3. Synthesis and characterisation
3.2 Synthesis 5
The synthetic approach to compounds of the first series of 13 com pounds (37 to 49, table 2.5) was to prepare a single common intermediate that would be functionalised by different amines at the last stage of the synthesis (scheme 3.1). The intermediate chosen was l-bromo-5-phenoxypentane (160), a compound described in the literature as early as
3. Synthesis and characterisation 55
1 9 0 5 2 0 1. The brom ine atom is a good leaving group w ith regard to nucleophilic
substitution by the different secondary amines (R1R2NH) chosen.
The common intermediate 160 was prepared by reacting 1,5-dibrom opentane with phenol in the presence o f aqueous base following a method described in 1937202.
37-49
&
&
Schem e 3.1: Retrosynthesis for com pounds 37 to 49
The synthesis of interm ediate 160 involves a biphasic system w here the sodium phenolate formed is water soluble and the substrate for substitution, 1,5-dibromopentane, forms a separate layer. An attempt to use a phase-transfer catalyst (tetrabutylammonium hydroxide) in order to bring the two reacting species together (Scheme 3.2)203 did not improve the yield significantly enough for systematic use. The yield o f the reaction was typically around 60-70% and the excess 1,5-dibrom opentane was recovered during distillation under reduced pressure.
NaOH ArOH
Bu^N+X- --- ^ BU4N+HO- Bu^N+ArQ- Water
Dichloromethane
/V A A A A A A /W \/\A A A A A A A A A A A A A A A A A A A /W \A A /\A /\A A A /> r> (V\AA/*
Bu4N'"X‘ + ArOR RX + BiuN'^ArO' Schem e 3.2: Phase-transfer catalysis
3. Synthesis and characterisation 56 The next part of the synthesis, nucleophilic substitution by a secondary amine at the bromine-bearing carbon atom, was first perform ed by heating to reflux temperature a solution of the intermediate in a large excess (about ten-fold) of the amine. This method was applied to the cyclic amines 45 to 49, giving crude yields between 75 and 100% and isolated yields o f the recrystallised salts betw een 32 and 58%. Compound 37 was p repared by stirrin g the solution at room tem perature (the boiling point of methylethylamine is 36-37°C). For the preparation o f compounds 41 to 44, the method applied to com pounds 45 to 49 was not satisfactory, the high reflux temperatures involved giving rise to extensive degradation of the intermediate. It was then decided to use a solvent with a moderate boiling point. Ideally, a polar, aprotic solvent should be used for this type of reaction (nucleophilic substitution, SN2 type, scheme 3.3).
R ,N H
- B r '
Schem e 3.3: Nucleophilic substitution, SN2 type
The first solvent chosen was toluene which is aprotic but relatively non polar, with a boiling point close to that o f piperidine (bp = 111°C). However, the results were not satisfactory. Hence absolute ethanol, which is polar but protic, with a lower boiling point (bp = 78°C) was used. This gave the desired products in various yields (19 to 31% for the recrystallised salts). The method was then applied to the preparation of compounds 38 to 4 0(1 1 to 53% yield).
The unsymetrical secondary amines 161 and 162 used in the preparation of compounds 38 and 39 were prepared by reductive alkylation o f the corresponding primary amines in a two-step procedure involving the formation of an imine followed by catalytic reduction w ith hydrogen (schem e 3.4). The procedure was adapted from Campbell-®-^. The dehydration of the interm ediate iminoalcohol formed between the primary amine and acetaldehyde is favoured by the presence of crushed potassium hydroxide which displaces the equilibrium by absorbing the water produced.
The imine formed was distilled over potassium hydroxide and subsequently reduced with hydrogen in the presence of about 5% platinum oxide. An alternative method for imine reduction using sodium borohydride in methanol-®^ gave a very poor yield of compound 161 (13% from the imine) compared with the catalytic hydrogenation (46% from the
3. Synthesis and characterisation 57
imine, 15% overall). Compound 162^06 was prepared in a 17% overall yield from isobutylamine. CH CH NH CH HO H R = H, CH KOH CH CH CH CH 161: R = H 162: R = CH
Schem e 3.4: Reductive alkylation of amines
Second series o f com pounds (5 0 to 7 4 , table 2.7): for these substituted phenoxypentylpyrrolidines and other aryloxypentylpyrrolidines, we had a choice of two different approaches to the preparation of the final products. The first approach is similar to that of the first series: preparation of a brom opentyl intermediate followed by substitution with pyrrolidine. The advantage of the first approach is that the intermediate can be substituted with other secondary amines if required. The other approach is to introduce the various aromatic groups at the last stage of the synthesis. This approach has the advantage of involving a single intermediate for the whole series. The first approach was chosen, because it proved successful with compounds 37 to 49 and the l-bromo-5- aryloxypentane interm ediates (163 to 184) were prepared follow ing different procedures.
The synthesis of intermediates 163 to 168, 170 and 175 to 184 was similar to that of interm ediate 160, giving products with an isolated yield betw een 11 and 60%. Compounds 166 and 181 were obtained after removal of the excess 1,5-dibromopentane by distillation under reduced pressure. Attempted distillation of the 8-quinolinyl intermediate 184 resulted in decomposition of the product. The reaction was repeated and the product isolated after purification by column chromatography (yield: 13%).
3. Synthesis and characterisation 58
- O
' "
Br or Ar' N° 163207 1 64208 1 65209 1 66210 1 6 7 2 '' R 4-CH3 4-OCH3 4-F 4-Cl 4-CN 168217 4-NO2 R 170213 4-C6H5 175 3-NO2 1 7 6 3-CN 1 7 7 3-CF3 1 7 8 3-Cl 1 7 9 3-C6H5 Ar 180214 181215 1 8 2 1 8 3c a C O o a 0 Ç
1 8 4 N° 1 69216 1 7 1 2 ) 7 1 7 2 2 1 6 1 7 3 1 7 4R 4-NHCOCH3 4-QC6H5 4-COCH3 4-COC6H5 4-COCH2C6H5
Intermediates 169 and 171 to 174 were prepared following a procedure adapted from Appleton2i6. The phenol and 1,5-dibromopentane formed a solution in acetone and the base (potassium carbonate) was suspended in the mixture. The reaction was vigorously stirred and heated to reflux for 8 to 16 hours. The solid product was isolated and purified by crystallisation (169,172 to 174). The isolated yields were between 29 and 57%. The intermediate 171 was obtained in a 47% yield after distillation under reduced pressure. In the next step, the intermediates 163 to 184 were reacted with an ten-fold excess pyrrolidine in absolute ethanol at reflux temperature to give the final compounds 50 to 55, 57 and 60 to 74 in a 13 to 82% isolated yield.
The aniline 56 was prepared from the corresponding nitro compound (55) by catalytic hydrogenation of the nitro group in the presence of palladium on carbon catalyst (scheme 3.5)218. The hydrogenation was carried out on the oxalate salt 55 because the resulting aniline 56 seems to be much less stable as the free base (the clear yellow oil turned dark brown overnight and mass spectra showed extensive fragm entation). This is not su rp risin g as it had been observed p re v io u sly th a t a series o f para- dialkylaminoalkoxyanilines were unstable both as the free bases and as the corresponding hydrochlorides2i9.
3. Synthesis and characterisation 59 O2N / 5v ^ O - ( C H2)5- N f ^ I .H2 Pd/C Â J ^ --- ---- ^ (C 00H )2 2. (C 0 0 H )2 H .N 55 0-(C H 2)5'N 2 (C 0 0 H )2 56 0
Scheme 3.5: Catalytic hydrogenation o f nitrophenoxy com pound
Compound 58 was prepared by acylation o f the corresponding aniline 56 with benzoyl chloride at 0°C using pyridine as a base (scheme 3.6). The product was isolated in 24% yield.
Schem e 3.6: Benzoylation o f aniline 56
Compound 59 was prepared by reduction o f the ketone 62 w ith lithium aluminium hydride in dry diethyl ether in 52% yield. The product was subm itted as a racemic mixture of the R and S isomers.
UAIH4 H3C
O H
Schem e 3.7: Reduction o f ketone 62
The second approach to the synthesis of these substituted phenoxypentylpyn olidines was investigated. The aromatic moiety can be introduced at the last stage o f the synthesis via a Mitsunobu ether synthesis^®. The intermediate l-(5-hydroxypentyl)pyrrolidine 186--'
3. Synthesis and characterisation 60
was prepared in a two-step synthesis from pyrrolidine and ethyl 5-bromovalerate (scheme 3.8). N H Ethanol 185 LiAlH OH 186
S chem e 3.8: Preparation o f intermediate 186
Alkylation of pyrrolidine took place in absolute ethanol in five hours at reflux temperature in 90% yield. Reduction o f the ester 185 with lithium aluminium hydride in dry ether gave the primary alcohol 186 in 96% yield. The overall yield for the preparation of 186 from the commercially available starting materials was 8 6%.
This intermediate was used in the attempted syntheses of l-[5-(4-trifluoromethylphenoxy) pentyljpyrrolidine (X = CH, = 4-CF3) and 3-[5-(l-pyrrolidinyl)pentyloxy]pyridine
(X = N, R^ = H) via a M itsunobu ether synthesis (scheme 3.9)^-°.
+ H 0(C H 2)sN
TH F
3. Synthesis and characterisation 61
The Mitsunobu reaction is a versatile method for the obtention of esters, ethers, amines or amides under very mild conditions. The reaction can be carried out at room temperature or below, without the need for strong acids or bases^^o. In the ether formation, an acidic com pound (phenol) reacts with an alcohol-triphenylphosphine adduct which forms a good leav in g g ro u p (schem e 3.10). An ary l e th er is o b ta in e d w hile the diethylazodicarboxylate (DEAD, = C2H5) or diisopropylazodicarboxylate (DIAD, R- = CH(CH3)2) is reduced to the hydrazino derivative and triphenylphosphine is oxidised to the phosphine oxide.
OR OR OR ArO-H 2 R ‘0 H OR OR OR OR ArO ArO-H + ArO (C6H5)3P= 0 + ArO-R
3. Synthesis and characterisation 62
However, the M itsunobu synthesis did not prove successful for the preparation o f l-(5- aryloxypentyi)pyrrolidines. Since the aromatic moiety is acidic enough for the Mitsunobu reaction in both cases, w e can conclude that the hydroxypentylpyrrolidine moiety is not a suitable reagent for this type of reaction. An intram olecular cyclisation o f the alkoxyphosphonium intermediate leading to a six-membered ring is possibly competing with the desired reaction (scheme 3.11).
(C 6H ;))P=0 + AtO - ( C H 2 ) 5 - N
ArO
Schem e 3.11: Possible reason for the failure of the Mitsunobu reaction
Synthetically, the third series (compounds 75 to 97, table 2.8) is not homogenous: the linker between the arom atic moiety and the pyrrolidine ring was modified and most analogues had to be prepared in different ways.
A nalogues 75 to 77 are very similar to the parent compound 45 with an alkyl chain comprising a different num ber of carbon atoms. Compounds 78 and 79 are similar to 76 and 45 with sulfur in place of oxygen. They were prepared from the corresponding bromo intermediates 187 to 191.
X . (CH2)n . B r
187223 188224 189225.226 190227 191228
X
0 0 0s
s
3. Synthesis and characterisation 63
The preparation of the interm ediates 187 to 189 followed the same procedure as previously described for compound 160. The yields were 38, 44 and 28% respectively after distillation under reduced pressure. Compound 187 is also commercially available. In te rm e d ia te s 1 9 0 and 191 were prepared using the p h ase-tran sfer catalyst tetrabutylammonium hydroxide. The reaction took place at room temperature for 30 to 45 minutes under nitrogen. After distillation under reduced pressure, the yields obtained were 62 and 33%.
Compound 80 was prepared in 3 steps from 5-phenylvaleric acid (scheme 3.12). The acid was converted to the acid chloride 192^29 by heating a solution in thionyl chloride under reflux for 3 hours. After removal of the excess thionyl chloride by distillation, the acid chloride was obtained in a quantitative yield. The acid chloride was then reacted with an excess pyrrolidine in diethyl ether at 0°C for 30 minutes. The amide 1932^» was obtained in 74% yield. Reduction of the amide to the amine with a borane/THF complex under nitrogen at 0°C then under reflux for 16 hours gave the final product 80 in 11% yield after recrystallisation of the oxalate. The overall yield for the preparation of compound 80 from 5-phenylvaleric acid was 8%.
O SOCh OH BH3.THF O 192 Cl
c
K JL V
193 Schem e 3.12; Preparation of compound 80The higher analogue 81 was prepared from com m ercially available l-b ro m o -6- phenylhexane in 62% yield.
3. Synthesis and characterisation 64 195: R = H R = H, CH, 196: R = CH, L iA H 82: R = H 83: R = CH3 84: R = H 85: R = CH3
Schem e 3.13: Preparation of amines 82-83 and amides 84-85
The preparation of compounds 82 to 85 followed parallel paths (scheme 3.13) starting from either aniline (82 and 84) or N -m ethylaniline (83 and 85). 5-B rom ovaleryl chloride 194 was obtained in 93% yield by reacting 5-bromovaleric acid with thionyl chloride. The anilines were acylated with the acid chloride in diethyl ether at 0°C to give the phenylamides of 5-bromopentanoic acid (195-^* R = H, yield: 69% and 196 R = CH3, yield: 8 6%). The amides were alkylated with pyrrolidine giving the crude products in 92-93% yield. A portion of the products 84 and 85 was converted to the salts (64 and 74% yield) and another fraction was reduced using lithium aluminium hydride in dry diethyl ether under nitrogen at reflux for 16 hours. Lithium aluminium hydride was chosen because of the disappointing yield of reduction leading to compound 80 using the borane/THF complex. With lithium aluminium hydride, the yields were improved to 75 and 85% for the free base giving the final salts of 82 and 83 in 47 and 37% overall yields respectively.
Compounds 8 6 and 87 were prepared by Williamson ether synthesis starting with benzyl
alcohol (scheme 3.14). The alcohol was deprotonated with sodium hydride in THF at room temperature and then heated with the dibromoalkane under reflux for 24/48 hours. A fter purification by column chromatography, the bromo interm ediates 1 9 7 - - and 198^33 were obtained in 26 and 58% yield respectively. The intermediates were reacted with pyrrolidine in the usual way to give compounds 8 6 (39%) and 87 (43%).
3. Synthesis and characterisation 65 OH NaH THF 197: n = 2 198: n = 3 ONa B r (C H2)n Br O (C H2)n B r
C " "
8 6: n = 2 87: n = 3Schem e 3.14: Preparation o f com pounds 8 6 and 87
Compound 8 8 was synthesised by preparing the bromo intermediate 199-^^ from phenol and 2-bromoethyl ether, in the same way as intermediate 160, in 61% yield, then reacting the intermediate with pyrrolidine (48% yield).
Compound 89 was prepared by Williamson ether synthesis (scheme 3.15). Pyrrolidine was alkylated with 2-chloroethanol in 48% yield after distillation under reduced pressure (compound 200)^35, The intermediate 200 was then deprotonated with sodium metal in dry toluene and reacted with phenylbromopropane to give compound 89 in 25% isolated yield.
3. Synthesis and characterisation 66 OH OH
200
Na ONaS chem e 3.15: Preparation o f compound 89
Compounds 90 and 91 were prepared as a mixture and separated at the end. Phenol was reacted in the usual way with 1,4-dibromopentane which resulted in a mixture 201 of interm ediates l-brom o-4-phenoxypentane and 4 -b ro m o -1 -phenoxypentane-^^ (32% yield). Reaction with pyrrolidine gave a mixture o f the products 90 and 91. The two products were separated by preparative HPLC, the total yield for 90 and 91 was 35% after separation.
+ C^HnLi
O
C
S ch em e 3.16: Preparation of compound 92
Compound 92 was prepared by deprotonation of phenylacetylene with butyl lithium followed by alkylation w ith 1,4-dibromobutane-^^ (46% after distillation). The 6-bromo- 1 -phenylhex-1 -yne intermediate 202^^^ was reacted with pyrrolidine and furnished 92 in 55% isolated yield (scheme 3.16).
3. Synthesis and characterisation 67 M EK Br --- ^ (CgH5)3P+(CH2)5Br, Br NaOH 203
O'
[ ^ N H ___ C H = C H -(C H ;)4 - ^ | ^ C H = C H - CHO (CH2)4Br 93 and 94 204S ch em e 3.17: Preparation o f compounds 93 and 94
The cis (Z) and trans (B) isomers o f l-(6-phenylhex-5-enyl)pyrrolidine have been subm itted as the m ixtures 93 and 94 (scheme 3.17). Compound 93 corresponds to 97.8% trans (E) isom er and 2.2% cis (Z) isomer while compound 94 contains 35% trans (E) isomer and 65% cis (Z) isomer.
(C6H5)3P^(C H2)5Br, Br 203 H NaOH '(C6H5)3P^CH(CH2)4Br
t
.(CéH5)3P=CH(CH2)4BrO
' ^
O
+
(C6H5)3P=CH(CH2)4Br
, J D
O — CH " --- ^ O — CH \ ^ \ (C6H;)3P+ (CgH;)3P C H .jO
(CH2)4Br (C6H 5)3P=0 + ^ C H = C H - (CH2)4Br 2043. Synthesis and characterisation 6 8
The bromo intermediate 204 (mixture of cis and trans isomers) was prepared by Wittig reaction (scheme 3.18)239 and purified by column chromatography. In the Wittig reaction, an y lid is formed by deprotonation of an alkylphosphonium salt (such as 203) with a base. The ylid reacts with a carbonyl compound (benzaldehyde) to form an adduct that can be present as a betaine (open zwitterionic form, scheme 3.18) in equilibrium with an oxaphosphetane (cyclic neutral form). The cyclic adduct breaks down to the phosphine oxide and an alkene (204).
Because of the instability of Cû-bromoalkylphosphonium bromides under the strong base conditions (such as butyl lithium or sodium alkoxide) often used in the Wittig reaction, a m ilder method using powdered sodium hydroxide was used^^o. Dichloromethane was preferred to tetrahydrofuran as solvent because it does not favour the cis (Z) or trans (E) isomer of the product 204.
After reaction of 204 with pyrrolidine, the cis and trans isomers o f l-(6-phenylhex-5- enyl)pyrrolidine were partially separated by preparative HPLC (yield 20%).
4- AlCb 4-
c
O
LiAlH4
O
Schem e 3.19: Preparation o f compounds 95 and 96
Com pounds 95 and 96 were obtained from the bromo intermediate 2052-^' prepared through the Friedel-Crafts acylation of benzene^^^ (scheme 3.19). Benzene was acylated with 6-bromohexanoyl chloride in the presence of aluminium chloride (scheme 3.2 0). The reaction conditions have to be carefully set to avoid the risk of alkylation leading to unw anted side-products. The reactive species is a complex formed between the acid
3. Synthesis and characterisation 69 chloride and aluminium chloride. The complex can be present in different forms (figure 3.1) depending on the reactants and the reaction conditions-^-. The product 205 was obtained in 40% yield. Alkylation of pyrrolidine gave the ketone 95 in 53% yield. Reduction of 95 with lithium aluminium hydride in diethyl ether afforded the alcohol 96 (mixture of R and S isomers) in 44% yield after purification by preparative HPLC.
complex O.AICI
AlCl
AlCl AlCl
Figure 3.1: The acylating acid chloride-aluminium chloride complex
R Cl + II + AICI3
o
-HCl R 0 :A1C13 H .O AlCl: R + 3A1(0H)3 + 3 HClSchem e 3.20: Friedel-Crafts acylation
Compound 97 was prepared in 3 steps from 3-phenoxyphenylacetic acid (scheme 3.21). The acid was first converted quantitatively to the acid chloride 206^^^ then reaction with pyrrolidine gave the amide 207 (99% yield) and the amide was finally reduced to the amine 97 with lithium aluminium hydride in diethyl ether (63% yield).
3. Synthesis and characterisation 70
c
O
L1AIH4Schem e 3.21: Preparation of compound 97
All the compounds in the fourth series (98 to 113, table 2.9) were prepared from the common bromo intermediate 160. Most of the secondary amines used were commercially available. The cis and trans 3,5-dim ethylpiperidine adducts 105 and 106 were synthesised as a mixture and then separated by column chromatography on silica gel. The major product is the cis dimethyl compound 105 because the commercial stai ting material is probably derived from the hydrogenation of 3,5-dimethylpyridine (3,5-lutidine).
An attempt at reducing pyrrole with zinc dust and hydrochloric acid-^^ to prepare 3- pyrroline (dihydropyrrole) as starting material for the synthesis of com pound 1 1 0 gave a mixture of the desired pyrroline (8 8%) and fully reduced pyrrolidine (1 2%) in low yield (17%), and thus compound 110 was prepared from commercially available 3-pyrroline.
CH Br Na OH N - S ' CH --- NH CH3CH2COOH HBr 208 209
3. Synthesis and characterisation 11 Isoindoline 209 (for the preparation of derivative 112) was synthesised from ortho-
xylylene dibromide and pam -toluene sulfonamide in 12% yield (scheme 3.22)-"^^. The amine was alkylated with intermediate 160 in boiling ethanol under nitrogen for 7 hours and the product was purified by column chromatography. The final product 112 was obtained in 64% yield.
Com pound 114 was prepared in 53% yield by reacting 3-methyl piperidine with 1- bromo-5-(4-nitrophenoxy)pentane 168.
Compounds 115 to 125 (table 2.10) were prepared via the M itsunobu reaction, using commercially available 3-hydroxypropyldiethylamine as a starting material and either diisopropylazodicarboxylate or diethylazodicarboxylate (for com pound 123) as a coupling reagent. Products 115 to 120 and 123 to 125 were thus obtained in a convenient one-step reaction. Their isolation was facilitated by the basic character of the product: a slight excess o f the aromatic alcohol was used to ensure that all the hydroxypropyldiethylamine would react. At the end o f the reaction, after concentration of