Variations to the styrene-yne tether of the styrenyl precursor

To further expand the scope of the DDDA reaction, modifications were made to the styrene-yne tether in the form of additional substitution to the tether, incorporation of heteroatoms into the tether, and extension of the tether length. Until this point, the DDDA reactions that we explored contained an all carbon tether that contained no substituents; however, almost all previously reported DDDA reactions were performed on styrene-ynes that contained heteroatoms in their tether, usually in the form of esters, amides, or amines, or contained some form of substitution, such as a carbonyl. A typical limitation of DDDA reactions that contained heteroatoms in their styrene-yne tether was the formation of dihydronaphthalene along with the desired naphthalene product. In order to determine if our DDDA reaction would have comparable limitations, in addition to potentially expanding the reaction’s scope, changes were made to the styrene-yne tether of the styrenyl precursor.

As an initial study, modifications were made to styrenyl precursors containing an all carbon styrene-yne tether. First, increasing the tether length by one methylene unit was explored. The synthesis of the styrene-yne 1.118 commenced by subjecting commercially available hept-3- yn-1-ol (1.114) to a zipper reaction with sodium hydride and ethylenediamine to provide hept-6- yn-1-ol (1.115) in 72% yield (Scheme 1.26). The remainder of the synthesis of styrene-yne 1.118 was carried out in an analogous manner to that conducted for the synthesis 1.88 and in comparable yield (Scheme 1.18); however, the Horner-Wadsworth-Emmons reaction to produce 1.117 proceeded in a significantly reduced yield of 20% (Scheme 1.26).

Scheme 1.26. Synthesis of styrene-yne 1.118 containing an elongated styrenyl tether

A series of styrenyl precursors containing carbonyl substitution within the styrene-yne tether, rather than on the terminus of the alkyne, were also synthesized to provide substrates with tethers similar to those utilized in DDDA reactions by Terashima.46 The benefit of this modification to the styrene-yne tether is that an EWG is still appended to the dienophile, but other substituents can easily be incorporated at the alkyne terminus. The commercially available chlorobenzaldehydes 1.119 were employed as starting materials and converted to allylic alcohols 1.120 in 60-78% yield by addition of vinyl magnesium bromide (Scheme 1.27). Subsequent treatment of the allylic alcohols 1.120 with phosphorous tribromide provided 70 -83% yield of cinnamyl bromides 1.121, which were then transformed to dimethylamides 1.122 in 73-74% yield by addition to dimethylacetamide and LDA. To access the desired styrenyl precursors, the dimethylamides of 1.122 were substituted with phenyl or trimethylsilylacetylides, producing styrene-ynes 1.123 in 80 -96% or 40-55% yield, respectively.

Scheme 1.27. Synthesis of styrene-ynes containing carbonyl substitution in the styrenyl tether

One final modification to styrenyl precursors containing all carbon styrene-yne tethers was the incorporation of a central diester group. Generation of the enolate of diethyl 2-(prop-2- yn-1-yl)malonate (1.125) and subsequent reaction with cinnamyl bromide 1.126 yielded the styrene-yne 1.127 in 81% yield (Scheme 1.28). Acylation of the lithium acetylide of 1.127 was achieved by addition of N-methoxy-N-methylacetamide to produce the styrene-yne 1.128 in 86% yield.

Scheme 1.28. Synthesis of styrene-yne containing diester substitution in the styrenyl tether

In addition to styrenyl precursors in which modifications were made to styrene-yne tethers consisting exclusively of methylene units, variants of the precursors in which heteroatoms were incorporated into the styrene-yne tether were also synthesized. A more concise and convergent synthesis could be employed to access these heteroatom-containing substrates by combination of commercially available propargyl amines or alcohols and cinnamyl derivatives (Scheme 1.29). To test this proposed synthetic pathway, propargyl amine (1.129) was first tosylated to generate sulfonamide 1.130 in quantitative yield (Scheme 1.30). Subsequent treatment of 1.130 with potassium carbonate and cinnamyl bromide formed styrene-yne 1.131 in 94% yield, the lithium acetylide of which was then acylated in 45% yield using dimethylacetamide and boron trifluoride diethyl etherate to afford styrene-yne 1.132a. An ortho- chloro derivative of this styrene-yne 1.132b was also generated via an analogous synthetic route. Additionally, a styrene-yne containing an oxygen atom in its tether was synthesized via a coupling of propargyl alcohol (1.133) and cinnamyl acetate using diethyl zinc and tetrakis(triphenylphosphine)palladium(0) to generate the styrene-yne 1.134, which was then

subjected to a second palladium-catalyzed cross-coupling reaction with benzoyl chloride to produce the benzoyl-substituted styrene-yne 1.135 in 68% yield.

Scheme 1.29. Retrosynthetic analysis of styrene-ynes with heteroatom-substituted tethers

To test the effect of the DDDA reaction on styrene-ynes containing modified carbon tethers, styrenyl precursors 1.118, 1.123a-c, 1.124a-c, and 1.128 were subjected to microwave irradiation. Irradiation of 1.118 containing an elongated carbon tether for 50 min at 300 °C formed the cyclohexane-fused naphthalene 1.136 in quantitative yield (Scheme 1.31). Irradiation of 1.118 at lower temperatures of 225-250 °C only resulted in recovery of starting material. Although these reaction conditions to produce naphthalene 1.136 are harsh, this is the first example, to our knowledge, of a cyclohexane-fused naphthalene being generated via a DDDA reaction of styrenes. Irradiation of 1.128 for 30 min at 180 °C in o-DCB produced naphthalene 1.137 in quantitative yield, while irradiation of the phenyl-substituted alkynones 1.123a-c at 225 °C in o-DCB generated cyclopenta[b]naphthalenones 1.138-1.141 in high yields of 77-96% after only 40 min; higher reaction temperatures were necessary for product formation in reasonable irradiation times. Under the same DDDA reaction conditions, TMS-substituted alkynones 1.124a-c required 90 min of irradiation time to afford cyclopenta[b]naphthalenones 1.142-1.145 in comparable yields. Similar to the chloronaphthalenes 1.94 described in Scheme 1.22, halogens could be incorporated at all positions of the A ring of the cyclopenta[b]naphthalenones, and irradiation of meta-chlorostyrene-ynes resulted in a mixture of 6- and 8-substituted chloronaphthalenes, the ratio of which depended upon the steric bulk of the substituent at the 1- position. In contrast to phenyl and TMS-substituted examples, an unsubstituted alkynone was relatively unsuccessful in the DDDA reaction, providing the cyclopenta[b]naphthalenone in low yields after long reaction time.

Scheme 1.31. DDDA reaction of styrene-ynes with varied carbon tethers.

a_{Crude yields where no byproducts or impurities were observed by} 1_{H NMR spectroscopy.} b_{Isolated yields after}

While modifications to the all carbon tether of styrene-ynes were well tolerated in the DDDA reaction and allowed for the formation of naphthalene products exclusively and in high yields, introduction of heteroatoms into the styrene-yne tether resulted in mixtures of naphthalene and dihydronaphthalene products that were inseparable by column chromatography. This is in line with previously reported DDDA results where mixtures of naphthalene and dihydronaphthalene substrates were commonly obtained from styrene-ynes containing esters, amides, or nitrogen atoms in their tethers.44-45,47 Irradiation at 180 °C for only 10 min of both the non-halogenated and halogenated styrenyl precursors 1.132a and 1.132b containing a sulfonamide in their styrene-yne tethers produced an approximate 1:2 ratio of the naphthalenes 1.146 or 1.148 to the dihydronaphthalenes 1.147 or 1.149 in high combined yields of 72-86% (Scheme 1.32). These product ratios and yields are comparable to those reported by Matsubara et al. for when the alkyne terminus of the styrene-yne was substituted with an ester.47 As an additional example, styrenyl precursor 1.135 containing an oxygen atom in the styrene-yne tether was irradiated at 180 °C for 30 min, producing naphthalene 1.150 and dihydronaphthalene 1.151 in a 1.8:1 ratio and 43% combined yield. Although the yield of the naphthalene products was similar for both sulfonamide- and oxygen-containing tethers, the yield of dihydronaphthalene 1.151 was significantly reduced when compared to 1.147 and 1.149, which was attributed to decomposition of the dihydronaphthalene product upon the longer irradiation time of 30 min. Similar decomposition of sulfonamide-substituted dihydronaphthalene 1.147 was also observed upon prolonged irradiation. Attempts to oxidize the mixture of 1.146 and 1.147 using cerric ammonium nitrate, dichlorodicyanobenzoquinone, and palladium on carbon to provide naphthalene 1.146 exclusively resulted in either complete decomposition of the reaction mixture or selective decomposition of the dihydronaphthalene 1.147.

Scheme 1.32. DDDA reaction of styrene-ynes with heteroatom-containing tethers.

Yields shown are isolated yields for the product mixture after purification by column chromatography. Ratio of naphthalene and dihydronaphthalene products was determined by 1H NMR spectroscopy.