On the 6-endo selectivity in 4-penten-1-oxyl radical cyclizations

Article abstract of DOI:10.1021/ja049010g

Regioselectivities in cyclizations of 4-substituted 4-penten-1-oxyl radicals have been investigated in a combined experimental and computational study (density functional theory). The progressive increase of the 6-endo-trig selectivity along the series of 4-substituents H < CH₃ < C(CH₃)₃ < C₆H₅ has been interpreted to originate from a balance between strain and FMO interactions. Torsional strain, which is associated with geometrical changes upon an approach of the reacting entities, is relevant for the 6-endo-trig but not for the 5-exo-trig reactions, as seen, for instance, in selective tetrahydrofuran formation from the 4-penten-1-oxyl radical and its 4-methyl derivative. The preference for tetrahydropyran formation in cyclizations of the 4-tert-butyl and the 4-phenyl-4-penten-1-oxyl radical has been attributed to FMO interactions between the terminal carbon atom of the π bond and the O-radical center thus favoring the 6-endo-trig reaction on the basis of lower transition state energies.

Full text of DOI:10.1021/ja049010g

Published on Web 09/01/2004
On the 6-endo Selectivity in 4-Penten-1-oxyl Radical
Cyclizations
Jens Hartung,*,† Rainer Kneuer, Christian Rummey, and Gerhard Bringmann*
Contribution from the Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg, Am Hubland,
D-97074 Wu¨rzburg, Germany
Received February 21, 2004; E-mail: hartung@chemie.uni-kl.de; bringman@chemie.uni-wuerzburg.de
Abstract: Regioselectivities in cyclizations of 4-substituted 4-penten-1-oxyl radicals have been investigated
in a combined experimental and computational study (density functional theory). The progressive increase
of the 6-endo-trig selectivity along the series of 4-substituents H < CH3 < C(CH3)3 < C6H5 has been
interpreted to originate from a balance between strain and FMO interactions. Torsional strain, which is
associated with geometrical changes upon an approach of the reacting entities, is relevant for the 6-endo-
trig but not for the 5-exo-trig reactions, as seen, for instance, in selective tetrahydrofuran formation from
the 4-penten-1-oxyl radical and its 4-methyl derivative. The preference for tetrahydropyran formation in
cyclizations of the 4-tert-butyl and the 4-phenyl-4-penten-1-oxyl radical has been attributed to FMO
interactions between the terminal carbon atom of the π bond and the O-radical center thus favoring the
6-endo-trig reaction on the basis of lower transition state energies.
Introduction1
Scheme 1. Modes of 4-Penten-1-oxyl Radical Cyclizations and
Indexing of Compounds 1-5
The 4-penten-1-oxyl radical (1a) cyclizes regioselectively to
furnish, after hydrogen atom trapping, a 98:2 mixture of
2-methyltetrahydrofuran (4a) and tetrahydropyran (5a) (T ) 30
°C, Scheme 1, R2 ) H).2-4 This fingerprint-type regioselectivity
is retained in ring closure reactions of 1-, 2-, and 3-methyl- or
phenyl-substituted 4-penten-1-oxyl radicals.5 A considerable
change in this reactivity and selectivity was observed for the
4-phenyl-4-penten-1-oxyl radical (1d), which cyclizes at 30 °C
approximately 8 times faster via the 6-endo-trig pathway than
the 4-penten-1-oxyl radical (1a) undergoes a 5-exo-trig ring
closure.5a
† Current address: Fachbereich Chemie, Organische Chemie, Technische
Universita¨t Kaiserslautern, Erwin-Schro¨dinger-Strasse, D-67663 Kaiser-
slautern, Germany.
(1) The following abbreviations have been applied: C ) chair conformer (for
tetrahydropyran-derived structures); DTA ) differential thermoanalysis;
E ) envelope conformer (for tetrahydrofuran-derived structures); T ) twist
conformer (for tetrahydrofuran-derived structures); TB ) twist boat
conformer (for tetrahydropyran-derived structures); ZPVE ) zero-point
vibrational energy.
(2) For the discovery of the 5-exo-trig-cyclization of 1a, see: (a) Surzur, J.-
M.; Bertrand, M.-P.; Nougier, R. Tetrahedron Lett. 1969, 4197-4200. For
early work on the 5-exo-trig cyclization 1af2a, see: (b) Rieke, R. D.;
Moore, N. A. J. Org. Chem. 1972, 37, 413-418. (c) Gilbert, B. C.; Holmes,
R. G. G.; Laue, H. A. H.; Normann, R. O. C. J. Chem. Soc., Perkin Trans.
2 1976, 1047-1052. (d) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc.
1988, 110, 4415-4416. (e) Beckwith, A. L. J.; Hay, B. P.; Williamson, G.
M. J. Chem. Soc., Chem. Commun. 1989, 1202-1203.
The 5-exo-trig cyclization of alkenoxyl radicals is a trans-
formation of notable synthetic utility.6 It provides, for example,
regioselectivities in a radical version of the halocyclization,
which are not attainable from traditional electrophile-induced
alkenol cyclizations.7-9 In view of this mechanistic and synthetic
(3) For the discovery of the 6-endo-trig-mode of cyclization of the 4-penten-
1-oxyl radical (1a) see: Hartung, J.; Gallou, F. J. Org. Chem. 1995, 60,
6706-6716.
(4) For reviews on the 4-penten-1-oxyl radical cyclization, see: (a) Hartung,
J. Eur. J. Org. Chem. 2001, 619-632. (b) Hartung, J. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;
Vol. 2, pp 425-439.
(5) (a) Hartung, J.; Hiller, M.; Schmidt, P. Chem.sEur. J. 1996, 2, 1014-
1023. (b) Hartung, J.; Hiller, M.; Schmidt, P. Liebigs Ann. Chem. 1996,
1425-1436. (c) Hartung, J.; Schwarz, M.; Svoboda, I.; Fuess, H. Eur. J.
Org. Chem. 1999, 1275-1290.
(6) Hartung, J.; Gottwald, T.; Sˇpehar, K. Synthesis 2002, 1469-1498.
(7) (a) Hartung, J.; Kneuer, R.; Laug, S.; Schmidt, P.; Sˇpehar, K.; Svoboda,
I.; Fuess, H. Eur. J. Org. Chem. 2003, 4033-4052. (b) Hartung, J.; Kopf,
T. M.; Kneuer, R.; Schmidt, P. C. R. Acad. Sci. Paris, Chemie/Chemistry
2001, 649-666. (c) Hartung, J.; Kneuer, R. Eur. J. Org. Chem. 2000,
1677-1683.
9
10.1021/ja049010g CCC: $27.50 © 2004 American Chemical Society
J. AM. CHEM. SOC. 2004, 126, 12121-12129
12121

A R T I C L E S
Hartung et al.
Table 1. Preparation of
N-(Alkenoxy)-4-(p-chlorophenyl)thiazolethiones 9
Table 2. Synthesis of Tetrahydrofurans 4 and Tetrahydropyrans 5
from N-(Alkenoxy)Thiazolethiones 9a
entry
6,7
8
R1
R2
9
yield [%]
1
2
3
6
6
7
8b
8c
8g
H
H
CH3
CH3
C(CH3)3
C(CH3)3
9b
9c
9g
67
71
64
background it was the aim of the present study,10 to uncover in
a combined experimental and computational investigation
principles that favor 6-endo-trig-selective alkenoxyl radical
cyclizations. The results of this investigation will contribute to
the development of syntheses of tetrahydropyran-derived target
compounds in future applications of this hitherto largely
unexplored reaction.
yield [%]
entry
1, 4, 5, 9
R1
R2
X
−
Y
4
5
1b
2b
3c
b
c
g
H
H
CH3
CH3
C(CH3)3
C(CH3)3
H Si(Si(CH3)3
H Si(Si(CH3)3
H Sn(C4H9)3
56
34
18
25
40
31
Results
a CP ) p-ClC6H4. 10: Y ) [Si(Si(CH3)3]. 11: Y ) Sn(C4H9)3.
b Photoreaction in C6D6; yields were determined by 1H NMR using anisole
as internal standard (estimated error: (5%). c Photoreaction in C6H6; 4g
(cis/trans ) 50:50) and 5g (cis/trans ) 13:87) were purified by column
chromatography. The ratio of purified 4g versus 5g was identical to the
value determined by GC from the reaction mixture (quantitative GC
analysis: n-C14H30 as internal standard; estimated errors for cis/trans and
4g:5g ratios: (2%).
1. Preparation and Photochemical Conversion of Alkoxyl
Radical Precursors. N-(4-Methyl-4-penten-1-oxy)-4-(p-chlo-
rophenyl)thiazole-2(3H)thione (9b) was prepared in 67% yield
from the reaction of N-(hydroxy)-4-(p-chlorophenyl)thiazole-
2(3H)-thione tetrabutylammonium salt (6)11 and 4-methyl-4-
penten-1-yl tosylate (8b)12 in anhydrous DMF (Table 1).
Treatment of ammonium salt 6 and 4-(tert-butyl)-4-penten-1-
yl tosylate 8c13 afforded N-[4-(tert-butyl)-4-penten-1-oxy]thia-
zolethione 9c in 71% yield. N-[5-(tert-Butyl)-5-hexen-2-oxy]-
4-(p-chlorophenyl)thiazolethione 9g was prepared from the
corresponding tosylate 8g and tetraethylammonium salt 7 in 64%
yield. All thiazolethiones 9 were obtained as colorless and
crystalline air stable materials that were stored in standard
glassware in a refrigerator.
N-(4-Methyl-4-penten-1-oxy)thiazolethione 9b and [(H3C)3-
Si]3SiH (2.2 equiv, co ) 0.18 M) were dissolved in deaerated
C6D6. Photolysis of this solution at 20 °C was performed in a
Rayonet chamber photoreactor equipped with λ ) 350 nm light
bulbs (Supporting Information). The starting material 9b was
consumed within 25 min to provide 56% of 2,2-(dimethyl)-
tetrahydrofuran (4b)14 and 25% of 3-methyltetrahydropyran (5b)
(1H NMR, Table 2). 4-Methyl-4-penten-1-ol, i.e., the product
of direct hydrogen atom trapping of O-radical 1b, was not
detected in the reaction mixture (1H NMR). The structural
formula of 2-[tris(trimethylsilyl)]silylsulfanyl-4-(p-chlorophe-
nyl)thiazole (10) has been disclosed in the graphics on the basis
of its close analogy to the familiar tributyltin-derivative 11
(Table 2).5c
Photolysis of N-[4-(tert-butyl)-4-penten-1-oxy]thiazolethione
9c in the presence of [(H3C)3Si]3SiH (2.2 equiv, co ) 0.18 M)
in C6D6 afforded 34% of 2-methyl-2-(tert-butyl)tetrahydrofuran
4c, 40% of 3-(tert-butyl)tetrahydropyran 5c, and traces of 4-(tert-
butyl)-4-penten-1-ol (1H NMR, Supporting Information).15
Irradiation of a solution of N-[5-(tert-butyl)-5-hexen-2-oxy]-4-
(p-chlorophenyl)thiazole-2(3H)-thione (9g) and (H9C4)3SnH in
C6H6 furnished, after purification of the reaction mixture by
chromatography, 18% of 2,5-dimethyl-2-(tert-butyl)tetrahydro-
furan 4g (cis/trans ) 50:50) and 31% of 2-methyl-5-(tert-butyl)-
tetrahydropyran (5g) (cis/trans ) 13:87). This workup process
was monitored by GC in order to verify that the ratio of cyclic
ethers 4 and 5 reported in Table 2 corresponds to the information
that was present in the original reaction mixture.
2. Computational Studies on the Regioselectivity in Cy-
clizations of 4-Substituted 4-Penten-1-oxyl Radicals. The
energetically most favorable conformer of alkoxyl radicals 1a-
d, cyclized radicals 2a-d and 3a-d, and relevant transition
structures in 4-penten-1-oxyl radical cyclizations (Table 4) were
computed on a density functional (DF) level of theory using
the 6-31+G* split valence basis set.16,17 The data from previous
investigations had shown that diffuse and polarization wave
functions are necessary in order to satisfactorily reproduce the
experimentally observed 5-exo/6-endo-selectivity in ring closure
(8) Hartung, J.; Kneuer, R. Tetrahedron: Asymmetry 2003, 14, 3019-3031.
(9) (a) Hartung, J.; Greb, M. Tetrahedron Lett. 2003, 44, 6091-6063. (b) Jung,
M. E.; Fahr, B. T.; D’Amico, D. C. J. Org. Chem. 1998, 63, 2982-2987.
(c) Corey, E. J.; Ha, D.-C. Tetrahedron Lett. 1988, 29, 3171-3174. (d)
Gonza´lez, A. G.; Mart´ın, J. D.; Pe´rez, C.; Ram´ırez, M. A.; Ravelo, F.
Tetrahedron Lett. 1981, 22, 5071-5072. (e) Harmange, J.-C.; Figade`re,
B. Tetrahedron: Asymmetry 1993, 4, 1711-1754. (f) Bartlett, P. A. In
Asymmetric Synthesis; Morrision, J. D., Ed.; Academic Press: New York,
1984; Vol. 3, pp 411-453.
(10) Hartung, J.; Stowasser, R.; Vitt, D.; Bringmann, G. Angew. Chem. 1996,
108, 3056-3059; Angew. Chem., Int. Ed. Engl. 1996, 35, 2820-2823.
(11) (a) Hartung, J. In Encyclopedia for Reagents in Organic Synthesis; Crich,
D., Ed.; John Wiley & Sons: New York, NY, in press. (b) Hartung, J.;
Schwarz, M. Org. Synth. 2002, 79, 228-235.
(12) (a) Ansell, M. F.; Thomas, D. A. J. Chem. Soc. 1961, 539-542. (b) Larock,
R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org. Chem. 1994, 59, 4172-
4178.
(13) Matlin, A. R.; Clifford, C. F.; Wolff, S.; Agosta, W. C. J. Am. Chem. Soc.
1986, 108, 3385-3394.
(14) Eliel, E. L.; Hargrave, K. D.; Pietrusiewicz, K. M.; Manoharan, M. J. Am.
Chem. Soc. 1982, 104, 3635-3643.
(15) Mihailovic, M. L.; Gojkovic, S.; Milosavljevic, S.; Konstantinovic, S. Indian
J. Chem. 1999, 38B, 101-105.
9
12122 J. AM. CHEM. SOC. VOL. 126, NO. 38, 2004

4-Penten-1-oxyl Radical Cyclizations
A R T I C L E S
Table 3. Synopsis of Selectivities from 4-Penten-1-oxyl Radical
Cyclizations in the Presence of Reactive Hydrogen Atom Donors
H-Ya
potential energy surfaces. The computed energies (E + ZPVE),
zero-point vibrational energies (ZPVE), expectation values of
the spin operator ( S2 ), and relative heats of formation (∆∆Hf)
of radicals 1-3 are listed in Table 4. The illustration in Figure
1 has been restricted to phenyl-substituted radicals 1d-3d.24,25
Differences between the latter and the remaining computed
structures [i.e., for R2 ) H, CH3, C(CH3)3] have been included
into Table 4.
entry
1
R1
R2
4:5
1
2
3
4
5
6
7
a
b
c
d
e
f
H
H
H
H
CH3
CH3
CH3
H
CH3
C(CH3)3
C6H5
H
98:2a
The search for the two energetically lowest transition
structures associated with each mode of ring closure was
conducted as follows: A chair- and a boatlike folding of the
4-penten-1-oxyl radical 1a and of its 4-substituted derivatives
69:31b
46:54b
7:93a
98:2a
CH3
C(CH3)3
82:18a
37:63b
1b-d served as input geometries (Scheme 2, center left).26
A
g
successive shortening of the C4,O (for 12 and 13) or the C5,O
(for 14 and 15) bond from 3.00 Å to 1.48 Å led to high energy
intermediates along the associated reaction coordinates on an
AM1 level of theory.27 The highest energy structure from each
linear transit served as input geometry for successfully perform-
ing ab initio calculations. Stationary points were located by
gradient optimization procedures using the first and second
derivatives. The existence of one imaginary harmonic vibrational
frequency that was associated with the trajectory of C,O bond
formation classified intermediates 12-15 as authentic transition
structures. The calculated energies (E + ZPVE), zero-point
vibrational energies (ZPVE), expectation values of the spin
operators ( S2 ), relative heats of formation (∆∆Hf, referenced
versus the associated alkoxyl radical 1), sum of electronic and
thermal free energies G, ∆G (referenced versus the energetically
lowest transition structure of each series of intermediates),
Boltzmann-weighted populations P, and a short summary of
relevant conformational parameters of transition structures 12a-
d, 13a-d, 14a-d, and 15a-d are listed in Tables 5 and 6. For
the sake of clarity, the illustration of computed geometries has
been restricted to transition structures of cyclizations associated
with the 4-phenyl-4-pentenoxyl radical 1d (Figure 2).
a H-Y ) H-Sn(C4H9)3 or H-Si[Si(CH3)]3. Reaction temperature: 30
b
°C; see ref 5. Reaction temperature: 20 °C.
reactions of the 4-penten-1-oxyl radical (1a).10,18 According to
information from an assessment of methods that provide reliable
relative heats of formation in radical additions to C,C double
bonds,19,20 we restricted ourselves to the use of Becke’s three
parameter hybrid functional21,22 for calculations that are outlined
below.
Selectivities from kinetically controlled reactions, for instance
from cyclizations of O-radicals 1 under the conditions applied
above,5,18 may be analyzed by transition state theory, i.e., by
taking a Boltzmann distribution of thermal, rotational, and
vibrational energies in addition to the computed electronic
energies of a complete ensemble of transition states into
account.23 To keep computational time at a reasonable level
without losing essential information, simplifications have been
made in the present study. The ensemble of transition states
was reduced to two energetically lowest transition structures
per mode of ring closure (Scheme 2), which simplified the
Boltzmann statistics considerably. An assessment of this ap-
proach is outlined in the Discussion (see below).
The absence of imaginary harmonic frequencies pointed to
minimum structures for radicals 1-3 on the corresponding
Discussion
1. Experimental Regioselectivities. The 5-exo/6-endo-
selectivity in cyclizations of 4-penten-1-oxyl radicals 1 gradually
changes along the series of 4-substituents from 98:2 (1a, R2 )
H),3 via 69:31 (1b, R2 ) CH3), 46:54 [1c, R2 ) C(CH3)3], to
7:93 (R2 ) C6H5)5a (Table 3). The product analysis of volatile
cyclic ethers 4b, 5b (81% combined yield) and 4b, 5b (74%
combined yield) has been performed directly from the corre-
sponding reaction mixtures (1H NMR, GC). The choice of
[(H3C)3Si]3SiH as hydrogen atom donor for this purpose was
guided by the observation that 1H NMR resonances originating
(16) Quantum chemical calculations were carried out on Intel LinuX Worksta-
tions using the Gaussian 98 (revision A.7) software: Frisch, M. J.; Trucks,
G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Zakrzewski, V. G.; Montgomery, J. A., Jr.; 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.; Baboul, A.
G.; 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.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.7;
Gaussian, Inc.: Pittsburgh, PA, 1998.
(17) (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54,
724-728. (b) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys.
1972, 56, 2257-2261. (c) Hariharan, P. C.; Pople, J. A. Mol. Phys. 1974,
27, 209-214.
(18) Maxwell, B. J.; Smith, B. J.; Tsanaktsidis, J. J. Chem. Soc., Perkin Trans.
2000, 425-431.
(24) The following notation has been applied for tetrahydrofuran and tetrahy-
dropyran-derived structures: C ) chair, E ) Envelope, T ) twist, TB )
twist boat. For reasons of symmetry, the following notations are equiva-
lent: 2T3 3T2, 3T4 4T3, 4C1 1C4, 3TB5 5TB3: Lehmann, J.
) ) ) )
Kohlenhydrate; Thieme: Stuttgart, 1996; pp 16-37.
(19) (a) Barckholtz, C.; Barckholtz, T. A.; Hadad, C. M. J. Phys. Chem. A 2001,
105, 140-152. (b) Ricca, A.; Bauschlicher, C. W., Jr. Chem. Phys. Lett.
2000, 328, 396-402. (c) Alvarez-Idaboy, J. R.; Mora-Diez, N.; Vivier-
Bunge, A. J. Am. Chem. Soc. 2000, 122, 3715-3720. (d) Wong, M. W.;
Radom, L. J. Phys. Chem. 1995, 99, 8582-8588.
(25) Nomenclature for twist and envelope conformers: superscripts are used
for atoms which are displaced above the plane of three (T conformers) or
four atoms (E conformer). Subscripts refer to atoms which are located
underneath these planes. For a proper assignment of subscripts and
superscripts of conformers, the atoms of the heterocyclic core, which define
a plane, follow a clockwise arrangement with increasing atom count (i.e.,
O1-C2-C3): (a) Romers, C.; Altona, C.; Buys, H. R.; Havinga, E. Top.
Stereochem. 1969, 4, 39-97. (b) Zschunke, A. Moleku¨lstruktur; Spektrum
Akademischer Verlag: Heidelberg, 1993; pp 118-136.
(20) (a) Jursic, B. S. THEOCHEM 1999, 492, 285-291. (b) Van Speybroeck,
V.; Borremans, Y.; Van Neck, D.; Waroquier, M.; Wauters, S.; Saeys, M.;
Marin, G. B. J. Phys. Chem. A 2001, 105, 7713-7723. (c) Milet, A.;
Arnaud, R. J. Org. Chem. 2001, 66, 6074-6082.
(21) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
(22) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. 1998, B37, 785-789.
(23) Eyring, J. J. Chem. Phys. 1935, 3, 107-115.
(26) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-3941.
(27) Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J. Am.
Chem. Soc. 1985, 107, 3902-3909.
9
J. AM. CHEM. SOC. VOL. 126, NO. 38, 2004 12123

A R T I C L E S
Hartung et al.
Scheme 2. Presentation of the Reaction Model for a Computational Analysis on the Regioselectivity in 4-Penten-1-oxyl Radical Cyclizations
(Indexing for Radicals 1-3 and Transition Structures 12-15: a for R2 ) H, b for CH3, c for C(CH3)3, d for C6H5)24,25
Table 4. Computed Energies (E + ZPVE), Zero-Point Vibrational
Energies (ZPVE), S2 Values, and Relative Heats of Formation
(∆∆Hf) of Radicals 1-3a
parameter
1
2
3
1a f 2a + 3a
(R2 ) H)
E + ZPVEb -270.961 894 -270.977 889 -270.981 720
ZPVEc
S2
334.091
0.754
≡ 0
341.243
0.754
-42.0
3T4
345.696
0.754
-52.1
4C1
∆∆Hfd
conformere
f
1b f 2b + 3b
(R2 ) CH3)
E + ZPVEb -310.250 355 -310.267 820 -310.275 300
ZPVEc
S2
412.089
0.754
≡0
414.868
0.754
-45.9
2T3
419.858
0.754
-65.5
4C1
∆∆Hfd
conformere
f
1c f 2c + 3c
E + ZPVEb -428.101 774 -428.120 426 -428.127 387
[R2 ) C(CH3)3] ZPVEc
632.787
0.754
≡0
637.533
0.754
-49.0
5T1
644.378
0.754
-67.2
4C1
S2
∆∆Hfd
conformere
f
1d f 2d + 3d
(R2 ) C6H5)
E + ZPVEb -501.942 909 -501.950 292 -501.976 864
ZPVEc
S2
548.674
0.754
≡0
556.882
0.754
-19.4
3T4
562.431
0.777
-89.1
4C1
Figure 1. Ball and stick presentation of computed structures for the
4-phenyl-4-penten-1-oxyl radical (1d) and cyclization products 2d and 3d.
Oxygen atoms are depicted in red, carbon atoms, in gray, and hydrogen
atoms, in white.24,25
∆∆Hfd
conformere
f
a UB3LYP//6-31+G*//UB3LYP/6-31+G*. b E (not temperature cor-
rected) + ZPVE in au; 1 au ) 2625.50 kJ mol-1
.
c ZPVE in kJ mol-1
.
strain originating from a transit of the tert-butyl substituent past
both pseudoequatorially located neighboring hydrogen atoms.28
2. Equilibrium Conformations of Alkoxyl Radicals and
Cyclized Radicals. The computed geometries of alkoxy radicals
1a-d show the typical alignment of an oxy-functionalized
aliphatic chain that is terminated on one side by an olefinic π
bond. The 4-phenyl substituent in O-radical 1d is twisted out
d ∆∆Hf in kJ mol-1 (ZPVE-corrected). e For cyclization products 2 and 3.
f Open chain conformation; see Figure 1.1
from its derived silicon compounds do not interfere with signals
belonging to products from alkoxyl radical reactions thus
allowing us to determine reliable product ratios. In an additional
experiment, 2-methyl-5-(tert-butyl)tetrahydropyran 5g and 2-(tert-
butyl)-2,5-(dimethyl)tetrahydrofuran 4g have been prepared from
N-(alkenoxy)thiazolethione 9g and Bu3SnH. The formation of
tetrahydropyran trans-5g as major product (4g:5g ) 37:63, 49%
combined yield of analytically pure compounds, Supporting
Information) from the 6-endo-trig reaction of intermediate 1g
and subsequent hydrogen atom transfer onto cyclized radical
3g is in agreement with the well-known preference of alicyclic
six-membered radicals to furnish products of axial trapping in
homolytic substitution reactions (Scheme 3).28 A hydrogen atom
delivery from the opposite face gives rise to additional torsional
of a plane that is defined by C4, C5, and the ipso-carbon (Cipso
)
(40.25°, Figure 1), unlike the planar structure of R-methylstyrene
in the solid state.29 The heterocyclic core of 5-exo-trig cycliza-
tion products 2a-d adopts either a T4 (in 2a and 2b: CH2
•
3
3
substituent located in a pseudoequatorial position) or a T4
conformation [in 2c and 2d: C(CH3)3 or C6H5 in pseudoequa-
torial and CH2 in pseudoaxial location; Figure 1, Table 4).1,24,25
•
(28) This interpretation is based on results from an investigation on diastereo-
selective 4-tert-butyl cyclohexyl radical reactions: Damm, W.; Giese, B.;
Hartung, J.; Hasskerl, T.; Houk, K. N.; Hu¨ter, O.; Zipse, H. J. Am. Chem.
Soc. 1992, 114, 4067-4079.
(29) Bond, A. D.; Davies, J. E. Acta Crystallogr. 2002, E58, o331-o333.
9
12124 J. AM. CHEM. SOC. VOL. 126, NO. 38, 2004

4-Penten-1-oxyl Radical Cyclizations
A R T I C L E S
Table 5. Calculated Data, Boltzmann-Weighted Population P and Conformational Details of Transition Structures 12-151,24-26 a
12−15
data
12
13
14
15
a
E + ZPVEb
-270.954 669
-270.951 341
-270.951 861
-270.947 240
R2 ) H
ZPVEc
S2
338.988
0.779
19.0
338.628
0.779
27.7
340.895
0.773
26.3
339.852
0.776
38.5
∆∆Hfd
Ge
-270.984 621
-270.981 713
-270.981403
-270.977 204
∆Gf
≡0
7.6
8.4
19.5
P [%]g
conf.h
subst.i
E + ZPVEb
92.53
4.31
3.12
0.04
2T3
3T4
1C4
5TB3
bendo/bexo
-310.245 926
pe/pa
-310.243 446
j
j
b
-310.245 422
-310.241 082
R2 ) Me
ZPVEc
S2
412.214
0.777
11.6
412.073
0.774
18.1
414.274
0.770
13.0
413.588
0.773
24.3
∆∆Hfd
Ge
-310.277 574
-310.275 498
-310.277 121
-310.273 270
∆Gf
≡0
5.5
1.2
11.3
P [%]g
conf.h
subst.i
E + ZPVEb
57.62
6.27
35.51
0.60
2T3
3T4
4C1
5TB3
bendo/bexo
-428.097 226
pe/pa
-428.095 559
j
j
c
-428.098 425
-428.094 640
R2 ) tBu
ZPVE c
S2
636.696
0.775
11.9
636.310
0.774
16.3
639.339
0.769
8.8
638.221
0.772
18.7
∆∆Hfd
Ge
-428.132976
-428.132003
-428.134407
-428.131101
∆Gf
3.8
6.3
≡ 0
8.7
P [%]g
conf.h
subst.i
E + ZPVEb
16.30
5.95
75.50
2.26
2T3
3T4
4C1
5TB3
bendo/bexo
-501.933 851
pe/pa
-501.931 163
j
j
d
-501.937 365
-501.933 842
R2 ) Ph
ZPVEc
S2
551.986
0.779
23.8
552.161
0.776
30.8
554.894
0.770
14.6
554.440
0.774
23.8
∆∆Hfd
Ge
-501.970 808
-501.974 096
-501.974 096
-501.971 029
∆Gf
8.6
16.0
≡0
93.39
4C1
j
8.1
3.56
5TB3
j
P [%]g
conf.h
subst.i
2.91
0.15
2T3
3T4
bendo/bexo
pe/pa
a UB3LYP//6-31+G*//UB3LYP/6-31+G*. b E (not temperature corrected) + ZPVE in au; 1 au ) 2625.50 kJ mol-1 c ZPVE in kJ mol-1 d ∆∆Hf values
. .
(ZPVE-corrected) in kJ mol-1, referenced versus the associated alkenoxyl radical 1 (Table 4). e G (298.15) in au. f ∆G in kJ mol-1, referenced versus the
a
energetically lowest transition structure in each series of intermediates. g P [%] was calculated according to the to the following equation: Pa ) [(e-∆G /RT)/
(Σ4
e
)] × 100, where Pa denotes the percentrage contribution of a transition structure “a” to the formation of a cyclization product. h Classification
-∆Gi/RT
i)1
of the transition structure as a distorted tetrahydrofuran conformer (T ) twist conformer; E ) envelope conformer) or a distorted tetrahydropyran conformer
(C ) chair conformer, TB ) twist-boat conformer).24,25 i Arrangement of substituents in tetrahydrofuran-derived transition structures: R2/dCH2 (b )
bisectional, pa ) pseudoaxial, pe ) pseudoequatorial; the exo/endo-notation is referenced to the spatial arrangement of the terminal methylene group toward
tetrahydrofuran atom number 3; see also Figure 3). j Geometry defined by an approximately planar arrangement of atoms C3, C4, C5, and R2.
4
The 6-endo-trig cyclization products 3 exhibit C1 conforma-
tions. The flattening at C3 in tetrahydropyranyl radicals 3a-d
originates from the propensity of nucleophilic carbon radicals
to adopt a planar geometry (Figure 1, Table 4).30,31
4. Transition Structures, Activation Enthalpies, and Re-
gioselectivities. Regioselectivities in alkenoxyl radical ring
closure reactions have been deduced from a Boltzmann-weighted
population of the intermediates 12-15, which has in turn been
determined on the basis of ab initio computed ∆G (298.15)
values. To perform this analysis, simplifications have been made
that relate to temperature effects and the correlation between
data from the experiment with those from theory:
(i) Temperature effects: The effect of the reaction temperature
in the range of 20-80 °C on regioselectivities in alkenoxyl
radical cyclizations is in most instances smaller than the
experimental precision for elucidating such product distribu-
tions.3,5a,31,32 Therefore, calculated selectivities at 25 ° were
compared to experimental data that refer reaction temperatures
of 20 °C (for cyclizations of 1b, 1c, 1g) or 30 °C (for
cyclizations 1a, 1d-f).
3. Reaction Enthalpies. DF theory predicts that 5-exo-trig
cyclizations of 4-penten-1-oxyl radicals 1 are -42 to -49 kJ
mol-1 exothermic for 4-H, 4-CH3-, and 4-C(CH3)3-substituted
intermediates 1a-c (Table 4). The 5-exo-trig reaction of the
4-phenyl-4-pentenoxyl radical 1d is less exothermic (-19 kJ
mol-1), since the O-radical addition step is associated with a
loss of the R-methylstyrene-type stabilization of the olefinic π
bond. The reaction enthalpy for 6-endo-trig reactions decreases
along the series of cyclizations 1af3a (-52 kJ mol-1) <
1bf3b (-66 kJ mol-1) ≈ 1cf3c (-67 kJ mol-1) < 1df3d
(-89 kJ mol-1). This sequence is considered to reflect the ability
of a substituent at C3 to stabilize heterocyclic radicals 3b-d
via either hyperconjugation (3b, 3c) or mesomeric interactions
(3d).31
(ii) Correlation between theory and experiment: Trapping
of structurally simple primary, secondary, and tertiary alkyl
radicals with either (H9C4)3SnH or [(H3C)3Si]3SiH proceeds with
(30) Leffler, J. E. An Introduction to Free Radicals; Wiley: New York, 1993.
(31) Beckwith, A. L. J.; Moad, G. J. Chem. Soc., Chem. Commun. 1974, 472-
473.
(32) Gottwald, T.; Greb, M.; Hartung, J. Synlett 2004, 65-68.
9
J. AM. CHEM. SOC. VOL. 126, NO. 38, 2004 12125

A R T I C L E S
Hartung et al.
Table 6. Geometrical Parameters for Description of Transition
Structures 12 and 13 (5-exo-Reaction, Left) and 14 and 15
(6-endo-Cyclization, Right)a
12−15
parameter
12
13
14
15
a
r1 [Å]
2.050
2.086
2.538
2.599
R2 ) H
r2 [Å]
r3 [Å]
φ [deg]
2.644
1.377
99.14
2.654
1.373
98.09
2.060
1.370
93.26
2.036
1.373
97.48
δ1 [deg] 174.14
174.84
166.18
2.105
165.11
162.42
2.558
162.95
165.30
2.615
δ2 [deg] 162.17
b
r1 [Å]
2.066
R2 ) CH3
r2 [Å]
r3 [Å]
φ [deg]
2.571
1.381
94.37
2.583
1.377
93.43
2.067
1.373
93.91
2.045
1.374
97.84
δ1 [deg] 173.94
175.15
164.15
2.118
165.00
166.22
2.578
163.00
168.05
2.614
δ2 [deg] 161.31
c
r1 [Å]
2.078
R2 ) C(CH3)3
Figure 2. UB3LYP/6-31+G*-optimized geometries of transition structures
12d-15d for cyclization of the 4-phenyl-4-penten-1-oxyl radical (1d) (see
also Figure 1). Oxygen atoms are depicted in red, carbon atoms, in gray,
and hydrogen atoms, in white.1,24,25
r2 [Å]
r3 [Å]
φ [deg]
2.519
1.383
91.14
2.539
1.38
90.55
174.49
161.41
2.066
2.086
1.373
94.10
165.99
172.27
2.624
2.047
1.375
97.69
163.40
170.88
2.659
δ1 [deg] 173.78
δ2 [deg] 159.51
Scheme 3. Formation of Tetrahydropyran trans-5g from
6-endo-trig-Cyclized Radical 3g
d
r1 [Å]
2.013
R2 ) C6H5
r2 [Å]
r3 [Å]
φ [deg]
2.574
1.392
95.12
2.537
1.384
92.53
2.189
1.370
92.05
2.134
1.371
96.24
δ1 [deg] 174.39
δ2 [deg] 158.57
173.36
161.74
171.19
171.11
165.98
172.27
a r1 ) O-C4; r2 ) O-C5; φ ) O-C4-C5; δ1 ) C4-C5-Ha-Hb;
δ2 ) C5-C4-C3-R2.
Table 7. Experimental and Calculated Regioselectivities in
Cyclizations of 4-Penten-1-oxyl Radicals 1a-d
a similar efficiency. Therefore, it is reasonable to directly
compare relative yields of heterocycles 4 versus 5 (experiment)
to regioselectivies for the formation of derived radicals 2 and 3
(theory) (Table 7).33,34
(a) Conformational Aspects of Calculated Transition
Structures. Two transition structures have been located on the
potential energy surface of alkenoxyl radicals 1a-d for each
mode of ring closure. Intermediates 12-15 are considered to
represent the most significantly populated transition structures
for 5-exo- and 6-endo-trig cyclization for the following reasons:
(i) If classified as distorted conformers of tetrahydrofuran and
tetrahydropyran, intermediates 12-15 represent either low-
energy conformers (the twist tetrahydrofuran conformer 2T3 or
4:5
2:3
entry
1
R1
R2
(experiment)
(theory)
1
2
3
4
a
b
c
H
H
H
H
H
98:2a
97:3
CH3
C(CH3)3
C6H5
69:31b
46:54b
7:93a
64:36
22:78
2:97
d
the twist-boat conformer TB5 for tetrahydropyran) or global
3
a Reaction temperature 30 °C. b Reaction temperature ) 20 °C; H-Y
) H-Sn(C4H9)3 or H-Si[Si(CH3)]3.
minima (3T4 for tetrahydrofuran and the chair conformation 1C4
for tetrahydropyran).24,25,35-38 The fact that a T3 conformer
2
(Figure 3) is consistently favored over a T4 arrangement is
3
(33) (a) Hartung, J.; Gottwald, T.; Kneuer, R. Synlett 2001, 749-752. (b) Kneuer,
R. Diploma Thesis, Universita¨t Wu¨rzburg, 1996.
(34) Chatgilialoglou, C. In Radicals in Organic Synthesis; Renaud, P., Sibi, M.
P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 28-49.
(35) The atom count changes by +1 in going from a 4-penten-1-oxyl radical
(i.e., numbering of carbon atoms) to the corresponding 5-exo-trig cycliza-
tionproduct or a tetrahydrofuran-derived transition structure, since the
Hantzsch-Widman convention applies for all conformers with a hetero-
cyclic core (i.e., oxygen has a higher priority than carbon).
(36) A twist-like transition structure has recently been observed in a 5-exo-trig
cyclization of an an acetal-derived alkyl radical: Corminboef, O.; Renaud,
P.; Schiesser, C. H. Chem.sEur. J. 2003, 9, 1578-1584.
(37) (a) Sˇtrajbl, M.; Floria´n, J. Theor. Chem. Acc. 1998, 99, 166-170. (b) Han,
J. S.; Kang, Y. K. THEOCHEM 1996, 363, 157-165.
(38) Freeman, F.; Kasner, J. A.; Kasner, M. L.; Hehre, W. J. J. THEOCHEM
2000, 496, 19-39.
9
12126 J. AM. CHEM. SOC. VOL. 126, NO. 38, 2004

4-Penten-1-oxyl Radical Cyclizations
A R T I C L E S
Figure 3. Atom count in alkoxyl radical 1a and tetrahydrofuran-derived
transition structures (2T3 conformers) 12a (bexo arrangement of the dCH2
group) and 13a (bendo positioning of the dCH2 group) for the 5-exo-trig
mode of cyclization.35
Figure 4. Transition structure 16 for the methoxyl radical addition to
propene (UB3LYP/6-31+G*//UB3LYP/6-31+G*). φ ) O-C1-C2 )
103.06°.44,45
thought to originate from a combination of strain and stereo-
electronic effects. Thus, the favored path for O-radical addition
to an olefinic π-bond proceeds along a Bu¨rgi-Dunitz-type
trajectory.39 The computed angle O-C4-C5 ) 99.14° (for 1a,
Table 6) is smaller than the expected value of ∼120°. The
restricted chain length of the alkenoxyl radical causes the
approach of the O-radical center onto C4 to follow a path that
leads to an E3 arrangement, which relaxes via minor confor-
mational changes into the less strained 2T3-configured interme-
diate 12.
(entry 3, Table 7), these values agree remarkably well with the
ratios of the corresponding cyclic ethers that have been measured
experimentally. The correlation of the experimental and the
computed regioselectivity for cyclization of 4-(tert)-butyl-
substituted 4-penten-oxyl radicals 1c and 1g (for 1g: 4:5 )
37:63) still is satisfactory, in particular due to the fact that the
selected method is able to reproduce the reversal in the 5-exo-
trig selectivity toward tetrahydropyran formation adequately.
5. Origin of the 6-endo-trig Selectivity in Cyclizations of
4-Penten-1-oxyl Radicals. The addition of the methoxyl radical
to propene41 serves as an archetype for alkoxyl radical additions
to olefins in general, since no conformational restraints are
imposed by a hydrocarbon backbone that links the reacting
entities. According to results from UB3LYP/6-31+G* calcula-
tions, the O-radical approaches the olefin at C1 with its methyl
entity oriented into a direction opposite to the (Z)-arranged
hydrogen Ha (Figure 4, Supporting Information). The sum of
Mulliken charges for the H3CO entity in intermediate 16 is
-0.16 (likewise +0.16 for the propene subunit), which points
to electrophilic properties of the O-radical center in the addition
reaction. The distance C1,O ) 2.078 Å in transition structure
16 is comparable to C,O values obtained for energetically lowest
transition structures in alkenoxyl radical cyclizations (e.g., 2.050
Å for 12a, 2.067 Å for 14d). The angle O-C1-C2 ) 103.06°
of O-radical attack onto the π bond is consistently larger than
that for the investigated cyclizations (e.g., 99.14° for 12a, 92.05°
for 14d). The O-radical approach to the π bond leads to minor
geometrical changes, such as orientation of substituents at C2
toward the incoming radical, whereas hydrogen atoms located
at C1 move into the opposite direction (δ1 ) C2-C1-Hb-Ha
) 163.36 °, δ2 ) C1-C2-CH3-Hc ) 175.53°). The magnitude
and the signs of torsion angles δ1 and δ2 agree with the
corresponding values of energetically favored transition struc-
tures in 4-penten-1-oxyl radical cyclizations (e.g., 162.17° and
174.14° for 12a, 171.19° and 171.11° for 14d).
(ii) The positioning of substituents in transition structures 12-
13 for the 5-exo-trig mode of cyclization follows the trend that
the dCH2 group prefers an exo-bisectional position (hereafter
bexo), if R2 ) H, CH3 (Figure 3).40 In the case of R2 ) C(CH3)3,
C6H5, the dCH2 group is located in the endo-bisectional
(hereafter bendo) and the larger substituent in bexo arrangement.
The positioning of substituents in transition structures 14-15
from the 6-endo-trig reactions is governed by a virtually planar
configuration of the olefinic subunits at that stage of the reaction.
(b) Activation Enthalpies. The computed activation enthal-
pies ∆∆H‡ for 5-exo-trig cyclizations of 1a-1c via 2T3-arranged
transition structures 12a-c (∆∆H‡ ) 19 kJ mol-1 for 1a, 12
kJ mol-1 for 1b and 1c) are smaller than the value obtained for
the 4-phenyl-4-pentenoxyl radical 1d (∆∆H‡ ) 24 kJ mol-1).
The enthalpic barrier is consistently larger for the alternative
5-exo-trig pathway that proceeds via T4-arranged transition
3
structures 13a-d (∆∆H‡ ) 28 kJ mol-1 for 1a, 18 kJ mol-1
for 1b, 16 kJ mol-1 for 1c, 31 kJ mol-1 for 1d). Similar
differences were noted for the two 6-endo-trig routes. Reactions
4
that proceed via C1-arranged intermediates 14a-d (∆∆H‡ )
26 kJ mol-1 for 1a, 13 kJ mol-1 for 1b, 9 kJ mol-1 for 1c, 15
kJ mol-1 for 1d) are characterized by lower activation enthalpies
than those which occur via the twist-boat-derived transition
structures 15a-d (∆∆H‡ ) 39 kJ mol-1 for 1a, 24 kJ mol-1
for 1b, 19 kJ mol-1 for 1c, 24 kJ mol-1 for 1d). A comparison
of activation enthalpies from competing reaction channels points
to comparatively low barriers for 6-endo-trig cyclizations of the
4-(tert-butyl)-4-penten-1-oxyl radical 1c and its 4-phenyl deriva-
tive 1d via 4C1-arranged transition structures 14c and 14d. This
observation is in agreement with the kinetic effect that favors
formation of tetrahydropyran 5d from intermediate 1d in the
experiment.5a
The comparison between intermediate 16 and 2T3-configured
transition structure 12a (5-exo-trig reaction) and the 4C1-arranged
intermediate 14d (6-endo-trig cyclization) indicates that stereo-
electronic requirements for the addition reaction are fulfilled
in either mode of cyclization. The notable preference for 5-exo-
trig ring closure of radical 1a therefore is considered to originate
from strain that is imposed by the alkenoxyl chain, when
adopting the energetically disfavored transition structure 14a
(6-endo-trig pathway). Parts of these unfavorable contributions
arise from a minor but significant structural change that occurs
within the olefinic subunit during the O-radical encounter. In
(c) Regioselectivities in Alkenoxyl Radical Ring Closures.
The computed regioselectivities point to an increasing preference
for formation of the 6-endo-trig cyclization product 3 along the
series of radicals 1a (2a:3a ) 97:3), 1b (2b:3b ) 64:36), 1c
(2c:3c ) 22:78), and 1d (2d:3d ) 3:97). With one exception
(39) Kirby, A. J. Stereoelectronic Effects; Oxford University Press: New York,
1996.
(40) Bogner, J.; Duplan, J.-C.; Infarnet, Y.; Delmut, J.; Huet, J. Bull. Chim.
Soc. Fr. 1972, 3616-3624.
(41) Houk, K. N.; Paddon-Row, M. N.; Spellmeyer, D. C.; Rondan, N. G.;
Nagase, S. J. Org. Chem. 1986, 51, 2874-2879.
9
J. AM. CHEM. SOC. VOL. 126, NO. 38, 2004 12127

A R T I C L E S
Hartung et al.
an early phase of the addition, R2 ) H moves toward the oxygen
atom, where it is still located in transition structure 14a (δ2 )
166.18°). Upon shortening of the C,O distance and thus
formation of the 6-endo-trig cyclization product 3a, the geometry
at C4 gradually changes from almost planar with respect to C5,
R2, Ha, Hb to approximately planar with respect to C3,C5, R2
(for 3d see Figure 2). This structural change requires a transit
of R2 past Ha and the proximate hydrogen atom at C3, which
gives rise to van der Waals repulsions. Similar steric interactions
are not present in intermediates 12 and 13 thus providing an
interpretation for the preferred 5-exo-trig cyclization of 4-pen-
tenoxyl radicals 1a (R2 ) H) and 1b (R2 ) CH3).
The fact that alkoxyl radicals 1c [R2 ) C(CH3)3] and 1d (R2
) C6H5) prefer the 6-endo-trig mode of ring closure requires a
free activation enthalpy lowering contribution from R2, to
compensate the unfavorable torsional strain that is imposed by
the substituent in transition structures 14 and 15. Intramolecular
O-radical additions are fast and strongly exothermic reactions
with their transition states located early on a reaction coordin-
ate.3,42-45 Thus, frontier molecular orbital (FMO) theory may
be applied in order to analyze selectivities of the underlying
addition reactions.46 Since O-radicals exhibit electrophilic
properties in addition reactions (see above),47 the most signifi-
cant stabilizing contribution in the C,O bond forming transition
state should arise from interactions between the radical center
(SOMO) and the HOMO, the π-type orbital in alkenoxyl radicals
1. An orbital analysis indicates that the SOMO-HOMO energy
gap for radicals 1a-1d is similar. A change, however, is seen
in the relative size of the HOMO coefficient at C5, which
increases relative to C4 along the series of radicals 1a (+7%),
1b (+18%), 1c (+19%) to +47% for the 4-phenyl-4-pentenoxyl
radical 1d (Figure 5). The relative increase of the HOMO
coefficient at C5 correlates with the propensity of an alkenoxyl
radical to undergo the 6-endo-trig cyclization. In view of these
arguments, the origin of the 6-endo-selectivity in 4-penten-1-
oxyl radical cyclizations may be summarized as follows:
(i) Substituents that increase the HOMO coefficient at C5
(i.e., the terminal atom of the π bond) direct 4-penten-1-oxyl
cyclizations into the 6-endo-trig reaction channel.
Figure 5. Presentation of HOMOs (left) and SOMOs (right) of alkoxyl
radicals 1b (top) and 1d (bottom) (UB3LYP/6-31+G*).
butyl-substituted 4-penten-1-oxyl radicals 1c and 1g furnish
tetrahydropyrans 5c and 5g as major products.
(ii) Regioselectivities in 4-penten-1-oxyl radical cyclizations,
which were calculated from a Boltzmann-weighted population
of two energetically lowest and therefore most significantly
populated transition structures per mode of ring closure, agree
qualitatively and quantitatively with the experimental data.
(iii) The propensity of the 4-(tert-butyl)-4-pentenoxyl radical
1c and the 4-phenyl derivative 1d to undergo 6-endo-trig-
selective cyclizations has been attributed to favorable FMO
interactions between the terminal carbon atom of the π bond
and the O-radical center thus favoring the 6-endo-trig reaction
on the basis of lower transition state energies.
Experimental Section
Instrumentation and general remarks have been disclosed previously
(see also Supporting Information).7a
1. Synthesis of Thiohydroxamic Acid O-Esters: General Proce-
dure. A flame-dried round-bottomed flask was charged with anhydrous
DMF and an equimolar amount of N-hydroxy-4-(p-chlorophenyl)-
thiazole-2(3H)-thione tetraalkylammmonium salt 6 or 711 and alkenyl
tosylate 8. The solution was stirred in an atmosphere of argon for 4-7
d at 20 °C in the dark. Afterward, the reaction mixture was poured
into water (40 mL) and extracted with Et2O (2 × 40 mL). The combined
organic phases were washed with 2 N NaOH (30 mL) and dried
(MgSO4). The solvent was removed in vacuo to afford a brown oil,
which was purified by column chromatography (SiO2).
N-(4-Methyl-4-penten-1-oxy)-4-(p-chlorophenyl)thiazole-2(3H)-
thione (9b). Thiazolethione 9b was prepared from 4-methyl-4-penten-
1-yl p-toluenesulfonate (8b)12 (661 mg, 2.60 mmol) and N-hydroxy-
4-(p-chlorophenyl)thiazole-2(3H)-thione tetrabutylammonium salt (6)
(1.39 g, 2.87 mmol) in anhydrous DMF (3 mL) as described above.
The crude product was purified by column chromatography [SiO2,
petroleum ether/Et2O ) 1:1 (v/v)] to afford 570 mg (67%) of
thiazolethione 9b as a colorless solid: mp 68 ( 2 °C (DTA). 1H NMR
(250 MHz): δ ) 1.61 (s, 3 H, CH3), 1.71 (mc, 2 H, 2-H), 1.95 (dd, 2
H, J ) 7.0, 8.2 Hz, 3-H), 4.07 (t, 2 H, J ) 6.7 Hz, 1-H), 4.51 (s, 1 H,
5-H), 4.64 (s, 1 H, 5-H), 6.51 (s, 1 H, 5′-H), 7.45 (d, 2 H, J ) 8.9 Hz,
ArH), 7.54 (d, 2 H, J ) 8.9 Hz, ArH). 13C NMR (63 MHz): δ ) 22.2,
25.4, 33.3, 76.0, 105.4, 110.3, 126.6, 129.1, 129.6, 136.3, 139.8, 144.1,
180.6. MS (70 eV, EI): m/z (%) ) 325 (2) [M+], 227 (18) [C9H6-
ClNS2], 168 (19) [C8H5ClS+], 41 (100) [C3H5+]. IR: ν ) 3099, 2942,
(ii) If the coeffiecients of the two C atoms that describe the
olefinic π bond are approximately equal in size, 4-penten-1-
oxyl radicals preferentially undergo 5-exo-trig ring closures
because the competing 6-endo-trig reaction is disfavored on the
basis of strain effects.
Conclusions
Three major results have been obtained in a combined
experimental and computational study (density functional theory)
on the 6-endo-selectivity in cyclizations of 4-substituted 4-pen-
tenoxyl radicals 1:
(i) Upon cyclization and subsequent trapping with the reactive
hydrogen atom donors (H9C4)3SnH or [(H3C)3Si]3SiH, 4-tert-
(42) Howard, J. A.; Scaiano, J. C. In Kinetische Daten Von Radikalreaktionen
in Lo¨sung - Oxyl, Peroxyl und Verwandte Radikale in Landolt-Bo¨rnstein,
Zahlenwerte und Funktionen aus Naturwissenschaft und Technik, New
Series Part D.; Fischer, H., Ed.; Springer: Berlin, 1984; Vol. 13, pp 1-127.
(43) Rothenberg, G.; Sasson, Y. Tetrahedron 1998, 54, 5417-5422.
(44) Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334-338.
(45) (a) Bell, R. P. Proc. R. Soc. London, 1936, 154A, 414. (b) Evans, M. G.;
Polanyi, Trans. Faraday Soc. 1938, 34, 11.
(46) Fleming, I. Grenzorbitale und Reaktionen organischer Verbindungen;
Wiley-VCH: Weinheim, 1990.
(47) Jones, M. J.; Moad, G.; Rizzardo, E.; Solomon, D. H. J. Org. Chem. 1989,
54, 1607-1611.
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12128 J. AM. CHEM. SOC. VOL. 126, NO. 38, 2004

4-Penten-1-oxyl Radical Cyclizations
A R T I C L E S
1487, 1334, 1216, 1162, 1093, 1052, 1018, 976, 932, 890, 835, 761
cm-1. Anal. Calcd for C15H16ClNOS2 (325.89): C, 55.28; H, 4.95; N,
4.30; S, 19.68. Found: C, 55.31; H, 4.72; N, 4.32; S, 19.54.
135.9, 141.6, 156.9, 181.1. IR: ν ) 3060, 2940, 2840, 1610, 1580,
1470, 1390, 1370, 1350, 1300, 1200, 1140 cm-1. MS (70 eV, EI): m/z
(%) ) 243 (1) [C9H5ClNS2O+], 227 (3) [C9H5ClNS2], 155 (3)
[C10H19O+], 97 (35) [C7H13+]. Anal. Calcd for C19H24ClNOS2
(381.99): C, 59.74; H, 6.33; N, 3.67; S, 16.79. Found: C, 59.91; H,
6.42; N, 3.65; S, 16.60.
N-[4-(1,1-Dimethyl-1-ethyl)-4-penten-1-oxy]-4-(p-chlorophenyl)-
thiazole-2(3H)thione (9c). Thiazolethione 9c was obtained from 4-(2-
methyl-2-propyl)-4-penten-1-yl p-toluenesulfonate (8c)13 (131 mg, 0.440
mmol) and N-hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thione tet-
rabutylammonium salt (6) (181 mg, 0.484 mmol) in anhydrous DMF
(1 mL) as described above. Purification of the crude product by column
chromatography (SiO2, CH2Cl2) afforded 115 mg (71%) of product 9c
as a colorless solid: mp 102-103 °C. 1H NMR (250 MHz): δ ) 0.99
(s, 9 H, CH3), 1.67-1.79 (m, 2 H, 2-H), 1.97 (dd, 2 H, J ) 6.4, 8.9
Hz, 3-H), 4.11 (t, 2 H, J ) 6.4 Hz, 1-H), 4.51 (s, 1 H, 5-H), 4.80 (s,
1 H, 5-H), 6.55 (s, 1 H, 5′-H), 7.45 (d, 2 H, J ) 8.9 Hz, ArH), 7.54 (d,
2 H, J ) 8.9 Hz, ArH). 13C NMR (63 MHz): δ ) 26.8, 27.1, 29.2,
36.1, 76.5, 105.4, 106.0, 126.6, 129.1, 129.6, 136.3, 139.9, 156.5, 180.6.
2. Photolysis of N-(Alkenoxy)thiazole-2(3H)-thiones 9 in the
Presence of Reactive Hydrogen Atom Donors (1H NMR Analysis).
A Schlenk flask was charged with a solution of N-alkenoxy-4-(p-
chlorophenyl)thiazole-2(3H)-thione 9 in C6D6 in the dark. A defined
amount of anisole (internal standard) was added, and the flask was
sealed with a rubber septum and cooled to liquid-nitrogen temperature.
After thorough evacuation (10-2 mbar), the flask was flushed with
argon. [(H3C)3Si]3SiH (Fluka) was added via a syringe. The reaction
mixture was deaerated by means of two freeze-pump-thaw cycles
(Ar was used as flushing gas) and was subsequently warmed in a water
bath to 20 °C. The colorless solution was photolyzed for 25 min in a
Rayonet chamber photoreactor (λ ) 350 nm) and was immediately
IR: ν ) 3081, 2967, 1336, 1158, 1092, 1053, 976, 886, 831, 764 cm-1
.
MS (70 eV, EI): m/z (%) ) 243 (39) [C9H6ClNOS2], 227 (27) [C9H6-
ClNS2], 168 (27) [C8H5ClS+], 83 (87) [C6H11+], 55 (100) [C4H7+]. Anal.
Calcd for C18H22ClNOS2 (367.96): C, 58.76; H, 6.03; N, 3.81; S, 17.43.
Found: C, 58.29; H, 6.22; N, 3.77; S, 17.37.
1
analyzed by H NMR.
Acknowledgment. In memory of Dr. Anne Giese-Ghosez.
This work was generously supported by the Deutsche Fors-
chungsgemeinschaft (Funds Ha1705/5-1 and 5-2) and the Fonds
der Chemischen Industrie.
N-[5-(1,1-Dimethyl-1-ethyl)-5-hexen-2-oxy]-4-(p-chlorophenyl)-
thiazole-2(3H)thione (9g). Thiazolethione 9g was prepared from 5-(1,1-
dimethyl-1-ethyl)-5-hexen-2-yl p-toluenesulfonate (8g) (289 mg, 0.931
mmol) and N-hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thione tetra-
ethylammonium salt (7) (386 mg, 1.04 mmol) in anhydrous DMF (3
mL) as described above. Purification of the crude product was achieved
by column chromatography [SiO2, petroleum ether/Et2O ) 3:1 (v/v)]
to afford 226 mg (64%) of thiazolethione 9g as a colorless solid: mp
Supporting Information Available: Detailed experimental
procedure for the synthesis of thiazolethione 9g, spectral data
and characterization of tetrahydrofurans 4 and tetrahydropyrans
5, atomic coordinates of radicals 1-3 and intermediates 12-
15, transition structure 16, and UHF/6-31+G* computed
energies and geometrical parameters of radicals 1-3 and
intermediates 12-15 (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
1
56 ( 2 °C (DTA). H NMR (250 MHz): δ ) 0.96 (d, 3 H, J ) 6.4
Hz, 1-H), 1.01 (s, 9 H, CH3), 1.35-1.52 (m, 1 H, 3-H), 1.64-1.79 (m,
1 H, 3-H), 2.03 (mc, 2 H, 4-H), 4.49 (s, 1 H, 6-H), 4.80 (s, 1 H, 6-H),
5.05 (mc, 1 H, 2-H), 6.51 (s, 1 H, 5′-H), 7.44 (d, 2 H, J ) 8.9 Hz,
Ar-H), 7.51 (d, 2 H, J ) 8.9 Hz, Ar-H). 13C NMR (100 MHz): δ )
18.0, 26.3, 29.2, 33.7, 36.1, 82.6, 105.2, 105.9, 127.4, 129.0, 129.9,
JA049010G
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J. AM. CHEM. SOC. VOL. 126, NO. 38, 2004 12129