Thermodynamic Control of Isomerizations of Bicyclic Radicals: Interplay of Ring Strain and Radical Stabilization

Article abstract of DOI:10.1021/acs.orglett.5b03112

The rearrangements of 4-substituted bicyclo[2.2.2]oct-5-en-2-yl radicals, generated from the corresponding Diels-Alder adducts with phenylseleno acrylates by radical-induced reductive deselenocarbonylations, give the 2-substituted bicyclo[3.2.1]oct-6-en-2-yl radicals with some substituents, e.g., alkoxy and phenyl, but not for silyloxymethyl or benzyl substituents. Theoretical calculations with DFT give the thermodynamics of these reactions and the origins of these processes.

Full text of DOI:10.1021/acs.orglett.5b03112

Letter
pubs.acs.org/OrgLett
Thermodynamic Control of Isomerizations of Bicyclic Radicals:
Interplay of Ring Strain and Radical Stabilization
Michael E. Jung,* Courtney A. Roberts, Felix Perez, Hung V. Pham, Lufeng Zou, and K. N. Houk*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
ABSTRACT: The rearrangements of 4-substituted bicyclo[2.2.2]oct-5-en-2-yl radicals, generated from the corresponding
Diels−Alder adducts with phenylseleno acrylates by radical-induced reductive deselenocarbonylations, give the 2-substituted
bicyclo[3.2.1]oct-6-en-2-yl radicals with some substituents, e.g., alkoxy and phenyl, but not for silyloxymethyl or benzyl
substituents. Theoretical calculations with DFT give the thermodynamics of these reactions and the origins of these processes.
Scheme 1. Rearrangement of Anthracene Adduct 7
ecently, we reported the development of phenylseleno
Racrylate 1 as an “ethylene equivalent” in Diels−Alder
reactions.1 Thus, heating 1 with various dienes 2 gave the
expected cycloadducts 3, which could be reduced cleanly using
tris(trimethylsilyl)silane 4, the Chatgilialoglu reagent,2 to give
the desired formal cycloadducts of ethylene 5 (Figure 1).
calculations show the interplay of ring strain and relative
stabilities of these substituted radical systems.
The substrates for the radical rearrangement studies were all
prepared by the Diels−Alder reaction of the freshly prepared 1-
substituted 1,3-cyclohexadienes 106 with the phenylseleno
acrylate 1, which were carried out in refluxing toluene for 14 h
(Table 1). The cycloadducts were obtained in yields of 55−
97% as mixtures of endo and exo isomers 11 and 12. In all
cases, the endo isomers 11 were the major products, with the
endo/exo ratio varying from 3.3−8 to 1.7
With the Diels−Alder products 11 and 12 in hand, we next
examined their reductive decarbonylation to produce the
reduced products. A mixture of the endo and exo esters was
treated with tris(trimethylsilyl)silane and AIBN in refluxing
benzene for several hours to give the reduction products (Table
2). The reduction of the parent unsubstituted compound 11a/
12a gave predominately the expected bicyclo[2.2.2]octene 13a,
with very little rearranged products (>20:1). However, the
behavior of the substituted analogues was quite different.
Reduction of the 4-methoxy esters 11b/12b afforded only a
minor amount of the unrearranged product 13b and gave
Figure 1. Use of 1 as an ethylene equivalent in Diels−Alder reactions.
The majority of substrates were reduced under the normal
conditions without any rearrangement of the generated
radicals.3 However, we reported that the adduct 7, prepared
by the Diels−Alder reaction of anthracene 6 with the
dienophile 1, underwent significant rearrangement to give a
1:3 mixture of the expected dibenzobicyclo[2.2.2]octane
product 8 and the rearranged dibenzobicyclo[3.2.1]octane
product 9 (Scheme 1).1 This was attributed to the well-known
homoallyl−cyclopropyl carbinyl radical rearrangement pathway
leading to a more stable radical.4 This specific transformation is
also known as a neophyl rearrangement.5 We now report that
this rearrangement is general and proceeds for all systems in
which the radical in the new bicyclo[3.2.1]octyl ring system is
more stable than the radical in the original bicyclo[2.2.2]octyl
ring system. We observe an interesting result, namely that a
secondary bicyclo[2.2.2]oct-5-en-2-yl radical is more stable
than a tertiary bicyclo[3.2.1]oct-6-en-2-yl radical. Theoretical
Received: October 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03112
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Diels−Alder Reaction of 1-Substituted Dienes 10
and Phenylseleno Acrylate 1
Scheme 2. Proposed Mechanism of Reduction of
Selenophenyl Esters
a
a
entry
compd
R
yield (%)
ratio 11:12
1
2
3
4
5
6
a
b
c
d
e
f
H
97
87
76
66
83
88
8:1
5.1:1
3.4:1
4.4:1
3.3:1
4.1:1
OMe
OTBS
Ph
CH2OTBS
CH2Ph
a
The ratios of all products were determined by careful integration of
7
1
the appropriate peaks in the H NMR spectra.
Table 2. Reduction of Bicyclo[2.2.2]oct-2-enyl-5-
selenophenyl Esters 11 and 12
a
Relative computed Gibbs free energies for the parent compound (R =
H) are given in red.
treatment, gave the rearranged products 14c and 15c as the
major products in a 2.5:1 ratio with the unrearranged product
13c. Again, the stability of the intermediate radical leading to
the rearranged product would be expected to be greater than
that of the unrearranged product. The 4-phenyl analogue 11d/
12d behaved similarly and afforded the rearranged products
14d and 15d in a 10:1 ratio with the unrearranged product 13d.
Here the bicyclo[3.2.1]octenyl radical 19d is tertiary and
benzylic and, therefore, is much more stable than the secondary
homobenzylic radical in 17d. On the basis of these foregoing
results, the reduction of the 4-silyloxymethyl analogue 11e/12e
seems surprising, since in this case the unrearranged product
13e predominated, formed in a 7:1 ratio with the rearranged
products 14e and 15e. This implied that the bicyclo[2.2.2]-
octenyl intermediate leading to 13e, containing a secondary
radical, is more stable than the rearranged bicyclo[3.2.1]octenyl
intermediate with a tertiary radical. We also reduced the 4-
benzyl analogue 11f/12f, and the unrearranged product 13f was
formed preferentially over the rearranged products 14f and 15f,
again in a ratio of 7:1.
To further investigate these varying product ratios, we
performed density functional calculations at the M06-2X/6-
311G(d,p)//B3LYP/6-31G(d) level of theory using the
Gaussian09 program.10 Activation free energies for the
homoallyl−cyclopropyl carbinyl radical rearrangement of
17a−18a and 18a−19a were also computed.
Figure 2 shows the relative energies of radicals, transition
states for rearrangement, and products for the parent system (R
= H). The bicyclo[2.2.2]octene, 13a, is 1.8 kcal/mol more
stable than the bicyclo[3.2.1]octene 14a. The corresponding
radicals 17a and 19a differ in energy by 2.3 kcal/mol in the
same direction. This results from the greater strain of the
bicyclo[3.2.1] skeleton. The low activation barriers for TS17−18
and TS18−19 are consistent with the proposed equilibrium
between radical species 17 and 19.
a
entry
compd
R
ratio 13:14 + 15
ratio 14:15
1
2
3
4
5
6
a
b
c
d
e
f
H
>20:1
1:5.6
1:2.5
1:10
7:1
NA
OCH3
OTBS
Ph
2.6:1
2.5:1
2.4:1
2.9:1
3.8:1
CH2OTBS
CH2Ph
7:1
a
The ratios of all products were determined by careful integration of
8
1
the appropriate peaks in the H NMR spectra.
mainly the rearranged 2-methoxybicyclo[3.2.1]oct-6-enes 14b
and 15b, with the ratio of unrearranged to rearranged product
being 1:5.6.8
The proposed mechanism for the reduction is shown in
Scheme 2. Treatment of the selenophenyl esters 11 and 12 with
tris(trimethylsilyl)silane generates the acyl radicals 16, which
undergo decarbonylation to give the secondary radicals 17.9
Reduction of 17 by the silane affords the unrearranged
bicyclo[2.2.2]octene product 13. However, in competition
with this reduction, the radical 17 can rearrange via the
cyclopropyl carbinyl radical 18 to give the bicyclo[3.2.1]oct-6-
en-2-yl radical 19. Reduction of this radical by the silane gives a
mixture of the equatorial and axial products 14 and 15.
The prevalence of the rearranged products 14b/15b is not
surprising since intermediate 19b, leading to the bicyclo[3.2.1]-
octene product, has a radical adjacent to a methoxy group. In
contrast, intermediate 17b, leading to the bicyclo[2.2.2]octene
product, has a simple secondary radical (Scheme 2). As
expected, the more substituted radical is more stable. In a like
manner, the 4-silyloxy analogue 11c/12c, upon similar
Table 3 shows the computed energy differences between
substituted radical species 17 and 19, along with the
corresponding equilibrium ratios from these energies. The
energy differences are in good accord with the expected
energies of radical stabilization by these substituents.11
B
DOI: 10.1021/acs.orglett.5b03112
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 3. Newman projections for 19a, viewing from (a) C2−C1 and
(b) C2−C3.
the radical center and the attached carbon. Moreover, this
preference is reinforced in the transition states in order to
minimize eclipsing with the newly forming bond, a well-known
phenomenon in C−C bond-forming reactions, sometimes
referred to as torsional steering.12 For instance, in Figure 3,
hydrogen abstraction from silane will occur from the top of the
radical center of 19a to avoid torsional strain from eclipsing
bonds. This favors formation of product 14 over 15.
In conclusion, we have found that the in situ generated
[2.2.2] radicals are generally more stable than the correspond-
ing [3.2.1] rearrangement counterparts, but radical-stabilizing
substituents can reverse this preference. The relative stabilities
of these radicals control the product ratios, while torsional
effects control the stereochemistry of hydrogen transfer from
silane to the alkyl radicals.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03112.
Experimental methods, NMR spectra, and analytical data
for all new products (PDF)
Figure 2. Structures of bicyclo[2.2.2]oct-2-ene 13a, bicyclo[3.2.1]oct-
6-ene 14a, and their radicals 17a and 19a, with relative M06-2X/6-
311G(d,p)//B3LYP/6-31G(d) Gibbs free energies in kcal/mol.
AUTHOR INFORMATION
Corresponding Authors
■
Table 3. Computed Radical Stabilities and Equilibrium
Ratios of Bicyclic Compounds with Various Substituents
*E-mail: jung@chem.ucla.edu.
*E-mail: houk@chem.ucla.edu.
ΔΔG17−19
predicted ratio
experimental ratio
Notes
entry
R
(kcal/mol)
17:19
13:14 + 15
The authors declare no competing financial interest.
1
2
3
4
H
2.3
−1.0
−6.7
1.2
48:1
>20:1
1:5.6
1:10
OCH3
Ph
1:5
ACKNOWLEDGMENTS
1:>8 × 104
8:1
■
a
We are grateful to the National Science Foundation for
research support (CHE-0548209) and for equipment grant
CHE-1048804.
CH3
7:1
a
Experimental value for the CH2OTBS and CH2Ph substituents.
REFERENCES
Comparing these computed ratios with those observed
experimentally confirms our initial assumptions that radical-
stabilizing substituents promote the ring rearrangement−
methoxy and phenyl substituents favor formation of the
bicyclo[3.2.1]octene system, while a methyl substituent,
although also stabilizing, prefers to remain unrearranged as
the [2.2.2] system.
Furthermore, in the rearranged 2-substituted bicyclo[3.2.1]-
oct-6-ene products, the equatorial product 14 is always favored
over the axial, 15, and the ratio of 14/15 varies from a low of
2.3:1 to a high of 3.8:1. The radical is only slightly nonplanar, as
shown in Figure 3, to minimize eclipsing between the bonds to
■
(1) Jung, M. E.; Perez, F.; Regan, C. F.; Yi, S.-W.; Perron, Q. Angew.
Chem., Int. Ed. 2013, 52, 2060; Correction: Angew. Chem., Int. Ed.
2013, 52, 11963.
(2) (a) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
(b) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. Rev.
1999, 99, 1991. (c) Back, T. G.; Press, D. J. Advances in Free Radical
Reactions of Organoselenium and Organotellurium Compounds. In
The Chemistry of Organic Selenium and Tellurium Compounds;
Rappoport, Z., Ed.; Wiley: Chichester, 2012; Vol. 3, Part 1, Chapter
8. (d) Giese, B.; Dickhaut, J.; Chatgilialoglu, C. Tris(trimethylsilyl)-
silane. Encyclopedia of Reagents for Organic Synthesis; Wiley-
Interscience, 2007; DOI: 10.1002/9780470842898.rt420.pub2.
C
DOI: 10.1021/acs.orglett.5b03112
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) For a discussion of radical reactions and rearrangements and their
use in synthesis, see: (a) Jasperse, C. P.; Curran, D. P.; Fevig, T. L.
Chem. Rev. 1991, 91, 1237. (b) Crich, D.; Yao, Q. J. Org. Chem. 1995,
60, 84. (c) Toyota, M.; Wada, T.; Fukumoto, K.; Ihara, M. J. Am.
Chem. Soc. 1998, 120, 4916. (d) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions: Concepts, Guidelines, and Synthetic
Applications; Wiley-Interscience, 1996. (e) Newcomb, M.; Glenn, A. G.
J. Am. Chem. Soc. 1989, 111, 275. (f) Motherwell, W. B.; Crich, D. Free
Radical Chain Reactions in Organic Synthesis. In Best Synthetic
Methods; Katritzky, A. R., Meth-Cohn, O., Rees, C., Motherwell, W.,
Crich, D., Eds.; Academic Press, 1992.
(4) (a) Montgomery, L. K.; Matt, J. W. J. Am. Chem. Soc. 1967, 89,
934. (b) Batey, R. A.; Harling, J. D.; Motherwell, W. B. Tetrahedron
1992, 48, 8031. (c) Toyota, M.; Yokota, M.; Ihara, M. Tetrahedron
Lett. 1999, 40, 1551.
(5) (a) Urry, W. H.; Kharasch, M. S. J. Am. Chem. Soc. 1944, 66,
1438. (b) Winstein, S.; Seubold, F. H., Jr. J. Am. Chem. Soc. 1947, 69,
2916.
(6) Most of the 1-substituted 1,3-cyclohexadienes 10 were known.
The new 1-silyloxymethyl diene 10e was prepared by reduction of the
known methyl 1,3-cyclohexadiene-1-carboxylate with DIBAL followed
by silylation. Harding, K. E.; Strickland, J. B.; Pommerville, J. J. Org.
Chem. 1988, 53, 4877. The new benzyl analogue 10f was prepared by
reaction of benzyl Grignard reagent with the known 1-(triflyloxy)-1,3-
cyclohexadiene using NiCl2(dppp) as catalyst. Corey, E. J.; Kigoshi, H.
Tetrahedron Lett. 1991, 32, 5025.
(7) The mixture of isomers could not be separated, but the
assignment of the stereochemistry of the two diastereomeric
cycloadducts was made by NMR measurements since all of the exo
isomers 12 showed an additional small coupling (J = 1.6−2.0 Hz) for
the proton α to the carbonyl group due to W coupling which is not
possible in the endo isomer 11.
(8) The mixture of diastereomers could not be separated, but their
stereochemistry was assigned by analysis of the crude NMR spectra.
The proton α to the R group in 14 always exhibited a very large
coupling constant (J = 9.0−12.0) due to the axial−axial coupling,
whereas that large coupling was absent from the isomeric compounds
15.
(9) The acyl radical A can also be reduced before decarbonylation,
and indeed small amounts of aldehydes are occasionally isolated from
these reductions.
(10) Gaussian 09, Revision D.01: Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji,
H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;Peralta, J. E.; Ogliaro,
F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V.
N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell,
A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam,
J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford, CT, 2013.
(11) Luo, Y. R. Comprehensive Handbook of Chemical Bond Energies;
CRC Press, Boca Raton, FL, 2007.
(12) (a) Paddon-Row, M. N.; Houk, K. N. J. Am. Chem. Soc. 1982,
104, 7162. (b) Paddon-Row, M. N.; Houk, K. N. J. Phys. Chem. 1985,
89, 3771. (c) Dalgard, J. E.; Rychnovsky, S. D. Org. Lett. 2004, 6, 2713.
D
DOI: 10.1021/acs.orglett.5b03112
Org. Lett. XXXX, XXX, XXX−XXX