Exopericyclic stereocontrol in Johnson-Claisen rearrangements of allylic sulfides

Article abstract of DOI:10.1039/c0cc01039a

A study of the effects of exopericyclic stereocentres on the stereoselectivity of Johnson-Claisen rearrangements of thioether-containing allylic alcohols shows that selectivity is highly dependent upon allylic substitution patterns.

Full text of DOI:10.1039/c0cc01039a

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Exopericyclic stereocontrol in Johnson–Claisen rearrangements of allylic
sulfidesw
Donald Craig,*a John W. Harvey,b Alexander G. O’Briena and Andrew J. P. Whitec
Received 20th April 2010, Accepted 30th July 2010
DOI: 10.1039/c0cc01039a
A study of the effects of exopericyclic stereocentres on the
stereoselectivity of Johnson–Claisen rearrangements of
thioether-containing allylic alcohols shows that selectivity is
highly dependent upon allylic substitution patterns.
and demonstrates that the geometry of the allylic double bond has
a pronounced effect on the stereochemical outcome of these
transformations.
Our expectation at the outset was that Z-isomers would
show enhanced selectivity through the maximisation of allylic
1,3-strain.6 Accordingly, a series of allylic alcohols 4a–f were
prepared via a convenient four-step route which delivered one
or other of the geometric isomers according to the nature of
the olefination step (Scheme 2).7 Treatment of aliphatic aldehydes
Since its discovery, the Claisen rearrangement1a has become
established as an important transformation in organic synthesis.
The rearrangement often proceeds with high and predictable
stereoselectivity on account of its well-defined six-membered
transition state. Stereoselectivity in rearrangements of substrates
possessing substituents bound directly to atoms within the
pericyclic array has been comprehensively investigated.1b,c
However, comparatively little is known about how the
configuration of exopericyclic stereocentres, which are external
to the pericyclic array, affects the stereochemistry of C–C bond
formation during the [3,3]-sigmatropic process (Scheme 1).
Scattered reports in the literature, including examples from
our own laboratory indicate that high exopericyclic st
ereoselectivities are attainable.2–4 Where the stereocentre bears
a heteroatom X, predominant formation of the syn product is
generally observed. This has been explained in terms of
favourable antiperiplanar alignment of the C–X and incipient
C–C bonds in the reactive conformation, with the allylic,
exopericyclic C–H bond eclipsing the adjacent CQC bond.2d,3,5
This communication describes our recent investigations of this
selectivity in the context of the Johnson–Claisen rearrangement,
8
with SO2Cl2 or with N-chlorosuccinimide–D,L-proline9 gave
a-chloroaldehydes, from which the corresponding thioethers
310 were prepared by treatment with triethylammonium
thiophenolate generated in situ. Compounds 3 decomposed
upon isolation, and so were added directly to a solution of
the appropriate phosphonate anion in THF. The use of
triethylphosphonoacetate in these Horner–Wadsworth–
Emmons reactions provided the E-configured a,b-unsaturated
esters, while use of the Ando phosphonate11 gave the
Z-isomers. Subsequent reduction using DIBAL–H afforded
the allylic alcohols 6a–f in 9–40% overall yield for the
four-step sequence from RCH2CHO (Scheme 2).
During the preparation of the unsaturated ester intermediates
4, base-catalysed isomerisation to the corresponding
b,g-unsaturated compounds
5 was frequently observed.
Further investigation showed that this transformation could
be carried out quantitatively by exposure of Z-4 (R = CH3) to
sub-stoichiometric amounts of t-BuOK in DMSO, which gave
5 (R = CH3) as a 70 : 30 mixture of E- and Z-isomers in
quantitative yield.w Accordingly, our study was confined to
allylic alcohol substrates 6 possessing R = alkyl, since we
Scheme 1 Exopericyclic stereoselectivity.
a Department of Chemistry, Imperial College London, South
Kensington Campus, London, SW7 2AZ, UK.
E-mail: d.craig@imperial.ac.uk; Fax: +44 (0)20 7594 5868;
Tel: +44 (0)20 7594 5771
b Pfizer Global Research and Development, Ramsgate Road,
Sandwich, Kent, CT13 9NJ, UK
c Chemical Crystallography Laboratory, Imperial College London,
South Kensington Campus, London, SW7 2AZ, UK
w Electronic supplementary information (ESI) available: Experimental
procedures and full characterisation of compounds 3, 6a–f, 7, 8, and
details of the t-BuOK-mediated conversion of Z-4 (R = CH3) into E-
and Z-5 (R = CH3). CCDC 770168. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0cc01039a
Scheme 2 Synthesis of allylic alcohols 6. Reagents and conditions:
(i) SO2Cl2, CH2Cl2; (ii) N-chlorosuccinimide, D,L-proline, CH2Cl2;
(iii) PhSH, Et3N, THF, rt; (iv) (EtO)2P(O)CH2CO2Et, NaH, THF,
0 1C; (v) (PhO)2P(O)CH2CO2Et, NaH, THF, ꢀ78 1C; (vi) DIBAL–H,
THF, 0 1C.
ꢁc
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Scheme 3 Johnson–Claisen rearrangement reactions of 6. Reagents
and conditions: (i) CH3C(OEt)3 (solvent), EtCO2H (0.2 equiv.); see
Table 1 for reaction times.
anticipated that this undesired isomerisation would be rendered
even more facile by the presence of a conjugating aryl group in
place of the alkyl substituent.
Treatment of alcohols 6 with rigorously degassed12 triethyl
orthoacetate (as solvent) and sub-stoichiometric propionic
acid under reflux13 afforded the g,d-unsaturated ester products
7 (R = CH3, nC5H11, iC3H7,). Initial experiments showed that
while 6a (E-geometry, R = CH3) underwent completely
unselective rearrangement, analogous reaction of the Z-isomer
6b gave a 3 : 1 mixture of products 7 (R = CH3) in good yield.
This contrasting behaviour was subsequently observed with
geometric isomers 6c,d and 6e,f (Scheme 3, Table 1).
The structure of syn-7 (R = CH3) was established by the
synthesis of a derivative. Hydrolysis (LiOH, THF–H2O) of the
3 : 1 mixture of diastereoisomeric products of Johnson–
Claisen reaction of 6b gave a mixture of isomeric acids, which
were converted into the corresponding 2,4-dinitroanilides by
treatment with 2,4-dinitroaniline–DCC–DMAP. Separation
of the diastereoisomeric amides gave a pure sample of the
major isomer syn-8, whose stereochemistry was assigned by
X-ray crystallography (Fig. 1).14 Following this result, syn
stereochemistry was inferred also for the major products of the
Johnson–Claisen reactions of 6d and 6e,f.
Scheme 4 Rationale for stereoselectivity of rearrangement of E- and Z-6.
C1–C6 bonds. For Z-6, the major product syn-7 arises from
an orientation in which the C60–H bond (transition state A)
rather than the C60–R bond (transition state B) eclipses the
allylic C4–C5 double bond. For E-6, the corresponding allylic
1,3-interactions are between C5–H and the C60–H (transition
state C leading to syn-7) or C60–R (transition state D leading
to anti-7) bonds; the lesser steric bulk associated with C5–H
compared to C4–C5 leads to lower selectivity for the
E-substrates. This lack of discrimination is in contrast to
that observed in the rearrangement reactions of analogous
dioxolane- and proline-containing systems reported by Cha
and Lewis2a and by Mulzer and Shanyoor,2d respectively, and
may be a consequence of the lack of substitution at C1 in our
acetate-derived substrates.
We rationalise the difference in behaviour of E- and Z-6 by
comparison of the diastereomeric transition states A–D for
the rearrangement of 6 (Scheme 4). In all cases there is
antiperiplanar alignment of the C60–SPh and incipient
Table 1 Johnson–Claisen rearrangement reactions of 6a–f
Ratio
syn : antia
E/Z Time/h % Yield of 7
Entry Substrate
R
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
CH3
CH3
nC5H11
nC5H11
iC3H7
iC3H7
E
Z
E
Z
E
Z
7
24
12
48
24
48
98
97
98
94
93
87
1 : 1
3 : 1
1 : 1
5 : 1
3 : 2
3 : 1
In summary, through variation of the allylic substitution
pattern, we have shown that stereoelectronic effects play a
key role in determining the stereoselectivity of Claisen
rearrangements. Investigations into this mode of selectivity
are ongoing, and in particular, we are studying its deployment
in the synthesis of small molecules and heterocycles. The
results of these investigations will be reported in due course.
We thank EPSRC and Pfizer for support (supported DTA
studentship to A.G.O.).
a
1
Determined by H NMR analysis of crude reaction mixtures.
Notes and references
1 (a) L. Claisen, Ber. Dtsch. Chem. Ges., 1912, 45, 3157; (b) For recent
reviews of the Claisen rearrangement, see: A. M. Castro, Chem. Rev.,
2004, 104, 2939; (c) The Claisen Rearrangement, ed. M. Hiersemann
and U. Nubbemeyer, Wiley-VCH, Weinheim, 2006.
2 For previous examples of exopericyclic control in Claisen
rearrangements see: (a) J. K. Cha and S. C. Lewis, Tetrahedron
Lett., 1984, 25, 5263; (b) T. Suzuki, E. Sato, S. Kamada, H. Tada,
Fig. 1 The molecular structure of syn-8.
ꢁc
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K. Unno and T. Kametani, J. Chem. Soc., Perkin Trans. 1, 1986,
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6 R. W. Hoffmann, Chem. Rev., 1989, 89, 1841.
7 All compounds in this study were prepared as racemates.
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D. Bellus, Angew. Chem., Int. Ed. Engl., 1991, 30, 1465;
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12 Degassing of the solvent was found to be necessary to avoid
decomposition of both substrate and product, which occurred
presumably via S-oxidation of the thioether moiety.
13 W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J. Brocksom,
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ꢀ
14 Crystal data for syn-8: C19H19N3O5S, M = 401.43, triclinic, P1
(no. 2), a = 7.0330(2), b = 11.6869(4), c = 12.9973(5) A, a =
69.170(3)1, b = 78.712(3)1, g = 82.731(3)1, V = 977.27(6) A3, Z =
2, Dc = 1.364 g cmꢀ3, m(Mo-Ka) = 0.201 mmꢀ1, T = 173 K,
yellow tabular needles, Oxford Diffraction Xcalibur 3 diffract-
ometer; 6353 independent measured reflections (Rint = 0.0204),
F2 refinement, R1(obs) = 0.0556, wR2(all) = 0.1467, 4267 inde-
pendent observed absorption-corrected reflections [|Fo| 4 4s(|Fo|),
2ymax = 651], 270 parameters. CCDC 770168.
ꢁc
This journal is The Royal Society of Chemistry 2010
6934 | Chem. Commun., 2010, 46, 6932–6934