Divinyl ketone, preparation

The reaction of alkenyl iodides or triflates, alkenylstannanes, and CO affords divinyl ketones[397,398]. Thus the capnellene skeleton 538 has been synthesized by the carbonylation of the cyclopentenyl triflate 536 with the alkenyltin 537[392], The macrocyclic divinyl ketone 540 has been prepared in a moderate yield by the carbonylative cyclization of 539[399]. 

For the preparation of divinyl ketones, as required for the Nazarov reaction, various synthetic routes have been developed. A large variety of substituted divinyl ketones, including vinylsilane derivatives, can thus be prepared. The Nazarov cyclization, and especially the vinylsilane variant, has found application for the synthesis of complex cyclopentanoids. 

Symmetrical ketones can be prepared in good yields by the reaction of organo-mercuric halides with dicobalt octacarbonyl in THF, or with nickel carbonyl in DMF or certain other solvents. The R group may be aryl or alkyl. However, when R is alkyl, rearrangements may intervene in the C02(CO)g reaction, though the Ni(CO)4 reaction seems to be free from such rearrangements. Divinylic ketones... 

Si-directed Nazarov cyclization (13, 133-134). Denmark2 has extended the Si-directed cyclization of (i-silyl divinyl ketones to preparation of linear tricycles (triquinanes). These cyclizations proceed very readily even at low temperatures, and the position of the double bond is controlled by the silyl group. The reactions... 

Addition of P—H bonds to unsaturated systems also continues to be used as a route to heterocyclic systems. Thus base-catalysed cyclization of the phosphine (32) [prepared by the addition of methyl methacrylate (2 moles) to phenylphosphine], followed by subsequent hydrolysis and decarboxylation, affords the phosphorinanone (33). The phosphorinanone system is also directly accessible by the addition of phenylphosphine to divinyl ketones.28 The radical-initiated addition of phenylphosphine to dialkynyl systems (34) gives the heterocyclohexadienes (35).29 80 The stereochemistry of the addition of phenylphosphine to cyclo-octa-2,7-dienone to give... 

Freshly prepared 11 reacts readily with phenylacetylene 13 to give divinyl ketone 108 and Rh4(GO)i2 at room temperature under a GO pressure or GO atmosphere. The result strongly suggests that insertion of 13 into an Rh-Si bond in 11 must be involved at the first stage of the conversion of 11 to 108. The resulting vinyl-rhodium species 109 reacts with GO to form an acyl-rhodium intermediate 108, coupling of which with another molecule of 109 would afford 108 (Scheme 4). ... 

AH- Thiopyrans are directly accessible only in relatively poor yield, and then only by condensation of a suitable 1,5-dicarbonyl compound with sulfide (690PP21). As has been described earlier, this particular reaction is bedevilled with the problem of disproportionation to tetrahydrothiopyrans and thiopyrylium compounds. Thiopyran-4-ones may be prepared in a related manner by addition of sulfur dichloride to divinyl ketones, followed by base treatment (76MI22500). 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

Cyclopentenones. Trimethylvinylsilane has been used to prepare annelated cyclopentenones by cyclization of intermediate divinyl ketones (9, 498-499). The major limitation is that the double bond in the product is located at the most stable position (ring fusion). A modification using the Grignard reagent derived from 1 results in 4,5-annelated-2-cyclopentenones, as outlined in equation (I) for a typical case. The overall yields are in the range 39-65%. The c/s-isomers are formed predominately or exclusively. The same sequence can be applied to acyclic a,/i-unsaturated aldehydes to furnish 4- and 5-substituted 2-cyclopentenones, a cyclization that is not possible in the absence of the /f-trimcthylsilyl group.2... 

Several 4-piperidone syntheses are based on the addition of a primary amine to a divinyl ketone and methods for the preparation of l,2,5-trimethyl-4-piperidone (the precursor of the promedols) and the 2,3-dimethyl analog by this means are shown (Schemes 7.2 and 7.3). 3,5-Dimethyl-4-piperidone is prepared on a similar basis/41 while the 2,6-dimethyl ketone is made either by a Mannich procedure from dimethyl acetonedicarboxylate and acetaldehyde (leading to c-t mixtures)(26) or by catalytic reduction of l,2,6-trimethyl-4(lH)-pyridone (37) and oxidation of the resultant 4-piperidinols, giving a cis product.(58)... 

The facile elimination of -heterosubstituents in ketones allows for the ready construction of a,p-enones. Three different heteroatoms have been employed, chlorine, nitrogen and oxygen. The -chloro enones (products of Friedel-Crafts acylation) suffer Nazarov cyclization under standard conditions. -" Jacquier has prepared a series of -amino enones (31) from Mannich condensations." These substrates undergo cyclization in modest yields under standard conditions (equation 23). Takeda has found that the readily available" tetrahydro-4-pyranones (32) produce 2-cyclopentenone-4-carboxylates upon treatment with TMS-I (equation 24). " It is noteworthy that the putative a-carboalkoxy divinyl ketones have been independently cyclized by Marino using TMS-I. ... 

A significant advance in the use of Friedel-Crafts acylation of alkenes to prepare divinyl ketones was the employment of vinylsilanes to control the site of electrophilic substitution. Two groups have developed this approach to cyclopentenone annulation using slightly different strategies. In the method described by Magnus the reagent vinyltrimethylsilane (80) is used primarily as an ethylene equivalent (equation 44). The construction of bicyclic systems followed readily as Nazarov cyclization proceeded under the reaction conditions. Tin(lV) chloride was found to be the most effective promoter of the overall transformation. As expected the position of the double bond is thermodynamically controlled. 

The Nazarov cyclization has been featured in a variety of synthetic endeavors involving both natural and unnatural products. In the area of polyquinane natural products ( )-hirsutene (88), ( )-mod-hephene (89), ( )-silphinene (90), ( )-A 2)-capnellene (91) and ( )-cedrene, have all been prepared (Scheme 37). The synthesis of (91) is noteworthy in the iterative use of the silicon-directed Nazarov cyclization. TIk divinyl ketones were constructed by the carbonylation-coupling of enol triflates (92) and (95) with the -silylvinylstannane (Scheme 38). llie diquinane (94), obtained from Nazarov cyclization of (93), was transformed into enol triflate (95) which was coupled with the -silylvinylstaimane as before. Silicon-directed Nazarov cyclization of (96) was highly diastereoselective to provide the cis,anti,cis isomer of (16). The synthesis was completed by routine manipulations. 

These have been much less popular, but some examples have been reported. These involve only alkenyltins containing one additional moiety on the G-carbon this substituent can be trimethylsilylmethyl (leading to functionalized allylsilanes [37] or divinyl ketones (Scheme 4-10) [38]) or trifluoromethyl [39]. The substituent can also be in the /3-position (E-geometry) examples have been reported by Parrain et al. [40] and Castano et al., the latter having used the coupling reaction of a jS-stannyl enone as the key step in the preparation of the indolizidine alkaloid ( )-monomorine here the coupling step is followed by an immediate in-situ reduction of the intermediate enone, the mechanism of which is unclear (Scheme 4-11) [41J. 

There have been few transformations of vinylcupiate reagents with acid chlorides (Section 1.13.3.1.1). Marino and Linderman have reported a gener preparation of divinyl ketones useful in a Nazarov sense for the formation of cyclopentenones (Scheme 33). Addition of various cuprate species to ethyl propio-late formed a mixed cuprate which is peibaps best represented as the allene (91). In the case of heterocuprates (89) and (90), acylation proceeded in good yield to form the divinyl ketone. Dimethylcuprate afforded none of the desired product but instead produced 1-acetylcyclohexene. The method was generalized for several different acid chlorides. 

The Nazarov cyclization is well suited for the construction of simple cyclopentenones adorned with various substimtion patterns. A collection of representative structures prepared from either allyl vinyl or divinyl ketones is shown in Scheme 10. Many different alkyl groups are compatible with the substimtion patterns. Aromatic substiments, especially at the a-position, have a benefici effect on the reaction rate and yield. In all of those cases where a choice is possible, the double bond resides in the thermodynamically most stable position. 

The same approach was also used to prepare the truncated YCK analogues, 116-119 (69,70). Cheng also prepared inverto-YCK (124) from the add chloride 120 (Scheme 9). The key steps involved the coupling of 3-indolezinc reagent with the acid chloride 120, followed by Nazarov cyclization of the divinyl ketone 121, to the tetracyclic ketone intermediate, 122. The indolyl moiety was introduced by Pd(0)-mediated cross coupling between the indolezinc reagent and the acetate derivative, 123 (71). 

An Inspired variant in the preparation of divinyl ketones, which then undergo Nazarov-type cyclizations to cyclopentenones, is shown in Scheme 7. The reaction involves the treatment of a tetrahydro-... 

Figure 15.18 shows several examples of electrocyclic processes. Since the reactions are always allowed in either a conrotatory or disrotatory manner, the key issue is the control of stereochemistry. Electrocyclic reactions provide a good example of the power of pericyclic reactions in this regard. In all cases, the reaction proceeds as predicted from the various theoretical approaches. The restrictions placed by the orbital analysis on the reaction pathway are nicely demonstrated by examples D and E in Figure 15.18 only the stereochemistry given is found. An instructive example of the fact that it is the number of electrons that controls the process, not the number of atoms or orbitals, is the conrotatory ring closure of the four-electron pentadienyl cation prepared by protonation of a divinyl ketone (example G). 

Nazarov cyclization of divinyl ketones is a powerful method for the preparation of cyclopentenones. Two complementary routes to fused bicyclic ketones via acylation of vinyl silanes followed by Nazarov cyclization have been described [equations (45) and (46)]/ The same sequence can also be used with simple... 

Electrocyclization reactions are powerful synthetic tools to prepare compounds of great molecular diversity. These reactions allow for the formation of many substituted cyclic and polycychc compounds important in medicine, materials science, cosmetics, and so on. The well-established mechanisms and predictable outcomes of electrocyclization reactions permit the elaboration of logical blueprints for the synthesis of important molecules. Among these, the Nazarov cyclization is a salient member of the family. Reported first in 1941 by Ivan Nikolaevich Nazarov [1], this reaction has been studied extensively and many variations and applications have been developed over the years. In this chapter, we will present selected examples highlighting the versatility and synthetic power of this transformation [2]. In its simplest form, the Nazarov employs a divinyl ketone as the starting material, a cross-conjugated compound which can be regarded as a 3 -oxa-[3]dendralene. 

In 1998, the first deliberate attempt to trap the oxyallyl cation with a nucleophile during a thermal Nazarov reaction was reported by West and coworkers [23]. Coining the term interrupted Nazarov reaction, they described the interception of the oxyallyl intermediate of a Nazarov reaction by a tethered alkene (Scheme 3.20). Upon submission of divinyl ketones 87 to the LA, a conrotatory ring closure generates the oxyallyl cation intermediate 89. The alkene moiety adds selectively to the oxyallyl cation intermediate to form bicycle 90. The stabilized tertiary carbocation is then trapped by the enolate oxygen to give intermediate 91, which, under acidic aqueous conditions, is converted to the final hemiketal product 88. The reaction provides an efficient and stereoselective method to prepare tricychc compounds 88 in yields ranging from 42 to 89% [24]. 

The ( )-p-alkoxy divinyl ketones 129, potential Nazarov reaction precursors, are prepared according to the torquoselective olefination methodology with ynolates (Fig. 45). For example, ethyl 3-phenylpropionate (127) is olefinated by the ynolate to afford the p-alkoxy-ot,p-unsaturated acid 128 with high -selectivity. The acid 128 is converted into the Weinreb amide, which is subjected to alkenylation to provide the p-alkoxy divinyl ketone 129 in good overall yield. 

Z)-Ethylenic mixed anhydrides are easily prepared without isomerization and react with vinyl cuprates (and other organometallics) under Pd° catalysis with >99% stereochemical control to give unsymmetrical divinyl ketones (eq 18). Alternative routes via (Z)-ethylenic acyl chlorides produce ( /Z) mixtures. 

Parrain and coworkers described an efficient cascade involving the ring opening of cyclopropene ketal of type 71 followed by CM with a variety of alkenes in the presence of catalyst [Ru]-I for the synthesis of protected divinyl ketones [42]. This sequence was employed by Kozmin and coworkers for the preparation of the linear center portion of bistramide A, a marine metabolite isolated from Lissodinum bistratum which exhibits potent cytotoxicity against several cell lines [43], as well as... 

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