Regioselectivity of the interaction of (1s,2s)-2-amino-1-(4-nitrophenyl)-1, 3-propanediol with some symmetrical ketones

Article abstract of DOI:10.1007/s10593-005-0067-x

The interaction of (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol with a series of symmetrical ketones has been studied. As a result isomeric oxazolidines are formed in a ratio of 85:15. These oxazolidines were shown to decompose readily under the action of hydrazine.

Full text of DOI:10.1007/s10593-005-0067-x

Chemistry of Heterocyclic Compounds, Vol. 40, No. 11, 2004
SYNTHESIS OF 3,9,9,9a-TETRAMETHYL-
1,2,3,9a-TETRAHYDRO-9H-IMIDAZO[1,2-a]-
INDOL-2-ONES BY REACTION OF 2,3,3-TRIMETHYL-
3H-INDOLE WITH 2-BROMOPROPIONAMIDES
E. Valaityte, V. Martynaitis, and A. Sackus
Alkylation of 2,3,3-trimethyl-3H-indole with 2-bromopropionamide and the subsequent treatment of the
formed 1-(1-carbamoylethyl)-2,3,3-trimethyl-3H-indolium bromide with
3,9,9,9a-tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one. Condensation
a
base afforded
of the
1-(1-carbamoylethyl)-2,3,3-trimethyl-3H-indolium salt with 2-hydroxy-1-naphthaldehyde gave a mixture
of diastereomeric 1-(1-carbamoylethyl)spiro[2H-indole-2,3'-[3H]naphtho[2,1-b]pyrans].
Keywords: 2-bromopropionamide, imidazo[1,2-a]indole, spiro[2H-indole-2,3'-[3H]naphtho[2,1-b]-
pyran], 2,3,3-trimethyl-3H-indole.
N-Alkylated derivatives of 2,3,3-trimethyl-3H-indole are useful starting materials for the synthesis of
cyanine dyes and photochromic indolinobenzopyrans [1, 2]. The reaction of 2,3,3-trimethyl-3H-indole with such
bifunctional reagents as α-haloacetamides and subsequent treatment of the formed 1-carbamoylmethyl-3H-
indolium salts with a base leads to the formation of 1-carbamoylmethyl-3,3-dimethyl-2-methylene-2,3-dihydro-
1H-indoles, which may then undergo cyclization to give 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one
derivatives [3]. It was found that the presence of such substituent as allyl or benzyl group at the amide nitrogen
atom promotes nucleophilic addition of the mentioned nitrogen atom to the α-carbon of the indole nucleus, while
phenyl substituent suppress imidazolidine ring closure [4]. 1-Carbamoylmethyl-3,3-dimethyl-2-methylene-2,3-
dihydro-1H-indoles and their cyclic forms have found application in the preparation of photochromic indoline
spiropyrans [5] and thermochromic styrylimidazo[1,2-a]indoles [6, 7]. It was found recently, that 1-(N-
substituted carbamoylmethyl)indoline spiropyrans under influence of a strong base rearrange to pyrrolo[1,2-
a]indole derivatives via short-living methylides [8, 9].
In the present work, we studied annelation of a five-membered lactam ring to the indole nucleus by the
reaction of 2,3,3-trimethyl-3H-indole with 2-bromopropionamides.
Alkylation of indole 1a with 2-bromopropionamide was carried out at 135°C in xylene. Treatment of the
formed salt 2a with a strong base gave 3,9,9,9a-tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one
3a.
The structure of compound 3a was confirmed by means of NMR spectroscopy. Compound 3a has two
1
chiral centers at C-3 and C-9a. However, the H NMR spectrum shows only one set of proton signals, thus
1
pointing to the formation of 3a as a single diastereomer in a racemic form. In the H NMR spectrum three
__________________________________________________________________________________________
Department of Organic Chemistry, Kaunas University of Technology, LT-3028 Kaunas, Lithuania;
e-mail: algirdas.sackus@ktu.lt. Published in Khimiya Geterotsiklicheskikh Soedinenii, No 11, pp. 1690-1694,
November, 2004. Original article submitted July 7, 2003.
1460
0009-3122/04/4011-1460©2004 Springer Science+Business Media, Inc.

singlets of 10,10,10a-CH3 groups are present in the 1.16-1.49 ppm region and a doublet of CH3-3 group appears
at 1.55 ppm (J = 15.5 Hz). The 13C NMR spectrum of 3a contains the characteristic signals of annelated
imidazolidinone ring skeleton carbons at 63.91 (C-3), 89.19 (C-9a), and 177.31 ppm (C=O). The absorption
band at 1720 cm-1 that is due to the carbonyl group and the band at the 3190 cm-1 that corresponds to stretching
vibrations of the N–H bond are observed in the IR spectrum of 3a.
Me Me
R
1
MeCHBrCONHR
Me
N
1a,b
Me Me
Me
Me Me
R
R
–HX
+HX
NR1
Me
+
N
N
NHR1
X –
O
Me
2a–f
Me
O
3a–d
1 a R = H, b R = Me; 2 a R = R1 = H, b R = H, R1 = Bn, c R = Me, R1 = Bn, d R = H, R1 = Ph,
e R = R1 = H, f R = Me, R1 = Bn; a-d X = Br, e, f X = ClO4; 3a R = R1 = H; b R = H, R1 = Bn;
c R = Me, R1 = Bn; d R = H, R1 = Ph
1-Benzyl-3,9,9,9a-tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones 3b,c were obtained as
single diastereomers from 3H-indoles 1a,b and N-benzyl-2-bromopropionamide. The characteristic signal in the
1H NMR spectra of the compounds 3b,c is an AB-quadruplet of diastereotopic benzyl protons in the area of
4.06-5.10 ppm.
Reaction of 3H-indole 1a with N-phenyl-2-bromopropionamide and the subsequent treatment of the
reaction mixture with a base afforded 3,9,9,9a-tetramethyl-1-phenyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]-
indol-2-one 3d as the only isolable product. It has been shown earlier that a similar reaction of 1a with
N-phenyl-1-chloroacetamide gave 2-methylene-1-(N-phenylcarbamoyl)methyl-2,3-dihydro-1H-indole, which
did not undergo further cyclization to imidazo[1,2-a]indole [4]. Therefore, it could be assumed that the presence
of the methyl group instead of the hydrogen atom at the carbon atom located between indole ring nitrogen and
carbonyl group of the salt 2d facilitates ring closure. A similar effect of easy ring closure induced by gem-dialkyl
groups, known as the Thorpe–Ingold effect, is explained by a significant entropy change when an open branched
chain molecule transforms to a small or medium size cycle [10].
The structure of compound 3d is confirmed by the presence of the signal of sp3-hybridized α-carbon
(C-9a) of the indole ring system at 91.51 ppm.
Opening of the imidazolidine ring occurred, and formation of 3H-indolium perchlorates 2e,f took part,
when compounds 3a,c were treated with perchloric acid. The structure of perchlorate 2f is proved by the
1
presence in the H NMR spectrum of the benzyl CH2 group doublet at 4.25 ppm (J = 6.8 Hz), and absorption
bands in the IR spectrum at 3330 (N–H), 1685 (C=O) and 1550 cm-1 (amide II) characteristic of the secondary
amides.
Synthesis of diastereomeric indoline spiropyrans in a racemic form with chiral centers at C-2 and C-3 of
the indole moiety was described in [11]. Coupling of (3R)-1,3-dimethyl-2-methylene-3-propylindoline with
5-nitro-salicylaldehyde afforded optically active diastereomeric (2R,3R)- and (2S,3R)-indoline spiropyrans,
which demonstrated switchable optical activity [12].
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piperidine,
EtOH
OHC
+
2e
reflux
HO
Me
Me
Me
Me
N
+
O
N
O
O
O
H
Me
Me
H
NH2
NH2
4b
4a
Condensation of perchlorate 2e with 2-hydroxy-1-naphthaldehyde in ethanol containing a catalytic
amount of piperidine afforded a mixture of two diastereomeric 1-(1-carbamoyl)ethylindoline naphtho[2,1-b]-
pyrans 4a,b as racemates. Compounds 4a,b possess chiral centers at C-2 of the indole ring system and C-1 of the
1
N-(1-carbamoyl)ethyl side chain. H and 13C NMR spectra indicated a 3:2 ratio of the diastereomers in the
mixture.
The 1H NMR spectrum of the mixture of 4a,b contains overlapped doublets of H-2' at 5.74 (J = 10.5 Hz)
and 5.76 ppm (J = 10.5 Hz) for the major and minor isomers, respectively. The signals of spiro atom C-2,3' at
104.35 (minor isomer) and 105.54 ppm (major isomer) in the 13C NMR spectrum of the mixture 4a,b were
identified by the DEPT method.
EXPERIMENTAL
All melting points were determined with a Kleinfeld melting point apparatus and are uncorrected.
1H NMR spectra were recorded with JEOL FX-100 (100 MHz, compounds 3b,c, 2e,f) and Bruker ASW 300
13
instruments (300 MHz, CDCl3, compounds 3a,d, 4a,b). C NMR spectra were obtained on a Bruker ASW 300
instrument (75 MHz, CDCl3). Chemical shifts (ppm) are given relative to tetramethylsilane (TMS). IR spectra
were recorded on a Perkin–Elmer Spectrum BXII spectrometer (KBr pellets). Mass spectra were recorded on a
Waters ZQ 2000 spectrometer (ion spray). For thin layer chromatographic (TLC) analyses, Merck precoated
TLC plates (silica gel 60 F254) were used.
3,9,9,9a-Tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one (3a).
A
mixture of
2,3,3-trimethyl-3H-indole 1a (1.99 g, 12.5 mmol) and 2-bromopropionamide (2.10 g, 13.8 mmol) was heated at
135°C for 12 h in an atmosphere of nitrogen. The reaction mixture was dissolved in 15 ml of acetone and poured
into 150 ml of 5% hydrochloric acid. The solution was extracted with ether (2 × 20 ml); then the acidic layer was
alkalified with 10% potassium hydroxide and extracted with ether (3 × 20 ml). The extract was washed with 1%
hydrochloric acid (2 × 20 ml) and water (20 ml), and dried over calcium chloride. The solvent was evaporated
under reduced pressure and the residue crystallized from ethanol to give 0.92 g (32%), of compound 3a; mp 180-
181°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.16 (3H, s, CH3-9); 1.21 (3H, s, CH3-9); 1.49 (3H, s, CH3-9a); 1.55
(3H, d, J = 7.5, CH3-3); 3.72 (1H, q, J = 7.5, H-3); 6.65-7.10 (4H, m, ArH); 8.11 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm: 19.77 (CH3); 24.98 (CH3); 25.80 (CH3); 26.51 (CH3); 47.50 (C-9); 63.91 (C-3); 89.19 (C-9a);
112.77 (CH); 122.11 (CH); 122.51 (CH); 127.96 (CH); 139.18 (C); 151.01 (C); 177.31
1462

(C=O). Mass spectrum (ES+), m/z (rel. intensity): 253 (M+Na, 100), 231 (M+1, 26); mass spectrum (ES-), m/z
(rel. intensity): 229 (M-1, 100). Found, %: C 73.31; H 7.70; N 12.09. C14H18N2O. Calculated, %: C 73.01;
H 7.88; N 12.16.
1-Benzyl-3,9,9,9a-tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one (3b). A mixture of
3H-indole 1a (3.18 g, 20 mmol) and 2-bromo-N-benzylpropionamide (7.26 g, 30 mmol) was heated at 135°C for
6 h. The reaction mixture was dissolved in 20 ml of acetone, poured into 200 ml of 5% hydrochloric acid, and
extracted with ether (2 × 30 ml). The acidic layer was basified with 10% potassium hydroxide and extracted with
ether (2 × 20 ml). The extract was washed with 1% hydrochloric acid (2 × 20 ml) and water (20 ml), dried over
calcium chloride, and evaporated under reduced pressure. The residue was purified by flash chromatography
1
on aluminum oxide (eluent acetone–hexane, 3:5) to give 3.01 g (47%) of compound 3b as a pale yellow oil. H
NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.93 (3H, s, CH3-9); 1.18 (3H, s, CH3-9); 1.41 (3H, s, CH3-9a); 1.60
(3H, d, J = 6.6, CH3-3); 3.79 (1H, q, J = 6.6, CH); 4.06-5.08 (2H, AB-q, J = 15.4, CH2); 6.74-7.40 (9H, m, ArH).
Found, %: N 8.61. C21H24N2O. Calculated, %: N 8.74.
1-Benzyl-3,7,9,9,9a-pentamethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one (3c) was obtained
similarly to compound 3b from (3.46 g, 20 mmol) of 3H-indole 1b (3.46 g, 20 mmol) and 2-bromo-N-
1
benzylpropionamide (7.26 g, 30 mmol). Yield of 3c was 3.61 g (54%); mp 71-72°C (ether). H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 0.94 (3H, s, CH3-9); 1.18 (3H, s, CH3-9); 1.39 (3H, s, CH3-9a); 1.60 (3H, d, J = 6.6,
CH3-3); 2.24 (3H, s, CH3-7); 3.75 (1H, q, J = 6.6, CH), 4.06-5.10 (2H, AB-q, J = 15.4, CH2); 6.66-7.47 (8H, m,
ArH). Found, %: N 8.50. C22H26N2O. Calculated, %: N 8.38.
3,9,9,9a-Tetramethyl-1-phenyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one (3d). The reaction of
3H-indole 1a (1.99 g, 12.5 mmol) and 4.28 g (18.75 mmol) of 2-bromo-N-phenylpropionamide was carried out
according to the procedure described for compound 3a and yielded 0.95 g (25%) of the title compound; mp 132-
1
134°C (ethanol). IR spectrum: 1703 cm-1 (C=O). H NMR spectrum, δ, ppm (J, Hz): 1.15 (3H, s, CH3-9); 1.24
(3H, s, CH3-9); 1.41 (3H, s, CH3-9a); 1.60 (3H, d, J = 6.9, CH3-3); 3.97 (1H, q, J = 6.9, H-3); 6.84-7.40 (9H, m,
ArH). 13C NMR spectrum, δ, ppm: 21.32 (CH3); 21.81 (CH3); 26.45 (CH3); 30.33 (CH3); 50.26 (C-9); 61.06 (C-
3); 91.51 (C-9a); 114.47 (CH); 122.25 (CH); 122.84 (CH); 127.71 (CH); 128.18 (3CH); 129.11 (2CH); 136.75
(C); 142.53 (C); 147.87 (C); 174.28 (C=O). Found, %: C 78.02; H 7.40; N 9.16. C20H22N2O. Calculated, %: C
78.40; H 7.23; N 9.14.
1-(1-Carbamoylethyl)-2,3,3-trimethyl-3H-indolium Perchlorate (2e). To a solution of compound 3a
(0.46 g, 2 mmol) in 3 ml of ethanol, 60% perchloric acid was added to pH 2 and the solution was stored at 0°C
for 14 h. The precipitated crystals were isolated by filtration and recrystallized from ethanol to yield 0.40 g
(60%) of perchlorate 2e; mp 139-140°C. IR spectrum, ν, cm-1: 3420 (N–H), 3220 (N–H), 1720 (C=O), 1115
-
1
(ClO4 ). H NMR spectrum (TFA + acetone-d6), δ, ppm (J, Hz): 1.53 (6H, s, CH3-3,3); 1.98 (3H, d, J = 7.2,
CHCH3); 2.87 (3H, s, CH3-2); 5.90 (1H, q, J = 7.2, CHCH3); 7.42-8.05 (6H, m, ArH, CONH2). Found, %:
C 50.55; H 6.08; N 7.98. C14H19ClN2O5. Calculated, %: C 50.84; H 5.78; N 8.47.
1-[1-(N-Benzylcarbamoyl)ethyl]-2,3,3,5-tetramethyl-3H-indolium Perchlorate (2f) was obtained
similarly to 2e from 3c (2.01 g, 6 mmol) and 60% perchloric acid in 1.10 g (42%) yield; mp 138-139°C
-
1
(ethanol). IR spectrum, ν, cm-1: 3330 (N–H), 1685 (C=O), 1550 (amide II), 1110 (ClO4 ). H NMR spectrum
(TFA), δ, ppm (J, Hz): 1.21 (3H, s, CH3-3); 1.25 (3H, s, CH3-3); 1.70 (3H, d, J = 7.4, CHCH3); 2.11 (3H, s,
CH3-5); 2.50 (3H, s, CH3-2); 4.25 (2H, d, J = 6.8, NHCH2); 5.51 (1H, q, J = 7.4, CHCH3); 6.91-7.18 (8H, m,
ArH). Found, %: Cl 8.40. C22H27ClN2O5. Calculated, %: Cl 8.15.
1-[(R*)-1-(Carbamoyl)ethyl](2R*)-3,3-dimethyl-1,3-dihydrospiro[2H-indole-2,3'-[3H]naphtho-
[2,1-b]pyran] (4a) and Its (2R*)-1-[(S*)-1-(Carbamoyl)ethyl]isomer (4b). To a solution of perchlorate 2e
(0.33 g, 1.0 mmol) and 2-hydroxy-1-naphthaldehyde (0.19 g, 1.1 mmol) in ethanol (4 ml) was added 2 drops of
piperidine and the mixture was refluxed for 5 h. Then the reaction mixture was poured into 5% sodium acetate
(30 ml) and extracted with ether (2 × 15 ml). The organic extract was washed with water (15 ml) and dried over
MgSO4; the solvent was evaporated and the residue crystallized from ethanol to afford 0.23 g (60%) of a
1463

1
mixture of diastereomers 4a,b. H NMR spectrum of the mixture of 4a,b, δ, ppm (J, Hz): 1.17 (3H, s, CH3,
major isomer); 1.22 (3H, s, CH3, minor isomer); 1.33 (3H, s, CH3, major isomer); 1.37 (3H, s, CH3, minor
isomer); 1.45 (3H, d, J = 7.2, CHCH3, minor isomer); 1.55 (3H, d, J = 7.2, CHCH3, major isomer); 4.22 (1H, q, J
= 7.2, CHCH3, minor isomer); 4.44 (1H, q, J = 7.2, CHCH3, major isomer); 5.35 (1H, br. s, NH, major isomer);
5.55 (1H, br. s, NH, minor isomer); 5.74 (1H, d, J = 10.5, H-2', major isomer); 5.76 (1H, d, J = 10.5, H-2', minor
isomer); 6.41 (1H, br. s, NH, minor isomer); 6.52-8.03 (22H, m, ArH, major and minor isomers; NH, major
isomer). 13C NMR spectrum, δ, ppm: 11.91, 14.89, 19.94, 20.18, 26.32, 26.80, 51.85, 52.28, 52.43, 52.77,
104.35, 105.54, 107.76, 109.98, 110.09, 110.70, 116.42, 116.47, 117.23, 117.72, 119.36, 120.30, 120.56,
120.74, 122.07, 122.20, 123.62, 123.89, 125.93, 126.53, 127.01, 127.19, 127.29, 127.51, 128.67, 127.70,
128.92, 129.18, 129.77, 129.80, 130.68, 130.85, 135.81, 137.33, 142.92, 143.09, 151.31, 151.59, 173.95,
175.25. Found, %: C 78.27; H 6.08; N 7.35. C25H24N2O2. Calculated, %: C 78.10; H 6.29; N 7.29.
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