Syntheses of melatonin and its derivatives

Article abstract of DOI:10.3987/COM-00-8930

Two simple synthetic methods for melatonin are newly developed from tryptamine through intermediates, which are promising lead compounds for drug developing research. Novel chemical reactivities of melatonin in its bromination, lithiation, and acylation are also reported.

Full text of DOI:10.3987/COM-00-8930

HETEROCYCLES, Vol. 53, No. 8, 2000, pp. 1725 - 1736, Received, 26th April, 2000
1
SYNTHESES OF MELATONIN AND ITS DERIVATIVES
Masanori Somei,* Yoshikazu Fukui, Masakazu Hasegawa, Naoki Oshikiri, and
Toshikatsu Hayashi
Faculty of Pharmaceutical Sciences, Kanazawa University,
13-1 Takara-machi, Kanazawa 920-0934, Japan
Abstract — Two simple synthetic methods for melatonin are newly developed
from tryptamine through intermediates, which are promising lead compounds for
drug developing research. Novel chemical reactivities of melatonin in its bromi-
nation, lithiation, and acylation are also reported.
2
Melatonin (1, Scheme 1) is a hormone secreted from pineal gland and is well known to control the
2
3
circadian rhythms. Its multimodality of biological activities has recently been disclosed such as inhibi-
3a 3b
tion of Alzheimer β-fibrillogenesis, anti-aging properties relating to radical scavenging, antiprolif-
erative effect on melanoma cells, etc. Although several synthetic methods for 1 have been reported thus
3c
3
4
far, they still have subjects to be improved in synthetic steps, overall yields, and economical efficiency.
From the point of creating new biologically active compounds, we have engaged for some time in finding
1a
a novel synthetic method for 1 and proposed that it should involve value added intermediates as many as
possible, which can function as lead compounds for drug developing. In this paper, we wish to describe
5
the desired two synthetic methods for 1 from tryptamine (2) based on 1-hydroxyindole chemistry.
Interesting results of bromination, lithiation and subsequent reaction with an electrophile, and acylation of
1 are also reported.
Nb-Acetyl- (3a) and Nb-methoxycarbonyltryptamine (3b), readily available in quantitative yields from 2
5
6
by the respective reactions with either Ac O or methyl chloroformate, were reduced with Et SiH in
2
3
TFA to afford the corresponding 2,3-dihydrotryptamines, (4a) and (4b), in 99 and 97% yields, re-
5
spectively. Application of our 1-hydroxyindole synthetic method to 4a, using 30% H O and Na WO ·
2 2
2
4
5
2H O as a catalyst, provided 5a in 66% yield. Under similar reaction conditions, 4b provided 5b in
2
65% yield. These two compounds, (5a) and (5b), are found to be promising lead compounds for
7
inhibitors of blood platelet aggregation.
We next examined nucleophilic substitution reaction of 5a in MeOH with acids having weak nucleophilic
nature of the conjugated base and the results are summarized in Table 1. In cases where H SO was
8
2
4
employed, we could obtain 1 in no better than 17% yield (Entry 1) under variously examined reaction
conditions. When the acid was changed to HF, the yield of 1 was dramatically improved to 55% (Entry
2). We finally found that BF was an acid of choice (Entries 3–6). At an optimum reaction conditions
3
shown in Entry 5, 1 was provided in 80% yield together with 3a in 5% yield. In case of large scale
production, however, their separations are not always easy due to their close Rf values. The synthetic 1
was identical with an authentic commercial sample. Consequently, four steps synthesis of 1 from 2 was

9
established in 52% overall yield with 60% originality rate.
Scheme 1
H2N
N
RHN
RHN
RHN
4
7
Na2WO4
Et3SiH
5
6
3
2
N
30% H2O2
N
H
N
H
1
H
OH
2
3
4
5
Table 1
20% BF3/MeOH
AcHN
H2N
MeOOCHN
MeO
MeO
MeO
a) R = Ac
b) R = COOMe
H2O
N
H
N
H
Ac2O
NaOH
N
H
1
7
6
Acid
+
5a
1
3a
Table 1
MeOH
Reaction Conditions
Temp. (°C) Time (h)
Yield (%) of
Entry
Reagent
1
3a
rt
17
55
54
10
10
5
1
2
22% H2SO4
11%HF
24
8
70
52
20%BF3
4.5
3
4
70
2
65
80
72
5
5
3
"
reflux
reflux
2/3
0.5
5
6
"
"
As an alternative route, the reaction of 5b with 20% BF was examined in refluxing MeOH. Interestingly,
3
8d
the reaction was relatively faster than that of 5a and, without any contamination of 3b,
6 was obtained
in 94% yield. Even if the formation of 3b were observed by chance, the reaction would be suitable for
large scale production because there are wide differences in Rf values between 6 and 3b. Alkaline
4f
hydrolysis of 6 gave 5-methoxytryptamine (7) in 99% yield, which is known to be a potent agonist of
4c
serotonin. Acetylation of 7 with Ac O gave 92% yield of 1. The final two steps could be carried out in
2
92% overall yield without isolation of 7. As a result, six steps synthesis of 1 from 2 was established in
9
55% overall yield with 43% originality rate.
With simple synthesis of 1 established, we examined its bromination taking into consideration that
10
halogen containing melatonin derivatives had been utilized for various studies in brain chemistry.
A
conventional bromination in AcOH with 0.95 mol eq. of Br provided 4-bromo- (8), 2-bromo- (9),
2
10a
2,4-dibromomelatonin
(1 1), and unreacted 1 in 8, 28, 15, and 34% yields, respectively, as shown in
Table 2 (Entry 1). When 2 mol eq. of Br was employed, 1 reacted completely to afford 8,
2
10b
2,6-dibromomelatonin
(1 0), and 1 1 in 10, 34, and 49% yields, respectively (Entry 2). The reaction
with 3 mol eq. of Br provided 2,4,6-tribromomelatonin (1 2) as a sole product in 60% yield (Entry 3).
2
Structures of 8—1 1 except for 1 2 were determined by spectral data. As for 1 2, however, 2,4,7-tri-

bromomelatonin is an alternative possible candidate. Therefore, 1 2 was further converted to 1-acetyl de-
rivative (1 3) in 53% yield by treatment with NaH, followed by the reaction with AcCl. Comparison of the
1
H-NMR spectrum of 1 2 with that of 13 clearly showed the anisotropy effect of 1-acetyl group on the
singlet C(7)-proton by ca. 1 ppm, proving that 1 2 and 1 3 are 7-unsubstituted indoles.
It is interesting to note that the selective debromination of 1 1 could be realized in the following ways.
Thus, upon reaction with 1 1 at room temperature, Mg/MeOH selectively removed the bromine atom at the
2 position to give 8 in 21% yield together with 44% yield of recovery, while such reagent systems as
Mg/PrOH, Mg/THF, and Zn/AcOH/NH Cl did not react at all. Contrastively, n-BuLi in THF at –19°C,
4
followed by the addition of H O, replaced the bromine atom at the 4-position for hydrogen to provide 9
2
in 51% yield together with unreacted 1 1 in 27% yield.
R = CH2CH2NHAc
Table 2
Br
Br
Br
R
R
R
R
R
MeO
MeO
MeO
MeO
MeO
Br2/AcOH
rt
1
1
N
Br
Br
N
Br Br
N
Br
Br
N
H
N
H
H
H
H
8
9
10
11
12
Yield
(%)
of
Bromine Reaction Time
Entry
(mol eq)
(h)
8
9
10
11
12
1
1
2
3
0.95
1.9
3
5
8
28
0
0
15
49
0
0
34
0
2.5
10
0
34
2
0
0
0
60
0
NHAc
Br
MeO
Br
1) NaH, DMF
2) AcCl
Mg/MeOH
1) n-BuLi
;
8
11
9
12
13
Br
N
2) H2O
Ac
Table 3
Ac2O/Pyridine
MeO
H
H
N
H
N
N
1) n -BuLi
(3 mol eq),
THF
O
O
O
MeO
MeO
OAc
Ac
OH
1
1
N
N
H
N
H
2) Electrophile
H
16
14
15
Yield (%) of
Electrophile
(mol eq)
Reaction
Time (h)
Entry
Gas
14
15
1
MeCONMe2 (4)
0
4
1
2
Ar
5
6
30
66
43
23
_
"
_
"
O2
3
4
1.5
5
16
36
76
39
_
_
"
Next, direct lithiation of 1 was examined with n-BuLi in THF under Ar at –18°C, followed by reaction
with N,N-dimethylacetamide. The result was the formation of Nb-acetoacetyl- (1 4) and/or Nb-hydroxy-

acetyl-5-methoxytryptamine (1 5) as shown in Entries 1 and 2 (Table 3). Since the trace amount of oxygen
contaminated in Ar seemed to be responsible for the formation of 1 5, lithiation of 1 was carried out under
oxygen atmosphere in the absence of an electrophile culminating in the formation of 1 5 in good yields
(Entries 3 and 4). Further acetylation of 1 5 with Ac O/pyridine afforded 91% yield of Nb-acetoxy-
2
acetyl-5-methoxytryptamine (1 6) proving the presence of a primary alcohol in the side chain.
The structure of 1 5 was confirmed by the following alternative synthesis (Scheme 2). The reaction of 7
11
with chloroacetyl chloride in the presence of Et N afforded 93% yield of 1 7. Subsequent heating of 1 7
3
in formamide/H O mixed solvent at reflux provided 87% yield of 1 5 which was identical with the sample
2
obtained from the above lithiation method.
Scheme 2
H
N
H
NH2
N
O
O
Et3N
NH2CHO
H2O
MeO
MeO
MeO
Cl
OH
ClCOCH2Cl
N
H
N
N
H
H
17
15
7
NHAc
NHAc
NAc2
MeO
NaH, AcCl
DMF
MeO
Ac2O
MeO
N
R
N
N
H
H
a) R = Ac
b) R = CHO
19
18
1
Acylation of 1 is also worthy of mention. Thus, the initial treatment of 1 with NaH in DMF and
subsequent reaction with AcCl provided 1-acetylmelatonin (18a) exclusively in 77% yield, while the
reaction with refluxing Ac O afforded Nb,Nb-diacetyl-5-methoxytryptamine (1 9) in 92% yield.
2
1-Formylation of 1 occurred easily at room temperature by treatment with 85% HCOOH affording 18b in
92% yield.
In conclusion, we have established two efficient and economical synthetic methods for 1 involving
intermediates such as 2a, 2b, and 7, which are promising lead compounds for future growth in drug
developing studies. Furthermore, several novel chemical reactivities of 1 were found in its bromination,
lithiation, and acylation. Utilizing the resultant building blocks, preparations of various derivatives of 1
and their biological evaluations are now in progress.
E X PE R IM E N T A L
Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected. IR
1
spectra were determined with a Shimadzu IR-420 spectrophotometer, and H-NMR spectra with either a
JEOL JNM FX100S or JEOL GSX-500 spectrometer with tetramethylsilane as an internal standard. MS
spectra were recorded on a JEOL SX-102A spectrometer. Column chromatography was performed on
silica gel (SiO , 100-200 mesh, from Kanto Chemical Co. Inc.) or activated alumina (Al O , 300 mesh,
2
2 3
from Wako Pure Chemical Industries, Ltd.).
N b-Acetyl-2,3-dihydrotryptamine (4a) from N b-Acetyltryptamine (3a) — Et SiH (3.10 mL,
3

19.4 mmol) was added to a solution of 3a (1.971 g, 9.76 mmol) in CF COOH (97 mL) and the mixture
3
was heated at 60°C for 3 h with stirring. After evaporation of the solvent, H O was added to the residue.
2
The whole was made basic by adding 2N aqueous NaOH under ice cooling and extracted with CHCl –
3
MeOH (95:5, v/v). The extract was washed with brine, dried over Na SO , and evaporated under
2
4
reduced pressure to leave an oil, which was column-chromatographed on SiO with MeOH–AcOEt (1:99,
2
-1
v/v) to give 4a (1.970 g, 99%). 4a: Colorless oil. IR (film): 3295, 1642 (br), 1556 (br), 747 cm .
1
H-NMR (CDCl ) δ: 1.59—1.83 (1H, m), 1.94 (3H, s), 1.95—2.06 (1H, m), 2.89 (1H, br s,
3
disappeared on addition of D O), 3.21—3.42 (4H, m), 3.70 (1H, t, J=8.4 Hz), 5.77 (1H, br s), 6.66
2
(1H, d, J=7.6 Hz), 6.73 (1H, t, J=7.6 Hz), 7.04 (1H, t, J=7.6 Hz), 7.09 (1H, d, J=7.6 Hz). High
resolution MS m/z: Calcd for C H N O: 204.1262. Found: 204.1269.
12 16 2
N b-Methoxycarbonyl-2,3-dihydrotryptamine (4b) from N b-Methoxycarbonyltryptamine
(3b) — Et SiH (7.50 mL, 46.9 mmol) was added to a solution of 3b (5.030 g, 23.0 mmol) in
3
CF COOH (100 mL) and the mixture was heated at 60°C for 3 h with stirring. After evaporation of the
3
solvent, H O was added to the residue. The whole was made basic by adding 2N aqueous NaOH under
2
ice cooling and extracted with CHCl –MeOH (95:5, v/v). The extract was washed with brine, dried over
3
Na SO , and evaporated under reduced pressure to leave an oil, which was column-chromatographed on
2
4
SiO with CHCl –MeOH (95:5, v/v) to give 4b (4.930 g, 97%). 4b: mp 64—65°C (colorless prisms,
2
3
-1 1
recrystallized from AcOEt-hexane). IR (KBr): 3407, 3345, 1716, 1521, 1247, 752 cm . H-NMR
(CDCl ) δ: 1.59 (1H, br s), 1.71—1.79 (1H, m), 1.96—2.04 (1H, m), 3.20—3.36 (4H, m), 3.66 (1H,
3
t, J=8.0 Hz), 3.70 (1H, t, J=8.0 Hz), 4.82 (1H, br s), 6.64 (1H, d, J=7.5 Hz), 6.72 (1H, t, J=7.5 Hz),
7.03 (1H, t, J=7.5 Hz), 7.09 (1H, d, J=7.5 Hz). MS m/z: 220 (M+). Anal.Calcd for C H N O : C,
12 16 2 2
65.43; H, 7.32; N, 12.72. Found: C, 65.31; H, 7.35; N, 12.65.
N b-Acetyl-1-hydroxytryptamine (5a) from 4a — 30% Aq. H O (8.50 mL, 76.4 mmol) was
2 2
added to a solution of 4a (1.560g, 7.64 mmol) and Na WO ·2H O (500.0 mg, 1.53 mmol) in MeOH
2
4
2
(150 mL)–H O (15.0 mL) at 0°C with stirring. Stirring was continued at rt for 30 min and then the whole
2
was extracted with CHCl . The extract was washed with brine, dried over Na SO , and evaporated
3
2
4
under reduced pressure to leave an oil, which was column-chromatographed on SiO with MeOH-AcOEt
2
(1:99, v/v) to give 5a (1.104 g, 66%). 5a: mp 138—139°C (colorless prisms, recrystallized from
-1 1
AcOEt). IR (KBr): 3250, 3105, 1619, 1602, 1580, 743 cm . H-NMR (CD OD) δ: 1.89 (3H, s), 2.89
3
(2H, t, J=7.3 Hz), 3.43 (2H, t, J=7.3 Hz), 6.99 (1H, t, J=8.3 Hz), 7.10 (1H, s), 7.12 (1H, t, J=8.3
+
Hz), (1H, d, J=8.3 Hz), 7.52 (1H, d, J=8.3 Hz). MS m/z: 218 (M ). Anal. Calcd for
C H N O : C, 66.04; H, 6.47; N, 12.84. Found: C, 66.02; H, 6.53; N, 12.77.
12 14
2 2
N b-Methoxycarbonyl-1-hydroxytryptamine (5b) from 4b —30% Aq. H2O2 (1.0 mL, 9.18
mmol) was added to a solution of 4b (201.9 mg, 0.92 mmol) and Na2WO4·2H2O (63.2 mg, 0.18 mmol)
in MeOH–H2O (1:1, v/v, 22.0 mL) at 0°C with stirring. Stirring was continued at rt for 30 min and then
the whole was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and
evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO2 with
AcOEt-hexane (1:2, v/v) to give 5b (237.4 mg, 65%). 5b: mp 114—115°C (colorless needles, re-
crystallized from CH2Cl2–hexane). IR (KBr): 3380, 3190, 1698, 1533, 1267, 983, 751 cm-1. 1H-NMR

(CD OD) δ: 2.89 (2H, t, J=7.5 Hz), 3.36 (2H, t, J=7.5 Hz), 3.61 (3H, s), 6.99 (1H, t, J=7.9 Hz), 7.09
3
(1H, s), 7.13 (1H, t, J=7.9 Hz), 7.34 (1H, d, J=7.9 Hz), 7.53 (1H, d, J=7.9 Hz). MS m/z: 234 (M+).
Anal. Calcd for C H N O : C, 61.53; H, 6.02; N, 11.96. Found: C, 61.40; H, 6.02; N, 11.90.
12 14 2 3
Melatonin (1) from N b-acetyl-1-hydroxytryptamine (5a) — Entry 1: Conc. H SO (2.0 mL)
2
4
was added to a solution of 5a (29.7 mg, 0.14 mmol) in MeOH (7 mL) at 0°C with stirring. After stirring at
rt for 24 h, H O was added under ice cooling and the whole was extracted with CH Cl –MeOH (95:5,
2
2 2
v/v). The extract was washed with brine, dried over Na SO , and evaporated under reduced pressure to
2
4
leave an oil, which was subjected to HPLC on SiO with AcOEt–hexane (3:1, v/v) to give 3a (2.8 mg,
2
10%) and 1 (5.3 mg, 17%) in the order of elution. The obtained sample (1) was identical with a
commercially available 1 in every respects.
Entry 2: 55% Aq. HF (2.0 mL) was added to a solution of 5a (29.9 mg, 0.14 mmol) in MeOH (8.0
mL) under ice cooling and the mixture was heated at 70°C for 8 h. After evaporation of the solvent, H O
2
was added to the residue and the whole was made neutral by adding sat. NaHCO under ice cooling and
3
extracted with CH Cl –MeOH (95:5, v/v). After the same work-up and separation as described in Entry
2 2
1, 3a (2.9 mg, 10%) and 1 (17.7mg, 55%) were obtained.
Entry 5: 50% BF –methanol complex (2.0 mL) was added to a solution of 5a (30.0 mg, 0.14 mmol) in
3
MeOH (3.0 mL) under ice cooling and the mixture was refluxed for 40 min with stirring. After
evaporation of the solvent, the whole was made neutral by adding 2N NaOH under ice cooling and
extracted with CH Cl –MeOH (95:5, v/v). After the same work-up and separation as described in Entry
2 2
1, 3a(1.4 mg, 5%) and 1 (25.5 mg, 80%) were obtained.
5-Methoxy-N b-methoxycarbonyltryptamine (6) from 5b — Example 1 (g scale): 50%
BF –methanol complex (10.0 mL) was added to a solution of 5b (1.50 g, 6.41 mmol) in MeOH (100
3
mL) and the mixture was refluxed for 40 min with stirring. After addition of ice and H O, the whole was
2
made neutral by adding 40% aq. NaOH and extracted with CHCl . The extract was washed with brine,
3
dried over Na SO , and evaporated under reduced pressure to leave an oil, which was column-
2
4
chromatographed on SiO with CHCl to give 6 (1.50 g, 94%). 6: mp 80—82°C (colorless prisms,
2
3
-1 1
recrystallized from CHCl –hexane). IR (KBr): 3330, 1670, 1536, 1486, 1035, 926, 775 cm . H-NMR
3
(CDCl ) δ: 2.94 (2H, t, J=6.7 Hz), 3.52 (2H, q, J=6.7 Hz), 3.66 (3H, s), 3.87 (3H, s), 4.77 (1H, br s),
3
6.87 (1H, dd, J=8.7 and 2.3 Hz), 7.01 (1H, d, J=2.3 Hz), 7.03 (1H, br s), 7.26 (1H, d, J=8.7 Hz),
7.94 (1H, br s). MS m/z: 248 (M+). Anal. Calcd for C H N O : C, 62.89; H, 6.50; N, 11.28. Found:
13 16 2 3
C, 62.74; H, 6.44; N, 11.10.
Example 2 (10 g scale): 50% BF –methanol complex (180.0 mL) was added to a solution of 5b
3
(9.64 g, 41.2 mmol) in MeOH (500 mL) and the mixture was refluxed for 30 min with stirring. After
addition of ice and H O, the whole was made neutral by adding 40% aq. NaOH and extracted with
2
CHCl . The extract was washed with brine, dried over Na SO , and evaporated under reduced pressure
3
2
4
to leave an oil, which was column-chromatographed on SiO with CHCl to give 6 (8.52 g, 83%).
2
3
5-Methoxytryptamine (7) from 6 — 20% Aq. NaOH (1.0 mL) was added to a solution of 6 (51.2
mg, 0.20 mmol) in MeOH (1.0 mL) and the mixture was refluxed for 4 h with stirring. After addition of
ice and H O, the whole was extracted with CHCl –MeOH (95:5, v/v). The extract was washed with
2
3

brine, dried over Na SO , and evaporated under reduced pressure to leave an oil, which was
2
4
column-chromatographed on SiO with CHCl –MeOH–28% aq. NH (46:5:0.5, v/v) to give 7 (38.8
2
3
3
4f
mg, 99%). 7: mp 124—126°C (lit., mp 120°C, colorless prisms, recrystallized from CHCl –hexane).
3
-1 1
IR (KBr): 2880 (br), 1586, 1490, 790 cm . H-NMR (CDCl ) δ: 2.88 (2H, t, J=6.7 Hz), 3.03 (2H, t,
3
J=6.7 Hz), 3.87 (3H, s), 6.86 (1H, dd, J=8.8, 2.4 Hz), 7.03 (1H, d, J=2.4 Hz), 7.05 (1H, d, J=2.4
Hz), 7.26 (1H, d, J=8.8 Hz), 7.91 (1H, br s). Anal. Calcd for C H N O: C, 69.44; H, 7.42; N,
11 14 2
14.73. Found: C, 69.14; H, 7.43; N, 14.50.
Melatonin (1) from 7 — Ac O (3.0 mL, 31.7 mmol) was added to a solution of 7 (918.0 mg, 4.83
2
mmol) in pyridine (6.0 mL) and the mixture was stirred at rt for 40 min. After evaporation of the solvent
under reduced pressure, the whole was made alkaline by adding 2N aq. NaOH under ice cooling and
extracted with CHCl –MeOH (95:5, v/v). The extract was washed with brine, dried over Na SO , and
3
2
4
evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO with
2
CHCl –MeOH (99:1, v/v) to give 1 (1.03 g, 92%).
3
4-Bromomelatonin (8), 2-bromomelatonin (9),
2,6-dibromomelatonin (10), 2,4-di-
bromomelatonin (11), and 2,4,6-tribromomelatonin (12) from 1 — Entry 1: A 0.57 M
solution of Br in AcOH (1.55 mL, 0.95 mmol) was added to a solution of 1 (217.5 mg, 0.92 mmol) in
2
AcOH (10 mL) and the mixture was stirred for 5 h at rt. After addition of H O, the whole was made basic
2
by adding 40% aq. NaOH under ice cooling and extracted with CHCl –MeOH (95:5, v/v). The extract
3
was washed with brine, dried over Na SO , and evaporated under reduced pressure to leave an oil,
2
4
which was column-chromatographed on SiO successively with AcOEt and CHCl –MeOH (99:1, v/v) to
2
3
10a
give unreacted 1 (73.8 mg, 34%), 9 (82.4 mg, 28%), 1 1
(56.5 mg, 15%), and 8 (24.5 mg, 8%) in
the order of elution. 8: mp 171—173°C (colorless powder, recrystallized from CHCl –hexane). IR
3
-1 1
(KBr): 3210, 1655, 1630, 1540, 1240, 775 cm . H-NMR (CDCl ) δ: 1.96 (3H, s), 3.25 (2H, t,
3
J=6.6 Hz), 3.63 (2H, q, J=6.6 Hz), 3.92 (3H, s), 5.63 (1H, br s), 6.92 (1H, d, J=8.8 Hz), 7.09 (1H, br
s), 7.27 (1H, d, J=8.8 Hz), 8.05 (1H, br s). MS m/z: 312, 310 (M+). Anal. Calcd for C H N O Br·
13 15 2 2
1/4H O: C, 49.46; H, 4.95; N, 8.87. Found: C, 49.57; H, 4.70; N, 8.74. 9: mp 148—149°C (colorless
2
-1
prisms, recrystallized from CHCl –MeOH). IR (KBr): 3230 (br), 1625, 1580, 1485, 1210, 743 cm .
3
H-NMR (DMSO-d ) δ: 1.78 (3H, s), 2.73 (2H, t, J=7.0 Hz), 3.19 (2H, q, J=7.0 Hz), 3.76 (3H, s),
1
6
6.73 (1H, dd, J=8.5, 2.4 Hz), 7.01 (1H, d, J=2.4 Hz), 7.17 (1H, d, J=8.5 Hz), 7.96 (1H, t, J=7.0 Hz),
11.50 (1H, s). MS m/z: 312, 310 (M+). Anal. Calcd for C H N O Br : C, 50.18; H, 4.86; N, 9.00.
13 15 2 2
10a
Found: C, 50.07; H, 4.77; N, 8.83. 1 1 : mp 177—179°C (pale brown powder, recrystallized from
-1 1
CHCl –hexane). IR (KBr): 3410, 1648, 1530, 1245, 790 cm . H-NMR (CDCl ) δ: 1.94 (3H, s),
3
3
3.21 (2H, t, J=6.5 Hz), 3.61 (2H, q, J=6.5 Hz), 3.91 (3H, s), 5.72 (1H, br s), 6.89 (1H, d, J=8.8 Hz),
7.21 (1H, d, J=8.8 Hz), 8.41 (1H, br s). MS m/z: 392, 390, 388 (M+). Anal. Calcd for
C H N O Br ·1/4H O: C, 39.57; H, 3.70; N, 7.10. Found: C, 39.56; H, 3.59; N, 6.76.
13 14 2 2 2
2
Entry 2: A 0.61 M solution of Br in AcOH (6.70 mL, 4.09 mmol) was added to a solution of 1 (499.5
2
mg, 2.15 mmol) in AcOH (15.0 mL) and the mixture was stirred at rt for 2.5 h. After the same work-up
as described in Entry 1, the resultant residue was repeatedly column-chromatographed on SiO succes-
2
10b
sively with CHCl and CHCl –MeOH (99:1, v/v) to give 1 0
(285.4 mg, 34%), 1 1 (409.1 mg, 49%),
3
3

10b
and 8 (65.8 mg, 10%) in the order of elution. 1 0
: mp 146—148°C (colorless prisms, recrystallized
-1
from CHCl –MeOH). IR (KBr): 3160 (br), 1610 (br), 1568 (br), 1465, 1433, 1045, 822 cm .
3
1
H-NMR (DMSO-d ) δ: 1.76 (3H, s), 2.75 (2H, t, J=7.0 Hz), 3.21 (2H, q, J=7.0 Hz), 3.84 (3H, s),
6
7.19 (1H, s), 7.45 (1H, s), 7.94 (1H, t, J=7.0 Hz), 11.63 (1H, br s). MS m/z: 392, 390, 388 (M+).
Anal. Calcd for C H N O Br ·1/2CHCl : C, 36.02; H, 3.22; N, 6.23. Found: C, 36.01; H, 3.06; N,
13 14 2 2 2
3
5.98.
Entry 3: A 1 M solution of Br in AcOH (3.04 mL, 3.04 mmol) was added to a solution of 1 (236.1 mg,
2
1.02 mmol) in AcOH (17.0 mL) and the mixture was stirred at rt for 2 h. After the same work-up as
described in Entry 1, the resultant residue was column-chromatographed on Al O with CHCl –AcOEt–
2 3
3
hexane (4:1:4, v/v) to give 12 (286.5 mg, 60%). 1 2: mp 122—125°C (decomp, colorless powder,
-1 1
recrystallized from MeOH). IR (KBr): 3350, 1650, 1540, 1023 cm . H-NMR (CD OD) δ: 1.90 (3H,
3
s), 3.13 (2H, t, J=6.9 Hz), 3.45 (2H, t, J=6.9 Hz), 3.84 (3H, s), 7.49 (1H, s). Anal. Calcd for
C H N O Br ·1/2H O: C, 32.67; H, 2.74; N, 5.86. Found: C, 32.76; H, 2.78; N, 5.69.
13 13 2 2 3
2
1-Acetyl-2,4,6-tribromomelatonin (13) from 12 — A solution of 1 2 (85.0 mg, 0.18 mmol) in
anhydrous DMF (1.5 mL) was added to 60% NaH (23.4 mg, 0.58 mmol, washed with dry benzene) at 0°C
with stirring. To the resultant solution was added a solution of AcCl (66.4 mg, 0.85 mmol) in DMF (0.5
mL) and the mixture was stirred at rt for 24 h. After addition of H O under ice cooling, the whole was
2
extracted with AcOEt. The extract was washed with brine, dried over Na SO , and evaporated under
2
4
reduced pressure to leave an oil, which was column-chromatographed on SiO with AcOEt–hexane (2:1,
2
v/v) to give unreacted 12 (26.1 mg, 31%) and 13 (49.5 mg, 53%) in the order of elution. 1 3: mp 165—
168°C (colorless powder, recrystallized from CHCl –hexane). IR (KBr): 3260, 1705, 1630, 1550, 1010
3
-1 1
cm . H-NMR (CDCl ) δ: 1.94 (3H, s), 2.86 (3H, s), 3.30 (2H, t, J=7.1 Hz), 3.59 (2H, q, J=7.1 Hz),
3
3.90 (3H, s), 5.62 (1H, br s), 8.58 (1H, s). Anal. Calcd for C H N O Br : C, 35.26; H, 2.96; N,
15 15 2 3 3
5.48. Found: C, 35.26; H, 2.92; N, 5.44.
4-Bromomelatonin (8) from 11 — Finely chopped Mg (319.5 mg, 13.1 gram atom) was added to a
solution of 11 (50.4 mg, 0.13 mmol) in MeOH (10 mL) and the mixture was stirred at rt for 2.5 h. The
whole was made acidic by adding 2N aq. HCl under ice cooling and extracted with CHCl –MeOH (95:5,
3
v/v). The extract was washed with brine, dried over Na SO , and evaporated under reduced pressure to
2
4
leave an oil, which was column-chromatographed on SiO with CHCl –MeOH (99:1, v/v) to give
2
3
unreacted 11 (21.9 mg, 44%) and 8 (8.5 mg, 21%) in the order of elution.
2-Bromomelatonin (9) from 11 — A 1.58 M n-BuLi solution in hexane (0.25 mL, 0.39 mmol) was
added to a solution of 1 1 (50.3 mg, 0.13 mmol) in anhydous THF (3.0 mL) and the mixture was stirred at
–19°C for 4.5 h under Ar atmosphere. After addition of H O under ice cooling, the whole was extracted
2
with CHCl –MeOH (95:5, v/v). The extract was washed with brine, dried over Na SO , and evaporated
3
2
4
under reduced pressure to leave an oil, which was column-chromatographed on SiO with CHCl –MeOH
2
3
(99:1, v/v) to give 9 (20.5 mg, 51%) and unreacted 1 1 (13.4 mg, 27%) in the order of elution.
N b-Acetoacetyl-5-methoxytryptamine (14) from 1 — A 1.58 M n-BuLi solution in hexane (0.85
mL, 1.34 mmol) was added to a solution of 1 (105.5 mg, 0.45 mmol) in anhydrous THF (4.0 mL) and
the mixture was stirred at –19°C for 4 h under Ar atmosphere. To the mixture was added N,N-dimethyl-

acetamide (0.15 mL, 1.84 mmol) and the resultant mixture was stirred at –19°C for additional 1 h under Ar
atmosphere. After addition of H O under ice cooling, the whole was made acidic by adding 2N aq. HCl
2
and extracted with CHCl –MeOH (95:5, v/v). The extract was washed with brine, dried over Na SO ,
3
2
4
and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO with
2
AcOEt to give 1 4 (36.9 mg, 30%) and unreacted 1 (69.3 mg, 66%) in the order of elution. 1 4:
-1 1
Colorless oil. IR (film): 3300, 1710, 1640, 1540, 1215, 1170, 800 cm . H-NMR (CDCl ) δ: 2.23
3
(3H, s), 2.96 (2H, t, J=7.0 Hz), 3.37 (2H, s), 3.61 (2H, q, J=7.0 Hz), 3.87 (3H, s), 6.87 (1H, dd,
J=8.5, 2.4 Hz), 6.93 (1H, br s), 7.03 (1H, d, J=2.4 Hz), 7.05 (1H, d, J=2.4 Hz), 7.26 (1H, d, J=8.5
Hz), 7.95 (1H, br s). High resolution MS m/z: Calcd for C H N O : 274.1318. Found: 274.1319.
15 18 2 3
N b-Hydroxyacetyl-5-methoxytryptamine (15) from 1 — A 1.58 M n-BuLi solution in hexane
(0.85 mL, 1.34 mmol) was added to a solution of 1 (106.5 mg, 0.46 mmol) in anhydrous THF (4.0 mL)
and the mixture was stirred at –18°C for 4 h under Ar atmosphere.Then, the mixture was stirred at –18°C
for 1 h under O atmosphere. After addition of H O under ice cooling, the whole was made acidic by
2
2
adding 2N aq. HCl and extracted with CHCl –MeOH (95:5, v/v). The extract was washed with brine,
3
dried over Na SO , and evaporated under reduced pressure to leave an oil, which was
2
4
column-chromatographed on SiO with CHCl –MeOH (99:1, v/v) to give unreacted 1 (41.6 mg, 39%)
2
3
and 1 5 (41.5 mg, 36%) in the order of elution. 1 5: mp 142—143°C (colorless prisms, recrystallized from
-1 1
CHCl –hexane). IR (KBr): 3320, 3180, 1628, 1483, 1220, 1060, 805 cm . H-NMR (DMSO-d ) δ:
3
6
2.80 (2H, t, J=7.3 Hz), 3.38 (2H, q, J=7.3 Hz), 3.76 (3H, s), 3.79 (2H, d, J=5.6 Hz, collapsed to s on
addition of D O), 5.47 (1H, t, J=5.6 Hz, disappeared on addition of D O), 6.71 (1H, dd, J=8.8, 2.4
2
2
Hz), 7.06 (1H, d, J=2.4 Hz), 7.11 (1H, d, J=2.4 Hz), 7.21 (1H, d, J=8.8 Hz), 7.78 (1H, br t, J=7.3
Hz), 10.63 (1H, br s). MS m/z: 248 (M+). Anal. Calcd for C H N O ·1/8H O: C, 62.33; H, 6.44; N,
13 16 2 3
2
11.18. Found: C, 62.46; H, 6.31; N, 11.14.
N b-Acetoxyacetyl-5-methoxytryptamine (16) from 15 — Acetic anhydride (0.5 mL, 5.28
mmol) was added to a solution of 1 5 (30.1 mg, 0.12 mmol) in pyridine (1.0 mL) and the mixture was
stirred at rt for 1 h. After evaporation of the solvent under reduced pressure, the whole was made basic by
adding sat. aq. NaHCO under ice cooling and extracted with CHCl –MeOH (95:5, v/v). The extract was
3
3
washed with brine, dried over Na SO , and evaporated under reduced pressure to leave an oil, which
2
4
was column-chromatographed on SiO with CHCl -hexane (1:2, v/v) to give 1 6 (32.1 mg, 91%). 1 6:
2
3
-1 1
Colorless oil. IR (film): 3310, 1745, 1662, 1545, 1220, 1060, 800, 752 cm . H-NMR (CDCl ) δ:
3
1.97 (3H, s), 2.98 (2H, t, J=6.6 Hz), 3.64 (2H, q, J=6.6 Hz), 3.86 (3H, s), 4.52 (2H, s), 6.19 (1H, br
s), 6.88 (1H, dd, J=8.8, 2.4 Hz), 7.04 (1H, br s), 7.04 (1H, d, J=2.4 Hz), 7.27 (1H, d, J=8.8 Hz),
7.98 (1H, br s). High–resolution MS m/z: Calcd for C H N O : 290.1267. Found: 290.1264.
15 18 2 4
N b-Chloroacetyl-5-methoxytryptamine (17) from 7 — A solution of chloroacetyl chloride
(127.7 mg, 1.13 mmol) in CHCl (1.0 mL) was added to a solution of 7 (103.2 mg, 0.54 mmol) in
3
CHCl (2.0 mL) and Et N (0.3 mL, 2.15 mmol). The mixture was stirred at rt for 1 h. After addition of
3
3
H O under ice cooling, the whole was extracted with CHCl –MeOH (95:5, v/v). The extract was washed
3
2
with brine, dried over Na SO , and evaporated under reduced pressure to leave an oil, which was
2
4
9
column-chromatographed on SiO with CHCl to give 1 7 (134.3 mg, 93%). 1 7: mp 130—131°C (lit.,
2
3

mp 125—127°C, colorless prisms, recrystallized from CHCl –hexane). IR (KBr): 3300, 1650, 925, 805
3
-1 1
cm . H-NMR (CDCl ) δ: 2.99 (2H, t, J=6.8 Hz), 3.65 (2H, q, J=6.8 Hz), 3.88 (3H, s), 4.03 (2H, s),
3
6.68 (1H, br s), 6.89 (1H, dd, J=8.8, 2.4 Hz), 7.04 (2H, d, J=2.4 Hz), 7.28 (1H, d, J=8.8 Hz), 7.96
(1H, br s). MS m/z: 268, 266 (M+). Anal. Calcd for C H N O Cl·1/8H O: C, 58.05; H, 5.71; N,
13 15 2 2
2
10.41. Found: C, 58.04; H,5.57; N, 10.45.
N b-Hydroxyacetyl-5-methoxytryptamine (15) from 17 — A solution of 17 (50.0 mg, 0.19
mmol) in NH CHO–H O (10:1, v/v, 2.2 mL) was heated at 120°C for 3 h with stirring. After addition of
2
2
H O, the whole was extracted with CHCl –MeOH (95:5, v/v). The extract was washed with brine, dried
2
3
over Na SO , and evaporated under reduced pressure to leave an oil, which was column-
2
4
chromatographed on SiO with CHCl –MeOH (99:1, v/v) to give 1 5 (40.3 mg, 87%).
2
3
1-Acetylmelatonin (18a) from 1 —A solution of 1 (103.2 mg, 0.45 mmol) in anhydrous DMF (4.0
mL) was added to 60% NaH (35.5 mg, 0.89 mmol, washed with dry benzene) at 0°C with stirring. To
the resultant solution was added a solution of AcCl (124.2 mg, 1.58 mmol) in DMF (1.0 mL) and the
mixture was stirred at rt for 5 h. After addition of H O under ice cooling, the whole was extracted with
2
AcOEt. The extract was washed with brine, dried over Na SO , and evaporated under reduced pressure to
2
4
leave an oil, which was column-chromatographed on SiO with AcOEt to give unreacted 1 (10.7 mg,
2
10%) and 18a (93.9 mg, 77%) in the order of elution. 18a: mp 135—137°C (colorless prisms,,
-1 1
recrystallized from CHCl –hexane). IR (KBr): 3250, 1712, 1638, 1390, 1260 cm . H-NMR (DMSO-
3
d6) δ: 1.81(3H, s), 2.58 (3H, s), 2.77 (2H, t, J=7.0 Hz), 3.36 (2H, q, J=7.0 Hz), 3.81 (3H, s), 6.92
(1H, dd, J=8.9, 2.4 Hz), 7.13 (1H, d, J=2.4 Hz), 7.63 (1H, s), 8.01 (1H, br t, J=7.0 Hz), 8.19 (1H,
d, J=8.9 Hz). MSm/z: 274 (M+). Anal. Calcd for C H N O ·1/8H O: C, 65.14; H, 6.65; N, 10.13.
15 18 2 3
2
Found: C, 64.96; H, 6.53; N, 10.18.
N b-Acetyl-1-formyl-5-methoxytryptamine (18b) from 1— Compound (1) (23.2 mg, 0.10
mmol) was dissolved in 85% HCOOH (5.0 mL, 111 mmol) and the solution was stirred at rt for 94 h.
Evaporation of the solvent under reduced pressure afforded an oil, which was column-chromatographed
on SiO with CH Cl –MeOH (97:3, v/v) to give 18b (23.9 mg, 92%) and unreacted 1 (1.2 mg, 5%) in
2 2
2
the order of elution. 18b: Colorless oil. IR (film): 3275, 1705, 1653, 1477, 1386, 1240, 1040, 783
-1. 1
H-NMR (DMSO-d , 120°C) δ: 1.80 (3H, s), 2.81 (2H, dt, J=5.8, 1.0 Hz), 3.38 (2H, dt, J=4.8,
cm
6
5.8 Hz), 3.82 (3H, s), 6.94 (1H, dd, J=7.5, 2.4 Hz), 7.14 (1H, d, J=2.4 Hz), 7.51 (1H, br s), 7.52
(1H, s), 8.03 (1H, d, J=7.5 Hz), 9.23 (1H, s). High resolution MS m/z: Calcd for C H N O :
14 16 2 3
260.1159. Found: 260.1151.
N b-Acetylmelatonin (19) from 1 — A solution of 1 (49.4 mg, 0.21 mmol) in Ac O (1.0 mL) was
2
refluxed for 2 h with stirring. After evaporation of the solvent under reduced pressure, the whole was
made alkaline by adding 2N aq. NaOH under ice cooling and extracted with CHCl –MeOH (95:5, v/v).
3
The extract was washed with brine, dried over Na SO , and evaporated under reduced pressure to leave
2
4
an oil, which was column-chromatographed on SiO with CHCl –MeOH (99:1, v/v) to give 1 9 (53.5
2
3
mg, 92%). 1 9: mp 158—159°C (colorless prisms, recrystallized from CHCl –hexane). IR (KBr): 3340,
3
-1 1
1690 (br), 1590, 1375, 1260, 1170, 830, 820 cm . H-NMR (CDCl ) δ: 2.33 (6H, s), 2.99—3.02
3
(2H, m), 3.88 (3H, s), 3.92—3.95 (2H, m), 6.87 (1H, dd, J=8.8, 2.4 Hz), 6.98 (1H, d, J=2.4 Hz),

7.13 (1H, d, J=2.4 Hz), 7.26 (1H, d, J=8.8 Hz), 7.92 (1H, br s). MS m/z: 274 (M+). Anal. Calcd for
C H N O : C, 65.67; H, 6.61; N, 10.21. Found: C, 65.43; H, 6.56; N, 10.21.
15 18 2 3
REFERENCES AND NOTES
1. a) This is reported, Book of Abstracts, No. 2, The 119th Annual Meeting of Pharmaceutical Society of
Japan, Tokushima, March 1999, p. 22. b) This is Part 100 of a series entitled “The Chemistry of
Indoles” and a full paper of a part of the previous communication: M. Somei, N. Oshikiri, M.
Hasegawa, and F. Yamada, Heterocycles, 1999, 5 1, 1237. Part 99: M. Somei and F. Yamada, ibid.,
in press.
2. A. B. Lerner, J. D. Case, Y. Takahashi, T. H. Lee, and W. Mori, J. Am. Chem. Soc., 1958, 8 0,
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1993, 246, 89; d) H. Schmid, Gerontology, 1993, 3 9, 189; e) F. Waldhauser, B. Ehrart, and E.
Forster, Experientia, 1993, 4 9, 671; f) W. Pierpaoli, Aging, 1991, 3, 99.
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Soc., 1956, 4589; c) J. Szmuszkovicz, W. C. Anthony, and R. V. Heinzelman, J. Org. Chem., 1960,
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[Chem. Abstr., 1961, 5 5, 15458g]; e) J. Barchas, F. DaCosta, and S. Spector, Nature, 1967, 214,
919; f) T. Güngör, P. Malabre, J-M. Teuron, F. Camborde, J. Meignen, F. Hertz, A. Virone-Oddos,
F. Caussade, and A. Cloarec, J. Med. Chem., 1994, 3 7, 4307 and references cited therein.
5. M. Somei and T. Kawasaki, Heterocycles, 1989, 2 9, 1251; Review: M. Somei, J. Synth. Org.
Chem., 1991, 4 9, 205 and M. Somei, Heterocycles, 1999, 5 0, 1157 and references cited therein.
6. A. E. Lanzilotti, R. Littell, W. J. Fanshawe, T. C. McKenzie, and F. M. Lovell, J. Org. Chem.,
1979, 44, 4809.
7. M. Somei, K. Yamada, M. Hasegawa, M. Tabata, Y. Nagahama, H. Morikawa, and F. Yamada,
Heterocycles, 1996, 4 3, 1855.
8. a) F. Yamada, D. Shinmyo, and M. Somei, Heterocycles, 1994, 3 8, 273 and see the reference 2 in
the report; b) M. Somei, H. Morikawa, K. Yamada, and F. Yamada, ibid., 1998, 4 8, 1117; c) J. A.
Joule, "Progress in Heterocyclic Chemistry", Vol. 11, ed. by G. W. Gribble and T. L. Gilchrist,
Elsevier Science Ltd., Oxford, 1999, pp. 45—65; d) M. Hasegawa, K. Yamada, Y. Nagahama, and
M. Somei, Heterocycles, 1999, 5 1, 2815; e) M. Hasegawa, Y. Nagahama, K. Kobayashi, M.
Hayashi, and M. Somei, ibid., 2000, 5 2, 483; f) F. Yamada, A. Goto, and M. Somei, ibid., 2000,
5 3 (6), 1255. See also references 1b and 5.
9. M. Somei, J. Synth. Org. Chem., 1982, 4 0, 387; M. Somei, Y. Makita, and F. Yamada, The 3rd
International Kyoto Conference on New Aspects of Organic Chemistry, Abstracts Papers, Nov.,
1985, p. 128; M. Somei, Yakugaku Zasshi, 1988, 108, 361.

5
8
In the synthesis of 1, the reactions developed by us are utilized in the third and the fourth steps.
Originality rate is the result of the following calculation.
Originality Rate (%) = 100 x [Number of Newly Developed Steps + 1 ] ÷ [Total Number of Synthetic
Steps + 1]
10. a) J-B. Fourtillan, M. Fourtillan, J-C. Jacquesy, M-P. Jouannetaud, B. Violeau, and O. Karam, PCT
Int. Appl. WO 95 27,712 [Chem. Abstr., 1996, 124, 175864r]; b) F. Fraschini, B. Stankov, M.
Borgonovo, C. Introini, A. Laguzzi, E. Duranti, and M. T. Moni, U. S. Patent, US 5,552,428
[Chem. Abstr., 1996, 125, 266035h].
11. A. L. Mndzhoyan and G. L. Papayan, Izv. Aksd. Nauk Arm. SSR, Khim. Nauki, 1961, 1 4, 603
[Chem. Abstr., 1963, 5 8, 4497f].