Novel Preparation of Hemiaminal Derivatives with BPO and N,N-Dimethylamides and Their Synthetic Use for (Aminomethyl)indoles

Article abstract of DOI:10.1002/ejoc.202000680

A novel preparation of hemiaminal derivatives bearing both an amide group and a benzoate group was carried out in good yields by the treatment of BPO in N,N-dimethylamides under warming condition at 80 °C or irradiation with a mercury lamp. Further treatment of the obtained hemiaminal derivatives with indoles in 1,1,1,3,3,3-hexafluoro-2-propanol generated the corresponding C–C bonded indoles bearing an amide group in good yields. The formed indoles bearing an amide group were smoothly transformed into the corresponding indoles bearing an aminomethyl group.

Full text of DOI:10.1002/ejoc.202000680

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Novel Preparation of Hemiaminal Derivatives with BPO
and N,N-Dimethylamides, and Their Synthetic Use for
(Aminomethyl)indoles
Authors: Kohei Nakamura and Hideo Togo
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000680
Link to VoR: https://doi.org/10.1002/ejoc.202000680
01/2020

10.1002/ejoc.202000680
European Journal of Organic Chemistry
FULL PAPER
DOI: 10.1002/ejoc.200((will be filled in by the editorial staff))
Novel Preparation of Hemiaminal Derivatives with BPO and N,N-Dimethylamides,
and Their Synthetic Use for (Aminomethyl)indoles
Kohei Nakamura[a] and Hideo Togo[a]*
Keywords: BPO / Hemiaminal / Friedel-Crafts Alkylation / Amide / (Aminomethyl)indole
A novel preparation of hemiaminal derivatives bearing both an 1,1,1,3,3,3-hexafluoro-2-propanol generated the corresponding
amide group and a benzoate group was carried out in good yields C-C bonded indoles bearing an amide group in good yields. The
by the treatment of BPO in N,N-dimethylamides under warming formed indoles bearing an amide group were transformed into
condition at 80 °C or irradiation with a mercury lamp. Further the corresponding indoles bearing an aminomethyl group
treatment of the obtained hemiaminal derivatives with indoles in
smoothly.
____________
a) Electron-deficient Heteroarmatics2b
[a]
Graduate School of Science, Chiba University, Yayoi-cho 1-33,
Inage-ku, Chiba 263-8522 Japan
Fax: 81-43-290-2792
R
R
R
Hg-hν
Me
N
E-mail: togo@faculty.chiba-u.jp
BPO
Homepage: http://reaction-2.chem.chiba-u.jp/index.html
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ejoc.xxxxxxxxx.
R
O
N
N
NMe2
O
R
R
Hg-hν
Introduction
BPO
N
O
N
R
Benzoyl peroxide (BPO) is one of the most useful radical
initiators and has been used for the bromination of the benzylic
position with N-bromosuccinimide (NBS), and the reduction and
C-C bond formation of alkyl halides, aryl halides, and xanthate
esters with Bu3SnH, (Me3Si)3SiH, Ph4Si2H2, etc.1 Recently, we
reported the introduction of ethers, cyclic ethers, and 18-crown-6
onto electron-deficient heteroaromatic bases, such as quinolines,
isoquinolines, and pyridines, by using BPO under warming
condition at 80 °C or irradiation with a mercury lamp;2a the
introduction of tertiary amide groups onto quinolines and
isoquinolines by using BPO and tertiary amides, such as N,N-
NMe2
R
N
O
Me
N
Me
R
H2C
•
O
nucleophilic radical I
b) Electron-rich Heteroaromatics
Hg-hν
BPOOX
Me
N
N
H
dimethylacetamide,
N,N-dimethylpropionamide,
and
N-
N
R
H
acetylpyrrolidine, under irradiation with a mercury lamp;2b and the
introduction of cycloalkyl groups onto quinolines, isoquinolines,
and benzothiazole by using BPO and cycloalkanes, such as
cyclopentane, cyclohexane, cycloheptane, and cyclooctane, under
warming condition (100 °C),2c as shown in Scheme 1 (a). In those
reactions, BPO was used as the radical initiator and the oxidant.
Based on those previous studies,2 we tried to carry out an
oxidative introduction of a tertiary amide group onto electron-rich
heteroaromatics, such as indole and N-methylindole, by using BPO
and N,N-dimethylacetamide under irradiation with a mercury lamp
(Scheme 1, b). However, oxidative C-C bonded products were not
formed at all because amide radicals I had a highly nucleophilic
character and a small amount of hemiaminal derivative 1A (R =
CH3), which was a C-O bonded product of the reaction of BPO and
N,N-dimethylacetamide, was formed. Then, we attempted to
perform the reaction of BPO and N,N-dimethylacetamide under
irradiation with a mercury lamp and surprisingly, we obtained
hemiaminal derivative 1A in good yield. To the best of our
knowledge, the synthetic use of BPO, i.e., the introduction of the
benzoate group of BPO to the product is quite limited. Recently,
the preparation of secondary aromatic amides with diaroyl
peroxides and isocyanides in the presence of Bu4NI,3a asymmetric
O
NMe2
R
c) Introduction of Amide Groups onto Indoles (This work)
Me
N
Hg-hν
Me
N
O
R
BPO
Ph
R
Me
O
O
O
Aminal Derivatives
1
(1A: R = CH3)
R'
R'
Me
N
1
N
N
H
R
H
O
reduction
R'
Me
N
N
H
R
Indoles bearing aminomethyl group
Scheme 1. Introduction of Amide Groups onto Aromatics
Submitted to the European Journal of Organic Chemistry
1
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10.1002/ejoc.202000680
European Journal of Organic Chemistry
α-benzoyloxylation of aldehydes with BPO,3b,3c the preparation of
α-aroyloxy chromones with tertiary enaminones and diaroyl
peroxides,3d and the preparation of α-benzoyloxyketones with
First, treatment of BPO (purity 75% containing 25% water, 1.0
mmol) in N,N-dimethylacetamide A (0.5 mL, 1.0 mL, 2.0 mL, and
3.0 mL) in the presence of MS 3Å in a 30 mL screw-capped flask
under irradiation with a mercury lamp (400 W) for 24 h in the
temperature range of 35 °C~38 °C gave hemiaminal derivative 1A
in 72%, 83%, 77%, and 72% yields, respectively, as shown in
Table 1 (entries 1~4). The yield of hemiaminal derivative 1A was
slightly decreased to 60%~65% in the absence of MS 3Å because
3e
tertiary enaminones and BPO in the presence of Mn(OAc)2 were
reported. On the other hand, the preparation of hemiaminal
derivatives by the reaction of cyclic ethers and TsNH2 in the
presence of Cu(O3SCF3)2,4a the reaction of ethers, diazoles, and
tBuOOH in the presence of FeCl3•6H2O,4b the reaction of aromatic
α-ketocarboxylic acids, tBuOOH, and amides, such as N,N-
dimethylformamide and N,N-dimethylacetamide, in the presence of
BPO contained water.
When BPO (1.0 mmol) in N,N-
dimethylacetamide A (2.0 mL and 3.0 mL) in a 30 mL screw-
capped flask was heated at 80 °C for 2 h, hemiaminal derivative
1A was also obtained in 65% and 75% yields, respectively (entries
5, 6). On the other hand, when a solution of BPO (1.0 mmol) in
N,N-dimethylacetamide A (3.0 mL) was irradiated with a tungsten
lamp (300 W) in the temperature range of 35 °C~38 °C for 8 h, the
yield of hemiaminal derivative 1A was decreased to 38% (entry 7).
Thus, hemiaminal derivative 1A was obtained in good yields when
the reaction was carried out under irradiation with a mercury lamp
for 24 h or under warming condition at 80 °C for 2 h (entries 2 and
6). As gram-scale experiments, treatment of BPO (8.0 mmol) in
N,N-dimethylacetamide A (24.0 mL) in 100 mL screw-capped
flasks under the same irradiation and warming conditions gave
hemiaminal derivative 1A in 68% and 79% yields, respectively
(entries 8 and 9). When those two reactions were carried out in the
t
Bu4NI,4c and the reaction of tertiary amides and BuOOBut in the
presence of FeCl3, and their use for C-C bond formation on indoles
through the Friedel-Crafts alkylation4d were reported.
Indoles bearing aminoalkyl groups are quite important because
they are found in many natural products isolated from animals and
plants and show potent biological activities.5 In particular,
serotonin and melatonin, which are 3-(β-aminoethyl)indoles, are,
respectively, a neurotransmitter and a hormone, and both regulate
the circadian rhythm.5c
Recent reports of the preparation of
indoles bearing aminoalkyl groups with indoles under transition-
metal-free conditions are as follows:6 the preparation of 3-(α-N-p-
t
tosylamino)methylindoles with indole, BuLi, and aromatic N-p-
tosylaldimines;6a the preparation of N-acetyl 3-indolyl-α-amino
acid esters with indoles and methyl α-(acetylamino)acrylate in the
presence of 2,6-di-tert-butyl-p-cresol (BHT, 2.1 equiv.),
a
EtAlCl2;6b
the
preparation
of
3-(N,N-
hydrogen-atom donor, under the same conditions, hemiaminal
derivative 1A was not obtained at all in both reactions (entries 10
and 11). Thus, the results suggest that those reactions proceed
through radical-mediated pathways. In addition, when those two
reactions were carried out in the presence of p-ethylbenzoic acid
(4.0 equiv.), an analog of benzoic acid derived from BPO, under
the same conditions, hemiaminal derivative 1A’ was obtained in
2% and 12% yields, together with hemiaminal derivative 1A in
67% and 34% yields, respectively (entries 12 and 13).
presence
of
dialkylamino)methylindoles with indoles, formaldehyde, and
secondary amines in a mixture of AcOH and water under ultrasonic
irradiation (Mannich reaction);6c the preparation of α-(indole-3-
yl)glycine ester derivatives with indoles, ethyl α-aminoacetate, and
mCPBA;6d the preparation of 4-(2’-amino-1’-arylethyl)-5-
hydroxyindoles via the reduction of 4-(1’-aryl-2’-nitroethyl)-5-
hydroxyindoles formed from 5-hydroxyindole and β-nitrostyrene
(Friedel-Crafts alkylation);6e and the preparation of 4-hydroxy-3-
[β-(N,N-dimethylamino)ethyl]indole by the reaction of 4-
acetoxyindole and oxalyl chloride, followed by the reaction with
dimethylamine and the reduction with LiAlH4.6f Moreover, recent
reports of the preparation of indoles bearing aminoalkyl groups
using transition metals are as follows:7 the preparation of 3-
(aminoalkyl)indoles with phenylhydrazine and aminoalkenes in the
presence of Rh(acac)(CO)2 and XANTPHOS;7a the preparation of
chiral 3-[(α-aryl)(α-p-tosylamino)]methylindoles with indoles and
N-p-tosylaldimines in the presence of Cu(OTf)2 and chiral
Table 1. Optimization for Formation of Hemiaminal 1A with BPO in N,N-
Dimethylacetamide
O
O
O
O
MS 3Å
O
Ph
Ph
O
N
N
O
Ph
Conditions,
Time (h)
O
BPO
(1.0 mmol)
A (X mL)
1A
Entry
X (mL)
Conditions
Time (h)
Yield (%)
bisoxazoline;7b
methyl)amino]methylindoles
the
preparation
with
of
indoles
3-[(N-acetyl,N-
and N-tert-
1
2
0.5
1.0
2.0
3.0
2.0
3.0
3.0
24.0
24.0
3.0
3.0
3.0
3.0
1.0
3.0
Hg-hν, 35-38 °C
Hg-hν, 35-38 °C
Hg-hν, 35-38 °C
Hg-hν, 35-38 °C
80 °C
24
24
24
24
2
72
83
butoxymethyl,N-methylacetamide in the presence of FeCl3;7c the
preparation of 3-(α-phenylamino,α-acyl)methylindoles with
indoles, α-(phenylamino)acetophenones, and (NH4)2S2O8 in the
presence of Ru(bpy)3Cl2 under blue LED irradiation;7d the
preparation of 3-β-(N-acetylamino)ethylindoles with indoles and β-
(N-acetylamino)ethanol in the presence of [Cp*IrCl2]2;7e the
preparation of 3-[(N-acetyl,N-methyl)amino]methylindoles with
indoles and tBuOOBut in the presence of Fe3O(BDC)3;7f and the
preparation of N-heteroaryl-3-(phenylamino)indoles with N-
(heteroaryl)indoles and α-(phenylamino)acetic acid in the presence
of [RhCp*Cl2]2 and AgSbF6.7g
3
77
4
72
5
65
6
80 °C
2
75
7
W-hν
8
38
8[a]
9 [a]
10 [b]
11 [b]
12 [c]
13 [c]
14 [e]
15 [e]
Hg-hν, 35-38 °C
80 °C
24
2
68
79
Hg-hν, 35-38 °C
80 °C
24
2
0
0
Hg-hν, 35-38 °C
80 °C
24
2
67 (2)[d]
34 (12)[d]
Hg-hν, 35-38 °C
80 °C
24
2
3
0
Here, as synthetic studies of the radical reactions with BPO,2 we
would like to report a novel and simple preparation of hemiaminal
derivatives 1 with BPO in N,N-dimethylamides, and synthetic use
for the introduction of amide groups onto indoles through the
Friedel-Crafts alkylation.
[a] BPO (8.0 mmol) was used. [b] BHT (2.1 equiv.) was added. [c] 4-
Ethylbenzoic Acid (4.0 equiv.) was added. [d] Yield of 1A’. [e]
PhCO3But (1.0 mmol) was used instead of BPO.
O
O
Results and Discussion
1A' :
N
O
Submitted to the European Journal of Organic Chemistry
Et 2
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10.1002/ejoc.202000680
European Journal of Organic Chemistry
Scheme 3. Transformation of Hemiaminals 1 into Amides 2
On the other hand, the same treatment of tert-butyl peroxybenzoate
(PhCO3But, 1.0 mmol) in N,N-dimethylacetamide
A under
O
O
irradiation with a Hg lamp for 24 h and warming at 80 ° C for 2 h
generated hemiaminal 1A in 3% and 0 % yields, respectively
(entries 14 and 15).
(1.2 equiv.)
R1
N
O
Ph
O
R2
1A~1E
ArH
Ar
N
R1
(CF3)2CHOH (1.0 mL),
r.t., Time (h)
(1.0 mmol)
R2
2A~2E
Based on those results, solutions of BPO (1.0 mmol) in N,N-
dimethylpropionamide B (1.0 mL), N,N-dimethylbutyramide C
Product, Yield, (Time)
O
O
O
(3.0 mL), N-methylacetamide
D
(3.0 mL), and N,N-
dimethylformamide E (3.0 mL) in 30 mL screw-capped flasks
were irradiated with a mercury lamp for 24 h to give hemiaminal
derivatives 1B, 1C, 1D, and 1E, in 80%, 84%, 58%, and 59%
yields, respectively, as shown in Scheme 2 (entries 2~5). In
contrast, the same treatment of BPO in N,N-diethylacetamide (3.0
mL) and 1-methyl-2-pyrrolidone (3.0 mL) under the irradiation
N
N
N
N
N
H
N
H
68% (9 h)
83% (7 h)
71% (5 h)
2Aa
2Ab
2Ac
O
O
with
a mercury lamp did not generate the corresponding
hemiaminal derivatives 1F and 1G at all (entries 6 and 7).
N
N
N
O
O
N
H
Scheme 2. Preparation of Hemiaminals 1 with BPO in Dimethylamides
N
N
O
H
O
O
O
MS 3Å
O
Ph
66%[a] (4 h)
77% (24 h)
55% (24 h)
Ph
O
R1
N
R1
N
O
Ph
Hg-hν, 35-38 °C,
24 h
2Ad
2Ae
2Af
O
R2
R2
O
O
(1.0 mmol)
Entry
(1.0 mL)
1A~1E
N
N
N
O
O
Amide
O
Product
O
Yield (%)
Cl
O
O
O
O
O
N
H
1
83
80
84
1A
(A)
(B)
(C)
(D)
N
N
N
N
N
N
O
O
O
O
Ph
Ph
Ph
Ph
62%[a,b] (4 h)
91%[a,c] (30 h)
93%[a,c] (48 h)
2Ai
2Ag
2Ah
O
O
O
O
O
O
O
N
O
N
2
1B
1C
1D
O
O
N
3[a]
O
O
N
N
H
67%[a] (48 h)
88%[d] (3 h)
65%[d] (5 h)
2Bb
4[a]
5[a]
6
58
59
2Aj
2Ba
N
H
N
H
O
N
O
O
H
O
O
O
O
N
N
(E)
1E
1F
N
H
N
N
O
O
Ph
Ph
O
N
H
N
O
N
N
H
0
0
(F)
65%[d] (1.5 h)
74%[d] (8 h)
66%[e] (1 h)
2Bc
2Bd
2Be
O
O
O
O
O
7
N
(G)
1G
N
O
Ph
N
N
N
O
O
O
Cl
[a] Amide (3.0 mL) was used.
N
H
N
H
Here, obtained hemiaminals 1A~1E bearing an amide group
are mixtures of anti and syn forms. Then, as the synthetic use of
hemiaminal derivatives 1A~1E, they were subjected to the Friedel-
Crafts alkylation of indoles because indoles bearing aminoalkyl
groups have potent biological activities, as mentioned previously.
Thus, treatment of hemiaminal 1A (1.2 equiv.) and 3-methylindole
d (1.0 mmol) in the presence of ZnCl2 (1.0 equiv.), BF3•Et2O (1.0
equiv.), and FeCl3 (1.0 equiv.) in CH2Cl2 (2.0 mL) at room
temperature for 1 h provided 2-(N-acetyl,N-methylamino)methyl-
3-methylindole (2Ad) in 64%, 73%, and 29% yields, respectively.
When the same reaction of 1A and 3-methylindole d was carried
out in nitromethane (1.0 mL), 2,2,2-trifluoroethanol (1.0 mL), and
1,1,1,3,3,3-hexafluoro-2-propanol (1.0 mL) at room temperature
for 24 h without Lewis acids, 2-(N-acetyl,N-methylamino)methyl-
3-methylindole (2Ad) was obtained in 0%, 48% and 77% yields,
59%[d] (18 h)
64%[b,d] (2 h)
87%[d] (8 h)
2Bf
2Bg
2Bh
O
O
O
N
N
O
N
O
O
N
H
O
92%[e] (24 h)
59%[e] (9 h)
76%[f] (4 h)
2Bi
2Bj
2Ca
O
O
N
H
N
H
N
H
N
H
50%[g,h] (48 h)
71%[h.i] (72 h)
2Da
2Ea
Submitted to the European Journal of Organic Chemistry
3
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10.1002/ejoc.202000680
European Journal of Organic Chemistry
Scheme 5. Transformation of Amides 2 into Amines 3
[a] 1A (2.0 equiv.) was used. [b] 1,1,1,3,3,3-Hexafluoro-2-propanol (1.0
mL) and CH2Cl2 (1.0 mL) were used. [c] Reaction was carried out at
35 °C. [d] 1B (1.5 equiv.) was used. [e] 1B (2.0 equiv.) was used. [f]
1C (1.5 equiv.) was used. [g] 1D (1.2 equiv.) was used. [h] Reaction
was carried out at 40 °C. [i] 1E (1.5 equiv.) was used.
O
LiAlH4 (2.0 equiv.)
Ar
N
R
Ar
N
R
dry THF (1.0 mL),
70 °C, 2 h
2A~2E
(0.5 mmol)
3A~3E
together with the recovery of 3-methylindole in 93%, 40%, and 0%
yields, respectively. Recently, it was shown that 1,1,1,3,3,3-
hexafluoro-2-propanol promotes the Friedel-Crafts alkylation and
acylation reactions through hydrogen bonding.8 Thus, treatment of
Product, Yield, (Time)
N
N
N
hemiaminal derivative 1A and 3-methylindole d in 1,1,1,3,3,3-
hexafluoro-2-propanol at room temperature was the best choice,
forming 2-(N-acetyl,N-methylamino)methyl-3-methylindole 2Ad
in the highest yield.
N
N
H
N
H
94%
88%
93%
3Aa
3Ab
3Ac
Based on those results, hemiaminal derivative 1A (1.2 equiv.)
was treated with indoles (1.0 mmol), such as indole (a), 1-
methylindole (b), 2-methylindole (c), 3-methylindole (d), 1,2-
dimethylindole (e), 5-methoxyindole (f), and 5-chloro-2-
methylindole (g), in 1,1,1,3,3,3-hexafluoro-2-propanol (1.0 mL) at
room temperature to give the corresponding indoles 2Aa~2Ag
bearing a (N-acetyl,N-methylamino)methyl group in good to
moderate yields, as shown in Scheme 3. The same treatment of
electron-rich aromatics, such as 1-methoxynaphthalene (h), 2-
methoxynaphthalene (i), and 1,3,5-trimethoxybenzene (j), with
hemiaminal derivative 1A gave also the corresponding aromatics
2Ah~2Aj bearing a (N-acetyl,N-methylamino)methyl group in
good yields, respectively. Treatment of hemiaminal derivative 1B
with indoles (a)~(g) also gave the corresponding indoles 2Ba~2Bg
bearing a (N-methyl,N-propionylamino)methyl group in good to
moderate yields, respectively. 1-Methoxynaphthalene (h), 2-
methoxynaphthalene (i), and 1,3,5-trimethoxybenzene (j) also
reacted with hemiaminal derivative 1B to form the corresponding
aromatics 2Bh~2Bj bearing a (N-methyl,N-propionylamino)methyl
group in good to moderate yields, respectively. In addition, indole
(a) reacted with hemiaminal derivatives 1C, 1D, and 1E to give
indoles 2Ca bearing a (N-butyryl,N-methylamino)methyl group,
2Da bearing a (N-acetylamino)methyl group, and 2Ea bearing a
(N-formyl,N-methylamino)methyl group in good to moderate
yields, respectively.
N
N
N
O
N
H
N
N
H
98%
88%
3Ad
96%
3Ae
3Af
N
N
N
O
Cl
O
N
H
88%
92%
99%
3Ag
3Ah
3Ai
O
N
N
N
O
O
N
N
H
78%
81%
83%
3Aj
3Ba
3Bb
N
N
N
N
H
N
N
H
Scheme 4. One-pot preparation of 3-(N-Acetyl,N-methylamino)methylindole 2Aa
86%
84%
92%
1) BPO (1.5 mmol)
Hg-hν or 80 °C
O
O
O
3Bc
3Bd
3Be
N
N
O
Ph
2) evaporation
N
N
N
1A
A (4.5 mL)
O
N
O
O
Cl
N
H
N
H
N
H
(1.0 mmol)
80%
92%
91%
3Bh
(CF3)2CHOH (1.0 mL)
r.t., 6 h
N
H
3Bf
3Bg
2Aa
63%
61%
Hg-hν 24 h
O
N
O
80 °C 2 h
N
N
Treatment of BPO in N,N-dimethylacetamide A under irradiation
with a Hg lamp for 24 h and warming at 80 °C for 2 h, followed by
evaporation, and then reaction with indole (a) in 1,1,1,3,3,3-
O
N
O
H
85%
89%
82%
hexafluoro-2-propanpl
gave
3-(N-acetyl,N-
3Bi
3Bj
3Ca
methylamino)methylindole 2Aa in one pot in 63% and 61% yields,
respectively, as shown in Scheme 4. Thus, one-pot preparation of
indoles 2A bearing an amide group without isolation of
hemiaminal 1A can be carried out.
NH
N
N
H
N
H
Here, all obtained amides 2 are mixtures of anti and syn forms.
Then, the reduction of amides 2 was carried out to furnish indoles 3
bearing an aminomethyl group. Treatment of indoles 2Aa~2Ag
94%
95%
3Da
3Ea
Submitted to the European Journal of Organic Chemistry
4
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10.1002/ejoc.202000680
European Journal of Organic Chemistry
(0.5 mmol) bearing a (N-acetyl,N-methylamino)methyl group with
LiAlH4 (2.0 equiv.) in THF (1.0 mL) at 70 °C for 2 h gave the
Conclusions
corresponding indoles 3Aa~3Ag bearing
a
(N-ethyl,N-
A novel preparation of hemiaminal derivatives 1 bearing an
amide group and benzoate group with BPO in N,N-
methylamino)methyl group in good yields, respectively, as shown
in Scheme 5. The same reduction of indoles 2Ba~2Bg bearing a
(N-methyl,N-propionylamino)methyl group with LiAlH4 also
generated the corresponding indoles 3Ba~3Bg bearing a (N-
methyl,N-propylamino)methyl group in good yields, respectively.
In addition, the same reduction of 3-(N-butyryl,N-
methylamino)methylindole 2Ca, 3-(N-acetylamino)methylindole
2Da, and 3-(N-formyl,N-methylamino)methylindole 2Ea produced
a
dimethylamides under irradiation with a mercury lamp or warming
condition could be simply carried out. Treatment of formed
hemiaminal derivatives 1 with indoles in 1,1,1,3,3,3-hexafluoro-2-
propanol gave the corresponding indoles 2 bearing a (N-acyl,N-
methylamino)methyl group through the Friedel-Crafts alkylation.
Reduction of indoles 2 bearing a (N-acyl,N-methylamino)methyl
group gave indoles bearing a (N-alkyl,N-methylamino)methyl
group. We believe the present method for the preparation of
hemiaminal derivatives 1 would be useful because hemiaminal
derivatives 1 could be obtained in good yields from easily available
BPO and N,N-dimethylamides, and the formed hemiaminal
derivatives 1 could be used for the introduction of (N-acyl,N-
methylamino)methyl groups onto electron-rich aromatics, such as
indoles, via the Friedel-Crafts alkylation.
3-(N-butyl,N-methylamino)methylindole
ethylamino)methylindole 3Da,
3Ca,
and
3-(N-
3-(N,N-
dimethylamino)methylindole 3Ea in good yields, respectively. 1-
Methoxynaphthalenes 2Ah and 2Bh, 2-methoxynaphthalenes 2Ai
and 2Bi, and 1,3,5-trimethoxybenzenes 2Aj and 2Bj bearing a (N-
acetyl,N-methylamino)methyl
group
or
a
(N-methyl,N-
propionylamino)methyl group were also reduced to the
corresponding tertiary amines 3Ah~3Aj and 3Bh~3Bj in good
yields, respectively.
Experimental Section
A possible reaction pathway for the formation of hemiaminal
derivatives 1 is shown in Scheme 6. Homolytic bond cleavage of
the O-O bond in BPO under irradiation with a mercury lamp or
warming condition would occur to form a benzoyloxyl radical.
The benzoyloxyl radical would abstract a hydrogen atom from the
N-methyl group of N,N-dimethylamide to form nucleophilic radical
I and benzoic acid. Nucleophilic radical I would react with
benzoyloxyl radical to form hemiaminal derivatives 1 (path A).
However, generally, the concentration of radical species is quite
low and therefore, the radical coupling reaction is not efficient.
Thus, nucleophilic radical I would be oxidized by BPO via SET to
form electrophilic cation II, together with the generation of
benzoyloxyl radical and benzoate anion. Once electrophilic cation
II is formed, it would smoothly react with benzoate anion to form
hemiaminal derivative 1 (path B). Practically, when the present
reaction was carried out in the presence of p-ethylbenzoic acid (4.0
equiv.), hemiaminal derivative 1A’ was obtained in 12% yield, as
shown in Table 1. In addition, benzoic acid was obtained
quantitatively as a co-product.
General. : 1H NMR and 13C NMR spectra were obtained with
JEOL-JNM-ECX400 and JEOL-JNM-ECS400 spectrometers.
Chemical shifts were recorded as follows: chemical shift in ppm
from internal tetramethylsilane (TMS) on the δ scale, multiplicity
(s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; b =
broad), coupling constant (Hz) and integration. High-resolution
mass spectra (HRMS) were recorded by a Thermo Fisher Scientific
Exactive Orbitrap mass spectrometer. IR spectra were measured
with a JASCO FT/IR-4100 spectrometer. Melting points were
determined with a Yamato Melting Point Apparatus Model MP-21.
Silica gel 60F254 (Merck) was used for TLC and Silica gel 60N
(63~210 mesh, Kanto Kagaku Co.) was used for short column
chromatography.
Typical Procedure for Preparation of Hemiaminals 1A: To a
solution of BPO (purity 75% containing 25% water, 1.0 mmol,
323.0 mg) in N,N-dimethylacetamide (1.0 mL) in a 30 mL screw-
capped flask was added 3 Å molecular sieves (Ca. 1.0 g). The
flask was flashed by argon gas, and then, the mixture was stirred in
the temperature range of 35 °C~38 °C for 24 h under irradiation
with a high-pressure mercury lamp (Hg-lamp, 400 W: AHH400S,
1.7 mW/cm2). Sat. NaHCO3 aq. solution (10.0 mL) was added to
the reaction mixture and the product was extracted with CHCl3
(15.0 mL × 3). The organic layer was dried over Na2SO4. After
filtration and removal of the solvent under reduced pressure, the
residue was purified by silica-gel column chromatography (eluent:
Scheme 6. Possible Reaction Pathway for Hemiaminal Derivatives 1
O
O
O
O
Ph
R
N
O
Ph
Ph
O
O
(BPO)
Hemiaminal Derivatives 1
n-hexane/EtOAc
=
1:1) to give N-(benzoyloxy)methyl,N-
methylacetamide 1A (171.7 mg, 83% (anti/syn mixture = 59/24)).
N-(Benzoyloxy)methyl,N-methylacetamide 1A: Yield: 171.7
mg (83%, anti/syn mixture = 59/24); colorless oil; IR (neat): 1716,
1601, 1176 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 2.17 and 2.30 (s,
3H), 3.10 and 3.20 (s, 3H), 5.63 and 5.69 (s, 2H), 7.42-7.49 (m,
2H), 7.55-7.63 (m, 1H), 8.03-8.10 (m, 2H); HRMS (ESI): Calcd
for C11H14O3N [M+H]+ = 208.0968, Found = 208.0971.
N-(Benzoyloxy)methyl,N-methylpropionamide 1B: Yield: 177.2
mg (80%, anti/syn mixture = 54 /26); colorless oil; IR (neat): 1715,
1602, 1176 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.16-1.22 (m,
3H), 2.41 and 2.58 (q, 2H, J = 7.5 Hz), 3.11-3.18 (bs, 3H), 5.65
and 5.70 (s, 2H), 7.42-7.49 (m, 2H), 7.55-7.63 (m, 1H), 8.02-8.10
(m, 2H); HRMS (ESI): Calcd for C12H16O3N [M+H]+ = 222.1125,
Found = 222.1126.
path A
O
Ph
O
2
O
Ph
O
O
BPO
O
R
N
path B
(SET)
CH2
R
N
I
O
O
O
II
R
N
Ph
OH
Ph
O
N-(Benzoyloxy)methyl,N-methylbutyramide 1C: Yield: 197.4
mg (84%, anti/syn mixture = 58/26); colorless oil; IR (neat): 1714,
1601, 1176 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 0.99 (t, 3H, J =
7.3 Hz), 1.67-1.77 (m, 2H), 2.36 and 2.52 (t, 2H, J = 7.7 Hz), 3.11
and 3.18 (s, 3H), 5.65 and 5.70 (s, 2H), 7.42-7.49 (m, 2H), 7.55-
Submitted to the European Journal of Organic Chemistry
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000680
European Journal of Organic Chemistry
7.62 (m, 1H), 8.02-8.11 (m, 2H) ; HRMS (ESI): Calcd for
C13H18O3N [M+H]+ = 236.1281, Found = 236.1279.
(dd, 1H, J = 8.7, 2.3 Hz), 6.94-7.04 (m, 1H), 7.15 and 7.21 (d, 1H,
J = 2.5 Hz), 7.24-7.26 and 7.29-7.31 (m, 1H), 7.98 and 8.07 (bs,
1H); HRMS (ESI): Calcd for C13H17O2N2 [M+H]+ = 233.1285,
Found = 233.1282.
N-(Benzoyloxy)methylacetamide 1D: Yield: 111.2 mg (58%,
anti/syn mixture = 56/2); colorless oil; IR (neat): 3065, 1709, 1601,
1584, 1541 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 2.04 and 2.24 (s, 3-(N-Acetyl,N-methylamino)methyl-5-chloro-2-methylindole
3H), 5.45 and 5.49 (d, 2H, J = 7.4 Hz), 6.79 (bs, 1H), 7.43-7.47 (m,
2H), 7.56-7.61 (m, 1H), 8.04-8.07 (m, 2H); HRMS (ESI): Calcd
for C10H12O3N [M+H]+ = 194.0812, Found = 194.0811.
2Ag: Yield: 154.7 mg (62%, anti/syn mixture = 51/11); pale purple
solid; mp: 171-175 °C; IR (neat): 1653, 1558, 1541 cm-1; 1H-NMR
(400 MHz, CDCl3): δ = 2.12 and 2.34 (s, 3H), 2.42 and 2.46 (s,
3H), 2.78 and 2.85 (s, 3H), 4.59 and 4.69 (s, 2H), 7.06-7.12 (m,
N-(Benzoyloxy)methy,N-methylformamide 1E: Yield: 113.9 mg
(59%, anti/syn mixture = 52/7); colorless oil; IR (neat): 2975, 2881, 1H), 7.19 and 7.22 (d, 1H, J = 8.7 Hz), 7.36-7.55 (m, 1H), 7.97 and
1718, 1601, 617 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 3.04 and
3.14 (s, 3H), 5.56 and 5.66 (s, 2H), 7.43-7.49 (m, 2H), 7.57-7.63
(m, 1H), 8.02-8.12 (m, 2H), 8.18 and 8.44 (s, 1H); HRMS (ESI):
Calcd for C10H12O3N [M+H]+ = 194.0812, Found = 194.0812.
Typical Procedure for Preparation of Amides 2Aa~2Ea: To a
solution of N-(benzoyloxy)methyl,N-methylacetamide 1A (1.2
mmol, 248.7 mg) in 1,1,1,3,3,3-hexafluoro-2-propanol (1.0 mL)
was added indole a (1.0 mmol 117.2 mg) at room temperature. The
mixture was stirred at room temperature for 9 h under argon
atmosphere. Sat. NaHCO3 aq. solution (10.0 mL) was added to the
reaction mixture and the product was extracted with CHCl3 (15.0
mL × 3). The organic layer was dried over Na2SO4. After
filtration and removal of the solvent under reduced pressure, the
residue was purified by silica-gel column chromatography (eluent:
EtOAc) to give 3-(N-acetyl,N-methylamino)methylindole 2Aa
(138.2 mg, 68% (anti/syn mixture = 44/24)).
8.06 (bs, 1H) ; HRMS (ESI): Calcd for C13H16ON235Cl [M+H]+ =
251.0946, Found = 251.0943.
4-(N-Acetyl,N-methylamino)methyl-1-methoxynaphthalene
2Ah: Yield: 220.6 mg (91%, anti/syn mixture = 58/33); colorless
solid; mp: 111-114 °C; IR (neat): 1637, 1584, 1514 cm-1; 1H-NMR
(400 MHz, CDCl3): δ = 2.15 and 2.16 (s, 3H), 2.80 and 3.04 (s,
3H), 4.00 and 4.01 (s, 3H), 4.91 and 4.98 (s, 2H), 6.75 and 6.79 (d,
1H, J = 7.9 Hz), 7.12 and 7.26 (d, 1H, J = 7.9 Hz), 7.47-7.60 (m,
2H), 7.79 and 8.05 (d, 1H, J = 7.7 Hz), 8.29-8.31 and 8.34-8.37 (m,
1H); HRMS (ESI): Calcd for C15H18O2N [M+H]+ = 244.1332,
Found = 244.1331.
1-(N-Acetyl,N-methylamino)methyl-2-methoxynaphthalene
2Ai: Yield: 226.4 mg (93%, anti/syn mixture = 77/16); colorless
solid; mp: 103-105 °C; IR (neat): 1648, 1558, 1542 cm-1; 1H-NMR
(400 MHz, CDCl3): δ = 2.11 and 2.43 (s, 3H), 2.63 and 2.74 (s,
3H), 3.97 and 3.98 (s, 3H), 4.97 and 5.17 (s, 2H), 7.30 and 7.31 (d,
1H, J = 9.1 Hz), 7.34-7.38 (m, 1H), 7.49-7.53 (m, 1H), 7.78-7.89
(m, 2H), 7.93 and 8.11 (d, 1H, J = 8.5 Hz); HRMS (ESI): Calcd for
3-(N-Acetyl,N-methylamino)methylindole 2Aa: Yield: 138.2 mg
(68%, anti/syn mixture = 44/24); reddish brown solid; mp: 86-
95 °C; IR (neat): 1616, 1541, 1507, 1457 cm-1; 1H-NMR (400 MHz, C15H18O2N [M+H]+ = 244.1332, Found = 244.1330.
CDCl3): δ = 2.12 and 2.26 (s, 3H), 2.91 and 2.99 (s, 3H), 4.69 and
4.76 (s, 2H), 7.06-7.25 (m, 3H), 7.38 and 7.41 (d, 1H, J = 8.2 Hz),
7.53 and 7.72 (d, 1H, J = 8.0 Hz), 8.09 and 8.17 (bs, 1H) ; HRMS
(ESI): Calcd for C12H15ON2 [M+H]+ = 203.1179, Found =
203.1182.
2-(N-Acetyl,N-methylamino)methyl-1,3,5-trimethoxybenzene
2Aj: Yield: 169.5 mg (67%, anti/syn mixture = 55/12); colorless
solid; mp: 80-82 °C; IR (neat): 1647, 1558, 1542 cm-1; 1H-NMR
(400 MHz, CDCl3): δ = 2.07 and 2.29 (s, 3H), 2.71 (s, 3H), 3.79
and 3.80 (s, 6H), 3.83 (s, 3H), 4.45 and 4.63 (s, 2H), 6.12 (s, 2H);
HRMS (ESI): Calcd for C13H20O4N [M+H]+ = 254.1387, Found
=254.1384.
3-(N-Acetyl,N-methylamino)methyl-1-methylindole 2Ab: Yield:
179.3 mg (83%, anti/syn mixture = 54/29); red oil; IR (neat): 1627,
1614, 1551 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 2.11 and 2.26 (s, 3-[(N-Methyl,N-propionylamino)methyl]indole 2Ba: Yield:
3H), 2.91 and 2.98 (s, 3H), 3.76 and 3.78 (s, 3H), 4.67 and 4.73 (s,
2H), 6.91 and 7.04 (s, 1H), 7.10- 7.16 (m, 1H), 7.22-7.27 (m, 1H),
7.29-7.34 (m, 1H), 7.52 and 7.70 (d, 1H, J = 7.9 Hz); HRMS (ESI):
Calcd for C13H17ON2 [M+H]+ = 217.1335, Found = 217.1335.
3-(N-Acetyl,N-methylamino)methyl-2-methylindole 2Ac: Yield:
154.1 mg (71%, anti/syn mixture = 56/15); reddish brown solid;
mp: 99-101 °C; IR (neat): 1647, 1558, 1542 cm-1; 1H-NMR (400
MHz, CDCl3): δ = 2.11 and 2.36 (s, 3H), 2.42 and 2.46 (s, 3H),
2.80 and 2.84 (s, 3H), 4.64 and 4.75 (s, 2H), 7.07-7.11 (m, 1H),
7.11-7.15 (m, 1H), 7.27-7.32 (m, 1H), 7.41 and 7.61 (d, 1H, J = 7.7
Hz), 7.97 and 8.06 (bs, 1H); HRMS (ESI): Calcd for C13H17ON2
[M+H]+ = 217.1335, Found = 217.1337.
2-(N-Acetyl,N-methylamino)methyl-3-methylindole 2Ad: Yield:
155.4 mg (77%, anti/syn mixture = 76/1); yellow solid; mp: 171-
173 °C; IR (neat): 1699, 1558, 1541, 1507 cm-1; 1H-NMR (400
MHz, CDCl3): δ = 2.11 and 2.26 (s, 3H), 2.29 and 2.34 (s, 3H),
2.92 and 3.01 (s, 3H), 4.57 and 4.65 (s, 2H), 7.07-7.11 (m, 1H),
7.14-7.18 (m, 1H), 7.28 (d, 1H, J = 7.9 Hz), 7.52 (d, 1H, J = 7.9
Hz), 8.77 (bs, 1H); HRMS (ESI): Calcd for C13H17ON2 [M+H]+ =
217.1335, Found = 217.1332.
190.5 mg (88%, anti/syn mixture = 59/29); brown solid; mp: 84-
1
93 °C; IR (neat): 1617, 1558, 1541 cm-1; H-NMR (400 MHz,
CDCl3): δ = 1.17-1.22 (m, 3H), 2.36 and 2.53 (q, 2H, J = 7.4 Hz),
2.90 and 3.00 (s, 3H), 4.70 and 4.78 (s, 2H), 7.03-7.24 (m, 3H),
7.37 and 7.41 (d, 1H, J = 8.1 Hz), 7.52 and 7.71 (d, 1H, J = 7.8 Hz),
8.24 and 8.36 (bs, 1H); HRMS (ESI): Calcd for C13H17ON2
[M+H]+ = 217.1335, Found = 217.1333.
1-Methyl-3-(N-methyl,N-propionylamino)methylindole
2Bb:
Yield: 139.9 mg (65%, anti/syn mixture = 44/21); brown solid; mp:
111-116 °C; IR (neat): 1653, 1558, 1541 cm-1; 1H-NMR (400 MHz,
CDCl3): δ = 1.16-1.22 (m, 3H), 2.34 and 2.53 (q, 2H, J = 7.4 Hz),
2.91 and 2.99 (s, 3H), 3.77 and 3.77 (s, 3H), 4.68 and 4.74 (s, 2H),
6.88 and 7.05 (s, 1H), 7.10-7.15 (m, 1H), 7.21-7.34 (m, 2H), 7.51
and 7.69 (d, 1H, J = 7.9 Hz); HRMS (ESI): Calcd for C14H19ON2
[M+H]+ = 231.1492, Found = 231.1492.
2-Methyl-3-(N-methyl,N-propionylamino)methylindole
2Bc:
Yield: 149.0 mg (65%, anti/syn mixture = 52/13); yellowish brown
solid; mp: 111-115 °C; IR (neat): 1653, 1558, 1541 cm-1; 1H-NMR
(400 MHz, CDCl3): δ = 1.19 and 1.26 (t, 3H, J = 7.5 Hz), 2.35 and
2.65 (q, 2H, J = 7.5 Hz), 2.40 and 2.44 (s, 3H), 2.82 (s, 3H), 4.64
and 4.77 (s, 2H), 7.05-7.15 (m, 2H), 7.26-7.31 (m, 1H), 7.39 and
7.59 (d, 1H, J = 7.7 Hz), 8.27 and 8.46 (bs, 1H); HRMS (ESI):
Calcd for C14H19ON2 [M+H]+ = 231.1492, Found = 231.1492.
3-(N-Acetyl,N-methylamino)methyl-1,2-dimethylindole
2Ae:
Yield: 153.1 mg (66%, anti/syn = 53/13); pale yellow solid; mp:
92-98 °C; IR (neat): 1616, 1558, 1507 cm-1; 1H-NMR (400 MHz,
CDCl3): δ = 2.10 and 2.36 (s, 3H), 2.39 and 2.44 (s, 3H), 2.76 and
2.83 (s, 3H), 3.67 and 3.69 (s, 3H), 4.66 and 4.77 (s, 2H), 7.07-7.11
(m, 1H), 7.16-7.22 (m,1H), 7.26 and 7.29 (d, 1H, J = 8.2 Hz), 7.43
and 7.62 (d, 1H, J = 7.9 Hz); HRMS (ESI): Calcd for C14H19ON2
[M+H]+ = 231.1492, Found = 231.1493.
3-Methyl-2-(N-methyl,N-propionylamino)methylindole
2Bd:
Yield: 169.6 mg (74%, anti/syn mixture = 73/1); colorless solid;
mp: 124-127 °C; IR (neat): 1627, 1541, 1507 cm-1; 1H-NMR (400
MHz, CDCl3): δ = 1.17 (t, 3H, J = 7.5 Hz), 2.32-2.37 (m, 5H), 2.94
and 3.00 (s, 3H), 4.57 and 4.65 (s, 2H), 7.06-7.10 (m, 1H), 7.14-
7.18 (m, 1H), 7.28-7.30 (m, 1H), 7.50-7.52 (m, 1H), 8.78 (bs, 1H);
HRMS (APCI): Calcd for C14H17ON2 [M-H]+ = 229.1335, Found =
229.1334.
3-(N-Acetyl,N-methylamino)methyl-5-methoxyindole
2Af:
Yield: 127.5 mg (55%, anti/syn mixture = 37/18); brown solid; mp:
113-116 °C; IR (neat): 1616, 1558, 1541, 1211, 1065 cm-1; 1H-
NMR (400 MHz, CDCl3): δ = 2.12 and 2.26 (s, 3H), 2.90 and 2.99
(s, 3H), 3.85 and 3.86 (s, 3H), 4.66 and 4.72 (s, 2H), 6.87 and 6.90
1,2-Dimethyl-3-(N-methyl,N-propionylamino)methylindole
2Be: Yield: 161.3 mg (66%, anti/syn mixture = 56/10); brown
Submitted to the European Journal of Organic Chemistry
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000680
European Journal of Organic Chemistry
solid; mp: 91-95 °C; IR (neat): 1621, 1558, 1507 cm-1; 1H-NMR
(400 MHz, CDCl3): δ =1.18 and 1.26 (t, 3H, J = 7.4 Hz), 2.34 and
2.65 (q, 2H, J = 7.4 Hz), 2.39 and 2.44 (s, 3H), 2.77 and 2.82 (s,
3H), 3.67 and 3.69 (s, 3H), 4.66 and 4.78 (s, 2H), 7.07-7.11 (m,
1H), 7.15-7.19 (m, 1H), 7.25-7.30 (m, 1H), 7.41 and 7.61 (d, 1H, J
= 7.6 Hz); HRMS (ESI): Calcd for C15H21ON2 [M+H]+ = 245.1648,
Found = 245.1647.
5-Methoxy-3-(N-methyl,N-propionylamino)methylindole 2Bf:
Yield: 145.8 mg (59%, anti/syn mixture = 42/17); reddish brown
solid; mp: 118-125 °C; IR (neat): 1653, 1558, 1541, 1049 cm-1; 1H-
NMR (400 MHz, CDCl3): δ = 1.19 and 1.20 (t, 3H, J = 7.5 Hz),
2.36 and 2.54 (q, 2H, J = 7.5 Hz), 2.88 and 3.00 (s, 3H), 3.83 and
3.85 (s, 3H), 4.66 and 4.74 (s, 2H), 6.85 and 6.89 (dd, 1H, J = 8.6,
2.5 Hz), 6.94 and 7.13 (d, 1H, J = 2.3 Hz), 6.99 and 7.19 (d, 1H, J
= 2.3 Hz), 7.25 and 7.29 (d, 1H, J = 8.6 Hz), 8.27 and 8.44 (bs,
1H); HRMS (ESI): Calcd for C14H19O2N2 [M+H]+ = 247.1441,
Found = 247.1441.
3-(N-Formyl,N-methylamino)methylindole 2Ea: Yield: 134.2
mg (71%, anti/syn mixture = 39/32); pale yellow solid; mp: 132-
139 °C; IR (neat): 3675, 2901, 1653, 878, 687 cm-1; 1H-NMR (400
MHz, CDCl3): δ = 2.82 and 2.83 (s, 3H), 4.60 and 4.71 (s, 2H),
7.12-7.17 (m, 1H), 7.20-7.25 (m, 1H), 7.37- 7.42 (m, 1H), 7.53-
7.55 (m, 1H), 7.71-7.73 (m, 1H), 8.13 and 8.43 (s, 1H), 8.17 and
8.25 (bs, 1H); HRMS (ESI): Calcd for C11H13ON2 [M+H]+
189.1022, Found = 189.1024.
=
Typical Procedure for Preparation of Amines 3Aa~3Ea: To a
solution of 3-(N-acetyl,N-methylamino)methylindole 2Aa (0.5
mmol, 101.1 mg) in THF (1.0 mL) was added LiAlH4 (1.0 mmol,
41.3 mg) at room temperature. The mixture was stirred at 70 °C
for 2 h under argon atmosphere. Ice water (10.0 mL) was added to
the reaction mixture. The quenched mixture was filtrated, and then
the product was extracted with CHCl3 (15.0 mL × 3). The organic
layer was dried over Na2SO4. Filtration and removal of the solvent
5-Chloro-2-methyl-3-(N-methyl,N-propionylamino)methyl-
indole 2Bg: Yield: 168.2 mg (64%, anti/syn mixture = 54/10);
purple solid; mp: 124-130 °C; IR (neat): 1615, 1541, 1507 cm-1;
1H-NMR (400 MHz, CDCl3): δ = 1.19 and 1.26 (t, 3H, J = 7.5 Hz),
2.36 and 2.62 (q, 2H, J = 7.5 Hz), 2.40 and 2.45 (s, 3H), 2.79 and
2.83 (s, 3H), 4.59 and 4.71 (s, 2H), 7.06-7.10 (m, 1H), 7.17-7.22
(m, 1H), 7.34 and 7.53 (s, 1H), 8.02 and 8.14 (bs, 1H); HRMS
(ESI): Calcd for C14H18ON235Cl [M+H]+ = 265.1102, Found =
265.1099.
under
reduced
pressure
gave
3-(N-ethyl,N-
methylamino)methylindole 3Aa (88.4 mg, 94%).
3-(N-Ethyl,N-methylamino)methylindole 3Aa: Yield: 88.4 mg
(94%); brown solid; mp: 93-94 °C; IR (neat): 1233, 1209, 1171,
1129, 1093 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.13 (t, 3H, J =
7.2 Hz), 2.25 (s, 3H), 2.49 (q, 2H, J = 7.2 Hz), 3.71 (s, 2H), 7.10-
7.14 (m, 2H), 7.19 (td, 1H, J = 7.0, 1.1 Hz), 7.37 (d, 1H, J = 8.1
Hz), 7.72 (d, 1H, J = 7.9 Hz), 8.07 (bs, 1H); 13C-NMR (100 MHz,
CDCl3): δ = 12.6, 41.7, 51.0, 52.1, 111.0, 112.9, 119.2, 119.3,
121.8, 123.7, 128.0, 136.1; HRMS (ESI): Calcd for C12H17N2
[M+H]+ = 189.1386, Found = 189.1385.
3-(N-Ethyl,N-methylamino)methyl-1-methylindole 3Ab: Yield:
88.9 mg (88%); red oil; IR (neat): 1245, 1199, 1173, 1126, 1061,
1038 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.13 (t, 3H, J = 7.2
Hz), 2.24 (s, 3H), 2.48 (q, 2H, J = 7.2 Hz), 3.69 (s, 2H), 3.77 (s,
3H), 7.00 (s, 1H), 7.09-7.13 (m, 1H), 7.20-7.24 (m, 1H), 7.30 (d,
1H, J = 8.1 Hz), 7.70 (d, 1H, J = 7.9 Hz); 13C-NMR (100 MHz,
CDCl3): δ = 12.6, 32.5, 41.5, 50.9, 51.9, 109.0, 111.2, 118.9, 119.3,
121.3, 128.3, 128.4, 136.8; HRMS (ESI): Calcd for C13H19N2
[M+H]+ = 203.1543, Found = 203.1541.
3-(N-Ethyl,N-methylamino)methyl-2-methylindole 3Ac : Yield:
93.8 mg (93%); reddish brown oil; IR (neat): 1239, 1147, 1056,
1014 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.14 (t, 3H, J = 7.2
Hz), 2.20 (s, 3H), 2.41 (s, 3H), 2.49 (q, 2H, J = 7.2 Hz), 3.59 (s,
2H), 7.05-7.12 (m, 2H), 7.24-7.26 (m, 1H), 7.61-7.63 (m, 1H), 7.84
(bs, 1H); 13C-NMR (100 MHz, CDCl3): δ = 8.4, 12.3, 41.6, 51.4,
52.7, 108.5, 110.5, 118.3, 118.7, 121.3, 129.1, 132.1, 135.4;
HRMS (ESI): Calcd for C13H19N2 [M+H]+ = 203.1543, Found =
203.1543.
1-Methoxy-4-(N-methyl,N-propionylamino)methyl-
naphthalene 2Bh: Yield: 224.3 mg (87%, anti/syn mixture =
57/30); colorless solid; mp: 117-121 °C; IR (neat): 1635, 1541,
1508 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.16 and 1.21 (t, 3H, J
= 7.5 Hz), 2.36-2.42 (m, 2H), 2.79 and 3.05 (s, 3H), 4.01 (s, 3H),
4.92 and 5.00 (s, 2H), 6.75 and 6.78 (d, 1H, J = 7.8 Hz), 7.10 and
7.26 (d, 1H, J = 7.8 Hz), 7.47-7.60 (m, 2H), 7.80 and 8.04 (d, 1H, J
= 7.9 Hz), 8.29-8.31 and 8.34-8.36 (m, 1H); HRMS (ESI): Calcd
for C16H20O2N [M+H]+ = 258.1489, Found = 258.1486.
2-Methoxy-1-(N-methyl,N-propionylamino)methyl-
naphthalene 2Bi: Yield: 236.6 mg (92%, anti/syn mixture =
79/13); colorless solid; mp: 78-84°C; IR (neat): 1653, 1558, 1541
cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.19 and 1.29 (t, 3H, J =
7.4 Hz), 2.35 (q, 2H, J = 7.4 Hz), 2.63 and 2.72 (s, 3H), 3.96 and
3.97 (s, 3H), 4.97 and 5.19 (s, 2H), 7.29 and 7.30 (d, 1H, J = 9.2
Hz), 7.37-7.38 (m, 1H), 7.48-7.52 (m, 1H), 7.78 and 7.82 (d, 1H, J
= 8.1 Hz), 7.83 and 7.87 (d, 1H, J = 9.2 Hz), 7.91 and 8.10 (d, 1H,
J = 8.1 Hz); HRMS (ESI): Calcd for C16H20O2N [M+H]+
258.1489, Found = 258.1488.
=
2-(N-Methyl,N-propionylamino)methyl-1,3,5-trimethoxy-
benzene 2Bj: Yield: 156.5 mg (59%, anti/syn mixture = 45/14);
colorless solid; mp: 61-73 °C; IR (neat): 1698, 1558, 1541, 1507
cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.16 and 1.19 (t, 3H, J =
7.5 Hz), 2.31 and 2.62 (q, 2H, J = 7.5 Hz), 2.70 and 2.71 (s, 3H),
3.78 and 3.79 (s, 6H), 3.82 (s, 3H), 4.46 and 4.64 (s, 2H), 6.12 (s,
2H); HRMS (ESI): Calcd for C14H22O4N [M+H]+ = 268.1543,
Found = 268.1543.
3-(N-Butyryl,N-methylamino)methylindole 2Ca: Yield: 174.1
mg (76%, anti/syn mixture = 52/24); reddish brown solid; mp: 61-
68 °C ; IR (neat): 1653, 1558, 1541, 1507 cm-1; 1H-NMR (400
MHz, CDCl3): δ = 0.95-1.00 (m, 3H), 1.72 (sext, 2H, J = 7.6 Hz),
2.32 and 2.48 (t, 2H, J = 7.6 Hz), 2.90 and 2.99 (s, 3H), 4.71 and
4.77 (s, 2H), 7.03-7.24 (m, 3H), 7.37 and 7.41 (d, 1H, J = 8.1 Hz),
7.53 and 7.71 (d, 1H, J = 7.6 Hz), 8.16 and 8.26 (bs, 1H); HRMS
(ESI): Calcd for C14H19ON2 [M+H]+ = 231.1492, Found =
231.1490.
3-(N-Acetylamino)methylindole 2Da: Yield: 94.1 mg (50%,
anti/syn mixture = 49/1); red solid; mp: 120-126 °C; IR (neat):
3321, 1611, 1542 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.99 and
2.16 (s, 3H), 4.57 and 4.62 (d, 2H, J = 5.2 Hz), 5.63 (bs, 1H), 7.14-
7.19 (m, 2H), 7.22-7.26 (m, 1H), 7.39-7.41 (m, 1H), 7.65 (d, 1H, J
= 7.9 Hz), 8.18 (bs, 1H); HRMS (ESI): Calcd for C11H13ON2
[M+H]+ = 189.1022, Found = 189.1023.
2-(N-Ethyl,N-methylamino)methyl-3-methylindole 3Ad : Yield:
89.1 mg (88%); white solid; mp: 63-66 °C; IR (neat): 1256, 1232,
1206, 1151, 1125, 1008 cm-1; 1H-NMR (400 MHz, CDCl3): δ =
1.09 (t, 3H, J = 7.0 Hz), 2.21 (s, 3H), 2.26 (s, 3H), 2.47 (q, 2H, J =
7.0 Hz), 3.61 (s, 2H), 7.06-7.10 (m, 1H), 7.12-7.16 (m, 1H), 7.29
(d, 1H, J = 7.7 Hz), 7.51 (d, 1H, J = 7.7 Hz), 8.31 (bs, 1H); 13C-
NMR (100 MHz, CDCl3): δ = 8.4, 12.3, 41.6, 51.4, 52.7, 108.5,
110.5, 118.3, 118.7, 121.3, 129.1, 132.1, 135.4; HRMS (ESI):
Calcd for C13H19N2 [M+H]+ = 203.1543, Found = 203.1538.
1,2-Dimethyl-3-(N-ethyl,N-methylamino)methylindole
3Ae:
Yield: 104.3 mg (96%); yellow oil; IR (neat): 1245, 1217, 1135,
1059 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.14 (t, 3H, J = 7.0
Hz), 2.20 (s, 3H), 2.41 (s, 3H), 2.49 (q, 2H, J = 7.0 Hz), 3.62 (s,
2H), 3.67 (s, 3H), 7.06-7.10 (m, 1H), 7.13-7.17 (m, 1H), 7.25 (d,
1H, J = 8.4 Hz), 7.62 (d, 1H, J = 7.7 Hz); 13C-NMR (100 MHz,
CDCl3): δ = 10.5, 12.8, 29.4, 41.7, 51.3, 51.4, 108.0, 108.4, 118.4,
118.9, 120.4, 128.5, 135.2, 136.4; HRMS (ESI): Calcd for
C14H21N2 [M+H]+ = 217.1699, Found = 217.1700.
3-(N-Ethyl,N-methylamino)methyl-5-methoxyindole 3Af: Yield:
107.0 mg (98%); brown solid; mp: 103-106 °C; IR (neat): 1245,
1213, 1172, 1027 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.14 (t,
3H, J = 7.2 Hz), 2.25 (s, 3H), 2.50 (q, 2H, J = 7.2 Hz), 3.67 (s, 2H),
3.87 (s, 3H), 6.85 (dd, 1H, J = 8.8, 2.5 Hz), 7.10 (d, 1H, J = 2.2
Hz), 7.16 (d, 1H, J = 2.5 Hz), 7.24 (d, 1H, J = 8.8 Hz), 8.03 (bs,
Submitted to the European Journal of Organic Chemistry
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000680
European Journal of Organic Chemistry
1H); 13C-NMR (100 MHz, CDCl3): δ = 12.7, 41.7, 51.0, 52.2, 55.8,
101.1, 111.7, 111.9, 112.8, 124.4, 128.4, 131.3, 153.9; HRMS
(ESI): Calcd for C13H19ON2 [M+H]+ = 219.1492, Found =
219.1490.
5-Chloro-3-(N-ethyl,N-methylamino)methyl-2-methylindole
3Ag: Yield: 104.5 mg (88%); pale yellow solid; mp: 135-141 °C;
IR (neat): 1236, 1170, 1150, 1065, 1036, 1011 cm-1; 1H-NMR (400
MHz, CDCl3): δ = 1.14 (t, 3H, J = 7.3 Hz), 2.18 (s, 3H), 2.40 (s,
3H), 2.47 (q, 2H, J = 7.3 Hz), 3.52 (s, 2H), 7.04 (dd, 1H, J = 8.4,
2.0, Hz), 7.15 (d, 1H, J = 8.6 Hz), 7.59 (d, 1H, J = 1.8 Hz), 7.85
(bs, 1H); 13C-NMR (100 MHz, CDCl3): δ = 11.8, 12.7, 41.7, 51.1,
51.5, 109.0, 110.9, 118.1, 121.0, 125.0, 130.5, 133.4, 134.8 ;
HRMS (ESI): Calcd for C13H18N235Cl [M+H]+ = 237.1153, Found
= 237.1150.
3-Methyl-2-(N-methyl,N-propylamino)methylindole 3Bd: Yield:
91.0 mg (84%); pale yellow oil; IR (neat): 1167, 1040, 1007 cm-1;
1H-NMR (400 MHz, CDCl3): δ = 0.90 (t, 3H, J = 7.3 Hz), 1.53
(sext, 2H, J = 7.5 Hz), 2.21 (s, 3H), 2.25 (s, 3H), 2.35 (t, 2H, J =
7.5 Hz), 3.60 (s, 2H), 7.06-7.10 (m, 1H), 7.12-7.16 (m, 1H), 7.29
(td, 1H, J = 7.7, 1.1 Hz), 7.50-7.52 (m, 1H), 8.27 (bs, 1H); 13C-
NMR (100 MHz, CDCl3): δ = 8.4, 11.8, 20.5, 42.2, 53.1, 59.6,
108.4, 110.4, 118.2, 118.7, 121.3, 129.2, 132.2, 135.3; HRMS
(ESI): Calcd for C14H21N2 [M+H]+ = 217.1699, Found = 217.1699.
1,2-Dimethyl-3-(N-methyl,N-propylamino)methylindole
3Be:
Yield: 105.6 mg (92%); yellow oil; IR (neat): 1245, 1211, 1170,
1128 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 0.91 (t, 3H, J = 7.5
Hz), 1.58 (sext, 2H, J = 7.5 Hz), 2.16 (s, 3H), 2.37 (t, 2H, J = 7.5
Hz), 7.41 (s, 3H), 3.60 (s, 2H), 3.66 (s, 3H), 7.05-7.09 (m, 1H),
7.12-7.16 (m, 1H), 7.23-7.25 (m, 1H), 7.63 (d, 1H, J = 7.7 Hz);
13C-NMR (100 MHz, CDCl3): δ = 10.4, 12.0, 20.8, 29.3, 42.2, 51.9,
59.9, 108.3 (2C), 118.4, 118.8, 120.3, 128.5, 135.0, 136.3; HRMS
4-(N-Ethyl,N-methylamino)methyl-1-methoxynaphthalene
3Ah: Yield: 105.4 mg (92%); colorless oil; IR (neat): 1240, 1223,
1158, 1052, 1025 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.16 (t,
3H, J = 7.2 Hz), 2.19 (s, 3H), 2.53 (q, 2H, J = 7.2 Hz), 3.79 (s, 2H), (ESI): Calcd for C15H23N2 [M+H]+ = 231.1856, Found = 231.1854.
3.99 (s, 3H), 6.73 (d, 1H, J = 7.9 Hz), 7.30 (d, 1H, J = 7.9 Hz),
7.45-7.49 (m, 1H), 7.51-7.55 (m, 1H), 8.23 (d, 1H, J = 8.1 Hz),
8.26-8.29 (m, 1H); 13C-NMR (100 MHz, CDCl3): δ = 12.4, 41.7,
51.7, 55.4, 60.0, 102.7, 122.2, 124.4, 124.8, 125.8, 126.4, 126.9,
127.4, 133.3, 155.0; HRMS (ESI): Calcd for C15H20ON [M+H]+ =
230.1539, Found = 230.1535.
1-(N-Ethyl,N-methylamino)methyl-2-methoxynaphthalene 3Ai:
Yield: 114.5 mg (99%); colorless oil; IR (neat): 1247, 1177, 1086,
1058, 1023 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.17 (t, 3H, J =
5-Methoxy-3-(N-methyl,N-propylamino)methylindole
3Bf:
Yield: 92.6 mg (80%); brown solid; mp: 91-96 °C; IR (neat): 1212,
1176, 1087, 1047 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 0.93 (t,
3H, J = 7.3 Hz), 1.58 (sext, 2H, J = 7.5 Hz), 2.22 (s, 3H), 2.38 (t,
2H, J = 7.3 Hz), 3.65 (s, 2H), 3.86 (s, 3H), 6.85 (dd, 1H, J = 8.8,
2.5 Hz), 7.09 (d, 1H, J = 2.5 Hz), 7.18 (d, 1H, J = 2.5 Hz), 7.25 (d,
1H, J = 8.8 Hz), 7.94 (bs,1H); 13C-NMR (100 MHz, CDCl3): δ =
12.0, 20.7, 42.2, 52.8, 55.8, 59.5, 101.3, 111.7, 112.0, 113.1, 124.3,
128.4, 131.4, 153.9; HRMS (ESI): Calcd for C14H21ON2 [M+H]+ =
7.0 Hz), 2.21 (s, 3H), 2.58 (q, 2H, J = 7.3 Hz), 3.93 (s, 2H), 3.94 (s, 233.1648, Found = 233.1646.
3H), 7.27 (d, 1H, J = 8.6 Hz), 7.31-7.35 (m, 1H), 7.46-7.50 (m,
1H), 7.76 (d, 1H, J = 7.5 Hz), 7.78 (d, 1H, J = 9.1 Hz), 8.20 (d, 1H,
J = 8.6 Hz); 13C-NMR (100 MHz, CDCl3): δ = 12.4, 41.5, 50.4,
51.9, 56.5, 113.2, 120.0, 123.3, 124.3, 126.4, 128.1, 129.0, 129.1,
5-Chloro-2-methyl-3-(N-methyl,N-propylamino)methylindole
3Bg: Yield: 115.0 mg (92%); pale yellow solid; mp: 109-111 °C;
IR (neat): 1242, 1216, 1057 cm-1; 1H-NMR (400 MHz, CDCl3): δ =
0.92 (t, 3H, J = 7.0 Hz), 1.57 (sext, 2H, J = 7.5 Hz), 2.15 (s, 3H),
2.36 (t, 2H, J = 7.3 Hz), 2.41 (s, 3H), 3.52 (s, 2H), 7.05 (dd, 1H, J
= 8.6, 2.0 Hz), 7.15-7.17 (m, 1H), 7.59 (d, 1H, J = 2.0 Hz), 7.81
(bs, 1H); 13C-NMR (100 MHz, CDCl3): δ = 11.9, 12.0, 20.7, 42.1,
51.6, 60.0, 109.3, 110.9, 118.2, 121.0, 125.0, 130.5, 133.4, 134.6;
HRMS (ESI): Calcd for C14H20N235Cl [M+H]+ = 251.1310, Found
134.1, 155.5; HRMS (ESI): Calcd for C15H20ON [M+H]+
230.1539, Found = 230.1535.
=
2-(N-Ethyl,N-methylamino)methyl-1,3,5-trimethoxybenzene
3Aj: Yield: 93.1 mg (78%); colorless oil; IR (neat): 1227, 1185,
1060, 1038, cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.12 (t, 3H, J =
7.3 Hz), 2.18 (s, 3H), 2.48 (q, 2H, J = 7.3 Hz), 3.48 (s, 2H), 3.79 (s, = 251.1307.
6H), 3.81 (s, 3H), 6.12 (s, 2H); 13C-NMR (100 MHz, CDCl3): δ =
12.3, 41.7, 47.5, 51.4, 55.2, 55.6 (2C), 90.2 (2C), 107.7 159.9 (2C),
160.3; HRMS (ESI): Calcd for C13H22O3N [M+H]+ = 240.1594,
Found = 240.1592.
1-Methoxy-4-(N-methyl,N-propylamino)methylnaphthalene
3Bh: Yield: 110.6 mg (91%); pale yellow oil; IR (neat): 1240,
1225, 1158, 1054, 1023 cm-1; 1H-NMR (400 MHz, CDCl3): δ =
0.90 (t, 3H, J = 7.5 Hz), 1.59 (sext, 2H, J = 7.5 Hz), 2.17 (s, 3H),
2.41 (t, 2H, J = 7.3 Hz), 3.79 (s, 2H), 4.00 (s, 3H), 6.73 (d, 1H, J =
7.9 Hz), 7.29 (d, 1H, J = 7.7 Hz), 7.44-7.48 (m, 1H), 7.50-7.54 (m,
1H), 8.24-8.28 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ = 12.0,
20.5, 42.1, 55.4, 60.1, 60.7, 102.7, 122.1, 124.6, 124.9, 125.8,
126.3, 127.1, 127.4, 133.3, 155.0; HRMS (ESI): Calcd for
C16H22ON [M+H]+ = 244.1696, Found = 244.1693.
2-Methoxy-1-(N-methyl,N-propylamino)methylnaphthalene
3Bi: Yield: 103.4 mg (85%); yellow oil; IR (neat): 1147, 1085,
1057, 1023 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 0.90 (t, 3H, J =
7.3 Hz), 1.61 (sext, 2H, J = 7.5 Hz), 2.19 (s, 3H), 2.47 (t, 2H, J =
7.3 Hz), 3.92 (s, 2H), 3.94 (s, 3H), 7.27 (d, 1H, J = 7.9 Hz), 7.31-
7.35 (m, 1H), 7.46-7.50 (m, 1H), 7.76 (d, 1H, J = 7.7 Hz), 7.78 (d,
1H, J = 8.8 Hz), 8.21 (d, 1H, J = 8.6 Hz); 13C-NMR (100 MHz,
CDCl3): δ = 12.0, 20.4, 41.9, 51.0, 56.6, 60.4, 113.3, 123.3 (2C),
124.4, 126.4, 128.0, 129.1 (2C), 134.1, 155.6; HRMS (ESI): Calcd
for C16H22ON [M+H]+ = 244.1696, Found = 244.1693.
3-(N-Methyl,N-propylamino)methylindole 3Ba : Yield: 81.9 mg
(81%); pale yellow solid; mp: 75-78 °C; IR (neat): 1231, 1066,
1004 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 0.91 (t, 3H, J = 7.3
Hz), 1.58 (sext, 2H, J = 7.5 Hz), 2.23 (s, 3H), 2.38 (t, 2H, J = 6.6
Hz), 3.70 (s, 2H), 7.10-7.14 (m, 2H), 7.19 (td, 1H, J = 7.0, 1.1 Hz),
7.4 (d, 1H, J = 8.2 Hz), 7.73 (d, 1H, J = 7.7 Hz), 8.11 (bs, 1H);
13C-NMR (100 MHz, CDCl3): δ = 12.0, 20.7, 42.2, 52.5, 59.5,
111.0, 113.0, 119.3 (2C), 121.7, 123.6, 128.0, 136.1; HRMS (ESI):
Calcd for C13H19N2 [M+H]+ = 203.1543, Found = 203.1541.
1-Methyl-3-(N-methyl,N-propylamino)methylindole 3Bb: Yield:
89.5mg (83%); pale yellow oil; IR (neat): 1244, 1197, 1157, 1126,
1063, 1010 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 0.91 (t, 3H, J =
7.3 Hz), 1.57 (sext, 2H, J = 7.7 Hz), 2.22 (s, 3H), 2.37 (t, 2H, J =
7.7 Hz), 3.68 (s, 2H), 3.77 (s, 3H), 6.98 (s, 1H), 7.09-7.13 (m, 1H),
7.20-7.24 (m, 1H), 7.29 (td, 1H, J = 8.4, 0.9 Hz), 7.70 (td, 1H, J =
7.9, 0.9 Hz); 13C-NMR (100 MHz, CDCl3): δ = 12.0, 20.7, 32.6,
42.2, 52.5, 59.4, 109.0, 111.8, 118.8, 119.5, 121.3, 128.2, 128.4,
136.9; HRMS (ESI): Calcd for C14H21N2 [M+H]+ = 217.1699,
Found = 217.1697.
2-(N-Methyl,N-propylamino)methyl-1,3,5-trimethoxybenzene
3Bj: Yield: 112.3mg (89%); colorless oil; IR (neat): 1227, 1203,
1042, 1011 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 0.90 (t, 3H, J =
7.5 Hz), 1.58 (sext, 2H, J = 7.7 Hz), 2.18 (s, 3H), 2.37 (t, 2H, J =
7.7 Hz), 3.47 (s, 2H), 3.79 (s, 6H), 3.81 (s, 3H), 6.12 (s, 2H); 13C-
NMR (100 MHz, CDCl3): δ = 12.0, 20.3, 42.3, 47.7, 55.2, 55.6
(2C), 60.1, 90.2 (2C), 107.8, 159.9 (2C), 160.3; HRMS (ESI):
2-Methyl-3-(N-methyl,N-propylamino)methylindole 3Bc: Yield:
100.0 mg (86%); colorless solid; mp: 94-96 °C; IR (neat): 1241,
1065, 1057, cm-1; 1H-NMR (400 MHz, CDCl3): δ = 0.91 (t, 3H, J =
7.2 Hz), 1.58 (sext, 2H, J = 7.6 Hz), 2.17 (s, 3H), 2.37 (t, 2H, J =
7.6 Hz), 2.42 (s, 3H), 3.58 (s, 2H), 7.05-7.12 (m, 2H), 7.25-7.27 (m, Calcd for C14H24O3N [M+H]+ = 254.1751, Found = 254.1746.
1H), 7.62-7.64 (m, 1H), 7.80 (bs, 1H); 13C-NMR (100 MHz,
CDCl3): δ = 11.9, 12.0, 20.8, 42.2, 51.6, 59.9, 109.2, 109.9, 118.7,
119.3, 120.8, 129.4, 133.1, 135.0; HRMS (ESI): Calcd for
C14H21N2 [M+H]+ = 217.1699, Found = 217.1697.
3-(N-Butyl,N-methylamino)methylindole 3Ca: Yield: 89.0 mg
(82%); pale yellow solid; mp: 58-65 °C; IR (neat): 1236, 1194,
1107, 1072, 1011 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 0.91 (t,
3H, J = 7.3 Hz), 1.34 (sext, 2H, J = 7.3 Hz), 1.50-1.58 (m, 2H),
Submitted to the European Journal of Organic Chemistry
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000680
European Journal of Organic Chemistry
16222. (i) R. S. J. Proctor, R. J. Phipps, Angew. Chem. Int. Ed. 2019,
58, 13666-13699.
2.23 (s, 3H), 2.42 (t, 2H, J = 7.3 Hz), 3.70 (s, 2H), 7.10-7.11 (m,
1H), 7.12-7.14 (m, 1H), 7.17-7.21 (m, 1H), 7.35 (d, 1H, J = 8.2
Hz), 7.72 (d, 1H, J = 7.9 Hz), 8.12 (bs, 1H); 13C-NMR (100 MHz,
CDCl3): δ = 14.1, 20.7, 29.7, 42.3, 52.6, 57.3, 111.0, 113.2, 119.4
(2C), 121.8, 123.5, 128.0, 136.1; HRMS (ESI): Calcd for C14H21N2
[M+H]+ = 217.1699, Found = 217.1696.
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3-(N-Ethylamino)methylindole 3Da: Yield: 81.6 mg (94%);
1
colorless oil; IR (neat): 3409, 1645, 1620, 1549 cm-1; H-NMR
(400 MHz, CDCl3): δ = 1.15 (t, 3H, J = 7.3 Hz), 1.44 (bs, 1H), 2.77
(q, 2H, J = 7.3 Hz), 4.00 (d, 2H, J = 0.45 Hz), 7.11-7.16 (m, 2H),
7.19-7.23 (m, 1H), 7.37 (d, 1H, J = 8.2 Hz), 7.67 (d, 1H, J = 7.9
Hz), 8.07 (bs, 1H); 13C-NMR (100 MHz, CDCl3): δ = 15.2, 43.8,
44.5, 111.2, 114.7, 118.5, 119.3, 121.9, 122.6, 127.0, 136.3;
HRMS (ESI): Calcd for C11H15N2 [M+H]+ = 175.1230, Found =
175.1228.
3-(N,N-Dimethylamino)methylindole 3Ea: Yield: 83.1 mg
(95%); pale yellow solid; mp: 123-128 °C; IR (neat): 1250, 1065,
1057 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 2.29 (s, 6H), 3.63 (s,
2H), 7.11-7.15 (m, 2H), 7.18-7.22 (m, 1H), 7.37 (td, 1H, J = 8.1,
0.9 Hz), 7.70-7.72 (m, 1H), 8.10 (bs, 1H); 13C-NMR (100 MHz,
CDCl3): δ = 45.3 (2C), 54.4, 111.1, 112.9, 119.1, 119.4, 121.8,
123.8, 127.8, 136.1; HRMS (ESI): Calcd for C11H15N2 [M+H]+ =
175.1230, Found = 175.1227.
Supporting Information (see footnote on the first page of this article): … .
Copies of 1H NMR spectra of all hemiaminal derivatives 1A~1E and
amides 2Aa~2Ea, and 1H NMR and 13C NMR spectra of all amines
3Aa~3Ea.
Acknowledgments
This work was supported by JSPS KAKENHI Grant Number JP18K05118
in Japan.
____________
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Received: ((will be filled in by the editorial staff))
Published online: ((will be filled in by the editorial staff))
Submitted to the European Journal of Organic Chemistry
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000680
European Journal of Organic Chemistry
Layout 2:
(Aminals and Indoles bearing Amino
Group)
R'
R'
R'
Me
Me
O
O
O
N
H
LiAlH4
BPO
N
N
O
Kohei Nakamura, Hideo Togo*……....
N
O
Ph
N
R
R
Hg-hν or
80 °C
THF, 70 °C
R
R
N
H
(CF3)2CHOH,
r.t.
N
H
Page No. – Page No.
5 examples
up to 84% yield
Novel Preparation of Aminals
23 examples
up to 99%
23 examples
up tp 93%
Nobel Preparation of Hemiaminal
Derivatives with BPO and N,N-
Dimethylamides, and Their Synthetic
Use for (Aminomethyl)indoles
Hemiaminal derivatives could be
obtained in good yields by the reaction of
BPO and N,N-dimethylamides under
irradiation or warming condition. By
using the hemiaminal derivatives, indoles
smoothly obtained by the reduction of the
indoles bearing (N-acyl,N-
methylamino)methyl group that were
obtained through the Friedel-Crafts
alkylation reaction of indoles and the
hemiaminal derivatives.
a
Keywords: (BPO / Hemiaminal /
Friedel-Crafts Alkylation / Amide /
(Aminomethyl)indole)
bearing
a
(N-alkyl,N-
methylamino)methyl group could be
Submitted to the European Journal of Organic Chemistry
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000680
European Journal of Organic Chemistry
Supporting Information
((Please insert the Supporting Information here))
Submitted to the European Journal of Organic Chemistry
11
This article is protected by copyright. All rights reserved.