Hallucinogenic Tryptamines: Ring Fluorination
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 24 4707
N,N-Dim eth yl-4-ben zyloxy-6-flu or oin d ol-3-ylglyoxa lyl-
a m id e (14a ). This compound was obtained in 68% yield from
4-benzyloxy-6-fluoroindole (17a ) as colorless crystals: mp 222
fumarate-H), 6.13 (dd, 2, ArH, J ) 3.0 and 12 Hz), 2.89 (t, 4,
CH2, J ) 6.0 Hz), 2.70 (t, 4, CH2, J ) 6.0 Hz), 2.34 (s, 12, CH3);
CIMS 223 (MH+). Anal. (C28H34F2N4O6) C, H, N.
1
°C; H NMR (acetone-d6) δ 12.75 (s, 1, NH), 8.03 (s, 1, ArH),
7-F lu or o-4-h yd r oxy-N,N-d im eth yltr yp ta m in e (4). This
compound was obtained in 98% yield as a white solid: mp 170
°C dec; 1H NMR δ 8.03 (br s, 1, NH), 6.88 (d, 1, ArH-2, J ) 2.0
Hz), 6.75 (dd, 1, ArH, J ) 8.4 and 10 Hz), 6.40 (dd, 1, ArH, J
) 3.7 and 8.5 Hz), 2.94 (m, 2, CH2), 2.69 (m, 2, CH2), 2.38 (s,
6, CH3); CIMS 223 (MH+). Anal. (C12H15FN2O) C, H, N. The
fumarate salt was prepared (2:1 base:acid) and recrystallized
7.47 (m, 5, benzyl-ArH), 6.87 (d, 1, ArH, J ) 9.0 Hz), 6.59 (d,
1, ArH, J ) 12 Hz), 5.33 (s, 2, CH2), 2.98 (s, 3, CH3), 2.93 (s,
3, CH3); CIMS 341 (MH+). Anal. (C19H17FN2O3) C, H, N.
N,N-Dim eth yl-4-ben zyloxy-7-flu or oin d ol-3-ylglyoxa lyl-
a m id e (14b). This compound was obtained from 17b in 38%
1
yield as colorless crystals: mp 211 °C; H NMR (DMSO-d6) δ
1
12.80 (br s, 1, NH), 8.09 (s, 1, ArH-2), 7.42 (m, 5, benzyl-ArH),
6.96 (t, 1, ArH, J ) 9.0 Hz), 6.58 (dd, 1, ArH, J ) 3.3 and 9.0
Hz), 5.22 (s, 2, CH2), 2.90 (s, 3, CH3), 2.86 (s, 3, CH3); CIMS
341 (MH+). Anal. (C19H17FN2O3) C, H, N.
(EtOH/EtOAc): mp 220 °C dec; H NMR (DMSO-d6) δ 11.09
(br s, 2, NH), 7.02 (d, 2, ArH, J ) 1.9 Hz), 6.62 (dd, 2, ArH, J
) 8.3 and 11 Hz), 6.49 (s, 2, fumarate-H), 6.16 (dd, 2, ArH, J
) 3.4 and 8.0 Hz), 1.85 (t, 4, CH2, J ) 7.0 Hz), 2.75 (t, 4, CH2,
J
) 7.0 Hz), 2.37 (s, 12, CH3); CIMS 223 (MH+). Anal.
Gen er a l P r oced u r e for th e P r ep a r a tion of N,N-Di-
a lk yltr yp ta m in es 1b a n d 15a ,b. A solution of the appropri-
ate N,N-dialkyl-3-indoleglyoxylamide in dry THF was added
dropwise to a slurry of LiAlH4 (5 equiv) in dry THF at reflux.
The mixture was held at reflux for 6-51 h until TLC indicated
the reaction was complete. The mixture was then cooled,
quenched with water, filtered through Celite, and the filtrate
was concentrated under reduced pressure. The residue was
taken up into ether, washed with aqueous 1 N NaOH and
brine, dried over MgSO4 and concentrated under reduced
pressure. The product was purified either by sublimation or
recrystallization from ethyl acetate.
(C28H34F2N4O6) C, H, N.
2-F lu or o-4-n itr oa n isole (17). Nitric acid (2.6 mL) was
added to a stirred mixture of 2-fluoroanisole48 (5.01 g, 39.7
mmol), sulfuric acid (96%, 675 mL) and water (250 mL) at 0
°C. A solution of sodium nitrite (2.71 g, 39.2 mmol) in water
(50 mL) was added dropwise. The reaction mixture was
warmed to room temperature and stirred for 3 h, then diluted
with 3000 mL of water and placed in the refrigerator over-
night. The precipitate that formed (containing the ortho-
nitrated product 18 in less than 1% yield as detected by 1H
NMR) was collected by filtration and purified by column
chromatography over silica gel with CH2Cl2 as eluent to obtain
pure 23 in 66% yield (4.08 g) as a white solid: mp 95-96 °C
(lit.48 mp 104-104.5 °C); 1H NMR δ 8.08 (m, 1, ArH), 7.99 (dd,
1, ArH, J ) 11 and 2.7 Hz), 7.04 (t, 1, ArH, J ) 8.6 Hz), 4.01
(s, 3, OCH3); CIMS 172 (MH+).
6-F lu or o-N,N-d ieth yltr yp ta m in e (1b).7,14 The reflux time
was 6 h. This amine was obtained in 67% yield as a white solid
1
(sublimation): mp 59-60 °C (lit.7 mp 69-70 °C); H NMR δ
8.02 (br s 1, NH), 7.51 (dd, 1, ArH, J ) 5.5 and 8.8 Hz), 7.04
(dd, 1, ArH, J ) 2.2 and 9.9), 7.01 (d, 1, ArH, J ) 2.2, 6.89 (td,
1, ArH, J ) 2.2 and 9.9 Hz), 2.91 (m, 2, CH2), 2.79 (m, 2, CH2),
2.67 (q, 4, CH2, J ) 6.9), 1.10 (t, 6, CH3, J ) 7.5 Hz); CIMS
235 (MH+). The fumarate salt was prepared (1:1 base:acid)
and recrystallized (EtOH/EtOAc): mp 134 °C; 1H NMR
(DMSO-d6) δ 10.98 (s, 1, NH), 7.54 (dd, 1, ArH, J ) 6.0 and
9.0 Hz), 7.21 (d, 1, ArH, J ) 3.0 Hz), 7.10 (dd, 1, ArH, J ) 3.0
and 9.0 Hz), 6.84 (td, 1, ArH, J ) 3.0 and 12 Hz), 6.51 (s, 2,
fumarate-H), 2.93 (m, 8, CH2), 1.11 (t, 6, CH3, J ) 9.0 Hz);
CIMS 235 (MH+). Anal. (C18H23FN2O4) C, H, N.
3-F lu or o-4-m eth oxya n ilin e (19). A solution of 17 (9.20
g, 53.8 mmol) in 95% ethanol (200 mL) was hydrogenated at
45 psig for 16 h over 10% Pd/C (1.50 g). The catalyst was
removed by filtration, washed with ethanol, and the filtrate
was evaporated under reduced pressure to provide 19 (7.52 g,
1
99%) as a solid: mp 75 °C (lit.49 mp 83-83.5 °C); H NMR δ
6.80 (t, 1, ArH, J ) 9.0 Hz), 6.49 (dd, 1, ArH, J ) 13 and 2.6
Hz), 6.39 (m, 1, ArH), 3.82 (s, 3, OCH3), 3.50 (br s, 2, NH2);
CIMS 142 (MH+).
4-Ben zyloxy-6-flu or o-N,N-d im eth yltr yp ta m in e (15a ).
The reflux time was 49 h. This tryptamine was obtained in
87% yield as a white solid (recrystallized from EtOAc): mp
3-F lu or o-4-m et h oxyp h en ylh yd r a zin e H yd r och lor id e
(20). A solution of sodium nitrite (2.58 g, 37.4 mmol) in water
(8 mL) was added dropwise to a solution of 2-fluoro-4-
methoxyaniline (19) (5.28 g, 37.4 mmol) in aqueous 2.35 N HCl
at 0 °C. The solution was stirred for 10 min and then slowly
added dropwise to a rapidly stirred mixture of SnCl2‚2H2O
(33.74 g, 149.5 mmol) in concentrated HCl (140 mL) at 0 °C.
The reaction was allowed to warm to room temperature,
stirred for 15 min, and filtered. The collected precipitate was
washed on the filter with several large portions of ether and
dried under vacuum to give 20 (4.73 g, 66%), which was used
in the next step without further purification: mp > 100 °C
dec; 1H NMR (DMSO-d6) δ 10.20 (br s, 3, NH3+), 8.15 (br s, 1,
NH), 7.10 (t, 1, ArH, J ) 9.2 Hz), 6.97 (dd, 1, ArH, J ) 13 and
2.6 Hz), 6.97 (m, 1, ArH), 3.80 (s, 3, OCH3).
6-F lu or o- a n d 4-F lu or o-5-m eth oxy-N,N-d im eth yltr yp t-
a m in e (5 a n d 6). To a heated (80 °C) solution of hydrazine
20 (530 mg, 2.75 mmol) in 24% aqueous acetic acid (40 mL)
was added 4-(N,N-dimethylamino)butanal dimethylacetal21
(710 mg, 4.40 mmol) and the reaction was stirred at 85 °C for
28 h. After cooling, the solution was basified to pH 10-11 with
concentrated ammonium hydroxide and was then extracted
with ether (3 × 30 mL). The organic extract was dried (Na2-
SO4), evaporated under reduced pressure, and the residue was
purified by centrifugal radial chromatography (chromatotron,
Harrison Research, Palo Alto, CA), on a 4-mm silica gel plate,
eluting with 5% MeOH/CH2Cl2 under an atmosphere of
nitrogen and ammonia to afford 6-fluoro-5-methoxy-N,N-
dimethyltryptamine (5) (318 mg, 49%): mp 73 °C; 1H NMR δ
7.99 (br s, 1, NH), 7.09 (m, 2, ArH), 6.98 (s, 1, ArH), 3.93 (s, 3,
OCH3), 2.90 (t, 2, CH2, J ) 9.0 Hz), 2.62 (t, 2, CH2, J ) 9.0
Hz), 2.38 (s, 6, NCH3); CIMS 237 (MH+). Anal. (C13H17FN2O)
C, H, N. Characterized as the fumarate salt (2:1 base:acid)
and recrystallized (EtOH/EtOAc): mp 208 °C; 1H NMR
1
131 °C; H NMR (CD3OD) δ 7.41 (m, 5, benzyl-ArH), 6.87 (s,
1, ArH-2), 6.63 (dd, 1, ArH-5, J ) 2.1 and 9.0 Hz), 6.39 (dd, 1,
ArH-7, J ) 3.0 and 12 Hz), 3.10 (s, 2, CH2), 2.95 (m, 2, CH2),
2.60 (m, 2, CH2), 2.10 (s, 6, CH3); CIMS 313 (MH+). Anal.
(C19H21FN2O) C, H, N.
4-Ben zyloxy-7-flu or o-N,N-d im eth yltr yp ta m in e (15b).
The reflux time was 51 h. This tryptamine was obtained in
88% yield as a white solid (recrystallized from EtOAc): mp
155 °C; 1H NMR δ 8.25 (br s, 1, NH), 7.39 (m, 5, benzyl-ArH),
6.92 (d, 1, ArH-2, J ) 1.7 Hz), 6.72 (dd, 1, ArH, J ) 9.0 and
11 Hz), 6.36 (dd, 1, ArH, J ) 8.5 and 3.1 Hz), 5.15 (s, 2, CH2),
3.03 (t, 2, CH2, J ) 7.5 Hz), 2.58 (t, 2, CH2, J ) 7.6 Hz), 2.15
(s, 6, CH3); CIMS 313 (MH+). Anal. (C19H21FN2O) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of F lu or i-
n a ted An a logu es of P silocin (3 a n d 4). The appropriate
benzyloxytryptamine (3.20 mmol) was hydrogenated at 50 psig
in 95% EtOH (250 mL) over 10% Pd/C (340 mg) for 4 h. The
catalyst was removed by filtration and the filtrate was
concentrated under reduced pressure to give a solid which was
purified by sublimation to afford the respective hydrox-
ytryptamine.
6-F lu or o-4-h yd r oxy-N,N-d im eth yltr yp ta m in e (3). This
compound was obtained in quantitative yield as a white
solid: mp 178 °C dec; 1H NMR (CD3OD) δ 6.83 (s, 1, ArH),
6.46 (dd, 1, ArH, J ) 3.0 and 9.0 Hz), 6.10 (dd, 1, ArH, J )
3.0 and 12 Hz), 2.98 (t, 2, CH2, J ) 6.0 Hz), 2.75 (t, 2, CH2, J
) 6.0 Hz), 2.37 (s, 6, CH3); CIMS 223 (MH+). Anal. (C12H15
-
FN2O) C, H, N. The fumarate salt was prepared (2:1 base:
acid) and recrystallized (EtOH/EtOAc): mp 226 °C dec; 1H
NMR (DMSO-d6) δ 10.69 (br s, 2, NH), 6.92 (d, 2, ArH, J )
2.0 Hz), 6.49 (dd, 2, ArH, J ) 2.0 and 10 Hz), 6.50 (s, 2,