Palladium and nickel catalyzed thio-claisen rearrangements of chiral bicyclic thiolactams (via N,S-ketene acetals)

Article abstract of DOI:10.1016/S0040-4039(99)02294-7

Pd, Ni, and Lewis acid catalyzed rearrangements occur under milder conditions than the thermal version of the titled rearrangements. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02294-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1363–1367
Palladium and nickel catalyzed thio-Claisen rearrangements of
chiral bicyclic thiolactams (via N,S-ketene acetals)
Daniel J. Watson, Paul N. Devine and A. I. Meyers ∗
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
Received 17 November 1999; revised 6 December 1999; accepted 9 December 1999
Abstract
Pd, Ni, and Lewis acid catalyzed rearrangements occur under milder conditions than the thermal version of the
titled rearrangements. © 2000 Elsevier Science Ltd. All rights reserved.
Recently, we reported1 the highly stereoselective thio-Claisen rearrangement starting from 1 and a
number of allylic halides to generate N,S-ketene acetals 2a–c (Scheme 1). The resulting thiolactams
3a–c bearing vicinal stereogenic quaternary centers or quaternary–tertiary centers were then transformed
into 4,4-disubstituted cyclohexenones, 4.
Further application of this thio-Claisen rearrangement has led to the first asymmetric synthesis of
the sesquiterpene (−)-trichodiene,2 as well as providing an asymmetric route to chiral cyclohexeno-
nes with spiro-connected cyclopentenes.3 Based upon our early work, Rawal has recently achieved
highly diastereoselective thio-Claisen rearrangements employing a C2-symmetric amine as the chiral
auxiliary.4a Apart from the classical thermal version of [3,3]-sigmatropic rearrangments4b–f there has
been increasing interest in the use of transition metals (HgII, PdII) to catalyze these transformations
under mild conditions.5 Although extensive studies are known in the transition metal catalyzed [3,3]-
sigmatropic rearrangements, we have found no examples of metal catalyzed thio-Claisen rearrangements.
We now describe, in preliminary form, our findings that N,S-ketene acetals 2a and 2b undergo both Lewis
acid and transition metal promoted [3,3]-sigmatropic rearrangements, under mild conditions, to afford
thiolactams 3a and 3b, a process which would significantly enhance its synthetic utility.
Although Lewis acids are known to accelerate aromatic and aliphatic O-Claisen rearrangements,6
the thio-Claisen rearrangement of 2a to 3a has failed in our hands using common Lewis acids. TiCl4,
Bu2BOTf and ZnCl2 resulted in cleavage of the S-allylic-C bond in 2b affording the starting α-
methylated thiolactam 1. Alkylaluminums implemented the thio-Claisen rearrangement at room tempera-
ture and although the diastereomeric ratio of the newly formed quaternary center in 3 was poor (<3:1), we
obtained significantly higher yields (68–78%) than those obtained in the thermal rearrangement. When
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02294-7
tetl 16222

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Scheme 1.
prenyl bromide was used to prepare the N,S-ketene acetal 2b, Me3Al provided the rearranged product 3b
in 75% yield when heated in ethylene dichloride at 83°C.
We then examined metal salts of Pd and Ni, which have been shown to catalyze a wide variety of
[3,3]-sigmatropic rearrangements. Yoshida7 has reported several examples of the regioselective S→N
allylic rearrangement of S-allylthioimidates into N-allylthioamides catalyzed by palladium(II) chloride.
In addition, rearrangements such as the O-allyl thiocarboxylate rearrangement8 and the O-allyl phospho-
rothionate (C–O→C–S) rearrangement9 have also been reported to proceed under mild conditions. To
our knowledge, none of these metals have ever been utilized in the thio-Claisen rearrangement.10
N,S-Ketene acetal 2a, when treated with 10 mol% of the palladium(II) catalyst resulted in the
rearrangement at 25°C to produce the desired thiolactam 3a. The rearrangement of 2a occurred with a
variety of palladium(II) catalysts at room temperature whereas the thermal rearrangement of 2a required
heating at 140°C (Table 1). Initially, the use of PdCl2(MeCN)2, PdCl2(PPh3)2 and Pd(OAc)2 (Table
1, entries 2–4) provided thiolactam 3a as a 3:1 mixture of exo (β) and endo (α) diastereoisomers,
respectively. When palladium(0) was employed as a potential catalyst for this rearrangement it was found
that Pd(PPh3)4 (entry 6) catalyzed the rearrangement at 25°C and afforded a diastereomeric ratio of
3.4:1 in favor of the exo (β) diastereomer 3a. However, the best result came from a Pd2(dba)2 catalyzed
rearrangement of 2a to provide 3a in a diastereomeric ratio of 5.6:1 (entry 7). Although moderate
diastereoselectivity was observed under catalytic conditions it is important to note that the isolated
yield of the major exo diastereomer 3a was somewhat higher than that obtained during the thermal
rearrangement (entry 1).
NiCl2(Ph3P)2 also effected the rearrangement at room temperature affording the thiolactam
3a as a 4:1 mixture of exo:endo diastereoisomers, respectively, (entry 8). However, with
tetrakis(triphenylphosphine)-nickel(0) reagent prepared from the treatment of a nickel(II) salt with
either zinc metal or nBuLi,11 the ratio of exo to endo diastereomers decreased (2:1 and 2.6:1,
respectively, entries 9 and 10). The Lewis acid by-products, from the preparation of these catalysts were
shown to render them ineffective in the thio-Claisen rearrangement and thus the Ni(PPh3)4 suffers from
the same limitations as the Lewis acid catalysis. Ni(COD)2 effected the rearrangement much the same as

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Table 1
Thio-Claisen rearrangement of N,S-ketene acetal 2a to thiolactam 3a with palladium and nickel
catalysts
palladium to provide the thiolactam 3a in a 3.3:1 mixture of exo:endo diastereomers (entry 11). Solvent
changes resulted in little change in product ratios.
The prenyl bromide derived N,S-ketene acetal 2b underwent a [3,3]-sigmatropic rearrangement with
both palladium and nickel catalysts to afford thiolactam 3b bearing vicinal quaternary stereogenic
centers. In all the examples the rearrangement occurred with high diastereoselectivity (>20:1, exo:endo)
and good chemical yield although heating to 65°C in THF was required (Table 2, entries 2–5 and 8).
The 1H NMR spectrum derived from the crude mixture indicated the presence of a single diastereomer
corresponding to the rearrangement to the exo (β) face of the bicyclic system. Again, in the case of
the Ni(PPh3)4 (entries 6 and 7), the ratio of exo:endo diastereomers decreased dramatically due to the
presence of Lewis acid by-products. However, it is noteworthy that in entries 6 and 7 the rearrangement
occurred at room temperature.
Table 2
Thio-Claisen rearrangement of N,S-ketene acetal 2b to thiolactam 3b with palladium and nickel
catalysts
The stereochemistry of products 3a was shown to be identical to that observed from the thermal [3,3]-
sigmatropic rearrangement indicating palladium(II) most likely catalyzes the rearrangement through a
chair transition state.12 Rationale for the stereoselective outcomes is presented below (Figs. 1 and 2). The
palladium(II) pathway5 (Fig. 1) coordinates to the double bond of 2a and subsequent nucleophilic attack
of the thioenol ether provides a six-membered palladated intermediate 5 which undergoes elimination

1366
of Pd(II) to afford the [3,3] rearranged thiocarbonyl 3a. The palladium(0) pathway (Table 1, entry 6) is
shown in Fig. 2. The low selectivity shown by N,S-ketene acetal 2a may be due to the proximity of Pd
and the phenyl group in 5 (Fig. 1), or the regioselectivity in thioenolate addition to the π-allyl complex
in 6 (Fig. 2).13
Fig. 1.
Fig. 2.
Thio-Claisen rearrangements derived from a thioketone have been reported to be reversible.14 Howe-
ver, [3,3]-sigmatropic rearrangements from thioamides are rarely reversible.2 When we subjected both
the 3:1 mixture and the pure endo diastereomer 3a to thermal conditions (xylenes, 140°C, 12 h), we

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observed excellent conversion via N,S-ketene acetal 2a, providing >95% of the major exo diastereomer
3a (Scheme 2). This further supports the reversibility of the thio-Claisen rearrangement,2 and the
thermodynamic preference of the exo diastereomer 3a.
Scheme 2.
In summary, we have shown that the thio-Claisen, [3,3]-rearrangement proceeds efficiently, with
moderate stereoselectivity in the presence of Lewis acids, Pd, and Ni catalysts. The mild conditions
required to bring this about may find broad applications for thermally sensitive compounds.
Acknowledgements
The authors are grateful to the National Institutes of Health for support of this work. A postdoctoral
fellowship from Merck is gratefully acknowledged (PND).
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