Organoseleno-catalyzed synthesis of α,β-unsaturated α′-Alkoxy ketones from allenes enabled by se···o interactions

Article abstract of DOI:10.1021/acs.orglett.0c01288

α,β-Unsaturated α′-Alkoxy ketones have been prepared under mild conditions from allenes using water as the oxygen source and without the necessity of metals. The organocatalytic oxygenation-rearrangement sequence displays an exquisite chemo-, stereo-, and

Full text of DOI:10.1021/acs.orglett.0c01288

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Letter
Organoseleno-Catalyzed Synthesis of α,β-Unsaturated α′-Alkoxy
Ketones from Allenes Enabled by Se···O Interactions
́
Mireia Toledano-Pinedo, Teresa Martínez del Campo,* Marta Tiemblo, Israel Fernandez,*
and Pedro Almendros*
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ABSTRACT: α,β-Unsaturated α′-alkoxy ketones have been prepared under mild conditions from allenes using water as the oxygen
source and without the necessity of metals. The organocatalytic oxygenation−rearrangement sequence displays an exquisite chemo-,
stereo-, and site-selectivity as well as good functional group compatibility. DFT calculations suggest that stabilizing noncovalent Se···
O interactions may be responsible for the observed reactivity.
he α,β-unsaturated α′-alkoxy ketone moiety is a recurrent
selenated adducts (Scheme 2a).7i Control experiments
revealed that both the organoselenium compound and the
oxidant were crucial for this transformation. Aimed at
exploiting this accidental result in connection with a general
synthetic protocol, we speculated that a selenium-catalyzed
rearrangement−functionalization sequence of allenyl ethers
could be established. For this proposal, we initially decided to
reduce the stoichiometric quantity of (PhSe)2 to catalytic
amounts. Disappointingly, the use of 10 mol % of (PhSe)2
yielded α′-alkoxy enone 2a in a diminished 12% yield. The
major product (82% yield) of this reaction was enone 3a, a
Meyer−Schuster-type product lacking the methoxy moiety
(Scheme 2b). We suspect that the catalytic version using 10
mol % is kinetically slow and higher catalyst loading is
required. Noteworthy, when the reaction of allenyl methyl
ether 1a was catalyzed by 20 mol % of (PhSe)2, α,β-
unsaturated α′-alkoxy ketone 2a was obtained in a good 69%
yield as a single (E)-isomer (Scheme 2c). Similar figures, with
just a slight improvement in yield, were obtained using 50 mol
% of (PhSe)2 (Scheme 2d). Consequently, we decided that 20
mol % of the organoselenium catalyst should be used as
T
structural motif in natural products and bioactive
molecules which has been also identified as a valuable platform
for the preparation of more complex products.1 Despite the
synthesis of the naked α-hydroxy ketone moiety can be
smoothly accomplished from alkenes,2 the preparation of the
more functionalized α,β-unsaturated α′-alkoxy ketone scaffold
is not an easy task.3 Consequently, alternative protocols for this
framework are highly desirable.
One subject in the continuously growing field of organo-
catalyzed reactions is the appearance of organoselenium
catalysis as a versatile synthetic tool.4 In particular, electro-
philic transformations of isolated alkenes through selenium-
based π-acid-type catalysis have been developed (Scheme 1a).5
Other π-systems have rarely been studied; only Zhao et al.
have recently reported the organoseleno-catalyzed functional-
ization of alkynes (Scheme 1b) and the pyridination of 1,3-
dienes (Scheme 1c).6 Although many efforts have been made
in the preparation of seleno derivatives by the stoichiometric
reaction of allenes with selenenylating reagents,7 the use of
selenium catalysis in allene chemistry remais unexplored. We
wish to report herein the oxygenative rearrangement of the
allene skeleton via organoselenium catalysis (Scheme 1d).
During our program focused on studying the reactivity of the
allene moiety, an unanticipated observation captured our
interest. The reaction of allenyl methyl ether 1a with
stoichiometric amounts of diphenyl diselenide in the presence
of 1-fluoropyridinium triflate formed the unexpected α′-alkoxy
enone 2a as the major product (25% yield) along with
Received: April 13, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01288
© XXXX American Chemical Society
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transformation. The generality of the reaction was first studied
using differently substituted allenyl methyl ethers 1. The
corresponding products 2a−m were achieved in reasonable
yields (40−76%) and good or great (E)-diastereoselectivity
(Scheme 3). The reaction proved to be general because both
Scheme 1. State-of-the-Art and Current Work
Scheme 3. Controlled Synthesis of α,β-Unsaturated α′-
Alkoxy Ketones 2a−n
Scheme 2. Impact of the Diphenyl Diselenide Amount on
the Selenium-Catalyzed Rearrangement−Functionalization
Sequence of Allenyl Methyl Ether 1a
electron-donating (4-MeO and 4-Me) and electron-with-
drawing groups (Cl and Br) were well accommodated.
Interestingly, the bromine and chlorine moieties on the
arene are compatible with enone formation conditions,
which may offer further functionalization through selective
cross-coupling protocols. Reactions of derivatives 1 bearing
substituents on the phenyl nucleus at the ortho, meta, and para
positions proceeded smoothly. Hetaryl moieties such as 2-
thienyl were also well suited, albeit the E/Z ratio of 2l (78:22)
was lower compared to other examples. Next, substitution at
the allene moiety was examined. Replacement of the methyl
group by hydrogen also provided the desired α′-alkoxy enones
2h,i in fair yields. To judge by the reactions of (1-
methoxybuta-2,3-dien-2-yl)benzenes 1j,k, the steric hindrance
imparted by the phenyl group on the cumulene moiety did
exert unquestionable influence on enone formation; the
reaction of phenyl allenes 1j,k afforded adducts 2j,k in a
diminished yield (Scheme 3; 2b,d vs 2j,k). Noteworthy, the
alkyne portion may also be tolerated and methyl ether 1m
provided α′-methoxy conjugated enynone 2m with exquisite
chemoselectivity (allene vs alkyne). Noteworthy, when allenyl
methyl ether 1n decorated with a methyl substituent at the
terminal allene carbon was used as the starting material, the
reaction also worked well to provide the α′-methyl α′-methoxy
gem-substituted enone 2n (Scheme 3). However, when the
protocol was applied to alkyl-substituted allenyl methyl ether
1o, enone formation could not be achieved (Scheme 3). The
(E)-stereochemistry of enones 2 was established by means of
NOE experiments performed in compound 2c (see the
Supporting Information).
optimized amount for studying the scope of the organoseleno-
catalyzed reaction of allenes. When the reaction of precursor
1a was carried out replacing (PhSe)2 by PhSeCl (20 mol %), a
complicated mixture was obtained and product 2a was
obtained in a poor 14% yield.
After fixing a productive catalyst system, different tests were
conducted to inspect the substrate scope of the above
Next, we sought to develop a more general protocol by
replacing the methyl ether framework by different oxygenated
B
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functionalities. Initial efforts were a little bit frustrating because
the reaction of allenol 1p yielded enone 3b, while allenyl
acetate 1q was unreactive.9 Fortunately, allenyl ethers 1r−x
bearing extra benzyl, allyl, propargyl, and cumulenyl moieties
provided the desired rearranged functionalized adducts 2r−x
in synthetically useful yields (Scheme 4). It should be noted
the possible participation of atmospheric oxygen in the
formation of the carbonyl group can be ruled out in view of
the observed drastic reduction of the yield of enone 2a when
conducting a control reaction in dehydrated solvents in the
presence of an O2 balloon (Scheme 5).
A possible pathway for the generation of functionalized
enones 2 from allenes 1 through organoselenium catalysis is
outlined in Scheme 6. First, and similar to the pathway
Scheme 4. Controlled Synthesis of α,β-Unsaturated α′-
Alkoxy Ketones 2r−x
Scheme 6. Rationalization for the Formation of α,β-
Unsaturated α′-Alkoxy Ketones 2 by Organoselenium
Catalysis
that the mild reaction conditions allow for a complete
chemoselectivity, with the unsaturated allyloxy, propargyloxy,
and allenyloxy components present in allene precursors 1
being transferred unaltered to the final rearranged products 2.
Simultaneously, functionalized α′-alkoxy enones (E)-2r−x
were stereoselectively formed in a high E/Z ratio (up to
97:3) comparable to methyl ethers 2a−n.
The accessible water of regular (HPLC grade) acetonitrile
and THF was adequate for the reaction to progress profitably.
In order to confirm the participation of adventitious water in
the formation of polyfunctional adducts 2, an 18O-labeling
experiment was conducted (Scheme 5). Indeed, the use of
H218O in the reaction of 1e in anhydrous solvents resulted in
the formation of 18O-labeled 2e, as observed by high-resolution
mass spectrometry (see the Supporting Information). Besides,
proposed by Zhao and co-workers,6a the selenium-based π-acid
species PhSe(OTf) is originated from PhSeSePh by way of the
oxidative reagent [pyF][OTf]. Subsequently, an alkenyl
seleniranium INT-1 may be formed through regioselective
carbophilic interaction to the terminal allene double bond. The
proposed formation of the cyclic selenium intermediate INT-1
in a syn manner toward the OR1 group is in agreement with
recent reports on stabilizing noncovalent Se...O interactions.8,9
Then, controlled water attack to the three-membered
heterocyclic species with concomitant release of ring strain
and triflic acid liberation should afford enol INT-2, which is in
equilibrium with its more stable keto-tautomer INT-3. The
presence of free pyridine in the reaction medium should
provoke the abstraction of the acidic hydrogen, that is
associated with alcohol elimination and formation of
selenoenone INT-4. Further [pyF][OTf]-mediated oxidation
of the PhSe group in INT-4 should give rise to selenonium
species INT-5.10 α,β-Unsaturated α′-alkoxy ketones 2 would
be finally formed by SN2 displacement of the phenyl-
selenonium moiety by the in situ generated alcohol, with
concurrent loss of FH and regeneration of the selenium−π-
acid catalyst.
Scheme 5. Labeling and Control Studies
Density functional theory (DFT) calculations at the
dispersion-corrected PCM(MeCN)-B3LYP-D3/def2-
C
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TZVPP//PCM(MeCN)-B3LYP-D3/def2-SVP level11 were
carried out to gain more insight into the suggested occurrence
of a Se···O noncovalent interaction in the initial stages of the
transformation. To this end, we computed the reaction
involving allene 1b and PhSeOTf which leads to the
corresponding seleniranium INT-1b (see Figure 1). Our
adventitious water as the oxygen source and without the
involvement of metals has been satisfactorily accomplished.
This chemo-, stereo-, and site-selective oxygenative rearrange-
ment process involves an organoselenium-based π-acid-type
catalysis. DFT calculations provide further support to the
occurrence of a stabilizing LP(O)···Se noncovalent interaction
which significantly facilitates the transformation.14
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01288.
Experimental procedures, characterization data of new
compounds, copies of NMR spectra, computational
details, and alternative reaction pathway (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Teresa Martínez del Campo − Grupo de Lactamas y
́
́
Heterociclos Bioactivos, Departamento de Quımica Organica,
́
Unidad Asociada al CSIC, Facultad de Quımica, Universidad
Complutense de Madrid, 28040 Madrid, Spain;
Email: tmcampo@quim.ucm.es
́
́
́
Israel Fernandez − Departamento de Quımica Organica and
Figure 1. Computed reaction profile for the formation of intermediate
INT-1b from 1b and PhSeOTf. Relative free energies and bond
lengths are given in kcal/mol and angstroms, respectively. All data
have been computed at the PCM(MeCN)-B3LYP-D3/def2-
TZVPP//PCM(MeCN)-B3LYP-D3/def2-SVP level. Inset: Contour
plots of the reduced density gradient isosurfaces (density cutoff of
0.03 au) for compound INT-1b. The green surfaces indicate attractive
noncovalent interactions.
́
́
Centro de Innovacion en Quımica Avanzada
́
(ORFEO−CINQA), Facultad de Quımica, Universidad
Complutense de Madrid, 28040 Madrid, Spain; orcid.org/
0000-0002-0186-9774; Email: israel@quim.ucm.es
́
́
Pedro Almendros − Instituto de Quımica Organica General,
IQOG, CSIC, 28006 Madrid, Spain; orcid.org/0000-0001-
6564-2758; Email: palmendros@iqog.csic.es
Authors
Mireia Toledano-Pinedo − Grupo de Lactamas y Heterociclos
calculations indicate that the formation of INT-1b occurs
concertedly via TS, a saddle point associated with the
simultaneous (yet asynchronous) formation of the new C−
Se bonds and the rupture of the Se−OTf bond. The low
barrier (ΔG⧧ = 4.6 kcal/mol) and the high exergonicity (ΔGR
= −15.6 kcal/mol) computed for this reaction is fully
compatible with a process occurring at room temperature.
Interestingly, the Se···O distance in either TS or intermediate
INT-1b (3.199 and 3.029 Å, respectively) are shorter than the
sum of their respective van der Waals radii (3.42 Å), therefore
suggesting a significant noncovalent interaction involving these
atoms. The occurrence of this stabilizing intramolecular
interaction can be computationally visualized and confirmed
by means of the NCIPLOT method.12 As clearly shown in the
inset of Figure 1, there exists a significant noncovalent
attractive interaction (green surface) between the oxygen and
selenium atoms in INT-1b.13
Moreover, the crucial role of this LP(O)···Se noncovalent
interaction in the process is supported by comparing the
reaction profile involving the OAc counterpart of 1b (see
Figure S1). For this system, the Se···O distance of the
corresponding transition state is much longer (3.333 Å)
therefore indicating a weaker Se···O interaction as a
consequence of the reduced donor ability of the oxygen
atom. As a result, the computed barrier for this transformation
is significantly higher (ΔG⧧ = 7.4 kcal/mol) and the process
becomes much less exergonic (ΔGR = −8.5 kcal/mol) than the
reaction involving its OMe counterpart 1b.
́
́
Bioactivos, Departamento de Quımica Organica, Unidad
́
Asociada al CSIC, Facultad de Quımica, Universidad
Complutense de Madrid, 28040 Madrid, Spain
Marta Tiemblo − Grupo de Lactamas y Heterociclos Bioactivos,
́
́
Departamento de Quımica Organica, Unidad Asociada al
́
CSIC, Facultad de Quımica, Universidad Complutense de
Madrid, 28040 Madrid, Spain
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01288
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported in part by the Spanish Agencia
■
́
Estatal de Investigacion and European Regional Development
Fund (Projects PGC2018-095025-B-I00, CTQ2016-78205-P,
and CTQ2016-81797-REDC). We are grateful to Prof. B.
Alcaide for continued support.
DEDICATION
■
Dedicated to Professor Benito Alcaide on the occasion of his
70th birthday
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Organic Letters
pubs.acs.org/OrgLett
Letter
(9) The failure of allene 1q, bearing an AcO group instead of an
alkoxy moiety, may be tentatively explained through a weaker Se...O
interaction, which should not impart stabilization enough to the
putative phenylseleniranium intermediate INT-1q.
(10) The application of selenonium cations as Lewis acids in
organocatalytic reactions has been recently documented: He, X.;
Wang, X.; Tse, Y.-L.; Ke, Z.; Yeung, Y.-Y. Applications of Selenonium
Cations as Lewis Acids in Organocatalytic Reactions. Angew. Chem.,
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(11) See the Computational Details in the Supporting Information.
́
(12) Johnson, E. R.; Keinan, S.; Mori-Sanchez, P.; Contreras-García,
J.; Cohen, A. J.; Yang, W. Revealing Noncovalent Interactions. J. Am.
Chem. Soc. 2010, 132, 6498−6506.
(13) A similar interaction is found by the NCIPLOT method for the
saddle point TS.
(14) Taking into account both that electrophiles are usually added to
the internal double bond of the allene moiety15 as well as the
possibility of isomerization of 2,3-allenols to 2-oxy-1,3-diene under
certain conditions,16 another possible mechanism (see Scheme S1 in
the Supporting Information) may be contemplated: Precursors 1
should be converted under acidic conditions to allene-type allyl
cations I through OP release. Next, π-bond migration followed by
water attack should form 2-oxy-1,3-dienes II, which can isomerize to
enones 3. Next, PhSe+ can react with intermediates II to form α-PhSe-
ketones INT-4, which followed by oxidation and displacement should
generate α,β-unsaturated α′-alkoxy ketones 2. The formation of
compounds 3a,b might go through the picture depicted in Scheme S1.
However, we think that this alternative path is not operative for the
formation of compounds 2a−n and 2r−x, because it may not account
for the different reactivity observed for AcO-allene 1q and
alkoxyallenes 1a−n and 1r−x.
(15) (a) Fu, C.; Li, J.; Ma, S. Efficient Two-Step Synthesis of 3-
Halo-3-enals or 2-Halo-2-alkenyl ketones from Propargylic Bromides
via a Unique Cationic 1,2-Aryl or Proton Shift in Electrophilic
Addition Reaction of 2,3-Allenols with X+. Chem. Commun. 2005,
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Arno, M.; Domingo, L. R. Controlled Rearrangement of Lactam-
Tethered Allenols with Brominating Reagents. A Combined
Experimental and Theoretical Study on the α-Keto- versus β-Keto
Lactam Formation. Chem. - Eur. J. 2011, 17, 11559−11566.
(c) Murai, K.; Shimizu, N.; Fujioka, H. Enantioselective Iodolacto-
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(16) (a) Zhang, X.; Fu, C.; Ma, S. Highly Stereoselective Facile
Synthesis of 2-Acetoxy-1,3(E)-alkadienes via a Rh(I)-Catalyzed
Isomerization of 2,3-Allenyl Carboxylates. Org. Lett. 2011, 13,
1920−1923. (b) Jin, Z.; Hidinger, R. S.; Xu, B.; Hammond, G. B.
Stereoselective Synthesis of Monofluoroalkyl α,β-Unsaturated Ke-
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