Cyclization Reactions of Oxyallyl Cation. A Method for Cyclopentane Ring Formation

Article abstract of DOI:10.1021/acs.orglett.9b03791

Unsaturated oxyallyl cations with a suitably positioned alkene bond undergo 5-exo-cyclization with the formation of vinylcyclopentane derivatives. Alkyne analogues provide allenes. The reaction proceeds with a moderate to excellent level of stereoselectiv

Full text of DOI:10.1021/acs.orglett.9b03791

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cyclization Reactions of Oxyallyl Cation. A Method for Cyclopentane
Ring Formation
Bojan Vulovic,† Milena Trmcic,‡ Radomir Matovic,§ and Radomir N. Saicic*,†,∥
†Faculty of Chemistry, University of Belgrade, Studentski trg 16, P.O. Box 51, 11158 Belgrade, Serbia
‡Innovation Centre of the Faculty of Chemistry, University of Belgrade, 11158 Belgrade, Serbia
§ICTM Center for Chemistry, Njegoseva 12, 11158 Belgrade, Serbia
∥Serbian Academy of Sciences and Arts, Knez Mihailova 35, 11158 Belgrade, Serbia
S
* Supporting Information
ABSTRACT: Unsaturated oxyallyl cations with a suitably positioned
alkene bond undergo 5-exo-cyclization with the formation of vinyl-
cyclopentane derivatives. Alkyne analogues provide allenes. The reaction
proceeds with a moderate to excellent level of stereoselectivity and allows
for asymmetric induction in the reaction with chiral substrate.
Scheme 1. Previous Reports of Oxyallyl Cation Cyclization
and This Work
eactive intermediates are the cornerstones of chemical
Rreactivity. Depending on the reaction conditions, these
species can (more or less selectively) pursue one of many
available pathways within a rich mechanistic manifold,
resulting in a number of synthetically useful reactions that
surpasses by far the number of known reactive intermediates
(radicals, diradicals, carbenes, carbocations, carbanions, and
their heteroatom analogues). However, to the best of our
knowledge, oxyallyl cations have found limited synthetic
application,1 which includes the Favorskii rearrangement,2
[4 + 3] cycloadditions,3 and intermolecular reactions with
nucleophiles;4 this last reaction can be combined with a second
bond-forming reaction to give products of a formal [3 + 2]
cycloaddition.5 Apart from [4 + 3] cycloadditions and few
isolated examples of reductive [3 + 2] cycloadditions of
dihaloketones, intramolecular reactions of oxyallyl cations have
not been systematically investigated.6 We set out to explore in
more detail cyclization reactions of these species.
Intermolecular reactions of oxyallyl cations with nucleo-
philes (including alkenes) work well only with strongly
activated ones.4,7 We presumed that the oxyallyl cation should
undergo cyclization with suitably positioned, unactivated
alkene, where the spatial proximity would compensate for
the lack of electronic activation. Scarce literature data inferred
the feasibility of this conception. Thus, Noyori reported iron
carbonyl-induced reductive cyclization of dihaloketones into
camphor derivatives, which probably proceeds as a stepwise
[3 + 2] cycloaddition (Scheme 1, example 1).8 West
accomplished the intramolecular olefin trapping in the
interrupted Nazarov cyclization9 of polyunsaturated substrates
(Scheme 1, example 2).10 However, dihaloketones used in the
first example may not always be readily accessible; in addition,
several structurally related precursors failed to cyclize. In its
turn, the Nazarov reaction requires specific precursor structure.
We endeavored to explore a cyclization of oxyallyl cations
generated by a more general method, from readily accessible
precursors, such as hydroxyketone derivatives (Scheme 1,
example 3).4 We surmised that unsaturated oxyallyl cations
should undergo cyclization, which may proceed with 5-exo- or
6-endo-selectivity. In addition to these two most probable
reaction pathways, formal [3 + 2] cycloaddition with the
formation of bicyclic, carbocyclic product, and/or [3 + 2]
cycloaddition with the formation of bicyclic, heterocyclic
product, could also be envisaged.11
Received: October 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03791
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In the first experiment, tosylate 1syn12 was treated with
triethylamine in trifluoroethanol. To our delight, the product
of the reaction was vinylcyclopentane derivative 2, i.e., the
product of 5-exo-cyclization, which was isolated in 63% yield as
a mixture of three diastereoisomers (Scheme 2, entry 1).
cyclization (8) was accompanied by the [3 + 2] hetero-
cycloadduct (9), the former was obtained as a single
diastereoisomer (out of four possible), indicating the complete
transfer of the stereochemical information in the transition
state, from the single stereogenic center (in the precursor 7) to
the two newly created stereocenters (in the product 8). Again,
the configuration of the mesyloxy-bearing carbon atom is
irrelevant for the stereochemical outcome of the reaction; this
fact has mechanistic implications (vide infra), but it also allows
for flexibility in the preparation of the precursors. Also of note
is the translocation of the reaction center: the cyclization
occurs at the α-position of ketone 7, although the leaving
group is in the α′-position; this is a useful feature of oxyallyl
cation cyclization that contributes positively to the synthetic
applicability. The cyclization of substrate 7 with a defined
absolute configuration at the methyl-bearing carbon atom
produced optically pure ketone 8 (entry 8). Substrates with
terminal alkene do not react; however, a single (E)-configured
methyl (entry 9) or methylene substituent (entries 6 and 10) is
sufficient for the cyclization to occur; no cyclization was
observed with the (Z)-configured precursor. This observation
is relevant for establishing the reaction mechanism (vide infra).
We have not observed other cyclization modes apart from 5-
exo. Substrate 16 that contains both Δ5 and Δ6 alkene bonds
(with respect to the reaction center) affords exclusively
cyclopentane derivative 17 (entry 11).
Scheme 2. Cyclizations of Oxyallyl Cations: Reactions of
a
All-Carbon, Acyclic Alkene Precursors
Heteroatom can be present in the chain when heterocyclic
derivatives are obtained (Scheme 3, entries 1−3). A couple of
cyclic precursors have also been submitted to the cyclization
conditions, aiming to obtain bi- or polycyclic products.
Cyclohexanone-derived precursor 25 afforded tricyclic deriv-
ative 26, which is structurally quite similar to the product
obtained by West in the interrupted Nazarov cyclization (entry
3);10a the important difference, however, is that Nazarov-type
products inevitably contain cyclopentane as the core structure,
whereas the generation of oxyallyl cation from α-mesyloxy
ketone is not limited by such a constraint. Transannular
cyclization of 27 stereoselectively produced (E)-configured,
trans-condensed bicyclo[7.3.0]dodec-7-en-2-one 28 (entry 4).
Cyclization of alkynes proceeds as well: thus, ynone 29
afforded allene derivative 30 (67%, entry 5), which could be
isomerized into dienone 31. The cyclization/isomerization
tandem occurred spontaneously with the oxygen-containing
analogue 32 (entry 6). It is of note that in all examples
cyclopentane derivatives were obtained exclusively; this is in
contrast to the scarce literature examples of related
systems,10,14 where transient oxyallyl cationic species afforded
six-membered ringsthe expected regiochemical outcome of
cationic polyene cyclizations.
a
Reagents and conditions: Method A, Et3N, TFE, 45 °C; Method B,
Et3N, SiO2, DCM, rt; Method C, Et3N, LiClO4, PhMe, 60 °C; (a) dr
= 5:1; only the major isomer is represented; (b) isolated as a mixture
of geometrical isomers in a ratio 14E:14Z = 5.2:1.
Some side reactions have been observed, as well. These
include the Favorskii rearrangement (Scheme 4, example 1),
cheletropic elimination of carbon monoxide (example 2),15
formation of trifluoroethoxy acetals from the starting
mesyloxyketone, and the unexpected intramolecular attack of
an oxygen nucleophile to the oxyallyl cation with the
tetrahydrofuran ring closure (example 3). The Favorskii
rearrangement and the acetal formation can be suppressed
by performing the reaction in toluene in the presence of
lithium perchlorate. This procedure improved the yield in
entry 2 (Scheme 3) from 25% to 40%.
Stereoisomeric precursor 1anti (X = Ts) gave a similar result
(74%; entry 2), indicating that the product distribution does
not depend on the stereochemistry of the nucleofuge-bound
carbon atom. Therefore, the next experiment was performed
with a stereoisomeric mixture of mesylates 1syn+anti to obtain
product 2 in 70% yield, with similar dr (entry 3).13 The
reaction was also performed in toluene, in the presence of
LiClO4, on a gram scale, with comparable results (entry 4).
Cyclohexane-derived precursor 3 gave spiro product 4 as a
single diastereoisomer (67%; entry 5). However, in the
reaction with structurally related substrate 5, spirobicyclic
product 6 was obtained as a mixture of diastereoisomers (dr =
2.6:1; entry 6). The example represented in entry 7 is
important for several reasons: although the product of 5-exo-
As for the mechanism of the reaction, two pathways can be
envisaged: concerted and stepwise. For the related intermo-
lecular ene reaction of allylic cations with isobutylene, Noyori
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DOI: 10.1021/acs.orglett.9b03791
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Cyclizations of Oxyallyl Cations: Reactions of
Heteroatom-Containing Presursors, Cyclic Precursors, and
Alkynes
Scheme 5. Proposed Reaction Mechanism
a
attack of the enolate oxygen (which produces dihydrofuran-
type product, e.g., 9). In this mechanistic scenario, the
formation of endo-products would also be expected, at least
with compounds 10 or 23. However, the exo-products were
exclusively formed in all cases. Also, it is not clear why E-
isomers of 10 and 23 cyclize, whereas the Z-isomers do not. In
addition, Noyori has provided evidence which, apparently,
rules out the intermediacy of carbocationic intermediate of
type 39 in the intermolecular reaction.16 Preliminary modeling
of the transition state at DFT/BLYP/TZ2P level of theory
failed to explain the experimental results and additional
calculations, and experiments are needed to clarify this issue.
To summarize, a stereoselective cyclization of oxyallyl
cations was developed which proceeds with the translocation
of the reactive center and affords unsaturated cyclopentane
derivatives in moderate to good yields. Studies toward the
application of this method in the synthesis of natural products
are underway in our laboratory and will be reported in due
course.
a
Reagents and conditions: Method A, Et3N, TFE, 45 °C; Method C,
Et3N, LiClO4, PhMe, 60 °C.
Scheme 4. Side Reactions
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03791.
Experimental procedures, spectral data and copies of
NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rsaicic@chem.bg.ac.rs.
ORCID
proposed a concerted mechanism.16 An intramolecular variant
of this mechanistic possibility is represented in Scheme 5 (eq
1). The pericyclic reaction would be expected to produce
predominantly (if not exclusively) the cis-configured product
8-cis.17 However, in all of our experiments trans-configured
products were favored, or even obtained exclusively, such as 8,
whose relative configuration was unambiguously established by
a NOESY experiment.18 Therefore, the stereochemical out-
come of the cyclization does not support the concerted
mechanism. The second possibility would be a stepwise
mechanism where the reaction proceeds via a cationic
intermediate 39 (Scheme 5, eq 2), which can further undergo
either a proton elimination (with the formation of the
vinylcyclopentane-type product, e.g., 8) or intramolecular
Radomir N. Saicic: 0000-0003-3653-8294
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the contribution of Filip Opincal
(University of Belgrade, Faculty of Chemistry, UBFC), who
performed the experiments with cyclohexanone-derived
substrate (entry 4 in Scheme 3), as well as the contribution
of Prof. Maja Gruden (UBFC), who performed modeling of
the transition state for cyclization. The authors are grateful to
Dr. Miroslav Novakovic (ICTM Center for Chemistry) for
providing HRMS of compounds. This work was supported by
C
DOI: 10.1021/acs.orglett.9b03791
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(12) The assignation of syn and anti stereochemistry to the
diastereoisomers of 1 is tentative.
(13) The diastereoisomeric ratio of 2a, 2b, and 2c apparently does
not depend on the reaction time. The reaction was performed several
times with monitoring by GC: the initial dr (i.e., after 1 h) did not
change after up to 48 h (see the Supporting Information for details).
the Ministry of Education, Science and Technological
Development of the Republic of Serbia (Project No.
172027), and by the Serbian Academy of Sciences and Arts
(Project No. F193). The authors acknowledge the support of
the FP7 RegPot project FCUB ERA GA No. 256716. The EC
does not share responsibility for the content of the article.
̈
(14) (a) Browder, C. C.; Marmsater, F. P.; West, F. G. Org. Lett.
̈
2001, 3, 3033−3035. (b) Browder, C. C.; Marmsater, F. P.; West, F.
G. Can. J. Chem. 2004, 82, 375−385.
REFERENCES
■
(15) For examples of cheletropic elimination of carbon monoxide,
see: (a) Wasserman, H. H.; Clark, G. M.; Turley, P. C. Top. Curr.
Chem. 1974, 47, 73−156. (b) For a recent example of synthetic
application, see: Kulyk, S.; Khatri, B. B.; Sieburth, S. Angew. Chem.,
Int. Ed. 2017, 56, 319−323.
(1) For a review on the synthetic utility of oxyallyl cations, see:
Mann, J. Tetrahedron 1986, 42, 4611−4659.
(2) (a) Mann, J. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, p 839−859.
(b) Butkas, E. In Comprehensive Organic Synthesis, 2nd ed.; Knochel,
P., Molander, G. A., Eds.; Elsevier: Amsterdam, 2014; Vol. 3, p 853−
886.
(3) Review articles on [4 + 3] cycloaddition of allylic cations:
(a) Mascarenas, J. L.; Gulias, M.; Lopez, F. in Comprehensive Organic
Syntheses, 2nd ed.; Knochel, P.; Molander, G., Eds.; Elsevier:
Amsterdam, 2014; Vol. 5, pp 595−655;. (b) Harmata, M. Chem.
Commun. 2010, 46, 8886−8903. (c) Harmata, M. Chem. Commun.
2010, 46, 8904−8922. (d) Rigby, J. H.; Pigge, F. C. Org. React. 1997,
51, 351−476. (e) Noyori, R.; Hayakawa, Y. Org. React. 1983, 29,
163−344. (f) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984,
23, 1−19. (g) Review article on [4 + 3] cycloaddition of nitrogen-
stabilized oxyallyl cations: Lohse, A. G.; Hsung, R. P. Chem. - Eur. J.
2011, 17, 3812−3822.
(16) Noyori, R.; Shimizu, F.; Hayakawa, Y. Tetrahedron Lett. 1978,
19, 2091−2094.
(17) Alternatively, the proton transfer could occur from carbon to
oxygen, with the same stereochemical outcome. We thank the
Reviewer for this suggestion.
(18) In the representation of transition state in Scheme 5, one of two
methyl groups at the alkene bond is omitted for clarity. Detailed
NOESY analyses are provided for compounds 2, 4, 8, and 28. See the
Supporting Information for details.
(4) (a) Vander Wal, M. N.; Dilger, A. K.; MacMillan, D. W. C.
Chem. Sci. 2013, 4, 3075−3079. (b) For a catalytic asymmetric
variant of this reaction, see: Liu, C.; Oblak, Z.; Vander Wal, M. N.;
Dilger, A. K.; Almstead, D. K.; MacMillan, D. W. C. J. Am. Chem. Soc.
2016, 138, 2134−2137.
(5) (a) A review article: Li, H.; Wu, J. Synthesis 2014, 47, 22−33.
(b) [3 + 2] cycloaddition with dearomatization of indole: Li, H.;
Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2014, 136, 6288−6296. (c) [3
+ 2] cycloaddition onto the carbonyl group: Krenske, E. H.; He, S.;
Huang, J.; Du, Y.; Houk, K. N.; Hsung, R. P. J. Am. Chem. Soc. 2013,
135, 5242−5245. (d) Pd-catalyzed formal cycloaddition with the
formation of tetrahydrofurane derivatives which can be isomerized
into cyclopentanones: Trost, B. M.; Huang, Z.; Murhade, G. M.
Science 2018, 362, 564−568.
(6) For a review article on intramolecular cycloaddition reactions of
allylic cations, see: Harmata, M. Tetrahedron 1997, 53, 6235−6280.
(7) (a) Leitich, J.; Heise, I. Eur. J. Org. Chem. 2001, 2001, 2707−
2718. (b) Harmata, M.; Huang, C.; Rooshenas, P.; Schreiner, P. R.
Angew. Chem., Int. Ed. 2008, 47, 8696−8699. (c) Tang, Q.; Chen, X.;
̈
Tiwari, B.; Chi, Y. R. Org. Lett. 2012, 14, 1922−1925. (d) Fohlisch,
B.; Joachimi, R. Chem. Ber. 1987, 120, 1951−1960.
(8) (a) Noyori, R.; Nishizawa, M.; Shimizu, F.; Hayakawa, Y.;
Maruoka, K.; Hashimoto, S.; Yamamoto, H.; Nozaki, H. J. Am. Chem.
Soc. 1979, 101, 220−222. (b) Mechanistic study: Noyori, R.;
Hayakawa, Y.; Takaya, H.; Murai, S.; Kobayashi, R.; Sonoda, N. J. Am.
Chem. Soc. 1978, 100, 1759−1765.
(9) (a) For a review article on the interrupted Nazarov cyclization,
see: Grant, T. N.; Rieder, C. J.; West, F. G. Chem. Commun. 2009,
5676−5688. For review articles on Nazarov cyclization (including the
interrupted variant), see: (b) Frontier, A. J.; Collison, C. Tetrahedron
2005, 61, 7577−7606. (c) West, F. G.; Scadeng, O.; Wu, Y.-K.;
Fradette, R. J.; Joy, S. In Comprehensive Organic Synthesis, 2nd ed.;
Knochel, P., Molander, G. A., Eds.; Elsevier: Amsterdam, 2014; Vol. 5,
pp 828−866.
(10) (a) Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese, S.; West,
F. G. J. Org. Chem. 1998, 63, 2430−2431. (b) Bender, J. A.; Arif, A.
M.; West, F. G. J. Am. Chem. Soc. 1999, 121, 7443−7444.
(11)
D
DOI: 10.1021/acs.orglett.9b03791
Org. Lett. XXXX, XXX, XXX−XXX