Synthesis of 4,6-difluoro-5-hydroxy-(α-methyl)tryptamine and 4,6-difluoro-5-hydroxy-(β-methyl)tryptamine as potential selective monoamine oxidase B inhibitors

Article abstract of DOI:10.1016/S0022-1139(98)00248-6

Condensation of 4-nitro-1-pentanal and 4-nitropentanal 3-methylbutanal with 3,5-difluoro-4-methoxyphenylhydrazine afforded 4,6-difluoro-5-methoxy-3-(2′-nitro)propylindole 4a and 4,6-difluoro-5-methoxy-3-(1′-methyl-2′-nitro)ethylindole 4b, respectively, in one step. Reduction of the nitro group with lithium aluminum hydride followed by removal of the methyl ether with boron tribromide produced the title compounds. They were inactive as MAO B inhibitors.

Full text of DOI:10.1016/S0022-1139(98)00248-6

Journal of Fluorine Chemistry 92 (1998) 41±44
Synthesis of 4,6-di¯uoro-5-hydroxy-(a-methyl)tryptamine and
4,6-di¯uoro-5-hydroxy-(b-methyl)tryptamine as potential
selective monoamine oxidase B inhibitors
Hauh-Jyun Candy Chen1, Terrence Applewhite, B. Jayachandran, Kenneth L. Kirk*
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, MD 20892, USA
Received 22 April 1998; accepted 2 July 1998
Abstract
Condensation of 4-nitro-1-pentanal and 4-nitropentanal 3-methylbutanal with 3,5-di¯uoro-4-methoxyphenylhydrazine afforded 4,6-
di¯uoro-5-methoxy-3-(20-nitro)propylindole 4a and 4,6-di¯uoro-5-methoxy-3-(10-methyl-20-nitro)ethylindole 4b, respectively, in one step.
Reduction of the nitro group with lithium aluminum hydride followed by removal of the methyl ether with boron tribromide produced the
title compounds. They were inactive as MAO B inhibitors. # 1998 Elsevier Science S.A. All rights reserved.
Keywords: Monoamine oxidase; Serotonin (5HT); Enzyme selectivity; Fischer indole synthesis
1. Introduction
these neurons a target for pharmacological and potential
therapeutic studies. To explore the effects of such inhibition,
a drug is required that can be taken up readily into the
serotonergic neuron, but which has a preference for inter-
action with the MAO-B rather than for MAO-A, the enzyme
for which 5-HT is a preferred substrate. The identi®cation of
structural parameters which favor recognition by 5-HT
uptake mechanisms but which reverses substrate selectivity
for MAO enzymes represents a major challenge to the
development of such an agent.
As seen frequently with other enzyme substrates, intro-
duction of halogen can have signi®cant effects on the
interactions of compounds with the MAO enzymes. For
example, ring ¯uorination of 5-HT [3] causes this predo-
minantly MAO A substrate to be metabolized signi®cantly
by the MAO B enzyme [4]. The trend in selectivity seen with
¯uorinated analogues of 5-HT and other biogenic amines,
including dopamine and tyramine, appears to re¯ect greater
lipophilicity of the ¯uorinated analogues.
The ¯avin-linked monoamine oxidases (MAO) that oxi-
dize monoamines to carbonyl compounds have many impor-
tant physiological roles. MAO inactivates catecholamine
and indolamine neurotransmitters, intestinal MAO metabo-
lizes pressor amines found in food, vascular MAO protects
organs from circulating pressor amines, and liver MAO
controls blood levels of amines. The mood elevating effect
of MAO inhibitors has provided impetus to the examination
of such inhibitors as drugs for the treatment of depressive
illnesses. An important aspect of this research was prompted
by the discovery in 1968 of two forms of MAO ± MAO A and
MAO B ± which have different substrate and inhibitor
selectivities. For example, 5-hydroxytryptamine (serotonin,
5-HT) is oxidized preferentially by MAO-A, whereas less
polar amines such as phenethylamine, tyramine and dop-
amine are metabolized mainly by MAO-B. Design of selec-
tively acting compounds that can function as reversible or
irreversible inhibitors of the different isozymes has been an
important goal of medicinal chemists [1].
We have also shown that ¯uorine enhances the uptake of
5-HT into platelets [5], an observation that suggests that
¯uorinated analogues of 5-HT may also be good substrates
for serotonergic neuron uptake mechanisms. In this regard,
¯uorinated analogues of other biogenic amines, for example,
¯uorinated norepinephrines, are taken up into neurons and
serve as false neurotransmitters [6].
Consideration of the potential protective role of MAO-B
in serotonergic neurons, through degradation of extraneous
amines [2], has made the selective inhibition of MAO-B in
*Corresponding author. Fax: +1-301-402-4182.
1Present address: Department of Chemistry, National Chung Cheng
University, 160 San Hsing, Ming-Hsiung, Chia-Ti 621, Taiwan
Although many reversible competitive inhibitors selective
for MAO A have been developed, including a large number
0022-1139/98/$ ± see front matter # 1998 Elsevier Science S.A. All rights reserved.
P I I : S 0 0 2 2 - 1 1 3 9 ( 9 8 ) 0 0 2 4 8 - 6

42
H.-J.C. Chen et al. / Journal of Fluorine Chemistry 92 (1998) 41±44
of a-methylamines, very few effective MAO B-selective
inhibitors have been reported. These a-substituted amines
apparently derive their MAO selectivity from steric hin-
drance to binding to the B enzyme [1]. Recent studies,
however, suggest that b-alkylation may favor B-selectivity.
For example, p-chloro-b-methylphenylethylamine has a
618-fold selectivity for MAO B [7].
Taken together, these considerations indicate that a ¯uori-
nated analogue of 5-HT with appropriate side chain modi-
®cation may meet the criteria outlined above for selective
MAO-B inhibitors that can be targeted to serotonergic
neurones. b-Methyl-4,6-di¯uoroserotonin (1b) was our
initial synthetic goal. a-Methyl-4,6-di¯uoroserotonin (1a)
was also targeted as an analogue to study more fully the
effects of side chain methylation on MAO activity.
obtained on a Finnigan/extrel Model 1015 mass spectro-
meter with ammonia as reagent gas.
4.1. 3,5-Difluoro-4-methoxyphenylhydrazine 3
To a stirred suspension of 3,5-di¯uoro-4-methoxyaniline
[3] (3.18 g, 20 mmol) in 8 ml of concentrated HCl was
added dropwise 20 mmol of sodium nitrite in 7 ml of cold
water with stirring. After the mixture was stirred for 0.5 h at
08C, a solution of 60 mmol stannous chloride dihydrate in
14 ml of cold concentrated HCl was added dropwise. The
slurry produced was refrigerated overnight, ®ltered and the
precipitate was washed with brine, followed by 2:1 petro-
leum ether/ethyl ether. The ®ltered solid was then added to
excess concentrated aqueous NaOH and the hydrazine was
extracted into ether. The ether extract was washed with
brine, dried over anhydrous sodium sulfate and evaporated
to give the hydrazine 3 as a pale yellow solid, mp 61±628C
(3.10 g, 89%). 1H-NMR (CDCl3) d 3.55 (broad s, 2H), 3.88
(s, 3H), 5.17 (broad s, 1H), 6.39 (d, Jˆ5.3 Hz, 2H); MS (CI,
2. Chemistry
The Fischer indole synthesis was used to construct the
indole nucleus. The alumina-catalyzed condensation of
acrolein with nitroethane, as described by Ballini and
Petrini, provided 4-nitropentanal 2a [8]. Using the same
procedure, condensation of nitromethane with crotonalde-
hyde afforded 4-nitro-3-methyl-butanal 2b. Condensation
of the aldehydes 2a and 2b with 3,5-di¯uoro-4-methoxy-
phenylhydrazine (3), prepared according to the procedure of
Hunsberger and coworkers [9] from 3,5-di¯uoro-4-anisi-
dine [3], was carried out under conditions that produced 4,6-
di¯uoro-5-methoxy-3-(20-nitro)propylindole 4a and 4,6-
di¯uoro-5-methoxy-3-(10-methyl-20-nitro)ethylindole 4b,
respectively, without isolation of the intermediate hydra-
zones. This one step procedure was superior in terms of
convenience and overall yield compared to the sequence
that involved isolation of the hydrazones. The correspond-
ing tryptamines 5a and 5b were formed by lithium alumi-
num hydride reduction of 4a and 4b, respectively.
Demethylation with boron tribromide produced the title
compounds 1a and 1b (Scheme 1).
‡
‡
‡
NH3): m/z 175 [M‡1] , 192 [M‡18] , 209 [M‡35] .
4.2. 4-Nitropentanal 2a
Nitroaldehyde 2a was prepared by alumina-catalyzed
condensation of acrolein with nitroethane according to
the literature procedure [8]. From 3.59 ml (50 mmol) of
nitroethane and 3.34 ml (50 mmol) of acrolein there was
obtained 1.79 g of 2a (27%) as a yellow oil. The 1H-NMR
(CDCl3) was in complete agreement with that reported [8].
‡
‡
‡
MS (CI, NH3): m/z 148 [M‡17] , 131 [M] , 116 [M-15] .
4.3. 4-Nitro-3-methylbutanal 2b
The literature procedure used to prepare 2a was adapted
to the preparation of 2b. To a two-necked round bottom ¯ask
containing nitromethane (3.05 g, 50 mmol) was added cro-
tonaldehyde (3.5 g, 50 mmol) at 08C and the mixture was
stirred with a mechanical stirrer for 5 min. Chromatographic
alumina (Neutral, Brockman Activity 1, 80±200 mesh,
10 g) was added and stirring was continued for 5 h at room
temperature. The alumina was ®ltered, washed with ether
and the ®ltrate was evaporated under reduced pressure to
give a pale yellow oil. 4-Nitro-3-methylbutanal was
obtained in 18% yield after silica gel chromatographic
puri®cation (hexane/ethyl acetate [4/1]). 1H-NMR (CDCl3)
ꢀ 1.12 (d, Jˆ6.90 Hz, 3H), 2.48±2.92 (m, 3H), 4.33±4.46
3. Biological results and discussion
4,6-Di¯uoro-5-hydroxytryptamines 1a,b, as well as the
precursor 4,6-di¯uoro-5-methoxytryptamines 5a,b, were
examined as inhibitors of the MAO B-catalyzed oxidation
of 14C-phenylethylamine. At concentrations as high as
10 mM no signi®cant inhibition was observed with either
of the analogues. Under the conditions used, 10 nm pargy-
line produced approximately 80% inhibition.
‡
(m, 2H), 9.78 (s, 1H); MS (CI, NH3): m/z 148 [M‡17] , 131
‡
‡
[M ], 116 [M 15] .
4.4. 4,6-Difluoro-5-methoxy-3-(20-nitro)propylindole 4a
4. Experimental details
To a stirred solution of 3,5-di¯uoro-4-methoxyphenylhy-
drazine 3 (1.33 g, 7.6 mmol) in 30 ml of 90% formic acid
was added 4-nitropentanal 2a (1.00 g, 7.6 mmol) at room
temperature. After stirring for 2 h at room temperature, the
Proton NMR spectra were performed on a Varian 220
spectrometer. Chemical ionization mass spectra were

H.-J.C. Chen et al. / Journal of Fluorine Chemistry 92 (1998) 41±44
43
Scheme 1.
solution was re¯uxed for 1 h. After the reaction mixture was
cooled, it was diluted with water and extracted with CHCl3
(3Â50 ml). The CHCl3 extract was washed with brine, dried
over anhydrous Na2SO4, and the solvent was evaporated by
rotary evaporation. The resulting brown oil was puri®ed by
silica gel chromatography [hexane/ethyl acetate (4/1)] to
afford 4a as a yellow oil (1.22 g, 59%). 1H-NMR (CDCl3) ꢀ
1.62 (d, Jˆ6.6 Hz, 3H), 3.24 (dd, Jˆ5.3, 14.8 Hz, 1H), 3.43
(dd, Jˆ8.7, 14.8 Hz, 1H), 3.98 (s, 3H), 4.94 (m, 1H), 6.89
(dd, Jˆ1.5, 10.3 Hz, 1H), 6.92 (d, Jˆ2.6 Hz, 1H), 8.08
3.91 (m, 1H), 3.98 (s, 3H), 4.54 (dd, Jˆ7.8, 11.8 Hz, 1H),
4.77 (dd, Jˆ7.8, 11.8 Hz, 1H), 6.91 (dd, Jˆ1.4, 10.2 Hz,
1H), 6.99 (d, Jˆ2.3 Hz, 1H), 8.15 (broad s, 1H); MS (CI,
‡
‡
NH3): m/z 288 [M‡18] , 271 [M‡1] .
4.6. 4,6-Difluoro-5-methoxy-3-(a-methyl)tryptamine 5a
To a suspension of LiAlH4 (902 mg, 23.7 mmol) in 30 ml
of anhydrous THF was added a THF solution of 4a (3.0 mol)
at 08C with stirring. After the addition, the mixture was
re¯uxed for 30 min, and cooled to 08C, 0.90 ml of water was
added dropwise with stirring until decomposition was com-
plete. This was followed by dropwise addition of 15%
NaOH (0.90 ml), followed by the dropwise addition of
2.7 ml of water [10]. After the reaction mixture was stirred
for 1 h at 08C, it was ®ltered. The solution was evaporated to
obtain the crude product which was puri®ed by silica gel
chromatography [methanol/ethyl acetate (65/35)] to afford
5a as yellow crystals (344 mg, 54%). 1H-NMR (MeOH-d4)
d 1.11 (d, Jˆ6.4 Hz, 3H), 2.61 (dd, Jˆ7.6, 14.1 Hz, 1H),
‡
(broad s, 1H); MS (CI, NH3): m/z 271 [M‡1] , 288
‡
[M‡18] .
4.5. 4,6-Difluoro-5-methoxy-3-(10-methyl-20-nitro)ethyl
indole 4b
A similar procedure was performed using 4-nitro-3-
methylbutanal 2b as the aldehyde component for reaction
with 3. The product was obtained in 39% yield after
1
puri®cation. H-NMR (CDCl3) ꢀ 1.47 (d, Jˆ7.1 Hz, 3H),

44
H.-J.C. Chen et al. / Journal of Fluorine Chemistry 92 (1998) 41±44
2.69 (dd, Jˆ5.8, 14.0 Hz, 1H), 3.17 (m, 1H), 3.87 (s, 3H),
6.92 (dd, Jˆ1.4, 10.7 Hz, 1H), 7.01 (s, 1H); MS (CI, NH3):
(d, Jˆ10.5 Hz, 1H), 7.05 (s, 1H); MS (CI, NH3): m/z 244
‡ ‡
[M‡18] , 227 [M‡1] .
‡
m/z 241 [M‡1] .
4.9. 4,6-Difluoro-5-hydroxy-3-(b-methyl)tryptamine 1b
4.7. 4,6-Difluoro-5-methoxy-3-(b-methyl)tryptamine 5b
A procedure similar to that described above for 1a was
used to prepare 1b from 5b in 47% yield. 1H-NMR (MeOH-
d4) ꢀ1.41 (d, Jˆ6.9 Hz, 3H), 3.11 (dd, Jˆ6.6, 12.5 Hz, 1H),
3.24 (dd, Jˆ7.9, 12.5 Hz, 1H), 3.38 (m, 1H), 6.93 (d,
Jˆ10.5 Hz, 1H), 7.10 (s, 1H); MS (CI, NH3): m/z, 244
A similar procedure as described above for the prepara-
tion of 5a was used to prepare 5b in 43% yield starting with
4b. 1H-NMR (MeOH-d4) ꢀ 1.33 (d, Jˆ6.9 Hz, 3H), 2.85 (m,
1H), 2.97 (m, 1H), 3.23 (m, 1H), 3.88 (s, 3H), 6.94 (d, Jˆ
‡
‡
‡
10.7 Hz, 1H), 7.06 (s, 1H); MS (CI, NH3): m/z 241 [M‡1] .
[M‡18] , 227 [M‡1] .
4.8. 4,6-Difluoro-5-hydroxy-3-(methyl)tryptamine 1a
References
To a solution of 5a (229 mg, 0.95 mmol) in anhydrous
CH2Cl2 (20 ml) cooled to 788C was added a solution of
1 M boron tribromide (2.0 ml, 2.0 equivalent) in anhydrous
CH2Cl2 with stirring. The temperature gradually warmed to
room temperature and the reaction was stirred overnight.
Excess methanol was added and the resulting trimethylbo-
rate and solvent were evaporated to dryness. Hot isopropa-
nol was added and the insoluble salt was ®ltered and washed
with hot isopropanol. The combined ®ltrate was evaporated
to afford a brown oil which was puri®ed by a preparative
TLC (20Â20 cm, 500 mm thickness, Analtech, Newark,
DE) eluting with NH4OH/iPrOH/EtOAc (35/25/40). The
product fraction was extracted from silica gel with metha-
nol. The product 1a (95 mg, 42% yield) was obtained as a
[1] C.J. Fowler, S.B. Ross, Med. Res. Rev. 4 (1984) 323.
[2] K.N. Westland, R.M. Denney, L.M. Kochersperger, R.M. Rose, C.W.
Abell, Science 230 (1985) 181.
[3] K.L. Kirk, J. Heterocycl. Chem. 13 (1976) 1253.
[4] K.L. Kirk, C.R. Creveling, in: R. Filler, Y. Kobayashi (Eds.),
Biomedicinal Aspects of Fluorine Chemistry, Kodansha, 1982, pp.
75±91.
[5] J.L. Costa, K.L. Kirk, H. Stark, Br. J. Pharmacol. 75 (1982) 237.
[6] C.C. Chieuh, Z. Zukowska-Crojec, I.J. Kopin, K.L. Kirk, C.R.
Creveling, J. Pharmacol. Exp. Ther. 224 (1983) 539.
[7] H. Kinemuchi, Y. Arai, Y. Toyoshima, T. Tadona, K. Kisara, Jpn.
J. Pharmacol. 46 (1987) 197.
[8] R. Ballini, M. Petrini, Synthesis (1986) 1024.
[9] I.M. Hunsberger, E.R. Shaw, J. Fugger, R. Ketcham, D. Lednicer,
J. Org. Chem. 21 (1956) 394.
1
partially crystalline yellow solid. H-NMR (MeOH-d4) ꢀ
1.28 (d, Jˆ6.5 Hz, 3H), 3.02 (m, 2H), 3.53 (m, 1H), 6.92
[10] L.F. Fieser, M. Fieser, Reagents for Organic Synthesis, Vol. I, Wiley,
New York, 1967, p. 584.