Synthesis and transformations of 1,4-diethynyl-2-nitrobenzene

Article abstract of DOI:10.1007/s11172-006-0160-z

Heating 2-nitro-1,4-bis(1,3,3-trimethylindolin-2-ylideneacetyl)benzene with POCl₃ followed by treatment with an aqueous solution of NaOH gave 2-nitro-1,4-diethynylbenzene. Some transformations involving this product were considered. 2-Acetylami

Full text of DOI:10.1007/s11172-006-0160-z

2586
Russian Chemical Bulletin, International Edition, Vol. 54, No. 11, pp. 2586—2589, November, 2005
Synthesis and transformations of 1,4ꢀdiethynylꢀ2ꢀnitrobenzene
D. L. Tarshits,aꢀ S. Yu. Tarasov,b and V. N. Buyanovc
aMoscow Institute of Open Education, Moscow Department of Education,
6 Aviatsionnyi pr., 125167 Moscow, Russian Federation.
Fax: +7 (495) 601 2183. Eꢀmail: adm@mioo.ru
bResearch and Production Center "Farmzashchita" of the Federal Agency "Medbioextrem",
11 Vashutinskoe shosse, Khimki, 141400 Moscow Region, Russian Federation.
Fax: +7 (495) 572 4600. Eꢀmail: pharmg92@mtuꢀnet.ru
cD. I. Mendeleev Russian University of Chemical Technology,
9 Miusskaya ploshchad´, 125047 Moscow, Russian Federation.
Fax: +7 (495) 200 4204. Eꢀmail: rector@muctr.edu.ru
Heating 2ꢀnitroꢀ1,4ꢀbis(1,3,3ꢀtrimethylindolinꢀ2ꢀylideneacetyl)benzene with POCl3 folꢀ
lowed by treatment with an aqueous solution of NaOH gave 2ꢀnitroꢀ1,4ꢀdiethynylbenzene.
Some transformations involving this product were considered. 2ꢀAcetylaminoꢀ1,4ꢀdiethynylꢀ
benzene and its dimorpholinomethyl derivative underwent heterocyclization, resulting in the
terminal and methine carbonꢀsubstituted indolylacetylenes.
Key words: acetylene fragmentation, indoline enaminoketones, Fischer base, 2ꢀnitroꢀ1,4ꢀ
diethynylbenzene, aminomethylation, heterocyclization, 6ꢀethynylindole.
Previously, we have shown1,2 that the acetylene fragꢀ
mentation of indoline enaminoketones is a versatile
method for the synthesis of various terminal arylꢀ and
hetarylacetylenes irrespective of the electronic properties
or the number of substituents in the nucleus. The method
involves treatment of enaminoketones, formed in good
yields upon condensation of carboxylic acid chlorides with
Fischer bases (1), with phosphorus oxychloride in hot
dioxane and the subsequent cleavage of the resulting
indoleninium salts with aqueous alkali. The scope of this
method for the synthesis of ethynyl derivatives is restricted
only by availability of the starting acids, as the Fischer
base, 1,3,3ꢀtrimethylꢀ2ꢀmethyleneindoline (1), is comꢀ
mercially available.
Scheme 1
Similarly, treatment of the Fischer base 1 with nitroꢀ
terephthalic dichloride (2) resulted in the synthesis of
diketone 3, which was converted into 2ꢀnitroꢀ1,4ꢀdiꢀ
ethynylbenzene (4a) in ~80% yield (Scheme 1).
Condensation of 1,4ꢀdiethynylꢀ2ꢀnitrobenzene (4a)
with formaldehyde and secondary amines, e.g., morphoꢀ
line, piperidine, Nꢀ(2ꢀfuroyl)piperazine, in dioxane at
80—90 °C in the presence of CuCl yielded diaminomethyl
derivatives 4b—d* (Scheme 2).
Treatment of nitrodiacetylenes 4a,b with zinc dust in
aqueous ammonia results in amines 5a,b; one is an oil
rapidly darkening in air, while the other is a crystalline
solid quite stable in air. These amines react with acetic
Reagents and conditions: i. Benzene, 24 h; ii. (1) POCl3,
(2) NaOH.
anhydride in benzene, giving rise to compounds 6a,b
* Bases 4c,d could be isolated and characterized only as diꢀ
hydrochlorides.
(Scheme 3).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2505—2508, November, 2005.
1066ꢀ5285/05/5411ꢀ2586 © 2005 Springer Science+Business Media, Inc.

2ꢀNitroꢀ1,4ꢀdiethynylbenzene transformations
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005 2587
Scheme 2
Scheme 4
Reagents, conditions, and yields: i. NaH, DMF, 1 h at 80—85 °C
and 12 h at ~20 °C; yields 45% (7a) and 50% (7b).
Reagents and conditions: i. R2NH, CH2O, CuCl, dioxane,
80—90 °C, 1 h.
Scheme 5
Scheme 3
Reagents and conditions: i. CH2O, AcOH,
, 85 °C, 1 h.
sidered to be a new method for the synthesis of terminal
alkynes of the indole series, because all known methods
for the preparation of ethynylindoles consist of transforꢀ
mation of structural fragments linked directly to the inꢀ
dole nucleus.3—11
Thus, we synthesized 2ꢀnitroꢀ1,4ꢀdiethynylbenzene
(4a) and studied some of its transformations. It was also
shown that Nꢀacetyl derivatives 6a,b cyclize on heating
with sodium hydride to give ethynylindoles with simultaꢀ
neous removal of the acetyl protection. Alkyne 7b was
found to undergo 3ꢀaminomethylation.
Reagents, conditions, and yields: i. Zn, NH4OH, 20 °C, 48 h;
ii. Zn, NH4OH, 70—80 °C, 3 h; iii. Ac2O, benzene, reflux,
2—4 h; yields 30% (6a) and 92% (6b).
Heating of acetamides 6a,b with sodium hydride in
freshly distilled DMF with subsequent keeping of the reꢀ
action mixture for 12 h at room temperature induced
heterocyclization accompanied by the removal of the
acetyl protective group to give 6ꢀethynylindole (7a) and
bisꢀmorpholinomethyl derivative (7b). All attempts to
carry out cyclization directly of amines 5a and 5b in a
similar way failed. Our search for other cyclization condiꢀ
tions for these compounds has been unsuccessful either
(Scheme 4).
The Mannich base 7b enters into electrophilic substiꢀ
tution typical of indole. For example, it reacts with
morpholine and formaldehyde in glacial acetic acid giving
rise to tris(aminomethyl) derivative 8, which was isolated
and characterized as the trihydrochloride (Scheme 5).
The structure of all the synthesized compounds was
confirmed by elemental analysis and spectroscopy.
Note also that heterocyclization of 2ꢀacetylaminoꢀ1,4ꢀ
diethynylbenzene (6a) to 6ꢀethynylindole (7a) can be conꢀ
Experimental
1
H NMR spectra were recorded on a Bruker WPꢀ200 specꢀ
trometer (operation frequency 200 МHz) in CDCl3, DMSOꢀd6,
acetoneꢀd6, or DMFꢀd7 relative to internal Me4Si. IR spectra
were measured on a URꢀ20 instrument in mineral oil for comꢀ
pounds 4a—d, 5b, 6a—b, and 7a and as KBr pellets for comꢀ
pound 7b. Thin layer chromatography was carried out on Silufol
UVꢀ254 plates, which were visualized using a UV lamp. Preꢀ
parative chromatography was performed on columns with silica
gel (100—160 mesh, Kavalier).
2ꢀNitroꢀ1,4ꢀbis(1,3,3ꢀtrimethylindolinꢀ2ꢀylidenacetyl)benꢀ
zene (3). A mixture of nitroterephthalic acid (45.1 g, 0.21 mol),
thionyl chloride (151 g, 1.27 mol) and DMF (1 mL) in anꢀ
hydrous benzene (200 mL) was refluxed until dissolution of the
starting acid was complete, cooled, and concentrated on a roꢀ
tary evaporator. To remove excess thionyl chloride, the residue
was shaken with petroleum ether (60 mL), which was then evapoꢀ
rated. The resulting dichloride 2 was dissolved in anhydrous

2588
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005
Tarshits et al.
benzene (100 mL) and this solution was added with stirring and
water cooling to a solution of Fischer base (1) (90 g, 0.52 mol)
and triethylamine (52.3 g, 0.52 mol) in anhydrous benzene
(400 mL). The reaction mixture was kept for 24 h at room
temperature, the precipitate was filtered off, washed on a filter
successively with 3% hydrochloric acid, water, 10% aqueous
Na2CO3, and PriOH, and dried. Yield 84 g (75%), m.p.
246—247 °C (from АcOH). Found (%): C, 73.83; H, 5.77;
N, 7.95. C32H31N3O4. Calculated (%): C, 73.68; H, 5.99;
1,4ꢀBis{3ꢀ[4ꢀ(2ꢀfuroyl)piperazino]propꢀ1ꢀynyl}ꢀ2ꢀnitrobenꢀ
zene dihydrochloride (4d). Diacetylene 4a (1 g, 6 mmol), formaꢀ
lin (1.8 mL), Nꢀ(2ꢀfuroyl)piperazine (2.6 g, 14.5 mmol), and
CuCl (0.12 g, 1.2 mmol) were mixed in dioxane (20 mL). The
reaction mixture was stirred for 1 h at 80 °C, cooled, and filꢀ
tered, the filtrate was evaporated, and the residue was dissolved
in chloroform. The solution was washed with 10% aqueous amꢀ
monia and water and dried with sodium sulfate. The solvent was
removed and the resulting oil was dissolved in chloroform and
acidified with an ethanol solution of HCl. The resulting oil was
covered with acetone and kept for 12 h at room temperature.
The precipitate was filtered off, washed on the filter with acꢀ
etone, dried in a desiccator over CaCl2 and paraffin, and reꢀ
crystallized from anhydrous EtOH. Yield 1.4 g (37%), m.p.
199—202 °C. Found (%): C, 57.50; H, 5.03; Cl, 11.70; N, 11.20.
1
N, 8.06. H NMR (CDCl3), δ: 1.86 (s, 12 H, H 2 gemꢀCМе2);
3.21, 3.35 (both s, 3 H each, NМе); 5.43, 5.93 (both s,
1 H each, =CH); 6.79—8.46 (m, 11 H, Harom).
1,4ꢀDiethynylꢀ2ꢀnitrobenzene (4a). Compound 3 (23.5 g,
0.14 mol) was heated with phosphorus oxychloride (15.16 mL,
0.17 mol) in diоxane (100 mL) for 6 h at 90 °C. The reaction
mixture was cooled, poured into a stirred 10% solution of NaOH
(670 mL), and filtered. The filtrate was extracted with chloroꢀ
form (3×200 mL) and the precipitate on the filter was washed
with chloroform (100 mL). The chloroform extracts were comꢀ
bined and dried with sodium sulfate, the solvent was evaporated,
and the residue was chromatpgraphed on a column eluting with
carbon tetrachloride. Yield 5 g (78%), m.p. 127—128 °C (from
EtOH). Found (%): C, 69.93; H, 3.05; N, 8.13. C10H5NO2.
Calculated (%): C, 70.18; H, 2.94; N, 8.18. IR, ν/cm–1: 1350,
C
30H29N5O6•2HCl. Calculated (%): C, 57.33; H, 4.97;
Cl, 11.28; N, 11.14. 1H NMR (DMFꢀd7), δ: 3.60 (s, 8 H,
H of both piperazine rings); 4.54, 4.58 (both s, 2 H each, CCH2);
6.68—7.89 (m, 3 H each, H of both furan rings); 7.89—8.37 (m,
3 H, Harom).
2ꢀAminoꢀ1,4ꢀbis(3ꢀmorpholinopropꢀ1ꢀynyl)benzene (5b).
Water (100 mL) was added to a mixture of diacetylene 4a (5 g,
29.2 mmol), zinc dust (15 g, 230 mmol), and 25% aqueous
ammonia (50 mL), the reaction mixture was stirred for 3 h at
70—80 °C and filtrered, the filtrate was extracted with chloroꢀ
form, and the precipitate was also thoroughly washed with chloꢀ
roform on the filter. The combined chloroform extracts were
dried with sodium sulfate and the solvent was evaporated. Yield
3 g (65.5%), m.p. 125—127 °C (from PriOH). Found (%):
C, 69.97; H, 7.17; N, 12.49. C20H25N3O2. Calculated (%):
C, 70.77; H, 7.42; N, 12.38. IR, ν/cm–1: 2235 (C≡C);
3365—3470 (NH2). 1H NMR (CDCl3), δ: 2.63—3.77 (m,
8 H each, CH2NCH2, CH2OCH2, H of both morpholine rings);
3.50, 3.58 (both s, 2 H each, ≡CCH2); 4.18 (br.s, 2 H, NH2);
6.74 (d, 1 H, Harom, J = 8.12 Hz); 6.77 (s, 1 H, Harom); 7.20 (d,
1 H, Harom, J = 8.12 Hz).
2ꢀAcetylaminoꢀ1,4ꢀdiethynylbenzene (6a). A mixture of
diacetylene 4a (4.5 g, 26.3 mmol), zinc dust (10.45 g, 160 mmol),
25% aqueous ammonia (19 mL), and water (4.5 mL) was stirred
at room temperature for 48 h and filtered. The filtrate was exꢀ
tracted with ether, and the precipitate was washed with ether on
the filter. The combined ether extracts were dried with sodium
sulfate, the solvent was evaporated, and the remaining oil was
dissolved in benzene (50 mL). Acetic anhydride (15 mL) was
added and the mixture was refluxed for 4 h. The solvent was
evaporated, the residue was chromatographed on a column elutꢀ
ing with chloroform. Yield 1.42 g (30%, based on the startꢀ
ing nitrodiacetylene 4a), m.p. 123—125 °C (from EtOH).
Found (%): C, 78.87; H, 5.10; N, 7.76. C12H9NO. Calcuꢀ
lated (%): C, 78.67; H, 4.95; N, 7.64. IR, ν/cm–1: 1650
(MeC=O); 2090 (C≡C); 3200 (NH); 3300 (≡CH). 1H NMR
(CDCl3), δ: 3.13, 3.55 (both s, 1 H each, ≡CH); 2.20 (s, 3 H,
1
1530 (NO2); 2105 (C≡C); 3270 (≡CH). H NMR (CDCl3), δ:
3.32, 3.61 (both s, 1 H each, ≡CH); 7.66 (s, 2 H, Harom); 8.14 (s,
1 H, Harom).
1,4ꢀBis(3ꢀmorpholinopropꢀ1ꢀynyl)ꢀ2ꢀnitrobenzene (4b). Diꢀ
acetylene 4a (3 g, 18 mmol) was dissolved in dioxane (150 mL),
and CuCl (0.18 g, 1.8 mmol), 40% formalin (5.4 mL), and
morpholine (6.26 mL, 72 mmol) were added to the solution.
The reaction mixture was stirred for 1 h at 90 °C and cooled, the
solvent was evaporated, ether (5 mL) was added to the resulting
oil, and the precipitated crystals were filtered off and washed
with ether on the filter. Yield 5.6 g (87%), m.p. 98—99 °C (from
EtOH). Found (%): C, 64.85; H, 6.34; N, 11.61. C20H23N3O4.
Calculated (%): C, 65.03; H, 6.28; N, 11.37. IR, ν/cm–1: 2240
(CH2C≡CCH2). 1H NMR (CDCl3), δ: 2.61—2.69 (m, 4 H each,
CH2NCH2, H of both morpholine rings); 3.53, 3.56 (both s,
2 H each, CCH2), 3.75—3.80 (m, 4 H each, CH2OCH2
,
H of both morpholine rings); 7.56 (s, 2 H, Harom); 8.07 (s,
1 H, Harom).
2ꢀNitroꢀ1,4ꢀbis(3ꢀpiperidinopropꢀ1ꢀynyl)benzene dihydroꢀ
chloride (4c). A mixture of CuCl (0.53 g, 5.3 mmol), formalin
(3.95 mL), and piperidine (5.2 mL, 53 mmol) in dioxane (50 mL)
was added with stirring to a solution of diacetylene 4a (3 g,
18 mmol) in dioxane (50 mL). The reaction mixture was stirred
for 1 h at 80 °C and cooled, the solvent was evaporated, the
residue was dissolved in benzene and washed with a 10% aqueꢀ
ous solution of ammonia and water, and dried with sodium
sulfate. The solvent was removed and the resulting oil was disꢀ
solved in chloroform and acidified with an ethanol solution of
HCl. The precipitate was filtered off and washed with chloroꢀ
form on the filter. Yield 1.2 g (16%), m.p. 220—225 °C (with
dec.). Found (%): C, 60.45; H, 6.89; Cl, 16.47; N, 9.78.
COCH3); 7.10 (d, 1 H, Harom, J = 7.6 Hz); 7.36 (d, 1 H, Harom
,
J = 7.6 Hz); 7.86 (br.s, 1 H, Harom); 8.50 (s, 1 H, NHCOMe).
2ꢀAcetylaminoꢀ1,4ꢀbis(3ꢀmorpholinopropꢀ1ꢀynyl)benzene
(6b). A mixture of amine 5b (3 g, 8.84 mmol) and Аc2O (1.8 mL)
in benzene (50 mL) was refluxed for 2 h and cooled, the solvent
was evaporated, and the residue was recrystallized from PriOH.
Yield 3.1 g (92%), m.p. 177—179 °C. Found (%): C, 69.96;
H, 7.10; N, 10.89. C22H27N3O3. Calculated (%): C, 69.27;
H, 7.13; N, 11.02. IR, ν/cm–1: 1680 (MeC=O); 2210 (C≡C);
C
22H27N3O2•2HCl. Calculated (%): C, 60.27; H, 6.67;
1
Cl, 16.19; N, 9.56. H NMR (DMSOꢀd6), δ: 1.43—1.85 (m,
10 H each, CH2CH2CH2, CH2NCH2, H of both piperidine
rings); 4.32, 4.39 (both s, 2 H each, CCH2), 7.92—8.34 (m,
4 H each, CH2OCH2, H of both piperidine rings); 7.92—8.37
(m, 3 H, Harom); 11.63 (br.s, 2 H, NHCl).

2ꢀNitroꢀ1,4ꢀdiethynylbenzene transformations
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005 2589
3310 (NH). 1H NMR (CDCl3), δ: 2.20 (s, 3 H, COMe);
2.60—2.66 (m, 4 H each, CH2NCH2, H of both morpholine
rings); 3.48, 3.59 (both s, 2 H each, ≡CCH2); 3.69—3.80 (m,
4 H each, CH2OCH2, H of both morpholine rings); 7.04 (d,
1 H, Harom, J = 7.9 Hz); 7.29 (d, 1 H, Harom, J = 8.0 Hz); 7.79
(br.s, 1 H, Harom); 8.40 (br.s, 1 H, NHCOMe).
residual oil was dissolved in an ethanol solution of HCl. Acetone
was added to the resulting solution. The precipitated crystals
were filtered off, washed with acetone on the filter, and dried.
Yield 0.7 g (85%); hygroscopic crystals decomposing in air in
about three weeks, m.p. 182—186 °C (with dec.). Found (%):
C, 55.10; H, 6.92; Cl, 19.67; N, 10.35. C25H34N4O3•3HCl.
Calculated (%): C, 54.80; H, 6.81; Cl, 19.41; N, 10.22. 1H NMR
(DMFꢀd7), δ: 3.55, 4.05 (both s, 12 H each, CH2NCH2,
CH2OCH2, H of all morpholine rings); 4.47 (s, 1 H, C≡CCH2),
4.99, 5.19 (both s, 2 H each, NCH2); 7.32 (d, 1 H, Harom, J =
8.77 Hz); 7.75 (s, 1 H, Harom); 8.10 (d, 1 H, Harom, J = 8.04 Hz);
12.81 (br.s, 1 H, NH).
6ꢀEthynylindole (7a). A mixture of acetamide 6a (0.5 g,
2.73 mmol) and sodium hydride (0.01 g, 0.42 mmol) in freshly
distilled DMF (20 mL) was heated for 80—85 °C and allowed to
stand for 12 h at room temperature. The excess of sodium hyꢀ
dride was neutralized with a 10% aqueous solution of ammoꢀ
nium chloride, and water (100 mL) was added. The mixture was
extracted with ether, the organic layer was washed with water,
and dried with sodium sulfate, the solvent was evaporated, and
the residue was subjected to TLC on silica gel plates (5—40 mesh,
Kavalier), the product being eluted with benzene. Yield 0.17 g
(45%), Rf 0.64 (chloroform), yellow oil. Found (%): C, 85.24;
H, 5.12; N, 11.78. C10H7N. Calculated (%): C, 85.08; H, 5.00;
N, 11.66. IR, ν/cm–1: 2115 (C≡C); 3280 (≡CH); 3420 (NH).
1H NMR (CDCl3), δ: 3.04 (s, 1 H, ≡CH); 6.53—6.59, 7.20—7.26
(both m, 1 H each, H(3)Ar, H(2)Ar); 7.26—7.59 (m, 3 H, Harom);
8.15 (br.s, 1 H, NH).
References
1. N. M. Przhiyalgovskaya, L. I. Kon´kov, D. L. Tarshits, S. V.
Salmina, N. T. Segizova, and N. N. Suvorov, Khim.
Geterotsikl. Soedinen., 1987, 915 [Chem. Heterocycl. Compd.,
1987 (Engl. Transl.)].
2. D. L. Tarshits, N. M. Przhiyalgovskaya, and N. N. Suvorov,
Khim. Geterotsikl. Soedinen., 1988, 1472 [Chem. Heterocycl.
Compd., 1988 (Engl. Transl.)].
2ꢀMorpholinomethylꢀ6ꢀ(3ꢀmorpholinopropꢀ1ꢀynyl)indole
(7b). A mixture of acetamide 6b (1.5 g, 3.93 mmol) and sodium
hydride (0.288 g, 12 mmol) in 35 mL of freshly distilled DMF
was stirred for 1 h at 80 °C and allowed to stand for 12 h at room
temperature. The excess of sodium hydride was neutralized with
a 25% aqueous solution of ammonium chloride. The mixture
was extracted with methylеne dichloride and the organic layer
was dried with sodium sulfate. The solvent was evaporated and
the residue was chromatographed on a column eluting with
acetone. The resulting oil was treated with pentane and the
precipitated crystals were filtered off and dried. Yield 0.7 g (50%),
m.p. 121—123 °C (from PriOH). Found (%): C, 71.28; H, 6.86;
N, 11.97. C20H25N3O2. Calculated (%): C, 70.77; H, 7.42;
N, 12.38. IR, ν/cm–1: 2240 (C≡C); 3270 (NH). 1H NMR
(CDCl3), δ: 2.54—2.71 (m, 4 each, CH2NCH2, H of both
morpholine rings); 3.52 (s, 2 H, C≡CCH2); 3.60—3.82 (m,
4 H each, CH2OCH2, H of both morpholine rings, 2 H, NCH2);
6.30—6.39 (m, 1 H, H(3)Ar); 7.06—7.43 (m, 3 H, Harom); 9.07
(br.s, 1 H, NH).
3. I. L. Kotlyarevskii and L. A. Pavlyukhina, Izv. Akad. Nauk
SSSR. Ser. Khim., 1976, 2363 [Bull. Acad. Sci. USSR, Div.
Chem. Sci., 1976, 25 (Engl. Transl.)].
4. N. N. Suvorov, A. B. Kamenskii, and Yu. I. Smushkevich,
Zhurn. Organ. Khim., 1977, 13, 197 [J. Org. Chem. USSR,
1977, 13 (Engl. Transl.)].
5. S. Wentrup and H. W. Winter, Angew. Chem., 1978, 90, 643.
6. T. A. Prikhod´ko, Z. P. Trotsenko, and S. F. Vasilevskii, Izv.
Akad. Nauk SSSR. Ser. Khim., 1980, 1690 [Bull. Acad. Sci.
USSR, Div. Chem. Sci., 1980, 29 (Engl. Transl.)].
7. W. M. D. Benzies, P. M. Fresneda, R. A. Jones, and
H. McNab. Hamish, J. Chem. Soc., Perkin Trans. 1, 1986,
6, 1651.
8. M. S. Shvartsberg, S. F. Vasilevskii, and T. A. Prikhod´ko,
Izv. Akad. Nauk SSSR. Ser. Khim., 1982, 2524 [Bull. Acad.
Sci. USSR, Div. Chem. Sci., 1982, 31 (Engl. Transl.)].
9. A. P. Kozikowski, M. Okita, M. Kobayashi, and H. G. Floss,
J. Org. Chem., 1988, 53, 863.
10. C. Sab, D. D. Crotts, G. Hsu, and K. P. C. Vollhardt,
Synlett, 1994, 489.
11. G. Abbiati, E. M. Beccalli, A. Marchesini, and E. Rossi,
Synthesis, 2001, 2477.
2,3ꢀBis(morpholinomethyl)ꢀ6ꢀ(3ꢀmorpholinopropꢀ1ꢀynyl)inꢀ
dole trihydrochloride (8). A mixture of compound 7b (0.5 g,
1.47 mmol), morpholine (0.19 mL, 2.18 mmol), and formalin
(0.165 mL) in 10 mL of glacial AcOH was stirred for 1 h at
85 °C, diluted with cold water, neutralized with 10% aqueous
NaOH, and extracted with chloroform. The organic layer was
dried with sodium sulfate, the solvent was evaporated, and the
Received July 15, 2005;
in revised form October 14 2005