HOT TOPICS: MULTIFUNCTIONAL MATERIALS AND ORGANIC SYNTHESIS 276 CHIMIA 2006, 60, No. 5 Chimia 60 (2006) 276–284 © Schweizerische Chemische Gesellschaft ISSN 0009–4293 Intramolecular Schmidt Reaction: Applications in Natural Product Synthesis Erich Nyfeler and Philippe Renaud* Abstract: The intramolecular Schmidt reaction was first described at the beginning of the 1990s and rapidly proved to be a powerful tool for the fast assembly of complex nitrogen-containing heterocycles. This review focuses on the application of this reaction in the synthesis of natural products and other biologically relevant compounds. Keywords: Alkaloids · Alkyl azides · Iminium ions · Lactams · Rearrangement · Tertiary amines · Total synthesis 1. Introduction ment. Cation 1.8a loses water to give the [11]. (+)-Camphoric acid 2.1 reacts with so- iminodiazonium intermediate 1.9, which dium azide in the presence of sulfuric acid The Schmidt reaction describes the reaction undergoes a 1,2 shift of an alkyl group de- to afford diamine 2.2 in 91% yield. of carbonyl compounds, such as carboxylic livering the nitrilium ion 1.10. Trapping of acids, ketone and aldehydes, with hydra- 1.10 by water gives the amide 1.7. In few zoic acid under protic conditions resulting cases, a pinacol-like mechanism involving in the insertion of a nitrogen atom in a C–C concerted rearrangement of the tetrahedral bond [1–6]. The reaction is also known as intermediate 1.8b with concomitant loss of the Schmidt rearrangement and is closely nitrogen has also been proposed [9][10]. related to the Hofmann and the Curtius re- A recent application of the carboxylic arrangements [7]. Carboxylic acid 1.1 re- acid Schmidt reaction is shown in Scheme 2 Scheme 2. Schmidt reaction for the conversion acts with hydrazoic acid to afford primary of carboxylic acids into amines [11] amines 1.2 (Scheme 1(a)). The reaction goes through the protonated acyl azide 1.3 that undergoes a rearrangement to give the protonated isocyanate 1.4. Hydrolysis of The regioselectivity of the Schmidt re- 1.4 affords the carboxylated amine 1.5 that arrangement is controlled by a delicate bal- ance between the two mechanisms depicted spontaneously loses CO2 to deliver the final primary amine 1.2. The Schmidt reaction in Scheme 1(b) and by the stereochemistry with ketones is depicted in Scheme 1(b). of the intermediate iminodiazonium salts. Treatment of ketone 1.6 with hydrazoic For example, the reaction of bicyclic ketone acid gives the amide 1.7. The mechanism 3.1 affords a 77:23 mixture of 3.2 and 3.3 in involves the formation of the intermediate 62% yield (Scheme 3) [12][13]. The pref- triaz-1-yn-2-ium ion 1.8 [8]. Two pathways erential formation of 3.2 results from the have been proposed depending on the nature preferential formation of the E-iminodia- of the starting ketone. The first pathway is zonium cation E-3.4 followed by 1,2-shift closely related to the Beckmann rearrange- of the bridgehead substituent. The Z-isomer Z-3.4 affords 3.3; the product resulting from the migration of the methylene residue. An interesting rearrangement of alkyl azides has been reported by Andrieux et al. [14]. Dihydropyrrole 4.2 is obtained by treatment of cyclobutanol 4.1 with hydra- zoic acid and sulfuric acid (Scheme 4). Re- duction of 4.2 followed by N-methylation gives nicotine 4.3. The rearrangement in- volves the formation of the azide 4.4 fol- *Correspondence: Prof. Dr. P. Renaud Universität Bern lowed by protonation to the aminodiazo- Departement für Chemie und Biochemie nium ion 4.5 and ring expansion via a C to Freiestrasse 3 N 1,2 alkyl shift. CH-3012 Bern Despite the synthetic usefulness of the Tel.: +41 31 631 4359 Fax: +41 31 631 3426 Scheme 1. Intermolecular Schmidt reactions with reaction involving the formation of lactams E-Mail: [email protected] carboxylic acids and ketones from ketones and amines from carboxylic HOT TOPICS: MULTIFUNCTIONAL MATERIALS AND ORGANIC SYNTHESIS 277 CHIMIA 2006, 60, No. 5 selection of recent applications of the in- tramolecular Schmidt reaction. Results are organized according to the method used to generate the electrophilic species. 2. Reactions of Azido Ketones Aubé and coworkers reported that azido ketone 5.1 affords the fused bicyclic lactam 5.2 in 83% yield under treatment with tri- fluoroacetic acid (Scheme 5) [15][17]. The protonated ketone 5.3 reacts with the azide moiety to form the azidohydrin 5.4 that re- arranges readily to the lactam 5.2. Similar results are obtained under Lewis acid acti- vation with titanium tetrachloride. Benzylic azides afford variable mixtures of Schmidt and Mannich reactions [18]. Intermolecular reactions between cyclic ketones and alkyl azides are possible in some cases under Scheme 3. Regioselectivity in the rearrangement strong Lewis acidic conditions [19][20]. of bridged bicyclic ketones [12] Scheme 6. Total synthesis of (+)-aspidospermidine 6.5 by Aubé and coworkers [21][22] Scheme 5. Bicyclic lactam by Aubé and coworkers [15][17] Aubé and coworkers applied the in- tramolecular Schmidt reaction to the to- Scheme 4. Synthesis of nicotine 4.3 by Andrieux tal synthesis of (+)-aspidospermidine 6.5 et al. [14] (Scheme 6) [21][22]. Azido diketone 6.3 is obtained in ten steps starting from the easily acids, the intermolecular Schmidt reaction available enone 6.1 and cyclopentanone 6.2. suffers from two important drawbacks. First, Intramolecular Schmidt reactions are more the strongly acidic conditions are not com- facile when six-membered ring azidohy- patible with sensitive substrates and second, drins such as 6.6 are involved rather than hydrazoic acid is highly toxic and explosive five-membered ring azidohydrins [15][17]. upon heating. For a very long time, the reac- Therefore, diketone 6.3 reacts with com- plete regioselectivity under treatment with Scheme 7. Total synthesis of alkaloid 251F 7.4 by tion was unjustifiably suspected to be limit- Aubé and coworkers [25][26] ed to hydrazoic acid and similar reagents as TiCl4 to deliver the tricyclic ketolactam 6.4 azide sources. Alkyl azides were believed as a single product in 82% yield. Conver- to be too weak as nucleophiles for this kind sion of 6.4 to (+)-aspidospermidine 6.5 is of rearrangements. However, in the early achieved in seven steps and 43% yield. loid 251F 7.4 is obtained by reduction of the 1990s, Aubé and Milligan [15] and Pear- Aubé and coworkers reported the total lactam with lithium aluminium hydride. son and Schkeryantz [16] independently synthesis of indolizidine 209B [23], (–)- The first total synthesis of (+)-sparteine reported the first examples of intramolecu- lasubine II [24], and dendrobatid alkaloid 8.1, the enantiomer of naturally occurring lar Schmidt reaction of alkyl azides with 251F 7.4 using the rearrangement of an (–)-sparteine was recently achieved by Aubé ketones and tertiary carbocations generated azido ketone (Scheme 7) [25][26]. Easily and coworkers (Scheme 8) [27]. The elegant from alkenes and alcohols. These pioneer accessible enantioenriched carboxylic acid retrosynthetic analysis consists in preparing works have triggered many developments 7.1 is converted in eight steps and 13% yield the tetracyclic structure 8.2 of the target by and applications towards the total syntheses into the azido ketone 7.2. Treatment of 7.2 using sequential nitrogen ring-expansion of natural products and other biologically with trifluoromethanesulfonic acid affords reactions on a bicyclic substrate that would relevant molecules. This review presents a the tricyclic lactam 7.3 in 79% yield. Alka- ultimately be derived from the C2-symmet- HOT TOPICS: MULTIFUNCTIONAL MATERIALS AND ORGANIC SYNTHESIS 278 CHIMIA 2006, 60, No. 5 rical ketone 8.3. Diketone 8.3 is prepared Desmaële and d’Angelo and coworkers tions. The first example of such a sequential in optically pure form via enantioselective applied the intramolecular Schmidt reaction process was developed by the Aubé group bishydrosilylation of norbornadiene and is of azido ketones to access the homoeryth- and is based on an intramolecular Diels-Al- converted in six steps to the azido ketone 8.4, rina skeleton (Scheme 9) [28]. Starting der reaction followed by an intramolecular which undergoes a titanium tetrachloride from 6,7-dimethoxy-2-tetralone 9.1 and the Schmidt reaction. It was applied to a for- promoted Schmidt reaction affording the iodoester 9.2, the spirocyclic azidoketone mal synthesis of (±)-stenine 10.6 (Scheme first ring expanded lactam 8.5. The iodide 9.3 is prepared in five steps. Under treat- 10) [29]. The azidodiene 10.1 is treated 8.6 was prepared from 8.5 in five steps and ment with trifluoroacetic acid, 9.3 leads with methylaluminium dichloride to afford 72% yield and could be easily converted to to the lactam 9.4 in 85% yield as a single a mixture of the three lactams 10.2, 10.3, the corresponding azide. However, the sec- product. Reduction with lithium aluminium and 10.4. The major product 10.2 is easily ond intramolecular Schmidt reaction failed, hydride gives 3-demethoxy-1,2-dihydroco- converted to 10.5, an advanced intermedi- presumably due to the absence of coordina- mosidine 9.5. ate for the synthesis of (±)-stenine 10.6. tion of the ketone carbonyl group by protic The regioselective formation of 10.2 during and Lewis acids. The second ring expansion the Schmidt reaction is rationalized assum- could be achieved under neutral conditions ing an antiperiplanar C to N bond migra- with a variant of the photo-Beckmann re- tion from the intermediate azidohydrin 10.7 arrangement. For this purpose, the nitrone possessing an equatorial diazonium leaving 8.7 is prepared and irradiated at 254 nm to group (migrating bonds are shown in bold give the oxaziridine 8.8, which undergoes in structure 10.7).