Fast oxy-cope rearrangements of bis-alkynes: Competition with central C-C bond fragmentation and incorporation in tunable cascades diverging from a common bis-allenic intermediate

Article abstract of DOI:10.1021/jo101838a

Fast anionic oxy-Cope rearrangements of 1,5-hexadiyn-3,4-olates can be incorporated into cascade transformations which rapidly assemble densely functionalized cyclobutenes or cyclopentenones via a common bis-allenic intermediate. The competition between f

Full text of DOI:10.1021/jo101838a

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transition state is very sensitive to the nature and position of
Fast Oxy-Cope Rearrangements of Bis-alkynes:
Competition with Central C-C Bond Fragmentation
and Incorporation in Tunable Cascades Diverging
from a Common Bis-allenic Intermediate
substituents.3 For example, Evans reported a dramatic accelera-
tion of the oxy-Cope rearrangement via introduction of anionic
substituents,4 while Doering and others controlled the electro-
nic character of the Cope transition state with appropriately
positioned Ph groups.5
The rich mechanistic spectrum of reactions “under the
umbrella of Cope rearrangement family” was further illu-
strated by predictions of unusual Cope rearrangement
patterns based on a comprehensive heuristic approach.6 Pre-
vious computational evidence suggested that some anion-
ic Cope rearrangements proceed via a dissociative mechanism
initiated by a homolytic cleavage of the central C-C bond
(Scheme 1).7
Runa Pal,† Ronald J. Clark,† Mariappan Manoharan,‡ and
Igor V. Alabugin*,†
†Department of Chemistry and Biochemistry, Florida State
University, Tallahassee, Florida 32306-4390, United States,
and ‡Bethune-Cookman University, Daytona Beach,
Florida 32114, United States
alabugin@chem.fsu.edu
Received September 19, 2010
SCHEME 1. (Top) Alternative Descriptions of the Cope Rear-
rangement TS. (Bottom) Cumulative Accelerating Substituent
Effects on the Cope Rearrangent of Bis-alkynes
Fast anionic oxy-Cope rearrangements of 1,5-hexadiyn-
3,4-olates can be incorporated into cascade transformations
which rapidly assemble densely functionalized cyclobutenes
or cyclopentenones via a common bis-allenic intermediate.
The competition between fragmentation, 4π-electrocyclic
closure, and aldol condensation can be efficiently con-
trolled by the nature of the acetylenic substituents. The
rearrangement of bis-alkynes with two hydroxyl substit-
uents opens a conceptually interesting entry in the chemistry
of ε-dicarbonyl compounds and suggests a new approach to
analogues of rocaglamide/aglafolin.
Taking into account the tunable nature of the Cope
transition state and our previous explorations of alkyne
reactivity,8 we decided to investigate how this process responds
to weakening of the central C-C bond in bis-alkynes by two
pairs of accelerating substituents.9 Our exploratory compu-
tations (Scheme 1 and Supporting Information) predicted
that such accelerating effects are likely to be substantial. In
this work, we report experimental observations regarding the
(3) (a) Doering, W.; von, E.; Wang, Y. J. Am. Chem. Soc. 1999, 121, 10112.
(b) Doering, W.; von, E.; Wang, Y. J. Am. Chem. Soc. 1999, 121, 10967.
(c)Doering, W.; von, E.; Birladeanu, L.; Sarma, K.; Blaschke, G.; Scheidemantel,
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U.; Boese, R.; Benet-Bucholz, J.; Klarner, F.-G.; Gehrke, J. -S.; Zinny, B. U.;
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Hanna, I.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5, 3631. (e) Staroverov,
V. N.; Davidson, E. R. J. Am. Chem. Soc. 2000, 122, 186. (f ) Hrovat, D. A.; Beno,
B. R.; Lange, H.; Yoo, H. -Y.; Houk, K. N.; Borden, W. T. J. Am. Chem. Soc.
1999, 121, 10529. (g) Hrovat, D. A.; Chen, J.; Houk, K. N.; Borden, W. T. J. Am.
Chem. Soc. 2000, 122, 7456.
(4) (a) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765.
(b) Carpenter, B. K. Tetrahedron 1978, 34, 1877. (c) Evans, D. A.; Ballallargeon,
D. J.; Nelson, J. V. J. Am. Chem. Soc. 1978, 100, 2242.
Efficient control of the Cope rearrangement and related
reactions1 is important for incorporation of this useful C-C
bond-forming process in subsequent reaction cascades, espe-
cially if these cascades have to be tunable.2 Extensive experi-
mental and computational data suggest that the rearrangement
(5) Roth, W. R.; Lennartz, H.-W.; Doering, W. v. E.; Birladeanu, L.;
Guyton, C. A.; Kitagawa, T. J. Am. Chem. Soc. 1990, 112, 1722.
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(1) (a) Hopf, H. Classics in Hydrocarbon Chemistry; Wiley-VCH:
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2007, 22, 2211. (c) Butenschon, H. Pure Appl. Chem. 2002, 74, 57.
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(b) Paquette, L. A. Tetrahedron 1997, 53, 13971. (c) Dahnke, K. R.; Paquette,
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Chem. 1995, 46, 2199. (e) Barriault, L.; Deon, D. H. Org. Lett. 2001, 3, 1925.
DOI: 10.1021/jo101838a
r
Published on Web 11/23/2010
J. Org. Chem. 2010, 75, 8689–8692 8689
2010 American Chemical Society

Pal et al.
JOCNote
FIGURE 1. ORTEP diagram for (a) compound 3-TMS-cis, (b) compound 7a, (c) compound 6b, and (d) compound 9b.
fast anionic oxy-Cope rearrangement of 1,5-hexadiyn-3,4-olates
as well as the remarkable sensitivity of subsequent cascade
transformations to the nature of alkyne substituents.
The starting materials can be prepared conveniently via
reaction of 1,4-diphenyl-2,3-ethanedione (benzil) with 2 equiv of
metal acetylides. Remarkably, oxy-Cope rearrangement of the
resulting bis-adduct occurs readily as the reaction mixture
warms to room temperature. The essential role of the two Ph
substituents at the central bond is illustrated by the lack of oxy-
Cope rearrangement of analogous adducts formed from
2,3-butanedione10 and 1-phenyl-1,2-propanedione. The Ph
groups weaken the central C-C bond in the bis-alkyne 1 and
provide additional thermodynamic stabilization to the newly
formed CdC bonds in the product 2.
Subsequent rearrangement of the bis-allene oxy-Cope
products 2 can be controlled efficiently by the nature of sub-
stituents in the acetylenic nucleophiles. Depending on the alkyne,
divergent anionic cascades of the bis-allenic intermediates either
transform simple acyclic starting materials into densely func-
tionalized cyclobutene and cyclopentenone products or produce
fragmentation products via a dissociative pathway.
In particular, the bis-allenic Cope product 2 formed in situ in
the reaction of benzil with TMS-substituted acetylide under-
goes rapid 4π-electrocyclic closure to a mixture of cis- and trans-
cyclobutenes 3-TMS in ∼80% overall yield.11 Structure of the
cis-isomer (3-TMS-cis) was confirmed by X-ray crystallography
(Figure 1a). This isomer is initially present as the major product
in the reaction mixture (∼10:1 cis/trans selectivity, Scheme 2).
This selectivity suggests that kinetic protonation of the keto-
enol intermediate favors formation of a less stable product.12
The cis-isomer can be epimerized quantitatively into the more
(8) (a) Zeidan, T. A.; Kovalenko, S. V.; Manoharan, M.; Clark, R. J.;
Ghiviriga, I.; Alabugin, I. V. J. Am. Chem. Soc. 2005, 127, 4270. (b) Alabugin,
I. V.; Manoharan, M. J. Am. Chem. Soc. 2003, 125, 4495. (c) Breiner, B.;
Schlatterer, J. C.; Kovalenko, S. V.; Greenbaum, N. L.; Alabugin, I. V. Proc.
Natl. Acad. Sci. U.S.A. 2007, 104, 13016. (d) Breiner, B.; Schlatterer, J. C.;
Kovalenko, S. V.; Greenbaum, N. L.; Alabugin, I. V. Angew. Chem., Int. Ed.
2006, 45, 3666. (e) Vasilevsky, S. F.; Mikhailovskaya, T. F.; Mamatyuk, V. I.;
Bogdanchikov, G. A.; Manoharan, M.; Alabugin, I. V. J. Org. Chem. 2009, 74,
8106. (f) Alabugin, I. V.; Gilmore, K.; Patil, S.; Manoharan, M.; Kovalenko,
S. V.; Clark, R. J.; Ghiviriga, I. J. Am. Chem. Soc. 2008, 30, 11535. (g) Yang,
W.-Y.; Breiner, B.; Kovalenko, S. V.; Ben, C.; Singh, M.; LeGrand, S. N.;
Sang, Q.-X.; Strouse, G. F.; Copland, J. A.; Alabugin, I. V. J. Am. Chem. Soc.
2009, 131, 11458. (h) Vasilevsky, S. F.; Baranov, D. S.; Mamatyuk, V. I.;
Gatilov, Y. V.; Alabugin, I. V. J. Org. Chem. 2009, 74, 6143. (i) Alabugin, I. V.;
Manoharan, M. J. Am. Chem. Soc. 2005, 127, 12583. (j) Alabugin, I. V.;
Manoharan, M. J. Am. Chem. Soc. 2005, 127, 9534. (k) Zeidan, T.; Manoharan,
M.; Alabugin, I. V. J. Org. Chem. 2006, 71, 954. (l) Baroudi, A.; Mauldin, J.;
Alabugin, I. V. J. Am. Chem. Soc. 2010, 132, 967.
(11) (a) An analogous cascade of 1,5-hexadiyne proceeds only at tem-
peratures >250 °C: Huntsman, W. D.; Wristers, H. J. J. Am. Chem. Soc.
1967, 89, 342. (b) 4π-Electrocyclization was not able to compete with
ketonization of bis-allenol formed in the oxy-Cope rearrangement of a 1,5-
hexadiyne-3,4-diol: Manisse, N.; Chuche, J. Tetrahedron 1975, 35, 3095.
Viola, A.; Collins, J. J.; Filipp, N. Tetrahedron 1981, 37, 3765. (c) Similar
electrocyclizations of bis-allenes produced via [2,3]-sigmatropic shifts:
Braverman, S.; Kumar, E. V. K. S; Cherkinsky, M.; Sprecher, M.; Goldberg,
I. Tetrahedron 2005, 61, 3547.
(9) Similar reactions of bis-alkenes: Clausen, C.; Wartchow., R.;
€
€
Butenschon, H. Eur. J. Org. Chem. 2001, 93. Butenschon, H. Pure Appl.
Chem. 2002, 74, 57.
(10) (a) Alabugin, I. V.; Timokhin, V. I.; Abrams, J. N.; Manoharan, M.;
Ghiviriga, I.; Abrams, R. J. Am. Chem. Soc. 2008, 130, 10984. (b) See also:
Cognacq, J. C.; Skowronski, R.; Chodkiewicz, W.; Cadiot, P. Bull. Soc.
Chim. Fr. 1967, 3, 880.
(12) (a) Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263. (b) Zimmerman,
H. E.; Pushechnikov, A. Eur. J. Org. Chem. 2006, 3491.
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SCHEME 2. Cope Rearrangement/4π-Electrocyclic Ring-Closure
SCHEME 4. Yields, Selectivity, and Proposed Mechanism for the
Formation of Keto and Enol Forms of the Cyclopentenone Products
Sequence for the Formation of Cyclobutenesa
aB3LYP/6-31þG** energies of the two stereoisomers of enol and keto-
tautomers (R = SiH3; M = H) are given at the bottom of the scheme.
of the weakened C-C bond. The ratio between the cyclobutene
and fragmented product is controlled by the size of the silyl
substituents. Although cyclobutenes are the major products for
R = TMS, a mixture of cyclobutene and fragmented product
is formed when 2 equiv of TES-acetylide are used. The frag-
mentation path becomes dominant for R = triisopropylsilyl
(TIPS where only ketone 4-TIPS and alcohol 5-TIPS) were
obtained in ratios dependent upon the amount of lithium
acetylide. Ketone 413 was formed as the major product with 2
equiv of acetylide, whereas a larger excess (4.5 equiv) of acetylide
led to the formation of 5-TIPS exclusively.
SCHEME 3. Competition between the Oxy-Cope Rearrangement
and Fragmentation in the Reactions of TES- and TIPS-Substituted
Acetylenes
The structure of the fragmented products has been con-
firmed by their independent synthesis (described in the Support-
ing Information),14 but the exact mechanism for their formation
remains unclear. Minor products isolated from the reaction
mixtures suggest that it includes either an ene reaction or a retro-
pinacol fragmentation, topologically analogous to the Cope
rearrangement diverted via a fully dissociative transition state
(Scheme 3). Because the rate of the second TIPS-acetylide
addition to the diketone is relatively slow, contribution from an
additional fragmentation pathway from the monoadducts is
also plausible.
Because of the presence of two hydroxyl groups at the
central bond of the bis-acetylenes 1, these compounds can be
considered as a latent dicarbonyl functionality that is revealed
by the oxy-Cope process in its bis-enolized state. As a result, one
can couple the pericyclic step with typical carbonyl chemistry,
such as intramolecular aldol condensations. In accord with
this notion, reactions of benzil with aryl and alkyl substi-
tuted acetylides proceed with the formation of cyclopentenones
in 75-85% yield (∼2:1 mixture of keto and enol forms,
Figure 1b-d). Neither p-CH3 nor p-F substituents have a large
effect on the reaction yield or the keto/enol ratio. Although
the reaction with methyl propargyl ether produced the same
5-cyclopentenone framework, the cascade continued one step
further toward the formation of an exo-cyclic double bond via
methanol elimination. In the latter case, the tautomeric
equilibrium is shifted toward enol (Scheme 4).
stable trans 3-TMS isomer under basic conditions (stirring with
the LiOH/THF/H2O system or keeping the reaction mixture for
6 h at pH ∼9).
The Cope rearrangement step is expected to be highly
asynchronous due to the accumulative weakening of the central
C-C bond by four substituents: the two anionic oxygens and the
two Ph groups (Scheme 3). Related anionic rearrangements
have been suggested to proceed through a dissociative mecha-
nism via the central bond cleavage.7 In accord with this model,
we found that an increase in the steric bulk of the alkyne sub-
stituents prevents the formation of the new C-C bond in the
Cope product and diverts the reaction to the fragmentation
(13) Shintani, R.; Okamoto, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127,
2872.
(14) The ketone was prepared via a literature procedure: Feng, L.;
Kumar, D.; Kerwin, S. M. J. Org. Chem. 2003, 68, 2234. The bis-alkyne
alcohol was synthesized in 89% yield via reaction of 2.2 equiv of TIPS-
acetylide with ethyl benzoate (see the Supporting Information for details).
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Pal et al.
JOCNote
SCHEME 5. Calculation of Relative Energies (kcal/mol) for
Keto-enol Tautomerizations and Energies in Parentheses Obtained
from the Single-Point Calculations at the SCRF(PCM)-B3LYP/
6-31þG**//B3LYP/6-31þG** Level with THF Solvent
SCHEME 6. Summary of Cascade Transformations Initiated
by Anionic Oxy-Cope Rearrangements of Activated Bis-acetylenes
and Structural Resemblance between Cyclopentenones and
Natural Products of the Rocaglamide/Aglafolin Family
The path leading to the formation of the cyclopentenones9
diverges from the same bis-allenic intermediate. Subsequent to
the Cope step, aldol condensation closes the cycle in a favor-
able 5-(enolexo)-exo-trig fashion.15 Due to the high migratory
aptitude of the phenyl group in the intermediate, the cyclization
is accompanied by a highly exothermic (∼32.4 kcal/mol at the
B3LYP/6-31þG** level) 1,2-phenyl migration and concomitant
enolization as depicted in Scheme 4.
The structures of the keto and enol products were unambigu-
ously confirmed by X-ray crystallography (Figure 1b,c). Only
the trans ketone was isolated, possibly due to the equilibration
into the most stable tautomer under the thermodynamic control
conditions. The thermodynamic origin of the observed selectivity
is supported by the calculated relative energies for the keto and
enol products. Even though the enol form (6b-8b) is stabilized
by a relatively strong resonance-assisted hydrogen bond
(RAHB) with the β-ketone moiety, there is still ∼1 kcal/mol
thermodynamic preference for the keto form (6a-8a).
In contrast, the computations suggest that the enol form (9b)
is the most stable tautomer in the keto-enol equibrium in the
β-diketone (9a) system formed in the reaction of CH2OMe-
substituted alkyne (Scheme 5). Gratifyingly, this is exactly what
we observe experimentally (see Figure 1d for the crystal structure
of the enol form). Neither the cis-ketone nor the endocyclic enol,
both of which are calculated to be less stable, were detected
experimentally.
this cascade offers a conceptually interesting entry in the
ε-dicarbonyl chemistry and, if a regio- and stereoselective ver-
sion of this process is developed in the future, a potentially useful
shortcut to the rocaglamide and aglafolin16 analogues.
Experimental Section
General Procedure. n-BuLi (4.46 mL, 1.6 M in hexanes,
5.24 mmol) was slowly added to a 10 mL THF solution of the
terminal acetylene (5.24 mmol) at -78 °C. The reaction mixture
was kept at this temperature for 60 min and then warmed to 0 °C
for 45 min. After that time, the reaction mixture was recooled
to -78 °C, and a solution of 1,4-diphenyl-2,3-ethanedione
(2.60 mmol) in 5 mL of THF was added. The reaction mixture
was warmed to room temperature and then quenched with 15 mL
of saturated aqueous ammonium chloride after 5 h of stirring. The
aqueous layer was extracted with dichloromethane, which was
washed with brine, dried over anhydrous Na2SO4, and filtered. The
filtrate was concentrated and purified by column chromatography
to afford compound 3-TMS-cis as white crystals NMR δH
(300 MHz, CDCl3) 7.62 (d, J = 7.2 Hz, 4H), 7.33 (t, J = 7.4 Hz,
2H), 7.19 (t, J = 7.7 Hz, 4H), 5.08 (s, 2H), 0.14 (s, 18H); NMR δC
(75 MHz, CDCl3) 197.8, 167.5, 137.0, 132.4, 128.1, 127.8, 55.1, 0.7;
MS (ESI) m/z 407 [M þ H]þ, 429 [M þ Na]þ; HRMS (ESI) calcd
for C24H30O2Si2 [M]þ 406.1784, found 406.1790. Compound 7a has
been obtained analogously as white crystals: NMR δH (300 MHz,
CDCl3) 8.06 (d, J = 7.2 Hz, 2H), 7.56 (d, J = 7.5 Hz, 1H), 7.48 (t,
J = 7.8 Hz, 2H), 7.25-7.22 (m, 5H), 7.13 (d, J = 8.1 Hz, 2H), 7.03
(m, 4H), 6.92 (d, J = 8.1 Hz, 2H), 5.19 (d, J = 1.8 Hz, 1H), 4.64 (d,
J = 1.8 Hz, 1H), 2.23 (s, 3H), 2.20 (s, 3H); NMR δC (75 MHz,
CDCl3) 199.9, 193.3, 170.8, 140.0, 138.3, 137.5, 136.8, 136.2, 133.4,
131.8, 131.4, 131.3, 130.0, 129.7, 129.1, 128.9, 128.4, 128.3, 127.9,
127.5, 66.4, 50.2, 21.3, 21.0; MS (ESI) m/z 465 [M þ Na]þ; HRMS
(ESI) calcd for C32H26O2 [M]þ 442.1933, found 442.1934.
In summary, simultaneous weaking of the central C-C
bond in 1,5-hexadiyn-3,4-olates leads to fast anionic oxy-
Cope rearrangements (Scheme 6). This process can be either
redirected down a dissociative path or coupled with subse-
quent reactions in efficient cascade trasformations which
provide densely substituted cyclobutenes and cyclopente-
nones via a common bis-allenic intermediate. Furthermore,
Acknowledgment. I.V.A. is grateful to the National Science
Foundation (CHE-0848686) for partial support of this research.
(15) Baldwin, J. E. Tetrahedron 1982, 38, 2939.
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McPhail, A. T. J. Chem. Soc., Chem. Commun. 1982, 1150. (c) Zhu, J. Y.; Lavrik,
I. N.; Mahlknecht, U.; Giaisi, M.; Proksch, P.; Krammer, P. H.; Li-Weber, M.
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Supporting Information Available: Experimental, procedures,
crystallographic data, and full characterization data for all com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
8692 J. Org. Chem. Vol. 75, No. 24, 2010