Rhodium(III)-catalyzed dearomatizing (3 + 2) annulation of 2-alkenylphenols and alkynes

Article abstract of DOI:10.1021/ja5034952

Appropriately substituted 2-alkenylphenols undergo a mild formal [3C+2C] cycloaddition with alkynes when treated with a Rh(III) catalyst and an oxidant. The reaction, which involves the cleavage of the terminal C-H bond of the alkenyl moiety and the dearomatization of the phenol ring, provides a versatile and efficient approach to highly appealing spirocyclic skeletons and occurs with high selectivity.

Full text of DOI:10.1021/ja5034952

Communication
pubs.acs.org/JACS
Rhodium(III)-Catalyzed Dearomatizing (3 + 2) Annulation of
2‑Alkenylphenols and Alkynes
Andres Seoane, Noelia Casanova, Noelia Quinones, Jose L. Mascarenas,* and Moises Gulías*
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́
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Centro Singular de Investigacion en Química Bioloxica e Materiais Moleculares (CIQUS) and Departamento de Química Organica,
Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
S
* Supporting Information
ABSTRACT: Appropriately substituted 2-alkenylphenols
undergo a mild formal [3C+2C] cycloaddition with
alkynes when treated with a Rh(III) catalyst and an
oxidant. The reaction, which involves the cleavage of the
terminal C−H bond of the alkenyl moiety and the
dearomatization of the phenol ring, provides a versatile
and efficient approach to highly appealing spirocyclic
skeletons and occurs with high selectivity.
etal-catalyzed cycloadditions are among the most efficient
Mtools to construct target-relevant cyclic products from
simpler starting materials.1 While most of these reactions require
the activation of π-electrons of unsaturated precursors, the
advent of the C−H activation chemistry2 has brought new ways
of achieving related annulations through a dehydrogenative
cleavage of X−H and/or C−H bonds.3 Given that the C−H
activation step usually requires a heteroatom-directed group,
most of these annulations have been used for the synthesis of
heterocycles.4 In clear contrast, cycloadditions that lead to
Figure 1. Rhodium(III)-catalyzed annulations of phenols with alkynes.
carbocycles are much scarcer and essentially restricted to
processes involving the activation of aromatic C−H bonds.5
The discovery of new cycloadditions based on the activation of
olefinic or aliphatic C−H bonds, which would allow the
formation of carbocyclic products other than fused aromatic
systems, is of foremost interest.6
To our surprise, treatment of 2-(prop-1-en-2-yl)phenol (1a)
with 1,2-diphenylethyne (2a), under the standard conditions
developed for the synthesis of benzoxepines ([Cp*RhCl2]2 (Cp*
= pentamethylcyclopentadienyl) and 0.5 equiv of Cu(OAc)2·
H2O, CH3CN at 85 °C, 4 h, under air), gave a very low yield of
the expected benzoxepine 3aa (15% yield, entry 1, Table 1). The
main products of the reaction were the spirocycle 4aa, formally
resulting from a [3C+2C] cycloaddition, and the azulenone 5aa.
Other solvents such as t-AmOH (entry 2) or toluene (entry 3)
led to lower conversions. Performing the reaction in CH3CN at
room temperature led to moderate conversions, even after 24 h;
however, the chemoselectivity was enhanced (entry 4). Slightly
heating the reaction mixture at 40 °C allowed the formation of
product 4aa in an excellent 97% yield after less than 2 h of
reaction (entry 5). The amount of Cu(OAc)2 can be decreased
up to 10% without significantly compromising the efficiency of
the reaction (entry 6). We also tested the reaction in the presence
of other metal complexes, such as [Ru(p-cymene)Cl2]2 or
Pd(OAc)2, but the conversions were extremely poor (entries 7
and 8). As expected, the reaction does not take place in the
absence of the Rh(III) complex (entry 9).
Herein we describe a formal [3C+2C] cycloaddition between
2-alkenylphenols and alkynes that is catalyzed by Rh(III) under
oxidative conditions. The reaction generates spirocyclic products
in high yields and excellent regioselectivity and entails a
dearomatization of the phenol ring (Figure 1, bottom).
Preliminary experiments demonstrate that the spiro-cyclo-
adducts can rearrange to interesting azulenones upon heating.
This work stems from our previous observation that ortho-
vinylphenols react with alkynes in the presence of Rh(III)
catalysts to give benzoxepine products (Figure 1, top).7 In
contrast to commonly proposed concerted metalation−depro-
tonation (CMD) mechanisms for the C−H activation step, some
of our data suggested that in these reactions the formation of the
key rhodacycle intermediate B might involve an alternative
pathway involving the attack of the terminal position of the
conjugated alkene to the electrophilic Rh complex, followed by
rearomatization. To further study the scope of the process and
gain more mechanistic insights, we explored the performance of
alkenylphenol derivatives equipped with a substituent at the
internal position of the alkene.
Received: April 10, 2014
Published: May 12, 2014
© 2014 American Chemical Society
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a
Next, we also analyzed the scope with respect to the
alkenylphenol component by testing substrates 1b−n, which
were easily assembled from the corresponding salicylketones
using a Wittig reaction with a methylenephosphorous ylide.8
As shown in Scheme 2, the success of the reaction is not
restricted to the methylalkene derivative 1a but also works with
Table 1. Optimization of the Reaction
b
yield (%)
Scheme 2. Reaction with Phenols Equipped with Different
Substituents
ab
T
entry
catalyst
solvent
(°C) 3aa
4aa
5aa
1
2
3
4
5
6
7
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
CH3CN
t-amylOH
toluene
85
100
100
rt
15
12
8
51
18
19
44
25
15
17
4
CH3CN
CH3CN
CH3CN
CH3CN
c
40
97
trace
8
d
40
91
[Ru(p-cymene)
Cl2]2
40
15
5
8
9
Pd(OAc)2
none
CH3CN
CH3CN
40
85
<10%
a
With 0.33 mmol of 2a, 0.50 mmol of 1a, 2 mL of solvent, 0.5 equiv of
b
c
Cu(OAc)2·H2O/air balloon. Isolated yield of based on 2a. In 2 h.
d
With 0.1 equiv of Cu(OAc)2·H2O, 16 h.
With the optimized conditions in hand, we investigated the
scope with regard to the alkyne component (Scheme 1).
a b
,
Scheme 1. Scope with Respect to the Alkyne Component
a
Reaction conditions: 0.33 mmol of 2, 0.50 mmol of 1, [Cp*RhCl2]2
(2.5 mol %), 0.5 equiv of Cu(OAc)2·H2O, 2 mL of CH3CN at 40 °C,
b
c
d
air balloon. Isolated yield based on 2. At 60 °C. With 18% of the
azulenone also isolated in this reaction.
2-alkenylphenols bearing other substituents at the internal
position of the alkene, such as ethyl, phenyl, or other aromatic
groups. In all cases, the expected spirocyclic products were
obtained in excellent yields (4ba−4ea, 70−98% yields), although
in the substrates with aromatic substituents (1c−e), the reaction
is slower and required heating at higher temperatures (60 °C) to
obtain full conversions in 2 h. We also analyzed the reactivity of
precursors with different substituents in the phenyl moiety of the
alkenylphenol. Substituents para to the hydroxyl group are well-
tolerated. While the methyl derivative 4fa was isolated in an
excellent 89% yield, the reaction of methoxy-substituted 1g is
slower and the expected product was isolated in 54% after 8 h
(91% based on recovered starting material). The reaction of the
bromo derivative 1h was better carried out at 60 °C (67% of
4ha), although at the cost of formation of 18% of the azulenone
(5ha). Substrates 1i and 1j, equipped with a fluoro and a chloro
group para to the alkenyl moiety, are excellent cycloaddition
partners (85 and 97% yield, respectively).9 The reaction is also
compatible with the presence of a methoxy substituent at that
position, although 4ka was isolated in low yield due to the
stability problems. In the case of substrates with substituents
ortho to the alkenyl unit, the reaction does not proceed under
standard conditions, perhaps because of a steric clash with the
a
Reaction conditions: 0.33 mmol of 2, 0.50 mmol of 1a, [Cp*RhCl2]2
(2.5 mol %), 0.5 equiv of Cu(OAc)2·H2O, 2 mL of CH3CN at 40 °C,
b
air balloon. Isolated yield based on 2.
Symmetrical alkynes bearing electron-rich or electron-deficient
aryl substituents (2b and 2c) led to the expected products 4ab
and 4ac in good yields (93 and 71%). Similar results were
obtained with symmetrical dialkyl-substituted alkynes like 2d and
2e (93 and 81% isolated yields, respectively).
With nonsymmetrical alkynes, the reaction takes place with
regioselectivity >20:1, as only one regioisomer was detected in
the crude NMR mixture. Thus, alkyne 2f afforded the product
4af in an excellent 89% yield, and the cyclopropyl derivative 2g
gave 4ag in 78% yield. The reaction tolerates free hydroxy groups
in the alkyne substituents, therefore 4ah could be isolated in 78%
yield. The reaction also works with enynes like 2i, which led to
the expected cycloadducts with excellent chemo- and regio-
selectivity (4ai, 80% yield).
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alkene substituent. Meanwhile, the phenyl-disubstituted sub-
strates 1m−1n gave the corresponding spirocycles 4ma and 4na
in very good yields (78 and 77%). As expected, substrates with
substituents at the phenyl ring also react with nonsymmetrical
alkynes with total regioselectivity, as exemplified for the synthesis
of 4jf.
Scheme 4. Stoichiometric Experiments with Base
To obtain mechanistic information, we carried out several
competition and deuteration experiments. An intermolecular
competition between 1c and the dideuterated analogue 1c-d2
allowed calculating a kinetic isotope effect kH/kD ∼2.3, which
suggests that the C−H bond cleavage is involved in a rate-
determining step (Scheme 3, eq a). Interestingly, treatment of
normally associated with a CMD mechanism,11 is not essential
for the reaction (Scheme 4).
Based on the above information, a putative mechanism for the
reaction is shown in Scheme 5. The catalytic cycle is likely
Scheme 3. Competition Experiments
Scheme 5. Proposed Mechanistic Cycle
initiated by the phenolic substrate 1 replacing one of the ligands
of the catalyst to give intermediate I. The subsequent C−H
activation leading to the rhodacycle II would involve an
intramolecular attack of the conjugated alkene to the electro-
philic rhodium followed by rearomatization. Alkyne coordina-
tion followed by migratory insertion gives the eight-membered
rhodacycle III that is in equilibrium with the keto form IV. While
in the case of alkenylphenol substrates equipped with a
nonsubstituted vinyl group the reductive elimination yields
oxepine products, the presence of substituents in the alkenyl
moiety generates a steric clash that favors a reductive elimination
from the less strained rhodacyclohexane IV.12 After the reductive
elimination, the Rh(I) species is reoxidized by Cu(OAc)2 to
enter a new catalytic cycle.
As shown in Table 1, the annulation reaction, when carried out
at higher temperatures (entry 1), in addition to the spirocyclic
products generates significant amounts of an azulenone
derivative (5aa). This product comes from the spirocycle
because heating 4aa in CH3CN at 85 °C for 12 h produces a
∼1:1 mixture of 4aa and 5aa. Interestingly, independent heating
of an isolated sample of 5aa for several hours leads to a mixture of
both products, a result that confirms the reversibility of the
process. This equilibrium may be explained in terms of a
rearrangement involving the formation of a zwitterionic
cyclopropyl alkoxide species V (Scheme 6, eq a).13 Therefore,
extremely simple substrates (1a and 1,2-diphenylethyne) can be
converted into much more relevant, and structurally unrelated,
substrate 1a with the standard reagents, in the absence of 2a, and
in the presence of D2O, led to recovery of starting material with a
significant incorporation of deuterium in both positions of the
alkene (eq b). Carrying out the same reaction in the presence of
diphenylacetylene 2a at partial conversions led to the isolation of
the nondeuterated products and starting materials (eq c). This
lack of deuterium incorporation in this experiment suggests that
the alkyne carbometalation is irreversible under the reaction
conditions.10
Treatment of 1a with a mixture of electron-rich and electron-
poor alkynes 2b and 2c under standard conditions led to a
preferential formation of product 4ac, which would be explained
in terms of an easier coordination and carbometalation of the
electron-poor alkyne (eq d).
Control experiments using stoichiometric amounts of
[Cp*RhCl2]2 showed that, while this complex by itself is not
able to produce cycloadducts, addition of CsOAc triggers a clean
formation of the products (Scheme 4). Interestingly, the reaction
can also be induced using other bases instead of acetate (Et3N,
TMP, or KHPO42−). Therefore, the acetate ligand, which is
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Communication
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
́
2014, 356, 319−324. (o) Mehta, V. P.; García-Lopez, J.-A.; Greaney, M.
F. Angew. Chem., Int. Ed. 2014, 53, 1529−1533. (p) Pham, M. V.;
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AUTHOR INFORMATION
■
Corresponding Authors
joseluis.mascarenas@usc.es
moises.gulias@usc.es
(6) Nakao, Y.; Morita, E.; Idei, H.; Hiyama, T. J. Am. Chem. Soc. 2011,
133, 3264−3267. (b) Wang, D.; Wang, F.; Song, G.; Li, X. Angew. Chem.,
Int. Ed. 2012, 51, 12348−12352. (c) Dong, L.; Huang, J.-R.; Qu, C.-H.;
Zhang, Q.-R.; Zhang, W.; Han, B.; Peng, C. Org. Biomol. Chem. 2013, 11,
6142−6149.
Notes
The authors declare no competing financial interest.
(7) Seoane, A.; Casanova, N.; Quinones, N.; Mascarenas, J. L.; Gulías,
̃
̃
ACKNOWLEDGMENTS
■
M. J. Am. Chem. Soc. 2014, 136, 834−837.
We thank the financial support provided by the Spanish Grants
SAF2010-20822-C02 and CSD2007-00006 Consolider Ingenio
2010, the Xunta de Galicia Grants GR2013-041 and EM2013/
036, the ERDF, and the European Research Council (Advanced
Grant No. 340055). M.G. thanks Xunta de Galicia for a Parga
Pondal contract.
(8) See Supporting Information for more details.
(9) CCDC 995496 contains the crystallographic data of 4aj, which can
be obtained via www.ccdc.cam.ac.uk/data_request/cif. See Supporting
Information for more information.
(10) Control experiments indicate that in the presence of Cu(OAc)2
alone or CsOAc no deuterium incorporation was observed.
(11) For discussion on concerted metallation−deprotonation
mechanisms, see: Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39,
1118−1126 and references therein.
(12) At higher temperatures, we observe formation of some
benzoxepine product, which suggests that intermediates III and IV
are in equilibrium.
(13) (a) A [1,5] sigmatropic rearrangement or radical-mediated
mechanism may also be possible: Spangler, C. W. Chem. Rev. 1976, 76,
187−217. (b) For a recent, related rearrangement, see: Li, X.-Y.; Yang,
Y.-F.; Peng, X.-R.; Li, M.-M.; Li, L.-Q.; Deng, X.; Qin, H.-B.; Liu, J.-Q.;
Qiu, M.-H. Org. Lett. 2014, 16, 2196−2199.
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