Abstract
A double migratory cascade reaction of α-halogen-substituted propargylic phosphates to produce highly functionalized 1,3-dienes has been developed. This transformation features 1,3-phosphatyloxy group migration followed by 1,3-shifts of bromine and chlorine, as well as unprecedented 1,3-migration of iodine atom. The reaction is stereodivergent; (Z)-1,3-dienes are formed in the presence of copper catalyst, whereas gold-catalyzed reactions invert the stereoselectivity producing the corresponding E products.
Processes involving 1,n-halogen migrations are a powerful tool for obtaining valuable functionalized synthons for organic chemistry. 1–6 Among known methods are base-mediated 1,2-migration of halogen atoms to the anionic center, namely halogen dance reaction, 1 migrations via halonium-,2 allyl cation-,3 and α-halo metal carbene4 intermediates, halogen shifts during radical processes,5 and metal-mediated alkyne-vinylidene isomerizations.6 Furthermore, various migrations of a range of other functionalizable groups are well precedented.7 However, double migration reactions employing two functionalizable groups are exceedingly rare.8 Herein we wish to report a double 1,3-phosphatyloxy and 1,3-halogen migration relay toward highly functionalized 1,3-dienes. This cascade transformation features a stereodivergent formation of Z- and E-dienes, 1,3-shifts of bromine and chlorine atoms, as well as unprecedented 1,3-iodine migration (eq 1).
 |
(1) |
We have previously shown that propargylic esters and phosphates can undergo a facile double 1,3/1,2-migratory cascade to produce (E)-1,3-dienes7e (eq 2). We hypothesized that it should be possible to expand the scope of the migrating group to halogen (MG = Hal), thus aiming at the synthesis of difunctionalized 1,3-dienes A (eq 3).
To this end, the isomerization of α-bromo propargylic phosphate 1a9 was examined under a variety of conditions (Table 1). We found 1a to be unaffected by the original catalytic system (entry 1). Likewise, employing gold (I) complexes with alternative counterions such as SbF6 or BF4 did not provide product formation at all (entries 2, 3). Similarly, silver and platinum catalysts provided no reaction as well (entries 4, 5). However, employment of gold(I) and gold(III) halides unexpectedly produced a mixture of stereoisomeric 1,3-dienes 2a and 3a, the products of double 1,3/1,3-migration sequence (entries 6–8), with no 1,3-diene A observed. Employment of Ph3PAuCl catalyst resulted in good Estereoselectivity of the reaction and moderate yield (entry 9). Use of a more electron deficient phosphine ligand led to E-diene 3a in an excellent yield and good stereoselectivity (entry 10). Further catalyst screening led to another surprising observation: the [CuOTf]2•PhH catalyst provided the 1,3/1,3-migration product 2a with excellent Z-selectivity (entry 11)! Gratifyingly, performing the reaction at a higher temperature resulted in the efficient and exclusive formation of Z-1,3-diene 2a (entry 12). In addition, a control experiment indicated that no product formation occurred in the absence of a catalyst (entry 13).
 |
(2) |
 |
(3) |
Table 1.
Optimization of the reaction conditions
 | |||||
|---|---|---|---|---|---|
| entry | catalyst (mol%) | solvent | T(°C) | 2a : 3aa | yield,%b |
| 1 | Ph3PAuOTf (5) | DCE | rt | - | 0 |
| 2 | Ph3PAuSbF6 (5) | DCE | rt | - | 0 |
| 3 | Ph3PAuBF4 (5) | DCE | rt | - | 0 |
| 4 | AgOTf (10) | DCE | 50 | - | 0 |
| 5 | PtCl2 (5) | DCM | 40 | - | 0 |
| 6 | AuI (5) | PhH | 50 | 1 : 6 | ND d |
| 7 | AuCl3 (5) | PhH | 40 | 1 : 1.5 | ND d |
| 8 | LAuCl2c (5) | DCE | 80 | 1 : 2 | ND d |
| 9 | Ph3PAuCl (5) | DCE | 80 | 1 : 9 | 65 |
| 10 | (p-F3CC6H4)3PAuCl (5) | PhMe | 100 | 1 : 9 | 96 |
| 11 | [CuOTf]2•PhH (10) | DCE | 50 | 24 : 1 | 50 |
| 12 | [CuOTf]2•PhH (10) | DCE | 80 | 100 : 0 | 85 |
| 13 | None | PhMe | 0 | - | 0 |
Determined by 1H NMR.
Isolated yield.
L = 2-pyridinecarboxylato.
Yield was not determined.
Inspired by these observations, we first investigated the scope of the Cu-catalyzed Z-selective reaction under the optimized conditions (Table 2). Acyclic compounds 1a–c underwent this tandem transformation to efficiently produce dienes 2a–c (entries 1–3). Chlorine-containing compound 1b gave a better yield of the isomerization product compared to its bromine-bearing analog 1a. Propargylic phosphate possessing cyclic substituent 1d was also effectively converted into the exocyclic diene 2d in both good yield and stereoselectivity. Likewise, heterocyclic compound 1e also provided 1,3-diene 2e as a sole Z-isomer in a good yield. To our delight, cyclic ketone-derived substrates 1f–j provided the corresponding products in moderate to excellent yields. Notably, these substrates possessing hydrogen atom adjacent to a halogen provided 1,3-diene 2f–j, the products of the exclusive halogen over hydrogen atom migration. Isomerization of five-membered ring-containing substrates 1f–g gave diene products 2f–g as sole stereoisomers in excellent yields (entries 6–7). Similarly, substrates 1h–j bearing six-membered ring furnished the desired products in good yields.10 Remarkably, compound 1j underwent a 1,3-iodine migration in this tandem transformation to produce the Z-diene 2j as a single stereoisomer in moderate yield (entry 10). To the best of our knowledge, this is the first example of 1,3-migration of iodine.
Table 2.
Cu-Catalyzed Synthesis of Z-Dienes
Major stereoisomer shown.
Isolated yield.
Z:E =19:1.
Z:E =9:1
Next, we investigated the Au-catalyzed cascade 1,3-phosphatyloxy/1,3-halogen double migration reaction leading to E-1,3-diene products (Table 3). Several halogenated propargylic phosphates bearing acyclic substituents were converted into the corresponding E-dienes in excellent yields and with good to excellent selectivities (entries 1–4). Likewise, exocyclic E-dienes 3d,n could also be efficiently obtained via this transformation. Finally, cyclohexyl-containing substrate 1j underwent this cascade transformation with exclusive 1,3-migration of iodine atom to produce the corresponding 1,3-diene 3j in high yield, albeit with a lower level of stereocontrol.
Table 3.
Au-Catalyzed Synthesis of E-Dienes
 | |||
|---|---|---|---|
| entry | substrate | producta | yield, %b (E:Z ratio)c |
| 1 |  |
 |
95 (9:1) |
| 2 |  |
 |
89 (6:1) |
| 3 |  |
 |
97 (8:1) |
| 4 |  |
 |
98 (13:1) |
| 5 |  |
 |
91 (9:1) |
| 6 |  |
 |
90 (19:1) |
| 7 |  |
 |
89 (1.5:1) |
Major stereoisomer shown.
Isolated yield.
Determined by 1H NMR.
We propose the following plausible mechanism for these cascade transformations (Scheme 1). First, coordination of the metal to the π-system of the alkyne 4 renders a 1,3-migration of phosphatyloxy group to produce the cyclic intermediate 5, which upon elimination of the metal produces allenyl phosphate 6 or 8.7d–g In the case of Au catalyst, π-allyl cation 711 is produced upon a halogen abstraction from 6. A subsequent delivery of a halide from gold halide species to 7 occurs anti to the phosphate group giving the E-diene 3. Alternatively, in the case of copper catalysis, additional coordination of the metal to the phosphate group of allene takes place (8). The halogen abstraction by copper produces phosphate-coordinated π-allyl complex 9.12 In this way, a subsequent delivery of the halogen is directed by the phosphate group and occurs syn to it to produce the corresponding isomeric Z-product 2.13
Scheme 1.
Proposed mechanism for double phosphatyloxy-Halogen migration relay
Next, synthetic utility of 1,3-dienes obtained in the Cu-catalyzed isomerization reactions was examined (Scheme 2). Thus, Diels-Alder reaction of 2a with N-phenylmaleimide and 2f with bromomaleic anhydride7o efficiently produced cycloadduct 10 and pen-tasubstituted benzene derivative 11, respectively. Furthermore, Miyaura-Suzuki cross-coupling reaction14 of dienes 2a,f with phenylboronic acid proceeded well to give phenylated 1,3-dienes 12 and 13 in 78% and 91% yields, respectively. Notabaly, the phosphatyloxy terminus of Z diene 2f could also be functionalized after the Miyaura-Suzuki cross-coupling reaction of a vinyl bromide moiety. Thus, the diene 13 underwent Kumada cross-coupling reaction on the phosphatyloxy moiety in the presence of iron catalyst15 to give diene 14. Finally, a sequential Miyaura-Suzuki reaction on vinyl bromide14 and phosphate16 groups of diene 2f furnished highly functionlized diene 15 in good overall yield (Scheme 2).
Scheme 2.
Selected Transformations of (Z)-1,3-dienes 29
(i) N-Phenylmaleimide (1.5 equiv), anisole, 150 °C, 12h. (ii) bromomaleic anhydride (1.5 equiv), anisole, 150 °C, 12h. (iii) Pd2(dba)3 (4 mol%), XPhos (8 mol%), ArB(OH)2 (2.0 equiv), K3PO4 (3.0 eqiv), toluene, 80 °C, 15h (iv) Fe(acac)3 (6 mol%), TMEDA (2.0 equiv), n-BuMgCl (1.5 equiv), THF, 0 °C. (v) Ni(cod)2 (5 mol%), PCy3• HBF4 (10 mol%), PhB(OH)2 (2.0 equiv), K3PO4 (3.0 equiv), THF, 75 °C. dba = trans, trans-dibenzylideneacetone, XPhos = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, acac = acetylacetonato, TMEDA= N,N,N,N-tetramethylethylenediamine, cod = 1,5-cyclooctadiene.
In summary, a stereocontrolled isomerization of α-halo-substituted propargylic phosphates into valuable highly functionalized 1,3-dienes has been developed. This methodology features a double 1,3-phosphatyloxy/1,3-halogen migration relay. Dependingon a choice of catalyst, synthesis of either Z- or E-1,3-dienes could be achieved selectively in typically high yields. Thus, Z-dienes could be obtained with the exclusive stereoselectivity in the presence of copper catalyst, whereas the employment of gold catalyst afforded predominantly E-dienes. Notably, these transformations feature unprecedented 1,3-migration of iodine atom. Finally, the synthetic utiity of obtained 1,3-dienes was demonstrated in efficient Diels-Alder and cross-coupling reactions.
Supplementary Material
ACKNOWLEDGMENT
We thank the National Institute of Health (GM-64444) for financial support of this work.
Footnotes
ASSOCIATED CONTENT
Supporting Information. Detailed experimental procedures and characterization data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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