Synthesis and spectral features of new 1-alkyl-5-(indol-2(3)-yl)pyrrolidin- 2-ones

Article abstract of DOI:10.1007/s10593-013-1185-5

The mass spectrometric behavior of 1-alkyl-5-(1H-indol-2-yl)pyrrolidin-2- ones and 1-alkyl-5-(1H-indol-3-yl)pyrrolidin-2-ones was studied and the fragmentation of these compounds was established. The product of N-methylindole reaction with 1-benzyl-5-hydroxypyrrolidin-2-one was shown to be 1-benzyl-5-(1-methylindol-3-yl)pyrrolidin-2-one.

Full text of DOI:10.1007/s10593-013-1185-5

Chemistry of Heterocyclic Compounds, Vol. 48, No. 11, February, 2013 (Russian Original Vol. 48, No. 11, November, 2012)
SYNTHESIS AND SPECTRAL FEATURES OF NEW
1-ALKYL-5-(INDOL-2(3)-YL)PYRROLIDIN-2-ONES
N. E. Mysova2, A. E. Kovrov 1, A. V. Sadovoy1*, L. A. Sviridova1,
G. A. Golubeva1, and N. I. Vorozhtsov1
The mass spectrometric behavior of 1-alkyl-5-(1H-indol-2-yl)pyrrolidin-2-ones and 1-alkyl-5-(1H-indol-
3-yl)pyrrolidin-2-ones was studied and the fragmentation of these compounds was established. The
product of N-methylindole reaction with 1-benzyl-5-hydroxypyrrolidin-2-one was shown to be
1-benzyl-5-(1-methylindol-3-yl)pyrrolidin-2-one.
Keywords: 5-hydroxypyrrolidin-2-ones, indoles, amidoalkylation, mass spectrometry.
In previous work [1], we reported the synthesis of new 1-alkyl-5-(1H-indolyl)pyrrolidin-2-ones 1 and
2, and found that these compounds do not undergo the Plancher rearrangement during their formation.
1
However, in a continuation of this research, we found that the H NMR signal at 6.88 ppm, which
belongs to the indole system pyrrole ring proton in the product obtained from N-methylindole (3e) and 1-benzyl-
5-hydroxypyrrolidin-2-one (4a), appears almost exactly in the middle between the signals for H-3 (6.45 ppm)
and H-2 (7.26 ppm) in unsubstituted indole [2]. Thus, the spectrum does not permit us to establish the
substitution pattern of the indole system, i.e., to clearly distinguish between the structures 1d and 2b (Table 1).
In order to resolve this problem, we investigated the mass spectrometric behavior of compounds 1a-g
and 2a.
Compounds 1a-g and 2a were prepared from the indoles 3a-f and 1-alkyl-5-hydroxypyrrolidin-2-ones
4a and 4b according to our published procedure [1].
The proposed schemes for electron impact fragmentation of indoles 1a-g and 2a are given in Figures
1-3. The numbering sequence of the fragment ions and the quantitative characteristics of this fragmentation are
given in Tables 2 and 3.
_______
*To whom correspondence should be addressed, e-mail: sadovoy@mail.ru.
1M. V. Lomonosov Moscow State University, 1, Build. 3 Leninskie Gory, Moscow 119991, Russia.
2A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova St.,
Moscow 119991, Russia; e-mail: nemysova@yandex.ru.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1748-1754, November, 2012.
Original article submitted May 3, 2012.
1634
0009-3122/13/4811-1634©2013 Springer Science+Business Media New York

O
R3
N
(R2 = H)
R1
R2
N
O
BF3·Et2O
R1
+
R
1a–g
N
N
R2
HO
R3
R
4a,b
3a–f
(R1 = H
R2 = H)
N
R3
N
O
/
R
2a,b
1 a R = H, R1 = Me, R3 = Bn; b R = H, R1 = Ph, R3 = Bn; c R = Me, R1 = Ph, R3 = Bn;
d R = Me, R1 = H, R3 = Bn; e R = R1 = Me, R3 = s-Bu; f R = H, R1 = Ph, R3 = s-Bu;
g R = Me, R1 = Ph, R3 = s-Bu; 2 a R = H, R2 = Me, R3 = Bn; b R = Me, R2 = H, R3 = Bn;
3 a R = R2 = H, R1 = Me; b R = R2 = H, R1 = Ph; c R = R1 = H, R2 = Me;
d R = Me, R1 = Ph, R2 = H; e R = Me, R1 = R2 = H; f R = R1 = Me, R2 = H;
4 a R3 = Bn, b R3 = s-Bu
O
HN
C+
N+ R3
CH2
R1,2
–HNCO
R1,2
N+
N
R1
N
F2+
–C2H2
R
F8+
R
R
F1+
–R3·
+
R1,2
C7H7
F15+
–C2H5CO·
N+
R
O
F12+
–H·
R3
N+
F14+ H
N
–R3NCO
–C2H2
Me
R1,2
R1,2
N+
N+·
·
F11+·
N+
R3
R
M+·
–R3NCOCH2
O
R
·
–H2
F7+·
·
CH2
–H·
F10+
N+
N+
R
R1,2
·
H
F13+·
F9+·
Fig. 1. Proposed scheme for the general mass spectral fragmentation pathways of indoles 1a-g and 2a.
The mass spectral fragmentation of indoles 1e-g differs from the fragmentation of indoles 1a-d by
greater diversity, where the additional fragmentation directions are shown in Figure 2. These features are
attributed to the significant difference in the stability of sec-butyl and benzyl fragments. The quantitative
characteristics of the additional fragmentation directions for indoles 1e-g are given in Table 3.
1635

1636

1637

H
O
C+
CH2
O
Me
Me
N+
N+
H
N+
F22+
–H·
F24+
O
Me
F23+
O
Me
R1
–C2H5·
–F24·
Me
N
N
F16+
Me
R
O
O
R1
N+
–C2H4
O
N+
–C4H10N·
N+·
F21+·
·
·
Me
Me
M+·
R
F7+·
–C4H8
–F7
R1
O
HN
N+
R
HN+
F18+
R1
–C2H2
–CHO·
R1
–HNCHO·
R1
F12+
F8+
N+
N+
R
·
N
R
·
R
F20+·
F19+
F17+·
Fig. 2. Proposed scheme for the mass spectral fragmentation pattern of indoles 1e-g due to the presence of
sec-butyl group.
The data in Table 2 indicate that the mass spectral behavior of indole 2a is similar to the behavior of
indoles 1a-d, but there are two significant differences. The most noticeable of them is the presence of fragment
ions F3-F6, whose formation is outlined in Figure 3. However, as Figure 3 indicates, this feature cannot serve as
a criterion for distinguishing between indoles 1d and 2b, since it is due not only to localization of the
pyrrolidinone fragment at the C-2 position of indole, but also to the absence of a substituent at the indole N-1
atom.
Me
Me
–C7H7N
–H·
N+
N+
N+·
H
N
·
O
O
F3+·
M+·
2a
O
Ph
F4+
–H2
–CH3·
Me
N+
N+
·
F5+·
F6+
O
O
Fig. 3. Additional mass spectral fragmentation patterns of indole 2a.
The second and most important difference in the mass spectrum of indole 2a lies in the absence of the
peak corresponding to ion F7, which is strong in the spectra of all indoles 1a-g (Table 2). The decomposition
direction M+· → F7 may be considered to be the reverse process to the synthesis of indoles 1a-g. Thus, we may
propose that the above-mentioned Plancher type rearrangements [3, 4] are observed when the loss of a
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TABLE 3. Quantitative Characteristics of Additional Fragmentation
Patterns of Indoles 1e-g*
Com-
pound
Mass numbers of ions, m/z (Irel, %)
M+.
F16+
F17+.
F18+
F19+
F20+.
F21+.
F22+
F23+
F24+
284
(100)
255
(14)
228
(7)
212
(10)
199
(6)
145
(17)
111
(16)
110
(17)
84
(59)
55
(6)
1e
1f
332
(100)
303
(56)
276
(27)
260
(12)
247
(10)
193
(15)
111
(7)
—
84
(38)
55
(7)
346
(100)
317
(31)
290
(21)
274
(7)
261
(10)
207
(24)
111
(13)
110
(22)
84
(51)
55
(6)
1g
_______
*The values of the mass numbers of ions with a relative intensity of at least
5% are shown.
substituent from one indole position and its transfer to another position by any mechanism is facilitated by
thermodynamic and kinetic factors. Hence, in our case, the formation of 1-alkyl-5-(indol-3-yl)pyrrolidin-2-ones
1 appears to be under kinetic rather than thermodynamic control, while 1-alkyl-5-(indol-2-yl)pyrrolidin-2-ones
2 are more stable thermodynamically. Since the peak of fragment ion F7 is lacking only in the spectrum of
indole 2a and is present in the spectra of all other compounds, we may conclude that the product of the reaction
of N-methylindole (3e) with 1-benzyl-5-hydroxypyrrolidin-2-one (4a) corresponds specifically to indole 1d,
rather than indole 2b.
Thus, we conclude that, as in the case of indole itself [1], the pyrrolidinone substituent enters at the C-3
atom in N-methylindole.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker Avance-400 spectrometer (400 MHz) in CDCl3 with
TMS as internal standard. The electron impact mass spectra at 70 eV were recorded on a VG 70-70E mass
spectrometer with direct sample inlet into the ion source. The elemental analysis was carried out on a Carlo Erba
ER-20 CHN analyzer. The melting points were determined on an Electrothermal IA9100 instrument with sealed
capillaries. The reaction course and purity of the products were monitored by thin layer chromatography on
Silufol UV-254 and Merck Silicagel 60 F254 precoated silica gel plates. Merck silica gel (0.035-0.070 mm, pore
diameter 6 nm, 500 m2/g) was used for purification of the compounds by column chromatography. Indoles 1a,d
and 2a were obtained according to our previous procedure [1], while the indoles 1b,c,e-g were obtained by an
analogous procedure from the corresponding indoles and 1-alkyl-5-hydroxypyrrolidin-2-ones.
1-Benzyl-5-(2-phenyl-1H-indol-3-yl)pyrrolidin-2-one (1b). Yield 83%; mp 256-258°C (Et2O). Found,
%: C 81.88; H 6.27; N 7.26. C25H22N2O. Calculated, %: C 81.94; H 6.05; N 7.64.
1-Benzyl-5-(1-methyl-2-phenyl-1H-indol-3-yl)pyrrolidin-2-one (1c). Yield 82%; mp 167-168°C
(hexane). Found, %: C 81.93; H 5.95; N 7.77. C26H24N2O. Calculated, %: C 82.07; H 6.36; N 7.36.
1-sec-Butyl-5-(1,2-dimethyl-1H-indol-3-yl)pyrrolidin-2-one (1e). Yield 49%; mp 108-109°C (hexane).
Found, %: C 75.89; H 8.36; N 10.02. C18H24N2O. Calculated, %: C 76.02; H 8.51; N 9.85.
1-sec-Butyl-5-(2-phenyl-1H-indol-3-yl)pyrrolidin-2-one (1f). Yield 60%; mp 209-210°C (Et2O).
Found, %: C 79.61; H 7.18; N 8.73. C22H24N2O. Calculated, %: C 79.48; H 7.28; N 8.43.
1-sec-Butyl-5-(1-methyl-2-phenyl-1H-indol-3-yl)pyrrolidin-2-one (1g). Yield 77%; mp 126-128°C
(hexane). Found, %: C 79.88; H 7.32; N 8.11. C23H26N2O. Calculated, %: C 79.73; H 7.56; N 8.09.
1639

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