Graphical Abstract

Graphical Abstract

Leave this area blank for abstract info.

Microwave-assisted Conversion of Carbonyl Compounds into formylated secondary Amines: New Contribution to the Leuckart reaction mechanism in N-methyl formamide. F. Barba*, J. Recio and B. Batanero* Me

O R

R´ 1

M.W.

O

N

H-CO-NHMe

R

E.T.

+ R´

H

OH

-CO2

O

Me NH R

Transformation of 1 to 2 in only one-pot

H

Me N

OH

R´ M.W.

R

CHO R´

2

Tetrahedron Letters

1

Microwave-assisted Conversion of Carbonyl Compounds into formylated secondary Amines: New Contribution to the Leuckart reaction mechanism in N-methyl formamide Fructuoso Barba*, Javier Recio and Belen Batanero* Department of Organic Chemistry. University of Alcalá. 28871 Alcalá de Henares (Madrid). Spain. Abstract— The reductive amination of several carbonyl compounds (Leuckart reaction) has been performed using N-methylformamide and microwave technology. Under these conditions, a new mechanism is proposed via the initial formation of an imine, followed by reduction to the amine by “in situ” generated formic acid, and further formylation of the amine. Using this methodology, the formyl derivatives of several secondary amines were obtained in good to excellent yields. Keywords: Reductive amination/ Leuckart reaction/ microwave technology/ redox process/ formylation of amines. © 2018 Elsevier Science. All rights reserved

The Leuckard reaction is a process commonly used for the reductive amination of aldehydes and ketones.[1] When formamide is used in the reaction, the N-formyl derivatives of the amines are obtained, instead of the free amines. [2] Formamides are regarded as useful intermediates in organic and medicinal chemistry.[3,4] In fact they have found many important applications in organic synthesis, in reactions such as allylations, [5] hydrosilylations,[6] the Vilsmeier reaction,[7] etc. A single universal mechanism for the Leuckart reaction has not been established yet. There seems to be a general acceptance that the mechanism involves an initial addition of ammonium formate, formamide or substituted formamide to the carbonyl function derived from an aldehyde or ketone, to yield an unstable carbinolamine intermediate, which then suffers either reduction, dehydration to an imine, or formylation to the formic ester.[8] The following step involves a hydrogen transfer to the substrate via hydride from the formic acid generated or added to the reaction.[9] However, these mechanistic proposals have some uncertainties that make further experimental considerations regarding the Leuckard reaction process welcome. The first objection to the mechanistic proposals is the acceptance of formamide as the nucleophile towards the carbonyl group of the substrate, even when it is well known the low nucleophilicity of amides compared to amines. The second objection is the proposed transfer of hydride proceeding from the formic acid formed in the reaction. In recent years, microwave-assisted organic synthesis (MAOS) has became a very rapidly developing area of chemistry, as it provides a number of advantages over the standard heating techniques, such as cleaner reactions, ——— *

improved product yields, shorter reaction times, easy workups and solvent-free reaction conditions.[10] In the literature, there are several examples of reactions using MAOS via decomposition of formamides.[11] For example, the Leuckart reaction employing formamide and a series of ketones has been previously reported[12] to proceed with excellent yields by microwave irradiation. In the present paper, a reasonable and novel pathway to the Leuckard reaction is postulated without the assumption of the previously mentioned inconveniences. This pathway is supported by recent experimental results employing Nmethylformamide and MAOS. As far as we know, only one paper has been published to date concerning the Leuckard reaction between N-methylformamide and ketones.[13] Results and Discussion The amine formylation is a well known reaction, both in the presence[14] and in the absence[15] of catalyst. We have carried out the microwave (MW) heating of benzylamine in formic acid during 10 minutes, in absence of catalyst, and quantitative formylated amine was obtained. On the other hand, when this MW-reaction is performed with the Schiff base: Ph-N=CH-Ph, the expected N-benzyl-Nphenylformamide was formed as the main product. These experimental results suggested the need to reconsider the Leuckart reaction mechanism. For this purpose, we run the microwave assisted heating of different carbonyl derivatives in N-methylformamide (instead of formamide as the classical formylating agent), the reasons for this will be discussed later. The microwave-assisted Leuckart reaction in Nmethylformamide of a serie of aldehydes and ketones (1) has thus been performed (Scheme 1) to obtain the reductive

Corresponding authors. Tel.: 34 91 8854617/2517; fax: 34 91 8854686; e-mail: [email protected], [email protected]

2

Tetrahedron Letters

formylation products (2) in good yields, as indicated in Table 1. O R´ +

R

microwave

H-CO-NHMe

Me N

CHO

R

1

R´ 2

Scheme 1. Microwave-assisted Leuckart reaction in N-methylformamide.

1

Yield of 2 (%)

a: Cyclohexanone b: Acetophenone c: Propiophenone d: 2-Acetylpyridine e: Thiophene-2-carbaldehyde f: Benzaldehyde

90 85 88 85 92 90

Table 1. Obtained yields of 2 by MW radiation in N-methylformamide.

In view of the obtained results, our proposed first step for the Leuckart reaction is as follows: N-methylformamide, under our experimental microwave-assisted heating (see experimental section), suffers a heterolytic cleavage to MeNH- and H-CO+ which, immediately evolves to methylamine and formic acid by reaction with the water of hygroscopic N-methylformamide (not previously dried). Generation of ammonia via thermal decomposition of formamide has already been studied under microwave conditions to provide an efficient tool for the synthesis of nitrogen-containing heterocycles.[16] The obtained methylamine then reacts “in situ” with the carbonyl substrates (1) to form the corresponding imines (detected in all cases). In contrast to the formamide reaction, where ammonia was produced, now the methylated imine is stable enough to be detected as a minor product. Once these imines are formed they suffer a redox process by reaction with the generated formic acid to give the secondary amine through a plausible radical pathway, as indicated in Scheme 2. At this point, the imine is reduced to its radical anion at the same time that easy oxidation of formic acid occurs. It should be noted that anodic oxidation of formic acid [17] at nickel oxide nanoparticles modified electrode is only +0.25V (vs Ag/Ag+).

There is enough evidence in the literature to support this mechanism: 1) The carbon dioxide formation is indicative of the participation of formic acid as the reducing agent. [18] 2) It has been found, investigating the reduction of enamines by D-COOH, that hydrogen (deuterium) bonded to the carbon of the formic acid suffers association with the -carbon of the enamine.[19] 3) It was found that both the evolution of carbon dioxide and the formation of the reduction product occur in equivalent quantities.[20] 4) The rate of the reaction is known to decrease by the addition of hydroquinone. This fact indicates that reduction takes place according to a free-radical mechanism.[21] Exceptions to this microwave-assisted Leuckart reaction were observed with substrates such as phenanthrene 9,10dione (1g), benzyl(1h) or furil (1i). In these cases, the corresponding oxazoles (3) and N-methyl-imidazoles (4) were formed instead of the double N-formylated amines. The obtained yields are summarized in Table 2, and the formation of these heterocycles can be rationalized, as indicated in Scheme 3, through the initial attack of methylamine to the carbonyl group to give the imine, and subsequent cyclization catalyzed by the in situ generated formic acid. 1

Yield of 3 (%)

Yield of 4 (%)

g: Phenanthrene 9,10-dione h: Benzil i: Furil

97 5 17

2 6 55

Table 2. Obtained yields of 3 and 4 by MW radiation in N-methyl formamide. O

O

R

R´ O

-1eOH

O

N

CH3

HO

N

CH2 H CH2

HCOOH

-H+ HO

N

1 2 CH3NH2 CH3 N

N

CH3

O

N

aromat.

O

NH

N

N

3 HCOOH(catalyst)

N

+1e-

N R

CH3NH2

catalysis

Me

Me

H

the formic acid oxidation are needed to be close to each other for the coupling to occur. Last step takes place as indicated in bibliography and mentioned above in the beginning of the discussion.

R´

H. + CO2 + H+

Me NH R

+ CO2 R´

CH3 HN

N

CH3

H3C H N -H+

CH2 N

H3C

N

H3C NH aromat.

4

Scheme 2. Redox process by reaction of an imine with generated formic acid to give a secondary amine.

Scheme 3. Reaction pathway to explain the formation of Oxazoles (3) and Imidazoles (4).

It is important to remark that electrons never “jump”within the reaction media. An electron-transfer reaction between two compounds needs a previous and indispensable adsorption of both molecules. For this reason, the radical anion of the Schiff base and the hydrogen atom formed in

Experimental Section The microwave reactions were performed in a Biotage MW apparatus model Initiator 2.5 at constant temperature (variable pressure) of 250 ºC during 10 min. Mass spectra

Tetrahedron Letters (EI, ionizing voltage 70 eV) were registered using a Thermofisher Scientific ITQ900 equipped with a Thermofisher Trace GC-Ultra. IR spectra were obtained, as dispersions in KBr or NaCl, on a Perkin-Elmer Model 583 spectrophotometer. 1H NMR and 13C NMR (300 MHz & 75.4 MHz respectively) spectra were recorded on a Varian Unity 300 apparatus with deuterochloroform as an internal standard. The chemical shifts are given in ppm. Melting points were determined on a Reichert Thermovar microhot stage apparatus. Elemental analyses were performed on a Leco CHNS Model 932 analyzer. General Procedure: A solution of carbonyl compound 1 (1 mmol) in 10 mL of N-methylformamide (purchased from Aldrich, 99%) was heated at 250 ºC under stirring by microwave radiation for ten minutes and subsequently analyzed by GC-MS and TLC. The residue was extracted with ether (3x) /H2O. The organic phase was dried over MgSO4 and concentrated by evaporation under reduced pressure. The resulting residue was chromatographed on silica gel 60 (35-70 mesh) in a (28 × 2.5 cm) column, using a mixture CH2Cl2/EtOH (15:1) as eluent. The experimental physical and spectroscopical properties of the new obtained products are summarized bellow. Known product properties were coincident with the previously described data. N-Benzyl-N-Phenylformamide: Mp 44-45 ºC [Lit.[14] 45-46 ºC]. 13C NMR (75.4 MHz, CDCl3) δ: 48.9, 54.2, 124.1, 126.7, 127.0, 127.5, 127.8, 128.7, 129.6, 136.6, 140.9, 159.4, 162.5. MS m/z (relative intensity) EI: 211 (M+, 80), 210 (M+-1, 21), 194 (6), 166 (9), 91 (100), 77 (7), 65 (24). N-Cyclohexyl-N-methylformamide (2a): oil [Lit.[22] -1 = 2932, 2856, 1668, 1452, 1 1409, 1068, 895, 724. H NMR (300 MHz; CDCl3) δ (ppm): 1.0-1.8 (m, 10H), 2.72 (s, 3H) (duplicated signal: 2.76 (s, 3H)), 3.1-3.3 (m, 1H), 8.07 (s, 1H). 13C NMR (75.4 MHz, CDCl3) δ: 25.4, 25.5, 29.5, 31.3, 50.8, 58.2, 162.4. MS m/z (relative intensity) EI: 141 (M+, 60), 112 (20), 98 (90), 84 (19), 70 (83), 60 (100). IQ: 182 (M++41, 6), 170 (M++29, 20), 142 (M++1, 100), 60 (36). N-Methyl-N-(1-phenylethyl)formamide [23] (2b): oil. -1 = 3064, 2976, 1669, 1405, 1316, 1081, 1 913, 737. H NMR (300 MHz; CDCl3) δ (ppm): 1.5 (d, J= 7.2 Hz, 3H) (duplicated signal: 1.62 (d, J=6.9 Hz, 3H)), 2.6 (s, 3H), 4.58 (q, J=7.2 Hz, 1H) (duplicated signal: 5.6 (q, J=6.9 Hz, 1H), 7.2-7.4 (m, 5H), 8.1 (s,1H) (duplicated signal: 8.35 (s, 1H)). 13C NMR (75.4 MHz, CDCl3) δ: 15.3, 17.9, 26.0, 29.5, 48.7, 56.5, 126.7, 127.3, 127.5, 127.8, 128.5, 128.7, 139.4, 139.5, 162.4, 162.6. MS m/z (relative intensity) EI: 163 (M+, 29), 162 (M+-1, 100), 120 (20), 105 (19), 77 (18), 51 (11). N-Methyl-N-(1-phenylpropyl)formamide (2c): oil. IR -1 = 3058, 2970, 1674, 1409, 1089, 929, 763. 1 H NMR (300 MHz; CDCl3) δ (ppm): 0.92 (m, 3H), 2.0 (m, 2H), 2.6 (m, 3H), 4.4 (m, 1H) (duplicated signal: 5.5 (m)), 7.1-7.3 (m, 5H), 8.1 (s, 1H) (duplicated signal: 8.3 (s)). 13C

3

NMR (75.4 MHz, CDCl3) δ: 10.7, 10.9, 21.7, 23.0, 25.5, 29.4, 54.9, 63.0, 127.0, 127.5, 127.8, 128.4, 128.6, 129.7, 138.5, 162.7, 163.0. MS m/z (relative intensity) EI: 177 (M+, 18), 176 (M+-1, 28), 148 (100), 121 (69), 107 (22), 91 (39), 77 (11). Anal. Calc. for C11 H15 N O: C, 74.58; H, 8.47; N, 7.91. Found: C, 74.43; H, 8.12; N, 8.13. N-Methyl-N-(1-(pyridine-2-yl)ethyl) formamide (2d): -1 = 3052, 2978, 1668, 1588, 1434, 1 1087, 751. H NMR (300 MHz; CDCl3) δ (ppm): 1.62 (d, J=7.0 Hz, 2H) (duplicated signal: 1.72 (d, J=7.0 Hz, 2H)), 2.75 (s, 3H) (duplicated signal: 2.84 (s, 3H)), 4.85 (q, J=7.0 Hz, 1H), (duplicated signal: 5.8 (d, J=7.0 Hz, 2H)), 7.2-7.4 (m, 2H), 7.6-7.8 (m, 1H), 8.4 (s, 1H). 8.5-8.6 (m, 1H). 13C NMR (75.4 MHz, CDCl3) δ: 15.1, 17.1, 26.5, 29.7, 50.8, 58.5, 121.1, 122.4, 122.6, 122.7, 136.7, 136.8, 149.0, 149.4, 158.9, 162.6, 162.8. MS m/z (relative intensity) CI: 205 (M++41, 7), 193 (M++29, 20), 165 (M++1, 58), 137 (100), 106 (58). Anal. Calc. for C9 H12 N2 O: C, 65.85; H, 7.32; N, 17.08. Found: C, 66.21; H, 7.01; N, 16.79. N-Methyl-N-((thiophen-2-yl)methyl)formamide (2e): -1 = 3092, 2962, 1672, 1397, 1260, 1 1079, 713. H NMR (300 MHz; CDCl3) δ (ppm): 2.58 (s, 3H) (duplicated signal: 2.65 (s, 3H)), 4.31 (s, 2H) (duplicated signal: 4.41 (s, 2H)), 6.6-6.8 (m, 2H), 6.9-7.1 (m, 1H), 7.81 (s, 1H) (duplicated signal: 8.0 (s, 1H)). 13C NMR (75.4 MHz, CDCl3) δ: 29.1, 33.7, 42.1, 48.1, 125.4, 125.6, 126.3, 126.5, 126.8, 126.9, 138.0, 138.7, 161.9, 162.1. MS m/z (relative intensity) EI: 155(M+, 50), 126 (27), 112 (19), 98 (53), 97 (100), 85 (32), 53 (21). Anal. Calc. for C7 H9 N O S: C, 54.19; H, 5.81; N, 9.03. Found: C, 53.82; H, 5.61; N, 9.07. N-Benzyl-N-Methylformamide (2f): oil. [Lit.[24] Bp (14 torr) 124-126 ºC]. MS m/z (relative intensity) EI: 149 (M+, 55), 148 ((M+-1, 100), 134 (12), 121 (13), 106 (39), 91 (82), 79 (64), 65 (27). Phenanthro[9,10-d][1,3]oxazole (3g): Mp 136-138 ºC [Lit.[25] 137-139 ºC]. MS m/z (relative intensity) EI: 219 (M+, 100), 192 (22), 190 (25), 163 (36), 82 (5). 1-Methylphenanthrimidazole (4g): Mp 192-194 ºC -1 [Lit.[26] = 3051, 2953, 2852, 1633, 1612, 1529, 1456, 1377, 1079, 1018, 750, 722. 1H NMR (300 MHz; CDCl3) δ (ppm): 4.25 (s, 3H), 7.5-7.7 (m, 4H), 7.82 (s, 1H), 8.3 (d, J=9.6 Hz, 1H), 8.62 (d, J=9.6 Hz, 2H), 8.74 (d, J=9.6 Hz, 1H). 13C NMR (75.4 MHz, CDCl3) δ: 35.7, 120.7, 122.4, 123.1, 123.5, 124.4, 125.1, 125.4, 125.7, 126.7, 127.4, 128.0, 129.1, 132.6, 142.1. MS m/z (relative intensity) EI: 232 (M+, 100), 217 (6), 204 (14), 190 (24), 177 (8), 163 (7), 88 (5). 4,5-Diphenyloxazole (3h): Mp 40 ºC [Lit.[27] 42-43 ºC]. MS m/z (relative intensity) EI: 221 (M+, 85), 193 (71), 165 (100). CI: 262 (M++41, 3), 250 (M++29, 25), 222 (M++1, 100).

4

Tetrahedron Letters

1-Methyl-4,5-diphenyl-1H-imidazole (4h): Mp 159161 ºC [Lit.[28] 162-164 ºC]. IR (KBr) ν/cm-1 = 3038, 2924, 1638, 1600, 1507, 1445, 1194, 1068, 951, 772, 701. -1

4,5-Di(furan-2-yl)oxazole (3i): IR (KBr) ν/cm = 3136, 1613, 1458, 1315, 1121, 1011, 739. 1H NMR (300 MHz; CDCl3) δ (ppm): 6.5-6.6 (m, 2H), 7.0-7.1 (m, 2H), 7.5-7.6 (m, 2H), 7.9 (s, 1H). 13C NMR (75.4 MHz, CDCl3) δ: 109.3, 110.0, 111.6, 111.8, 125.5, 132.6, 142.6, 146.4, 149.4, 149.5. MS m/z (relative intensity) EI: 201 (M +, 100), 173 (15), 145 (11), 117 (29), 89 (21), 63 (11). Anal. Calc. for C11 H7 N O3: C, 65.67; H, 3.48; N, 6.97. Found: C, 65.91; H, 3.90; N, 6.68. 4,5-Di(furan-2-yl)-1-methyl-1H-imidazole (4i): Mp 73 -1 ºC [Lit.[29] 74= 3119, 1605, 1 1457, 1259, 1012, 886, 736. H NMR (300 MHz; CDCl3) δ (ppm): 3.6 (s, 3H), 6.33 (s, 1H), 6.49 (bs, 2H), 6.64 (s, 1H), 7.32 (s, 1H), 7.46 (s, 1H), 7.5 (s, 1H). 13C NMR (75.4 MHz, CDCl3) δ: 33.1, 106.3, 111.0, 111.2, 111.9, 138.8, 141.4, 143.1, 149.2. MS m/z (relative intensity) EI: 214 (M+, 100), 185 (32), 171 (15), 157 (23), 130 (9), 116 (14), 103 (3), 89 (10), 63 (6). Conclusion Several secondary amines, obtained by reduction of certain carbonyl imines, were formylated in good to excellent yields employing microwave methodology and Nmethylformamide as solvent. Novel experimental results have prompted us to reconsider the Leuckart reaction mechanism and to propose a feasible alternative pathway. On the other hand, when the reaction conditions are applied to 1,2-diketones the corresponding oxazoles (3) and imidazoles (4) are obtained.

[8]

Awachie, P.I.; Agwada, V.C. Tetrahedron 1990, 46, 18991910.

[9]

Brewer, Alice R.E. in Name reactions for functional group transformations. (Eds. Li, J.J. and Corey, E.J.), 2007, pp. 451-455.

[10] Dallinger, D.; Kappe, C.O. Chem. Rev. 2007, 107, 25632591. [11] L. Cechova, P. Jansa, M. Dracinsky, A. Holy, K. Janeba, Tetrahedron 2011, 67, 866-871. [12] Loupy, A.; Monteux, D.; Petit, A.; Aizpurua, J.M.; Dominguez, E.; Palomo, C. Tetrahedron Lett. 1996, 45, 8177-8180. [13] Mastagli, P.; de Bievre-Gallin, G. Compt. Rend. 1947, 224, 1290-1292. [14] Saidi, O.; Bamforf, M.J.; Blacker, A.J. ; Lynch, J.; Marsden, S.P.; Plucinski, P. R.J. Watson, J.M.J. Williams, Tetrahedron Lett. 2010, 51, 5804-5806. [15] Rahman, M.; Kundu, D.; Hajra, A.; Majee, A. Tetrahedron Lett. 2010, 51, 2896-2899. [16] Nouira, I.; Kostakis, I.K.; Dubouilh, C.; Chosson, E.; Iannelli, M.; Besson, T. Tetrahedron Lett. 2008, 49, 70337036. [17] El-Nagar, G.A.; Mohammad, A.M.; El-Deab, M.S.; ElAnadovli, B.E. J.Electrochem. Soc. 2012, 159, F249-254. [18] Ito, K.; Oba, H.; Sekiya, M. Bull. Chem. Soc. Jpn. 1976, 49, 2485-2490. [19] Leonard, N.J.; Sauers, R.R. J. Am. Chem. Soc. 1957, 79, 6210-6214. [20] Staple, E.; Wagner, E.C. J. Org. Chem. 1949, 14, 559-578.

Acknowledgments

[21] Lukasiewicz, A. Tetrahedron 1963, 19, 1789-1799.

This study was financed by the Spanish Ministry of Science and Education supporting the I3 Program to B. Batanero.

[22] Lukes, R.; Jizbar, J. Chem. Listy pro Vedu a Prumysp 1953, 47, 1366-1372.

References and Notes

[23] Gajda, T.; Koziara, A.; Zawadzki, S.; Zwierzak, A. Synthesis 1979, 549-552.

[1]

Leuckart, R. Ber. Dtsch.Chem.Ges. 1885, 18, 2341-2344.

[24] Katritzky, A.; Yao, G.; Lan, X. J. Org. Chem. 1993, 58, 2086-2093.

[2]

Advanced Organic Chemistry (Eds. Smith, M.B; March, J.), 5th ed. John Wiley and Sons Inc. 2001, p.1188.

[25] Katritzky, A.R. J. Org.Chem. 2003, 68, 9093-9099.

[3]

Kobayashi, K; Nagato, S.; Kawakita, M.; Morikawa, O.; Konishi, H. Chem. Lett. 1995, 575-576.

[4]

Chen, B.-C; Bednarz, M.S.; Zhao, R.; Sundeen, J.E.; Chen, P.; Shen, Z.; Skoumbourdis, A.P.; Barrish, J.C. Tetrahedron Lett. 2000, 41, 5453-5456.

[5]

Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 66206628.

[6]

Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 407-408.

[7]

Downie, I.M.; Earle, M.J.; Heaney, H.; Shuhaibar, K.F. Tetrahedron 1993, 49, 4015-4034.

[26] Jaffe, G.M.; Day, A.R. J. Org. Chem. 1943, 8, 43-51. [27] Davies, J.R.; Kane, P.D. Moody, Ch.J. Tetrahedron 2004, 60, 3967-3977. [28] Bellina, F.; Cauteruccio, S.; DiFiore, A.; Rossi, R. Eur. J. Org. Chem. 2008, 5436-5445. [29] Cawkill, E. J. Chem. Soc. Perkin Trans 1 1980, 244-248.