Rhodium-catalyzed carbonylative [3 + 2 + 1] cycloaddition of alkyne-tethered alkylidenecyclopropanes to phenols in the presence of carbon monoxide

Article abstract of DOI:10.1021/ol5015224

A novel Rh-catalyzed carbonylative [3 + 2 + 1] cycloaddition of alkyne-tethered alkylidenecyclopropanes for the facile synthesis of bicyclic phenols in high yields has been developed. The reaction tolerated carbon and heteroatoms in the tether.

Full text of DOI:10.1021/ol5015224

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed Carbonylative [3 + 2 + 1] Cycloaddition of
Alkyne-Tethered Alkylidenecyclopropanes to Phenols in the
Presence of Carbon Monoxide
Seyun Kim and Young Keun Chung*
Center for New Directions in Organic Synthesis, Department of Chemistry, College of Natural Sciences, Seoul National University,
Seoul 151-747, Korea
S
* Supporting Information
ABSTRACT: A novel Rh-catalyzed carbonylative [3 + 2 + 1] cycloaddition of
alkyne-tethered alkylidenecyclopropanes for the facile synthesis of bicyclic phenols in
high yields has been developed. The reaction tolerated carbon and heteroatoms in
the tether.
any useful reactions have been developed for the
2a and 3a were isolated in 21% and 15% yield, respectively (eq
Msynthesis of cyclic compounds. Transition-metal-cata- 1).Compound 2a was the product of a formal [3 + 2 + 1]
lyzed cycloadditions have been extensively used in the synthesis
of cyclic compounds.1 Alkylidenecyclopropanes can undergo a
number of interesting metal-assisted transformations. For
example, alkylidenecyclopropanes have been used in nickel-
catalyzed cycloadditions with activated alkenes.2 Mascarenas et
̃
al. reported a palladium-catalyzed intramolecuar [3 + 2]
cycloaddition with similar substrates.3 However, the rhodium-
catalyzed intramolecular carbocyclization of alkylidenecyclo-
cycloaddition, a phenol derivative. Compound 2a was
synthesized by a rhodium-catalyzed [2 + 2 + 2] cycloaddition
propanes is known to form a complex mixture of products.4
Several years ago, Shi et al. developed the first intramolecular
rhodium(I)-catalyzed [3 + 2] cycloaddition of alkylidenecyclo-
propanes4 and the Evans group reported a rhodium-catalyzed
[3 + 2 + 1] cycloaddtion.5 During our catalyst screening
process, we discovered a formal [3 + 2 + 1] cycloaddition of
alkylidenecyclopropanes to afford phenol derivatives in the
presence of a rhodium catalyst and carbon monoxide. In
contrast to our expectation, the carbonylative [3 + 2 + 1]
cycloaddition reaction has been rarely reported.6 In addition,
the formation of a six-membered ring by [3 + 2 + 1]
carbonylative carbocyclization has not been well developed,
because of the difficulty in introducing the required three-
carbon component. Herein, we communicate the Rh(I)-
catalyzed [3 + 2 + 1] carbonylative carbocyclization of
alkylidenecyclopropanes, for the synthesis of bicyclic phenols.
A few years ago, Wang and co-workers7 reported a
carbocyclization of yne-cyclopropenes to afford phenol
derivatives. Recently, Shi et al. reported8 a Rh(I)-catalyzed
tandem Pauson−Khand type reaction of 1,4-enynes, resulting
in the formation of similar phenol derivatives.
of 1,6-diynes with vinylene carbonate.10 Compound 3a was the
Pauson−Khand reaction product. Similar Pauson−Khand
reaction products have been reported by de Meijere.11
Encouraged by the formation of compound 2a, we endeavored
to optimize the reaction conditions to obtain 2a as a major
product. The reaction conditions used in our processes are
shown in Table 1. The yield of desired product 2a was highly
sensitive to the rhodium catalyst, the reaction solvent, and the
reaction temperature used. When the same reaction was carried
out using 1,4-dioxane as the solvent at 100 °C for 6 h, a mixture
containing 2a and 3a in 61% and 11% yield, respectively, was
isolated (entry 2). When [Rh(dppp)2Cl] was used as the
catalyst in 1,4-dioxane, the yields of 2a and 3a were decreased
to 44% and 2%, respectively (entry 3). To our delight, the use
of Rh(PPh3)3Cl as a catalyst in 1,4-dioxane at 100 °C for 13 h
afforded 2a as the sole product in 64% yield (entry 4).
Encouraged by this result, we studied the use of a cationic
rhodium complex generated by the reaction of Rh(PPh3)3Cl
with AgX as a catalyst in 1,4-dioxane at 100 °C (entries 5−13).
Interestingly, when AgSbF6 or AgClO4 was used as the
source of a counteranion, no reaction was observed (entries 5
and 8). In the presence of AgBF4, AgPF6, AgOTs, and
AgSO3CF3 as the source of a counteranion in 1,4-dioxane at
100 °C, a 39−59% yield of 2a was isolated (entries 6, 7, 9, and
The requisite alkylidenecyclopropane substrates were easily
prepared by using known procedures.9 Compound 1a (N-(but-
2-yn-1-yl)-N-(2-cyclopropylideneethyl)-4-methylbenzene-
sulfonamide) was chosen as a model substrate. A solution of 1a
and [Rh(COD)Cl]2 (10 mol %) in toluene was heated at 100
°C under an atmosphere of CO (1 atm) for 11 h. Compounds
Received: May 29, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
Table 1. Optimization for Rh(I)-Catalyzed Carbonylative
Cycloaddition
Table 2. Rh(I)-Catalyzed [3 + 2 + 1] Cycloaddition
Reactions
a
a
c
c
temp
(°C)
time
(h)
2a
3a
entry
catalyst/AgX
solvent
(%)
(%)
1
[Rh(COD)Cl]2
[Rh(COD)Cl]2
Rh(dppp)2Cl
Rh(PPh3)3Cl
toluene
100
″
″
″
″
″
″
″
″
″
″
″
120
11
6
21
61
44
64
NR
55
56
NR
59
39
69
77
91
15
11
2
2
dioxane
3
″
″
″
″
″
″
″
″
6
4
13
6
b
5
″/AgSbF6
b
6
″/AgBF4
″/AgPF6
6
b
7
6
b
8
″/AgClO4
″/AgOTs
6
b
9
12
7
b
10
11
12
13
″/AgSO3CF3
b
″/AgCO2CF3
″
″
6
″/ ″
″/ ″
6
xylenes
2
b
a
Conditions: Substrate concentration 0.055 M. Rh(PPh3)3Cl (5 mol
%) and AgX (7.5 mol %) were used. Isolated yields.
c
10). When the reaction was carried out using AgCO2CF3 in
1,4-dioxane at 100 °C for 6 h, the yield of 2a increased to 69%
(entry 11). Increasing the quantity of Rh(PPh3)3Cl (10 mol %)
and AgCO2CF3 (15 mol %) increased the yield of 2a (77%)
(entry 12). Furthermore, the reaction time was decreased to 2 h
by using xylenes as the reaction solvent at 120 °C. The highest
yield of 2a (91%) was obtained in the presence of 10 mol %
Rh(PPh3)3Cl and 15 mol % AgCO2CF3 (entry 13). The
structure of 2a was confirmed by using X-ray diffraction
crystallography (Figure 1).
a
Reaction conditions: 10 mol % Rh(PPh3)3Cl, 15 mol % AgCO2CF3, 1
b
atm of CO in xylenes (0.055 M) at 120 °C for 3 h. Isolated yields.
reaction proceeded smoothly to afford a cyclopropylbenzene
derivative in 85% yield (entry 8). Both carbon- and oxygen-
linked 1,6-enynes could be used in the reaction with similar
results (entries 9−12). When 1,7-enynes were used in the
reaction, the yield of a reaction was highly dependent upon the
substituent on the alkyne. When a 1,7-enyne bearing a methyl
group on the alkyne was used as the substrate, the
corresponding product, tetrahydroisoquinolinol, was isolated
in 52% yield (entry 13). This is the first report for the
transformation of nitrogen-tethered 1,7-enynes to isoquinoli-
nols.13 Tetrahydroisoquinolines are present in various potent
cytotoxic agents that display a range of antitumor, antimicro-
bial, and other interesting biological activities depending on
their structures.14 However, for a 1,7-enyne bearing a phenyl
substituent on the alkyne, known to be inert in the gold-
catalyzed cycloisomerization,15 the reaction was sluggish under
our optimized reaction conditions. The phenol derivative was
isolated in a low yield (14%), whereas the 1-methylene-
hexahydro-1H-indene (4n) was isolated as the major product in
49% yield (entry 14 and eq 2). The presence of a gem-dimethyl
group at the propargylic position does not result in any
carbonylation and the 4-methylene-hexahydropentalene deriv-
ative was isolated in 33% yield (eq 3). The formation of
compound 4 from alkylidenecyclopropanes has been reported
Figure 1. X-ray structure of 2a.
To further expand the scope of the reaction, a variety of
alkylidenecyclopropanes were investigated under the optimized
reaction conditions (Table 2). A diverse range of substrates
were tolerated under the optimized reaction conditions,
resulting in the high yields (74%−91%) of compound 2.
However, the nitrogen-tethered 1,6-enynes with a terminal
alkyne or a vinyl group on the terminal alkyne afforded
relatively lower yields (19% and 23% yields, respectively)
(entries 2 and 7).12 For nitrogen-tethered substrates, the
introduction of an electron-donating group (−OMe) or
electron-withdrawing group (−Cl or −CF3) on the aryl ring
did not improve the reaction (entries 4−6). Interestingly, for an
enyne with a cyclopropyl group on the terminal alkyne, the
B
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Organic Letters
Letter
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedure and characterization of all
compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ykchung@snu.ac.kr.
Notes
in the palladium-catalyzed cycloaddition reaction.16 When the
same reaction was conducted without CO, the reaction became
slow and the yield of 4-methylene-hexahydropentalene did not
improve. The presence of CO is beneficial for the reaction,
even though the reaction to form 4 is not related to the
carbonylation reaction.12,17
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea (NRF) (2007-0093864 and 2014-011165). S.K.
thanks the Brain Korea 21 Plus Fellowships.
On the basis of the related previous studies,18,19 a plausible
reaction mechanism is outlined in Scheme 1. Alkylidenecyclo-
REFERENCES
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Scheme 1. Proposed Reaction Mechanism
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