An Enolate-Structure-Enabled Anionic Cascade Cyclization Reaction: Easy Access to Complex Scaffolds with Contiguous Six-, Five-, and Four-Membered Rings

Article abstract of DOI:10.1002/ange.202008317

Catalyst-free addition of ketone enolate to non-activated multiple C?C bonds involves non-complementary reaction partners and typically requires super-basic conditions. On the other hand, highly aggregated or solvated enolates are not reactive enough to undergo direct addition to alkenes or alkynes. Herein, we report a new anionic cascade reaction for one-step assembly of intriguing molecular scaffolds possessing contiguous six-, five-, and four-membered rings, representing a formal [2+2] enol–allene cycloaddition. Reaction proceeds under very mild conditions and with excellent diastereoselectivity. Deeper mechanistic and computational studies revealed unusually slow proton transfer phenomenon in cyclic ketone intermediate and explained peculiar stereochemical outcome.

Full text of DOI:10.1002/ange.202008317

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Titel: Enolate Structure Enabled Anionic Cascade Cyclization Reaction:
An Easy Access to Complex Scaffolds with Contiguous Six-,
Five- and Four-Membered Rings
Autoren: Edvinas Orentas, Tomas Javorskis, Ieva Karpavičienė,
Arminas Jurys, Gustautas Snarskis, and Rita Bukšnaitienė
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Zitierweise: Angew. Chem. Int. Ed. 10.1002/anie.202008317
Link zur VoR: https://doi.org/10.1002/anie.202008317

10.1002/ange.202008317
Angewandte Chemie
RESEARCH ARTICLE
Enolate Structure Enabled Anionic Cascade Cyclization Reaction:
An Easy Access to Complex Scaffolds with Contiguous Six-, Five-
and Four-Membered Rings
Tomas Javorskis[a][b], Ieva Karpavičienė[a], Arminas Jurys[a], Gustautas Snarskis[b], Rita Bukšnaitienė[a]
and Edvinas Orentas[a]*
[a]
Dr. T. Javorskis, Dr. I. Karpavičienė, A. Jurys, Dr. R. Bukšnaitienė, Prof. E. Orentas
Department of Organic Chemistry
Vilnius University
Naugarduko 24, LT-03225 Vilnius, Lithuania
E-mail: edvinas.orentas@chf.vu.lt
http://www.orentasgroup.chf.vu.lt/
[b]
Dr. T. Javorskis, G. Snarskis
Center for Physical Sciences and Technology
Saulėtekio av. 3, LT-10257 Vilnius, Lithuania
Supporting information for this article is given via a link at the end of the document.
Abstract: Catalyst-free addition of ketone enolate to non-activated
multiple C-C bonds involves non-complementary reaction partners
and typically requires super-basic conditions. On the other hand,
highly aggregated or solvated enolates are not reactive enough to
undergo direct addition to alkenes or alkynes. Herein, we report a new
anionic cascade reaction for one-step assembly of intriguing
molecular scaffolds possessing contiguous six-, five- and four-
membered rings, representing
a
formal [2+2] enol-allene
cycloaddition. Reaction proceeds under very mild conditions and with
excellent diastereoselectivity. Deeper mechanistic and computational
studies revealed unusually slow proton transfer phenomenon in cyclic
ketone intermediate and explained peculiar stereochemical outcome.
Introduction
Cascade cyclization reactions, where several chemical steps
occur one after another in a well-defined sequence, is a powerful
tool to access complex polycyclic molecular scaffolds in a single
synthetic operation with high overall yield and stereoselectivity.[1]
The required acyclic precursors for such transformations are
usually obtained using well-established synthetic methods from
readily available materials. In this regard, the utilization of
polyunsaturated substrates to affect multiple C-C bond formation
is very attractive, and in fact, is extensively utilized by Nature as
in cation-induced cyclase-catalyzed transformation of polyenes
into terpenoids.[2] Recent elegant studies aiming at applying the
lessons learned from biological systems in synthetic chemistry
has resulted in the development of multitude efficient cyclization
cascades.[3] On the other hand, anion-induced cyclizations of
alkenes require the inversion of innate electron density of -bond
either by introducing the electron withdrawing groups or activation
with Lewis acids or transition metals. Thus, non-catalyzed addition
of nucleophiles to non-activated alkenes is rare..[4]
Figure 1. a) Addition of enolates (enols) to a non-activated carbon-carbon -
bonds. Currently known examples and reported development. b) Bioactive
natural products featuring fused oxygenated five-membered rings and
cyclobutane.
ene reaction, known as the intramolecular addition of enols to
alkenes or alkynes, represents a versatile synthetic tool, however,
it proceeds via concerted (pericyclic) rather than ionic mechanism
(Figure 1a).[5] Moreover, non-catalytic version of this reaction
requires very harsh conditions, not compatible with heavily
functionalized substrates. Taguchi et. al. has shown that more
reactive allene -bond can be engaged in intramolecular addition
reaction with lithium enolates of 1,3-dicarbonyl compounds
In this context, the enolate addition to non-activated - bond
is a highly sought-after transformation having huge potential to
deliver valuable carbonyl compounds in a single step. The Conia-
1
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10.1002/ange.202008317
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(Figure 1a).[6] Based on high basicity of an anion produced after
cyclization, the reaction can be conducted using only catalytic
amount of base.
proved to be less efficient (Table 1, entry 6). Switching the solvent
to tetrahydrofuran (THF) required increasing the temperature to
80C for NaH to afford 58% of the product 2a as Z/E mixture.
Using KOtBu as a base, a mixture of E-2a and Z-2a was obtained
in DMSO whereas in THF 2b was also formed in considerable
amount. Control experiment in THF where E-2a was treated with
KOtBu showed that Z-2a but not 2b derived from the E-2a, initially
formed during the cyclization (Page S28). In contrast to slow
cyclization of alkyl derivatives,[8] all reactions with 1a, except using
NaH in THF, were complete within 5 min, in line with higher anion
stabilizing effect of the phenyl group. Unexpectedly, none of the
conditions provided enone product. Weaker base such as MeONa
or K2CO3 were not effective. The above screening results
indicates high reactivity of dissociated enolate towards non-
activated triple bond.
Recently, Trofimov et al. have developed an efficient
procedure for -vinylation of ketones based on enolate addition
to terminal alkynes under super basic conditions (Figure 1a).[7]
The reaction requires high temperature and highly coordinating
dimethyl sulfoxide solvent pointing toward the necessity of using
dissociated (i.e. “naked”) and therefore very reactive enolate.
Much earlier, similar intramolecular addition of sodium
enolate to tethered alkyne in 2-hydroxyacetonaphthone
derivatives has been described by Schmid and co-workers[8]
(Figure 1a) and later expended to other intramolecular variations
by Dixon[9] and Trauner[10]. Although the isomerization of
propargylic ether into the corresponding allene under basic
conditions seems very plausible, the reaction is believed to
proceed via direct addition of an enolate to a triple bond as judged
from the configuration of exocyclic double bond and nearly
stoichiometric amount of the base used. The seven-membered
product obtained may undergo competing double bond migration
and rearrangement reactions, resulting in a complex mixture.
Intrigued by the possibility to employ the addition reaction of
enolates to simple triple bonds based on the above report, we
have set up to investigate the possible reaction mechanism and
synthetic scope of this transformation. This has led to a discovery
of new cascade cyclization to afford unique polycyclic scaffold
consisting of fused six-, five- and four-membered rings (Figure 1a).
The novel reaction documented herein features enolate addition
to allene as a key step followed by intramolecular addition of a
carbanion to the carbonyl group and formally represents currently
unknown [2+2] enol-allene addition reaction. The reaction
reported opens up the way for the synthesis of novel molecular
scaffolds reminiscent of the ones found in the structure of a variety
of bioactive natural products, possessing oxygenated five-
membered ring fused with cyclobutane (Figure 1b).[11]
Table 1. Screening of reaction conditions
aIsolated yields; bInseparable mixture. Product ratios were determined by NMR;
cStarting material was recovered; dComplex mixture; ND – not detected.
Results and Discussion
Further screening was continued with less polar solvents to
deliberately reduce the enolate activity. Using 2.1 equivalents of
lithium diisopropylamide (LDA) as a base in THF at low
temperature, complex intractable mixture of products was
obtained.
Conditions Screening In contrast to alkyl propargylic
substrates reported by Schmid et al. (R = alkyl, Figure 1a), we
have instead decided to use the arylated analogues as starting
materials. Besides the novelty of substrates, we have reasoned
that in this case, base induced isomerization of propargyl moiety
into the respective allene would be facilitated and the weaker
base could be employed. The starting materials 1 were obtained
by modular approach starting from various commercially available
2-hydroxyacetophenone derivatives via propargylation followed
by Sonogashira coupling (see the Supporting Information) or by
alkylation with arylpropargyl bromides.
Remarkably, weaker base, lithium hexamethyldisilazane
(LiHDMS), resulted in spot to spot conversion of 1a into a new
product with 86% isolated yield. Using less than 2.0 equivalents
of LiHMDS (1.0 equiv. < LiHDMS < 2.0 equiv.), the formation of
the product was also observed, however, the reaction rate and
conversion were slightly lower. Starting material was recovered
almost quantitively when stoichiometric amount of LiHMDS was
used. To our surprise, the product 3a obtained turned out to be
not the expected seven-membered unsaturated ketone (Table 1),
but tricyclic tertiary alcohol, comprising of fused five- and four-
membered rings (Figure 2). The compound 3a was obtained as a
single diastereomer as indicated by NMR and its structure was
secured by X-ray crystallography.
The initial optimization results with 1a revealed that
expected seven membered ketone 2 having exocyclic double
bond was exclusively formed in moderate yields (24-42%) using
NaH as a base in dimethylsulfoxide (DMSO) (Table 1). Only E-
stereoisomer was obtained as confirmed by ROESY spectrum
(see the Supporting Information). Dimsyl lithium (Li+CH3SOCH2 )
-
2
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10.1002/ange.202008317
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Figure 2. Exploration of substrate scope. aYield based on recovered starting material. Standard reaction conditions: 1 (1.0 equiv), LiHMDS (2.1 equiv), THF (1.0 -
2.0 M), -60°C ÷ 20°C, 2-5 h.
The reaction scope was further evaluated as outlined in Figure 2.
The reaction is compatible with various substituents on both
acetophenone and aryl rings of the propargylic fragment.
Heteroaromatic derivatives with indole, pyridine, thiophene and
carbazole moieties were also successfully converted into
respective products. The reaction was also applied for sulfur
analogue to give 3x in 73% yield. Notably, starting materials
substituted at -position of the carbonyl group as well as at the
propargylic positions (3d, 3g-j) were competent substrates,
indicating high tolerance of steric hindrance in this transformation.
In these cases, higher reaction temperatures were usually
required to reach full conversion. Of special note is the compound
3i possessing four consecutive quaternary carbons, obtained in
86% yield with full diastereoselectivity. The reaction was
successfully reproduced on a gram scale with only slight decrease
in the yield (3e, Figure 2). Interestingly, the stereochemistry of the
double bond seems to be a function of substitution at -position
and not of the size of the aryl substituent. Namely, all
unsubstituted acetophenone starting materials provided E-
products even with large carbazole moiety (3s, X-ray structure),
whereas substituted ones selectively afforded Z-products.
From a mechanistic point of view, the observed cyclization
reaction can be rationalized assuming the formation of the
corresponding allene as an intermediate. Regioselective addition
3
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10.1002/ange.202008317
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RESEARCH ARTICLE
of lithium enolate to allene double bond would result in C(sp3)
carbanion of allylic ether. An ensuing intramolecular addition of
the latter to the carbonyl group would afford the observed product
(vide infra). Despite of apparent simplicity, this transformation is
intriguing for several reasons. First, stereochemistry of the alkene
double bond in E-products is opposite to what is expected
considering an addition of a nucleophile to allene from a less
hindered side. Second, the proton transfer from ketone -position
does not quench the more basic intermediate carbanion indicating
either a very fast addition to the carbonyl group or unfavorable
proton transfer. Finally, dramatic solvent and cation effect on the
reaction outcome was noted.
compound 1y possessing strongly electron withdrawing o-nitro
group on the alkyne aromatic ring. In this case deprotonation of
propargylic position is faster due to lower pKa resulting in the
attack of the carbonyl group by propargylic anion to afford product
6.
Although lithium enolates dominate the field of enolate
chemistry, the strong dependence of enolate structure and
reactivity on counterion nature is also well documented in
literature.[13] In fact, sodium and potassium enolates in most cases
are more reactive than lithium enolates. Unexpectedly, NaHMDS
base, even used in excess, provided neither the expected product
3a nor seven-membered product 2a from starting material 1a. To
find out whether the absent reactivity of sodium enolate in THF
was related with too low basicity of NaHMDS for allene generation,
quenching experiment with D2O was performed. Indeed, no
deuterium was incorporated at propargylic position. Interestingly,
Mechanistic Investigations In order to elucidate
mechanistic details further, we conducted a series of control
experiments. First, subjecting compound
4
having alkyl
substituent on the triple bond, analogous to the ones used by
Schmid et al., to LiHMDS, no reaction was observed (Scheme 1a). when non-enolizable ketone 7a was used as a control, cyclization
Quenching with D2O gave no deuterium incorporation at
propargylic carbon. This result shows that isomerization of
propargylic ether to allene is a prerequisite, and the direct addition
of enolate to triple bond is not taking place. On the other hand,
increasing the strength of the base by switching from LiHMDS
(pKa = 24) to LDA (pKa = 35) indeed afforded the tricyclic product
5 as a mixture of Z/E-stereoisomers, albeit in low yield.[12]
product 8 was obtained by using both LiHMDS and NaHMDS
bases (Scheme 1b). This observation can be explained by higher
acidity at the propargylic position in 7a possessing electron
withdrawing benzoyl group, whereas in enolate of 1a, the
electronic properties of substituent are inversed. NaH/DMSO
system gave benzofuran product 9 after carbonyl group attack
and subsequent loss of H2O, however, was incapable to
deprotonate less acidic alkyl propargylic substrate 7b and
therefore ruled out allene involvement in Schmid cyclization
(Figure 1a). NaHMDS is a stronger base compared to LiHMDS,
however the lithium ion is significantly more oxophilic than sodium
and therefore, deprotonation might be facilitated by the directing
effect of the oxygen atom. By changing counterion from lithium to
potassium, product 3a was also obtained in slightly lower yield as
compared to LiHMDS; however, cyclization reaction proceeded at
lower temperature (Scheme 1b). The intrinsic basicity of KHMDS
is high enough to allow efficient isomerization of propargylic ether
to the corresponding allene. Although no formation of 3a was
observed when using NaHMDS as a base, the reactivity of the
sodium enolate could be restored by replacing sodium
coordination shell and weakening the O-Na bond with 10 equiv.
of DMSO to afford enolate-alkyne addition product 2a, analogous
to pure DMSO. Interestingly, other commonly used complexation
agent N,N’-dimethylpropylene urea (DMPU) was fully ineffective,
perhaps due to its weaker cation coordination ability. We have
also shown that the enolate of compound 2a is not an
intermediate en route to 3 by a control experiment wherein
starting material was recovered after treatment with LiHMDS
(Scheme 1b).
Taken together, all the above results show that: a)
deprotonation of propargylic methylene group is essential for
cascade cyclization reaction (1 to 3) in THF to take place,
corroborating the involvement of allene as an intermediate. b) pKa
of C-H bond in -position to carbonyl group is lower than pKa of
C-H bond in propargylic position, c) successful deprotonation of
propargylic C-H bond in 7a suggests that at least in theory allene
pathway can also be operating during the cyclization of 1 to 2
(Table 1) in DMSO, and d) naked enolate is required for the
cyclization of 1 to 2.
Scheme 1. Control experiments to probe a) role of the base strength and b) role
of the counterion and solvent.
Based on the above insights, we proposed possible reaction
mechanisms outlined in Scheme 2 to explain solvent-dependant
reactivity modes of 1.
The reactivity and selectivity of lithium enolates are greatly
influenced by the structures and reaction conditions, including
The importance of relative acidities of C-H bonds at carbonyl -
position and propargylic position was further revealed with
4
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10.1002/ange.202008317
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RESEARCH ARTICLE
particularly the solvents and additives interacting with lithium ion
as recognized by early work of Jackman,[13] Seebach,[14] Willard
Trofimov et al. in intermolecular reaction with limited success
using superbase KOH (KOtBu)-DMSO conditions.[21] The yields
were low, mixture of mono- and diallylated products were
obtained, but most importantly, the addition never occurred to
generate carboanion adjacent to oxygen atom as in II. In terms of
addition regioselectivity, the reported results were analogous to
our case using KOtBu in THF (Table 1, entry 4, compound 2b).
Given the well-reported utility of KOtBu as a base for propargylic
ether and amine isomerization to the corresponding allenes, 7-
exo-trig addition of enolate to allene seems very reasonable to
account for the formation of 2b.[22]The fact that 3a and not 2b is
obtained using KHMDS derived potassium enolate stress the
paramount importance of enolate structure (dissociated vs
aggregated) for the reaction outcome. Intermediate II then
undergoes a second cyclization reaction to afford final product 3a.
It is worth noting that 1,3-proton transfer in intermediate II must
be very slow for such cyclization to occur despite the much higher
acidity of C-H bond in carbonyl -position.
[15]
and others.[16] According to detailed fundamental studies on
lithium amide-mediated enolization of ketones reported by
Arnett,[17] and later by Reich[18] and Collum[19], the lithium enolate
most likely exist in a form of mixed aggregate with lithium ion
coordinating to both solvent THF and lithium hexamethylsilazide,
present in excess (denoted as -OLi(THF)n(N(TMS)2)m in Scheme
2a). Such mixed aggregate structure seems to provide an
optimum reactivity of enolate for this cascade transformation;
more aggregated lithium enolate of 1a in toluene started to react
only at room temperature and gave mere 37% of product 3a
(Scheme 1b). On the other hand, metal enolates in DMSO are
believed to exist either as highly reactive free ions, solvent-
separated ions or the mixture thereof in equilibrium with other
aggregates.[20] To date, no reliable structural characterization of
Li enolates in this solvent has been reported.
In DMSO, the enolate formed is reactive enough to directly
add to a triple bond to afford product III (2a-Li) after intra- or
intermolecular proton transfer to vinylic carboanion intermediate.
To gain more insights into proton transfer process, deuterium
labelling studies were performed (Scheme 2b). Cyclization
reaction in d6-DMSO unexpectedly delivered product 2a
deuterated at vinylic position indicating that proton transfer is
realized by deuterium abstraction from solvent d6-DMSO (pKa =
31) rather than from ketone -position (pKa = 25). Moreover, in
contrast to fully diastereoselective process in non-deuterated
DMSO, reaction in d6-DMSO afforded mixture of Z/E
diastereomers. Most likely, the deuteron abstraction from d6-
DMSO is much slower due to kinetic isotopic effect and as a result
vinylic anion has enough time for inversion. Indeed, aryl
substituted vinyl anions are known to be configurationally labile.[23]
The above assumption was further confirmed with alkyl derivative
4 (for structure see Scheme 1) as starting material which afforded
diastereomerically pure Z-product in both deuterated and non-
deuterated solvents via configurationally stable alkyl vinyl anion.
The very sluggish proton transfer might also account for very slow
reaction of 1a with NaH in aprotic THF (Table 1, entry 3) and the
formation of Z/E mixture of the product under these conditions. If
a direct addition of enolate to triple bond is assumed, the
stereochemical outcome of the reaction is easily explained by
trans-addition of nucleophile commonly observed in such
reactions.[24] Although the scrambling of the alkene
stereochemistry in d6-DMSO and isotope labelling position serve
as a very strong support for direct addition of enolate to alkyne
triple bond, a small possibility for allene mechanism still exists.
Namely, deuterated allene I produced from starting material via
base catalysed isomerization may undergo cyclization to produce
seven-membered carboanion II which then could give III after
proton transfer (Scheme 2b). To unambiguously rule out such
possibility, deuterated starting material 1a-d3 was used as a
model substrate. No deuterium was introduced to neither vinylic
nor allylic position corroborating enolate-alkyne addition
mechanism and the absence of intra- or intermolecular proton
transfer involving cyclic product. Partial D to H exchange at -
position was observed due to enolization of product during the
quench.
Scheme 2. a) Proposed reaction mechanism. b) Control deuterium labelling
experiments.
In THF, complexed lithium enolate is not nucleophilic enough for
direct addition to a triple bond.
In the presence of excess of LiHMDS in THF, 1a is
converted into the corresponding enolate followed by
deprotonation at propargylic position based on the results of the
control reaction from 7a to 8 (Scheme 1b). The metalated
propargylic ether undergoes isomerization to allene via proton
transfer from HMDS, however the extent of such isomerization is
very low. This assumption was confirmed by another control
reaction where simple phenylpropargylic ether of phenol was
subjected to identical reaction conditions; no allene product was
detected in the reaction mixture. In case of 1a, very small amount
of allene intermediate I formed is immediately consumed in the
following cyclization step to afford carboanion II thus shifting the
isomerization reaction further. To our knowledge, addition of
enolate to allenyl ethers has only been attempted once by
Alternatively, one may argue that the reaction with LiHMDS
in THF could also proceed by direct addition of lithium enolate to
alkyne to first produce IV which then would isomerize to the
5
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Figure 3. a) DFT-computed energy profile of the reaction starting from anti-I and syn-I lithium enolate rotamers leading to stereoisomers E-3a (path a) and Z-3a
(path b). The dashed line in the transition structures indicates the forming bond together with the distance between the connecting atoms. The dashed line in syn-I
indicates C-H···-dispersive interactions. TS, transition state; ΔGrel, Gibbs free energy with respect to anti-I (given in kJ mol−1); ΔG‡, Gibbs free energy of activation.
Energies are computed at the SMD/IEF-PCM/B3LYP-D3/6-31G(d,p) (tetrahydrofuran) level of theory (see Supplementary Information for more details and
references). b) Structure of the enolate used for calculations in a). c) Kinetic scheme for E-II and Z-II formation and general equation (1) describing their ratio P as
a function of all k involved. d) Theoretical simulation of the reaction course (T = 253 K) using computationally derived activation energies. The fast establishment of
equilibrium (left) and subsequent conversion of syn-I to E-II. The concentration of Z-II is negligible and coincides with the baseline. e) Stereochemical model
indicating destabilizing steric interaction between-substituent (grey ball) of Z-enolate and both THF and phenyl group in syn-I rotamer.
an oversimplification of the real enolate aggregation mode, it
required intermediate II. This possibility is ruled out by the
fact that cyclization reaction does not take place using one or less
equivalent of LiHMDS.
should correctly reflect the reactivity trends from both steric and
electronic perspective.
The computed free energy profile of the key steps along the
reaction path is shown in Figure 3a. Calculations of two alternative
reaction pathways a and b leading to E-3a and Z-3a, respectively,
were carried out starting from two rotamers (anti and syn) of
allenyl ether Li-enolates. As anticipated, the first cyclization step
of syn-1 rotamer into intermediate E-II requires 6 kJ mol-1 higher
energy than that of anti-1 rotamer forming intermediate Z-II. Both
anion intermediates are essentially isoenergetic. Analysis of the
whole energy profile shows that the first cyclization step plays a
decisive role in establishing alkene stereochemistry in product 3a.
Indeed, the subsequent step of second cyclization of allylic anion
is more favourable for E-II by 7 kJ mol-1 leading to experimentally
observed product E-3a. Higher activation energy towards E-II
from syn-I would imply the preferential formation of product Z-3a,
Computational Studies. Regarding the cyclization
mechanism in THF outlined in Scheme 2a, one issue remained to
be rationalized, i.e. the unexpected E-configuration of the
exocyclic double bond in products 3 derived from -unsubstituted
acetophenones. If one assumes the addition of enolate to an
allene, the addition is expected to take place from the opposite
side to phenyl substituent leading to Z-alkene. To resolve this
matter, we addressed the reaction mechanism computationally
using density functional theory (DFT) (Figure 3). As a starting
point, we selected a variation of heterodimeric enolate structure
featuring tetracoordinated lithium ions with THF and HMDS anion
ligands, similar to the one first proposed by Arnett[17] for LiHMDS
derived enolates (Figure 3b). Although such structure perhaps is
6
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10.1002/ange.202008317
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however, we noticed that syn-I rotamer is significantly stabilized
in the ground state as compared to anti-congener. If one assumes
a possible low-barrier channel for the interconversion of syn- and
anti-rotamers that would lead to a Curtin-Hammett scenario with
inversed rates for Z-II and E-II formation as compared to non-
interconverting rotamers. The Curtin–Hammett principle[25]
outlined in Figure 3c in the most general form (1) shows that
product selectivity P in competitive pathways depend both on the
relative reactivity of the two intermediates syn-I and anti-I,
forcing conditions such as treatment with trifluoromethane- or
methanesulfonic acids. The reason for this is likely the geometric
constrain of the bicyclic scaffold where C(sp3) atom adjacent to
carbocation renders planarization of the latter impossible. In
addition, the presence of the double bond in the cyclobutene ring
also prevents stabilization of the forming cation via ring
fragmentation. On the other hand, the saturated compound 10
obtained by diastereoselective hydrogenation of 3a undergoes
fragmentation reaction to 11 upon treatment with p-
expressed by the ratio of their rate constants for product formation, toluenesulphonic acid. The cleavage of cyclobutane ring
k3/k4, as well as on the ratio of syn/anti isomerization constants k1
and k2. In special case for rapidly equilibrating reactants (k1, k2 >>
k3, k4), equation (1) can be simplified to P ≈ Keqk3/k4 ≈ exp(-
G‡/RT) and it can be shown that the ratio of products depends
not solely on the absolute values of activation energy but rather
on the difference G‡. In our case, less active but more stable
intermediate syn-1 leads to the major product, the Curtin-
Hammett scenario termed “monopolyzing kinetics” by Blackmond
et al.[26] DFT calculations revealed that syn and anti-rotamers can
be interconverted by a series of rotation around single C-O and
C-C bonds with the highest barrier not exceeding 30 kJ mol-1 (see
Figure S12). Simulation of time-dependent speciation of syn-I,
anti-I, E-II and Z-II at -20ºC starting from pure anti-I and by solving
a set of differential equations describing the kinetic scheme in
Figure 3c indeed resulted in high P (E-II/Z-II) = 165 values and
subsequently full selectivity for E-3a formation.[27] Higher stability
of syn rotamer most likely stems from C-H··· dispersive
interaction between THF ligands and phenyl substituent located
in close proximity, stressing the importance of the role of lithium
ion coordination shell beyond simple attenuation of enolate
reactivity. For comparison, the free energy profile was also
obtained for a hypothetical reaction based on the same
mechanism and solvent but involving enolate with non-
coordinated lithium ion (see Figure S13). In this case, the
activation barrier for path b remains lower than for path a, but the
energy of TS1a becomes higher compared to TS1b, which leads
to the formation of “wrong” stereoisomer Z-3a. In addition,
computational studies also predicted very high activation barrier
(G = 118 kJ mol-1) for the intramolecular proton transfer in
intermediate E-II in accord to experimental data. In fact, combined
with data from Scheme 2, it seems that intramolecular 1,3-proton
transfer in seven-membered ring from -position is extremely
sluggish to both vinylic and ether carboanions.
produces secondary carbocation which is then captured with
sulfonate anion to afford benzofuran derivative 11 in good yield.
In another test reaction we explored 10 as a substrate for a
photocatalytic ring-opening reaction enabled by proton-coupled
electron transfer (PCET), recently developed by Knowles and co-
workers.[28] In this reaction, the cyclic alcohols are isomerized into
acyclic carbonyl compounds and during the process C-C bond
adjacent to oxygen atom of alkoxy radical is cleaved in a direction
to produce the most stable carbon radical. We speculated that
The inverse of stereochemical outcome for - substituted
substrates can also be explained based on the computed
geometries. The use of LiHMDS in THF is known to selectively
produce Z-enolate.[19] For Z-enolates, transition state similar to
TS1b derived from syn-I and leading to E-products becomes
impossible due to sterically crowding imparted by the alkyl
substituent (Figure 3e). Therefore, reaction proceeds via path b
rather than path a, where steric interaction of alkyl group with
phenyl ring is avoided. Moreover, close examination of the
geometry of transition states TS1b and TS2b also provided a
simple model to explain the observed all-syn geometry of the
products 3j, 3g and 3x derived from more substituted substrates
(Table 2).
Chemical Reactivity. With products 3 in hand, we
preliminary probed some of their properties in the context of
reactivity and synthetic applicability (Scheme 3a). In our initial
attempts to accomplish an SN1 type reaction with 3a we noticed
its high reluctance to form tertiary carbocation V even under
Scheme 3. Synthetic elaboration of the reaction products.
7
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10.1002/ange.202008317
Angewandte Chemie
RESEARCH ARTICLE
dihydrobenzofuran ring in 10 could serve the same purpose as p-
methoxyaryl substituent in providing radical cation intermediate
upon oxidation with the excited state of Ir(III) photocatalyst. We
were surprised to find out that in case of 10, the -scission in
cyclobutane ring resulted in the formation of primary radical rather
than expected secondary radical VI enjoying an additional
stabilization from adjacent oxygen atom. (Scheme 3b). Although
the exact reason for such selectivity remains elusive, it represents
the first example of alkoxy radical fragmentation displaying
features of -elimination[29] rather than -scission mechanism
where the choice between the two is given. The obtained mixture
of diastereomers 12 was converted into a single benzofuran
derivative 13.
The facile fragmentation of the fused ring system was also
demonstrated in ozonolysis reaction (Scheme 3c). Instead of
expected cyclobutanone, seven-membered diketone 14 was
obtained from 3a as a major product. The formation of 14 might
be explained by two alternative fragmentation pathways involving
either carbonyl oxide (Criegee intermediate, fragmentation 1) or
secondary ozonide (fragmentation 2). The fact that only
benzaldehyde and not 14 was observed in the reaction mixture
before the reductive quench with PPh3 strongly supports the
former pathway. Few examples of anomalous ozonolysis of
strained allylic alcohols are reported in literature, however, to our
knowledge, no such fragmentation has ever been reported for
homoallylic alcohols.[30],[31]
rotational interconversion of two reactive conformations of the
latter is responsible for unorthodox stereochemical outcome of
the reaction. Our findings confirm, and reinforce, in yet another
context, the importance of enolate structure on its reactivity. As
opposed to very polar solvents such as DMSO, where direct
addition of enolate to triple bond is extremely fast, the attenuated
reactivity of aggregated lithium enolate in THF enables the
precise orchestration of enolization-isomerization-addition events
in time, necessary for herein disclosed cascade transformation.
Besides from providing unique molecular scaffolds in just one step
from trivial starting materials, the possible extension of this
cascade reaction to other substrates having different
arrangement of ketone and propargylic ether functionalities is
easy to spot and is pursued in ongoing studies.
Acknowledgements
This research was funded by the Research Council of Lithuania
(grant no. S-MIP-17-46). We are grateful to Dr. A. Bučinskas
(Kaunas University of Technology) and Dr. G. Kreiza (Vilnius
University) for X-ray crystallographic analysis, M. Malikėnas
(Vilnius University) for HRMS analysis.
Keywords: Enolate • Allenes • Domino reactions • Cyclobutane
• Rearrangements
Although the newly developed cascade reaction presented
herein is limited to alkenylaryl derivatives, by performing alkene
metathesis reaction of 3a with methylacrylate we have shown that
the alkenylaryl moiety can be successfully replaced with
synthetically useful Michael acceptor to give 15 in 58% yield
(Scheme 3d).
[1]
a) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. Int. Ed.
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Shi, Y. Xiong, E. A. Anderson, Chem. Soc. Rev. 2016, 45, 1557–1569;
c) L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Organic
Synthesis, Wiley-VCH, Weinheim, 2006.
Finally, the possibility of chirality transfer from propargylic
stereogenic center throughout cascade transformation was
evaluated by using easily available enantiomerically pure
propargyl ether 1c (Scheme 3e). The postulated transformation
would constitute an example of point (single)-axial-point (multiple)
chirality transfer. Disappointingly, the first attempt using LiHMDS
base delivered the product 3c in 29% ee only. This is likely related
to significant racemization of carboanion stereogenic center
before isomerization to allene as the reaction proceeded at
relatively high temperature. Indeed, by using more basic KHMDS,
the reaction temperature could be lowered to -40 ºC and the ee of
the product drastically increased to 80%; the value is within a
range of ee suitable for potential further enrichment by
crystallization. The absolute configuration of the major
enantiomer of 3c was predicted based on the computationally
derived mechanism (Figure 3) and verified by single-crystal X-ray
analysis of the derived 3,5-dinitrobenzoate (Page S128).
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In summary, we have developed a novel anionic cascade
transformation initiated by the addition of lithium enolate to non-
activated allene, generated in situ from propargylic ethers.
Intriguingly, the cascade was not interrupted by the presence of
thermodynamically more acidic protons within the intermediate,
resulting in simultaneous forging of fused five and four -
membered rings. Mechanistic and theoretical studies corroborate
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an enolate with LiHMDS and then deprotonating propargylic ether with
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8
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10.1002/ange.202008317
Angewandte Chemie
RESEARCH ARTICLE
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[32] CCDC 2009326 (compound 3a), 2009325 (compound 3s) and 2009268
(3,5-dinitrobenzoate of 3c) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
9
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10.1002/ange.202008317
Angewandte Chemie
RESEARCH ARTICLE
All sizes in one fell swoop. Anionic cascade reaction initiated by an addition of enolate to an in situ generated non-activated allene
has been developed. Herein presented formal [2+2] enol-allene cycloaddition cleanly provides functionalized molecular scaffolds with
fused six-, five- and four-membered rings with full diastereoselectivity.
10
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