Ynol Ethers as Ketene Equivalents in Rhodium-Catalyzed Intermolecular [5 + 2] Cycloaddition Reactions

Article abstract of DOI:10.1021/acs.orglett.7b02765

The previously unexplored metal-catalyzed [5 + 2] cycloadditions of vinylcyclopropanes (VCPs) and electron-rich alkynes (ynol ethers) have been found to provide a highly efficient, direct route to dioxygenated seven-membered rings, a common feature of num

Full text of DOI:10.1021/acs.orglett.7b02765

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Ynol Ethers as Ketene Equivalents in Rhodium-Catalyzed
Intermolecular [5 + 2] Cycloaddition Reactions
Paul A. Wender,* Christian Ebner, Brandon D. Fennell, Fuyuhiko Inagaki,† and Birte Schroder‡
̈
Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, California 94305, United States
S
* Supporting Information
ABSTRACT: The previously unexplored metal-catalyzed [5 +
2] cycloadditions of vinylcyclopropanes (VCPs) and electron-
rich alkynes (ynol ethers) have been found to provide a highly
efficient, direct route to dioxygenated seven-membered rings, a
common feature of numerous natural and non-natural targets
and building blocks for synthesis. The reactions proceed in
high yield at room temperature and tolerate a broad range of functionalities. Substituted VCPs were found to react with high
regioselectivity.
ew reactions, reagents, and catalysts change how we think
about bond construction, thereby enabling new strategic
ynol ethers as 2C components in [5 + 2] cycloadditions is further
motivated by the potential use of such a process in accessing
diverse targets.2,14 Numerous natural (estimated at >3000)15 and
non-natural products, including many of research and
therapeutic importance,16 incorporate functionalities derivable
from cycloheptan-1,4-diones (CHDs).17,18 Yet few methods
exist for the direct construction of such systems.19 We have now
found that the metal-catalyzed cycloaddition of ynol ethers and
VCPs provides a solution to this problem.
N
choices for step economical and greener, if not ideal, syntheses.1
As part of our studies on new cycloaddition reactions,2,3 we
previously reported a route to seven-membered rings involving
the metal-catalyzed [5 + 2] cycloaddition of vinylcyclopropanes
(VCPs) and π-components.4 Rhodium catalysts have proven to
be the most general for this CC bond activation process, working
thus far intramolecularly with alkynes, alkenes and allenes and
intermolecularly with alkynes and activated allenes as 2C
components.2,3,5
To determine the suitability of ynol ethers as substrates20 in [5
+ 2] cycloadditions, 1-ethoxy-1-octyne (2c, R = n-hexyl) was
chosen as a test reactant in an initial catalyst screening (for
substrate syntheses, see Supporting Information (SI)).
To extend the reach of these [5 + 2] cycloaddition reactions
and more generally other [m + n] processes, we have been
exploring the use of π-component equivalents of otherwise
inaccessible, difficult to use, or unsafe π-systems including allene6
and buta-1,2,3-triene4c equivalents of gaseous allenes and
cumulenes as well as tetramethyleneethane7 (TME) equivalents
of the unstable and difficult to access TME. Here we report the
use of ynol ethers (Scheme 1, left) as ketene (Scheme 1, right)
equivalents in [5 + 2] cycloadditions with VCPs.8
We first tested [RhCl(CO)2]2 as a catalyst in the reaction of 2c
at 25 °C with commercially available VCP 1a. Cycloadduct 3c
did not form. Upon heating at 90 °C, the reaction gave 3c albeit
in only 52% yield. A recently introduced cationic Rh(I) catalyst
([Rh(dnCOT)(MeCN)2]SbF6)4a,b provided only complex
mixtures. In contrast, [Rh(naph)(COD)]SbF6, another cationic
Rh catalyst,21 gave promising initial results (Table 1, entry 1:60%
of 3c), working even at 25 °C in 2,2,2-trifluorethanol (TFE), and
was thus selected for further study.
Scheme 1. Use of Ynol Ethers as Ketene Equivalents
Interestingly, when excess ynol ether 2c (3.0 equiv) was used
to increase the yield, cycloadduct 3c was obtained but in only
35% yield, suggesting that the ynol ether inhibits catalysis (Table
1, entry 2). To test this point, the catalyst was stirred with ynol
ether 2c for 2 h after which VCP 1a was added (entry 3). No
cycloadduct was formed and only starting materials were
isolated. To overcome this substrate inhibition problem, the
catalyst loading was increased (5 mol %) and the amount of the
ynol ether was decreased (1.1 equiv, entry 4). An improved yield
(74%) was obtained. Finally, to further minimize the inhibitory
effect of the ynol ether, 2c was added dropwise over 2 h. Under
these conditions, the cycloadduct was formed in excellent yield
While ketenes can be used as π-components in some metal-
catalyzed cycloadditions,9 their electron-poor nature, propensity
to dimerize, and incompatibility with a range of functionalities
limits their utility.10 In contrast, ynol ethers are electron-rich and
easily prepared by alkylation of the parent metal alkoxyacety-
lide.11 However, their use in metal-catalyzed cycloadditions is
largely unexplored and potentially problematic due to their
reported “instability” in the presence of cationic rhodium
complexes.12,13 Beyond their mechanistic interest, the study of
Received: September 5, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02765
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
coordinative deactivation of the catalyst. Supporting this idea,
slower addition of the ynol ether produced cycloadduct 3n in
80% yield (see SI, Table S1). Nitro-groups (3l), esters (3m),
additional ethers (3n) and aryl-bromides (3j, 3o−3q) were also
well tolerated. Bromide substitution was accommodated at all
aryl positions, providing versatile handles for subsequent
diversification.
Table 1. Optimization Studies
While many alkyl-substituted ynol ethers can be made in pure
form,20 their purification over silica results in substantial
decomposition. The use of crude ynol ethers was therefore
tested as an alternative. Two substrates (2c and 2d), purified and
unpurified (see SI, Table S2), gave identical yields. The aryl
substrates were more robust and were purified using triethyl-
amine neutralized silica.
Next, catalyst loading and reaction scale were investigated (see
SI, Table S3). With 5 mol % catalyst, ynol ether, 2a gave
cycloadduct 3a in 87% isolated yield (Scheme 2). Significantly, a
near equivalent yield (86%) was obtained with 1 mol % of
catalyst. When tested on a 1 mmol scale at room temperature
using 1 mol % of catalyst, 3a was obtained in 87% yield (Scheme
3). To check substrate generality, 2e was also tested, giving 3e in
93% isolated yield (Scheme 3).
catalyst loading
ynol ether
[equiv]
yield
[%]
entry solvent
[mol %]
t [h]
1
2
3
4
5
6
TFE
TFE
TFE
TFE
TFE
TFE
3
3
3
5
5
0
1.1
3.0
1.1
1.1
8
60
35
12
4.5
4
ab
,
0
74
c
1.1
2
91
d
1.1
4
0
a
b
[Rh] and 2c were stirred in TFE for 2 h prior to the reaction. 1a was
recovered. 2c was added dropwise over the course of 2 h. Reaction
was carried out at 80 °C.
c
d
(91%, entry 5). No reaction was observed in the absence of
catalyst, even when the reaction was heated for 4 h (entry 6).
Using the above conditions, a broad range of ynol ethers
yielded CHDs in good to excellent yields (Scheme 2). Terminal
alkyne 2a (EtOCCH) and TMS-analogue 2b (EtOCCTMS),
equivalents of ketene itself, reacted efficiently, both giving dione
3a after workup. Alkyl-substituted (2c−2g, 2i−2j) and aryl-
substituted ynol ethers (2k−2q) were also effective substrates.
Halogen containing substrates (2e, 2f) reacted efficiently along
with terminal alkene 2g (84% yield). Of mechanistic interest,
trisubstituted alkene 2h gave a complex mixture, potentially due
to catalyst deactivation by chelative coordination. Supporting
this hypothesis, the otherwise efficient reaction of 2d with VCP
1a, in the presence of 2h, yielded no cycloadduct 3d. Benzyl
substituted ynol ethers (2i and 2j) also worked moderately well.
For aryl-containing ynol ethers, a solvent mixture of 1,2-
dichloroethane (DCE) and TFE (1:1) was used.6 Phenyl
derivative 2k gave cycloadduct 3k in 94% isolated yield and
65−80% yields were obtained for both electron-rich and
electron-poor aryl derivatives. The electron-rich anisole 2n
required slower addition (4 h) to overcome its hypothesized
Scheme 3. Cycloaddition with Reduced Catalyst Loading at 1
mmol Scale
To explore regioselectivity, the reactivity of VCP 1b was
examined. In this case, 2 equiv of VCP 1b provided improved
yields. Significantly, only the 5,7-dialkyl substituted cycloadducts
4d and 4e were isolated to indicate a 1:1 mixture of
diastereomers (Scheme 4).
Two regioisomers are possible depending on the ynol ether
orientation during insertion. Previous studies have shown that
alkyl-substituted terminal alkynes exhibit moderate regioselec-
d
Scheme 2. Substrate Scope
a
b
c
d
Additional 12% of double bond migration byproduct were isolated. Complex product mixture was formed. 2n was added over 4 h. Reaction
conditions: 5 mol % catalyst, 1.0 equiv VCP, 1.1 equiv ynol ether added dropwise over 2 h. Solvent: TFE (3a−3h), TFE/DCE 1:1 (3i−3q). For aryl
substituted ynol ether (3k−3q), the reaction mixture was stirred for additional 2 h.
B
DOI: 10.1021/acs.orglett.7b02765
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Organic Letters
Letter
halogenated solvent option for both aryl- and alkyl-ynol ether
substrates.
Scheme 4. Regioselective Access to 5,7-Disubstituted
Cyclohepta-1,4-diones
Scheme 7. Use of Acetone As a Solvent
tivity (up to 7:1) using VCP 1b.22 Internal ynol ethers have not
been tested previously. Providing the first experimental data on
this issue of more general mechanistic and synthetic importance,
ynol ethers 2d and 2e were found to react with excellent
regioselectivity (>20:1).
To determine whether access to 6-substituted CHDs could
also be achieved, the reaction of VCP 1c was examined. As
observed with ynol ethers 2d and 2e (Scheme 4), the
cycloaddition of VCP 1c and ynol ether 2a proceeded with
excellent regioselectivity to give only one regioisomer, CHD 5a,
in 76% yield (Scheme 5).
In summary, we report the first use of ynol ethers as ketene
equivalents in the rhodium-catalyzed intermolecular [5 + 2]
cycloaddition reaction with VCPs and the first study of reaction
regioselectivity. The cycloaddition proceeds at room temper-
ature within minutes to hours and provides substituted
cyclohepta-1,4-diones in good to excellent yields. The reaction
tolerates a wide range of functionality commonly encountered in
synthesis and can be run in various solvents (DCE, TFE,
acetone). Substituted VCPs can also be used and react with
unprecedentedly high regioselectivity. For cost, safety and time
considerations, these exploratory experiments were conducted
on a small scale but are not affected by a 10-fold scale increase
and can be done with a catalyst loading of 1 mol %. The use of
these substituted CHDs in synthesis and as scaffolds in designed
libraries will be reported in due course.
Scheme 5. Regioselective Access to 6-Substituted Cyclohepta-
1,4-dione
ASSOCIATED CONTENT
* Supporting Information
■
S
Significantly, this method is not limited to oxygen substituted
VCPs. Alkyl substituted VCPs also work well, as shown by the
reaction of VCP 1d with ynol ether 2a, which gave cyclo-
heptenone 6a in 73% (Scheme 6, top). This method provides a
strategically complementary route to cycloheptenones, as one
can choose the more accessible VCPs and alkynes to produce a
common product.5a
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02765.
Experimental procedures and characterization data for all
reactions and products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wenderp@stanford.edu.
ORCID
Scheme 6. Application of an Alkyl-Substituted VCP
Paul A. Wender: 0000-0001-6319-2829
Fuyuhiko Inagaki: 0000-0003-2999-083X
Present Addresses
†Kanazawa University, Kanazawa, 920−1192, Japan.
‡Universitat Konstanz, 78462 Konstanz, Germany.
̈
Author Contributions
The manuscript was written through contributions of all authors.
Notes
The authors declare no competing financial interest.
To further test functional group tolerance, the reaction of VCP
1a with ynol ether 2k was conducted in the combined presence of
acetone, ethyl acetate, diethyl ether, triethyl amine, cyclohexene
and maleic anhydride (0.3 equiv of each). Using the conditions
given in Scheme 2, cycloadduct 3k was isolated in 86% yield,
indicating broad functional group tolerance. Prompted by these
results and the previously reported preference for DCE and TFE
as solvents,21b the cycloaddition was conducted in acetone.
Significantly, excellent yields were obtained in a room temper-
ature reaction that was complete in 30 min (Scheme 7). Slow
addition was not required. Acetone is thus a superb non-
ACKNOWLEDGMENTS
■
Fellowship support was graciously provided by the Swiss
National Science Foundation (C.E.), the National Science
Foundation Graduate Research Fellowship (B.F., DGE-
114747), the Japan Society for the Promotion of Science
(F.I.), and the German Academic Exchange Service (B.S.). Grant
support provided by the National Science Foundation
(CHE848280) and National Institute of Health (R37
CA031845) is gratefully acknowledged.
C
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Organic Letters
Letter
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D
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