molecules Review Review Synthesis of Substituted α-Trifluoromethyl Synthesis of Substituted α-Trifluoromethyl Piperidinic Derivatives Piperidinic Derivatives
Sarah Rioton, Domingo Gomez Pardo and Janine Cossy * Sarah Rioton, Domingo Gomez Institute Pardo and Cossy * Laboratoire de Chimie Organique, of Janine Chemistry, Biology and Innovation (CBI), CNRS UMR 8231, ESPCI Paris, PSL Research University, 10 rue Vauquelin,Biology 75231 Paris CEDEX 05, France; Laboratoire de Chimie Organique, Institute of Chemistry, and Innovation (CBI), CNRS UMR 8231, ESPCI
[email protected] (S.R.);
[email protected] (D.G.P.) Paris, PSL Research University; 10 rue Vauquelin, 75231 Paris Cedex 05, France;
[email protected] (S.R.); * Correspondence:
[email protected];
[email protected] (D.G.P.) Tel.: +33-140-794-429; Fax: +33-140-794-660 * Correspondence:
[email protected]; Tel.: +33-140-794-429; Fax: +33-140-794-660 Academic Editor: Margaret A. Brimble CNZM, FRSNZ Academic Editor: 2017; Margaret A. Brimble CNZM,2017; FRSNZ Received: 2 March Accepted: 14 March Published: 19 March 2017 Received: 2 March 2017; Accepted: 14 March 2017; Published: date
Abstract: A comprehensive survey of pathways leading to the generation of α-trifluoromethyl monocyclic piperidinic derivatives references). These compounds have been Abstract: A comprehensive survey is of provided pathways (65 leading to the generation of α-trifluoromethyl synthesized either from 6-membered rings e.g., pipecolic acid or lactam derivatives by introduction monocyclic piperidinic derivatives is provided (65 references). These compounds have been a trifluoromethyl group, from pyridine rings or pyridinone derivatives by reduction, andby from 5-membered synthesized either from 6-membered e.g., pipecolic acid or lactam derivatives introduction a trifluoromethyl group, from pyridine or pyridinone derivatives by reduction, andcyclization from 5-membered rings e.g., prolinol derivatives by ring expansion, from linear amines by or from rings e.g., prolinolbyderivatives by ring expansion, from linear amines by cyclization or from dienes/dienophiles [4 + 2]-cycloaddition. dienes/dienophiles by [4 + 2]-cycloaddition. Keywords: nitrogen heterocycles; fluorine; piperidine; trifluoromethyl group; ring expansion; Keywords:cycloaddition nitrogen heterocycles; fluorine; piperidine; trifluoromethyl group; ring expansion; cyclization; cyclization; cycloaddition
1. Introduction 1. Introduction Functionalized piperidinic derivatives are among the most ubiquitous heterocyclic cores in Functionalized piperidinic derivatives are among the most ubiquitous heterocyclic cores in natural natural products and bioactive compounds, therefore a huge number of methods has been developed products and bioactive compounds, therefore a huge number of methods has been developed to prepare to prepare piperidinic derivatives [1–7]. With respect to the biologically active targets, there is great piperidinic derivatives [1–7]. With respect to the biologically active targets, there is great interest in interest in introducing substituents that can increase their biological activity which can be related introducing substituents that can increase their biological activity which can be related to an increase of to the an increase of the and theInmetabolic stability. In this context, lipophilicity, thelipophilicity, bioavailabilitythe andbioavailability the metabolic stability. this context, the trifluoromethyl groupthe trifluoromethyl group is oftenofused as a bioisostere of group a chloride or a methyl group modulate is often used as a bioisostere a chloride or a methyl to modulate the steric andtoelectronic theproperties steric andofelectronic properties of a lead compound or to protect a reactive methyl group from a lead compound or to protect a reactive methyl group from metabolic oxidation. This metabolic oxidation. This substituent can also increase the substituent can also increase the lipophilicity of molecules [8].lipophilicity of molecules [8]. R'
X
+
I
X
R' X
CF3 H
RNH R'' CF3
R'
N R B
N R A
G R' N R F
R'' CF3
R'
R'' OH CF3
R' N R
O
C
R' O
CO2H
N N R E
CF3
CF3
D
Scheme piperidinic derivatives. derivatives. Scheme 1. 1. Precursors Precursors of of α-trifluoromethyl α-trifluoromethyl piperidinic Molecules 2017, 22, 483; doi:10.3390/molecules22030483
Molecules 2017, 22, 483; doi:10.3390/molecules22030483
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Herein, we report the synthesis of α-trifluoromethylpiperidinic derivatives of type A. These Herein, reportthe thesynthesis synthesisofofα-trifluoromethylpiperidinic α-trifluoromethylpiperidinic derivatives type These Herein, wewe report derivatives of of type A. A. These compounds have been synthesized either from 6-membered rings B and C by introduction of a CF3 Herein, we report the synthesis of α-trifluoromethylpiperidinic of type A. compounds have been synthesized either from 6-membered rings Bderivatives and C by introduction of a CF compounds have been synthesized either from 6-membered rings B and C by introduction of These a CF 3 3 group, from have pyridines D or pyridinones E from by reduction, fromrings 5-membered rings F by ring expansion, compounds been synthesized either 6-membered B and C by introduction of a CF 3 group, from pyridines D or pyridinones E by reduction, from 5-membered rings F by ring expansion, group, from pyridines D or pyridinones E by reduction, from 5-membered rings F by ring expansion, from linear amines G by cyclization, fromEdienes/dienophiles H/I by cycloaddition (Scheme 1). We will group, from pyridines D by or cyclization, pyridinones by dienes/dienophiles reduction, fromH/I 5-membered rings F(Scheme by ring expansion, from linear amines G from H/I by cycloaddition (Scheme from linear amines G by cyclization, from dienes/dienophiles by cycloaddition 1). We 1). willWe only report the formation of monocyclic piperidinic derivatives, and of bicyclic derivatives only when from linear amines G by cyclization, from dienes/dienophiles H/I by cycloaddition (Scheme 1). We will will only report the formation of monocyclic piperidinic derivatives, and of bicyclic derivatives only only report the formation of monocyclic piperidinic derivatives, and of bicyclic derivatives only when they were transformed intoofthe monocyclic derivatives. only report the formation monocyclic piperidinic derivatives, and of bicyclic derivatives only when when were transformed into the monocyclic they werethey transformed into the monocyclic derivatives.derivatives. they were transformed into the monocyclic derivatives. 2. From Cyclic Substrates 2. From Cyclic Substrates 2. From Cyclic Substrates 2. From Cyclic Substrates 2.1. From 6-Membered Rings From 6-Membered Rings 2.1.2.1. From 6-Membered Rings 2.1. From 6-Membered Rings The synthesis of α-trifluoromethylpiperidines A has been achieved from pipecolic acid, from The synthesis α-trifluoromethylpiperidines A has been achieved from pipecolic acid, from The synthesis of of α-trifluoromethylpiperidines A has been achieved from pipecolic acid, from δ-lactams, from pyridines and from pyridinones. δ-lactams, from pyridines pyridinones. A has been achieved from pipecolic acid, from The synthesis of α-trifluoromethylpiperidines δ-lactams, from pyridines andand fromfrom pyridinones. δ-lactams, from pyridines and from pyridinones. 2.1.1. From Pipecolic Acid 2.1.1. From Pipecolic Acid 2.1.1. From Pipecolic Acid 2.1.1. The From Pipecolic Acid The first synthesis 2-(trifluoromethyl)piperidine was realized in 1962 Raash from first synthesis of of 2-(trifluoromethyl)piperidine (2) (2) was realized in 1962 by by Raash [9],[9], from thethe The first synthesis of 2-(trifluoromethyl)piperidine (2) was realized in 1962 by Raash [9], from the sodium salt of pipecolic acid treated tetrafluoride ) Raash inpresence the presence ofatHF sodium salt ofsynthesis pipecolic acid (1) (1) thatthat waswas treated withwith sulfur tetrafluoride (SF 4)(SF inby of HFthe 4the Thesalt first 2-(trifluoromethyl)piperidine (2)sulfur was realized in(SF 1962 [9], from sodium pipecolicof acid (1) that was treated with sulfur tetrafluoride 4) in the presence of HF at ◦ C.of at 120 However, 2 was isolated in a very low yield of 9.6% (Scheme 2). 120 °C. However, 2 was isolated in a very low yield of 9.6% (Scheme 2). sodium salt of pipecolic acid (1) in that was low treated with sulfur tetrafluoride (SF4) in the presence of HF at 120 °C. However, 2 was isolated a very yield of 9.6% (Scheme 2). 120 °C. However, 2 was isolated in a very low yield of 9.6% (Scheme 2). O O O O O Na O Na Na
N N H H N H 1 1 1
SF4 (0.4 equiv) SF equiv) 4 (0.4 HF (1 equiv) SF equiv) HF (1 equiv) 4 (0.4 HF equiv) 120(1°C, 8h 120 °C, 8 h 1209.6% °C, 8 h 9.6% 9.6%
N N H H N H2 2 2
CF3 CF3 CF3
Scheme 2. Synthesis of 2-trifluoromethyl piperidine from pipecolic acid. Scheme 2. Synthesis of 2-trifluoromethyl piperidine frompipecolic pipecolicacid. acid. Scheme 2. Synthesis of 2-trifluoromethyl piperidine from Scheme 2. Synthesis of 2-trifluoromethyl piperidine from pipecolic acid. 2.1.2. From 2-Trifluoromethylpyridine 2.1.2. From 2-Trifluoromethylpyridine 2.1.2. From 2-Trifluoromethylpyridine 2.1.2. One Fromeasy 2-Trifluoromethylpyridine access toto2-trifluoromethylpiperidine (2) was realized by hydrogenation of thethe One easyaccess accessto 2-trifluoromethylpiperidine was realized hydrogenation One easy 2-trifluoromethylpiperidine (2) (2) was realized bybyhydrogenation of of the commercially available 2-trifluoromethylpyridine (3) in the presence of Pd, Pt or Rh catalysts (Scheme 3) One easy access to 2-trifluoromethylpiperidine (2) was realized by hydrogenation of the commercially available 2-trifluoromethylpyridine (3) in the presence of Pd, Pt or Rh catalysts commercially available 2-trifluoromethylpyridine (3) in the presence of Pd, Pt or Rh catalysts (Scheme 3) [10–12]. commercially (Scheme 3) available [10–12]. 2-trifluoromethylpyridine (3) in the presence of Pd, Pt or Rh catalysts (Scheme 3) [10–12]. [10–12]. N N N 3 3 3
CF CF33 CF3
H H22 H2or Rh" "Pd, Pt "Pd, Pt or Rh" "Pd, Pt or Rh"
N N H H N H2 2 2
CF CF33 CF3
Scheme 3. Hydrogenation of α-trifluoromethylpyridine. Scheme 3. Hydrogenation of α-trifluoromethylpyridine. Scheme 3. Hydrogenation of α-trifluoromethylpyridine. Scheme 3. Hydrogenation of α-trifluoromethylpyridine. 2.1.3. From Trifluoromethyl Pyridinones 2.1.3. From Trifluoromethyl Pyridinones 2.1.3. From Trifluoromethyl Pyridinones 2.1.3. From Trifluoromethyl Pyridinones Access to trifluoromethylpiperidinones 5 from trifluoromethylpyridinones 4 has been developed by Access to trifluoromethylpiperidinones 5 from trifluoromethylpyridinones 4 has4been developed by Access to trifluoromethylpiperidinones 5 from trifluoromethylpyridinones has been developed hydrogenation in the presence of Pd/C. Lactams 5 were isolated in 45%–88% yield and subsequent Access to trifluoromethylpiperidinones 5 from trifluoromethylpyridinones 4 has been developed by hydrogenation in the presence of Pd/C. Lactams 5 were isolated in 45%–88% yield and subsequent by hydrogenation the of Pd/C. Lactams 5 were isolated in 45%–88% yield subsequent reduction should lead to thepresence 5-amino 2-trifluoromethylpiperidines 6 in (Scheme 4) [13]. hydrogenation inlead theinto presence of Pd/C. Lactams 5 were isolated 45%–88% yield andand subsequent reduction should the 5-amino 2-trifluoromethylpiperidines 6 (Scheme 4) [13]. reduction should to 5-amino the 5-amino 2-trifluoromethylpiperidines 6 (Scheme reduction should leadlead to the 2-trifluoromethylpiperidines 6 (Scheme 4) [13].4) [13]. R 1 R 2N R 1 R 2N R 1 R 2N O O O
N N R N R R4 4 4
H2 (25 atm.), Pd/C (5 mol %) H2 (25 atm.), Pd/C (5 mol %) Pd/C CF3 H2 (25 atm.), MeOH, rt, 6(5h mol %) CF3 MeOH, rt, 6 h CF3 MeOH, rt, 6 h 45–88% 45–88% 45–88%
R 1R 2 N R 1R 2 N R 1R 2 N O O O
N N R N R R5 5 5
CF3 CF3 CF3
R11R22N Reduction R1 R2 N Reduction R R N Reduction
Scheme 4. Hydrogenation of trifluoromethylpyridinones. Scheme 4. Hydrogenation of trifluoromethylpyridinones. Scheme 4. Hydrogenation of trifluoromethylpyridinones. Scheme 4. Hydrogenation of trifluoromethylpyridinones.
N N R N R R6 6 6
CF3 CF3 CF3
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2.1.4. From δ-Lactams 2.1.4. From δ-Lactams Since first access 2-trifluoromethylpiperidine different methods have been developed Since thethe first access to to 2-trifluoromethylpiperidine (2) (2) different methods have been developed to to produce α-trifluoromethylpiperidines of type A from δ-lactams via either enamines or imines produce α-trifluoromethylpiperidines of type A from δ-lactams C viaCeither enamines C1, orC1, imines C2 C2 (Scheme or C3 (Scheme 5). or C3 5). R' R'
N N R R
CF CF33
C1 C1 R' R'
R' R'
R' R' N N R R
O O
N N
N N R R A A
CF CF33
C2 C2
C C
CF CF33 R'' R''
R' R' N N
R R
C3 C3
Scheme 5. Synthesis of α-trifluoromethylpiperidines from Scheme 5. Synthesis of α-trifluoromethylpiperidines fromδ-lactams. δ-lactams. From Enamines C1 C1 From Enamines α-Trifluoromethyl cyclic enamines C1 can good precursors of A asofthey easily from cyclic enamines C1be can be good precursors A asare they areobtained easily obtained α-Trifluoromethyl δ-lactams. When lactam was treated trichloroborane in the presence of an excess CF33Br from δ-lactams. When7lactam 7 was with treated with trichloroborane in the presence of an of excess of and CF3 Br HEPT, enamine 8 was formed in 30% yield via the formation of iminium species I which can be attacked and HEPT, enamine 8 was formed in 30% yield via the formation of iminium species I which can be by attacked the CF33–– anion, from CF33Br. Intermediate was thus produced a β-elimination, by thegenerated CF3 – anion, generated from CF3 Br.IIIntermediate II wasand thusafter produced and after a enamine 8 was formed (Scheme 6) [14]. A reduction of this enamine should leadlead to to β-elimination, enamine 8 was formed (Scheme 6) [14]. A reduction of this enamine should 2-trifluoromethylpiperidine 9. It is worth noting that CF 3 Br is not easy to handle as it is a gas and 2-trifluoromethylpiperidine 9. It is worth noting that3CF3 Br is not easy to handle as it is a gas and alternatives to synthesize 2-trifluoromethylpiperidines from δ-lactams from imines C2 andC2 C3 and haveC3 been alternatives to synthesize 2-trifluoromethylpiperidines from δ-lactams from imines have devised. been devised. BCl BCl33 (1 (1 equiv) equiv) CF Br (excess) (excess) CF33Br N N Me Me 77
O O
P(NEt P(NEt22))33 (3 (3 equiv) equiv) 00 °C °C 30% 30%
Reduction Reduction N N Me Me
CF CF33
88
N N Me Me 99
CF CF33
BCl BCl33
N N Me Me II
Cl Cl Cl Cl B B O Cl O Cl
CF CF33Br Br P(NEt P(NEt22))33
N N Me Me IIII
H H CF Cl CF33Cl Cl Cl B B O Cl O Cl BrP(NEt BrP(NEt22))33
Scheme 6. Synthesis of α-trifluoromethylpiperidine from δ-lactam via enamine. Scheme 6. Synthesis of α-trifluoromethylpiperidine from δ-lactam via enamine. From Imines C2 From Imines C2 Imines of of type C2C2 were synthesized inin four (10). Imines type were synthesized foursteps stepsfrom fromN-(diethoxymethyl)piperidin-2-one N-(diethoxymethyl)piperidin-2-one (10). First, 10 was subjected to a Claisen condensation with ethyl trifluoroacetate (NaH, CF 33CO22Et) and, after First, 10 was subjected to a Claisen condensation with ethyl trifluoroacetate (NaH, CF3 CO2 Et) and, deprotection under acidicic conditions (HCl), the corresponding fluorinated acyl lactam 11 was isolated
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under acidicic conditions (HCl), the corresponding fluorinated acyl lactam411 was of 22 4 of 22 isolated as the hydrate, due to the ability of the electron-withdrawing CF group to stabilize the as the hydrate, due to the ability of the electron-withdrawing CF3 group to 3stabilize the tetrahedral as adducts the hydrate, due to the ability of the electron-withdrawing CF 3 group to stabilize the tetrahedral tetrahedral adducts type of[15]. compounds [15]. of such type of such compounds as the hydrate, due to the ability of the electron-withdrawing CF3 group to stabilize the tetrahedral adductsThe of such type ofand compounds [15]. The hydrolysis andthe thedecarboxylation decarboxylation perfluoro lactam 11 under conditions hydrolysis of of perfluoro acylacyl lactam 11 under acidicacidic conditions (6 M adducts of such type of compounds [15]. The hydrolysis and the decarboxylation of perfluoro acyl lactam 11 under acidic conditions (6 M (6 M HCl) and heating at reflux led to III. When the decarboxylation was complete, the reaction was HCl) and heating at reflux led to III. When the decarboxylation was complete, the reaction was carefully The hydrolysis and the decarboxylation of perfluoro acyl lactam 11 under acidic conditions (6 M HCl) and heating at reflux led to III. When the decarboxylation was complete, the reaction was carefully carefully madewith alkaline and hemiaminal 12 was obtained. After azeotropic removal of made alkaline KOHwith andKOH hemiaminal 12 was obtained. After azeotropic removal of water or HCl) and heating at reflux led to III. When the decarboxylation was complete, the reaction was carefully made alkaline andtransformed hemiaminal 12(Scheme was obtained. azeotropic removal of water or water or distillation, 12 was into imine 13 7) [15]. distillation, 12with was KOH transformed into imine 13 7) (Scheme [15]. After made alkaline with KOH and hemiaminal 12 was obtained. After azeotropic removal of water or distillation, 12 was transformed into imine 13 (Scheme 7) [15]. distillation, 12 was transformed into imine 13 (Scheme 7) [15]. CF3 CF3 OH 6 M HCl CF3 distillation OH OH 6reflux, M HCl60 h OH OH reflux, 6M 60HCl h distillation N OH O N N CF3 OH then 50%60 KOH reflux, h 86% distillation H OH H CFOH 3 N O N N CF 3 then 50% KOH 86% H N O H NCF3 N CF3 89% KOH then 50% 86% CF H 11 12 13 H 3 89% 11 6 M HCl 12 13 89% 50% KOH 12 13 611 Mreflux, HCl 60 h 50% KOH 6 M 60 HCl reflux, h HO 50% KOH HO OH reflux,OH 60 h HO OHCF HO OH CF HO O OH 3 HO OH 3 CF3 CF3 NH3 O CF3 NH3 CF3 CO2 OH O NH3 NH3 CO OH 2 NH NH3IV CO2 III 3 OH IV III IV III Scheme 7. Synthesis of α-trifluoromethylpiperidine from δ-lactam via imine.
CF3CO2Et (1.05 equiv) (1.3 equiv) CF3CONaH 2Et (1.05 equiv) CF (1.05 equiv) 3CO 2Etequiv) NaH (1.3 N O THF, reflux, 1h NaH (1.3 equiv) N O then1 h reflux, EtO N OEtO THF, 3 then M HCl reflux THF, reflux, 1h 10 EtO OEt then 3 M HCl reflux EtO 10 OEt 83%reflux 3 M HCl 10 83% 83%
Scheme 7. Synthesis of α-trifluoromethylpiperidine from δ-lactam via imine.
Scheme 7. Synthesis of α-trifluoromethylpiperidine from δ-lactam via imine. Scheme 7. Synthesis of α-trifluoromethylpiperidine from δ-lactam via imine. Imine 13 can be involved in a variety of reactions such as reduction, phosphorylation, alkylation Imine 13 can involved a variety reactions suchasasreduction, reduction,phosphorylation, phosphorylation, alkylation Imine 13 can bebe involved in in a and variety ofofreactions such alkylation under Friedel-Craft conditions, Ugi-type reactions, producing a diversity of α-trifluoromethyl Imine 13 can be involved in a variety of reactions such as reduction, phosphorylation, alkylation under Friedel-Craft conditions, and Ugi-type reactions, producing diversity of α-trifluoromethyl under Friedel-Craft conditions, and reactions, producing a a diversity of piperidinic derivatives. Imine 13 wasUgi-type transformed to 2-trifluoromethylpiperidine (2) α-trifluoromethyl in a yield of 71% by under Friedel-Craft conditions, Ugi-type reactions, producing a diversity of α-trifluoromethyl piperidinic derivatives. Imine 13and was transformed to 2-trifluoromethylpiperidine in a yield ofby 71% piperidinic Imine transformed to [15]. 2-trifluoromethylpiperidine (2) in(2) a yield of 71% reductionderivatives. with NaBH(OAc) 313 inwas MeOH (Scheme 8) piperidinic derivatives. Imine 133 was transformed to 2-trifluoromethylpiperidine (2) in a yield of 71% by by reduction with NaBH(OAc) in MeOH (Scheme 8) [15]. reduction with NaBH(OAc)3 in MeOH (Scheme 8) [15]. reduction with NaBH(OAc)3 in MeOH (Scheme 8) [15]. N
N CF3 H N CF3 H N CF3 2 H 13 2 Scheme 8. Synthesis13 of α-trifluoromethylpiperidine from an2 imine by reduction. N
CF3 CF3 N CF3 13
NaBH(OAc)3 (2 equiv) NaBH(OAc)3 (2 equiv) NaBH(OAc) MeOH, rt, 12equiv) h 3 (2 MeOH, rt, 12 h MeOH, rt, 12 h 71% 71% 71%
Scheme 8. Synthesis of α-trifluoromethylpiperidine from ananimine by reduction. Scheme Synthesisofofα-trifluoromethylpiperidine α-trifluoromethylpiperidine from reduction. Scheme 8. 8. Synthesis from animine iminebyby reduction. When 13 was treated with diethyl phosphite in the presence of boron trifluoride etherate (BF3.OEt2) . 3 OEt2) 13 was treated with diethyl phosphite in the presence of boron trifluoride etherate as When theWhen catalyst, 2-(trifluoromethyl)-2-ethylphosphonate piperidine was obtained (92%)(BF and easily . When 13was was treated with diethyl phosphite the presence oftrifluoride boron trifluoride etherate 3 OEt2) 13 treated with diethyl phosphite in thein presence of(14) boron etherate (BF . as transformed the catalyst, 2-(trifluoromethyl)-2-ethylphosphonate piperidine (14) was obtained (92%) and easily thecatalyst, corresponding α-trifluoromethyl substituted cyclic α-aminophosphonic acid 15 by (BF the 2-(trifluoromethyl)-2-ethylphosphonate piperidine (14) was obtained (92%) 3 OEt 2 ) asto as the catalyst, 2-(trifluoromethyl)-2-ethylphosphonate piperidine (14) was obtained (92%) and easily transformed to thetrimethylbromosilane corresponding α-trifluoromethyl substituted α-aminophosphonic acid 15worth by 3 followed by thecyclic addition of aqueous MeOH. It is treatment with in CHClα-trifluoromethyl and easily transformed to the corresponding substituted cyclic α-aminophosphonic transformed to the corresponding α-trifluoromethyl substituted cyclic α-aminophosphonic acid 15 by 3 followed by 3the addition aqueous MeOH. It is worththe treatment with trimethylbromosilane in CHCl pointing out that to avoid the formation of the ammonium salt, due by toof the liberation ofaqueous HBr during acid 15 by treatment with trimethylbromosilane in CHCl the byfollowed the addition of addition aqueous of MeOH. It isMeOH. worth treatment with trimethylbromosilane in CHCl3 followed pointing out that to avoid the formation of the ammonium salt, due to the liberation of HBr during hydrolysis of the ester, addition propylene oxide was necessary and due the free amino acid 15 was It is worth pointing outthe that avoidofthe formation of the ammonium to the ofthe HBr pointing out that to avoid thetoformation of the ammonium salt, due to salt, the liberation ofliberation HBr during the hydrolysis of the ester, the addition ofthe propylene oxide was necessary and necessary the free amino acidfree 15 amino was isolated (Scheme 9) [16]. during the hydrolysis of the ester, addition of propylene oxide was and the hydrolysis of the ester, the addition of propylene oxide was necessary and the free amino acid 15 was isolated (Scheme 9) [16].(Scheme 9) [16]. acid 15 was isolated isolated (Scheme 9) [16]. (EtO) P(O)H 2
(EtO)(22P(O)H equiv) 1) Me3SiBr/CHCl3 (EtO)2P(O)H (2 equiv) P(O)(OEt)21) Me3SiBr/CHCl3 P(O)(OH)2 Cat. BF Et O 2) Me aq. MeOH 3 2 (2 equiv) N CF3 1) N P(O)(OEt) N P(O)(OH) 3SiBr/CHCl3 2 Et2O, 12–48 h Et 2 CF CF Cat. BFrt, O H 3 H 2) aq. MeOH 3 3 2 P(O)(OEt)2 3) propylene oxide N P(O)(OH) N CF3 N 2 Cat. BF3Eth2O 2) aq. MeOH Et2O, rt, 12–48 CF CF H N CF 3 N H 3 N 3 3) propylene oxide 13 15 CF Et2O, 92% rt, 12–48 h 14 H CF3 H 3 3) propylene oxide 13 15 92% 14 13 9. Synthesis 15 from imine. 92% 14 Scheme of 2-(trifluoromethyl)-2-ethylphosphonate piperidine
Scheme 9. Synthesis of 2-(trifluoromethyl)-2-ethylphosphonate piperidine from imine. Scheme 9. 9. Synthesis 2-(trifluoromethyl)-2-ethylphosphonatepiperidine piperidine from imine. Scheme Synthesisofof from imine. Imine 13 was transformed to2-(trifluoromethyl)-2-ethylphosphonate the piperidinic derivatives 16 when subjected to an Ugi-type reaction Imine 13 was transformed to 13 thewas piperidinic 16 when(RNC) subjected to an Ugi-type using isocyanides. Thus, when treated derivatives with an isocyanide in the presence of reaction CF3CO2H, Imine 13 was transformed to the piperidinic derivatives 16 when subjected to an Ugi-type reaction using isocyanides. Thus, when was treated V with an isocyanide in isthe presence of CF3CO 2H,an piperidine 16 was formed via13intermediate (Scheme 10, eq. 1)(RNC) [17]. It worth mentioning that using isocyanides. Thus, when 13 was treated with an isocyanide (RNC) in the presence of CF3CO2H, piperidine 16 was formed via intermediate V (Scheme 10, eq. 1) [17]. It is worth mentioning that an azido-Ugi reaction was performed using isocyanate (RNC) in the presence of TMSN3 in MeOH. Under piperidine 16 was formed via intermediate V (Scheme 10, eq. 1) [17]. It is worth mentioning that an azido-Ugi reaction was performed using isocyanate (RNC) in the presence of TMSN3 in MeOH. Under azido-Ugi reaction was performed using isocyanate (RNC) in the presence of TMSN3 in MeOH. Under
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Imine 13 was transformed to the piperidinic derivatives 16 when subjected to an Ugi-type reaction using isocyanides. Thus, when 13 was treated with an isocyanide (RNC) in the presence of CF3 CO2 H, piperidine 16 was formed via intermediate V (Scheme 10, eq. 1) [17]. It is worth mentioning that an Molecules 2017, 22, 483 5 of 22 azido-Ugi reaction was performed using isocyanate (RNC) in the presence of TMSN3 in MeOH. Under these conditions, tetrazole 17 17 was these conditions, tetrazole was obtained obtained via via intermediate intermediate VI. VI. In In addition, addition, when when benzylisocyanate benzylisocyanate (BnNC) was used, the corresponding piperidyltetrazole (17, R = Bn) was isolated and by (BnNC) was used, the corresponding piperidyltetrazole (17, R = Bn) was isolated and debenzylated debenzylated by hydrogenolysis (H , Pd/C, MeOH) to produce 18 in good yield (96%) (Scheme 10, eq. 2) [18]. hydrogenolysis (H2,2 Pd/C, MeOH) to produce 18 in good yield (96%) (Scheme 10, eq. 2) [18]. CF3CO2H (1 equiv) RNC (1 equiv) N
O N
CH2Cl2, −20 °C to rt, 12 h
CF3
F 3C
44−89%
13
R
(eq 1)
16
O O
CF3 O
N H
CF3
N N CF3 R H V
RNC (1.1 equiv) TMSN3 (1.1 equiv) N
CF3
MeOH, rt 58−84%
13
N N N N N H CF3 R 17
N N CF3 H VI
N N
H2, Pd/C MeOH 96% R= Bn
N N N N N H CF3 H
(eq 2)
18
N R
R = Bn, t-Bu, CH2CO2Et, allyl, Bu, (CH2)2CO2Et, EtO2C
i-Pr
MeO2C
i-Pr
OO
O
N H
Scheme 10. Synthesis of α-trifluoromethylpiperidines by Ugi-type reactions. Scheme 10. Synthesis of α-trifluoromethylpiperidines by Ugi-type reactions.
If tetrazole can be introduced at the α-position of α-trifluoromethylpiperidyl derivatives, using an If tetrazole canother be introduced at the of α-trifluoromethylpiperidyl derivatives, using an Ugi-type reaction, heterocycles suchα-position as pyrroles, indoles can also be introduced in the α-position Ugi-type reaction, other heterocycles such as pyrroles, indoles can also be introduced in the α-position by using a Friedel-Craft reaction. When imine 13 was treated with the non-protected pyrrole 19 in the by using a Friedel-Craft reaction. When imine 13 was treated with the non-protected pyrrole 19 in presence of BF3.OEt2,. the unexpected piperidine 20, possessing a C2-substituted pyrrole was obtained the presence of BF3 OEt2 , the unexpected piperidine 20, possessing a C2-substituted pyrrole was (67%) (Scheme 11, eq. 1). contrary, when when the N-methylpyrrole 21 was involved in the obtained (67%) (Scheme 11,On eq. the 1). On the contrary, the N-methylpyrrole 21 was involved in Friedel-Craft reaction, piperidine 22, substituted in the α-position by the C3-substituted pyrrole, was the Friedel-Craft reaction, piperidine 22, substituted in the α-position by the C3-substituted pyrrole, isolated (Scheme 11, eq11, 2). eq. The 2). sameThe regioselectivity at C3 wasatobserved pyrrole 23. pyrrole It is worth was isolated (Scheme same regioselectivity C3 was with observed with 23. mentioning that no diastereoselectivity was observed with pyrrole 23 as a ratio of 1 to 1 was observed It is worth mentioning that no diastereoselectivity was observed with pyrrole 23 as a ratio of 1for to 24 (Scheme 11, eq 3). As noticed, the reaction with non-protected and protected pyrroles is very 1 was observed for 24 (Scheme 11, eq. 3). As noticed, the reaction with non-protected and protected regioselective. regioselectivity be the result can of steric between the N-substituent of pyrroles is veryThis regioselective. Thiscan regioselectivity be theinteractions result of steric interactions between the the pyrrole and the cyclic imine which can be quite significant due to the bulkiness of the trifluoromethyl N-substituent of the pyrrole and the cyclic imine which can be quite significant due to the bulkiness of group and its specific nature the C3nature isomers were When lessformed. steric interactions were the trifluoromethyl group andand, its specific and, theformed. C3 isomers were When less steric present, e.g., with unprotected pyrroles, the C2-isomers were formed (Scheme 11, eq. 1) [19,20]. interactions were present, e.g., with unprotected pyrroles, the C2-isomers were formed (Scheme 11, eq. 1) [19,20].
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N
CF3 + CF3 + 13 N CF3 13
N H N 19 H N 19 H
N
19
13 +
N
67% BF3Et2O (1 equiv) BF3 Et2O (1 equiv) CH2Cl2, rt, 5 days Et O (1 equiv) BF 2 CH32Cl 2, rt, 5 days 83% CH2Cl83% 2, rt, 5 days
N
CF3 + N CF3 13 + N CF3 13
21
13
N
BF3Et2O (1 equiv) BF3Et2O (1 equiv) CH2Cl2, rt, 24 h BF 3 Et 2O (1 equiv) CH 2Cl2, rt, 24 h 67% CH2Cl 2, rt, 24 h 67%
N N 21 21
83% BF3Et2O (1 equiv)
+
13 N
N + N CF3 Me EtO + 2C CF3 EtO2C N Me 23
13
EtO2C23 Me
CF3
N
BF3Et2O (1 equiv) CH2Cl2, rt, 5 days Et O (1 equiv) BF 2 rt, 5 days Cl2, CH3275% rt, 5 days CH2Cl2,75% 75%
6 of 22 (eq 1) (eq 1)
N H N N CF3 H N H CF 3 N 20 H H N 20 H CF3
20
(eq 1)
N
N
(eq 2) N N (eq 2) H CF3 N (eq 2) 22 H CF3 N Me 22 CF H 3 Me CO2Et 22 N CO2Et Me (eq 3) N CO 2Et (eq 3) N N H CF3 N (eq 3) H CF3 N 24 (dr 1/1) H =CF 3 24 (dr = 1/1)
Scheme 11. Synthesis of α-trifluoromethylpiperidines by Friedel-Craft reactions with pyrroles. Scheme 11. Synthesis of α-trifluoromethylpiperidines by Friedel-Craft with pyrroles. 13 24 (dr =reactions 1/1) 23 Scheme 11. Synthesis of α-trifluoromethylpiperidines by Friedel-Craft reactions with pyrroles. Indoles such 25 can also be involved in a Friedel-Craft reaction with imine 13 leading to the Scheme 11. Synthesis of α-trifluoromethylpiperidines by Friedel-Craft reactions with pyrroles. Indoles 2525can reactionwith withimine imine leading piperidines 26such in good yield (Scheme 12) [21]. in Indoles such canalso alsobe beinvolved involved in aa Friedel-Craft Friedel-Craft reaction 1313 leading to to thethe piperidines 26 in good yield (Scheme 12) [21]. piperidines 26 in good yield (Scheme 12) [21]. Indoles such 25 can also be involved in a Friedel-Craft reaction with imine 13 leading to the R2
piperidines 26 in good yield (Scheme 12) [21]. R2
R3
+
R1 N
R2
BF3Et2O (1 equiv)
R1 N 1 R N R3
N Et2O (1 equiv) R2 N 3 CHBF 6−12 h 2Cl 2, rt, R2 H CF3 R1 N Et2O (1 equiv) BF N N CF3 3Cl CH 3 2 2, rt, 6−12 h R2 47−79% 25 26 13 H CF3 R3 + R R1 N N N CF3 CH Cl rt, 6−12 h 2 2, CF3 47−79% 25 R1 H 26 R3 Scheme 12.13Synthesis of α-trifluoromethylpiperidines by a Friedel-Craft reaction with indoles. 47−79% 25 26 13 N
CF3
+
R3
Scheme 12. Synthesis of α-trifluoromethylpiperidines by a Friedel-Craft reaction with indoles. Scheme From Imines C312. Synthesis of α-trifluoromethylpiperidines by a Friedel-Craft reaction with indoles. Scheme 12. Synthesis of α-trifluoromethylpiperidines by a Friedel-Craft reaction with indoles. From C3 the CF3 group is initially located in the α-position and then different R substituents can In Imines imines 13,
From Imines C3 From C3 also beInImines introduced From an imine intermediate, the reverse strategy can be used to imines 13, in thethe CFα-position. 3 group is initially located in the α-position and then different R substituents can In compound imines 13, A, thee.g., CFimines is synthesized initially located the α-position and different Rgroup substituents access are ainintermediate, δ-lactam and then the then trifluoromethyl is to 3 group also be introduced in CF the3 group α-position. Fromlocated an from imine the then reverse strategy can be used In imines 13, the is initially in the α-position and different R substituents can can also be introduced the α-position. From imine intermediate, the reverse strategy canthe be used introduced. Thus, wheninimines 27, prepared fromanthe corresponding δ-lactams, were treated with access are synthesized fromintermediate, a δ-lactam and the trifluoromethyl is also becompound introducedA,ine.g., the imines α-position. From an imine thethen reverse strategy can begroup used to reagent (TMSCF 3) in the presence of from TFA and KHF2, in MeCN, the α,α-disubstituted toRuppert-Prakash access compound A, e.g., imines are synthesized a δ-lactam and then trifluoromethyl group introduced. Thus, A, when from the acorresponding δ-lactams, were treated with access compound e.g.,imines imines27, areprepared synthesized from δ-lactam and then the trifluoromethyl groupthe is 28Thus, were when isolated in good yields. Thefrom activation of imines 27 under acidicwere conditions ispiperidines introduced. imines 27, prepared theTFA corresponding treatedwas with the Ruppert-Prakash (TMSCF 3) prepared in the presence of and KHF2,δ-lactams, inδ-lactams, MeCN, were the α,α-disubstituted introduced. Thus,reagent when imines 27, from the corresponding treated with the necessary to obtained piperidines 283(Scheme 13) [22]. of TFA and KHF2 , in MeCN, the α,α-disubstituted Ruppert-Prakash reagent (TMSCF ) in the presence piperidines 28 were isolated in good The activation of imines under acidic conditions was Ruppert-Prakash reagent (TMSCF 3) inyields. the presence of TFA and KHF2, 27 in MeCN, the α,α-disubstituted piperidines 28 were isolated in good yields. The activation of imines 27 under acidic conditions was necessary to obtained piperidines 28 (Scheme 13) [22]. piperidines 28 were isolated in good yields. activation of imines 27 under acidic conditions was TMSCFThe 3 (1.25 equiv) necessary to obtained piperidines 28 (Scheme 13) [22]. TFA (1.25 equiv) necessary to obtained piperidines 28 (Scheme 13) [22]. N 27N
R
R
KHF equiv) 2 (0.75 TMSCF 3 (1.25 equiv) TFA (1.25 equiv) TMSCF MeCN, rt, 12 equiv) h equiv) 3 (1.25 KHF2 (0.75 TFA (1.25 equiv) KHF equiv) 49−67% 2 (0.75 MeCN, rt, 12 h
R N CF H 3 R 28 N H CFR 3 N 28 H CF3 28
N Cy, R Ph, 2-furyl, MeCN, R = t-Bu, 3-pyridinyl 27 rt, 12 h 49−67% 27 Scheme 13. Synthesis of α,α-disubstituted piperidines. 49−67% R = t-Bu, Cy, Ph, 2-furyl, 3-pyridinyl R = t-Bu, Cy, Ph, 2-furyl, 3-pyridinyl
Scheme of α,α-disubstituted piperidines. It is worth mentioning that all13. theSynthesis 2-trifluoromethylpiperidines were obtained in a racemic form, Scheme 13. Synthesis of α,α-disubstituted piperidines. however, recently, we haveScheme reported a method that allows the synthesis of optically active substituted 13. the Synthesis of α,α-disubstituted piperidines. It is worth mentioning that all 2-trifluoromethylpiperidines obtained in applied a racemic form, 2-trifluoromethylpiperidines by using a stereospecific ringwereexpansion to however, recently, we have reported a method that allows the synthesis of optically active substituted It is worth mentioning that all the 2-trifluoromethylpiperidines were obtained in a racemic form, 2′-trifluoromethylprolinols of type F. It is worth mentioning that all the 2-trifluoromethylpiperidines were obtained in a racemic 2-trifluoromethylpiperidines by using a stereospecific ring expansion applied to however, recently, we have reported a method that allows the synthesis of optically active substituted form, however, recently, we have reported a method that allows the synthesis of optically 2′-trifluoromethylprolinols of type F. 2-trifluoromethylpiperidines by using a stereospecific ring expansion applied to active substituted 2-trifluoromethylpiperidines by using a stereospecific ring expansion applied to 2′-trifluoromethylprolinols of type F.
20 -trifluoromethylprolinols of type F.
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2.2. From 5-Membered Rings 2.2. From 5-Membered Rings
The ring expansion of pyrrolidines to piperidines via an aziridinium intermediate under kinetic The ring expansion of pyrrolidines to piperidines via an This aziridinium kinetic and and thermodynamic conditions is well-established [23–28]. methodintermediate was used tounder access piperidines 0 0 thermodynamic conditions is well-established [23–28]. This method was used to access piperidines 30, 30, 30 from prolinols 29, 29 . 30′Prolinols from prolinols 29, 29′. 0 29 and 29 were prepared from L-proline in a seven-step sequence [29]. When Prolinols and 29′ were prepared L-proline in a seven-step sequence [29]. When prolinols 29 0 were prolinols 29 and2929 treated withfrom DAST, I2 /PPh3 or by Tf2 O, followed by the addition of and 29′ were treated with DAST, I2/PPh3 or by Tf2O, followed by the addition of different nucleophiles different nucleophiles (alcohols, amines, thiols, cuprates, cyanides), a diversity of 2-(trifluoromethyl)(alcohols, amines, thiols, cuprates, cyanides), a diversity of 2-(trifluoromethyl)- 3-substituted piperidines 3-substituted piperidines 30 and 300 were obtained with good diastereo- and enantioselectivities 30 and 30′ were obtained with good diastereo- and enantioselectivities (de > 94% and ee > 99%). The (de > 94% and ee > 99%). The regioselective attack of the nucleophiles on the aziridinium intermediates regioselective attack of the nucleophiles on the aziridinium intermediates VII/VII′ is due to the presence 0 is due to the presence of the CF group (Scheme 14) [29,30]. VII/VII 3 of the CF3 group (Scheme 14) [29,30]. O N H
H OH
7 steps N Bn
OH
L-Proline
H
+
N Bn
CF3
29 (12%, ee>95%)
Bn
2'
reagent
Nu
2
CF3
29' (16%, ee>95%)
reagent
N
CF3
VII
Bn
Nu
2
N 2'
CF3
VII' Nu
Nu Nu
Nu N Bn
OH
CF3
N Bn
CF3
30'
30 Reagent
F
F DAST, THF N Bn
CF3
30a (89%)
N Bn
CF3
30'a (81%)
I
I
I2, PPh3, Imidazole, THF N Bn
CF3
30b (69%)
N Bn
30'b (86%)
Nu 1/ Tf2O, proton sponge, CH2Cl2 2/ Nucleophile Nu = OR, NRR', SR, CN, alkyl
N Bn
CF3
30c
CF3
Nu N Bn
CF3
30'c
Scheme 14. Synthesis of C3-substituted α-trifluoromethylpiperidines from L-proline. Scheme 14. Synthesis of C3-substituted α-trifluoromethylpiperidines from L-proline. 3. From Non-cyclic Substrates
3. From Non-cyclic Substrates
To synthesize 2-trifluoromethyl-substituted piperidines from non-cyclic substrates, a cyclisation Toor synthesize 2-trifluoromethyl-substituted piperidines from non-cyclic substrates, a cyclisation step a cycloaddition is necessary to access the piperidine skeleton.
step or a cycloaddition is necessary to access the piperidine skeleton.
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3.1. Cyclization Molecules 2017, 22, 483
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3.1. Cyclization
3.1.1. By Metathesis 3.1. Cyclization 3.1.1. By Metathesis
Metathesis reactions have changed the way molecules are constructed due to the 3.1.1. Byreactions Metathesis Metathesis have changed the way molecules are constructed due to the commercialization commercialization of robust catalysts such as the Grubbs first and second generation catalysts, G-I and of robust catalysts such as the Grubbs first and generation catalysts, G-I G-II, and the reactions have changed thesecond way molecules are constructed dueand to the commercialization G-II, and the Metathesis Grubbs-Hoveyda catalysts GH-II (Figure 1). Metathesis is a powerful method to access Grubbs-Hoveyda catalysts GH-II (Figure 1). Metathesis is a powerful method to access both carboand of robust catalysts such as the Grubbs first and second generation catalysts, G-I and G-II, and the both carbo- and heterocyclic ring systems [31–35] and the reaction is useful to synthesize piperidines heterocyclic ring systems [31–35] and the reaction is useful to synthesize piperidines particularly to and Grubbs-Hoveyda catalysts GH-II (Figure 1). Metathesis is a powerful method and to access both carboand particularly to synthesize 2-trifluoromethylpiperidinic derivatives. synthesize 2-trifluoromethylpiperidinic derivatives. heterocyclic ring systems [31–35] and the reaction is useful to synthesize piperidines and particularly to synthesize 2-trifluoromethylpiperidinic derivatives. N
PCy3 Cl Ru PCy3 Cl Ph PCy3 Cl Ru Cl Ph PCy3
N
N
Cl N N Ru Cl Ph PCy3 Cl Ru Cl PCy3 Ph
G-I
N
Cl Ru Cl O
N
N
Cl Ru Cl O
G-II
GH-II
G-I
G-II
GH-II
Figure 1. Catalysts for olefin metathesis. Figure 1. Catalysts for olefin metathesis. Figure 1. Catalysts for olefin metathesis.
From Dienes
From Dienes From Dienes .
The ammonium ammonium salt 2 HCl was was formed from from 36, which was was The saltofofthe the2-trifluoromethylpiperidine 2-trifluoromethylpiperidine 2. HCl formed 36, which .HCl was formed from 36, which was The ammonium salt of the 2-trifluoromethylpiperidine 2 obtained from 35 when treated with with G-I. This been synthesized in obtained fromthe theα-trifluoroaminodiene α-trifluoroaminodiene 35 when treated G-I.diene This has diene has been synthesized obtained from the α-trifluoroaminodiene 35 when into treated with G-I. This diene with has been synthesized in six steps from the hemiacetal 31 which was transformed imine 32 by treatment the imine of in six steps from the hemiacetal 31 which was transformed into imine 32 by treatment with the imine six steps from the hemiacetal 31 which was transformed into imine 32 by treatment with the imine of 3). After an allylation under acidic conditions benzophenone followed by by a silylation stepstep (ImSiMe of benzophenone followed a silylation (ImSiMe an allylation under acidic conditions 3 ). 3After ). After an allylation under acidic conditions benzophenone followed by a silylation step (ImSiMe . . by a deprotection/protection sequence, the allyltrifluoroamine 34 was34 was (allylTMS, BF BF33 OEt (allylTMS, OEt2),2 ),followed followed by a deprotection/protection sequence, the allyltrifluoroamine (allylTMS, BF3.OEt2), followed by a deprotection/protection sequence, the allyltrifluoroamine 34 was isolated and allylated to produce the piperidinic core precursor 35. Thus, after treatment of 35 with isolated allylated to produce the piperidinic core precursor 35. Thus, after treatment of 35G-I with G-I isolated and allylated to produce the piperidinic core precursor 35. Thus, after treatment of 35 with G-I catalyst (1 (1 mol mol %) at at rt, rt, thethe unsaturated piperidine 36 was in 91%inyield. catalyst %) in in dichloromethane dichloromethane unsaturated piperidine 36 isolated was isolated 91% yield. catalyst (1 mol %) in dichloromethane at rt, the unsaturated piperidine 36 was isolated in 91% yield. After (Pd/C,EtOH, EtOH, and treatment 2. HCl isolated quantitatively was was isolated quantitatively Afterhydrogenation hydrogenation (Pd/C, rt, rt, 24 24 h) h) and treatment withwith HCl,HCl, 2.HCl After hydrogenation (Pd/C, EtOH, rt, 24 h) and treatment with HCl, 2.HCl was isolated quantitatively (Scheme 15)[36,37]. [36,37].Compared Compared to synthesis the synthesis of 2pipecolic from pipecolic the synthesis from 31 is (Scheme 15) to the of 2 from acid the acid synthesis of 2 from 31ofis2more (Scheme 15) [36,37]. Compared to the synthesis of 2 from pipecolic acid the synthesis of 2 from 31 is more more efficient inof terms yieldversus (47.9% versus 9.6%). efficient in terms yieldof (47.9% 9.6%). efficient in terms of yield (47.9% versus 9.6%). 1) OH MeO
NH
NH
1) Ph Ph Ph CH2Cl2, rt, 48 h OH 48 h CH2Cl2, rt, Ph Ph
CF3 MeO 2) ImSiMe CF3 32) ImSiMe Ph 3 THF, rt, 5 h 31 31 90% THF, rt, 5 h 90%
OSiMe3 N Ph CF3 N Ph 32 32
allylTMS allylTMS BF33Et2O (1 equiv) OSiMe BF3Et2O (1 equiv) Ph
NPh CF3 N CF32Cl2, 50 °C, 24 h CH Ph CH2Cl2, 50 °C, 24 h Ph 84% 33 84% 33 1) HCl (2M) 1) HCl (2M) 24 h CH2Cl2, 50 24 h CH°C, 2Cl2, 50 °C,87% 2) CbzCl,2)NaHCO CbzCl, 3NaHCO3 h H2O, rt, 12 H2O, rt, 12 h
N CF3 N CF3Cl rt, 5 h DMF, rt, 5DMF, h rt, 5 h CH 2 2, CH2Cl2, rt, 5 hN CF3N CF3 Cbz 80 % Cbz 80 % 91% 91% Cbz Cbz 35
36
87%
NaH (1.2NaH equiv) (1.2 equiv) AllylBr (14 equiv) AllylBr (14 equiv)
G-I (1 mol G-I %) (1 mol %)
36
CF3
35
HN CF HN CF3 3 Cbz Cbz 34
34
1) Pd/C, H1) 2, Pd/C, H2, EtOH, EtOH, rt, 24 h rt, 24 h 2) HCl N 2) HCl Cl H2 quant. quant.
2.HCl
CF3 N Cl H2
CF3
2.HCl
Scheme 15. Synthesis of α-trifluoromethylpiperidine from trifluoromethylhemiacetal.
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Scheme 15. Synthesis of α-trifluoromethylpiperidine from trifluoromethylhemiacetal. Scheme 15. Synthesis of α-trifluoromethylpiperidine from trifluoromethylhemiacetal. A shorter synthesis unsaturated piperidines imines 37 ausing a Barbier-type A shorter synthesis of of unsaturated piperidines fromfrom imines 37 using Barbier-type reactionreaction (allylBr, A shorter synthesis of unsaturated piperidines from imines 37 using a Barbier-type reaction (allylBr, Zn, DMF, rt) followed by a N-allylation has been reported. The resulting dienic(allylBr, amino Zn, DMF, rt) followed by a N-allylation has been reported. The resulting dienic amino compound 38 was Zn, DMF, rt) followed by a N-allylation has been reported. The resulting dienic amino compound 38 was compound 38 was isolated in good yied. After treatment with G-I (5–10 mol %) the unsaturated isolated in good yied. After treatment with G-I (5–10 mol %) the unsaturated piperidines 39 were isolated (Scheme in good yied. After (Scheme treatment16) with piperidines 39 were isolated [38].G-I (5–10 mol %) the unsaturated piperidines 39 were isolated 16) [38]. isolated (Scheme 16) [38]. 1) allylBr (1.4 equiv) 1) allylBr Zn*, DMF,(1.4 rt, 1equiv) h R Zn*, DMF, rt, 1 h CF N 3 R CF3 2) allylBr (4 equiv), reflux N 2) allylBr (4 equiv), reflux 54−86% 37 54−86% 37 R = Bn, PMP, CH(Ph)(CH2OMe) R = Bn, PMP, CH(Ph)(CH2OMe)
R'' R'' R' R'
N N R 38R 38
CF3 CF3
G-I (5−10 mol %) G-I (5−10 mol %) CH2Cl2, rt, 2 −48 h CH2Cl2, rt, 2 −48 h 41−98% 41−98%
R'' R'' R' R'
N N R R 39 39
CF3 CF3
Scheme 16.16. Synthesis fromtrifluoromethylimines. trifluoromethylimines. Scheme Synthesisofofα-trifluoromethylpiperidines α-trifluoromethylpiperidines from Scheme 16. Synthesis of α-trifluoromethylpiperidines from trifluoromethylimines. Starting from imines, the strategy is very versatile to access a variety of unsaturated piperidines and, Starting from fromimines, imines,the thestrategy strategyisisvery very versatile access a variety of unsaturated piperidines Starting versatile to to access a variety unsaturated piperidines and, particularly, 2-(trifluoromethyl)-2-substituted tetrahydropyridines. Thus,ofwhen imines 40 were treated and, particularly, 2-(trifluoromethyl)-2-substituted tetrahydropyridines. Thus, when imines 40 were particularly, 2-(trifluoromethyl)-2-substituted tetrahydropyridines. Thus, when dienes imines 42 40were wereisolated treated with allylmagnesium bromide (THF, –78 °C) then (NaH, allylbromide) ◦allylated treated with allylmagnesium bromide (THF, –78 C) then allylated (NaH, allylbromide) dienes 42 were with allylmagnesium bromide (THF, –78 °C) then allylated (NaH, allylbromide) dienes 42 were isolated in good yields and then involved in a ring-closing metathesis (RCM) using different catalysts such as G-I isolated in good yields and then involved in a ring-closing metathesis (RCM) using different catalysts in good yields andcatalyst then involved ring-closing (RCM) using different G-I or the ruthenium J [39]. Itinisaworth noting metathesis that the yields obtained with G-I catalysts are bettersuch thanaswith such as G-I or thecatalyst ruthenium catalyst J [39]. It isthat worth noting that the yields obtained with G-Iwith are or the ruthenium J [39]. It is worth noting the yields obtained with G-I are better than catalyst J (Scheme 17) [40–43]. better than with catalyst J (Scheme 17) [40–43]. catalyst J (Scheme 17) [40–43]. R'' R''
MgBr (1 equiv) MgBr (1 equiv)
R'' R'' HN N CF3 CF THF,1 h, −78 °C 3 HN N CF R 3 CF3 R THF,1 h, −78 then 2−6 h at°C rt R R 40 then68−75% 2−6 h at rt 41 68−75% 40 41 R'' = CO2Me, P(O)(OMe)2, P(O)(OEt2) R''==Cbz, CO2SO Me,2Ph, P(O)(OMe) R Boc 2, P(O)(OEt2) R = Cbz, SO2Ph, Boc
Cl Ru C C Cy Cl3PRu C C Cy3P J J
Ph Ph Ph Ph
NaH (2 equiv) (2 equiv) DMF, 0NaH °C then 0.5 h at rt DMF, 0 °C then 0.5 h at rt then Br (2 equiv) then Br (2 equiv) rt, 6−8 h rt, 6−8 h 55−72% 55−72%
R'' R'' N CF3 N R CF 3 R 42 42
G-I or J (5−10 mol %) mol 80 %) °C CH2G-I Cl2,orrtJor(5−10 Toluene, CH2Cl2,65−98% rt or Toluene, 80 °C 65−98% OTf OTf
R'' R'' N N CF3 R CF3 R 43 43
Scheme 17. Synthesis of α,α-disubstituted unsaturated piperidines from trifluoromethylimines. Scheme 17. Synthesis of α,α-disubstituted unsaturated piperidines from trifluoromethylimines. Scheme 17. Synthesis of α,α-disubstituted unsaturated piperidines from trifluoromethylimines.
It is worth noting that the dienes, precursors of 2-(trifluoromethyl)-unsaturated piperidines, could It is worthfrom noting that the dienes, precursors of 2-(trifluoromethyl)-unsaturated piperidines, could be synthesized trifluorodiazo derivatives 44. Treatment of N,N-diallyl-N-methylamine by the diazo It is worthfrom noting that the dienes, precursors of 2-(trifluoromethyl)-unsaturated piperidines, could be synthesized trifluorodiazo derivatives 44. Treatment of N,N-diallyl-N-methylamine by the diazo compound 44 in the presence of the copper catalyst [Cu(F3-acac)2], produced ylide VIII which, after a be synthesized from trifluorodiazo derivatives 44. Treatment of2],N,N-diallyl-N-methylamine by thea compound 44 in the presence of the copper catalyst [Cu(F 3-acac) produced ylide VIII which, after [2,3]-sigmatropic rearrangement, led to the dienic derivatives 45, precursor of the unsaturated diazo compound 44 in the presence of the copper catalyst [Cu(F3 -acac) VIII which, [2,3]-sigmatropic rearrangement, led to the dienic derivatives 45, precursor of ylide the unsaturated 2 ], produced piperidines 46 (Scheme 18) [43]. after a [2,3]-sigmatropic rearrangement, led to the dienic derivatives 45, precursor of the unsaturated piperidines 46 (Scheme 18) [43]. piperidines 46 (Scheme 18) [43]. When the ring-opening metathesis (ROM)/ ring-closing metathesis (RCM) was applied to 47, using the G-I catalyst (10 mol %), the unsaturated piperidines 48, substituted at C4, were isolated in good yields (74%–86%) (Scheme 19) [44].
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10 of 22 10 of 22 (1 equiv) N Me (1 equiv) N Cu(F3-acac) Me 2 (5 mol %) toluene, 100 (1 °C,equiv) 1−2 h N Cu(F355–75% -acac)2 (5 mol %) Me100 °C, 1−2 h toluene,
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N2 R'' CF3
CF3 R'' 44 CF3 N2 R'' =44CO2Me, P(O)(OEt) 2 355–75% Cu(F -acac)2 (5 mol %) toluene, 100 °C, 1−2 h R'' = CO2Me, P(O)(OEt)2 55–75% 44 N2
C R'' N CF3 Me C R'' N CF3 VIII Me C R'' N VIIICF 3 Me VIII
10 of 22
[2,3]-sigmatropic
[2,3]-sigmatropic rearrangement rearrangement [2,3]-sigmatropic G-II (5 mol %) rearrangement CH2Cl2, rt, 4−5 h 83–91% G-II (5 mol %) CH2Cl2, rt, 4−5 h 83–91% G-II (5 mol %) CH2Cl2, rt, 4−5 h 83–91%
R'' N CF3R'' Me N 45 CF3 Me R'' N45 CF3 Me 45
R'' N CF3 R'' Me 46N CF 3 Me R'' N Scheme 18. Synthesis of α,α-disubstituted piperidines from trifluorodiazo derivatives. 46 CF3 Me Scheme 18. Synthesis of α,α-disubstituted piperidines from trifluorodiazo derivatives. 46 When the ring-opening metathesis (ROM)/ ring-closing metathesis (RCM) was applied to 47, R'' = CO2Me, P(O)(OEt)2
using the G-I catalyst (10 %), the piperidines 48, substituted at C4, were isolated in good 18.mol Synthesis of unsaturated α,α-disubstituted piperidines from trifluorodiazo derivatives. WhenScheme the ring-opening metathesis (ROM)/ ring-closing metathesis (RCM) was applied to 47, using Scheme 18. Synthesis of α,α-disubstituted piperidines from trifluorodiazo derivatives. yields (74%–86%) (Scheme 19) [44]. the G-I catalyst (10 mol %), the unsaturated piperidines 48, substituted at C4, were isolated in good When the ring-opening metathesis (ROM)/ ring-closing metathesis (RCM) was applied to 47, using yields (74%–86%) (Scheme 19) [44]. the G-I catalyst (10 mol n%), = 0, 1the unsaturated piperidines 48, substituted n = 0, 1 at C4, were isolated in good yields (74%–86%) (Scheme 19) [44]. G-I (10 mol %) CO2Me n = 0, 1CO2Me n = 0, 1 N N CH2Cl2, rt, 6−8 h CF3 CF 3 G-I (10 mol %) R n = 0,CO 1 n = 0, 1 R CO2Me 2Me 74−86% N N rt, 6−8 CH 48 CF3 47 CF3 G-I2Cl (10 %) h 2, mol COMe, CO2Me R R 2MeSO Ph, Boc R = SO 2 2 N N 74−86% CH2Cl2, rt, 6−8 h CF3 CF 3 47 R R48 Scheme 19. Synthesis of SO α-trifluoromethylpiperidines using a ROM/RCM sequence. R = SO2Me, 74−86% 2Ph, Boc Scheme 19. Synthesis of α-trifluoromethylpiperidines using a ROM/RCM sequence. 48 47 R = SO2Me, SO2Ph, Boc Scheme 19. Synthesis of α-trifluoromethylpiperidines using a ROM/RCM sequence. From Enynes
From Enynes
Scheme 19. Synthesis of α-trifluoromethylpiperidines using aon ROM/RCM sequence. It is worth noting that a substituent at C4 could not be introduced the piperidinic core by using a From It isEnynes worthtonoting a substituent not2-(trifluoromethyl) be introduced onunsaturated the piperidinic core by RCM applied enyne that 49 (Scheme 20, eq 1).at OnC4 thecould contrary, piperidines using aItRCM applied enyne 49 (Scheme 20,could 1). On the contrary, From Enynes is worth noting that a substituent at C4 not be introduced on2-(trifluoromethyl) thelatter piperidinic coreunsaturated by using substituted at C5 canto be produced by applying aeq. RCM to enyne 51. When this was treated with G-I a piperidines substituted at C5 can be produced by applying a RCM to enyne 51. When this latter RCM applied to enyne 49 (Scheme 20, eq 1). On the contrary, 2-(trifluoromethyl) unsaturated piperidines (5 molIt %) the resulting unsaturated piperidine 52 wasnot obtained with anon excellent yield (95%) 20,awas is worth noting that a substituent at C4 could be introduced the piperidinic core(Scheme by using treated with G-I (5 mol %) the resulting unsaturated piperidine 52 was obtained with an excellent substituted at C5 can be49 produced RCM to enyne 51. When this latter was treated with G-I eq. 2).applied RCM to enyne (Schemeby 20,applying eq 1). Onathe contrary, 2-(trifluoromethyl) unsaturated piperidines yield (95%) (Scheme 20, eq. 2). (5substituted mol %) the resulting unsaturated piperidine 52 was obtained with an excellent yield (95%) (Scheme 20, at C5 can be produced by applying a RCM to enyne 51. When this latter was treated with G-I G-I (10 mol %) eq. 2). (5 mol %) the resulting unsaturated piperidine 52 was obtained with an excellent yield (95%) (Scheme 20, eq. 2).
N Bn
CF3
49 N Bn N
CF3
51 N Bn MeN Bn 51
Me
(eq 1)
N Bn
X CHX 2Cl2, rt
G-I (10 mol %) CF3
CH2Cl2, rt G-I (5 mol %)
CF3
CF3
CH2Cl2, rt, 12 h G-I (5 mol %) 95% G-I (5 mol %) CH2Cl2, rt, 12 h
CF3
CH2Cl2, rt, 12 h 95%
49 Bn 49 N Bn
X
G-ICH (10 mol 2Cl 2, rt%)
51
MeN CF3 Cbz 53 N CF3 N CF3 Cbz Cbz 53 53
95% G-II (5 mol %)
50 N CF3 NBn CF3 50 Bn 50 N Bn
Me
Scheme 20. Cont.
Me Me
(eq 1) (eq 1) (eq 2)
CF3
52 N CF3 NBn CF3 52 Bn
CH2Cl2, 50 °C, 24 h
G-II (5 mol %) 75% G-II (5 mol %) CH2Cl2, 50 °C, 24 h CH2Cl2, 50 °C, 24 h 75% 75%
CF3
(eq 2) (eq 2)
52 (eq 3) N CF3 Cbz 54 N CF3 NCbz CF3 Cbz 54 54
(eq 3) (eq 3)
Molecules 2017, 22, 483
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Molecules 2017, 22, 483
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R
G-II (5 mol %) CO2Me N CF3 Me
Toluene, 80 °C, 2 h
CO2Me N CF3 Me
R
60−74%
56
55 O
(eq 4)
R R
H-II (5 mol %) CO2Me
CO2Me N CF3 Me
O
Toluene, 80 °C, 3 h ethylene (1 atm.)
N CF3 Me
48−75%
57
(eq 5)
58
Scheme 20. Synthesis of α-trifluoromethylpiperidines by a RCM to enynes. Scheme 20. Synthesis of α-trifluoromethylpiperidines by a RCM to enynes.
The alkyne can be substituted by different alkyl groups (compound 53), aryl groups (compound 55) alkyne(compound can be substituted alkyl groups (compound 53), aryl groups (compound andThe ketone 57). In by all different cases, the corresponding unsaturated piperidinic compounds55) and ketone (compound 57). Ininall cases, the corresponding piperidinic compounds substituted at C5, were isolated good yields (Scheme 20, eqs 3, 4unsaturated and 5) [37,38,45]. substituted at C5,mentioning were isolated yields 20,aryl eqs. 3, 4 and 5) [37,38,45]. It is worth that in in good the case of 55,(Scheme when the group is substituted in the para position is worth mentioning that in the case of 55, when the aryl group is substituted in the in para theItyields in 56 are good (60%–74%). On the contrary, when the aryl group is substituted theposition ortho into 56 whatever catalystwhen used, the either thegroup G-II oristhe GH-II catalysts theposition, yields 55 in is 56not aretransformed good (60%–74%). On the the contrary, aryl substituted in the [45].position, 55 is not transformed into 56 whatever the catalyst used, either the G-II or the GH-II ortho catalysts [45]. 3.1.2. By Cycloaddition 3.1.2. By Cycloaddition Only the cycloadditions leading to the monocyclic piperidinic core will be reported thus, the [2 + 2]-cycloaddition of allenynes leading [46] and to thethe Paulson-Khan [38,43,47] Only the cycloadditions monocyclicreaction piperidinic core will will be beexcluded. reported thus, the [2 + 2]-cycloaddition of allenynes [46] and the Paulson-Khan reaction [38,43,47] will be excluded. [4 + 2]-Cycloaddition: Aza Diels-Alder [4 + 2]-Cycloaddition: Aza Diels-Alder If imines are used as dienophiles, activation of the imine moiety either by electron-withdrawing If imines or areby used as dienophiles, activation of the imine either by Imines electron-withdrawing substituents a Lewis acid is required for a successful [4 + moiety 2]-cycloaddition. 59, possessing substituents or by a Lewis acid is required forreactive a successful [4 + 2]-cycloaddition. Imines possessing three electron-withdrawing groups, are very and the aza Diels-Alder reaction was59, achieved at three groups,ofare very reactive aza Diels-Alder reaction was achieved lowelectron-withdrawing temperature in the presence different dienes and 60, tothe produce the corresponding unsaturated at piperidines low temperature in theyields. presence different dienes that 60, to produce the corresponding unsaturated 61 in good It is of worth mentioning phosphonylimines were less reactive than sulfonylimines the reaction be performed at higher and longer reaction times were piperidines 61 inasgood yields. has It istoworth mentioning that temperature phosphonylimines were less reactive than required (120 has forthe phosphonylimines versus 14 h for sulfonylimines) (Table 1)and [48].longer reaction times sulfonylimines reaction has to be performed at higher temperature were required (120 h for phosphonylimines versus 14 h for sulfonylimines) (Table 1) [48]. 1. Aza Diels-Alder cycloadditions. When the silyloxydiene 62Table was involved in the aza Diels-Alder reaction, piperidinone 63 was 2 R2 isolated after acidic treatment (Scheme 21)R[48] CO2Me
N R
+
CF3
R1
CH2Cl2
R1
T, t
R3
R3
59
60
CO2Me N CF3 R 61
R = SO2Me, SO2Ph, P(O)(OEt)2
Entry 1 2 3
R SO2Ph SO2Me P(O)(OEt)2
R1 Me Me Me
R2 Me Me Me
R3
T (°C)
t (h)
Yield
H H H
–30 to 20 –30 to 20 20
13 14 120
71% 91% 95%
substituents or by a Lewis acid is required for a successful [4 + 2]-cycloaddition. Imines 59, possessing three electron-withdrawing groups, are very reactive and the aza Diels-Alder reaction was achieved at low temperature in the presence of different dienes 60, to produce the corresponding unsaturated piperidines 61 in good yields. It is worth mentioning that phosphonylimines were less reactive than sulfonylimines as the reaction has to be performed at higher temperature and longer reaction times12were Molecules 2017, 22, 483 of 22 required (120 h for phosphonylimines versus 14 h for sulfonylimines) (Table 1) [48]. Table1.1.Aza AzaDiels-Alder Diels-Alder cycloadditions. cycloadditions. Table
+
CF3
N R
R1 R3
59 Molecules 2017, 22, 483 Molecules 2017, 22, 483
R2
R2
CO2Me
CH2Cl2
R1
T, t
R3
60
CO2Me N CF3 R 61 12 of 22 12 of 22
R = SO2Me, SO2Ph, P(O)(OEt)2
Entry Entry 4 4 1551 2662 3773 4 8 85
SORR 2Ph SO2Ph SO 2 Me SO22Ph Ph SO Me SO22Me Me 2 P(O)(OEt) SO P(O)(OEt)2 P(O)(OEt) SO2Ph 22 P(O)(OEt) SO SO22Ph Ph P(O)(OEt) 2 SO2 Me 2 P(O)(OEt)
R R H11 H H Me Me H Me H Me H Me H Me H H H H
R2R2 Me Me Me Me Me Me Me Me Me Me HMe Me H Me H Me H
RH3 R3 H HH H H HH H H Me H H Me H Me MeH
P(O)(OEt)2
H
Me
H
6
T (°C) (h) T C) t 13 t (h) –30 to(◦20 –30 to 20 13 –30 to –30–30 to 20 20 13 13 –30 to to 2020 13 13 to 20 150 14 20 –30–30 to 20 14 20 150 120 4 20 120 20 120 4 to 20 120 –30 13 20 720 –30 13 20 to 20 720 20
Yield Yield 81% 81% 97% 71% 71% 97% 91% 68% 91% 68% 95% 75% 95% 75% 81% 89% 97% 89%
150
68%
7 SO62 H H 4 120 75% 2 Phwas involved When the silyloxydiene in the Me aza Diels-Alder reaction, piperidinone 63 was When the silyloxydiene 62 was involved in the Me aza Diels-Alder reaction, piperidinone 63 was P(O)(OEt) H H 20 720 89% 8 2 isolated after acidic treatment (Scheme 21) [48] isolated after acidic treatment (Scheme 21) [48] CO2Me CO2Me N CF3 N CF3 R R
OSiMe3 OSiMe3 + +
59 62 59 62 R = SO2Ph, P(O)(OEt)2 R = SO2Ph, P(O)(OEt)2
1) CH2Cl2, −50 °C–rt 1) CH14– −50 2Cl2,48 h °C–rt 14– 48 h 2) HCl 3M 2) HCl 3M 61–73% 61–73%
O O CO2Me CO2Me N N CF3 R CF3 R 63 63
Scheme by an an azaDiels-Alder Diels-Alder reaction. Scheme21. 21.Synthesis Synthesisof ofpiperidinones piperidinones by Scheme 21. Synthesis of piperidinones by anaza aza Diels-Alderreaction. reaction. Aza Aza Diels-Alder Diels-AlderReaction Reactionwith with1-Azadiene 1-Azadiene Diels-Alder Reaction with 1-Azadiene The unsaturated 67 67 was obtained fromfrom an aza reactionreaction between the iso-butyl The unsaturatedpiperidine piperidine obtained anDiels-Alder aza Diels-Alder the The unsaturated piperidine 67 waswas obtained from an aza Diels-Alder reaction betweenbetween the iso-butyl vinyl ether 66 and the sulfinimine intermediates IX generated in situ from the trifluoromethyl iso-butyl vinyl andsulfinimine the sulfinimine intermediates IX generated situfrom from the the trifluoromethyl vinyl ether 66ether and 66the intermediates IX generated in in situ trifluoromethyl α,β-unsaturated ketone 6464 and thethe sulfinamine 65. In65. thisInaza Diels-Alder reaction,reaction, the HOMO of α,β-unsaturated ketone and sulfinamine this aza Diels-Alder theorbital HOMO α,β-unsaturated ketone 64 and the sulfinamine 65. In this aza Diels-Alder reaction, the HOMO orbital of 66 reactsofwith the LUMO orbital of the azadienes IX.azadienes The trifluoromethyl-piperidines 67 were obtained orbital 66 reacts with the LUMO orbital of the IX. The trifluoromethyl-piperidines 67 66 reacts with the LUMO orbital of the azadienes IX. The trifluoromethyl-piperidines 67 were obtained with aobtained good diastereoselectivity in favor of theinendo In addition, the reaction were with a good diastereoselectivity favorproduct. of the endo product.when In addition, whenwas the with a good diastereoselectivity in favor of the endo product. In addition, when the reaction was performed with an optically active sulfinamine, the cycloadduct was obtained with a with gooda reaction was performed with an optically active sulfinamine, the cycloadduct was obtained performed with an optically active sulfinamine, the cycloadduct was obtained with a good enantioselectivity (ee > 99%) (Scheme 22) [49].22) [49]. good enantioselectivity (ee > 99%) (Scheme enantioselectivity (ee > 99%) (Scheme 22) [49]. O O F3 C F3 C 64 64
R R Ti(Oi-Pr)4 (3 equiv) CF CF Cl H 2N Ti(Oi-Pr)4 (3 equiv) H2N S CF22CF22Cl + Oi-Bu R ++ S + Oi-Bu R O CH2Cl2, rt i-BuO O CH2Cl2, rt i-BuO 66 (2 equiv) 65 (1.2 equiv) 66 (2 equiv) 65 (1.2 equiv) O 32−67% O 32−67%
O O S N S CF2CF2Cl N CF2CF2Cl R F 3C R F 3C IX IX
N CF3 N CF3 S S CF2CF2Cl CF2CF2Cl 67 67 (21/1 < endo/exo < 60/1) (21/1 < endo/exo < 60/1) (10/1 < df < 50/1) (10/1 < df < 50/1)
Oi-Bu Oi-Bu
Scheme 22. Aza Diels-Alder reaction with 1-azadienes. Scheme 22. Aza Diels-Alder reaction with 1-azadienes.
Scheme 22. Aza Diels-Alder reaction with 1-azadienes.
3.1.3. 1,4-Addition: Aza-Michael 3.1.3. 1,4-Addition: Aza-Michael A Michael acceptor, tethered to a nucleophilic amine, can undergo an intramolecular 1,4-addition A Michael acceptor, tethered to a nucleophilic amine, can undergo an intramolecular 1,4-addition with concomitant formation of a piperidinic core. After the preparation of the optically active ω-amino with concomitant formation of a piperidinic core. After the preparation of the optically active ω-amino α,β-unsaturated ketone 70 in three steps from the trifluoromethylhemiacetal 68, the aminoketone 70 was α,β-unsaturated ketone 70 in three steps from the trifluoromethylhemiacetal 68, the aminoketone 70 was treated under basic conditions to produce the 2-trifluoromethyl-substituted piperidine 71 in 80% yield treated under basic conditions to produce the 2-trifluoromethyl-substituted piperidine 71 in 80% yield and with an excellent diastereoselectivity of 94:6 in favor of the cis-isomer. This piperidine was
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3.1.3. 1,4-Addition: Aza-Michael A Michael acceptor, tethered to a nucleophilic amine, can undergo an intramolecular 1,4-addition with concomitant formation of a piperidinic core. After the preparation of the optically active ω-amino α,β-unsaturated ketone 70 in three steps from the trifluoromethylhemiacetal 68, the aminoketone 70 was treated under basic conditions to produce the 2-trifluoromethyl-substituted piperidine 71 in 80% yield and with an excellent diastereoselectivity of 94:6 in favor of the cis-isomer. This piperidine was transformed Molecules 2017,to22,an 483analog of pinidinol (Scheme 23) [50]. 13 of 22 Molecules 2017, 22, 483
13 of 22
F3C OHOEt F 3C
68
H N t-Bu H S F3C OEtN O t-Bu S OEt O X
Ti(OEt)4
OH
OEt
68
Ti(OEt) O 4 S t-Bu O NH2 S NH2 t-Bu
OH N CF3 H HCl Me N CF3 H analog of HCl (–)-pinidinolHCl analog of (–)-pinidinolHCl
3 Steps
O Me O Me
t-Bu
N S N
HN CF3 S t-BuHN O CF3 THF, °C 67% (dr−40 = 97:3) 69 S t-Bu O 67% (dr = 97:3) G II, Ti(i-PrO) 694 O CH2Cl2, Δ G II, Ti(i-PrO) 4 Me O 99% CH2Cl2, Δ 99% Me O t-BuOK, THF Me O HN CF3 t-BuOK, THF −40 °C at rt S Me t-BuHN O CF3 −40(dr °C=at94:6) rt 80% 70 S O t-Bu 80% (dr = 94:6) 70
BrMg(CH THF, −40 °CCH2 2)3CH
X
3 Steps
Me OH
BrMg(CH2)3CH CH2
F 3C
CF3 O CF3
71 S O t-Bu 71
Scheme 23. Synthesis of α-trifluoromethylpiperidine by aza-Michael addition. Scheme 23. Synthesis of α-trifluoromethylpiperidine by aza-Michael addition.
Scheme 23. Synthesis of α-trifluoromethylpiperidine by aza-Michael addition. 2-Trifluoromethylpiperidines with a quaternary center at C2 were synthesized from hemiaminal 72 2-Trifluoromethylpiperidines with a73quaternary center at C2ofwere synthesized from and 2-Trifluoromethylpiperidines an α,β-unsaturated ketone in center theat C2presence amine with a quaternary were synthesizedafromchiral hemiaminal 72 hemiaminal 72 and an α,β-unsaturated ketone 73 in the presence of under a chiral acidic amine ((2S,3S)-2-amino-N-((S)-1-hydroxy-3-phenyl-propan-2-yl)-3-methyl-pentanamide) and an α,β-unsaturated ketone 73 in the presence of a chiral amine ((2S,3S)-2-amino-N-((S)-1-hydroxy-3-phenyl-propan-2-yl)-3-methyl-pentanamide) under acidic conditions [para-nitrobenzoic acid (PNBA)]. Hemiaminal 72 reacts with the chiralunder amine to acidic form ((2S,3S)-2-amino-N-((S)-1-hydroxy-3-phenyl-propan-2-yl)-3-methyl-pentanamide) conditions [para-nitrobenzoic acid (PNBA)]. Hemiaminal 72 reacts with the chiral amine to form intermediate 74 which then reacts with the Hemiaminal enolized form 73 towith produce intermediate An conditions [para-nitrobenzoic acid (PNBA)]. 72 of reacts the chiral amine to75.form intermediate which reacts the form of compounds 73 to to produce produce intermediate intramolecular then and the form tricyclic 76 were isolated in good intermediate7474aza-Michael whichthen thenreaction reacts with withoccurs the enolized enolized of 73 intermediate 75.75. AnAn intramolecular aza-Michael reaction then occurs and the tricyclic compounds 76 were isolated yields and with excellent dr(s) and ee(s). After reduction of the ketone (NaBH 4 ) and cleavage of the C–S intramolecular aza-Michael reaction then occurs and the tricyclic compounds 76 were isolated in good in 1 = Ph) was good yields and excellent dr(s) and ee(s). After ofisolated the ketone (NaBH ) and cleavage and N–S (sodium naphthalide), piperidine 77 (Rreduction with a cleavage good4enantiomeric yields andbonds with with excellent dr(s) and ee(s). After reduction of the ketone (NaBH 4) and of the C–S 1 of excess the C–S N–S bondsnaphthalide), (sodium 77 (R = Ph)with wasaisolated with a good (eeand = 92%) (Scheme 24) [51]. naphthalide), and N–S bonds (sodium piperidine 77piperidine (R1 = Ph) was isolated good enantiomeric enantiomeric excess (ee = 92%) (Scheme 24) [51]. excess (ee = 92%) (Scheme 24) [51]. O O S O NH O + S NH + F3C OH
O O
R1 R1
OH F 3C 72
73 (2 equiv)
72
73 (2 equiv)
R* NH2 (20 mol %) PNBA (20 mol %) R* NH2 (20 mol %) PNBA mol CHCl(2030 °C%) 3,
CHCl 3, 30 °C 83−99% 83−99%
R*–NH2
O O S O NO S F 3C N
R1 R1
O F 3C 76 O (89% < ee < 96%) 76< 26/1) (6/1 < dr (89% < ee < 96%) (6/1 < dr < 26/1)
1) NaBH4 CH2Cl2, −30 °C 1) NaBH 4 (98%, ee = 94%) CH2Cl2, −30 °C (98%, ee = 94%) 2) Na/naphtalene
F 3C
R*–NH2 = OH OH
R1 R1
O 1 O R S O 1 NH O R S * NH F3C* O F3 C 75
R*–NH2 =
R1 R1 OH
77 OH (R1 = Ph) 77 (R1 = Ph) O
PNBA
74
F3C HN
−78 °C 2) Na/naphtalene (36%, ee = 92%) −78 °C (36%, ee = 92%)
PNBA R*–NH2
O O S O NH O S * NH F3C* N R* HH F3C N R* H 74 H
HN
Bn
O N Bn H NH2 N H NH2
OH OH
O
75
Scheme 24. Synthesis of chiral α-trifluoromethylpiperidines.
Scheme Scheme 24. 24. Synthesis Synthesis of of chiral chiral α-trifluoromethylpiperidines. α-trifluoromethylpiperidines. 3.1.4. Electrophilic-Induced Cyclization 3.1.4.Amino-iodo Electrophilic-Induced Cyclization cyclization has been used to prepare 2-trifluoromethylpipecolic acid derivatives starting from the ω-unsaturated Thetotransformation of 79 to 80 was realized a one-pot Amino-iodo cyclization hasimine been 78. used prepare 2-trifluoromethylpipecolic acidinderivatives process yield of imine 80%. After treatment of imine 78 in realized the presence NaH, starting with froman theexcellent ω-unsaturated 78. The transformation of with 79 toiodine 80 was in a of one-pot the bicyclic 79 was formed and,After when reacted with I2, a78 migration of the group took place process withproduct an excellent yield of 80%. treatment of imine with iodine in CF the3 presence of NaH, leading to the diiodo derivative 80 via an iminium alcoholate intermediate XI. The bicyclic compound 80
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3.1.4. Electrophilic-Induced Cyclization Amino-iodo cyclization has been used to prepare 2-trifluoromethylpipecolic acid derivatives starting from the ω-unsaturated imine 78. The transformation of 79 to 80 was realized in a one-pot process with an excellent yield of 80%. After treatment of imine 78 with iodine in the presence of NaH, the bicyclic product 79 was formed and, when reacted with I2 , a migration of the CF3 group took place leading to the diiodo derivative 80 via an iminium alcoholate intermediate XI. The bicyclic compound 80 was then transformed into a variety of 2-trifluoromethylpipecolic acid derivatives 81 in a few steps (Scheme2017, 25) 22, [52,53]. Molecules 483 14 of 22 Molecules 2017, 22, 483
Ph Ph
14 of 22
CF3 CFOH 3
N N
O OH O 78 78
I2 (5 equiv), NaH (2.5 equiv) I2 (5 equiv), NaH (2.5 equiv) THF, 60 °C, 0,5 h, MW THF, 60 °C, 0,5 h, MW 80% 80%
I I Ph Ph
N N
N N
Ph Ph 79
R' R'
80 80
CF3 CF32R CO CO2R
N H N H 81 81
– NaI – NaI
I2, NaH I2, NaH I I
I CF I 3 CF3O O O O
I I I I
I2 I2
CF3 CFO3
O O Na O Na
Ph Ph
79
N N XI XI
I ICF3 CFO3
O O Na O Na
Scheme 25. acidderivatives. derivatives. Scheme 25.Synthesis Synthesisof ofα-trifluoromethylpipecolic α-trifluoromethylpipecolic acid Scheme 25. Synthesis of α-trifluoromethylpipecolic acid derivatives. If in the electrophilic-induced cyclization of ω-aminoalkenes the CF3 group was present in the If the cyclization of of ω-aminoalkenes the CF CF33 group group was was present present in in the If in inmaterial, the electrophilic-induced electrophilic-induced ω-aminoalkenes the the3 starting on the contrary, incyclization the electrophilic-induced cyclization of ω-amino alkynes the CF starting material, on the contrary, in the electrophilic-induced cyclization of ω-amino alkynes the CF 33 starting material, on the contrary, in the electrophilic-induced cyclization of ω-amino alkynes the CF was introduced after the cyclization. was introduced after the cyclization. was introduced after the cyclization. When the ω-amino alkynes 82 were treated with AgF in the presence of H2O, a hydroamination When the ω-amino alkynes 82 82 were treated AgF in presence of H aa hydroamination When the ω-amino alkynes treated with with in the the H22O, O, hydroamination takes place to produce the enaminewere intermediate XII,AgF which waspresence reacted of with TMSCF 3 to produce takes place to produce the enamine intermediate XII, which was reacted with TMSCF takes place to produce the enamine intermediate which (Scheme was reacted with TMSCF33 to to produce produce 2-trifluoromethylpiperidines 83 with excellent yields XII, (88%–92%) 26) [54]. 2-trifluoromethylpiperidines 83 with excellent yields (88%–92%) (Scheme 26) [54]. 2-trifluoromethylpiperidines 83 with excellent yields (88%–92%) (Scheme 26) [54]. R' R'
R N H R N H
+ TMSCF3 + TMSCF3
82 82 AgF, H20 AgF, H20 R = Bn, Ph, allyl R' H, CPh, R == Bn, 4H9allyl R' = H, C4H9
N N R R XII XII
AgF (1,5 equiv) (1 equiv) H2O(1,5 AgF equiv) H2O (1 equiv) Dioxane, 100 °C MW, 40 min Dioxane, 100 °C MW, 40 min 88−92% 88−92%
R' R'
R' R' N CF3 N R CF3 R83 83
TMSCF3 TMSCF3
Scheme 26. Synthesis of α-trifluoromethylpiperidines by electrophilic-induced cyclization. Scheme 26. Synthesis of α-trifluoromethylpiperidines by electrophilic-induced cyclization. Scheme 26. Synthesis of α-trifluoromethylpiperidines by electrophilic-induced cyclization. 3.1.5. Nucleophilic Attack of Iminium Ions 3.1.5. Nucleophilic Attack of Iminium Ions 3.1.5.InNucleophilic Attack of Iminium reaction where iminium ions areIons involved, the iminium ion is attacked by a nucleophile such as In reaction where iminium ions are involved, iminium ionAis attacked by a nucleophile such of as in aIn Mannich type iminium reaction ions and are a involved, Prins the cyclization. diastereoselective reaction where the iminium ion is attacked by asynthesis nucleophile in a Mannich type reaction and a Prins cyclization. A diastereoselective synthesis of 2-trifluoromethylpiperidines realizedand by using an intramolecular reaction starting from the such as in a Mannich typewas reaction a Prins cyclization. AMannich diastereoselective synthesis of 2-trifluoromethylpiperidines wascondensation realized by using anlatter intramolecular Mannich starting from the trifluoromethyl amine 84. After the with aldehydes, thereaction formed imines 85 were 2-trifluoromethylpiperidines was realized by of using an intramolecular Mannich reaction starting from trifluoromethyl amine 84. After condensation of the latter with aldehydes, the formed imines 85 were transformed to the iminium intermediates XIII underofacidic conditions (p-TsOH, refluxing toluene). A the trifluoromethyl amine 84. After condensation the latter with aldehydes, the formed imines transformed isto the iminium under acidic conditions (p-TsOH,derivatives refluxing toluene). A cyclization taking placeintermediates to produceXIII the 2-trifluoromethylpiperidinic 86. The cyclization is taking place to produce the 2-trifluoromethylpiperidinic derivatives 86. The diastereoselectivity can be explained by the six-membered ring chair transition states XIV, in which the diastereoselectivity can be explained by the six-membered ring chair transition states XIV, in which the steric interactions are minimized (Scheme 27) [55–57]. steric interactions are minimized (Scheme 27) [55–57].
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85 were transformed to the iminium intermediates XIII under acidic conditions (p-TsOH, refluxing toluene). A cyclization is taking place to produce the 2-trifluoromethylpiperidinic derivatives 86. The diastereoselectivity can be explained by the six-membered ring chair transition states XIV, in which Molecules 22, 483 15 of 22 the steric2017, interactions are minimized (Scheme 27) [55–57].
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O O
O O
H 2N H 2N
+ R' H CF3 + R' H CF3 R' = alkyl, aryl 84 R' = alkyl, aryl 84
O O
O O R' R'
1) p-TsOH cat. 1) p-TsOH cat. MgSO 4, CH2Cl2, reflux MgSO4, CH2Cl2, reflux 2) p-TsOH 2) p-TsOH toluene, 80−110 °C toluene, 80−110 °C 40−80% 40−80%
O O N N
O O R' R'
CF3 N H CF3 N H 86 86 (50%< de < 96%) (50%< de < 96%)
O HO H
H H CF3 CF3
O O
R' R'
85 85
H H
R' R' HN HN
O O CF3 CF3 XIV XIV
OH OH
O O CF3 N CF3 N H H XIII XIII
Scheme 27. Synthesis of α-trifluoromethylpiperidines by anintramolecular intramolecular Mannich reaction. Scheme Synthesis α-trifluoromethylpiperidines by reaction. Scheme 27.27. Synthesis ofofα-trifluoromethylpiperidines by an an intramolecularMannich Mannich reaction. A silyl-aza-Prins reaction was also used to prepare highly functionalized 2-trifluoromethylreaction was was also used A silyl-aza-Prins silyl-aza-Prins reaction used to to prepare prepare highly highly functionalized functionalized 2-trifluoromethyl2-trifluoromethylpiperidines. Treatment of the vinyl silyl trifluoromethyl amine 87 with ethyl glyoxylate in the presence of piperidines. Treatment of the vinyl silyl trifluoromethyl amine 87 with ethyl glyoxylate presence piperidines. Treatment of the vinyl silyl trifluoromethyl amine 87 with ethyl glyoxylate in in thethe presence of InCl3 led to 88 via the iminium intermediate XV. After an intramolecular attack of the iminium XV by the of InCl led88tovia 88the viaiminium the iminium intermediate XV.anAfter an intramolecular attack of theXV iminium InCl 3 led intermediate XV. After intramolecular attack of the iminium by the 3 to vinyl silane, intermediate XVI was formed, a desilylation took place and piperidine 88 was isolated in XV bysilane, the vinyl silane, intermediate XVI was formed, atook desilylation place and piperidine vinyl intermediate XVI was formed, a desilylation place andtook piperidine 88 was isolated 88 in 65% yield. This piperidine can then be transformed to the highly functionalized was isolated 65% yield. This piperidine be transformed highly functionalized 65% yield. inThis piperidine can then can bethen transformed to to thethehighly functionalized 2-trifluoromethylpiperidine 89 (Scheme 28) [58]. 2-trifluoromethylpiperidine8989(Scheme (Scheme28) 28) [58]. 2-trifluoromethylpiperidine [58]. O O
TMS TMS
CF3 CF3 NHBn NHBn 87 87
CF3 CF3 NBn H NBn TMS H TMS OEt O OEt XV O XV
H H
1) OsO4 cat. 1) OsO 4 cat. NMO, THF, H 2O NMO, H 2O rt, 48THF, h, (83%) rt, 48 h, (83%)
OEt OEt
O O InCl3, MeCN InClrt, MeCN 3, 48 h rt, 48 h 65% 65%
Cl Cl
EtO EtO
N CF3 N CF3 Bn Bn 88 88= 85:15) (trans/cis (trans/cis = 85:15) O O
TMS TMS EtO EtO O O
N N Bn Bn XVI XVI
2) Ac2O, DMAP 2) AcCl 2O, DMAP CH 2 2, rt, 20 h CH2Cl(50%) 2, rt, 20 h (50%)
AcO AcO EtO EtO O O
OAc OAc N N Bn Bn 89 89
CF3 CF3
CF3 CF3
Scheme 28. Synthesis of an α-trifluoromethylpiperidine by a silyl-aza-Prins reaction. Scheme 28.28. Synthesis byaasilyl-aza-Prins silyl-aza-Prins reaction. Scheme Synthesisofofan anα-trifluoromethylpiperidine α-trifluoromethylpiperidine by reaction. 3.1.6. Intramolecular Condensation of Aminoketones and Aminoesters 3.1.6. ofof Aminoketones and Aminoesters 3.1.6. Intramolecular IntramolecularCondensation Condensation Aminoketones and Aminoesters Intramolecular lactamization and hemiaminalization were used to build up the C–N bond of the Intramolecular and hemiaminalization werewere usedused to buildbuild up the C–N bond the Intramolecularlactamization lactamization and hemiaminalization C–N of bond 2-trifluoromethylpiperidine derivatives. 2-Trifluoromethyllactam 93, whichtocan led toup thethe corresponding 2-trifluoromethylpiperidine derivatives. 2-Trifluoromethyllactam 93, which can led to the corresponding of the 2-trifluoromethylpiperidine derivatives. 93, which can led the piperidine by reduction, was synthesized in three2-Trifluoromethyllactam steps from ketoester 90. After treatment of 90towith piperidine by reduction, was synthesized in three steps frominketoester 90. After treatment of 90 After with corresponding piperidine by reduction, was synthesized three steps from ketoester 90. aniline (p-TsOH, toluene, reflux), imine 91 was reduced to the δ-aminoester 92 which was cyclized to the aniline (p-TsOH, toluene, reflux), imine 91 was reduced toimine the δ-aminoester 92 which was cyclized to the treatment of 90lactam with aniline (p-TsOH, toluene, reflux), 91 was29) reduced corresponding 93 under basic conditions (NaH, THF) (Scheme [59]. to the δ-aminoester 92 corresponding lactam 93 under basic conditions (NaH, THF) (Scheme 29) [59]. which was cyclized to the corresponding lactam 93 under basic conditions (NaH, THF) (Scheme 29) [59].
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PhNH2 (2 equiv) p-TsOH (5 equiv) mol %) PhNH (2 2
MeO2C
O MeO2C O 90
CF3 CF3
p-TsOH (5 mol %) MeO2C toluene, reflux, 72 h MeO2C toluene, reflux, 72 h 77% 77%
90
N CF3 NPh CF3 91 Ph 91 NaBH4 (0.5 equiv) MeOH, 1h NaBH (0.5rt,equiv) 4
MeOH, rt, 1 h NaH (1.1 equiv) O O
N CF3 NPh CF3 93 Ph
NaH (1.1 equiv) THF, rt, 2 h THF, rt, 2 h 91% 91%
MeO2C HN MeO2C Ph HN 92 Ph
CF3 CF3
92 Scheme93 29. Synthesis of a trifluoromethyllactam from a ketoester. Scheme 29. Synthesis of a trifluoromethyllactam from a ketoester. Scheme 29. Synthesis of a trifluoromethyllactam from a ketoester. The α-substituted trifluoromethyl-δ-lactam 96 was prepared from the α-trifluoromethyl The α-substituted trifluoromethyl-δ-lactam 96 was was prepared prepared from from the nitrosulfinamine 94, prepared in two steps from trifluoromethylhemiacetal 68. After 1,4-addition of 94 The α-substituted trifluoromethyl-δ-lactam 96 the aα-trifluoromethyl α-trifluoromethyl nitrosulfinamine 94, prepared in two steps from trifluoromethylhemiacetal 68. After a 1,4-addition to ethyl acrylate 94, under basic conditions, resulting aminoester 95 was treated with TFA to produce, nitrosulfinamine prepared in two stepsthe from trifluoromethylhemiacetal 68. After a 1,4-addition of 94 of 94 to ethyl acrylate under basic conditions, the resulting aminoester 95 was treated with TFA to after deprotection (NH3basic , MeOH), the trifluoromethyl-δ-lactam 96 (Scheme 30) [60].with TFA to produce, to ethyl acrylate under conditions, the resulting aminoester 95 was treated produce, after deprotection (NHthe the trifluoromethyl-δ-lactam 96 [60]. (Scheme 30) [60]. 3 , MeOH), after deprotection (NH3, MeOH), trifluoromethyl-δ-lactam 96 (Scheme 30) 1) 1)
Tol NH2 S 42 TolTi(OEt) NH 70 °C, 24 h Ti(OEt)4 70 °C, 24 h 2) MeNO 2, NaOH 100 °C, 50 h 2) MeNO2, NaOH 100 °C, 50 h 50%
OEt HO OEtCF3 HO
O OS
CF3 68 68
NO2 NO2 HN CF3 HNS(O)Tol CF3
O
N H N H 96
1)
96
NO2 CF3
2) TFA, rt, 2 h
EtO O
2) TFA, rt, 2 h 3) NH3, MeOH, 2 h
EtO
CF3
3) NH3, 37% MeOH, 2 h 37%
+
NO2 HN CF3 HNS(O)Tol CF3 94' (23%) S(O)Tol
94' (23%) CO2Et (5 equiv)
94 (27%) 1)
O
O
+
94 (27%) S(O)Tol
50%
NO2
NO2
DBU (0,4 equiv) CO 2Et (5 equiv) 0 °C DBU (0,4 equiv) 0 °C NO2
NO2 HN CF3 HNS(O)Tol CF3 S(O)Tol 95 95
Scheme 30. Synthesis of a trifluoromethyllactam from a trifluoromethylhemiacetal. Scheme 30.30. Synthesis ofofa atrifluoromethyllactam trifluoromethylhemiacetal. Scheme Synthesis trifluoromethyllactam from from aatrifluoromethylhemiacetal. A lactamization was also utilized to access 2-trifluoromethyl-3-hydroxypiperidine 102. The latter was Asynthesized from 97 and the 2-trimethylsilyloxyfuran 98, and transformed into the lactamization wasaldimine also utilized to access 2-trifluoromethyl-3-hydroxypiperidine 102. The latter A lactamization was also utilized to access 2-trifluoromethyl-3-hydroxypiperidine 102. The unsaturated lactone 99 after treatment withthe TBSOTf. After hydrogenation, obtained lactoneinto 100 was was synthesized from aldimine 97 and 2-trimethylsilyloxyfuran 98,the and transformed the latter was synthesized from aldimine 97 and the 2-trimethylsilyloxyfuran 98, and transformed into transformedlactone to the δ-lactam 101 underwith acidic conditions 2SO4, 80%), andthe then to the 2,3-disubstituted unsaturated 99 after treatment TBSOTf. After(Hhydrogenation, obtained lactone 100 was the unsaturated lactone 99 after treatment with TBSOTf. After hydrogenation, the obtained lactone piperidine 102 4, AlCl 3) (Scheme 31) [61]. transformed to by thereduction δ-lactam (LiAlH 101 under acidic conditions (H2SO4, 80%), and then to the 2,3-disubstituted 100 was transformed to the δ-lactam 101 under acidic conditions (H2 SO4 , 80%), and then to the piperidine 102 by reduction (LiAlH4, AlCl3) (Scheme 31) [61]. 2,3-disubstituted piperidine 102 by reduction (LiAlH4 , AlCl3 ) (Scheme 31) [61].
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N Bn N Bn
CF3 CF3
97 97
O O
TBSOTf (0.5 equiv) TBSOTf (0.5 equiv) CH2Cl2, 0.5 h, −78 °C CH2Cl2, 0.5 h, −78 °C 97% 97%
OSiMe3 OSiMe3
98 98
OH OH N N Bn Bn 102 102
+ +
CF3 CF3
LiAlH4, AlCl3 LiAlH4, AlCl3 THF THF 90% 90%
OH OH O O
N N Bn Bn 101 101
H2SO4 cat. H2SO4 cat. MeOH MeOH 80% 80%
CF3 CF3
O O O O
H
H 3 HN CF HN CF Bn 3 99 Bn(de>98%) 99 (de>98%) 85% 85% O O O O
H2, Pd/C H2THF , Pd/C THF
H H 3 HN CF HN CF Bn 3 Bn 100 100
Scheme 31.31.Synthesis bylactamization. lactamization. Scheme Synthesisofofan anα-trifluoromethylpiperidine α-trifluoromethylpiperidine by Scheme 31. Synthesis of an α-trifluoromethylpiperidine by lactamization. Due to the high reactivity of trifluoromethyl ketones they can be attacked by weak nucleophiles Due to high reactivity of ketones they can by nucleophiles to the the to high reactivity of trifluoromethyl trifluoromethyl ketones they can be be attacked attacked by weak weak nucleophiles such Due as amines form a hemiaminal. When the carboxylic trifluoromethyl ketones 103 were treated such as amines to form a hemiaminal. When the carboxylic trifluoromethyl ketones 103 were treated such as amines to form a hemiaminal. When the carboxylic trifluoromethyl ketones 103 were treated with ammonium carbonate in refluxing toluene, the six-membered ring hemiaminal intermediates 104 with ammoniumcarbonate carbonateininrefluxing refluxingtoluene, toluene, the six-membered ring hemiaminal intermediates with ammonium the six-membered ring hemiaminal intermediates 104 were formed and dehydrated under acidic conditions (p-TsOH, reflux) to furnish the unsaturated 104 were formed and dehydrated under acidic conditions (p-TsOH, reflux) to furnish the unsaturated were formed and dehydrated lactams 105 (Scheme 32) [62]. under acidic conditions (p-TsOH, reflux) to furnish the unsaturated lactams 105 105(Scheme (Scheme32) 32)[62]. [62]. lactams R2 R1 R2 R1 O O
CF3 CF3
(NH4)2CO3 (NH4)2CO3 Toluene, Δ Toluene, Δ
OH O OH O 103 103 R1 = Ph, R2 = H R1 = H, Ph,RR2 2==4-MeO-C H 6 H4 4-MeO-C R1 = H, (CHR32)2=CH, R2 = H6H4 2 =R R1 = C (CH CH, H2 = H 4H39),2R 1 2 R = C 4H 9, R = H
R2 R1 R2 R1 O O
CF3 CF3 OH
N H N H OH 104 104
p-TsOH p-TsOH Δ Δ 75–80% 75–80%
R2 R 1 R2 R 1 O O
N H N H 105 105
CF3 CF3
Scheme 32. Synthesis of unsaturated lactams from carboxylic trifluoromethyl ketones. Scheme 32. Synthesis of unsaturated lactams from carboxylic trifluoromethyl ketones. Scheme 32. Synthesis of unsaturated lactams from carboxylic trifluoromethyl ketones.
Highly substituted 2-trifluoromethylpiperidines 112 were obtained from isoxazoles 106, Highly substituted107, 2-trifluoromethylpiperidines 112 acetate were inobtained from isoxazoles 106, trifluoromethylketoester aldehydes 108 and ammonium ethanol. In this multicomponent Highly substituted107, 2-trifluoromethylpiperidines 112acetate wereinobtained from isoxazoles 106, trifluoromethylketoester aldehydes 108 and ammonium ethanol. In this multicomponent reaction, isoxazoles 106 react with the enolized β-ketoester 107, to form intermediates 109 which can trifluoromethylketoester 107, aldehydes 108 and ammonium acetate in ethanol. In this multicomponent reaction, 106(obtained react withby thecondensation enolized β-ketoester 107, to108 form intermediates which can react withisoxazoles imines 110 of aldehydes with NH4OAc) to109 produce the reaction, isoxazoles 106 react with the enolized β-ketoester 107, to form intermediates 109 which can react with imines 110 (obtained by condensation of aldehydes 108 with NH 4OAc) to produce the aminotrifluoromethylketones 111. The intramolecular attack of the amino group to the highly reactive react with imines 110 (obtained by ofattack aldehydes 108 withgroup NH4 OAc) to produce the aminotrifluoromethylketones 111.trifluoromethylpiperidines Thecondensation intramolecular of the amino trifluoromethylketones led to the 112 (Scheme 33) [63]. to the highly reactive aminotrifluoromethylketones 111. The intramolecular attack112 of (Scheme the amino trifluoromethylketones led to the trifluoromethylpiperidines 33)group [63]. to the highly reactive trifluoromethylketones led to the trifluoromethylpiperidines 112 (Scheme 33) [63].
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Molecules 2017, 22, 483 Ar
+
N Ar O O N O106 O
+
O
O O OEt
F3 C O F3 C
106
107
OEt
+ +
EtOH, rt
O Ar O H Ar
107
108
H
N O N O
O CF3 O CF3 109
NH4OAc
+
NH4OAc
NH CO2Et
Ar NHH
CO O 2Et
15−35 EtOH,min rt 55−88% 15−35 min
Ar
O N O Ar O Ar
Ar
55−88%
108
Ar Ar
+
N
O
Ar
H
110 110
O
OH CO2Et N H CFOH 3 112 N H CF3 112
N
Ar
O N O Ar O Ar
Ar
O
18 of 22
CO2Et
CO2Et
O NH2 CO2Et CF3 O NH 2 111 CF3
109 111 Scheme α-trifluoromethylpiperidines. Scheme33. 33.Synthesis Synthesisof ofhighly highly substituted substituted α-trifluoromethylpiperidines.
Scheme 33. Synthesis of highly substituted α-trifluoromethylpiperidines. 3.1.7. Intramolecular Nucleophilic Substitution 3.1.7. Intramolecular Nucleophilic Substitution 3.1.7. The Intramolecular Nucleophilic Substitution intramolecular nucleophilic displacement of a good leaving group by an amine is one of the The intramolecular nucleophilic displacement of a good leaving group by an amine is one of the must common methods to prepare six-membered nitrogen heterocycles. This method was used to intramolecular displacement ofnitrogen a good leaving group This by anmethod amine is oneused of the mustThe common methodsnucleophilic to prepare six-membered heterocycles. was to synthesize 2-trifluoromethylpiperidines 114 from the highly reactive aziridines 113. The high reactivity must common methods to prepare six-membered heterocycles. This113. method wasreactivity used to synthesize 2-trifluoromethylpiperidines 114 from thenitrogen highly reactive aziridines The high of 113 is due to the presence of the trifluoromethyl group and the N-tosyl group. The attack of aziridine synthesize 2-trifluoromethylpiperidines 114 from the highly reactive aziridines The high of 113 is due to the presence of the trifluoromethyl group and the N-tosyl113. group. The reactivity attack of 113 by a variety of nucleophiles was very regioselective and produced intermediates XVII that cyclized of 113 is due presence the trifluoromethyl group and the N-tosyl group. The attack of aziridine aziridine 113tobythe a variety ofof nucleophiles was very regioselective and produced intermediates XVII according to an intramolecular nucleophilic substitution of the chloride to produce 114 (Scheme 34) [64]. 113 a variety of nucleophiles was very regioselective andsubstitution produced intermediates XVII cyclized thatby cyclized according to an intramolecular nucleophilic of the chloride to that produce 114 according to an intramolecular nucleophilic substitution of the chloride to produce 114 (Scheme 34) [64]. (Scheme 34) [64].
Cl Cl
2
Ts N Ts N CF 3
2
113 CF 3 113
Nu or NuH (1−5 equiv) NaI (0−5 equiv) or DMF Nu orMeCN NuH (1−5 equiv) NaI (0−5 equiv) Δ, 5 h −or7 DMF days MeCN 14−77% Δ, 5 h − 7 days
Cl Cl
14−77% Nu = Cl, i-PrNH, i-BuNH, CN, SCN, OMe, OEt
Ts N Ts N CF
CF3
Nu
XVIICF 3
N Ts N 114 Ts
XVII
114
2
3
2
Nu
Nu CF 3 Nu
Cl, i-PrNH,of i-BuNH, CN, SCN, OMe, OEt Scheme Nu 34.=Synthesis α-trifluoromethylpiperidines from trifluoromethylaziridines.
Scheme 34.34. Synthesis fromtrifluoromethylaziridines. trifluoromethylaziridines. Scheme Synthesisofofα-trifluoromethylpiperidines α-trifluoromethylpiperidines from 3.1.8. Intramolecular Nucleophilic Attack of Aldehydes 3.1.8. Intramolecular Attack of Aldehydes annulationNucleophilic of aminoaldehyde 115 was realized by an intramolecular attack of a diphenyl 3.1.8.The Intramolecular Nucleophilic Attack of Aldehydes sulfonium species on an aldehyde. When aminoaldehyde 115 was reacted with the trifluoromethylThe annulation annulation of aminoaldehyde 115 by an an intramolecular intramolecular attack diphenyl of aminoaldehyde 115 was was realized realized attack of oftook aa diphenyl vinylThe diphenylsulfonium 116, the ylide intermediate XVIII by was formed and a cyclization place to sulfonium species on an aldehyde. When aminoaldehyde 115 was reacted with the trifluoromethylsulfonium species on an aldehyde. When aminoaldehyde 115 was reacted with the trifluoromethylproduce XIX which led to the piperidino-epoxide 117. It is worth noting that 117 was isolated with a vinyl diphenylsulfonium 116, the XVIII was and vinyl diphenylsulfonium 116,diastereoselectivity the ylide ylide intermediate intermediate was formed formed and aa cyclization cyclization took took place place to to good yield (72%) and a good (dr > XVIII 20:1) (Scheme 35) [65]. produce XIX which led to the piperidino-epoxide 117. It is worth noting that 117 was isolated with produce XIX which led to the piperidino-epoxide 117. It is worth noting that 117 was isolated with aa good (dr(dr > 20:1) (Scheme 35) 35) [65].[65]. good yield yield(72%) (72%)and andaagood gooddiastereoselectivity diastereoselectivity > 20:1) (Scheme
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Molecules 2017, 22, 483
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F3 C
O
Me
116
H
Me
NHTs 115
Me
O
Me N Ts XVIII
OTf SPh2 (1,2 equiv)
O
Me Me
Et3N (2 equiv), CH2Cl2 rt, 36 h
CF3 N Ts 117 (dr>20/1)
72%
H SPh2 CF3
Me
O
Me N Ts XIX
SPh2 CF3
Scheme Scheme35. 35.Synthesis Synthesisof of α-trifluoromethylpiperidino-epoxides α-trifluoromethylpiperidino-epoxides. 4. 4. Conclusion Conclusions Despite the considerable considerable synthetic synthetic efforts efforts spent spent toto synthesize synthesize 2-trifluoromethylpiperidinic 2-trifluoromethylpiperidinic Despite the derivatives, most of these compounds have been obtained in a racemic form. are they optically derivatives, most of these compounds have been obtained in a racemic When form. they When are active, the methods involve a chiral auxiliary or the starting material comes from the chiral pool. Thus, optically active, the methods involve a chiral auxiliary or the starting material comes from the chiral there is still a isstrong demand for catalytic enantioselective methods totoefficiently access pool. Thus, there still a strong demand for catalytic enantioselective methods efficiently access 2-trifluoromethylpiperidine derivatives in high diastereoand enantioselectivity. 2-trifluoromethylpiperidine derivatives in high diastereo- and enantioselectivity. Acknowledgments: One of us, S. R. thanks GSK for a grant. Acknowledgments: One of us, S. R. thanks GSK for a grant. Author Contributions: All authors were involved in the preparation of the manuscript: The articles were collected Author Contributions: All authors were involved in the preparation of the manuscript: The articles were collected by of of thethe manuscript were realized by J.by C.J.and the typing by D.by G.D. P..G. P. by S. S. R., R.,the theorganization organizationand andthe thewriting writing manuscript were realized C. and the typing Conflicts of nono conflict of interest . of Interest: Interest:The Theauthors authorsdeclare declare conflict of interest.
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