Access to coumarins by rhodium-catalyzed oxidative annulation of aryl thiocarbamates with internal alkynes

Article abstract of DOI:10.1021/acs.orglett.5b00364

A Rh-catalyzed annulation of aryl thiocarbamates with internal alkynes via C-H bond activation has been developed. This protocol provides a new route to 3,4-disubstituted coumarins.

Full text of DOI:10.1021/acs.orglett.5b00364

Letter
pubs.acs.org/OrgLett
Access to Coumarins by Rhodium-Catalyzed Oxidative Annulation of
Aryl Thiocarbamates with Internal Alkynes
Yingwei Zhao, Feng Han, Lei Yang, and Chungu Xia*
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: A Rh-catalyzed annulation of aryl thiocarba-
mates with internal alkynes via C−H bond activation has been
developed. This protocol provides a new route to 3,4-
disubstituted coumarins.
alkenyl C−H bonds of 2-hydroxystyrenes (Scheme 1, c).10
oumarin is a well-known structural motif found in
Cnumerous natural products and pharmaceuticals with However, most of these methods are limited to 4-substituted
interesting biological activities.1 It is also frequently employed
products. Retrosynthetic analysis suggested that the coupling of
in highly efficient organoelectroluminescent materials.2 The
a phenyl ester and an internal alkyne might offer a promising
route to 3,4-disubstituted coumarins, though only one
successful example was subsequently achieved via cleavage of
two carbon−carbon σ bonds of an o-arylcarboxybenzonitrile.11
We aimed to construct such molecules by transition-metal-
catalyzed oxidative coupling of alkyne with an aryl C−H
bond.12 In our recent study on the ortho C−H bond activation
of aryl thiocarbamates,13 we found that the iminium group in
one polarization form of a thiocarbamate could transform to a
carbonyl easily in the presence of acetic acid. Along with the
fact that a C−S bond tends to cleave in the presence of some
transition metals,14 we expected that the coupling of an aryl
thiocarbamate and internal alkyne would form 3,4-disubstituted
coumarins (Scheme 1, d).
To test our hypothesis, we initially examined palladium,
ruthenium, and rhodium catalysts, respectively, using O-phenyl-
N,N-dimethylthiocarbamate (1a) and diphenylacetylene (2a)
as our standard substrates and Cu(OAc)2 as the oxidant. The
reactions were carried out in tert-amyl alcohol at 120 °C for 12
h. It was shown that Pd(OAc)2 and Ru complex are not
effective for this reaction (entries 1 and 2, Table 1). To our
delight, in the presence of a catalytic amount of AgOTf (10 mol
%), [Cp*RhCl2]2 could readily promote the reaction, affording
3,4-diphenylcoumarin (3aa) in high yield (entry 4). The
requirement for a Ag salt (entry 3) implied that the in situ
formation of cationic RhIII species was essential for the success
of this reaction. AgSbF6 is slightly less efficient than AgOTf but
also led to a satisfactory result (entry 5).
most common approach for the synthesis of coumarins is the
Pechmann reaction.3 Other classic methods involve strong acid-
or base-catalyzed condensations.4 In recent years, much
research emphasis has been focused on transition-metal-
catalyzed coupling5 and carbonylation reactions.6 Direct C−H
bond activation has also provided a powerful route to replace
typical couplings in a lot of cases.7 The application of this
strategy to coumarin synthesis is attractive, and some successful
examples have been developed, including Pd-catalyzed intra-
(Scheme 1, a)8 and intermolecular9 (Scheme 1, b) arylation of
aryl propiolates or acrylate esters and direct carboxylation of
Scheme 1. Preparation of Coumarins through C−H
Activation: Retrosynthetic Disconnections
Our screening of different oxidants revealed that only copper
acetate was suitable. Although Ag salts prove to be good
oxidants in many Rh- or Pd-catalyzed reactions, they were not
efficient in this case (entries 6 and 7). Compared to anhydrous
Cu(OAc)2, its crystalline hydrate led to a relatively lower yield
of the product (entry 8). Examination of copper salts with
Received: February 4, 2015
Published: March 11, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00364
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Organic Letters
Letter
a
Table 1. Effect of Reaction Parameters
Scheme 2. Substrate Scope*
b
entry
catalyst
oxidant
Cu(OAc)2
yield (%)
c
1
Pd(OAc)2
0
2
[(p-cymene)RuCl2]2/AgOTf
[Cp*RhCl2]2
[Cp*RhCl2]2/AgOTf
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
AgOAc
0
3
trace
81
71
trace
0
4
5
6
7
[Cp*RhCl2]2
AgOTf
8
[Cp*RhCl2]2/AgOTf
[Cp*RhCl2]2/AgOTf
[Cp*RhCl2]2/AgOTf
[Cp*RhCl2]2/AgOTf
[Cp*RhCl2]2/AgOTf
[Cp*RhCl2]2/AgOTf
Cu(OAc)2·H2O
CuSO4
67
12
0
9
10
Cu(OTf)2
Cu(OTf)2/KOAc
Cu(CF3CO2)2
O2/AcOH
d
11
42
25
trace
12
e
13
a
Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), catalyst
(0.0125 mmol), Ag salt (0.05 mmol), oxidant (0.5 mmol), t-AmOH
(1.5 mL). All the reactions were performed in sealed tubes under Ar.
b
c
d
e
Isolated yield. 0.025 mmol of Pd(OAc)2. 1 mmol of KOAc. 1 atm
of O2 and 1 mmol of AcOH.
other anions indicated the importance of the acetate anion
(entries 9−12). These results are consistent with the
mechanism we proposed in our previous work related to the
intramolecular cyclization of 1a.13 The acetate anion is most
efficient in attacking the iminium intermediate, leading to its
transformation to the carbonyl group. Finally, the Rh/O2
catalytic system12q is not applicable for the reaction, even
under acidic conditions (also see the Supporting Information).
Having gained preliminary insight into this novel reaction
and identified the optimized reaction conditions, we next
explored the scope and generality of this process. First, a variety
of substituted aryl thiocarbamates 1, which could be readily
prepared from the condensation of corresponding phenols with
dimethylthiocarbamoyl chloride, were allowed to react with
diphenylacetylene (2a) (Scheme 2). Generally, the aryl
thiocarbamates with electron-donating substituents such as
alkyl and methoxyl group on the phenyl ring at the para
position gave good yields (3aa−ca). However, when the
substituent was on the ortho position (3da−ga,na), the
corresponding coumarin was obtained in relatively lower
yield. The m-methoxyl-substituted precursor cyclized to give a
mixture of 7-substituted 3ia and 5-substituted 3ia′ in 67% total
yield with 5:1 regioselectivity, indicating that the cyclization
tends to take place at the side of less steric hindrance.
The electron-deficient thiocarbamates also exhibited medium
reactivity (3ja−ma). It is noteworthy that the potentially labile
halogen group was inert in this reaction (3ja and 3ka). In
addition, a series of other functional groups, such as a ketone
(3la) and an ester (3ma), were also compatible. Next, the
scope of the internal alkynes was also surveyed. Annulation of
the model thiocarbamate 1a with the electron-rich 4-
methylphenyl-substituted alkyne (2b) or 4-methoxylphenyl-
substituted alkyne (2d) produced the desired coumarins 3ab
and 3ad in 70% and 52% yields, respectively. Similarly, the
electron-deficient 4-fluorophenyl-substituted alkyne 2c under-
went annulation with 1a efficiently. Reaction of 1a with
*
All reactions were performed with 1 (0.5 mmol), 2 (0.75 mmol),
[Cp*RhCl2]2 (0.0125 mmol), AgOTf (0.05 mmol), Cu(OAc)2 (0.5
mmol), in t-AmOH (1.5 mL) at 120 °C under Ar for 12 h. Yields
a
shown are of isolated products. The ratio of these two isomers was
determined by GC.
phenylpropyne (2e) afforded 4-methyl-3-phenyl-2H-chromen-
2-one (3ae) as the sole product, the structures of which were
established on the basis of comparison of NMR spectra with
those reported in the literature.6a The present reaction was
successfully extended to aliphatic alkyne. The expected
coumarin 3af was furnished from 1a and 5-decyne in 61% yield.
To obtain insight into the reaction mechanism, some control
experiments were carried out (Scheme 3). The reaction of
phenyl dimethylcarbamate (3a) with diphenylacetylene (2a)
under “standard conditions” as described in Table 1 led to
complex unknown products, and no desired coumarin 3aa was
observed (eq 1). In addition, S-phenyl dimethylcarbamothioate
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Letter
occurs, two possible pathways can be considered. In path A,
desulfurization followed by migratory insertion gives the seven-
membered rhodacycle V, while in path B, alkyne insertion takes
place at first to afford the eight-membered ring IV which could
then transfer to V. Next, reductive elimination releases the
iminium salt 4 and RhI (VI) which can be reoxidized by
Cu(OAc)2 in the presence of trifluoromethanesulfonic acid to
complete the catalytic cycle. The nucleophilic attack of acetic
anion onto the iminium carbon followed by C−N bond
cleavage affords the desired coumarin 3 and dimethylacetamide,
which has been confirmed in our previous work.13
Scheme 3. Control Experiments
In summary, we have developed a new and efficient Rh-
catalyzed oxidative annulation protocol to construct coumarins.
This process exploits a thiocarbamate group directed C−H
bond activation, an annulation with an alkyne, and a
desulfurization. Control experiments and mechanism studies
revealed that Cu(OAc)2 acts both as the oxidant for RhI and as
the oxygen source of the carbonyl group. Further investigations
to gain a detailed mechanistic understanding of this reaction
and the extension of this reaction are currently underway in our
laboratory.
(4a) was inert in this catalytic system (eq 2). These results
indicate that the soft but easily removable sulfur atom
containing thiocarbamate group is essential for the success of
the annulation with alkyne to afford coumarins.
In addition, a stoichiometric Rh catalyst (50 mol % of
[Cp*RhCl2]2) was allowed to react with 1a and 2a under
standard conditions, except for the addition of 2 equiv of KOAc
instead of Cu(OAc)2 (eq 3). A 72% yield of 3aa could be
obtained, which indicates that a RhI−RhIII cycle might be
involved in this reaction. This experiment could also prove that
in the catalytic reaction it is Cu2+ that reoxidizes RhI to RhIII,
and the acetic anion is required to form the carbonyl in the final
coumarin product.
Although XPS experiments were carried out to identify the
final form of sulfur in the reaction system (see Supporting
Information), the detailed desulfurization process in this
reaction system is still unclear. Based on previous mechanistic
studies on C−S bond cleavage13,14 and Rh-catalyzed C−H
activation involving the insertion of alkyne into Rh−C bond of
a Rh−Het intermediate complex,15 we could propose the
following mechanism as illustrated in Scheme 4. In the presence
ASSOCIATED CONTENT
* Supporting Information
Experimental details and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: cgxia@licp.cas.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Chinese Academy of
Sciences and the National Natural Science Foundation of China
(21203222, 21303231, 21173241, and 21133011). We thank
Prof. Hanmin Huang (Lanzhou Institute of Chemical Physics)
for helpful suggestions and comments.
Scheme 4. Proposed Mechanism
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