Synthesis of spirocyclic enones by rhodium-catalyzed dearomatizing oxidative annulation of 2-alkenylphenols with alkynes and enynes

Article abstract of DOI:10.1002/chem.201403454

The dearomatizing oxidative annulation of 2-alkenylphenols with alkynes and enynes proceeds with high yields and regioselectivities under Rh^III catalysis. These reactions are successful using Cu(OAc)₂ or air as the stoichiometric oxi

Full text of DOI:10.1002/chem.201403454

DOI: 10.1002/chem.201403454
Communication
&
CꢀH Activation
Synthesis of Spirocyclic Enones by Rhodium-Catalyzed
Dearomatizing Oxidative Annulation of 2-Alkenylphenols with
Alkynes and Enynes
Szymon Kujawa, Daniel Best, David J. Burns, and Hon Wai Lam*[a]
Abstract: The dearomatizing oxidative annulation of 2-al-
kenylphenols with alkynes and enynes proceeds with high
yields and regioselectivities under RhIII catalysis. These re-
actions are successful using Cu(OAc)2 or air as the stoi-
chiometric oxidant, and provide spirocyclic enones, the
basic ring system of which appears in several natural
products. Application of this process to the preparation of
a highly functionalized tetracycle is also demonstrated.
The heteroatom-directed CꢀH functionalization[1] of aromatic
C(sp2)ꢀH bonds with alkynes has become a versatile and con-
ceptually attractive approach for the synthesis of a diverse
range of heterocyclic compounds.[2–4] We have recently ex-
plored enol-directed catalytic oxidative annulations that pro-
vide carbocyclic, rather than heterocyclic products, and have
demonstrated the ruthenium-, rhodium-, or palladium-cata-
lyzed formation of spiroindenes from 2-aryl cyclic-1,3-dicarbon-
yl compounds and alkynes (Scheme 1a).[5] Given the electronic
similarity between the enol group of cyclic 1,3-dicarbonyls and
the hydroxyl group of phenols, and the broad significance of
phenols as chemical building blocks, we became interested in
Scheme 1. Oxidative annulations of related substrates with alkynes.
the use of 2-alkenylphenols in dearomatizing oxidative spi-
roannulations (Scheme 1d).[6] This process would provide spiro-
cyclic enones, the basic ring system of which appears in sever-
al natural products (Figure 1).[7]
The dearomatization of phenols and naphthols has played
an important role in organic synthesis,[8] but has emerged only
relatively recently in the context of transition metal-catalyzed
CꢀC bond formation.[9,10] Furthermore, until recently, no exam-
ples of such transformations initiated by direct CꢀH functional-
ization of phenol derivatives had been reported.[11] During the
Figure 1. Examples of relevant spirocyclic natural products.
early stages of our investigations, Luan and co-workers report-
ed a ruthenium-catalyzed dearomatizing oxidative annulation
of 1-aryl-2-naphthols with alkynes (Scheme 1b).[12] Nevertheless,
it is important to note that this reaction did not proceed in
a synthetically useful yield with phenol-derived substrates.[12]
A
further indication of the energetic challenges associated with
the dearomatization of phenols compared to naphthols is evi-
dent in recent work from the group of MascareÇas and Gulꢀas,
in which rhodium-catalyzed oxidative annulation of 2-vinylphe-
nol with alkynes provided benzoxepines and not dearomatized
products (Scheme 1c).[13] Herein, we report the dearomatizing
oxidative annulation of 2-alkenylphenols[14] with alkynes and
enynes (Scheme 1d). The presence of a substituent at the 1-po-
[a] S. Kujawa, Dr. D. Best, Dr. D. J. Burns, Prof. H. W. Lam
EaStCHEM, School of Chemistry, University of Edinburgh
Joseph Black Building, The King’s Buildings
West Mains Road, Edinburgh, EH9 3 JJ (UK) and School of Chemistry
University of Nottingham
University Park, Nottingham, NG7 2RD (UK)
E-mail: hon.lam@nottingham.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403454.
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Cu(OAc)2 (5 mol%) and [{Cp*RhCl2}2] (1 mol%) under air (bal-
loon) at 858C (bath temperature).[16]
Table 1. Reactions of 2-(1-arylalkenyl)phenols with alkynes.[a]
Under these conditions, a range of 2-alkenylphenols under-
went oxidative annulation with various alkynes (1.2 equiv) to
give spirocyclic enones 3a–f in 70–84% yield (Table 1). In addi-
tion to 2-(1-phenylvinyl)phenol (Table 1, entry 1), substrates
containing substituents of varying electronic character at the
ortho- (Table 1, entries 2 and 3), meta- (Table 1, entries 4 and 5),
or para-position (Table 1, entry 6) of the non-phenolic aryl
group of 1 were tolerated. In all cases, a single regioisomer of
the product was detected by NMR analysis of the unpurified
reaction mixtures.[17]
Entry
1
Product
Time [h]
1.5
Yield [%][b]
83
3a
Next, the scope of the process with respect to the alkyne
was examined. The use of 1-phenyl-1-propyne in place of di-
phenylacetylene in the reaction with 2-(1-phenylvinyl)phenol
gave spirotetraenone 3g in only moderate yield using air as
the stoichiometric oxidant, even using slightly higher loadings
of [{Cp*RhCl2}2] (2.5 mol%) and Cu(OAc)2 (20 mol%; Table 1,
entry 7). Alkyl aryl alkynes are less reactive than diaryl alkynes
in this process, and under the extended reaction times re-
quired for complete consumption of the 2-alkenylphenols, de-
composition of the products becomes significant. Nevertheless,
greatly improved results can be obtained by using superstoi-
chiometric Cu(OAc)2 (2.1 equiv) at a lower temperature of 658C
(Table 1, entries 8 and 9). Attempted reactions using terminal,
2
3
3b R2 =OMe
3c R2 =F
3.5
4
76
84
4
5
3d R2 =Me
3e R2 =CF3
3
4
71
77
6
3f
2
70
7[c]
8[d]
9[d]
3g R1 =Me
3g R1 =Me
3h R1 =n-Pr
3
1
1
51
76
60
[a] Using 0.50 mmol of 1;>19:1 regioselectivity in all cases. [b] Yield of
isolated product. [c] Reaction conducted with [{Cp*RhCl2}2] (2.5 mol%)
and Cu(OAc)2 (20 mol%) under air. [d] Reaction conducted with
[{Cp*RhCl2}2] (2.5 mol%) and Cu(OAc)2 (2.1 equiv) at 658C.
sition of the alkenyl group is essential for the success of these
reactions. Application of this process to the preparation of
a complex tetracyclic product is also demonstrated.
Our studies began with the reaction of various 2-alkenylphe-
nols with diphenylacetylene using Cu(OAc)2 (2.1 equiv) as the
stoichiometric oxidant. A brief survey of precatalysts, previous-
ly found to be effective in oxidative spiroannulations with al-
kynes,[5] revealed that only [{Cp*RhCl2}2] exhibited good reactiv-
ity.[15] In the case of 2-vinylphenol, we observed the formation
of benzoxepines, a finding that was confirmed by MascareÇas,
Gulꢀas, and co-workers shortly thereafter (Scheme 1c).[13] Fur-
ther exploration revealed that 2-alkenylphenols containing an
additional substituent at the 1-position of the alkene provided
spirocyclic enones 3, with no detectable formation of the cor-
responding benzoxepine (Table 1). Of the solvents tested, ace-
tonitrile was superior to DMF, 1,4-dioxane, and tert-amyl alco-
hol. Furthermore, it was possible to limit the stoichiometric by-
products to water by performing the reaction with catalytic
Scheme 2. Reactions of 2-[1-(hetero)arylalkenyl]phenols with conjugated
enynes. Reactions proceeded with>19:1 regioselectivity in all cases. Yields
are of isolated single regioisomers. [a] Reaction time was 15 min. [b] Reac-
tion time was 30 min. [c] Reaction conducted with Cu(OAc)2 (5 mol%) under
air at 858C for 5 h. [d] Using 1.2 equiv of enyne. [e] Reaction conducted at
408C for 2 h.
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trimethylsilyl-substituted, or dialkyl alkynes all resulted in com-
plex mixtures.
However, conjugated enynes 4 proved to be excellent sub-
strates for oxidative annulation[18] and provided a range of spi-
rocyclic products 5 in high yields with superstoichiometric
Cu(OAc)2 (2.1 equiv) at 658C (Scheme 2). Appreciable variation
of the alkene component of the enyne is tolerated, with p-
methylstyryl (5a–e), vinyl (5f), benzyl enoate (5g–j), and cyclo-
hexenyl groups (5j)[19] all giving excellent results with a range
of electronically diverse 2-[1-(hetero)arylvinyl]phenols. Enynes
containing simple alkyl (5f–k) and oxygenated alkyl substitu-
ents (5a–e) on the alkyne were effective, and an unprotected
alcohol (5e) was also compatible. Furthermore, Scheme 2 illus-
trates the use of 2-(1-arylalkenyl)phenols not employed in the
examples shown in Table 1, such as those containing 2-chloro
(5b), 2-allyloxyl (5e), 2-hydroxy (5i), 3-chloro (5j), and 4-bromo
substituents (5k). Thienyl-containing substrates were also com-
patible with this process, despite the potential for catalyst poi-
soning (5c and d). The spiroannulation using enynes was also
effective using catalytic Cu(OAc)2 (5 mol%) under air, albeit
with a small reduction in yield, as illustrated by the formation
of spirocycle 5g in 87% yield, compared with 95% yield using
the standard conditions with 2.1 equivalents of Cu(OAc)2.
The dearomatizing oxidative spiroannulation is not limited
to substrates containing a (hetero)aryl substituent at the 1-po-
sition of the alkene, as illustrated by the reaction of 2-alkenyl-
phenol 6, which reacted with enyne 4d to give spirocycle 7 in
82% yield [Eq. (1)].
Scheme 3. Possible catalytic cycle.
with Et3N promoted an intramolecular 1,6-conjugate addition
of the phenoxide onto the dienone to give the highly func-
tionalized tetracycle 14 in 62% yield, along with recovered
starting material in 18% yield [Eq. (2)].
In summary, we have developed a catalytic CꢀH functionali-
zation method for the dearomatizing spiroannulation of 2-alke-
nylphenols with alkynes and enynes.[20] The process exhibits
good generality, leading to highly functionalized spirocyclic
compounds in high yields and regioselectivities from relatively
simple starting materials. Compared with prior art,[12] the pres-
ence of a naphthol in the substrate is not required, and dearo-
matization occurs with more readily available phenols. The de-
velopment of enantioselective variants of this process, along
with studies into other dearomatizing oxidative annulations,
are ongoing in our laboratories.
A possible catalytic cycle for these reactions is presented in
Scheme 3. Reaction of [{Cp*RhCl2}2] with Cu(OAc)2 forms the
rhodium diacetate complex 8, which can then participate in
a phenol-directed CꢀH functionalization of the alkene of the
substrate 1 to generate rhodacycle 9.[13] Coordination and mi-
gratory insertion of the alkyne then provides the rhodacycle
10. When R1 =H, CꢀO bond-forming reductive elimination of
10 results in benzoxepine 11, as reported previously.[13] In our
reactions, in which R1 ¼H, we speculate that isomerization of
10 into rhodacycle 12 occurs to relieve an unfavorable steric
interaction between R1 and the phenoxide ring, despite this
isomerization resulting in a decrease in conjugation. A CꢀC
bond-forming reductive elimination of 12 then gives the spiro-
cyclic product 3, 5, or 7 and Cp*RhI (13), which can then un-
dergo reoxidation by Cu(OAc)2 to regenerate 8.
Acknowledgements
We thank the ERC, EPSRC, GlaxoSmithKline, and the University
of Nottingham for financial support. We are grateful to the
EPSRC for a Leadership Fellowship to H.W.L.
Finally, to demonstrate the further synthetic utility of the
products, we exploited the presence of the electrophilic dien-
one and a nucleophilic phenol in spirocycle 5i. Treatment of 5i
Keywords: alkyne · CꢀH activation · enyne · phenol · rhodium
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[16] No reaction occurred in the absence of either [{Cp*RhCl2}2] or Cu(OAc)2.
[17] The regioselectivities of the reactions were determined by analogy with
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Received: May 8, 2014
Published online on June 6, 2014
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