Copper-Catalyzed Ring Opening of [1.1.1]Propellane with Alkynes: Synthesis of Exocyclic Allenic Cyclobutanes

Article abstract of DOI:10.1021/acs.orglett.9b03999

Despite the long history and interesting properties of propellanes, these compounds still have tremendous potential to be exploited in synthetic organic chemistry. Herein we disclose an experimentally simple procedure to achieve cyclobutane-containing allenes and alkynes through a copper-catalyzed ring opening of [1.1.1]propellane and subsequent reaction with ethynes.

Full text of DOI:10.1021/acs.orglett.9b03999

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Ring Opening of [1.1.1]Propellane with Alkynes:
Synthesis of Exocyclic Allenic Cyclobutanes
́
́
Daniel Lasanyi and Gergely L. Tolnai*
Institute of Chemistry, Eotvos Lorand University, Pazmany P. setany. 1/a, 1117 Budapest, Hungary
S
* Supporting Information
ABSTRACT: Despite the long history and interesting properties of propellanes, these compounds still have tremendous
potential to be exploited in synthetic organic chemistry. Herein we disclose an experimentally simple procedure to achieve
cyclobutane-containing allenes and alkynes through a copper-catalyzed ring opening of [1.1.1]propellane and subsequent
reaction with ethynes.
ropellanes are fascinating molecules.1 The unique
structure and behavior of these molecules have captivated
of the most comprehensive early studies on the reactions of
[1.1.1]propellane briefly mentions these kinds of reactions.11
Wiberg and Waddel found analytical evidence that 1 in the
presence of transition metals is prone to undergo dimerization
and trimerization (Scheme 2). This might happen through a
P
the imagination of chemists from the time they were predicted
to exist to the present day.2 Their most interesting properties
include high ring strain and the “inverted” charge-shift type
central C−C bond.3 This property can be used to open up
[1.1.1]propellane (1) in various interesting ways. Owing to the
practical preparation of 1 developed by Szeimies,4 most of the
available synthetic methods are aiming for the valuable
[1.1.1]bicyclopentane scaffold in one or more steps.5 On the
other hand the ring opening to cyclobutanes are not widely
explored (Scheme 1). The first synthesis of 1 was immediately
Scheme 2. Transition-Metal-Catalyzed Ring Opening of 1
carbenoid intermediate (2). Despite the potentially interesting
cyclobutane products, no synthetic study was done on this
catalytic type of ring opening of [1.1.1]propellane. This might
be due to the fact that cyclobutylidenecarbenes are known to
undergo various kinds of rearrangements by C−C or C−H
insertion of the carbene in an intramolecular manner.12
We were interested in exploring the chemical behavior of
[1.1.1]propellane over various transition metals and exploiting
their chemical behavior in synthetic methods. Our starting
experiments have confirmed the earlier observed dimerization
phenomena over Pd and Pt catalyst. In our hand, dimerization
could also have been induced by iron(II) chloride13 and
copper iodide.
Scheme 1. Ring-Opening Reactions of [1.1.1]Propellane
Our attempts to utilize this carbenoid to cyclopropanate
double bonds are yet unsuccessful, but recent publications on
the application of copper carbenoids in reactions of alkynes14
raised the possibility of a synthetic procedure to gain valuable
allenic cyclobutane product 6 through 5a or 5b (Scheme 3).
followed by showcasing the double ring opening by acetic
acid.6 This ring opening can also be achieved by XeF2 in ether,
resulting in fluorinated cyclobutane.7 Szeimies and Walsh ran a
series of interesting experimental and theoretical studies of
thermal ring opening of propellane in the gas phase. Their
calculations show the intermediate is reminiscent of a
cyclobutylcarbene and bicyclo[1.1.0]butane. This intermediate
then rearranges to various cyclopropanes.8
́
Crabbe-like allene synthesis has great limitations with cyclic
products,15 and only a few other catalytic methods are able to
build up alkylidenecyclobutanes. Those often utilize complex
In contrast to the reactions of bicyclo[n.1.0]alkanes with
nickel,9 the chemical properties of 1 in the presence of
transition metals are scarcely examined in the literature.10 One
Received: November 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03999
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Letter
little as 1% led complete conversion. For the sake of
experimental convenience, 10 mol % of CuI was used.
During the preparation of the scope, we had a reproduci-
bility issue while changing batch of copper iodide. A minor
inseparable impurity of about 5% appeared in the reaction
mixture. The main important factor turned out to be the purity
of copper source. CuI with a purity of 99.999% did not
produce the unidentified side product. After experimenting
with different copper iodide sources, we found that most of
them do not support this side product formation.
Scheme 3. Envisioned Reaction Mechanism
and expensive starting materials and catalysts.16 On the other
hand, the methylidenecyclobutane scaffold is present in
biologically interesting natural products, as the pink hibiscus
mealybug sex pheromone,17 or it is used as key intermediate
during total synthesis.18
According to the few literature precedents, ring strain
enhances the formation of the alkyne product instead of an
isomer exocyclic allene.19 This effect is more notable with
cyclopropanes and earlier described synthetic procedures to
obtain exoallenic cyclobutanes, which suffered from the
formation of isomeric mixtures.20
It is noteworthy that allenes are also important in
pharmaceutical applications, such as in enprostil,21 and as a
synthetic building block.22 Therefore, we aimed to develop a
simple synthetic method to build up this cyclobutane-
containing scaffold.
With this goal in mind, we identified optimal conditions for
the reaction of phenylpropargyl ether (4a) and 1, which
resulted in the conditions in Table 1, entry 1. To offer deeper
insight into this reaction, some alternative conditions are
shown in Table 1.23
Lowering the amount of propellane solution resulted in a
slightly inferior result (entry 8). The base plays an important
role in removing the proton from 4. A 2 equiv amount of non-
nucleophilic Hunig’s-base was utilized to achieve the best
̈
result in yields and reproducibility, but good yields could be
achieved by TEA as well (entry 9). Addition of DBU (entry
10) was inferior to weaker bases, as it resulted in side reactions
in our hand. No conversion of 4a was observed with inorganic
base Cs2CO3. This reaction is very robust to the variation of
solvent; thus, technical-grade THF was used. The trans-
formation generally takes place in 30 min; however, for
convenience, 1 h reaction time was set as the standard in the
optimized conditions.
It was important to establish a scope in order to prove the
general utility of this reaction (Scheme 4). Various propargyl
ethers have been converted to the corresponding allene 6. As
expected, the electronic properties on the phenyl part did not
play crucial role in the observed yields, as compounds with
electron-donating and -withdrawing substituents worked with
equal efficiency to provide the products. Starting materials
Table 1. Optimization of Reaction Conditions
a
Scheme 4. Scope of the Reaction with Terminal Alkynes
a
1
yield
(%)
entry
catalyst
base
(equiv)
1
2
3
4
5
6
7
8
CuI (0.1 equiv)
DIPEA (2 equiv)
DIPEA (2 equiv)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.5
1.5
1.5
1.5
1.5
99
0
Cu(acac)2 (0.1 equiv) DIPEA (2 equiv)
Cu(OAc)2 (0.1 equiv) DIPEA (2 equiv)
20
57
95
99
99
86
98
12
0
CuCl (0.1 equiv)
CuI (0.01 equiv)
CuI (0.15 equiv)
CuI (0.1 equiv)
CuI (0.1 equiv)
CuI (0.1 equiv)
CuI (0.1 equiv)
CuI (0.1 equiv)
CuI (0.1 equiv)
DIPEA (2 equiv)
DIPEA (2 equiv)
DIPEA (2 equiv)
DIPEA (2 equiv)
TEA (2 equiv)
9
10
11
12
13
DBU (2 equiv)
Cs2CO3 (2 equiv)
DIPEA (1 equiv)
DIPEA (5 equiv)
89
99
a
Determined by GC−MS. Starting from 0.5 mmol of 4a
In contrast to our optimal conditions, it was confirmed that
the addition of catalyst is crucial for the reaction (entry 2), but
other explored copper catalysts did not lead to a complete
conversion of the alkyne. The only observed exception was
CuCl (entry 5), but due to the inseparable impurities it was
proven to be impractical for use, in contrast to the air-stable
CuI, which gave the allene as the only observable product. The
amount of CuI did not play a crucial role (entries 6 and 7), as
a
Alkyne (1 mmol), [1.1.1]propellane (1.4 mmol), isolated yields.
B
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Letter
bearing aryl halides were converted to the corresponding
cyclobutanes (6e−l), offering a wide range of products through
cross-coupling or cyclization. The procedure was able to
convert alkynes bearing functional groups such as ester (6m),
aldehyde (6n), amide (6o), or amine (6p) into the exocyclic
allenes in good to excellent yields.
Scheme 6. X-ray Structure of Product 6x
Finally, 4-bromophenylacetylene and phenylacetylene (4t,u)
was also effectively converted to the corresponding exoallenic
cyclobutane. The last reaction of this table was extended to 10
mmol scale, providing 6u in the same yield (83%, 1.38 g) as 1
mmol.
Other aromatic alkynes are not readily available, so we
turned our attention to silylacetylenes. These are easy to make
via Sonogashira coupling from aryl halides and TMS-acetylene.
Our recent findings on a simple catalytic desilylation strategy,
with the cheap and nontoxic water solution of hexafuorosilicic
acid,24 encouraged us to develop a one-pot procedure directly
from silylalkynes. In the conditions of the cyclobutylation, the
desilylation by catalytic H2SiF6 occurred smoothly and gave
free terminal alkyne. This acetylene could be used in situ for
the reaction with 1, avoiding an extra step in the preparation of
such substances. In this manner, a range of cyclobutanes were
synthesized. (Scheme 5). In general, high yields have been
groups making the cyclobutylcopper intermediate more
nucleophilic; thus, it is easier to directly protonate it.
Both TIPS and TMS acetylene form in high efficiency, over
85 and 95% GC conversion, respectively, but these product
molecules remain a challenge in gaining a pure form due to
their apolar character or volatility. In contrast, it is convenient
to exploit this phenomenon in the preparation of different
alkynycyclobutanes. The product 1-methylidene-3-alkynylcy-
clobutanes are not easy synthetic targets, as only a handful of
compounds were found in the literature, made by cyclization,25
or Wittig reaction in a very low yield while preparing some
antibacterial agents.26 Again, hexafluorosilicic acid came handy
in this step for the one-pot Sonogashira coupling. The TMS-
alkynyl cyclobutane 8a was converted into various aromatic
and hetroaromatic products 8b−8e (Scheme 7).
a
Scheme 5. Substrate Scope from Silylacetylenes
Scheme 7. Synthesis of Alkynylcyclobutanes through TMS
a
Acetylene
a
Silylalkyne (1 mmol), [1.1.1]propellane (1.5 mmol), isolated yields.
observed for these products derived from 1-aryl-2-silylalkynes.
It was possible to synthesize arylallenes in this manner,
including ones bearing keto (6y), amide (6ab), or ester (6ac)
functional groups. Even a trifluoromethylated aniline deriva-
tive, 6ae was transformed to the corresponding cyclobutane.
To gain more knowledge on this novel structural motif, we
attempted to acquire information on its structure. We were
able to produce a suitable single crystal of 6x for X-ray
spectroscopy (Scheme 6). As expected, the new scaffold is a
linear motif with a 6.025 Å distance from the first allene carbon
to the methylidene.
a
Alkyne (1 mmol), [1.1.1]propellane (1.4 mmol), isolated yields.
Regarding the mechanism, radical ring opening of 1 seems
unlikely, as such a rearrangement has a very high activation
energy barrier.27 To confirm the absence of activity of radicals
in this reaction, 0.1 and 1 equiv of TEMPO was added to the
reaction mixture (Scheme 8). This had no effect on the
outcome of the reaction. Somewhat surprisingly, we did not
even observe the product of the reaction of 1 and TEMPO,
which emphasizes the fast reaction rate of ring opening by
copper. Deuterated acetylene was allowed to react this time in
In the case of 1H-2-silylacetylenes, exclusive alkynylcyclo-
butane (8) formation was observed. It is possible that the
sterical hindering and electron donating the effect of the silyl
C
DOI: 10.1021/acs.orglett.9b03999
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Letter
explore similar ring opening pathways to use the resulting
carbenes generated from strained propellanes in various
organic reactions.
Scheme 8. Mechanistic Investigation
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03999.
Experimental details; spectra of products (PDF)
Accession Codes
anhydrous THF, to give product in a level of deuteration of
more than 75% (6af).
Recent experimental and computational results from the
field of allene synthesis from hydrazones can provide some
suggestions for the mechanistic cycles.14b,d,f It is possible
(Scheme 9, path A) that from 4 in the slightly basic condition
CCDC 1947306 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Scheme 9. Depicted Working Hypotheses
■
Corresponding Author
*E-mail: tolnai@chem.elte.hu.
ORCID
Gergely L. Tolnai: 0000-0002-5253-5117
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to Dr. L. Burai and S. Szabo (Servier) for
HRMS measurements. Dr. Veronika Harmat and Anna J. Kiss-
■
́
́
Szeman are acknowledged for X-ray diffraction experiment
́
structure solution. Prof. Z. Novak (ELTE) is acknowledged for
providing some necessary analytical and technical background.
́
We are grateful to Ferenc Beke for proofreading the
manuscript. This research was supported by the Hungarian
Academy of Sciences (PPD003/2016). D.L. is grateful to
Servier for a Servier−Beregi Scholarship. This work was
completed in the ELTE Institutional Excellence Program
supported by the National Research, Development and
Innovation Office (NKFIH-1157-8/2019-DT). The X-ray
crystallography part of the research was supported by the
E.U. and Hungary, cofinanced by the ERDF within projects
No. VEKOP-2.3.3-15-2017-00018 and VEKOP-2-3-2-16-2017-
00014.
with copper a Cu acetylide (I) forms. This copper(I) species is
able to coordinate to 1 through its charge shift type central
bond, causing the ring opening that gives 5a. Then carbene
insertion occurs, resulting in alkynyl cyclobutane (II).
The other envisioned route (path B) is more similar to the
one calculated by Bai to be lower in energy in the case of
carbenes generated from hydrazones. In the first step, the
cyclobutylcarbene (III) is formed. This is then attacked by the
terminal acetylene to give a vinylcation intermediate (5b),
which is deprotonated by the base, resulting in II. The strong
electron-donating property of silyl groups might facilitate the
direct protonation of this intermediate, while in other observed
cases rearrangement happens to the allene 6.
DEDICATION
Dedicated to the memory of Professor Dr. Gyorgy Hajos.
■
́
̈
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