[3,3] Migrations of propargylacyloxy, phosphatyloxy, and sulfonyloxy groups are important transformations in organic synthesis.[1] In addition to these sigmatropic migrations, radical 1,2-acyloxy and -phosphatyloxy migrations [Eq. (1)]
 |
(1) |
have been used extensively in carbohydrate and nucleoside chemistry.[2] 1,2-Acyloxy migration has also been proposed as a key step in the Pd-catalyzed propargyl–propenyl isomerization [Eq. (2)].[3] In both cases, 1,2-migration of acetate or
 |
(2) |
phosphate proceeds from an sp3 carbon. To the best of our knowledge, no 1,2-migrations of the acyloxy, phosphatyloxy, and sulfonyloxy groups from an sp2 carbon have been disclosed. Herein we wish to report a novel 1,2-migration of the acyloxy, phosphatyloxy, and sulfonyloxy groups in the allenyl system [Eq. (3)]. This unprecedented migration, incorporated into the cycloisomerization reaction, is the key to an efficient synthesis of valuable tri- and tetrasubstituted furans.[4]
 |
(3) |
The recently discovered Cu-catalyzed cycloisomerization of alkynyl ketones and imines is an efficient method for the synthesis of up to trisubstituted heterocycles.[5] While attempting to expand the scope of this cycloisomerization reaction, we explored the possibility of utilizing [3,3] acyloxy migration to proceed from 1 to allene 2 en route to acyloxy-substituted furan 3 (Scheme 1). As expected, furan 3 was formed, albeit in moderate yields; however, it was accompanied by traces of the unexpected regioisomer 4. Addition of triethylamine to the reaction mixture shifted the product distribution toward predominant formation of furan 4. It was rationalized that 4 arises from initial base-assisted propargyl–allenyl isomerization 5→6[5] (Scheme 2), as opposed to a [3,3] acyloxy shift (Scheme 1). Allene 6 undergoes intramolecular nucleophilic attack to form the aromatic dioxolenylium zwitterion 7,[6] which is transformed into furan 4 by a subsequent intramolecular AdN-E process (Scheme 2).[7]
Scheme 1.
Formation of the unexpected regioisomer 4.
Scheme 2.
Rationale for the formation of the unexpected regioisomer 4.
We were pleased to find that by using phenyl and tert-butyl alkynyl ketones, we were able to dramatically improve the regioselectivity and yields of this unusual reaction. Thus, when we employed a series of alkynyl ketones 5 possessing different acyloxy groups, selective cycloisomerization occur-red to produce furans 4 as single regioisomers in high yields (Table 1)!
Table 1.
Cu-catalyzed synthesis of trisubstituted furans.[[a]]
| Substrate | t [h] | Product | Yield [%][[b]] | ||
|---|---|---|---|---|---|
|
5a | 22 |
|
4a | 82[[c]] |
|
5b | 1 |
|
4b | 81 |
|
5c | 9 |
|
4c | 69 |
|
5d | 2 |
|
4d | 90 |
|
5e | 17 |
|
4e | 86 |
|
5f | 23 |
|
4f | 80 |
|
5g | 32 |
|
4g | 80 |
|
5h | 46 |
|
4h | 83[[d],[d]] |
All reactions carried out on a 1-mmol scale.
Yields of isolated products.
Reactions carried out at 80°C.
TBS=tert-butyldimethylsilyl.
To gain additional support for the proposed allenic intermediate 6 in the formation of furan 4 (Scheme 2), we attempted approaching allenes of type 6 by an independent route. An attractive possibility would be to access acyloxy allene 9 by the [3,3] sigmatropic shift of 8 (Scheme 3). In the event that the sequential cascade transformation of 8 into 9 proves successful, it would not only offer strong support for involvement of allenic intermediates 6/9, but would also allow expansion of our cycloisomerization methodology to the synthesis of tetrasubstituted furans 10. We were thrilled to find that in the presence of AgBF4,[8,9] ketones 8 smoothly underwent the postulated [3,3] shift/1,2-migration/cycloisomerization sequence to directly[10] afford tetrasubstituted furans[11] 10 in excellent yields (Table 2)! Most remarkably, this new mode of cyclization enables facile access to the fused furan 10e, which was inaccessible by our standard cycloisomerization techniques.[5]
Scheme 3.
Different approach to acyloxy allenyl ketones.
Table 2.
Ag-catalyzed synthesis of tetrasubstituted furans.[[a]]
| Substrate | t [min] | Product | Yield [%][[b]] | ||
|---|---|---|---|---|---|
|
8a | 2 |
|
10a | >99 |
|
8b | 15 |
|
10b | 73 |
|
8c | 15 |
|
10c | 84 |
|
8d | 15 |
|
10d | 90 |
|
8e | 10 |
|
10e | 86 |
Reactions carried out on a 1-mmol scale.
Yields of isolated products.
Encouraged by these results, we attempted incorporation of hetero migrating groups into the [3,3] shift/1,2-migration/ cycloisomerization cascade. It was found that the phosphatyloxy analogue of 8a, ketone 11, underwent cycloisomerization at 60°C in the presence of 5% AgBF4 to afford furanyl phosphate 12 in 65% yield (Scheme 4). When the reaction was conducted at room temperature, the allenyl phosphate intermediate 13 was isolated in 56% yield. Subjecting the latter to the same conditions as those used for the transformation 11→12 led to formation of furan 12 in 77% yield (Scheme 4).
Scheme 4.
1,2-Phosphatyloxy migration. DCE= dichloroethane.
Next, we attempted the analogous transformation with propargyl tosylates 14. We were pleasantly surprised to find that attempts to synthesize 14[12] led directly to the formation of tosyl allene 15, apparently through a thermal [3,3] tosyloxy shift. Allene 15 underwent smooth cycloisomerization at 60°C in the presence of 1% AgBF4 to produce tosyl furan 16[13] in 82% yield (Scheme 5). Thus, the successful employment of the phosphatyloxy and sulfonyloxy groups not only expands the scope of the recently found cycloisomerization reaction, but also provides strong support for the involvement of the acyloxy allene intermediate in the formation of acyloxy furans 4 and 10.
Scheme 5.
1,2-Tosyloxy migration.
In conclusion, a novel 1,2-migration of the acyloxy, phosphatyloxy, and sulfonyloxy groups in allenyl systems has been discovered. Incorporation of this transformation in a cycloisomerization sequence led to the development of an efficient method for the synthesis of tri- and tetrasubstituted furans.
Supplementary Material
Footnotes
We are grateful to the NIH (GM 64444) for financial support of this work. We also thank D. Yap for technical assistance.
Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author.
References
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