Addition of Organocerium Reagents to Morpholine Amides: Synthesis of Important Pheromone Components of Achaea janata Michele Badioli, Roberto Ballini, Massimo Bartolacci, Giovanna Bosica, Elisabetta Torregiani, and Enrico Marcantoni* Department of Chemical Sciences, University of Camerino, Via S. Agostino 1, I-62032 Camerino (MC), Italy
[email protected] Received August 12, 2002
Readily preparable morpholine amides hitch in good yields with organocerium reagents to produce ketones. Even in the presence of substrates and reagents with high steric hindrance, the organometallic compounds prepared from dry cerium(III) chloride and organomagnesium or organolithium compounds at -78 °C add cleanly to morpholine amides. The low cost of starting materials makes this new scheme of synthesis very interesting for the preparation of biologically important pheromones. Introduction The nucleophilic addition of an organometallic reagent to carbonyl compounds is one of the most important strategies to obtain new carbon-carbon bonds. In particular, the addition of RMgX or RLi to an electrophilic carbon-oxygen double bond represents one of most important methods for introducing an alkyl group in a given substrate. However, despite its broad utility, the use of these organometallic reagents has serious limitations and the reaction is often accompanied by competing enolization, self-condensation, and reduction side processes.1 Since the undesired reactivity is mainly due to the high basicity and redox potential of Grignard and lithium reagents, many efforts have been devoted in the last years to the development of less basic organometallic species. For this, recent years have seen the development of synthetic procedures involving organolanthanoid compounds,2 especially organocerium derivatives.3 After the pioneering works of Imamoto,4 it has been reported that organocerium reagents retain strong nucleophilicity but show a very reduced tendency to effect deprotonation.5 In the course of our program aimed to explore the important role that cerium(III) chloride plays in exerting a strong activation of carbonyl compounds toward addition of organometallics,6 we sought to extend Kishi’s method7 on the addition of organocerium species to * To whom correspondence should be addressed. Tel: +39 0737 402255. Fax: +39 0737 637345. (1) March, J. Advanced Organic Chemistry; 5th ed.; Wiley-Interscience: New York, 2001; pp 1205-1209. (2) (a) Imamoto, T. Lanthanides in Organic Synthesis; Academic Press: London, 1994. (b) Molander, G. A. Chem. Rev. 1992, 92, 29. (3) Imamoto, T. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Screiber, S. L., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, pp 231-250. (4) (a) Imamoto, T. Pure Appl. Chem. 1990, 62, 747. (b) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392. (c) Imamoto, Y.; Takiyama, N.; Nakamura, K. Tetrahedron Lett. 1985, 26, 4763. (d) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Mita, T.; Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984, 49, 3904.
morpholine amides in the development of new and general strategies for the synthesis of biologically important natural substances.8 Since in the past decade there has been a growing attention in the synthesis of semiochemicals, biomolecules that spread information between individuals,9 and given that over several years one of us has been involved in developing newer methodologies allowing the synthesis of important pheromones,10 in this paper we have elaborated a novel synthetic approach to pheromone components of Achaea janata, a destructive oligophagus insect for castor crop especially when young crops are attacked. The chemicals isolated as pheromone combine (Figure 1) included (6Z,9Z)-henicosa-6,9-diene (1), (3Z,6Z,9Z)-henicosa-3,6,9triene (2), and henicosane (3).11 The availability of these (5) (a) Panev, S.; Dimitrov, V. Tetrahedron: Asymmetry 2000, 11, 1517. (b) Dimitrov, V.; Kostova, K.; Genov, M. Tetrahedron Lett. 1996, 37, 6787. (c) Bartoli, G.; Marcantoni, E.; Sambri, L.; Tamburini, M. Angew. Chem., Int. Ed. Engl. 1995, 34, 2046. (d) Bartoli, G.; Bosco, M.; Sambri, L.; Marcantoni, E. Tetrahedron Lett. 1994, 35, 8651. (e) Bartoli, G.; Sambri, L. Marcantoni, E.; Petrini, M. Tetrahedron Lett. 1994, 35, 8453. (f) Bartoli, G.; Marcantoni, E.; Petrini, M. J. Chem. Soc., Chem. Commun. 1993, 1373. (g) Johnson, C. R.; Tait, B. D. J. Org. Chem. 1987, 52, 281. (6) (a) Bartoli, G.; Bosco, M.; Di Martino, E.; Marcantoni, E.; Sambri, L. Eur. J. Org. Chem. 2001, 2901. (b) Dalpozzo, R.; De Nino, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Marcantoni, E. J. Org. Chem. 1998, 63, 3745. (c) Greeves, N.; Pease, J. E. Tetrahedron Lett. 1996, 37, 5821. (d) Bartoli, G.; Marcantoni, E.; Petrini, M.; Sambri, L. Chem. J. Eur. 1996, 2, 913. (e) Denmark, S. E.; Weber, T.; Piotrowski, D. W. J. Am. Chem. Soc. 1987, 109, 2224. (7) Kurosu, M.; Kishi, Y. Tetrahedron Lett. 1998, 39, 4793. (8) (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi, M.; Petrini, M.; Sambri, L. J. Org. Chem. 2000, 65, 4563. (b) Ballini, R.; Marcantoni, E.; Perella, S. J. Org. Chem. 1999, 64, 2954. (c) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817. (9) (a) Mori, K. Acc. Chem. Res. 2000, 33, 102. (b) Kurosawa, S.; Takenaka, M.; Dunkelblum, E.; Mendel, Z.; Mori, K. ChemBioChem 2001, 1, 56. (10) (a) Ballini, R.; Bosica, G. J. Nat. Prod. 1998, 61, 673. (b) Ballini, R. In Studies in Natural Products Chemistry; Atta-ur Rahman, Ed.; Elsevier: Amsterdam, 1997; Vol. 19, pp 117-184. (c) Ballini, R. Synthesis 1993, 687. (d) Ballini, R.; Marcantoni, E.; Petrini, M. J. Org. Chem. 1992, 57, 1316. (e) Rosini, G.; Ballini, R.; Petrini, M.; Marotta, E. Angew. Chem., Int. Ed. Engl. 1986, 25, 941. (f) Rosini, G.; Marotta, E.; Petrini, M.; Ballini, R. Tetrahedron 1985, 41, 4633. 10.1021/jo0263061 CCC: $22.00 © 2002 American Chemical Society
8938
J. Org. Chem. 2002, 67, 8938-8942
Published on Web 11/09/2002
Pheromone Components of Achaea janata SCHEME 2
FIGURE 1. Pheromone components of Achaea janata. SCHEME 1
long-chain molecules in large quantities is essential for establishing bioefficacy and also for later application in the fields. A number of works have thus been developed for the total synthesis of these pheromones,12 and each of these syntheses has its merits but is limited by length or difficult chemistry. Then, there still remains a need to develop a short, practical synthesis of these important compounds, and therein we present details relating to the synthesis of three pheromone molecules of this type. Results and Discussion It is known that pheromones 1 and 2 have structures and configurations correlative to those of linoleic and linolenic acids of wide distribution in nature. The possibility that these acids may serve as biosynthetic precursors for related insect pheromones13 has been noted. In our approach to the synthesis of pheromones 1, 2, and 3 we could visualize starting from the application of this strategy and Scheme 1 illustrates the retrosynthetic analysis. The long-chain hydrocarbons 4a-c could be prepared from reductive deoxygenation of carbonyl compounds 5a-c, which can be easily synthesized starting from the readily available simple fatty acids 6a-c. This simple retrosynthetic analysis suggests that the key intermediates of the strategy are the ketones 5a-c, and, thus, in our program directed toward synthesis of biologically active molecules such as components of important pheromones, we were in need of a procedure for the preparation of ketones starting from inexpensive substrates. The most common synthetic route is the nucleophilic acylation reaction of carboxylic acids,14 (11) Persoons, C. J.; Vos, J. D.; Yadav, J. S.; Prasad, A. R.; Jyothi, K. N.; Prasuma, A. L. IOBC/WPRS Bull. 1993, 16, 136. (12) (a) Yadav, J. S.; Rajashaker, K.; Venkatram Reddy, K.; Chandrasekhar, S. Synth. Commun. 1998, 28, 4249. (b) Vig, O. P.; Kad, G. L.; Sharma, M. L.; Dogra, V.; Sharma, S.; Huq, M. A.; Sabharwal, A. Collect. Czech. Chem. Commun. 1990, 55, 2252. (c) O’Connor, B.; Just, G. J. Org. Chem. 1987, 52, 1801. (d) Jain, S. C.; Dussord, D. E.; Conner, W. E.; Eisner, T.; Guerrero A.; Meinwald, J. J. Org. Chem. 1983, 48, 2266. (13) Hill, A. S.; Kovalev, B. G.; Nikolaeva, L. N.; Roelofs, W. L. J. Chem. Ecol. 1982, 8, 383.
important building blocks in organic chemistry, where an excess of an organometallic reagent (generally RMgX or RLi) is reacted with acid derivatives. Among them, the method developed by Weinreb15 is most popular, in which the reactions of N-methoxy-N-methylamides16 with organometallic reagents lead to the corresponding ketones in good yields with no formation of tertiary alcohols due to overaddition.17 In this regard we have recently shown18 that the (Z)-9,10-epoxynonacosane (11), the major component of the waxy coating of Rubus thibetanus Franck (Rosaceae), a blackberry species, can be synthesized in four steps starting from oleic acid (Scheme 2). The first step has required the conversion to Weinreb’s amide (8), which, after treating with Grignard reagent and succeeding transformation of the corresponding ketone 9 to alkene 10 by reduction of the tosylhydrazone intermediate,19 permits obtaining the molecule target 11 by epoxidation reaction. However, the high cost of starting materials such as MeONHMe‚HCl, which is needed to make the Weinreb amides, excluded their use on a large scale as acid derivatives.20 A more suitable and general synthetic approach was designed for the synthesis of ketones; therefore, we looked for new carboxylic acid derivatives and have developed the morpholine amides. A search in the literature indicated that morpholine amides may be used with success for nucleophilic acylation reactions from carboxylic acids and replacing Weinreb amides in ketone synthesis.21 However, there is an important limitation to the preparative use of morpholine amides in ketone synthesis; particularly, the reactions are sus(14) O’Neil, B. T. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford; 1991; Vol. 1, p 397. (15) (a) Lipshutz, B. H.; Pfeiffer, S. S.; Chrisman, W. Tetrahedron Lett. 1999, 40, 7889. (b) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (16) Sibi, M. P.; Stessman, C. C.; Schultz, J. A.; Christensen, S. W.; Lu, J.; Marvin, M. Synth. Commun. 1995, 25, 1255, and references cited. (17) (a) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685. (b) Williams, J. M.; Jobson. R. B.; Yasuda, N.; Marchesini, G.; Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461. (18) Ballini, R.; Marcantoni, E.; Torregiani, E. J. Nat. Prod. 2000, 60, 505. (19) Caglioti, L. Tetrahedron 1966, 22, 636. (20) Tiller, R.; Frey, L. F.; Tschaen, D. M.; Dolling, U.-H. Synlett 1996, 225. (21) (a) Donat, C.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron Lett. 2000, 41, 37. (b) Sengupta, S.; Mondal, S.; Das, D. Tetrahedron Lett. 1999, 40, 407. (c) Gomtsyan, A. Org. Lett. 1999, 2, 11. (d) Martin, R.; Ronica, P.; Tey, C.; Urpı`, F.; Villarasa, J. Synlett 1997, 1414. (e) Tasaka, A.; Tamura, N.; Matsushita, Y.; Kitazaki, T.; Hayashi, R.; Okonogi, K.; Itoh, K. Chem. Pharm. Bull. 1995, 43, 432. (f) Brown, J. D. Tetrahedron: Asymmetry 1992, 3, 1551.
J. Org. Chem, Vol. 67, No. 25, 2002 8939
Badioli et al. SCHEME 3
ceptible to steric hindrance, on the part of both the organometallic reagents and the starting amides, probably due to the undesired enolization4d and to the release of the product ketone in the medium, which further reacts with organomagnesium or organolithium compounds to give the tertiary alcohol. To overcome these drawbacks, a different ketone synthetic strategy was planned by Kishi,7 who found that the organometallic reagent prepared from CeCl3 and methyllithium adds to morpholine amides to give the corresponding methyl ketones. However, Kishi’s method is limited to organocerium species22 supposedly as “MeCeCl2” since in this procedure with tertiary amides the organocerium species generated under the originally reported conditions4 presented a poor reproducibility. In our opinion, the efficiency of this ketone synthesis by organocerium strategy could be influenced by the temperature, and, in fact, a solution to this problem we have found is by running the reaction at low temperature such as -78 °C (Scheme 3). In these conditions the enhancement of reactivity could be attributed to the fact that organocerium reagent acts as a Lewis acid, coordinating to the morpholine oxygen atom, decreasing the basicity of morpholine nitrogen and thereby increasing the electrophilicity of amide carbonyl. Even in the presence of excess organocerium reagent no tertiary alcohol was detected, indicating that a metalchelated tetrahedral intermediate 14 was perfectly stable under the reaction conditions. We began an investigation in which the reaction of 1-morpholin-4-yldecan-1-one (12a)23 with n-propylmagnesium chloride-CeCl3 (13a) was examined under a variety of conditions. Best results were obtained by adding morpholine amides 12 at -78 °C to Grignard reagents in the presence of dry CeCl3,24 followed by acidic quenching, directly affording ketones 15 in satisfactory (22) Addition of organocerium compounds to Weinreb’s amides, see: Brenner-Weiss, G.; Giannis, A.; Sandhoff, K. Tetrahedron 1992, 48, 5855. (23) Morpholine amides of type 12 have been efficiently prepared by reaction of anhydrous morpholine with corresponding acid chloride in the presence of dry pyridine. This reaction works well with linear alkyl and R-branched chain acids and provides a mild and general method for the synthesis of amides. On the other hand, the preparation of amides from acids via the mixed anhydride method does not always provide satisfactory results. (24) It has been reported (Evans, W. J.; Feldman, J. D.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 4581) that the material obtained after drying of CeCl3‚H2O (at 150 °C and 0.03 Torr for 12 h) was [CeCl3‚ (H2O)n]. We have not analyzed the CeCl3 prepared by the Imamoto procedure; however, the material was highly efficient without the need of a large excess of Grignard or organolithium reagent.
8940 J. Org. Chem., Vol. 67, No. 25, 2002
yields (Table 1). We have studied the reaction with several carbon-based nucleophiles, in THF,25 and the highest yields were obtained with a 3 molar excess of the reagent 13 prepared from a 1:1 ratio of the organometallic reagent precursor and dry CeCl3. Generally organolithium-derived cerium reagents show slightly lower yields (Table 1, entries 3, 5, and 9) than the organocerium ones. This different behavior cannot be rationalized by the lack of information on the actual structure of the organometallic reagents. Indeed, despite continued years of intensive interest in the chemistry of organocerium compounds and their applications as reagents for organic synthesis, the solution structure of these reagents is not well understood.26 Moreover, we have observed that the organomagnesium-derived secondary cerium reagent was unable to provide the corresponding ketone with satisfactory yield, likewise to Grignard precursor,21d emphasizing the problem of the nature of the reagent used. Organocerium reagents are indeed usually prepared by transmetalation reaction, and the reactions involving organomagnesium reagents are often carried out at 0 °C.27 Thus, the transmetalation process proceeds slowly at low temperature, and at -78 °C it would be practically ineffective, so that a reactive species of type RMgX‚CeCl3 is postulated.28 This RMgX‚CeCl3 complex still retains a consistent degree of basicity, which could be the basis of the lack of reactivity under these conditions of the isopropylmagnesium chloride-CeCl3. To overcome this drawback, we have used the organocerium reagent prepared at 0 °C from isopropyl Grignard and then cooled to -78 °C and then added morpholine amide. This modification of the procedure gave a reaction mixture from which the ketone 15ab was isolated in good yield (Table 1, entry 2). The versatility of this addition of organocerium compounds to morpholine amides for obtaining carbonyl compounds has suggested that our finding could provide a new useful method for the transformation of easily available carboxylic acids to hydrocarbon moieties of important natural products. Indeed, in connection with our project directed at the preparation of important pheromones (1-3), we have reasoned that key intermediate ketones (5a-c) can be prepared from corresponding commercial acids as such linoleic, linolenic, and stearic acids, utilizing this chemistry. We decided to start (Scheme 4) from commercially available starting materials (6a-c), which are transformed into the amides 17a-c by reaction of acid chlorides 16a-c with morpholine according to standard procedures. These compounds show normal tertiary amide stability and thus require no special handling or storage. The morpholine amides were treated with propylmagnesium chloride,29 producing the ketones 5a-c in good yields after hydrolysis and purification by employing a silica gel column. Finally, for the preparation of long(25) Diethyl ether (Et2O) was also examined as a solvent and found to be less desirable than THF, as the reaction in Et2O was slower and not as clean. (26) (a) Enders, D.; Schankat, J.; Klatt, M. Synlett 1994, 795. (b) Denmark, S. E.; Edwards, P. J.; Nicaise, O. J. Org. Chem. 1993, 58, 569. (27) Bartoli, G.; Marcantoni, E.; Sambri, L. In Seminars in Organic Synthesis; XXV Summer School “A. Corbella”, Gargnano (BS); Italian Chemical Society: Rome, 2000; pp 117-138. (28) Liu, H.-J.; Shia, K.-S.; Shang, X.; Zhu, B.-Y. Tetrahedron 1999, 55, 3803.
Pheromone Components of Achaea janata TABLE 1. Reaction of Amides (12) with Organolithium or Organomagnesium Reagent in the Presence of Dry CeCl3 (13) entry
R′
R′′
amidea
organocerium
ketone
yield (%)c
1 2 3 4 5 6 7 8 9 10
CH3(CH2)7CH2 CH3(CH2)7CH2 CH3(CH2)3CH2 CH3CH2CH(CH3) CH3CH2CH(CH3) CH3CH2CH(CH3) CH3CH(C6H5) (E)-C6H5CHdCH (E)-C6H5CHdCH CH3(CH2)7CHdCH(CH2)7
CH3CH2CH2MgBr (CH3)2CHMgBr CH3CH2Li n-C4H9MgBr n-C4H9Li n-C10H21MgCl n-C10H21MgCl n-C4H9Li C6H5CH2MgCl CH3CH2CH2MgBr
12a 12a 12b 12c 12c 12c 12d 12e 12e 12f
13a 13b 13c 13d 13d 13e 13e 13e 13f 13a
15aa 15ab 15bc 15cd 15cd 15ce 15de 15ed 15ef 15fa
92 85 71 92 73 90 87 68 85 90
a All amides were prepared from commercially available acids and dry morpholine. b All products were identified by their IR, NMR, and GC/MS. c The yields are of isolated, purified products.
SCHEME 4
chain hydrocarbon pheromones a deoxygenation of ketones is necessary without the production of any side products and above all no Z-E isomerization of double bonds for 5a and 5b. Various methods have been developed for this conversion of carbonyl functions in ketones to methylene groups,30 but generally these procedures require drastic conditions, which prompted us to investigate another strategy. Thus, to accomplish our objective, we turned to tosylhydrazone formation and reduction strategy, which has been demonstrated to be a convincing alternative to the direct/indirect deoxygenation methods. Between many different reduction procedures known in the literature we have tried the inexpensive NaBH4 in methanol reflux.19 We found that this mild deoxygenation method reduces henicosan-4-one (p-tolylsulfonyl)hydrazone (18c) in good yield (>80% isolated product) to give the corresponding hydrocarbon. Attempted deoxygenation of ketones 5a and 5b by Caglioti’s procedure, however, gave a complex mixture of alkenes with Z-E isomerization and double-bond migration. This problem was not circumvented by repeating the deoxygenation (29) It is desirable to use the Grignard reagent as the source of transferable alkyl group, which was purchased as solutions in THF and titrated just before use (Bergbreit, D. E.; Pendergross, E. J. Org. Chem. 1981, 46 (6), 219). (30) (a) Hutchins, R. O.; Hutchins, M. C. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8, pp 327-349. (b)Yamamura, S.; Nishiyama, S. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8, pp 307-325. (c) Hudlicky, M. Reductions in Organic Chemistry; Wiley: New York, 1984.
using a mild reducing agent such as sodium cyanoborohydride for reduction31 of tosyl hydrazones derived from 5a and 5b. Fortunately, diisobutylaluminum hydride (DIBAL-H) has proven to be a suitable reagent for this purpose. The reduction was carried out at low temperature (0 °C) in CH2Cl2, and the alkaline workup of the reaction mixture32 allows obtaining the desired (6Z,9Z)henicosa-6,9-diene (4a), (3Z,6Z,9Z)-henicosa-3,6,9-triene (4b), and henicosane (4c) with an overall yield of 62%, 61%, and 70%, respectively. In conclusion, this work is a further demonstration of less basicity and higher oxophilicity of organocerium species than the precursors from which they are derived. This allows us to develop the synthetically useful procedure previously reported by Kishi for the preparation of ketones from a carboxylic functionality. The optimized addition of organocerium compounds to morpholine amides has been applied to the synthesis of long-chain hydrocarbon saturated and polyunsaturated pheromones from commercially available starting materials. Further investigations utilizing the addition of organocerium reagents to acid derivatives for the synthesis of biologically active products are currently in progress in our laboratory.
Experimental Section General Methods. All the chemically pure solvents, i.e., THF and CH2Cl2, were purchased from standard firms and further dried whenever needed by standard procedures. Stearic, linoleic, and linolenic acids were purchased from commercial suppliers and used as such. n-Propylmagnesium chloride was purchased as solutions in THF and titrated just before use. All reactions with compounds sensitive to air or moisture were performed under nitrogen atmosphere with flame-dried glassware. The 1H and 13C NMR spectra were obtained at 200 and 75.5 MHz, respectively. All NMR spectra were obtained in CDCl3 using CHCl3 (1H δ 7.26 ppm) and CDCl3 (13C δ 77.00 ppm) as internal standards. Mass spectra were determined on a capillary gas chromatograph operating in splite mode with helium carrier gas and fitted with a mass selective detector (MSD). Analytical TLC were performed on silica gel plates (60 F254), and flash column chromatography33 was carried out using silica gel (0.040-0.063 mm). (31) (a) Miller, V. P.; Yang, D.; Weigel, T. M.; Han, O.; Liu, H. J. Org. Chem. 1989, 54, 4175. (b) Han, O.; Shih, Y.; Liu, L.; Liu, H. J. Org. Chem. 1988, 53, 2105. (32) Lightner, D. A.; Gawronski, J. K.; Bonman, T. D. J. Am. Chem. Soc. 1980, 102, 1983. (33) Still, W. C.; Khan, M.; Mitra, A. J. Org. Chem. 1978, 43, 2953.
J. Org. Chem, Vol. 67, No. 25, 2002 8941
Badioli et al. Representative Procedure for the Preparation of Morpholine Amides. Synthesis of (9Z,12Z)-1-Morpholin4-yloctadeca-9,12-dien-1-one (17a). To a mixture containing 5.0 mmol of linoleic acid and 25 mL of dry benzene was added thionyl chloride (30 mL), and the mixture was stirred for 24 h at 50 °C. The solvent and excess of thionyl chloride were evaporated off under reduced pressure, and the residual acid chloride was used in the next stage of preparation without purification. To a stirred solution of the acid chloride in 60 mL of EtOHfree CHCl3 was added dry morpholine (0.48 g, 5.5 mmol) in EtOH-free CHCl3 (1 mL). The mixture was cooled at 0 °C, and pyridine (0.43 g, 5.5 mmol) was added dropwise via syringe. Stirring was continued for 20 h at room temperature, and then the mixture was evaporated under reduced pressure. The residue was diluted with a 1:1 mixture of Et2O and CH2Cl2, washed with brine containing sufficient 2 N HCl to remove the amines, washed with saturated aqueous NaHCO3, and dried over Na2SO4. After evaporation of solvent the crude product was purified by flash chromatography (30% EtOAc/ hexane), affording 17a (88% yield) as a pale yellow oil: IR (neat, cm-1) 3025, 1670, 1575; 1H NMR δ 0.92 (t, 3H, J ) 6.97 Hz), 1.15-1.37 (m, 14H), 1.58-1.70 (m, 2H), 1.96-2.10 (m, 4H), 2.31 (t, 2H, J ) 6.54 Hz), 2.75-2.85 (m, 2H), 3.40-3.51 (m, 2H), 3.53-3.67 (m, 6H), 5.25-5.40 (m, 4H); 13C NMR δ 18.95, 20.67, 24.65, 25.01, 25.96, 26.01, 26.76, 27.05, 27.80, 29.77, 30.05, 34.00, 42.60, 44.76, 46.92, 66.96, 127.04, 128.54, 131.26, 133.05, 170.96. Anal. Calcd for C22H39NO2: C, 75,59; H, 11,25; N, 4,01. Found: C, 75,19; H, 11,35; N, 4,02. Reaction between Morpholine and Organocerium Reagents. A 250 mL three-neck flask fitted with septum and gas inlet was charged with CeCl3‚7H2O (4.46 g, 12 mmol), which was dried by heating to 140 °C at 0.2 Torr for 2 h.34 The flask was allowed to cool at room temperature and vented to dry nitrogen, and THF (40 mL) was added from a syringe. This slurry was stirred overnight at room temperature and cooled to -78 °C. To this white suspension was added slowly organomagnesium or organolithium compound (12 mmol) from a syringe, and the reaction mixture was stirred for 2 h at -78 °C. A solution of morpholine amides (4 mmol) in THF (25 mL) was added dropwise, and the reaction mixture was stirred for 1.5 h at -78 °C. Then, it was quenched by addition of 10% aqueous acetic acid (90 mL) and extracted with Et2O (5 × 75 mL). The combined organic layers were washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated to afford an oil. Purification by flash chromatography on a silica gel column by a mixture of hexane/ethyl acetate (8:2) as eluent afforded ketone in good yield. Synthesis of Pheromones 4a-c. Typical Procedure. A solution of (p-tolylsulfonyl)hydrazine (0.47 g, 2.5 mmol) in (34) Imamoto, T.; Takeda, N. Org. Synth. 1998, 76, 228.
8942 J. Org. Chem., Vol. 67, No. 25, 2002
EtOH (18 mL) was added to a solution of ketones 5a-c (2.25 mmol), and the mixture was stirred for 24 h until the formation of tosylhydrazone was completed. Then, the reaction mixture was evaporated to dryness under reduced pressure and washed with pentane to give a crystalline product, which was used in the next stage without purification. To tosylhydrazone in 4.5 mL of dry CH2Cl2 was added at 0 °C under N2 5.2 mL of 1 M diisobutylaluminum hydride (DIBAL-H) in hexane. All the tosylhydrazone was dissolved during DIBAL-H addition. Stirring was continued for 30 min, and the solution was carefully decomposed with 2.5 mL of 3 N aqueous NaOH and extracted with pentane (4 × 40 mL). The organic layer was dried (MgSO4), the solvent was removed by distillation, and the crude product was purified by column chromatography (1% ethyl acetate in petroleum ether) to give pure C-21 hydrocarbons 4a-c. (6Z,9Z)-Henicosa-6,9-diene (4a): pale yellow oil (80%); IR (neat, cm-1) 3009,1475; 1H NMR δ 0.90 (t, 6H, J ) 6.85 Hz), 1.24-1.40 (m, 24H), 2.03-2.09 (m, 4H), 2.92 (t, 2H, J ) 6.05), 5.29-5.36 (m, 4H); 13C NMR δ 14.60, 14.74, 21.04, 21.46, 23.22, 26.04, 26.10, 27.89, 29.72, 30.01, 30.15, 30.24, 32.51, 128.15, 128.84, 128.99, 132.68; EI-MS m/z 292 [M+], 99, 96, 81, 67 (100), 55, 43, 41. Anal. Calcd for C21H40: C, 86.21; H, 13.78. Found: C, 86.19; H, 13.82. (3Z,6Z,9Z)-Henicosa-3,6,9-triene (4b): pale yellow oil (82%); IR (neat, cm-1) 3015, 1494; 1H NMR δ 0.88 (t, 3H, J ) 6.63 Hz), 0.92 (t, 3H, J ) 6.19 Hz),1.25-1.42 (m, 18H), 2.012.13 (m, 4H), 2.82 (t, 4H, J ) 6.05 Hz), 5.31-5.42 (m, 6H); 13C NMR δ 14.48, 14.75, 21.04, 21.37, 23.18, 26.01, 26.10, 27.74, 29.71, 29.84, 30.05, 30.14, 32.41, 36.06, 127.61, 128.10, 128.72, 128.77, 130.89, 132.42; EI-MS m/z 290 [M+], 99, 96, 85, 81, 67 (100), 55, 43, 41. Anal. Calcd for C21H38: C, 86.81; H, 13.18. Found: C, 86.79; H, 13.15. Henicosane (4c): colorless oil (87%); 1H NMR δ 0.88 (t, 6H, J ) 7.03 Hz), 1.25-1.39 (m, 38H); 13C NMR δ 14.10, 21.64, 23.76, 29.07, 29.25, 29.46, 29.79, 30.04, 32.02; EI-MS m/z 296 [M+], 267, 113, 99, 85, 71, 57 (100), 43, 41. Anal. Calcd for C21H44: C, 85,05; H, 14,95. Found: C, 85.08; H, 14.96.
Acknowledgment. Financial support from Fondazione Cassa di Risparmio della Provincia di Macerata (Italy) is gratefully acknowledged. The authors warmly also thank University of Camerino and MIUR (Research National Project “Stereoselection in Organic Synthesis. Methodologies and Applications”) for the continued financial support of their programs. Supporting Information Available: Detailed experimental procedures and spectral and analytical data of amides 12 and 17 and ketones 15. This material is available free of charge via the Internet at http://pubs.acs.org. JO0263061
