substrate
6b (eqn (4)). In these cases, the highest yields were obtained using
substoichiometric Cu(OAc) and molecular oxygen (balloon) as
2
the terminal oxidant, using MeCN as the solvent.
We thank the ERC, EPSRC, University of Edinburgh, and
University of Nottingham for financial support. We are grateful
to the EPSRC for a Leadership Fellowship to H.W.L. We thank
Dr William Lewis at the University of Nottingham for assistance
with X-ray crystallography.
Notes and references
1
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2
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8
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1
1212–11222.
3
4
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2
complex 8, which can then undergo cyclometallation with 1a to
give palladacycle 9, liberating two equivalents of acetic acid.
2
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5
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6
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(
2
(
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2
1
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1
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7
0
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