Oxidative Nucleophilic Substitution of Hydrogen versus Ring-Opening

Oxidative Nucleophilic Substitution of Hydrogen versus Ring-Opening in the Reaction of 4-R-2-Nitrothiophenes with Amines. The Crucial Effect of 4-Alkyl Groups Lara Bianchi, Massimo Maccagno, Giovanni Petrillo,* Fernando Sancassan,* and Cinzia Tavani Dipartimento di Chimica e Chimica Industriale, UniVersita` di GenoVa, Via Dodecaneso 31, I-16146 GenoVa, Italy

Stefano Morganti, Egon Rizzato, and Domenico Spinelli* Dipartimento di Chimica Organica “A. Mangini”, UniVersita` di Bologna, Via San Giacomo 11, I-40126 Bologna, Italy [email protected] ReceiVed April 18, 2007

4-Alkyl-2-nitrothiophenes [10: R ) CH3, CH(OH)CH3, CH(OCH3)CH3] react with secondary aliphatic amines, in the presence of AgNO3, to give 3-alkyl-2-amino-5-nitrothiophenes (12) through an oxidative nucleophilic substitution of hydrogen (ONSH) of synthetic interest. This behavior is in striking contrast with that of the parent 2-nitrothiophene (6), which was found to undergo ring-opening in analogous reaction conditions. A possible rationale for the crucial effect of alkyl groups is suggested, grounded also on a study of the corresponding Meisenheimer-like adducts.

Introduction Electron-deficient homo- or hetero-aromatic compounds, such as nitroarenes or nitrothiophenes, react promptly with neutral or anionic nucleophiles: the transfer of electrons from the nucleophile to the electrophilic nitro compound can either lead to a Meisenheimer-like adduct or, by means of a single-electron transfer (SET), to a radical anion and a free radical.1,2 Both pathways have been actually observed, and their courses have been deeply investigated from the mechanistic1 as well as from the synthetic1,2 viewpoint. For instance, a σ-adduct can participate as the very first intermediate in a number of different reaction pathways, such as ipso-substitution (SNAr),1 cine- or tele-substitution,3 ring opening4 (possibly followed by ring closing: e.g., addition of * Corresponding author. Tel.: +39 051 2095689; Fax.: +39 051 2095688.

nucleophile followed by ring opening and ring closure, ANRORC),5 covalent addition,6 direct substitution of hydrogen7 Via vicarious nucleophilic substitution (VNS)8 or Via oxidation9 (1) (a) Bunnett, J. F.; Zahler, R. E. Chem. ReV. 1951, 49, 273-412. (b) Bunnett, J. F. Q. ReV. Chem. Soc. 1958, 12, 1-16. (c) Miller, J. Aromatic nucleophilic substitution; Eaborn, C., Chapman, N. B., Eds.; Elsevier: Amsterdam, 1968. (d) Bernasconi, C. F. MTP Int. ReV. Sci.: Org. Chem. Ser. One 1973, 3, 33-63. (e) Ma¸ kosza, M.; Jaguszlyn-Groehowska, M.; Ludwikow, M.; Jawdosiuk, M. Tetrahedron 1974, 30, 3723-3735. (f) Illuminati, G.; Stegel, F. In AdVanced Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: Orlando, FL, 1983; Vol. 34, pp 305-444. (g) Buncel, E.; Crampton, M. R.; Strauss, M. J.; Terrier, F. Electron-Deficient Aromatic and Heteroaromatic-Base Interactions; Elsevier: Amsterdam, 1984. (h) Terrier, F. Nucleophilic aromatic displacement: The influence of the nitro group; Feuer, H., Ed.; VCH Publishers: New York, 1991. (i) Spinelli, D.; Consiglio, G.; Dell’Erba, C.; Novi, M. Nucleophilic substitution in thiophene derivatives. In The chemistry of heterocyclic compounds. Thiophene and its deriVatiVes; Gronowitz, S., Ed.; J. Wiley & Sons: New York, 1991; part IV, pp 295-396. (j) Consiglio, G.; Spinelli, D.; Dell’Erba, C.; Novi, M.; Petrillo, G. Gazz. Chim. Ital. 1997, 127, 753-769. (k) Lu, Z.; Twieg, R. J. Tetrahedron 2005, 61, 903-918.

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(“spontaneous” or by an external oxidant: oxidative nucleophilic substitution of hydrogen, ONSH), etc. On the other hand, SET processes10 have been proposed in substitution reactions with organometallic reagents11 or in coupling reactions,12 while radical anions derived from solvated-electron transfer have been ascertained as intermediates in SRN1 reactions.13 Several of the above-mentioned interesting facets of the reactivity between nitro aromatics and nucleophiles have been deeply investigated by our research group with particular regard to the nonbenzenoid behavior of nitrothiophenes. In this framework, 3,4-dinitrothiophene 1a (Scheme 1) was found to undergo ring-opening with secondary amines leading (2) (a) Dell’Erba, C.; Mugnoli, A.; Novi, M.; Pani, M.; Petrillo, G.; Tavani, C. Eur. J. Org. Chem. 2000, 903-912. (b) Dell’Erba, C.; Gabellini, A; Mugnoli, A.; Novi, M.; Petrillo, G.; Tavani, C. Tetrahedron 2001, 57, 9025-9031. (c) Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Mugnoli, A.; Novi, M.; Petrillo, G.; Sancassan, F.; Tavani, C. J. Org. Chem. 2003, 68, 5254-5260. (d) Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Morganti, S.; Novi, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.; Spinelli, D.; Tavani, C. Tetrahedron 2004, 60, 4967-4973. (e) Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.; Tavani, C. J. Org. Chem. 2005, 70, 8734-8738. (f) Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Morganti, S.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.; Spinelli, D.; Tavani, C. ArkiVoc 2006, 169-185. (g) Bianchi, L.; Maccagno, M.; Petrillo, G.; Sancassan, F.; Spinelli, D.; Tavani, C. In Targets in Heterocyclic Systems: Chemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.; Societa` Chimica Italiana: Rome, 2006; Vol. 10, pp 1-23. (3) (a) Dell’Erba, C.; Spinelli, D.; Leandri, G. Gazz. Chim. Ital. 1969, 99, 535-541. (b) Suwı´n´ski, J.; Swierczek, K. Tetrahedron 2001, 57, 16391662. (c) Ma¸ kosza, M.; Varvounis, G.; Surowiec, M.; Giannopoulo, T. Eur. J. Org. Chem. 2003, 3791-3797. (d) Blazej, S.; Kwast, A.; Ma¸ kosza, M. Tetrahedron Lett. 2004, 45, 3193-3195. (4) (a) Dell’Erba, C.; Spinelli, D.; Leandri, G. J. Chem. Soc., Chem. Commun. 1969, 549. (b) Guanti G.; Dell’Erba, C.; Leandri, G. J. Chem. Soc., Chem. Commun. 1972, 1060. (c) Guanti, G.; Dell’Erba, C.; Leandri, G.; Thea, S. J. Chem. Soc., Perkin Trans. 1 1974, 2357-2360. (d) Surange, S. S.; Kumaran, G.; Rajappa, S.; Rajalakshmi, K.; Pattabhi, V. Tetrahedron 1997, 53, 8531-8540. (e) Dell’Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.; Tavani, C.; Cosimelli, B.; Spinelli, D. Tetrahedron 2001, 57, 81598165. (f) Spinelli, D.; Armanino, V.; Corrao, A. J. Heterocycl. Chem. 1970, 7, 1441-1442. (g) Dell’Erba, C.; Novi, M.; Guanti, G.; Spinelli, D. J. Heterocycl. Chem. 1975, 12, 327-331. (5) (a) Rykowski, A.; Wolinska, E. Tetrahedron Lett. 1996, 37, 57955796. (b) Rykowski, A.; Wolinska, E.; van der Plas, H. C. J. Heterocycl. Chem. 2000, 37, 879-883. (c) Rykowski, A.; Wolinska, E.; van der Plas, H. C. Chem. Heterocycl. Compd. 2001, 37, 1418-1423. (6) Mugnoli, A.; Dell’Erba, C.; Guanti, G.; Novi, M. J. Chem. Soc., Perkin Trans. 2 1980, 1764-1767. (7) (a) Chupakhin, O. N.; Postovskii, I. Ya. Russ. Chem. ReV. 1976, 45, 454-468. (b) Chupakhin, O. N.; Chupakhin, V. N.; Van der Plas, H. C. Nucleophilic Aromatic Substitution of Hydrogen; Academic Press: San Diego, 1994. (c) Ma¸ kosza, M.; Krzysztof, W. Chem. ReV. 2004, 104, 26312666. (d) Seko, S.; Kawamura, N. J. Org. Chem. 1996, 61, 442-443. (8) (a) Ma¸ kosza, M.; Winiarski, J. Acc. Chem. Res. 1987, 20, 282-289. (b) Ma¸ kosza, M.; Kwast, A. J. Phys. Org. Chem. 1998, 11, 341-349. (c) Florio, S.; Lorusso, P.; Granito, C.; Ronzini, L.; Troisi, L. Eur. J. Org. Chem. 2003, 4053-4058. (d) Florio, S.; Lorusso, P.; Granito, C.; Luisi, R.; Troisi, L. J. Org. Chem. 2004, 69, 4961-4965. (9) (a) Bartoli, G. Acc. Chem. Res. 1984, 17, 109-115. (b) Ma¸ kosza, M.; Stalinski, K. Chem. Eur. J. 1997, 3, 2025-2031. (c) Adam, W.; Ma¸ kosza, M.; Stalinski, K.; Zhao, C. G. J. Org. Chem. 1998, 63, 43904391. (d) Surange, S. S.; Rajappa, S. Tetrahedron Lett. 1998, 39, 71697172. (e) Surowiec, M.; Ma¸ kosza, M. Tetrahedron 2004, 60, 5019-5024. (f) Van der Plas, H. C. In AdVanced Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: Orlando, FL, 2004; Vol. 86, pp 1-40. (g) Ma¸ kosza, M.; Kamienska-Trela, K.; Paszewski, M.; Bechcicka, M. Tetrahedron 2005, 61, 11952-11964. (h) Florio, S.; Ma¸ kosza, M.; Lorusso, P.; Troisi, L. ArkiVoc 2006, 59-66. (i) Ma¸ kosza, M.; Synpniewski, M. Tetrahedron 1994, 50, 4913-4920. (j) Ma¸ kosza, M.; Stalinski, K. Pol. J. Chem. 1999, 73, 151-161. (10) Terrier, F.; Mokhtari, M.; Goumont, R.; Halle, J.; Buncel, E. Org. Biomol. Chem. 2003, 1, 1757-1763. (11) (a) Bunnett, J. F. Tetrahedron 1993, 49, 4477-4485. (b) Save`ant, J.-M. Tetrahedron 1994, 50, 10117-10165. (12) (a) Manzo, P. G.; Palacios, S. M.; Alonso, R. A.; Rossi, R. A. Org. Prep. Proced. Int. 1995, 27, 660-663. (b) Kurbatov, S.; Tatarov, A.; Minkin, V.; Goumont, R.; Terrier, F. Chem. Commun. 2006, 4279-4281.

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to 24a or cine-substitution with arenethiolates to 3.3a In these reactions a σ-adduct can participate as the very first intermediate. On the other hand, 2,5-dimethyl-3,4-dinitrothiophene (1b) can either undergo proton abstraction from a methyl group, leading to the tele-substitution products 4,14 or nucleophilic addition, followed by replacement of one nitro group, with the eventual production of 5.6 From a synthetic point of view, the dinitrobutadienes 2 have proven to be versatile polyfunctionalized building blocks which have been transformed, in the past few years, into a number of acyclic as well as homo- or heterocyclic derivatives.2 As far as mononitrothiophenes are concerned, both 2-nitrothiophene (6)4b,c and 3-nitro derivatives (8, X ) H: Y ) H, SPh, SO2Ph, SMe, SO2Me, COMe, CO2Me, CN; X ) SO2Ph: Y ) H; X-Y ) CHdCH-CΗdCH)4d,e were found to undergo, with secondary amines and silver nitrate, a different ring-opening process (Scheme 1). The resulting 7 and 9 are both interesting, highly functionalized nitrobutadienes that could be employed for the synthesis of more complex aliphatic or aromatic molecules.2 Herein we report on a rather unexpected outcome from the reaction of some 4-alkyl-2-nitrothiophenes with secondary aliphatic amines in the presence of silver nitrate. Results and Discussion Amination Reaction of 4-Methyl-2-nitrothiophene with Piperidine. When treated with excess piperidine (11f′) and silver nitrate, 4-methyl-2-nitrothiophene (10a) furnished the ringsubstitution derivative 12af′ (Scheme 2). The formation of 12af′ was confirmed by comparison with an authentic sample prepared by treatment of 2-bromo-3-methyl5-nitrothiophene with piperidine.15 The reaction is regioselective, as it occurs at the quasi-para (C-5) position, with no detectable substitution product at the hyper-ortho (C-3)-carbon and no detectable ring-opening derivatives. Such a kind of regioselectivity in a nucleophilic attack to a thiophene derivative recalls that observed for the reaction of 3-methoxy-2-nitrothiophene4f or of 2-nitrothiophene4g with sodium methoxide. The behavior herein, which represents an example of oxidative nucleophilic substitution of hydrogen (ONSH) where AgNO3 acts as an external oxidant, is in striking contrast with the high-yielding ring-opening to 7 undergone by the parent 2-nitrothiophene 6 in the same reaction conditions (Scheme 1).4b,c Conversely, it bears some similarities with what was more recently observed for 2-nitrobenzo[b]thiophene, which leads to the corresponding 3-amino derivative when treated with primary amines in the presence of cerium ammonium nitrate (CAN).9d Actually, nucleophilic substitution of hydrogen is a general method for the introduction of carbon as well as heteroatom substituents Via direct replacement of hydrogen in electrondeficient aromatic or heteroaromatic rings.7-9 The reaction proceeds Via an initial addition of the nucleophile to the electrondeficient ring in a position occupied by a hydrogen atom to give an anionic σH-adduct which can be converted into the final product in one of several ways. In particular, when the carbanion (13) Medebielle, M.; Pinson, J.; Saveant, J.-M. Electrochim. Acta 1997, 42, 2049-2055. Costentin, C.; Hapiot, P.; Me´debielle, M.; Save´ant, J.-M. J. Am. Chem. Soc. 1999, 121, 4451-4460. (14) Novi, M.; Sancassan, F.; Guanti, G.; Dell’Erba, C. J. Chem. Soc., Chem. Commun. 1976, 303-304. (15) Spinelli, D.; Consiglio, G.; Noto, R.; Corrao, A. J. Chem. Soc., Perkin Trans. 2 1975, 620-622.

ReactiVity of 4-R-2-Nitrothiophenes SCHEME 1.

Examples of the Nonbenzenoid Behavior of Nitrothiophenes toward Nucleophiles

SCHEME 2. ONSH Reaction of 4-Methyl-2-nitrothiophene with Piperidine

contains a leaving group X at the side chain, a base-induced β-elimination of HX from the σH-adduct gives products of vicarious nucleophilic substitution (VNS).8 On the other hand, oxidation of the σH-adduct (e.g., with an external oxidant) gives ONSH.9 In order to optimize the yield of 12af′, we carried out several further experiments on 10a, testing different reaction conditions (time, solvent, oxidant, and substrate/amine/AgNO3 molar ratio). The best conditions were eventually found to require the treatment of 10a and AgNO3 (2.2 mol equiv) in absolute ethanol with a large excess (9.0 mol equiv) of piperidine for 48 h at 50 °C. Under these conditions, besides 12af′ (35%), unreacted starting material (10%) was the only compound identified and/ or recovered from the final mixture. It is noteworthy that oxidants different from AgNO3 afforded worse results. In particular, lower yields (about 20-30%) have been observed with CAN.9d The use of an organic oxidant such as dichlorodicyano-1,4-benzoquinone (DDQ)9a,g also gave poor

yields (20%), and the “auto-oxidation” processes9 do not seem to be involved, as in the absence of AgNO3 the starting material can be recovered practically unchanged. Extension of the Amination to Different Substrates (10ac) and Amines (11a′-f′). In order to explore the scope of the direct amination observed, we have examined the reactions of some 4-alkyl-2-nitrothiophenes [10a-c: R ) CH3,16 CH(OH)CH3,17 and CH(OCH3)CH3, respectively] with a series of secondary amines [diethylamine (11a′), dimethylamine (11b′), N-benzylmethylamine (11c′), pyrrolidine (11d′), morpholine (11e′), and piperidine (11f′)] of different basicity (pKb values ranging from 5.5 to 3.0),18 nucleophilicity, or steric requirements. In every case an ONSH reaction at C-5 was the only detectable process (Scheme 3). Yields of isolated products from reactions carried out in the experimental conditions optimized for 10a as described above are collected in Table 1: they clearly depend on both the nitrothiophene and the secondary amine, but generally range from acceptable to good particularly considering that ONSH′s are usually characterized by low yields. Only dimethylamine (16) Rinkes, I. J. Rec. TraV. Chim. Pays-Bas 1933, 52, 1052-1060. (17) (a) Newcombe, P. J.; Norris, R. K. Aust. J. Chem. 1981, 34, 18791886. (b) Benoit, R.; Dupas, G.; Bourguignon, J.; Queguiner, G. J. Heterocycl. Chem. 1989, 26, 1595-1600. (18) Frenna, V.; Vivona, N.; Consiglio, G.; Spinelli, D. J. Chem. Soc., Perkin Trans. 2 1985, 1865-1868.

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Bianchi et al. SCHEME 3. Reactions of Some 4-Alkyl-2-nitrothiophenes (10a-c) with Amines

(11b′, entries 2, 8, and 14 in Table 1) provided significantly lower yields in some cases, probably because of its physical properties (high volatility). In every case a significant amount (5-10%) of unreacted substrate was recovered throughout. We also tested the two primary amines 1-butanamine and aniline: both failed to give any ONSH product under our experimental conditions, possibly because of (i) their easier oxidability and/or (ii) in the case of aniline, a lower nucleophilicity. Some First Comments on the Observed ONSH Reaction. From a practical point of view, the results obtained suggest that the procedure of Scheme 3 can be considered an effective route for the direct amination of nitrothiophenes, as in several cases good yields have been observed. It can be a useful alternative to indirect amination (e.g., halogen replacement on halothiophenes, described and reviewed elsewhere).1i-k From a mechanistic point of view, we think that the observed dichotomic behavior of 6 and 10a-c has to be discussed and rationalized in the light of the different electronic effects exhibited by alkyl groups in the benzene and thiophene series, although steric effects could also play a role. In nucleophilic aromatic substitutions (SNAr) on halogenonitrobenzenes with both neutral and anionic nucleophiles, in the absence of significant steric effects an alkyl group meta or para to the reaction center generally decreases the reactivity by a factor between 2 and 6.1,24 Similar effects have been observed studying the formation rate and the stability of gem and nongem Meisenheimer adducts in benzenes. Conversely, some of us have observed that the reactivity of 3-alkyl-5-bromo-2-nitrothiophenes (alkyl ) Me, Et, Prn, n-hexyl, Pri, But) with piperidine in methanol is from two to five times higher than that of the 3-unsubstituted derivative in analogous reaction conditions.25a Moreover, we have found that the Meisenheimer adduct obtained from 2-methoxy-5-methyl-3nitrothiophene and sodium methoxide in methanol is nine times more stable and is formed about three times faster than the (19) De Maria, P.; Noto, R.; Consiglio, G.; Spinelli, D. J. Chem. Soc., Perkin Trans. 2 1989, 791-795. (20) Consiglio, G.; Frenna, V.; Guernelli, S.; Macaluso, G.; Spinelli, D. J. Chem. Soc., Perkin Trans. 2 2002, 965-970 and 971-975. (21) Noto, R.; Gruttadauria, M.; Dattolo, D.; Arnone, C.; Consiglio, G.; Spinelli, D. J. Chem. Soc., Perkin Trans. 2 1991, 1477-1480. (22) Liebscher, J.; Abegaz, B.; Areda, A. J. Prakt. Chem. 1983, 325, 168-172. (23) Spinelli, D.; Consiglio, G.; Noto, R.; Corrao, A. J. Chem. Soc., Perkin Trans. 2 1975, 620-622. (24) Greizerstein, W.; Bonelli, R. A.; Brieux, J. A. J. Am. Chem. Soc. 1962, 84, 1026-1032. (25) (a) Consiglio, G.; Spinelli, D.; Gronowitz, S.; Ho¨rnfeldt, A. B.; Maltesson, B.; Noto, R. J. Chem. Soc., Perkin Trans. 2 1982, 625-630. (b) Consiglio, G.; Arnone, C.; Ferroni, F.; Noto, R.; Sancassan, F. J. Chem. Soc., Perkin Trans. 2 1988, 1169-1172.

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corresponding 5-unsubstituted adduct.25b In these two studies the alkyl group was respectively meta and para to the reaction center. These experimental results clearly show that alkyl groups, usually considered “only” as electron-repelling substituents (and then bound to reduce the reactivity in SNAr processes and/or in the formation of Meisenheimer adducts)1,24 can actually play different roles in different circumstances, e.g., according to the different polarizability and/or electron demand of the ring system to which they are attached. As the reaction pattern exhibited by both 2-nitrothiophene and its 4-methyl derivative initially leads to the formation of a σH-adduct (Scheme 4), it seemed appropriate to study the electronic effects of the 4-methyl group in this intermediate. Meisenheimer-like complexes have been extensively studied as models for σ-adducts in nucleophilic aromatic substitutions1g,h and NMR spectroscopy proved to be very useful in detecting their formation, lifetime, and decomposition.26 This prompted us to run a comparative NMR study of the Meisenheimer-like adducts obtained by addition of sodium methoxide to 2-nitroand 4-methyl-2-nitro-thiophene. On the Behavior of 4-Methyl-2-nitrothiophene (10a) and of 2-Nitrothiophene (6) with Sodium Methoxide in DMSO: Effect of the 4-Methyl Group on the Lifetime and Hence on the Fate of Meisenheimer Adducts. We have found that 10a actually reacts with sodium methoxide in DMSO-d6 giving the adduct M10a- (Scheme 5), as unequivocally shown by the 1H and 13C NMR data reported in Table 2 (together with those relevant to the previously studied 6 and M6- for an easier comparison). It can be noticed that all of the 1H and 13C signals of 10a undergo additional shielding in M10a-, which also exhibits the expected signals for the methoxyl group (in particular the methoxyl carbon correctly appearing as a quartet of doublets). The occurrence of the attack at C-5 is testified by the decrease in the J(H3H5) and particularly in the J(C5H5) values. After ascertaining the formation of Meisenheimer adducts, we carried out a competitive experiment, treating a mixture of 10a and 6 with a shortcoming of sodium methoxide at 1:1:1 molar ratios, i.e., adding only one-half of the methoxide which would be required to allow complete reaction for the two nitrothiophenes. By integration of 1H NMR signals, we could detect that after a short reaction time (5′), i.e. in experimental conditions well simulating a kinetic control of the process, 10a and 6 show similar reactivity (the reactivity ratio has been evaluated to be ca. 1.0 ( 0.1). Interestingly enough after a longer reaction time (15 min), the decomposition of M6- was already significant. Thus we could not follow the reaction further to simulate the conditions of a thermodynamic control of the process. Then, in order to put this result on a semiquantitative base we performed two parallel experiments with 1 equiv of 6 (or 10a), 1 equiv of sodium methoxide, and a weighted amount of an inert compound (durene) as an internal standard. 1H NMR spectra showed that after 25 min the extent of decomposition was ca. 25% for M6- and 3% for M10a-, and after 45 min 53% and 6%, respectively. Thus we can conclude that M10aunequivocally exhibits, with respect to M6-, a longer lifetime and a higher stability toward further transformation. A reduced rate of the ring-opening reaction due to steric congestion in the transition state could concur to the longer lifetime of M10a- with respect to M6-: it is actually conceiv(26) Terrier, F. Chem. ReV. 1982, 82, 77-152.

ReactiVity of 4-R-2-Nitrothiophenes TABLE 1. Direct Amination (ONSH) of 4-Alkyl-2-nitrothiophenes 10a-c by Secondary Amines in the Presence of AgNO3 entry

substrate

amine

producta

yield (%)b

HRMS calcd/found

mp (°C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

10a 10a 10a 10a 10a 10a 10b 10b 10b 10b 10b 10b 10c 10c 10c 10c 10c 10c

11a′ 11b′ 11c′ 11d′ 11e′ 11f′ 11a′ 11b′ 11c′ 11d′ 11e′ 11f′ 11a′ 11b′ 11c′ 11d′ 11e′ 11f′

12aa 12ab′c 12ac′d 12ad′d,e 12ae′d,f 12af′c,d,g 12ba′ 12bb′ 12bc′ 12bd′ 12be′ 12bf′ 12ca′ 12cb′ 12cc′ 12cd′ 12ce′ 12cf′

48 10 30 46 44 35 52 14 54 20 48 48 28 15 54 45 55 75

214.07760/214.07762 244.08816/244.08831 216.05687/216.05632 292.08817/292.08844 242.07252/242.07232 258.06743/258.06711 256.08817/256.08785 258.10382/258.10376 230.07252/230.07195 306.10382/306.10371 256.08817/256.08892 272.08308/272.08311 270.10382/270.10374

30.0-31.0 92.0-93.0 186.0 169.0-170.0 132.0-133.0 75.0 oil 115.0-117.0 94.0-96.0 119.0-121.0 101.0-102.0 oil 30.0 106.0-108.0 115.0-116.0 157.0 95.8-96.4 oil

a All of the products 12aa′-12cf′ are yellow solids or yellow oils. Solid compounds have been crystallized from methanol. b Yields of isolated products. Some unreacted substrate (5-10% ca.) was recovered throughout from the final mixture. c Reference 19. d Reference 20. e Reference 21. f Reference 22. g Reference 23.

SCHEME 4

SCHEME 5. Methoxide

Reactivity of 6 and 10a with Sodium

able that in the ring-opening of mononitrothiophenes the presence of the 4-methyl group can cause a repulsive interaction with the sulfur atom within the incipient diene system (cf. structure 7). However, it seems interesting to take advantage of the NMR data to investigate the electronic effect of the 4-methyl group in a thiophene system, to check if this can play a role in determining the observed dichotomic behavior. Some 13C chemical shift differences (∆δ) are reported in Table 2, because they can mirror π-electron-density changes, as other effects should appreciably cancel out in the comparison between closely related structures, when hybridization changes are not involved. The values of ∆δ(10a - 6) reported in Table 2 illustrate the effect of the 4-methyl group on the chemical shifts of the starting compound. It can be noticed that the presence of the 4-methyl group in 10a leaves C-2 and C-3 practically unaffected, deshields C-4, and shields C-5, which is the only effective orthocarbon with respect to the 4-methyl group. Conversely, when comparing the data of the adducts M6- and M10a-, the 4-methyl group, while still deshielding C-4, appears to exert a significant shielding effect on C-3, which is now the effective ortho-carbon. This can be interpreted on the basis of a +R effect of the 4-methyl group, shielding the carbon which is the effective

ortho one, i.e., C-5 in 10a and C-3 in M10a-. This resonance effect could imply a charge-transfer from the methyl group to the ring (hyperconjugation: Sketch 1) and/or a dipole-dipole interaction (π-polarization: Sketch 2).

Inspection of carbon-proton coupling constants (footnotes of Table 2) reveals that the methyl 1JCH value remains unchanged when going from the substrate 10a to the corresponding adduct M10a-, suggesting that no hybridization change of the methyl carbon occurs as a consequence of the adduct formation: it is actually well-known that 1JCH coupling constants are very sensitive indicators of the s character of the orbitals of the relevant carbon. Furthermore, the comparison between 10a and M10a- shows that also the value of 3JCH J. Org. Chem, Vol. 72, No. 15, 2007 5775

Bianchi et al. 1H and 13C NMR Data for 2-Nitrothiophene 6, 4-Methyl-2-nitrothiophene 10a, and the Corresponding Meisenheimer Adductsa M6- and M10a-, 0.2 M in DMSO-d6

TABLE 2.

δ (ppm from TMS) 6b M6-b 10a M10a-

J (Hz)

H-3

H-4

H-5

Th-CH3

OCH3

H-3/H-4

H-3/H-5

H-4/H-5

H-3/Me

H-5/Me

8.08 6.67 8.00 6.43

7.18 5.44 -

8.01 6.06 7.69 5.89

2.26 1.77

3.15 3.13

4.0 5.9 -

1.5

5.7 3.1 -

0.4 1.5

1.1 1.1

1.9 0.5

δ (ppm from TMS) 6c M6- c 10ad M10a- e ∆δ (10a - 6) ∆δ (M10a - M6-) ∆δ (M6- - 6)c ∆δ (M10a- - 10a)

C-2

C-3

C-4

C-5

∑(C-2 to C-4)

ThCH3

OCH3

151.51 120.56 150.63 118.70 -0.88 -1.86 -30.95 -31.93

129.79 128.39 131.28 124.50 1.49 -3.89 -1.40 -6.78

127.72 122.85 138.01 132.25 10.29 9.40 -4.87 -5.76

135.32 92.95 130.82 93.73 -4.50 0.78 -42.37 -37.09

-37.2 -44.5

15.42 15.12 -0.30

52.58 51.44 -

a Numbering of ring carbons in the adducts coherent with that in the neutral thiophenes for easier comparison. b References 4g, 27. c Reference 29e. C-2: br d, J ) 7.1. C-3: ddq, J ) 174.6, 7.7 and 4.6. C-4: dm, J ) 6.6. C-5: ddq, J ) 189.0, 10.6, and 5.7. Th-CH3: qm, J ) 128.4. e C-2: br s. C-3: ddq, J ) 167.5, 5.6 and 4.6. C-4: m. C-5: dm, J ) 166.4. ThCH3: qm, J ) 128.4. OCH3: qd, J ) 141.7 and 6.0.

d

between C-3 and the 4-methyl protons remains unchanged, suggesting no bond-order variation at the connection between the 4-methyl and the ring when the adduct is formed. Both these outcomes indicate that no charge transfer occurs between the ring and the 4-methyl group as a consequence of the adduct formation. This appears to match the hypothesis depicted in Sketch 2 rather than the hyperconjugative effect of Sketch 1. Thus, the strong suggestion offered by the 13C NMR data is that of a dipole-dipole stabilizing interaction between the 4-methyl group and the ring in both the substrate 10a and the adduct M10a-. This is a consequence of the ability of the thiophene ring of redirecting the 4-methyl π-polarization effect from C-5 to C-3 when going from the substrate to the adduct. Further information could come from the values of ∆δ(M6- 6) and ∆δ(M10a- - 10a) (see Table 2), i.e., the chemical shift differences accompanying the formation of Μ6- from 6 or of Μ10a- from 10a. While C-5 obviously undergoes a dramatic shielding as a result of its hybridization change, the ∆δ values of C-2 to C-4 provide information about the distribution of the negative charge of the adduct among sp2 ring carbons.28 On this basis, in an extensive study of numerous Meisenheimer adducts we have drawn29 a broad self-consistent picture where all of the experimental stability constants of the studied adducts have been interpreted on the basis of the two possible components30 of the stabilizing R effect of substituents, e.g., through-conjugation (involving a charge transfer from the ring to the substituent) and π-polarization (charge-dipole or dipoledipole interactions). In this light the values of ∆δ(M6- - 6) and ∆δ(M10a- - 10a) reported in Table 2 suggest that in Μ10a- the presence of the 4-methyl group allows the sp2 ring

carbons (and particularly C-3) to allocate a larger fraction of the negative charge of the adduct: an outcome which has been generally associated to a larger stability of the adduct itself.29 It seems worth recalling that the shielding effect of the 4-methyl on C-3 in the adduct is not matched by a similar effect in the starting compound, where the 4-methyl affects C-5 rather than C-3. Therefore, it is the redirection of the π-polarization effect of the methyl group that causes the observed difference. In conclusion the 4-methyl group in 10a appears to stabilize the corresponding Meisenheimer-like adduct M10a- with respect to further reactivity mainly by redirecting its polarization effect from C-5 to C-3. This kind of effect could be of lower or minor importance in a benzene system, because of its expected lower polarizability. It can be noted that if the 4-substituent exhibited a polarization in the opposite direction, it would show anyway a stabilizing effect on the adduct. Therefore it can also be suggested that the 4-substituents in 10b, 10c and Μ10b-, M10c- would exhibit an analogous effect.

(27) Doddi, G.; Illuminati, G.; Stegel, F. J. Chem. Soc., Chem. Commun. 1969, 953. (28) Sbarbati Nudelman, N.; MacCormack, P. J. Chem. Soc., Perkin Trans. 2 1987, 227-229. (29) (a) Consiglio, G.; Spinelli, D.; Arnone, C.; Sancassan, F.; Dell’Erba, C.; Noto, R.; Terrier, F. J. Chem. Soc., Perkin Trans. 2 1984, 317-323. (b) Dell’Erba, C.; Consiglio, G.; Arnone, C.; Spinelli, D.; Sancassan, F.; Dell’Erba, C.; Leandri, G.; Terrier, F. Gazz. Chim. Ital. 1987, 117, 267274. (c) Sancassan, F.; Dell’Erba, C.; Gronowitz, S.; Consiglio, G.; Spinelli, D. Chem. Scr. 1988, 28, 349-352. (d) Sancassan, F.; Novi, M.; Spinelli, D.; Consiglio, G.; Arnone, C.; Ferroni, F. J. Chem. Soc., Perkin Trans. 2

1989, 1779-1782. (e) Dell’Erba, C.; Sancassan, F.; Novi, M.; Spinelli, D.; Consiglio, G. J. Chem. Soc., Perkin Trans. 2 1991, 1631-1636. (f) Consiglio, G.; Dell’Erba, C.; Frenna, V.; Novi, M.; Petrillo, G.; Sancassan, F.; Spinelli, D. Gazz. Chim. Ital. 1996, 126, 165-172. (30) (a) Dell’Erba, C.; Sancassan, F.; Novi, M.; Petrillo, G.; Mugnoli, A.; Spinelli, D.; Consiglio, G.; Gatti, P. J. Org. Chem. 1988, 53, 35643568. (b) Dell’Erba, C.; Sancassan, F.; Novi, M.; Spinelli, D.; Consiglio, G.; Arnone, C.; Ferroni, F. J. Chem. Soc., Perkin Trans. 2 1989, 17791782. (c) Dell’Erba, C.; Mele, A.; Musio, R.; Novi, M.; Petrillo, G.; Sancassan, F.; Sciacovelli, O.; Spinelli, D. J. Org. Chem. 1992, 57, 40614063.

5776 J. Org. Chem., Vol. 72, No. 15, 2007

Conclusion A study of the reactivity of some 4-alkyl-2-nitrothiophenes (10a-c) with secondary amines (11a′-f′) in the presence of silver nitrate in ethanol has furnished a useful pathway for the synthesis of several 3-alkyl-2-amino-5-nitrothiophenes (12aa′af′/12ca′-cf′) Via an ONSH process with yields (10-35%; 4475%) which generally range from acceptable to good, considering the moderate yields usually observed in ONSH.9 The striking contrast with the behavior of the parent 2-nitrothiophene (which, in the same reaction conditions, gives ring-opening

ReactiVity of 4-R-2-Nitrothiophenes

products in high yields) can be explained on the basis of steric effects and/or of a stabilizing effect of the 4-alkyl group on the σH adduct which is formed as the first step in both cases: the longer lifetime of the adduct 14 (Scheme 4) coming from the 4-methyl derivative appears to be crucial to allow the attack of the oxidizing reagent. The dichotomic behavior of alkyl groups favoring nucleophilic substitutions in thiophene but not in benzene derivatives is confirmed. Experimental Section General Methods. 1H and 13C NMR spectra were recorded at 298 K on a spectrometer operating at 300 MHz for proton and 75 MHz for carbon or on a spectrometer at 200 MHz for proton and 50 MHz for carbon, in CDCl3 unless otherwise stated, using tetramethylsilane (TMS) as the internal standard. Chemical shifts are reported in ppm (δ) downfield from TMS. ESI-MS and HRMS were recorded by a ESI-MS or a MS instrument, respectively. Melting points were determined with a hot-stage apparatus and are uncorrected. All reactions were carried out in oven-dried glassware under an atmosphere of dry nitrogen.

Materials. All reagents were commercially available and were used without further purification, unless otherwise stated. Petroleum ether refers to the fraction with bp 40-60 °C. Syntheses of 10a-c. 4-Methyl-2-nitrothiophene (10a)16 and 1-[2nitrothiophene-4-yl]ethanol (10b)17 were prepared according to literature and matched the reported physical constants and NMR spectra. 1H NMR of 10b,c are reported in Supporting Information.

Acknowledgment. Financial support was provided by grants from the Universities of Bologna and Genova and from MIURRoma (PRIN 2005034305). We also thank Compagnia di San Paolo, Torino (Italy), for generous funding for the purchase of part of the NMR equipment. Supporting Information Available: Synthesis of 10c, general procedure for ONSH, synthesis of 12aa′-af′, compound characterization for 12aa′-cf′ (1H and 13C NMR as well as ESI-MS data), and 1H NMR of 10b,c and 12aa′-cf′. This material is available free of charge via the Internet at http://pubs.acs.org. JO070610I

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