Nucleophilic Substitution of Hydrogen Atom in Initially Inactivated

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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Nucleophilic Substitution of Hydrogen Atom in Initially Inactivated Pyrrole Ring Alexander F. Pozharskii,*,† Valery A. Ozeryanskii,† Olga V. Dyablo,† Olga G. Pogosova,† Gennady S. Borodkin,‡ and Aleksander Filarowski§ †

Department of Organic Chemistry, Southern Federal University, Zorge str 7, 344090 Rostov-on-Don, Russian Federation Institute of Physical and Organic Chemistry, Southern Federal University, Stachki Ave 194/2, 344090 Rostov-on-Don, Russian Federation § Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland and Institute of Chemistry, St. Petersburg State University, Universitetskij pr 26, 198504 St. Petersburg, Russian Federation

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‡

S Supporting Information *

ABSTRACT: It has been found that 1-dialkylamino-8-(pyrrolyl-1)naphthalenes 1 and 6, upon treatment with an equimolar amount of HBF4 under ambient conditions, produce 1-dialkylammonium salts which are transformed into 7,7-dialkyl-7H-pyrrolo[1,2-a]perimidine-7ium tetrafluoroborates 5 and 7, respectively. The reaction proceeds in a highly selective manner and represents the first case of nucleophilic substitution of hydrogen in the initially inactivated pyrrole ring. The scope and limitations of the transformation, apparently operating due to the joint action of the “proximity effect” and proton catalysis, are outlined.

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used 1-(dimethylamino)-8-(pyrrolyl-1)naphthalene (2), the situation developed completely differently.

t is well-known that nucleophilic substitution of ring hydrogen atom, SNH, in aromatic series proceeds in a very difficult manner and requires activation of the substrate.1−4 Commonly, this is achieved by placing into the ring one or, better, several strong electron-withdrawing substituents such as the aza-, −N (pyridine and other azines), or nitro group (nitroaromatics). In the case of azines, additional ring activation is often required. Usually, it consists of proton (Lewis) catalysis or conversion of the substrate into N-oxide. A separate problem is the elimination of the hydride ion, which is an extremely poor leaving group because of its high basicity (pKa > 30).5 To overcome the last difficulty, powerful oxidizing agents, for example, KMnO4, have been brought into practice.6,7 It is probable that only in the thermal version of the Chichibabin reaction (sodamide amination of some azines and azoles) is hydrogen gas is uniquely released in molecular form without addition of any external oxidant, but in this case strong evidence of the Lewis catalysis was documented.8,9 For a long time, the SNH reactions in π-excessive aromatics such as pyrroles were considered to be impossible, but later, the so-called vicarious nucleophilic substitution breached this area through the use of specially preorganized substrates and nucleophiles.10−12 In this paper, we report the first case, to our knowledge, of the SNH amination of initially inactivated pyrrole ring. Primarily, we aimed to clarify whether the pyrrole nitrogen atom can serve as a proton acceptor (n-donor) in the formation of the NHN hydrogen bond. This has indeed been confirmed for a number of protonated 9(dimethylamino)benzo[g]indoles 1.13 However, when we © XXXX American Chemical Society

Upon treatment of 2 dissolved in MeCN in an NMR ampule with an equimolar quantity of HBF4, the formation of tetrafluoroborate 2·HBF4 takes place as judged by two signs: a considerable low field shift of the NMe2 and pyrrole ring signals and an unchanged overall pattern of the spectrum relative to 2 (Figures 1a,b). Incidentally, after 3−4 h, we needed to record the spectrum again. This time, a trace of the second substance was noticed in the sample. The subsequent NMR monitoring (Figure 1c) showed a gradual increase in its concentration and a decrease in that of the original salt 2H+. During the entire reaction time, the ampule was kept under ambient conditions. The process proceeded rather slowly, but after 1 month the reaction was complete (Figure 1d; for more detailed spectral data, see also Figures S3−S17 and Table S2). The resulting colorless crystalline product isolated nearly in quantitative yield was subjected to X-ray study and was found to be pyrrolo[1,2-a]dihydroperimidinium tetrafluoroborate 5 (Figure 2). Thus, to our great surprise, a nucleophilic substitution of hydrogen in the pyrrole ring of 2 by the Received: December 22, 2018

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DOI: 10.1021/acs.orglett.8b04098 Org. Lett. XXXX, XXX, XXX−XXX

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Figure 1. NMR monitoring transformation of compound 2 into 5 upon treatment with an equimolar quantity of HBF4 (CD3CN, 20−25 °C, 600 MHz): (a) base 2; (b) reaction mixture 10 min after the addition of HBF4 (2·HBF4); (c) after 14 days (70% conversion); (d) after 30 days (full conversion).

2 (see Scheme 1). The obvious path of such activation under applied conditions is an acid catalysis, most likely proceeding through the formation of the pyrrolium cation 3H+. Indeed, according to theoretical calculations (DFT, B3LYP/6-311+ +G**), the curve showing dependence of the potential energy of cation 2H+ on the distance between the amine nitrogen atom and the acidic proton does not have any minimum corresponding to proton transfer to the pyrrole nitrogen

dimethylamino group occurred. The proposed mechanism for the entire process is shown in Scheme 1. There is some evidence that the real mechanism is more complex and includes another reaction channel associated with the parallel formation of a 3H-pyrrolium ion. For more discussion on this, see the Supporting Information. Evidently, the formation of salt 5 should be triggered by some kind of an electrophilic activation of the pyrrole cycle in B

DOI: 10.1021/acs.orglett.8b04098 Org. Lett. XXXX, XXX, XXX−XXX

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Figure 3. Potential energy curves for the gas phase: (left) for the proton transfer in cation 2H+ to the pyrrole nitrogen atom (squares) or the Cα atom (circles); (right) for the rotation of pyrrolium ring in cation 3H+(a) around the Car−N bond to produce conformation 3H+(b) and then cyclization product 4 (atoms forming the CCNC dihedral angle are marked in structure 3H+(b) by asterisks).

Figure 2. Molecular structure of heterocyclic salt 5 (120 K, P = 50%, tetrafluoroborate anion is not shown). Key parameters: C(1)−N(1) 1.500, N(1)−C(11) 1.456, N(2)−C(11) 1.373, N(2)−C(14) 1.378, N(2)−C(9) 1.409 Å, ∠C(8)−C(9)−N(2)−C(14) 20.0°.

Scheme 1. Proposed Mechanistic Pathway for the SNH Amination of the Pyrrole Ring in 2

preparative-scale reaction conducted in an open vial flows much faster; see the experimental details in the Supporting Information). Regrettably, no reliable information was found in the existing databases concerning oxidative behavior of Δ3pyrrolines. In addition, some other remarkable features of the discovered reaction should be noted. The first one is involvement of a weak nucleophile such as the aniline NMe2 group. Second, the process of oligomerization, which is so characteristic for the pyrrolium cation,15 is not observed. Third, the rate and selectivity of the reaction are strongly dependent on the nature of acid used (Supporting Information). Lastly, the reaction conditions are close to biological ones. In fact, like many biological processes, our reaction is easily reversible, and salt 5 is quantitatively converted into 2 upon treatment with NaBH4 (MeCN, rt, 20 min). All of these peculiarities can be attributed to the socalled “proximity effect” (see the SI for details), which occurs in concert with proton catalysis. In fact, by now, a general opinion exists that the main reason for the high softness and selectivity of biochemical reactions lies in the close proximity of the reaction centers, which is provided by the enzyme catalysis, especially the proton one.16 Currently, we are studying the scope and limitations of the discovered cyclization. To date, in addition to 1, it has been also extended to 1-pyrrolidino-8-(pyrrolyl-1)naphthalene (6), giving compound 7 in good yield (Figure 4). However, the process in this case proceeds much slower, apparently because of the greater basicity of the pyrrolidine nucleus as compared with the dimethylamine (pKa = 11.27 and 10.76, respectively, in H2O), which hampers the proton transfer and the formation of the corresponding α-pyrrolium ion. In spite of this, the reverse reaction, 7 → 6, was found to flow equally fast as in the case of salt 5 (see the SI for details).17 On the other hand, 1(dimethylamino)-2-(pyrrolyl-1)naphthalene (8) and 5-pyrrolyl-4-(dimethylamino)quinolines 9 and 10 under similar conditions remain unchanged (the last two even under the action of 2 equiv of the acid). We believe that in the case of 8 this is due to the insufficient approach of the dimethylammonium and pyrrolyl groups from each other as well as the unfavorable (outlying) location of the acidic NH proton from the pyrrole ring in salt 8·HBF4 (Figure S1).18 With respect to 9/10, they are protonated at the quinoline nitrogen atom (see δNH values of their cations in SI, cf. pairs of Figures S39/S40 and S42/S44 and note the quite strong deshielding of both 2-

atom,14 but such a minimum does exist for the pyrrolium cation 3H+(a) (Figure 3, left). The activation energy required for the generation of 3H+(a) in the gas phase and acetonitrile is 14.5 and 17.12 kcal mol−1, respectively, and there is little doubt that this stage is rate-limiting. Further events are obviously the rotation of the pyrrolium group around the Car− N bond, cyclization into pyrroline σ-complex 4, and oxidation of the latter by air oxygen to the final product 5. It is noteworthy that during the NMR monitoring no peaks of any intermediates are registered in the spectra. This indicates their low stationary concentration caused by high reactivity. Thus, the transition from conformation 3H+(a) to 3H+(b) is actually a barrier-free process, and cyclization 3H+(b) → 4 requiring an activation barrier of just 2.4 kcal mol−1 (Figure 3, right) starts when the dihedral angle CCNC reaches ∼30°. Apparently, the oxidation of the pyrroline intermediate 4 also proceeds rapidly on the NMR time scale and is limited only by the passing oxygen content (the C

DOI: 10.1021/acs.orglett.8b04098 Org. Lett. XXXX, XXX, XXX−XXX

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ACKNOWLEDGMENTS

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REFERENCES

This work was supported by the Russian Foundation for Basic Research (Project No. 17-03-00035). The DFT investigation of the proton transfer in the studied molecules was performed by A.F. within the framework of Russian Science Foundation Grant No. 18-13-00050. X-ray studies were performed by Dr. Kyrill Y. Suponitsky (A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow).

(1) Gulevskaya, A. V.; Pozharskii, A. F. Nucleophilic Aromatic Substitution of Hydrogen as a Tool for Heterocyclic Ring Annulation. Adv. Heterocycl. Chem. 2007, 93, 57−115. (2) Gulevskaya, A. V.; Pozharskii, A. F. The SNH-Amination of Heteroaromatic Compounds. In Metal Free C−H Functionalization of Aromatics. Nucleophilic Displacement of Hydrogen; Charushin, V. N., Chupakhin, O. N., Eds.; Springer, 2014; 179−240. DOI: 10.1007/ 7081_2013_114. (3) Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C. Nucleophilic Aromatic Substitution of Hydrogen; Academic Press: New York, 1994. (4) Chupakhin, O. N.; Charushin, V. N. Recent advances in the field of nucleophilic aromatic substitution of hydrogen. Tetrahedron Lett. 2016, 57, 2665−2672. (5) Buncel, E.; Menon, B. C. Metallation of Weak Hydrocarbon Acids by Potassium Hydride-18-Crown-6 Polyether in Tetrahydrofuran and the Relative Acidity of Molecular Hydrogen. Can. J. Chem. 1976, 54, 3949−3954. (6) van der Plas, H. C. Oxidative Amino-Dehydrogenation of Azines. Adv. Heterocycl. Chem. 2004, 86, 1−40. (7) Gulevskaya, A. V.; Maes, B. U. W.; Meyers, C.; Herrebout, W. A.; van der Veken, B. J. C−N Bond Formation by the Oxidative Alkylamination of Azines: Comparison of AgPy2MnO4 versus KMnO4 as Oxidant. Eur. J. Org. Chem. 2006, 2006, 5305−5314. (8) Pozharskii, A. F.; Simonov, A. M.; Doron’kin, V. N. Advances in the Study of the Chichibabin Reaction. Russ. Chem. Rev. 1978, 47, 1042−1060. (9) Katritzky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic Chemistry, 2nd ed.; Pergamon: Amsterdam, 2000; p 734. (10) Donskaya, O. V.; Dolgushin, G. V.; Lopyrev, V. A. Vicarious nucleophilic substitution of hydrogen in nitro-substituted pyrroles, azoles and benzannelated systems based on them. Chem. Heterocycl. Compd. 2002, 38, 371−384. (11) Joule, C. N. Nucleophilic Substitution of C-Hydrogen on the Five-membered Ring of Indoles. Prog. Heterocycl. Chem. 1999, 11, 45−65. (12) Makosza, M.; Wojciechowski, K. Nucleophilic Substitution of Hydrogen in Heterocyclic Chemistry. Chem. Rev. 2004, 104, 2631− 2666. (13) Pozharskii, A. F.; Ozeryanskii, V. A.; Filatova, E. A.; Dyablo, O. V.; Pogosova, O. G.; Borodkin, G. S.; Filarowski, A.; Steglenko, D. V. Neutral pyrrole nitrogen atom as a π- and mixed n,π-donor in hydrogen bonding. J. Org. Chem. 2019, 84, 726−737. (14) Actually, the calculations have shown that the N−H bond in 2H+(a) is precisely directed to the nitrogen heteroatom with the pyrrole ring plane being faced to it.13 This fact was interpreted as a result of two factors: purely molecular arrangement and the NH···π interaction existing between the acidic proton and the pyrrole πsystem. (15) Schofield, R. Hetero-aromatic Nitrogen Compounds. Pyrroles and Pyridines; Butterworths: London, 1967; pp 83−86. (16) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry; University Science Books: Sausalito, CA, 2006; pp 179− 185. The type of acid used has a strong influence on this conversion (see p S41 of the SI for details).

Figure 4. Related pyrrolyl compounds studied in this work.

and 4-substituents on protonation),19 which sharply reduces the nucleophilicity of the 4-NMe2 group. The soft conditions and the high selectivity of this reaction suggest that it may serve as a yet unknown method for posttranslational modification of proteins. To support this hypothesis, we plan to investigate the possibility of this conversion for 1-(dimethylamino)-8-(indolyl-1)naphthalene, as well as to extend it to more similar examples.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b04098. Experimental details, X-ray crystallographic data, spectroscopic data for new compounds, additional tables, and computational details (PDF) Accession Codes

CCDC 1880102−1880104 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Alexander F. Pozharskii: 0000-0003-3612-1392 Valery A. Ozeryanskii: 0000-0002-3797-3805 Aleksander Filarowski: 0000-0003-1013-4945 Notes

The authors declare no competing financial interest. D

DOI: 10.1021/acs.orglett.8b04098 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters (17) Salts 5 and 7 are rather stable in the solid and can be kept in closed vials at ambient temperature for weeks. However, in MeCN solution they gradually decompose, especially 7 (colorless solutions turn yellow and yellow-brown). The process is likely initiated by air oxygen, and the degassed solutions of their predecessors, 2·HBF4 and 6·HBF4, are also quite stable. (18) Attention should be drawn to the almost orthogonal orientation of the pyrrole ring relative to the naphthalene system in 8·HBF4 (interplane angle φ = 81.0°). Judging by the short MeN+(H)CH2− H···centroid (2.469 Å) and MeN+(H)CH2−H···Npyrr (2.451 Å) distances, this may originate from rather weighty CH···π interactions. (19) Dyablo, O. V.; Pozharskii, A. F.; Shmoilova, E. A.; Ozeryanskii, V. A.; Fedik, N. S.; Suponitsky, K. Yu. Molecular structure and protonation trends in 6-methoxy- and 8-methoxy-2,4,5-tris(dimethylamino)quinolines. J. Mol. Struct. 2016, 1107, 305−315.

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DOI: 10.1021/acs.orglett.8b04098 Org. Lett. XXXX, XXX, XXX−XXX