Selective N-alkylation of indoles with α,β-unsaturated compounds catalyzed by a monomeric phosphate

Article abstract of DOI:10.1002/cctc.201402309

Catalytic N-alkylation of indoles is challenging because the N1 nitrogen atoms are inert toward electrophilic reagents. Herein, an organic-solvent- soluble alkylammonium salt of a simple monomeric phosphate ion, [PO ₄]^3-, with a high charge density acts as an efficient homogeneous catalyst for selective N-alkylation of indoles with α,β-unsaturated compounds. For the reaction of indole with ethyl acrylate, the turnover number reached up to 36 and the turnover frequency was 216 h^-1; these values are the highest among those reported for base-mediated systems so far. In the presence of [PO₄]^3- ions, various combinations of nitrogen nucleophiles (ten examples) and α,β-unsaturated compounds (four examples) were efficiently converted to the desired N-alkylated products in high yields. NMR and IR spectroscopies showed formation of the indolyl anion through the activation of indole by the [PO₄]^3- ion, which plays an important role in the present N-alkylation.

Full text of DOI:10.1002/cctc.201402309

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DOI: 10.1002/cctc.201402309
Selective N-Alkylation of Indoles with a,b-Unsaturated
Compounds Catalyzed by a Monomeric Phosphate
Hanako Sunaba, Keigo Kamata, and Noritaka Mizuno*[a]
Catalytic N-alkylation of indoles is challenging because the N1
nitrogen atoms are inert toward electrophilic reagents. Herein,
an organic-solvent-soluble alkylammonium salt of a simple
monomeric phosphate ion, [PO4]3À, with a high charge density
acts as an efficient homogeneous catalyst for selective N-alky-
lation of indoles with a,b-unsaturated compounds. For the re-
action of indole with ethyl acrylate, the turnover number
these values are the highest among those reported for base-
mediated systems so far. In the presence of [PO4]3À ions, vari-
ous combinations of nitrogen nucleophiles (ten examples) and
a,b-unsaturated compounds (four examples) were efficiently
converted to the desired N-alkylated products in high yields.
NMR and IR spectroscopies showed formation of the indolyl
anion through the activation of indole by the [PO4]3À ion,
which plays an important role in the present N-alkylation.
reached up to 36 and the turnover frequency was 216 hÀ1
;
Introduction
Heterocyclic compounds such as indoles are of great interest
because they widely occur in nature as partial structures of al-
kaloids.[1] Catalytic functionalization of indoles at the C1, C2,
and N1 positions has attracted much attention because of the
sustainable nature of the reaction, for example, the use of cat-
alysts and minimization of hazardous wastes.[1,2] Although sev-
eral N-alkylated indoles are known as biologically active com-
pounds, regioselective introduction of alkyl substituents at the
N1 positions in indoles is generally difficult because the N1 ni-
trogen atoms are inert toward electrophilic reagents in com-
parison with the C3 carbon atoms.[1,2] Stoichiometric and cata-
lytic synthetic methods of N-alkylated indoles from indoles
have been reported, for example, the treatment of alkyl halides
with higher than stoichiometric amounts of strong bases,
base-catalyzed reactions with dialkyl carbonates, and alkyla-
tions with alcohols in the presence of Pd and Ru catalysts,
among others. (see the Supporting Information, Table S1).[3–6]
However, these systems have some drawbacks: 1) significant
amounts of byproducts are formed, 2) severe reaction condi-
tions are required, and 3) applicabilities to substituted indoles
and/or introduction of alkyl substitutents with functional
groups are limited. Very recently, Hartwig and co-workers have
reported an atom-efficient Ir-catalyzed hydroamination of in-
doles with unactivated alkenes, but indoles with substituents
at the 2- or 7-positions cannot be N-alkylated.[7] Michael-type
addition of indoles to a,b-unsaturated compounds is also
a useful, simple, and atom-efficient synthetic method toward
N-alkylated indoles.[8] In contrast with many examples for acid-
catalyzed C3-alkylation of indoles,[9] relatively few examples are
known for base-catalyzed N-alkylation (only six examples) and
these base-catalyzed systems require high catalyst loadings
(13–120 mol%) and/or microwave irradiation (see the Support-
ing Information, Table S2).[8] Therefore, developments of effi-
cient-based catalyzed systems for N-alkylation of indoles are
still challenging subjects.
Inorganic bases including solid-base catalysts are important
materials that have frequently been utilized for organic reac-
tions in the laboratory as well as chemical industry.[10] Despite
their availabilities and stabilities, control of the chemical prop-
erties is difficult in comparison with organic bases.[11] Recently,
we have focused on developments of a series of polyoxometa-
late (POM) catalysts efficient for various functional-group trans-
formations.[12] POMs are discrete anionic metal–oxygen cluster
molecules consisting of early transition metals, and their chem-
ical and physical properties can be finely controlled at atomic
and molecular levels.[13] During the course of our investigation,
we found unique basic properties of metal oxo moieties (M=O
and MÀOÀM species) in a simple monomeric tungstate,[14] rare-
earth-metal-containing POMs,[15] and highly negatively charged
lacunary POMs.[16] Initially, we applied these basic POM-cata-
lyzed systems to N-alkylation of indole (1a) with ethyl acrylate
(2a) in acetonitrile at 298 K (Figure 1). POM catalysts, such as
TBA2[WO4] (TBA=[(nC4H9)4N]+), TBA6[g-H2GeW10O36], and
TBA8[H2(g-SiYW10O36)2], did not promote the N-alkylation, and
the corresponding N-alkylated indole (3aa) was not obtained.
A monomeric molybdate, TBA2[MoO4], with a stronger basicity
than [WO4]2À ions [pKa values of conjugate acid in water: 3.5
(W) and 3.9 (Mo)][17] was also inactive. Herein, we focus on the
basic property of a monomeric phosphate, [PO4]3À (pKa value
of conjugate acid in water: 12.3),[18] having a higher charge
density than [MO4]2À (M=W and Mo). As expected, a TBA salt
of a monomeric phosphate, TBA3[PO4]·9H2O (I), exhibited high
[a] H. Sunaba, Dr. K. Kamata, Prof. Dr. N. Mizuno
Department of Applied Chemistry, School of Engineering
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
Fax: (+81)3-5841-7220
E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201402309.
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Table 1. Effects of catalysts and solvents on N-alkylation of 1a with 2a.[a]
Entry
Catalyst
Solvent
Yield of 3aa
[%]
1
2
I
I
THF
acetonitrile
90
64
3
I
dimethyl sulfoxide
32
4
I
toluene
11
5
I
dichloromethane
7
6
7
8
9
10
11
12
13
14
15
16
17
18
Na3PO4
K3PO4
K2CO3
Cs2CO3
tBuOK
DABCO
DBU
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
<1
<1
<1
<1
26
<1
<1
<1
<1
7
Et3N
pyridine
TBAOH·30H2O
TBA2[WO4]
TBA2[MoO4]
without
Figure 1. N-alkylation of indole (1a) with ethyl acrylate (2a) in acetonitrile
catalyzed by various basic POMs.
<1
<1
<1
[a] Reaction conditions: Catalyst (2.5 mol% with respect to 1a), 1a
(1.0 mmol), 2a (1.5 mmol), solvent (0.5 mL), 298 K, 10 min, under air
(1 atm). Yield of 3aa was determined by LC analysis by using an internal
standard (biphenyl).
catalytic activity for the N-alkylation of 1a with 2a in acetoni-
trile to give 3aa in 64% yield (Figure 1). In addition, I could act
as an efficient homogeneous catalyst for selective N-alkylation
of various kinds of indoles with a,b-unsaturated compounds.
The I-catalyzed system has the following advantages: 1) high
turnover number (TON) and turnover frequency (TOF) under
the mild reaction conditions, 2) high selectivity to N-alkylated
indoles, and 3) wide substrate scope.
The scope of the present I-catalyzed system for N-alkylation
of various kinds of nitrogen nucleophiles with 2a was exam-
ined (Table 2). Indoles with electron-donating and electron-
withdrawing substituents on the aromatic rings (1a–1e) were
converted into the corresponding N-alkylated indoles (3aa–
3ea) in good yields (64–90%, Table 2, entries 1–5). An indole
with the methyl substituent at the 2-position (2-methylindole,
1 f) could be N-alkylated (entry 6). For the reaction of carbazole
(1g) with 2a, the corresponding N-alkylated product (3ga)
could be isolated in 78% yield (entry 7). Not only nitrogen nu-
cleophiles based on indole structures, but also an aromatic
amine (aniline, 1h) and cyclic amide [(S)-4-benzyl-2-oxazolidi-
none (1i)], were selectively N-alkylated (entries 8 and 9). N-al-
kylation of 1a with acrylonitrile (2b), acrylamide (2c), and cro-
tononitrile (2d) efficiently proceeded to give the correspond-
ing products (3ab, 3ac, and 3ad) in 84, 75, and 95% isolated
yields, respectively (entries 10–12). Compound I also efficiently
catalyzed the N-alkylation of a cyclic aliphatic amine (piperi-
dine, 1j) with 2a to give the corresponding N-alkylated prod-
uct (3ja) in 88% yield, even with 0.5 mol% of I (see the Sup-
porting Information, Scheme S1). The present system was ap-
plicable to a gram-scale reaction of 1a (20 mmol scale) with
2b and 3.37 g of analytically pure N-alkylated product 3ab
could be isolated [Eq. (1)]. To the best of our knowledge, effi-
cient base-catalyzed systems applicable to N-alkylation of
structurally diverse amines including unreactive indoles with
a,b-unsaturated compounds have not been reported. The
combinations of 2a/pyrrole with a higher pKa value than that
of 1a or 1a/sterically hindered a,b-unsaturated compounds
(ethyl crotonate and ethyl cinnamate) were converted to the
desired N-alkylated products with poor yield. The reaction of
Results and Discussion
N-Alkylation of nitrogen nucleophiles with a,b-unsaturated
compounds
Firstly, effects of solvents on the I-catalyzed N-alkylation of 1a
with 2a were investigated (Table 1, entries 1–5). Among the
solvents tested, tetrahydrofuran (THF) was the most effective.
The reaction was completed within 10 min under the mild con-
ditions (2.5 mol% of I, 298 K) and 3aa was obtained in 90%
yield without formation of the C3-alkylated indole. In this case,
the TON reached up to 36 and the TOF was 216 hÀ1. These
values are much larger than those of the reported base-cata-
lyzed systems (TON=0.5–6.9, TOF= <0.1–28 hÀ1, see the Sup-
porting Information, Table S2).[8] Acetonitrile and dimethyl sulf-
oxide gave 3aa in 64% and 32% yields, respectively, and the
reactions hardly proceeded in toluene and dichloromethane.
Next, N-alkylation of 1a with 2a in THF was investigated in
the presence of various base catalysts (Table 1, entries 1 and 6–
17). In the absence of catalysts, the reaction did not proceed
(entry 18). Compound I exhibited higher catalytic activity than
commonly used strong inorganic and organic bases (Na3PO4,
K3PO4, K2CO3, Cs2CO3, and tBuOK) as well as N bases, such as
1,4-diazabicyclo[2.2.2]octane
(DABCO),
1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU), Et3N, and pyridine, which were
almost inactive under the present reaction conditions. In the
presence of TBAOH and TBA2[MO4] (M=W and Mo), the reac-
tion hardly proceeded, suggesting that [PO4]3À plays an impor-
tant role in the present reaction.
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new signals (7.39–7.12 (m, 3H),
6.63–6.35 (m, 2H), and 6.04 (s,
1H)), and the signal at
10.11 ppm assignable to the NH
proton in 1a disappeared (Fig-
ure 2b). Similarly, the 13C NMR
spectrum showed eight new sig-
nals at 146.7, 137.7, 131.2, 117.8,
116.5, 114.6, 113.5, and 96.2 ppm
(Figure 2d). These 1H and
13C NMR spectra are almost iden-
tical to those of Grignard deriva-
tives of indole in THF,[19] in
agreement with the formation of
indolyl anion species. In contrast,
these 1H signals were not ob-
served in the presence of bases
that were almost inactive for the
present N-alkylation (see the
Supporting Information, Fig-
ure S1).[20] Upon addition of 1a
into the [D8]THF solution con-
taining I, the 8.1 ppm 31P signal
of I shifted to 7.3 ppm (Fig-
ure 2e and 2 f). Separately, it was
confirmed that the 31P signal of I
also shifted to 7.2 ppm upon ad-
dition of one equivalent of
HClO4 with respect to I. In addi-
tion, the IR band at 983 cmÀ1, as-
Table 2. N-Alkylation of amines (1) with a,b-unsaturated compounds (2) catalyzed by I.[a]
Entry
Amine
a,b-Unsaturated
Product
Yield
[%]
compound
1
90 (82)
75 (71)
(66)
2
2a
2a
2a
2a
2a
3
4
85 (83)
90 (82)
67 (60)
5
6[b]
7
2a
2a
(78)
8[c]
81 (80)
9
2a
(66)
10[d]
11
1a
1a
85 (84)
(75)
signable to n(PÀO)asym, almost
disappeared (see the Supporting
Information, Figure S2). These re-
sults suggest the formation of
an indolyl anion and [HPO4]2À by
the reaction of I with 1a. The in-
tensities of the signals assigna-
ble to an indolyl anion were
weakened by addition of 2a
(one equivalent with respect to
1a) into the solution containing
I and 1a, and the signals of 3aa
appeared. These findings sup-
12[e]
1a
(95)
[a] Reaction conditions: I (2.5 mol% with respect to 1), 1 (1.0 mmol), 2 (1.5 mmol), THF (0.5 mL), 298 K, under
air (1 atm), reaction times: 10 min (entries 1, 5, 6, 7, 9, and 10), 15 min (entry 12), 40 min (entries 2 and 3),
60 min (entry 4), 20 h (entry 11), or 48 h (entry 8)). Yields of 3 were determined by LC analysis by using an inter-
nal standard (biphenyl). Values in the parentheses are isolated yields. [b] I (10.0 mol% with respect to 1 f),
323 K. [c] I (5.0 mol% with respect to 1h), 323 K. [d] 273 K. [e] cis/trans of 2d=65:35.
1a with 3-buten-2-one did not proceed efficiently, probably
because of the polymerization of the enone.
port the proposed mechanism, in which nucleophilic attack of
the nitrogen atom in an activated indolyl anion intermediate
on the b-carbon atom in 2a takes place to give 3aa (see the
Supporting Information, Figure S3).[21,22]
Conclusions
An organic-solvent-soluble monomeric phosphate I could act
as an efficient homogeneous catalyst for selective N1-alkylation
of indoles with a,b-unsaturated compounds, and various com-
binations of nitrogen nucleophiles (ten examples) and a,b-un-
saturated compounds (four examples) were efficiently convert-
ed to the desired N-alkylated products in high yields.
Mechanistic investigations
To investigate the role of I on the present N-alkylation, the re-
activity of I with 1a was investigated by using NMR (1H, 13C,
and 31P) and IR spectroscopies. Upon addition of one equiva-
1
lent of I with respect to 1a, the H NMR spectrum displayed
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field from Si(CH3)4 (solvent, CDCl3) for 1H and 13C NMR
spectra and 85% H3PO4 for 31P NMR spectra. To avoid
the disappearance of the NH group signal in 1a owing
to the H/D exchange reaction between 1a and deuterat-
ed solvents (CD3CN and [D8]THF) in the presence of
1
strong base catalysts, H NMR spectra were measured in
commonly used solvents (CH3CN and THF) by using a ca-
pillary tube with deuterated solvents (CD3CN and
[D8]THF) for locking. 1H NMR measurements were per-
formed by using the coaxial NMR tube. Inductively cou-
pled plasma atomic emission spectroscopy analyses
were performed with a Shimadzu ICPS-8100 spectrome-
ter. GC analyses were performed on Shimadzu GC-2014
with a flame ionization detector equipped with an Inert-
Cap-5 capillary column (internal diameter=0.25 mm,
length=60 m). Mass spectra were recorded on a Shimad-
zu GCMS-QP2010 equipped with a TC-5HT capillary
column at an ionization voltage of 70 eV. Argon-filled
MBraun Labmaster 130 and VAC Omni-Lab glove boxes
were employed for manipulation and storage of all
oxygen- and moisture-sensitive compounds.
Synthesis and characterization of TBA3[PO4]·9H2O
(I)
Although the synthesis of a TBA salt of a monomeric
phosphate was reported in Ref. [26], the detailed proce-
dure and characterization are still unclear. Therefore, we
synthesized and characterized TBA3[PO4]·9H2O (I) as fol-
lows: H3PO4 (1.0 mmol, 85% aqueous solution) and
TBAOH (3.0 mmol, 1.0m aqueous solution) were placed
into a glass screw-cap vial containing a magnetic stir bar.
The reaction mixture was stirred for 3 h at RT under an
Ar atmosphere. The resulting solution was evaporated to
dryness at 273 K for 48 h, giving the analytically pure I as
a white powder (98% yield). Compound I was character-
ized by NMR (1H and 31P) and IR spectroscopies and ele-
mental analysis. The 31P NMR spectrum of
[D3]acetonitrile showed one signal at 4.8 ppm (see the
Supporting Information, Figure S4), and the chemical
shift was close to that (5.5 ppm) of [PO4]3À in water.[18]
I
in
Figure 2. a,b) 1H; c,d) 13C; and e,f) 31P NMR spectra of a,c) 1a; e) I; and b,d,f) 1a with ad-
dition of I. Conditions: 1a (0.1m), I (0.1m), solvent (THF/[D8]THF), RT.
The IR spectrum of I showed a band at 1009 cmÀ1, assignable to
n(PÀO)asym, and the band position was close to that (1008 cmÀ1) of
aqueous [PO4]3À (see the Supporting Information, Figure S5).[27] The
1H NMR spectrum of I displayed no signal assignable to tributyla-
mine, suggesting that Hofmann elimination of TBA did not pro-
ceeded. A signal assignable to water hydrogen bonded to [PO4]3À
was observed at 5.4 ppm. The integrated intensity of the 5.4 ppm
signal and elemental analysis revealed that the formula of I is
TBA3PO4·9H2O. Owing to its highly hygroscopic properties, I was
stored and handled in the glove box. 31P NMR (109.3 MHz, CD3CN,
298 K, H3PO4): d=4.8 ppm; IR (KBr): n˜ =3768, 2958, 2874, 1672,
1489, 1474, 1381, 1323, 1274, 1254, 1152, 1108, 991, 922, 883, 800,
738, 583 cmÀ1; elemental analysis calcd (%) for TBA3[PO4]·9H2O
(984.51): C 58.56, H 12.90, N 4.27, P 3.15; found: C 58.20, H 12.97,
N 4.19, P 3.15.
Experimental Section
Materials
Solvents and substrates were obtained from Kanto, TCI, or Aldrich
(reagent grade) and purified prior to use.[23] Substrates were puri-
fied according to the reported procedures.[24] The products were
1
isolated and identified by comparison of their H and 13C NMR sig-
nals with literature data. Deuterated solvents (D2O, CDCl3,
[D6]DMSO, and [D8]THF) were purchased from ACROS, C/D/N Iso-
topes, or Aldrich and used as received. Tungstates (TBA2[WO4],[14,25]
TBA6[g-H2GeW10O36],[16] and TBA8[H2(g-SiYW10O36)2][15]) were synthe-
sized according to literature procedures and characterized by IR
and NMR (29Si and 183W) spectroscopy and elemental analysis.
Instruments
IR spectra were measured on a Jasco FT/IR-460 spectrometer Plus
by using KBr disks. NMR spectra were recorded on a JEOL JNM-EX-
270 spectrometer (1H, 270.0 MHz; 31P, 109.3 MHz; 13C, 67.8 MHz) by
Synthesis and characterization of TBA2[MoO4]
The tetra-n-butylammonium salt of a monomeric molybdate was
synthesized according to the following procedure: MoO3 (0.65 g,
4.5 mmol) was added, in five portions (one minute apart), into an
aqueous solution of TBAOH (28.1 mL, 0.35m, 9.0 mmol) at 353 K.
1
using 5 mm tubes (for H and 13C) or 10 mm tubes (for 31P) or on
a JEOL ECA-500 spectrometer (1H, 495.1 MHz; 13C, 124.5 MHz) by
using 5 mm tubes. Chemical shifts (d) were reported in ppm down-
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[2] a) P. A. Gale, Chem. Commun. 2008, 4525–4540; b) M. Bandini, A. Eich-
holzer, Angew. Chem. Int. Ed. 2009, 48, 9608–9644; Angew. Chem. 2009,
121, 9786–9824; c) A. V. Karchava, F. S. Melkonyan, M. A. Yurovskaya,
Chem. Heterocycl. Compd. 2012, 48, 391–407; d) G. Bartoli, G. Benciven-
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After the addition was complete, the mixture was stirred for
10 min at 353 K and then cooled to RT. Insoluble materials were re-
moved by filtration. The resulting clear solution was evaporated to
dryness at 338 K for 24 h, giving the analytically pure TBA2[MoO4]
as a white powder (2.51 g, 87% yield). Owing to its highly hygro-
scopic properties, TBA2[MoO4] was stored and handled in the glove
box. 95Mo NMR (17.5 MHz, [D6]DMSO, 298 K): d=14.6 ppm; IR (KBr):
n˜ =836 cmÀ1; Raman: 870 (n(Mo(=O)2)sym), 814 (n(Mo(=O)2)asym), 305
(n(OÀMoÀO)) cmÀ1; MS (positive ion, cold-spray ionization, acetoni-
trile): m/z (%): 887 [(TBA)3MoO4]+ and 1532 [(TBA)5(MoO4)2]+; ele-
mental analysis calcd for TBA2[MoO4] (644.87): C 59.60, H 11.25, N
4.34, Mo 14.88; Found: C 59.40, H 11.38, N 4.37, Mo 14.63.
I-catalyzed reaction of amines with a,b-unsaturated
compounds
[4] a) X. Jiang, A. Tiwari, M. Thompson, Z. Chen, T. P. Cleary, T. B. K. Lee, Org.
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ˇ
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Typical procedure: The catalytic reactions were performed with
a glass screw-cap vial containing a magnetic stir bar. Compound I,
THF, and 1a were added to the reaction vessel and the reaction
was initiated by the addition of 2a. The reaction solution was peri-
odically analyzed by LC. Detailed reaction conditions are given in
the footnotes of Tables 1 and 2. The reaction products were isolat-
ed and confirmed by GC–MS, NMR (1H and 13C) spectroscopy, and
elemental analysis. The isolation of products was performed by
column chromatography on silica gel (Silica Gel 60N, spherical,
neutral, 63–210 mm, Kanto, Cat. No. 37565–79) by using chloro-
form/methanol (15:1, for 3ac), n-hexane/ethyl acetate/acetone
(10:1:1, for 3 fa), and n-hexane/ethyl acetate (10:1–2.5:1, for all
other products) as eluents.
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with enantioselective variants (Table S1), their applicabilities are limited
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Large-scale production of 3ab
I (20 mmol), 1a (20 mmol), and THF (10 mL) were successively
placed into a glass reactor. The reaction was initiated by the addi-
tion of 2b (30 mmol), and the reaction mixture was stirred at
298 K. The LC yield of 3ab reached up to ꢀ99% after 30 min.
Then, THF was removed by evaporation, and ethyl acetate (70 mL)
was added into the concentrated solution. Residual 2b and cata-
lyst were extracted with water followed by addition of anhydrous
Na2SO4 into the collected organic layer. After removal of Na2SO4 by
filtration, ethyl acetate was removed by evaporation, giving 3.37 g
of 3ab (99% yield) with 99% purity as determined by 1H NMR
spectroscopy.
Acknowledgements
This work was supported in part by the Japan Society for the
Promotion of Science (JSPS) through its “Funding Program for
World-Leading Innovative R&D on Science and Technology (FIRST
Program)” and Grants-in-Aid for JSPS Fellows and Scientific Re-
search from the Ministry of Education, Culture, Science, Sports,
and Technology of Japan.
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Keywords: alkylation
· alkenes · electrophilic addition ·
nitrogen heterocycles · phosphorus
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Received: May 7, 2014
Published online on July 8, 2014
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 2333 – 2338 2338