Synthetic studies of psilocin analogs having either a formyl group or bromine atom at the 5- or 7-position.

Article abstract of DOI:10.1248/cpb.50.92

Psilocin analogs having either a formyl group (9-12) or a bromine atom (13-18) at the 5- or 7-position have been prepared for the first time. Syntheses of 5- and 7-bromo derivatives of 4-hydroxy- (23, 24, 28) and 4-benzyloxyindole-3-carbaldehyde (19, 25,

Full text of DOI:10.1248/cpb.50.92

92
Chem. Pharm. Bull. 50(1) 92—99 (2002)
Vol. 50, No. 1
Synthetic Studies of Psilocin Analogs Having Either a Formyl Group or
Bromine Atom at the 5- or 7-Position1)
Fumio YAMADA, Mayumi TAMURA, Atsuko HASEGAWA, and Masanori SOMEI*
Faculty of Pharmaceutical Sciences, Kanazawa University, 13–1 Takara-machi, Kanazawa 920–0934, Japan.
Received August 29, 2001; accepted October 2, 2001
Psilocin analogs having either a formyl group (9—12) or a bromine atom (13—18) at the 5- or 7-position
have been prepared for the first time. Syntheses of 5- and 7-bromo derivatives of 4-hydroxy- (23, 24, 28) and 4-
benzyloxyindole-3-carbaldehyde (19, 25, 29, 30), 4-benzyloxyindole-3-acetonitriles (20, 31), and 4-benzyloxy-N,N-
dimethyltryptamine (32, 34, 35) have also been established.
Key words 5-formylpsilocin; 5-bromopsilocin; 4-benzyloxy-5-bromoindole-3-carbaldehyde; 4-benzyloxy-5-bromo-N,N-di-
methyltryptamine; psilocin
Psilocin2—6) (1a, Chart 1) and psilocybin2) (1b) are well
proved to 26%, while the recovery of 1a was still observed.
Another interesting finding is that the yield of 9 seems to be
almost constant irrespective of the examined reaction condi-
tions (entries 2—5).
known indole alkaloids which cause powerful psychoto-
mimetic effect.2) With an aim to carry out their structure–ac-
tivity relationship studies, several efforts have thus far been
reported.3,4) In 1959, Hofmann and co-workers,3) and in
1985, Repke and co-workers4) had undertaken syntheses of
psilocin analogs. Their interests were focused mainly on the
modification of the side chain at the 3-position of 1a. As a
result, various compounds shown in a general formula 2 were
produced. However, to our knowledge, no reports are known
about the modification on the benzene part of indole nucleus
of 1a.
With an expectation that suitable lead compounds for
psychotic diseases, such as depression, schizophrenia,
Alzheimer’s disease, and so on, could be discovered among
psilocin derivatives and analogs, we have created a simple
preparative method5) for 1a in 50% overall yield as shown in
Chart 1 in 1998. Since then, two groups have reported an-
other synthetic methods for 1a.6)
Our synthesis of 1a consists of only five steps from in-
dole-3-carbaldehyde (3) through 4-benzyloxyindole-3-carb-
aldehyde (4), -indole-3-acetonitrile (5), -tryptamine (6), and
-N,N-dimethyltryptamine (7) as useful synthetic intermedi-
ates.
In this paper, we wish to report about the success in the
preparations of analogs of 1a as shown in a general formula
8, and also bromine derivatives of 4, 5, and 7.
Syntheses of 5- and 7-Formyl-4-hydroxy-N,N-dimethyl-
tryptamines from Psilocin As psilocin analogs and key
intermediates for further structural manipulations, we needed
5-formyl- (9, 5-formylpsilocin, Chart 2) and 7-formyl-4-hy-
droxy-N,N-dimethyltryptamine (10, 7-formylpsilocin). With
1a in hand, its Vilsmeier reaction with N,N-dimethylform-
amide (DMF) and phosphorus oxychloride (POCl3) was car-
ried out to afford 9 as an unstable oil and 10 as stable crystals
in varied yields, depending on the reaction conditions. Typi-
cal results are summarized in Table 1.
To our surprise, in all cases (entries 1—4), significant
amount of unreacted starting material was recovered in spite
of employing excess amount of Vilsmeier reagent (5—
10 mol eq). For this reason, the yields of 9 and 10 are low
within the range of 17—31% and 11—13%, respectively.
When the reaction temperature was raised from room tem-
perature to 58 °C (entry 5), the yield of 10 was slightly im-
For the structural confirmations of 9 and 10, they were
converted to 5-formyl- (11) and 7-formyl-1-tert-butoxycar-
bonyl-4-tert-butoxycarbonyloxy-N,N-dimethyltryptamine
(12) in 78 and 66% yields, respectively, by treating with ex-
cess di-tert-butyl dicarbonate [(Boc)2O] in the presence of 4-
(dimethylamino)pyridine (DMAP).
1
Comparison of H-NMR spectrum of 11 with that of 9
clearly shows that the C-7 proton signal of 11 resonated at
lower magnetic field by ca. 1.3 ppm than that of 9. This
anisotropy effect, caused by the Boc group introduced into
the 1-position, proves that 9 and 11 are 5-formyl compounds.
On the other hand, no anisotropic effect on the aromatic pro-
tons was observed in the cases of 10 and 12. Therefore, 10
and 12 are determined to be 7-formyl derivatives. Conse-
quently, we have succeeded in the first syntheses of 5-formyl-
(9) and 7-formylpsilocins (10).
Syntheses of 5- and 7-Bromo-4-hydroxy-N,N-dimethyl-
tryptamines from Psilocin We next attempted to introduce
a bromine atom directly onto the benzene part of 1a for ob-
taining 5-bromo-(13, 5-bromopsilocin, Chart 3) and 7-
bromo-4-hydroxy-N,N-dimethyltryptamines (14, 7-bromo-
psilocin). It is interesting to note that bromination of 1a with
such reagents as Br2 in AcOH, N-bromosuccinimide (NBS)
in CHCl3, and pyridinium bromide perbromide (Py·HBr·
Br2) in CHCl3–Et2O,7) did not occur. Under forced reaction
conditions, only a small amount of brominated compounds
were produced. Finally, we have found that bromination with
Py·HBr·Br2 proceeds in moderate yield in CH2Cl2 contain-
ing a small amount of AcOH. As a result, an inseparable
mixture of unstable 13 and 14 (in a ratio of 1 : 9), quite unsta-
ble 5,7-dibromo-4-hydroxytryptamine (15), and 1a were ob-
tained in 44, 16, and 14% yields, respectively, by the reaction
of 1a with Py·HBr·Br2 (1.2 mol eq) in CH2Cl2–AcOH
(10 : 1, v/v) at room temperature.
Acetylation of the mixture of 13 and 14 with Ac2O–pyri-
dine produced readily separable 4-acetoxy-5-bromo-N,N-
dimethyltryptamine (16) and 4-acetoxy-7-bromo-N,N-di-
methyltryptamine (17) as stable compounds, respectively.
Acetylation of 15 with the same reagent afforded stable 18.
Based on these findings, the isolation process of products
To whom correspondence should be addressed. e-mail: somei@dbs.p.kanazawa-u.ac.jp
© 2002 Pharmaceutical Society of Japan

January 2002
93
Chart 1
Chart 2
with Py·HBr·Br2 in CHCl3–Et2O (1 : 1, v/v).7) Regioselec-
tive introduction of a bromine atom into the 7-position was
observed to give 4-benzyloxy-7-bromoindole-3-carbaldehyde
(19) in 62% yield. Under similar reaction conditions, 5 pro-
vided a 63% yield of 4-benzyloxy-7-bromoindole-3-acetoni-
trile (20). The compound 20 was alternatively obtained in
74% yield directly from 19 together with a 17% yield of N-
(4-benzyloxy-7-bromoindol-3-yl)methylformamide (21), by
employing our reaction8) using NaCN in the presence of
NaBH4 in NH2CHO–MeOH.
Table 1. Vilsmeier Reaction of Psilocin (1a)
DMF, POCl
1a
3 → 9ϩ10ϩrecovery
Reaction conditions
Entry POCl3
(mol eq) Temp. (°C) Time (h)
Yield (%)
9
10
1a
1
2
3
4
5
5
5
5
10
5
r.t.
r.t.
r.t.
r.t.
58
14
23
72
95
23
17
29
31
27
28
11
13
11
12
26
47
46
30
40
29
Bromination of 22, prepared by catalytic hydrogenation
of 4 over 10% Pd–C in 76% yield, with Py·HBr·Br2 in
CHCl3–tetrahydrofuran (THF) (1 : 1, v/v)9) provided 5-
was improved as follows. After bromination of 1a, the reac- bromo- (23) and 7-bromo-4-hydroxyindole-3-carbaldehyde
tion mixture was subjected to column chromatography. Read- (24) in 10 and 84% yields, respectively. Treatments of 19 and
ily isolated unstable 15 and the mixture of 13 and 14 were 24 with an excess amount of benzyl bromide and K2CO3 in
immediately acetylated, separately. Consequently, 16—18 DMF afforded the same 1-benzyl-4-benzyloxy-7-bromoin-
were obtained from 1a in 4, 34, and 14% overall yields, re- dole-3-carbaldehyde (25) in 98 and 93% yields, respectively.
spectively. Alkaline hydrolysis of 16 with LiOH in MeOH
In order to attain regioselective bromination at the 5-posi-
provided 5-bromopsilocin (13) but the yield was 29% be- tion, an attempt was made by putting a sterically bulky group
cause of its unstable nature. Under the same reaction condi- onto the 1-position. The reaction of 22 with (Boc)2O (1 mol
tions, hydrolysis of 17 smoothly provided 7-bromopsilocin eq) in CH2Cl2 in the presence of Et3N and N,N-dimethyl-
(14) in 82% yield.
aminopyridine (DMAP) gave 1-tert-butoxycarbonyl-4-hy-
Preparations of Bromine Containing 4-Hydroxy- and droxyindole-3-carbaldehyde (26) in 97% yield. The introduc-
4-Benzyloxyindole-3-carbaldehydes, 4-Hydroxy-, and 4- tion of Boc group into the 1-position instead of the phenolic
Benzyloxyindole-3-acetonitriles Structure–activity rela- oxygen is confirmed by the following reactions; 1) treatment
tionship study requires a lot of compounds structurally re- of 26 with benzyl bromide and KO-tert-Bu in DMF afforded
lated to the target compound. From this point of view, we 27 in 63% yield, 2) subsequent hydrolysis of 27 with NaOH
next planned to prepare various 4-hydroxy- and 4-benzyl- in MeOH produced 4 in a quantitative yield.
oxyindole-3-carbaldehydes, and 4-hydroxy- and 4-benzyl-
oxyindole-3-acetonitriles, having a bromine atom either at 5- examined with Py·HBr·Br2 in CHCl3–THF (1 : 1, v/v). As
or 7-Position (Chart 4).
expected, 5-bromo-1-tert-butoxycarbonyl-4-hydroxyindole-
As the structure of 26 was established, its bromination was
Making use of synthetic intermediates involved in the 3-carbaldehyde (28) was produced as a sole product in 85%
pathway to 1a (Chart 1), we first examined bromination of 4 yield. Removal of Boc group in 28 with NaOH in MeOH

94
Vol. 50, No. 1
Chart 3
Chart 4
gave a 93% yield of 23, which was identical with the sample containing derivatives, and to find another synthetic approach
1
obtained by bromination of 22. Comparison of H-NMR to 5- (13) and 7-bromopsilocin (14) (Chart 5).
spectra of 23 and 28 clearly shows an anisotropy effect of the
Boc group on the C-7 proton by about 0.6 ppm, proving that v/v) provided 4-benzyloxy-7-bromo-N,N-dimethyltryptamine
these are 5-brominated compounds. (32) in 31% yield. Attempts to improve the yield were made
Bromination of 7 with Py·HBr·Br2 in CHCl3–Et2O (1 : 1,
Further structural confirmations were obtained in the by employing Br2 in AcOH and NBS in CHCl3 under various
process of preparing 4-benzyloxy-5-bromoindole-3-carbalde- reaction conditions in vain. Use of the HBr salt of 7 as a sub-
hyde (30) and -acetonitrile (31) from 28. Thus, the com- strate was unsuccessful, either, under the same reaction con-
pound 28 was converted to 4-benzyloxy-5-bromo-1-tert-bu- ditions. Subsequent catalytic hydrogenation of 32 over 10%
toxycarbonylindole-3-carbaldehyde (29) in 98% yield by the Pd–C in MeOH completely removed the bromine atom and
reaction with benzyl bromide and K2CO3. Subsequent hy- produced 1a in almost quantitative yield. However, BBr3 was
drolysis of 29 with NaOH in MeOH afforded 30 in 97% found to be the reagent of choice for debenzylation. As a re-
yield. Treatment of 30 with NaCN in the presence of NaBH4 sult, 7-bromopsilocin (14) was obtained in 41% yield.
in NH2CHO–MeOH8) afforded 31 in 97% yield.
The compound 32 could also be prepared in an alternative
Bromine Containing Derivatives of 7 and Another Syn- route. Reduction of 20 with LiAlH4 in Et2O afforded 4-ben-
thetic Approach to 5- and 7-Bromopsilocin With the zyloxy-7-bromotryptamine (33) in 86% yield together with a
compound 7 in hand, we next tried to produce its bromine 11% yield of 6.5) Subsequent dimethylation of 33 with

January 2002
95
Chart 5
IR-420 or Horiba FT-720 spectrophotometer, and 1H-NMR spectra with a
JEOL GSX-500 spectrometer, with tetramethylsilane as an internal standard.
MS spectra were recorded on a JEOL SX-102A or JEOL JMS-GCmate
spectrometer. Column chromatography was performed on silica gel (SiO2,
100—200 mesh, from Kanto Chemical Co., Inc.). Preparative thin layer
chromatography (p-TLC) was performed on Merck Kiesel-gel GF254 (type
60) (SiO2).
formaldehyde and NaBH3CN in AcOH10) furnished 32 in
91% yield.
On the other hand, treatment of 7 with (Boc)2O in CH2Cl2
in the presence of DMAP afforded 4-benzyloxy-1-tert-bu-
toxycarbonyl-N,N-dimethyltryptamine (36) in 96% yield.
Debenzylation of 36 by the catalytic hydrogenation over 10%
Pd–C in MeOH produced 1-tert-butoxycarbonyl-N,N-di-
methyl-4-hydroxytryptamine (37) in 93% yield. Bromination
of 37 with Py·HBr·Br2 in CHCl3–Et2O (1 : 1, v/v) proceeded
regioselectively to give 5-bromo-1-tert-butoxycarbonyl-4-hy-
droxy-N,N-dimethyltryptamine (38) in 87% yield, just as ob-
served in the bromination of 26. Finally, deprotection of the
Boc group of 38 with CF3COOH furnished 5-bromopsilocin
(13) in 97% yield. Thus, preparation of relatively unstable 13
by this route is far better than the direct bromination of 1a as
described above.
Both N- and O-protected bromopsilocin would be a good
synthetic intermediate for future use. So, we prepared 4-ben-
zyloxy-7-bromo-1-tert-butoxycarbonyl-N,N-dimethyltrypta-
mine (34) in 83% yield by treating 32 with (Boc)2O in
CH2Cl2 in the presence of DMAP. The other isomer, 4-ben-
zyloxy-5-bromo-1-tert-butoxycarbonyl-N,N-dimethyltrypta-
mine (35) was obtained in 43% yield by benzylation of 38
using KH and benzylbromide in DMF.
In conclusion, we have succeeded for the first time in de-
veloping synthetic methods for psilocin analogs having either
a formyl group (9—12) or bromine atom (13—18) at the 5-
or 7-position. Preparations of 5- and 7-bromo derivatives of
4-hydroxy- (23, 24, 28) and 4-benzyloxyindole-3-carbalde-
hydes (19, 25, 29, 30), 4-benzyloxyindole-3-acetonitriles (20,
31), and 4-benzyloxy-N,N-dimethyltryptamines (32, 34, 35)
have also been established. These compounds would be suit-
able for further manipulations. Biological evaluations of new
compounds described in this paper are in progress.
5-Formyl-4-hydroxy-N,N-dimethyltryptamine (9) and 7-Formyl-4-hy-
droxy-N,N-dimethyltryptamine (10) from Psilocin (1a) Entry 1: Anhy-
drous DMF (1 ml) was added to an ice-cooled POCl3 (91.0 mg, 0.59 mmol)
and the mixture was stirred for 10 min at room temperature. To the resulting
viscous solution was added a solution of 1a (22.4 mg, 0.11 mmol) in anhy-
drous DMF (2 ml) and stirring was continued for 14 h at room temperature.
The reaction mixture was made basic by adding 2 N NaOH at 0 °C and the
whole was stirred at room temperature for 1 h. After adjusting pH to 7—8
with 1 N HCl, the whole was extracted with CHCl3–MeOH (95 : 5, v/v). The
extract was washed with brine, dried over Na2SO4, and evaporated under re-
duced pressure to leave an oil, which was column-chromatographed on SiO2
with CHCl3–MeOH–28% aq. NH3 (46 : 5 : 0.5, v/v) to give 10 (2.8 mg, 11%),
unreacted 1a (10.6 mg, 47%), and 9 (4.2 mg, 17%) in the order of elution. 9:
Unstable yellow oil. IR (film): 3200, 1628 cmϪ1. 1H-NMR (CD3OD) d: 2.43
(6H, s), 2.82 (2H, t, Jϭ7.5 Hz), 3.10 (2H, t, Jϭ7.5 Hz), 6.89 (1H, d, Jϭ
8.5 Hz), 6.99 (1H, s), 7.28 (1H, d, Jϭ8.5 Hz), 9.88 (1H, s). High-resolution
MS m/z: Calcd for C13H16N2O2: 232.1212. Found: 232.1213. 10: mp
220.5—222.5 °C (colorless prisms, recrystallized from AcOEt–hexane). IR
1
(KBr): 3380, 1634, 1583 cmϪ1. H-NMR (CD3OD) d: 2.62 (6H, s), 3.04—
3.09 (2H, m), 3.10—3.15 (2H, m), 6.38 (1H, d, Jϭ8.3 Hz), 6.98 (1H, s),
7.43 (1H, d, Jϭ8.3 Hz), 9.59 (1H, s). MS m/z: 232 (Mϩ). Anal. Calcd for
C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.30; H, 6.96; N,
12.03.
Entry 2: Anhydrous DMF (1 ml) was added to an ice-cooled POCl3
(95.6 mg, 0.62 mmol) and the mixture was stirred for 10 min at room tem-
perature. To the resulting viscous solution was added a solution of 1a
(19.0 mg, 0.093 mmol) in anhydrous DMF (2 ml) and stirring was continued
for 23 h at room temperature. After work-up and purification as described in
entry 1, 10 (2.9 mg, 13%), unreacted 1a (8.8 mg, 46%), and 9 (6.2 mg, 29%)
were obtained in the order of elution.
Entry 3: Anhydrous DMF (1 ml) was added to an ice-cooled POCl3
(102.4 mg, 0.67 mmol) and the mixture was stirred for 10 min at room tem-
perature. To the resulting viscous solution was added a solution of 1a
(21.4 mg, 0.11 mmol) in anhydrous DMF (2 ml) and stirring was continued
for 72 h at room temperature. After work-up and purification as described in
entry 1, 10 (2.6 mg, 11%), unreacted 1a (6.4 mg, 30%), and 9 (7.5 mg, 31%)
were obtained in the order of elution.
Experimental
Melting points were determined on a Yanagimoto micro melting point ap-
paratus and are uncorrected. IR spectra were determined with a Shimadzu
Entry 4: Anhydrous DMF (1 ml) was added to an ice-cooled POCl3

96
Vol. 50, No. 1
for C14H1679Br81BrN2O2: 403.9558. Found: 403.9559. C14H1681Br2N2O2:
405.9537. Found: 405.9543.
(170.8 mg, 1.11 mmol) and the mixture was stirred for 10 min at room tem-
perature. To the resulting viscous solution was added a solution of 1a
(21.2 mg, 0.10 mmol) in anhydrous DMF (2 ml) and stirring was continued
for 95 h at room temperature. After work-up and purification as described in
entry 1, 10 (3.0 mg, 12%), unreacted 1a (8.5 mg, 40%), and 9 (6.4 mg, 27%)
were obtained in the order of elution.
Entry 5: Anhydrous DMF (1 ml) was added to an ice-cooled POCl3
(96.4 mg, 0.62 mmol) and the mixture was stirred for 10 min at room tem-
perature. To the resulting viscous solution was added a solution of 1a
(21.6 mg, 0.11 mmol) in anhydrous DMF (2 ml) and stirring was continued
for 23 h at 58 °C. After work-up and purification as described in entry 1, 10
(6.4 mg, 26%), unreacted 1a (6.2 mg, 29%), and 9 (6.8 mg, 28%) were ob-
tained in the order of elution.
5-Bromo-4-hydroxy-N,N-dimethyltryptamine (13) from 16 LiOH
(11.5 mg, 0.48 mmol) was added to a solution of 16 (12.8 mg, 0.039 mmol)
in MeOH (2 ml), and the mixture was stirred at room temperature for 2 h.
After addition of AcOH (0.1 ml) to the reaction mixture, the solvent was
evaporated under reduced pressure to leave an oil, which was column-chro-
matographed on SiO2 with CHCl3–MeOH– 28% aq. NH3 (46 : 5 : 0.5, v/v) to
give unstable 13 (3.7 mg, 29%) and unreacted 16 (3.3 mg, 22%) in the order
of elution. 13·1/2AcOEt: mp 139—141 °C (dec., colorless prisms, recrys-
tallized from AcOEt). IR (KBr): 3230, 1726, 1471, 1439 cmϪ1 1H-NMR
.
(CDCl3) d: 1.26 (3/2H, t, Jϭ7.1 Hz), 1.60 (1H, br s, disappeared on addition
of D2O), 2.04 (3/2H, s), 2.41 (6H, s), 2.70—2.73 (2H, m), 2.92—2.95 (2H,
m), 4.12 (1H, q, Jϭ7.1 Hz), 6.73 (1H, d, Jϭ8.6 Hz), 6.83 (1H, br d,
Jϭ2.2 Hz, collapsed to s on addition of D2O), 7.26 (1H, d, Jϭ8.6 Hz), 7.90
(1H, br s, disappeared on addition of D2O). MS m/z: 282 and 284 (Mϩ 79Br,
81Br). Anal. Calcd for C12H15BrN2O·1/2C4H8O2: C, 51.39; H, 5.85; N, 8.56.
Found: C, 51.17; H, 5.79; N, 8.40.
1-tert-Butoxycarbonyl-4-tert-butoxycarbonyloxy-5-formyl-N,N-di-
methyltryptamine (11) from 9 A solution of 9 (10.4 mg, 0.045 mmol),
DMAP (5.6 mg, 0.046 mmol), and Boc2O (0.04 ml, 0.17 mmol) in CH2Cl2
(1 ml) was stirred for 18 h at room temperature. The mixture was evaporated
under reduced pressure to leave an oil, which was column-chromatographed
on SiO2 with CHCl3–MeOH (95 : 5, v/v) to give 11 (15.1 mg, 78%). 11: mp
109—111 °C (colorless prisms, recrystallized from hexane). IR (KBr): 1751,
7-Bromo-4-hydroxy-N,N-dimethyltryptamine (14) from 17 LiOH
(10.8 mg, 0.45 mmol) was added to a solution of 17 (12.8 mg, 0.039 mmol)
in MeOH (2 ml), and the mixture was stirred at room temperature for
10 min. After addition of AcOH (0.1 ml) to the reaction mixture, the solvent
was evaporated under reduced pressure to leave an oil, which was column-
chromatographed on SiO2 with CHCl3–MeOH– 28% aq. NH3 (46 : 5 : 0.5,
v/v) to give 14 (9.2 mg, 82%). 14: mp 148—150 °C (dec., colorless prisms,
1734, 1690, 1608 cmϪ1 1H-NMR (CD3OD) d: 1.57 (9H, s), 1.68 (9H, s),
.
2.38 (6H, s), 2.72 (2H, t, Jϭ7.9 Hz), 2.94 (2H, t, Jϭ7.9 Hz), 7.56 (1H, s),
7.81 (1H, d, Jϭ8.7 Hz), 8.21 (1H, d, Jϭ8.7 Hz), 10.05 (1H, s). MS m/z: 432
(Mϩ). Anal. Calcd for C23H32N2O6: C, 63.87; H, 7.46; N, 6.48. Found: C,
63.79; H, 7.58; N, 6.42.
recrystallized from AcOEt). IR (KBr): 3246, 1498, 1342, 833 cmϪ1 1H-
.
1-tert-Butoxycarbonyl-4-tert-butoxycarbonyloxy-7-formyl-N,N-di-
methyltryptamine (12) from 10 A solution of 10 (6.0 mg, 0.026 mmol),
DMAP (3.0 mg, 0.025 mmol), and Boc2O (0.05 ml, 0.22 mmol) in CH2Cl2
(1 ml) was stirred for 18 h at room temperature. The mixture was evaporated
under reduced pressure to leave an oil, which was column-chromatographed
on SiO2 with CHCl3–MeOH (95 : 5, v/v) to give 12 (7.4 mg, 66%). 12: Col-
orless oil. IR (film): 1758, 1735, 1689 cmϪ1. 1H-NMR (CDCl3) d: 1.57 (9H,
s), 1.62 (9H, s), 2.36 (6H, s), 2.66 (2H, t, Jϭ7.8 Hz), 2.93 (2H, t, Jϭ7.8 Hz),
7.19 (1H, d, Jϭ8.3 Hz), 7.39 (1H, s), 7.75 (1H, d, Jϭ8.3 Hz), 10.44 (1H, s).
High-resolution MS m/z: Calcd for C23H32N2O6: 432.2260. Found:
432.2261.
NMR (CD3OD) d: 2.36 (6H, s), 2.74 (2H, t, Jϭ6.7 Hz), 3.00 (2H, t,
Jϭ6.7 Hz), 6.28 (1H, d, Jϭ8.1 Hz), 6.95 (1H, s), 7.00 (1H, d, Jϭ8.1 Hz).
MS m/z: 282 and 284 (Mϩ 79B, 81Br). Anal. Calcd for C12H15BrN2O: C,
50.90; H, 5.34; N, 9.89. Found: C, 51.00; H, 5.34; N, 9.62.
4-Benzyloxy-7-bromoindole-3-carbaldehyde (19) from 4-Benzyloxyin-
dole-3-carbaldehyde (4) Py·HBr·Br2 (57.4 mg, 0.18 mmol) was added to
a solution of 4 (38.8 mg, 0.16 mmol) in CHCl3–Et2O (1 : 1, v/v, 16 ml), and
the mixture was stirred at room temperature for 5 h. The reaction mixture
was washed with brine, dried over Na2SO4, and evaporated under reduced
pressure to leave an oil, which was column-chromatographed on SiO2 to
give 19 (31.4 mg, 62%) from AcOEt–hexane (1 : 3, v/v) eluent and unreacted
4 (7.8 mg, 20%) from AcOEt–hexane (1 : 1, v/v) eluent. 19: mp 186—
188 °C (colorless needles, recrystallized from MeOH). IR (KBr): 3300,
4-Acetoxy-5-bromo-N,N-dimethyltryptamine (16), 4-Acetoxy-7-bro-
mo-N,N-dimethyltryptamine (17), and 4-Acetoxy-5,7-dibromo-N,N-di-
11)
methyltryptamine (18) from 1a Py·HBr·Br2 (42.2 mg, 0.13 mmol)
1
1635 cmϪ1. H-NMR (CDCl3) d: 5.25 (2H, s), 6.70 (1H, d, Jϭ8.3 Hz), 7.31
was added to a solution of 1a (22.4 mg, 0.11 mmol) in CH2Cl2 (3 ml) and
AcOH (0.3 ml), and the mixture was stirred at room temperature for 5 h.
After evaporation of the solvent under reduced pressure, the residue was col-
umn-chromatographed repeatedly on SiO2 with CHCl3–MeOH–28% aq.
NH3 (46 : 5 : 0.5, v/v) to give quite unstable 15 (6.3 mg, 16%), a mixture
(1H, d, Jϭ8.3 Hz), 7.33—7.43 (3H, m), 7.45—7.49 (2H, m), 7.97 (1H, d,
Jϭ2.9 Hz, collapsed to s on addition of D2O), 8.93 (1H, br s, disappeared on
addition of D2O), 10.48 (1H, s). MS m/z: 329 and 331 (Mϩ 79Br, 81Br). Anal.
Calcd for C16H12BrNO2: C, 58.20; H, 3.66; N, 4.24. Found: C, 58.19; H,
3.63; N, 4.15.
1
(13.8 mg, 44%) of unstable 13 and 14 (in a ratio of 1 : 9, calculated by H-
NMR) and unreacted 1a (3.1 mg, 14%) in the order of elution. Compound
15 was so unstable that spectral data of pure sample were not obtained.
Ac2O (1 ml) was added to a solution of the mixture of 13 and 14 (13.8 mg)
in pyridine (2 ml), and the mixture was stirred at room temperature for 23 h.
After evaporation of the solvent under reduced pressure, the residue was col-
umn-chromatographed repeatedly on SiO2 with CHCl3–MeOH–28% aq.
NH3 (46 : 5 : 0.5, v/v) to give 17 (12.0 mg, 34% from 1a) and 16 (1.3 mg, 4%
from 1a) in the order of elution. 16: Colorless oil. IR (film): 3390,
4-Benzyloxy-7-bromoindole-3-acetonitrile (20) from 4-Benzyloxyin-
dole-3-acetonitrile (5) Py·HBr·Br2 (53.8 mg, 0.17 mmol) was added to a
solution of 5 (41.4 mg, 0.16 mmol) in CHCl3–Et2O (1 : 1, v/v, 8 ml), and the
mixture was stirred at room temperature for 4 h. The reaction mixture was
washed with brine, dried over Na2SO4, and evaporated under reduced pres-
sure to leave an oil, which was column-chromatographed on SiO2 with
AcOEt–hexane (1 : 4, v/v) to give 20 (33.7 mg, 63%) and unreacted 5
(6.4 mg, 15%). 20: mp 150—151 °C (colorless leaves, recrystallized from
Et2O–hexane). IR (KBr): 3350, 2260, 1616 cmϪ1. 1H-NMR (CDCl3) d: 3.99
(2H, d, Jϭ1.0 Hz), 5.16 (2H, s), 6.49 (1H, d, Jϭ8.3 Hz), 7.19 (1H, dt,
Jϭ2.2, 1.0 Hz, collapsed to br s on addition of D2O), 7.23 (1H, d, Jϭ8.3 Hz),
7.33—7.44 (3H, m), 7.45—7.49 (2H, m), 8.27 (1H, br s, disappeared on ad-
dition of D2O). MS m/z: 340 and 342 (Mϩ 79Br, 81Br). Anal. Calcd for
C17H13BrN2O: C, 59.84; H, 3.84; N, 8.21. Found: C, 60.12; H, 3.79; N, 8.10.
Compound 20 and N-(4-Benzyloxy-7-bromoindol-3-yl)methylform-
amide (21) from 19 NaBH4 (3.5 mg, 0.092 mmol) was added to a solution
of 19 (18.6 mg, 0.056 mmol) in NH2CHO–MeOH (1 : 1, v/v, 4 ml), and the
mixture was stirred for 0.5 h. To the reaction mixture was added NaCN
(30.2 mg, 0.62 mmol) and the whole was refluxed on oil bath at 100 °C for
3 h with stirring. After cooling to room temperature, brine was added and
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 to give 20 (14.2 mg, 74%)
from CHCl3 eluent and 21 (3.4 mg, 17%) from CHCl3–MeOH (95 : 5, v/v)
eluent. 21: mp 182—183 °C (colorless needles, recrystallized from AcOEt).
1763 cmϪ1 1H-NMR (CDCl3) d: 2.31 (6H, s), 2.45 (3H, s), 2.59 (2H, t,
.
Jϭ7.7 Hz), 2.85 (2H, t, Jϭ7.7 Hz), 6.93 (1H, dt, Jϭ2.2, 1.1 Hz, collapsed to
s on addition of D2O), 7.04 (1H, d, Jϭ8.5 Hz), 7.28 (1H, d, Jϭ8.5 Hz), 8.30
(1H, br s, disappeared on addition of D2O). High-resolution MS m/z: Calcd
for C14H1779BrN2O2: 324.0473. Found: 324.0463. Calcd for C14H1781BrN2O2:
326.0453. Found: 326.0458. 17: Colorless oil. IR (film): 3367, 1763 cmϪ1
.
1H-NMR (CDCl3) d: 2.31 (6H, s), 2.40 (3H, s), 2.59 (2H, t, Jϭ7.9 Hz), 2.90
(2H, t, Jϭ7.9 Hz), 6.72 (1H, d, Jϭ8.3 Hz), 7.04 (1H, dt, Jϭ2.2, 1.1 Hz, col-
lapsed to s on addition of D2O), 7.28 (1H, d, Jϭ8.3 Hz), 8.26 (1H, br s,
disappeared on addition of D2O). High-resolution MS m/z: Calcd for
C14H1779BrN2O2: 324.0473. Found: 324.0470. Calcd for C14H1781BrN2O2:
326.0453. Found: 326.0444. Ac2O (0.5 ml) was added to a solution of 15
(6.3 mg, 0.017 mmol) in pyridine (1 ml), and the mixture was stirred at room
temperature for 20 h. After evaporation of the solvent under reduced pres-
sure, the residue was column-chromatographed repeatedly on SiO2 with
CHCl3–MeOH–28% aq. NH3 (46 : 5 : 0.5, v/v) to give 18 (6.1 mg, 14% from
1a). 18: Colorless oil. IR (film): 3359, 1759 cmϪ1. 1H-NMR (CDCl3) d: 2.30
(6H, s), 2.45 (3H, s), 2.57 (2H, t, Jϭ7.8 Hz), 2.84 (2H, t, Jϭ7.8 Hz),
7.05 (1H, br d, Jϭ2.2 Hz, collapsed to s on addition of D2O), 7.50 (1H,
s), 8.34 (1H, br s, disappeared on addition of D2O). High-resolution
MS m/z: Calcd for C14H1679Br2N2O2: 401.9579. Found: 401.9566. Calcd
1
IR (KBr): 3290, 3230, 1639 cmϪ1. H-NMR (CDCl3, rotational isomers ex-
isted) d: 4.53 (2/7H, d, Jϭ6.4 Hz), 4.58 (12/7H, d, Jϭ6.1 Hz), 5.17 (2/7H,
s), 5.20 (12/7H, s), 5.99 (1/7H, br s, disappeared on addition of D2O), 6.22
(6/7H, br s, disappeared on addition of D2O), 6.52 (1/7H, d, Jϭ8.3 Hz), 6.56

January 2002
97
(6/7H, d, Jϭ8.3 Hz), 7.05 (1/7H, d, Jϭ2.1 Hz), 7.14 (6/7H, d, Jϭ2.4 Hz),
7.24 (1/7H, d, Jϭ8.3 Hz), 7.25 (6/7H, d, Jϭ8.3 Hz), 7.34—7.49 (5H, m),
7.92 (6/7H, d, Jϭ1.7 Hz, collapsed to s on addition of D2O), 8.02 (1/7H, d,
Jϭ12.0 Hz, collapsed to s on addition of D2O), 8.24 (1H, br s, disappeared
on addition of D2O). MS m/z: 358 and 360 (Mϩ 79Br, 81Br). Anal. Calcd for
C17H15BrN2O2: C, 56.84; H, 4.21; N, 7.80. Found: C, 56.99; H, 4.18; N,
7.58.
4-Hydroxyindole-3-carbaldehyde (22) from 4 A suspension of 4
(187.1 mg, 0.75 mmol) and 10% Pd–C (82.0 mg) in MeOH (15 ml) was
stirred at room temperature for 1 h under H2 atmosphere. The reaction mix-
ture was filtered through SiO2 to remove Pd–C and the filtrate was evapo-
rated under reduced pressure to leave a crystalline solid, which was recrys-
tallized from CHCl3–MeOH to give 22 (70.6 mg). The mother liquor was
purified by p-TLC on SiO2 with CH2Cl2–MeOH (97 : 3, v/v) as a developing
solvent. Extraction of the band having an Rf value of 0.42—0.31 with
CH2Cl2–MeOH (95 : 5, v/v) gave 22 (20.4 mg). The total yield of 22 was
91.0 mg (76%). mp, 1H-NMR, and IR spectra of 22 were identical with those
of the authentic sample 22 reported by us.12)
KO-tert-Bu (17.3 mg, 0.15 mmol) was added to a solution of 26 (29.1 mg,
0.11 mmol) in anhydrous DMF (2 ml) at 0 °C, and the mixture was stirred at
0 °C for 10 min. To this orange solution was added a solution of benzyl bro-
mide (18.8 mg, 0.11 mmol) in anhydrous DMF (1 ml) and stirring was con-
tinued at room temperature for 1 h. Saturated NH4Cl solution was added at
0 °C and the whole was extracted with AcOEt. The extract was washed with
brine, dried over Na2SO4, and evaporated under reduced pressure to leave a
crystalline solid, which was column-chromatographed on SiO2 with CHCl3
to give 27 (24.7 mg, 63%). 27: mp 171—173 °C (colorless prisms, recrystal-
1
lized from AcOEt). IR (KBr): 1730, 1665 cmϪ1. H-NMR (CDCl3) d: 1.67
(9H, s), 5.26 (2H, s), 6.89 (1H, d, Jϭ8.3 Hz), 7.30 (1H, t, Jϭ8.3 Hz), 7.32—
7.42 (3H, m), 7.44—7.48 (2H, m), 7.87 (1H, d, Jϭ8.3 Hz), 8.24 (1H, s),
10.54 (1H, s). MS m/z: 351 (Mϩ). Anal. Calcd for C21H21NO4: C, 71.78; H,
6.02; N, 3.99. Found: C, 71.70; H, 6.08; N, 3.89.
Compound 4 from 27 A solution of NaOH (17.9 mg, 0.45 mmol) in
MeOH (0.6 ml) was added to a solution of 27 (26.4 mg, 0.075 mmol) in
MeOH (2 ml), and the mixture was stirred for 2 h at room temperature. Satu-
rated NH4Cl solution was added and the whole was extracted with AcOEt.
The extract was washed with brine, dried over Na2SO4, and evaporated
under reduced pressure to leave a crystalline solid, which was column-chro-
matographed on SiO2 with CHCl3–MeOH (99 : 1, v/v) to give 45) (18.8 mg,
100%).
5-Bromo-4-hydroxyindole-3-carbaldehyde (23) and 7-Bromo-4-hy-
droxyindole-3-carbaldehyde (24) from 22 Py·HBr·Br2 (172.4 mg, 0.54
mmol) was added to a solution of 22 (77.6 mg, 0.48 mmol) in CHCl3–THF
(1 : 1, v/v, 40 ml), and the mixture was stirred for 1 h at room temperature.
The reaction mixture was washed with brine, dried over Na2SO4, and evapo-
rated under reduced pressure to leave a crystalline solid, which was column-
chromatographed on SiO2 with AcOEt–hexane (1 : 1, v/v) to give 24
(96.7 mg, 84%), unreacted 22 (6.8 mg, 6%), and 23 (11.5 mg, 10%) in the
order of elution. 23: mp 224—226 °C (dec., pale yellow needles, recrystal-
5-Bromo-1-tert-butoxycarbonyl-4-hydroxyindole-3-carbaldehyde (28)
from 26 Py·HBr·Br2 (119.6 mg, 0.37 mmol) was added to a solution of 26
(84.7 mg, 0.32 mmol) in CHCl3–THF (1 : 1, v/v, 8 ml), and the mixture was
stirred at room temperature for 22 h. The reaction mixture was washed with
brine, dried over Na2SO4, and evaporated under reduced pressure to leave a
crystalline solid, which was recrystallized from AcOEt to give 28 (70.0 mg)
as pale yellow needles. The mother liquor was column-chromatographed on
SiO2 with AcOEt–hexane (1 : 4, v/v) to give 28 (23.3 mg). The total yield of
28 was 93.3 mg (85%). 28: mp 236—238 °C (dec.). IR (KBr): 1764,
1
lized from MeOH). IR (KBr): 3300, 1600 cmϪ1. H-NMR (Dimethylsulfox-
ide (DMSO-d6)) d: 6.94 (1H, d, Jϭ8.5 Hz), 7.36 (1H, d, Jϭ8.5 Hz), 8.43 (1H,
s), 9.65 (1H, s), 11.40 (1H, s, disappeared on addition of D2O), 12.54 (1H,
br s, disappeared on addition of D2O). MS m/z: 239 and 241 (Mϩ 79Br, 81Br).
Anal. Calcd for C9H6BrNO2: C, 45.03; H, 2.52; N, 5.83. Found: C, 45.11; H,
2.52; N, 5.63. 24: mp 212—214 °C (dec., pale yellow needles, recrystallized
1640 cmϪ1 1H-NMR (DMSO-d6) d: 1.66 (9H, s), 7.52 (1H, d, Jϭ8.8 Hz),
.
7.56 (1H, d, Jϭ8.8 Hz), 8.80 (1H, s), 9.88 (1H, s), 11.08 (1H, br s, disap-
peared on addition of D2O). MS m/z: 339 and 341 (Mϩ 79Br, 81Br). Anal.
Calcd for C14H14BrNO4: C, 49.43; H, 4.15; N, 4.12. Found: C, 49.47; H,
4.08; N, 3.92.
from MeOH). IR (KBr): 3220, 1618 cmϪ1 1H-NMR (DMSO-d6) d: 6.53
.
(1H, d, Jϭ8.4 Hz), 7.32 (1H, d, Jϭ8.4 Hz), 8.43 (1H, s), 9.70 (1H, s), 10.64
(1H, s, disappeared on addition of D2O), 12.57 (1H, br s, disappeared on ad-
dition of D2O). MS m/z: 239 and 241 (Mϩ 79Br, 81Br). Anal. Calcd for
C9H6BrNO2: C, 45.03; H, 2.52; N, 5.83. Found: C, 45.13; H, 2.50; N, 5.55.
1-Benzyl-4-benzyloxy-7-bromoindole-3-carbaldehyde (25) from 19
A solution of benzyl bromide (28.3 mg, 0.17 mmol) in DMF (1 ml) was
added to a suspension of 19 (20.0 mg, 0.061 mmol) and K2CO3 (27.2 mg,
0.20 mmol) in DMF (1 ml), and the mixture was stirred at room temperature
for 24 h. After addition of brine, the whole was extracted with AcOEt. The
extract was washed with brine, dried over Na2SO4, and evaporated under re-
duced pressure to leave a crystalline solid, which was column-chro-
matographed on SiO2 with CHCl3–hexane (7 : 3, v/v) to give 25 (25.0 mg,
98%). 25: mp 171—172 °C (colorless needles, recrystallized from AcOEt).
Compound 23 from 28 A solution of NaOH (10.2 mg, 0.23 mmol) in
MeOH (0.5 ml) was added to a solution of 28 (10.7 mg, 0.031 mmol) in
MeOH (2 ml), and the mixture was stirred for 2.5 h at room temperature.
Saturated NH4Cl solution was added and the whole was extracted with
AcOEt. The extract was washed with brine, dried over Na2SO4, and evapo-
rated under reduced pressure to leave a crystalline solid, which was column-
chromatographed on SiO2 with AcOEt–hexane (1 : 1, v/v) to give 23
(7.1 mg, 93%).
4-Benzyloxy-5-bromo-1-tert-butoxycarbonylindole-3-carbaldehyde
(29) from 28 KO-tert-Bu (24.5 mg, 0.22 mmol) was added to a solution of
28 (36.2 mg, 0.11 mmol) in anhydrous DMF (2 ml) at 0 °C, and the mixture
was stirred at 0 °C for 10 min. To this orange solution was added a solution
of benzyl bromide (36.3 mg, 0.21 mmol) in anhydrous DMF (1 ml) and stir-
ring was continued at room temperature for 1 h. Saturated NH4Cl solution
was added and the whole was extracted with AcOEt. The extract was
washed with brine, dried over Na2SO4, and evaporated under reduced pres-
sure to leave a crystalline solid, which was column-chromatographed on
SiO2 with AcOEt–hexane (1 : 4, v/v) to give 29 (44.9 mg, 98%). 29: mp
154—156 °C (colorless needles, recrystallized from MeOH). IR (KBr):
1
IR (KBr): 1662 cmϪ1. H-NMR (CDCl3) d: 5.24 (2H, s), 5.84 (2H, s), 6.67
(1H, d, Jϭ8.5 Hz), 7.04—7.08 (2H, m), 7.26—7.43 (7H, m), 7.44—7.48
(2H, m), 7.80 (1H, s), 10.47 (1H, s). MS m/z: 419 and 421 (Mϩ 79Br, 81Br).
Anal. Calcd for C23H18BrNO2: C, 65.73; H, 4.32; N, 3.33. Found: C, 65.72;
H, 4.26; N, 3.19.
Compound 25 from 24
A solution of benzyl bromide (64.1 mg,
0.38 mmol) in DMF (1 ml) was added to a suspension of 24 (16.0 mg,
0.067 mmol) and K2CO3 (29.8 mg, 0.22 mmol) in DMF (1 ml), and the mix-
ture was stirred at room temperature for 24 h. After addition of brine, the
whole was extracted with AcOEt. The extract was washed with brine, dried
over Na2SO4, and evaporated under reduced pressure to leave a crystalline
solid, which was column-chromatographed on SiO2 with CHCl3–hexane
(1 : 1, v/v) to give 25 (26.1 mg, 93%).
1743, 1678 cmϪ1 1H-NMR (CDCl3) d: 1.68 (9H, s), 5.15 (2H, s), 7.34—
.
7.42 (3H, m), 7.49—7.54 (2H, m), 7.59 (1H, d, Jϭ8.8 Hz), 7.95 (1H, d,
Jϭ8.8 Hz), 8.23 (1H, s), 10.31 (1H, s). MS m/z: 429 and 431 (Mϩ 79Br,
81Br). Anal. Calcd for C21H20BrNO4: C, 58.62; H, 4.69; N, 3.26. Found: C,
58.52; H, 4.69; N, 3.06.
1-tert-Butoxycarbonyl-4-hydroxyindole-3-carbaldehyde (26) from 22
DMAP (14.3 mg, 0.12 mmol) and a solution of Boc2O (134.8 mg, 0.62
mmol) in CH2Cl2 (2 ml) were successively added to a solution of 22 (98.0
mg, 0.61 mmol) in CH2Cl2–Et3N (9 : 1, v/v, 10 ml), and the mixture was
stirred at room temperature for 2 h. The reaction mixture was evaporated
under reduced pressure to leave a crystalline solid, which was column-chro-
matographed on SiO2 with CHCl3–hexane (1 : 1, v/v) to give 26 (153.3 mg,
97%). 26: mp 169—171 °C (pale yellow needles, recrystallized from
AcOEt). IR (KBr): 1756, 1637 cmϪ1. 1H-NMR (CDCl3) d: 1.71 (9H, s), 6.84
(1H, dd, Jϭ8.1, 0.7 Hz), 7.31 (1H, dd, Jϭ8.3, 8.1 Hz), 7.61 (1H, d,
Jϭ8.3 Hz), 8.25 (1H, s), 9.76 (1H, s), 10.13 (1H, s, disappeared on addition
of D2O). MS m/z: 261 (Mϩ). Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79;
N, 5.36. Found: C, 64.20; H, 5.80; N, 5.19.
4-Benzyloxy-5-bromoindole-3-carbaldehyde (30) from 29 A solution
of NaOH (161.8 mg, 4.05 mmol) in MeOH (10 ml) was added to a solution
of 29 (288.8 mg, 0.67 mmol) in MeOH (20 ml), and the mixture was stirred
at room temperature for 2 h. Saturated NH4Cl solution was added and the
whole was extracted with AcOEt. The extract was washed with brine, dried
over Na2SO4, and evaporated under reduced pressure to leave a crystalline
solid, which was recrystallized from MeOH to give 30 (141.2 mg) as color-
less needles. The mother liquor was column-chromatographed on SiO2 with
AcOEt–hexane (1 : 1, v/v) to give 30 (72.7 mg). Total yield of 30 was
213.9 mg (97%). 30: mp 167—170 °C. IR (KBr): 3153, 1651, 1630 cmϪ1
.
1H-NMR (CDCl3) d: 5.15 (2H, s), 7.14 (1H, d, Jϭ8.6 Hz), 7.33—7.42 (3H,
m), 7.47 (1H, d, Jϭ8.6 Hz), 7.56—7.60 (2H, m), 7.91 (1H, d, Jϭ2.9 Hz, col-
lapsed to s on addition of D2O), 9.15 (1H, br s, disappeared on addition of
D2O), 10.29 (1H, s). MS m/z: 329 and 331 (Mϩ 79Br, 81Br). Anal. Calcd for
4-Benzyloxy-1-tert-butoxycarbonylindole-3-carbaldehyde (27) from 26

98
Vol. 50, No. 1
C16H12BrNO2: C, 58.20; H, 3.66; N, 4.24. Found: C, 58.21; H, 3.61; N, 4.05.
MeOH (10 ml) was stirred at room temperature for 2 h under H2 atmosphere.
4-Benzyloxy-5-bromoindole-3-acetonitrile (31) from 30 NaBH4 (5.7 The solvent was evaporated under reduced pressure to leave an oil, which
mg, 0.15 mmol) was added to a solution of 30 (32.2 mg, 0.098 mmol) in was column-chromatographed on SiO2 with CHCl3–MeOH–28% aq. NH3
NH2CHO–MeOH (1 : 1, v/v, 4 ml), and the mixture was stirred at room tem- (46 : 2 : 0.2, v/v) to give 37 (89.7 mg, 93%). 37: mp 142—144 °C (colorless
perature for 0.5 h. To the reaction mixture was added NaCN (52.8 mg, prisms, recrystallized from MeOH–H2O). IR (KBr): 2950, 1726 cmϪ1 1H-
.
1.08 mmol) and the whole was refluxed on oil bath at 100 °C for 2 h with NMR (CDCl3) d: 1.65 (9H, s), 2.37 (6H, s), 2.70—2.75 (2H, m), 2.88—2.93
stirring. After cooling to room temperature, brine was added and the whole (2H, m), 6.71 (1H, dd, Jϭ8.1, 1.0 Hz), 7.17 (1H, t, Jϭ8.1 Hz), 7.24 (1H,
was extracted with CHCl3. The extract was washed with brine, dried over br s), 7.65 (1H, br d, Jϭ8.1 Hz), 13.45 (1H, br s, disappeared on addition of
Na2SO4, and evaporated under reduced pressure to leave an oil, which was D2O). MS m/z: 304 (Mϩ). Anal. Calcd for C17H24N2O3: C, 67.08; H, 7.95; N,
column-chromatographed on SiO2 with CHCl3–MeOH (99 : 1, v/v) to give 9.20. Found: C, 67.04; H, 8.03; N, 9.08.
31 (32.2 mg, 97%). 31: mp 134—136 °C (colorless needles, recrystallized
from AcOEt–hexane). IR (KBr): 3435, 2247 cmϪ1 1H-NMR (CDCl3) d: (38) from 37 Py·HBr·Br2 (123.5 mg, 0.39 mmol) was added to a solution
3.78 (2H, d, Jϭ1.2 Hz), 5.18 (2H, s), 7.07 (1H, d, Jϭ8.5 Hz), 7.19 (1H, dt, of 37 (89.4 mg, 0.29 mmol) in CHCl3–Et2O (20 ml, 1 : 1, v/v), and the mix-
5-Bromo-1-tert-butoxycarbonyl-4-hydroxy-N,N-dimethyltryptamine
.
Jϭ2.7, 1.2 Hz, collapsed to br s on addition of D2O), 7.38 (1H, d, Jϭ8.5 Hz), ture was stirred for 4 h at room temperature. The reaction mixture was col-
7.38—7.45 (3H, m), 7.54—7.57 (2H, m), 8.23 (1H, br s, disappeared on ad- umn-chromatographed on SiO2 with CHCl3–MeOH–28% aq. NH3 (46 : 5 :
dition of D2O). MS m/z: 340 and 342 (Mϩ 79Br, 81Br). Anal. Calcd for 0.5, v/v) to give 38 (98.0 mg, 87%). 38: mp 160—161 °C (colorless prisms,
C17H13BrN2O: C, 59.84; H, 3.84; N, 8.21. Found: C, 59.84; H, 3.81; N, 8.07.
recrystallized from MeOH). IR (KBr): 1723 cmϪ1 1H-NMR (CD3OD) d:
.
4-Benzyloxy-7-bromo-N,N-dimethyltryptamine (32) from 4-Benzyl- 1.64 (9H, s), 2.52 (6H, s), 2.92—2.97 (2H, m), 2.99—3.04 (2H, m), 7.27
oxy-N,N-dimethyltryptamine (7) Py·HBr·Br2 (112.8 mg, 0.35 mmol) (1H, s), 7.30 (1H, d, Jϭ8.8 Hz), 7.41 (1H, d, Jϭ8.8 Hz). MS m/z: 382 and
was added to a solution of 7 (51.5 mg, 0.18 mmol) in CHCl3–Et2O (1 : 1, v/v, 384 (Mϩ 79Br, 81Br). Anal. Calcd for C17H23BrN2O3: C, 53.27; H, 6.05; N,
10 ml), and the mixture was stirred at room temperature for 25 h. The reac- 7.31. Found: C, 53.22; H, 6.13; N, 7.19.
tion mixture was column-chromatographed on SiO2 with CHCl3–MeOH–
Compound 13 from 38 CF3COOH (0.1 ml) was added to a solution of
28% aq. NH3 (46 : 5 : 0.5, v/v) to give 32 (20.0 mg, 31%). 32: mp 163— 38 (10.0 mg, 0.028 mmol) in CH2Cl2 (1 ml) at 0 °C and the mixture was
164 °C (colorless prisms, recrystallized from AcOEt). IR (KBr): 2780 (br), stirred at room temperature for 24 h. After evaporation of the solvent under
1614, 1511 cmϪ1. 1H-NMR (CDCl3) d: 2.14 (6H, s), 2.58 (2H, t, Jϭ7.9 Hz), reduced pressure, the residue was column-chromatographed repeatedly on
3.02 (2H, t, Jϭ7.9 Hz), 5.17 (2H, s), 6.45 (1H, d, Jϭ8.3 Hz), 6.96 (1H, br d, SiO2 with CHCl3–MeOH–28% aq. NH3 (46 : 5 : 0.5, v/v) to give 13 (7.3 mg,
Jϭ2.2 Hz, collapsed to s on addition of D2O), 7.17 (1H, d, Jϭ8.3 Hz), 97%).
7.30—7.41 (3H, m), 7.46—7.50 (2H, m), 8.15 (1H, br s, disappeared on ad-
4-Benzyloxy-7-bromo-1-tert-butoxycarbonyl-N,N-dimethyltryptamine
dition of D2O). MS m/z: 372 and 374 (Mϩ 79Br, 81Br). Anal. Calcd for (34) from 32 (Boc)2O (0.03 ml, 0.13 mmol) was added to a solution of 32
C19H21BrN2O: C, 61.13; H, 5.67; N, 7.50. Found: C, 61.16; H, 5.57; N, 7.39.
Compound 14 from 32 BBr3 in heptane (1 M, 0.23 ml, 0.23 mmol) was
(20.0 mg, 0.054 mmol) and DMAP (4.3 mg, 0.035 mmol) in CH2Cl2 (2 ml),
and the mixture was stirred at room temperature for 1 h. The reaction mix-
added to a solution of 32 (20.7 mg, 0.056 mmol) in CH2Cl2 (2 ml) at 0 °C, ture was column-chromatographed on SiO2 with CHCl3–MeOH (95 : 5, v/v)
and the mixture was stirred at 0 °C for 1 h under Ar atmosphere. After addi- to give 34 (21.8 mg, 83%). 34: mp 80—82 °C (colorless prisms, recrystal-
tion of MeOH (2 ml), the mixture was stirred for an additional 1 h. The lized from petroleum ether). IR (KBr): 1748 cmϪ1 1H-NMR (CDCl3) d:
.
whole was column-chromatographed repeatedly on SiO2 with CHCl3– 1.64 (9H, s), 2.17 (6H, s), 2.65 (2H, t, Jϭ8.1 Hz), 2.99 (2H, t, Jϭ8.1 Hz),
MeOH–28% aq. NH3 (46 : 5 : 0.5, v/v) to give 14 (6.4 mg, 41%). 5.14 (2H, s), 6.62 (1H, d, Jϭ8.5 Hz), 7.20 (1H, s), 7.32—7.42 (3H, m), 7.38
4-Benzyloxy-7-bromotryptamine (33) and 4-Benzyloxytryptamine (6) (1H, d, Jϭ8.5 Hz), 7.44—7.48 (2H, m). MS m/z: 472 and 474 (Mϩ 79Br,
from 20 LiAlH4 (111.4 mg, 2.94 mmol) was added to a solution of 20
81Br). Anal. Calcd for C24H29BrN2O3·1/4H2O: C, 60.32; H, 6.22; N, 5.86.
(209.9 mg, 0.62 mmol) in Et2O (15 ml) at 0 °C, and the mixture was stirred Found: C, 60.33; H, 6.14; N, 5.77.
at room temperature for 1.5 h. After addition of MeOH and saturated
4-Benzyloxy-5-bromo-1-tert-butoxycarbonyl-N,N-dimethyltryptamine
Rochelle salt under ice cooling, the whole was extracted with AcOEt. The (35) from 38 A solution of 38 (31.7 mg, 0.083 mmol) in anhydrous DMF
extract was washed with brine, dried over Na2SO4, and evaporated under re- (1 ml) was added to 35% KH (13.7 mg, 0.12 mmol) at 0 °C with stirring, and
duced pressure to leave a solid, which was column-chromatographed on the mixture was stirred at room temperature for 10 min. To the resulting sus-
SiO2 with CHCl3–MeOH–28% aq. NH3 (46 : 5 : 0.5, v/v) to give 33 (181.7 pension was added a solution of benzyl bromide (15.4 mg, 0.09 mmol) in an-
mg, 86%) and 65) (18.4 mg, 11%) in the order of elution. 33: mp 145—
hydrous DMF (1 ml), and stirring was continued at room temperature for
146 °C (colorless needles, recrystallized from AcOEt). IR (KBr): 3350, 2 h. Water was added at 0 °C and the whole was extracted with CHCl3–
1
3292, 1614, 1508 cmϪ1. H-NMR (CD3OD) d: 2.85 (2H, t, Jϭ6.8 Hz), 2.94 MeOH (95 : 5, v/v). The extract was washed with brine, dried over Na2SO4,
(2H, t, Jϭ6.8 Hz), 5.15 (2H, s), 6.50 (1H, d, Jϭ8.3 Hz), 6.99 (1H, s), 7.12
and evaporated under reduced pressure to leave a yellow oil, which was col-
(1H, d, Jϭ8.3 Hz), 7.30—7.35 (1H, m), 7.37—7.42 (2H, m), 7.47—7.52 umn-chromatographed on SiO2 with CHCl3–MeOH (95 : 5, v/v) to give 35
1
(2H, m). MS m/z: 344 and 346 (Mϩ 79Br, 81Br). Anal. Calcd for (16.9 mg, 43%). 35: Colorless oil. IR (film): 1730 cmϪ1. H-NMR (CDCl3)
C17H17BrN2O: C, 59.14; H, 4.96; N, 8.11. Found: C, 59.19; H, 5.01; N, 8.08.
d: 1.66 (9H, s), 2.22 (6H, s), 2.76 (2H, t, Jϭ7.9 Hz), 3.00 (2H, t, Jϭ7.9 Hz),
Compound 32 from 33 A solution of NaBH3CN (71.4 mg, 1.14 mmol) 5.09 (2H, s), 7.34—7.44 (3H, m), 7.38 (1H, s), 7.48 (1H, d, Jϭ8.5 Hz),
in MeOH (2 ml) and a solution of 35% HCHO (153.8 mg, 1.79 mmol) in 7.56—7.61 (2H, m), 7.88 (1H, br d, Jϭ8.5 Hz). High-resolution MS m/z:
MeOH (2 ml) were successively added to a solution of 33 (144.1 mg, Calcd for C24H2979BrN2O3: 472.1362. Found: 472.1344. Calcd for
0.42 mmol) in AcOH (0.6 ml), and the mixture was stirred at room tempera- C24H2981BrN2O3: 474.1341. Found: 474.1363.
ture for 4 h. After evaporation of the solvent under reduced pressure, 2 N
NaOH was added and the whole was extracted with CHCl3. The extract was References and Notes
washed with brine, dried over Na2SO4, and evaporated under reduced pres-
sure to leave a solid, which was column-chromatographed on SiO2 with
CHCl3–MeOH–28% aq. NH3 (46 : 5 : 0.5, v/v) to give 32 (141.8 mg, 91%).
4-Benzyloxy-1-tert-butoxycarbonyl-N,N-dimethyltryptamine (36)
from 7 (Boc)2O (0.05 ml, 0.22 mmol) was added to a solution of 7 (30.0
mg, 0.10 mmol) and DMAP (3.2 mg, 0.026 mmol) in CH2Cl2 (1 ml), and the
mixture was stirred at room temperature for 3 h. The reaction mixture was
column-chromatographed on SiO2 with CHCl3–MeOH (95 : 5, v/v) to give
36 (38.7 mg, 96%). 36: mp 76—78 °C (colorless needles, recrystallized from
1) This is Part 109 of a series entitled “The Chemistry of Indoles,” Part
108: Somei M., Yamada F., Kato J., Suzuki Y., Ueda Y., Heterocycles,
56, (2002), in press.
2) Stoll A., Troxler F., Peyer J., Hofmann A., Helv. Chim. Acta, 38,
1452—1472 (1955); Hofmann A., Heim R., Kobel H., Experientia,
14, 107—109 (1958); Hofmann A., Heim R., Brack A., Kobel H., Frey
A., Ott H., Petrzilka T., Troxler F., Helv. Chim. Acta, 42, 1557—1572
(1959); Downing D. F., Quarterly Reviews (London), 16, 133—162
(1962); Hofmann A., Bull. Narcotics, 23, 3—14 (1971); Brimble-
combe R. W., Pinder R. M., “Hallucinogenic Agents,” Wright-Scien-
technica, 1975, pp. 106—108.
3) Troxler F., Seemann F., Hofmann A., Helv. Chim. Acta, 42, 2073—
2103 (1959).
4) Repke D. B., Ferguson W. J., Bates D. K., J. Heterocycl. Chem., 18,
175—179 (1981); Repke D. B., Ferguson W. J., ibid., 19, 845—848
(1982); Repke D. B., Grotjahn D. B., Shulgin A. T., J. Med. Chem., 28,
892—896 (1985) and references cited therein.
MeOH–H2O). IR (KBr): 1735 cmϪ1 1H-NMR (CD3OD) d: 1.65 (9H, s),
.
2.09 (6H, s), 2.58 (2H, t, Jϭ8.1 Hz), 2.94 (2H, t, Jϭ8.1 Hz), 5.17 (2H, s),
6.81 (1H, d, Jϭ8.1 Hz), 7.18 (1H, dd, Jϭ8.3, 8.1 Hz), 7.28 (1H, s), 7.31—
7.36 (1H, m), 7.37—7.42 (2H, m), 7.48—7.52 (2H, m), 7.73 (1H, d,
Jϭ8.3 Hz). MS m/z: 394 (Mϩ). Anal. Calcd for C24H30N2O3: C, 73.06; H,
7.67; N, 7.10. Found: C, 73.13; H, 7.74; N, 6.98.
1-tert-Butoxycarbonyl-4-hydroxy-N,N-dimethyltryptamine (37) from
36 A suspension of 36 (125.1 mg, 0.28 mmol) and 10% Pd–C (39.7 mg) in

January 2002
99
5) Yamada F., Tamura M., Somei M., Heterocycles, 49, 451—458 (1998).
6) Sakagami H., Ogasawara K., Heterocycles, 51, 1131—1135 (1999);
Nichols D. E., Frescas S., Synthesis, 1999, 935—938.
7) Grieco P. A., Hon Y. S., Perez-Medrano A., J. Am. Chem. Soc., 110,
1630—1631 (1988).
10) Street L. J., Baker R., Castro J. L., Chambers M. S., Guiblin A. R.,
Hobbs S. C., Matassa V. G., Reeve A. J., Beer M. S., Middlemiss D.
N., Noble A. J., Stanton J. A., Scholey K., Hargreaves R. J., J. Med.
Chem., 36, 1529—1538 (1993).
11) Py·HBr·Br2 was prepared from pyridine, hydrobromic acid, and
bromine: Fieser L. F., Fieser M., “Reagents for Organic Chemistry,”
Vol. 1, John wiley, New York, 1967, pp. 967—970.
8) Yamada F., Hashizume T., Somei M., Heterocycles, 47, 509—516
(1998).
9) Chu L., Fisher M. H., Goulet M. T., Wyvratt M. J., Tetrahedron Lett.,
38, 3871—3874 (1997).
12) Somei M., Iwasa E., Yamada F., Heterocycles, 24, 3065—3069 (1986).