Iron-Catalyzed Direct C3-Benzylation of Indoles with Benzyl Alcohols through Borrowing Hydrogen

Article abstract of DOI:10.1021/acs.joc.7b01603

We present the coupling of primary and secondary benzyl alcohols with indoles to form 3-benzylated indoles and H₂O that is catalyzed, for the first time, by a complex of earth-abundant iron. This transformation accommodates a variety of substrates and is distinguished by its operational simplicity, sustainability, high functional-group tolerance, and amenability to gram-scale synthesis. On the basis of the preliminary experimental observations, we propose that the reaction proceeds through a borrowing hydrogen process.

Full text of DOI:10.1021/acs.joc.7b01603

Note
pubs.acs.org/joc
Iron-Catalyzed Direct C3-Benzylation of Indoles with Benzyl Alcohols
through Borrowing Hydrogen
Giovanni Di Gregorio, Michele Mari, Francesca Bartoccini, and Giovanni Piersanti*
Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, P.zza Rinascimento 6, 61029 Urbino, Pesaro and Urbino
(PU), Italy
S
* Supporting Information
ABSTRACT: We present the coupling of primary and secondary benzyl alcohols with indoles to form 3-benzylated indoles and
H2O that is catalyzed, for the first time, by a complex of earth-abundant iron. This transformation accommodates a variety of
substrates and is distinguished by its operational simplicity, sustainability, high functional-group tolerance, and amenability to
gram-scale synthesis. On the basis of the preliminary experimental observations, we propose that the reaction proceeds through a
borrowing hydrogen process.
he catalytic alkylation of indoles with alcohols represents
an environmentally benign and atom-economic pathway
Scheme 1. Representative Reaction Pathway for the C3-
Alkylation of Indoles by Transition-Metal-Catalyzed
Borrowing Hydrogen Methodology
T
for the synthesis of substituted indoles and indolenine, which
have important synthetic applications in the synthesis of dyes,
fragrances, pharmaceuticals (including controlling bacterial
behavior), and agricultural chemicals.1 In terms of sustain-
ability, the choice of alcohols as substrates is highly desirable as
they are readily available by a variety of industrial processes,
inexpensive because they can be obtained renewably via
fermentation or catalytic conversion of lignocellulosic biomass,
relatively nontoxic, and easy to use.2 The best known method
for the alkylation of indoles is the Friedel−Crafts reaction with
haloalkanes and related alkyl agents mediated by Lewis acid.3
However, this method can be problematic due to over
alkylation, toxic nature of many alkyl (pseudo)halides, and it
also produces large amounts of inorganic salt. The so-called
‘borrowing hydrogen methodology’4 has aroused great interest
in recent years and is an excellent protocol for the catalytic C-
alkylation of ketones and related compounds, using nontoxic
alcohols.5 The catalytic cycle, for the indole alkylation, involves
three or four successive steps: (i) acceptorless dehydrogenation
of alcohols, (ii) alkylideneindolenine formation (which behaves
as an actual vinylogous imine), and (iii) in situ hydrogenation of
the double bond (borrowing hydrogen methodology) and
aromatization generate the alkylated-indole compound. Key
features are that the process is hydrogen neutral and that the
only stoichiometric byproduct is water (Scheme 1).
precious metals such as Pt,6 Pd,7 Ir,8 and Ru.9 In comparison,
the same reaction with catalysts that utilize nonprecious, less
toxic earth-abundant metals10 is much less developed.
However, base metals have been found to readily oxidize
alcohols via acceptorless dehydrogenation.11
On the other hand, the groups of Feringa and Barta, Wills,
and Zhao have reported the alkylation of primary amines with
alcohols to give secondary and tertiary amines by utilizing iron
catalysts featuring functionalized cyclopentadienone or hydroxy
Despite the significance of such coupling reactions,
homogeneous and heterogeneous catalysts mostly employ
Received: June 28, 2017
Published: July 26, 2017
© 2017 American Chemical Society
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Note
cyclopentadienyl ligands based on Knolker’s complex or
absence of light as well as in the presence of radical scavengers
such butylated hydroxytoluene (BHT), thus discarding the
involvement of radical species in the reaction pathway (Table 1,
entries 11 and 12).18
̈
derivatives thereof.12 Applications of this methodology based
on an iron-catalyzed hydrogen-borrowing strategy process also
include the formation of new carbon−carbon bonds.13
Inspired by these recent discoveries, we report herein a
green, economical, and efficient iron-catalyzed C3-selective
alkylation of indole. This reaction employs iron(II) phthalo-
cyanine (Fe(II)Pc), an inexpensive commercially available
compound that is typically used as an industrial additive for
ink as well as photonic and optical material manufacturing. Of
note, to date, Fe(II)Pc complexes have not been applied as
catalysts for the formation of new carbon−carbon bonds via the
borrowing hydrogen process.14
Once the optimal reaction conditions were achieved, we
examined the scope of the alkylation with respect to alcohols
catalyzed by Fe(II)Pc, and these results are outlined in Scheme
2. The C3-alkylation of indole with primary benzylic alcohols
bearing an electron-donating substituent such as methyl,
phenyl, and methoxy groups afforded the corresponding
products 3b−f in 46−98% yields. Also, (2-aminophenyl)-
methanol and 2-(hydroxymethyl)phenol provided the products
3g−h in good yield, 56% and 42%, respectively. Similarly,
electronically deactivated benzylic alcohols, which are very poor
substrates in Lewis- or Brønsted acid-catalyzed Friedel−Crafts
reactions,19 bearing an electron-withdrawing group such as
chloro, fluoro, cyano and trifluoromethyl groups were
converted to the desired products 3i−m in 37−71% yields. A
trisubstituted benzyl alcohol, such as 3,4,5-trimethoxybenzyl
alcohol, was successfully transformed to 3-(3,4,5-trimethox-
ybenzyl)-1H-indole in 62% yield. A naphthyl alcohol
(naphthalen-2-ylmethanol), (3,5-dichlorophenyl)methanol,
and benzo[1,3]dioxonyl were converted to give the corre-
sponding alkylated indole products 3o−q in good yields.
Heteroaromatic alcohols with furanyl and thienyl groups were
also tolerated, and the corresponding indoles 3r−s were
obtained in 95% and 78% yields, respectively.
This reaction sequence was demonstrated for the preparation
of symmetrical bisindole compound 3t, whereby indole, used in
excess, was double alkylated with 1,3-phenylenedimethanol
through a one-pot process in satisfactory yield. Moreover,
sequential functionalization of diols is undoubtedly a valuable
synthetic tool to obtain compounds with great diversity. We
explored a selective iron-catalyzed method that allows for the
preparation of nonsymmetrical, functionalized bisindoles. This
reaction sequence was demonstrated for the preparation of
compound 3u, whereby 1,3-phenylenedimethanol was selec-
tively monoalkylated with indole to form (3-((1H-indol-3-
yl)methyl)phenyl)methanol and subsequently treated with 6-
fluoroindole to provide 3u.
The reaction of unsubstituted indole (1a) with benzyl
alcohol (2a) was selected as the model reaction to establish the
best reaction conditions. Initially, the effect of various iron-
based catalysts was investigated (Table 1). The reaction did not
Table 1. Optimization of the Reaction Conditions for C3-
Alkylation of Indole with Benzyl Alcohol
a
b
entry
catalyst
yield of 3a (%)
1
−
FeSO4
−
−
−
c
2
d
3
FeCl2
4
Fe(acac)3
Fe(II)Pc
−
99
5
e
6
Fe(II)Pc
8
f
7
Fe(II)Pc
trace
−
8
Fe-Knolker
̈
9
Fe-Knolker with PPh
−
̈
3
10
11
12
Fe-Knolker with Me NO
−
97
̈
3
Fe(II)Pc in the dark
Fe(II)Pc with BHT
98
a
Reaction conditions: indole (0.5 mmol), benzyl alcohol (1 mmol),
b
Cs2CO3 (0.55 mmol), catalyst (1 mol %) at 140 °C for 16 h. Isolated
yield. Only 4 was isolated in 13% yield Only 4 was isolated in 21%
yield Cs2CO3 (0.05 mmol). Without base.
c
d
Next, secondary benzylic alcohols, which are less prone to
the condensation and hydrogenation step in comparison to
primary ones, were used as the substrate. 1-Phenylethanol,
diphenylmethanol, and 2-acetamido-1-phenylethanol reacted
smoothly with indole, and the corresponding products 3v−x
were obtained in moderate to good yields.
When cinnamyl alcohol was utilized, the desired product was
obtained in poor yield due to large contamination of saturated
derivatives; whereas with aliphatic alcohols such as cyclo-
hexanol, cyclopropyl methanol, and 1-octanol, the reaction
failed.
e
f
proceed without any catalyst in the presence of Cs2CO3, which
excluded the contribution of the base itself as a catalyst (Table
1, entry 1).15 The highest activity was observed with Fe(II)Pc
and a stoichiometric amount of Cs2CO3 (Table 1, entries 5−7).
Other iron salts were found to be ineffective and, not
surprisingly, led to the formation of bis(indolyl)methane (4)
in poor yields (Table 1, entries 2−4).16 Due to its inherent
redox properties, the iron(0)tricarbonyl complex such as the
Next, we examined some representative substituted indoles
to explore the generality of this novel reaction. For example, the
electron-rich and sterically hindered 4-methoxyindole was
converted to the desired product 3x in a very good yield and
selectivity. The 6-methyl-, 5-fluoro-, and 6-chloroindole-
benzylated derivatives 3z and 3aa−3ab were also obtained in
decent yields, although the yields were lower than those of the
4-OMe analog. Pleasingly, the presence of a substituent at C2
did not impair the reaction, despite the potential steric
crowding around the reaction site. Thus, 2-phenylindole
reacted efficiently with benzyl alcohol to give the corresponding
product 3ac. Not surprisingly, N-methylindole proved to be
Knolker-type catalyst is widely known to activate inert
̈
substrates via dehydrogenation/hydrogenation reactions and
has been reported previously for C−C bond formation.17
Neither alone (Table 1, entry 8) nor in the presence of 10 mol
% Me3NO oxidant (to form active catalyst) and PPh3 ligand did
the alkylated product form (Table 1, entries 9 and 10). This
solvent-free reaction with Fe(II)Pc as the catalyst was excellent
in terms of both yield and selectivity as compared with the
corresponding reaction in toluene (1.0 M, 54% yield; 0.5 M,
10% yield) or tert-amyl alcohol (at reflux under air atmosphere
for 16 h afforded the desired alkylated product 3a in 31%
yield). The desired coupling product was also obtained in the
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Note
inert, suggesting the involvement of the indole N−H in a key
interaction with the base during the rate-determining step.
However, nearly complete recovery of the starting material was
observed when C3-substituted indole, such as 3-methyl or 3-
benzylindole, was allowed to react with benzyl alcohol under
the reaction conditions reported above. Neither dearomatiza-
tion of the indole nucleus to 3-benzylindolenine products nor
C3- to C2-benzyl migration and rearomatization to afford 2,3-
disubstituted indoles were detected, in spite of recent reports.20
To highlight the synthetic utility of the present protocol, a
gram-scale reaction with indole (1a) and benzylic alcohol (2a)
was performed, and the efficiency of the small-scale reaction
was retained upon scale-up, delivering 3a in 92% yield.
Scheme 2. Scope of C3-Alkylation of Indole with Benzyl
Alcohol
a
To obtain insight into the reaction mechanism of the
catalytic process, other experiments were carried out, thus
providing significant evidence for a plausible borrowing
hydrogen mechanism rather than a general acidic strategy
involving the formation of a stabilized benzylic cation. The
reaction of indole with benzyl bromide (2 equiv) under the
optimized reaction conditions gave a mixture of 1-benzyl-1H-
indole (45%) and 1,3-dibenzyl-1H-indole (28%). Then, we
repeated the reaction using triphenylmethanol, and the starting
unchanged indole was recovered, which is another indirect
proof that the cationic benzyl intermediate is not involved.
When benzylic alcohol was heated in the presence of Fe(II)Pc
and cesium carbonate at 140 °C in a sealed tube for 16 h,
formation of a small amount of benzaldehyde (11% according
to GC-analysis of the crude mixture) was observed. Finally, the
competitive reaction of indole with benzaldehyde and (4-
methoxyphenyl)methanol (Scheme 3) gave a mixture 6:1 of 3-
1
benzylated compounds (based on H NMR spectra), in which
the main product was that arising from the condensation with
benzaldehyde followed by reduction of benzylideneindolenine
(obviously, large formation of p-methoxybenzaldehyde was also
observed). All of these data together with the presence of
bisindole side product 4, obtainable only in the presence of
aldehyde on the reaction mixture, and the good yields obtained
with electronpoor benzylic alcohols (compounds 3l, 3m) are
confirming our initial borrowing hydrogen mechanistic
hypothesis.
In conclusion, we have established, for the first time, a
general methodology for the catalytic formation of value-added
3-benzylindoles through the use of indole and primary,
secondary, and heteroaromatic benzyl alcohols using an easily
handled, air- and moisture-stable earth-abundant iron complex
catalyst that operates through a hydrogen-borrowing mecha-
nism. Many synthetically challenging routes were systematically
explored, starting from readily accessible substrates that do not
require prior alcohol activation by stoichiometric methods. This
included the one-pot synthesis of symmetrical bisindoles, the
sequential functionalization of diols, and the use of a secondary
alcohol coupling partner under the catalytic conditions, which
then enabled the formation of the desired branched alkylated
indole cross-coupled products.
EXPERIMENTAL SECTION
■
General Methods. All reactions were run in air unless otherwise
noted. Column chromatography purifications were performed in flash
chromatography conditions using 230−400 mesh silica gel. Analytical
thin-layer chromatography (TLC) was carried out on silica gel plates
(Silica Gel 60 F254) that were visualized by exposure to ultraviolet
a
Reaction conditions: indole (0.5 mmol), alcohol (1 mmol), Cs2CO3
b
(0.55 mmol), Fe(II)Pc (0.055 mmol) at 140 °C for 16 h. Indole (1
mmol), alcohol (0.5 mmol). 1H-indole (0.5 mmol), 6-fluoro-1H-
indole (0.5 mm0l), 2-(hydroxymethyl)phenol (0.5 mmol). 140 °C
c
d
light and an aqueous solution of KMnO4. H NMR and 13C NMR
1
for 36h.
spectra were recorded on a 400 spectrometer, using CDCl3 and
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Note
Scheme 3. Competitive Experiments between an Aldehyde and an Alcohol
acetone-d6 as solvent. Chemical shifts (δ scale) are reported in parts
per million (ppm) relative to the central peak of the solvent. Coupling
constants (J values) are given in hertz (Hz). ESI-MS spectra were
taken on a Waters Micromass ZQ instrument. IR spectra were
obtained on FT-IR spectrometer, and absorbance is reported in cm−1.
Melting points were determined on a capillary melting point apparatus
and are uncorrected. HRMS analysis was performed using a Q-TOF
microTM mass spectrometer.
Starting Materials. 1H-indole, 6-fluoro-1H-indole, 4-methoxy-1H-
indole, 6-methyl-1H-indole, 5-fluoro-1H-indole, 6-chloro-1H-indole,
2-phenyl-1H-indole, benzyl alcohol, p-tolylmethanol, m-tolylmethanol,
o-tolylmethanol, biphenyl-3-ylmethanol, (N-(2-hydroxy-2-
phenylethyl)acetamide, 4-methoxyphenyl)methanol, (2-
aminophenyl)methanol, 2-(hydroxymethyl)phenol, (4-chlorophenyl)-
methanol, (2-chlorophenyl)methanol, (4-fluorophenyl)methanol, (4-
(trifluoromethyl)phenyl)methanol, 4-(hydroxymethyl)benzonitrile,
(3,4,5-trimethoxyphenyl)methanol, naphthalen-2-ylmethanol, (3,5-
dichlorophenyl)methanol, furan-2-ylmethanol, thiophen-2-ylmethanol,
benzo[d][1,3]dioxol-5-ylmethanol, 1-phenylethanol, and diphenylme-
thanol are commercially available.
General Procedure for C3-Alkylation of Indole with Benzyl
Alcohol. A vial was charged with the appropriate indole (0.5 mmol),
the appropriate alcohol (1 mmol), iron(II) phthalocyanine (Fe(II)Pc)
(3 mg, 0.005 mmol), and Cs2CO3 (179 mg, 0.55 mmol). The vial was
immersed in a preheated (140 °C) oil bath and stirred at this
temperature for 16 h. The reaction mixture was diluted with ethyl
acetate and filtered over a plug of Celite. The solvent was evaporated
under reduced pressure, and the residue obtained was purified by flash
chromatography.
(gradient from cyclohexane/EtOAc 8:2 to cyclohexane/EtOAc 7:3) to
give 3d (83 mg, 75%) as pinkish solid. 1H NMR (400 MHz, CDCl3): δ
7.85 (br s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H),
7.30−7.15 (m, 6H), 6.74 (s, 1H), 4.15 (s, 2H), 2.41 (s, 3H); HRMS
(ESI) m/z calcd for C16H16N (M + H)+ 222.1277; found 222.1274.
The chemical-physical data are in accordance with literature.7a
3-(Biphenyl-3-ylmethyl)-1H-indole (3e). The title compound was
prepared according to the general procedure using 1H-indole and
biphenyl-3-ylmethanol. The product was purified by flash chromatog-
raphy (cyclohexane/EtOAc 9:1) to give 3e (65 mg, 46%) as orange
1
solid. H NMR (400 MHz, CDCl3) δ 7.99 (br s, 1H), 7.61−7.57 (m,
3H), 7.53 (d, J = 8.0 Hz, 3H), 7.44 (t, J = 8.0 Hz, 2H), 7.40−7.32 (m,
3H), 7.24−7.20 (m, 1H), 7.14−7.10 (m, 1H), 6.98 (br s, 1H), 4.18 (s,
2H); 13C NMR (101 MHz, CDCl3) δ 141.1, 140.4, 138.8, 136.4,
129.1, 128.7, 127.5, 127.1, 127.0, 122.4, 122.1, 119.4, 119.2, 115.7,
111.1, 31.2; mp 194−196 °C; IR (film): 3412, 3056 cm−1; HRMS
(ESI) m/z calcd for C21H18N (M + H)+ 284.1434; found 284.1439.
3-(4-Methoxybenzyl)-1H-indole (3f). The title compound was
prepared according to the general procedure using 1H-indole and (4-
methoxyphenyl)methanol. The product was purified by flash
chromatography (gradient from cyclohexane/EtOAc 95:5 to cyclo-
1
hexane/EtOAc 90:10) to give 3f (89 mg, 75%) as brown solid. H
NMR (400 MHz, CDCl3) δ 7.96 (br s, 1H), 7.58 (d, J = 8.0 Hz, 1H),
7.39 (d, J = 8.0 Hz, 1H), 7.29−7.22 (m, 3H), 7.14 (t, J = 8.0 Hz, 1H),
6.93 (s, 1H), 6.88 (d, J = 8.0 Hz, 2H), 4.11 (s, 2H), 3.83 (s, 3H);
HRMS (ESI) m/z calcd for C16H16NO (M + H)+ 238.1226; found
238.1221. The chemical-physical data are in accordance with
literature.8a
2-((1H-Indol-3-yl)methyl)aniline (3g). The title compound was
prepared according to the general procedure using 1H-indole and (2-
aminophenyl)methanol. The product was purified by flash chromatog-
raphy (cyclohexane/EtOAc 8:2) to give 3g (62 mg, 56%) as off-white
solid. 1H NMR (400 MHz, acetone-d6) δ 10.05 (br s, 1H), 7.53−7.51
(m, 1H), 7.40 (dt, J = 8.0, 1.0 Hz, 1H), 7.13−7.05 (m, 3H), 7.01−6.95
(m, 2H), 6.72 (dd, J = 8.0, 1.5 Hz, 1H), 6.59 (dt, J = 7.5, 1.5 Hz, 1H),
4.40 (br s, 2H), 3.99 (s, 2H). 13C NMR (101 MHz, Acetone-d6) δ
146.0, 137.1, 129.7, 127.7, 126.8, 125.0, 122.9, 121.3, 118.8, 118.5,
117.1, 115.1, 113.0, 111.3, 27.4; HRMS (ESI) m/z calcd for C15H15N2
(M + H)+ 223.1230; found 223.1241. The chemical-physical data are
in accordance with literature.22
2-((1H-Indol-3-yl)methyl)phenol (3h). The title compound was
prepared according to the general procedure using 1H-indole and 2-
(hydroxymethyl)phenol. The product was purified by flash chroma-
tography (cyclohexane/EtOAc 1:1) to give 3h (47 mg, 42%) as pale
yellow solid. 1H NMR (400 MHz, acetone-d6) δ 9.99 (br s, 1H), 8.28
(s, 1H), 7.57−7.54 (m, 1H), 7.38 (dt, J = 8.0, 1.0 Hz, 1H), 7.12−7.06
(m, 3H), 7.04−6.96 (m, 2H), 6.88 (dd, J = 8.0, 1.0 Hz, 1H), 6.71 (dt, J
= 7.5, 1.0 Hz, 1H), 4.10 (s, 2H); HRMS (ESI) m/z calcd for
C15H14NO (M + H)+ 224.1070; found 224.1079. The chemical-
physical data are in accordance with literature.23
3-(4-Chlorobenzyl)-1H-indole (3i). The title compound was
prepared according to the general procedure using 1H-indole and
(4-chlorophenyl)methanol. The product was purified by flash
chromatography (cyclohexane/EtOAc 8:2) to give 3i (54 mg, 45%)
as off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.95 (br s, 1H), 7.51
(d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.33−7.22 (m, 5H), 7.12
(t, J = 7.0 Hz, 1H), 6.93 (s, 1H), 4.12 (s, 2H); HRMS (ESI) m/z calcd
for C15H13ClN (M + H)+ 242.0731; found 242.0726. The chemical-
physical data are in accordance with literature.2
3-Benzyl-1H-indole (3a). The title compound was prepared
according to the general procedure using 1H-indole and benzyl
alcohol. The product was purified by flash chromatography (cyclo-
hexane/EtOAc 8:2) to give 3a (102 mg, 99%) as white solid. 1H NMR
(400 MHz, CDCl3): δ 7.92 (br s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.38
(d, J = 8.0 Hz, 1H), 7.33−7.30 (m, 4H), 7.24−7.14 (m, 2H), 7.12 (t, J
= 7.0 Hz, 1H), 6.93 (s, 1H), 4.16 (s, 2H); HRMS (ESI) m/z calcd for
C15H13NNa (M + Na)+ 230.0940; found 230.0946. The chemical-
physical data are in accordance with literature.21
3-(4-Methylbenzyl)-1H-indole (3b). The title compound was
prepared according to the general procedure using 1H-indole and p-
tolylmethanol. The product was purified by flash chromatography
(cyclohexane/EtOAc 9:1) to give 3b (78 mg, 71%) as pinkish solid.
1H NMR (400 MHz, CDCl3) δ 7.87 (br s, 1H), 7.59 (d, J = 8.0 Hz,
1H), 7.37 (d, J = 8.0 Hz, 1H), 7.26−7.22 (m, 3H), 7.16−7.12 (m,
3H), 6.92−6.91 (m, 1H), 4.14 (s, 2H), 2.38 (s, 3H); HRMS (ESI) m/
z calcd for C16H16N (M + H)+ 222.1277; found 222.1286. The
chemical-physical data are in accordance with literature.7a
3-(3-Methylbenzyl)-1H-indole (3c). The title compound was
prepared according to the general procedure using 1H-indole and
m-tolylmethanol. The product was purified by flash chromatography
(cyclohexane/EtOAc 8:2) to give 3c (108 mg, 98%) as brown solid.
1H NMR (400 MHz, CDCl3): δ 7.76 (br s, 1H), 7.70 (d, J = 8.0 Hz,
1H), 7.40 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 2H), 7.27−7.23 (m,
3H), 7.17 (d, J = 7.0 Hz, 1H), 6.92 (s, 1H), 4.22 (s, 2H), 2.46 (s, 3H);
HRMS (ESI) m/z calcd for C16H16N (M + H)+ 222.1277; found
222.1283. The chemical-physical data are in accordance with
literature.7a
3-(2-Methylbenzyl)-1H-indole (3d). The title compound was
prepared according to the general procedure using 1H-indole and o-
tolylmethanol. The product was purified by flash chromatography
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3-(2-Chlorobenzyl)-1H-indole (3j). The title compound was
prepared in according to the general procedure using 1H-indole and
(2-chlorophenyl)methanol. The product was purified by flash
chromatography (cyclohexane/EtOAc 8:2) to give 3j (44 mg, 37%)
3-(Benzo[d][1,3]dioxol-5-ylmethyl)-1H-indole (3q). The title com-
pound was prepared according to the general procedure using 1H-
indole and benzo[d][1,3]dioxol-5-ylmethanol. The product was
purified by flash chromatography (cyclohexane/EtOAc 8:2) to give
1
1
as white solid. H NMR (400 MHz, CDCl3): δ 7.98 (br s, 1H), 7.58
3q (105 mg, 84%) as brown solid. H NMR (400 MHz, CDCl3) δ
(d, J = 8.0 Hz, 1H), 7.43−7.38 (m, 2H), 7.25−7.11 (m, 5H), 6.96 (s,
1H), 4.25 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 138.7, 136.4,
134.0, 130.6, 129.4, 127.4, 127.3, 126.7, 122.7, 122.1, 119.5, 119.1,
114.0, 111.1, 29.1; HRMS (ESI) m/z calcd for C15H13ClN (M + H)+
242.0731; found 242.0742.
7.95 (br s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.23
(t, J = 8.0 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.94 (s, 1H), 6.82−6.76
(m, 3H), 5.93 (s, 2H), 4.07 (s, 2H); HRMS (ESI) m/z calcd for
C16H14NO2 (M + H)+ 252.1019; found 252.1013. The chemical-
physical data are in accordance with literature.8a
3-(4-Fluorobenzyl)-1H-indole (3k). The title compound was
prepared according to the general procedure using 1H-indole and
(4-fluorophenyl)methanol. The product was purified by flash
chromatography (cyclohexane/EtOAc 8:2) to give 3k (76 mg, 68%)
as white solid. 1H NMR (400 MHz, CDCl3) δ 7.99 (br s, 1H), 7.58 (d,
J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.23−7.14 (m, 3H), 7.13−
6.99 (m, 4H), 4.15 (s, 2H); HRMS (ESI) m/z calcd for C15H13FN (M
+ H)+ 226.1027; found 226.1036. The chemical-physical data are in
accordance with literature.7a
3-(Thiophen-2-ylmethyl)-1H-indole (3r). The title compound was
prepared according to the general procedure using 1H-indole and
thiophen-2-ylmethanol. The product was purified by flash chromatog-
raphy (cyclohexane/EtOAc 8:2) to give 3r (101 mg, 95%) as brown
solid. 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.60 (d, J = 8.0 Hz,
1H), 7.38 (d, J = 8.0 Hz, 1H), 7.25−7.21 (m, 1H), 7.16−7.11 (m,
2H), 7.06−7.05 (m, 1H), 6.95 (dd, J = 5.0, 4.0 Hz, 1H), 6.91−6.90
(m, 1H), 4.35 (s, 2H); HRMS (ESI) m/z calcd for: C13H12NS (M +
H)+ 214.0685; found 214.0677. The chemical-physical data are in
accordance with literature.8a
3-(Furan-2-ylmethyl)-1H-indole (3s). The title compound was
prepared according to the general procedure using 1H-indole and
furan-2-ylmethanol. The product was purified by flash chromatography
(cyclohexane/EtOAc 95:5) to give 3s (76 mg, 78%) as brown solid.
1H NMR (400 MHz, CDCl3) δ 7.80 (br s, 1H), 7.71 (d, J = 8.0 Hz,
1H), 7.45 (s, 1H), 7.34 (dt, J = 8.0, 7.6 Hz, 2H), 7.27−7.21 (m, 1H),
7.02 (s, 1H), 6.41 (dd, J = 3.0, 2.0 Hz, 1H), 6.16 (d, J = 3.0 Hz, 1H),
4.24 (s, 2H); HRMS (ESI) m/z calcd for C13H11NONa (M + Na)+
220.0733; found 220.0737. The chemical-physical data are in
accordance with literature.8a
3-(4-(Trifluoromethyl)benzyl)-1H-indole (3l). The title compound
was prepared according to the general procedure using 1H-indole and
(4-(trifluoromethyl)phenyl)methanol. The product was purified by
flash chromatography (cyclohexane/EtOAc 9:1) to give 3l (97 mg,
1
71%) as off-white solid. H NMR (400 MHz, CDCl3) δ 8.01 (br s,
1H), 7.54 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.41−7.39 (m,
3H), 7.23 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.02−6.93 (m,
1H), 4.19 (s, 2H); HRMS (ESI) m/z calcd for C16H13F3N (M + H)+
276.0995; found 275.0988. The chemical-physical data are in
accordance with literature.7a
4-((1H-Indol-3-yl)methyl)benzonitrile (3m). The title compound
was prepared according to the general procedure using 1H-indole and
4-(hydroxymethyl)benzonitrile. The product was purified by flash
chromatography (from cyclohexane/EtOAc 1:1 to cyclohexane/
1,3-Bis((1H-indol-3-yl)methyl)benzene (3t). The title compound
was prepared according to the general procedure using 1H-indole (234
mg, 2 mmol) and 1,3-phenylenedimethanol (138 mg, 1 mmol). The
product was purified by flash chromatography (cyclohexane/EtOAc
1
EtOAc 1:9) to give 3m (83 mg, 72%) as off-white solid. H NMR
(400 MHz, acetone-d6) δ 10.11 (br s, 1H), 7.86 (d, J = 8.0 Hz, 2H),
7.46 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.19−7.18 (m,1H),
7.11−7.07 (m,1H), 6.99−6.95 (m,1H), 4.18 (s, 2H); HRMS (ESI) m/
z calcd for C16H13N2 (M + H)+ 233.1073; found 233.1068. The
chemical-physical data are in accordance with literature.24
3-(3,4,5-Trimethoxybenzyl)-1H-indole (3n). The title compound
was prepared according to the general procedure using 1H-indole and
(3,4,5-trimethoxyphenyl)methanol. The product was purified by flash
chromatography (cyclohexane/EtOAc 8:2) to give 3n (92 mg, 62%) as
orange solid. 1H NMR (400 MHz, CDCl3) δ 8.01 (br s, 1H), 7.57 (d, J
= 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.11
(t, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.54 (s, 2H), 4.07 (s, 2H), 3.84 (s,
3H), 3.81 (s, 6H); HRMS (ESI) m/z calcd for C18H20NO3 (M + H)+
298.1438; found 298.1435. The chemical-physical data are in
accordance with literature.21
1
8:2) to give 3t (97 mg, 58%) as brown oil. H NMR (400 MHz,
CDCl3): δ 7.88 (br s, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0
Hz, 2H), 7.28 (br s, 1H), 7.23−7.19 (m, 3H), 7.15−7.04 (m, 4H),
6.87 (s, 2H), 4.09 (s, 4H); 13C NMR (101 MHz, CDCl3): δ 141.2,
136.4, 129.2, 128.3, 127.5, 126.3, 122.3, 122.0, 119.3, 119.2, 116.0,
111.1, 31.6; IR (film): 3165, 2929, 2820, 1556 cm−1; HRMS (ESI) m/
z calcd for C24H21N2 (M + H)+ 337.1699; found 337.1691.
3-(3-((1H-Indol-3-yl)methyl)benzyl)-6-fluoro-1H-indole (3u). A
vial was charged with 1H-indole (59 mg, 0.5 mmol), 1,4-phenyl-
enedimethanol (69 mg, 1 mmol), iron(II) phthalocyanine (2.5 mg,
0.005 mmol), and Cs2CO3 (179 mg, 0.55 mmol). The vial was
immersed in a preheated (140 °C) oil bath and stirred at this
temperature for 16 h. Than the vial was removed from oil bath, and 6-
fluoro-1H-indole (67 mg, 0.5 mmol) was added to the reaction
mixture and stirred again for 16 h at 140 °C. The reaction mixture was
diluted with ethyl acetate and filtered over a plug of silica gel. The
solvent was evaporated under reduced pressure, and the residue
obtained was purified by flash chromatography (cyclohexane/EtOAc
7:3) to give 3u (93 mg, 52%) as off-white solid. 1H NMR (400 MHz,
CDCl3): δ 7.93 (br s, 1H), 7.94 (br s, 1H), 7.49 (d, J = 8.0 Hz, 1H),
7.23−7.18 (m, 3H), 7.14−7.01 (m, 5H), 6.88−6.78 (m, 3H), 4.08 (s,
2H), 4.04 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 159.9 (d, J = 236
Hz), 141.0 (d, J = 39 Hz), 136.43, 136.39, 136.3, 129.1, 128.3, 127.4,
126.4, 126.3, 126.2, 124.1, 122.5 (d, J = 3 Hz), 122.2, 122.0, 120.0,
119.9 (d, J = 10 Hz), 119.2 (d, J = 10 Hz), 116.0 (d, J = 12 Hz), 111.0,
108.0 (d, J = 25 Hz), 97.3 (d, J = 25 Hz), 31.59, 31.57; mp 166−168
°C; IR (film): 3161, 2932, 2816, 1549 cm−1; HRMS (ESI) m/z calcd
for C24H20FN2 (M + H)+ 355.1605; found 355.1611.
3-(Naphthalen-2-ylmethyl)-1H-indole (3o). The title compound
was prepared according to the general procedure using 1H-indole and
naphthalen-2-ylmethanol. The product was purified by flash
chromatography (cyclohexane/EtOAc 8:2) to give 3o (91 mg, 71%)
1
as off-white solid. H NMR (400 MHz, CDCl3) δ 7.98 (br s, 1H),
7.83−7.74 (m, 4H), 7.56 (dd, J = 8.0, 1.0 Hz, 1H), 7.46−7.41 (m,
3H), 7.39 (dt, J = 8.0, 1.0 Hz, 1H), 7.21 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H),
7.09 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.96−6.95 (m, 1H), 4.30 (s, 2H);
HRMS (ESI) m/z calcd for C19H16N (M + H)+ 258.1277; found
258.1271. The chemical-physical data are in accordance with
literature.25
3-(3,5-Dichlorobenzyl)-1H-indole (3p). The title compound was
prepared according to the general procedure using 1H-indole and (3,5-
dichlorophenyl)methanol. The product was purified by flash
chromatography (cyclohexane/EtOAc 98:2) to give 3p (53 mg,
3-(1-Phenylethyl)-1H-indole (3v). The title compound was
prepared according to the general procedure using 1H-indole and 1-
phenylethanol. The product was purified by flash chromatography
(cyclohexane/EtOAc 8:2) to give 3v (79 mg, 72%) as yellowish solid.
1H NMR (400 MHz, CDCl3) δ 7.88 (br s, 1H), 7.45 (dd, J = 8.0, 2.5
Hz, 1H), 7.38−7.35 (m, 4H), 7.26−7.21 (m, 2H), 7.11−7.07 (m, 1H),
7.02 (s, 1H), 4.45 (q, J = 7.0 Hz, 1H), 1.78 (d, J = 7.0 Hz, 3H); HRMS
1
39%) as brown oil. H NMR (400 MHz, CDCl3) δ 8.02 (br s, 1H),
7.49 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.29−7.12 (m, 5H),
6.98 (s, 1H), 4.08 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 144.8,
136.4, 134.7, 127.14, 127.08, 126.2, 122.6, 122.4, 119.7, 118.9, 114.0,
111.2, 31.1; IR (film): 3170, 2949, 2824, 1555 cm−1; HRMS (ESI) m/
z calcd for C15H12Cl2N (M + H)+ 276.0341; found 276.0334.
8773
DOI: 10.1021/acs.joc.7b01603
J. Org. Chem. 2017, 82, 8769−8775

The Journal of Organic Chemistry
Note
(ESI) m/z calcd for C16H16N (M + H)+ 222.1277; found 222.1269.
The chemical-physical data are in accordance with literature.7a
3-Benzhydryl-1H-indole (3w). The title compound was prepared
according to the general procedure using 1H-indole and diphenylme-
thanol. The product was purified by flash chromatography (cyclo-
3-Benzyl-2-phenyl-1H-indole (3ac). The title compound was
prepared according to the general procedure using 2-phenyl-1H-
indole and benzyl alcohol. The product was purified by flash
chromatography (cyclohexane/DCM 1:9) to give 3ac (69 mg, 49%)
1
as off-white solid. H NMR (400 MHz, CDCl3) δ 8.15 (br s, 1H),
1
7.55−7.52 (m, 2H), 7.46−7.44 (m, 4H), 7.38−7.31 (m, 2H), 7.26−
7.16 (m, 5H), 7.10−7.06 (m, 1H), 4.29 (s, 2H); HRMS (ESI) m/z
calcd for C21H18N (M + H)+ 284.1434; found 284.1438. The
chemical-physical data are in accordance with literature.27
hexane/EtOAc 9:1) to give 3w (52 mg, 37%) as yellowish solid. H
NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.38−7.19 (m, 13H), 7.04
(dt, J = 7.5, 1.0 Hz, 1H), 6.57 (t, J = 2.0, 1.0 Hz, 1H), 5.73 (s, 1H);
HRMS (ESI) m/z calcd for C21H18N (M + H)+ 284.1434; found
284.1439. The chemical-physical data are in accordance with
literature.7a
Procedure for Large-Scale Synthesis of Compound 3a. A 50
mL Schlenk flask equipped with a magnetic stir bar was charged with
indole (1 g, 8.5 mmol), benzyl alcohol (1.8 g, 17 mmol), iron(II)
phthalocyanine (48 mg, 0.085 mmol), and Cs2CO3 (3 g, 9.35 mmol).
The reaction mixture was immersed in a preheated (140 °C) oil bath
and stirred at this temperature for 16 h. The reaction mixture was
diluted with ethyl acetate and filtered over a plug of Celite. The solvent
was evaporated under reduced pressure, and the residue obtained was
purified by flash chromatography (cyclohexane/EtOAc 8:2) to give 3a
(1.6 g, 92%) as white solid. The chemical-physical data are in
accordance as reported above.
N-(2-(1H-indol-3-yl)-2-phenylethyl)acetamide (3x). The title
compound was prepared according to the general procedure using
1H-indole and N-(2-hydroxy-2-phenylethyl)acetamide. The product
was purified by flash chromatography (EtOAc) to give 3x (62 mg,
1
45%) as yellowish solid. H NMR (400 MHz, CDCl3) δ 8.23 (br s,
1H), 7.46 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.32−7.31 (m,
4H), 7.24 (dd, J = 5.0, 4.0 Hz, 1H), 7.21−7.16 (m, 1H), 7.09 (br s,
1H), 7.07−7.03 (m, 1H), 5.51 (br s, 1H), 4.44 (t, J = 8.0 Hz, 1H),
4.11−4.04 (m, 1H), 3.86−3.79 (m, 1H), 1.91 (s, 3H); HRMS (ESI)
m/z calcd for C18H19N2O (M + H)+ 279.1492; found 279.1486. The
chemical-physical data are in accordance with literature.8d
ASSOCIATED CONTENT
* Supporting Information
■
4-Methoxy-3-(4-methoxybenzyl)-1H-indole (3y). The title com-
pound was prepared according to the general procedure using 4-
methoxy-1H-indole and (3-((1H-indol-3-yl)methyl)phenyl)methanol.
The product was purified by flash chromatography (gradient from
cyclohexane/EtOAc 8:2 to cyclohexane/EtOAc 6:4) to give 3y (117
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b01603.
Copies of 1H NMR, 13C NMR spectra for all compounds
were reported (PDF)
1
mg, 88%) as brown oil. H NMR (400 MHz, CDCl3): δ 7.88 (br s,
1H), 7.25 (d, J = 8.0 Hz, 2H), 7.11 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0,
1H), 6.87−6.85 (m, 2H), 6.64 (br s, 1H), 6.51 (d, J = 8.0 Hz, 1H),
4.26 (s, 2H), 3.90 (s, 3H), 3.82 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 157.6, 155.1, 138.1, 134.7, 129.8, 122.8, 120.9, 117.4, 117.2,
113.6, 104.4, 99.5, 55.3, 55.1, 32.2; IR (film): 3397, 2848,1387 cm−1;
HRMS (ESI) m/z calcd for: C17H18NO2 (M + H)+ 268.1332; found
268.1338.
AUTHOR INFORMATION
Corresponding Author
*E-mail: giovanni.piersanti@uniurb.it.
ORCID
Giovanni Piersanti: 0000-0003-0418-7143
Notes
The authors declare no competing financial interest.
■
3-(4-Methoxybenzyl)-6-methyl-1H-indole (3z). The title com-
pound was prepared according to the general procedure using 6-
methyl-1H-indole and (3-((1H-indol-3-yl)methyl)phenyl)methanol.
The product was purified by flash chromatography (cyclohexane/
1
EtOAc 8:2) to give 3z (79 mg, 63%) as pinkish solid. H NMR (400
ACKNOWLEDGMENTS
We are grateful to Professor Rita Mazzoni and Dott. Andrea
Cingolani for generous samples of their Fe-Knolker catalyst.
■
MHz, CDCl3) δ 7.78 (br s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.29−7.23
(m, 2H), 7.16 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.88 (m, 2H), 6.84 (s,
1H), 4.09 (s, 2H), 3.83 (s, 3H), 2.51 (s, 3H); HRMS (ESI) m/z calcd
for C17H18NO (M + H)+ 252.1383; found 252.1379. The chemical-
physical data are in accordance with literature.26
̈
REFERENCES
■
5-Fluoro-3-(2-methylbenzyl)-1H-indole (3aa). The title compound
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was purified by flash chromatography (cyclohexane/EtOAc 9:1) to
give 3aa (95 mg, 80%) as orange solid. 1H NMR (400 MHz, CDCl3) δ
7.94 (br s, 1H), 7.30−7.26 (m, 2H), 7.23−7.14 (m, 4H), 6.95 (td, J =
9.0, 2.5 Hz, 1H), 6.80 (s, 1H), 4.03 (s, 2H), 2.33 (s, 3H); 13C NMR
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EtOAc 8:2) to give 3ab (82 mg, 64%) as brown solid. H NMR (400
MHz, CDCl3) δ 7.93 (br s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.35 (d, J =
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