Drawing from a pool of radicals for the design of selective enyne cyclizations

Article abstract of DOI:10.1021/ol4028072

Despite the possibility of intermolecular attack at four different locations, the Bu₃Sn-mediated radical cyclization of aromatic enynes is surprisingly selective. The observed reaction path originates from the least stable of the equilibrating pool of isomeric radicals produced by intermolecular Bu₃Sn attack at the π-bonds of substrates. The radical pool components are kinetically self-sorted via 5-exo-trig closure, the fastest of the four possible cyclizations. The resulting Sn-substituted indenes are capable of further transformations in reactions with electrophiles.

Full text of DOI:10.1021/ol4028072

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5650–5653
Drawing from a Pool of Radicals for the
Design of Selective Enyne Cyclizations
Sayantan Mondal,† Rana K. Mohamed,† Mariappan Manoharan,‡ Hoa Phan,† and
Igor V. Alabugin*,†
Department of Chemistry and Biochemistry, Florida State University, Tallahassee,
Florida 32306, United States, and School of Science, Engineering and Mathematics,
Bethune-Cookman University, Daytona Beach, Florida 32114, United States
alabugin@chem.fsu.edu
Received September 6, 2013
ABSTRACT
Despite the possibility of intermolecular attack at four different locations, the Bu3Sn-mediated radical cyclization of aromatic enynes is
surprisingly selective. The observed reaction path originates from the least stable of the equilibrating pool of isomeric radicals produced by
intermolecular Bu3Sn attack at the π-bonds of substrates. The radical pool components are kinetically self-sorted via 5-exo-trig closure, the
fastest of the four possible cyclizations. The resulting Sn-substituted indenes are capable of further transformations in reactions with
electrophiles.
Alkenes and alkynes are close chemical cousins. Both
have reactivity determined by the presence of the relatively
weak π-bonds capable of undergoing addition reactions.
Both functionalities commonly participate in reaction
cascades where the π-bonds are sacrificed for the forma-
tion of multiple CÀC bonds in the construction of poly-
cyclic moieties. As the complexity of synthetic targets
continues to increase, the subtle differences between al-
kenes and alkynes become increasingly important for the
chemo-, regio-, and stereoselectivity of such cascades.1
Although alkyne π-bonds are stronger and less reactive2
than π-bonds of alkenes, the present work will show how
the less reactive functionality (alkyne) is activated in the
presence of a more reactive functionality (alkene). In order
to achieve this “inversion of reactivity,” the combination
of reversible addition to the two π-targets (alkene vs
alkyne) is coupled with stereoelectronic guidelines in order
to “funnel” the potentially multichannel reactivity of a
“pool” of intermediate radicals toward the formation of
one major product. Conceptually, this is dynamic covalent
chemistry with kinetic self-sorting.3
Although selective radical attacks at a terminal alkyne in
enynesareknown(Scheme1),4 a chemoselective attack at a
disubstituted alkyne in the presence of an electronically
and sterically similar alkene is a greater challenge.
In this work, we report a chemo- and regioselective
radical transformation of enynes which is mediated by
intermolecularradicaladdition tothe triplebond, followed
by intramolecular 5-exo-trig closure of the vinyl rad-
ical onto the tethered alkene. This reaction provides a
convenient approach to Bu3Sn-functionalized indenes,
† Florida State University.
‡ Bethune-Cookman University.
(1) (a) Wille, U. Chem. Rev. 2013, 113, 813. Selected examples: (b)
Alabugin, I. V.; Gilmore, K.; Patil, S.; Manoharan, M.; Kovalenko,
S. V.; Clark, R. J.; Ghiviriga, I. J. Am. Chem. Soc. 2008, 130, 11535. (c)
Byers, P.; Alabugin, I. V. J. Am. Chem. Soc. 2012, 134, 9609.
(2) Alabugin, I. V.; Gold, B. J. Org. Chem. 2013, 78, 7777.
(3) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.;
Stoddart, J. F. Angew. Chem. 2002, 114, 938.
(4) (a) He, W.; Huang, J.; Sun, X.; Frontier, A. J. Am. Chem. Soc.
2007, 129, 498. (b) Kaliappan, K. P.; Ravikumar, V. Org. Lett. 2007, 9,
2417.
r
10.1021/ol4028072
Published on Web 11/04/2013
2013 American Chemical Society

Scheme 1. Chemo- and Regioselective Addition of Sn Radical to
Terminal Alkyne Moiety of Enynes in the Preparation of
Complex Polycyclic Frameworks
Scheme 2. Synthetic Strategies for the Enyne Synthesis
Table 1. Optimizing Conditions for the 5-exo-trig Radical
Cyclization of Enynes
with potential applications as metallocene complex pre-
cursors, NHC ligands, and functional materials.5
Reported methods for indene preparation have included
the cyclization of phenyl-vinyl or phenyl-substituted allylic
alcohols,6 metal-mediated (Pd, Ni, Pt, Co, Au, Fe) car-
boannulations of alkynes,7 reductive photocyclizations of
enediynes,8 and Brønsted acid catalyzed cyclizations of
aryl-1,3-dienes.9 Despite the variety of reported synthetic
approaches, the intramolecular radical cyclization of en-
ynes to yield functionalized indenes has, to the best of our
knowledge, remained undiscovered until the present report.
The library of enynes was synthesized by varying sub-
stituents at both the alkynyl and alkenyl ends. Depending
on the availability of starting materials, we used strategies
based on the combination of either Wittig or Heck reac-
tions with Sonogashira coupling, as shown in Scheme 2 (see
Supporting Information (SI) for the details).
reagent (1.2 equiv)/
entry
initiator (0.4 equiv)
solvent
yield (%)
1
2
3
4
Bu3SnH/AIBN
Bu3SnH/AIBN
Bu3SnH/AIBN
(Me3Si)3SiH/AIBN
benzene
acetonitrile
toluene
40
24
87
toluene
complex
mixture
NR
20
5
6
7
8
9
Et3SiH/AIBN
toluene
toluene
toluene
toluene
toluene
Ph3SnH/AIBN
Bu3SnH/DTBPB
Bu3SnH/TOOT
Bu3SnH/ABCN
52
18
60
The cyclization of enyne 1 was screened with a variety of
initiators and radical reagents, as shown in Table 1. The
combination of Bu3SnH and AIBN in refluxing toluene
was the most efficient, producing indene 1a in 87% yield.
The Bu3SnH/AIBN ratios and reaction times were sepa-
rately optimized for each substrate, as detailed in the SI. It
was essential to maintain a relatively low concentration of
reacting radicals using syringe pump addition.
The scope of this reaction is demonstrated by the
successful cyclization of enynes shown in Table 2. The
variations of substituents at the alkyne terminus illustrates
that the reaction is particularly efficient when the vinyl
radical, formed via the intermolecular attack, enjoys delo-
calization with an electron rich π-system. Alkyl and TMS-
substituted alkynes also give acceptable yields (Table 2,
entries 6, 7), but the reaction proceeds considerably slower.
The reaction retains its efficiency when the alkene sub-
stitution was changed from ester to amide, cyano, and aryl
groups (Table 2, entries 8, 9, 10).
(5) (a) Chirik, P. J. Organometallics 2010, 29, 1500. (b) Guo, S.; Liu,
Y. Org. Biomol. Chem. 2008, 6, 2064. (c) Guan, Z.-H.; Ren, Z.-H.; Zhao,
L.-B.; Liang, Y.-M. Org. Biomol. Chem. 2008, 6, 1040. (d) Enders, M.;
€
Baker, R. W. Curr. Org. Chem. 2006, 10, 937. (e) Silver, S.; Leppanen,
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A.-S.; Sjoholm, R.; Penninkangas, A.; Leino, R. Eur. J. Org. Chem.
2005, 1058. (f) Leino, R.; Lehmus, P.; Lehtonen, A. Eur. J. Inorg. Chem.
2004, 3201. (g) Hummel, S.; Kirsch, S. F. J. Org. Chem. 2011, 7, 847.
(6) (a) Usanov, D. L.; Yamamoto, H. Org. Lett. 2012, 14, 414. (b)
Panteleev, J.; Huang, R. Y.; Lui, H. E. K.; Lautens, M. Org. Lett. 2011,
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Miller, W. G.; Pittman, C. U., Jr. J. Org. Chem. 1974, 39, 1955.
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Liang, Y.-M. Org. Lett. 2007, 9, 3527. (b) Zhang, D.; Liu, Z.; Yum,
E. K.; Larock, R. C. J. Org. Chem. 2007, 72, 251. (c) Quan, L. G.;
Gevorgyan, V.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 3545. (d)
Deng, R.; Sun, L.; Li, Z. Org. Lett. 2007, 9, 5207. (e) Rayabarapu, D. K.;
Yang, C.-H.; Cheng, C.-H. J. Org. Chem. 2003, 68, 6726. (g) Zhao, J.;
Clark, D. A. Org. Lett. 2012, 14, 1668. (h) Sanz, R.; Miguel, D.;
Rodriguez, F. Angew. Chem., Int. Ed. 2008, 47, 7354. (i) Ye, L.; Wang,
Y.; Aue, D. H.; Zhang, L. J. Am. Chem. Soc. 2011, 134, 31. (j) Liu, C.-R.;
Yang, F.-L.; Jin, Y.-Z.; Ma, X. T.; Cheng, D.-J.; Li, C. N.; Tian, S.-K.
Org. Lett. 2010, 12, 3832.
The highly selective cyclization of enyne 10 having the
identical substituents at the ene and yne termini is parti-
cularly interesting. In the latter case, it is evident that it is
the differences between the close chemical cousins, alkene
and alkyne, rather than the substituent effects that are
responsible for the observed selectivity.
(8) (a) Alabugin, I. V.; Kovalenko, S. V. J. Am. Chem. Soc. 2002, 124,
9052. (b) Breiner, B.; Kaya, K.; Roy, S.; Yang, W.-Y.; Alabugin, I. V.
Org. Biomol. Chem. 2012, 10, 3974.
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14, 5392.
Org. Lett., Vol. 15, No. 22, 2013
5651

Table 2. Library of Indenes Obtained from the 5-exo-trig
Cyclization of Enynes
Table 3. Enynes Which Did Not Follow the 5-exo-trig Pathway
and ProductsObtainedfromTheirReactionwithBu3SnH/AIBN
Scheme 3. Further Transformations of the Sn-Containing
Indene
Structures of the indene products were confirmed by
heteronuclear single quantum coherence (HSQC), hetero-
nuclear multiple bond correlation (HMBC), and X-ray
crystallography (Figure 1; see SI for the details).
converted into an electrophilic indene building block via
iodination.
The nature of the products 1aÀ10a suggests chemo-
selective intermolecular addition of the tin radical to the
alkyne. This stepgenerates a reactivevinyl radical for rapid
intramolecular trapping by the tethered alkene (Figure 1).
It hasbeensuggested that electronic effects disfavor radical
additions to alkynes relative to alkenes.12 These literature
data are fully consistent with the notion that alkyne π-bonds
are stronger and less reactive than alkene π-bonds.3,13
Computational analysis compared the four possible
pathways for the formation of five-membered rings in this
system(5-exo-dig, 5-endo-dig, 5-exo-trig, and 5-endo-trig).
As expected, all reactions of alkynes have higher bar-
riers and are less exothermic14 relative to the analogous
reactions of alkenes (Figure 2). This trend has two reasons:
stronger π-bonds in alkynes and greater reactivity of vinyl
radicals. Due to the combination of these effects, the
5-exo-trig attack of a vinyl radical at a double bond has
a barrier ∼11 kcal/mol lower than that of the “mismatched”
5-exo-dig15 attack of an alkyl radical at the triple bond.
This result fully agrees with the experimentally observed
5-exo-trig selectivity.
Figure 1. ORTEP diagram of indene 1a and the proposed
mechanism.
As expected, terminal alkynes such as enyne 11 (Table 3,
entry 1) failed to cyclize due to the instability of primary
vinyl radicals. The more stable vinyl radical formed by
addition to the terminal alkyne carbon did not provide
5-endo-trig products.10 Instead, the reaction produced the
over-reduced product 11a and diene 11b. More interest-
ingly, the cyclization did not work with vinyl ketones;
i.e., the reaction of ketone 12 led to selective partial
reduction of the triple bond.11 Subjecting the respective
aldehyde to the optimized conditions produced a mixture
without the characteristic aldehyde NMR signals.
As shown in Scheme 3, synthetic utility of the new
enyneÀindene transformation is extended by subsequent
cross-coupling reactions. Alternatively, the product can be
(12) Fischer, H.; Radom, L. Angew. Chem., Int. Ed. 2001, 40, 1340.
(13) Nicolaides, A.; Borden, W. T. J. Am. Chem. Soc. 1991, 113, 6750.
(14) Unlike the other 5-membered radicals, the 5-endo-dig product is
not stabilized by benzylic conjugation. Furthermore, such cyclizations
are slow: (a) Alabugin, I. V.; Timokhin, V. I.; Abrams, J. N.; Manoharan,
M.; Ghiviriga, I.; Abrams, R. J. Am. Chem. Soc. 2008, 130, 10984. (b)
Alabugin, I. V.; Manoharan, M. J. Am. Chem. Soc. 2005, 127, 9534.
(15) Note that similar 5-exo-dig cyclizations of vinyl radical are much
faster: (a) Kovalenko, S. V.; Peabody, S.; Manoharan, M.; Clark, R. J.;
Alabugin, I. V. Org. Lett. 2004, 6, 2457. (b) Alabugin, I. V.; Manoharan,
M. J. Am. Chem. Soc. 2005, 127, 12583.
(10) 5-endo-trig: Chatgilialoglu, C.; Ferreri, C.; Guerra, M.; Timokhin,
V.; Froudakis, G.; Gimisis, T. J. Am. Chem. Soc. 2002, 124, 10765.
(11) The reasons for this unusual behavior will be analyzed in future
work. However, the lack of reactivity in the absence of AIBN does rule
out direct carbonyl reduction of enones via a nonradical mechanism:
Krafft, M. E.; Vidhani, D. V.; Cran, J. W. Synlett 2011, 16, 2355.
5652
Org. Lett., Vol. 15, No. 22, 2013

compound 15a indicates that the initial intermolecular
attack of a tin radical proceeds exclusively at the CÀI
bond and that the intermediate vinyl radical can attack the
CdC moiety of the vinyl ketone. From a mechanistic
perspective, this finding suggests that the absence of
cyclization products in the case of 12 is not due to the
inefficiency of the 5-exo-trig step but probably lies at
earlier stages of the cascade. We will investigate this
question in our future work.
The subsequent sequence of two radical exo-cyclizations
is fully consistent with the stereoelectronic preferences of
radical cyclizations.18 The chemoselective radical attack at
the alkyl halide in the presence of an alkyne and alkene
establishes a useful hierarchy of substituent reactivity in
Bu3Sn-radical mediated reactions: CH2I > π-bonds.
Scheme 4. Selective Attack of Bu3Sn-Radical on Alkyl Iodide in
Presence of an Alkyne and an Alkene
Figure 2. Computational analysis of the four competing reac-
tion pathways at the M06-2X/Lanl2dZ level.
The counterintuitive feature of this selective process is
that the productive cyclization path originates from the
least stable of the four equilibrating radicals. Nevertheless,
according to the CurtinÀHammett principle, as long as
equilibration of such radicals through β- Bu3Sn-group
scission16 proceeds faster than any of their subsequent
reactions, the reaction outcome is determinedbythe lowest
energy transition state (Figure 2). The relative energies of
the rapidly interconverting reactants are unimportant.
Conceptually, this formation of a single product from a
complex mixture can be considered as an example of
dynamic covalent chemistry (DCC) in a radical process17
where a fast cyclization provides a mechanism for kinetic
self-sorting.
In conclusion, we have shown that the intermolecular
addition of a tin radical to enynes proceeds selectively at
alkynes, despite the presence of the more reactive pendant
alkene functionality. This selectivity is a consequence of
the CurtinÀHammett principle since the observed 5-exo-
trig radical ring closure derives from the reaction of the
least stable from the pool of equilibrating radical species
but proceeds through the lowest absolute activation bar-
rier. This example illustrates the potential of dynamic
covalent chemistry with kinetic self-sorting in the design
of selective radical reactions. Aromatic enynes are readily
converted into Sn-containing indenes which can be used as
convenient building blocks for the preparation of functio-
nalized indenes.
Intrigued by the lack of cyclic product formation from
ketone 12, we investigated whether introduction of a more
reactive functionality (CH2I group) will initiate the cycli-
zation (Scheme 4). The structure of the major tricyclic
Acknowledgment. I.A. is grateful to the National
Science Foundation (CHE-1213578) for support of this
research project.
(16) Uenoyama, Y.; Fukuyama, T.; Nobuta, O.; Matsubara, H.;
Rye, I. Angew. Chem., Int. Ed. 2005, 44, 1075.
(17) For DCC with the much longer lived persistent radicals, see:
Otsuka, H.; Aotani, K.; Higaki, Y.; Amamoto, Y.; Takahara, A.
Macromolecules 2007, 40, 1429.
(18) (a) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513. (b)
Alabugin, I.; Gilmore, K.; Manoharan, M. J. Am. Chem. Soc. 2011, 133,
12608. (c) For an earlier work, see also: Beckwith, A. L. J.; Easton, C. J.;
Serelis, A. K. J. Chem. Soc., Chem. Commun. 1980, 482.
Supporting Information Available. Full synthetic proce-
dures, 1H NMR, 13C NMR, and 2D NMR spectra, X-ray
structure of 1a, and computational details. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
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