Alkenoxyl Radical 6-exo-trig Cyclizations
Table 1. Formation of tetrahydropyrans 3a and 11 from (tetrahydropyran-2-yl)-2-propanols 9.
Entry
(Ϯ)-9/
BrCCl3/
Conversion[a]
(Ϯ)-3a/%
(Ϯ)-11/%
(cis/trans ratio)[b]
(cis/trans ratio)[b]
1
2
3
4
cis-9/8.3ϫ10–3
cis-9/8.3ϫ10–4
trans-9/8.3ϫ10–3
trans-9/8.3ϫ10–4
8.3ϫ10–2
8.3ϫ10–3
8.3ϫ10–2
8.3ϫ10–3
87 %
49 %
77 %
75 %
58 (Ͼ 99:1)
34 (Ͼ 99:1)
27 (Ͻ 1:99)
13 (Ͻ 1:99)
7 (Ͼ 99:1)
8 (Ͼ 99:1)
12 (Ͻ 1:99)
8 (Ͻ 1:99)
[a] Referenced vs. unreacted alcohol 9. [b] Stereochemical analysis was performed via GC of crude reaction mixtures using authentic
1
samples as reference, H NMR, and NOESY investigations of purified products.
decomposition of mixed oxalates 10 (c0 = 8ϫ10–3 to notably stretched (ca. 2.1 Å)[16] C,O-bond, similar to the
8ϫ10–4 ) afforded derived tertiary carbon radicals,[14,15] scenario outlined in the heuristic chair-E model[6] for car-
i.e. cis-2a (from cis-10) and trans-2a (from trans-10). Radi- bon radical 6-exo-trig cyclizations. Sterically demanding
cals cis-2a and trans-2a, respectively, were trapped with an phenyl groups are considered to preferentially adopt sites
at least 10-fold excess of BrCCl3 (c0 = 8ϫ10–2 to that are similar to equatorial positions in tetrahydropyran.
8ϫ10–3 ). The former reaction afforded cis-3a (cis/trans Ͼ In extension to results from a theoretical treatment of the
99:1), olefin cis-11, and minor amounts of unreacted 4-penten-1-oxyl radical ring closure[16] it is furthermore ex-
alcohol cis-9, starting from cis-9 (Table 1, entries 1–2). In a pected that the isopropylidene entity resides in a location,
similar manner trans-3a (cis/trans Ͻ 1:99), olefin trans-11, where it experiences least severe synclinal interactions, i.e.
and unspent substrate trans-9 were obtained, if trans-9 equatorial-like, in order to adhere with the tetrahydropyran
served as starting material (Table 1, entries 3–4). 6-Methyl- notation (Scheme 5). A gradual decrease in stereodirecting
1-phenylhept-5-en-1-ol and/or 6-methyl-1-phenylhept-5-en- effect as the distance between reacting entities increases (1a
1-one were detected (GC) in neither of the runs.
Ͼ 1b Ͼ 1c), and estimated ∆∆G‡ values of 1.8–5.6 kJmol–1
According to results from stereochemical analysis, ring (ca. 80 °C) for stereodifferentiating processes are in accord
opening reactions cis-2aǞ1a and trans-2aǞ1a were not with this interpretation.[16]
relevant under selected conditions. This argumentation is
based on the stereochemical integrity within both tetra-
hydropyran series (cis and trans isomers). Observed dia-
stereoselectivities of product 3a, and presumably also of de-
Concluding Remarks
The use of transition structures as mnemonic device for
interpreting and predicting stereoselecitivity in the investi-
gated type of alkenoxyl radical 6-exo-trig cyclization is ex-
pected to serve as impetus for application of the method in
stereoselective synthesis, possibly by increasing efficiency of
tetrahydropyran synthesis using polar substituents other
than CH3 attached to the terminal position of the vinyl en-
tity. From what is known in 4-penten-1-oxyl radical chemis-
try it is expected that substitution at this site will change
rates but not facial selectivity of intramolecular alkoxyl rad-
ical additions.[17,18] The motivation for pursuing this chem-
istry originates from unique selectivity of 5-hexen-1-oxyl
radicals. Ionic bromocyclizations of ω,ω-dimethyl-substi-
tuted hex-5-en-1-ols (not shown), for example, will not pre-
fer the 6-exo-mode of ring closure.[19,20]
rivatives 3b–c, thus originated from kinetically controlled
reactions. Since 5-hexen-1-oxyl radicals are neutral interme-
diates, their chains are expected to fold upon an approach
of reacting entities in a chair-like manner, for minimizing
strain and steric repulsion. The underlying transition struc-
ture that is formed in this scenario is expected to resemble a
1
distorted C4-conformation of tetrahydropyran having one
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures, characterization data of
compounds 3–6.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) (Grant Ha1705/5-2).
Scheme 5. Transition structure-based stereochemical model for pre-
dicting major product formation in 6-exo-trig cyclizations of sub-
stituted 5-hexen-1-oxyl radicals 1a–c [1C4 denotes the chair confor-
mation of distorted tetrahydropyran, with atoms 1 (O) and 4 (C)
offset in opposite direction from the tetrahydropyran plane; letters
printed in italics refer to positioning of substituent R1–R3 = H or
Ph (first descriptor) and isopropylidene substituent (second de-
scriptor)].
[1] J. Hartung, T. Gottwald, Tetrahedron Lett. 2004, 45, 5619–
5621.
[2] M. P. Bertrand, J. M. Surzur, M. Boyer, M. L. Mihailovic´, Tet-
rahedron 1979, 35, 1365–1372.
[3] R. D. Rieke, B. J. A. Cooke, J. Org. Chem. 1971, 36, 2674–2677.
Eur. J. Org. Chem. 2009, 797–800
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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