83
Chapter 5
Conclusions
The main goal of this work was the development of new synthetic routes to alk-1-enyl sulfoxides and sulfones. As already stated, these compounds are very valuable as building blocks and chiral auxiliaries in organic synthesis, due to their peculiar stereoelectronic properties, which allow excellent diastereo- or enantiocontrol even on remote reaction centers.
The current approaches to these derivatives, described in Chapter 1, are however not always efficient, and for this reason new approaches are desirable. Surprisingly, among the reported routes to sulfones and sulfoxides, use of dialkyl alk-1-enyl aluminum reagents was almost completely unexplored, in contrast with what reported on other alkenyl organometallic reagents. Considering that dialkyl alkenyl aluminum reagents are easily obtained by hydroalumination of alanes, our attention was directed to these easily available reagents.
The first attempts were performed using the modification of a procedure reported in the 1960s by Reinheckel (Section 2.2). In this approach, an aluminum sulfinate was prepared from a sulfonyl chloride and Et3Al. Subsequent addition of the suitable dialkyl alkenyl aluminum in hexane solution afforded the pure sulfoxide. The reaction was tested on several alkynes and sulfonyl chlorides, and no appreciable dependence on the nature of the substrates employed was found (Scheme 5.1).
84 Chapter 5 + R S O S R Cl AlEt3 R S OAlEt2 O + O O CH2Cl2 r.t. S R OAlEt2 O Hexane, rfx. 5h (i-Bu)2Al R' R' + EtCl (i-Bu)2Al O AlEt2 + 72-75% / RSO2Cl 1.5/1 (i-Bu)2Al R'
Scheme 5.1: Modification of Reinheckel protocol applied to the synthesis of alk-1-enyl
sulfoxides
Although the reaction seemed reasonably efficient, it was necessary to employ 1.5 molar equivalents of the alane in order to achieve a good yield of sulfoxide; this resulted in a rather poor yield with respect to the starting organo metallic reagent. Any attempt to improve the yields failed, thus limiting the synthetic applicability of this reaction.
A different approach was adopted in the synthesis of sulfoxides, starting from pyridine-complexed alanes (Section 2.3.2). Ph3P was chosen as reducing agent, and acceptable yields of sulfoxide were obtained. The reaction was improved by studying the effect of temperature, solvents and ratio between reagents, by means of a chemiometric analysis; this led to optimized reaction conditions (Scheme 5.2). Ar S Cl O O (i-Bu)2Al R N + PPh3 Ar S R O CH2Cl2 0 oC, 5min + Ph3PO + (i-Bu)2Al N Cl 70-94% / ArSO2Cl/Ph3P 1/0.92/1.35 (i-Bu)2Al R N
Scheme 5.2: Synthesis of alk-1-enyl sulfoxides from pyridine-alanes complexes, sulfonyl
chlorides and Ph3P.
Preliminary mechanistic investigations were performed on this reaction (Section 2.3.3); in particular, NMR analysis of the reaction intermediates, and reactions performed with benzene sulfinyl chloride, allowed to propose a rationale. This hypothesis, although not fully demonstrated, explains all the experimental evidence available.
The study of the synthesis of alk-1-enyl sulfones took first into consideration the reactivity of sulfonyl chloride-pyridine complex with unsolvated alanes
Conclusions 85
(Section 3.2). It was found that good to excellent conversions can be achieved when a fast addition of the alane to the sulfonyl chloride-pyridine complex was performed (Scheme 5.3). Conversions and yields seemed to depend on the steric hindrance of the residue present on the alkenyl chain.
+ (i-Bu)2Al N Cl R' S Cl O O (i-Bu)2Al R R' S R O O N R' S N O O Cl CH2Cl2, r.t., 5min 40-90%
Scheme 5.3: Synthesis of alk-1-enyl sulfones starting from TsCl-Py complex and
uncomplexed alanes.
Further investigations showed that the less than quantitative conversion was likely due to the complexation of pyridine with unreacted dialkyl alkenyl aluminum; this hypothesis was confirmed by NMR analysis performed on the reaction mixtures. Addition of copper chloride as pyridine complexant led to better yields (Section 3.2.2).
In order to achieve more general results, a different approach was studied which employed Ph3PO as catalyst. In this case, pyridine-alane complexes gave best results, allowing the synthesis of aryl alkenyl sulfones in good yields (Section 3.3). Ar S Cl O O (i-Bu)2Al R N + Ph3PO Ar S R CH2Cl2 rfx., 1h O O + (i-Bu)2Al N Cl 70-76%
Scheme 5.4: Synthesis of alk-1-enyl sulfones from pyridine-alane complexes and sulfonyl
chlorides in the presence of Ph3PO
This procedure gave similar results regardless of the chain transferred (Scheme 5.4).
Although the synthesis of aryl alkynyl and diaryl sulfones was not a goal of this work, a brief investigation was performed on their preparation; acetylenic and aryl Grignard reagents, whose synthesis is particularly easy, were tested. In these cases acceptable, even though rather erratic, yields were obtained (Section 3.2.3).
Considering the good and unexpected results obtained in the previously summarized rections, as last part of this work, the reactivity of di-i-butyl alk-1-enyl aluminum-pyridine complexes towards compounds different from sulfonyl
86 Chapter 5
chlorides was tested (Chapter 4). It was found that N-acyl-2-alk-1’-enyl-2H-dihydropyridine derivatives were formed in nearly quantitative yields upon addition of acid chlorides under very mild reaction conditions (Scheme 5.5).
R' Cl (i-Bu)2Al R N + CH2Cl2 0 oC, 5min O N O R' R + (i-Bu)2AlCl 90-94%
Scheme 5.5: Synthesis of N-acyl-2-alk-1’-enyl-2H-dihydropyridine and dihydroisoquinoline
derivatives by reaction of acid chlorides with complexed alanes
This protocol afforded synthetically interesting derivatives and was extended to benzoyl imidazole and 8-trimethylsilyloxyquinoline. In all cases the reaction afforded the desired compounds in excellent yields, without any trace of byproducts.
