Easy access to a library of alkylindoles: Reductive alkylation of indoles with carbonyl compounds and hydrosilanes under indium catalysis

Article abstract of DOI:10.1002/adsc.201500502

By applying carbonyl compounds as sources of alkyl groups to the indium-catalyzed reductive alkylation of indoles, a reliable and practical method capable of offering a wide range of alkylindoles with structural diversity has been developed. An important

Full text of DOI:10.1002/adsc.201500502

UPDATES
DOI: 10.1002/adsc.201500502
Easy Access to a Library of Alkylindoles: Reductive Alkylation
of Indoles with Carbonyl Compounds and Hydrosilanes under
Indium Catalysis
Shota Nomiyama,a Takehiro Hondo,a and Teruhisa Tsuchimotoa,*
a
Department of Applied Chemistry, School of Science and Technology, Meiji University, 1-1-1 Higashimita, Tama-ku,
Kawasaki 214-8571, Japan
Fax: (+81)-44-934-7228; e-mail: tsuchimo@meiji.ac.jp
Received: May 25, 2015; Revised: December 9, 2015; Published online: March 3, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500502.
Abstract: By applying carbonyl compounds as sour-
ces of alkyl groups to the indium-catalyzed reduc-
tive alkylation of indoles, a reliable and practical
method capable of offering a wide range of alkylin-
doles with structural diversity has been developed.
An important feature of this method is that the
loading of the indium catalyst can be reduced by
more than that of the original alkyne-based system.
using carbonyl compounds 5 instead of 2 would lead
to elimination of the above limitations while keeping
the advantage of the original indium reaction. That is
because carbonyl compounds have much higher skele-
tal and substitutional diversities than alkynes as com-
mercial sources.[4] There are some precedents for the
reductive alkylation of indoles with carbonyl com-
pounds,[5] and the redox system through in situ oxida-
tion of alcohols to carbonyl compounds then reacting
with indoles has also emerged in the literature.[6,7]
Among these, however, there has been no method
that can provide alkylindoles with primary, secondary
and tertiary alkyl groups. These three types are able
Keywords: aldehydes; heterocycles; hydrides; ke-
tones; Lewis acids
Organic molecules containing an indole skeleton are
prominent structural motifs, due to their significance
not only as natural products and pharmaceuticals but
also as functional materials.[1] In this context, a large
number of synthetic transformations of indoles have
been reported,[2] and we have also been engaging in
exploring new catalytic reactions of indoles under
Lewis acid catalysis.[3] One of these is the reductive al-
kylation of indoles performed by simply mixing in-
doles 1, alkynes 2 and hydrosilanes 3 under indium
Lewis acid catalysis (Scheme 1).[3d] The features are
(i) high to excellent levels of reaction efficiency capa-
ble of providing alkylindoles in 70–99% isolated
yields, (ii) perfect regioselection on both indoles and
alkynes, and (iii) a remarkable degree of functional
group compatibility. These are significant aspects that
a reliable and practical organic transformation should
fulfill. However, cyclic and primary alkyl groups as
well as a diarylmethyl unit (CHAr2) are unable to be
installed intrinsically onto 1 when using alkynes 2 as
sources of alkyl groups. Regioselective introduction of
a dialkylmethyl group with two identical alkyl groups,
CH(alkyl)2, is also a difficult task. We therefore envis-
Scheme 1. Indium-catalyzed reductive alkylation of indoles:
alkynes versus carbonyl compounds as sources of alkyl
aged that development of an indium-catalyzed variant groups (In=indium salt).
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Easy Access to a Library of Alkylindoles: Reductive Alkylation of Indoles
to be prepared by utilizing simple non-reductive pro- use of PhMe (dried) as a solvent gave no enhance-
cesses, in which, however, highly reactive alkylating ment of the yield (entry 3). However, the reactions
agents including alkenes,[8] alcohols,[9] alkyl halides,[10] carried out in other solvents (dried) including DCE,
and others[11] as well as intramolecularly reacting sub- EtCN, MeNO2, THF, EtOAc, DME and 1,4-dioxane
strates[12] have only been the starting substrate of provided 4a in higher yields (entries 4–10). Among
choice, to the best of our knowledge.[13] In contrast to the solvents tested, 1,4-dioxane was found to be the
the studies reported thus far, we disclose a reliable most effective medium to afford 4a in 94% GC yield
system capable of providing a variety of alkylindoles and in 86% isolated yield (entry 10). We subsequently
with structural diversity, based on the reductive ap- tested non-dried 1,4-dioxane as a solvent, and found
proach with carbonyl compounds and hydrosilanes.[14] that pre-drying of 1,4-dioxane is unnecessary (en-
Due to the potent activity of In(NTf2)3 (Tf= tries 10 vs. 11). Accordingly, non-dried 1,4-dioxane
SO2CF3) found in our preceding research,[3d] this was used as a solvent hereafter. The use of such
study began with its testing in the reductive alkylation a non-dried solvent should thus be a technical advant-
of indole (1a) with 2-octanone (5a) (Table 1). Thus, age of this reaction. Screening of other hydrosilanes
treating 1a, 5a and HSiMePh2 (3a) with 30 mol% of 3b–3e showed that 3a is the most promising (en-
In(NTf2)3 in PhCl (dried) at 458C for 24 h gave 3-(1- tries 12–15). Under the conditions with 3a in 1,4-diox-
methylheptyl)-1H-indole (4a) in 17% yield (entry 1). ane, fine-tuning by changing the reaction temperature
Reducing the catalyst loading to 10 mol% resulted in from 45 to 508C raised the isolated yield to 88%
a much lower reaction rate but, in contrast, in an im- (entry 16).[15]
provement of the reaction efficiency (entry 2). The
As shown in Scheme 2, the introduction of a 2-octyl
group can be also achieved by 1-octyne (2a) instead
of 2-octanone (5a), as previously demonstrated.[3d]
While the most favorable conditions for 5a are slight-
ly different from those for 2a, the same high per-
formance was also observed here, and, preferably,
using carbonyl compound 5a has the following two
advantages over alkyne 2a: (i) the reaction of 5a can
be carried out with a more reduced amount of
In(NTf2)3 (10 mol%) than that (30 mol%) of the reac-
tion of 2a, and (ii) 5a is much more reasonable in
price than 2a.
Table 1. Indium-catalyzed reductive alkylation of indole
with 2-octanone and hydrosilanes.[a]
Entry Solvent[b]
HnSiR4Àn
Conv. [%] Yield [%]
of 5a[c]
of 4a[c,d]
With the suitable reaction conditions in hand, we
next explored the scope of this reaction (Table 2). Be-
sides the simple indole (1a) in Table 1, N, C-2 and/or
C-5 substituted indoles with Me, Ph, OMe, Br, CN,
and B(pin) (pin=pinacolate) groups participated well
in this reaction, giving the corresponding 2-octylated
1
2
3
4
5
6
7
8
PhCl
PhCl
HSiMePh2 (3a) 68
17
22
2
31
27
44
48
70
3a
3a
3a
3a
3a
3a
3a
3a
37
47
45
62
45
94
91
97
97
97
97
PhMe
DCE[e]
EtCN
MeNO2
THF
EtOAc
9
DME[f]
93
10
11
12
13
14
15
16[g]
1,4-dioxane 3a
1,4-dioxane 3a
1,4-dioxane HSiPh3 (3b)
1,4-dioxane HSiMe2Ph (3c) 60
1,4-dioxane HSiEt3 (3d)
1,4-dioxane H3SiPh (3e)
1,4-dioxane 3a
94 (86)
95 (86)
48
49
42
74
59
99
18
95 (88)
[a]
Reagents: 1a (0.60 mmol), 5a (0.40 mmol), 3 (0.60 mmol),
In(NTf2)3 (0.12 mmol for entry 1, 0.040 mmol for other
entries), solvent (0.40 mL).
Dried solvents were used for entries 1–10. Non-dried 1,4-
dioxane was used for entries 11–16. See the Experimental
Section for further details.
Determined by GC.
Isolated yields are shown in parentheses.
DCE=1,2-dichloroethane.
[b]
[c]
[d]
[e]
[f]
Scheme 2. Reductive 2-octylation of indole: 2-octanone
versus 1-octyne as sources of alkyl groups. Isolated yields of
4a are shown here.
DME=1,2-dimethoxyethane.
The reaction was performed at 508C.
[g]
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Shota Nomiyama et al.
Table 2. Indium-catalyzed reductive alkylation of indoles with carbonyl compounds and HSiMePh2.[a]
[a]
Reagents: 1 (0.60 or 1.2 mmol), 5 (0.40 mmol), 3a (0.60 mmol), In(NTf2)3 (4.0–40 mmol), 1,4-dioxane (0.40 mL). Yields of
isolated 4 based on 5 are shown here. The method (A or B) used, and the yield of 4x when performed on a 5.0-mmol
scale are shown in parentheses. See the Experimental Section for further details.
[b]
In(NTf2)3 (20 mol%) was used.
and 2-propylated indoles in good to excellent yields ophilic attack by the indole, was retained here (4k).
3
À
(4a and 4b–4j). The C(sp ) Cl part with the good The 5-nonyl group, which is difficult to install regiose-
leaving Cl group, which is possible to undergo a nucle- lectively when using 4-nonyne as an unsymmetrical
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Easy Access to a Library of Alkylindoles: Reductive Alkylation of Indoles
alkyne, is readily available from 5-nonanone (5b) ble from alkynes can be easily connected with the
(4l).[16] However, in order to obtain 4l in a high yield, indole rings (4o–q and 4v). The scope of the reaction
method A in which all of the starting substrates are can be extended to aryl ketones (4q–4v). Importantly,
mixed concurrently with the indium catalyst is ineffec- the diarylmethyl unit (CHAr2) including the fluorenyl
tive, thus resulting in a lower conversion of 5b (53%) group is a framework installable only by this carbon-
and yield of 4l (53%), as separately indicated in yl-based reaction (4u and 4v). One of the major high-
Scheme 3. After checking the reaction mixture, the lights is to ensure installation of primary alkyl groups
that are impossible to handle in our previous sys-
tem,[3d] because terminal alkynes accept indoles exclu-
ꢀ
sively at the internal carbon atom of the C C bond.
Linear and a-branched aliphatic aldehydes as well as
aromatic ones and ferrocenecarboxaldehyde thus re-
acted with indoles 1 and 3a under indium catalysis to
afford good to high yields of the corresponding alkyl-
indoles (4w–4ac). The C=C bond in the cyclohexene
ring remained intact without isomerization[18] and hy-
drosilylation[19] (4y). The less nucleophilic C-2 com-
pared to C-3 is also available as a reaction site (4ad).
With this system, alkylindoles are readily prepared
on a gram scale. For example, the synthesis of 4x was
Scheme 3. 5-Nonylation of N-methylindole by method A.
performed on a 5.0-mmol scale to provide 1.0 g of the
reaction was found to have co-produced: a significant target in 88% yield (4x in Table 2).
amount of N-methylindoline (6) that is likely to have
Our approach can be applied to the use of carbon
been formed via reduction of N-methylindole (1b) by nucleophiles such as Me3SiCN (3f) and 2-methoxy-
3a. It was then assumed that the slow reaction could thiophene (3g) instead of HSiMePh2 to introduce ter-
be ascribed to a lowering of the catalytic activity of tiary alkyl groups onto indoles (Scheme 5). Worthy of
In(NTf2)3 by coordination of the nitrogen atom of 6 note is that when using 3g as a nucleophile, two differ-
to the indium center. In fact, as a control experiment, ent heteroaryl units can be introduced onto the car-
adding 20 mol% of 6 to the reaction of 1a with 5a bonyl carbon in one shot. The results discussed so far
proved to inhibit completely the progress of the reac- show that choosing a proper combination of carbonyl
tion (Scheme 4), in sharp contrast to the reaction compounds and nucleophiles enables us to prepare all
without 6 (see entry 16 of Table 1). With the intention of the three types of alkylindoles with primary, secon-
of suppressing the undesired reduction of N-methylin- dary and tertiary alkyl groups. This is the first demon-
dole (1b), the synthesis of 4l was performed by modi- stration of the reductive alkylation of indoles.
fying the procedure to method B where 3a is added
We next performed some reactions to get insights
after promoting the consumption of 1 and 5. As ex- into the reaction mechanism (Scheme 6). To begin
pected, method B is effective for this case, and the with, the indium-catalyzed reaction of N-methylindole
yield of 4l was improved to 76%. Accordingly, (1b) with acetophenone (5c) was conducted in the ab-
method B was adopted hereafter when a non-negligi- sence of 3a, and thereby provided di(indolyl)alkane
ble reduction of not only indoles but also carbonyl
compounds was observed with method A (4m–p, 4u
and 4ad). The ester group was tolerated without acid
hydrolysis under the reaction conditions including the
indium Lewis acid catalyst and in situ generated H2O
(4n).[17] The cyclic alkyl groups that are also inaccessi-
Scheme 4. A control experiment: effect of N-methylindoline
in the reaction of 1a with 5a.
Scheme 5. Indium-catalyzed alkylation of indoles with car-
bonyl compounds and carbon nucleophiles.
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Shota Nomiyama et al.
resulted in the much slower reaction (120 h). More-
over, no 4r was produced in the presence of H2O but
without In(NTf2)3. Interestingly, the use of C-2 substi-
tuted indole 1c instead of 1b gave not the correspond-
ing di(indolyl)alkane, but alkenylindole 9a as a sole
product, which was then readily converted to alkylin-
dole 4s by treatment with 3a under indium catalysis.
Here again, H2O greatly accelerated the hydride re-
duction of 9a. These results suggest that the di(indol-
yl)alkane and alkenylindole are likely to be inter-
mediates, and that the structure of the intermediate
should depend on whether the indole substrate has
a substituent at the C-2 position, and, in addition, that
H2O possibly works as an activator for enhancing nu-
cleophilicity of 3a by its coordination.[20,21] The exclu-
sive generation of 8a from 1b should be due mainly to
little or no steric congestion in the structure of 8a, in
contrast to steric stress that would arise between the
two methyl groups at the C-2, in the case that 9a
would further react with 1c to give the corresponding
di(indolyl)alkane.
On the basis of the above results and our previous
discussion,[3d] path A and B for C-2 unsubstituted and
C-2 substituted indoles, respectively, are proposed as
plausible reaction routes in Scheme 7. In path A
where C-2 unsubstituted indole 1 (R2 =H) partici-
pates, the indium salt (In) first catalyzes the forma-
tion of di(indolyl)alkane 8 and H2O from 1 and 5.[22]
One indolyl ring of 8 then coordinates to the In and
eliminates to give cationic species 10 by way of the
Scheme 6. Indium-catalyzed reactions for mechanistic stud-
ies.
8a quantitatively, while no 8a was formed in the ab- C(sp ) C(indolyl) bond cleavage.[23] The hydride
3
À
À
sence of In(NTf2)3. In the presence of H2O formed transfer to 10 from H SiR3·H2O complex 11, which
along with 8a in the above reaction, the treatment of would possess higher nucleophilicity than the free
8a and 3a with In(NTf2)3 (10 mol%) for 30 min pro- HSiR3, gives alkylindole 4. On the other hand, path B
vided 4r in 98% yield, whereas the absence of H2O starts with providing alkenylindole 9 via nucleophilic
Scheme 7. Proposed reaction mechanisms.
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attack of C-2 substituted indole 1 (R2 ¼ H) to 5 fol-
lowed by dehydration. The activation of the C=C
bond of 9 by the In[24] induces the hydride reduction
from 11. Finally, the protonation of the C In bond of
12 affords alkylindole 4.
H2O is co-produced in the early stage of the pres-
ent reaction, as discussed thus far. This is clearly dif-
ferent from the corresponding alkyne-based reaction
without producing H2O.[3d] However, H2O is not just
a by-product here but it effectively affects the prog-
ress of the reaction by accelerating the process of the
hydride reduction. It can thus be assumed that the
formation of H2O positively contributes to reducing
the amount of In(NTf2)3 used, compared to that of
the alkyne-based reaction.
sodium was used. Other solvents used in this research were
pre-dried as follows: toluene (PhMe) and chlorobenzene
(PhCl) were distilled under argon from calcium chloride just
prior to use; 1,2-dichloroethane (DCE), nitromethane
(MeNO2), ethyl acetate (EtOAc) and 1,2-dimethoxyethane
(DME) were stored over molecular sieves 4Š (MS 4Š)
under argon; propionitrile (EtCN) was distilled under argon
from P2O5 just prior to use; tetrahydrofuran (THF) was dis-
tilled under argon from sodium benzophenone ketyl just
before use. In(NTf2)3 was prepared by the reported
method.[25] Unless otherwise noted, other substrates and re-
agents were commercially available and used as received.
À
Synthesis of 1,5-Dimethyl-3-propyl-1H-indole as
a Substrate
Under an argon atmosphere, potassium hydroxide (449 mg,
8.00 mmol) and dimethyl sulfoxide (5.0 mL) were placed in
a flame-dried 20-mL Schlenk tube, and stirred at room tem-
perature for 10 min. To the tube was added 5-methyl-3-
propyl-1H-indole[26] (347 mg, 2.00 mmol), and then iodome-
thane (284 mg, 2.00 mmol) was slowly added dropwise with
stirring. After stirring at room temperature for 45 min, the
reaction mixture was filtered to remove an excess amount of
potassium hydroxide, and the filtrate was diluted with Et2O
(100 mL). The organic layer was washed with water
(10 mL”4) and brine (10 mL), and then dried over anhy-
drous sodium sulfate. Filtration and evaporation of the sol-
vent followed by column chromatography on silica gel
In conclusion, we have developed a new approach
for alkylating indoles by using carbonyl compounds in
a reductive process. This method features a wide
range of substrate coverage, and thus would be
a useful and reliable tool to obtain alkylindoles with
structural diversity. In fact, our process makes it possi-
ble to provide indoles with primary, secondary and
tertiary alkyl groups including CHAr2, CH(alkyl)2 and
cyclic structures. The reaction mechanism in which
two different routes depending on the structure of the
indole substrate operate is also unique.
(hexane/EtOAc=30/1)
gave
1,5-dimethyl-3-propyl-1H-
1
indole as a pale yellow oil; yield: 342 mg (91%). H NMR
(500 MHz, CDCl3): d=0.99 (t, J=7.4 Hz, 3H), 1.71 (sext,
J=7.5 Hz, 2H), 2.46 (s, 3H), 2.68 (t, J=7.5 Hz, 2H), 3.71 (s,
3H), 6.77 (s, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.16 (d, J=
8.1 Hz, 1H), 7.36 (s, 1H); 13C NMR (CDCl3, 125 MHz): d=
14.2, 21.5, 23.6, 27.2, 32.5, 108.8, 114.8, 118.8, 122.9, 126.2,
127.6, 128.2, 135.5; HRMS (FI): m/z=187.1382, calcd. for
C13H17N [M]: 187.1361.
Experimental Section
General Remarks
All manipulations were conducted with a standard Schlenk
technique under an argon atmosphere. Nuclear magnetic
resonance (NMR) spectra were taken on a JEOL JMN-
ECA 400 (1H, 400 MHz; 13C, 100 MHz) or JEOL JMN-ECA
500 (1H, 500 MHz; 13C, 125 MHz) spectrometer using tetra-
methylsilane (1H and 13C) as an internal standard. Analytical
gas chromatography (GC) was performed on a Shimadzu
Indium-Catalyzed Reductive Alkylation of Indoles
with Carbonyl Compounds and HSiMePh2; General
Procedure of Method A in Scheme 2 and Table 2
model GC-2014 instrument equipped with
a capillary
column of InertCap 5 (5% diphenyl- and 95% dimethylpoly-
siloxane, 30 m”0.25 mm”0.25 mm) using nitrogen as carrier
gas. Gas chromatography-mass spectrometry (GC-MS) anal-
yses were performed with a Shimadzu model GCMS-
QP2010 instrument equipped with a capillary column of ID-
BPX5 (5% phenyl polysilphenylene-siloxane, 30 m”
0.25 mm”0.25 mm) or InertCap 5 (5% diphenyl- and 95%
dimethylpolysiloxane, 30 m”0.25 mm”0.25 mm) by electron
ionization at 70 eV using helium as carrier gas. Preparative
recycling gel permeation chromatography (GPC) was per-
formed with JAI LC-9105 equipped with JAIGEL-1H and
JAIGEL-2H columns using chloroform as eluent. High-reso-
lution mass spectra (HR-MS) were obtained with a JEOL
JMS-T100GCV spectrometer. All melting points were mea-
sured with a Yanaco Micro Melting Point apparatus and are
uncorrected. Kugelrohr bulb-to-bulb distillation was carried
out with a Sibata glass tube oven GTO-250RS apparatus.
1,4-Dioxane was purchased from Kanto Chemical Co. and
used as received without pre-drying. For the reaction of
entry 10 in Table 1, 1,4-dioxane distilled under argon from
In(NTf2)3 [(3.82 mg, 4.00 mmol), (11.5 mg, 12.0 mmol),
(19.1 mg, 20.0 mmol), (38.2 mg, 40.0 mmol) or (76.4 mg,
80.0 mmol)] was placed in a 20-mL Schlenk tube, which was
heated at 1508C under vacuum for 2 h. The tube was cooled
down to room temperature and filled with argon. 1,4-Diox-
ane (0.40 mL) was added to the tube, and then the mixture
was stirred at room temperature for 5 min. To this were
added carbonyl compound 5 (0.400 mmol), indole derivative
1 (0.600 mmol) and HSiMePh2 (3a) (119 mg, 0.600 mmol)
successively, and the resulting solution was then stirred at
the temperature shown in Scheme 2 and Table 2 (see T1).
After the time specified in Scheme 2 and Table 2 (see t1),
a saturated aqueous NaHCO3 solution (0.5 mL) was added,
and the aqueous phase was extracted with EtOAc (5 mL”
3). The combined organic layer was washed with brine
(1 mL) and then dried over anhydrous sodium sulfate. Fil-
tration and evaporation of the solvent followed by purifica-
tion gave the corresponding product (4). The results are
summarized in Scheme 2 and Table 2. Unless otherwise
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Shota Nomiyama et al.
noted, products 4 synthesized here were fully characterized
1H NMR (500 MHz, CDCl3): d=0.83 (t, J=7.2 Hz, 3H),
1.10–1.33 (m, 8H), 1.38 (d, J=7.2 Hz, 3H), 1.65–1.74 (m,
1H), 1.79–1.88 (m, 1H), 2.36 (s, 3H), 2.87–2.97 (m, 1H),
7.02 (ddd, J=8.0, 7.0, 1.1 Hz, 1H), 7.07 (ddd, J=8.1, 7.1,
1.1 Hz, 1H), 7.26 (dt, J=8.1, 0.9 Hz, 1H), 7.62 (d, J=
8.1 Hz, 1H), 7.63 (bs, 1H).
by 1H and 13C NMR spectroscopy, and HR-MS.
Indium-Catalyzed Reductive Alkylation of Indoles
with Carbonyl Compounds and HSiMePh2; General
Procedure of Method B in Table 2
1,2-Dimethyl-3-(1-methylheptyl)-1H-indole (4d): The title
compound was synthesized with the following reagents
based on method A: 1,2-dimethyl-1H-indole (1c)
(0.600 mmol), 5a (0.400 mmol), 3a (0.600 mmol), In(NTf2)3
(20.0 mmol) and 1,4-dioxane (0.40 mL), and isolated by
column chromatography on silica gel (hexane/EtOAc=40/1)
In(NTf2)3 (38.2 mg, 40.0 mmol) was placed in a 20-mL
Schlenk tube, which was heated at 1508C under vacuum for
2 h. The tube was cooled down to room temperature and
filled with argon. 1,4-Dioxane (0.40 mL) was added to the
tube and then the mixture was stirred at room temperature
for 5 min. To this were added carbonyl compound 5
(0.400 mmol) and indole derivative 1 (1.20 mmol), and the
resulting solution was then stirred at 50, 60, 85 or 1008C
(see T2) for 18, 20, 24 or 48 h (see t2). HSiMePh2 (3a)
(119 mg, 0.600 mmol) was then added, and the resulting so-
lution was stirred further at 50, 70, 85 or 1008C (see T3).
After the time specified in Table 2 (see t3), the work-up pro-
cess was carried out similarly as above. The results are sum-
marized in Table 2. Unless otherwise noted, products 4 pre-
pared here were fully characterized by 1H and 13C NMR
spectroscopy, and HR-MS.
3-(1-Methylheptyl)-1H-indole (4a): The title compound
was synthesized with the following reagents based on
method A: indole (1a) (0.600 mmol), 2-octanone (5a)
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by column chromatogra-
phy on silica gel (hexane/EtOAc=40/1). Compound 4a has
already appeared in the literature, and its spectral and ana-
lytical data are in good agreement with those reported in
ref.[3d] Therefore, only 1H NMR data are provided here.
1H NMR (500 MHz, CDCl3): d=0.86 (t, J=7.2 Hz, 3H),
1.16–1.41 (m, 8H), 1.34 (d, J=6.9 Hz, 3H), 1.56–1.67 (m,
1H), 1.71–1.85 (m, 1H), 3.02 (sext, J=7.1 Hz, 1H), 6.95 (d,
J=2.3 Hz, 1H), 7.09 (ddd, J=8.0, 6.9, 1.1 Hz, 1H), 7.17
(ddd, J=8.3, 7.2, 1.2 Hz, 1H), 7.35 (dd, J=7.4, 1.1 Hz, 1H),
7.65 (dd, J=8.0, 1.2 Hz, 1H), 7.87 (bs, 1H).
1-Methyl-3-(1-methylheptyl)-1H-indole (4b): The title
compound was synthesized with the following reagents
based on method A: N-methylindole (1b) (0.600 mmol), 5a
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (12.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by column chromatogra-
phy on silica gel (hexane/EtOAc =60/1). Compound 4b has
already appeared in the literature, and its spectral and ana-
lytical data are in good agreement with those reported in
ref.[3d] Therefore, only 1H NMR data are provided here.
1H NMR (500 MHz, CDCl3): d=0.86 (t, J=6.9 Hz, 3H),
1.19–1.39 (m, 8H), 1.33 (d, J=6.9 Hz, 3H), 1.55–1.64 (m,
1H), 1.71–1.82 (m, 1H), 3.00 (sext, J=7.0 Hz, 1H), 3.74 (s,
3H), 6.79 (s, 1H), 7.08 (ddd, J=8.0, 6.9, 1.2 Hz, 1H), 7.20
(ddd, J=8.4, 7.0, 1.3 Hz, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.63
(dt, J=6.9, 1.2 Hz, 1H).
1
as a viscous yellow oil. H NMR (500 MHz, CDCl3): d=0.83
(t, J=6.9 Hz, 3H), 1.05–1.30 (m, 8H), 1.38 (d, J=7.5 Hz,
3H), 1.65–1.75 (m, 1H), 1.77–1.88 (m, 1H), 2.34 (s, 3H),
2.89–2.99 (m, 1H), 3.63 (s, 3H), 7.01 (ddd, J=8.0, 6.9,
1.2 Hz, 1H), 7.12 (ddd, J=8.0, 6.9, 1.2 Hz, 1H), 7.23 (d, J=
8.0 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3): d=10.5, 14.1, 21.6, 22.7, 28.4, 29.42, 29.44, 31.7,
31.9, 37.2, 108.6, 115.9, 118.1, 119.5, 120.0, 126.4, 131.8,
136.8; HR-MS (FI): m/z=257.2173, calcd. for C18H27N [M]:
257.2144.
3-(1-Methylheptyl)-1-phenyl-1H-indole (4e): The title
compound was synthesized with the following reagents
based on method A: 1-phenyl-1H-indole (0.600 mmol), 5a
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by recycling GPC after
column chromatography on silica gel (hexane/CHCl3 =20/1)
1
as a light green oil. H NMR (500 MHz, CDCl3): d=0.87 (t,
J=6.9 Hz, 3H), 1.21–1.43 (m, 8H), 1.38 (d, J=6.9 Hz, 3H),
1.59–1.69 (m, 1H), 1.79–1.87 (m, 1H), 3.07 (sext, J=6.9 Hz,
1H), 7.11 (s, 1H), 7.15 (ddd, J=7.9, 7.0, 1.0 Hz, 1H), 7.20
(ddd, J=8.5, 7.0, 1.3 Hz, 1H), 7.28–7.34 (m, 1H), 7.47–7.52
(m, 4H), 7.56 (dd, J=7.5, 1.2 Hz, 1H), 7.69 (dd, J=7.5,
1.2 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=14.1, 21.4,
22.7, 27.7, 29.5, 30.8, 31.9, 37.6, 110.5, 119.6, 119.7, 122.2,
123.8, 124.0, 124.1, 125.9, 128.5, 129.5, 136.2, 140.1; HR-MS
(FI): m/z=305.2157, calcd. for C22H27N [M]: 305.2144.
1-Methyl-3-(1-methylethyl)-2-phenyl-1H-indole (4f): The
title compound was synthesized with the following reagents
based on method A: 1-methyl-2-phenyl-1H-indole
(0.600 mmol), acetone (0.400 mmol), 3a (0.600 mmol),
In(NTf2)3 (40.0 mmol) and 1,4-dioxane (0.40 mL), and isolat-
ed by recycling GPC after column chromatography on silica
gel (hexane/CHCl3 =5/1) as a pale yellow oil. 1H NMR
(500 MHz, CDCl3): d=1.38 (d, J=6.9 Hz, 6H), 3.07 (sept,
J=7.1 Hz, 1H), 3.51 (s, 3H), 7.12 (ddd, J=8.0, 6.9, 1.1 Hz,
1H), 7.23 (ddd, J=8.0, 6.9, 1.2 Hz, 1H), 7.31–7.38 (m, 3H),
7.40–7.50 (m, 3H), 7.81 (d, J=8.1 Hz, 1H); 13C NMR
(125 MHz, CDCl3): d=23.4, 26.3, 30.6, 109.5, 118.7, 119.3,
120.5, 121.3, 126.0, 128.0, 128.2, 130.9, 132.6, 136.5, 137.4;
HR-MS (FI): m/z=249.1533, calcd. for C18H19N [M]:
249.1518.
5-Methoxy-2-methyl-3-(1-methylheptyl)-1H-indole (4g):
The title compound was synthesized with the following re-
agents based on method A: 5-methoxy-2-methyl-1H-indole
(0.600 mmol), 5a (0.400 mmol), 3a (0.600 mmol), In(NTf2)3
(20.0 mmol) and 1,4-dioxane (0.40 mL), and isolated by
column chromatography on silica gel (hexane/EtOAc=15/1)
as a colorless oil. H NMR (500 MHz, acetone-d6): d=0.83
(t, J=6.9 Hz, 3H), 1.12–1.34 (m, 8H), 1.36 (d, J=7.2 Hz,
3H), 1.65–1.74 (m, 1H), 1.82–1.93 (m, 1H), 2.35 (s, 3H),
2-Methyl-3-(1-methylheptyl)-1H-indole (4c): The title
compound was synthesized with the following reagents
based on method A: 2-methyl-1H-indole (0.600 mmol), 5a
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (12.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by column chromatogra-
phy on silica gel (hexane/EtOAc=40/1). Compound 4c has
already appeared in the literature, and its spectral and ana-
lytical data are in good agreement with those reported in
ref.[3d] Therefore, only 1H NMR data are provided here.
1
1142
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1136 – 1149

UPDATES
Easy Access to a Library of Alkylindoles: Reductive Alkylation of Indoles
2.90–3.00 (m, 1H), 3.78 (s, 3H), 6.64 (dd, J=8.6, 2.4 Hz,
1H), 7.05 (d, J=2.4 Hz, 1H), 7.14 (dd, J=8.7, 0.5 Hz, 1H),
9.54 (bs, 1H); 13C NMR (125 MHz, acetone-d6): d=12.2,
14.3, 21.7, 23.3, 29.0, 30.6, 31.9, 32.7, 37.7, 55.9, 102.6, 110.1,
111.7, 116.0, 128.8, 132.12, 132.14, 154.1; HR-MS (FI): m/z=
273.2092, calcd. for C18H27NO [M]: 273.2093.
5-Bromo-3-(1-methylheptyl)-1H-indole (4h): The title
compound was synthesized with the following reagents
based on method A: 5-bromo-1H-indole (0.600 mmol), 5a
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (20.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by column chromatogra-
phy on silica gel (hexane/EtOAc =15/1). Compound 4h has
already appeared in the literature, and its spectral and ana-
lytical data are in good agreement with those reported in
ref.[3d] Therefore, only 1H NMR data are provided here.
1H NMR (500 MHz, CDCl3): d=0.86 (t, J=6.9 Hz, 3H),
1.17–1.36 (m, 8H), 1.31 (d, J=7.1 Hz, 3H), 1.51–1.65 (m,
1H), 1.68–1.80 (m, 1H), 2.96 (sext, J=7.0 Hz, 1H), 6.95 (d,
J=2.5 Hz, 1H), 7.22 (dd, J=8.6, 0.6 Hz, 1H), 7.23–7.26 (m,
1H), 7.72–7.77 (m, 1H), 7.92 (bs, 1H).
3H), 2.88–3.00 (m, 1H), 3.37–3.51 (m, 2H), 7.02 (td, J=7.4,
1.1 Hz, 1H), 7.08 (td, J=7.6, 1.2 Hz, 1H), 7.25 (d, J=
7.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.66 (ds, 1H);
13C NMR (100 MHz, CDCl3): d=12.1, 21.3, 25.7, 31.3, 32.8,
36.2, 45.1, 110.3, 116.1, 118.7, 119.3, 120.6, 127.4, 130.1,
135.5; HR-MS (FI): m/z=249.1310, calcd. for C15H20ClN
[M]: 249.1284.
3-(1-Butylpentyl)-1-methyl-1H-indole (4l): The title com-
pound was synthesized with the following reagents based on
method A: 1b (0.600 mmol), 5-nonanone (5b) (0.400 mmol),
3a (0.600 mmol), In(NTf2)3 (40.0 mmol) and 1,4-dioxane
(0.40 mL), and isolated by column chromatography on silica
gel twice (first: hexane/EtOAc/Et3N=90/5/5; second:
hexane/EtOAc=20/1), or with the following reagents based
on method B: 1b (1.20 mmol), 5b (0.400 mmol) 3a
(0.600 mmol), In(NTf2)3 (40.0 mmol) and 1,4-dioxane
(0.40 mL), and isolated by recycling GPC after column chro-
matography on silica gel (hexane/EtOAc=10/1) as a color-
1
less oil. H NMR (400 MHz, CDCl3): d=0.82 (t, J=6.9 Hz,
6H), 1.15–1.33 (m, 8H), 1.69 (q, J=7.3 Hz, 4H), 2.80 (quint,
J=7.1 Hz, 1H), 3.74 (s, 3H), 6.77 (s, 1H), 7.06 (ddd, J=8.0,
6.9, 1.2 Hz, 1H), 7.19 (ddd, J=8.1, 7.0, 1.0 Hz, 1H), 7.28 (dt,
J=7.8, 1.1 Hz, 1H), 7.63 (dt, J=7.8, 0.9 Hz, 1H); 13C NMR
(125 MHz, CDCl3): d=14.1, 22.9, 30.0, 32.6, 36.0, 36.8,
109.1, 118.2, 119.4, 119.7, 121.1, 125.6, 127.7, 137.1; HR-MS
(FI): m/z=257.2131, calcd. for C18H27N [M]: 257.2144.
5-Cyano-3-(1-methylheptyl)-1H-indole (4i): The title com-
pound was synthesized with the following reagents based on
method
A:
5-cyano-1H-indole
(0.600 mmol),
5a
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by column chromatogra-
phy on silica gel (hexane/EtOAc=5/1) as a colorless oil.
1H NMR (500 MHz, CDCl3): d=0.86 (t, J=6.9 Hz, 3H),
1.17–1.37 (m, 8H), 1.34 (d, J=6.9 Hz, 3H), 1.54–1.67 (m,
1H), 1.68–1.80 (m, 1H), 3.01 (sext, J=7.0 Hz, 1H), 7.07 (d,
J=2.3 Hz, 1H), 7.36–7.43 (m, 2H), 7.99 (s, 1H), 8.26 (bs,
1H); 13C NMR (125 MHz, CDCl3): d=14.1, 21.4, 22.7, 27.6,
29.4, 30.7, 31.8, 37.7, 101.7, 112.1, 121.2, 122.2, 123.7, 124.5,
125.1, 126.8, 138.2; HR-MS (FI): m/z=254.1779, calcd. for
C17H22N2 [M]: 254.1783.
N-Methylindoline (6): The title compound was formed as
a by-product in the reaction of 5b with 1b by method A
1
(Scheme 3) as a colorless oil. H NMR (500 MHz, CDCl3):
d=2.76 (s, 3H), 2.94 (t, J=8.0 Hz, 2H), 3.29 (t, J=8.2 Hz,
2H), 6.47–6.51 (m, 1H), 6.67 (td, J=7.3, 0.9 Hz, 1H), 7.05–
7.11 (m, 2H); 13C NMR (125 MHz, CDCl3): d=28.7, 36.3,
56.1, 107.2, 117.7, 124.2, 127.3, 130.3, 153.4; HR-MS (FI):
m/z=133.0918, calcd. for C9H11N [M]: 133.0892.
1-Methyl-3-(1-methylheptyl)-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-indole (4j): The title compound was
synthesized with the following reagents based on method A:
1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
indole (0.600 mmol), 5a (0.400 mmol), 3a (0.600 mmol),
In(NTf2)3 (40.0 mmol) and 1,4-dioxane (0.40 mL), and isolat-
ed by column chromatography on silica gel (hexane/EtOAc/
1-Methyl-3-(1-propylhexyl)-1H-indole (4m): The title
compound was synthesized with the following reagents
based on method B: 1b (1.20 mmol), 4-nonanone
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by column chromatogra-
phy on silica gel (hexane/EtOAc=100/1) as a colorless oil.
1H NMR (500 MHz, CDCl3): d=0.83 (t, J=6.6 Hz, 3H),
0.85 (t, J=7.5 Hz, 3H), 1.18–1.30 (m, 8H), 1.62–1.72 (m,
4H), 2.83 (quint, J=7.1 Hz, 1H), 3.74 (s, 3H), 6.77 (s, 1H),
7.06 (ddd, J=8.0, 7.0, 1.1 Hz, 1H), 7.19 (ddd, J=8.2, 7.0,
1.2 Hz, 1H), 7.27 (dt, J=8.3, 0.9 Hz, 1H), 7.62 (dt, J=8.0,
0.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=14.1, 14.3,
20.9, 22.7, 27.5, 32.1, 32.6, 36.2, 36.6, 38.6, 109.1, 118.2, 119.5,
119.7, 121.1, 125.6, 127.8, 137.2; HR-MS (FD): m/z=
257.2138, calcd. for C18H27N [M]: 257.2144.
1
Et3N=88/9/3) as a viscous yellow oil. H NMR (500 MHz,
CDCl3): d=0.86 (t, J=6.9 Hz, 3H), 1.19–1.37 (m, 8H), 1.31
(d, J=6.9 Hz, 3H), 1.37 (s, 12H), 1.54–1.64 (m, 1H), 1.71–
1.80 (m, 1H), 3.08 (sext, J=6.9 Hz, 1H), 3.74 (s, 3H), 6.78
(s, 1H), 7.26 (dd, J=8.0, 0.6 Hz, 1H), 7.65 (dd, J=8.0,
1.2 Hz, 1H), 8.13 (t, J=1.1 Hz, 1H); 13C NMR (125 MHz,
CDCl3): d=14.1, 22.0, 22.7, 24.88, 24.90, 27.6, 29.5, 30.4,
31.9, 32.6, 37.8, 83.3, 108.5, 122.5, 124.7, 127.07, 127.12,
127.6, 139.0 (a signal of the boron-bound carbon atom was
not detected due to quadrupolar relaxation of boron); HR-
MS (FI): m/z=369.2859, calcd. for C23H36BNO2 [M]:
369.2839.
b-Ethyl-1-methyl-1H-indole-3-propanoic acid methyl ester
(4n): The title compound was synthesized with the following
reagents based on method B: 1b (1.20 mmol), methyl 3-oxo-
valerate (0.400 mmol), 3a (0.600 mmol), In(NTf2)3
(40.0 mmol) and 1,4-dioxane (0.40 mL), and isolated by
column chromatography on silica gel (hexane/EtOAc =8/1)
3-(5-Chloro-1-methylpentyl)-2-methyl-1H-indole
(4k):
The title compound was synthesized with the following re-
agents based on method A: 2-methyl-1H-indole
1
as a colorless oil. H NMR (400 MHz, CDCl3): d=0.86 (t,
(0.600 mmol),
6-chlorohexan-2-one
(0.400 mmol),
3a
J=7.3 Hz, 3H), 1.78 (quint, J=7.3 Hz, 2H), 2.71 (d, J=
7.4 Hz, 2H), 3.37 (quint, J=7.2 Hz, 1H), 3.59 (s, 3H), 3.74
(s, 3H), 6.84 (s, 1H), 7.08 (ddd, J=8.0, 6.9, 1.1 Hz, 1H),
7.20 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.28 (dt, J=8.2, 0.9 Hz,
1H), 7.63 (dt, J=8.0, 0.9 Hz, 1H); 13C NMR (125 MHz,
CDCl3): d=12.0, 28.4, 32.6, 35.1, 40.8, 51.4, 109.2, 117.1,
(0.600 mmol), In(NTf2)3 (40.0 mmol) and 1,4-dioxane
(0.40 mL), and isolated by column chromatography on silica
gel (hexane/EtOAc =10/1) as a pale yellow oil. 1H NMR
(400 MHz, CDCl3): d=1.21–1.46 (m, 2H), 1.40 (d, J=
6.9 Hz, 3H), 1.65–1.79 (m, 3H), 1.81–1.94 (m, 1H), 2.36 (s,
Adv. Synth. Catal. 2016, 358, 1136 – 1149
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1143

UPDATES
Shota Nomiyama et al.
118.6, 119.4, 121.4, 125.8, 127.2, 137.1, 173.4; HR-MS (FD):
m/z=245.1407, calcd. for C15H19NO2 [M]: 245.1416.
(0.600 mmol), In(NTf2)3 (40.0 mmol) and 1,4-dioxane
(0.40 mL), and isolated by recycling GPC after column chro-
matography on silica gel (hexane/EtOAc=30/1). Compound
4s has already appeared in the literature, and its spectral
and analytical data are in good agreement with those report-
ed in ref.[3d] Therefore, only 1H NMR data are provided
here. 1H NMR (500 MHz, CDCl3): d=1.78 (d, J=7.3 Hz,
3H), 2.33 (s, 3H), 3.65 (s, 3H), 4.44 (q, J=7.4 Hz, 1H), 6.96
(t, J=7.5 Hz, 1H), 7.07–7.17 (m, 2H), 7.22–7.25 (m, 3H),
7.34 (d, J=7.6 Hz, 2H), 7.40 (d, J=8.0 Hz, 1H).
3-Cyclooctyl-1-methyl-1H-indole (4o): The title com-
pound was synthesized with the following reagents based on
method B: 1b (1.20 mmol), cyclooctanone (0.400 mmol), 3a
(0.600 mmol), In(NTf2)3 (40.0 mmol) and 1,4-dioxane
(0.40 mL), and isolated by column chromatography on silica
1
gel (hexane/EtOAc=5/1) as a viscous yellow oil. H NMR
(500 MHz, CDCl3): d=1.56–1.89 (m, 12H), 1.96–2.05 (m,
2H), 3.13 (tt, J=9.5, 3.6 Hz, 1H), 3.73 (s, 3H), 6.81 (s, 1H),
7.08 (ddd, J=8.0, 6.9, 1.1 Hz, 1H), 7.20 (ddd, J=8.0, 6.9,
1.2 Hz, 1H), 7.27 (dd, J=7.8, 0.9 Hz, 1H), 7.61 (dd, J=8.0,
1.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=25.8, 26.3,
27.4, 32.6, 33.0, 35.0, 109.1, 118.3, 119.4, 121.3, 122.9, 124.6,
127.0, 137.0; HR-MS (FI): m/z=241.1826, calcd. for
C17H23N [M]: 241.1831.
3-(Adamantan-2-yl)-1-methyl-1H-indole (4p): The title
compound was synthesized with the following reagents
based on method B: 1b (1.20 mmol), 2-adamantanone
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by recycling GPC after
column chromatography on silica gel (hexane/CHCl3 =4/1)
as a white solid; mp 138–1398C. 1H NMR (500 MHz,
CDCl3): d=1.61 (d, J=12.6 Hz, 2H), 1.80 (s, 2H), 1.86
(quint, J=3.0 Hz, 1H), 1.93–2.15 (m, 7H), 2.33 (s, 2H), 3.37
(s, 1H), 3.76 (s, 3H), 6.98 (s, 1H), 7.06 (ddd, J=8.0, 6.9,
1.2 Hz, 1H), 7.20 (ddd, J=8.0, 6.9, 1.1 Hz, 1H), 7.28 (dd,
J=7.5, 1.2 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3): d=28.1, 28.3, 32.4, 32.6, 32.7, 38.2, 39.5,
42.5, 109.0, 118.3, 118.9, 119.7, 121.3, 126.1, 127.9, 136.8;
HR-MS (FI): m/z=265.1823, calcd. for C19H23N [M]:
265.1831.
3-[1-(4-Hydroxyphenyl)ethyl]-1-methyl-1H-indole
(4t):
The title compound was synthesized with the following re-
agents based on method A: 1b (0.600 mmol), p-acetylphenol
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by recycling GPC after
column chromatography on silica gel (hexane/EtOAc =4/1)
as a white solid; mp 101–1028C. 1H NMR (500 MHz,
CDCl3): d=1.65 (d, J=7.2 Hz, 3H), 3.75 (s, 3H), 4.31 (q,
J=7.2 Hz, 1H), 4.50 (s, 1H), 6.72 (dt, J=8.6, 2.5 Hz, 2H),
6.81 (s, 1H), 6.99 (ddd, J=8.0, 7.0, 1.0 Hz, 1H), 7.12–7.22
(m, 3H), 7.26–7.29 (m, 1H), 7.36 (dt, J=7.8, 0.9 Hz, 1H);
13C NMR (125 MHz, CDCl3): d=22.6, 32.6, 36.0, 109.1,
115.1, 118.6, 119.8, 120.2, 121.5, 125.9, 127.2, 128.5, 137.3,
139.3, 153.5; HR-MS (FI): m/z=251.1308, calcd. for
C17H17NO [M]: 251.1310.
3-(Diphenylmethyl)-1-methyl-1H-indole (4u): The title
compound was synthesized with the following reagents
based on method B: 1b (1.20 mmol), benzophenone
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (80.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by column chromatogra-
phy on silica gel (hexane/CHCl3 =4/1). Compound 4u has al-
ready appeared in the literature, and its spectral and analyti-
cal data are in good agreement with those reported in ref.[28]
3-(2,3-Dihydro-1H-inden-1-yl)-1-methyl-1H-indole (4q):
The title compound was synthesized with the following re-
agents based on method A: 1b (0.600 mmol), 1-indanone
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by column chromatogra-
phy on silica gel (hexane/CHCl3 =4/1). Compound 4q has al-
ready appeared in the literature, and its spectral and analyti-
cal data are in good agreement with those reported in ref.[27]
1
1
Therefore, only H NMR data are provided here. H NMR
(400 MHz, CDCl3): d=3.70 (s, 3H), 5.66 (s, 1H), 6.41 (d,
J=0.9 Hz, 1H), 6.97 (ddd, J=8.0, 7.0, 1.0 Hz, 1H), 7.16–
7.25 (m, 8H), 7.26–7.30 (m, 5H).
3-(Fluoren-9-yl)-1H-indole (4v): The title compound was
synthesized with the following reagents based on method A:
1a
(0.600 mmol),
9-fluorenone
(0.400 mmol),
3a
1
1
Therefore, only H NMR data are provided here. H NMR
(400 MHz, CDCl3): d=2.21 (dq, J=12.4, 8.4 Hz, 1H), 2.58
(ddt, J=12.3, 7.8, 4.4 Hz, 1H), 2.91–3.11 (m, 2H), 3.73 (s,
3H), 4.65 (t, J=8.0 Hz, 1H), 6.74 (s, 1H), 7.05 (ddd, J=7.9,
7.0, 0.9 Hz, 1H), 7.09–7.15 (m, 2H), 7.15–7.24 (m, 2H),
7.28–7.33 (m, 2H), 7.46 (dt, J=8.0, 0.9 Hz, 1H).
(0.600 mmol), In(NTf2)3 (40.0 mmol) and 1,4-dioxane
(0.40 mL), and isolated by column chromatography on silica
gel (hexane/EtOAc =5/1) as a pale purple solid; mp 121–
1
1228C. H NMR (500 MHz, CDCl3): d=5.38 (s, 1H), 6.94 (t,
J=8.0 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 7.09 (d, J=8.1 Hz,
1H), 7.13 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.22 (td, J=7.5,
1.2 Hz, 2H), 7.33 (dt, J=8.0, 0.9 Hz, 1H), 7.38 (t, J=7.5 Hz,
2H), 7.42 (dd, J=7.6, 0.7 Hz, 2H), 7.84 (d, J=7.7 Hz, 2H),
7.96 (bs, 1H); 13C NMR (125 MHz, CDCl3): d=45.9, 111.2,
115.5, 119.41, 119.44, 119.8, 122.1, 122.2, 125.2, 126.7, 127.1,
136.6, 140.7, 147.7 (one carbon signal is missing due to over-
lapping); HR-MS (FD): m/z=281.1214, calcd. for C21H15N
[M]: 281.1205.
1-Methyl-3-(1-phenylethyl)-1H-indole (4r): The title com-
pound was synthesized with the following reagents based on
method A: 1b (0.600 mmol), acetophenone (5c)
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by recycling GPC after
column chromatography on silica gel (hexane/EtOAc=30/
1). Compound 4r has already appeared in the literature, and
its spectral and analytical data are in good agreement with
3-Decyl-1-methyl-1H-indole (4w): The title compound
was synthesized with the following reagents based on
method A: 1b (0.600 mmol), 1-decanal (0.400 mmol), 3a
(0.600 mmol), In(NTf2)3 (20.0 mmol) and 1,4-dioxane
(0.40 mL), and isolated by column chromatography on silica
1
those reported in ref.[3d] Therefore, only H NMR data are
1
provided here. H NMR (500 MHz, CDCl3): d=1.69 (d, J=
7.5 Hz, 3H), 3.75 (s, 3H), 4.36 (q, J=7.1 Hz, 1H), 6.83 (s,
1H), 6.99 (ddd, J=8.0, 6.9, 1.2 Hz, 1H), 7.14–7.21 (m, 2H),
7.24–7.31 (m, 5H), 7.36 (dd, J=8.1, 1.2 Hz, 1H).
gel (hexane/CHCl3 =4/1) as
a
colorless oil. 1H NMR
1,2-Dimethyl-3-(1-phenylethyl)-1H-indole (4s): The title
compound was synthesized with the following reagents
based on method A: 1c (0.600 mmol), 5c (0.400 mmol), 3a
(500 MHz, CDCl3): d=0.88 (t, J=6.9 Hz, 3H), 1.20–1.43
(m, 14H), 1.69 (quint, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz,
2H), 3.74 (s, 3H), 6.82 (s, 1H), 7.09 (ddd, J=8.0, 6.9,
1144
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Adv. Synth. Catal. 2016, 358, 1136 – 1149

UPDATES
Easy Access to a Library of Alkylindoles: Reductive Alkylation of Indoles
1.2 Hz, 1H), 7.20 (ddd, J=8.5, 7.0, 1.3 Hz, 1H), 7.27 (dd,
J=7.5, 1.2 Hz, 1H), 7.59 (dd, J=6.9, 1.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3): d=14.1, 22.7, 25.1, 29.4, 29.6, 29.7, 30.5,
31.9, 32.5, 109.0, 115.7, 118.4, 119.1, 121.3, 125.9, 128.0, 137.0
(two carbon signals are missing due to overlapping); HR-
MS (FI): m/z=271.2303, calcd. for C19H29N [M]: 271.2300.
3-(Cyclohexylmethyl)-2-methyl-1H-indole (4x): The title
compound was synthesized with the following reagents
based on method A: 2-methylindole (0.600 mmol), cyclohex-
128.2 (q, J=32.1 Hz), 128.89, 128.91, 137.2, 145.6; HR-MS
(FI): m/z=289.1056, calcd. for C17H14F3N [M]: 289.1078.
1,2-Dimethyl-3-(3-thienylmethyl)-1H-indole (4ab): The
title compound was synthesized with the following reagents
based on method A: 1c (0.600 mmol), 3-thienylaldehyde
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (40.0 mmol) and
1,4-dioxane (0.40 mL), and isolated by recycling GPC after
column chromatography on silica gel (hexane/EtOAc=10/1)
1
as a white solid; mp 84–858C. H NMR (500 MHz, CDCl3):
d=2.36 (s, 3H), 3.66 (s, 3H), 4.06 (s, 2H), 6.85 (dd, J=3.2,
1.5 Hz, 1H), 6.93 (dd, J=4.6, 1.1 Hz, 1H), 7.03 (t, J=
7.5 Hz, 1H), 7.14 (ddd, J=8.0, 6.9, 1.2 Hz, 1H), 7.18 (dd,
J=5.2, 2.9 Hz, 1H), 7.24 (s, 1H), 7.43 (d, J=8.1 Hz, 1H);
13C NMR (125 MHz, CDCl3): d=10.3, 25.3, 29.5, 108.5,
109.5, 118.2, 118.8, 120.2, 120.5, 125.2, 127.7, 128.2, 133.2,
136.5, 142.5; HR-MS (FI): m/z=241.0947, calcd. for
C15H15NS [M]: 241.0925.
(1H-Indol-3-ylmethyl)ferrocene (4ac): The title compound
was synthesized with the following reagents based on
method A: 1a (0.600 mmol), ferrocenecarboxaldehyde
(0.400 mmol), 3a (0.600 mmol), In(NTf2)3 (4.00 mmol) and
1,4-dioxane (0.40 mL), and isolated by column chromatogra-
phy on silica gel (hexane/EtOAc=5/1) as an orange solid;
mp 159–1608C. 1H NMR (500 MHz, CDCl3): d=3.83 (s,
2H), 4.06 (t, J=1.8 Hz, 2H), 4.14 (s, 5H), 4.18 (t, J=1.7 Hz,
2H), 6.87–6.91 (m, 1H), 7.11 (ddd, J=8.0, 6.9, 1.2 Hz, 1H),
7.18 (ddd, J=8.0, 6.9, 1.2 Hz, 1H), 7.33 (dd, J=7.7, 0.9 Hz,
1H), 7.62 (dd, J=8.0, 1.2 Hz, 1H), 7.89 (bs, 1H); 13C NMR
(100 MHz, CDCl3): d=25.6, 67.2, 68.6, 68.7, 88.2, 111.0,
116.9, 119.0, 119.2, 121.6, 121.9, 127.3, 136.2; HR-MS (FI):
m/z=315.0726, calcd. for C19H17FeN [M]: 315.0710.
1,5-Dimethyl-2-decyl-3-propyl-1H-indole (4ad): The title
compound was synthesized with the following reagents
based on method B: 1,5-dimethyl-3-propyl-1H-indole
(1.20 mmol), 1-decanal (0.400 mmol), 3a (0.600 mmol),
In(NTf2)3 (40.0 mmol) and 1,4-dioxane (0.40 mL), and isolat-
ed by recycling GPC after column chromatography on silica
gel (hexane/EtOAc =10/1) as a pale yellow oil. 1H NMR
(500 MHz, CDCl3): d=0.88 (t, J=7.0 Hz, 3H), 0.97 (t, J=
7.3 Hz, 3H), 1.21–1.42 (m, 14H), 1.54 (quint, J=7.6 Hz,
2H), 1.64 (sext, J=7.5 Hz, 2H), 2.44 (s, 3H), 2.64 (t, J=
7.6 Hz, 2H), 2.70 (t, J=7.7 Hz, 2H), 3.62 (s, 3H), 6.96 (dd,
J=8.2, 1.3 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.28–7.31 (m,
1H); 13C NMR (125 MHz, CDCl3): d=14.1, 14.4, 21.5, 22.7,
24.5, 24.6, 26.8, 29.3, 29.5, 29.60, 29.61, 30.3, 31.9, 108.2,
110.9, 118.1, 121.8, 127.6, 128.1, 135.1, 137.3 (two carbon sig-
nals are missing due to overlapping); HR-MS (FD): m/z=
327.2942, calcd. for C23H37N [M]: 327.2926.
anecarboxaldehyde
(0.400 mmol),
3a
(0.600 mmol),
In(NTf2)3 (4.00 mmol) and 1,4-dioxane (0.40 mL), and isolat-
ed by column chromatography on silica gel (hexane/
EtOAc=10/1) as a white solid; mp 102–1038C. 1H NMR
(500 MHz, CDCl3): d=0.93–1.04 (m, 2H), 1.09–1.21 (m,
3H), 1.53–1.77 (m, 6H), 2.34 (s, 3H), 2.55 (d, J=6.9 Hz,
2H), 7.01–7.12 (m, 2H), 7.24 (dt, J=8.0, 1.0 Hz, 1H), 7.48
(d, J=8.0 Hz, 1H), 7.65 (bs, 1H); 13C NMR (125 MHz,
CDCl3): d=11.8, 26.4, 26.6, 32.1, 33.6, 39.4, 110.0, 111.1,
118.4, 118.8, 120.6, 129.3, 131.2, 135.1; HR-MS (FI): m/z=
227.1700, calcd. for C16H21N [M]: 227.1674.
3-(3-Cyclohexen-1-ylmethyl)-1-methyl-1H-indole
(4y):
The title compound was synthesized with the following re-
agents based on method A: 1b (0.600 mmol), 3-cyclohexene-
1-carboxaldehyde (0.400 mmol), 3a (0.600 mmol), In(NTf2)3
(40.0 mmol) and 1,4-dioxane (0.40 mL), and isolated by bulb-
to-bulb distillation (1008C/100 Pa) after column chromatog-
raphy on silica gel (hexane/CHCl3 =6/1) as a colorless oil.
1H NMR (500 MHz, CDCl3): d=1.24–1.35 (m, 1H), 1.72–
1.86 (m, 2H), 1.89–2.15 (m, 4H), 2.64–2.76 (m, 2H), 3.74 (s,
3H), 5.61–5.69 (m, 2H), 6.82 (s, 1H), 7.08 (ddd, J=7.9, 7.0,
1.0 Hz, 1H), 7.20 (ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.28 (dt, J=
8.3, 0.9 Hz, 1H), 7.59 (dt, J=7.8, 0.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=25.3, 28.8, 32.02, 32.04, 32.6, 34.7,
109.0, 113.6, 118.5, 119.2, 121.3, 126.6, 126.8, 127.0, 128.4,
137.0; HR-MS (FD): m/z=225.1501, calcd. for C16H19N [M]:
225.1518.
3-(2,2-Dimethylpropyl)-2-methyl-1H-indole (4z): The title
compound was synthesized with the following reagents
based on method A: 2-methylindole (0.600 mmol), trimethy-
lacetaldehyde (0.400 mmol), 3a (0.600 mmol), In(NTf2)3
(4.00 mmol) and 1,4-dioxane (0.40 mL), and isolated by
column chromatography on silica gel (hexane/EtOAc=10/1)
1
as a white solid; mp 71–728C. H NMR (500 MHz, CDCl3):
d=0.96 (s, 9H), 2.35 (s, 3H), 2.57 (s, 2H), 7.02–7.12 (m,
2H), 7.25 (dd, J=6.6, 0.9 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H),
7.74 (bs, 1H); 13C NMR (125 MHz, CDCl3): d=12.6, 30.0,
34.1, 38.0, 109.9, 110.3, 118.9, 119.3, 120.6, 130.1, 132.2,
135.1; HR-MS (FI): m/z=201.1489, calcd. for C14H19N [M]:
201.1518.
1-Methyl-3-{[4-(trifluoromethyl)phenyl]methyl}-1H-indole
(4aa): The title compound was synthesized with the follow-
ing reagents based on method A: 1b (0.600 mmol), 4-(tri-
fluoromethyl)benzaldehyde (0.400 mmol), 3a (0.600 mmol),
In(NTf2)3 (40.0 mmol) and 1,4-dioxane (0.40 mL), and isolat-
ed by column chromatography on silica gel (hexane/
Indium-Catalyzed Alkylation of Indoles with
Carbonyl Compounds and Carbon Nucleophiles;
General Procedure for Scheme 5
In(NTf2)3 (38.2 mg, 40.0 mmol) was placed in a 20-mL
Schlenk tube, which was heated at 1508C under vacuum for
2 h. The tube was cooled down to room temperature and
filled with argon. 1,4-Dioxane (0.40 mL) was added to the
tube and then the mixture was stirred at room temperature
for 5 min. To this were added indole 1 (1.20 mmol) and car-
bonyl compound 5 (0.400 mmol), and the resulting mixture
was stirred at 708C for 0.5 or 3 h. Carbon nucleophile 3
(0.800 or 1.20 mmol) was then added, and the resulting solu-
1
EtOAc=4/1) as a colorless oil. H NMR (500 MHz, CDCl3):
d=3.75 (s, 3H), 4.15 (s, 2H), 6.78 (s, 1H), 7.08 (ddd, J=7.9,
7.0, 1.0 Hz, 1H), 7.22 (ddd, J=8.5, 7.0, 1.3 Hz, 1H), 7.31
(dd, J=8.0, 1.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.46 (dd,
J=8.3, 0.9 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=31.4, 32.6, 109.3, 113.1, 119.0, 121.8,
124.4 (q, J=270.4 Hz), 125.2 (q, J=3.7 Hz), 127.2, 127.6,
Adv. Synth. Catal. 2016, 358, 1136 – 1149
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1145

UPDATES
Shota Nomiyama et al.
1
tion was stirred further at 508C for 8 or 30 h. A saturated
aqueous NaHCO3 solution (0.5 mL) was added to the mix-
ture, and the aqueous phase was extracted with EtOAc
(5 mL”3). The combined organic layer was washed with
brine (1 mL) and then dried over anhydrous sodium sulfate.
Filtration and evaporation of the solvent followed by
provided here. H NMR (400 MHz, CDCl3): d=2.35 (s, 3H),
3.66 (s, 6H), 6.48 (s, 2H), 6.92 (ddd, J=8.1, 7.0, 1.0 Hz,
2H), 7.13–7.36 (m, 9H), 7.37–7.47 (m, 2H).
Indium-Catalyzed Reduction of 3,3’-(1-Phenyl-
column chromatography on silica gel using hexane/EtOAc ethylidene)bis[1-methyl-1H-indole] (8a) with
as eluent gave the corresponding product 7a or 7b.
2-Methyl-2-(1-methyl-1H-indol-3-yl)octanenitrile
HSiMePh2 (3a) in the Presence or Absence of H2O;
Procedure for Synthesis of 1-Methyl-3-(1-
phenylethyl)-1H-indole (4r) (Scheme 6)
(7a):
The title compound was synthesized with the following re-
agents: 1b (1.20 mmol), 5a (0.400 mmol), Me3SiCN (3f)
(0.800 mmol), In(NTf2)3 (40.0 mmol) and 1,4-dioxane
(0.40 mL), and isolated by column chromatography on silica
gel (hexane/EtOAc=20/1). Compound 7a has already ap-
peared in the literature, and its spectral and analytical data
are in good agreement with those reported in ref.[3d] There-
fore, only 1H NMR data are provided here. 1H NMR
(400 MHz, CDCl3): d=0.84 (t, J=6.9 Hz, 3H), 1.16–1.41
(m, 7H), 1.42–1.53 (m, 1H), 1.82 (s, 3H), 1.92–2.02 (m, 1H),
2.10–2.21 (m, 1H), 3.77 (s, 3H), 7.06 (s, 1H), 7.14 (ddd, J=
8.1, 7.0, 1.1 Hz, 1H), 7.23–7.28 (m, 1H), 7.33 (dt, J=8.2,
0.9 Hz, 1H), 7.74 (dt, J=8.0, 0.9 Hz, 1H).
In(NTf2)3 (19.1 mg, 20.0 mmol) was placed in a 20-mL
Schlenk tube, which was heated at 1508C under vacuum for
2 h. The tube was cooled down to room temperature and
filled with argon. 1,4-Dioxane (0.20 mL) was added to the
tube, and the resulting mixture was stirred at room tempera-
ture for 5 min. To this were added 8a (72.9 mg, 0.200 mmol)
and 3a (59.5 mg, 0.300 mmol). In the case of the reaction
with H2O, to the tube was further added H2O (3.60 mg,
0.200 mmol). The resulting mixture was stirred at 858C for
30 min for the reaction with H2O, or 120 h for the reaction
without H2O.
A saturated aqueous NaHCO3 solution
(0.5 mL) was added to the mixture, and the aqueous phase
was extracted with EtOAc (5 mL”3). The combined organic
layer was washed with brine (1 mL) and then dried over an-
hydrous sodium sulfate. Filtration and evaporation of the
solvent followed by column chromatography on silica gel
(hexane/EtOAc=30/1) gave 4r; yield: 46.3 mg (98% for the
reaction with H2O) or 41.7 mg (88% for the reaction with-
out H2O). Compound 4r has already appeared in this experi-
3-{1-(5-Methoxythiophen-2-yl)-1-[4-(trifluoromethyl)phe-
nyl]ethyl}-1H-indole (7b): The title compound was synthe-
sized with the following reagents: 1a (1.20 mmol), 4’-(tri-
fluoromethyl)acetophenone (0.400 mmol), 2-methoxythio-
phene (3g) (1.20 mmol), In(NTf2)3 (40.0 mmol) and 1,4-diox-
ane (0.40 mL), and isolated by recycling GPC after column
chromatography on silica gel (hexane/EtOAc =5/1). Com-
pound 7b has already appeared in the literature, and its
spectral and analytical data are in good agreement with
1
mental section, and its full data on H NMR, 13C NMR spec-
1
those reported in ref.[3d] Therefore, only H NMR data are
troscopy and HR-MS analysis have also been collected in
ref.[3d]
1
provided here. H NMR (400 MHz, CDCl3): d=2.23 (s, 3H),
3.83 (s, 3H), 5.99 (d, J=3.9 Hz, 1H), 6.33 (d, J=3.9 Hz,
1H), 6.73 (d, J=2.5 Hz, 1H), 6.96 (ddd, J=8.1, 7.0, 1.1 Hz,
1H), 7.12 (dd, J=8.1, 0.9 Hz, 1H), 7.16 (ddd, J=8.2, 7.1,
1.1 Hz, 1H), 7.36 (dt, J=8.1, 0.8 Hz, 1H), 7.45 (dt, J=8.2,
0.7 Hz, 2H), 7.52 (dt, J=8.2, 0.7 Hz, 2H), 7.98 (bs, 1H).
Indium-Catalyzed Reaction of Acetophenone (5c)
with 1,2-Dimethylindole (1c); Procedure for Synthesis
of 1,2-Dimethyl-3-(1-phenylethenyl)-1H-indole (9a)
(Scheme 6)
In(NTf2)3 (38.2 mg, 40.0 mmol) was placed in a 20-mL
Schlenk tube, which was heated at 1508C under vacuum for
2 h. The tube was cooled down to room temperature and
filled with argon. 1,4-Dioxane (0.40 mL) was added to the
tube, and the resulting mixture was stirred at room tempera-
ture for 5 min. To this were added 5c (48.1 mg, 0.400 mmol)
and 1c (174 mg, 1.20 mmol), and the resulting mixture was
stirred at 508C for 40 h. A saturated aqueous NaHCO3 solu-
tion (0.5 mL) was added to the mixture, and the aqueous
phase was extracted with EtOAc (5 mL”3). The combined
organic layer was washed with brine (1 mL) and then dried
over anhydrous sodium sulfate. Filtration and evaporation
of the solvent followed by column chromatography on silica
gel (hexane/EtOAc/Et3N=92/5/3) gave 1,2-dimethyl-3-(1-
phenylethenyl)-1H-indole (9a); yield: 80.7 mg (81%). Com-
pound 9a has already appeared in the literature, and its
spectral and analytical data are in good agreement with
Indium-Catalyzed Reaction of Acetophenone (5c)
with N-Methylindole (1b); Procedure for Synthesis of
3,3’-(1-Phenylethylidene)bis[1-methyl-1H-indole] (8a)
(Scheme 6)
In(NTf2)3 (38.2 mg, 40.0 mmol) was placed in a 20-mL
Schlenk tube, which was heated at 1508C under vacuum for
2 h. The tube was cooled down to room temperature and
filled with argon. 1,4-Dioxane (0.40 mL) was added to the
tube, and the resulting mixture was stirred at room tempera-
ture for 5 min. To this were added 5c (48.1 mg, 0.400 mmol)
and 1b (157 mg, 1.20 mmol), and the resulting mixture was
stirred at 508C for 12 h. A saturated aqueous NaHCO3 solu-
tion (0.5 mL) was added to the mixture, and the aqueous
phase was extracted with EtOAc (5 mL”3). The combined
organic layer was washed with brine (1 mL) and then dried
over anhydrous sodium sulfate. Filtration and evaporation
of the solvent followed by column chromatography on silica
gel (hexane/EtOAc=10/1) gave 3,3’-(1-phenylethylidene)-
bis[1-methyl-1H-indole] (8a); yield: 145 mg (99%). Com-
pound 8a has already appeared in the literature, and its
spectral and analytical data are in good agreement with
1
those reported in ref.[3d] Therefore, only H NMR data are
1
provided here. H NMR (500 MHz, CDCl3): d=2.28 (s, 3H),
3.72 (s, 3H), 5.30 (d, J=1.2 Hz, 1H), 5.75 (d, J=1.1 Hz,
1H), 6.99 (ddd, J=7.7, 6.9, 0.9 Hz, 1H), 7.14 (ddd, J=7.6,
7.0, 0.7 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 7.26–7.34 (m, 4H),
7.36–7.45 (m, 2H).
1
those reported in ref.[3d] Therefore, only H NMR data are
1146
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1136 – 1149

UPDATES
Easy Access to a Library of Alkylindoles: Reductive Alkylation of Indoles
2009, 121, 9786; Angew. Chem. Int. Ed. 2009, 48, 9608;
f) A. Palmieri, M. Petrini, R. R. Shaikh, Org. Biomol.
Chem. 2010, 8, 1259; g) G. Bartoli, G. Bencivenni, R.
Dalpozzo, Chem. Soc. Rev. 2010, 39, 4449; h) S. M.
Bronner, A. E. Goetz, N. K. Garg, Synlett 2011, 2599;
i) C.-X. Zhuo, C. Zheng, S.-L. You, Acc. Chem. Res.
2014, 47, 2558.
Indium-Catalyzed Reduction of 1,2-Dimethyl-3-(1-
phenylethenyl)-1H-indole (9a) with HSiMePh2 (3a) in
the Presence or Absence of H2O; Procedure for
Synthesis of 1,2-Dimethyl-3-(1-phenylethyl)-1H-
indole (4s) (Scheme 6)
In(NTf2)3 (19.1 mg, 20.0 mmol) was placed in a 20-mL
Schlenk tube, which was heated at 1508C under vacuum for
2 h. The tube was cooled down to room temperature and
filled with argon. 1,4-Dioxane (0.20 mL) was added to the
tube, and the resulting mixture was stirred at room tempera-
ture for 5 min. To this were added 9a (49.5 mg, 0.200 mmol)
and 3a (59.5 mg, 0.300 mmol). In the case of the reaction
with H2O, to the tube was further added H2O (3.60 mg,
0.200 mmol). The resulting mixture was stirred at 858C for
15 min for the reaction with H2O, or 24 h for the reaction
[3] a) T. Tsuchimoto, Y. Ozawa, R. Negoro, E. Shirakawa,
Y. Kawakami, Angew. Chem. 2004, 116, 4327; Angew.
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[4] For example, see: SIGMA-ALDRICH Product Catalog
without H2O.
A saturated aqueous NaHCO3 solution
(0.5 mL) was added to the mixture, and the aqueous phase
was extracted with EtOAc (5 mL”3). The combined organic
layer was washed with brine (1 mL) and then dried over an-
hydrous sodium sulfate. Filtration and evaporation of the
solvent followed by column chromatography on silica gel
(hexane/EtOAc=30/1) gave 4s; yield: 44.7 mg (89% for the
reaction with H2O) or 45.2 mg (90% for the reaction with-
out H2O). Compound 4s has already appeared in this experi-
at
http://www.sigmaaldrich.com/chemistry/chemistry-
products.html?TablePage=16273490.
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1
mental section, and its full data on H NMR, 13C NMR spec-
troscopy and HR-MS analysis have also been collected in
ref.[3d]
Acknowledgements
Partial financial support from Nissan Chemical Industries,
L.T.D. is gratefully acknowledged.
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À
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was formed under the same reaction conditions as
those used for entry 16 of Table 1.
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3
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