Practical, Large-Scale Preparation of Benzoxepines and Coumarins through Rhodium(III)-Catalyzed C-H Activation/Annulation Reactions

Article abstract of DOI:10.1021/acs.oprd.9b00191

Herein we disclose the assembly of benzoxepines and coumarins from 2-alkenylphenol precursors using [Cp*RhCl₂]₂ as the precatalyst and alkynes or carbon monoxide as reacting partners. The preparation of benzoxepines and coumarins can be scaled up to 33 mmol using low catalyst loadings.

Full text of DOI:10.1021/acs.oprd.9b00191

Communication
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Practical, Large-Scale Preparation of Benzoxepines and Coumarins
through Rhodium(III)-Catalyzed C−H Activation/Annulation
Reactions
́
́
Moises Gulías,* Daniel Marcos-Atanes, Jose L. Mascarenas,* and Marc Font*
̃
́
́
́
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
Scheme 1. Rh-Catalyzed Synthesis of Benzoxepines and
Coumarins: Previous Contributions
ABSTRACT: Herein we disclose the assembly of
benzoxepines and coumarins from 2-alkenylphenol
precursors using [Cp*RhCl2]2 as the precatalyst and
alkynes or carbon monoxide as reacting partners. The
preparation of benzoxepines and coumarins can be scaled
up to 33 mmol using low catalyst loadings.
KEYWORDS: multigram-scale synthesis, benzoxepines,
coumarins, cycloadditions, Rh catalysis, C−H activation
INTRODUCTION
■
Transition metal-catalyzed cycloadditions provide atom-
economical approaches to heterocyclic products from simple
and readily available reactants.1−3 Recently, a number of
cycloaddition methodologies based on metal-promoted C−H
activation have flourished.4 These strategies are very attractive
for the pharmaceutical industry, as they avoid the use of
prefunctionalized substrates and facilitate the shortening of
synthetic routes.5 However, despite the clear advantages of
these ring-building methodologies, there are still important
challenges to overcome for these technologies to be adopted
for large-scale transformations. In many cases, metal-promoted
C−H functionalization reactions require relatively complex
experimental conditions, stoichiometric oxidants, high temper-
atures, and water-free atmospheres, making scale-up of these
processes very difficult. Moreover, the usual need for high
catalyst loadings of precious metals is an important limitation.
Therefore, most experiments dealing with transition metal-
catalyzed reactions based on C−H activation have been carried
out on a small scale.
Recently, as part of our research program on the discovery of
metal-catalyzed C−H activation/annulation methods,6 we
disclosed rhodium-catalyzed formal (5 + 2) and (5 + 1)
cycloadditions of 2-alkenylphenols with alkynes and carbon
monoxide, respectively (Scheme 1). These reactions provide a
simple route towards benzoxepine and coumarin skeletons,6g,7
which are frameworks that form the basic structural motifs of
many bioactive natural products8−11 (Figure 1) and/or can be
used as fluorescent probes in chemical biology.12
that it would be worth expanding the scope and exploring
large-scale applications. Herein we demonstrate that these
annulations can be efficiently carried out in a large-scale
multigram setup (33 mmol scale) using small amounts of the
rhodium catalyst (<1 mol % catalyst). We also demonstrate
that the rhodium-catalyzed (5 + 1) synthesis of coumarins
presents a very good scope and can be used for the
straightforward synthesis of relevant products.
RESULTS AND DISCUSSION
■
In the aforementioned rhodium-catalyzed processes, most of
the experiments were carried out using between 2.5 and 5 mol
% loadings of the precious metal catalyst, which are too high in
terms of cost and sustainability (Table 1). Therefore, we first
explored the viability of decreasing the loading of the catalyst.
Gratifyingly, using only a 0.5 mol % loading of the rhodium
complex, we were able to obtain benzoxepine 3aa in a quite
good 71% yield (entry 1, Table 1). A slight increase in the
amount of catalyst (0.75 mol %) yielded 3aa in 79% yield
(entry 2). The observation that after several hours the reaction
mixture turned brown suggested that the copper oxidant was
readily consumed, and therefore, we tested the reaction using
an oxygen atmosphere. However, the yield was lower, likely
Our initial reports presented a limited scope, especially in
the case of the coumarins, and dealt with the synthesis of the
products on a very small scale.6g Considering that the
experimental setup is very simple and that the reactions are
tolerant to moisture and carried out under air, we reasoned
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
Received: April 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00191
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Organic Process Research & Development
Communication
Figure 1. Representative compounds bearing benzoxepine or coumarin cores.
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Large-Scale Preparation of Benzoxepines via Rh-
Catalyzed (5 + 2) Cycloaddition of 2-Vinylphenols and
Alkynes
a b
,
b
entry [Rh] loading (mol %) equiv of Cu(OAc)2·H2O yield of 3aa (%)
1
2
3
4
5
0.5
0.5
0.5
0.5
0.2
0.5
71
79
70
68
84
0.75
0.75
0.75
0.75
c
d
de
,
a
Reaction conditions: 5.6 mmol of 2a, 8.4 mmol of 1a, and 35 mL of
b
c
MeCN. Yields of pure isolated products. Using an O2 atmosphere.
d
A continuous flow of air was bubbled through the reaction mixture.
a
e
Reaction conditions: 33 mmol of 2, 49.5 mmol of 1, 0.75 mol %
2-Vinylphenol 1a was added over 2.5 h with a syringe pump.
[Cp*RhCl2]2, and 0.5 equiv of Cu(OAc)2·H2O in 200 mL of MeCN.
b
c
Yields of pure isolated products are shown. Using 1 mol %
d
[Cp*RhCl2]2. The reaction was run for 36 h.
because the vinylphenol partially degraded (entry 3).
Decreasing the amount of the copper-based oxidant to prevent
this degradation resulted in a lower efficiency, even when air
was bubbled through the mixture (entry 4). We finally found
that slow addition of the 2-vinylphenol into the reaction
mixture helped to prevent its degradation and allowed the
cycloadduct to be isolated in a satisfactory 84% yield (entry 5).
At this point we explored the feasibility of performing the
annulation on a multigram scale (33 mmol of the alkyne)
(Scheme 2). We were glad to find that the reaction can be
efficiently performed on this large scale, not only with 2-
vinylphenol (1a) but also with other precursors containing
substitutions on the aromatic ring. Therefore, products 3ba
and 3ca were obtained in synthetically useful yields. The
formation of 3ba confirmed that the reaction tolerates aryl
bromides, which are usually sensitive to transition metals. On
the other hand, when diphenylacetylene was replaced by but-1-
yn-1-ylbenzene, the corresponding cycloadduct 3ab was also
obtained in nearly 60% yield with complete control of the
regioselectivity.
the aromatic moiety and the alkene moiety of the substrate.
Therefore, products 4d and 4e resulting from the use of aryl-
substituted vinylphenols were obtained in good yields (56% for
4d and 74% for 4e; Scheme 3). Substituents at the internal
position of the alkene are compatible with the reaction, with 4f
being isolated in 86% yield. 2-Alkenylphenols bearing a methyl
group at the internal position of the alkene, and with m- and p-
halogen substitution relative to the hydroxy substituent also
participated in the annulation to give the corresponding
coumarin products 4g in 53% yield and 4h in 69% yield. 2-
Alkenylphenols with more than one substituent on the
aromatic ring also led to very good yields of the expected
highly functionalized products (4j and 4k). Finally, the
reaction not only works with methyl-substituted alkenes, but
ethyl and aryl substituents are also well-tolerated, and products
4l and 4m were efficiently formed and isolated. Importantly,
the synthesis of coumarins can also be carried out on a
multigram scale with no erosion of the reaction yield, as
exemplified by the 33 mmol scale synthesis of 4f. This reaction
allowed up to 4.7 g of this product to be obtained in a single
reaction.
We then devoted our efforts to expanding the scope of the
rhodium-catalyzed formal (5 + 1) cycloaddition between 2-
alkenylphenols and carbon monoxide. In 2014, our group
reported preliminary examples demonstrating the feasibility of
the process, but we did not explore its scope.6g We have now
found that the reaction tolerates different substitutions on both
The simplicity of the method prompted us to use it for the
synthesis of biorelevant coumarins, such as 7-(pyridin-3-
yl)coumarin (5), an inhibitor of the aromatase CYP19 that
B
DOI: 10.1021/acs.oprd.9b00191
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Organic Process Research & Development
Communication
other hand, osthole was prepared from commercially available
2-hydroxy-4-methoxybenzaldehyde (6) in a four-step se-
quence. Aldehyde 6 was transformed into brominated and
iodinated vinylphenols 1n and 1m by halogenation followed by
Wittig reaction with PPh3MeBr.16 Coumarins 4n and 4m were
then assembled using our rhodium-catalyzed carbonylation
protocol in 57% and 37% yield, respectively. The synthesis was
completed using a Stille coupling with the corresponding
allylstannane.17
Scheme 3. Assembly of Coumarins via Rh-Catalyzed (5 + 1)
Cycloaddition of 2-Alkenylphenols and Carbon
Monoxide
a b
,
CONCLUSION
■
A practical, economical, and scalable process for the
preparation of benzoxepines from simple 2-alkenylphenol
and alkyne precursors has been developed. The reactions can
be carried out using only a 0.75 mol % loading of the precious
metal catalyst (rhodium complex). Using carbon monoxide
instead of an alkyne as the reaction partner affords a variety of
coumarins featuring different substitutions. This reaction is
also amenable to being carried out on a multigram scale using a
very simple experimental setup. We have applied this last
reaction to the synthesis of two biorelevant coumarins.
EXPERIMENTAL SECTION
a
■
Reaction conditions: 0.5 mmol of 1, 2.5 mol % [Cp*RhCl2]2, and
b
Experimental Procedure for the Large-Scale Rh-
Catalyzed Preparation of Benzoxepines. In a two-neck
round-bottom flask equipped with a condenser and sealed with
a rubber septum, the corresponding alkyne (33 mmol) was
added to a solution of [Cp*RhCl2]2 (153 mg, 0.75 mol %) and
Cu(OAc)2·H2O (3.29 g, 0.5 equiv) in MeCN (200 mL) under
a continuous air flow. The reaction mixture was then heated to
85 °C, and the corresponding 2-vinylphenol (49.5 mmol, 1.5
equiv) was added dropwise over 2.5 h via a syringe pump. The
reaction mixture was stirred for the given time, filtered through
Celite, and washed with hexanes and diethyl ether. The
solvents were removed in vacuo, and the remaining residue was
purified by flash column chromatography on silica gel to afford
the corresponding benzoxepines.
1.2 equiv of Cu(OAc)2·H2O in 2 mL of MeCN. Yields of pure
isolated products are shown. 33 mmol scale reaction.
c
is used for postmenopausal breast cancer treatment,13 and the
natural product osthole (8), which has been found in several
medicinal plants such as Cnidium monnieri and presents
interesting medicinal properties.14 Coumarin 5 was obtained in
only two steps from 5-bromo-2-vinylphenol (1b) using our
carbonylation reaction to give 4b (67% yield) and a
subsequent Suzuki−Miyaura coupling15 (Scheme 4). On the
Scheme 4. Synthesis of CYP19 Inhibitor 5 and the Natural
Product Osthole (8)
Experimental Procedure for the Rh-Catalyzed Prep-
aration of Coumarins. To a solution of [Cp*RhCl2]2 (7.7
mg, 2.5 mol %) and Cu(OAc)2·H2O (120 mg, 1.2 equiv) in
MeCN (2 mL) purged with CO was added the corresponding
2-alkenylphenol (0.5 mmol). The flask containing the reaction
mixture was sealed with a rubber septum, and a CO
atmosphere was injected into the flask with a balloon. The
reaction mixture was heated to 85 °C, stirred for 16 h, cooled
to room temperature, filtered through Celite, and washed with
hexanes and diethyl ether. The solvents were removed in
vacuo, and the remaining residue was purified by flash column
chromatography on silica gel to afford the corresponding
coumarin.
Experimental Procedure for the Large-Scale Rh-
Catalyzed Preparation of Coumarins and Character-
ization of the Products. In a two-neck round-bottom flask
equipped with a condenser and sealed with a rubber septum,
the corresponding 2-alkenylphenol (33 mmol) was added to a
solution of [Cp*RhCl2]2 (510 mg, 2.5 mol %) and Cu(OAc)2·
H2O (7.91 g, 1.2 equiv) in MeCN (135 mL). The resulting
mixture was purged with CO, and a CO atmosphere was
injected into the system with a balloon. The reaction mixture
was heated to 85 °C, stirred for 16 h at that temperature,
cooled to room temperature, filtered through Celite, and
washed with hexanes and diethyl ether. The solvents were
C
DOI: 10.1021/acs.oprd.9b00191
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Metal-Catalyzed C−H Activation: Examples and Concepts. Chem.
removed in vacuo, and the remaining residue was purified by
flash column chromatography on silica gel to afford the
corresponding coumarin.
Soc. Rev. 2016, 45, 2900−2936. (i) Gulías, M.; Mascarenas, J. L.
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Metal-Catalyzed Annulations through Activation and Cleavage of C−
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̈
(j) Sambiagio, C.; Schonbauer, D.; Blieck, R.; Dao-Huy, T.;
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00191.
■
Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.; Wencel-
S
Delord, J.; Besset, T.; Maes, B. U. W.; Schnurch, M. A
̈
Comprehensive Overview of Directing Groups Applied in Metal-
Catalysed C−H Functionalisation Chemistry. Chem. Soc. Rev. 2018,
47, 6603−6743.
Detailed experimental procedures, characterization data,
and spectra (PDF)
(5) Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas,
A. W.; Wilson, D. M.; Wood, A. To Transform Drug Discovery. Nat.
Chem. 2018, 10, 383−394.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: marc.font@usc.es.
(6) (a) Vidal, X.; Mascarenas, J. L.; Gulías, M. Palladium-Catalyzed,
̃
■
Enantioselective Formal Cycloaddition between Benzyltriflamides and
Allenes: Straightforward Access to Enantioenriched Isoquinolines. J.
́
Am. Chem. Soc. 2019, 141, 1862−1866. (b) Font, M.; Cendon, B.;
*E-mail: moises.gulias@usc.es.
*E-mail: joseluis.mascarenas@usc.es.
ORCID
Seoane, A.; Mascarenas, J. L.; Gulías, M. Rhodium(III)-Catalyzed
̃
Annulation of 2-Alkenylanilides with Alkynes via C−H Activation: a
Direct Access to 2-Substituted Indolines. Angew. Chem., Int. Ed. 2018,
́
Moises Gulías: 0000-0001-8093-2454
́
57, 8255−8259. (c) Cendon, B.; Casanova, N.; Comanescu, C.;
́
̃
̃
Jose L. Mascaren
̃
as: 0000-0002-7789-700X
García-Fandino, R.; Seoane, A.; Gulías, M.; Mascarenas, J. L.
Palladium-Catalyzed Formal (5 + 2) Annulation between ortho-
Alkenylanilides and Allenes. Org. Lett. 2017, 19, 1674−1677.
̃ ̃
(d) Casanova, N.; Del Rio, K. P.; García-Fandino, R.; Mascarenas,
Marc Font: 0000-0002-4536-265X
Notes
The authors declare no competing financial interest.
J. L.; Gulías, M. Palladium(II)-Catalyzed Annulation between ortho-
Alkenylphenols and Allenes. Key Role of the Metal Geometry in
Determining the Reaction Outcome. ACS Catal. 2016, 6, 3349−3353.
ACKNOWLEDGMENTS
This work received financial support from Spanish grants
(SAF2016-76689-R, CTQ2016-77047-P, and Juan de la
■
(e) Casanova, N.; Seoane, A.; Mascarenas, J. L.; Gulías, M. Rhodium-
̃
Catalyzed (5 + 1) Annulation between 2-Alkenylphenols and Allenes:
A Practical Entry to 2,2-disubstituted 2H-Chromenes. Angew. Chem.,
Int. Ed. 2015, 54, 2374−2377. (f) Seoane, A.; Casanova, N.;
́
Cierva-Incorporacion Fellowship IJCI-2017-31450 to M.F.),
́
́
́
the Conselleria de Cultura, Educacion e Ordenacion
Universitaria (ED431C 2017/19, 2015-CP082, and Centro
Quinones, N.; Mascarenas, J. L.; Gulías, M. Rhodium(III)-Catalyzed
̃ ̃
Dearomatizing (3 + 2) Annulation of 2-Alkenylphenols and Alkynes.
́
Singular de Investigacion de Galicia Accreditation 2016−2019,
J. Am. Chem. Soc. 2014, 136, 7607−7610. (g) Seoane, A.; Casanova,
ED431G/09), the European Regional Development Fund
(ERDF), and the European Research Council (Advanced
Grant 340055). The orfeo-cinqa network (CTQ2016-81797-
REDC) is also kindly acknowledged.
N.; Quinones, N.; Mascarenas, J. L.; Gulías, M. Straightforward
̃ ̃
Assembly of Benzoxepines by Means of a Rhodium(III)-Catalyzed
C−H Functionalization of o-Vinylphenols. J. Am. Chem. Soc. 2014,
136, 834−837. (h) Quinones, N.; Seoane, A.; García-Fandino, R.;
̃ ̃
Mascarenas, J. L.; Gulías, M. Rhodium(III)-Catalyzed Intramolecular
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