Transition-metal-free stereoselective and regioselective hydroamination of 2-benzoylethynyl-4,5,6,7-tetrahydroindoles with amino acids

Article abstract of DOI:10.1055/s-0031-1290383

A new family of unnatural amino acids possessing a tetrahydroindole moiety is obtained by nucleophilic addition of various amino acids to the triple bond of 2-benzoylethynyl-4,5,6,7-tetrahydroindoles. The reaction proceeds chemo-, regio- and stereospecifically in the presence of sodium hydroxide to give the Z-isomeric products in 35-72% yields. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0031-1290383

2084▌
PAPER
paper
Transition-Metal-Free Stereoselective and Regioselective Hydroamination of
2-Benzoylethynyl-4,5,6,7-tetrahydroindoles with Amino Acids
Hydroamination of 2-Benzoylethynyl-4,5,6,7-tetrahydroindoles
Lyubov N. Sobenina, Denis N. Tomilin, Igor A. Ushakov, Albina I. Mikhaleva, Boris A. Trofimov*
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033, Irkutsk,
Russian Federation
Fax +7(3952)419346; E-mail: boris_trofimov@irioch.irk.ru
Received: 01.03.2012; Accepted after revision: 27.04.2012
considered as a short-cut route to amino acids containing
Abstract: A new family of unnatural amino acids possessing a tet-
a tetrahydroindole moiety.
rahydroindole moiety is obtained by nucleophilic addition of vari-
ous amino acids to the triple bond of 2-benzoylethynyl-4,5,6,7-
tetrahydroindoles. The reaction proceeds chemo-, regio- and stereo-
specifically in the presence of sodium hydroxide to give the Z-iso-
meric products in 35–72% yields.
These compounds, due to their easy aromatization, might
be suitable intermediates for the synthesis of amino acids
containing an indole function, for example, α-analogues
of tryptophan. Herein, we disclose an expedient method
for the synthesis of amino acid derivatives possessing a
tetrahydroindole moiety
Key words: amino acids, 2-benzoylethynyl-4,5,6,7-tetrahydroin-
doles, nucleophilic addition, Z-isomers
The method involves the nucleophilic addition of the nat-
ural amino acids glycine (4), β-alanine (5), γ-aminobutyr-
ic acid (6), phenylalanine (7) and tryptophan (8) to the
C≡C bond of 2-benzoylethynyl-4,5,6,7-tetrahydroindoles
1–3. The reaction was carried out in the presence of sodi-
um hydroxide (reflux, 40 h, EtOH–H2O), followed by
subsequent treatment of the mixture with aqueous hydro-
chloric acid to afford amino acid derivatives 10a–k and
11a–c in 35–72% yields (Table 1 and Table 2).
The synthesis of unnatural amino acids has attracted sig-
nificant attention in recent years.1 They represent a grow-
ing group of compounds required for a number of
biotechnological applications in pharmaceutical, cosmet-
ics and agrochemical fields. When modified with different
pharmacophore substituents, unnatural amino acids can
also be used as building blocks for the synthesis of mole-
cules with specific desired biological activity.2 Hence, re-
search on various derivatives of amino acids and the
development of new synthetic strategies for amino acid
modification is very important. The chemo- and regiose-
lective transformations of amino acids are considered to
be a major challenge and remain the subject of further in-
vestigations. It is envisaged that the synthesis of new ami-
no acid derivatives containing highly reactive pyrrole or
indole moieties would represent a promising approach in
this field.
In the absence of sodium hydroxide, addition of amino
acids 4–8 to the acetylenic moiety of indoles 1–3 did not
take place. The role of the base would seem to involve
transformation of the zwitterionic form of the amino acid
into the corresponding sodium salt and thus releasing the
free amino group. The free amino group of the salt serves
as a nucleophile undergoing addition to the triple bond of
indoles 1–3 to deliver the sodium salt adducts 9a–k. The
latter, after treatment of the reaction mixture with aqueous
hydrochloric acid, furnishes free amino acids 10a–k (Ta-
ble 1). In the case of L-tryptophan (Table 2), the corre-
sponding products 11a–c were isolated without the need
for acidification of the reaction mixture.
Examples of unnatural optically active amino acids con-
taining a pyrrole moiety have been synthesized by con-
densation of 1-vinylpyrrole- and 1-vinylindole-2-
carbaldehydes with L-lysine.3
The reaction proved to be regio- and stereoselective with
only Z-isomers of the adducts being formed in all cases.
Evidence for the Z-configuration of adducts 10a–k was
obtained from the 2D NOESY spectrum of compound
10f. Cross-peaks were apparent between the alkene proton
(5.65 ppm) and those at the ortho-positions of the phenyl
(7.45 ppm) and the CH2 of the benzyl fragment (5.19
ppm), and also between the pyrrolic proton (6.23 ppm)
and those of the NCH2 group (3.71 ppm) in conformer A.
In the 2D NOESY spectrum of conformer B, cross-peaks
were observed between the pyrrole and alkene protons,
and also between the CH2 protons of the benzyl and ala-
nine fragments (Figure 1). It is noteworthy that the N-vi-
nyl-substituted tetrahydroindole 3 tolerated the reaction
conditions retaining the vinyl double bond intact (Table 1
and Table 2).
Following the development of transition metal and sol-
vent-free ethynylations of the pyrrole nucleus with elec-
trophilic haloacetylenes on alumina,4 or other active
surfaces,5 2-ethynylpyrroles and 3-ethynylindoles pos-
sessing electron-withdrawing substituents, including an
example with an acyl group on the triple bond, became
readily available. This methodology has made 3-(4,5,6,7-
tetrahydroindol-2-yl)-2-propynones 1–3 particularly ac-
cessible using large-scale manufactured 4,5,6,7-
tetrahydroindole6 as the starting material. Consequently,
reactions of these compounds with amino acids can be
SYNTHESIS 2012, 44, 2084–2090
Advanced online publication: 14.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290383; Art ID: SS-2012-Z0223-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Hydroamination of 2-Benzoylethynyl-4,5,6,7-tetrahydroindoles
2085
As exemplified by the reaction with tryptophan (8), the
elaborated method can be employed for the synthesis of
amino acids containing both tetrahydroindolyl and indolyl
substituents.
O
H
H2C
CH
CH
O
OH
NH
N
N
O
NH
H2C
CH2
The reactions of 2-benzoylethynyl-4,5,6,7-tetrahydroin-
doles 1–3 with amino acids were accompanied by the for-
mation of minor amounts of 2-acetyl-4,5,6,7-
tetrahydroindoles. This might be the result of nucleophilic
addition of water to adducts 10a–k and subsequent de-
composition of the intermediates 12 to give diketones 13.
Addition of a second molecule of water gives intermedi-
H2C
OH
H
HC
O
A
B
Figure 1 Relevant cross-peaks in the 2D (1H–1H) NOESY spectrum
of amino acid 10f
Table 1 Synthesis of Amino Acid Derivatives 10a–k
O
O
O
ONa
OH
+
X
X
–
X
NH3
N
N
O
H
H
HCl
O
4–7
N
R
N
R
N
R
O
O
NaOH, EtOH–H2O
reflux, 40 h
Ph
1–3
Ph
Ph
9a–k
10a–k
Entry
Substrate
R
Amino acid
X
Product
Yield (%)
1
2
1
1
1
1
2
2
2
3
3
3
3
Me
4
5
6
7
4
5
6
4
5
6
7
CH2
10a
10b
10c
10d
10e
10f
10g
10h
10i
55
48
57
35
42
71
51
72
64
63
49
Me
(CH2)2
(CH2)3
CH(CH2Ph)
CH2
3
Me
4
Me
5
Bn
6
Bn
(CH2)2
(CH2)3
CH2
7
Bn
8
CH=CH2
CH=CH2
CH=CH2
CH=CH2
9
(CH2)2
(CH2)3
CH(CH2Ph)
10
11
10j
10k
Table 2 Synthesis of Amino Acid Derivatives 11a–c
H
N
H2N
1–3
+
HOOC
HN
COOH
NaOH, EtOH–H2O
reflux, 40 h
N
H
N
R
O
8
Ph
11a–c
Entry
Substrate
R
Product
Yield (%)
1
2
3
1
2
3
Me
11a
11b
11c
71
70
67
Bn
CH=CH2
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2084–2090

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L. N. Sobenina et al.
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O
OH
X
HO
OH
NH
O
H2O
N
R
N
R
O
N
R
10a–k
O
O
Ph
Ph
Ph
12
13
O
H2O
O
N
R
Ph
OH
+
N
R
15a–c
OH
O
HO
Ph
14
Scheme 1 Reaction of adducts 10a–k with water
ates 14, which decompose to 2-acetyl-4,5,6,7-tetrahydro- lyzed by proline acting as an active organic catalyst,10 is
indoles 15a–c and benzoic acid (Scheme 1). Both these the only possible outcome for the reaction.
compounds were present in the reaction mixtures in ap-
proximately 1:1 molar ratio. Also, the direct nucleophilic
addition of water to the triple bond of indoles 1–3 to gen-
erate diketones 13 cannot be ruled out.
Surprisingly, the reaction of N-unsubstituted 2-benzoyl-
ethynyl-4,5,6,7-tetrahydroindole (16) with glycine (4) un-
der the same conditions did not form the expected adduct.
Instead, almost quantitative cleavage into 2-acetyl-
Among the common proteinogenic amino acids, only pro- 4,5,6,7-tetrahydroindole (17) and benzoic acid took place
line exists as a secondary amine, and accordingly plays a (Scheme 3).
distinct role in protein chemistry and biology. In addition,
proline is of significant importance in organic chemistry
Of particular interest is the fact that, unlike 2-benzoyl-
ethynyl-4,5,6,7-tetrahydroindoles 1–3, ethyl 3-(4,5,6,7-
tetrahydro-1H-indol-2-yl)propynoate (18) did not form
the expected adduct on reaction with amino acid 5 (reflux,
as a chiral starting material for the synthesis of peptide mi-
metics,7 alkaloids,8 certain peptoid natural products,9 and
chiral molecules, which are used in asymmetric synthesis
40 h, EtOH–H2O). Surprisingly, a rather peculiar cleavage
and catalysis.
of the triple bond occurred to produce, almost quantita-
The combination of a pharmacophoric indole ring and tively, 2-acetyl-4,5,6,7-tetrahydroindole (15a). Apparent-
proline in the same molecule might result in synergism of ly, in this case, alkaline hydrolysis of the ester function
the properties of these important chemical structures, and occurred first, thereby consuming the sodium hydroxide.
could expand substantially the fields of application of Consequently, the amino acid remained in zwitterionic
such a new class of amino acids. Unfortunately, the reac- form and was unable to take part in nucleophilic addition
tion of indole 1 with L-proline using the above-described at the triple bond. Therefore, indole 18 underwent nucleo-
conditions gave, almost quantitatively, 2-acetyl-4,5,6,7- philic attack by hydroxide to give intermediate 19, which
tetrahydroindole (15a) and benzoic acid (Scheme 2).
decomposed to acetylindole 15a and sodium carbonate
(Scheme 4).
O
It should be emphasized that the formal one-pot cleavage
of the triple bond under mild conditions, as described
herein, is important since there are only a few examples of
such reactions reported in the literature.11
O
NaOH, EtOH–H2O
1
15a
Ph
+
+
N
H
OH
OH
Scheme 2 Reaction of 2-benzoylethynyl-4,5,6,7-tetrahydroindole 1
with L-proline
In conclusion, a general method for the synthesis of a new
family of unnatural amino acids, containing a tetrahydro-
indole moiety, has been developed. The procedure in-
volves the regio- and stereoselective addition of amino
acids to the triple bond of 2-benzoylethynyl-4,5,6,7-tetra-
hydroindoles. The synthesized products represent a com-
This may be rationalized as follows: the addition of L-pro-
line to the triple bond of the indole substrate is sterically
hindered, hence the competitive addition of water, cata-
O
4
NaOH, EtOH–H2O
O
N
H
Ph
N
H
+
OH
O
Ph
16
17
Scheme 3 Reaction of 2-benzoylethynyl-4,5,6,7-tetrahydroindole (16) with glycine (4)
Synthesis 2012, 44, 2084–2090
© Georg Thieme Verlag Stuttgart · New York

PAPER
Hydroamination of 2-Benzoylethynyl-4,5,6,7-tetrahydroindoles
2087
After cooling to r.t., the mixture was diluted with H2O (50 mL) and
extracted with Et2O (3 × 20 mL) to isolate the by-products. The
aqueous layer was neutralized with 10% HCl and extracted with
Et2O (5 × 20 mL). The combined organic layer was washed with
H2O (5 × 20 mL), dried over MgSO4 and evaporated. The residue
was purified by flash chromatography on alumina (Et2O) to give the
pure product as a yellow solid. The structures of the products were
confirmed by NMR and IR techniques.
5
O
O
N
NaOH, EtOH–H2O
N
H2O
Me
Me
ONa
OEt
19
18
O
O
OH
H2O
O
(Z)-2-{[1-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-
phenylprop-1-en-1-yl]amino}acetic Acid (10a)
Yield: 0.465 g (55%); yellow solid; mp 186–188 °C.
+
HO
15a
N
N
O
ONa
Me
Me
IR (KBr): 3092–2500 (NH, OH), 1727 [C(=O)OH], 1592 (C=O)
cm–1.
ONa
ONa
Scheme 4 Reaction of ethyl 3-(4,5,6,7-tetrahydro-1H-indol-2-yl)pro-
pynoate (18) with alanine (5)
1H NMR (400.13 MHz, CDCl3): δ = 11.45 (br s, 1 H, NH), 9.32 (br
s, 1 H, OH), 7.87–7.85 (m, 2 H, o-HPh), 7.38–7.36 (m, 3 H, m,p-
HPh), 6.13 (s, 1 H, H-3), 5.83 (s, 1 H, CH=), 4.19 (s, 2 H, NCH2),
3.48 (s, 3 H, NMe), 2.55–2.53 (m, 2 H, CH2-7), 2.50–2.48 (m, 2 H,
CH2-4), 1.85–1.83 (m, 2 H, CH2-5), 1.74–1.72 (m, 2 H, CH2-6).
13C NMR (100.6 MHz, CDCl3): δ = 187.5, 171.9, 158.2, 139.5,
133.0, 130.5, 127.8, 126.7, 124.1, 117.9, 110.8, 94.7, 46.2, 31.0,
22.9, 22.5, 22.4, 21.8.
bination of pharmacophoric indole and amino acid
moieties, and may serve as novel building blocks for drug
design. The method was also shown to be applicable for
the synthesis of amino acids containing N-vinyl-4,5,6,7-
tetrahydroindole moieties. These compounds represent
promising monomers which might take part in various ad-
dition reactions across the double bond.
Anal. Calcd for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28. Found: C,
70.64; H, 6.31; N, 8.42.
(Z)-3-{[1-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-
phenylprop-1-en-1-yl]amino}propanoic Acid (10b)
Yield: 0.422 g (48%); yellow solid; mp 152–153 °C.
Commercially available amino acids and sodium hydroxide were
used. 2-Ethynyl-4,5,6,7-tetrahydroindoles 1–3, 16 and 18 were ob-
tained from 4,5,6,7-tetrahydroindoles and haloacetylenes using the
reported method.5 Column chromatography was performed using
Sigma-Aldrich neutral Al2O3 (150 mesh). TLC was carried out us-
ing silica gel 60 F254 plates. Melting points were recorded on a Stu-
art melting point apparatus and are uncorrected. IR spectra were
obtained using a Bruker IFS 25 spectrometer. 1H (400.13 MHz) and
13C (100.6 MHz) NMR spectra were recorded on Bruker DPX 400
or AV-400 spectrometers with HMDS as the internal standard. The
1H and 13C NMR resonances were assigned with the aid of 2D ho-
monuclear COSY and NOESY, and 2D heteronuclear HSQC and
HMBC experiments. Elemental analyses were recorded using an
EA FLASH 1112 Series (CHN Analyzer) instrument.
IR (KBr): 3092–2500 (NH, OH), 1726 [C(=O)OH], 1592 (C=O)
cm–1.
1H NMR (400.13 MHz, CDCl3): δ = 11.49 (br s, 1 H, NH), 11.07 (br
s, 1 H, OH), 7.80–7.78 (m, 2 H, o-HPh), 7.37–7.35 (m, 3 H, m,p-
HPh), 6.10 (s, 1 H, H-3), 5.71 (s, 1 H, CH=), 3.62 (br s, 2 H, NCH2),
3.45 (s, 3 H, NMe), 2.65 (br s, 2 H, CH2COO), 2.55–2.53 (m, 2 H,
CH2-7), 2.50–2.48 (m, 2 H, CH2-4), 1.85–1.83 (m, 2 H, CH2-5),
1.74–1.72 (m, 2 H, CH2-6).
13C NMR (100.6 MHz, CDCl3): δ = 187.5, 173.9, 159.4, 140.1,
132.8, 130.7, 128.2, 127.1, 125.0, 118.1, 110.7, 94.8, 40.8, 35.1,
31.4, 23.4, 23.0, 22.9, 22.2.
Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C,
71.42; H, 6.99; N, 7.61.
1-Phenyl-3-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-2-yl)prop-2-
yn-1-one (3)
An equimolar mixture of 1-vinyl-4,5,6,7-tetrahydroindole (0.5 g,
3.4 mmol) and 1-benzoyl-2-bromoacetylene (0.711 g, 3.4 mmol)
containing K2CO3 (12 g, 10 equiv by wt) was ground in a china mor-
tar using a pestle at r.t. for 1–2 min. After 60 min, the products were
extracted with Et2O (5 × 20 mL). Evaporation of the solvent and pu-
rification of the residue by column chromatography on alumina (n-
hexane) gave tetrahydroindole 3.
(Z)-4-{[1-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-
phenylprop-1-en-1-yl]amino}butanoic Acid (10c)
Yield: 0.522 g (57%); yellow solid; mp 153–154 °C.
IR (KBr): 3058–2500 (NH, OH), 1711 [C(=O)OH], 1596 (C=O)
cm–1.
1H NMR (400.13 MHz, CDCl3): δ = 11.31 (br s, 1 H, NH), 9.05 (br
s, 1 H, OH), 7.85–7.83 (m, 2 H, o-HPh), 7.38–7.36 (m, 3 H, m,p-
HPh), 6.10 (s, 1 H, H-3), 5.75 (s, 1 H, CH=), 3.46 (s, 3 H, NMe), 3.38
(br s, 2 H, NCH2), 2.55–2.53 (m, 2 H, CH2-7), 2.50–2.48 (m, 2 H,
CH2-4), 2.43–2.41 (m, 2 H, CH2COO), 1.93–1.91 (m, 2 H, CH2),
1.85–1.83 (m, 2 H, CH2-5), 1.74–1.72 (m, 2 H, CH2-6).
13C NMR (100.6 MHz, CDCl3): δ = 187.6, 177.2, 159.2, 140.3,
132.6, 130.7, 128.3, 127.1, 125.3, 118.1, 110.6, 94.4, 44.2, 31.4,
31.2, 25.8, 23.4, 23.1, 22.9, 22.2.
Yield: 0.702 g (75%); yellow needles; mp 73–74 °C.
IR (KBr): 1645 (NCH=CH2), 1596 (CO) cm–1.
1H NMR (400.13 MHz, CDCl3): δ = 7.39–7.37 (m, 3 H, m,p-HPh),
7.14–7.12 (m, 2 H, o-HPh), 7.00 (dd, J = 16.0, 9.2 Hz, 1 H, HN=CH),
6.71 (s, 1 H, H-3), 5.46 (d, J = 16.0 Hz, 1 H, Htrans), 5.05 (d, J = 9.2
Hz, 1 H, Hcis), 2.63–2.61 (m, 2 H, CH2-7), 2.49–2.47 (m, 2 H, CH2-
4), 1.84–1.82 (m, 2 H, CH2-5), 1.75–1.73 (m, 2 H, CH2-6).
13C NMR (100.6 MHz, CDCl3): δ = 177.3, 137.4, 135.2, 133.5,
130.0, 129.3, 128.5, 122.1, 121.3, 110.4, 105.1, 96.0, 89.1, 24.1,
23.0, 22.9, 22.8.
Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C,
71.87; H, 6.98; N, 7.71.
(Z)-2-{[1-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-
phenylprop-1-en-1-yl]amino}-3-phenylpropanoic Acid (10d)
Yield: 0.375 g (35%); yellow solid; mp 90–92 °C.
Anal. Calcd for C19H17NO: C, 82.88; H, 6.22; N, 5.09. Found: C,
82.64; H, 6.01; N, 4.74.
Amino Acids 10a–k; General Procedure
IR (KBr): 3060–2500 (NH, OH), 1736 [C(=O)OH], 1590 (C=O)
cm–1.
A soln of 2-benzoylethynyl-4,5,6,7-tetrahydroindole 1–3 (2.5
mmol), amino acid 4–7 (2.5 mmol) and NaOH (2.5 mmol) in
EtOH–H2O (1:1, 16 mL) was heated at reflux temperature for 40 h.
© Georg Thieme Verlag Stuttgart · New York
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L. N. Sobenina et al.
PAPER
1H NMR (400.13 MHz, CDCl3): δ = 11.52 (br s, 1 H, NH), 7.78–
7.76 (m, 2 H, o-HPh), 7.31–7.28 (m, 1 H, p-HPh), 7.20–7.16 (m, 2 H,
m-HPh), 7.01–6.98 (m, 5 H, Ph), 6.46 (br s, 1 H, OH), 5.85 (s, 1 H,
H-3), 5.68 (s, 1 H, CH=), 4.41–4.39 (m, 1 H, NCH), 3.27–3.23 (m,
1 H, CH2-Ph), 3.15 (s, 3 H, NMe), 3.09–3.05 (m, 1 H, CH2-Ph),
2.45–2.43 (m, 4 H, CH2-4,7), 1.82–1.80 (m, 2 H, CH2-5), 1.71–1.69
(m, 2 H, CH2-6).
13C NMR (100.6 MHz, CDCl3): δ = 188.1, 174.7, 158.5, 140.2,
136.8, 132.6, 130.9, 129.7, 128.4, 128.3, 127.3, 126.8, 124.5, 118.0,
110.6, 95.5, 59.9, 40.2, 30.9, 23.5, 23.1, 22.9, 22.2.
(Z)-2-{[3-Oxo-3-phenyl-1-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-
2-yl)prop-1-en-1-yl]amino}acetic Acid (10h)
Yield: 0.630 g (72%); yellow solid; mp 114–115 °C.
IR (KBr): 3087–2500 (NH, OH), 1727 [C(=O)OH], 1643 (N-
CH=CH2), 1592 (C=O) cm–1.
1H NMR (400.13 MHz, CDCl3): δ = 11.38 (br s, 1 H, NH), 7.87–
7.85 (m, 2 H, o-HPh), 7.38–7.36 (m, 3 H, m,p-HPh), 7.23 (br s, 1 H,
OH), 6.77 (dd, J = 15.9, 8.9 Hz, 1 H, HN=CH), 6.21 (s, 1 H, H-3), 5.93
(s, 1 H, CH=), 5.06 (d, J = 15.9 Hz, 1 H, Htrans), 4.85 (d, J = 8.9 Hz,
1 H, Hcis), 4.07 (s, 2 H, NCH2), 2.64–2.62 (m, 2 H, CH2-7), 2.49–
2.47 (m, 2 H, CH2-4), 1.82–1.80 (m, 2 H, CH2-5), 1.74–1.72 (m, 2
H, CH2-6).
Anal. Calcd for C27H28N2O3: C, 75.68; H, 6.59; N, 6.54. Found: C,
75.30; H, 6.84; N, 6.15.
13C NMR (100.6 MHz, CDCl3): δ = 188.1, 172.0, 158.1, 139.5,
132.1, 130.8, 129.8, 127.9, 127.0, 124.3, 119.6, 113.5, 104.4, 95.1,
29.4, 23.5, 22.9, 22.7, 22.6.
(Z)-2-{[1-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-
phenylprop-1-en-1-yl]amino}acetic Acid (10e)
Yield: 0.435 g (42%); yellow solid; mp 192–194 °C.
Anal. Calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 7.99. Found: C,
72.31; H, 6.67; N, 7.63.
IR (KBr): 3060–2500 (NH, OH), 1726 [C(=O)OH], 1593 (C=O)
cm–1.
1H NMR (400.13 MHz, CDCl3): δ = 11.39 (br s, 1 H, NH), 9.66 (br
s, 1 H, OH), 7.48–7.46 (m, 2 H, o-HPh), 7.30–7.25 (m, 6 H, Ph),
6.93–6.91 (m, 2 H, o-HBn), 6.21 (s, 1 H, H-3), 5.74 (s, 1 H, CH=),
5.16 (s, 2 H, CH2-Ph), 4.15 (s, 2 H, NCH2), 2.54–2.52 (m, 2 H, CH2-
7), 2.45–2.43 (m, 2 H, CH2-4), 1.79–1.77 (m, 2 H, CH2-5), 1.76–
1.74 (m, 2 H, CH2-6).
13C NMR (100.6 MHz, DMSO-d6): δ = 187.6, 172.5, 158.5, 141.1,
140.2, 134.2, 132.2, 130.2, 129.7, 128.5, 128.0, 127.1, 126.1, 119.2,
112.7, 94.6, 48.8, 47.6, 24.6, 24.1, 24.0, 23.0.
(Z)-3-{[3-Oxo-3-phenyl-1-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-
2-yl)prop-1-en-1-yl]amino}propanoic Acid (10i)
Yield: 0.582 g (64%); yellow solid; mp 69–70 °C.
IR (KBr): 3056–2500 (NH, OH), 1729 [C(=O)OH], 1643 (N-
CH=CH2), 1591 (C=O) cm–1.
1H NMR (400.13 MHz, CDCl3): δ = 11.41 (br s, 1 H, NH), 8.31 (br
s, 1 H, OH), 7.79–7.77 (m, 2 H, o-HPh), 7.37–7.35 (m, 3 H, m,p-
HPh), 6.77 (dd, J = 15.9, 8.9 Hz, 1 H, HN=CH), 6.19 (1 H, s, H-3), 5.81
(s, 1 H, CH=), 5.06 (d, J = 15.9 Hz, 1 H, Htrans), 4.86 (d, J = 8.9 Hz,
1 H, Hcis), 3.55 (br s, 2 H, NCH2), 2.71–2.69 (m, 2 H, CH2-7), 2.66–
2.64 (m, 2 H, CH2-4), 2.51–2.49 (m, 2 H, CH2COO), 1.83–1.81 (m,
2 H, CH2-5), 1.75–1.73 (m, 2 H, CH2-6).
Anal. Calcd for C26H26N2O3: C, 75.34; H, 6.32; N, 6.76. Found: C,
74.97; H, 6.05; N, 6.95.
(Z)-3-{[1-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-
phenylprop-1-en-1-yl]amino}propanoic Acid (10f)
Yield: 0.760 g (71%); yellow solid; mp 158–160 °C.
13C NMR (100.6 MHz, CDCl3): δ = 187.7, 173.5, 159.0, 139.7,
131.6, 130.5, 129.9, 127.9, 126.9, 124.5, 119.5, 112.9, 104.1, 94.8,
40.4, 34.5, 23.5, 22.9, 22.7, 22.6.
IR (KBr): 3061–2500 (NH, OH), 1738, 1719 [C(=O)OH], 1588
(C=O) cm–1.
Anal. Calcd for C22H24N2O3: C, 72.50; H, 6.64; N, 7.69. Found: C,
72.24; H, 6.43; N, 7.39.
1H NMR (400.13 MHz, CDCl3): δ = 11.44 (br s, 1 H, NH), 9.90 (br
s, 1 H, OH), 7.48–7.45 (m, 2 H, o-HPh), 7.36–7.34 (m, 3 H, m,p-
HPh), 7.30–7.25 (m, 3 H, m,p-HPh), 6.95–6.93 (m, 2 H, o-HBn), 6.23
(s, 1 H, H-3), 5.65 (s, 1 H, CH=), 5.19 (s, 2 H, CH2-Ph), 3.71 (s, 2
H, NCH2), 2.66 (m, 2 H, CH2COO), 2.54–2.52 (m, 2 H, CH2-7),
2.45–2.43 (m, 2 H, CH2-4), 1.79–1.77 (m, 2 H, CH2-5), 1.77–1.75
(m, 2 H, CH2-6).
13C NMR (100.6 MHz, CDCl3): δ = 187.2, 173.9, 159.2, 139.9,
138.5, 133.1, 130.6, 128.9, 128.2, 127.3, 127.1, 125.9, 125.0, 118.7,
111.8, 94.4, 47.9, 40.9, 35.1, 23.5, 23.2, 23.1, 22.4.
(Z)-4-{[3-Oxo-3-phenyl-1-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-
2-yl)prop-1-en-1-yl]amino}butanoic Acid (10j)
Yield: 0.595 g (63%); yellow solid; mp 60 °C.
IR (KBr): 3057–2500 (NH, OH), 1728 [C(=O)OH], 1643 (N-
CH=CH2), 1592 (C=O) cm–1.
1H NMR (400.13 MHz, CDCl3): δ = 11.22 (br s, 1 H, NH), 8.84 (br
s, 1 H, OH), 7.86–7.84 (m, 2 H, o-HPh), 7.38–7.36 (m, 3 H, m,p-
HPh), 6.74 (dd, J = 15.9, 9.0 Hz, 1 H, HN=CH), 6.17 (s, 1 H, H-3), 5.85
(s, 1 H, CH=), 5.04 (d, J = 15.9 Hz, 1 H, Htrans), 4.82 (d, J = 9.0 Hz,
1 H, Hcis), 3.26 (br s, 2 H, NCH2), 2.65–2.63 (m, 2 H, CH2-7), 2.50–
2.48 (m, 2 H, CH2-4), 2.40–2.38 (m, 2 H, CH2COO), 1.89–1.87 (m,
2 H, CH2CH2CH2), 1.82–1.80 (m, 2 H, CH2-5), 1.74–1.72 (m, 2 H,
CH2-6).
Anal. Calcd for C27H28N2O3: C, 75.68; H, 6.59; N, 6.54. Found: C,
75.38; H, 6.62; N, 6.53.
(Z)-4-{[1-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-
phenylprop-1-en-1-yl]amino}butanoic Acid (10g)
Yield: 0.564 g (51%); yellow solid; mp 168 °C.
13C NMR (100.6 MHz, CDCl3): δ = 188.6, 177.7, 159.6, 140.8,
132.2, 131.4, 130.8, 128.9, 127.7, 125.7, 120.3, 113.6, 104.6, 95.2,
44.7, 31.8, 26.1, 24.4, 23.9, 23.6, 23.5.
IR (KBr): 3060–2500 (NH, OH), 1710 [C(=O)OH], 1586 (C=O)
cm–1.
Anal. Calcd for C23H26N2O3: C, 72.99; H, 6.92; N, 7.40. Found: C,
72.64; H, 6.57; N, 7.44.
1H NMR (400.13 MHz, CDCl3): δ = 11.28 (br s, 1 H, NH), 10.54 (br
s, 1 H, OH), 7.53–7.51 (m, 2 H, o-HPh), 7.28–7.25 (m, 6 H, Ph),
6.91–6.89 (m, 2 H, o-HBn), 6.17 (s, 1 H, H-3), 5.68 (s, 1 H, CH=),
5.15 (s, 2 H, CH2-Ph), 3.35–3.33 (m, 2 H, NCH2), 2.54–2.52 (m, 2
H, CH2-7), 2.46–2.44 (m, 2 H, CH2-4), 2.36–2.33 (m, 2 H,
CH2COO), 1.81–1.79 (m, 2 H, CH2-5), 1.77–1.75 (m, 2 H, CH2-6),
1.75–1.73 (m, 2 H, CH2).
(Z)-2-{[3-Oxo-3-phenyl-1-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-
2-yl)prop-1-en-1-yl]amino}-3-phenylpropanoic Acid (10k)
Yield: 0.539 g (49%); yellow solid; mp 104–106 °C.
IR (KBr): 3060–2500 (NH, OH), 1735 [C(=O)OH], 1643 (N-
CH=CH2), 1593 (C=O) cm–1.
13C NMR (100.6 MHz, CDCl3): δ = 187.1, 177.2, 158.8, 140.1,
138.5, 132.8, 130.5, 128.8, 128.1, 127.2, 127.0, 125.9, 125.2, 118.6,
111.7, 93.8, 47.9, 44.4, 29.7, 25.7, 23.5, 23.1, 23.0, 22.4.
1H NMR (400.13 MHz, CDCl3): δ = 11.37 (br s, 1 H, NH), 7.86–
7.84 (m, 2 H, o-HPh), 7.38–7.36 (m, 3 H, m,p-HPh), 7.19–7.17 (m, 3
H, m,p-HPh), 7.15–7.13 (m, 2 H, o-HPh), 6.39 (dd, J = 16.0, 8.6 Hz,
1 H, HN=CH), 5.75 (s, 1 H, H-3), 5.73 (s, 1 H, CH=), 4.85 (d, J = 16.0
Hz, 1 H, Htrans), 4.64 (d, J = 8.6 Hz, 1 H, Hcis), 4.58 (br s, 1 H, OH),
Anal. Calcd for C28H30N2O3: C, 75.99; H, 6.83; N, 6.33. Found: C,
75.81; H, 6.60; N, 5.97.
Synthesis 2012, 44, 2084–2090
© Georg Thieme Verlag Stuttgart · New York

PAPER
Hydroamination of 2-Benzoylethynyl-4,5,6,7-tetrahydroindoles
2089
4.43–4.41 (m, 1 H, CHCOO), 3.21–3.18 (m, 1 H, CH2Ph), 3.03–
2.97 (m, 1 H, CH2Ph), 2.59–2.57 (m, 2 H, CH2-7), 2.42–2.40 (m, 2
H, CH2-4), 1.77–1.75 (m, 2 H, CH2-5), 1.71–1.69 (m, 2 H, CH2-6).
13C NMR (100.6 MHz, CDCl3): δ = 188.3, 174.7, 157.7, 140.2,
136.7, 131.8, 130.9, 130.1, 129.8, 128.4, 128.3, 127.3, 126.8, 124.4,
119.7, 113.4, 104.3, 95.8, 59.8, 40.3, 23.9, 23.3, 23.0, 22.9.
Anal. Calcd for C35H33N3O3: C, 77.32; H, 6.12; N, 7.73. Found: C,
76.94; H, 6.01; N, 7.38.
(Z)-3-(1H-Indol-3-yl)-2-{[3-oxo-3-phenyl-1-(1-vinyl-4,5,6,7-tet-
rahydro-1H-indol-2-yl)prop-1-en-1-yl]amino]propanoic Acid
(11c)
Yield: 0.802 g (67%); yellow solid; mp 96–98 °C.
Anal. Calcd for C28H28N2O3: C, 76.34; H, 6.41; N, 6.36. Found: C,
76.66; H, 6.52; N, 5.99.
IR (KBr): 3425 (NH of indole), 3057–2500 (NH, OH), 1733
[C(=O)OH], 1643 (N-CH=CH2), 1592 cm–1.
1H NMR (400.13 MHz, CDCl3): δ = 11.44 (br s, 1 H, NH), 8.29 (br
s, 1 H, NH of indole), 7.85–7.83 (m, 2 H, o-HPh), 7.40–7.36 (m, 5
H, m,p-HPh, CH-4 of indole, OH), 7.23–7.21 (m, 1 H, CH-7 of in-
dole), 7.07–7.04 (m, 2 H, CH-2,6 of indole), 6.97–6.94 (m, 1 H,
CH-5 of indole), 6.38 (dd, J = 15.6, 9.0 Hz, 1 H, HN=CH), 5.81 (s, 1
H, H-3 of pyrrole), 5.78 (s, 1 H, CH=), 4.86 (d, J = 15.6 Hz, 1 H,
Amino Acids 11a–c; General Procedure
A soln of 2-benzoylethynyl-4,5,6,7-tetrahydroindole 1–3 (2.5
mmol), tryptophan (8) (2.5 mmol) and NaOH (2.5 mmol) in EtOH–
H2O (1:1, 16 mL) was heated at reflux temperature for 40 h. After
cooling to r.t., the mixture was diluted with H2O (50 mL) and ex-
tracted with Et2O (5 × 30 mL). The combined organic layer was
washed with H2O (5 × 30 mL), dried over MgSO4 and evaporated.
The residue was purified by flash chromatography on alumina
(Et2O–n-hexane, 1:5, then Et2O) to give the pure product as a yel-
low solid.
Htrans), 4.60 (d, J = 9.0 Hz, 1 H, Hcis), 4.57 (m, 1 H, CH), 3.29–3.20
(m, 2 H, CH2Ph), 2.54–2.52 (m, 4 H, CH2-7,4), 1.80–1.71 (m, 4 H,
CH2-5,6).
13C NMR (100.6 MHz, CDCl3): δ = 187.2, 173.2, 157.1, 140.3,
136.7, 131.5, 131.4, 130.6, 128.8, 127.6, 127.3, 124.6, 121.4, 119.2,
118.8, 118.6, 113.1, 111.8, 111.1, 109.2, 104.9, 95.0, 58.5, 41.6,
23.5, 23.0, 22.9, 21.8.
(Z)-3-(1H-Indol-3-yl)-2-{[1-(1-methyl-4,5,6,7-tetrahydro-1H-
indol-2-yl)-3-oxo-3-phenylprop-1-en-1-yl]amino}propanoic
Acid (11a)
Yield: 0.829 g (71%); yellow solid; mp 128–130 °C.
Anal. Calcd for C30H29N3O3: C, 75.13; H, 6.10; N, 8.76. Found: C,
75.40; H, 6.39; N, 8.66.
IR (KBr): 3412 (NH of indole), 3084–2500 (NH, OH), 1732
[C(=O)OH], 1589 cm–1.
2-Acetyl-4,5,6,7-tetrahydroindole (17)
1H NMR (400.13 MHz, CDCl3): δ = 11.53 (br s, 1 H, NH), 8.45 (br
s, 1 H, NH of indole), 7.87–7.85 (m, 2 H, o-HPh), 7.40–7.37 (m, 2
H, m-HPh), 7.36–7.34 (m, 1 H, p-HPh), 7.33–7.30 (m, 1 H, CH-4 of
indole), 7.22–7.20 (m, 1 H, CH-7 of indole), 7.08–7.06 (m, 1 H,
CH-6 of indole), 7.07–7.05 (m, 1 H, CH-2 of indole), 6.95–6.93 (m,
1 H, CH-5 of indole), 6.36 (br s, 1 H, OH), 5.92 (s, 1 H, H-3 of pyr-
role), 5.71 (s, 1 H, CH=), 4.82 (m, 1 H, CH), 3.34–3.32 (m, 1 H,
CH2), 3.22–3.20 (m, 1 H, CH2), 3.02 (s, 3 H, NMe), 2.56–2.54 (m,
2 H, CH2-7), 1.83–1.81 (m, 2 H, CH2-4), 1.79–1.77 (m, 2 H, CH2-
5), 1.70–1.68 (m, 2 H, CH2-6).
A soln of 2-benzoylethynyl-4,5,6,7-tetrahydroindole (16) (620 mg,
2.5 mmol), glycine (4) (189 mg, 2.5 mmol) and NaOH (100 mg, 2.5
mmol) in EtOH–H2O (1:1, 16 mL) was heated at reflux temperature
for 40 h. After cooling to r.t., the mixture was diluted with H2O (50
mL) and extracted with Et2O (3 × 20 mL). The combined organic
layer was dried over MgSO4 and evaporated to afford the title prod-
uct 17. The aqueous layer was neutralized with 10% HCl, extracted
with Et2O (5 × 20 mL) and the combined organic layer dried over
MgSO4. The solvent was evaporated to give benzoic acid (244 mg,
80%).
13C NMR (100.6 MHz, CDCl3): δ = 186.9, 173.4, 157.6, 140.4,
136.7, 132.3, 131.3, 128.8, 127.5, 127.4, 124.8, 124.6, 121.4, 118.8,
118.6, 117.2, 111.8, 110.1, 109.3, 94.5, 58.4, 31.0, 30.4, 23.6, 23.2,
23.1, 22.0.
Yield: 375 mg (91%); yellow oil.
1H NMR (400.13 MHz, CDCl3): δ = 8.94 (br s, 1 H, NH), 6.62 (s, 1
H, H-3), 2.58 (m, 2 H, CH2-7), 2.49 (m, 2 H, CH2-4), 2.33 (s, 3 H,
COMe), 1.79 (m, 2 H, CH2-5), 1.73 (m, 2 H, CH2-6).
Anal. Calcd for C29H29N3O3: C, 74.50; H, 6.25; N, 8.99. Found: C,
74.16; H, 6.18; N, 8.70.
2-Acetyl-1-methyl-4,5,6,7-tetrahydroindole (15a)
A soln of ethyl 3-(1-methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)pro-
pynoate (18) (542 mg, 2.5 mmol), alanine (5) (228 mg, 2.5 mmol)
and NaOH (100 mg, 2.5 mmol) in EtOH–H2O (1:1, 16 mL) was
heated at reflux temperature for 10 h (TLC at this point did not show
any traces of the starting acetylene). After cooling to r.t., the mix-
ture was diluted with H2O (50 mL) and extracted with Et2O (3 × 20
mL). The combined organic layer was dried over MgSO4 and evap-
orated to afford tetrahydroindole 15a.
(Z)-2-{[1-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-
phenylprop-1-en-1-yl]amino}-3-(1H-indol-3-yl)propanoic Acid
(11b)
Yield: 0.950 g (70%); yellow solid; mp 76–78 °C.
IR (KBr): 3421 (NH of indole), 3057–2500 (NH, OH), 1731
[C(=O)OH], 1591 cm–1.
1H NMR (400.13 MHz, DMSO-d6): δ = 11.38 (br s, 1 H, NH), 10.92
(br s, 1 H, NH of indole), 7.39–7.34 (m, 3 H, o-HPh, CH-4 of indole),
7.31–7.23 (m, 8 H, m,p-HPh, CH-7 of indole, OH), 7.13–7.11 (m, 1
H, CH-6 of indole), 7.09–7.06 (m, 1 H, CH-2 of indole), 6.92–6.88
(m, 1 H, CH-5 of indole), 6.82–6.80 (m, 2 H, o-HBn), 5.92 (s, 1 H,
H-3 of pyrrole), 5.49 (s, 1 H, CH=), 4.63 (m, 1 H, CH), 4.52 (s, 2 H,
CH2-Ph), 3.21–3.17 (m, 1 H, CH2), 3.07–3.01 (m, 1 H, CH2), 2.45–
2.43 (m, 2 H, CH2-7), 2.23–2.22 (m, 2 H, CH2-4), 1.65 (m, 4 H,
CH2-5,6).
Yield: 398 mg (89%); yellow oil.
IR (KBr): 1704 (CO) cm–1.
1H NMR (400.13 MHz, CDCl3): δ = 6.71 (s, 1 H, H-3), 3.76 (s, 3 H,
NMe), 2.52–2.48 (m, 4 H, CH2-7,4), 2.35 (s, 3 H, COMe), 1.83–
1.81 (m, 2 H, CH2-5), 1.72–1.70 (m, 2 H, CH2-6).
13C NMR (100.6 MHz, CDCl3): δ = 187.6, 138.2, 129.4, 118.4,
118.0, 32.5, 26.9, 23.3, 22.8, 22.7, 22.1.
13C NMR (100.6 MHz, DMSO-d6): δ = 186.3, 173.8, 157.1, 140.2,
139.3, 136.8, 132.3, 131.1, 129.2, 128.6, 127.6, 127.3, 127.0, 125.9,
125.1, 124.6, 121.4, 118.8, 117.8, 111.9, 110.8, 109.7, 93.7, 65.4,
58.9, 47.0, 23.6, 23.1, 23.0, 22.1.
Acknowledgment
This work was carried out under financial support from the Russian
Foundation of Basic Research (Grant No. 09-03-00064a).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2084–2090

2090
L. N. Sobenina et al.
PAPER
Vasil’tsov, A. M.; Ivanov, A. V.; Trofimov, B. A.
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