Ring-methylation of pyrrole and indole using supercritical methanol

Article abstract of DOI:10.1016/j.tet.2010.04.122

The ring-methylation of pyrrole or indole using supercritical methanol proceeded at 623 K without the further addition of catalysts. Pyrrole produced a mixture of unreacted pyrrole and mono-, di-, tri-, and tetra-methylpyrroles at the reaction time of 8 h. On the other hand, indole was selectively methylated at the C3 position to afford 3-methylindole in 79% yield at the reaction time of 5 h. The ring-methylation of indole using supercritical methanol was claimed to proceed via (1H-indol-3-yl)methanol. The conversion of indole to (1H-indol-3-yl)methanol would be achieved by the electrophilic aromatic substitution between the indol-1-ide (indole anion) and H₂C ⁺-OH. The (1H-indol-3-yl)methanol must be reduced to 3-methylindole in the presence of supercritical methanol.

Full text of DOI:10.1016/j.tet.2010.04.122

Tetrahedron 66 (2010) 5059e5064
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ring-methylation of pyrrole and indole using supercritical methanol
a
a
,
b
,
a
a
*
Nobuhiro Kishida , Takashi Kamitanaka
, Masafumi Fusayasu , Takashi Sunamura ,
c
d
a
Tomoko Matsuda , Tsutomu Osawa , Tadao Harada
a
Department of Materials Chemistry, Ryukoku University, Otsu 520-2194, Japan
Industrial Research Center of Shiga Prefecture, 232 Kamitoyama, Ritto, Shiga 520-3004, Japan
Department of Bioengineering, Graduate School of Bioscience & Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan
Graduate School of Science & Engineering for Research, University of Toyama, Gofuku, Toyama 930-8555, Japan
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
The ring-methylation of pyrrole or indole using supercritical methanol proceeded at 623 K without the
further addition of catalysts. Pyrrole produced a mixture of unreacted pyrrole and mono-, di-, tri-, and
tetra-methylpyrroles at the reaction time of 8 h. On the other hand, indole was selectively methylated at
the C3 position to afford 3-methylindole in 79% yield at the reaction time of 5 h. The ring-methylation of
indole using supercritical methanol was claimed to proceed via (1H-indol-3-yl)methanol. The conversion
Received 12 January 2010
Received in revised form 28 April 2010
Accepted 28 April 2010
Available online 4 May 2010
of indole to (1H-indol-3-yl)methanol would be achieved by the electrophilic aromatic substitution be-
Keywords:
Pyrrole
Indole
Supercritical methanol
Ring-methylation
þ
tween the indol-1-ide (indole anion) and H
2
C eOH. The (1H-indol-3-yl)methanol must be reduced to 3-
methylindole in the presence of supercritical methanol.
Ó 2010 Elsevier Ltd. All rights reserved.
3-Methylindole
(
1H-Indol-3-yl)methanol
1. Introduction
is well known that supercritical methanol can be employed as an
3
,6e8
N-methylating reagent for amines.
Thus, it is interesting which
The transformation of organic compounds using supercritical
atom, the C or the N of the nitrogen heterocycles, is methylated. In
this article, we report the results of the ring-methylation of pyrrole
and indole using supercritical methanol. Moreover, we propose
a reaction mechanism for the ring-methylation of indole.
fluids as the reaction media and reagents has attracted much at-
1,2
tention in the field of organic syntheses. For example, super-
ꢀ
3
critical methanol (T
c
¼513 K,
p
c
¼8.1 MPa,
d
c
¼0.273 kg dm
)
methylates the hydroquinone ring without adding additional cat-
3
,4
alysts to afford 2-methylbenzene-1,4-diol as the major product.
2
2
. Results and discussion
Thus far aromatic compounds containing no phenolic OH group
have not methylated using supercritical methanol. These findings
indicate that the phenolic OH group plays an important role in the
ring-methylation. Takebayashi et al. investigated the non-catalytic
o-methylation of phenol in supercritical methanol and found that
the supercritical o-methylation was retarded by acid and acceler-
ated by base.5 Taking into account the acid/base effect and o-se-
lectivity, they proposed that the phenolic OH group acts as an acid
catalyst for the supercritical methylation of its own molecule.
Pyrroles and indoles containing NH groups are known to be as
acidic as typical alcohols. Thus, it is reasonable to assume that
pyrrole and indole rings could be methylated using supercritical
methanol without the further addition of catalysts. Furthermore, it
.1. Methylation of pyrrole using supercritical methanol
A 0.140ꢁ10ꢀ4 dm3 portion of a methanol solution of pyrrole,
ꢀ3
1
-methylpyrrole, furan or pyridine (0.10 mol dm ) was subjected
to reactions at 623 K in a sealed Pyrex reactor. The calculated
ꢀ3
densities of the methanol in the reactor are around 0.29 kg dm at
the critical temperature or above (ꢂ513 K). The densities are
ꢀ3
beyond the critical one for methanol (0.273 kg dm ). The reactions
were carried out without the further addition of any catalysts. After
the reaction for 8 h, the reaction mixture was analyzed using the GC
(DB-17) and GCeMS (DB-5MS). Table 1 shows the results of the
GCeMS and GC analyses of the reaction mixture.
þ
ꢃ
The prominent peaks of M (the molecular ion) indicate that
pyrrole is methylated at 623 K in the presence of supercritical
methanol to afford a mixture of unreacted pyrrole and mono-, di-,
tri-, and tetra-methylpyrroles. It appears that the pyrrole ring is
*
Corresponding author. Tel.: þ81 77 558 1500; fax: þ81 77 558 1373; e-mail
address: kamitanaka.takashi@shiga-irc.go.jp (T. Kamitanaka).
0
040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.122

5060
N. Kishida et al. / Tetrahedron 66 (2010) 5059e5064
Table 1
GCeMS and GC analyses of the reaction mixture from the methanol solution of
pyrrole
þ
ꢃ
MS m/z M
Change in molecular
weight (M ꢀ67)
Number of
CH group
3
Ratio of GC area
þ
ꢃ
a
(retention time/min)b
6
8
9
1
1
7
1
5
09
23
0
14
28
42
56
0
1
2
3
4
1.0 (6.7)
1.5 (9.1)
4.5 (11.1)
4.7 (12.9)
2.2 (14.9)
Reaction conditions: Initial concentration of pyrrole¼0.10 mol dmꢀ3, reaction
temperature¼623 K, reaction time¼8 h.
a
þ
ꢃ
The value of (M ꢀ67) is the molecular-weight difference between the product
(
molecular weight¼M) and pyrrole (molecular weight¼67).
b
Temperature program of the GC (DB-17 30-m column, FID); 313 K for
5
min/10 K rise/min to 523 K.
easily methylated at 623 K using supercritical methanol, and it is
difficult to stop the reaction after a single methylation. The
formation of the poly-methyl pyrroles appears to be unavoidable.
The supercritical methylation of pyrrole appears to have important
limitations as a procedure for the selective preparation of the
mono-, di-, tri-, or tetra-methylpyrrole, whereas it was reported
that the supercritical methylation of phenol would be a promising
Figure 1. 1H NMR spectra of authentic 2- and 3-methylindoles, and the reaction
mixture: (a) 2-methylindole, (b) 3-methylindole, and (c) the reaction mixture. Initial
ꢀ3
concentration of indole¼0.10 mol dm
.
Reaction temperature¼623 K. Reaction
time¼1 h.
5
way for preparing o-cresol. The smooth formation of poly-methyl
pyrroles suggests that the active methylating species is an elec-
trophile, because pyrrole is a p-sufficient heterocycle.
substitution on indole is preferred at the C3 with almost all elec-
trophiles, because the C3 is the most electron-rich, most nucleo-
philic position on the ring. Thus, the preferential formation of
3-methylindole during the supercritical methylation suggests that
the methylating species in supercritical methanol attacks at the C3
position of the indole as an electrophile.
The results of the GC analyses of the reaction mixtures from the
methanol solutions of 1-methylpyrrole, furan, and pyridine showed
no peaks other than the substrates and the solvent (data not
shown). These findings suggest that the pyrrol-1-ide (pyrrole an-
ion) generated from the pyrrole plays an important role in the
supercritical methylation of the pyrrole ring as the phenoxide
generated from phenol has an important role in the supercritical
Figure 2 shows the time courses of the reactions of indole in the
ꢀ
4
3
presence of supercritical methanol, when a 1.20ꢁ10 dm portion
ꢀ3
of the 0.10 mol dm methanol solution of indole was subjected to
reactions at 623 K.
5
o-methylation of the phenol ring.
2
.2. Methylation of indole using supercritical methanol
Indole contains a pyrrole ring with a benzene ring fused to the
side. Gopal et al. reported the methylation of indole using vapor-
9
phase methanol over zeolites. Methylation mainly occurs at the C3
position of the indole. The maximum 3-methylindole yield of 33.6%
at the 72.6% indole-conversion was attained over a 3 wt % CeHY
catalyst at 573 K. Under the best conditions with respect to the
yield of 3-methylindole, the selectivity for 3-methylindole was less
than 50%, and the major by-products were 2,3-dimethylindole and
polymethyl-indolenines, such as 3,3-dimethylindolenine, 2,3,3-
trimethylindolenine, and 1,2,3,3-tetramethylindolenine. This in-
dicates that the poly-methylation of indole reduced the selectivity
for 3-methylindole. In order to improve the selectivity and the yield
of 3-methylindole, we attempted the methylation of indole at 623 K
without the addition of the zeolite-catalyst, which would accele-
rate the poly-methylation. In our investigation, supercritical
methanol was employed instead of the vapor-phase one.
The 1H NMR spectrum of the reaction mixture at the reaction
time of 1 h was measured after removal of the solvent in vacuo.
1
Figure 1 shows the H NMR spectra (6.0e8.0 ppm, CDCl
3
, TMS) of
Figure 2. Time courses of the reactions of indole in the presence of supercritical
methanol: (A) indole; (-) 3-methylindole; (:) 2,3-dimethylindole. Initial concen-
tration of indole¼0.10 mol dm . Reaction temperature¼623 K.
the authentic 2- and 3-methylindoles, and the reaction mixture.
1
ꢀ3
In the H NMR spectrum of the reaction mixture there are peaks
at around 6.9e7.0 ppm (HeC2) and at around 7.8e7.9 ppm (HeN),
but there is no peak at around 6.2 ppm, which is the HeC3 signal of
The concentration of 3-methylindole reaches the maximum value
at the reaction time of 4e5 h, and thereafter gradually decreases. The
concentration of 2,3-dimethylindole is negligible for the first 10 h,
and then gradually increases with an increase in the reaction time. It
appears that the conversion of 3-methylindole to 2,3-dimethylindole
is difficult when compared to the single-methylation of indole. The
2
-methylindole. This finding indicates that the methylation of
indole using supercritical methanol preferentially gives rise to
-methylindole. The small peak at around 6.5e6.6 ppm in the
3
spectrum of the reaction mixture will be due to the HeC3 of the
unreacted indole. It is well known that electrophilic aromatic

N. Kishida et al. / Tetrahedron 66 (2010) 5059e5064
5061
methylation of 3-methylindole to 2,3-dimethylindole may proceed
via the 3,3-dimethyl-3H-indolium.
reported that supercritical methanol contains 5.16 wt % formalde-
hyde at 653 K. Their result indicates that the oxidation of meth-
10
13
In addition, it is not possible that an electrophile attacks an in-
dole molecule at the C2 without seriously disturbing the aroma-
ticity of the fused benzene ring. The loss of the aromaticity of the
intermediate giving 2-methylindole would be a reason why indole
afforded much less poly-methylated products than pyrrole did.
Table 2 shows the conversion of indole, the attained yield and the
selectivity of 3-methylindol using supercritical methanol at 623 K
for 4 h, together with the reported values using the vapor-phase
anol to formaldehyde appreciably occurs under supercritical
methanol conditions. In their experiments, it can be presumed that
oxygen in the air and the surface of their reactor made of the
EI-43BU-VD alloy containing Ni (77%) act as the oxidizing reagent
and the oxidizing catalyst, respectively. On the other hand, in our
experiments, all reactions were carried out in sealed Pyrex tubes.
Most of the air in the tube was replaced by argon, and then the open
end of the tube was sealed by the application of heat under reduced
pressure. Thus, our reaction system contains very little air and
nickel so that any formation of formaldehyde from the supercritical
methanol should be negligible. Based on this view, we examined
the amount of formaldehyde formed under our reaction conditions
based on Nash’s procedure. Sample (A) was prepared by the
simple distillation of commercial methanol (99.8%, Nacalai Tesque,
Inc.). Sample (B) was prepared by maintaining sample (A) under
our reaction conditions (623 K, in a sealed Pyrex reactor) for 3 h,
followed by cooling to room temperature. Table 4 shows the
formaldehyde concentration in the methanol samples.
9
methanol at 573 K for 1 h over the CeHY catalyst. As can be seen in
the table, the conversion, the yield, and the selectivity of the
supercritical methylation were much higher than those attained
using vapor-phase methanol over the CeHY catalyst. It can be
assumed that no added catalyst depresses the poly-methylation of
indole. Our procedure for the preparation of 3-methylindole is
superior to that using vapor-phase methanol over the CeHY catalyst.
14
Table 2
Ring-methylation of indole using vapor-phase methanol or supercritical methanol
Methanol
Indole
conversion/%
3-Methylindole
yield/%
3-Methylindole
selectivity/%
Table 4
Vapor-phasea
Determination of formaldehyde concentration in methanol
72.6
89.9
33.6
74.2
46.3
82.5
Supercriticalb
ꢀ3
Methanol
Concentration of formaldehyde/mol dm
a
a
ꢀ4
ꢀ4
5
6
73 K, 3 wt % CeHY catalyst, 1 h (Ref. 9).
23 K, no catalyst, 4 h.
A
B
0.67ꢁ10
b
b
2.33ꢁ10
a
Methanol (A): prepared by a simple distillation of commercial methanol (99.8%,
Nacalai Tesque, Inc.).
2
.3. Mechanism for methylation of indole using supercritical
b
Methanol (B): prepared by maintaining the sample (A) under the supercritical
methanol
conditions (623 K, in a sealed Pyrex reactor) for 3 h., and then cooled to room
temperature.
The methanol solutions of 5-methoxyindole, 5-bromoindole,
and 5-chloroindole were subjected to reactions at 623 K for 1 h or
h. Table 3 shows the substituent effects on the conversion of the
indoles using supercritical methanol. It is apparent that the elec-
tron-donating group (eOCH ) somewhat accelerates the reaction,
whereas the electron-attracting groups (eBr, eCl) remarkably
delay the reaction. This supports the idea that the methylation of
indole using supercritical methanol is an electrophilic aromatic
substitution and the methylating species acts as an electrophile.
It appears that the amount of formaldehyde slightly increased at
23 K in the sealed Pyrex reactor, but the amount of formaldehyde
in sample (B) is much less than that of indole in the reaction system.
Thus, the formaldehyde in the reaction system would disappear
during the very early stage of the methylation of indole so that the
contribution of the contaminant formaldehyde to the methylation
6
5
3
of indole would be negligibly small.
þ
Takebayashi et al. proposed that H
3
C
would be formed from
OHþHOC
O) during the o-methyla-
the supercritical methanol and phenol (CH
3
6 5
H /
þ
ꢀ
þ
þ
Table 3
CH
O H
þ OC
H
5
, CH
O H
/CH
þH
2
3
2
6
3
2
3
Substituent effects on the methylation of indoles with supercritical methanol
5
tion of phenol, and attack the o-position of the phenoxide. How-
þ
ever, in this study, the contribution of H
3
C
to the supercritical
Indoles
Conversion/%
methylation of indole would be negligibly small when compared to
Reaction time 1 h
Reaction time 5 h
þ
þ
that of [H
than phenol (pK
electrophile in the supercritical methylation of indole would be the
2
C]O H4H
2
C eOH], because indole is much less acidic
Indole
84
8
0
92
34
8
a
of indole: 16.2, pK
a
of phenol: 10.0). The main
5-Bromoindole
5-Chloroindole
5-Methoxyindole
þ
þ
2
C eOH].
89
100
[H
2
C]O H4H
As mentioned in Section 2.1, pyrrole is methylated in the pres-
ꢀ
3
Reaction conditions: 0.10 mol dm methanol solutions of indoles, 623 K.
ence of supercritical methanol, whereas 1-methylpyrrole is not
methylated under the same conditions. In order to examine
the reactivity of 1-methylindole in supercritical methanol,
þ
Cd eOH from
þ
We postulated the generation of R C eOH or R
the supercritical alcohol, R CHeOH.
2
2 2
11,12
The ionic species attacks at
ꢀ
3
a 0.10 mol dm
methanol solution of 1-methylindole was sub-
the C]C or C^C bond as an electrophile to hydroxyalkylate the
alkene or alkyne. For example, styrene gives rise to 3-phenyl-
propan-1-ol as a major product with supercritical methanol. For the
supercritical methylation of indole, it can be presumed that the
C eOH acts as an electrophile (Scheme 1).
jected to reactions at 623 K. In the reaction system, no indol-1-ide
þ
(
indole anion) and H would be generated from 1-methylindole.
Figure 3 shows the GC results of the reaction mixture at the re-
action time of 5 h.
þ
H
2
The peaks at around 1 and 7 min correspond to methanol and
1-methylindole, respectively. There are no peaks corresponding to
materials other than the starting ones. This finding indicates that
no methylation of 1-methylindole occurred at the C3 position and
supports the idea that the dissociation of indole to indol-1-ide is
essential for the methylation of indole at the C3 position.
+
+
1
)
CH OH
H C=O H
2
H C -OH
H
3
2
Scheme 1. Elimination of a-hydrogen of methanol.
þ
þ
The [H C]O H4H C eOH] can be also formed by the pro-
2 2
tonation of formaldehyde. The contribution of formaldehyde to the
methylation of indole would be dependent on the concentration of
the formaldehyde contaminant in the methanol. Brazaev et al.
Based on the idea that the reaction species for the supercritical
þ
methylation of indole are the indol-1-ide and H
2
C eOH, (1H-indol-
3-yl)methanol would be formed as follows (Scheme 2):

5062
N. Kishida et al. / Tetrahedron 66 (2010) 5059e5064
was allowed to stand at 623 K for 1 h in a Pyrex reactor. The GCeMS
of the reaction mixture was then measured. Figure 4 shows the GC
of the authentic (1H-indol-3-yl)methanol and 3-methylindole, and
the reaction mixture.
Figure 3. Attempts to methylate 1-methylindole using supercritical methanol: the GC
ꢀ
3
of the reaction mixture. Initial concentration of 1-methylindole¼0.10 mol dm . Re-
action temperature¼623 K. Reaction time¼5 h. the GC conditions: DB-17, 30-m col-
umn, 423 K, FID.
H
N
N
2
3
)
)
+
H
Indole
Indol-1-ide
+
H
N
Figure 4. Reaction of (1H-indol-3-yl)methanol in supercritical methanol: the GC of
authentic (1H-indol-3-yl)methanol, 3-methylindole, and the reaction mixture: (a)
authentic (1H-indol-3-yl)methanol, (b) authentic 3-methylindole and (c) the reaction
mixture. Initial concentration of (1H-indol-3-yl)methanol¼0.010 mol dm . Reaction
temperature¼623 K. Reaction time¼1 h. The GC conditions: UA-5, 30-m column, 373 K
for 1 min/10 K rise/min to 523 K, EI.
N
+
+
H C=O H
H C -OH
2
2
ꢀ
3
CH OH
(1H-indol-3-yl)methanol
2
Indol-1-ide
Scheme 2. Hydroxymethylation of indole.
The (1H-indol-3-yl)methanol in the methanol solution disappears
during the 1-h stand at 623 K. Moreover, the MS of the component
with the GC peak at around 7.2 min agrees with that of the authentic
3-methylindole. Thus, it is reasonable to claim that the (1H-indol-3-
yl)methanol is easily reduced to 3-methylindole under our experi-
mental conditions. It can be assumed that the reaction proceeds as
follows: the formation of a protonated alcohol intermediate/the
dehydration to give a carbocation intermediate/the addition of
a hydride ion to the carbocation intermediate (Scheme 3).
However, we detected no formation of (1H-indol-3-yl)methanol
in the GCeMS (UA-5, 30-m column, 373 K for 1 min/10 K rise/min
to 523 K, the retention time of the authentic (1H-indol-3-yl)
methanol: 10.8 min). There were no prominent peaks other than
3
-methylindole (7.2 min) and 2,3-methylindole (8.5 min) in the
reaction mixture. In order to examine the stability of (1H-indol-3-
ꢀ
4
3
yl)methanol in supercritical methanol, a 0.120ꢁ10 dm portion of
ꢀ
3
the 0.010 mol dm methanol solution of (1H-indol-3-yl)methanol
N-methylation
CH OH
2
CH OH
2
CH OH2
CH2
2
CH2
N
N
N
N
N
-
H O
H
2
etc.
CH3
N
H
C3-methylation
N
C
N
N
N
-
H O
H
2
-
H shift
CH OH
2
CH OH2
2
CH2
H
CH OH
2
H
H
H
N
N
N
N
N
N
etc.
CH3
CH3
CH3
CH3
CH3
CH3
H
N
H
CH3
Scheme 3. Plausible pathway for the ring-methylation of indole using supercritical methanol.

N. Kishida et al. / Tetrahedron 66 (2010) 5059e5064
5063
As can be seen in Scheme 3, (1H-indol-1-yl)methanol produces
a carbocation attached to the N atom of indole. The carbocation will
be extremely unstable because the N atom bears a partial positive
charge owing to resonance. On the other hand, (1H-indol-3-yl)
methanol produces a rather stable tertiary carbocation through
a hydride shift. The generated carbocation is more stable than
ordinary tertiary ones because the charge is delocalized around the
indole ring. The stability difference between the carbocations
generated from the 1- and 3-hydroxymethylated indoles may be
a reason why the supercritical methylation of indole occurs pre-
ferentially on the C3 instead of on the N1.
open end of the tube was sealed by the application of heat under
reduced pressure. After sealing, the tube was placed in an auto-
clave (SUS 316, 0.030 dm ) with the appropriate amount of
3
methanol. The methanol was used in order to prevent tube
breakage as a result of any pressure difference. The autoclave was
then heated to the reaction temperature (heating time from room
temperature to 623 K: w20 min). The reaction time mentioned in
the text indicates the period when the vessel was maintained at
the required reaction temperature. After a specific time, the au-
toclave was cooled using an air stream to quench the reaction
(cooling time from 623 K to 473 K: w10 min). The products in the
1
Supercritical methanol may act as the reducing reagent (hydride
donor) for the reaction of (1H-indol-3-yl)methanol to 3-methyl-
indole. It was reported that supercritical alcohols including meth-
tube were then identified using GC, H NMR, GCeMS, and IR.
Conversions were estimated by the GC analyses (DB-17) using the
internal standard method.
anol act as reducing reagents during the reduction of aldehydes or
ketones to alcohols,1
5e20
that of alkenes to alkanes and of diphe-
4
.3. Determination of formaldehyde in methanol
11
nylacetylene to stilbene and dibenzyl. Moreover, Hatano et al.
reported that supercritical 2-propanol acts as a reducing reagent
during the reduction of diarylmethanol to diarylmethane. To the
best of our knowledge, the reduction of (1H-indol-3-yl)methanol to
-methylindole using supercritical methanol represents the first
The amount of formaldehyde in the methanol employed in this
21
14
study was determined by Nash’s colorimetric procedure. The
color-producing solution was ammonium acetate (1.5 g) and 2,4-
3
ꢀ4
3
pentanedione (2.0ꢁ10 dm ) dissolved in a small portion of water,
example of the reduction of monoaryl methanol to monoaryl-
methane using supercritical alcohol.
3
and the aqueous solution made up to 0.10 dm with water. The
ꢀ4
3
sample solution was a 2.5ꢁ10 dm portion of the methanol made
3
ꢀ3
3
up to 0.10 dm with water. The sample solution (5.0ꢁ10 dm )
3
. Conclusions
was placed in a screw-cap bottle together with the color-producing
ꢀ
3
3
solution (5.0ꢁ10 dm ). The bottle was warmed to 338 K in a wa-
ter bath, and maintained at that temperature for 10 min. After
cooling to room temperature, the amount of formaldehyde was
colorimetrically determined at 412 nm.
We examined the reactions of pyrrole or indole in the presence
of supercritical methanol at 623 K. Ring-methylation of indole
selectively occurred at the C3 position without the further addition
of any catalyst, whereas pyrrole afforded the reaction mixture of
the unreacted pyrrole and mono-, di-, tri-, and tetra-methyl-
pyrroles. The supercritical ring-methylation of indole was assumed
to proceed via (1H-indol-3-yl)methanol. The H
from the supercritical methanol would attack the indol-1-ide at the
C3 position to form (1H-indol-3-yl)methanol (electrophilic aro-
matic substitution), and then the (1H-indol-3-yl)methanol would
be reduced to 3-methylindole in the presence of supercritical
methanol.
Acknowledgements
þ
2
C eOH generated
The authors are grateful to the ‘JKA-Keirin Foundation’ for fi-
nancial support in the acquisition of the GCeMS apparatus (Shi-
madzu GCMS-QP2010 Plus).
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.122.
4
4
. Experimental
.1. General
References and notes
All reagents other than methanol were purchased from com-
1
. Chemical Synthesis Using Supercritical Fluids; Jessop, P. G., Leitner, W., Eds.;
Wiley-VHC: Weinheim, 1999.
mercial sources and used without further purification. The meth-
anol employed in the present investigation as the solvent and the
ring-methylation reagent for the pyrrole or indole was purchased
from a commercial source (99.8%, Nacalai Tesque, Inc.) and used
after a simple distillation. The GC analyses were carried out using
a Shimadzu GC-15A (DB-17 (J & W Scientific), 30-m column, FID) for
the evaluation of the product distribution. The GCeMS spectra
were obtained using a JEOL GC-mate II R (DB-5MS (J & W Scientific),
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0-m column, EI) or a Shimadzu GCMS-QP2010 Plus (UA-5 (Frontier
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a Bruker DPX400. The UVevis spectra were measured using a Shi-
madzu UV-3100.
9
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methanol
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The reactions were carried out in sealed Pyrex tubes (ca.
1
ꢀ
4
3
0
.02 dm inner diameter, ca. 0.70 dm length, and ca. 3.2ꢁ10 dm
ꢀ
4 3 3
ꢀ4
inner volume). A 1.40ꢁ10 dm (pyrrole) or 1.20ꢁ10 dm (in-
dole) portion of the methanol solution (the concentration of
pyrrole or indole; specified in the text for each case) was placed in
a Pyrex tube. The air in the tube was replaced by argon, and the
1
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