Regioselectivity in the ring opening of 2-phenyl-1,3-dioxan-2-yl radicals derived from cyclic benzylidene acetals and comparison with deoxygenation of a carbohydrate diol via its cyclic thionocarbonate

Article abstract of DOI:10.1016/S0040-4039(01)00540-8

Ring-opening β-scission of monocyclic 2-phenyl-1,3-dioxan-2-yl radicals gives preferentially the more stabilised alkyl radical. However, analogous bicyclic radicals derived from two 4,6-O-benzylidene glucopyranosides afford primary radicals in preference to secondary radicals, a result that can be rationalised with the aid of DFT calculations. The report by Barton and Subramanian, that the opposite regioselectivity results from the tin hydride mediated reductive ring-opening of a corresponding glucosidic thionocarbonate, is shown to be in error.

Full text of DOI:10.1016/S0040-4039(01)00540-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3663–3666
Regioselectivity in the ring opening of 2-phenyl-1,3-dioxan-2-yl
radicals derived from cyclic benzylidene acetals and comparison
with deoxygenation of a carbohydrate diol via its cyclic
thionocarbonate
Brian P. Roberts* and Teika M. Smits
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
Received 15 February 2001; accepted 29 March 2001
Abstract—Ring-opening b-scission of monocyclic 2-phenyl-1,3-dioxan-2-yl radicals gives preferentially the more stabilised alkyl
radical. However, analogous bicyclic radicals derived from two 4,6-O-benzylidene glucopyranosides afford primary radicals in
preference to secondary radicals, a result that can be rationalised with the aid of DFT calculations. The report by Barton and
Subramanian, that the opposite regioselectivity results from the tin hydride mediated reductive ring-opening of a corresponding
glucosidic thionocarbonate, is shown to be in error. © 2001 Elsevier Science Ltd. All rights reserved.
We have reported recently1 that cyclic benzylidene
acetals derived from 1,2- and 1,3-diols undergo an
efficient radical-chain redox rearrangement to give ben-
zoate esters, in the presence of a thiol that acts as a
protic polarity-reversal catalyst.2 For example, in the
presence of 2,2-di-tert-butylperoxybutane (DBPB) as
initiator and tert-dodecanethiol or tri-tert-butoxysi-
lanethiol (TBST) as catalyst in refluxing octane (inter-
nal temperature ca. 130°C), the 1,3-dioxane 1 is
converted almost quantitatively into the benzoate esters
2 and 3 in the ratio 87:13.1,3 The propagation stage of
the chain mechanism is illustrated in Scheme 1 for the
unsubstituted 2-phenyl-1,3-dioxane and the selective
formation of the benzoate 2 results from the preference
of the intermediate 2-phenyl-4-methyl-1,3-dioxan-2-yl
radical to undergo b-scission to yield the more sta-
bilised secondary alkyl radical. Similarly, redox rear-
rangement of 4 gives 6 almost exclusively (6:5=99:1),
because the intermediate dioxanyl radical cleaves to
give a tertiary, rather than a secondary, alkyl radical.
Thus, the regioselectivity of the ring-opening b-scission
of these monocyclic 2-phenyl-1,3-dioxanyl radicals
reflects the stability of the alkyl radical formed.
However, under similar conditions in refluxing octane–
chlorobenzene the bicyclic 4,6-O-benzylidene glucoside
7 yielded mainly the 6-deoxybenzoate 8, resulting from
b-scission to give the less stabilised primary C6-centred
radical, along with only a small amount of the 4-deoxy-
benzoate 9 (8:9=97:3).1 We have now obtained com-
parable results with the 2,3-di-O-methylated analogue
10, which gives the benzoates 11 and 12 in the ratio
93:7, again reflecting contra-thermodynamic b-scission
of the intermediate bicyclic 2-phenyl-1,3-dioxanyl radi-
O
O
Ph
H
BzO
XS
XSH
XSH
O
O
BzO
Ph
R
R
O
O
R
Ph
H
R
R
Scheme 1.
BzO
BzO
R
Keywords: radicals and radical reactions; catalysis; thiols; diols; rear-
rangements; carbohydrates; thiocarbonyl compounds.
* Corresponding author.
1 R = H
2 R = H
3 R = H
4 R = Me
5 R = Me
6 R = Me
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00540-8

3664
B. P. Roberts, T. M. Smits / Tetrahedron Letters 42 (2001) 3663–3666
cal. Reactions were carried out under the conditions
described previously1 in the presence of DBPB, TBST
and collidine.3 In contrast, the galactoside analogue 13
gave more 12 than 14, indicating preferential cleavage
of the intermediate dioxanyl radical to give the sec-
ondary C4-centred radical, although the selectivity
(12:14=62:38) is much less than that shown by the
monocyclic dioxanyl radical derived from 1.
angles at the nascent radical centre have widened to a
point where this is nearly planar; in particular, the
angle a–b–d is 120.0°. If this angle is fixed at 110° and
the dihedral angle a–b–d–e is fixed at −60°, values close
to those imposed by the bicyclic framework present in
the glucosidic radical 19 derived from 10 (Scheme 3),
sec.
and the remainder of the structure is re-optimised, Ea
is increased to 84.8 kJ mol−1. The activation energy for
6
O
BzO
O
H
H
5
O
O
O
O
O
1
4
Ph
Ph
O
OMe BzO
OMe
OMe
O
OMe BzO
OMe
3
2
RO
OR
RO
OR
RO
OR
MeO
OMe MeO
OMe
7 R = Ac
8 R = Ac
9 R = Ac
13
14
10 R = Me
11 R = Me
12 R = Me
The activation energies for the two possible modes of
b-scission of the 2-phenyl-4-methyl-1,3-dioxanyl radical
15, derived from 1, were calculated using density func-
tional theory at the B3LYP/6-31G(d,p) level in con-
junction with the Gaussian 98 suite of programs.4
Geometries of 15 and of the two possible transition
states (Scheme 2) were optimised without any con-
straints and the normal vibrational frequencies were
computed at the same level of theory, enabling the
b-scission to give the primary radical is now lower by
5.9 kJ mol−1, which would translate into a benzoate
ratio 2:3 of ca. 1:5.8 at 130°C. Thus, it seems likely that
the contra-thermodynamic cleavage of 19 to give pre-
dominantly the primary radical 20 can be attributed
mainly to the prevention of bond-angle opening at the
C4-bridgehead site in the transition state for its
formation.
As estimated by molecular mechanics calculations,5 the
galactosidic radical 22 derived from 13 is less stable
than the glucosidic analogue 19 by 12.8 kJ mol−1. The
moderate preference of 22 for cleavage to give the
secondary radical 21, rather than the primary radical
23, can be understood in terms of the greater reduction
of strain present in this cis-fused bicyclic structure
when the axial bridgehead C4ꢀO bond stretches en
route to 21 (as compared with stretching of the C6ꢀO
bond leading to the cis-4,5-substituted 23), which acts
to offset the bridgehead angle strain effect that favours
formation of the primary radical.6
sec.
prim.
Arrhenius activation energies Ea
and Ea
to be
estimated as 71.8 and 78.9 kJ mol−1, respectively.
Assuming similar A-factors for the two modes of cleav-
age, b-scission to give the secondary radical 16 is
predicted to occur ca. 8.3 times faster than cleavage to
give the primary radical 17 at 130°C, as compared with
the experimental yields of the benzoates 2 and 3 which
are in the ratio 6.7:1.
The calculated structure of the transition state 18 lead-
ing to the secondary radical 16 occurs at a late stage
along the reaction coordinate, such that the bond
Scheme 2.
1.436
1.375
1.264
< a-b-c = 116.7o
d
c
< a-b-d = 120.0o
e
b
< c-b-d = 115.9o
1.945
a
(Bond lengths in Å)
18

B. P. Roberts, T. M. Smits / Tetrahedron Letters 42 (2001) 3663–3666
3665
Ph
O
O
Ph
O
O
O
O
E
MMX(rel.) = 0
E
MMX(rel.) = +12.8 kJ mol-1
MeO
MeO
MeO
MeO
OMe
OMe
22
19
BzO
MeO
BzO
O
BzO
MeO
O
O
MeO
MeO
MeO
MeO
OMe
OMe
OMe
20
21
23
Scheme 3.
As we have pointed out previously for the redox ring-
opening rearrangement of 7,1 the preference for forma-
tion of the 6-deoxybenzoates 8 and 11 from the
benzylidene glucosides 7 and 10, respectively, is appar-
ently at odds with the regiochemistry of tributyltin
hydride-mediated reductive ring opening of the cyclic
thionocarbonate 24, described by Barton and Subrama-
nian (B. and S.) in the first paper on this type of
reaction.7
(26:25=ca. 90:10), although it was difficult to measure
this ratio exactly because of the minute quantities of
alcohols produced. The methylene acetal 27 is pre-
sumably formed by tin hydride-trapping of the adduct
radical 28 before it undergoes b-scission, followed by
tin hydride reduction of the 2-stannylthiyl-1,3-dioxane
so produced.11
The reaction was repeated again, this time with very
slow addition (syringe pump) of a toluene solution
containing tin hydride (1.5 equiv.) and AIBN (10
mol%) to a solution of the thionocarbonate 24 in
refluxing toluene.12 Under these conditions, very much
less methylene acetal and much more alcohol were
obtained after hydrolysis, but still the 6-deoxy sugar
predominated (26:25=91:9); however, the reaction was
not clean and other products were also formed. Using
the procedure of B. and S., with tris(trimethylsi-
lyl)silane (TTMSS, 1.5 equiv., AIBN initiator) as a less
reactive hydrogen-atom donor than the tin hydride,13
gave the deoxy sugars cleanly (26:25=92:8) and the
methylene acetal was not now detected. Similar results
(26:25=88:12) were obtained, with all reagents present
initially, using the cheaper triphenylsilane (1.5 equiv.)
and 1,1-di-tert-butylperoxycyclohexane (10 mol%) as
initiator in refluxing toluene.14 With more triphenylsi-
lane (3 equiv.) and less solvent, the 4,6-dideoxy
compound15 was a major product, presumably arising
from reduction of the Ph3SiSC(O)O-group at C4 in the
initial 6-deoxy product.
Thus, reaction of the tin hydride with 24 in the presence
of azobis(isobutyronitrile) (AIBN) in refluxing toluene
was reported to give the 4-deoxyglucoside 25 in 61%
yield, after basic hydrolysis of the first-formed S-stan-
nylthiolester. However, identification of 25 relied on a
comparison of the optical rotation of its 6-O-tosyl
derivative with a value in the literature since, surpris-
ingly, the paper by B. and S. contains no NMR data.
The conditions used by B. and S. involved slowly
adding a toluene solution containing 24, excess Bu3SnH
and AIBN to refluxing toluene; more tin hydride and
AIBN were added subsequently. In our hands using a
standard dropping funnel, the tin hydride reduction of
24 as described by B. and S. afforded, reproducibly, the
methylene acetal 278 as the almost-exclusive carbohy-
drate product and neither of the alcohols 25 and 26
could be identified with certainty in the crude product
after hydrolysis. Authentic samples of these alcohols
were prepared by hydrolysis of the benzoate esters 11
and 12.9,10 When we repeated the reaction using a
smaller excess of the stannane (1.5 equiv.), the methyl-
ene acetal 27 was still the major product, although
small amounts of the alcohols were now detectable
after basic hydrolysis. However, the 6-deoxy sugar pre-
dominated to a large extent over the 4-deoxy compound
Contra-thermodynamic regioselectivity has been
observed on a number of occasions in the tin hydride
mediated deoxygenation of 1,2- and 1,3-diols via their
cyclic thionocarbonate esters.12,16 However, interpreta-
tion of the product distribution and the regioselectivity
O
HO
O
O
S
O
O
O
O
Bu3SnS
O
O
OMe
OMe HO
OMe
O
OMe
O
OMe
MeO
OMe
MeO
OMe MeO
OMe
MeO
OMe
MeO
OMe
24
25
26
27
28

3666
B. P. Roberts, T. M. Smits / Tetrahedron Letters 42 (2001) 3663–3666
obtained from this type of reaction is not always
straightforward17,18 because of its mechanistic complex-
ity. In particular, several elementary steps in the chain
propagation sequence are reversible and rearrangement
of the starting thionocarbonate with migration of the
sulfur atom into the ring can take place under the
influence of both radicals and nucleophiles, to give
monothiolcarbonate, subsequent reduction of which
can also yield alcohol. Indeed, Redlich et al.16 have
reported that the regiochemistry observed can depend
on the concentrations of the reagents used and clearly a
detailed re-examination of the reductive ring opening of
thionocarbonates by tin hydrides is indicated.
7. Barton, D. H. R.; Subramanian, R. J. Chem. Soc., Perkin
Trans. 1 1977, 1718.
8. Lipta´k, A.; Ola´h, V. A.; Kere´kgya´rto´, J. Synthesis 1982,
421.
9. Sato, K.-I.; Yoshimura, J. Carbohydr. Res. 1982, 103,
221.
10. NMR (500 MHz for 1H, 125 MHz for 13C, CDCl3
solvent, J in Hz). The use of [multiplet] indicates an
apparent multiplet with line spacing corresponding to an
average coupling constant. Compound 25; lH 1.31 (1H,
[q], J 12.1, H-4ax), 1.99 (1H, ddd, J 12.8, 5.1 and 2.3,
H-4eq), 2.06 (1H, dd, J 6.9 and 5.6, OH), 3.14 (1H, dd, J
9.4 and 3.6, H-2), 3.38 (3H, s, OMe), 3.40 (3H, s, OMe),
3.48 (3H, s, OMe), 3.50–3.64 (3H, m, H-3, H-6A, H-6B),
3.80 (1H, m, H-5), 4.85 (1H, d, J 3.6, H-1); lC 31.9, 55.1,
57.4, 58.7, 65.2, 68.0, 76.3, 82.2 and 98.0. IR (liq. film):
3454 cm−1. MS (FAB): 229.1060 (M+Na+); C9H18O5Na
requires 229.1052. [h]2D5 +153.0 (c 1.10, CHCl3); [h]2D5
+162.0 (c 1.00, MeOH); Ref. 7 reports [h]2D2 +70.0 (c 1.0,
MeOH). Compound 26;9 lH 1.17 (3H, d, J 6.2, H-6), 3.00
(1H, [t]d, J 9.1 and 3.2, H-4), 3.05 (1H, br.d, J 3.2, OH),
3.12 (1H, dd, J 9.6 and 3.6, H-2), 3.30 (1H, [t], J 9.2,
H-3), 3.31 (3H, s, OMe), 3.38 (3H, s, OMe), 3.52 (3H, s,
OMe), 3.55 (1H, dq, J 9.4 and 6.2, H-5), 4.67 (1H, d, J
3.6, H-1); lC 17.5, 54.9, 58.1, 60.9, 66.7, 75.1, 82.0, 82.7
and 97.1. IR (liq. film): 3454 cm−1. MS (FAB): 229.1045
(M+Na+); C9H18O5Na requires 229.1052. [h]2D5 +136.0 (c
1.25, CHCl3).
11. Williams, D. R.; Moore, J. L. Tetrahedron Lett. 1983, 24,
339. For use of the better hydrogen-atom donor Ph3SnH
to mediate this type of reaction, see: De Angelis, F.;
Marzi, M.; Minetti, P.; Misiti, D.; Muck, S. J. Org.
Chem. 1997, 62, 4159.
12. Ziegler, F. E.; Zheng, Z. J. Org. Chem. 1990, 55, 1416.
13. Chatgilialoglu, C. Chem. Rev. 1995, 95, 1229.
14. Cai, Y.; Roberts, B. P. Tetrahedron Lett. 2001, 42, 763.
15. Fuller, T. S.; Stick, R. V. Aust. J. Chem. 1980, 33, 2509.
16. Redlich, H.; Sudau, W.; Paulsen, H. Tetrahedron 1985,
41, 4253.
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6. The reverse of these b-scission processes, namely 6-endo-
cyclisation of substituted 3-benzoyloxypropyl radicals,
will proceed through the same (now early) transition
state. A complementary approach to the interpretation of
regioselectivity would be to consider the interactions that
develop during the cyclisation process.
.
.