Cascade Synthesis of 3-Alkylidene Dihydrobenzofuran Derivatives via Rhodium(III)-Catalyzed Redox-Neutral C-H Functionalization/Cyclization

Article abstract of DOI:10.1021/acs.orglett.5b03060

An efficient rhodium(III)-catalyzed coupling reaction of N-phenoxyacetamides with propargyl carbonates to yield 3-alkylidene dihydrobenzofuran derivatives via C-H functionalization/cascade cyclization has been developed. This transformation represents a r

Full text of DOI:10.1021/acs.orglett.5b03060

Letter
pubs.acs.org/OrgLett
Cascade Synthesis of 3‑Alkylidene Dihydrobenzofuran Derivatives
via Rhodium(III)-Catalyzed Redox-Neutral C−H Functionalization/
Cyclization
Zhi Zhou, Guixia Liu,* Yan Chen, and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: An efficient rhodium(III)-catalyzed coupling
reaction of N-phenoxyacetamides with propargyl carbonates to
yield 3-alkylidene dihydrobenzofuran derivatives via C−H
functionalization/cascade cyclization has been developed. This
transformation represents a redox-neutral process and features
the formation of three new bonds under mild conditions.
Scheme 1. RhIII-Catalyzed C−H Functionalization Using
Propargyl Carbonates as Coupling Partners
ver the past decades, transition-metal-catalyzed C−H
Ofunctionalization has been developed as an efficient and
versatile approach for the formation of carbon−carbon or
carbon−heteroatom bonds.1 Among the most investigated
metals, [Cp*RhIII] complexes have proven to be competent
catalysts for the oxidative couplings of C−H bonds with alkynes,
alkenes, allenes, diazo compounds, and other coupling partners.2
To obviate the use of a stoichiometric amount of external
oxidants, a redox-neutral strategy using an oxidizing directing
group has been employed in this field, which simplifies the
reaction conditions and increases the reactivity as well as the
selectivity.3 However, the cascade reaction has drawn continuous
interest in the field of synthetic chemistry due to its convenience
in constructing multiple new bonds via a simple one-pot
operation, thus providing a step-economical route for the
synthesis of complex molecules.4 We believe that the
combination of redox-neutral C−H functionalization and the
cascade strategy could provide a powerful method for the rapid
buildup of heterocycles.5
We recently designed a novel oxidizing directing group for
mild C−H functionalizations of N-phenoxyacetamide with
alkynes (Scheme 1a).3f,l In considering the development of the
cascade reaction triggered by C−H activation under redox-
neutral conditions, we became interested in the use of propargyl
carbonates as the coupling partner. Propargyl carbonates, having
a leaving group in propargylic position, are easily accessible and
valuable synthetic intermediates in organic synthesis. Although
they have been used in diverse reactions, especially cascade
reactions, propargyl carbonates are rarely exploited in C−H
functionalization. During the preparation of this Letter, Ma and
co-workers reported a C−H bond activation of arenes with
sterically congested tertiary propargyl carbonates affording fully
substituted allenes via regiospecific carborhodation/stereo-
specific β-oxygen elimination (Scheme 1b).6 We would like to
disclose herein the synthesis of 3-alkyl-idene dihydrobenzofuran
derivatives from propargyl carbonates by employing the
oxidizing directing group developed by our group (Scheme
1c). This synthetic protocol features both redox-neutral C−H
functionalization and cascade reaction, in which three new bonds
are formed in one step.
We commenced our investigation by examining reactions of
N-phenoxyamides with 3-phenyl propargylic carbonates using
rhodium(III) catalyzed conditions (Table 1). In the presence of
[Cp*RhCl2]2 (2.5 mol %) and CsOAc (0.5 equiv), the reaction
of N-phenoxyacetamide (1a) and methyl (3-phenylprop-2-yn-1-
yl)carbonate (2aa) took place in DCM at room temperature,
affording 3-alkylidene dihydrobenzofuran derivative 3aa in 46%
yield (Table 1, entry 1). The structure of 3aa was confirmed by
NMR, IR, HRMS, and X-ray crystallography.7a Further screening
Received: October 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03060
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Letter
a
N-phenoxyacetamides, the reaction proceeded smoothly to
afford the desired products in moderate to good yields (3ca−
3fa). In addition, the reaction efficiency was not affected by the
position of substituent. Substrates with methyl group at the
para-, meta-, or ortho-position were well tolerated affording the
desired products in good yields (3ba, 3ha, and 3ia). Of note,
when meta-substituted N-phenoxyacetamides were employed,
the C−H functionalization occurred at the less hindered site
selectively (3ia, 3ja). Moreover, the electron-deficient N-
phenoxyacetamides seemed to be less effective giving the desired
products in moderate yields even at higher temperature (3ga,
3ka).
Table 1. Reaction Conditions Screening
b
entry
R1
R2
solvent
yield (%)
1
2
3
4
5
6
7
8
Ac
Ac
Ac
Piv
Ts
Ac
Ac
Ac
Ac
Ac
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Ac
DCM
46
68
22
19
40
25
18
86
48
90
MeOH
dioxane
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
The effect of the substituents on tert-butyl propargyl
carbonates was next examined under the standard reaction
conditions (Scheme 3). The reaction is compatible with various
Ts
Boc
c
a
9
Boc
Scheme 3. Scope of Alkyne Substrates
d
10
Boc
a
Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), [Cp*RhCl2]2
(2.5 mol %), and CsOAc (0.5 equiv) in solvent (0.2 M) at rt for 24 h
b
c
d
under air. 1H NMR yield. 1 equiv of HOAc was added. 0.5 equiv of
K2CO3 was added.
indicated methanol appeared to be an ideal solvent (Table 1,
entries 1−3). Other N-phenoxyamides with different substitu-
ents on the nitrogen atom were less effective and gave the
corresponding products in lower yields (Table 1, entries 4 and
5). A variety of propargylic substrates with different leaving
groups were also tested, and tert-butyl carbonate 2a seemed to be
the best choice (Table 1, entries 6−8). The addition of acetic acid
(1 equiv) gave an inferior result, while K2CO3 (0.5 equiv) was
helpful to increase the yield of 3aa (Table 1, entries 9 and 10).
Control experiments showed that no reaction occurred in the
absence of either the rhodium catalyst or the base additives.7b
Utilizing the optimized conditions, a range of substituted N-
phenoxyacetamides were employed, and the corresponding 2,3-
dihydrobenzofuran derivatives were constructed effectively
(Scheme 2). With para alkyl-, phenyl-, and halogen-substituted
a
Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), [Cp*RhCl2]2
(2.5 mol %), CsOAc (0.5 equiv), and K2CO3 (0.5 equiv) in MeOH
(0.2 M) at rt for 24 h under air; isolated yield was reported.
tert-butyl 3-phenylpropargyl carbonates regardless of the
electronic properties of the substitution on the phenyl ring
(3ab−3af). Moreover, thienyl substituted propargyl carbonate
was also a good reactant for this transformation (3ag, 85%). 3-
Methylpropargyl carbonate readily participated in this cyclization
giving the desired product 3ah in 42% yield. It is noteworthy that
the specifically E-selective 3-alkylidene dihydrobenzofuran
derivatives were accessible using 1-substituted tert-butyl
propargyl carbonates as the substrates (3ai, 3aj). Nevertheless,
tert-butyl (2-methyl-4-phenylbut-3-yn-2-yl) carbonate was un-
reactive under reaction conditions (3ak, 0%) indicating that
tertiary 2-alkynylic carbonate are not compatible for this
transformation.
Scheme 2. Reaction Scope for Substituted N-
a
Phenoxyacetamides
Experiments were then carried out to gain more insight into
the reaction mechanism. With 3-phenylpropargyl acetate (2ab)
as the coupling partner, the desired 2,3-dihydrobenzofuran
derivative 3aa was obtained in a low yield under the standard
conditions. Further examination implied that ortho-hydroxy-
phenyl substituted enamide 4 was furnished as the major
product, which could be smoothly converted to 3aa via
intramolecular cyclization in a high yield at 60 °C (eq 1). On
the basis of these results, we believed that the 2,3-
dihydrobenzofuran derivative was derived from the enamide,
and different leaving groups on the propargylic position affected
the cyclization. Deuterium-labeling experiment was next
conducted in deuterated methanol. No deuterium incorporation
was observed in the recovered starting material 1a and the
a
Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), [Cp*RhCl2]2
(2.5 mol %), CsOAc (0.5 equiv), and K2CO3 (0.5 equiv) in MeOH
(0.2 M) at rt for 24 h under air; isolated yield was reported. Yield of
the product obtained at 60 °C was shown in the parentheses.
b
B
DOI: 10.1021/acs.orglett.5b03060
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Letter
directing coordination to Rh leading to the reversed
regioselectivity.6
Finally, we were pleased to find that this cascade cyclization
could be conducted on gram-scale with a lower catalyst loading,
and the desired 2,3-dihydrobenzofuran product 3aa was afforded
facilely without obvious decrease in yield (Scheme 5a). The
Scheme 5. Derivatization of the Product 3aa
product 3aa, indicating that the C−H activation might be
irreversible under the reaction conditions (eq 2).8 Furthermore,
a primary KIE value of 1.8 implies the C−H bond cleavage
process is not involved in the rate-determining step (eq 3),9
which is consistent with our previous work.3f
Based on the above experiments and the mechanism studies in
the precedent literature,10 a plausible mechanism involving
redox-neutral C−H functionalization and cyclization is shown in
Scheme 4. With the aid of cesium acetate, an active catalyst was
presence of the exocyclic double bond and the dihydrobenzofur-
an unit in 3aa made it a useful synthetic intermediate (Scheme
5b). For example, in the presence of Lewis acids and nucleophilic
reagents, 3aa could be converted to different substituted
benzofuran derivatives in moderate to high yields.12 Intriguingly,
treatment of 3aa with Grignard reagent led to ring opening
product 8 in moderate yield. Moreover, exposure of 3aa to either
m-CPBA or ozonolysis could cleave the exocyclic double bond
furnishing benzofuran-3-one derivative 9.13
Scheme 4. Proposed Reaction Mechanism
In summary, by using propargyl carbonates as the coupling
partners, an efficient RhIII-catalyzed cascade C−H functionaliza-
tion/cyclization was developed to furnish 3-alkylidene dihy-
drobenzofuran derivatives. The reaction was demonstrated to be
practical and scalable with remarkable features including mild
conditions, high yields, and good functional group tolerance.
Similar strategies for combining transition-metal-catalyzed C−H
activations and cascade cyclizations can be expected in
constructing complex compounds with bi- or polycyclic
structures.
generated via anion exchange, followed by the N−H/C−H
cleavage to yield a five-membered rhodacycle intermediate A.
Regioselective insertion of alkyne generated intermediate B,
which underwent reductive elimination to give intermediate C
and RhI species. Subsequently, O−N bond cleavage and
protonolysis regenerated the active RhIII species together with
the enamide E. With −OBoc as the leaving group, an
intramolecular substitution proceeded to form the C−O bond
and the exocyclic double bond simultaneously. The regiose-
lectivity observed in our work is consistent with the reported
rhodium catalyzed C−H functionalization with alkynes, in which
the insertion of an alkyl−aryl alkyne usually occurred
regioselectively with the alkyl-substituted carbon center being
installed with the arene substrate.2,3,8,11 In Ma’s allene synthesis
using sterically congested tertiary propargy carbonates, the
carbonyl group in carbonates are supposed to provide the
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03060.
■
S
Crystallographic data for compound 3aa (CIF)
Experimental procedures, compounds characterization
data, and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: guixia@sioc.ac.cn.
*E-mail: xylu@mail.sioc.ac.cn.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b03060
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Organic Letters
Letter
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ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China
(2015CB856600), the National Natural Science Foundation of
China (21202184, 21232006, 21572255), and the Chinese
Academy of Sciences for financial support.
(12) (a) Zhu, J.-B.; Wang, P.; Liao, S.; Tang, Y. Org. Lett. 2013, 15,
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D
DOI: 10.1021/acs.orglett.5b03060
Org. Lett. XXXX, XXX, XXX−XXX