Host-Catalyzed Cyclodehydration–Rearrangement Cascade Reaction of Unsaturated Tertiary Alcohols

Article abstract of DOI:10.1002/adsc.201601363

The Br?nsted acidic resorcin[4]arene hexamer can be applied as an effective catalyst in the dehydrative cyclization and subsequent rearrangement of unsaturated tertiary alcohols. This is the first report on catalyzing such a reaction with a Br?nsted acid. Scope and limitations of this cyclopentene-forming reaction sequence are presented. Furthermore, substrate-selective conversion as well as competitive inhibition are described and provide evidence that the reactions proceed within the cavity of the self-assembled structure. Additionally, a cyclobutanone-forming intramolecular hydride transfer of an encapsulated cyclopropyl acetate is reported. (Figure presented.).

Full text of DOI:10.1002/adsc.201601363

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DOI: 10.1002/adsc.201601363
Host-Catalyzed Cyclodehydration–Rearrangement Cascade
Reaction of Unsaturated Tertiary Alcohols
Lorenzo Catti,a Alexander Pçthig,b and Konrad Tiefenbachera,c,*
a
Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
Fax : (+41)-612-671-005; phone: (+41)-612-075-609; e-mail: konrad.tiefenbacher@unibas.ch
Catalysis Research Center, Technical University of Munich, Ernst-Otto-Fischer-Straße 1, D-85748 Garching, Germany
Department of Biosystems Science and Engineering, ETH Zꢀrich, Mattenstrasse 26, CH-4058 Basel, Switzerland
b
c
Received: December 10, 2016; Revised: January 23, 2017; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601363.
Abstract: The Brønsted acidic resorcin[4]arene hexa- dence that the reactions proceed within the cavity of
mer can be applied as an effective catalyst in the de- the self-assembled structure. Additionally, a cyclobu-
hydrative cyclization and subsequent rearrangement tanone-forming intramolecular hydride transfer of an
of unsaturated tertiary alcohols. This is the first encapsulated cyclopropyl acetate is reported.
report on catalyzing such a reaction with a Brønsted
acid. Scope and limitations of this cyclopentene-
forming reaction sequence are presented. Further- Keywords: carbocations; homogeneous catalysis; hy-
more, substrate-selective conversion as well as com- dride transfer; self-assembly; supramolecular chemis-
petitive inhibition are described and provide evi- try
Introduction
prepared on a multigram scale in a single step, start-
ing from 1,3-dihydroxybenzene. The octahedral-
The last two decades have seen a remarkable advance shaped assembly is held together by a network of 60
in the development of self-assembled supramolecular
host structures. Various non-covalent forces like
metal–ligand interactions,[1] hydrogen bonds[2] and the
hydrophobic effect[3] have been employed for the con-
struction of these molecular assemblies. The distinct
chemical environment, provided by these structures
to the encapsulated substrates, has been utilized in
several cases for catalytic transformations displaying
a high degree of substrate and/or product selectivity.[4]
Especially, reactions involving cationic transition
states have been catalyzed within self-assembled host
structures.[1e,5] These reactions are often accelerated
by stabilization of the transition state via cation–p in-
teractions[6] with the aromatic cavity walls. The in-
creasing implementation of self-assembled supra-
molecular structures into homogeneous catalysis
partly arises from their ease of preparation. Only
smaller subunits have to be synthesized, which then
spontaneously assemble to yield the desired catalyst
in situ.
A hydrophobic cavity of about 1400 ꢁ3 is formed
by the hexameric resorcin[4]arene structure I, which
self-assembles in apolar solvents like chloroform from
Figure 1. a) Structure of the resorcin[4]arene monomer 1,
accessible in one synthetic step; b) model of the hexameric
resorcin[4]arene capsule I (C=black; O=red; H=white);
alkyl groups have been omitted for clarity; c) competitive
six resorcin[4]arene units 1 and eight water molecules
(Figure 1).[7] The resorcin[4]arene unit 1 can be easily inhibitor Bu4NBr (2).
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hydrogen bonds and is capable of reversible guest en- quent 5-exo olefin cyclization results in cationic spe-
capsulation via a proposed pentameric intermediate.[8] cies 5, which is related to the protosterol cation ob-
Cationic species like quaternary ammonium ions served in the biosynthesis of lanosterol.[17] Next, a 1,2-
(e.g., 2) show a high affinity towards the capsule inte- hydride shift generates the thermodynamically more
rior due to strong cation–p interactions with the aro- stable[18] endocyclic cation 6. According to a detailed
matic cavity walls.[9] Additionally, also compounds ca- DFT study by Vrcek, the formation of intermediate 6
pable of hydrogen bonding, like carboxylic acids and represents the rate-determining step of the overall re-
alcohols, are known to be encapsulated well within action cascade.[18] The spiro-type cation 6 then under-
the capsule interior.[10] Depending on the size of the goes a Wagner–Meerwein ring expansion to give in-
guest molecule, residual solvent molecules are coen- termediate 7, which undergoes elimination to yield
capsulated to reach an optimum packing coefficient annulated cyclopentene 8 as the final product of the
of approximately 0.55.[11] The hexameric assembly has cyclorearrangement.
furthermore been shown by our group to act as
a mild phenol-based Brønsted acid (pKa ꢀ5.5–6), ca-
pable of activating suitable substrates by protona- Results and Discussion
tion.[12] The extended delocalization of the negative
charge renders the deprotonated capsule a non-nucle- We started our investigation by adding cyclopentyl al-
ophilic counter ion, which allows for the study of cat- cohol 3 to a solution of 10 mol% of hexamer I in
ionic cascade reactions. However, the application of CDCl3. Shortly after mixing, new upfield-shifted reso-
hexamer I as an acid catalyst is still limited.[12,13]
nances in the region of 0.5 to À0.6 ppm could be ob-
1
As part of our ongoing investigation of hexamer I- served in the H NMR spectrum of the reaction mix-
catalyzed cationic cyclizations, we became aware of ture (Figure 2). The observed upfield shift, caused by
an early report of the Epstein group regarding a selec- the aromatic anisotropy of the cavity walls, indicated
tive cyclodehydration–rearrangement cascade reac- successful encapsulation of the alcohol substrate. In
tion of hydroxy olefin 3 (Scheme 1). The report de- addition, the diffusion coefficient of those resonances
scribes the use of a seven-fold excess of trifluoroacetic matched the diffusion coefficient of the hexameric as-
acid (TFA) (pKa =0.2) to induce the depicted reac- sembly, which further corroborated
a successful
tion.[14] Indeed, similar cyclorearrangements have also uptake of the substrate (see the Supporting Informa-
been shown to require an excess of Brønsted acid and tion, Figure S3). A quantification of the encapsulated
in most cases also require an excess of Lewis acid.[15] guest via integration of the upfield-shifted resonances,
Catalytic approaches to related reactions are limited however, could not be performed due to the reactivity
to the use of expensive transition metal catalysts.[16] of the guest and the unknown correlation between
We therefore decided to probe if the reaction of sub- shifted and original resonances. In contrast to our pre-
strate 3 can be rendered catalytic by exploiting the vious studies,[12,13b,c] the reaction temperature was
unique microenvironment provided by the supra- raised to 508C in order to facilitate the dehydration
molecular hexamer I. Furthermore, prompted by the
report of only two substrates, we set out to investigate
the scope and limitations of this cationic cascade reac-
tion.
The reaction sequence starts with an initial proto-
nation of the hydroxy group, followed by dehydration
to yield cationic intermediate 4 (Scheme 1). Subse-
Figure 2. 1H NMR spectra in CDCl3 of a) hexamer
I
(3.3 mM); b) hexamer I (3.3 mM) and substrate 3 (33 mM),
10 min after mixing (area between 0.5 and À0.6 ppm en-
larged); c) hexamer I (3.3 mm), Bu4NBr (2) (5.0 mM) and
substrate 3 (33 mM) (silicone grease marked with an aster-
isk); d) substrate 3 (33 mM).
Scheme 1. Mechanism of the cyclodehydration–rearrange-
ment cascade reaction of hydroxyolefin 3.[18]
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process. Furthermore, literature data suggest an accel- dration products (see the Supporting Information,
eration of guest encapsulation at elevated tempera- chapter 15), slowly equilibrated over 4 days to give
tures.[8,19] According to GC analysis, complete con- the desired bicyclic structure 8 as the main product in
sumption of the starting material was achieved after 81% yield (Table 1). The slow equilibration process
2 h. The initially formed product mixture, consisting via reprotonation can be attributed to the low affinity
of the desired product and the two non-cyclized dehy- of the dehydrated side products towards the capsule
Table 1. Substrate scope of the cyclodehydration–rearrangement tandem reaction.[a]
[a]
Reaction conditions: substrate (33 mM), catalyst I (3.3 mM), CDCl3, 508C, 1–7 days.
Determined via GC.
Identical reaction conditions and reaction time, but in the presence of Bu4NBr (2)
[b]
[c]
(1.5 equiv.).
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interior. The weak binding of the dehydrated products product 11 was formed in moderate yield. Additional-
results from their inability to form hydrogen bonds ly, no significant amounts of electrophilic aromatic
and successfully prevents product inhibition, a prob- substitution products could be observed. When the b-
lem often encountered in supramolecular cata- residue was completely omitted, the reaction still pro-
ACHTUNGTRENNUNG
lysis.[5a,20] The applied catalyst loading is based on one ceeded, yielding annulated cyclopentene 13 in good
of our previous studies,[13b] which revealed a negative yield from hydroxyolefin 12. Following this, we inves-
effect of high hydroxyolefin concentrations on the tigated the influence of the substituents geminal to
overall reaction rate. This negative effect is believed the hydroxy group. An initial attempt, utilizing a cy-
to arise from the interaction of the hydroxy group of clobutyl analogue of substrate 3, failed to give a selec-
the substrate with the monomer units, which reduces tive transformation, probably due to the complex
the equilibrium concentration of the operational cata- mesomeric nature of the cyclobutyl cation.[23] Also
lyst.[21] Additionally, a low initial water content of the a cyclopropyl analogue of substrates 3 failed to under-
reaction mixture was found to be beneficial for the re- go the desired rearrangement process, apparently
action rate. It appears likely that excess water mole- forming the corresponding cyclic ether instead. Em-
cules compete with the alcohol substrate for the pro- ploying substrate 14, which features two ethyl groups,
tons of the hexamer.[13b] When the cavity was blocked restored the desired reactivity, giving cyclopentene 15
by addition of the high affinity guest Bu4NBr (2) in moderate yield. The corresponding methyl sub-
(1.5 equiv.), the yield of cyclopentene 8 was reduced strate 16 performed even better, despite the reduced
to 7% after 4 days under otherwise identical reaction migratory aptitude of methyl groups.[24] In this case,
conditions. This control experiment provided first evi- the desired product 17 was formed together with a cy-
dence that the reaction proceeds within the cavity of clohexene side product, which is assumed to result
the hexameric assembly. It is noteworthy that encap- from an intramolecular proton transfer step (see the
sulation of Bu4NBr (2) has been shown to increase Supporting Information, Scheme S7).[25] Derivative 18,
the acidity of hexamer I.[13c] This further enhances the which requires a 1,2-hydride shift after protonation
quality of the performed control experiment. When and cleavage of water, gave a reduced yield of prod-
the reaction was repeated in the presence of metha- uct 17, due to increased formation of the cyclohexene
nol, which disrupts the hydrogen-bonding network side product. In both cases, only traces of an acyclic
and leads to dissociation of hexamer I, no formation diene intermediate could be detected during reaction
of product 8 could be observed (see the Supporting monitoring. Additionally, no substantial amounts of
Information, chapter 10.4). This indicates that sub- other intermediates could be observed, which indi-
strate activation by simple hydrogen bonding from cates a ꢃnon-stopꢄ reaction mechanism. This can to
the phenolic units is not enough to accelerate the re- some extent be attributed to the high stabilization of
action. In addition, when hexamer I was replaced by the generated phenolate anion. The negative charge
10 mol% of TFA, only 5% of product were formed can freely shift through the entire hydrogen bond net-
after 4 days at 508C, although the acidity of TFA is work via proton migration, resulting in high stabiliza-
about five orders of magnitude higher than that of I. tion and therefore low nucleophilicity. Changing the
This significant difference is likely to result from the b-residue led to substrates 19 and 21, which cyclized
stabilization of cationic intermediates and transition in satisfactory yields to the corresponding cyclopen-
states via cation–p interactions in the cavity of hexa- tenes 20 and 22. To showcase a possible derivatization
mer I, as it has been observed in other reactions.[22]
of the obtained cyclopentenes and further confirm the
Next, we investigated the formation of product 8 rearranged structure, the crude mixture of product 20
starting from hydroxyolefin 9, the only other substrate was subjected to catalytic Sharpless alkene cleavage
reported by Epstein et al.[14] The structure of substrate conditions,[26] giving the corresponding diketone in
9 requires a hydride shift after protonation and cleav- 56% isolated yield over two steps (see the Supporting
age of water or a deprotonation–reprotonation se- Information, chapter 8). An attempt to induce polycy-
quence of an intermediary formed alkene prior to cle formation, by employing a substrate carrying
cyclization. Similar to exocyclic cation 5, the initial a second homoprenyl group in the b-position, failed,
hydride shift lowers the energy of the system by locat- resulting only in unselective conversion of the starting
ing the positive charge within the ring, as indicated by material (see the Supporting Information, chapter
DFT calculations.[18] Indeed, treatment of substrate 9 12). Subsequent investigation of alcohol 23 illustrated
with hexamer I for 3 days afforded product 8 in 75% the influence of the b-methyl group on the 1,2-methyl
yield. Reaction monitoring via GC furthermore ex- migration. The expected product 24 was formed in
cludes substantial deprotonation, favoring a 1,2-hy- only 45% yield, together with 32% of a cyclopentene
dride shift mechanism. After having proven the ap- that was formed by direct elimination after the 1,2-hy-
plicability of hexamer I as a catalyst, the tolerance of dride shift. A prolonged reaction time did not lead to
the reaction sequence towards b-residue variation was an increased formation of product 24 by reprotona-
probed utilizing substrate 10. In this case, the desired tion of the side product, but led to a slow consump-
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tion of both products. The 1,2-methyl migration ap-
pears to be favored by a b-substituent via hyperconju-
gative stabilization of the partial positive charge in
the transition state. An equilibrium between the two
products could be excluded by subjecting isolated
product 24 to the standard reaction conditions. Inter-
estingly, when the b-position was blocked by introduc-
tion of a second methyl group, an entirely different
pathway was followed, resulting in the formation of
a cyclohexene structure in high selectivity (see the
Supporting Information, chapter 13). Finally, the in-
fluence of preorganization was probed by employing
substrate 25. In this case, the bicyclic product 26 was
formed in good yield after 5 days of equilibration.
All substrates were tested in the presence of the
competitive inhibitor Bu4NBr (2), giving only a low
yield (ꢁ13%) of the desired product (see Table 1).
An exception regarding this observation was substrate
25, which formed product 26 in 55% despite the pres-
ence of Bu4NBr (2), presumably caused by its preor-
Scheme 2. a) Mechanism of the cyclobutanone formation; b)
crystalline derivative of the formed cyclobutanone.
ganization-based tendency for cyclization. Bu4NBr (2) ed mechanism for product formation is depicted in
has recently been shown to be encapsulated as an ion Scheme 2, assuming an intramolecular 1,5-hydride
pair,[27] which means the overall charge of the assem- transfer after initial protonation of the double bond.
bly does not change upon encapsulation. Further- Intramolecular hydride transfers have been recently
more, control experiments in the absence of catalyst I reviewed in detail as an attractive approach to C–H
were performed with substrates 3, 14 and 16, repre- bond functionalization.[28] To the best of our knowl-
senting the three different migrating groups em- edge, a 1,5-hydride transfer-induced ring expansion of
ployed. This was done in order to exclude a back- a substituted cyclopropane to a cyclobutanone has not
ground reaction, induced by trace amounts of HCl/ been described so far. The observed change in reac-
DCl, potentially generated by photodegradation of tivity can be explained by the high energy barrier to
CDCl3. In those cases, almost no conversion (ꢁ1%) generate a highly unstable cyclopropyl cation. In
could be detected via GC analysis. Additionally, all a control experiment, the reaction was completely
products were isolated and successfully enriched by suppressed in the presence of Bu4NBr (2), indicating
employing column chromatography utilizing AgNO3- that the hydride transfer proceeds within the cavity of
impregnated silica gel. The highly substituted, quater- hexamer I. Variation of the b-residue of the cyclo-
nary carbon center-bearing products, which are diffi- propyl acetate led to substrates that were either unse-
cult to prepare via other routes, represent useful pre- lective or did not undergo hydride transfer. This high-
cursors for further functionalizations using the instal- lights the sensitivity of hydride transfers towards
led double bond as a reactive handle.
structural variations.
To complete the study of this cascade reaction, the
After having investigated the scope and limitations
influence of the leaving group was tested for sub- of the catalyzed cascade reaction, the possibility of
strates showing no or diminished product formation. substrate-selective conversion using hexamer I was
Based on our terpene cyclization studies,[13c] acetate explored in a competition experiment utilizing sub-
was chosen as a leaving group displaying a reduced strate 16 and its large derivative 30. For this purpose,
nucleophilicity. The reduced nucleophilicity of the a mixture of 16 and 30 (5 equiv. each; Scheme 3) was
leaving group can result in less interception of inter- added to a solution of catalyst I (1 equiv.) in CDCl3
mediates and therefore provide a more ꢃnon-stopꢄ re- (3.3 mM) and the reaction was monitored via GC. In
action process. Unfortunately, neither an increased accordance with previous findings,[12] the reaction pro-
yield nor a change in selectivity was observed when ceeded highly selectively in favor of the smaller sub-
employing the corresponding acetates of substrate 16 strate due to its more efficient encapsulation. After
and 23. However, when cyclopropyl acetate 27 3 h, the small substrate showed almost complete con-
(Scheme 2) was subjected to the standard reaction version (95%), while substrate 30 remained nearly un-
conditions, the formation of an unexpected product in touched by the catalyst (4%). This corresponds to
80% yield was detected via GC analysis. The product a 96:4 ratio of conversion (see the Supporting Infor-
was subsequently identified as cyclobutanone 28, and mation, chapter 11). In contrast, when the reaction
further confirmed by X-ray crystal structure analysis was performed with an excess of TFA, no significant
of the corresponding semicarbazone 29. The postulat- differentiation of the two substrates could be ob-
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Experimental Section
General Information
1H and 13C NMR spectra were recorded at 300 MHz,
400 MHz or 500 MHz, using a Bruker AVHD 300, AVHD
400 and AVHD 500 spectrometer, respectively. Chemical
shifts of 1H NMR and 13C NMR (measured at 298 K) are
given in ppm by using CHCl3 and CDCl3 as references
(7.26 ppm and 77.16 ppm, respectively). GC analyses were
done on an Agilent GC6890 instrument equipped with an
FID detector and an HP-5 capillary column (length=
29.5 m). Hydrogen was used as the carrier gas and the con-
stant-flow mode (flow rate=1.8 mLmin-1) with a split ratio
of 1:20 was used. Analytical thin-layer chromatography
(TLC) was performed on Merck silica gel 60 F254 glass-
baked plates, which were analyzed after exposure to stan-
dard staining reagents. All chemicals were used without fur-
ther purification. CDCl3 was purchased from Deutero
GmbH and Sigma Aldrich and used as received.
Scheme 3. Selectivities observed with TFA [À58C, 10 s
(CH2Cl2)] and catalyst I [508C, 3 h (CDCl3)] in a competition
experiment towards cyclopentenes 17 and 31.
served. As a result, the ratio of conversion changed to
45:55 (73% conversion of 16 and 91% conversion of
30). This size-selectivity[29] achieved with catalyst I
marks a conceptual advantage of encapsulation-based
supramolecular catalysis,[4] which can be utilized for
multicatalyst tandem reactions[30] and working with
complex substrate mixtures. The observation further-
more provides strong evidence that the reaction
indeed proceeds within the cavity of the supramolec-
ular assembly.
Catalyst, Substrates and Products
Resorcin[4]arene 1 was synthesized according to modified
literature procedures.[31] After dissolving 1 (11.0 mg) in
CDCl3 (0.50 mL), a water content of 9–10 equiv. H2O/hexa-
1
mer I was determined via integration of the H NMR spec-
trum. The employed substrates were synthesized according
to the procedures reported in the Supporting Information.
All cyclodehydration–rearrangement products were isolated
and purified using AgNO3-coated silica, prepared according
to Cert et al.[32] Full characterization data and copies of rele-
vant spectra of all new products, as well as X-ray crystallo-
graphic analysis data of compound 29[33] are provided in the
Supporting Information.
Conclusions
In conclusion, we herein have presented the efficient
catalysis of a cyclodehydration–rearrangement cas-
cade reaction utilizing supramolecular assembly I,
a reaction which so far was only observed with an
excess of a strong Brønsted acid. The scope and limi-
tations of this reaction sequence were investigated in
detail for the first time by systematic variation of the
substitution pattern of the starting material. In this
process, several highly substituted cyclopentenes
could be obtained in moderate to good yield. Addi-
tionally, substrate-selectivity could be achieved start-
ing from a mixture of differently sized hydroxyolefins.
Thus, the reaction was shown to proceed within the
cavity of the hexamer after encapsulation of the sub-
strate. The cationic intermediates and transitions
states of the reaction are believed to be stabilized via
cation–p interactions with the surrounding cavity
walls. In addition, this study led to the discovery of an
unprecedented cyclobutanone formation through an
intramolecular 1,5-hydride transfer within the cavity
of I. Altogether, this study further corroborates the
important role of supramolecular structures in the
long-term goal of controlling cationic olefin cycliza-
tions in an enzymatic fashion. This future goal will re-
quire the rational modification of the capsule interior
to induce selective interactions between the catalyst
and the encapsulated substrate.
Catalytic Studies
An aliquot of a stock solution containing 11.0 mg C-undecyl-
calix[4]resorcinarene (1) (9.95 mmol, 6.0 equiv.) was trans-
ferred to a GC vial. Next CDCl3 was added to adjust an
overall CDCl3 volume of 0.50 mL. To this solution, n-decane
(internal standard) (2.59 mL, 13.3 mmol, 8.0 equiv.) and the
substrate (16.6 mmol, 10.0 equiv.) were added successively in
one portion and the mixture was immediately sampled after
30 s of vigorous agitation. The small sample (approximately
10 mL) was diluted with n-hexane (0.1 mL) containing
0.08% (v/v) DMSO, centrifuged, decanted and subjected to
GC analysis (initial sample). The GC vial was kept at 508C
(Æ18C) using a thermostatted heating block made from alu-
mina. Based on preliminary studies regarding reaction time
optimization, a second sample (final sample) was taken
after a given time frame. All substrates were tested in tripli-
cate. In order to precisely calculate the conversion and
yield, GC-response factors to n-decane as internal standard
(IS) were determined for the investigated substrates and
their corresponding products.
Control Experiments with Inhibitor 2
To
a
solution of C-undecylcalix[4]resorcinarene (1)
(11.0 mg, 9.95 mmol, 6.0 equiv.) in CDCl3 (0.46 mL), 40 mL of
Bu4NBr (2) (2.49 mmol, 1.5 equiv.) stock solution in CDCl3
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(62.3 mm) were added. Next, the sample was heated using
a heat gun to ensure complete uptake of the inhibitor. After
allowing the solution to cool to room temperature, n-decane
(internal standard) (2.59 mL, 13.3 mmol, 8.0 equiv.) and the
substrate (16.6 mmol, 10.0 equiv.) were added and the reac-
tion was subsequently monitored as described above.
[10] S. Slovak, Y. Cohen, Chem. Eur. J. 2012, 18, 8515–8520.
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Acknowledgements
This project was supported by funding from the Swiss Na-
tional Science Foundation as part of the NCCR Molecular
Systems Engineering and the Bayerische Akademie der Wis-
senschaften (Junges Kolleg). We thank PD Dr. Daniel Hꢀus-
singer for help with NMR-DOSY measurements.
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Host-Catalyzed Cyclodehydration–Rearrangement Cascade
Reaction of Unsaturated Tertiary Alcohols
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