Novel schemes for the synthesis of pyrrolocoumarins

Article abstract of DOI:10.1007/s10593-005-0069-8

Two novel schemes have been developed for the synthesis of pyrrolocoumarin derivatives. A series of previously unknown 4,9-dimethylpyrano[3,2-e]indol-7(3H) -ones have been prepared.

Full text of DOI:10.1007/s10593-005-0069-8

Chemistry of Heterocyclic Compounds, Vol. 40, No. 11, 2004
SYNTHESIS OF 1,2,3,9a-TETRAHYDRO-
9H-IMIDAZO[1,2-a]INDOLE-2-THIONE AND
1,5,6,10b-TETRAHYDROIMIDAZO[2,1-a]-
ISOQUINOLINE-2(3H)-THIONE DERIVATIVES
E. Valaityte, V. Martynaitis, and A. Sackus
Thionation of 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one derivative with Lawesson's reagent in
boiling toluene afforded 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indole-2-thione derivative. Alkylation of
the latter with ethyl iodide in DMF in the presence of a strong base gave 2-ethylthio-9,9,9a-trimethyl-
9,9a-dihydro-3H-imidazo[1,2-a]indole. 1,5,6,10b-Tetrahydroimidazo[2,1-a]isoquinoline-2(3H)-thiones
were synthesized by thionation of the corresponding carbonyl substrates.
Keywords: imidazo[1,2-a]indole, imidazo[2,1-a]isoquinoline, lactam, Lawesson's reagent, thionation.
Thionation of heterocyclic compounds bearing lactam moieties is most commonly performed using
phosphorus pentasulfide [1, 2] or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide
(Lawessons's reagent) [3, 4]. The latter reagent usually gives the expected thiolactams, while heating of the
lactam moiety containing heterocycles, e.g., 2,3,4,5-tetrahydro-1,5-benzodiazepin-2-one derivative, with
phosphorus pentasulfide in pyridine affords a mixture of tautomeric thiolactam and imino thiol [2].
In the present work we investigated the replacement of carbonyl oxygen of five-membered lactam-type
rings annelated to the a-edge of indole or isoquinoline nucleus by the use of Lawessons's reagent as a thionation
agent.
Starting imidazo[1,2-a]indol-2-one derivatives 1a,b were obtained from 2,3,3-trimethyl- and
2,3,3,5-tetramethyl-3H-indoles by the method described in [5]. Compound 1c was prepared from 4a-methyl-
2,3,4,4a-tetrahydro-1H-carbazole by a similar way [6].
Thionation reactions of compounds 1a-c with Lawesson's reagent were carried out in boiling toluene and
furnished thiolactams 2a-c in fairly good yields (63-72%). No tautomerization of the thiolactam moiety or
possible rearrangement of the annelated imidazolidine ring to the thiazolidine ring via ring opening-closure was
observed. The structure of prepared compounds 2a-c was proved by IR, 1H and 13C NMR, and microanalyses. In
the IR spectrum of 2a N–H stretching vibrations characteristic of secondary thioamides [7] were observed at
3135 cm-1, and no absorption band characteristic of stretching vibrations of C=O group of 1a at 1700 cm-1 was
found.
1
13
A comparison of the chemical shifts of the H and C nucleus of imidazo[1,2-a]indol-2-one 1a and the
corresponding thione 2a showed that substitution of carbonyl oxygen for sulfur at C-2 induces significant low-
1
field shifts of the imidazolidine ring atom nucleus. In the H NMR spectrum (CDCl3) of 2a, the diastereotopic
__________________________________________________________________________________________
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. 1695-1700,
November, 2004. Original article submitted July 28, 2003.
0009-3122/04/4011-1465©2004 Springer Science+Business Media, Inc.
1465

Me R1
Me R1
R2
NH
R
R2
NH
R
Lawesson's
reagent
N
N
EtI, KOH
DMF, r.t.
O
S
1a–c
2a–c
EtI, KOH
DMF, r.t.
Me Me
Me
Me Me
Me
NEt
Lawesson's
reagent
N
Me
Me
Me
N
SEt
NEt
N
N
3
O
S
4
5
1, 2 a R = H, R1 = R2 = Me; b R = R1 = R2 = Me; c R = H, R1 + R2 = CH2CH2CH2CH2
geminal protons on C-2 gave an AB-quadruplet at δ 4.23-4.38, and the signal of the N–H proton of the
thiolactam moiety was observed at 9.13 ppm, while the corresponding signals of the starting 1a were present at
δ 3.72-3.92 and 7.44 ppm, respectively. In the 13C spectrum of 2a, the signal attributed to the thiocarbonyl
carbon was observed at δ 199.22 ppm, and no signal of the carbonyl carbon of 1a at δ 174.50 ppm was detected.
The C-3 and C-9a chemical shift values for compound 2a were found at δ 66.90 and 98.86 ppm, respectively,
while the corresponding values in starting compound 1a were found at δ 55.21 and 91.25 ppm. Similar low-field
shift effects were observed when C=O groups of polylactams were converted to C=S groups [4].
In our previous work, it was found that alkylation of imidazo[1,2-a]indol-2-one derivative 1a by alkyl
iodides in aprotic polar solvent in the presence of a strong base afforded a mixture of N- and O-alkylated
products, in a ratio ~5:1 [8]. However, it is known that alkylation of the thiolactam moiety usually gives
S-alkylated products only [2, 9]. When imidazo[1,2-a]indole-2-thione 2a was treated with ethyl iodide in DMF
in the presence of sodium hydroxide as a strong base, the only isolable product was cyclic imidoyl thioester 3.
1
The H NMR spectrum of 3 showed three singlets and one triplet of four methyl groups in the δ 1.26-1.47 ppm
interval together with a quadruplet of the SCH2 group at δ 2.99 and the AB-system of the NCH2 group in the
1
δ 4.00-4.11 ppm interval. However, the H NMR spectrum gave no conclusive evidence regarding the structure
13
of the ethylated product formed. For compound 3 the C chemical shift value of the methylene carbon in the
13
ethyl substituent was especially valuable for the estimation of the S-ethylated product present. In the C NMR
spectrum of 3 the signal atributed to the mentioned carbon (SCH2) is observed at δ 25.31, while the
13
corresponding methylene group carbon signal (NCH2) of 4 is situated at δ 37.13 ppm. The C chemical shift
value of the methylene carbon of the model compound, ethyl sulfide, is δ 25.5 ppm [10].
N-Ethylimidazo[1,2-a]indole-2-thione 5 was obtained by thionation of compound 4. In the 13C NMR
spectrum of 5, the signal of the methylene carbon of the ethyl group is present at δ 41.61. The observed upfield
shift of ~16 ppm on going from 3 to 5 can be explained by the higher electronegativity of the nitrogen atom in
comparison with the sulfur atom.
R
R
R
R
Lawesson's
reagent
N
N
Me
Me
HN
HN
O
S
6a,b
7a,b
6, 7a R = H; b R = OMe
1466

Further, we investigated thionation of imidazo[2,1-a]isoquinolinone derivatives. Starting compound 6a
was synthesized by the known method [11], and compound 6b was obtained in a similar way. Heating to
refluxing of compounds 6a,b with Lawesson's reagent in toluene afforded 7a,b. However, yields of the target
13
products in such case did not exceed 30-32%. The C NMR spectra of 7a,b contained characteristic signals of
the thiocarbonyl group carbon at δ 198.57 and 196.93 ppm, respectively.
EXPERIMENTAL
All melting points were determined on a Kleinfeld melting point apparatus and are uncorrected. Infrared
1
spectra were obtained on a Perkin–Elmer Spectrum BXII spectrometer (KBr pellets). H NMR spectra were
13
measured with a Jeol FX-100 (100 MHz) and Varian Gemini 2000 (300 MHz) spectrometers. The C NMR
spectra were recorded at 75 MHz using Varian Gemini 2000. The chemical shifts are reported in ppm downfield
from tetramethylsilane, using residual CHCl3 (7.24 ppm) as reference for the proton spectra and CDCl3 (77 ppm)
as reference for the carbon spectra. For thin layer chromatographic (TLC) analyses, Merck precoated TLC
plates (Silica Gel 60 F254) were used. Column chromatography was performed with Silica Gel 60 (230-400
mesh) from Merck.
9,9,9a-Trimethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one (1a) was obtained in accordance
1
with the method [5]. IR spectrum, ν, cm-1: 3175 (N–H), 1700 (C=O). H NMR (300 MHz, CDCl3), δ, ppm
2
(J, Hz): 1.18 (3H, s, CH3); 1.37 (3H, s, CH3); 1.51 (3H, s, CH3); 3.72-3.92 (2H, AB-system, JAB = 16.5,
CH2CO); 6.70-7.17 (4H, m, ArH); 7.44 (1H, br. s, NH). 13C NMR spectrum (CDCl3), δ, ppm: 21.17 (CH3);
22.41 (CH3); 27.43 (CH3); 46.63 (C-9); 55.21 (C-3); 91.25 (C-9a); 112.63 (CH); 122.36 (CH); 122.51 (CH);
127.95 (CH); 138.70 (C-8a); 150.71 (C-4a); 174.50 (C=O).
9,9,9a-Trimethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indole-2-thione (2a). To a stirred solution of
imidazo[1,2-a]indolone 1a (3.68 g, 17 mmol) in 30 ml of toluene, Lawesson's reagent (3.44 g, 8.5 mmol) was
added and the mixture was refluxed for 2.0 h. The reaction mixture was then cooled to room temperature and
poured into 100 ml of 10% sodium carbonate solution. The mixture was extracted with ether (3 × 30 ml) and the
combined organic extracts were washed with water (30 ml) and dried over Na2SO4. The solvent was evaporated
under reduced pressure and the residue recrystallized from ethanol to yield 2.72 g (69%) of thione 2a;
mp 192-193°C. IR spectrum, ν, cm-1: 3135 (N–H). 1H NMR spectrum (300 MHz, CDCl3), δ, ppm (J, Hz) : 1.19
2
(3H, s, CH3); 1.42 (3H, s, CH3); 1.52 (3H, s, CH3); 4.23-4.38 (2H, AB-system, JAB = 17.4, NCH2); 6.73-7.18
13
(4H, m, ArH); 9.13 (NH). C NMR spectrum (CDCl3), δ, ppm: 19.57 (CH3); 22.57 (CH3); 27.68 (CH3); 46.68
(C-9); 66.90 (C-3); 98.86 (C-9a); 112.81 (CH); 122.41 (CH); 122.80 (CH); 128.18 (CH); 137.89 (C); 149.80
(C); 199.22 (C=S). Found, %: C 67.60; H 6.93; N 11.84; S 14.11. C13H16N2S. Calculated, %: C 67.20; H 6.94;
N 12.06; S 13.80.
7,9,9,9a-Tetramethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indole-2-thione (2b) was obtained
similarly to compound 2a from compound 1b (1.50 g, 6.5 mmol) and Lawesson's reagent (1.31 g, 3.25 mmol) in
1
1.15 g (72%) yield; mp 197-198°C (ethanol). IR spectrum, ν, cm-1: 3140 (N–H). H NMR spectrum (100 MHz,
CDCl3), δ, ppm: 1.17 (3H, s, CH3); 1.40 (3H, s, CH3); 1.50 (3H, s, CH3); 2.27 (3H, s, CH3-7); 4.27 (2H, s,
NCH2); 6.59-6.98 (3H, m, ArH); 9.09 (1H, br. s, NH). Found, %: C 68.27; H 7.42; N 11.08; S 12.65. C14H18N2S.
Calculated, %: C 68.25; H 7.36; N 11.37; S 13.02.
7a-Methyl-5,6,7,7a-tetrahydro-1H,4H-imidazo[2,1-k]carbazole-2(3H)-thione (2c) was obtained
similarly to compound 2a from 1c (0.30 g, 1.24 mmol) and Lawesson's reagent (0.25 g, 0.62 mmol) in 0.20 g
(63%) yield; mp 231-232°C (ethanol). IR spectrum, ν, cm-1: 3125 (N–H). 1H NMR spectrum (100 MHz, CDCl3),
δ, ppm (J, Hz): 1.26-2.15 (8H, m, 4 × CH2); 1.45 (3H, s, CH3); 4.15-4.55 (2H, AB-system, 2JAB = 16.3, NCH2);
6.76-7.31 (4H, m, ArH), 9.32 (1H, br. s, NH). Found, %: C 69.93; H 6.91; N 10.82; S 12.07. C15H18N2S.
Calculated, %: C 69.73; H 7.02; N 10.84; S 12.41.
1467

2-Ethylthio-9,9,9a-trimethyl-9,9a-dihydro-3H-imidazo[1,2-a]indole (3). To a stirred solution of
compound 2a (651 mg, 2.8 mmol) in dry DMF (8 ml) was added finely ground potassium hydroxide (219 mg,
5.6 mmol). After 10 min, ethyl iodide (0.46 ml, 5.6 mmol) was added dropwise at room temperature over a
period of 20 min. The mixture was stirred for 1 h, poured into water (50 ml), and extracted with ether
(3 × 15 ml). The combined extracts were washed with water (10 ml), dried with Na2SO4, and concentrated in
vacuo to give a residue, which was purified by column chromatography on silica gel (eluent acetone–hexane,
1
1:3) to yield 452 mg (62%) of 3 as an oil. H NMR spectrum (300 MHz, CDCl3), δ, ppm (J, Hz): 1.26 (3H, s,
3
3
CH3); 1.26 (3H, t, J = 7.5, CH2CH3); 1.33 (3H, s, CH3); 1.47 (3H, s, CH3); 2.99 (2H, q, J = 7.5, SCH2);
2
13
4.00-4.11 (2H, AB-system, JAB = 15.2, NCH2); 6.68-7.12 (4H, m, ArH). C NMR spectrum (CDCl3), δ, ppm:
14.34 (CH3); 19.91 (CH3); 24.27 (CH3); 25.31 (SCH2); 28.37 (CH3); 46.59 (C-9); 63.34 (NCH2); 106.85 (C-9a);
112.77 (CH); 121.93 (CH); 122.36 (CH); 127.45 (CH); 140.33 (C-8a); 151.13 (C-4a); 165.20 (C=N). Found, %:
C 69.43; H 7.90. C15H20N2S. Calculated, %: C 69.19; H 7.74.
1-Ethyl-9,9,9a-trimethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one (4) was obtained in
accordance with the method [8]. 1H NMR spectrum (300 MHz, CDCl3), δ, ppm (J, Hz): 1.04 (3H, s, CH3); 1.29
(3H, t, 3J = 7.2, CH2CH3); 1.41 (3H, s, CH3); 1.47 (3H, s, CH3); 3.00-3.11 (1H, m, CHAHBCH3); 3.57-3.68 (1H,
2
2
m, CHAHBCH3); 3.68 (1H, d, J = 15.3, CHAHBCO); 4.04 (1H, dd, J = 15.3, l°ng rangeJ = 0.3, CHAHBCO);
6.72-7.17 (4H, m, ArH). 13C NMR spectrum (CDCl3), δ, ppm: 13.88 (CH2CH3); 22.87 (CH3); 23.63 (CH3); 28.81
(CH3); 37.13 (CH2CH3); 49.46 (C-9); 54.74 (C-3); 92.01 (C-9a); 113.83 (CH); 121.97 (CH); 122.04 (CH);
128.20 (CH); 140.83 (C-8a); 148.44 (C-4a); 170.94 (C=O).
1-Ethyl-9,9,9a-trimethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indole-2-thione (5) was obtained
similarly to compound 2a from 4 (0.95 g, 3.9 mmol) and Lawesson's reagent (0.80 g, 2 mmol). Purification of
the crude product by column chromatography on silica gel (eluent acetone–hexane, 1:3) gave 0.41 g (40%) of
1
compound 5 as an oil. H NMR spectrum (300 MHz, CDCl3), δ, ppm (J, Hz): 1.07 (3H, s, CH3); 1.41 (3H, t,
3J = 7.2, CH2CH3); 1.47 (3H, s, CH3); 1.56 (3H, s, CH3); 3.27-3.38 (1H, m, CHAHBCH3); 4.14-4.24 (1H, m,
2
CHAHBCH3); 4.18-4.60 (2H, AB-system, JAB = 16.8, CH2CO); 6.74-7.20 (4H, m, ArH). 13C NMR spectrum
(CDCl3), δ, ppm: 12.31 (CH2CH3); 23.07 (CH3); 23.55 (CH3); 28.79 (CH3); 41.61 (CH2CH3); 50.29 (C-9); 67.06
(C-3); 90.04 (C-9a); 114.34 (CH); 122.09 (CH); 122.72 (CH); 128.64 (CH); 136.5 (C-8a); 149.60 (C-4a); 196.10
(C=S). Found, %: C 69.11; H 7.57. C15H20N2S. Calculated, %: C 69.19; H 7.74.
8,9-Dimethoxy-10b-methyl-1,5,6,10b-tetrahydroimidazo[2,1-a]isoquinolin-2(3H)-one (6b). A mixture
of 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline (6.16 g, 30 mmol) and α-chloroacetamide (4.21 g,
45 mmol) was heated to reflux in 10 ml of acetonitrile for 5 h and then left at room temperature for 18 h. The
crystalline solid that separated was filtered off and recrystallized from ethanol. The obtained salt (5.90 g) was
dissolved in 100 ml of ice-cooled water and to the solution saturated sodium carbonate solution added until
pH 9. The product was extracted with chloroform (5 × 50 ml), the combined extracts were washed with water
(50 ml), dried with MgSO4, and evaporated under reduced pressure, and the residue was recrystallized from
acetone to give 4.14 g (53%) of 6b; mp 162-163°C. 1H NMR spectrum (300 MHz, CDCl3), δ, ppm (J, Hz): 1.64
2
(3H, s, CH3-10b); 2.46-3.06 (4H, m, CH2CH2); 3.35-3.57 (2H, AB-system, JAB = 14.9, CH2CO); 3.82 (6H, s,
13
OCH3-8,9); 6.50 (1H, s, ArH); 6.75 (1H, s, ArH); 9.01 (1H, br. s, NH). C NMR spectrum (CDCl3), δ, ppm:
22.60 (CH3-10b); 29.36 (C-6); 43.09 (C-5); 52.60 (C-3); 55.38 (OCH3); 55.52 (OCH3); 75.81 (C-10b), 108.68
(CH); 110.34 (CH); 124.22 (C); 130.47 (C); 147.62 (C); 147.73 (C); 173.67 (C=O). Found, %: C 64.05; H 6.94;
N 10.62. C14H18N2O3. Calculated, %: C 64.11; H 6.92; N 10.68.
10b-Methyl-1,5,6,10b-tetrahydroimidazo[2,1-a]isoquinoline-2(3H)-thione (7a). To a solution of
compound 6a (2.02 g, 10 mmol) in 15 ml of toluene a solution of Lawesson's reagent (2.02 g, 5 mmol) was
added and the mixture was heated to reflux for 1.5 h. The reaction mixture was cooled to room temperature,
poured into 100 ml of 10% sodium carbonate solution, and extracted with ether (3 × 30 ml). The combined
organic extracts were washed with water (30 ml) and dried over Na2SO4, the solvent was evaporated under
reduced pressure, and the residue was purified by flash chromatography on silica gel (eluent toluene–ethyl
1468

acetate, 1:5) to give 0.70 g (32%) of compound 7a; mp 70-71°C (ethanol). IR spectrum, ν, cm-1: 3091 (N–H).
1H NMR spectrum (300 MHz, CDCl3), δ, ppm (J, Hz): 1.63 (3H, s, CH3); 2.72-3.07 (4H, m, CH2CH2); 3.73-4.19
2
(2H, AB-system, JAB = 17.0, CH2CS); 7.03-7.29 (4H, m, ArH); 9.72 (1H, br. s, NH). 13C NMR spectrum
(CDCl3), δ, ppm: 26.21 (CH3); 28.98 (C-6); 45.97 (C-5); 66.97 (C-3); 84.19 (C-10b); 126.17 (CH); 127.07 (CH);
127.87 (CH); 128.79 (CH); 133.68 (C); 135.75 (C); 198.57 (C=S). Found, %: C 65.74; H 6.60; N 12.58;
S 15.00. C12H16N2S. Calculated, %: C 66.02; H 6.46; N 12.83; S 14.68.
8,9-Dimethoxy-10b-methyl-1,5,6,10b-tetrahydroimidazo[2,1-a]isoquinoline-2(3H)-thione (7b) was
obtained similarly to compound 7a from 6b (2.62 g, 10 mmol) and Lawesson's reagent (2.02 g, 5 mmol).
Purification of the crude product by column chromatography on silica gel (eluent toluene–ethyl acetate, 1:3)
1
gave 0.84 g (30%) of compound 7b; mp 123-124°C (ethanol). H NMR spectrum (300 MHz, CDCl3), δ, ppm
2
(J, Hz) : 1.63 (3H, s, CH3-10b); 2.54-3.07 (4H, m, CH2CH2); 3.72-4.14 (2H, AB-system, JAB = 16.9, CH2CS);
3.78 (3H, s, OCH3); 3.84 (3H, s, OCH3); 6.49 (1H, s, ArH); 6.76 (1H, s, ArH); 10.33 (1H, br. s, NH). 13C NMR
spectrum (300 MHz, CDCl3), δ, ppm: 24.22 (CH3), 27.77 (C-6); 44.46 (C-5); 54.77 (OCH3); 55.19 (OCH3);
64.48 (C-3); 83.11 (C-10b); 107.81 (CH); 109.84 (CH); 124.74 (C); 126.62 (C); 147.05 (C); 147.51 (C); 196.93
(C=S). Found, %: C 60.50; H 6.56. C14H18N2O2S. Calculated, %: C 60.41; H 6.52.
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