Synthesis of 2-phenyl-4,5,6,7-tetrahydro-1H-indoles with a chiral substituent at the nitrogen atom

Article abstract of DOI:10.1007/s10593-012-1049-4

An efficient method has been developed for the enantioselective synthesis of 2-phenyl-4,5,6,7-tetra-hydro-1H-indoles containing chiral substituents at the nitrogen atom. It is based on opening of the epoxide fragment of 1-phenylethynyl-7-oxabicyclo[4.1.0]

Full text of DOI:10.1007/s10593-012-1049-4

Chemistry of Heterocyclic Compounds, Vol. 48, No. 5, August, 2012 (Russian Original Vol. 48, No. 5, May, 2012)
SYNTHESIS OF 2-PHENYL-4,5,6,7-TETRAHYDRO-1H-INDOLES
WITH A CHIRAL SUBSTITUENT AT THE NITROGEN ATOM
I. A. Andreev1, I. O. Ryzhkov1, A. V. Kurkin1*, and M. A. Yurovskaya1
An efficient method has been developed for the enantioselective synthesis of 2-phenyl-4,5,6,7-tetra-
hydro-1H-indoles containing chiral substituents at the nitrogen atom. It is based on opening of the
epoxide fragment of 1-phenylethynyl-7-oxabicyclo[4.1.0]heptane with chiral amines and/or amino acid
esters followed by intramolecular, metal catalyzed cyclization.
Keywords: 2-phenyl-4,5,6,7-tetrahydro-1H-indoles, trans-amino propargylic alcohols, chiral substituent at
nitrogen atom, palladium-catalyzed cyclization.
Current scientific studies in the area of indole chemistry are directed towards the search for convenient
and efficient methods to prepare indole derivatives containing a tetrahydroindole fragment in their structure.
The increased interest in this heterocyclic system relates to the occurrence of tetrahydroindoles in many natural
compounds, e.g. this component occurs in the molecule of the alkaloid dragmacidin F [1-4].
Ph
Ph
O
HO
POCl3
Ph
CH
MCPBA
CH2Cl2
BuLi, THF
–78°C
Py, C6H6
90%
–10 – 0°C
80%
82%
1
2
3
Ph
Ph
Pd(OAc)2, MeCN
or
R*NH2
AgNO3, THF
Ph
HO
O
N
LiClO4
MeCN
NHR*
73–80% (from 4)
R*
6a–c
5a–c
4
a R = CH(Me)Ph, b R = CH(CH2Ph)COOEt, c R = CH(CH2Ph)COO-t-Bu
_______
*To whom correspondence should be addressed, e-mail: kurkin@direction.chem.msu.ru.
1M. V. Lomonosov State University, 1 Build. 3 Leninskie Gory, Moscow 119991, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 769-774, May, 2012. Original
article submitted March 15, 2012.
0009-3122/12/4805-0715©2012 Springer Science+Business Media, Inc.
715

As a result of the synthesis of indole derivatives from amino propargylic alcohols it is possible to obtain
N-substituted tetrahydroindoles, which contain substituents (of different nature) only in the position 2 of the
pyrrole ring. It should be noted that this method has a broad potential for the synthesis of indoles with a chiral
substituent at the nitrogen atom.
In this work, we have shown the possibility of using amines containing a chiral substituent at the nitrogen
atom (e.g., (S)-(1-phenyl)ethylamine or natural amino acid esters) as N-nucleophiles for opening an epoxide and for
subsequent transformation of the trans-aminoethanols thus obtained to tetrahydroindoles. The route presented is an
efficient method for the preparation of novel, enantiomerically pure 2-phenyl-4,5,6,7-tetrahydro-1H-indoles.
The first stage of the synthesis was the addition of lithium acetylide (prepared in situ from
phenylacetylene and butyl lithium) to cyclohexanone (1). Cerium acetylides have been used previously [5] in
the preparation of tertiary alcohols, but in our case the reaction occurs with the more readily available lithium
phenylacetylide to give the tertiary alcohol 2 in high yield (82%).
We used the system POCl3–pyridine [6] for the dehydration of the tertiary alcohol 2. The absence of
heating and the weak acidity of the medium allows to avoid possible side processes, e.g. isomerization of a
propargylic cation to an allene system.
In our case, a most convenient reagent for preparation of epoxide 4 proved to be m-chloroperbenzoic
acid (m-CPBA) [7]. The epoxidation was carried out under standard conditions using a 20-30% excess of
m-CPBA. It should be noted that commercially available m-CPBA contains traces of water, hence we initially
dissolved the acid in methylene chloride and dried it using anhydrous sodium sulfate. The solution obtained was
added to the alkene with stirring below 0ºC. Ignoring this simple operation lowered the yields by 10-20%. It
was important to maintain the temperature conditions when carrying out the reaction since the m-chlorobenzoic
acid (pKa 3.82) present as an admixture in the m-CPBA is a much stronger acid than the m-CPBA itself (pKa
7.57), and this can lead to an undesired rearrangement of the carbon framework. Despite the possibility of the
epoxidation of acetylenes to oxirenes [8], the products of epoxidation at the triple bond (or the corresponding
ketone products of their rearrangement) were not observed.
Subsequent synthetic use of the epoxide 4 obtained was based on its opening by (S)-(1-phenyl)-
ethylamine and amino acid esters. Several efficient methods for such conversion under mild conditions have
recently been developed using Lewis acids (to increase the electrophilicity of the epoxide) [9] or with the initial
generation of anions from amines (to increase the nucleophilicity of the amine) [10]. Thus, we have employed
lithium perchlorate [9] as a catalyst for the nucleophilic opening of the obtained epoxide 4.
Under the influence of the nucleophiles the opening of the ring occurs by a bimolecular nucleophilic
substitution mechanism (SN2 mechanism). With the presence of the phenylethynyl substituent in the epoxide
ring, the nucleophilic attack is directed to the less substituted carbon atom, and the reaction occurs
stereoselectively with retention of configuration. The nucleophilic addition to the epoxide was carried out at
60-65ºC in acetonitrile, in the presence of 1.5 to 2.0 equivalents of the amine (or amino acid ester) and
1.5 equivalents of lithium perchlorate. The reaction of epoxide 4 with natural amino acid esters or with (S)-(1-phe-
1
nyl)ethylamine gave a 1:1 ratio mixture of the diastereomers 5a-c (determined by H NMR spectroscopy). If
needed, this mixture can be separated chromatographically. In our case, the separation of the diastereomeric
mixture was not required, since the metal-catalyzed cyclization gave a single tetrahydroindole with a chiral
substituent at the nitrogen atom.
Methods for the cyclization of amino propargylic and related systems to pyrroles using mercury salts
[11] and catalysts based on gold [12], copper [13], silver [14], and palladium [15] have been reported in the
literature.
As catalysts, we have used palladium acetate or silver nitrate. In the case of the palladium acetate, the
reaction mixture was refluxed in acetonitrile for 2 h, while with silver nitrate it was refluxed in THF for 1 h. The
course of the reaction was monitored by TLC. The yields of the obtained tetrahydroindoles 6a-c are given in
Table 1 and are based on compound 4 (opening of the epoxide with a nucleophile and the subsequent
cyclization to the corresponding tetrahydroindole 6).
716

TABLE 1. Yields of the Cyclization Products of the Amino Propargylic
Alcohols to Tetrahydroindoles
Compound
R
Yield*, %
ee*2, %
75 (64)
80 (66)
99 (98)
70 (67)
6a
6b
Me
Ph
Ph
CO2Et
73
98
6c
Ph
CO Bu
-t
2
_______
* Cyclization yield using silver nitrate as a catalyst is reported in the
brackets.
*2 Enantiomeric excess when cyclized using silver nitrate as a catalyst is
reported in the brackets.
The obtained tetrahydroindole derivatives showed optical activity. An HPLC analysis with a chiral
stationary phase showed that the enantiomeric excess of compounds 6a,c at the final stage was greater than
98%, while that of compound 6b did not exceed 70%. Racemization depends on the nature of the functional
groups bonded to the asymmetric carbon atom [16]. Hence an explanation of the partial loss of enantiomeric
purity in the tetrahydroindole derivative with the ethyl phenylalanine ester fragment can be related to the
previously reported observation that ethyl esters of amino acid derivatives are more readily racemized than tert-
butyl esters [17].
Thus, we have found an optimal approach to the synthesis of enantiomerically pure 2-phenyl-4,5,6,7-
tetrahydro-1H-indoles, which contain a chiral substituent at the nitrogen atom.
EXPERIMENTAL
IR spectra were recorded on a UR-20 instrument using KBr pellets. The 1H and 13C NMR spectra were
recorded on a Bruker Avance-400 spectrometer (400 and 100 MHz respectively) using CDCl3 with TMS as
internal standard. Chromatography and mass spectrometry studies were performed using an Agilent 1200
chromatograph with fluorimetric and diode array detectors (Chiralcel OD-RH column (4.6150 mm), UV
detector (250 nm), mobile phase H2O–MeCN, 2:3, 1 ml/min), and with an ITD-700 mass spectrometric detector
(Finnigan MAT, electron impact ionization, ionization energy 70 eV, mass range m/z 35-400 Da). The specific
rotation was measured on Perkin Elmer 241 (589 nm) and Jasco DIP-360 (589 nm) polarimeters in 5 and 10 cm
cuvettes. Methanol (c = 1.0 M) was used as solvent. The reaction course and the purity of the obtained
compounds was monitored by TLC, using petroleum ether and ethyl acetate as eluent in different ratios and
iodine vapor or KMnO4 solution for visualization. The commercially available (S)-(1-phenyl)ethylamine,
(S)-phenylalanine, phosphoryl chloride, and m-chloroperbenzoic acid were used without purification. The
(S)-phenylalanine ethyl ester hydrochloride was obtained using a standard method by refluxing in ethanol in the
presence of SOCl2 and converted to the free base before being used in the reaction. The tert-butyl ester of
(S)-phenylalanine was prepared as the free base according to a known method [16]. Commercially available
cyclohexanone and phenylacetylene were distilled in vacuo before use.
717

1-(Phenylethynyl)cyclohexanol (2). A 2.5 M solution of BuLi (40 ml, 0.010 mol) in hexane was added
over 15 min to a solution of the phenylacetylene (10.7 g, 0.105 mol) in THF (70 ml) at -78ºC. The reaction
mixture was stirred at this temperature for 15 min. Cooling was stopped and the temperature of the reaction
mixture was gradually raised to 20ºC over 1 h. The reaction mixture was maintained for 10 min at room
temperature, then cooled to -78ºC, and a solution of cyclohexanone (1) (10.8 g, 0.110 mol) in THF (20 ml) was
added dropwise over 10 min and then stirred for a further 30 min. The reaction temperature was again slowly
raised to ambient, 0.1 M aqueous solution of NH4Cl (200 ml) was added to the reaction mixture, and the product
was extracted with CH2Cl2 (3100 ml). The extract was dried over anhydrous sodium sulfate, and the solvent
was evaporated in vacuo. Yield 17.2 g (82%); mp 60-61ºC (petroleum ether) (mp 59-60ºC [18]). The 1H and 13C
NMR spectroscopic parameters were in agreement with the literature [19].
1-(Phenylethynyl)cyclohexene (3). A solution of POCl3 (57 ml, 0.710 mol) in benzene (750 ml) was
added over 30 min to a solution of compound 2 (50 g, 0.284 mol) and pyridine (119 g, 1.700 mol) in benzene
(500 ml) and stirred for 48 h at room temperature. A saturated aqueous solution of NaHCO3 (750 ml) was
added, the organic phase was separated, and the aqueous phase was extracted with additional benzene (500 ml).
The combined organic extracts were dried over anhydrous Na2SO4, the solvent was evaporated in vacuo, and the
residue was distilled in vacuo. Yield 41 g (90%); bp 126-130ºC (1 mm Hg) (bp 106ºC (0.6 mm Hg) [20]). The
1H and 13C NMR spectroscopic parameters agreed with the literature [20].
1-Phenylethynyl-7-oxobicyclo[4.1.0]heptane (4) was prepared according to a known method [20].
Opening of the Epoxide 4 by Amines (General Method). The amine (37.7 mmol) and LiClO4 (4.01 g,
37.7 mmol) were added to a solution of the epoxide 4 (4.96 g, 25.0 mmol) in MeCN (25 ml). The reaction
mixture was held for 16 h at 65ºC, cooled, poured into water (100 ml), and extracted with CH2Cl2 (3100 ml).
The organic extracts were dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The residue
was separated by chromatography on a silica gel column using petroleum ether–ethyl acetate (10:1). The
mixture of diastereomers 5a-c was obtained and used in the subsequent cyclization without separation.
Metal-Catalyzed Cyclization of the Amino Propargyl Alcohols 5a-c to 4,5,6,7-tetrahydroindoles
(General Method). A. Pd(OAc)2 (2.2 mg, 0.01 mmol) was added to a solution of the amino propargylic alcohol
derivative 5a-c (1.00 mmol) in MeCN (10 ml), and the reaction mixture was refluxed for 2 h. The course of the
reaction was monitored by TLC. The catalyst was filtered off, the organic solvent was removed in vacuo, and
the residue was separated by chromatography on a silica gel column using petroleum ether–ethyl acetate (100:1)
as eluent.
B. AgNO3 (1.70 mg, 0.01 mmol) was added to a solution of the amino propargylic alcohol derivative
5a-b (1.00 mmol) in THF (10 ml). The reaction mixture was refluxed for 1 h. The course of the reaction was
monitored by TLC. The organic solvent was removed in vacuo and the residue was separated by
chromatography on a silica gel column using petroleum ether–ethyl acetate (100:1) as eluent.
2-Phenyl-1-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydro-1H-indole (6a). Yield 75% (method A), 64%
(method B). []D +8.4º, ee 99% (HPLC, S 24.5 min, R 27.8 min). IR spectrum, , cm-1: 3054, 2931, 2856,
20
1
1490, 1444, 1371, 1108, 1056. H NMR spectrum, , ppm (J, Hz): 1.53-1.65 (1H, m) and 1.66-1.82 (3H, m,
5,6-СН2); 1.86 (3H, d, J = 7.1, CH3CH); 1.92-2.06 (1H, m) and 2.42-2.53 (1H, m, 4-СН2); 2.53-2.68 (2H, m,
7-СН2); 5.59 (1H, q, J = 7.1, СH3CH); 6.07 (1H, s, Н-3); 7.04-7.11 (2H, m, Н Ph); 7.21-7.44 (8H, m, Н Ph).
13C NMR spectrum, , ppm: 19.8; 23.4; 23.6; 23.7; 24.4; 52.9; 107.5; 118.6; 126.0 (2С); 126.7; 126.7; 128.3
(2С); 128.4 (2C); 129.2; 129.3 (2С); 134.5; 134.7; 142.9. Mass spectrum, m/z (Irel, %): 301 [M]+ (48), 197
(100), 196 (26), 169 (53), 105 (87), 79 (19), 77 (29), 65 (11). Found, %: C 87.69; H 7.77; N 4.59. C22H23N.
Calculated, %: C 87.66; H 7.69; N 4.65.
Ethyl (2S)-3-Phenyl-2-(2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)propionate (6b). Yield 80%
(method A), 66% (method B). []D +6.9º, ee 70% (HPLC: S 19.5 min, R 17.6 min). IR spectrum, , cm-1:
20
3109, 2940, 2875, 1750, 1507, 1420, 1380, 1110, 1052. 1H NMR spectrum, , ppm (J, Hz): 1.31 (3Н, t, J = 7.2,
CH2CH3); 1.75-1.90 (3H, m) and 1.90-2.02 (1H, m, 5,6-СН2); 2.49-2.64 (3H, m) and 2.71-2.82 (1H, m,
4,7-СH2); 3.12 (1H, dd, J = 13.9, J = 9.5) and 3.37 (1H, dd, J = 13.9, J = 5.5, CH2Ph); 4.21-4.35 (2Н, m,
718

CH3CH2); 4.94 (1H, dd, J = 9.5, J = 5.7, CHCH2); 5.84 (1H, s, Н-3); 6.74-6.80 (2H, m, Н Ph); 6.88-6.97 (2H,
m, Н Ph); 7.10-7.20 (3H, m, Н Ph); 7.20-7.27 (3H, m, Н Ph). 13C NMR spectrum, , ppm: 14.4; 23.4; 23.8;
23.9; 24.0; 37.7; 59.4; 61.8; 107.8; 119.0; 126.7; 126.9; 128.0 (2С); 128.4 (2C); 128.6; 129.3 (2С); 129.7 (2C);
133.7; 135.3; 137.4; 171.2. Mass spectrum, m/z (Irel, %): 373 [M]+ (88), 300 (28), 208 (26), 197 (39), 196 (100),
169 (29), 91 (57). Found, %: C 80.42; H 7.21; N 3.62. C25H27NO2. Calculated, %: C 80.40; H 7.29; N 3.75.
tert-Butyl (2S)-3-phenyl-2-(2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)propionate (6c). Yield 73%
(method A). []D +5.1º, ee 98% (HPLC: R 26.8 min, S 27.9 min). IR spectrum, , cm-1: 3087, 2940, 2864,
20
1748, 1510, 1430, 1364, 1140, 1034. 1H NMR spectrum, , ppm (J, Hz): 1.48 (9Н, s, (CH3)3C); 1.74-1.93 (3H,
m) and 1.93-2.04 (1H, m, 5,6-СH2); 2.57-2.72 (3H, m) and 2.78-2.88 (1H, m, 4,7-СН2); 3.19 (1H, dd, J = 14.1,
J = 9.7) and 3.36 (1H, dd, J = 14.1, J = 5.6, CH2Ph); 4.79-4.86 (1H, m, CHCH2); 5.84 (1H, s, Н-3); 6.83-6.95
13
(4H, m, Н Ph); 7.15-7.27 (6H, m, Н Ph). C NMR spectrum, , ppm: 23.5; 23.8; 24.0; 24.3; 28.0 (3С); 37.4;
60.3; 82.1; 107.8; 118.9; 126.6; 126.7; 128.1 (2С); 128.4 (2С); 128.7; 129.3 (2C); 129.7 (2С); 134.0; 135.7;
137.8; 170.0. Mass spectrum, m/z (Irel, %): 401 [M]+ (49), 346 (23), 345 (91), 344 (22), 300 (26), 209 (18), 208
(23), 197 (38), 196 (81), 194 (21), 180 (21), 169 (45), 91 (88), 77 (29), 57 (100), 41 (56). Found, %: C 80.71;
H 7.73; N 3.44. C27H31NO2. Calculated, %: C 80.76; H 7.78; N 3.49.
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