- Email: [email protected]
A novel synthesis of indolines by reaction of ortho-nitrophenylmalonates with bis(dimethylamino)methane
Tetrahedron Letters 52 (2011) 6713–6715
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
A novel synthesis of indolines by reaction of ortho-nitrophenylmalonates with bis(dimethylamino)methane Yuri G. Gololobov ⇑, Ale[ander S. Peregudov, Sergei V. Barabanov, Pavel V. Petrovskii, Victor N. Khrustalev A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 ul. Vavilova, 119991 Moscow, Russian Federation
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 28 June 2011 Revised 20 September 2011 Accepted 30 September 2011 Available online 14 October 2011
We report here a new and efficient synthesis of substituted indolines via reaction of dimethyl 2,4dinitrophenyl-(2,4,6-trinitrophenyl)malonates with bis(dimethylamino)methane. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Indolines Indoles Nitro compounds Nitrogen heterocycles
The year 2011 represents the 100-year anniversary of the first indoline synthesis.1 Thanks to their huge practical importance, indoline chemistry is well developed. Indoline-containing compounds have been utilized as drug candidates in a variety of therapeutic fields and are more often found as new therapeutic entities.2 It was found that substituted indolines increased the efficiency of solar batteries.3 To date, a large number of approaches have been designed for their synthesis. One of the key steps in indoline synthesis is the formation of the indoline ring through aryl amination. For example, indolines have been synthesized by intramolecular N-aryl amination of the respective intermediates containing primary or secondary amino groups in the presence of various catalytic systems resulting in substitution of inert aromatic halogens by the NH-groups.4 However, no examples of the formation of indolines via intramolecular N-aryl amination with tertiary amines have been reported.
We have discovered a new type of reaction that leads to the formation of substituted indolines 2 containing one or two nitro groups on the phenyl ring, a Me group at N-1 and ester groups at C-3 of the indoline 2. Novel indolines 2 were synthesized by reacting CH-acid 1 with bis(dimethylamino)methane (Scheme 1). The process did not require a catalyst or an absolutely inert anhydrous medium.5 The yields of compounds 2 were 40–50% (2a) or 75–80% (2b). Compounds 2a,b were fully characterized from IR, UV, 1H NMR, and 13C NMR spectral data and by X-ray6 analysis (Figs. 1 and 2). While the mechanism of this reaction has not been established, we believe that during the first step, regular dimethylaminomethylation of CH-acids 17,8 results in the formation of tertiary amine A and dimethylamine (Scheme 2). Next, the dimethylamino group of A displaces the ortho-nitro group resulting in indolines 2. In the reaction of 1a with bis(dimethylamino)methane, indole 3 is also
R
R Me2NCH2NMe2 (C6H6, 80 0C, 5-6 h)
O2N
CH(COOMe)2 - Me2NH NO2
O2N 2a,b
1a: R = H 1b: R = NO2 Scheme 1. Synthesis of indolines 2a,b
E-mail address: [email protected] (Y.G. Gololobov). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.09.145
COOMe COOMe + unidentified products N Me
6714
Y. G. Gololobov et al. / Tetrahedron Letters 52 (2011) 6713–6715
formed in small amounts. An experiment9 (Scheme 3) using 2 equiv of bis(dimethylamino)methane with 1a led to the formation of indole 3 in a yield of 30% after repeated crystallizations. Other examples of the formation of indolines and indoles on reactions of CH-acids of type 1 with bis(dimethylamino)methane and the characterization of the other unidentified products will be considered in subsequent publications. In summary, we have described a novel reaction for the synthesis of 6-nitro-(or 4,6-dinitro)-N-methylindolines by reaction of dimethyl ortho-nitrophenylmalonates with bis(dimethylamino)methane. This process requires no catalyst or inert conditions and is the first example of N-aryl amination with a tertiary amine. Further study of the reaction mechanism and the scope are currently in progress in our laboratory. Acknowledgments The authors gratefully acknowledge Dr. I. Garbuzova for recording UV and IR spectra and Dr. M. Gololobov for advice and helpful discussions.
Figure 1. Molecular structure of 2a.
References and notes 1. Braun, J. V.; Sobecki, W. Ber. 1911, 44, 2159. 2. Sun, H.; Ehlhardt, W. J.; Kulanthaivel, P.; Lanza, D. L.; Reilly, C. A.; Yost, G. S. J. Pharmacol. Exper. Ther. 2007, 843–851. 3. Kuang, D.; Uchida, S.; Humphry-Baker, R.; Zakeeruddin, S. M.; Michael, G. Angew. Chem., Int. Ed. 2008, 47, 1923. 4. Liu, D.; Zhao, G.; Xiang, L. Eur. J. Org. Chem. 2010, 3975–3984. 5. 3,3-Bis(methoxycarbonyl)-1-methyl-6-nitroindoline (2a). To a stirred solution of bis(dimethylamino)methane (341 mg, 3.34 mmol) in benzene (4 mL) was added a solution of dimethyl 2,4-dinitrophenylmalonate (500 mg, 1.67 mmol) in benzene (4 mL). After refluxing for 10 h, the mixture was evaporated in vacuo. The residue was purified by crystallization from EtOH to afford 2a as yellow–orange plates, mp 136–137 °C (270 mg, 55% yield). 1H NMR (400 MHz, CDCl3) d 2.86 (s, 3H, NCH3), 3.79 (s, 6H, OCH3), 4.02 (s, 2H, CH2), 7.21 (d, J = 2.0, 1H, CH-7), 7.48 (d, J = 8.2, 1H, CH-9), 7.61 (dd, J = 2.0, J = 8.2, 1H, CH-5); 13C NMR (CDCl3) d 34.6, 53.6, 61.4, 101.6, 113.3, 126.8, 128.3, 131.4, 150.1, 153.0, 168.5; IR (KBr) mmax: 1261, 1346, 1527, 1590, 1616, 1734 cm 1; UV (acetone) k = 405 nm; calcd for C13H14N2O6: C, 53.06; H, 4.76; N, 9.52. Found: C, 53.07; H, 4.81; N, 9.2. 3,3-Bis(methoxycarbonyl)-1-methyl-4,6-dinitroindoline (2b). To a stirred solution of bis(dimethylamino)methane (150 mg, 1.47 mmol) in benzene (5 mL) was added a solution of dimethyl 2,4,6-trinitrophenylmalonate (252 mg, 0.735 mmol) in benzene (5 mL). After refluxing for 6 h at 80 °C, the mixture was evaporated in vacuo. The residue was found to be 98% pure 2b according to the 1H NMR spectrum. Further purification by crystallization from EtOAc/ petroleum ether gave 2b (75% yield) as orange crystalline plates. Mp 155– 156 °C; 1H NMR (CDCl3) d 2.94 (s, 3H, NCH3), 3.76 (s, 6H, OCH3), 4.16 (s, 2H, CH2), 7.42 (s, 1H C-7), 8.2 (s, 1H C-5); 13C NMR (CDCl3) d 34.0, 53.6, 62.7, 63.6, 105.0, 108.3, 126.2, 146.0, 150.0, 154.8, 167.9; IR (KBr) mmax: 1220, 1265, 1339, 1376, 1461, 1531, 1557, 1594, 1730, 1752 cm 1; UV (acetone) k = 433 nm;
Figure 2. Molecular structure of 2b.
R
Me2N-CH2-NMe2 1
COOMe COOMe C CH2 N Me NO2 Me
O2N
- Me2NH 1a: R = H 1b: R = NO2
2 + unidentified products
A Scheme 2. Possible of pathway indolines 2a,b synthesis.
COOMe 1a
2 Me2NCH2NMe2 (120 0C, 3-5 h,no solvent ) - 2Me2NH
+ unidentified products N
O2N
Me 3 Scheme 3. Synthesis of the indole 3.
Y. G. Gololobov et al. / Tetrahedron Letters 52 (2011) 6713–6715 calcd for C13H13N3O8: C, 46.1; H, 3.83; N, 12.38. Found: C, 46.09; H, 3.74; N, 12.41. 6. X-ray crystal structure determination. The crystal of 2a (C13H14N2O6, M = 294.26) is triclinic, space group P-1, at T = 100 K: a = 7.9087(10) Å, b = 8.4151(11) Å, c = 10.9627(14) Å, a = 78.626(2)°, b = 73.000(2)°, c = 74.755(2)°, V = 667.41(15) Å3, Z = 2, dcalc = 1.464 g/cm3, F(0 0 0) = 308, l = 0.118 mm 1. 7384 total reflections (3180 unique reflections, Rint = 0.034) were measured on a three-circle Bruker SMART APEX-II CCD diffractometer [k(Mo Ka)-radiation, graphite monochromator, u and x scan mode, 2hmax = 56°]. The final divergence factors were R1 = 0.043 for 2318 independent reflections with I>2r(I) and wR2 = 0.104 for all independent reflections, S = 1.002. The crystal of 2b (C13H13N3O8, M = 339.26) is monoclinic, space group Cc, at T = 100 K: a = 8.6174(8) Å, b = 13.5254(13) Å, c = 24.858(2) Å, b = 95.154(2)°, V = 2885.5(5) Å3, Z = 8, dcalc = 1.562 g/cm3, F(0 0 0) = 1408, l = 0.132 mm 1. 12,724 total reflections (2819 unique reflections, Rint = 0.067) were measured on a three-circle Bruker SMART APEX-II CCD diffractometer [k(MoKa)-radiation, graphite monochromator, u and x scan mode, 2hmax = 52°]. The final divergence factors were R1 = 0.039 for 2322 independent reflections with I>2r(I) and wR2 = 0.078 for all independent reflections, S = 1.008. The structures were solved by direct methods and refined by full-matrix least squares technique on F2 with anisotropic displacement parameters for non-hydrogen atoms. The hydrogen atoms were placed in calculated positions and refined within the riding model with fixed isotropic displacement parameters [Uiso(H) = 1.5Ueq(C) for the CH3-groups and
7. 8. 9.
10.
6715
Uiso(H) = 1.2Ueq(C) for the other groups]. All calculations were carried out using the SHELXTL program.10 Crystallographic data for compounds 2a and 2b have been deposited with the Cambridge Crystallographic Data Cent, CCDC 826503 (2a) and CCDC 826502 (2b). Copies of this information may be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336033; e-mail: [email protected] or www.ccdc.cam.ac.uk). Kavàlek, J.; Machàcˇek, V.; Lycˇka, A.; Šteˇrva, V. Collect. Czech. Chem. Commun. 1976, 41, 590–597. Machàcˇek, V.; Šteˇrva, V.; Lycˇka, A. Collect. Czech. Chem. Commun. 1987, 52, 132– 139. Methyl 1-methyl-6-nitroindole-3-carboxylate (3). A mixture of bis(dimethyl amino)methane (350 mg, 3.4 mmol) and methyl 2,4-dinitrophenylmalonate (500 mg, 1.7 mmol) was heated for 3.5 h at 120 °C. The mixture was cooled and washed with petroleum ether. Crystallization of the residue from EtOH gave 3 (25% yield) as a black powder. Further purification by crystallization from HC(O)NMe2 gave light yellow crystalline plates (20% yield). Mp 213–214 °C; 1H NMR (CDCl3) d 3.92 (s, 3H, NCH3), 3.94 (s, 3H, OCH3), 7.99 (s, 1H, @CH), 8.14 (dd, J = 1.9, J = 8.8, 1H, CH-5), 8.23 (d, J = 8.8, 1H, CH-3), 8.32 (d, J = 1.9, 1H, CH-6); 13C NMR (d6-acetone) d 33.2, 50.5, 107.4, 116.4, 121.2, 131.2, 136.2, 140.6, 143.6, 163.8; IR (KBr) mmax: 1124, 1224, 1339, 1383, 1468, 1512, 1531, 1612, 1704 cm 1; UV (acetone) k = 356 nm; calcd for C11H10N2O4: C, 56.41; H, 4.27; N, 11.96. Found: C, 56.65; H, 4.45; N, 12.15. Sheldrick, G. M. Acta Cryst. 2008, A64, 112–122.
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
A novel synthesis of indolines by reaction of ortho-nitrophenylmalonates with bis(dimethylamino)methane Yuri G. Gololobov ⇑, Ale[ander S. Peregudov, Sergei V. Barabanov, Pavel V. Petrovskii, Victor N. Khrustalev A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 ul. Vavilova, 119991 Moscow, Russian Federation
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 28 June 2011 Revised 20 September 2011 Accepted 30 September 2011 Available online 14 October 2011
We report here a new and efficient synthesis of substituted indolines via reaction of dimethyl 2,4dinitrophenyl-(2,4,6-trinitrophenyl)malonates with bis(dimethylamino)methane. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Indolines Indoles Nitro compounds Nitrogen heterocycles
The year 2011 represents the 100-year anniversary of the first indoline synthesis.1 Thanks to their huge practical importance, indoline chemistry is well developed. Indoline-containing compounds have been utilized as drug candidates in a variety of therapeutic fields and are more often found as new therapeutic entities.2 It was found that substituted indolines increased the efficiency of solar batteries.3 To date, a large number of approaches have been designed for their synthesis. One of the key steps in indoline synthesis is the formation of the indoline ring through aryl amination. For example, indolines have been synthesized by intramolecular N-aryl amination of the respective intermediates containing primary or secondary amino groups in the presence of various catalytic systems resulting in substitution of inert aromatic halogens by the NH-groups.4 However, no examples of the formation of indolines via intramolecular N-aryl amination with tertiary amines have been reported.
We have discovered a new type of reaction that leads to the formation of substituted indolines 2 containing one or two nitro groups on the phenyl ring, a Me group at N-1 and ester groups at C-3 of the indoline 2. Novel indolines 2 were synthesized by reacting CH-acid 1 with bis(dimethylamino)methane (Scheme 1). The process did not require a catalyst or an absolutely inert anhydrous medium.5 The yields of compounds 2 were 40–50% (2a) or 75–80% (2b). Compounds 2a,b were fully characterized from IR, UV, 1H NMR, and 13C NMR spectral data and by X-ray6 analysis (Figs. 1 and 2). While the mechanism of this reaction has not been established, we believe that during the first step, regular dimethylaminomethylation of CH-acids 17,8 results in the formation of tertiary amine A and dimethylamine (Scheme 2). Next, the dimethylamino group of A displaces the ortho-nitro group resulting in indolines 2. In the reaction of 1a with bis(dimethylamino)methane, indole 3 is also
R
R Me2NCH2NMe2 (C6H6, 80 0C, 5-6 h)
O2N
CH(COOMe)2 - Me2NH NO2
O2N 2a,b
1a: R = H 1b: R = NO2 Scheme 1. Synthesis of indolines 2a,b
E-mail address: [email protected] (Y.G. Gololobov). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.09.145
COOMe COOMe + unidentified products N Me
6714
Y. G. Gololobov et al. / Tetrahedron Letters 52 (2011) 6713–6715
formed in small amounts. An experiment9 (Scheme 3) using 2 equiv of bis(dimethylamino)methane with 1a led to the formation of indole 3 in a yield of 30% after repeated crystallizations. Other examples of the formation of indolines and indoles on reactions of CH-acids of type 1 with bis(dimethylamino)methane and the characterization of the other unidentified products will be considered in subsequent publications. In summary, we have described a novel reaction for the synthesis of 6-nitro-(or 4,6-dinitro)-N-methylindolines by reaction of dimethyl ortho-nitrophenylmalonates with bis(dimethylamino)methane. This process requires no catalyst or inert conditions and is the first example of N-aryl amination with a tertiary amine. Further study of the reaction mechanism and the scope are currently in progress in our laboratory. Acknowledgments The authors gratefully acknowledge Dr. I. Garbuzova for recording UV and IR spectra and Dr. M. Gololobov for advice and helpful discussions.
Figure 1. Molecular structure of 2a.
References and notes 1. Braun, J. V.; Sobecki, W. Ber. 1911, 44, 2159. 2. Sun, H.; Ehlhardt, W. J.; Kulanthaivel, P.; Lanza, D. L.; Reilly, C. A.; Yost, G. S. J. Pharmacol. Exper. Ther. 2007, 843–851. 3. Kuang, D.; Uchida, S.; Humphry-Baker, R.; Zakeeruddin, S. M.; Michael, G. Angew. Chem., Int. Ed. 2008, 47, 1923. 4. Liu, D.; Zhao, G.; Xiang, L. Eur. J. Org. Chem. 2010, 3975–3984. 5. 3,3-Bis(methoxycarbonyl)-1-methyl-6-nitroindoline (2a). To a stirred solution of bis(dimethylamino)methane (341 mg, 3.34 mmol) in benzene (4 mL) was added a solution of dimethyl 2,4-dinitrophenylmalonate (500 mg, 1.67 mmol) in benzene (4 mL). After refluxing for 10 h, the mixture was evaporated in vacuo. The residue was purified by crystallization from EtOH to afford 2a as yellow–orange plates, mp 136–137 °C (270 mg, 55% yield). 1H NMR (400 MHz, CDCl3) d 2.86 (s, 3H, NCH3), 3.79 (s, 6H, OCH3), 4.02 (s, 2H, CH2), 7.21 (d, J = 2.0, 1H, CH-7), 7.48 (d, J = 8.2, 1H, CH-9), 7.61 (dd, J = 2.0, J = 8.2, 1H, CH-5); 13C NMR (CDCl3) d 34.6, 53.6, 61.4, 101.6, 113.3, 126.8, 128.3, 131.4, 150.1, 153.0, 168.5; IR (KBr) mmax: 1261, 1346, 1527, 1590, 1616, 1734 cm 1; UV (acetone) k = 405 nm; calcd for C13H14N2O6: C, 53.06; H, 4.76; N, 9.52. Found: C, 53.07; H, 4.81; N, 9.2. 3,3-Bis(methoxycarbonyl)-1-methyl-4,6-dinitroindoline (2b). To a stirred solution of bis(dimethylamino)methane (150 mg, 1.47 mmol) in benzene (5 mL) was added a solution of dimethyl 2,4,6-trinitrophenylmalonate (252 mg, 0.735 mmol) in benzene (5 mL). After refluxing for 6 h at 80 °C, the mixture was evaporated in vacuo. The residue was found to be 98% pure 2b according to the 1H NMR spectrum. Further purification by crystallization from EtOAc/ petroleum ether gave 2b (75% yield) as orange crystalline plates. Mp 155– 156 °C; 1H NMR (CDCl3) d 2.94 (s, 3H, NCH3), 3.76 (s, 6H, OCH3), 4.16 (s, 2H, CH2), 7.42 (s, 1H C-7), 8.2 (s, 1H C-5); 13C NMR (CDCl3) d 34.0, 53.6, 62.7, 63.6, 105.0, 108.3, 126.2, 146.0, 150.0, 154.8, 167.9; IR (KBr) mmax: 1220, 1265, 1339, 1376, 1461, 1531, 1557, 1594, 1730, 1752 cm 1; UV (acetone) k = 433 nm;
Figure 2. Molecular structure of 2b.
R
Me2N-CH2-NMe2 1
COOMe COOMe C CH2 N Me NO2 Me
O2N
- Me2NH 1a: R = H 1b: R = NO2
2 + unidentified products
A Scheme 2. Possible of pathway indolines 2a,b synthesis.
COOMe 1a
2 Me2NCH2NMe2 (120 0C, 3-5 h,no solvent ) - 2Me2NH
+ unidentified products N
O2N
Me 3 Scheme 3. Synthesis of the indole 3.
Y. G. Gololobov et al. / Tetrahedron Letters 52 (2011) 6713–6715 calcd for C13H13N3O8: C, 46.1; H, 3.83; N, 12.38. Found: C, 46.09; H, 3.74; N, 12.41. 6. X-ray crystal structure determination. The crystal of 2a (C13H14N2O6, M = 294.26) is triclinic, space group P-1, at T = 100 K: a = 7.9087(10) Å, b = 8.4151(11) Å, c = 10.9627(14) Å, a = 78.626(2)°, b = 73.000(2)°, c = 74.755(2)°, V = 667.41(15) Å3, Z = 2, dcalc = 1.464 g/cm3, F(0 0 0) = 308, l = 0.118 mm 1. 7384 total reflections (3180 unique reflections, Rint = 0.034) were measured on a three-circle Bruker SMART APEX-II CCD diffractometer [k(Mo Ka)-radiation, graphite monochromator, u and x scan mode, 2hmax = 56°]. The final divergence factors were R1 = 0.043 for 2318 independent reflections with I>2r(I) and wR2 = 0.104 for all independent reflections, S = 1.002. The crystal of 2b (C13H13N3O8, M = 339.26) is monoclinic, space group Cc, at T = 100 K: a = 8.6174(8) Å, b = 13.5254(13) Å, c = 24.858(2) Å, b = 95.154(2)°, V = 2885.5(5) Å3, Z = 8, dcalc = 1.562 g/cm3, F(0 0 0) = 1408, l = 0.132 mm 1. 12,724 total reflections (2819 unique reflections, Rint = 0.067) were measured on a three-circle Bruker SMART APEX-II CCD diffractometer [k(MoKa)-radiation, graphite monochromator, u and x scan mode, 2hmax = 52°]. The final divergence factors were R1 = 0.039 for 2322 independent reflections with I>2r(I) and wR2 = 0.078 for all independent reflections, S = 1.008. The structures were solved by direct methods and refined by full-matrix least squares technique on F2 with anisotropic displacement parameters for non-hydrogen atoms. The hydrogen atoms were placed in calculated positions and refined within the riding model with fixed isotropic displacement parameters [Uiso(H) = 1.5Ueq(C) for the CH3-groups and
7. 8. 9.
10.
6715
Uiso(H) = 1.2Ueq(C) for the other groups]. All calculations were carried out using the SHELXTL program.10 Crystallographic data for compounds 2a and 2b have been deposited with the Cambridge Crystallographic Data Cent, CCDC 826503 (2a) and CCDC 826502 (2b). Copies of this information may be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336033; e-mail: [email protected] or www.ccdc.cam.ac.uk). Kavàlek, J.; Machàcˇek, V.; Lycˇka, A.; Šteˇrva, V. Collect. Czech. Chem. Commun. 1976, 41, 590–597. Machàcˇek, V.; Šteˇrva, V.; Lycˇka, A. Collect. Czech. Chem. Commun. 1987, 52, 132– 139. Methyl 1-methyl-6-nitroindole-3-carboxylate (3). A mixture of bis(dimethyl amino)methane (350 mg, 3.4 mmol) and methyl 2,4-dinitrophenylmalonate (500 mg, 1.7 mmol) was heated for 3.5 h at 120 °C. The mixture was cooled and washed with petroleum ether. Crystallization of the residue from EtOH gave 3 (25% yield) as a black powder. Further purification by crystallization from HC(O)NMe2 gave light yellow crystalline plates (20% yield). Mp 213–214 °C; 1H NMR (CDCl3) d 3.92 (s, 3H, NCH3), 3.94 (s, 3H, OCH3), 7.99 (s, 1H, @CH), 8.14 (dd, J = 1.9, J = 8.8, 1H, CH-5), 8.23 (d, J = 8.8, 1H, CH-3), 8.32 (d, J = 1.9, 1H, CH-6); 13C NMR (d6-acetone) d 33.2, 50.5, 107.4, 116.4, 121.2, 131.2, 136.2, 140.6, 143.6, 163.8; IR (KBr) mmax: 1124, 1224, 1339, 1383, 1468, 1512, 1531, 1612, 1704 cm 1; UV (acetone) k = 356 nm; calcd for C11H10N2O4: C, 56.41; H, 4.27; N, 11.96. Found: C, 56.65; H, 4.45; N, 12.15. Sheldrick, G. M. Acta Cryst. 2008, A64, 112–122.