to THFs driven by the stability of the resulting benzylic cations
(cf. B, Scheme 1) and that 2,3-cis- rather than 2,3-trans-
configured products might be preferred via a dipseudoequatorial
transition state TSB-cis (Scheme 1). Herein, we describe our
exploration of this reaction manifold.
Scheme 1
.
Type III γ,δ-Unsaturated Oxonium-Prins
Cyclizations
Using (E)-4-phenylbut-3-en-1-ol11 as the homoallylic
alcohol component and 2-naphthylcarboxaldehyde (2-
NapCHO) as the aldehyde component, we initially explored
the use of SnBr4 and InBr3/TMSBr as Lewis acid promotors
in CH2Cl2 as described by Rychnovsky5a and Loh,3e respec-
tively, for the formation of THPs via oxonium-Prins
cyclizations (Table 1). The use of SnBr4 (1.1.equiv) led to
closure is dictated by the relative energies of the indicated
transition states, which in turn reflect the stabilities of
carbocations A and B. This means that for the terminal and
monoalkyl-substituted alkene-containing systems which are
most commonly employed (i.e., R′ ) H, alkyl), THP products
are formed exclusively.3 By contrast, THF products are
formed exclusively with dialkyl terminally substituted
alkenes,4c,d with enols/enol ethers (i.e., R′ ) OH, OR),4a,e,7e,f
and with allylsilanes (i.e., R′ ) CH2SiR3)4b,6,9 due to the
stabilization these substituents impart upon the exocyclic
carbocation B. Good 2,3-stereocontrol can be achieved for
stereodefined enols/enol ethers and allylsilane nucleophiles,
and moderate trans-2,3-stereoselectivity is observed with
dimethyl terminally substituted alkenes.4c,10
Intrigued by the absence in the chemical literature of type
III oxonium-Prins cyclizations in which the γ,δ-unsaturated
alkene is that of a styrene (i.e., R′ ) Ar), we considered that
these substrates could be valuable precursors for the stereo-
controlled synthesis of 2,3-substituted THFs. In particular, we
envisaged that E-configured styrenes would undergo cyclization
Table 1. Oxonium Prins Cyclizations: Optimization of Reaction
Conditions
entry time (h)
conditions
conv (%) dr (1a/1b/1ca)
1
2
3
4
6
24
4
SnBr4, -78 °C to rt
SnBr4, -78 °C
InBr3, TMSBr, -78 °C
SnBr4, TMSBr, -78 °C
70
20
75:14:11
75:18:7
62:38:0
90:10:0b
70
4
100
a Ratios by integration of 1H NMRs of the crude reaction mixtures;
assignment of 2,3-stereochemistry is via NOESY (see the Supporting
Information); the configuration at C1′ in the major 2,3-trans and 2,3-cis
isomers is assumed to be that of a/c by analogy with that determined by
X-ray for 6c (Scheme 2). b The isolated yield of this inseparable mixture
of isomers was 55%.
the formation of three isomeric, bromine-containing THF
products with dr 75:14:11 if the reaction mixture was allowed
to warm to rt and dr 75:18:7 if the reaction mixture was
maintained at low temperature (cf. entries 1 and 2). However,
these reactions were slow, particularly the one at low
temperature (entry 2). InBr3 (1.1 equiv)/TMSBr (1.1 equiv)
induced a more rapid reaction which gave just two isomers
but with lower selectivity even at low temperature (dr 62:
38:0, entry 3). The optimal conditions employed SnBr4 in
conjunction with TMSBr (1 equiv)12 and led to full conver-
sion within 4 h at -78 °C (dr 90:10:0, entry 4). As expected,
the products were those of trapping the carbocation at C1′
with bromine following a Prins cyclization to give a THF
ring. There was no evidence of elimination, but at this stage
¨
¨
(4) For THF formation, see, e.g.: (a) Unaldi, S.; Ozlu¨gedik, M.; Fro¨hlich,
R.; Hoppe, D. AdV. Synth. Catal. 2005, 347, 162. (b) Sarkar, T. K.; Haque,
S. A.; Basak, A. Angew. Chem., Int. Ed. 2004, 43, 1417. (c) Loh, T.-P.;
Hu, Q.-Y.; Tan, K.-T.; Cheng, H.-S. Org. Lett. 2001, 3, 2669. (d) Loh,
T.-P.; Hu, Q.-Y.; Ma, L.-T. J. Am. Chem. Soc. 2001, 123, 2450. (e) Hoppe,
D.; Kra¨mer, T.; Erdbru¨gger, C. F.; Egert, E. Tetrahedron Lett. 1989, 30,
1233
.
(5) See, e.g.: (a) Jasti, R.; Rychnovsky, S. D. J. Am. Chem. Soc. 2006,
128, 13640. (b) Vitale, J. P.; Wolckenhauer, S. A.; Do, N. M.; Rychnovsky,
S. D. Org. Lett. 2005, 7, 3255. (c) Dalgard, J. E.; Rychnovsky, S. D. Org.
Lett. 2005, 7, 1589. (d) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000,
2, 1217
.
(6) See, e.g.: Chen, C.; Mariano, P. S. J. Org. Chem. 2000, 65, 3252
.
(7) See, e.g.: (a) Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem.,
Int. Ed. 2005, 44, 3485. (b) Smith, A. B., III.; Safonov, I.; Corbett, R. M.
J. Am. Chem. Soc. 2002, 124, 11102. (c) Smith, A. B., III; Safonov, I.;
Corbett, R. M. J. Am. Chem. Soc. 2001, 123, 12426. (d) Smith, A. B., III.;
Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001,
123, 10942. (e) Takano, S.; Samizu, K.; Ogasawara, K. Synlett 1993, 785.
(f) Takano, S.; Samizu, K.; Ogasawara, K. J. Chem. Soc., Chem. Commun.
(11) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem.
Soc. 1998, 120, 11943.
1993, 1032
.
(8) See, e.g.: (a) Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003,
68, 7143. (b) Hanaki, N.; Link, J. T.; MacMillan, D. W. C.; Overman, L. E.;
Trankle, W. G.; Wurster, J. A. Org. Lett. 2000, 2, 223. Note: These
oxonium-Prins reactions give ring closure to a THP cation (cf. A, Scheme
1) which undergoes pinacol rearrangement to a THF final product.
(9) (a) Miles, S. M.; Marsden, S. P.; Leatherbarrow, R. J.; Coates, W. J.
J. Org. Chem. 2004, 69, 6874. (b) Miles, S. M.; Marsden, S. P.;
Leatherbarrow, R. J.; Coates, W. J. Chem. Commun. 2004, 2292. (c) Cassidy,
J. H.; Marsden, S. P.; Stemp, G. Synlett 1997, 1411. (d) Meyer, C.; Cossy,
(12) TMSBr appears to serve as a bromide source (cf. ref 3e). Trace
product formation occurred using only TMSBr as promoter.
(13) The isomeric ratios were unchanged after resubjection to the reaction
conditions (Table 2, entry 7), suggesting the products are formed under
kinetic control.
3
(14) The H2-H3 J coupling constants vary significantly and are not
diagnostic in THFs. Additionally, all the products/product mixtures (from
Table 2, entry 7, and Table 2, entries 1-7) were subject to debromination
(using NiCl2·6H2O/NaBH4, cf. Khurana, J. M.; Kumar, S.; Nand, B. Can.
J. Chem. 2008, 86, 1052). The results were consistent with the assignments
made by NOESY. For example, di-debromination of 5a and 5c gave the
same products as mono-debromination of 4a/b and 4c, respectively
(compounds 12 and 11, see the Supporting Information).
J. Tetrahedron Lett. 1997, 38, 7861
.
(10) Racemisation via various mechanisms can plague oxonium-Prins
reactions involving homoallyic alcohols; see ref 5a and references cited
therein.
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