Author Topic: Benzofuran, indan and tetralin analogues of MDA. -Nemesis  (Read 1528 times)

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Benzofuran, indan and tetralin analogues of MDA. -Nemesis
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Author  Topic:   Benzofuran, indan and tetralin analogues of MDA. 
Nemesis
Member   posted 11-11-1999 01:18 AM          
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TITLE: Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogues of 3,4-(methylenedioxy)amphetamine.
AUTHORS: Monte AP; Marona-Lewicka D; Cozzi NV; Nichols DE
AUTHOR AFFILIATION: Department of Medicinal Chemistry, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
SOURCE: J Med Chem 1993 Nov 12;36(23):3700-6
CITATION IDS: PMID: 8246240 UI: 94066120
ABSTRACT: Benzofuran, indan and tetrahydronaphthalene analogs of 3,4- (methylenedioxy)amphetamine (MDA) were prepared in order to examine the role of the dioxole ring oxygen atoms of MDA in interacting with the serotonin and catecholamine uptake carriers. The series of compounds was evaluated for discriminative stimulus effects in rats trained to discriminate saline from the training drugs (S)-(+)-MBDB (1c), MMAI (3), and (S)-(+)-amphetamine and for the ability to inhibit the uptake of [3H]serotonin, [3H]dopamine, and [3H]norepinephrine into crude synaptosome preparations. Behaviorally, the benzofuran and indan analogs 4-6 produced similar discriminative cues, whereas the tetralin derivative 7 did not fully substitute for the training drugs. The results in the in vitro pharmacology studies indicate that selectivity for 5-HT versus catecholamine uptake carriers may be modulated by the position and orientation of ring oxygen atoms. However, the nonoxygenated isostere 6 possessed high potency at all uptake sites examined. Enlargement of the saturated ring by one methylene unit to give the tetralin derivative resulted in a large (3-4-fold) reduction in activity at catecholamine sites.
MAIN MESH HEADINGS: Benzofurans/*chemical synthesis
Indenes/*chemical synthesis
3,4-Methylenedioxyamphetamine/*analogs & derivatives
ADDITIONAL MESH HEADINGS: Animal
Benzofurans/pharmacology
Brain/drug effects
Brain/metabolism
Discrimination Learning/drug effects
Dopamine/metabolism
Indenes/pharmacology
Male
Molecular Structure
Norepinephrine/metabolism
Rats
Rats, Sprague-Dawley
Serotonin/metabolism
Structure-Activity Relationship
Support, U.S. Gov't, P.H.S.
Synaptosomes/drug effects
Synaptosomes/metabolism
Tetrahydronaphthalenes/chemical synthesis
Tetrahydronaphthalenes/pharmacology
PUBLICATION TYPES: JOURNAL ARTICLE
CAS REGISTRY NUMBERS: 0 (Benzofurans)
0 (Indenes)
0 (Tetrahydronaphthalenes)
152623-93-3 (6-(2-aminopropyl)-2,3-dihydrobenzofuran)
152624-02-7 (5-(2-aminopropyl)-2,3-dihydro-1H-indene)
152624-03-8 (5-(aminopropyl)-2,3-dihydrobenzofuran)
4764-17-4 (3,4-Methylenedioxyamphetamine)
50-67-9 (Serotonin)
51-41-2 (Norepinephrine)
51-61-6 (Dopamine)
LANGUAGES: Eng
GRANT/CONTRACT ID: DA04758/DA/NIDA

Based on the info provided above, what would be the most potent analogue?


Nemesis
Member   posted 11-11-1999 01:35 AM          
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More Info:
TITLE: Nonneurotoxic tetralin and indan analogues of 3,4- (methylenedioxy)amphetamine (MDA).
AUTHORS: Nichols DE; Brewster WK; Johnson MP; Oberlender R; Riggs RM
AUTHOR AFFILIATION: Department of Medicinal Chemistry, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
SOURCE: J Med Chem 1990 Feb;33(2):703-10
CITATION IDS: PMID: 1967651 UI: 90133772
ABSTRACT: Four cyclic analogues of the psychoactive phenethylamine derivative 3,4- (methylenedioxy)amphetamine were studied. These congeners, 5,6- and 4,5- (methylenedioxy)-2-aminoindan (3a and 4a, respectively), and 6,7- and 5,6-(methylenedioxy)-2-aminotetralin (3b and 4b, respectively) were tested for stimulus generalization in the two-lever drug-discrimination paradigm. Two groups of rats were trained to discriminate either LSD tartrate (0.08 mg/kg) from saline, or (+/-)-MDMA.HCl (1.75 mg/kg) from saline. In addition, a 2-aminoindan (5a) and 2-aminotetralin (5b) congener of the hallucinogenic amphetamine 1-(2,5-dimethoxy-4- methylphenyl)-2-aminopropane (DOM) were also evaluated. None of the methylenedioxy compounds substituted in LSD-trained rats, while both 3a and 3b fully substituted in MDMA-trained rats. Compounds 4a and 4b did not substitute in MDMA-trained rats. Compounds 5a and 5b did not substitute in MDMA-trained rats, although 5a substituted in LSD-trained rats, but with relatively low potency compared to its open-chain counterpart. In view of the now well-established serotonin neurotoxicity of 3,4-(methylenedioxy)amphetamine and its N-methyl homologue 1, 3a and 3b were evaluated and compared to 1 for similar toxic effects following a single acute dose of 40 mg/kg sc. Sacrifice at 1 week showed that neither 3a nor 3b depressed rat cortical or hippocampal 5-HT or 5-HIAA levels nor were the number of binding sites (Bmax) depressed for [3H]paroxetine. By contrast, and in agreement with other reports, 1 significantly depressed all three indices of neurotoxicity. These results indicate that 3a and 3b have acute behavioral pharmacology similar to 1 but that they lack similar serotonin neurotoxicity.
MAIN MESH HEADINGS: *Amphetamines
Psychotropic Drugs/*chemical synthesis
*3,4-Methylenedioxyamphetamine
ADDITIONAL MESH HEADINGS: Amphetamines/chemical synthesis
Animal
Behavior, Animal/drug effects
Catecholamines/metabolism
Cerebral Cortex/metabolism
Hippocampus/metabolism
Indans
Lysergic Acid Diethylamide
Piperidines/metabolism
Psychotropic Drugs/pharmacology
Rats
Serotonin/metabolism
Structure-Activity Relationship
Support, U.S. Gov't, P.H.S.
Tetrahydronaphthalenes
3,4-Methylenedioxyamphetamine/analogs & derivatives
3,4-Methylenedioxyamphetamine/chemical synthesis
PUBLICATION TYPES: JOURNAL ARTICLE
CAS REGISTRY NUMBERS: 0 (Amphetamines)
0 (Catecholamines)
0 (Indans)
0 (Piperidines)
0 (Tetrahydronaphthalenes)
42542-10-9 (N-Methyl-3,4-methylenedioxyamphetamine)
4764-17-4 (3,4-Methylenedioxyamphetamine)
50-37-3 (Lysergic Acid Diethylamide)
50-67-9 (Serotonin)
61869-08-7 (Paroxetine)
LANGUAGES: Eng
GRANT/CONTRACT ID: DA-04758/DA/NIDA

Also interesting:

TITLE: Mescaline-like activity of 2-amino-7-hydroxytetralin.
AUTHORS: Green JP; Dressler KP; Khazan N
SOURCE: Life Sci 1973 May 15;12(10):475-9
CITATION IDS: PMID: 4696608 UI: 73154285
MAIN MESH HEADINGS: Naphthols/*pharmacology
Sleep/*drug effects
ADDITIONAL MESH HEADINGS: Animal
Drug Tolerance
Electroencephalography
Female
Lysergic Acid Diethylamide/pharmacology
Mescaline/pharmacology
Rats
Structure-Activity Relationship
Time Factors
PUBLICATION TYPES: JOURNAL ARTICLE
LANGUAGES: Eng

-Nemesis


Nemesis
Member   posted 11-24-1999 12:31 AM          
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I later found this for MDMA:
TITLE: Synthesis and pharmacological examination of 1-(3-methoxy-4- methylphenyl)-2-aminopropane and 5-methoxy-6-methyl-2-aminoindan: similarities to 3,4-(methylenedioxy)methamphetamine (MDMA).
AUTHORS: Johnson MP; Frescas SP; Oberlender R; Nichols DE
AUTHOR AFFILIATION: Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
SOURCE: J Med Chem 1991 May;34(5):1662-8
CITATION IDS: PMID: 1674539 UI: 91237660
ABSTRACT: The racemate and the enantiomers of 1-(3-methoxy-4-methyphenyl)-2- aminopropane (6) and racemic 5-methoxy-6-methyl-2-aminoindan (11) were tested for stimulus generalization in the two-lever drug-discrimination paradigm. Both 6 and 11 were found to substitute with high potency in 3,4-(methylenedioxy)methamphetamine (1) and (S)-1-(1,3-benzodioxol-5- yl)-2-(methylamino)butane (2) trained rats. In the latter assay, both enantiomers of 6 had identical potencies, but their dose-response curves were not parallel. Racemic 6, but not 11, partially substituted for LSD. Racemic 6 and 11 did not substitute in (S)-amphetamine-trained rats. All of the test compounds were potent inhibitors of [3H]-5-HT uptake into synaptosomes in vitro, with the S enantiomer of 6 being most active. Rat brain monoamine levels were unaltered 1 week following a single high dose (10 or 20 mg/kg, sc) of 6 or 11, or two weeks following a subacute dosing regimen (20 mg/kg, sc, twice a day for 4 days). In addition, radioligand-binding parameters in rat brain homogenate with the 5-HT uptake inhibitor [3H]paroxetine were unchanged after subacute dosing with either racemic 6 or 11. The results indicate that compounds 6 and 11 have animal behavioral pharmacology similar to the methylenedioxy compounds 1 and 2, but that they do not induce the serotonin neurotoxicity that has been observed for the latter two drugs.


Well here's the synthesis for the compounds in this article:

1-(3-Methoxy-4-methylphenyl)-2-nitropropene (13). Nitroethane (300 mL), 7.7 g (100 mmol) of ammonium acetate, and 15.0 g (100 mmol) of 3-methoxy-4-methylbenzaldehyde (12) were combined and heated at reflux in an oil bath for 2.5 h. The excess nitroethane was removed by rotary evaporation and the residue was partioned between CH2Cl2 (2 x 75 mL) and H2O. The organic extracts were combined and dried (Na2SO4), and the CH2Cl2 was evaporated. Crystallization was induced by dilution of the residual oil in MeOH. The product was recrystallized from MeOH-H2O to yield 17.3 g (83.5%) of a yellow solid; mp 51 degrees C (lit.1 mp 52 degrees C).

1-(3-Methoxy-4-methylphenyl)-2-propanone (14). W-2 Raney Ni (8.0 g), as a slurry in EtOH, was added to a mechanically stirred solution of 12.0 g (58 mmol) of nitroolefin (13) in 300 mL of 95% EtOH and 150 mL of 0.2 M aqueous acetate buffer (pH 5) contained in a 1-L round-bottom flask. The flask was suspended in a Branson B-220H ultrasonic bath maintained at 40 degrees C. While sonication was maintained, 54.0 g (0.61 mol) of NaH2PO4 in 120 mL of H2O was added at a rate sufficient to maintain moderate H2 evolution. The reaction was stirred with sonication at 40 degrees C for 1.5 h. The initial mixture had a green tint, which disappeared on completion of the reaction. The catalyst was removed by vacuum filtration through Celite, brine (200 mL) was added to the filtrate, and the solution was extracted with Et2O (3 x 200 mL). The organic layer was washed with 5% NaHCO3 and brine and was concentrated under vacuum. The residue was taken up into Et2O, dried (MgSO4), and filtered and the Et2O removed under vacuum. The crude ketone was distilled under vacuum to yield 5.5 g (53.4%) of (14) as a colorless oil; bp 90 degrees C (0.4 mmHg) [lit.18 bp 101 degrees C (1 mmHg)].

(R,S)-1-(3-Methoxy-4-methylphenyl)-2-aminopropane Hydrochloride (R/S-6*HCl). A solution of 7.0 g (33.8 mmol) of nitroolefin (13) in 20 mL of Et2O was added dropwise to a stirring suspension of 3.6 g (94.9 mmol) of LiAlH4 in 150 mL of dry Et2O. After the addition, the mixture was heated at reflux on a steam bath for 2.5 h. The excess LiAlH4 was decomposed by slow addition of 10 mL of H2O and the mixture was filtered through Celite. The ethereal filtrate was extracted with 2 N HCl (3 x 75 mL), and the combined aqueous extracts were basified with excess NaOH. The free base was extracted with CH2Cl2 (3 x 75 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation. The residual oil was dissolved in absolute ethanol, acidified with concentrated HCl, diluted with Et2O, and cooled to yield 4.9 (88.1%) of white crystalline R/S-6*HCl: mp 181 degrees C (lit.18 mp 181.5-183.5 degrees C); 1H NMR (CDCl3) 8.41 (s, 3, NH3+), 7.06 (d, 1, ArH, J = 7.5 Hz), 6.67 (d, 1, ArH, J = 7.5 Hz), 6.71 (s, 1, ArH), 3.82 (s, 3, OCH3), 3.57 (m, 1, CHN), 3.20 (dd, 1, ArCH2, J = 5.3, 13.4 Hz), 2.81 (dd, 1, ArCH2, J = 9.3, 13.4 Hz), 2.17 (s, 3, ArCH3), 1.39 (d, 3, CH3, J = 6.5 Hz).

(R,R)-(+)-N-(1-Phenethyl)-1-(3-methoxy-4-methylphenyl)-2-aminopropane Hydrochloride (R,R-15a*HCl). A solution of 9 g (50 mmol) of ketone (14) and 6.06 g (15 mmol) of (R)-(+)-alpha-phenethylamine (Aldrich, Milwaukee, WI) in 50 mL of benzene was heated at reflux under N2 for 2 h with continuous H2O removal with a Dean-Stark trap. The benzene was removed under vacuum, and the residual oil was taken up into 30 mL of absolute ethanol and shaken for 24 h with W-2 Raney Ni (2.5 g as a slurry in EtOH) at 50 psig of H2. The catalyst was removed by filtration through Celite and the filtrate was acidified with concentrated HCl. The solvents were removed under vacuum, and the crude salt was recrystallized from acetone to yield 10.23 g (64.6%) of white crystalline R,R-15a*HCl: mp 216-217 degrees C; [alpha]D + 17.23 degrees (c = 2, EtOH); 1H NMR (CDCl3) 7.67 (d, 2, ArH, J = 7.6 Hz), 7.47 (t, 2, ArH, J = 7.5 Hz), 7.41 (t, 1, ArH, J = 7.4 Hz), 6.99 (d, 1, ArH, J = 7.5 Hz), 6.51 (d, 1, ArH, J = 7.5 Hz), 6.42 (s, 1, ArH), 4.37 (m, 1, ArCHN), 3.72 (s, 3, OCH3), 3.37 (dd, 1, ArCH2, J = 9.9, 13.1 Hz), 2.15 (s, 3, ArCH3), 1.93 (d, 3, CH3, J = 6.8 Hz), 1.42 (d, 3, CCH3, J = 6.6 Hz). Anal. (C19H23ClNO) C, H, N.

(S,S)-(-)-N-(1-Phenethyl)-1-(3-methoxy-4-methylphenyl)-2-aminopropane Hydrochloride (S,S-15a*HCl). Following the above procedure but using 15.1 g (84.7 mmol) of ketone (14) and 10.17 g (84.7 mmol) of S-(-)-alpha-phenethylamine yielded 15.01 g (55.9%) of white crystalline S,S-15a*HCl; mp 215-216 degrees C; [alpha]D -17.04 degrees (c = 2, EtOH). Anal. (C19H23ClNO) C, H, N.

(R)-(-)-1-(3-Methoxy-4-methylphenyl)-2-aminopropane Hydrochloride (R-6*HCl). A solution of 9.60 g (30.3 mmol) of R,R-15a*HCl dissolved in 100 mL of MeOH was added to 0.9 g of 10% Pd-C (as a slurry in 10 mL of H2O) contained in a 500-mL Parr pressure bottle. The mixture was shaken at 50 psig of H2 for 48 h. The catalyst was removed by filtration through Celite, the solvent was removed by rotary evaporation, and the crude salt was recrystallized from EtOH-Et2O to yield 5.97 g (91.3%) of white crystalline R-6*HCl; mp 163 degrees C; [alpha]D -23.42 degrees (c = 2, H2O). Anal. (C11H18ClNO) C, H, N.

(S)-(+)-1-(3-Methoxy-4-methylphenyl)-2-aminopropane Hydrochloride (S-6*HCl). An exact replication of the above procedure using 15.01 (47.4 mmol) of S,S-15b*HCl yielded 6.73 g (65.4%) of white crystalline S-6*HCl; mp 163 degrees C; [alpha]D +23.30 degrees (c = 2, H2O). Anal. (C11H18ClNO) C, H, N.

3-Methoxy-4-methylcinnamic Acid (16). A mixture of 25 g (167 mmol) of (12), malonic acid (31.7 g, 310 mmol), and 1.3 mL of piperidine in 70 mL of pyridine was stirred on a steam bath for 5 h. The mixture was poured into 400 mL of ice water containing 100 mL of concentrated HCl. The resulting precipitate was collected by filtration and washed by resuspension in 300 mL of water. The precipitate was then collected, dried, and recrystallized from MeOH-H2O to yield 32.0 g (99.7%) of a white crystalline product; mp 181-182 degrees C; 1H NMR (DMSO4-d6) 7.57 (d, 1, ==CH, J = 16.0 Hz), 7.25 (s, 1, ArH), 7.15 (m, 2, arH), 6.52 (d, 1, ==CH, J = 16.0 Hz), 3.82 (s, 3, CH3O), 3.34 (s, 1, OH), 2.15 (s, 3, ArCH3). Anal. (C11H12O3) C, H.

3-(3-Methoxy-4-methylphenyl)-propanoic Acid (17). Cinnamic acid (16) (29 g, 151 mmol) was dissolved in 500 mL of 95% ethanol and shaken for 6 h in a Parr apparatus at 60 psig of H2 over 3.0 g of 10% Pd-C. The mixture was then filtered through a Celite pad and concentrated under vacuum. The resulting solid material was recrystallized from MeOH-H2O to give 29.2 g (99.7%) of a white crystalline solid: mp 73-74 degrees C; 1H NMR (CDCl3) 7.05 (d, 1, ArH, J = 7.4 Hz), 6.71 (d, 1, ArH, J = 7.5 Hz), 6.69 (s, 1, ArH), 3.82 (s, 3, CH3O), 2.94 (t, 2, CH2, J = 7.8 Hz), 2.69 (t, 2, CH2, J = 7.8 Hz), 2.18 (s, 3, ArCH3). Anal. (C11H14O3) C, H.

5-Methoxy-6-methyl-1-indanone (18). Propanoic acid (17) (20 g, 103 mmol) was dissolved in 30 mL of dry benzene containing a few drops of N,N-dimethylformamide, and 27 mL (209 mmol) of oxalyl chloride was added dropwise. The mixture was stirred for 4 h at room temperature and the benzene was removed by rotary evaporation. The crude acid chloride was redissolved in 400 mL of dry dichloromethane and placed in an ice bath. A solution of SnCl4 (14.8 mL, 129 mmol) in 50 mL of CH2Cl2 was added dropwise over 10 min. Stirring was continued for 10 min, the ice bath was removed, and the reaction was allowed to stir for 1 h. The reaction mixture was then poured over 50 g of crushed ice and the organic layer was washed with 3 N HCl (2 x 100 mL) and water (200 mL). The solution was dried with MgSO4, filtered, and passed through a short silica gel pad. After solvent removal the residue was recrystallized from benzene-hexanes to yield 13.2 g (72.5%): mp 114-115 degrees C; 1H NMR (CDCl3) 7.53 (s, 1, ArH), 6.84 (s, 1, ArH), 3.92 (s, 3, CH3O), 3.07 (t, 2, CH2, J = 5.7 Hz), 2.66 (t, 2, CH2, J = 5.7 Hz), 2.23 (s, 3, ArCH3). Anal. (C11H12O2) C, H.

2-(Hydroxyimino)-5-methoxy-6-methyl-1-indanone (19). Indanone (18) (12 g, 68 mmol) was dissolved in 375 mL of MeOH and heated to 45 degrees C. Isoamyl nitrite (10 mL, 75 mmol) was added, and then 7 mL of concentrated HCl was added dropwise over 5 min. After 20 min of stirring an off-white precipitate began to form. Excess isoamyl nitrite and HCl (1 mL of each) were added after 45 min of stirring. The precipitated product was collected by filtration and washed with cold methanol and then ether (100 mL). The filtrate was concentrated by rotary evaporation and the residue was recrystallized from MeOH. The two crops were combined to give 13.6 g (96.9%): mp 212-213 degrees C; 1H NMR (DMSO4-d6) 7.53 (s, 1, ArH), 7.13 (s, 1, ArH), 3.91 (s, 3, CH3O), 3.68 (s, 2, CH2), 2.18 (s, 3, ArCH3). Anal. (C11H11NO3) C, H, N.

5-Methoxy-6-methyl-2-aminoindan Hydrochloride (11). Hydroxyimino ketone (19) (10 g, 49 mmol) was dissolved by warming in 1 L of acetic acid. Concentrated H2SO4 (6 mL, 98 mmol) and 2.5 g of 10% Pd-C were added to this solution. The mixture was shaken at 60 psig of H2 for 18 h. The catalyst was then removed by filtration and the mixture was concentrated by rotary evaporation. The residue was dissolved in 400 mL of water and the acidic solution was washed with 3 x 200 mL of ethyl acetate and 200 mL of ether. The aqueous layer was basified with NaOH and the amine was extracted into 3 x 200 mL of dichloromethane. The organic layer was dried (MgSO4) and filtered, and the solvent was removed by rotary evaporation. The resulting oil was dissolved in EtOH and acidified with concentrated HCl. The resulting HCl salt was crystallized from EtOH-ether to yield 8.0 g (77.0%): mp 316-317 degrees C; 1H NMR (DMSO4-d6) 8.27 (s, 3, NH3+), 7.01 (s 1, ArH), 6.85 (s, 1, ArH), 3.93 (m, 1, CH), 3.73 (s, 3, CH3O), 3.19 (dd, 1, CH, J = 5.3, 16.0 Hz), 3.13 (dd, 1, CH, J = 5.3, 16.4 Hz), 2.92 (dd, 1, CH, J = 7.6, 16.0 Hz), 2.82 (dd, 1, CH, J = 7.6, 16.4 Hz), 2.09 (s, 3, ArCH3). Anal. (C11H16ClNO) C, H, N.


Well, that's all folks! Compound #6 looks to be the most promising. Let me know if anyone ever tries these or something like these.

-Nemesis


Nemesis
Member   posted 12-12-1999 06:52 PM          
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Well I've finally got around to it and typed up all the synthesis procedures for the first abstract above.
The ref is J Med Chem 1993 Nov 12;36(23):3700-6.

Here are the synthesis procedures:

N-(Trifluoroacetyl)-1-(3-methoxyphenyl)-2-aminopropane (9). To an ice-cooled solution of 2.7 g (16 mmol) of 1-(3-methoxyphenyl)-2-aminopropane (8) dissolved in 100 mL of dry CH2Cl2 was added 2.0 g (19.7 mmol) of triethylamine. The mixture was stirred for 10 min and 9.8 g (49 mmol) of trifluoroacetic anhydride in 50 mL of CH2Cl2 was introduced dropwise to the reaction vessel over a 10-min period. The reaction was allowed to warm to room temperature. After 1.5 h the solvent was removed by rotary evaporation and the oily, yellow residue was taken up in ether. The organic phase was washed with H2O (2 x 25 mL), 2 N HCl (25 mL), and brine and then dried over MgSO4 and filtered through Celite. After complete removal of solvent in vacuo, a quantitative yield of white solid was obtained. This was recrystallized from ethyl acetate-petroleum ether to afford 3.73 g (89%) of (9) as fluffy white crystals: mp 62-63 degrees C; 1H NMR (CDCl3) 1.1 (d, 3, CH3), 2.6 (m, 2, ArCH2), 3.2 (m, 1, ArCH2CH), 3.8 (s, 3, CH3O), 6.2 (bs, 1, NH), 6.7 (m, 3, ArH), 7.3 (m, 1, ArH); MS m/z 262 (M + 1). Anal. (C12H14F3NO2) C, H, N.

N-(Trifluoroacetyl)-1-[3-methoxy-4-(chloroacetyl)phenyl]-2-aminopropane (10). A solution of 3.5 g (13.4 mmol) of (9) in 75 mL of 1,2-dichloroethane was stirred and cooled to 0 degrees C on an ice bath. Chloroacetyl chloride (2.6 mL, 33.5 mmol) was added to the mixture at once, followed by the portionwise addition of 4.5 g (33.5 mmol) of AlCl3 through a powder addition funnel. After 20 min the ice bath was removed and the flask was gently warmed to 45 degrees C on an oil bath. The dark yellow reaction mixture was quenched after 4 h by pouring into 100 mL of an ice-cold solution of 1 N HCl. The layers were separated, and the aqueous phase was extracted with 2 x 25 mL of CH2Cl2. The organic fractions were combined and washed with water (50 mL) and brine (50 mL), dried (MgSO4), and filtered through a thin pad of silica gel on Celite. The solvent was removed by rotary vacuum evaporation, and the product was dried under high yield vacuum to yield 4.09 g (90%) of a light-yellow solid. This crude product was recrystallized from ethyl acetate-hexane to give 3.5 g of white crystalline (10): mp 145-145 degrees C; 1H NMR (CDCl3) 1.35 (d, 3, CH3), 3.0 (m, 2, ArCH2), 4.0 (s, 3, CH3O), 4.4 (m, 1, ArCH2CH), 4.8 (s, 2, COCH2Cl), 6.2 (bs, 1, NH), 6.8 (m, 2, ArH), 7.85 (d, 1, ArH); MS m/z 338 (M + 1). Anal. (C14H15ClF3NO3) C, H, N.

6-[2-[N-(Trifluoroacetyl)amino]propyl]-2,3-dihydrobenzofuran-3-one (11). A solution of 5.3 g (15.7 mmol) of (10) in 350 mL of dry CH2Cl2 was cooled to -78 degrees C in a solid CO2-acetone bath. BBr3 (7 mL, 62.7 mmol) was then added slowly by syringe. The reaction was allowed to proceed for 12 h as the cooling bath cooled to -78 degrees C and quenched by the addition of 100 mL of cold water. After warming to room temperature, another 100 mL of H2O was added, and the layers were separated. The aqueous phase was extracted with 3 x 50 mL of CH2Cl2, and the organic fractions were combined and washed with 50 mL water and 50 mL brine. The solvent was removed by rotary evaporation to yield a mass of off-white solid which was unstable to air. This product was therefore immediately taken up into 600 mL of CH3-OH, 7.5 g (55 mmol) of NaOAc was added, and the mixture was heated at reflux on an oil bath for 1.5 h to effect ring closure. After cooling to 0 degrees C, the mixture was filtered through Celite and the solvent was removed by rotary evaporation. The orange residue was taken up into 200 mL of ether and washed with water (2 x 50 mL) and brine (50 mL), dried over MgSO4, and filtered through a thin pad of silica gel on Celite. After removal of the solvent in vacuo, an orange solid was obtained which was recrystallized from ethyl acetate-hexane to yield 2.56 g (57%) of (11) as dense orange crystals. An analytical sample was further purified using radial chromatography ("Cromatotron") on a silica rotor and elution with dichloromethane. This gave a light-yellow solid with a sharp melting point: mp 127 degrees C; 1H NMR (CDCl3) 1.4 (d, 3, CH3), 3.0 (m, 2, ArCH2), 4.4 (m, 1, ArCH2CH), 4.6 (s, 2, COCH2O), 6.2 (bs, 1, NH), 6.9 (m, 2, ArH), 7.55 (d, 1, ArH); MS m/z 288 (M + 1). Anal. (C13H12F3NO3) C, H, N.

6-[2-[N-(Trifluoroacetyl)amino]propyl]-2,3-dihydrobenzofuran (12). A solution of 2.9 g (10 mmol) of (11) in 300 mL of absolute ethanol was placed in a Parr hydrogenation flask with 1 g of 20% PdOH/C. The mixture was shaken under 52 psig of H2 for 12 h and then filtered through Celite. The alcohol was removed by rotary vacuum evaporation to give, quantitatively, a yellow oil which spontaneiously crystallized upon standing. Recrystallization from ethanol-hexan produced (12) as white crystals: mp 95 degrees C; 1H NMR (CDCl3) 1.2 (d, 3, CH3), 2.7 (m, 2, ArCH2CH), 3.2 (t, 2, ArCH2CH2), 4.25 (m, 1, ArCH2CH), 4.5 (t, 2, ArOCH2), 6.1 (bs, 1 NH), 6.6 (m, 2, ArH), 7.1 (d, 1, ArH); MS m/z 273 (M). Anal. (C13H14F3NO2) C, H, N.

6-(2-Aminopropyl)-2,3-dihydrobenzofuran Hydrochloride (4). A solution of 1.4 g (5.12 mmol) of (12) in 110 mL of 2-propanol was vigorously stirred while 10 mL of 2 N KOH was added, and the mixture was heated at reflux for 5 h. After cooling the solvent was removed by rotary evaporation. The residue was taken up into 150 mL of 3 N NaOh and the aqueous solution was extracted with CH2Cl2 (4 x 50 mL). The organic fractions were combined and then extracted with 4 x 50 mL of 3 N HCl. The acidic aqueous extracts were combined and then basified with 5 N NaOH to pH 11 (external damp pH paper) while cooling on an ice bath. The free amine (4) was extracted into CH2Cl2 (4 x 25 mL) and the organic phase dried (MgSO4), filtered through Celite, and concentrated on the rotary evaporator. The residual yellow oil was dissolved in 15 mL of anhydrous ether, and the hydrochloride salt was formed by the addition of 6 mL of 1.0 N HCl: mp 252-254 degrees C; 1H NMR (DMSO-d6) 1.2 (d, 3, CH3), 2.6 (dd, 1, ArCH2CH), 3.1 (dd, 1, ArCH2CH), 3.2 (t, 2, ArCH2CH2), 3.4 (m, 1, ArCH2CH), 4.55 (t, 2, ArOCH2), 6.75 (d, 2, ArH), 7.2 (d, 2, ArH), 8.2 (bs, 3, NH3+); MS m/z 178 (M + 1). Anal. (C11H18ClNO) C, H, N.

5-Formyl-2,3-dihydrobenzofuran (14a). Dihydrobenzofuran (13a) (3.0 g, 25 mmol) was dissolved in 50 mL of CH2Cl2 and cooled to 0 degrees C on an ice bath. With vigorous stirring, 9.76 g (44 mmol) of SnCl4 was added all at once via syringe, followed by the dropwise introduction of 2.87 g (25 mmol) of dichloromethyl methyl ether over a 10-min period. After 20 min the ice bath was removed, and the dark mixture was quenched by the addition of 50 mL of ice-water. The aqueous layer was discarded, and the organic phase was washed with water (3 x 25 mL), 3 N HCl (3 x 25 mL), and brine (2 x 25 mL). The purple organic solution was treated with activated carbon and filtered through a thin pad of silica gel on Celite. After removal of the solvent under vacuum, 3.34 g (90%) of (14a) was obtained as a yellow oil which was sufficiently pure to carry on the next step. A portion of the aldehyde was purified for analysis by conversion to its bisulfite addition product, followed by decomposition in saturated K2CO3 solution and extraction into dichloromethane: 1H NMR (CDCl3) 3.25 (t, 2, ArCH2), 4.6 (t, 2, ArOCH2), 6.9 (d, 1, ArH), 7.7 (m, 2, ArH), 9.8 (s, 1, ArCHO); MS m/z 149 (M + 1), 297 (2M + 1); IR 1686 cm-1.

5-[1-(2-Nitrophenyl)]-2,3-dihydrobenzofuran (15a). To a solution of 3.3 g (22.3 mmol) of (14a) in 10 mL of nitroethane was added 0.92 g (12 mmol) of ammonium acetate. The mixture was heated with stirring to 110 degrees C on an oil bath for 3.5 h. The volatiles were then removed by rotary evaporation. The crude product was triturated in 10 mL of cold CH3OH, collected by suction filtration, and recrystallized from methanol to yield 3.06 g (67%) of (15a) as a fluffy yellow crystalline solid: mp 89-90 degrees C; 1H NMR (CDCl3) 2.51 (s, 3, CH3), 3.3 (t, 2, ArCH2), 4.7 (t, 2, ArOCH2), 6.85 (d, 1, ArH), 7.35 (m, 2, ArH), 8.1 (s, 1, ArCH==C); MS m/z 206 (M + 1). Anal. (C11H11NO3) C, H, N.

5-(2-Aminopropyl)-2,3-dihydrobenzofuran Hydrochloride (5). A solution of 2.3 g (11.5 mmol) of (15a) was dissolved in 75 mL of dry THF and added dropwise to a stirring suspension of 1.2 g (29 mmol) of LiAlH4 in 400 mL of dry THF. After complete addition, the mixture was heated at reflux for 5 h on an oil bath. The mixture was then cooled on an ice bath, and the excess LiAlH4 was decomposed by the careful addition of 10 mL of H2O. The mixture was filtered through Celite, the filter cake was rinsed well with ether, and the solvent was removed by rotary vacuum evaporation. The oily residue was taken up into 100 mL of ether and the product was extracted with 5 x 50 mL of 3 N HCl. The aqueous extracts were combined and rendered strongly basic with the addition of 5 N NaOH, and the free base was extracted into dichloromethane (4 x 50 mL). The combined organic extract was dried (MgSO4), filtered through Celite, and concentrated by rotary evaporation. The residual oil was dissolved in 20 mL of anhydrous ether and the hydrochloride salt was formed by the addition of 5 mL of 1.0 N HCl in anhydrous ethanol. After removal of the volatiles in vacuo, the resulting white solid was recrystallized from ethanol to yield 1.44 g (58%) of (5)*HCl as shimmering white crystals: mp 231-232 degrees C; 1H-NMR (DMSO-d6) 1.2 (d, 3, CH3), 2.6 (dd, 1, ArCH2CH), 3.06 (dd, 1, ArCH2CH), 3.3 (t, 2, ArCH2CH2), 3.4 (m, 1, ArCHNH), 4.52 (t, 2, ArOCH2), 6.75 (d, 1, ArH), 6.95 (d, 1, ArH), 7.1 (s, 1, ArH), 8.1 (bs, 2, NH3+); MS m/z 178 (M + 1). Anal. (C11H16ClNO) C, H, N.

2,3-Dihydro-1H-indene-5-carboxyaldehyde (14b). As in the procedure above for (14a), 10 g (84.6 mmol) of indan (13b) was treated with 15 mL (127 mmol) of SnCl4 and 9.72 g (84.6 mmol) of dichloromethyl methyl ether in 100 mL of CH2Cl2 for 30 min to give, after workup, 12.2 g (98%) of (14b) as a yellow oil which was purified via its bisulfite adduct: 1H NMR (CDCl3) 2.18 (p, 2, ArCH2CH2), 3.0 (m, 4, ArCH2), 7.38 (d, 1, ArH), 7.65 (dd, 1, ArH), 7.7 (d, 1, ArH), 9.95 (s, 1, ArCHO); MS m/z 147 (M + 1), 293 (2 M + 1); IR 1691 cm-1.

5-[1-(2-Nitropropenyl)]-2,3-dihydro-1H-indene (15b). As in the procedure for (15a), 4.0 g (15.9 mmol) of (14b) was heated at reflux with 30 mL of nitroethane and 1.22 g (15.9 mmol) of ammonium acetate for 4 h to yield 2.43 g (76%) of (15b) as a yellow oil which could be crystallized with difficulty from methanol after radial chromatography (CH2Cl2 as eluant): mp 33-34 degrees C; 1H NMR (CDCl3) 2.15 (p 2, ArCH2CH2), 2.45 (s, 3, CH3), 2.98 (t, 4, ArCH2), 7.22 (d, 1, ArH), 7.32 (d, 2, ArH), 8.16 (s, 1, ArCH==C); MS m/z 204 (M + 1). Anal. (C12H13NO2) C, H, N.

5-(2-Aminopropyl)-2,3-dihydro-1H-indene Hydrochloride (6). In a method similar to that for the formation of (5), 2.9 g (14.3 mmol) of (15b) in 100 mL of dry THF was added dropwise to a stirred suspension of 1.5 g (35.6 mmol) of LiAlH4 in 150 mL of THF and the reaction was stirred for 5 h at room temperature. After the usual workup, (6) was precipitated as its hydrochloride salt and recrystallized to give 2.18 g (72%) of the product as shimmering, white flakes: mp 218-219 degrees C; 1H NMR (CDCl3) 1.39 (d, 3, CH3), 2.05 (p, 2, ArCH2CH2), 2.8 (dd, 1, ArCH2CH), 2.85 (t, 4, ArCH2CH2), 3.21 (dd, 1, ArCH2CH), 3.57 (m, 1, ArCH2CH), 6.98 (d, 1, ArH), 7.1 (s, 1, ArH), 7.17 (d, 1, ArH), 8.42 (bs, 3, NH3+); MS m/z 176 (M + 1), 351 (2 M + 1). Anal. (C12H18ClN) C, H, N.

5,6,7,8-Tetrahydronaphthaline-2-carboxaldehyde (14c). As described above for compound (14a), 10.0 g (75.6 mmol) of 1,2,3,4-tetrahydronaphthalene (13c) was treated with 13.3 mL (113 mmol) of SnCl4 and 8.7 g (75.6 mmol) of dichloromethyl methyl ether in 90 mL of CHCl3 for 1 h. Workup afforded 12 g (98%) of (14c) as a yellow oil. The aldehyde was purified and could be stored as its bisulfite adduct: 1H NMR (CDCl3) 1.8 (m, 4, ArCH2CH2, 2.82 (m, 4, ArCH2), 7.2 (d, 1, ArH), 7.3 (dd, 1, ArH), 7.6 (d, 1, ArH), 9.92 (s, 1, ArCHO); MS m/z 161 (M + 1), 321 (2 M + 1); IR 1696 cm-1.

2-[1-(2-Nitropropenyl)]-5,6,7,8-tetrahydronaphthalene (15c). Using the method for (15a), but with 1.1 g (6.92 mmol) of (14c), 15 mL of nitroethane, and 0.54 g (6.92 mmol) of ammonium acetate and heating at reflux for 3 h, gave, after workup, 1.33 g (88%) of a crude yellow solid. One crop of (15c) as yellow crystals was obtained by recrystallization from methonal, and the remaining crude product was purified by radial chromatography (CH2Cl2 as eluant): mp 46-47 degrees C; 1H NMR (CDCl3) 1.82 (m, 4, ArCH2CH2), 2.45 (s, 3, CH3), 2.8 (m, 4, ArCH2), 7.1-7.2 (m, 3, ArH), 8.05 (s, 1, ArCH==C); MS m/z 218 (M + 1). Anal. (C13H15NO2) C, H, N.

2-(2-Aminopropyl)-5,6,7,8-tetrahydronaphthalene Hydrochloride (7). As in the method described for (5), 3.0 g (13.8 mmol) of (15c) in 50 mL of dry THF was added to a stirred suspension of 1.7 g (41.4 mmol) of LiAlH4 in 250 mL of THF and heated at reflux for 4 h. Workup afforded 2.04 g (65%) of (7)*HCl as shimmering white crystals: mp 216 degrees C; 1H NMR (CDCl3) 1.38 (d, 3, CH3), 1.78 (m, 4, ArCH2CH2), 2.7 (m, 4, ArCH2CH2), 2.8 (dd, 1, ArCH2CH), 3.2 (dd, 1, ArCH2CH), 3.53 (m, 1, ArCH2CH), 6.9 (d, 2, ArH), 7.0 (d, 1, ArH), 8.42 (br, 3, NH3+); MS m/z 190 (M + 1). Anal. (C13H20ClN) C, H, N.


-Nemesis