MN(III)-based oxidative free-radical cyclizations of substituted allyl α-methyl-β-ketoesters: Syntheses, DFT calculations, and mechanistic studies

Article abstract of DOI:10.1021/jo026681t

The cyclizations of the substituted allyl α-methyl-β-ketoester radicals 11, 14, and 18 were studied by the DFT method at the UB3LYP/6-31G* level; the results show that the cis cyclization is easier than the corresponding trans cyclization, but the generated cis radicals are not necessarily more stable than the corresponding generated trans radicals after the cyclizations. The free-radical cyclizations of 11, 14, and 18 in the presence of Mn(OAc)₃ in acetic acid or acetonitrile are all reversible and operate under thermodynamic control, and stereoselectivity of the cyclizations depends on relative stability of the cyclization-generated radicals. Therefore, the oxidative free-radical cyclization of allyl α-methyl-β-ketoester 5a with Mn(OAc)₃ gives a cis product as a major product, while the same oxidative free-radical cyclizations of substituted allyl α-methyl-β-ketoesters 5b and 5c with Mn(OAc)₃ produce trans products as major products.

Full text of DOI:10.1021/jo026681t

Mn (III)-Ba sed Oxid a tive F r ee-Ra d ica l Cycliza tion s of Su bstitu ted
Allyl r-Meth yl-â-k etoester s: Syn th eses, DF T Ca lcu la tion s, a n d
Mech a n istic Stu d ies
Kuangsen Sung* and Yu Yuan Wang
Department of Chemistry, National Cheng Kung University, Tainan, Taiwan, R.O.C.
kssung@mail.ncku.edu.tw
Received November 9, 2002
The cyclizations of the substituted allyl R-methyl-â-ketoester radicals 11, 14, and 18 were studied
by the DFT method at the UB3LYP/6-31G* level; the results show that the cis cyclization is easier
than the corresponding trans cyclization, but the generated cis radicals are not necessarily more
stable than the corresponding generated trans radicals after the cyclizations. The free-radical
cyclizations of 11, 14, and 18 in the presence of Mn(OAc)3 in acetic acid or acetonitrile are all
reversible and operate under thermodynamic control, and stereoselectivity of the cyclizations
depends on relative stability of the cyclization-generated radicals. Therefore, the oxidative free-
radical cyclization of allyl R-methyl-â-ketoester 5a with Mn(OAc)3 gives a cis product as a major
product, while the same oxidative free-radical cyclizations of substituted allyl R-methyl-â-ketoesters
5b and 5c with Mn(OAc)3 produce trans products as major products.
In tr od u ction
the application of the oxidant to the oxidative free-radical
cyclizations was investigated extensively.3,4 There are at
least three types of â-dicarbonyl compounds D-F that
have been used to undergo the oxidative free-radical
monocyclizations with Mn(OAc)3.4 To our knowledge,
there is no known example for monocyclization of 1 with
Mn(OAc)3, and the advantage for this type of monocy-
clization is that it may stereoselectively form a C-C bond
with two adjacent chiral centers after hydrolysis and
decarboxylation and leave R intact, which is a main part
of the original structure.
Because enantiomers of the same general compound
may have different biological activities, syntheses of
chiral compounds have been a hot topic in organic
chemistry.1 Stereoselective formation of C-C bonds is one
strategy for synthesizing chiral compounds, and ionic
Aldol condensation and pericyclic reactions are usual
methodologies for such syntheses.1 In this study, we
investigated the possibility of the stereoselective forma-
tion of a C-C bond through a free-radical cyclization
mechanism.
For the above retrosynthetic analysis, if one uses a
chiral catalyst or a chiral auxiliary at R or R′ of A and
B, it is possible to diastereoselectively make a ketone C
with two adjacent chiral centers on CR and Câ. In this
study, a chiral catalyst or a chiral auxiliary was not used,
but our major concern was whether the cyclization from
A to B through the free-radical mechanism was stereo-
selective.
Heiba and Dessau reported in 1974 that â-ketoesters
and related â-dicarbonyl compounds are oxidized to
radicals at 25-70 °C in acetic acid with Mn(OAc)3.2 Later,
Bertrand et al. has performed the oxidative free-radical
cyclization of allyl malonate 2a with Mn(OAc)3/Cu(OAc)2
in acetic acid to produce vinyl lactone 3a with an Z:E
ratio of 70:30.3j However, there was no explanation of the
stereoselectivity. The oxidative free-radical cyclization of
the allyl malonates usually produces 5-exo cyclization
products, and no 6-endo cyclization products have been
(1) (a) Gawley, R. E.; Aube, J . Principles of Asymmetric Synthesis;
Tetrahedron Organic Chemistry Series Volume 14; Elsevier Science,
Ltd.: New York, 1996. (b) Lin, G.-Q.; Li, Y.-M.; Chan, A. S. C.
Principles and Applications of Asymmetric Synthesis; Wiley & Sons:
New York, 2001.
(2) Heiba, E. I.; Dessau, R. M. J . Org. Chem. 1974, 39, 3456.
10.1021/jo026681t CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/26/2003
J . Org. Chem. 2003, 68, 2771-2778
2771

Sung and Wang
observed.3j,4,5 Structures of the substituted allyl â-ke-
toesters 1 are similar to that of allyl malonate 2a , so the
oxidative free-radical cyclization of 1 may give the 5-exo
cyclization products only, which makes system 1 a good
model for studying the stereoselectivity of the cyclization.
In this study, we investigated the mechanisms and
stereoselectivity of the free-radical cyclizations of sub-
stituted allyl R-methyl-â-ketoester radicals, which were
prepared from oxidation of 1 with Mn(OAc)3, by means
of syntheses and DFT calculations. Hopefully, the results
in this study help chemists to control the stereoselectivity
of the free-radical cyclization of this type of compound.
Com p u ta tion a l Deta ils
All calculations reported here were performed with
Gaussian98 program.6 Geometry optimizations of 11, cis-
12(TS), cis-13, cis-6, trans-12(TS), trans-13, trans-6, 14,
cis-15(TS), cis-16, cis-7, trans-15(TS), trans-16, trans-
7, 17, 18, cis-19(TS), cis-20, cis-9, trans-19(TS), trans-
20, trans-9, cis-22a , cis-22b, trans-22a , and trans-22b
were carried out at the UB3LYP/6-31G*7 level for radicals
and the B3LYP/6-31G*7 level for nonradicals without any
symmetry restriction except for cis-22a and cis-22b,
whose dihedral angle between propionyl CdO and the
five-membered ring is fixed at -15.8° in order to avoid
the attack of the carbonyl oxygen on the carbon cation.
The optimized structures of cis-22a , cis-22b, trans-22a ,
and trans-22b are shown in Figure 1, and the others are
shown in Figures 2-4 in Supporting Information. After
all the geometry optimizations were performed, analytical
F IGURE 1. Optimized structures of cis-22a , cis-22b, trans-
22a , and trans-22b at the B3LYP/6-31G* level.
vibration frequencies were calculated at the same level
to determine the nature of the located stationary points.
Thus, all the stationary points found were properly
characterized by evaluation of the harmonic frequencies.
The energies of all the stationary points were calculated
at the same level with scaled zero-point vibration ener-
gies included. The scaled factor of 0.9804 for the zero-
point vibration energies is used according to the
literature.7a Many possible conformations have been
optimized for each of the above configurations, and the
conformation with the lowest energy was chosen for each
configuration. Spin contamination from higher spin
states is significant for both HF and MP2 methods, but
it is much less for both UB3LYP and QCISD methods.7a,b
Therefore, the reliability of the calculations on the
radicals at the UB3LYP/6-31G* level in this study should
be good.7a,b
(3) (a) Corey, E. J .; Kang, M.-C. J . Am. Chem. Soc. 1984, 106, 5384.
(b) Snider, B. B.; Mohan, R. M.; Kates, S. A. J . Org. Chem. 1985, 50,
3659. (c) Ernst, A. B.; Fristad, W. E. Tetrahedron Lett. 1985, 26, 3761.
(d) Peterson, J . R.; Egler, R. S.; Horsley, D. B.; Winter, T. J .
Tetrahedron Lett. 1987, 28, 6109. (e) Curran, D. P.; Morgan, T. M.;
Schwartz, C. E.; Snider, B. B.; Dombroski, M. A. J . Am. Chem. Soc.
1991, 113, 6607. (f) Snider, B. B.; McCarthy, B. A. J . Org. Chem. 1993,
58, 6217. (g) Snider, B. B.; Kiselgof, J . Y. Tetrahedron 1998, 54, 10641.
(h) Garcia Ruano, J . L.; Rumbero, A. Tetrahedron: Asymmetry 1999,
10, 4427. (i) Garzino, F.; Meou, A.; Brun, P. Tetrahedron Lett. 2000,
41, 9803. (j) Oumar-Moustrou, H.; Moustrou, C.; Surzur, J .-M.;
Bertrand, M. P. J . Org. Chem. 1989, 54, 5684. (k) Snider, B. B.;
Patricia, J . J .; Kates, S. A. J . Org. Chem. 1988, 53, 2137.
Resu lts
(4) (a) Snider, B. B. Chem. Rev. 1996, 96, 339. (b) Melikyan, G. G.
Org. React. 1997, 49, 427.
DF T Ca lcu la tion s. It is known that the reactions of
the R-alkyl-â-ketoesters with Mn(OAc)3 generate the
R-alkyl-â-ketoester radicals with loss of Mn(II),3e,k so we
monitored the free-radical cyclization reactions of the
substituted allyl R-methyl-â-ketoester radicals by start-
ing from the generated radicals 11, 14, and 18. There
are two possible routes through which each of the
generated radicals could undergo the cyclization reac-
tions; one forms a cis product through the cyclization,
and the other produces a trans product. All of them are
monitored by the density functional theory at the
UB3LYP/6-31G* level for radicals and the B3LYP/6-31G*
level for nonradicals, and the results are shown in Table
1. Regarding the R-methyl-â-ketoester radical 11, activa-
tion energy to form cis-13 is 2.22 kcal/mol smaller than
that forming trans-13, and cis-13 is 0.08 kcal/mol more
stable than trans-13 (Scheme 1). After hydrogen abstrac-
tion, trans-6 is 0.62 kcal/mol more stable than cis-6. As
far as the R-methyl-â-ketoester radical 14 is concerned,
the activation energy to form cis-16 is 2.86 kcal/mol
smaller than that forming trans-16, while trans-16 is 1.97
kcal/mol more stable than cis-16 (Scheme 2). After
(5) (a) Kates, S. A.; Dombroski, M. A.; Snider, B. B. J . Org. Chem.
1990, 55, 2427. (b) Surzur, J . M.; Bertrand, M. P. Pure Appl. Chem.
1988, 60, 1659. (c) Oumar-Mahamat, H.; Moustrou, C.; Surzur, J .-M.;
Bertrand, M. P. Tetrahedron Lett. 1989, 30, 331. (d) Snider, B. B.;
McCarthy, B. A. Tetrahedron 1993, 49, 9447. (e) Bertrand, M. P.;
Surzur, J . M.; Oumar-Mahamat, H.; Moustrou, C. J . Org. Chem. 1991,
56, 3089.
(6) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.9; Gaussian, Inc.: Pittsburgh, PA,
1998.
(7) (a) Foresman, J . B.; Frisch, A. Exploring Chemistry with
Electronic Structure Methods, 2nd ed.; Gaussian, Inc.: Pittsburgh, PA,
1996. (b) Bernardi, F.; Bottoni, A. J . Phys. Chem. A 1997, 101, 1912.
(c) Parr, R. G.; Yang, W. Density-Functional Theory of Atoms and
Molecules; Oxford University Press: Oxford, 1989. (d) Perdew, J . P.;
Wang, Y. Phys. Rev. B 1992, 45, 13244. (e) Becke, A. D. J . Chem. Phys.
1993, 98, 1372. (f) Becke, A. D. Phys. Rev. A 1988, 38, 3098.
2772 J . Org. Chem., Vol. 68, No. 7, 2003

Mn(III)-Based Oxidative Free-Radical Cyclizations
TABLE 1. Ca lcu la ted En er gies, Im a gin a r y F r equ en cies, Rela tive En er gies, Sp in Den sity, a n d S2 of th e Sta tion a r y
P oin ts a lon g th e Cycliza tion P a th s of th e Ra d ica ls 11, 14, a n d 18 a t th e UB3LYP /6-31G* Levela
spin density on
imaginary
frequency
relative energy
(kcal/mol)
stationary point
energy (hartree)
cm-1
ketone oxygen
ester oxygen
carbon radical
S2
11
-576.20382
-576.17626
-576.20055
-576.85709
-576.17273
-576.20042
-576.85808
-654.78545
-654.75971
-654.77989
-654.21557
-654.75516
-654.78303
-654.21882
-654.22543
-807.18464
-807.16300
-807.19391
-1035.66227
-807.15993
-807.19510
-1035.66238
0.00
17.29
2.05
0.23
0.13
0.00
0.14
0.05
0.00
0.78
0.58b/0.57c
1.07
0.7501
0.7503
0.7500
cis-12(TS)
cis-13
cis-6
trans-12(TS)
trans-13
trans-6
14
cis-15(TS)
cis-16
-459
-448
19.51
2.13
0.14
0.00
0.04
0.00
0.55b/0.59c
1.07
0.7504
0.7500
0.00
16.15
3.49
0.23
0.13
0.00
0.14
0.05
0.00
0.78
0.52b/0.53c
0.96
0.7501
0.7503
0.7500
-440
-424
cis-7
trans-15(TS)
trans-16
trans-7
17
19.01
1.52
0.13
0.00
0.04
0.00
0.49b/0.57c
0.96
0.7503
0.7500
18
6.56
20.14
0.75
0.23
0.14
0.00
0.14
0.06
0.00
0.78
0.39b/0.58c
0.75
0.7501
0.7507
0.7506
cis-19(TS)
cis-20
cis-9
trans-19(TS)
trans-20
trans-9
-372
-341
22.07
0.00
0.16
0.00
0.05
0.00
0.35b/0.61c
0.75
0.7506
0.7506
a
Ea for (11-cis-12(TS)-cis-13) ) 17.29 kcal/mol; Ea for (11-trans-12(TS)-trans-13) ) 19.51 kcal/mol); Ea for (14-cis-15(TS)-cis-16)
) 16.15 kcal/mol; Ea for (14-trans-15(TS)-trans-16) ) 19.01 kcal/mol; Ea for (18-cis-19(TS)-cis-20) ) 13.58 kcal/mol; Ea for (18-
b
trans-19(TS)-trans-20) ) 15.51 kcal/mol. <S2> is the one after annihilation. Forming carbon radical. c Disappearing carbon radical.
SCHEME 1
SCHEME 2
further oxidative elimination (Hofmann â-elimination),
the generated trans-7 is 2.04 kcal/mol more stable than
the generated cis-7. On the other hand, the product 17
from Zaitsev â-elimination is 4.15 kcal/mol more stable
than the product trans-7 from Hofmann â-elimination.
As for the R-methyl-â-ketoester radical 18, the activation
energy to form cis-20 is 1.93 kcal/mol smaller than that
forming trans-20, while trans-20 is 0.75 kcal/mol more
stable than cis-20 (Scheme 3). After further oxidative
substitution, both cis-9 and trans-9 were produced and
trans-9 is 0.07 kcal/mol more stable than cis-9.
of catalytic sodium acetate produced the corresponding
R-methyl-â-ketoesters 5 in good yields (Scheme 4). Prod-
uct distribution, yields, and reaction conditions for the
oxidative free-radical cyclizations of 5a -d with 2 equiv
Syn th esis. Reactions of 4 with alcohols in the presence
J . Org. Chem, Vol. 68, No. 7, 2003 2773

Sung and Wang
SCHEME 3
SCHEME 5
CH3(a) (1.35 ppm) in trans-6 is 0.14 ppm more upfield
than that (1.49 ppm) in cis-6.
Reaction of 5b with 2 equiv of Mn(OAc)3 in either
acetonitrile or glacial acetic acid at 80 °C for 15 h
produced cis-7, trans-7, and trans-8 with the trans
isomers as major products (Scheme 2). The amount of
cis-8 was too small to be detected, and the Zaitsev
â-elimination product 17 was not found. The NOESY of
cis-7 shows a correlation between CH3(a) and H(b), while
there is no correlation between CH3(a) and H(b) in both
the NOESY of trans-7 and the NOESY of trans-8 (Scheme
5). Due to deshielding of propionyl moiety, H(b) in trans-7
is ca. 0.6 ppm more downfield than H(b) in cis-7. Due to
shielding of the i-propenyl group, CH3(a) (1.29 ppm) in
trans-7 is 0.31 ppm more upfield than that (1.60 ppm)
in cis-7. However, CH3(a) (1.59 ppm) in trans-8 is 0.30
ppm more downfield than that (1.29 ppm) in trans-7, and
this is due to deshielding of the carbonyl group of AcO
in trans-8.
SCHEME 4
Reaction of 5c with 2 equiv of Mn(OAc)3 in either
acetonitrile or glacial acetic acid at 50 or 80 °C for 15 h
produced both cis-9 and trans-9 with the trans isomer
as a major product (Scheme 3). The Zaitsev â-elimination
product 21 was not found. The NOESY of cis-9 shows a
correlation between CH3(a) and H(b), while there is no
correlation between CH3(a) and H(b) in the NOESY of
trans-9 (Scheme 5). Due to deshielding of the propionyl
moiety, H(b) in trans-9 is ca. 0.6 ppm more downfield
than H(b) in cis-9. Due to deshielding of carbonyl group
of AcO in trans-9, CH3(a) (1.48 ppm) in trans-9 is 0.08
ppm more downfield than that (1.40 ppm) in cis-9.
The oxidative free-radical cyclization of 5c with Mn-
(OAc)3 may produce both radicals cis-20 and trans-20,
followed by oxidative substitution by Mn(OAc)3 to give
both cis-9 and trans-9. During the oxidative substitution,
another stereocenter was generated, and its configuration
was assigned (Scheme 3) on the basis of 1H NMR spectra
and the computational results. The oxidative substitution
may involve carbon cations,8 so the carbon cations 22
were optimized at the B3LYP/6-31G* level (Figure 1).
Conformer cis-22a is 1.64 kcal/mol more stable than
conformer cis-22b, because the latter suffers more “butane-
gauche” nonbonding interactions. Similarly, conformer
trans-22a is also 4.67 kcal/mol more stable than con-
former trans-22b. During the oxidative substitution, due
to steric hindrance of both propionyl and methyl groups,
TABLE 2. P r od u ct Distr ibu tion , Yield s, a n d Rea ction
Con d ition s for th e Oxid a tive F r ee-Ra d ica l Cycliza tion s
of 5a -d w ith Mn (OAc)3
temp time
products
(yield)
reactant
solvent
(°C)
(h)
5a
5a
5b
CH3CN
CH3CO2H
CH3CN
80
80
80
15
15
15
cis-6 (37%), trans-6 (19%)
cis-6 (26%), trans-6 (14%)
cis-7 (12%), trans-7 (34%)
trans-8 (18%)
5b
CH3CO2H
80
15
cis-7 (12%), trans-7 (28%)
trans-8 (25%)
5c
5c
5c
5c
5d
5d
CH3CN
CH3CO2H
CH3CN
CH3CO2H
CH3CO2H
CH3CN
50
50
80
80
50
80
15
15
15
15
10
10
cis-9 (11%), trans-9 (20%)
cis-9 (9%), trans-9 (24%)
cis-9 (7%), trans-9 (28%)
cis-9 (7%), trans-9 (34%)
10 (38%)
10 (42%)
of Mn(OAc)3 are shown in Table 2. Reaction of 5a with 2
equiv of Mn(OAc)3 in acetonitrile or glacial acetic acid at
80 °C for 15 h produced both cis-6 and trans-6 with the
cis isomer as a major product (Scheme 1). The cis/trans
configurations were confirmed by their NOESY spectra
(Scheme 5). The NOESY of cis-6 shows a correlation
between CH3(a) and H(c), but there is no correlation
between CH3(a) and CH3(b). The NOESY of trans-6 shows
a correlation between CH3(a) and CH3(b), but there is no
correlation between CH3(a) and H(c). Due to deshielding
of propionyl moiety, H(c) in trans-6 is ca. 0.5 ppm more
downfield than H(c) in cis-6. Due to shielding of CH3(b),
(8) (a) Kochi, J . K.; Bemis, A.; J enkins, C. L. J . Am. Chem. Soc. 1968,
90, 4616. (b) Kochi, J . K.; Bemis, A. J . Am. Chem. Soc. 1968, 90, 4038.
2774 J . Org. Chem., Vol. 68, No. 7, 2003

Mn(III)-Based Oxidative Free-Radical Cyclizations
parallel planar sp2/planar sp2 interaction, while the latter
has a planar sp2/ball-shape sp3 interaction. That is why
the cis transition structures are more stable than the
corresponding trans transition structures in this study.
After the cyclization, the vinyl group is close to both the
propionyl group and methyl group for the generated cis
radicals (cis-13, cis-16, and cis-20), generating two steric
repulsive interactions, while in the generated trans
radicals (trans-13, trans-16, and trans-20), the vinyl
group is close to the methyl group but distant from the
propionyl group. When the substituents on the vinyl
group are hydrogen, the two steric repulsive interactions
of the cis radical are milder than that of the trans radical,
so cis-13 is more stable than trans-13. As the vinyl group
has bulky substituents, the two steric repulsive interac-
tions of the cis radicals are more significant than those
of the corresponding trans radicals, so trans-16 and trans-
20 are more stable than cis-16 and cis-20, respectively.
Curran et al.3e demonstrated that the nature of the
R-alkyl-â-ketoester radicals generated by either Mn(III)-
mediated oxidation or Me6Sn2-induced atom transfer is
the same, indicating the existence of free radicals 11, 14,
and 18 with loss of Mn(II) during the oxidation of the
R-alkyl-â-ketoesters with Mn(OAc)3. In addition, the
oxidation of 2-butanone with Mn(OAc)3 in the absence
of olefins produces 1- and 3-acetoxybutan-2-ones in a
ratio of 2.5:1,9a as opposed to the 1:3 ratio of addition of
the generated isomeric radicals to an alkene,9b implying
that the oxidative radical generation rate with Mn(OAc)3
has very little influence on either the regioselectivity or
the stereoselectivity of the cyclizations of the substituted
allyl R-methyl-â-ketoester radicals.
SCHEME 6
the facial selectivity of the carbon cations cis-22a and
trans-22a is very high when they are attacked by acetate.
In other words, the acetate prefers to attack the carbon
cations cis-22a and trans-22a from the face opposite to
both propionyl and methyl groups. Therefore, only one
diastereomer resulted from each isomer of radicals 20.
1
On the basis of their H NMR spectra, the other racemic
diastereomers could not be found for cis-9 or trans-9.
Reaction of 5d with 2 equiv of Mn(OAc)3 in either
acetonitrile or glacial acetic acid at 50 or 80 °C for 10 h
produced 10 in ca. 40% yield (Scheme 6). All the above
oxidative free-radical cyclizations of 5a -d with 2 equiv
of Mn(OAc)3 generated the 5-exo cyclization products, and
no 6-endo cyclization products could be found.
The free-radical cyclizations of the R-methyl-â-ke-
toesters such as 5a -d with Mn(OAc)3 usually produce a
significant amount of polar polymers as major by-
products.3k These polymeric byproducts are produced by
some monomers that are generated from the R-methyl-
â-ketoester radicals before the cyclizations,3k so the
amount of the polymeric byproducts should have nothing
to do with the stereoselectivity of the free-radical cycliza-
tions. In addition to the polymeric byproducts, most of
other products were collected for analysis of the stereo-
selectivity for the oxidative cyclization reactions, so the
synthetic results in the study should be reliable.
The cyclization of hex-5-en-1-yl radical generated by
1-bromohex-5-ene with tributyltin hydride in benzene
produces a 5-exo cyclization product.10 Because the
cyclization generated radical is trapped very fast by
hydrogen abstraction from tributyltin hydride at the rate
Discu ssion
According to the DFT calculations, the cis cyclization
is easier than the trans cyclization for radicals 11, 14,
and 18, but the generated cis radicals (cis-13, cis-16, and
cis-20) are not necessarily more stable than the corre-
sponding generated trans radicals (trans-13, trans-16,
and trans-20) after the cyclizations. Common features of
both cis and trans transition structures during the
cyclizations of radicals 11, 14, and 18 are (1) the spin on
R-carbon prefer to have resonance with the propionyl
carbonyl group, (2) the forming five-membered ring has
the shape of an envelope, and (3) the substituted vinyl
group, which sits on the out-of-plane carbon of the
envelope five-membered ring, is located at an equatorial
position. A major difference between the cis and trans
transition structures is that the substituted vinyl group
is closer to the propionyl group (dihedral angle ) 44.1°
for cis-12(TS), 48.7° for cis-15(TS), 43.1° for cis-19(TS))
than to the methyl group (dihedral angle ) 83.8° for cis-
12(TS), 80.0° for cis-15(TS), 84.3° for cis-19(TS)) in the
cis transition structures, while the substituted vinyl
group is closer to the methyl group (dihedral angle )
38.9° for trans-12(TS), 46.0° for trans-15(TS), 41.2° for
trans-19(TS)) than to the propionyl group (dihedral angle
) 89.1° for trans-12(TS), 82.6° for trans-15(TS), 86.6°
for trans-19(TS)) in the trans transition structures. The
steric repulsive interaction between the vinyl group and
the propionyl group is less than that between the vinyl
group and the methyl group, because the former has a
constant of ca. 106 M-1 s-1 10
the cyclization process is
,
irreversible and operates under kinetic control. On the
other hand, as the free-radical carbon atom is substituted
with resonance-stabilized substituents, it is more possible
that the cyclization becomes reversible.11 When cyano
esters 23/peroxide, 26, or 27 were heated in boiling
cyclohexane, cyclization products 24 and 25 were pro-
duced with 25 as a major product,11 indicating that the
resonance-stabilized radical 28 undergoes the cyclization
reversibly and the cyclization operates under thermody-
namic control. The poor hydrogen-donating solvent, cy-
clohexane, makes 29 and 30 prefer ring opening to
hydrogen abstraction. Therefore, the relative stability of
29 and 30 plays an important role on the proportion of
final products. However, addition of good hydrogen-
donating solvents such as cumene increased the propor-
tion of 24, indicating that faster hydrogen abstraction
may trap the rapidly formed 29 before the ring opening.11
(9) (a) Okano, M.; Aratani, T. Bull. Chem. Soc. J pn. 1976, 49, 2811.
(b) Vinogradov, M. G.; Verenchikov, S. P.; Fedorova, T. M.; Nikishin,
G. I. J . Org. Chem. USSR 1975, 11, 937.
(10) (a) Beckwith, A. L. J .; Blair, I.; Phillipou, G. J . Am. Chem. Soc.
1974, 96, 1613. (b) Beckwith, A. L. J .; Lawrence, T.; Serelis, A. K. J .
Chem. Soc., Chem. Commun. 1980, 484. (c) Beckwith, A. L. J .
Tetrahedron 1981, 37, 3073.
(11) (a) J ulia, M. Acc. Chem. Res. 1971, 4, 386. (b) J ulia, M.; Maumy,
M. Bull. Soc. Chim. Fr. 1969, 2415. (c) J ulia, M.; Maumy, M. Bull.
Soc. Chim. Fr. 1969, 2427. (d) Ruechardt, C. Angew. Chem., Int. Ed.
Engl. 1970, 9, 830.
J . Org. Chem, Vol. 68, No. 7, 2003 2775

Sung and Wang
clization of 11 is reversible and operates under thermo-
dynamic control. It is reasonable to assume that the
hydrogen-abstraction rates of the primary radicals trans-
13 and cis-13 are almost the same, so the stereoselectivity
of the reversible and thermodynamic-control cyclization
of 11 depends on the relative stability of trans-13 and
cis-13. According to the DFT calculations, cis-13 is 0.08
kcal/mol more stable than trans-13. On the basis of the
experimental results, the cyclization of 11 gives products
of both cis-6 and trans-6 in a ratio of 2:1, which indicates
that the proposed mechanism in Scheme 1 is very likely.
What is the result if the oxidative free-radical cycliza-
tion of 5a is carried out under kinetic control? The
oxidative free-radical cyclization of allyl malonate 2a ,
whose structure is very similar to that of 5a , has been
carried out under kinetic control by Mn(OAc)3/Cu(OAc)2
in acetic acid, and vinyl lactone 3a was produced with
the cis isomer as a major product.3j The oxidative free-
radical cyclization of 2a with Mn(OAc)3 generates a
secondary lactone radical, which is trapped quickly by
further oxidation with Cu(OAc)2, instead of the ring
opening, because Cu(OAc)2 oxidizes radicals 350 times
faster than Mn(OAc)3;15 this makes the further oxidation
rate of the generated secondary lactone radical faster
than its ring-opening rate. The reaction result under
kinetic control is consistent with our computation results.
Radicals 16 are tertiary radicals, which are oxidized
by Mn(OAc)3 more easily than a hydrogen atom can be
abstracted from the solvents for of the following reason.
It is known that Cu(OAc)2 oxidizes the tertiary radicals
350 times faster than Mn(OAc)315 and Cu(OAc)2 oxidizes
the tertiary radicals with the second-order rate constants
Curran12 performed atom transfer cyclization of R-iodo
ester 31 and found that the ring-opening rate constant
k-c of 32 is smaller than 4 × 103 s-1, which is much
smaller than the iodine-transfer rate constant kI (ca. 3
× 108 M-1 s-1) of 32, indicating that the cyclization
operates under kinetic control. Later, he performed the
atom transfer cyclization of R-halo-â-ketoester 33 and
found that 34 has a much faster ring-opening rate (k-c′
) 105-108 s-1), because the iodine transfer sufficiently
traps 34 but the bromine transfer does not.3e Radicals
13, 16, 20 in this study, like radical 34, have the moiety
of â-ketoester to stabilize the ring-opening-generated
radicals, but the ring-opening rates of the cyclopentyl-
carbinyl radicals are usually more rapid than those of
the corresponding cyclohexylcarbinyl radicals because the
former has a higher ring strain.13 Therefore, the ring-
opening rates of the radicals 13, 16, and 20 should be
much more rapid than that of the radical 34.
of ca. 107 M-1 s-1 16
Therefore, the second-order rate
.
constants for Mn(OAc)3 to oxidize the tertiary radicals
are expected to be ca. 2.9 × 105 M-1 s-1, whose pseudo-
first-order rate constant with 0.1 M Mn(OAc)3 is ca. 2.9
× 104 s-1, which is much bigger than the hydrogen
abstraction rate constants from the solvents but smaller
than the ring-opening rate constants of radicals 16,
causing the intramolecular free-radical cyclization of 14
to be reversible and to operate under thermodynamic
control. It is reasonable to assume that the further
oxidation rates of the tertiary radicals trans-16 and cis-
16 by Mn(OAc)3 are almost the same. Therefore, the
stereoselectivity of the reversible and thermodynamic-
control cyclization of 14 depends on the relative stability
of trans-16 and cis-16. The DFT calculations show that
trans-16 is 1.97 kcal/mol more stable than cis-16. Ac-
cording to the experimental results, the cyclization of 14
gives both cis and trans products in a ratio of 1:4.4, which
indicates that the proposed mechanism in Scheme 2 is
very likely.
What is the result if the oxidative free-radical cycliza-
tion of 5b is carried out under kinetic control? The
oxidative free-radical cyclization of allyl malonates 2b,
whose structure is very similar to that of 5b, has been
carried out under kinetic control by Mn(OAc)3/Cu(OAc)2
in acetic acid, and the major products are cis isomers.3j
The reaction result under kinetic control is consistent
with our computation results.
Radicals 13 are primary radicals, which are not readily
oxidized by Mn(OAc)3,4 so they abstract a hydrogen atom
from the solvents. It is known that the methyl radical
abstracts a hydrogen atom slowly from acetic acid (k ) 2
× 102 M-1 s-1) and acetonitrile (k < 3 × 102 M-1 s-1) in
the liquid phase.14 Therefore, the second-order rate
constants for the primary radicals to abstract a hydrogen
atom from either acetic acid or acetonitrile are expected
to be smaller than 2 × 102 M-1 s-1, whose pseudo-first-
order rate constants with 10 M acetic acid or acetonitrile
are smaller than 2 × 103 s-1, which are much smaller
than the ring-opening rate constants of the radicals 13;
this indicates that the intramolecular free-radical cy-
(12) Curran, D. P.; Chang, C.-T. J . Org. Chem. 1989, 54, 3140.
(13) (a) Beckwith, A. L. J .; Hay, B. P. J . Am. Chem. Soc. 1989, 111,
2674. (b) Beckwith, A. L. J .; Hay, B. P. J . Am. Chem. Soc. 1989, 111,
230.
(14) Gilbert, B. C.; Norman, R. O. C.; Placucci, G.; Sealy, R. C. J .
Chem. Soc., Perkin Trans. 2 1975, 885.
(15) Heiba, E. I.; Dessau, R. M. J . Am. Chem. Soc. 1971, 93, 524.
(16) (a) Kochi, J . K.; Subramanian, R. V. J . Am. Chem. Soc. 1965,
87, 4855. (b) Kochi, J . K.; Subramanian, R. V. Inorg. Chem. 1965, 4,
1527. (c) J enkins, C. L.; Kochi, J . K. J . Am. Chem. Soc. 1972, 94, 843.
2776 J . Org. Chem., Vol. 68, No. 7, 2003

Mn(III)-Based Oxidative Free-Radical Cyclizations
Mn(OAc)3 generated the 5-exo cyclization products, in-
stead of the 6-endo cyclization products. The ring-opening
rates of radicals 13 are much faster than their hydrogen
abstraction rates from the solvents, causing the free-
radical cyclization of the radical 11 to be reversible and
to operate under thermodynamic control, and the ste-
reoselectivity of the cyclization depends on the relative
stability of the cyclization-generated radicals trans-13
and cis-13. Since cis-13 is 0.08 kcal/mol more stable than
trans-13, the oxidative free-radical cyclization of 5a with
Mn(OAc)3 gives products of both cis-6 and trans-6 in a
ratio of 2:1. The ring-opening rates of radicals 16 and 20
are faster than their further oxidation rates by Mn(III),
causing the free-radical cyclizations of the radicals 14 and
18 to be reversible and to operate under thermodynamic
control, and the stereoselectivity of the cyclizations
depends on the relative stability of the cyclization-
generated radicals trans-16/cis-16 and trans-20/cis-20,
respectively. Since trans-16 is 1.97 kcal/mol more stable
than cis-16 and trans-20 is 0.75 kcal/mol more stable
than cis-20, the oxidative free-radical cyclizations of 5b
and 5c with Mn(OAc)3 give the trans products as major
products.
According to the DFT calculations, the cis cyclization
of 18 is 1.93 kcal/mol lower in energy than the corre-
sponding trans cyclization, but the resulting radical
trans-20 is 0.75 kcal/mol more stable than cis-20. On the
basis of the experimental results, the cyclization of 18
produces both cis-9 and trans-9 in ratios of 1:2 at 50 °C
and 1:4 at 80 °C, and the amount of trans-9 increases as
the reaction temperature increases, indicating that the
intramolecular free-radical cyclization of 18 is reversible
and operates under thermodynamic control. Radicals 20
are secondary benzyl radicals, which were reported to be
oxidized by Mn(OAc)3 more easily than a hydrogen atom
could be abstracted from the solvents.4b On the other
hand, the benzyl radicals 20 are stabilized by the phenyl
group significantly, and that makes the ring-opening
barriers of 20 higher, implying that the ring opening of
20 is getting more difficult. The knowledge of the oxida-
tive solvolysis rates of the secondary radicals by Mn(III)
might help to give an understanding of why a thermo-
dynamic control would operate in this case.
Exp er im en ta l Section
Gen er a l. Unless otherwise stated, reagents were obtained
from commercial suppliers and used as received. The â-lactone
4 was prepared according to a literature method.17 Preparation
and spectroscopic data of 5a -d are shown in Supporting
Information.
What is the result if the oxidative free-radical cycliza-
tion of 5c is carried out under kinetic control? The
oxidative free-radical cyclization of allyl malonates 2c,
whose structure is very similar to that of 5c, has been
carried out under kinetic control by Mn(OAc)3/Cu(OAc)2
in acetic acid, and the major products are cis isomers.3j
The reaction result under kinetic control is consistent
with our computation results.
Gen er a l Meth od for Oxid a tive Cycliza tion of 5 w ith
Mn (OAc)3. A solution of 5 (2 mmol) and Mn(OAc)3 (4 mmol)
in 10 mL of degassed acetonitrile or glacial acetic acid was
heated at 50 or 80 °C under nitrogen for 15 or 10 h. After
reaction, the reaction mixture was poured through a short
silica gel column and eluted with ether. The collected solution
was washed with saturated NaHCO3 aqueous solution, dried
over anhydrous MgSO4, and evaporated in a vacuum to give
crude products, which were purified by column chromatogra-
phy on silica gel with an eluent of 7:3 hexane/ethyl acetate.
cis-3,4-Dim eth yl-3-p r op ion yl-d ih yd r ofu r a n -2-on e (cis-
6): colorless oil; 1H NMR (CDCl3) δ 1.03 (6H, m, CH3), 1.49
(3H, s, CH3), 2.55 (3H, m, CH and CH2), 3.95 (1H, d of d, J )
9.5, 8.5 Hz, CH), 4.37 (1H, d of d, J ) 8.5, 8.2 Hz, CH); 13C
NMR (CDCl3) δ 6.92, 11.81, 19.00, 34.56, 42.62, 58.99, 71.53,
177.56, 207.70; IR (thin film) 1768, 1708 (CdO) cm-1; MS (EI)
m/z 170 (35, M+), 114 (95), 99 (100), 84 (30), 71 (30), 57 (60);
HRMS (EI) m/z calcd for C9H14O3 170.0943, found 170.0946.
tr a n s-3,4-Dim et h yl-3-p r op ion yl-d ih yd r ofu r a n -2-on e
(tr a n s-6): colorless oil; 1H NMR (CDCl3) δ 1.03 (6H, m, CH3),
1.35 (3H, s, CH3), 2.71 (2H, m, CH2), 3.05 (1H, m, CH), 3.83
(1H, d of d, J ) 8.5, 7.8 Hz, CH), 4.38 (1H, d of d, J ) 8.5, 10.1
Hz, CH); 13C NMR (CDCl3) δ 7.81, 12.34, 14.36, 31.49, 36.00,
58.74, 72.01, 177.06, 205.75; IR (thin film) 1770, 1712 (CdO)
cm-1; MS (EI) m/z 170 (35, M+), 114 (95), 99 (100), 84 (30), 71
(30), 57 (60); HRMS (EI) m/z calcd for C9H14O3 170.0943, found
170.0943.
According to the experimental results, the oxidative
free-radical cyclization of 5b with Mn(OAc)3 produced cis-
7, trans-7, and trans-8, but 17 could not be found,
indicating that both cis-16 and trans-16 undergo both
oxidative elimination and substitution. Because the
oxidative elimination does not go through carbon cations8
and because a â-H with less steric hindrance more easily
undergoes â-elimination, the Hofmann â-elimination
products were produced, but the Zaitsev â-elimination
17 was not, even though the latter is much more stable
than the former. Similar results were observed for the
oxidative free-radical cyclization of 5c with Mn(OAc)3,
which produced both cis-9 and trans-9 but did not
generate the Zaitsev â-elimination product 21, indicating
that both cis-20 and trans-20 undergo the oxidative
substitution rather than the oxidative elimination.
cis-4-Isop r op en yl-3-m eth yl-3-p r op ion yl-d ih yd r ofu r a n -
1
2-on e (cis-7): colorless oil; H NMR (CDCl3) δ 1.03 (3H, t, J
) 7.1 Hz, CH3), 1.60 (3H, s, CH3), 1.75 (3H, s, CH3), 2.63 (2H,
q, J ) 7.1 Hz, CH2), 3.01 (1H, t, J ) 9.1 Hz, CH), 4.36 (2H, d,
J ) 9.1 Hz, CH2), 4.79 (1H, s, CH), 5.01 (1H, s, CH); 13C NMR
(CDCl3) δ 7.05, 20.95, 23.10, 34.11, 53.52, 60.01, 68.24, 114.62,
139.04, 176.71, 206.93; IR (thin film) 1770, 1712 (CdO) cm-1
;
MS (EI) m/z 196 (30, M+), 140 (45), 99 (100), 84 (25), 57 (70);
HRMS (EI) m/z calcd for C11H16O3 196.1099, found 196.1103.
Con clu sion
The oxidative free-radical cyclizations of the substi-
tuted allyl R-methyl-â- ketoesters 5a -d with 2 equiv of
(17) Sung, K.; Wu, S.-Y. Synth. Commun. 2001, 31, 3069.
J . Org. Chem, Vol. 68, No. 7, 2003 2777

Sung and Wang
tr a n s-4-Isop r op en yl-3-m eth yl-3-p r op ion yl-d ih yd r ofu -
r a n -2-on e (tr a n s-7): colorless oil; 1H NMR (CDCl3) δ 1.05 (3H,
t, J ) 7.2 Hz, CH3), 1.29 (3H, s, CH3), 1.71 (3H, s, CH3), 2.63
(2H, m, CH2), 3.64 (1H, m, CH), 4.36 (2H, m, CH2), 4.77 (1H,
s, CH), 4.97 (1H, s, CH); 13C NMR (CDCl3) δ 7.88, 14.91, 21.86,
31.37, 47.81, 58.91, 69.10, 114.92, 140.33, 176.32, 206.26; IR
(thin film) 1770, 1714 (CdO) cm-1; MS (EI) m/z 196 (30, M+),
140 (45), 99 (100), 84 (25), 57 (70); HRMS (EI) m/z calcd for
1H NMR (CDCl3) δ 0.95 (3H, t, J ) 7.2 Hz, CH3), 1.48 (3H, s,
CH3), 2.13 (3H, s, CH3), 2.55 (2H, m, CH2), 3.60 (1H, m, CH),
4.30 (2H, m, CH2), 5.88 (1H, d, J ) 5.7 Hz, CH), 7.35 (5H, m,
ArH); 13C NMR (CDCl3) δ 7.67, 14.80, 20.87, 31.27, 46.28,
58.21, 66.98, 73.51, 126.32, 128.62, 128.82, 137.24, 169.58,
176.04, 205.70; IR (thin film) 1778, 1714 (CdO) cm-1; MS (EI)
m/z 304 (1, M+), 245 (M+ - AcO, 100), 189 (20), 57 (50); HRMS
(EI) m/z calcd for C15H17O3 (M+ - AcO) 245.1178, found
245.1179.
C
11H16O3 196.1099, found 196.1101.
tr a n s-Acetic Acid 1-Meth yl-1-(4-m eth yl-5-oxo-4-p r o-
3-Me t h yl-4-m e t h yle n e -3-p r op ion yl-d ih yd r ofu r a n -2-
on e (10): colorless oil; 1H NMR (CDCl3) δ 1.03 (3H, t, J ) 7.2
Hz, CH3), 1.55 (3H, s, CH3), 2.55 (2H, m, CH2), 4.84 (2H, s,
CH2), 5.12 (1H, s, CH), 5.22 (1H, s, CH); 13C NMR (CDCl3) δ
7.71, 19.44, 31.45, 59.85, 70.43, 110.22, 143.65, 176.17, 202.68;
IR (thin film) 1778, 1724 (CdO) cm-1; MS (EI) m/z 168 (3, M+),
112 (90), 84 (50), 57 (100); HRMS (EI) m/z calcd for C9H12O3
168.0786, found 168.0786.
p ion yl-tr tr a h yd r ofu r a n - 3-yl)-eth yl Ester (tr a n s-8): color-
less oil; 1H NMR (CDCl3) δ 1.08 (3H, t, J ) 7.2 Hz, CH3), 1.46
(3H, s, CH3), 1.52 (3H, s, CH3), 1.59 (3H, s, CH3), 1.97 (3H, s,
CH3), 2.73 (2H, m, CH2), 3.43 (1H, m, CH), 4.37 (2H, m, CH2);
13C NMR (CDCl3) δ 7.97, 15.87, 22.33, 24.86, 24.89, 31.72,
50.52, 58.33, 66.57, 80.70, 169.49, 176.43, 206.70; IR (thin film)
1773, 1740, 1718 (CdO) cm-1; MS (EI) m/z 256 (3, M+), 239
(20), 197 (20), 140 (40), 99 (100); HRMS (EI) m/z calcd for
C
13H20O5 256.1311, found 256.1310.
cis-Acetic Acid (4-Meth yl-5-oxo-4-p r op ion yl-tetr a h y-
Ack n ow led gm en t. Financial support from National
Science Council of Taiwan, Republic of China (NSC 91-
2113-M-006-011), is gratefully acknowledged. We thank
National Center For High-Performance Computing of
Taiwan for computer time.
d r ofu r a n -3-yl)-p h en yl- m eth yl Ester (cis-9): colorless oil;
1H NMR (CDCl3) δ 0.95 (3H, t, J ) 7.2 Hz, CH3), 1.40 (3H, s,
CH3), 2.02 (3H, s, CH3), 2.55 (2H, m, CH2), 2.93 (1H, m, CH),
4.46 (2H, m, CH2), 5.17 (1H, d, J ) 4.7 Hz, CH), 7.35 (5H, m,
ArH); 13C NMR (CDCl3) δ 7.03, 14.78, 19.99, 27.97, 57.29,
58.43, 70.99, 84.59,125.68, 128.61, 128.81, 140.53, 175.00,
177.07, 209.04; IR (thin film) 1778, 1714 (CdO) cm-1; MS (EI)
m/z 304 (1, M+), 245 (M+ - AcO, 100), 189 (20), 57 (50); HRMS
(EI) m/z calcd for C15H17O3 (M+ - AcO) 245.1178, found
245.1181.
Su p p or tin g In for m a tion Ava ila ble: Total energies; Car-
tesian or Z-matrix coordinates; optimized structures (Figure
2-4) of the reactants, intermediates, transition states, and
products discussed in this paper; and preparation and spec-
troscopic data of 5a -d . This material is available free of charge
via the Internet at http://pubs.acs.org.
tr a n s-Acetic Acid (4-Meth yl-5-oxo-4-p r opion yl-tr tr a h y-
d r ofu r a n -3-yl)-p h en yl-m eth yl Ester (tr a n s-9): colorless oil;
J O026681T
2778 J . Org. Chem., Vol. 68, No. 7, 2003