Regioselective synthesis of 1-alkyl-5-(indol-3-yl- and -2-yl)pyrrolidin-2- ones from available reagents

Article abstract of DOI:10.1007/s10593-011-0655-x

The reaction under mild conditions of 1-alkyl-5-hydroxypyrrolidin-2-ones with different indoles having a free 3 position leads exclusively to 1-alkyl-5-(indol-3-yl)pyrrolidin-2-ones but if position 3 is occupied to 1-alkyl-5-(indol-2-yl)pyrrolidin-2-ones.

Full text of DOI:10.1007/s10593-011-0655-x

Chemistry of Heterocyclic Compounds, Vol. 46, No. 10, 2011
REGIOSELECTIVE SYNTHESIS OF 1-ALKYL-
5-(INDOL-3-YL- AND -2-YL)PYRROLIDIN-2-ONES
FROM AVAILABLE REAGENTS
A. V. Sadovoy1*, A. E. Kovrov1, G. A. Golubeva1, and L. A. Sviridova1
The reaction under mild conditions of 1-alkyl-5-hydroxypyrrolidin-2-ones with different indoles having
a free 3 position leads exclusively to 1-alkyl-5-(indol-3-yl)pyrrolidin-2-ones but if position 3 is occupied
to 1-alkyl-5-(indol-2-yl)pyrrolidin-2-ones.
Keywords: 1-alkyl-5-hydroxypyrrolidin-2-ones, 1-alkyl-5-indolylpyrrolidin-2-ones, indoles, amido-
alkylation.
It is known that the combination of pharmacophoric fragments in a single molecule often leads to a
strengthening and/or to a change in the pharmacological properties of the molecule. In this connection there is
significant interest in studying compounds which contain indole and -aminobutyric acid (e.g. -butyrolactone)
fragments in the molecule. A single compound of this type has been synthesized previously [1] but the method
proposed by the authors is inconvenient and is not sufficiently general. Some time ago we carried a simple
synthesis of the 2-alkyl-3-(indol-3-yl- and -2-yl)isoindol-2-ones 1 and 2 [2].
O
R4
R3
N
O
N
R4
N
R2
R1
R1
N
2
1
We suggested that using this method can also prove useful for synthesizing the 1-alkyl-5-(indol-3-yl)-
pyrrolidin-2-ones 3a-k. The 5-hydroxypyrrolidin-2-ones 4a-d needed for this were prepared from succinic
anhydride and the corresponding amines 5a-d.
The intermediate succinamic acids 6a-d were readily prepared by mixing succinic anhydride with the
corresponding amine in stoichiometric quantities in chloroform. Their cyclization to the corresponding imides
7a-d occurs with prolonged refluxing in benzene in a DeanStark apparatus in the presence of equivalent
_______
* To whom correspondence should be addressed, e-mail: sadovoy@mail.ru.
1M. V. Lomonosov State University, Moscow 119992, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1505-1514, October, 2010.
Original article submitted May 17, 2010.
0009-3122/11/4610-1215©2011 Springer Science+Business Media, Inc.
1215

O
O
O
O
H
N
R1 NH2
R1
OH
R1
N
R1
O
+
N
O
5a–d
O
O
7a–d
OH
4a–d
6a–d
4–7 a R1 = Bn, b R1 = CH2CH2C6H4Cl-p, c R1 = sec-Bu, d R1 = CH(Me)Ph
amounts of Et3N and glacial acetic acid. A method has been reported in the literature [3] for reduction of the
succinimides to the corresponding 5-hydroxypyrrolidin-2-ones using sodium borohydride in methanol but
attempts to reproduce this method were unsuccessful. Hence at low temperatures imide 7a remains undissolved
in the reaction mixture and the reduction does not go to completion. On the other hand, at room temperature we
obtained the 4-hydroxybutyric acid N-benzylamide (8) as the product of further reduction.
O
H
NaBH4
Ph
N
N
HO
Ph
O
O
8
7a
We have found that the target 5-hydroxypyrrolidin-2-ones are optimally prepared used a mixture of
methanol and dichloromethane (3:1) as solvent in which imides 7 are completely soluble, even upon cooling.
When compared with the imides 7, whose 1H NMR spectra show all four heterocyclic ring protons in the
form of a singlet, the spectra of compounds 4 are much more complex. Hence the ring protons are no longer
equivalent and are shifted to higher field to different degrees (see Table 1). In addition, an H-5 proton multiplet
is seen in the region of 5 ppm and the signals for the OH group and the alkyl fragment also undergo marked
changes.
Compounds 4c,d were synthesized as a mixture of two diastereomeric pairs, each in the ratio of about
1:1*.
O
R1
N
R3
R1
N
R3
O
R2
R2
4a–d
+
N
N
N
H
H
H
3a–k
10a,b
9a–e
3 a R1 = Bn, R2 = H, b R1 = CH2CH2C6H4Cl-p, R2 = H, c R1 = sec-Bu, R2 = H, d R1 = CH(Me)Ph, R2 = H, e R1 = Bn, R2 = Me,
f R1 = CH2CH2C6H4Cl-p, R2 = Me, g R1 = sec-Bu, R2 = Me, h R1 = CH(Me)Ph, R2 = Me, i R1 = Bn, R2 = C6H4Me-p, j R1 = sec-Bu,
R2 = C6H4Me-p, k R1 = CH(Me)Ph, R2 = C6H4Me-p; 9 a R2 = R3 = H, b R2 = Me, R3 = H, c R2 = C6H4Me-p, R3 = H,
d R2 = H, R3 = Me, e R2 = H, R3 = C6H4Me-p; 10 a R1 = Bn, R3 = Me, b R1 = Bn, R3 = C6H4Me-p
_______
* Compound 4c was prepared and introduced in the subsequent reaction as a mixture with the starting imide 7c
in the ratio of about 3:2 because both compounds 4c and 7c exist as oils which could not be separated
chromatographically. In addition, imide 7c is chemically inert and does not interfere with the subsequent
reaction process. The spectroscopic characteristics of compound 4c were obtained and quoted here after
subtraction of the spectrum of compound 7c from that of the mixture of compounds produced in the reaction.
1216

The 5-hydroxypyrrolidin-2-ones 4a-d were introduced into the reaction with the indoles 9a-e in similar
conditions to those given in the study [2], i.e. in chloroform with a catalytic amount of boron trifluoride etherate,
to give good or satisfactory yields of the corresponding indol-3-yl- (or 2-yl)pyrrolidin-2-ones 3a-k, 10a,b.
1
In the H NMR spectra of the compounds obtained the characteristic broad indole NH proton signal is
retained and their IR spectra show an N–H stretching band. Hence, in contrast to the study [4], the
amidoalkylation occurs exclusively at a carbon atom, even in the absence of a substituent on the indole nitrogen
atom. Analysis of the multiplicity of the aromatic signals shows that, by contrast with [5, 6], the attack is
directed to the pyrrole ring of a neutral indole molecule and not to position 5 or 6 of the indole ring. In contrast
to [7-9] substitution is directed exclusively to the 3 positions when the 2 and 3 positions of the indole ring are
1
unoccupied (compound 9a) as shown by the absence in the H NMR spectra of compounds 3a-d of the
characteristic H-3 indole proton signal in the region of 6.5 ppm.
Compounds 3c,d,g,h,j,k have two chiral centers and were obtained by us as a mixture of two
diastereomeric pairs, each in a ratio close to 1:1.
The study [7] reported a double Wagner-Meerwein type rearrangement which occurred under mild
conditions during the amidoalkylation process. As a result of this rearrangement the substituent at position 2 of
the indole ring shifts to position 3 and the new substituent now occupies its place. We did not observe such a
rearrangement in [2] (compounds 1, 2). In order to reveal whether this rearrangement can occur in the reactions
studied by us here we have compared the compounds pairs 3e, 10a and 3i, 10b which were respectively obtained
from the isomeric indole pairs 9b,d and 9c,e and the hydroxypyrrolidin-2-one 4a. The pairs of compounds
indicated have different physicochemical properties. While their 1H NMR spectra are very similar they, none the
less, have no common signals. We did not observe isomeric reaction products in any of the examples. Hence it
can be considered as confirmed that in this reaction and in the conditions studied the double Wagner-Meerwein
reaction referred to does not occur and the reaction takes place regioselectively. We suggest that the
intermediate carbocation in the literature example [7] has a high stability as a result of the appearance of the
-effect of the neighboring nitrogen atom in the pyrazolidine derivatives.
Indole 9e used for this proof was prepared by us using the following scheme (Experimental).
Me
Me
+
–
1. PhN2 BF4
TsOH, PhH
2. NH3/H2O

EtO
Me
N
N
H
O
O
CO2Et
12
11
Me
Me

1. NaOH
2. HCl
9e
– CO2
CO2Et
N
H
CO2H
N
H
13
14
1
According to H NMR data (Table 1) and TLC, compound 9e does not contain an admixture of the
isomeric 2-(p-tolyl)indole 9c.
1217

TABLE 1. 1H NMR Spectra of the Compounds Prepared
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
1
2
3a
2.20-2.29 (1H, m, H-4); 2.38-2.47 (1H, m, H'-4); 2.56-2.65 (1H, m, H-3);
2.70-2.78 (1H, m, H'-3); 3.61 (1H, d, J = 14.7, CHH'Ph);
4.81 (1H, dd, J = 8.0, J = 6.6, H-5); 5.12 (1H, d, J = 14.6, CHH'Ph);
7.05 (1H, d, J = 2, arom); 7.10-7.17 (3H, m, arom); 7.24-7.34 (4H, m, arom);
7.45 (1H, d, J = 7.5, arom); 7.51 (1H, d, J = 7.9, arom); 8.43 (1H, br. s, NH)
3b
3c
2.15-2.25, 2.34-2.44 (2H, two m, H-4); 2.45-2.55, 2.60-2.65 (2H, two m, H-3);
2.65-2.70, 2.78-2.88 (2H, two m, CH2C6H4); 2.90-3.00, 3.81-3.91 (2H, two m, CH2N);
4.71-4.79 (1H, m, H-5); 6.98-7.54 (9H, m, arom); 8.15 (1H, br. s, NH)
0.76-0.82 (3H, m, CH3CH2); 0.82-0.89, 1.20-1.25 (3H, 2 m, ~3:4, CH3CH);
1.25-1.29, 1.36-1.39, 1.54-1.67, 1.67-1.79 (2H, four m, CH2CH3);
2.10-2.26, 2.39-2.48 (2H, two m, H-4); 2.48-2.55, 2.65-2.79 (2H, two m, H-3);
3.56-3.65, 3.92-4.04 (1H, two m, ~4:3, CHCH3); 4.99-5.05 (1H, m, H-5);
7.12-7.19 (2H, m, arom); 7.20-7.27 (1H, m, arom + CDCl3); 7.39-7.44 (1H, m, arom);
7.58-7.64 (1H, m, arom); 8.15-8.29 (1H, br., NH)
3d
3e
3f
1.65 (3H, d, J = 7.6, CH3); 2.18-2.28, 2.43-2.48 (2H, two m, H-4);
2.48-2.53, 2.66-2.76 (2H, two m, H-3); 4.76-4.82 (1H, m, CHCH3);
4.96-5.06 (1H, m, H-5); 6.84-7.61 (10H, m, arom); 8.29 (1H, br. s, NH)
2.06 (3H, br. s, CH3Ar); 2.21-2.39 (2H, br. m, H-4); 2.58-2.67, 2.69-2.79 (2H, two m, H-3);
3.41 (1H, d, J = 13.8, CHH'Ph); 4.68 (1H, t, J = 7.9, H-5); 5.13 (1H, d, J = 14.3, CHH'Ph);
7.01-7.50 (9H, m, arom); 7.90 (1H, br. s, NH)
2.12-2.22, 2.25-2.35 (2H, 2 m, H-4); 2.39 (3H, s, CH3); 2.44-2.54, 2.56-2.66 (2H, two m, H-3);
2.56-2.66 (1H, m, high field part of CH2N); 2.75-2.85 (2H, m, CH2C6H4);
3.78-3.88 (1H, m, low field part of CH2N); 4.63-4.73 (1H, m, H-5);
6.98-7.54 (8H, m, arom); 7.88 (1H, br. s, NH)
3g
3h
0.72-0.95 (4.6H, m, CH3CH2 + high field part of CH3CH);
1.10-1.31 (2.5H, m, low field part of CH3CH + high field part of CH2CH3);
1.47-1.74 (1.1H, two m, low field part of CH2CH3); 2.15-2.42 (2H, two m, H-4);
2.45 (3H, s, CH3Ar); 2.50-2.63, 2.65-2.81 (2H, two m, H-3);
3.40-3.53, 3.86-3.98 (1H, two m, ~3:2 NCH); 4.90-5.07 (1H, br. m, H-5);
7.03-7.58 (4H, m, arom + CDCl3); 7.94 (1H, br. s, NH)
1.04, 1.71 (3H, two br. d, J1 = 7.3, J2 = 6.9, ~1:1, CH3CH);
1.74, 2.31 (3H, two s, ~1:1, CH3Ar);
2.13-2.46, 2.47-2.58, 2.58-2.73, 2.77-2.89 (4H, four m, ~1.5:1:1:0.5, H-3,4);
4.36-4.55, 5.58 (1H, br. s + q, J = 7.3, CHCH3);
4.55, 4.75-4.95 (1H, t + br. s, ~1:1, J = 7.5, H-5); 6.85-7.55 (9H, m, arom);
7.76, 7.82 (1H, two br. s, ~1:1, NH)
3i
3j
2.28-2.36 (2H, m, H-4); 2.36 (3H, s, CH3); 2.52-2.60, 2.60-2.68 (2H, two m, H-3);
3.49 (1H, d, J = 14.7, CHH'Ph); 4.85-4.91 (1H, m, H-5); 5.10 (1H, d, J = 14.7, CHH'Ph);
6.88-7.57 (13H, m, arom); 8.26 (1H, br. s, NH)
0.56-0.74 (4.4H, m, CH3CH2 + high field part of CH3CH);
1.00 (1.6H, d, J = 6.9, low field part of CH3CH);
1.09-1.18, 1.28-1.40, 1.49-1.60 (2H, three m, ~2:3:2, CH3CH2);
2.31-2.62, 2.45, 2.45 (6H, m + two s, 2H-3+CH3Ar+H-4); 2.68-2.87 (1H, br. m, H'-4);
3.32-3.42, 3.76-3.86 (1H, two m, ~4:3, NCH); 5.03-5.13 (1H, m, H-5);
7.09-7.65 (8H, m, arom); 8.20, 8.22 (1H, two s, ~4:3, NH)
3k
1.03, 1.57 (3H, two d, ~6:7, J = 7.2, CHCH3); 2.42, 2.44 (3H, two s, ~6:7, ArCH3);
2.18-2.30, 2.32-2.50 (2H, two m, ~1:3, H-4);
2.51-2.62, 2.66-2.79, 2.82-2.94 (2H, three m, ~2:1:1, H-3);
4.54, 5.53 (1H, two q, ~7:6, J = 7.3, CHCH3); 4.83 (0.46H, dd, J1 = 5.6, J2 = 3.1, H-5);
5.06 (0.54H, t, J = 7.8, H-5); 6.92-7.63 (13H, m, arom); 8.53 (1H, br. s, NH)
4a
4b
4c
1.84-1.94 (1H, m, H-4); 2.12-2.32 (2H, m, H'-4 + H-3); 2.52-2.65 (1H, m, H'-3);
4.14 (1H, d, J = 14.8, CHH'Ph); 4.83 (1H, d, J = 14.8, CHH'Ph); 5.06 (1H, t, J = 6.5, H-5);
5.50 (1H, br. s, OH); 7.18-7.36 (5H, m, arom)
1.80-1.90, 2.26-2.36, 2.51-2.61 (4H, three m, ~1:2:1, H-3 + H-4); 2.08 (1H, d, J = 8.3, OH);
2.85-2.95 (2H, m, CH2C6H4); 3.40-3.50 (1H, m, CHH'N); 3.67-3.77 (1H, m, CHH'N);
5.01 (1H, t, J = 7.8, H-5); 7.15-7.34 (4H, m, arom)
0.55-0.61 (3H, m, MeCH2); 1.01-1.07 (3H, m, MeCH);
1.30-1.40, 1.44-1.54, 1.56-1.66 (2H, three m, ~1:2:1, MeCH2);
1.67-1.77, 2.00-2.07 (2H, two m, H-4); 2.07-2.10, 2.38-2.48 (2H, two m, H-3);
5.01-5.04 (1H, m, H-5)
1218

TABLE 1 (continued)
1
2
4d 1.59, 2.25 (1H, two d, ~1:1, J = 7.1, OH); 1.65, 1.70 (3H, two d, ~1:1, J = 7.6, CH3);
1.82-1.92, 2.12-2.22 (2H, two m, H-4); 2.30-2.40, 2.62-2.72 (1H, two m, H-3);
4.95, 5.43 (1H, two t, ~1:1, J = 7.0, H-5); 5.40-5.46 (1H, m, CHPh);
7.27-7.53 (5H, m, arom)
7b 2.67 (4H, s, COCH2CH2CO); 2.87 (2H, t, J = 7.7, CH2C6H4); 3.74 (2H, t, J = 7.7, NCH2);
7.16 (2H, d, J = 8.3, arom); 7.27 (2H, d, J = 8.3, arom)
7c 0.65 (3H, two t, ~1:1, J = 7.5, CH3CH2); 1.18 (3Н, two d, ~1:1, J = 7.0, CH3CH);
1.53 (1H, m, СHH'); 1.75 (1H, m, CHH'); 2.50 (4H, two s, ~1:1, CH2CH2);
3.94 (1H, m, CHN)
8
1.87 (2H, m, CH2CH2CH2); 2.36 (2H, t, J = 6.8, CH2CON); 3.42 (1H, br. t, OH);
3.66 (2H, br. m, CH2OH); 4.41 (2H, d, J = 5.7, CH2Ph); 6.44 (1H, br. s, NH);
7.23-7.39 (5H, m, arom)
9e 2.42 (3H, s, CH3); 7.18-7.22 (1H, dt, J1 = 6.9, J2 = 1.1); 7.24-7.29 (3H, m);
7.35 (1H, d, J = 2.5); 7.44 (1H, d, J = 8.7); 7.58 (2H, d, J = 8.1);
7.94 (1H, d, J = 8.7); 8.20 (1H, br. s, NH)
10a 2.09 (3H, s, CH3); 2.13-2.22 (1H, m, H-4); 2.36-2.47 (1H, m, H'-4);
2.55-2.66 (1H, m, H-3); 2.67-2.78 (1H, m, H'-3); 3.49 (1H, d, J = 14.6, CHH'Ph);
4.79 (1H, t, J = 7.6, H-5); 5.07 (1H, d, J = 14.3, CHH'Ph); 7.09-7.16 (3H, m, arom);
7.21 (1H, dt, J1 = 7.5, J2 = 1.1, arom); 7.26-7.34 (3H, m, arom);
7.38 (1H, d, J = 8.1, arom); 7.55 (1H, br. d, J = 7.8, arom); 8.96 (1H, br. s, NH)
10b 2.31-2.41 (1H, m, H-4); 2.49 (3H, s, CH3); 2.51-2.61 (1H, m, H'-4); 2.63-2.71 (1H, m, H-3);
2.80-2.88 (1H, m, H'-3); 3.69 (1H, d, J = 14.4, CHH'Ph);
5.00 (1H, dd, J1 = 8.2, J2 = 6.8, H-5); 5.07 (1H, d, J = 14.4, CHH'Ph);
7.06 (2H, d, J = 7.0, arom); 7.18-7.29 (6H, m, arom); 7.31-7.39 (3H, m, arom);
7.52 (1H, d, J = 8.1, arom); 7.75 (1H, d, J = 7.9, arom); 9.53 (1H, br. s, NH)
14 2.46 (3H, s, CH3); 7.17 (1H, t, J = 7.5, arom); 7.30 (2H, d, J = 7.7, arom);
7.40 (1H, t, J = 7.4, arom); 7.45 (1H, d, J = 8.2, arom); 7.49 (2H, d, J = 7.9, arom);
7.65 (1H, d, J = 8.2, arom); 8.99 (1H, br. s, NH)
In [2] there were discovered rotational isomers of compound 1 with a high barrier to internal rotation
around the -bond between the indole C-3 and the isoindolone C-3 when there was a substituent in position 2 of
the indole ring. We expected that, in our case, a similar effect might occur. However, no indications of hindered
internal rotation were observed in any of the obtained compounds 3, 10. Hence it can be proposed that the
rotational isomerism occurring in compounds 1 compared with compounds 3, 10 is due to the presence of the
additional condensed aromatic ring in the isoindolone fragment of these compounds.
EXPERIMENTAL
IR spectra were recorded on a UR-20 instrument as a thin layer. 1H NMR spectra were taken on a Varian
Avance-400 spectrometer (400 MHz) using DMSO-d6 with the residual signals for DMSO-d6 ( 2.50 ppm) and
CDCl3 ( 7.27 ppm) as internal standards. Mass spectra were recorded on a Bruker Autoflex II instrument.
Elemental analysis for C, H, and N was carried out on a Carlo-Erba ER-20 analyzer. Monitoring of the course of
the reaction and the compounds purity were performed on Silufol UV-254 and Merck Silicagel 60 F254 plates.
Compounds purification was carried out on Merck silica gel (column chromatography, 0.035-0.070 nm, 6 nm
pore diameter, 500 m2/g).
N-Benzylsuccinamic Acid (6a). An equivalent amount of succinic anhydride was added rapidly with
stirring to a solution of benzylamine (5a) in a fivefold excess of chloroform (by volume). After cooling the hot
reaction mixture to room temperature the precipitate formed was filtered off, washed with chloroform, and dried
in air to give white crystals (93%) with mp 135-137ºC (mp 137-139º [10]).
1219

N-(2-p-Chlorophenylethyl)succinamic Acid (6b). Prepared similarly from succinic anhydride and
2-chlorophenylethylamine (5b) as white crystals (97%) with mp 137-138ºC. IR spectrum, , cm-1: 1640
(HNC=O); 1695 (HOC=O); 2670 (OH), 3330 (NH). Found, %: C 56.46; H 5.66; N 5.51. C12H14ClNO3.
Calculated, %: C 56.37; H 5.52; N 5.48.
N-sec-Butylsuccinamic Acid (6c). Prepared from succinic anhydride and sec-butylamine (5c). The
product was cooled and solvent removed in vacuo to give a yellowish, oily residue in about 100% yield which
was used without further purification.
N-(1-Phenylethyl)succinamic Acid (6d). Prepared similarly from succinic anhydride and 1-phenyl-
ethylamine (5d). Removal of most of the solvent in vacuo gave white crystals (87%) with mp 99-100ºC
(mp 100.9-101.1ºC [11]).
Preparation of Imides 7a-d (General Method). Equimolar amounts of acetic acid and triethylamine
were added to a suspension of the corresponding succinamic acid in a tenfold excess of benzene and the product
was refluxed in a Dean and Stark apparatus until the separation of water had ceased (~ 24 h). The mixture
obtained was washed with water, saturated NaHCO3 solution, and then water again. The aqueous phases were
combined and extracted with benzene (2×50 ml). The benzene fractions were combined, dried over MgSO4,
passed through a thin layer of silica, and the solvent was distilled off in vacuo.
N-Benzylsuccinimide (7a). Yield 65%; mp 102-103ºC (mp 102.5-103.5ºC [10]).
N-[2-(p-Chlorophenyl)ethyl]succinimide (7b). Yield 37%; mp 113-115ºC (mp 113-114ºC [12]). IR
spectrum, , cm-1: 1690 (C=O).
N-sec-Butylsuccinimide (7c). Yield ~ 95%. Yellow oil, used without further purification.
N-(1-Phenylethyl)succinimide (7d). Yield 56%; mp 65-66ºC (mp 67-68.5ºC [13]).
Preparation of 1-Alkyl-5-hydroxypyrrolidin-2-ones 4a-d (General Method). Sodium borohydride
(2.36 g, 62.5 mmol) was added over 2 h with stirring keeping at 0 to 5°C to a solution of imide 7a-d (25 mmol)
in a mixture of dichloromethane (30 ml) and methanol (90 ml) which was cooled to 2-3ºC. The reaction mixture
was left overnight at ~ -15ºC, water (30 ml) was added, and the organic solvent was removed by distillation in
vacuo. The precipitate formed was washed several times with water and dried in air. The filtrate was extracted
with dichloromethane (4×20 ml), the extract was dried over MgSO4, and the solvent was distilled off in vacuo.
Both fraction of the reaction product were combined and recrystallized from benzene.
1-Benzyl-5-hydroxypyrrolidin-2-one (4a). White crystals, yield 62%; mp 105-106ºC. IR spectrum, , cm-1:
1640 (C=O), 3175 (OH). Found, %: C 68.91; H 6.72; N 7.14. C11H13NO2. Calculated, %: C 69.09; H 6.85; N 7.32.
5-Hydroxy-1-[2-(p-chlorophenyl)ethyl]pyrrolidin-2-one (4b). White crystals, yield 37%; mp 149-150ºC.
IR spectrum, , cm-1: 1650 (C=O), 3210 (OH). Found, %: C 60.25; H 5.80; N 5.82. C12H14ClNO2. Calculated,
%: C 60.13; H 5.89; N 5.84.
1-sec-Butyl-5-hydroxypyrrolidin-2-one (4c). A precipitate did not form upon dilution with water but a
1
yellow oil was formed which was used without further purification. According to H NMR spectroscopy the
yield was ~ 50%.
5-Hydroxy-1-(1-phenylethyl)pyrrolidin-2-one (4d). White crystals, yield 50%; mp 75-76ºC. IR
spectrum, , cm-1: 1645 (C=O), 3260 (OH). Found, %: C 69.99; H 7.15; N 6.77. C12H15NO2. Calculated, %:
C 70.22; H 7.37; N 6.82.
N-Benzyl-4-hydroxybutaneamide (8). An equimolar amount of NaBH4 was added in several aliquots
with stirring to a suspension of the N-benzylsuccinimide 7a (4.73 g, 25 mmol) in methanol (50 ml). The
suspension dissolved and the solution heated noticeably. The mixture was left overnight at room temperature,
water (30 ml) was added, and the methanol was distilled off in vacuo. The residue was extracted with
chloroform (3×20 ml), the organic layer was dried over MgSO4, passed through a thin silica layer, and solvent
was distilled off in vacuo. The residue was triturated with ether and the crystals formed were filtered off, washed
with ether, and dried in air. The colorless crystals (67%) had mp 70-71ºC (mp 70-72ºC [14]). Found, %:
C 68.80; H 7.46; N 7.11. C11H15NO2. Calculated, %: C 68.37; H 7.82; N 7.25.
1220

Ethyl 3-(p-Tolyl)pyruvate Phenylhydrazone (12). Phenyldiazonium fluoroborate previously prepared
and dried at room temperature (4.86 g, 25.3 mmol) was added with stirring to a solution of 3-(p-methyl-
benzyl)acetoacetic ester (4.93 g, 21.0 mmol) cooled to 2ºC. Et3N (3.5 ml, 25.2 mmol) was added with stirring
and cooling to 3-5ºC to the colorless suspension obtained. The suspension dissolved during the addition process
and became intensely red in color. The mixture was left overnight at room temperature. A 25% solution of NH3
(6.4 ml, 85 mmol) was added portionwise with stirring. The emulsion formed was left overnight and the partially
crystalline precipitate was filtered off, washed with ethanol and then petroleum ether, and dried to give light-red
crystals (0.52 g); mp 73-74ºC and Rf 0.9 (EtOAc–petroleum ether, 2: 3). The organic solvent was distilled off in
vacuo from the combined filtrate. The residual dark-red oil was treated with water, stirred, the aqueous layer
decanted, and the oil was treated with methanol and left overnight to give less pure compound (0.61 g). A
second similar treatment of the filtrate gave further compound (0.22 g). Overall yield 1.35 g (22%). The
compound was used in the subsequent reaction without additional purification.
Ethyl 3-(p-Tolyl)-1H-indole-2-carboxylate (13). A solution of anhydrous p-toluenesulfonic acid in
benzene was prepared by refluxing a suspension of p-toluenesulfonic acid monohydrate (1.04 g, 5.5 mmol) in
benzene (50 ml) with a DeanStark apparatus until the separation of water ceased and the suspension dissolved.
The solution obtained was cooled to room temperature, compound 12 (1.35 g, 4.6 mmol) was added, and the
mixture obtained was refluxed for 4 h with stirring. The mixture with the ammonium tosylate precipitate
produced was cooled to room temperature, washed with water (3×50 ml), the organic layer was dried over
MgSO4, and passed through a silica layer. The adsorbent was washed with benzene and then chloroform.
Solvent was removed from the combined eluate in vacuo and the residue was triturated with ether. The
precipitate formed was filtered off and washed with ether to give a yellow powder with mp 142-144ºC and Rf
0.5 (chloroform). The filtrate was diluted with petroleum ether and most of the solvent was distilled off in
vacuo. Trituration of the residue gave less pure reaction product. Overall yield 0.62 g (49%). The compound was
used in the subsequent reaction without further purification.
3-(p-Tolyl)-1H-indole-2-carboxylic Acid (14). A solution of NaOH (0.17 g, 4.25 mmol) in water
(2 ml) was added to a suspension of ester 13 (0.61 g, 2.2 mmol) in methanol (15 ml). The mixture was refluxed
for 5 h, cooled, methanol distilled off in vacuo, and the semicrystalline residue was treated with water (15 ml)
and filtered hot. The filtrate was cooled to room temperature, acidified with stirring using dilute HCl (1:1), and
the suspension obtained was stirred for 2 h, the precipitate filtered off, washed several times with water, and
dried. Light-yellow powder, yield 0.47 g (85%); mp 222-226ºC (decomp.) and Rf 0.05 (chloroform). Found, %:
C 76.03; H 4.77; N 5.71. C16H13NO2. Calculated, %: C 76.48; H 5.21; N 5.57.
3-(p-Tolyl)-1H-indole (9e). Acid 14 (0.43 g, 1.7 mmol) was heated for 3 h at 210-220ºC in a test tube
filled with inert gas. The vessel contents darkened and decomposed with the evolution of gas. The reaction
products were removed using chloroform, solvent was distilled off in vacuo, the residue was treated with warm
benzene, the solution passed through a silica layer, the solvent was removed in vacuo, and the residue was
recrystallized from heptane. Yield 0.24 g (69%); mp 100-101ºC (mp 107-108ºC [15]). Rf 0.62 (chloroform), 0.56
(EtOAc–hexane, 2:3)*. Found, %: C 87.41; H 6.64; N 6.52. C15H13N. Calculated, %: C 86.92; H 6.32; N 6.76.
1
According to H NMR and TLC data the compound is pure and does not contain an admixture of the
2-(p-tolyl)-1H-indole 9c.
Preparation of 1-Alkyl-5-indolylpyrrolidin-2-ones 3a-k, 10a,b (General Method). Indole 9a-e
(1 mmol) and about 0.01 ml (~ 0.1 mmol) of boron trifluoride etherate were added with stirring to a solution of
the 1-alkyl-5-hydroxypyrrolidin-2-one 4a-d (1 mmol) in chloroform (8 ml). The reaction mixture was stirred for
several hours at room temperature, left overnight, and then passed through a thin silica layer. Solvent was
evaporated in vacuo, the residue was triturated with ether, and the precipitate was filtered off, washed with ether,
and dried.
_______
* For the isomeric 2-(p-tolyl)-1H-indole (9c) in this system Rf = 0.75.
1221

1-Benzyl-5-(1H-indol-3-yl)pyrrolidin-2-one (3a). Yield 43%; mp 192-194ºC. IR spectrum, , cm-1:
1670 (C=O), 3260 (NH). Found, %: C 78.64; H 6.31; N 9.44. C19H18N2O. Calculated, %: C 78.59; H 6.25;
N 9.65.
1-[2-(p-Chlorophenyl)ethyl]-5-(1H-indol-3-yl)pyrrolidin-2-one (3b). Yield 25%; mp 245-246ºC. IR
spectrum, , cm-1: 1665 (C=O); 3170 (NH). Found, %: C 71.34; H 5.51; N 8.21. C20H19ClN2O. Calculated, %:
C 70.90; H 5.65; N 8.27.
1-sec-Butyl-5-(1H-indol-3-yl)pyrrolidin-2-one (3c). Yield 31%; mp 170-172ºC. IR spectrum, , cm-1:
1660 (C=O); 3230 (NH). Found, %: C 74.89; H 8.03; N 10.59. C16H20N2O. Calculated, %: C 74.97; H 7.86;
N 10.93.
5-(1H-Indol-3-yl)-1-(1-phenylethyl)pyrrolidin-2-one (3d). Yield 25%; mp 187-189ºC. IR spectrum, ,
cm-1: 1665 (C=O), 3180 (NH). Found, %: C 78.70; H 6.45; N 9.11. C20H20N2O. Calculated, %: C 78.92; H 6.62;
N 9.20.
1-Benzyl-5-(2-methyl-1H-indol-3-yl)pyrrolidin-2-one (3e). Yield 33%; mp 228-230ºC. IR spectrum,
, cm-1: 1670 (C=O), 3200 (NH). Found, %: C 78.56; H 6.72; N 8.94. C20H20N2O. Calculated, %: C 78.92;
H 6.62; N 9.20.
5-(2-Methyl-1H-indol-3-yl)-1-[2-(p-chlorophenyl)ethyl]pyrrolidin-2-one (3f). Yield 21%; mp 199-200ºC.
IR spectrum, , cm-1: 1665 (C=O), 3165 (NH). Found, %: C 71.75; H 6.72; N 7.84. C21H21ClN2O. Calculated,
%: C 71.48; H 6.00; N 7.94.
1-sec-Butyl-5-(2-methyl-1H-indol-3-yl)pyrrolidin-2-one (3g). Yield 19%; mp 151-152ºC. IR
spectrum, , cm-1: 1665, 1670 (C=O), 3200 (NH). Found, %: C 75.46; H 8.48; N 10.01. C17H22N2O. Calculated,
%: C 75.52; H 8.20; N 10.36.
5-(2-Methyl-1H-indol-3-yl)-1-(1-phenylethyl)pyrrolidin-2-one (3h). Yield 27%; mp 180-182ºC. IR
spectrum, , cm-1: 1665 (C=O), 3195 (NH). Found, %: C 79.47; H 7.18; N 8.66. C21H22N2O. Calculated, %:
C 79.21; H 6.96; N 8.80.
1-Benzyl-5-(2-p-tolyl-1H-indol-3-yl)pyrrolidin-2-one (3i). Yield 66%; mp 230-232ºC. IR spectrum, ,
cm-1: 1655 (C=O), 3160 (NH). Found, %: C 82.32; H 6.38; N 7.29. C26H24N2O. Calculated, %: C 82.07; H 6.36;
N 7.36.
1-sec-Butyl-5-(2-p-tolyl-1H-indol-3-yl)pyrrolidin-2-one (3j). Yield 39%; mp 201-202ºC. IR spectrum,
, cm-1: 1660 (C=O), 3235 (NH). Found, %: C 80.22; H 7.66; N 8.06. C23H26N2O. Calculated, %: C 79.73; H
7.56; N 8.09.
5-(2-p-Tolyl-1H-indol-3-yl)-1-(1-phenylethyl)pyrrolidin-2-one (3k). Yield 28%; mp 226-227ºC. IR
spectrum, , cm-1: 1660 (C=O), 3260 (NH). Mass spectrum (MALDI). Found: m/z 362. C27H26N2O. Calculated:
M
calc = 394. Mcalc-55 (C3H3O) + 23 (Na) = 362.
1-Benzyl-5-(3-methyl-1H-indol-2-yl)pyrrolidin-2-one (10a). Yield 22%; mp 140-142ºC. IR spectrum,
, cm-1: 1655 (C=O), 3200 (NH). Found, %: C 78.86; H 6.77; N 8.98. C20H20N2O. Calculated, %: C 78.92;
H 6.62; N 9.20.
1-Benzyl-5-(3-p-tolyl-1H-indol-2-yl)pyrrolidin-2-one (10b). Yield 22%; mp 202-203ºC. IR spectrum,
, cm-1: 1665 (C=O), 3200 (NH). Found, %: C 81.78; H 6.92; N 7.20. C26H24N2O. Calculated, %: C 82.07;
H 6.36; N 7.36.
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