Cp?Co(III)-Catalyzed Annulations of 2-Alkenylphenols with CO: Mild Access to Coumarin Derivatives

Article abstract of DOI:10.1021/acs.orglett.5b02728

Cp?Co(III)-catalyzed annulations of 2-alkenylphenols with CO for the synthesis of coumarin derivatives have been developed. The reaction features mild reaction conditions, broad substrate scope, and good functional group tolerance. Preliminary mechanistic studies were conducted, suggesting that C-H activation is the turnover limiting step. Furthermore, the efficiency of this reaction was demonstrated by the rapid total synthesis of three natural products herniarin, xanthyletin, and seselin.

Full text of DOI:10.1021/acs.orglett.5b02728

Letter
pubs.acs.org/OrgLett
Cp*Co(III)-Catalyzed Annulations of 2‑Alkenylphenols with CO: Mild
Access to Coumarin Derivatives
Xu-Ge Liu, Shang-Shi Zhang, Chun-Yong Jiang, Jia-Qiang Wu, Qingjiang Li, and Honggen Wang*
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
S
* Supporting Information
ABSTRACT: Cp*Co(III)-catalyzed annulations of 2-alkenylphenols
with CO for the synthesis of coumarin derivatives have been
developed. The reaction features mild reaction conditions, broad
substrate scope, and good functional group tolerance. Preliminary
mechanistic studies were conducted, suggesting that C−H activation
is the turnover limiting step. Furthermore, the efficiency of this
reaction was demonstrated by the rapid total synthesis of three natural products herniarin, xanthyletin, and seselin.
phenols with various carbonyl compounds.16 These methods
ver the past few decades, transition-metal-catalyzed direct
Ofunctionalization of relatively unreactive C−H bonds has usually occur under harsh conditions, and low regioselectivities
considerably expanded the toolbox for organic synthesis,1
providing an attractive alternative to traditional cross-coupling
are typically observed, which may lead to difficulty in product
separation. Other transition-metal-catalyzed routes,16c such as
Pd-catalyzed oxidative annulation of phenols with propargylic
esters,17 Pd-catalyzed carbonylative annulation of internal
alkynes by o-iodophenols,18 and ring-closing metathesis of
esterified 2-vinylphenols using Grubbs’ catalyst,19 were also
known.
reactions with no prefunctionalization of starting materials
necessitated. With the endeavor of many chemists, numerous
metals are found to be effective in C−H activation reactions. In
this regard, cobalt, as a cheap, earth-abundant, and low-toxic
early transition metal, is particularly appealing.2 Pioneered by
Kanai,3 and later advanced by the groups of Ackermann,4
Ellman,5 Glorius,6 Chang,7 and us,8 Cp*Co(III) was found to
be an interesting catalyst, which shows similar, and in some
cases complementary, reactivities to its counterparts Cp*Rh-
(III) and Cp*Ir(III). Furthermore, the reactions initiated by
Cp*Co(III) typically take place under relatively milder reaction
conditions compared to other first-row cheap metals.
The transition-metal-catalyzed direct cyclocarbonylation of
2-vinylphenols20−23 represents an atom-economic and environ-
mentally friendly method for coumarin synthesis. For example,
Alper reported a Pd(II)-catalyzed oxidative cyclocarbonylation
of 2-vinyphenols, with a relatively high pressure of CO applied
(Scheme 1a).21 Iwasawa disclosed an elegant Pd-catalyzed
direct carboxylation of alkenyl C−H bonds with CO2, which
lead to a redox-neutral access to coumarins (Scheme 1b).22
Coumarin and its derivatives9 display good biological and
pharmacological activities, such as antitumor,10 anti-HIV,11
antioxidant,12 antibacterial,11,13 antiinflammatory,14 and anti-
psychotic9c activity (Figure 1). They also exhibit good optical
properties and, thus, are widely used in laser devices, light-
emitting diodes, and fluorescent probes.15 Synthetically,
coumarins could be constructed by the condensation of
́
Mascarenas and Gulias realized a Cp*Rh(III)-catalyzed carbon-
̃
ylation of o-alkenyl phenols with CO, wherein a relatively high
temperature was used (Scheme 1c).23a Very recently, we have
developed a Cp*Co(III)-catalyzed aromatic C−H coupling
with diazomalonates.8 Herein, we would like to disclose our
realization of a Cp*Co(III)-catalyzed annulation reaction of 2-
alkenylphenols with CO (balloon pressure) under remarkably
mild conditions (Scheme 1d).
At the outset of our studies, 2-(prop-1-en-2-yl)phenol (1a)
was chosen as a model substrate (Table 1). The reaction of 1a
in the presence of Cp*Co(CO)I2 (10 mol %) and AgOAc (2.5
equiv) under atmospheric CO at 50 °C in toluene for 20 h
delivered the desired coumarin product 2a in 14% yield (entry
1). Ag2CO3 is a superior oxidant for this transformation
(entries 2 and 3). When the reaction was carried out in o-xylene
or chlorobenzene, the yield could be doubled (entries 4−9).
Interestingly, the use of Ag2CO3 (1.0 equiv) and Cu(OAc)2·
H2O (1.0 equiv) as co-oxidants led to a good yield of 70%
Received: September 22, 2015
Figure 1. Selected naturally occurring bioactive coumarin derivatives.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02728
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Organic Letters
Letter
Scheme 1. Synthesis of Coumarins from 2-Alkenylphenols
Scheme 2. Cp*Co(III)-Catalyzed Annulations of 2-
Alkenylphenols with CO
(entry 10).24 To our delight, lowering the reaction temperature
to 30 °C further improved the yield to 75% (entry 11). The use
of 5 mol % catalyst gave a moderate yield of 61% (entry 12).
Control experiments indicated that both the catalyst and
oxidant were essential for the reaction (entries 13 and 14).
With the optimized conditions established (Table 1, entry
11), the substrate scope was then investigated. As shown in
Scheme 2, a wide range of 2-vinylphenols bearing different
substitutents, regardless of their electronic properties, under-
went this reaction smoothly, giving the corresponding
coumarins in 31−87% yields. Some commonly encountered
functional groups such as halogen (2c−d, 2f, 2k−l, 2o−p),
nitro (2e, 2m), methoxy (2j, 2n, 2v), cyano (2w), and
trifluoromethyl (2x) were tolerated in this transformation, thus
giving good opportunities for further functionalizations. Simple
2-hydroxyl styrenes were also suitable substrates (2g−k).
However, relatively lower yields were observed, probably due
to the ease of the rotation of vinyl group, which lead to the
difficulty of a hydroxyl-directed metalation. It was found that
the introduction of steric hindrance next to the vinyl group led
to a diminished yield (2h). However, 1r with an ortho methyl
a
Table 1. Optimization of the Reaction Conditions
b
entry
oxidant (equiv)
AgOAc (2.5)
solvent (M)
toluene (0.1)
temp (°C)
yield (%)
1
50
50
50
50
50
50
50
50
50
50
30
30
30
30
14
27
19
20
41
17
39
27
12
70
2
Ag2CO3 (2.5)
toluene (0.1)
3
Cu(OAc)2·H2O (2.5)
Ag2CO3 (2.5)
toluene (0.1)
4
DCE (0.1)
5
Ag2CO3 (2.5)
o-xylene (0.1)
mesitylene (0.1)
chlorobenzene (0.1)
trifluorotoluene (0.1)
n-hexane (0.1)
o-xylene (0.2)
o-xylene (0.2)
o-xylene (0.2)
o-xylene (0.2)
o-xylene (0.2)
6
Ag2CO3 (2.5)
7
Ag2CO3 (2.5)
8
Ag2CO3 (2.5)
9
Ag2CO3 (2.5)
10
11
Ag2CO3 (1.0)/Cu(OAc)2·H2O (1.0)
Ag2CO3 (1.0)/Cu(OAc)2·H2O (1.0)
Ag2CO3 (1.0)/Cu(OAc)2·H2O (1.0)
−
c
75 (78)
d
12
61
0
13
e
14
Ag2CO3 (1.0)/Cu(OAc)2·H2O (1.0)
0
a
b
1
Reaction conditions: 1a (0.2 mmol), Cp*Co(CO)I2 (10 mol %), oxidant, CO balloon, solvent, 20 h. Yields are based on 1a, determined by H
c
d
e
NMR spectroscopy by using 1-iodo-4-methoxybenzene as the internal standard. Isolated yield. Cp*Co(CO)I2 (5 mol %). Without
Cp*Co(CO)I2.
B
DOI: 10.1021/acs.orglett.5b02728
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Organic Letters
Letter
substitutent to the phenolic hydroxyl group (2r) gave a
moderate yield of 55%. It should be noted that natural product
herniarin can be assembled directly in 61% yield using this
method (2n). A variety of diversely 1,1-disubstitued alkenes
underwent reaction without difficulty (2s−x). However, the use
of 1,1,2-trisubstituted alkene 1y and 2-allylphenol 1z showed
no desired reactivity probably because of steric hindrance. An
attempt to use nitrogen as a directing group also failed. Trivial
consumption of 1aa−1ac was found, which was suspected to be
due to the unfavored low acidity of the corresponding N−H
bonds. However, the more acidic substrate 1ad furnished an
indole product, with no insertion of CO observed.
Scheme 4. Proposed Mechanism
As an indication of the possible practical potential of this
catalyst system, a gram-scale reaction was conducted with 5 mol
% of catalyst Cp*Co(CO)I2 (eq 1). No significant erosion of
yield (2u, 74%, 1.4 g) was observed compared to a small scale
reaction.
Cu(OAc)2·H2O. The ligand replacement with 2-vinylphenol
gives intermediate I. For the formation of the cyclometalated
intermediate III, there are two possible pathways. An
intramolecular electrophilic attack of the conjugated alkene to
Cp*Co(III) followed by a base-assisted deprotonation would
deliver the rearomatized intermediate III (pathway A).
Alternatively, a concerted metalation deprotonation (CMD)
process would also give III (pathway B). Based on the KIE
experiment, we believe pathway B is more likely. Thereafter,
CO coordination is followed by a migratory insertion to
generate IV. The final coumarin product 2a is formed upon
reductive elimination. The resulting reduced Cp*CoI is
oxidized by the copper or silver salt to regenerate the active
catalyst.
To further demonstrate the utility of this new strategy, we
performed the total synthesis of the natural product xanthyletin
(9) and seselin (10), which have shown promising biological
activities. As shown in Scheme 3, the corresponding 2-
Scheme 3. Total Synthesis of Natural Products Xanthyletin
and Seselin
In summary, we have developed a Cp*Co(III)-catalyzed
direct cyclocarbonylation of 2-vinylphenols for the synthesis of
coumarins. The reaction occurred under rather mild reaction
conditions. Importantly, only balloon pressure CO was
sufficient to maintain high reactivity. The substrate scope was
generally good, and a variety of functional groups were well
tolerated. The synthetic utility of this reaction is demonstrated
by a practical gram-scale preparation and the facile synthesis of
three natural products.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02728.
vinylphenols 7 and 8 could be synthesized in two steps starting
from commercially available β-resorcylaldehyde and prenal
according to literature precedent.25,26 We are delighted to find
that, under the standard reaction conditions, xanthyletin and
seselin could be obtained in 42% and 48% yield, respectively.
To gain some mechanistic information, the kinetic isotope
effect (KIE) study was carried out (eq 2). A primary KIE value
Experimental procedures and full analytical data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wanghg3@mail.sysu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the support of this work by “1000-Youth
Talents Plan”, a Start-up Grant from Sun Yat-sen University
and National Natural Science Foundation of China (81402794
and 21472250).
of 3.4 was observed, indicating that C−H bond cleavage is the
turnover-determining step. A proposed mechanism was out-
lined in Scheme 4. The active catalyst Cp*Co(III)Ln is
generated by the reaction of Cp*Co(CO)I2 with Ag2CO3 or
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