Substitution of the Dimethylamino Group in Gramines and One-Pot Cyclization to Tetrahydro-β-carbolines Using a Triazine-Based Activating Agent

Article abstract of DOI:10.1021/acs.joc.9b00039

A new method for the substitution of 3-[(dimethylamino)methyl]indoles (gramines) with malonate-based nucleophiles was developed using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) as the activating agent for the dimethylamino group. The reaction was completed in 1.5-6 h at room temperature in the presence of a tert-amine base and lithium salt. CDMT afforded superior results to methyl iodide, a common activating agent for the dimethylamino group in Mannich bases, particularly in the reactions of 1-substituted gramines. The reactivity of the possible intermediates, bis(indol-3-ylmethyl)dimethylammonium salts, was examined to obtain mechanistic insights on the reaction. This substitution method with CDMT enabled the sequential transformation of gramines: substitution with (N-alkylidene)aminomalonates followed by the Pictet-Spengler reaction under acidic conditions afforded 1,2,3,4-tetrahydro-β-carboline derivatives in one pot.

Full text of DOI:10.1021/acs.joc.9b00039

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Article
Substitution of the Dimethylamino Group in
Gramines and One-Pot Cyclization to Tetrahydro-#-
carbolines Using a Triazine-Based Activating Agent
Hikaru Fujita, Riho Nishikawa, Ozora Sasamoto, Masanori Kitamura, and Munetaka Kunishima
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00039 • Publication Date (Web): 14 Jun 2019
Downloaded from http://pubs.acs.org on June 14, 2019
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Substitution of the Dimethylamino Group in Gramines and One-Pot Cyclization to
Tetrahydro-β-carbolines Using a Triazine-Based Activating Agent
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Hikaru Fujita, Riho Nishikawa, Ozora Sasamoto, Masanori Kitamura, and Munetaka Kunishima*
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
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Table of Contents
OMe
EtO2C
CO2Et
N
N
Cl
N
R3
+
CO2Et
CO2Et
R3
CO2Et
CO2Et
NH
OMe
NMe2
R2
R2
R2
CDMT
Et3N or iPr2EtN
Li salt
TFA
Ar
N
N
R1
N
R1
R1
one-pot
MeCN/THF, rt
(R3 = NCHAr)
Abstract
A new method for the substitution of 3-[(dimethylamino)methyl]indoles (gramines) with malonate-based
nucleophiles was developed using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) as the activating agent for the
dimethylamino group. The reaction was completed in 1.5–6 h at room temperature in the presence of a tert-amine
base and lithium salt. CDMT afforded superior results to methyl iodide, a common activating agent for the
dimethylamino group in Mannich bases, particularly in the reactions of 1-substituted gramines. The reactivity of the
possible intermediates, bis(indol-3-ylmethyl)dimethylammonium salts, was examined to obtain mechanistic insights
of the reaction. This substitution method with CDMT enabled the sequential transformation of gramines: substitution
with (N-alkylidene)aminomalonates followed by the Pictet-Spengler reaction under acidic conditions afforded
1,2,3,4-tetrahydro-β-carboline derivatives in one-pot.
Introduction
The Mannich reaction introduces a C1 unit to various nucleophilic species through electrophilic
aminomethylation. The (dimethylamino)methylation reaction with formaldehyde–dimethylamine1 or Eschenmoser's
salt2 is a representative of the Mannich reaction. The resulting aminomethylated products are referred to as Mannich
bases, which have established utility in organic syntheses owing to their ready accessibility and unique reactivity.3
We have recently reported the efficient elimination of the dimethylamino group in Mannich bases derived from esters
using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) as the activating agent (Figure 1a).4 CDMT was clearly
superior to methyl iodide, a classical reagent used to activate the dimethylamino group. Elimination via an N-
triazinylammonium intermediate was completed within a short reaction time (15 min) at room temperature owing to
the high leaving group ability of triazinylamine 1. In addition, CDMT reacted with the dimethylamino group
chemoselectively, even in the presence of tertiary amines such as Et3N. This was due to a previously reported type
of steric hindrance known as the gauche β-alkyl group effect.5–7 Thus, due to the mild reaction conditions and high
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chemoselectivity of CDMT, this methodology was applied to intermolecular substitution reactions of Mannich bases
in the presence of a nucleophile. This paper describes the substitution reactions of gramine derivatives (2) with
CDMT (Figure 1b). Gramines, the Mannich bases from indoles, are a versatile synthetic intermediate for indole
derivatives.8 Furthermore, this paper reports the one-pot substitution/cyclization of gramines for the preparation of
tetrahydro-β-carbolines, an important class of indole alkaloids.9
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(b) this work
NMe2
(a) previous work
NMe2
R4
R1O
R2
N
R3
O
2
OMe
N
N
N
Cl
OMe
CDMT
MeO
N
MeO
N
N
N
OMe
OMe
N
N
Cl
O
Cl
N
N
R4
Me
Me
Me
R2
Me
R1O
N
R3
Et3N
NuH
, Et3N
OMe
N
N
Me2N
elimination
substitution
N
OMe
1
Nu
R4
R1O
R2
N
R3
O
Figure 1. Activation of the dimethylamino group in Mannich bases using 2-chloro-4,6-dimethoxy-1,3,5-triazine
(CDMT): (a) elimination to form α,β-unsaturated esters (previous work) and (b) substitution of gramines (this work).
Results and Discussion
N-protected aminomalonates are widely-used as nucleophiles toward gramines in the synthesis of
tryptophan derivatives.10–15 Thus, the reaction between unsubstituted gramine 2a (Table 1) and N-Boc-
aminomalonate 3a was first studied. A traditional method for this substitution involves heating without activation of
the dimethylamino group, typically by refluxing in toluene with NaOH12,14,16–19 or in acetonitrile with
tributylphosphine.17,20–22 Since the leaving group ability of dimethylamine is poor, harsh thermal conditions are
inevitable. Another traditional method relies on the alkylation of the dimethylamino group with alkylating agents
such as methyl iodide,10,13,16,23,24 ethyl iodide,11,25 and dimethyl sulfate.11,25–30 However, this method typically requires
heating (>78 °C),10,11,13,16,24,25 a long reaction time (overnight or >20 h),10,16,23–25,27 and a two-step procedure10,13,16,23,24
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or prior triisopropylsilyl-protection of the indole nitrogen atom.31–33 In 2007, Williams and coworkers reported the
use of ethyl propiolate as an activating agent for the dimethylamino group.34 Although the substitution of gramines
with this reagent took place at room temperature, moderate yields (42−65%, seven examples) were observed for the
substitution with 3a. Therefore, the development of a mild high-yielding gramine substitution method is still desirable.
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Table 1. Screening of solvents and salt additives for the synthesis of 4aa from 2a and 3a using 2-chloro-4,6-
dimethoxy-1,3,5-triazine (CDMT).
EtO2C
CO2Et
CO2Et
CO2Et
NHBoc
NHBoc
(1.1 equiv)
NMe2
3a
CDMT (1.1 equiv)
Et3N (2 equiv), additive
N
H
N
H
2a
4aa
MeCN, rt
entry solvent additive (equiv) time (h)
yield (%)a
28
1
CH2Cl2
THF
-
-
-
-
24
24
24
24
4
2
8
3
EtOH
MeCN
49
4
52
5
MeCN LiClO4 (1.1)
MeCN LiCl (1.1)
MeCN LiBr (1.1)
MeCN LiI (1.1)
100
95
6
4
7
4
100
93
8
4
9
MeCN LiCl (0.1)
MeCN LiClO4 (0.1)
MeCN NaClO4 (1.1)
MeCN NaCl (1.1)
MeCN MgSO4 (0.1)
CH2Cl2 LiCl (0.1)
4
92 (91)b
80
10
11
12
13
14
15
16
17
18c
19d
20e
4
24
24
4
41
72
45
4
48
THF
Et2O
LiCl (0.1)
LiCl (0.1)
4
65
4
trace
trace
7
toluene LiCl (0.1)
MeCN LiClO4 (1.1)
MeCN LiClO4 (1.1)
MeCN LiClO4 (1.1)
4
4
24
24
10
69
aThe yield was calculated from 1H NMR spectroscopic analysis using p-nitrotoluene as the internal standard. bIsolated
yield. cThe reaction was carried out without CDMT. dThe reaction was carried out using Et3NHCl (1.1 equiv) instead
of CDMT. eThe reaction was carried out using methyl iodide (1.1 equiv) instead of CDMT.
When a mixture of 2a (1 equiv) and 3a (1.1 equiv) was treated with CDMT (1.1 equiv) in the presence of
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Et3N (2 equiv) in CH2Cl2, desired product 4aa formed at room temperature after 24 h; however, only in 28% yield
(Table 1, entry 1). After brief screening of the reaction solvent (entries 2–4), the yield of 4aa improved to 52% (entry
4, in MeCN). Next, lithium cations (LiClO4; 1.1 equiv) were added to the reaction mixture to promote the nucleophilic
attack of the malonates.35,36 This afforded a quantitative yield with a shorter reaction time (4 h, entry 5). The addition
of lithium halides also provided high yields (LiCl, 95%, entry 6; LiBr, 100%, entry 7; and LiI, 93%, entry 8).
Furthermore, a 91% yield was obtained with 0.1 equiv of LiCl (entry 9), while LiClO4 (0.1 equiv) afforded the
product in 80% yield (entry 10). Conversely, sodium and magnesium salts (NaClO4, NaCl, and MgSO4) did not
afford 4aa in high yield (41–72%, entries 11–13, respectively).37 Trace to moderate yields were obtained with LiCl
(0.1 equiv) in CH2Cl2, THF, Et2O, and toluene (entries 14–17, respectively). When the substitution reaction was
carried out in MeCN with LiClO4 (1.1 equiv) in the absence of CDMT, 4aa only formed in 7% yield after 4 h (entry
18). The addition of Et3NHCl (1.1 equiv) produced almost no effect (10% yield, entry 19). These observations
indicated that CDMT plays an important role in the gramine substitution reaction. When methyl iodide (1.1 equiv)
was used instead of CDMT, the yield remained at 69%, even after 24 h (entry 20), suggesting that CDMT is a better
activator than methyl iodide.
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The results in Table 1 reveal that LiCl acted as an effective catalyst under the conditions listed in entry 9.
Thus, the reaction conditions listed in entry 9 were used in the subsequent investigations. Figure 2 illustrates the
substitution reactions between various gramines and malonates. Here, MeCN/THF (8:1) was used as the solvent; for
convenience, a stock solution of LiCl in THF was prepared in advance and used for a series of the experiments.
Gramines comprising a chloro (4-Cl, 2b; 5-Cl, 2c) or alkoxy (5-BnO, 2d; 4-MeO, 2e; and 5-MeO, 2f) group reacted
with 3a to afford 4ba–4fa, respectively, in 90–97% yield. The reaction times for chlorogramines 2b,c (5 h) were
longer than those for alkoxygramines 2d–f (1.5–3 h). Additionally, the substitution of 2-methylgramine (2g) and 2-
phenylgramine (2h) with 3a provided 4ga and 4ha in 99% and 98% yield, respectively. Compared to the reported
synthesis of 4ba–4ha from 2b–h, respectively, and 3a with ethyl propiolate,34 this proposed method improved the
yields by 27–55%. The reaction with 3-[1-(dimethylamino)ethyl]indole (2i) afforded the product 4ia in 43% yield.
The moderate yield of 4ia could be due to the sensitivity of CDMT to the steric hindrance around the dimethylamino
group.5 The substitution of 2a with N-Cbz-protected aminomalonate 3b, diethyl malonate (3c), and diethyl
methylmalonate (3d) was also carried out. In this case, the desired products, 4ab–ad, respectively, were obtained in
88–95% yield. For the synthesis of 4ac, 2.5 equivalents of 3c was used to suppress the disubstitution side reaction.
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EtO2C
CO2Et
R2
(1.1 equiv)
CDMT (1.1 equiv)
Et3N (2 equiv)
5
6
7
8
CO2Et
CO2Et
R2
3a–d
R1
R1
NMe2
LiCl (0.1 equiv)
N
H
2a–h
N
9
H
MeCN/THF (8:1)
rt
a
10
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4
, time, yield
CO2Et
CO2Et
CO2Et
CO2Et
NHBoc
NHBoc
Cl
N
H
N
H
Cl
4ba
, 5 h, 97%
4ca
, 5 h, 90%
CO2Et
CO2Et
CO2Et
CO2Et
NHBoc
NHBoc
MeO
N
H
N
H
BnO
MeO
4da
, 3 h, 92%
4ea
, 1.5 h, 97%
CO2Et
CO2Et
CO2Et
CO2Et
NHBoc
NHBoc
Me
4ga
N
H
N
H
b
4fa
, 1.5 h, 95%
, 2.5 h, 99%
CO2Et
CO2Et
CO2Et
CO2Et
Me
NHBoc
NHBoc
Ph
4ha
N
H
N
H
4ia
, 1.5 h, 98%
, 5 h, 43%
CO2Et
CO2Et
CO2Et
CO2Et
NHCbz
H
N
H
N
H
c
4ab
4ac
, 3 h, 88%
, 4 h, 95%
CO2Et
CO2Et
Me
N
H
d
4ad
, 6 h, 91%
a
Figure 2. Substitution of the dimethylamino group with various gramines and diethyl malonates. Isolated yield.
bThe reaction was carried out in MeCN with LiCl (1.1 equiv). cMalonate 3c (2.5 equiv) was used. dThe reaction was
carried out in MeCN with Et3N (3 equiv) and LiCl (1.1 equiv).
Scheme 1 illustrates the CMDT-promoted substitution of 2a with potassium cyanide as a nucleophile. 3-
(Cyanomethyl)indole (4ae) was obtained in 83% yield using 18-crown-6 as a solubilizing agent for the nucleophile.
NMe2
CN
KCN (1.1 equiv)
CDMT (1.1 equiv)
Et3N (1 equiv)
18-crown-6 (1.1 equiv)
N
H
N
H
MeCN, rt, 1 h
2a
4ae
, 83%
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Scheme 1. Substitution reaction between gramine 2a and potassium cyanide promoted by CDMT.
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Gramines bearing a Boc or methyl group at the indole nitrogen were next examined. These substitution
reactions are more challenging than those of 1-unsubstituted gramines. Studies have reported that the dimethylamino
group of 1-Boc-gramines was converted into a chloro group in the first step and the resulting unstable 1-Boc-(3-
chloromethyl)indole intermediate was immediately used for the next substitution step.38,39 The substitution of 1-
alkylgramines also required a multi-step procedure that included pre-activation of the dimethylamino group with
methyl iodide, isolation of the resulting ammonium salt, and heating of the salt at high temperature in the presence
of a malonate anion.40–46 Thus, it is worth developing a one-step conversion of such 1-substituted gramines under
mild conditions.
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When CDMT was added in one portion to a mixture of 1-Boc-gramine 2j and 3a in MeCN in the presence
of LiCl and i-Pr2EtN, the substitution reaction proceeded at room temperature to afford desired product 4ja in 39%
yield (Table 2, entry 1). Careful analysis of the crude mixture suggested that 1-Boc-(3-chloromethyl)indole (5j) was
still present (33% yield); however, it could not be isolated because of its instability.47 As iodide salts can catalyze
nucleophilic substitution reactions, LiI was employed in the reaction instead of LiCl (entry 2); however, the yield of
4ja was unchanged. In this case, 5j was not detected but dimeric ammonium salt 6j (22% yield) was found in the
crude mixture. This byproduct is probably formed from two molecules of 2j. Therefore, 2j was added dropwise over
1 h (entry 3) to maintain a low concentration of 2j during the reaction. As a result, a 78% yield of 4ja was achieved
by suppressing the side reaction that forms 6j (7% yield). Similar trends were observed for the substitution of 1-
methylgramine (2k). The yield of 4ka was 28% when CDMT was added in one portion (entry 4). On the other hand,
the product was obtained in 84% yield following the dropwise addition of 2k (entry 5). The substitution of 2j and 2k
with methyl iodide as the activating agent was also attempted. However, the respective desired products 4ja and 4ka
did not form after 24 h (entries 6 and 7, respectively). These results again indicated the superiority of CDMT to
methyl iodide for the gramine substitution reaction.
Table 2. Substitution of gramines bearing a Boc or methyl group at the indole nitrogen.
CO2Et
CO2Et
NHBoc
3a
(1.1 equiv)
activating agent (1.1 equiv)
NMe2 Cl
NMe2
Cl
iPr2EtN (2 equiv)
LiX (1.1 equiv)
+
+
N
R
N
R
N
R
N
MeCN, rt
R
2
2
4
5
6
entry gramine 2 (addition method)
activating agent
X
time
(h)
4 (%)a
5 (%)a 6 (%)a
(addition method)
1
2
3
4
5
2j, R = Boc
2j, R = Boc
CDMT (one portion)
CDMT (one portion)
Cl 20
4ja, 39
4ja, 39
5j, 33
5j, ndb 6j, 22c
6j, ndb
I
I
I
I
20
6
2j, R = Boc (dropwise over 1 h) CDMT
4ja, 78d 5j, ndb 6j, 7c
e
e
2k, R = Me
CDMT (one portion)
25
5
4ka, 28
-
-
-
-
e
e
2k, R = Me (dropwise over 1 h) CDMT
4ka, 84d
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e
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2k, R = Boc (dropwise over 1 h) MeI
2k, R = Me (dropwise over 1 h) MeI
I
I
24
24
4ka, ndb
4ka, ndb
-
-
-
-
aThe yields were calculated from 1H NMR spectroscopic analysis unless otherwise noted. bNot detected. cThe counter
anion was assumed to be a chloride ion because the reaction mixture was washed with brine after quenching. dIsolated
yield. eNot determined.
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The formation of 6j (entries 2 and 3, Table 2) implied the intermediacy of the analogous dimeric ammonium
salts in the reaction of 1-unsubstituted gramines such as 2a. In fact, bis(indol-3-ylmethyl)dimethylammonium
chloride (7) was isolated in 97% yield upon treating 2a with CDMT (0.5 equiv) for 1 h in the absence of the
nucleophile (Figure 3a). The formation of the same ammonium salt paired with iodide is known as a side reaction of
the gramine methiodide preparation.48–51 Salt 7 is active for the substitution as it reacted with 3a smoothly to afford
4aa in 83% yield. Thus, a plausible reaction mechanism of the substitution between 2a and 3a (Figure 3b) was
proposed taking these facts into account: in the first step, CDMT activates the dimethylamino group in 2a to generate
triazinylammonium salt 8a. Due to the high leaving group ability of 1, the indole NH proton in 8a will be easily
deprotonated by Et3N to afford 3-methyleneindolenine 9, which is a key intermediate of the gramine substitution
reactions.8,52,53 Ammonium salt 7 is formed if 9 is captured by 2a. Although this reaction is under equilibrium, the
regeneration of 9 from 7 will be slower than its formation from 8a. LiCl probably facilitates the deprotonation of 3a
to produce lithium complex 10, which reacts with 9 to afford 4aa. Triazinylammonium salt 8a may be directly
converted to 2a and 4aa.
Similar to 2a, 2j provided the corresponding dimeric ammonium chloride 6j in 91% yield in the absence
of the nucleophile (Figure 3c). However, 6j was completely inert toward substitution by 3a. Therefore, the reaction
mechanism of the substitution of 2j is described by the pathway presented in Figure 3d. Triazinylammonium salt 8j,
which is generated from 2j and CDMT, releases 1 to form 5j. On the basis of previous studies, decomposition of the
triazinylammonium chloride is expected to be fast because the chloride would rapidly attack the activated benzylic
position of the triazinylammonium salts in the aprotic solvents.54,55 The electrophilicity of 5j is not sufficient to react
with 10 or 2j under the set reaction conditions. This is supported by the presence of unreacted 5j (entry 1, Table 3).
On the other hand, once the chloro group in 5j is replaced by an iodide group, the resulting intermediate 5j-I can be
attacked by 10 and 2j to form 4ja and 6j-I, respectively. As the formation of 6j-I is irreversible, the undesired reaction
between 5j-I and 2j should be suppressed by the dropwise addition of 2j. The possibility of the direct conversion of
8j into 5j-I and 4ja cannot be excluded. The substitution of 2k may occur in an analogous manner because similar
results were observed for 2j and 2k (Table 3).
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CO2Et
CO2Et
(a)
3a
(2.2 equiv)
NMe2
NMe2
Cl
CDMT (1.2 equiv)
Et3N (4.0 equiv)
LiCl (0.2 equiv)
NHBoc
CDMT (0.5 equiv)
Et3N (1.1 equiv)
7
8
9
N
H
N
H
N
MeCN
rt, 1 h, 97%
MeCN/THF = 8:1
rt, 4 h, 83%
H
2
2a
7
4aa
10
11
12
13
14
15
16
17
18
19
20
21
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45
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49
50
51
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53
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(b)
NMe2
Cl
2a
2a
2a
N
–
H
2
MeO
N
7
N
NMe2
OMe
N
CDMT
Et3N
Cl
N
Me
Me
N
H
2a
N
1
9
N
H
8a
CO2Et
CO2Et
10
Li
NHBoc
O
O
LiCl
3a
EtO
OEt
N
H
NEt3
NHBoc
10
4aa
CO2Et
CO2Et
(c)
3a
(2.2 equiv)
NMe2
Cl
NMe2
CDMT (1.2 equiv)
iPr2EtN (4.0 equiv)
LiI (0.2 equiv)
NHBoc
CDMT (0.5 equiv)
N
N
N
MeCN
rt, 3 h, 0%
MeCN
rt, 3 h, 91%
Boc
2
Boc
Boc
4ja
2j
6j
(d)
MeO
N
N
OMe
NMe2
Cl
N
CDMT
Cl
N
Me
Me
N
N
Boc
2j
Boc
N
5j
Boc
8j
1
I
Cl
I
10
CO2Et
CO2Et
NHBoc
NMe2
I
I
2j
10
N
N
N
Boc
2
Boc
4ja
Boc
5j-I
6j-I
Figure 3. Mechanistic considerations: (a) isolation of 7 and its conversion into 4aa. (b) Plausible reaction mechanism
of the substitution of 2a to 4aa with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT). (c) Isolation of 6j and an attempt
at its conversion into 4ja. (d) Plausible reaction mechanism of the substitution of 2j to 4ja with CDMT.
With the proposed substitution method for gramines in hand, 1-(2-hydroxyphenyl)-1,2,3,4-tetrahydro-β-
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carboline derivatives56–58 was next synthesized from gramines in one-pot (Table 3). To the best of our knowledge,
the one-pot synthesis of tetrahydro-β-carbolines from gramines has not been reported, likely due to limitations of the
traditional gramine substitution methods. N-[(2-Hydroxybenzylidene)amino]malonate 11, which is readily available
and easy-to-handle, was used as the nucleophile for the reaction. After treating 2a with 11 under the standard
conditions for gramine substitution with CDMT, trifluoroacetic acid (TFA, 5 equiv) was added at room temperature
to induce the Pictet-Spengler reaction. This afforded tetrahydro-β-carboline 12a in 93% yield (entry 1). Similarly,
gramines with a chloro or alkoxy group at the 5 or 6 position (5-Cl, 2b; 6-BnO, 2d; and 5-MeO, 2e) were converted
into the corresponding tetrahydro-β-carbolines (76%, entry 2; 78%, entry 3; and 100%, entry 4, respectively).
Cyclization to 12b was carried out at 50 °C with TFA (10 equiv). Additionally, 1-methyl derivative 12k was
successfully prepared from 2k in 48% yield, although a higher temperature (80 °C) was required for the cyclization
step. The reaction between 2a and 11-Br bearing a 5-bromo-2-hydroxypheny group afforded the corresponding
tetrahydro-β-carboline 12a-Br in 83% yield.
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13
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Table 3. One-pot synthesis of tetrahydro-β-carbolines 12 from gramines.
(1)
CO2Et
CO2Et 11 (R4 = H) or 11-Br ( R4 = Br)
(1.1 equiv)
R4
N
CO2Et
CO2Et
NMe2
OH
R2
R3
R2
R3
NH
CDMT (1.1 equiv), Et3N (2 equiv), LiCl (0.1 equiv)
MeCN/THF (8:1), rt, 1.5–5 h
OH
N
R1
N
R1
(2) TFA (5–10 equiv), MeCN/THF (8:1), rt to 80 °C, 19–24 h
R4
2
12
entry
2
R1
R2
R3
R4
the 1st step
the 2nd step TFA
12
yield
(%)a
93
time (h)
time, temp.
19 h, rt
(equiv)
1
2a
2b
2d
2e
2k
2a
H
H
H
H
H
H
H
H
Br
4
5
12a
12b
12d
12e
12k
2
H
Cl
H
H
5
19 h, 50 °C
19 h, rt
10
5
76
3
H
BnO
H
3
78
4
H
MeO
H
1.5
4
19 h, rt
5
100
48
5b
6
Me
H
H
24 h, 80 °C
12 h, rt
10
5
H
H
4
12a-Br 83
aIsolated yield. bThe first step was initiated by the dropwise addition of 2k in MeCN to a reaction mixture containing
iPr2EtN instead of Et3N. The reaction solvent was MeCN.
Scheme 2 describes the one-pot synthesis of 1-phenyl-tetrahydro-β-carboline 14 from gramine 2a and N-
[(benzylidene)amino]malonate 13. Unlike 11, 13 lacking the 2-hydroxy group is typically used as a crude material
due to its instability.59–61 Therefore, 13 was prepared in situ via condensation of diethyl aminomalonate with
benzaldehyde and used directly for the reaction. The desired product 14 was obtained in 34% yield based on 2a.
These results indicated that the 2-hydroxy group in the malonate was not necessary but desirable for this one pot
synthesis.
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CO2Et
+
H2N
CHO
5
CO2Et
6
(1.65 equiv)
(1.5 equiv)
7
8
MgSO4 (7.5 equiv), CH2Cl2, rt, 22 h
9
10
11
12
13
14
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CO2Et
CO2Et
N
13
2a
(1)
(1 equiv), CDMT (1.1 equiv)
Et3N (2 equiv), LiCl (0.1 equiv)
MeCN/CH2Cl2/THF, rt, 2 h
(2) TFA (3 equiv), rt, 30 min
CO2Et
CO2Et
NH
N
H
14
, 34%
Scheme 2. One-pot synthesis of tetrahydro-β-carboline 14 bearing a phenyl group.
Conclusion
A new method for the substitution of the dimethylamino group in gramines was developed using a unique
activating agent, CDMT. Gramines bearing a substituent at the 2, 5, or 6 position were derivatized with malonate
nucleophiles in the presence of Et3N and a catalytic amount of LiCl. Compared to the traditional procedures, this
proposed method is advantageous in terms of yields as well as reaction temperatures and times. In particular, a clear
difference was observed in the reaction of 1-substituted gramines 2j and 2k with N-Boc-aminomalonate 3a: the
addition of CDMT afforded the coupling product in good yield whereas methyl iodide, a classical activating agent
for the dimethylamino group, afforded no desired product under the same reaction conditions. Dimeric ammonium
salts 7 and 6j were isolated and evaluated to obtain mechanistic insights of the reaction. The formation of such salts
is likely to compete with the desired reaction pathway, reversibly (1-unsubstituted gramines) or irreversibly (1-
substituted gramines) under the employed reaction conditions. Additionally, this study demonstrated the one-pot
synthesis of tetrahydro-β-carboline derivatives from gramines as an application of the gramine substitution reaction
developed in this study. Thus, overall, the scope of the utility of CDMT employed for the dimethylamino group
activation was extended. The sequential transformations via Mannich bases, namely, the
(dimethylamino)methylation of indoles followed by the substitution of the dimethylamino group with CDMT show
great potential as a useful tool for indole alkaloid syntheses.
Experimental Section
General Information. NMR spectra were recorded on a JEOL JNM-ECS400 spectrometer [1H-NMR (400 MHz)
and 13C{1H}-NMR (100 MHz)] or a JEOL JNM-ECA600 spectrometer [1H-NMR (600 MHz)]. Chemical shifts for
1H-NMR are reported in parts per million (δ) relative to tetramethylsilane as the internal standard. Coupling constant
(J) are reported in hertz (Hz). The following abbreviations are used for spin multiplicity: s = singlet, d = doublet, t =
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triplet, m = multiplet. Chemical shifts for 13C{1H}-NMR are reported in parts per million (δ) relative to the solvent
[CDCl3, δ 77.16; or (CD3)2SO, δ 39.52]. IR spectra were recorded on a Horiba FT-720 FREEXACT-II
spectrophotometer and were reported in wavenumbers (cm−1). Mass spectra were measured on a JMS-T100TD
AccuTOF TLC (DART-MS and ESI-MS) spectrometer. Melting points were determined with a Yanagimoto melting
point apparatus and are uncorrected. Analytical thin layer chromatography (TLC) was performed using glass plates
precoated with 0.25 mm silica gel impregnated with a fluorescent indicator (254 nm). Preparative TLC separations
were performed using glass plates precoated with 0.25 mm silica gel impregnated with a fluorescent indicator (254
nm) or Chromatorex NH TLC plates (Fuji Silysia Chemical). Flash chromatography was performed using silica gel
(spherical, neutral, 40–100 mesh) or amine-functionalized silica gel (Chromatorex NH-DM2035, Fuji Silysia
Chemical). Recycling preparative HPLC was performed with Japan Analytical Industry LC-928 equipped with GPC
columns Jaigel-1H and 2H. All reactions sensitive to oxygen or moisture were conducted under a nitrogen atmosphere.
Heating for reactions was carried out with an oil bath. Reagents were commercial grades and were used without any
purification unless otherwise noted. Known compounds (3a,62 3b,63 11,64 and 11-Br65) were prepared according to
the reported procedure.
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11
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Diethyl 2-[(1H-indol-3-yl)methyl]-2-[(tert-butoxycarbonyl)amino]malonate (4aa).34 CDMT (120.9 mg, 0.69 mmol,
1.1 equiv) was added to a suspension of 2a (109.1 mg, 0.63 mmol, 1.0 equiv), 3a (189.6 mg, 0.69 mmol, 1.1 equiv),
Et3N (174 µL, 1.25 mmol, 2.0 equiv), and LiCl (2.7 mg, 0.063 mmol, 0.1 equiv) in MeCN (2.1 mL, 0.3 M) at room
temperature. After 4 h, the reaction mixture was passed through silica gel (EtOAc as an eluent). The filtrate was
concentrated under reduced pressure. Column chromatography (silica gel, hexane/EtOAc = 9:1 to hexane/acetone =
9:1) afforded a white solid (229.2 mg, 91%).
General Procedure for gramine derivatives 2b–h,k (GP-1). Dimethylamine hydrochloride (1.1 equiv), Et3N (1.1
equiv), formaldehyde aqueous solution (37%, 1.1 equiv), and acetic acid (1.5 equiv) were added to a suspension of
an indole derivative (1.0 equiv) in 1,4-dioxane/H2O (1:1, 0.3 M) at room temperature. The reaction mixture was
stirred until TLC monitoring indicated complete conversion. The reaction mixture was quenched with saturated
aqueous NaHCO3 and then extracted with EtOAc. The organic layer was washed with brine, dried with Na2SO4, and
filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography
(amine-functionalized silica gel) to afford the desired gramine derivative.
5-Chlorogramine (2b).66 GP-1 was followed using 5-chloroindole (227.4 mg, 1.50 mmol, 1.0 equiv), dimethylamine
hydrochloride (269.0 mg, 3.30 mmol, 2.2 equiv), Et3N (459 µL, 3.30 mmol, 2.2 equiv), formaldehyde aqueous
solution (253 µL, 3.30 mmol, 2.2 equiv), and acetic acid (257 µL, 4.50 mmol, 3.0 equiv) in 1,4-dioxane/H2O (1:1,
5.0 mL). The reaction mixture was stirred for 23 h. Column chromatography (silica gel, hexane/acetone = 4:1)
afforded a white solid (189.7 mg, 61%). 13C{1H}-NMR (100 MHz, CDCl3): δ 134.7, 129.1, 125.4, 125.0, 122.4,
119.0, 113.4, 112.2, 54.6, 45.5.
6-Chlorogramine (2c).67,68 GP-1 was followed using 6-chloroindole (227.4 mg, 1.50 mmol), dimethylamine
hydrochloride (134.5 mg, 1.65 mmol), Et3N (229 µL, 1.65 mmol), formaldehyde aqueous solution (126 µL, 1.65
mmol), and acetic acid (129 µL, 2.25 mmol) in 1,4-dioxane and H2O (1:1, 5.0 mL). The reaction mixture was stirred
at 40 ℃ for 19.5 h. Column chromatography (silica gel, hexane/EtOAc = 1:1) afforded a white solid (153.8 mg,
49%). 1H-NMR (600 MHz, CDCl3): δ 8.04 (br s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.12 (d, J =
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2.4 Hz, 1H), 7.09 (dd, J = 8.4, 1.8 Hz, 1H), 3.59 (s, 2H), 2.26 (s, 6H); 13C{1H}-NMR (100 MHz, CDCl3): δ 136.7,
128.1, 126.6, 124.2, 120.42, 120.40, 113.8, 111.1, 54.6, 45.5; LRMS (ESI-TOF): m/z 209 ([M + H]+).
6-Benzyloxygramine (2d).69 GP-1 was followed using 6-benzyloxyindole (334.9 mg, 1.50 mmol), dimethylamine
hydrochloride (134.5 mg, 1.65 mmol), Et3N (229 µL, 1.65 mmol), formaldehyde aqueous solution (126 µL, 1.65
mmol), and acetic acid (129 µL, 2.25 mmol) in 1,4-dioxane and H2O (1:1, 5.0 mL). The reaction mixture was stirred
at 40 ℃ for 20 h. Column chromatography (silica gel, EtOAc) and recrystallization from EtOH afforded a white
solid (225.3 mg, 54%). 1H-NMR (400 MHz, CDCl3): δ 7.91 (br s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 7.3 Hz,
2H), 7.39 (dd, J = 7.3, 7.3 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.89
(dd, J = 8.5, 2.3 Hz, 1H), 5.11 (s, 2H), 3.58 (s, 2H), 2.27 (s, 6H); 13C{1H}-NMR (100 MHz, CDCl3): δ 155.6, 137.6,
136.9, 128.7, 127.9, 127.6, 122.74, 122.65, 120.0, 113.2, 110.3, 96.1, 70.7, 54.7, 45.5; LRMS (ESI-TOF): m/z 281
([M + H]+).
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60
5-Methoxygramine (2e).70 GP-1 was followed using 5-methoxyindole (220.8 mg, 1.50 mmol), dimethylamine
hydrochloride (134.5 mg, 1.65 mmol), Et3N (229 µL, 1.65 mmol), formaldehyde aqueous solution (126 µL, 1.65
mmol), and acetic acid (129 µL, 2.25 mmol) in 1,4-dioxane and H2O (1:1, 5.0 mL). The reaction mixture was stirred
for 2.5 h. Column chromatography (silica gel, hexane/acetone = 4:1) afforded a white solid (228.6 mg, 75%).
6-Methoxygramine (2f).14 GP-1 was followed using 6-methoxyindole (220.8 mg, 1.50 mmol), dimethylamine
hydrochloride (134.5 mg, 1.65 mmol), Et3N (229 µL, 1.65 mmol), formaldehyde aqueous solution (126 µL, 1.65
mmol), and acetic acid (129 µL, 2.25 mmol) in 1,4-dioxane and H2O (1:1, 5.0 mL). The reaction mixture was stirred
for 4 h. Column chromatography (silica gel, hexane/acetone = 4:1 to 7:3) and PTLC (amine-functionalized silica gel)
1
afforded a white solid (231.7 mg, 76%). H-NMR (600 MHz, CDCl3): δ 7.92 (br s, 1H), 7.57 (d, J = 8.6 Hz, 1H),
7.02 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.80 (dd, J =8.6, 2.1 Hz, 1H), 3.85 (s, 3H), 3.59 (s, 2H), 2.27 (s,
6H); 13C{1H}-NMR (100 MHz, CDCl3): δ 156.5, 137.0, 122.5, 122.4, 120.0, 113.3, 109.6, 94.7, 55.8, 54.8, 45.5;
LRMS (ESI-TOF): m/z 205 ([M + H]+).
2-Methylgramine (2g).71,72 GP-1 was followed using 2-methylindole (3.9350 g, 30.0 mmol), dimethylamine
hydrochloride (2.6932 g, 33.0 mmol), Et3N (4.57 mL, 33.0 mmol), formaldehyde aqueous solution (2.53 mL, 33.0
mmol), and acetic acid (2.57 mL, 45.0 mmol) in 1,4-dioxane and H2O (1:1, 100 mL). The reaction mixture was stirred
at 40 ℃ for 3 h. Column chromatography (silica gel, hexane/EtOAc = 1:1 to EtOAc) and recrystallization from
EtOAc afforded a white solid (5.6481 g, 38%). 1H-NMR (600 MHz, CDCl3): δ 7.84 (br s, 1H), 7.61 (d, J = 7.2 Hz,
1H), 7.27–7.26 (m, 1H), 7.12–7.07 (m, 2H), 3.54 (s, 2H), 2.43 (s, 3H), 2.26 (s, 6H); 13C{1H}-NMR (100 MHz,
CDCl3): δ 135.2, 133.7, 129.5, 120.9, 119.5, 118.5, 110.2, 108.7, 53.4, 45.5, 11.8; LRMS (ESI-TOF): m/z 189 ([M +
H]+).
2-Phenylgramine (2h).72 GP-1 was followed using 2-phenylindole (289.9 mg, 1.50 mmol), dimethylamine
hydrochloride (134.5 mg, 1.65 mmol), Et3N (229 µL, 1.65 mmol), formaldehyde aqueous solution (126 µL, 1.65
mmol), and acetic acid (129 µL, 2.25 mmol) in 1,4-dioxane and H2O (1:1, 5.0 mL). The reaction mixture was stirred
for 14.5 h. Column chromatography (silica gel, hexane/EtOAc = 4:1) afforded a white solid (326.7 mg, 87%). 1H-
NMR (600 MHz, CDCl3): δ 8.17 (br s, 1H), 7.80–7.76 (m, 3H), 7.49 (dd, J = 7.7, 7.7 Hz, 2H), 7.40–7.36 (m, 2H),
7.21 (ddd, J = 7.5, 7.5, 1.3 Hz, 1H), 7.15 (ddd, J = 7.5, 7.5, 1.0 Hz, 1H), 3.62 (s, 2H), 2.30 (s, 6H); 13C{1H}-NMR
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(100 MHz, CDCl3): δ 136.8, 135.7, 133.1, 130.2, 128.9, 128.4, 127.9, 122.4, 120.0, 119.8, 111.0, 110.8, 53.7, 45.6;
LRMS (ESI-TOF): m/z 251 ([M + H]+).
6
7
8
9
3-[1-(Dimethylamino)ethyl]-1H-indole (2i).73 POCl3 (2.0 mL, 22 mmol) followed by indole (2.0 g, 17 mmol) in N,N-
dimethylacetamide (3.0 mL) was added to N,N-dimethylacetamide (7.5 mL) at 0 °C. The reaction mixture was heated
to 90 °C for 1 h and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure.
The residue was dissolved in MeOH (20 mL). Sodium borohydride (2261 mg, 59.7 mmol) was added to the mixture
at 0 °C. After 18.5 h, the reaction mixture was quenched by adding aqueous 1% K2CO3 and extracted with
CH2Cl2/EtOAc. The organic layer was washed with H2O and brine, dried (Na2SO4), and filtered. The filtrate was
concentrated under reduced pressure. Column chromatography (twice, amine-functionalized silica gel,
hexane/EtOAc = 11:9 for the first chromatography, CHCl3 for the second chromatography) afforded a pale yellow
solid (266.8 mg, 8%). 1H-NMR (400 MHz, CDCl3): δ 9.27 (br s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 8.2 Hz,
1H), 7.20–7.05 (m, 2H), 6.94 (d, J = 2.3 Hz, 1H), 3.89 (q, J = 6.9 Hz, 1H), 2.28 (s, 6H), 1.51 (d, J= 6.9 Hz, 3H);
13C{1H}-NMR (100 MHz, CDCl3): δ 136.1, 127.3, 122.3, 121.5, 119.5, 119.0, 117.0, 111.2, 56.8, 42.4, 18.9; HRMS
(ESI-TOF): Calcd for C12H17N2 [M + H]+: 189.1392; Found: 189.1401.General procedure for the substitution
reactions of 1-unsubstituted gramines (GP-2). LiCl (0.1 equiv) in THF (0.25 M), Et3N (2.0 equiv), and CDMT
(1.1 equiv) were added to a suspension of a gramine derivative (2a–h, 1.0 equiv) and a diethyl malonate derivative
(3a–d, 1.1 equiv) in MeCN (0.3 M) at room temperature. The reaction mixture was stirred until TLC monitoring
indicated complete conversion. The reaction mixture was diluted with EtOAc, washed with aqueous HCl (1 M) and
brine, dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified
by silica gel column chromatography to afford the desired product.
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Diethyl 2-[(tert-butoxycarbonyl)amino]-2-[(5-chloro-1H-indol-3-yl)methyl]malonate (4ba).34 GP-2 was followed
using 2b (100.6 mg, 0.48 mmol), 3a (146.1 mg, 0.53 mmol), LiCl in THF (194 µL, 0.048 mmol), Et3N (134 µL, 0.97
mmol), and CDMT (93.2 mg, 0.53 mmol) in MeCN (1.6 mL). The reaction mixture was stirred for 5 h. The residue
was purified by column chromatography (silica gel, hexane/EtOAc = 9:1 to 7:3) and recycling preparative HPLC to
afford a white solid (204.5 mg, 97%).
Diethyl 2-[(tert-butoxycarbonyl)amino]-2-[(6-chloro-1H-indol-3-yl)methyl]malonate (4ca).34 GP-2 was followed
using 2c (86.0 mg, 0.41 mmol), 3a (124.8 mg, 0.45 mmol), LiCl in THF (166 µL, 0.041 mmol), Et3N (115 µL, 0.82
mmol), and CDMT (79.5 mg, 0.45 mmol) in MeCN (1.4 mL). The reaction mixture was stirred for 5 h. The residue
was purified by column chromatography (silica gel, hexane/acetone = 4:1), preparative TLC (hexane/acetone = 4:1),
and recycling preparative HPLC to afford a white solid (163.3 mg, 90%).
Diethyl 2-{[6-(benzyloxy)-1H-indol-3-yl]methyl}-2-[(tert-butoxycarbonyl)amino]malonate (4da).34 GP-2 was
followed using 2d (128.1 mg, 0.46 mmol), 3a (138.5 mg, 0.50 mmol), LiCl in THF (184 µL, 0.046 mmol), Et3N (127
µL, 0.92 mmol), and CDMT (88.3 mg, 0.50 mmol) in MeCN (1.5 mL). The reaction mixture was stirred for 3 h.
Column chromatography (silica gel, hexane/acetone = 9:1) afforded a white solid (213.6 mg, 92%). 1H-NMR (400
MHz, CDCl3): δ 7.91 (s, 1H), 7.46–7.30 (m, 6H), 6.88–6.81 (m, 3H), 5.84 (s, 1H), 5.08 (s, 2H), 4.32–4.10 (m, 4H),
3.77 (s, 2H), 1.47 (s, 9H), 1.25 (t, J = 7.1 Hz, 6H); 13C{1H}-NMR (100 MHz, CDCl3): δ 168.1, 155.6, 154.2, 137.5,
136.5, 128.6, 127.9, 127.6, 123.0, 122.2, 119.7, 110.3, 109.4, 95.9, 80.3, 70.6, 67.6, 62.5, 28.7, 28.4, 14.1; LRMS
(ESI-TOF): m/z 533 [M + Na]+.
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Diethyl 2-[(tert-butoxycarbonyl)amino]-2-[(5-methoxy-1H-indol-3-yl)methyl]malonate (4ea).34 GP-2 was followed
using 2e (102.5 mg, 0.50 mmol), 3a (152.0 mg, 0.55 mmol), LiCl in THF (202 µL, 0.050 mmol), Et3N (140 µL, 1.00
mmol), and CDMT (96.9 mg, 0.55 mmol) in MeCN (1.7 mL). The reaction mixture was stirred for 1.5 h. Column
chromatography (silica gel, hexane/acetone = 9:1 to 7:3) afforded a pale pink solid (212.1 mg, 97%).
Diethyl 2-[(tert-butoxycarbonyl)amino]-2-[(6-methoxy-1H-indol-3-yl)methyl)]malonate (4fa).34 GP-2 was followed
using 2f (96.4 mg, 0.47 mmol), 3a (143.0 mg, 0.52 mmol), LiCl in THF (190 µL, 0.047 mmol), Et3N (131 µL, 0.94
mmol), and CDMT (91.1 mg, 0.52 mmol) in MeCN (1.6 mL). The reaction mixture was stirred for 1.5 h. The residue
was purified by column chromatography (silica gel, hexane/acetone = 4:1 to hexane/EtOAc = 7:3) to afforded a pale
pink solid (194.3 mg, 95%).
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Diethyl 2-[(tert-butoxycarbonyl)amino]-2-[(2-methyl-1H-indol-3-yl)methyl]malonate (4ga).34 GP-2 was followed
using 2g (108.8 mg, 0.58 mmol), 3a (174.9 mg, 0.64 mmol), LiCl (26.9 mg, 0.64 mmol, 1.1equiv), Et3N (161 µL,
1.16 mmol), and CDMT (111.5 mg, 0.64 mmol) in MeCN (1.9 mL). The reaction mixture was stirred for 2.5 h.
Column chromatography (silica gel, hexane/acetone = 9:1 to 7:3) afforded a white solid (238.7 mg, 99%).
Diethyl 2-[(tert-butoxycarbonyl)amino]-2-[(2-phenyl-1H-indol-3-yl)methyl]malonate (4ha).34 GP-2 was followed
using 2h (107.4 mg, 0.43 mmol), 3a (130.0 mg, 0.47 mmol), LiCl in THF (174 µL, 0.043 mmol), Et3N (119 µL, 0.86
mmol), and CDMT (82.9 mg, 0.47 mmol) in MeCN (1.4 mL). The reaction mixture was stirred for 1.5 h. Column
chromatography (silica gel, hexane/acetone = 9:1) afford a pale pink solid (201.3 mg, 98%).
Diethyl 2-[1-(1H-indol-3-yl)ethyl]-2-[(tert-butoxycarbonyl)amino]malonate (4ia). GP-2 was followed using 2i
(30 mg, 0.16 mmol), 3a (48 mg, 0.18 mmol), LiCl in THF (64 µL, 0.016 mmol), Et3N (44.5 µL, 0.32 mmol), and
CDMT (31 mg, 0.18 mmol) in MeCN (0.54 mL). The reaction mixture was stirred for 5 h. The residue was purified
by column chromatography (silica gel, hexane/EtOAc = 4:1) to afforded a white solid (28 mg, 42%). 1H-NMR (400
MHz, CDCl3): δ 8.17 (br s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.19–7.03 (m, 3H), 5.89 (br s,
1H), 4.29–4.15 (m, 3H), 4.03–3.90 (m, 1H), 3.71–3.65 (m, 1H), 1.55 (d, J = 6.9 Hz , 3H), 1.44 (s, 9H), 1.26 (t, J =
7.3 Hz, 3H), 1.06 (t, J = 6.9 Hz, 3H); 13C{1H}-NMR (100 MHz, CDCl3): δ 168.3, 167.5, 154.6, 135.6, 126.8, 122.5,
121.8, 119.4, 119.2, 115.9, 111.1, 79.9, 69.4, 62.3, 61.8, 36.6, 28.2, 18.1, 14.0, 13.6; HRMS (ESI-TOF): Calcd for
C22H31N2O6 [M + H]+: 419.21821; Found: 419.21668.
Diethyl 2-[(1H-indol-3-yl)methyl]-2-{[(benzyloxy)carbonyl]amino}malonate (4ab). GP-2 was followed using 2a
(183.8 mg, 1.06 mmol), 3b (359.0 mg, 1.16 mmol), LiCl in THF (428 µL, 0.11 mmol), Et3N (293 µL, 2.11 mmol),
and CDMT (203.8 mg, 1.16 mmol) in MeCN (3.5 mL). The reaction mixture was stirred for 4 h. Column
chromatography (silica gel, hexane/EtOAc = 9:1 to 7:3) afforded a pale red oil (441.1 mg, 95%). 1H-NMR (400 MHz,
CDCl3): δ 8.41 (s, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.33–7.25 (m, 6H), 7.10 (dd, J = 7.1, 7.1 Hz, 1H), 6.97 (dd, J = 7.6,
7.6 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 6.12 (s, 1H), 5.13 (s, 2H), 4.23–4.08 (m, 4H), 3.84 (s, 2H), 1.17 (t, J = 7.1 Hz,
6H); 13C{1H}-NMR (100 MHz, CDCl3): δ 167.8, 154.6, 136.2, 135.9, 128.5, 128.3, 128.2, 128.0, 123.6, 121.8, 119.3,
118.5, 111.3, 108.4, 67.7, 66.9, 62.6, 28.5, 13.8; IR (CHCl3): 3479, 3417, 3087, 3060, 3039, 3022, 3012, 2987, 2954,
2943, 2908, 1739, 1720, 1603, 1496, 1458, 1302, 1261, 1190, 1036, 812, 731; HRMS (ESI-TOF): Calcd for
C24H26N2NaO6 [M + Na]+: 461.1689; Found: 461.1674; Anal. Calcd for C24H26N2O6: C, 65.74; H, 5.98; N, 6.39.
Found: C, 65.49; H, 5.75; N, 6.40.
Diethyl 2-[(1H-indol-3-yl)methyl]malonate (4ac).66 GP-2 was followed using 2a (174.3 mg, 1.00 mmol), 3c (380
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µL, 2.50 mmol, 2.5 equiv), LiCl in THF (404 µL, 0.10 mmol), Et3N (278 µL, 2.00 mmol), and CDMT (193.1 mg,
1.10 mmol) in MeCN (3.3 mL). The reaction mixture was stirred for 3 h. Column chromatography (silica gel,
hexane/acetone = 9:1 to 7:3) afforded a white solid (253.7 mg, 88%). 13C{1H}-NMR (100 MHz, CDCl3): δ 169.5,
136.2, 127.1, 122.7, 122.0, 119.4, 118.6, 111.9, 111.3, 61.5, 53.1, 24.6, 14.0.
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Diethyl 2-[(1H-indol-3-yl)methyl]-2-methylmalonate (4ad).21 GP-2 was followed using 2a (174.3 mg, 1.00 mmol),
3d (188 µL, 1.10 mmol), LiCl (46.6 mg, 1.10 mmol), Et3N (417 µL, 3.00 mmol, 3.0 equiv), and CDMT (193.1 mg,
1.10 mmol) in MeCN (3.3 mL). The reaction mixture was stirred for 6 h. Column chromatography (silica gel,
hexane/acetone = 9:1) afforded a pale yellow oil (274.7 mg, 91%). 13C{1H}-NMR (100 MHz, CDCl3): δ 172.6, 135.9,
128.4, 123.6, 121.7, 119.3, 118.9, 111.2, 110.1, 61.4, 55.4, 30.7, 20.3, 14.0; LRMS (ESI-TOF): m/z 326 [M + Na]+.
3-(Cyanomethyl)-1H-indole (4ae).74 CDMT (56 mg, 0.32 mmol) was added to a suspension of 2a (50 mg, 0.29 mmol),
Et3N (40 µL, 0.29 mmol), potassium cyanide (21 mg, 0.32 mmol), and 18-crown-6 (85 mg, 0.32 mmol) in MeCN
(960 µL) at room temperature. After 1 h, the reaction mixture was diluted with EtOAc. The mixture was washed with
H2O and brine, dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure. Column
chromatography (amine-functionalized silica gel, hexane/EtOAc = 7:3) afforded a pale yellow solid (37.6 mg, 83%).
1-(tert-Butoxycarbonyl)gramine (2j).75 Di-tert-butyl dicarbonate (2.6190 g, 12.0 mmol, 1.2 equiv) was added to a
suspension of NaH (480.0 mg, 12.0 mmol, 1.2 equiv), N,N-dimethyl-4-aminopyridine (122.2 mg, 1.0 mmol, 0.1
equiv), and 2a (1.7425 g, 10.0 mmol, 1.0 equiv) in THF (33 mL, 0.3 M) at 0 ℃. After 3 h, the reaction mixture was
quenched with aqueous 1 M NaOH and then extracted with CH2Cl2. The organic layer was washed with brine, dried
with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. Twice column chromatography
(amine-functionalized silica gel, hexane/EtOAc = 7:3; silica gel, EtOAc to CHCl3/MeOH = 7:3) afforded a white
solid (2.1661 g, 79%).
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1-Methylgramine (2k).76 GP-2 was followed using 1-methylindole (1.25 mL, 10.0 mmol), dimethylamine
hydrochloride (896.9 mg, 11.0 mmol), Et3N (1.53 mL, 11.0 mmol), formaldehyde aqueous solution (0.84 mL, 11.0
mmol), and acetic acid (0.86 mL, 15.0 mmol) in 1,4-dioxane and H2O (1:1, 34 mL). The reaction mixture was stirred
at room temperature for 4 h. Column chromatography (silica gel, hexane/acetone = 9:1 to 7:3) afforded a brawn oil
(884.3 mg, 47%). LRMS (ESI): m/z 189 ([M + H]+).
Diethyl 2-{[1-(tert-butoxycarbonyl)-1H-indol-3-yl]methyl}-2-[(tert-butoxycarbonyl)amino]malonate (4ja).
Compound 2j (39.5 mg, 0.14 mmol, 1.0 equiv) in MeCN (1.0 mL) was added dropwise over 1 h to a mixture of 3a
(43.7 mg, 0.16 mmol, 1.1 equiv), LiI (21.3 mg, 0.16 mmol, 1.1 equiv), CDMT (27.9 mg, 0.16 mmol, 1.1 equiv), and
iPr2EtN (50 µL, 0.29 mmol, 2.0 equiv) in MeCN (0.4 mL) at room temperature. After 5 h, the reaction mixture was
diluted with EtOAc, washed with aqueous HCl (1 M) and brine, dried (Na2SO4), and filtered. The filtrate was
concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EtOAc
= 9:1) and recycling preparative HPLC to afford a colorless oil (56.4 mg, 78%). 1H-NMR (400 MHz, CDCl3): δ 8.09
(br s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.31–7.26 (m, 2H), 7.18 (dd, J = 7.6, 7.6 Hz, 1H), 5.87 (s, 1H), 4.34–4.15 (m,
4H), 3.76 (s, 2H), 1.65 (s, 9H), 1.48 (s, 9H), 1.28 (t, J = 7.1 Hz, 6H); 13C{1H}-NMR (100 MHz, CDCl3): δ 167.8,
154.2, 149.7, 135.2, 131.3, 124.7, 124.5, 122.5, 119.265, 119.255, 115.3, 114.4, 83.7, 80.4, 67.2, 62.8, 28.4, 28.3,
28.18, 28.17, 14.19, 14.16; IR (CHCl3): 3421, 3033, 2985, 2966, 2935, 2904, 2877, 1757, 1738, 1718, 1489, 1454,
1389, 1369, 1304, 1261, 1190, 1161, 1057, 1036, 768, 685; HRMS (ESI-TOF): Calcd for C26H36N2NaO8 [M + Na]+:
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Diethyl 2-[(tert-butoxycarbonyl)amino]-2-[(1-methyl-1H-indol-3-yl)methyl]malonate (4ka). Compound 2k
(29.0 mg, 0.154 mmol, 1.0 equiv) in MeCN (1.0 mL) was added dropwise over 1 h to a mixture of 3a (46.7 mg, 0.17
mmol, 1.1 equiv), LiI (22.8 mg, 0.17 mmol, 1.1 equiv), CDMT (29.8 mg, 0.17 mmol, 1.1 equiv), and iPr2EtN (54 µL,
0.31 mmol, 2.0 equiv) in MeCN (0.5 mL) at room temperature. After 4 h, the reaction mixture was diluted with
EtOAc, washed with aqueous HCl (1 M) and brine, dried (Na2SO4), and filtered. The filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 9:1) to afford a
white solid (54.1 mg, 84%). Mp: 95.5–97 ℃. 1H-NMR (400 MHz, CDCl3): δ 7.52 (d, J = 7.8 Hz, 1H), 7.25 (d, J =
8.2 Hz, 1H), 7.21–7.15 (m, 1H), 7.08–7.02) m, 1H), 6.75 (s, 1H), 5.83 (s, 1H), 4.23–4.12 (m, 4H), 3.80 (s, 2H), 3.72
(s, 3H), 1.49 (s, 9H), 1.26 (t, J = 7.1 Hz, 6H); 13C{1H}-NMR (100 MHz, CDCl3): δ 168.1, 154.1, 136.7, 128.8, 128.0,
121.6, 119.2, 119.0, 109.2, 107.8, 80.2, 67.5, 62.5, 32.8, 28.6, 28.4, 14.1; IR (KBr): 3431, 2981, 2939, 1765, 1718,
1477, 1367, 1313, 1298, 1250, 1201, 1171, 1090, 741; HRMS (ESI-TOF): Calcd for C22H30N2NaO6 [M + Na]+:
441.2002; Found: 441.1972; Anal. Calcd for C22H30N2O6: C, 63.14; H, 7.23; N, 6.69. Found: C, 62.91; H, 7.11; N,
6.70.
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Bis[(1H-indol-3-yl)methyl]dimethylammonium chloride (7). CDMT (175.5 mg, 1.00 mmol, 1.0 equiv) was added
to a suspension of 2a (348.5 mg, 2.00 mmol, 2.0 equiv) and Et3N (305.8 µL, 2.20 mmol, 2.2 equiv) in MeCN (6.7
mL, 0.3 M) at room temperature. After 1 h, the reaction mixture was filtered. The filtrate was washed with CH2Cl2
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and concentrated under reduced pressure to afford a white solid (331.0 mg, 97%). Mp: 174.5–176.5 ℃. H-NMR
[400 MHz, (CD3)2SO]: δ 11.75 (s, 2H), 7.88 (d, J = 7.8 Hz, 2H), 7.73 (d, J = 2.3 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H),
7.21–7.13 (m, 4H), 4.81 (s, 4H), 2.86 (s, 6H); 13C{1H}-NMR [100 MHz, (CD3)2SO]: δ 136.1, 130.4, 127.9, 121.8,
120.1, 118.6, 112.2, 101.6, 58.9, 47.2; IR (KBr): 3118, 3099, 3033, 2854, 1475, 1460, 1431, 1344, 1250, 818, 748;
HRMS (ESI-TOF): Calcd for C20H22N3 [M – Cl]+: 304.1814; Found: 304.1785.
Bis{[1-(tert-butoxycarbonyl)-1H-indol-3-yl]methyl}dimethylammonium chloride (6j). CDMT (52.7 mg, 0.30
mmol, 1.0 equiv) was added to a suspension of 2j (164.6 mg, 0.60 mmol, 2.0 equiv) in MeCN (2.0 mL, 0.3 M) at
room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure. Silica gel column
chromatography afforded a white solid (147.2 mg, 91%). Mp: 154–156 ℃. 1H-NMR (400 MHz, CDCl3): δ 8.18 (br
s, 2H), 8.08 (d, J = 7.8 Hz, 2H), 7.91 (br s, 2H), 7.31–7.28 (m, 4H), 5.55 (br s, 4H), 3.23 (br s, 6H), 1.67 (s, 18H);
13C{1H}-NMR (100 MHz, CDCl3): δ 149.0, 135.2, 130.8, 129.9, 125.4, 124.1, 120.5, 115.3, 107.6, 85.1, 59.5, 48.7,
28.3; IR (KBr): 3005, 2978, 2931, 1738, 1560, 1475, 1456, 1373, 1358, 1275, 1259, 1236, 1155, 1088, 835, 768,
750; HRMS (ESI-TOF): Calcd for C30H38N3O4 [M – Cl]+: 504.2862; Found: 504.2857.
General Procedure for the synthesis of 1,2,3,4-tetrahydro-β-carboline derivatives (GP-3). LiCl (0.1 equiv) in
THF (0.25 M), Et3N (2.0 equiv), and CDMT (1.1 equiv) were added to a suspension of a gramine derivative (2a, 2b,
2d, or 2e; 1.0 equiv) and 11 or 11-Br (1.1 equiv) in MeCN (0.3 M) at room temperature. After 1.5–5 h, TFA (5–10
equiv) was added to the reaction mixture. The reaction mixture was stirred for 19 h at room temperature or 50 °C.
The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4),
and filtered. The filtrate was concentrated under reduced pressure. The residue was purified to afford the desired
product.
Diethyl 1-(2-hydroxyphenyl)-1,2,4,9-tetrahydro-3H-pyrido[3,4-b]indole-3,3-dicarboxylate (12a). GP-3 was
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followed using 2a (69.7 mg, 0.40 mmol), 11 (122.9 mg, 0.44 mmol), LiCl in THF (160 µL, 0.040 mmol), Et3N (111
µL, 0.80 mmol), and CDMT (77.2 mg, 0.44 mmol) in MeCN (1.3 mL) for the first step (4 h) followed by TFA (153
µL, 2.00 mmol) for the second step (room temperature). Column chromatography (silica gel, hexane/acetone = 9:1)
afforded a white solid (152.0 mg, 93%). Mp: 70.5–72.5 ℃. 1H-NMR (400 MHz, CDCl3): δ 10.00 (s, 1H), 7.53–7.50
(m, 2H), 7.22–7.18 (m, 2H), 7.11–7.05 (m, 3H), 6.87 (dd, J = 6.9, 6.9 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 5.53 (s, 1H),
4.30–4.06 (m, 4H), 3.85–3.81 (m, 2H), 3.32 (dd, J = 15.8, 2.5 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz,
3H); 13C{1H}-NMR (100 MHz, CDCl3): δ 169.2, 168.6, 157.4, 136.6, 131.0, 130.1, 128.7, 126.9, 123.5, 122.2,
119.68, 119.67, 118.4, 117.9, 111.1, 105.9, 66.8, 62.8, 62.5, 55.6, 26.8, 14.08, 14.05; IR (KBr): 3443, 3305, 2983,
1736, 1491, 1454, 1315, 1248, 1198, 752; HRMS (ESI-TOF): Calcd for C23H24N2NaO5 [M + Na]+: 431.1583; Found:
431.1570; Anal. Calcd for C23H24N2O5: C, 67.63; H, 5.92; N, 6.86. Found: C, 67.56; H, 5.82; N, 6.83.
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Diethyl 6-chloro-1-(2-hydroxyphenyl)-1,2,4,9-tetrahydro-3H-pyrido[3,4-b]indole-3,3-dicarboxylate (12b). GP-
3 was followed using 2b (41.7 mg, 0.20 mmol), 11 (61.4 mg, 0.22 mmol), LiCl in THF (80 µL, 0.020 mmol), Et3N
(56 µL, 0.40 mmol), and CDMT (38.6 mg, 0.22 mmol) in MeCN (0.7 mL) for the first step (5 h) followed by TFA
(153 µL, 2.00 mmol) for the second step (50 °C). The residue was purified by column chromatography (silica gel,
hexane/acetone = 9:1 to 7:3) and recycling preparative HPLC to afford a white solid (67.5 mg, 76%). Mp: 79.5–81.5
℃. 1H-NMR (400 MHz, CDCl3): δ 9.87 (s, 1H), 7.49 (s, 1H), 7.41 (s, 1H), 7.29–7.25 (m, 2H), 7.09–7.04 (m, 2H),
6.94 (ddd, J = 7.4, 7.4, 1.2 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 5.51 (s, 1H), 4.37–4.10 (m, 4H), 3.82–3.75 (m, 2H),
3.27 (dd, J = 16.0, 2.8 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13C{1H}-NMR (100 MHz, CDCl3):
δ 169.1, 168.4, 157.5, 134.9, 132.6, 130.4, 128.7, 128.1, 125.6, 123.2, 122.6, 119.9, 118.2, 112.1, 106.0, 66.8, 63.0,
62.7, 55.6, 26.6, 14.18, 14.17; IR (KBr): 3410, 3311, 2935, 2900, 2862, 1736, 1718, 1491, 1471, 1444, 1278, 1196,
1043, 1003, 858, 752; HRMS (ESI-TOF): Calcd for C23H23ClN2NaO5 [M + Na]+: 465.1193; Found: 465.1171; Anal.
Calcd for C23H23ClN2O5: C, 62.37; H, 5.23; N, 6.33. Found: C, 62.18; H, 5.18; N, 6.20.
Diethyl
7-(benzyloxy)-1-(2-hydroxyphenyl)-1,2,4,9-tetrahydro-3H-pyrido[3,4-b]indole-3,3-dicarboxylate
(12d). GP-3 was followed using 2d (52.1 mg, 0.19 mmol), 11 (57.2 mg, 0.21 mmol), LiCl in THF (76 µL, 0.019
mmol), Et3N (52 µL, 0.37 mmol), and CDMT (36.0 mg, 0.21 mmol) in MeCN (0.6 mL) for the first step (3 h)
followed by TFA (71 µL, 0.93 mmol) for the second step (room temperature). The residue was purified by column
chromatography (silica gel, hexane/acetone = 9:1 to 7:3) and recycling preparative HPLC to afford a white solid
(74.8 mg, 78%). Mp: 195–196 ℃. 1H-NMR (400 MHz, CDCl3): δ 9.98 (s, 1H), 7.42–7.22 (m, 9H), 6.92 (dd, J = 7.3,
7.3 Hz, 1H), 6.85–6.82 (m, 2H), 6.73 (d, J = 1.8 Hz, 1H), 5.50 (s, 1H), 5.04 (s, 2H), 4.36–4.09 (m, 4H), 3.80–3.77
(m, 2H), 3.28 (dd, J = 16.0, 2.3 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13C{1H}-NMR (100 MHz,
CDCl3): δ 169.3, 168.6, 157.6, 155.8, 137.5, 137.3, 130.2, 129.9, 128.68, 128.65, 127.9, 127.5, 123.6, 121.7, 119.7,
119.1, 118.1, 110.3, 106.0, 96.5, 70.7, 66.9, 62.9, 62.6, 55.7, 26.8, 14.19, 14.16; IR (KBr): 3419, 3305, 2983, 2906,
2868, 1732, 1701, 1541, 1508, 1493, 1473, 1458, 1271, 1205, 1155, 754; HRMS (ESI-TOF): Calcd for
C30H30N2NaO6 [M + Na]+: 537.2002; Found: 537.1979; Anal. Calcd for C30H30N2O6: C, 70.02; H, 5.88; N, 5.44.
Found: C, 69.77; H, 5.80; N, 5.46.
Diethyl 1-(2-hydroxyphenyl)-6-methoxy-1,2,4,9-tetrahydro-3H-pyrido[3,4-b]indole-3,3-dicarboxylate (12e).
GP-3 was followed using 2e (40.9 mg, 0.20 mmol), 11 (61.4 mg, 0.22 mmol), LiCl in THF (80 µL, 0.020 mmol),
Et3N (56 µL, 0.40 mmol), and CDMT (38.6 mg, 0.22 mmol) in MeCN (0.7 mL) for the first step (1.5 h) followed by
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TFA (77 µL, 1.00 mmol) for the second step (room temperature). Column chromatography (silica gel, hexane/acetone
= 4:1) afforded a white solid (87.5 mg, quant.). Mp: 68–70 ℃. 1H-NMR (400 MHz, CDCl3): δ 9.97 (br, 1H), 7.31
(s, 1H), 7.26–7.22 (m, 2H), 7.04 (d, J = 9.2 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.91 (dd, J = 7.5, 7.5 Hz, 1H), 6.82 (d,
J = 7.5 Hz, 1H), 6.75 (dd, J = 9.2, 2.3 Hz, 1H), 5.52 (s, 1H), 4.34–4.09 (m, 4H), 3.83–3.78 (m, 5H), 3.30 (dd, J =
15.8, 2.0 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C{1H}-NMR (100 MHz, CDCl3): δ 169.3,
168.6, 157.5, 154.2, 131.8, 131.7, 130.2, 128.7, 127.4, 123.5, 119.7, 118.0, 112.2, 111.8, 105.9, 100.6, 66.9, 62.9,
62.6, 56.0, 55.7, 26.8, 14.2, 14.1; IR (KBr): 3392, 3315, 2981, 2935, 2902, 2831, 1738, 1591, 1489, 1458, 1292,
1254, 1215, 756; HRMS (ESI-TOF): Calcd for C24H26N2NaO6 [M + Na]+: 461.1689; Found: 461.1665.
Diethyl 1-(2-hydroxyphenyl)-9-methyl-1,2,4,9-tetrahydro-3H-pyrido[3,4-b]indole-3,3-dicarboxylate (12k).
iPr2EtN (71 µL, 0.41 mmol, 2.0 equiv) and LiCl in THF (81 µL, 0.020 mmol, 0.1 equiv) were added to a suspension
of 11 (62.6 mg, 0.22 mmol, 1.1 equiv) and CDMT (39.3 mg, 0.22 mmol, 1.1equiv) in MeCN (0.6 mL) at room
temperature. Compound 2k (38.3 mg, 0.20 mmol, 1.0 equiv) in MeCN (1.4 mL) was added dropwise to the mixture
over 2 h. After 2 h, TFA (156 µL, 2.03 mmol, 10 equiv) was added. The reaction mixture was heated to 80 °C for 24
h, and then cooled to room temperature. The reaction mixture was diluted with EtOAc, washed with saturated aqueous
NaHCO3 and brine, dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, hexane/EtOAc = 9:1 to 7:3) and recycling preparative HPLC to
afford a pale yellow solid (39.3 mg, 46%). Mp: 169–171 ℃. 1H-NMR (400 MHz, CDCl3): δ 8.97 (br s, 1H), 7.55
(d, J = 7.8 Hz, 1H), 7.26–7.10 (m, 5H), 6.90–6.83 (m, 2H), 5.65 (s, 1H), 4.26–4.05 (m, 4H), 3.71 (dd, J = 15.8, 1.6
Hz, 1H), 3.43 (dd, J = 15.8, 2.4 Hz, 1H), 3.27 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H); 13C{1H}-
NMR (100 MHz, CDCl3): δ 169.6, 168.6, 157.4, 138.0, 131.7, 130.6, 130.2, 126.2, 124.3, 122.0, 119.6, 119.3, 118.5,
117.9, 109.0, 106.3, 66.3, 62.7, 62.4, 55.0, 30.9, 27.5, 14.12, 14.09; IR (KBr): 3315, 2981, 2945, 1745, 1473, 1458,
1277, 1246, 1203, 1053, 752; HRMS (ESI-TOF): Calcd for C24H26N2NaO5 [M + Na]+: 445.1739; Found: 445.1755;
Anal. Calcd for C24H26N2O5: C, 68.23; H, 6.20; N, 6.63. Found: C, 68.02; H, 6.17; N, 6.62.
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Diethyl 1-(5-bromo-2-hydroxyphenyl)-1,2,4,9-tetrahydro-3H-pyrido[3,4-b]indole-3,3-dicarboxylate (12a-Br).
GP-3 was followed using 2a (36 mg, 0.21 mmol), 11-Br (81 mg, 0.23 mmol), LiCl in THF (82 µL, 0.021 mmol),
Et3N (57 µL, 0.41 mmol), and CDMT (40 mg, 0.23 mmol) in MeCN (680 μL) for the first step (4 h) followed by
TFA (78.5 µL, 1.03 mmol) for the second step (room temperature, 12 h). Column chromatography (silica gel,
hexane/acetone = 4:1) afforded a pale yellow solid (82.8 mg, 83%). 1H-NMR (600 MHz, CDCl3): δ 10.05 (br, 1H),
7.53 (d, J = 7.6 Hz, 1H), 7.46 (br s, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 7.22 (d, J = 7.9
Hz, 1H), 7.18–7.08 (m, 2H), 6.70 (d, J = 8.6 Hz, 1H), 5.49 (s, 1H), 4.39–4.27 (m, 2H), 4.26–4.19 (m, 1H), 4.15–4.08
(m, 1H), 3.89–3.75 (m, 2H), 3.31 (dd, J = 15.8, 2.7 Hz, 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H);
13C{1H}-NMR (150 MHz, CDCl3): δ 169.0, 168.3, 156.6, 136.6, 132.8, 131.0, 130.0, 126.8, 125.4, 122.5, 119.8,
119.7, 118.5, 111.2, 111.1, 106.3, 66.7, 62.8, 62.5, 55.1, 26.6, 14.02, 13.97; HRMS (ESI-TOF): Calcd for
C23H24BrN2O5 [M + H]+ : 487.0869; Found : 487.0892.
Diethyl 1-phenyl-1,2,4,9-tetrahydro-3H-pyrido[3,4-b]indole-3,3-dicarboxylate (14). Benzaldehyde (240 µL,
2.36 mmol) was added to a suspension of MgSO4 (1,29 mg, 10.7 mmol) and diethyl aminomalonate (334 µL, 2.15
mmol) in CH2Cl2 (5.5 mL) at room temperature. After 22 h, MeCN (5.5 mL), LiCl in THF (572 µL, 0.143 mmol),
2a (250 mg, 1.43 mmol), Et3N (400 µl, 2.86 mmol), and CDMT (276 mg, 1.57 mmol) were added to the reaction
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mixture at room temperature. After 2 h, TFA (330 µl, 4.29 mmol) was added to the reaction mixture at room
temperature. After 30 min, the reaction mixture was filtered. The filtrate was washed with saturated aqueous NaHCO3
and braine, dried (Na2SO4), and filtered. This filtrate was concentrated under reduced pressure. The residue was
purified by column chromatography (twice, silica gel with hexane/EtOAc = 4:1 for the first chromatography, amine-
functionalized silica gel with hexane/EtOAc = 4:1 for the second chromatography) to afford a white solid (192 mg,
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34%). H-NMR (600 MHz, CDCl3): δ 7.58–7.52 (m, 1H), 7.46 (br s, 1H), 7.39–7.27 (m, 5H), 7.14–7.05 (m, 3H),
5.44 (s, 1H), 4.30–4.14 (m, 3H), 4.12–4.03 (m, 1H), 3.74 (dd, J = 15.1, 1.4 Hz, 1H), 3.33 (dd, J = 15.1, 2.4 Hz 1H),
3.16 (br s, 1H), 1.28 (t, J = 7.3 Hz, 3H), 1.16 (t, J = 7.3 Hz, 3H); 13C{1H}-NMR (150 MHz, CDCl3): δ 170.4, 141.4,
136.3, 133.5, 128.7, 128.6, 128.3, 127.0, 121.7, 119.3, 118.2, 110.8, 106.7, 67.2, 62.2, 61.8, 55.4, 27.1, 14.0, 13.9;
HRMS (ESI-TOF): Calcd for C23H25N2O4 [M + H]+ : 393.1814; Found : 393.1801.
Associated Content
Supporting Information. This material is available free of charge on the ACS Publications website. Spectroscopic
data (PDF).
Author Information
Corresponding Author
*kunisima@p.kanazawa-u.ac.jp
Notes
The authors declare no competing financial interest.
Acknowledgment
This work was partially supported by the JSPS Grants-in-Aid for Scientific Research program (KAKENHI, grant
number 17H03970).
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