& Synthetic Methods
Access to Optically Active 3-Substituted Piperidines by RingExpansion of Prolinols and Derivatives
Domingo Gomez Pardo and Janine Cossy*[a]
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ConceptDOI: 10.1002/chem.201304924
Abstract: The ring expansion of prolinols via an aziridini-um intermediate gives C3-substituted piperidines in goodyields and enantiomeric excess, the substituent at the C3position being derived from the most reactive nucleophilein the reaction mixture. Depending on the nucleophile,the reaction proceeds under thermodynamic or kineticcontrol. The regioselectivity of attack of nucleophiles onthe aziridinium intermediate depends on the nature ofthe substituents on the nitrogen atom and the C4 posi-tion of the starting prolinols.
Introduction
C3-Substituted piperidines are among the most ubiquitousheterocyclic building blocks present in natural products andbioactive compounds. Among the natural products, we cancite nipecotic acid and vinblastine and, among the syntheticcompounds, we can cite paroxetine, zamifenacine and Ro 67-8867 (Figure 1).
Owing to the biological properties of C3-substituted piperi-dines, huge synthetic effort has been made to access thesecompounds;[1, 2] however, the synthesis of optically active C3-substituted piperidines remains a challenge. A number ofmethods exist and among these methods, the most commonones involve the hydrogenation of substituted pyridines fol-lowed by the resolution of the enantiomers by separation ofthe diastereomeric ammonium salts,[3] the enantioselective hy-drogenation of tetrahydropyridines,[3] the diastereoselective al-kylation and reduction of oxazolopiperidines[4] and/or the sepa-
ration of the diastereomers,[4] the cyclization of optically activelinear azido sulfonate derivatives after reduction of the azidogroup,[5] and the enantioselective ring expansion of prolinols(Scheme 1).[6]
The enantioselective ring expansion of 2-(halomethyl) or2-(hydroxymethyl)azaheterocycles into their homologues, viabicyclic aziridinium intermediates, is of high syntheticvalue.[7–10] In this review article, we will focus only on the enan-tioselective ring expansion of prolinols and derivatives, 2-(halo-methyl)pyrrolidines and 2-(mesyloxymethyl)pyrrolidines, eitherunder thermodynamic or kinetic control in order to produceoptically active C3-substituted piperidines. The ring expansionof bicyclic compounds will not be covered here.
In 1947, it was noticed that b-chloroamine hydrochlorides1 and 2 underwent a rearrangement under basic conditionsleading to 3 (Scheme 2, eq. 1).[11] Owing to this observation, itwas hypothesized that 2-(chloromethyl)heterocyclic amines
Figure 1. Substituted piperidine derivatives.
Scheme 1. Some methods to access C3-substituted piperidines.
Scheme 2. Formation of aziridinium intermediates.
[a] Dr. D. Gomez Pardo, Prof. J. CossyLaboratoire de Chimie OrganiqueESPCI ParisTech, CNRS10 rue Vauquelin 75231 Paris Cedex 05 (France)Fax: (+ 33) 1-40-79-46-60E-mail : [email protected]
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should undergo a similar rearrangement to produce ring-ex-panded products. The hypothesis was verified by using1-ethyl-2-(chloromethyl)pyrrolidine hydrochloride 4 ; whentreated with a cold aqueous solution of NaOH, 4 was trans-formed into 1-ethyl-3-chloropiperidine 5 (Scheme 2, eq. 2).[12]
Studies conducted to understand the ring expansion of 4 into5 have shown that aziridinium intermediate A was responsiblefor the ring expansion (Scheme 2, eq. 2).
When optically active pyrrolidine hydrochloride (S)-4 washeated at a temperature above the melting point of the am-monium salt (up to 165 8C), 3-chloropiperidine (R)-5 wasformed and the ring-expansion process was enantioselectiveas a complete inversion of configuration occurred upon theconversion of (S)-4 into (R)-5. When (S)-4 was heated withNaOH, a mixture of 3-hydroxypiperidine (R)-6 and prolinol(S)-7, in a 32:68 ratio favoring prolinol (S)-7, was obtainedowing to non-regioselective attack of the aziridinium by thehydroxide ion,[13] thus decreasing the synthetic value of the re-action. Therefore, it was of interest to find reaction conditionsthat would allow efficient access to 3-hydroxypiperidines(Scheme 3).
Synthesis of 3-hydroxypiperidines
2-(Hydroxymethyl)pyrrolidines can be transformed into 3-hy-droxypiperidines via an aziridinium intermediate by utilizing re-agents other than NaOH. When substituted (S)-prolinol 8 wastreated with mesyl chloride in pyridine in the presence of a cat-alytic amount of 4-(dimethylamino)pyridine, at room tempera-ture for 2 h, mesylate 9 was isolated (98 %). Treatment of thismesylate with NaOH (3 equiv) in H2O/dioxane or with AcONa(2 equiv) in DMF afforded a mixture of 3-hydroxypiperidine 10and pyrrolidine 11 in a 15:1 ratio.[14] Again, the attack of aziridi-nium intermediate B by oxygenated nucleophiles, such as HO�
and AcO� , is not regioselective (Scheme 4). However, whena prolinol possessing a secondary alcohol, such as 12, wastreated with mesyl chloride at �20 8C, followed by the additionof tetrabutyl ammonium acetate, 3-acetyl piperidine 14 wasexclusively obtained (85 % yield, 99 % ee), via the mesylate in-termediate 13 (Scheme 5).[6a, 15]
When 2-(halomethyl)pyrrolidines were treated with oxygen-ated nucleophiles, such as NaOH, KOAc, NaOR, and RCO2Na,a mixture of 2-oxymethylated pyrrolidine I’ and 3-oxygenated
piperidine II’ was obtained.[9b, 16] The only exception was theuse of sodium phenolate, which exclusively led to 3-phenyl-oxypiperidine[17] (Scheme 6).
In contrast to the treatment of 2-(mesyloxymethyl)- and 2-(chloromethyl)pyrrolidines with oxygenated nucleophiles, thetreatment of prolinols, possessing a primary alcohol, with tri-fluoroacetic anhydride (TFAA), then with triethylamine (Et3N)and then with NaOH, led to 3-oxygenated piperidines in goodyields. Thus, treatment of prolinol (S)-16 with TFAA in THF,then with Et3N and then with NaOH, led exclusively to the cor-responding 3-hydroxypiperidine (R)-17 in good yield (63 %)and excellent enantiomeric excess (95 % ee).[18] When treatedwith TFAA, the esterification of (S)-16 and the formation of thequaternary ammonium salt take place to produce intermediate
Scheme 3. Rearrangement of b-chloroamines.
Scheme 4. Non-selective ring-expansion via a mesylate intermediate.
Scheme 5. Selective ring-expansion via a mesylate intermediate.
Scheme 6. Treatment of 2-(halomethyl)pyrrolidines with oxygenated nucleo-philes.
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C. The addition of Et3N produces amino ester intermediate D,which undergoes an SNi process to give highly tight ion pair Ethat 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-hydroxypiperidinewas the only isolated compound.
The ring expansion of N-alkylated prolinols is a general andhighly stereoselective process allowing access to a diverserange of substituted 3-hydroxypiperidines in good yield andenantiomeric excess. A few examples are reported in Table 1.[6a]
Notably, the process is chemoselective as prolinols 18–21 weretransformed into the corresponding 3-hydroxypiperidines 24–27 in good yield and with excellent enantiomeric excess. Fur-thermore, 3-hydroxypiperidines, possessing a quaternarycenter at C3, such as 28, can be synthesized from the corre-sponding prolinol 22 ; also, 2-phenyl-3-hydroxypiperidine 29was obtained from prolinol 23, possessing a secondary alcoholat C2’. All the substituted piperidines were isolated in goodyields and with excellent enantiomeric excess.
The ring expansion of prolinols into 3-hydroxypiperidines,by using TFAA/Et3N/NaOH, has been utilized to synthesize nat-ural products such as pseudoconhydrine,[19] and non-naturalbioactive compounds such as isofagomine,[20] zamifenacine,[21]
l-733,060,[22] Ro 67-8867[23] (Scheme 8).
Synthesis of 3-halopiperidines
The stereoselective and enantioselective ring expansion of un-stable N-alkyl-2-(halomethyl)pyrrolidines was used to preparedN-alkyl-3-halopiperidines. Pyrrolidines 40 and 41 were rear-ranged into the thermodynamically more stable 3-chloropiperi-dines 43 and 44, respectively, in quantitative yields, when dis-solved in chloroform (Scheme 9).[24] In addition, a stereospecificrearrangement of iodo-pyrrolidine 42 was observed at 55 8C toproduce 3-iodopiperidine 45 in 24 % yield along with the pyr-
rolidino-butyrolactone 46 in 60 %. Thus, in the case of pyrroli-dine 42, the reaction was not selective (Scheme 9).[25]
Notably, N-alkyl prolinol derivatives could be transformedinto 3-chloropiperidines with good enantiomeric excess whenprolinols were treated with SOCl2 in CHCl3 followed by a ther-mal process. In the case of bromopiperidines, they wereformed when prolinols were treated with SOBr2 in DMF/cyclo-hexane (Scheme 10).[26] Intermediates G and H are probably re-sponsible for the transformation of prolinols into 3-halopiperi-dines (Scheme 10).
Cardiovascular compounds,[27] such as troglitazone ana-logues,[28] were prepared by using the ring expansion of proli-nol derivatives producing 3-halopiperidines, which were thentransformed in compounds of biological interest (Scheme 11).
Reagents other than thionyl halides, for example, mesylchloride, in the presence of Et3N, can transform N-alkyl proli-nols into 3-chloropiperidines. Thus, treatment of (S)-16 and 12with mesyl chloride, in the presence of Et3N in THF, led to 3-chloropiperidine (R)-49 (77 % yield) and 50 (quant.), respective-ly. It was postulated that upon formation of mesylate I, there isinternal assistance of the nitrogen atom, thus producing aziri-dinium salt J, which is then attacked by the more nucleophilic
Scheme 7. Transformation of prolinol (S)-16 into 3-hydroxypiperidines (R)-17by using TFAA/Et3N/NaOH.
Table 1. Synthesis of 3-hydroxypiperidines from prolinols.
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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 synthe-size (�)-paroxetine (Scheme 13).[30]
An important feature in medicinal chemistry is thereplacement of an sp3 C�H bond by an sp3 C�F bondbecause the introduction of a fluorine atom in organ-ic molecules can influence their physical, chemical,and biological properties.[31] As diethylaminosulfur tri-fluoride (DAST) and bis(2-methoxyethyl)aminosulfurtrifluoride (Deoxo-Fluor) can activated alcohols, thesereagents were used to induce the ring expansion ofprolinols to the corresponding optically active 3-fluo-ropiperidines via an aziridinium intermediate. Nota-bly, DAST and Deoxo-Fluor give similar yields in 3-flu-oropiperidines.[32]
When N-benzyl prolinol (S)-16 was treated withDAST in THF, at 0 8C for 1 h and then at room tem-perature for 1 h, an inseparable mixture of 3-fluoropi-peridine 54 and 2-(fluoromethyl)pyrrolidine 55 wasobtained in a ratio of 57:43 in favor of 3-fluoropiperi-dine 54 (60 % overall yield). This process is under ki-netic control and, notably, the selectivity of the rear-rangement can be improved when the nitrogenatom of the prolinol bears a sterically hindered alkylgroup (compounds 51 and 52), when a sterically hin-dered substituent is present at C4 (for example com-pound 19), or if a quaternary center is present at C2(for example compound 53) (Table 2).
The ring enlargement of prolinols induced byDAST is probably the result of the formation of inter-mediate L, which produces aziridinium intermediate
M that can be attacked by the fluorine ion liberated in themedium to produce intermediate N and/or O depending onthe substituents present in substrate K (Scheme 14). As no-ticed, the selectivity of the rearrangement in favor of the piper-idines depends on the bulkiness of the N-substituent and/orC2 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. Scheme 10. Formation of 3-halopiperidines.
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stituent. These observations suggest that non-symmetrical azir-idinium M, where the N�C2 bond is longer than the N�C2’bond, is responsible for this selectivity and/or is due to theconformation of the five-membered ring in the bicyclic aziridi-nium intermediate.[32a, b]
Synthesis of 3-aminopiperidines
A great number of patents are related to 3-aminopiperidinederivatives owing to their potential bioactivities. 3-Aminopiper-idine derivatives have been reported to possess antitumoral,[33]
antibacterial,[34] anti-inflammatory,[35] analgesic,[36] antiviral,[37]
anti-ischemic properties,[38] antidepressive,[39] and psychotropicproperties.[40] They have also been reported to be used in thetreatment of hormone deficiency[41] and neurological disordersrelated to b-amyloid production.[42]
Contrary to the synthesis of 3-hydroxy- and 3-halopiperi-dines from N-alkyl prolinols, via an aziridinium intermediate,the synthesis of 3-azido- and 3-aminopiperidines by ring ex-pansion of N-alkyl prolinols is very lengthy and/or problemat-ic.[43] When N-alkyl prolinols are treated with SOCl2 and thenwith an amine, 2-(aminomethyl)pyrrolidines were exclusivelyformed and no traces of the corresponding 3-aminopiperidinewas detected.[16b, 44] The treatment of N-alkyl prolinols withmesyl chloride and then with NaN3 in DMF at 100 8C led toa mixture of 3-azidopiperidines and 2-(azidomethyl)pyrroli-dines.[14] A solution to this problem was the use of kinetic con-
Scheme 11. Synthesis of troglitazone derivatives from prolinol derivatives.
Scheme 12. Ring expansion of prolinols via a mesylate intermediate.
Scheme 13. Synthesis of (�)-paroxetine.
Scheme 14. Ring expansion of prolinols induced by DAST.
Table 2. Formation of 3-fluoropiperidines from prolinols using DAST(Et2N�SF3).
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ditions and the use of prolinols with a bulky substitu-ent at N1, and/or a bulky substituent at C4, as thesesubstituted prolinols were transformed into the cor-responding 3-azidopiperidines as the major prod-ucts.[45]
Thus, when N-trityl prolinol 51 was treated with(diethylamino)difluorosulfonium tetrafluoroborate(XtalFluor-E) in the presence of nBu4NN3, azidopiperi-dine 67 and azidopyrrolidine 68 were obtained ina ratio of 88/12 with a global yield of 87 %. Whena sterically hindered substituent was introduced atC4, as in 61, only 3-azidopiperidine 69 was isolatedin 65 % yield and, the replacement of the N-tritylgroup by an N-benzyl group allowed the formationof 70/71 in a 97:3 ratio. Piperidine 70 was isolated in72 % yield, thus showing the importance of the sub-stituent at C4. In the case of N-benzyl prolinols 63and 64, substituted either by an N,N-dibenzylaminoor an N-trityl group at C4, the corresponding3-azidopiperidine 72 (57 %) and 73 (84 %) were exclu-sively formed. For 4-fluoroprolinol 65 and 4,4-difluor-oprolinol 66, a good piperidine/pyrrolidine ratio wasobtained (91:9—93:7) in favor of the piperidine(Table 3).[45] Notably, depending on the relative ste-reochemistry and the nature of the substituents atC4 in the starting prolinols, the ratio can be poor toexcellent, thus demonstrating the importance of theC4 substituent in determining the efficiency of thering enlargement.[45]
3-Azidopiperidines 74 can easily be transformedinto the corresponding amines in good yield byusing a Staudinger reduction of the azido group(Scheme 15). For example, 74 was converted into 78in 82 % yield.
Synthesis of 3-thiopiperidines
So far, no example of a ring expansion of prolinolsinto 3-thiopiperidines has been reported. However, the ring ex-pansion of halo-indolizidines into thio-quinolizidines, via anaziridinium intermediate, was realized using the methylthiolateanion,[46] a result that suggests that 3-thiopiperidines shouldbe accessible through ring expansion of 2-(halomethyl)pyrroli-dines.
Synthesis of 3-cyano- and 3-arylpiperidines(C�C bond formation)
3-Cyanopiperidines were formed either from prolinols or from2-(chloromethyl)pyrrolidines. Treatment of 80 under Kolbe con-ditions (NaCN, EtOH, reflux) led to carbonitrile 82 togetherwith minor amounts of the C2 epimer and rearranged product81.[44c] The yield in the piperidine carbonitrile was increased to18 % when 19 was treated with mesyl anhydride (Ms2O, Et3N)and then with LiCN (0.5 m in DMF) but, again, the major com-pound was pyrrolidine 84 (Scheme 16).[47]
Scheme 15. Formation of 3-amino 5-fluoropiperidines.
Scheme 16. Synthesis of 3-cyanopiperidines.
Table 3. Synthesis of 3-azidopiperidines.
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3-Arylpiperidines are important because they can be used asselective dopamine (DA) autoreceptor agonists, 3-(3-hydroxy-phenyl)-N-propylpiperidine (3-PPP, UH 106, 88) being an exam-ple. This compound was synthesized by treatment of (�)-(S)-N-propyl-2-(chloromethyl)pyrrolidine hydrochloride 85 with2 equivalents of phenyl magnesium bromide in the presenceof a catalytic amount of cuprous cyanide or cuprous iodide.Notably, the use of a copper salt is crucial for initiating nucleo-philic attack of the Grignard reagent. Under these conditions,3-arylpiperidine 86 and pyrrolidine 87 were obtained ina global yield of 82 %, albeit with a ratio 86/87 of 18:82 infavor of pyrrolidine 87 (Scheme 17).[48]
Summary and Outlook
The ring expansion of optically active prolinols gives access tovaluable optically active C3-substituted piperidines via an aziri-dinium intermediate. Depending on the nucleophile used toopen the aziridinium, the ring expansion is under either ther-modynamic or kinetic control. The regioselectivity of attack ofthe aziridinium intermediate by a nucleophile depends also onthe substituents on the prolinols at C4 as well as on the sterichindrance of the alkyl substituent at N1. Quantum chemicalcomputation studies will be necessary to fully understand theregioselectivity of the attack of nucleophiles on the aziridiniumintermediates.[49, 50]
In the future, it will be important to develop conditions toselectively synthesize optically active 3-alkyl, 3-aryl-, and3-cyano-piperidines from prolinols and derivatives by usingcarbanions or cyanide anions. It will also be important to useactivators in catalytic amounts to generate the aziridinium in-termediates from prolinols in order to access C3-substituted pi-peridines in good yields and enantiomeric excess.[51]
Acknowledgements
The students and internship students who worked on the ringexpansion of prolinols and derivatives are gratefully acknowl-
edged. Sanofi, Johnson & Johnson (USA), Janssen Pharmaceuti-ca, and Merck-Serono are acknowledged for financial support.
Keywords: enantioselectivity · piperidines · pyrrolidinols ·rearrangements · ring expansion
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Scheme 17. Synthesis of 3-arylpiperidines.
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Chem. Eur. J. 2014, 20, 1 – 11 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim9 &&
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Concept
[50] For a computational study of azide-induced ring opening of bicyclicaziridinium, see: Y.-H. Lam, K. N. Kendall, J. Cossy, D. Gomez Pardo, A.Cochi, Helv. Chim. Acta 2012, 95, 2265 – 2277.
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Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 11 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim10&&
�� These are not the final page numbers!
Concept
CONCEPT
& Synthetic Methods
D. Gomez Pardo, J. Cossy*
&& –&&
Access to Optically Active 3-Substituted Piperidines by RingExpansion of Prolinols and Derivatives
One-carbon expansion : The ring ex-pansion of enantiomerically pure proli-nols via an aziridinium intermediate,
either under thermodynamic or kineticcontrol, gives C3-substituted piperidinesin good yields and enantiomeric excess.
Ring-Expansion Reactions3-Substituted piperidines are important building blocks forthe preparation of many synthetic and natural biologicallyactive compounds. In their Concept article on page &&ff. ,D. Gomez Pardo and J. Cossy provide an overview on thepreparation of these compounds through the ringexpansion of the corresponding prolinol derivatives,a transformation that proceeds via an aziridiniumintermediate.
Chem. Eur. J. 2014, 20, 1 – 11 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim11 &&
These are not the final page numbers! ��
Concept
