DOI: 10.1002/chem.201304924
Concept
& Synthetic Methods
Access to Optically Active 3-Substituted Piperidines by Ring Expansion of Prolinols and Derivatives Domingo Gomez Pardo and Janine Cossy*[a]
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Concept Abstract: The ring expansion of prolinols via an aziridinium intermediate gives C3-substituted piperidines in good yields and enantiomeric excess, the substituent at the C3 position being derived from the most reactive nucleophile in the reaction mixture. Depending on the nucleophile, the reaction proceeds under thermodynamic or kinetic control. The regioselectivity of attack of nucleophiles on the aziridinium intermediate depends on the nature of the substituents on the nitrogen atom and the C4 position of the starting prolinols.
Introduction C3-Substituted piperidines are among the most ubiquitous heterocyclic building blocks present in natural products and bioactive compounds. Among the natural products, we can cite nipecotic acid and vinblastine and, among the synthetic compounds, we can cite paroxetine, zamifenacine and Ro 678867 (Figure 1).
Scheme 1. Some methods to access C3-substituted piperidines.
ration of the diastereomers,[4] the cyclization of optically active linear azido sulfonate derivatives after reduction of the azido group,[5] and the enantioselective ring expansion of prolinols (Scheme 1).[6] The enantioselective ring expansion of 2-(halomethyl) or 2-(hydroxymethyl)azaheterocycles into their homologues, via bicyclic aziridinium intermediates, is of high synthetic value.[7–10] In this review article, we will focus only on the enantioselective ring expansion of prolinols and derivatives, 2-(halomethyl)pyrrolidines and 2-(mesyloxymethyl)pyrrolidines, either under thermodynamic or kinetic control in order to produce optically active C3-substituted piperidines. The ring expansion of bicyclic compounds will not be covered here. In 1947, it was noticed that b-chloroamine hydrochlorides 1 and 2 underwent a rearrangement under basic conditions leading to 3 (Scheme 2, eq. 1).[11] Owing to this observation, it was hypothesized that 2-(chloromethyl)heterocyclic amines
Figure 1. Substituted piperidine derivatives.
Owing to the biological properties of C3-substituted piperidines, huge synthetic effort has been made to access these compounds;[1, 2] however, the synthesis of optically active C3substituted piperidines remains a challenge. A number of methods exist and among these methods, the most common ones involve the hydrogenation of substituted pyridines followed by the resolution of the enantiomers by separation of the diastereomeric ammonium salts,[3] the enantioselective hydrogenation of tetrahydropyridines,[3] the diastereoselective alkylation and reduction of oxazolopiperidines[4] and/or the sepa[a] Dr. D. Gomez Pardo, Prof. J. Cossy Laboratoire de Chimie Organique ESPCI ParisTech, CNRS 10 rue Vauquelin 75231 Paris Cedex 05 (France) Fax: (+ 33) 1-40-79-46-60 E-mail: [email protected]
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Scheme 2. Formation of aziridinium intermediates.
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Concept should undergo a similar rearrangement to produce ring-expanded products. The hypothesis was verified by using 1-ethyl-2-(chloromethyl)pyrrolidine hydrochloride 4; when treated with a cold aqueous solution of NaOH, 4 was transformed into 1-ethyl-3-chloropiperidine 5 (Scheme 2, eq. 2).[12] Studies conducted to understand the ring expansion of 4 into 5 have shown that aziridinium intermediate A was responsible for the ring expansion (Scheme 2, eq. 2). When optically active pyrrolidine hydrochloride (S)-4 was heated at a temperature above the melting point of the ammonium salt (up to 165 8C), 3-chloropiperidine (R)-5 was formed and the ring-expansion process was enantioselective as a complete inversion of configuration occurred upon the conversion of (S)-4 into (R)-5. When (S)-4 was heated with NaOH, a mixture of 3-hydroxypiperidine (R)-6 and prolinol (S)-7, in a 32:68 ratio favoring prolinol (S)-7, was obtained owing to non-regioselective attack of the aziridinium by the hydroxide ion,[13] thus decreasing the synthetic value of the reaction. Therefore, it was of interest to find reaction conditions that would allow efficient access to 3-hydroxypiperidines (Scheme 3).
Scheme 4. Non-selective ring-expansion via a mesylate intermediate.
Scheme 5. Selective ring-expansion via a mesylate intermediate.
Scheme 3. Rearrangement of b-chloroamines.
Synthesis of 3-hydroxypiperidines 2-(Hydroxymethyl)pyrrolidines can be transformed into 3-hydroxypiperidines via an aziridinium intermediate by utilizing reagents other than NaOH. When substituted (S)-prolinol 8 was treated with mesyl chloride in pyridine in the presence of a catalytic amount of 4-(dimethylamino)pyridine, at room temperature for 2 h, mesylate 9 was isolated (98 %). Treatment of this mesylate with NaOH (3 equiv) in H2O/dioxane or with AcONa (2 equiv) in DMF afforded a mixture of 3-hydroxypiperidine 10 and pyrrolidine 11 in a 15:1 ratio.[14] Again, the attack of aziridinium intermediate B by oxygenated nucleophiles, such as HO and AcO , is not regioselective (Scheme 4). However, when a prolinol possessing a secondary alcohol, such as 12, was treated with mesyl chloride at 20 8C, followed by the addition of tetrabutyl ammonium acetate, 3-acetyl piperidine 14 was exclusively obtained (85 % yield, 99 % ee), via the mesylate intermediate 13 (Scheme 5).[6a, 15] When 2-(halomethyl)pyrrolidines were treated with oxygenated nucleophiles, such as NaOH, KOAc, NaOR, and RCO2Na, a mixture of 2-oxymethylated pyrrolidine I’ and 3-oxygenated Chem. Eur. J. 2014, 20, 1 – 11
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Scheme 6. Treatment of 2-(halomethyl)pyrrolidines with oxygenated nucleophiles.
piperidine II’ was obtained.[9b, 16] The only exception was the use of sodium phenolate, which exclusively led to 3-phenyloxypiperidine[17] (Scheme 6). In contrast to the treatment of 2-(mesyloxymethyl)- and 2(chloromethyl)pyrrolidines with oxygenated nucleophiles, the treatment of prolinols, possessing a primary alcohol, with trifluoroacetic anhydride (TFAA), then with triethylamine (Et3N) and then with NaOH, led to 3-oxygenated piperidines in good yields. Thus, treatment of prolinol (S)-16 with TFAA in THF, then with Et3N and then with NaOH, led exclusively to the corresponding 3-hydroxypiperidine (R)-17 in good yield (63 %) and excellent enantiomeric excess (95 % ee).[18] When treated with TFAA, the esterification of (S)-16 and the formation of the quaternary ammonium salt take place to produce intermediate 3
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Concept Table 1. Synthesis of 3-hydroxypiperidines from prolinols.
Scheme 7. Transformation of prolinol (S)-16 into 3-hydroxypiperidines (R)-17 by using TFAA/Et3N/NaOH.
C. The addition of Et3N produces amino ester intermediate D, which undergoes an SNi process to give highly tight ion pair E that reacts to produce ester F. After saponification by NaOH (2.5 m), 3-hydroxypiperidine (R)-17 was isolated (Scheme 7). Thus, under thermodynamic conditions, 3-hydroxypiperidine was the only isolated compound. The ring expansion of N-alkylated prolinols is a general and highly stereoselective process allowing access to a diverse range of substituted 3-hydroxypiperidines in good yield and enantiomeric excess. A few examples are reported in Table 1.[6a] Notably, the process is chemoselective as prolinols 18–21 were transformed into the corresponding 3-hydroxypiperidines 24– 27 in good yield and with excellent enantiomeric excess. Furthermore, 3-hydroxypiperidines, possessing a quaternary center at C3, such as 28, can be synthesized from the corresponding prolinol 22; also, 2-phenyl-3-hydroxypiperidine 29 was obtained from prolinol 23, possessing a secondary alcohol at C2’. All the substituted piperidines were isolated in good yields and with excellent enantiomeric excess. The ring expansion of prolinols into 3-hydroxypiperidines, by using TFAA/Et3N/NaOH, has been utilized to synthesize natural products such as pseudoconhydrine,[19] and non-natural bioactive compounds such as isofagomine,[20] zamifenacine,[21] l-733,060,[22] Ro 67-8867[23] (Scheme 8).
rolidino-butyrolactone 46 in 60 %. Thus, in the case of pyrrolidine 42, the reaction was not selective (Scheme 9).[25] Notably, N-alkyl prolinol derivatives could be transformed into 3-chloropiperidines with good enantiomeric excess when prolinols were treated with SOCl2 in CHCl3 followed by a thermal process. In the case of bromopiperidines, they were formed when prolinols were treated with SOBr2 in DMF/cyclohexane (Scheme 10).[26] Intermediates G and H are probably responsible for the transformation of prolinols into 3-halopiperidines (Scheme 10). Cardiovascular compounds,[27] such as troglitazone analogues,[28] were prepared by using the ring expansion of prolinol derivatives producing 3-halopiperidines, which were then transformed in compounds of biological interest (Scheme 11). Reagents other than thionyl halides, for example, mesyl chloride, in the presence of Et3N, can transform N-alkyl prolinols into 3-chloropiperidines. Thus, treatment of (S)-16 and 12 with mesyl chloride, in the presence of Et3N in THF, led to 3chloropiperidine (R)-49 (77 % yield) and 50 (quant.), respectively. It was postulated that upon formation of mesylate I, there is internal assistance of the nitrogen atom, thus producing aziridinium salt J, which is then attacked by the more nucleophilic
Synthesis of 3-halopiperidines The stereoselective and enantioselective ring expansion of unstable N-alkyl-2-(halomethyl)pyrrolidines was used to prepared N-alkyl-3-halopiperidines. Pyrrolidines 40 and 41 were rearranged into the thermodynamically more stable 3-chloropiperidines 43 and 44, respectively, in quantitative yields, when dissolved in chloroform (Scheme 9).[24] In addition, a stereospecific rearrangement of iodo-pyrrolidine 42 was observed at 55 8C to produce 3-iodopiperidine 45 in 24 % yield along with the pyr&
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Concept anion present in the reaction medium, for example, the chloride anion rather than the mesylate anion (Scheme 12).[6a, 29] This procedure was used to synthesize ( )-paroxetine (Scheme 13).[30] An important feature in medicinal chemistry is the replacement of an sp3 C H bond by an sp3 C F bond because the introduction of a fluorine atom in organic molecules can influence their physical, chemical, and biological properties.[31] As diethylaminosulfur trifluoride (DAST) and bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) can activated alcohols, these reagents were used to induce the ring expansion of prolinols to the corresponding optically active 3-fluoropiperidines via an aziridinium intermediate. Notably, DAST and Deoxo-Fluor give similar yields in 3-fluoropiperidines.[32] When N-benzyl prolinol (S)-16 was treated with DAST in THF, at 0 8C for 1 h and then at room temperature for 1 h, an inseparable mixture of 3-fluoropiperidine 54 and 2-(fluoromethyl)pyrrolidine 55 was obtained in a ratio of 57:43 in favor of 3-fluoropiperidine 54 (60 % overall yield). This process is under kinetic control and, notably, the selectivity of the rearrangement can be improved when the nitrogen atom of the prolinol bears a sterically hindered alkyl group (compounds 51 and 52), when a sterically hindered substituent is present at C4 (for example compound 19), or if a quaternary center is present at C2 (for example compound 53) (Table 2). The ring enlargement of prolinols induced by DAST is probably the result of the formation of intermediate L, which produces aziridinium intermediate M that can be attacked by the fluorine ion liberated in the medium to produce intermediate N and/or O depending on the substituents present in substrate K (Scheme 14). As noticed, the selectivity of the rearrangement in favor of the piperidines depends on the bulkiness of the N-substituent and/or C2 being a quaternary center and/or C4 bearing a bulky sub-
Scheme 8. Synthesis of bioactive compounds from prolinols.
Scheme 9. Ring expansion of N-alkyl-2-(halomethyl)pyrrolidines. Chem. Eur. J. 2014, 20, 1 – 11
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Scheme 10. Formation of 3-halopiperidines.
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Concept Table 2. Formation of 3-fluoropiperidines from prolinols using DAST (Et2N SF3).
Scheme 11. Synthesis of troglitazone derivatives from prolinol derivatives.
Scheme 12. Ring expansion of prolinols via a mesylate intermediate.
Scheme 13. Synthesis of ( )-paroxetine.
stituent. These observations suggest that non-symmetrical aziridinium M, where the N C2 bond is longer than the N C2’ bond, is responsible for this selectivity and/or is due to the conformation of the five-membered ring in the bicyclic aziridinium intermediate.[32a, b]
Scheme 14. Ring expansion of prolinols induced by DAST.
Contrary to the synthesis of 3-hydroxy- and 3-halopiperidines from N-alkyl prolinols, via an aziridinium intermediate, the synthesis of 3-azido- and 3-aminopiperidines by ring expansion of N-alkyl prolinols is very lengthy and/or problematic.[43] When N-alkyl prolinols are treated with SOCl2 and then with an amine, 2-(aminomethyl)pyrrolidines were exclusively formed and no traces of the corresponding 3-aminopiperidine was detected.[16b, 44] The treatment of N-alkyl prolinols with mesyl chloride and then with NaN3 in DMF at 100 8C led to a mixture of 3-azidopiperidines and 2-(azidomethyl)pyrrolidines.[14] A solution to this problem was the use of kinetic con-
Synthesis of 3-aminopiperidines A great number of patents are related to 3-aminopiperidine derivatives owing to their potential bioactivities. 3-Aminopiperidine derivatives have been reported to possess antitumoral,[33] antibacterial,[34] anti-inflammatory,[35] analgesic,[36] antiviral,[37] anti-ischemic properties,[38] antidepressive,[39] and psychotropic properties.[40] They have also been reported to be used in the treatment of hormone deficiency[41] and neurological disorders related to b-amyloid production.[42] &
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Concept ditions and the use of prolinols with a bulky substituent at N1, and/or a bulky substituent at C4, as these substituted prolinols were transformed into the corresponding 3-azidopiperidines as the major products.[45] Thus, when N-trityl prolinol 51 was treated with (diethylamino)difluorosulfonium tetrafluoroborate (XtalFluor-E) in the presence of nBu4NN3, azidopiperidine 67 and azidopyrrolidine 68 were obtained in a ratio of 88/12 with a global yield of 87 %. When a sterically hindered substituent was introduced at C4, as in 61, only 3-azidopiperidine 69 was isolated in 65 % yield and, the replacement of the N-trityl group by an N-benzyl group allowed the formation of 70/71 in a 97:3 ratio. Piperidine 70 was isolated in 72 % yield, thus showing the importance of the substituent at C4. In the case of N-benzyl prolinols 63 and 64, substituted either by an N,N-dibenzylamino or an N-trityl group at C4, the corresponding 3-azidopiperidine 72 (57 %) and 73 (84 %) were exclusively formed. For 4-fluoroprolinol 65 and 4,4-difluoroprolinol 66, a good piperidine/pyrrolidine ratio was obtained (91:9—93:7) in favor of the piperidine (Table 3).[45] Notably, depending on the relative stereochemistry and the nature of the substituents at C4 in the starting prolinols, the ratio can be poor to excellent, thus demonstrating the importance of the C4 substituent in determining the efficiency of the ring enlargement.[45] 3-Azidopiperidines 74 can easily be transformed into the corresponding amines in good yield by using a Staudinger reduction of the azido group (Scheme 15). For example, 74 was converted into 78 in 82 % yield.
Table 3. Synthesis of 3-azidopiperidines.
Synthesis of 3-thiopiperidines So far, no example of a ring expansion of prolinols into 3-thiopiperidines has been reported. However, the ring expansion of halo-indolizidines into thio-quinolizidines, via an aziridinium intermediate, was realized using the methylthiolate anion,[46] a result that suggests that 3-thiopiperidines should be accessible through ring expansion of 2-(halomethyl)pyrrolidines.
Scheme 15. Formation of 3-amino 5-fluoropiperidines.
Synthesis of 3-cyano- and 3-arylpiperidines (C C bond formation) 3-Cyanopiperidines were formed either from prolinols or from 2-(chloromethyl)pyrrolidines. Treatment of 80 under Kolbe conditions (NaCN, EtOH, reflux) led to carbonitrile 82 together with minor amounts of the C2 epimer and rearranged product 81.[44c] The yield in the piperidine carbonitrile was increased to 18 % when 19 was treated with mesyl anhydride (Ms2O, Et3N) and then with LiCN (0.5 m in DMF) but, again, the major compound was pyrrolidine 84 (Scheme 16).[47] Chem. Eur. J. 2014, 20, 1 – 11
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Scheme 16. Synthesis of 3-cyanopiperidines.
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Concept 3-Arylpiperidines are important because they can be used as selective dopamine (DA) autoreceptor agonists, 3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP, UH 106, 88) being an example. This compound was synthesized by treatment of ( )-(S)-Npropyl-2-(chloromethyl)pyrrolidine hydrochloride 85 with 2 equivalents of phenyl magnesium bromide in the presence of a catalytic amount of cuprous cyanide or cuprous iodide. Notably, the use of a copper salt is crucial for initiating nucleophilic attack of the Grignard reagent. Under these conditions, 3-arylpiperidine 86 and pyrrolidine 87 were obtained in a global yield of 82 %, albeit with a ratio 86/87 of 18:82 in favor of pyrrolidine 87 (Scheme 17).[48]
edged. Sanofi, Johnson & Johnson (USA), Janssen Pharmaceutica, and Merck-Serono are acknowledged for financial support. Keywords: enantioselectivity · piperidines · pyrrolidinols · rearrangements · ring expansion [1] For reviews, see: a) M. G. P. Buffat, Tetrahedron 2004, 60, 1701 – 1729; b) J. Cossy, Chem. Rec. 2005, 5, 70 – 80; c) C. Escolano, M. Amat, J. Bosch, Chem. Eur. J. 2006, 12, 8198 – 8207. [2] a) E. Poupon, D. Francois, N. Kunesch, H. P. Husson, J. Org. Chem. 2004, 69, 3836 – 3841; b) K. M. Goodenough, W. J. Moran, P. Raubo, J. P. A. Harrity, J. Org. Chem. 2005, 70, 207 – 213; c) T. Kobayashi, F. Hasegawa, K. Tanaka, S. Katsumura, Org. Lett. 2006, 8, 3813 – 3816; d) L. C. Pattenden, R. A. J. Wybrow, S. A. Smith, J. P. A. Harrity, Org. Lett. 2006, 8, 3089 – 3091; e) C. Y. Legault, A. B. Charette, J. Am. Chem. Soc. 2005, 127, 8966 – 8967; f) R. P. Wurz, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 12234 – 12235; g) G. Barbe, M. St-Onge, A. B. Charette, Org. Lett. 2008, 10, 5497 – 5499; h) G. Lemonnier, A. B. Charette, J. Org. Chem. 2010, 75, 7465 – 7467; i) H. M. Lovick, F. E. Michael, J. Am. Chem. Soc. 2010, 132, 1249 – 1251; j) T. K. Beng, R. E. Gawley, J. Am. Chem. Soc. 2010, 132, 12216 – 12217. [3] For an example, see: N. A. Grayson, W. D. Bowen, K. C. Rice, Heterocycles 1992, 34, 2281 – 2292. [4] a) M. Amat, O. Lozano, C. Escolano, E. Molins, J. Bosch, J. Org. Chem. 2007, 72, 4431 – 4439; b) M. Amat, N. Llor, J. Hidalgo, C. Escolano, J. Bosch, J. Org. Chem. 2003, 68, 1919 – 1928; c) M. Amat, E. Brunaccini, B. Checa, M. Prez, N. Llor, J. Bosch, Org. Lett. 2009, 11, 4370 – 4373; d) Y. Nakamura, A. M. Burke, S. Kotani, J. W. Ziller, S. D. Rychnovsky, Org. Lett. 2010, 12, 72 – 75; e) D. Gnecco, A. M. Lumbreras, J. L. Teran, A. Galindo, J. R. Juarez, M. L. Orea, A. Castro, R. G. Enriquez, W. F. Reynolds, Heterocycles 2009, 78, 2589 – 2594. [5] a) H. Takahata, K. Inose, N. Araya, T. Momose, Heterocycles 1994, 38, 1961 – 1964; b) H. Takahata, M. Kubota, S. Takahashi, T. Momose, Tetrahedron: Asymmetry 1996, 7, 3047 – 3054; c) H. Takahata, M. Kubota, N. Ikota, J. Org. Chem. 1999, 64, 8594 – 8601. [6] For examples, see: a) J. Cossy, C. Dumas, D. Gomez Pardo, Eur. J. Org. Chem. 1999, 1693 – 1699; b) J. Cossy, D. Gomez Pardo, Chemtracts 2002, 15, 579 – 605; c) I. Dchamps, D. Gomez Pardo, J. Cossy, Arkivoc 2007, V, 38 – 45. [7] For examples of the rearrangement of aziridines to azetidines, see: a) S. Stankovic´, S. Catak, M. D’hooghe, H. Goossens, K. Abbaspour Tehrani, P. Bogaert, M. Waroquier, V. Van Speybroeck, N. De Kimpe, J. Org. Chem. 2011, 76, 2157 – 2167; b) S. Stankovic´, H. Goossens, S. Catak, M. Tezcan, M. Waroquier, V. Van Speybroeck, M. D’hooghe, N. De Kimpe, J. Org. Chem. 2012, 77, 3181 – 3190. [8] For examples of the rearrangement of azetidines to pyrrolidines, see: a) F. Couty, F. Durrat, D. Prim, Tetrahedron Lett. 2003, 44, 5209 – 5212; b) F. Durrat, M. Vargas Sanchez, F. Couty, G. Evano, J. Marrot, Eur. J. Org. Chem. 2008, 3286 – 3297; c) S. Dekeukeleire, M. D’hooghe, K. W. Tçrnroos, N. De Kimpe, J. Org. Chem. 2010, 75, 5934 – 5940. [9] For selected examples of the rearrangement of pyrrolidines to piperidines, see: a) S. G. Davies, R. L. Nicholson, P. D. Price, P. M. Roberts, A. J. Russell, E. D. Savory, A. D. Smith, J. E. Thomson, Tetrahedron: Asymmetry 2009, 20, 758 – 772; b) S. G. Davies, A. L. A. Figuccia, A. M. Fletcher, P. M. Roberts, J. E. Thomson, Org. Lett. 2013, 15, 2042 – 2045. [10] For examples of the rearrangement of piperidines to azepanes, see: a) H.-S. Chong, K. Garmestani, L. H. Bryant, Jr., M. W. Brechbiel, J. Org. Chem. 2001, 66, 7745 – 7750; b) K. Vervisch, M. D’hooghe, K. W. Tçrnroos, N. De Kimpe, J. Org. Chem. 2010, 75, 7734 – 7744. [11] a) E. M. Schultz, C. M. Robb, J. M. Sprague, J. Am. Chem. Soc. 1947, 69, 188 – 189; b) E. M. Schultz, C. M. Robb, J. M. Sprague, J. Am. Chem. Soc. 1947, 69, 2454 – 2459; c) S. D. Ross, J. Am. Chem. Soc. 1947, 69, 2982 – 2983; d) W. R. Brode, M. W. Hill, J. Am. Chem. Soc. 1947, 69, 724; e) J. F. Kerwin, G. E. Ullyot, R. C. Fuson, C. L. Zirkle, J. Am. Chem. Soc. 1947, 69, 2961 – 2965; f) E. M. Schultz, J. M. Sprague, J. Am. Chem. Soc. 1948, 70, 48 – 52. [12] a) C. Golumbic, J. S. Fruton, M. Bergmann, J. Org. Chem. 1946, 11, 518 – 535; b) C. Golumbic, M. Bergmann, J. Org. Chem. 1946, 11, 536 – 542; c) J. S. Fruton, M. Bergmann, J. Org. Chem. 1946, 11, 543 – 549; d) C. Golumbic, M. A. Stahmann, M. Bergmann, J. Org. Chem. 1946, 11, 550 –
Scheme 17. Synthesis of 3-arylpiperidines.
Summary and Outlook The ring expansion of optically active prolinols gives access to valuable optically active C3-substituted piperidines via an aziridinium intermediate. Depending on the nucleophile used to open the aziridinium, the ring expansion is under either thermodynamic or kinetic control. The regioselectivity of attack of the aziridinium intermediate by a nucleophile depends also on the substituents on the prolinols at C4 as well as on the steric hindrance of the alkyl substituent at N1. Quantum chemical computation studies will be necessary to fully understand the regioselectivity of the attack of nucleophiles on the aziridinium intermediates.[49, 50] In the future, it will be important to develop conditions to selectively synthesize optically active 3-alkyl, 3-aryl-, and 3-cyano-piperidines from prolinols and derivatives by using carbanions or cyanide anions. It will also be important to use activators in catalytic amounts to generate the aziridinium intermediates from prolinols in order to access C3-substituted piperidines in good yields and enantiomeric excess.[51]
Acknowledgements The students and internship students who worked on the ring expansion of prolinols and derivatives are gratefully acknowl&
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Concept
[13] [14] [15] [16]
[17] [18]
[19] [20] [21] [22] [23] [24]
[25] [26] [27] [28]
[29] [30] [31]
[32]
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D. Gomez Pardo, J. Cossy, Chem. Eur. J. 2014, DOI: 10.1002/ chem.201302423. a) H. S. Lin, M. E. Richett, WO99/52365, 1999; [Chem. Abstr. 1999, 131, 295575]; b) P. BenhoWe, S. Pecchi, T. Machajewski, C. Schafer, C. Taylor, B. McCrea, C. McBride, E. Jazan, M.-E. Wernette-Hammond, A. Harris, WO 02/22598; [Chem. Abstr. 2002, 136, 263158]. a) S. L. Dax, C. C. Wei, J. Org. Chem. 1992, 57, 744 – 746; b) D. Bouzard, P. Di Cesare, M. Essiz, J.-P. Jacquet, B. Ledoussal, P. Remuzon, R. E. Kessler, J. Fung-Tomc, J. Med. Chem. 1992, 35, 518 – 525. a) L. Alcaraz, M. Furber, M. Mortimore, WO 00/61569, 2000; [Chem. Abstr. 2000, 133, 309908a]; b) K. J. Moriarty, Y. Shimshock, G. Ahmed, J. Wu, J. Wen, W. Li, S. D. Erickson, J. J. Letourneau, E. McDonald, K. Leftheris, S. T. Wrobleski, WO 01/47897 A1, 2001; [Chem. Abstr. 2001, 135, 92655z]; c) N. E. Krauss, T. Mirzadegan, D. B. Smith, K. A. M. Walker, WO 01/83434 A2, 2001; [Chem. Abstr. 2001, 135, 357764t]; d) K. J. Moriarty, Y. Shimshock, G. Ahmed, J. Wu, J. Wen, W. Li, S. D. Erickson, J. J. Letourneau, E. McDonald, K. Leftheris, S. T. Wrobleski, Z. Hussain, I. Ilenderson, A. Metzger, J. J. Baldwin, A. J. Dyckman, US 2002/0137747 A1, 2002; [Chem. Abstr. 2002, 137, 247719]. a) B. Pelcman, E. Roberts, WO 98/28270 A1, 1998; [Chem. Abstr. 1998, 129, 108996a]; b) J. P. Chinn, S.-K. Choi, P. R. Fatheree, D. Marques, S. D. Turner, WO 02/18334 A2, 2002; [Chem. Abstr. 2002, 136, 216528]. R. A. Stokbroekx, M. J. M. van der Aa, J. J. M. Willems, M. G. M. Luyckx, EP 0156433 A2, 1985; [Chem. Abstr. 1986, 104, 129918a]. M. R. Myers, M. P. Maguire, A. P. Spada, W. R. Ewing, H. W. Pauls, Y. M. Choi-Sledeski, WO 00/23447 A1, 2000; [Chem. Abstr. 2000, 132, 293976 s]. a) T. Sugasawa, M. Adachi, K. Sasakura, A. Matsushita, M. Eigyo, T. Shiomi, H. Shintaku, Y. Takahara, S. Murata, J. Med. Chem. 1985, 28, 699 – 707; b) T. Sugasawa, M. Adachi, K. Sasakura, A. Matsushita, M. Eigyo, EP 0111864 A1, 1984; [Chem. Abstr. 1985, 102, 6558j]. I. R. Egle, J. Frey, M. B. Isaac, A. Slassi, L. E. Begleiter, L. G. Edwards, T. Stefanac, A. Tehim, S. P. Maddaford, H. L. A. Tse, WO 01/81308 A2, 2001; [Chem. Abstr. 2001, 135, 344380q]. P. K. Chakravarty, R. Nargund, R. W. Marquis, A. A. Patchett, L. Yang, WO 96/32943 A1, 1996; [Chem. Abstr. 1996, 125, 328512x]. L. A. Thompson, P. Kasireddy, WO 01/74796 A1, 2001; [Chem. Abstr. 2001, 135, 303912w]. S. Kovacˇkov, M. Dracˇnsky´, D. Rejman, Tetrahedron 2011, 67, 1485 – 1500. a) R. H. Reitsema, J. Am. Chem. Soc. 1949, 71, 2041 – 2043; b) J. H. Biel, W. K. Hoya, H. A. Leiser, J. Am. Chem. Soc. 1959, 81, 2527 – 2532; c) P. Carlier, J. A. L. Simond, A. J.-C. Monteil, FR 2608602 A1, 1988; [Chem. Abstr. 1989, 110, 57525]; d) P. Gmeiner, D. Junge, J. Org. Chem. 1995, 60, 3910 – 3915; e) T. Mino, A. Saito, Y. Tanaka, S. Hasegawa, Y. Sato, M. Sakamoto, T. Fujita, J. Org. Chem. 2005, 70, 1937 – 1940. a) A. Cochi, D. Gomez Pardo, J. Cossy, Org. Lett. 2011, 13, 4442 – 4445; b) A. Cochi, D. Gomez Pardo, J. Cossy, Eur. J. Org. Chem. 2012, 2023 – 2040. S. H. L. Verhelst, B. P. Martinez, M. S. M. Timmer, G. Lodder, G. A. van der Marel, H. S. Overkleeft, J. H. van Boom, J. Org. Chem. 2003, 68, 9598 – 9603.
[47] C. Heindl, H. Hbner, P. Gmeiner, Tetrahedron: Asymmetry 2003, 14, 3153 – 3172. [48] S.-O. Thorberg, L. Gawell, I. Csçregh, J. L. G. Nilsson, Tetrahedron 1985, 41, 129 – 139. [49] For a computational study of halide-induced ring opening of monocyclic aziridinium, see: a) M. D’hooghe, S. Catak, S. Stankovicˇ, M. Waroquier, Y. Kim, H.-J. Ha, V. Van Speybroeck, N. De Kimpe, Eur. J. Org. Chem. 2010, 4920 – 4931; b) S. Stankovicˇ, M. D’hooghe, S. Catak, H. Eum, M. Waroquier, V. Van Speybroeck, N. De Kimpe, H.-J. Ha, Chem. Soc. Rev. 2012, 41, 643 – 665; c) B. Baruah, S. Deuri, P. Phukan, Comp. Theor. Chem. 2014, 1027, 197 – 202 and references therein.
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Concept [50] For a computational study of azide-induced ring opening of bicyclic aziridinium, see: Y.-H. Lam, K. N. Kendall, J. Cossy, D. Gomez Pardo, A. Cochi, Helv. Chim. Acta 2012, 95, 2265 – 2277. [51] For examples of the rearrangement of prolinols to 3-hydroxypiperidines, see: a) T.-X. Mtro, D. Gomez Pardo, J. Cossy, J. Org. Chem. 2007,
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72, 6556 – 6561; b) T.-X. Mtro, D. Gomez Pardo, J. Cossy, Synlett 2007, 2888 – 2890.
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Concept
CONCEPT & Synthetic Methods D. Gomez Pardo, J. Cossy* && – && One-carbon expansion: The ring expansion of enantiomerically pure prolinols via an aziridinium intermediate,
either under thermodynamic or kinetic control, gives C3-substituted piperidines in good yields and enantiomeric excess.
Access to Optically Active 3Substituted Piperidines by Ring Expansion of Prolinols and Derivatives
Ring-Expansion Reactions 3-Substituted piperidines are important building blocks for the preparation of many synthetic and natural biologically active compounds. In their Concept article on page &&ff., D. Gomez Pardo and J. Cossy provide an overview on the preparation of these compounds through the ring expansion of the corresponding prolinol derivatives, a transformation that proceeds via an aziridinium intermediate.
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Concept
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Access to Optically Active 3-Substituted Piperidines by Ring Expansion of Prolinols and Derivatives Domingo Gomez Pardo and Janine Cossy*[a]
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Concept Abstract: The ring expansion of prolinols via an aziridinium intermediate gives C3-substituted piperidines in good yields and enantiomeric excess, the substituent at the C3 position being derived from the most reactive nucleophile in the reaction mixture. Depending on the nucleophile, the reaction proceeds under thermodynamic or kinetic control. The regioselectivity of attack of nucleophiles on the aziridinium intermediate depends on the nature of the substituents on the nitrogen atom and the C4 position of the starting prolinols.
Introduction C3-Substituted piperidines are among the most ubiquitous heterocyclic building blocks present in natural products and bioactive compounds. Among the natural products, we can cite nipecotic acid and vinblastine and, among the synthetic compounds, we can cite paroxetine, zamifenacine and Ro 678867 (Figure 1).
Scheme 1. Some methods to access C3-substituted piperidines.
ration of the diastereomers,[4] the cyclization of optically active linear azido sulfonate derivatives after reduction of the azido group,[5] and the enantioselective ring expansion of prolinols (Scheme 1).[6] The enantioselective ring expansion of 2-(halomethyl) or 2-(hydroxymethyl)azaheterocycles into their homologues, via bicyclic aziridinium intermediates, is of high synthetic value.[7–10] In this review article, we will focus only on the enantioselective ring expansion of prolinols and derivatives, 2-(halomethyl)pyrrolidines and 2-(mesyloxymethyl)pyrrolidines, either under thermodynamic or kinetic control in order to produce optically active C3-substituted piperidines. The ring expansion of bicyclic compounds will not be covered here. In 1947, it was noticed that b-chloroamine hydrochlorides 1 and 2 underwent a rearrangement under basic conditions leading to 3 (Scheme 2, eq. 1).[11] Owing to this observation, it was hypothesized that 2-(chloromethyl)heterocyclic amines
Figure 1. Substituted piperidine derivatives.
Owing to the biological properties of C3-substituted piperidines, huge synthetic effort has been made to access these compounds;[1, 2] however, the synthesis of optically active C3substituted piperidines remains a challenge. A number of methods exist and among these methods, the most common ones involve the hydrogenation of substituted pyridines followed by the resolution of the enantiomers by separation of the diastereomeric ammonium salts,[3] the enantioselective hydrogenation of tetrahydropyridines,[3] the diastereoselective alkylation and reduction of oxazolopiperidines[4] and/or the sepa[a] Dr. D. Gomez Pardo, Prof. J. Cossy Laboratoire de Chimie Organique ESPCI ParisTech, CNRS 10 rue Vauquelin 75231 Paris Cedex 05 (France) Fax: (+ 33) 1-40-79-46-60 E-mail: [email protected]
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Scheme 2. Formation of aziridinium intermediates.
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Concept should undergo a similar rearrangement to produce ring-expanded products. The hypothesis was verified by using 1-ethyl-2-(chloromethyl)pyrrolidine hydrochloride 4; when treated with a cold aqueous solution of NaOH, 4 was transformed into 1-ethyl-3-chloropiperidine 5 (Scheme 2, eq. 2).[12] Studies conducted to understand the ring expansion of 4 into 5 have shown that aziridinium intermediate A was responsible for the ring expansion (Scheme 2, eq. 2). When optically active pyrrolidine hydrochloride (S)-4 was heated at a temperature above the melting point of the ammonium salt (up to 165 8C), 3-chloropiperidine (R)-5 was formed and the ring-expansion process was enantioselective as a complete inversion of configuration occurred upon the conversion of (S)-4 into (R)-5. When (S)-4 was heated with NaOH, a mixture of 3-hydroxypiperidine (R)-6 and prolinol (S)-7, in a 32:68 ratio favoring prolinol (S)-7, was obtained owing to non-regioselective attack of the aziridinium by the hydroxide ion,[13] thus decreasing the synthetic value of the reaction. Therefore, it was of interest to find reaction conditions that would allow efficient access to 3-hydroxypiperidines (Scheme 3).
Scheme 4. Non-selective ring-expansion via a mesylate intermediate.
Scheme 5. Selective ring-expansion via a mesylate intermediate.
Scheme 3. Rearrangement of b-chloroamines.
Synthesis of 3-hydroxypiperidines 2-(Hydroxymethyl)pyrrolidines can be transformed into 3-hydroxypiperidines via an aziridinium intermediate by utilizing reagents other than NaOH. When substituted (S)-prolinol 8 was treated with mesyl chloride in pyridine in the presence of a catalytic amount of 4-(dimethylamino)pyridine, at room temperature for 2 h, mesylate 9 was isolated (98 %). Treatment of this mesylate with NaOH (3 equiv) in H2O/dioxane or with AcONa (2 equiv) in DMF afforded a mixture of 3-hydroxypiperidine 10 and pyrrolidine 11 in a 15:1 ratio.[14] Again, the attack of aziridinium intermediate B by oxygenated nucleophiles, such as HO and AcO , is not regioselective (Scheme 4). However, when a prolinol possessing a secondary alcohol, such as 12, was treated with mesyl chloride at 20 8C, followed by the addition of tetrabutyl ammonium acetate, 3-acetyl piperidine 14 was exclusively obtained (85 % yield, 99 % ee), via the mesylate intermediate 13 (Scheme 5).[6a, 15] When 2-(halomethyl)pyrrolidines were treated with oxygenated nucleophiles, such as NaOH, KOAc, NaOR, and RCO2Na, a mixture of 2-oxymethylated pyrrolidine I’ and 3-oxygenated Chem. Eur. J. 2014, 20, 1 – 11
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Scheme 6. Treatment of 2-(halomethyl)pyrrolidines with oxygenated nucleophiles.
piperidine II’ was obtained.[9b, 16] The only exception was the use of sodium phenolate, which exclusively led to 3-phenyloxypiperidine[17] (Scheme 6). In contrast to the treatment of 2-(mesyloxymethyl)- and 2(chloromethyl)pyrrolidines with oxygenated nucleophiles, the treatment of prolinols, possessing a primary alcohol, with trifluoroacetic anhydride (TFAA), then with triethylamine (Et3N) and then with NaOH, led to 3-oxygenated piperidines in good yields. Thus, treatment of prolinol (S)-16 with TFAA in THF, then with Et3N and then with NaOH, led exclusively to the corresponding 3-hydroxypiperidine (R)-17 in good yield (63 %) and excellent enantiomeric excess (95 % ee).[18] When treated with TFAA, the esterification of (S)-16 and the formation of the quaternary ammonium salt take place to produce intermediate 3
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Concept Table 1. Synthesis of 3-hydroxypiperidines from prolinols.
Scheme 7. Transformation of prolinol (S)-16 into 3-hydroxypiperidines (R)-17 by using TFAA/Et3N/NaOH.
C. The addition of Et3N produces amino ester intermediate D, which undergoes an SNi process to give highly tight ion pair E that reacts to produce ester F. After saponification by NaOH (2.5 m), 3-hydroxypiperidine (R)-17 was isolated (Scheme 7). Thus, under thermodynamic conditions, 3-hydroxypiperidine was the only isolated compound. The ring expansion of N-alkylated prolinols is a general and highly stereoselective process allowing access to a diverse range of substituted 3-hydroxypiperidines in good yield and enantiomeric excess. A few examples are reported in Table 1.[6a] Notably, the process is chemoselective as prolinols 18–21 were transformed into the corresponding 3-hydroxypiperidines 24– 27 in good yield and with excellent enantiomeric excess. Furthermore, 3-hydroxypiperidines, possessing a quaternary center at C3, such as 28, can be synthesized from the corresponding prolinol 22; also, 2-phenyl-3-hydroxypiperidine 29 was obtained from prolinol 23, possessing a secondary alcohol at C2’. All the substituted piperidines were isolated in good yields and with excellent enantiomeric excess. The ring expansion of prolinols into 3-hydroxypiperidines, by using TFAA/Et3N/NaOH, has been utilized to synthesize natural products such as pseudoconhydrine,[19] and non-natural bioactive compounds such as isofagomine,[20] zamifenacine,[21] l-733,060,[22] Ro 67-8867[23] (Scheme 8).
rolidino-butyrolactone 46 in 60 %. Thus, in the case of pyrrolidine 42, the reaction was not selective (Scheme 9).[25] Notably, N-alkyl prolinol derivatives could be transformed into 3-chloropiperidines with good enantiomeric excess when prolinols were treated with SOCl2 in CHCl3 followed by a thermal process. In the case of bromopiperidines, they were formed when prolinols were treated with SOBr2 in DMF/cyclohexane (Scheme 10).[26] Intermediates G and H are probably responsible for the transformation of prolinols into 3-halopiperidines (Scheme 10). Cardiovascular compounds,[27] such as troglitazone analogues,[28] were prepared by using the ring expansion of prolinol derivatives producing 3-halopiperidines, which were then transformed in compounds of biological interest (Scheme 11). Reagents other than thionyl halides, for example, mesyl chloride, in the presence of Et3N, can transform N-alkyl prolinols into 3-chloropiperidines. Thus, treatment of (S)-16 and 12 with mesyl chloride, in the presence of Et3N in THF, led to 3chloropiperidine (R)-49 (77 % yield) and 50 (quant.), respectively. It was postulated that upon formation of mesylate I, there is internal assistance of the nitrogen atom, thus producing aziridinium salt J, which is then attacked by the more nucleophilic
Synthesis of 3-halopiperidines The stereoselective and enantioselective ring expansion of unstable N-alkyl-2-(halomethyl)pyrrolidines was used to prepared N-alkyl-3-halopiperidines. Pyrrolidines 40 and 41 were rearranged into the thermodynamically more stable 3-chloropiperidines 43 and 44, respectively, in quantitative yields, when dissolved in chloroform (Scheme 9).[24] In addition, a stereospecific rearrangement of iodo-pyrrolidine 42 was observed at 55 8C to produce 3-iodopiperidine 45 in 24 % yield along with the pyr&
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Concept anion present in the reaction medium, for example, the chloride anion rather than the mesylate anion (Scheme 12).[6a, 29] This procedure was used to synthesize ( )-paroxetine (Scheme 13).[30] An important feature in medicinal chemistry is the replacement of an sp3 C H bond by an sp3 C F bond because the introduction of a fluorine atom in organic molecules can influence their physical, chemical, and biological properties.[31] As diethylaminosulfur trifluoride (DAST) and bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) can activated alcohols, these reagents were used to induce the ring expansion of prolinols to the corresponding optically active 3-fluoropiperidines via an aziridinium intermediate. Notably, DAST and Deoxo-Fluor give similar yields in 3-fluoropiperidines.[32] When N-benzyl prolinol (S)-16 was treated with DAST in THF, at 0 8C for 1 h and then at room temperature for 1 h, an inseparable mixture of 3-fluoropiperidine 54 and 2-(fluoromethyl)pyrrolidine 55 was obtained in a ratio of 57:43 in favor of 3-fluoropiperidine 54 (60 % overall yield). This process is under kinetic control and, notably, the selectivity of the rearrangement can be improved when the nitrogen atom of the prolinol bears a sterically hindered alkyl group (compounds 51 and 52), when a sterically hindered substituent is present at C4 (for example compound 19), or if a quaternary center is present at C2 (for example compound 53) (Table 2). The ring enlargement of prolinols induced by DAST is probably the result of the formation of intermediate L, which produces aziridinium intermediate M that can be attacked by the fluorine ion liberated in the medium to produce intermediate N and/or O depending on the substituents present in substrate K (Scheme 14). As noticed, the selectivity of the rearrangement in favor of the piperidines depends on the bulkiness of the N-substituent and/or C2 being a quaternary center and/or C4 bearing a bulky sub-
Scheme 8. Synthesis of bioactive compounds from prolinols.
Scheme 9. Ring expansion of N-alkyl-2-(halomethyl)pyrrolidines. Chem. Eur. J. 2014, 20, 1 – 11
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Scheme 10. Formation of 3-halopiperidines.
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Concept Table 2. Formation of 3-fluoropiperidines from prolinols using DAST (Et2N SF3).
Scheme 11. Synthesis of troglitazone derivatives from prolinol derivatives.
Scheme 12. Ring expansion of prolinols via a mesylate intermediate.
Scheme 13. Synthesis of ( )-paroxetine.
stituent. These observations suggest that non-symmetrical aziridinium M, where the N C2 bond is longer than the N C2’ bond, is responsible for this selectivity and/or is due to the conformation of the five-membered ring in the bicyclic aziridinium intermediate.[32a, b]
Scheme 14. Ring expansion of prolinols induced by DAST.
Contrary to the synthesis of 3-hydroxy- and 3-halopiperidines from N-alkyl prolinols, via an aziridinium intermediate, the synthesis of 3-azido- and 3-aminopiperidines by ring expansion of N-alkyl prolinols is very lengthy and/or problematic.[43] When N-alkyl prolinols are treated with SOCl2 and then with an amine, 2-(aminomethyl)pyrrolidines were exclusively formed and no traces of the corresponding 3-aminopiperidine was detected.[16b, 44] The treatment of N-alkyl prolinols with mesyl chloride and then with NaN3 in DMF at 100 8C led to a mixture of 3-azidopiperidines and 2-(azidomethyl)pyrrolidines.[14] A solution to this problem was the use of kinetic con-
Synthesis of 3-aminopiperidines A great number of patents are related to 3-aminopiperidine derivatives owing to their potential bioactivities. 3-Aminopiperidine derivatives have been reported to possess antitumoral,[33] antibacterial,[34] anti-inflammatory,[35] analgesic,[36] antiviral,[37] anti-ischemic properties,[38] antidepressive,[39] and psychotropic properties.[40] They have also been reported to be used in the treatment of hormone deficiency[41] and neurological disorders related to b-amyloid production.[42] &
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Concept ditions and the use of prolinols with a bulky substituent at N1, and/or a bulky substituent at C4, as these substituted prolinols were transformed into the corresponding 3-azidopiperidines as the major products.[45] Thus, when N-trityl prolinol 51 was treated with (diethylamino)difluorosulfonium tetrafluoroborate (XtalFluor-E) in the presence of nBu4NN3, azidopiperidine 67 and azidopyrrolidine 68 were obtained in a ratio of 88/12 with a global yield of 87 %. When a sterically hindered substituent was introduced at C4, as in 61, only 3-azidopiperidine 69 was isolated in 65 % yield and, the replacement of the N-trityl group by an N-benzyl group allowed the formation of 70/71 in a 97:3 ratio. Piperidine 70 was isolated in 72 % yield, thus showing the importance of the substituent at C4. In the case of N-benzyl prolinols 63 and 64, substituted either by an N,N-dibenzylamino or an N-trityl group at C4, the corresponding 3-azidopiperidine 72 (57 %) and 73 (84 %) were exclusively formed. For 4-fluoroprolinol 65 and 4,4-difluoroprolinol 66, a good piperidine/pyrrolidine ratio was obtained (91:9—93:7) in favor of the piperidine (Table 3).[45] Notably, depending on the relative stereochemistry and the nature of the substituents at C4 in the starting prolinols, the ratio can be poor to excellent, thus demonstrating the importance of the C4 substituent in determining the efficiency of the ring enlargement.[45] 3-Azidopiperidines 74 can easily be transformed into the corresponding amines in good yield by using a Staudinger reduction of the azido group (Scheme 15). For example, 74 was converted into 78 in 82 % yield.
Table 3. Synthesis of 3-azidopiperidines.
Synthesis of 3-thiopiperidines So far, no example of a ring expansion of prolinols into 3-thiopiperidines has been reported. However, the ring expansion of halo-indolizidines into thio-quinolizidines, via an aziridinium intermediate, was realized using the methylthiolate anion,[46] a result that suggests that 3-thiopiperidines should be accessible through ring expansion of 2-(halomethyl)pyrrolidines.
Scheme 15. Formation of 3-amino 5-fluoropiperidines.
Synthesis of 3-cyano- and 3-arylpiperidines (C C bond formation) 3-Cyanopiperidines were formed either from prolinols or from 2-(chloromethyl)pyrrolidines. Treatment of 80 under Kolbe conditions (NaCN, EtOH, reflux) led to carbonitrile 82 together with minor amounts of the C2 epimer and rearranged product 81.[44c] The yield in the piperidine carbonitrile was increased to 18 % when 19 was treated with mesyl anhydride (Ms2O, Et3N) and then with LiCN (0.5 m in DMF) but, again, the major compound was pyrrolidine 84 (Scheme 16).[47] Chem. Eur. J. 2014, 20, 1 – 11
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Scheme 16. Synthesis of 3-cyanopiperidines.
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Concept 3-Arylpiperidines are important because they can be used as selective dopamine (DA) autoreceptor agonists, 3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP, UH 106, 88) being an example. This compound was synthesized by treatment of ( )-(S)-Npropyl-2-(chloromethyl)pyrrolidine hydrochloride 85 with 2 equivalents of phenyl magnesium bromide in the presence of a catalytic amount of cuprous cyanide or cuprous iodide. Notably, the use of a copper salt is crucial for initiating nucleophilic attack of the Grignard reagent. Under these conditions, 3-arylpiperidine 86 and pyrrolidine 87 were obtained in a global yield of 82 %, albeit with a ratio 86/87 of 18:82 in favor of pyrrolidine 87 (Scheme 17).[48]
edged. Sanofi, Johnson & Johnson (USA), Janssen Pharmaceutica, and Merck-Serono are acknowledged for financial support. Keywords: enantioselectivity · piperidines · pyrrolidinols · rearrangements · ring expansion [1] For reviews, see: a) M. G. P. Buffat, Tetrahedron 2004, 60, 1701 – 1729; b) J. Cossy, Chem. Rec. 2005, 5, 70 – 80; c) C. Escolano, M. Amat, J. Bosch, Chem. Eur. J. 2006, 12, 8198 – 8207. [2] a) E. Poupon, D. Francois, N. Kunesch, H. P. Husson, J. Org. Chem. 2004, 69, 3836 – 3841; b) K. M. Goodenough, W. J. Moran, P. Raubo, J. P. A. Harrity, J. Org. Chem. 2005, 70, 207 – 213; c) T. Kobayashi, F. Hasegawa, K. Tanaka, S. Katsumura, Org. Lett. 2006, 8, 3813 – 3816; d) L. C. Pattenden, R. A. J. Wybrow, S. A. Smith, J. P. A. Harrity, Org. Lett. 2006, 8, 3089 – 3091; e) C. Y. Legault, A. B. Charette, J. Am. Chem. Soc. 2005, 127, 8966 – 8967; f) R. P. Wurz, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 12234 – 12235; g) G. Barbe, M. St-Onge, A. B. Charette, Org. Lett. 2008, 10, 5497 – 5499; h) G. Lemonnier, A. B. Charette, J. Org. Chem. 2010, 75, 7465 – 7467; i) H. M. Lovick, F. E. Michael, J. Am. Chem. Soc. 2010, 132, 1249 – 1251; j) T. K. Beng, R. E. Gawley, J. Am. Chem. Soc. 2010, 132, 12216 – 12217. [3] For an example, see: N. A. Grayson, W. D. Bowen, K. C. Rice, Heterocycles 1992, 34, 2281 – 2292. [4] a) M. Amat, O. Lozano, C. Escolano, E. Molins, J. Bosch, J. Org. Chem. 2007, 72, 4431 – 4439; b) M. Amat, N. Llor, J. Hidalgo, C. Escolano, J. Bosch, J. Org. Chem. 2003, 68, 1919 – 1928; c) M. Amat, E. Brunaccini, B. Checa, M. Prez, N. Llor, J. Bosch, Org. Lett. 2009, 11, 4370 – 4373; d) Y. Nakamura, A. M. Burke, S. Kotani, J. W. Ziller, S. D. Rychnovsky, Org. Lett. 2010, 12, 72 – 75; e) D. Gnecco, A. M. Lumbreras, J. L. Teran, A. Galindo, J. R. Juarez, M. L. Orea, A. Castro, R. G. Enriquez, W. F. Reynolds, Heterocycles 2009, 78, 2589 – 2594. [5] a) H. Takahata, K. Inose, N. Araya, T. Momose, Heterocycles 1994, 38, 1961 – 1964; b) H. Takahata, M. Kubota, S. Takahashi, T. Momose, Tetrahedron: Asymmetry 1996, 7, 3047 – 3054; c) H. Takahata, M. Kubota, N. Ikota, J. Org. Chem. 1999, 64, 8594 – 8601. [6] For examples, see: a) J. Cossy, C. Dumas, D. Gomez Pardo, Eur. J. Org. Chem. 1999, 1693 – 1699; b) J. Cossy, D. Gomez Pardo, Chemtracts 2002, 15, 579 – 605; c) I. Dchamps, D. Gomez Pardo, J. Cossy, Arkivoc 2007, V, 38 – 45. [7] For examples of the rearrangement of aziridines to azetidines, see: a) S. Stankovic´, S. Catak, M. D’hooghe, H. Goossens, K. Abbaspour Tehrani, P. Bogaert, M. Waroquier, V. Van Speybroeck, N. De Kimpe, J. Org. Chem. 2011, 76, 2157 – 2167; b) S. Stankovic´, H. Goossens, S. Catak, M. Tezcan, M. Waroquier, V. Van Speybroeck, M. D’hooghe, N. De Kimpe, J. Org. Chem. 2012, 77, 3181 – 3190. [8] For examples of the rearrangement of azetidines to pyrrolidines, see: a) F. Couty, F. Durrat, D. Prim, Tetrahedron Lett. 2003, 44, 5209 – 5212; b) F. Durrat, M. Vargas Sanchez, F. Couty, G. Evano, J. Marrot, Eur. J. Org. Chem. 2008, 3286 – 3297; c) S. Dekeukeleire, M. D’hooghe, K. W. Tçrnroos, N. De Kimpe, J. Org. Chem. 2010, 75, 5934 – 5940. [9] For selected examples of the rearrangement of pyrrolidines to piperidines, see: a) S. G. Davies, R. L. Nicholson, P. D. Price, P. M. Roberts, A. J. Russell, E. D. Savory, A. D. Smith, J. E. Thomson, Tetrahedron: Asymmetry 2009, 20, 758 – 772; b) S. G. Davies, A. L. A. Figuccia, A. M. Fletcher, P. M. Roberts, J. E. Thomson, Org. Lett. 2013, 15, 2042 – 2045. [10] For examples of the rearrangement of piperidines to azepanes, see: a) H.-S. Chong, K. Garmestani, L. H. Bryant, Jr., M. W. Brechbiel, J. Org. Chem. 2001, 66, 7745 – 7750; b) K. Vervisch, M. D’hooghe, K. W. Tçrnroos, N. De Kimpe, J. Org. Chem. 2010, 75, 7734 – 7744. [11] a) E. M. Schultz, C. M. Robb, J. M. Sprague, J. Am. Chem. Soc. 1947, 69, 188 – 189; b) E. M. Schultz, C. M. Robb, J. M. Sprague, J. Am. Chem. Soc. 1947, 69, 2454 – 2459; c) S. D. Ross, J. Am. Chem. Soc. 1947, 69, 2982 – 2983; d) W. R. Brode, M. W. Hill, J. Am. Chem. Soc. 1947, 69, 724; e) J. F. Kerwin, G. E. Ullyot, R. C. Fuson, C. L. Zirkle, J. Am. Chem. Soc. 1947, 69, 2961 – 2965; f) E. M. Schultz, J. M. Sprague, J. Am. Chem. Soc. 1948, 70, 48 – 52. [12] a) C. Golumbic, J. S. Fruton, M. Bergmann, J. Org. Chem. 1946, 11, 518 – 535; b) C. Golumbic, M. Bergmann, J. Org. Chem. 1946, 11, 536 – 542; c) J. S. Fruton, M. Bergmann, J. Org. Chem. 1946, 11, 543 – 549; d) C. Golumbic, M. A. Stahmann, M. Bergmann, J. Org. Chem. 1946, 11, 550 –
Scheme 17. Synthesis of 3-arylpiperidines.
Summary and Outlook The ring expansion of optically active prolinols gives access to valuable optically active C3-substituted piperidines via an aziridinium intermediate. Depending on the nucleophile used to open the aziridinium, the ring expansion is under either thermodynamic or kinetic control. The regioselectivity of attack of the aziridinium intermediate by a nucleophile depends also on the substituents on the prolinols at C4 as well as on the steric hindrance of the alkyl substituent at N1. Quantum chemical computation studies will be necessary to fully understand the regioselectivity of the attack of nucleophiles on the aziridinium intermediates.[49, 50] In the future, it will be important to develop conditions to selectively synthesize optically active 3-alkyl, 3-aryl-, and 3-cyano-piperidines from prolinols and derivatives by using carbanions or cyanide anions. It will also be important to use activators in catalytic amounts to generate the aziridinium intermediates from prolinols in order to access C3-substituted piperidines in good yields and enantiomeric excess.[51]
Acknowledgements The students and internship students who worked on the ring expansion of prolinols and derivatives are gratefully acknowl&
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[47] C. Heindl, H. Hbner, P. Gmeiner, Tetrahedron: Asymmetry 2003, 14, 3153 – 3172. [48] S.-O. Thorberg, L. Gawell, I. Csçregh, J. L. G. Nilsson, Tetrahedron 1985, 41, 129 – 139. [49] For a computational study of halide-induced ring opening of monocyclic aziridinium, see: a) M. D’hooghe, S. Catak, S. Stankovicˇ, M. Waroquier, Y. Kim, H.-J. Ha, V. Van Speybroeck, N. De Kimpe, Eur. J. Org. Chem. 2010, 4920 – 4931; b) S. Stankovicˇ, M. D’hooghe, S. Catak, H. Eum, M. Waroquier, V. Van Speybroeck, N. De Kimpe, H.-J. Ha, Chem. Soc. Rev. 2012, 41, 643 – 665; c) B. Baruah, S. Deuri, P. Phukan, Comp. Theor. Chem. 2014, 1027, 197 – 202 and references therein.
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Concept [50] For a computational study of azide-induced ring opening of bicyclic aziridinium, see: Y.-H. Lam, K. N. Kendall, J. Cossy, D. Gomez Pardo, A. Cochi, Helv. Chim. Acta 2012, 95, 2265 – 2277. [51] For examples of the rearrangement of prolinols to 3-hydroxypiperidines, see: a) T.-X. Mtro, D. Gomez Pardo, J. Cossy, J. Org. Chem. 2007,
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72, 6556 – 6561; b) T.-X. Mtro, D. Gomez Pardo, J. Cossy, Synlett 2007, 2888 – 2890.
Published online on && &&, 0000
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CONCEPT & Synthetic Methods D. Gomez Pardo, J. Cossy* && – && One-carbon expansion: The ring expansion of enantiomerically pure prolinols via an aziridinium intermediate,
either under thermodynamic or kinetic control, gives C3-substituted piperidines in good yields and enantiomeric excess.
Access to Optically Active 3Substituted Piperidines by Ring Expansion of Prolinols and Derivatives
Ring-Expansion Reactions 3-Substituted piperidines are important building blocks for the preparation of many synthetic and natural biologically active compounds. In their Concept article on page &&ff., D. Gomez Pardo and J. Cossy provide an overview on the preparation of these compounds through the ring expansion of the corresponding prolinol derivatives, a transformation that proceeds via an aziridinium intermediate.
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