Ruthenium-Catalyzed Cycloisomerization-6-Cyclization: A Novel Route to Pyridines

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070163t.html

From Prof. Barry M. Trost's group at Stanford University

Recently appeared in Org Lett ASAP, the article presented a novel method for the synthesis of pyridine derivative.

Following metal-catalyzed [2+2+2] cyclotrimerization methodology for the synthesis of 6-membered N-heterocycles (equation 1), it was reasoned that a similar 6-pi electrocyclization of 1-aza-1,3,5-triene may provide access to pyridine derivatives.

In addition, recently the authors had disclosed a ruthenium-catalyzed cycloisomerization in the formation of alpha,beta,gamma,delta-dienones and dienals from compound of type 2 (equation 2). It was perhaps possible to use the product from this reaction to produce the required 1-aza-1,3,5-triene for the electrocyclization.

It seemed that 1-aza-triene could be formed by condensation of the carbonyl in 3 with hydroxylamine to form an oxime 4 which could electrocyclize to give pyridine 6 upon dehydration of 5 (Scheme 1).

This idea seemed to work well with compound 2a. Although pyridine 6a was not formed on prolonged refluxing in toluene, it could be obtained efficiently with microwave irradiation (Scheme 2).

Therefore, 2b was chosen to screen for optimal reaction conditions. In this substrate, pyridine 6b could be synthesized efficiently when aldehyde 3b was heated with hydroxylamine and NaOAc in ethanol.

From this initial result, more conditions were explored and the results are summarized in the table below.

The reaction was found to proceed more rapidly when the reaction was heated at higher temerpature and especially very efficient under microwave irradiation (entry 3).

After having found the optimal conditions, the scope of the method was explored and results are summarized in the table below.

The heteroatom-tethered substrates tolerated well and proceeded to give the desired products in good yields (entries 3-5). Mixture of E and Z isomers of alkene were also found to proceed without the need to separate them before the reactions (entries 5-9). Mehtyl ketones also worked quite well (entries 4, 5, 9, 10).

In the case of terminal alkene as in 3d, the reaction also worked well. Aldehyde 3d was obtained as a mixture with ketone 7 in the reaction from primary alcohol 2d.

In addition, the reaction could be run in one pot. For example, pyridine 6h could be made in 54% overall yield from alcohol 2h. The key operation in this case was that after the first step, acetone (which could cause problem with hydroxylamine in the second step) had to be removed from the reaction. The crude material could then be subjected to the second step as shown in Scheme 5.