Preparation of Organic Nitrates from Aryldiazoacetates and Fe(NO3)3

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

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Preparation of Organic Nitrates from Aryldiazoacetates and Fe(NO3)3·9H2O Samuel Thurow,§,† Alessandra A. G. Fernandes,§,† Yovanny Quevedo-Acosta,†,‡ Matheus F. de Oliveira,† Marcelo G. de Oliveira,† and Igor D. Jurberg*,† †

Institute of Chemistry, State University of Campinas, Rua Monteiro Lobato 270, 13083-862, Campinas, SP, Brazil Laboratory of Organic Synthesis, Bio and Organocatalysis, Chemistry Department, Universidad de los Andes, Cra 1 No. 18A-12 Q:305, Bogotá 111711, Colombia

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‡

S Supporting Information *

ABSTRACT: A thermal protocol is reported for the formal insertion of nitric acid into aryldiazoacetates using Fe(NO3)3· 9H2O. This strategy is mild and high yielding and allows the preparation of a large variety of members of an unprecedented family of organic nitrates. The nitrate group can be also readily transformed into other functional groups and heterocyclic moieties and can possibly allow new biological explorations of untapped potential associated with their NO-releasing ability.

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rganic nitrates are one of the oldest classes of compounds clinically employed as nitric oxide (NO) donors. They generally release NO upon treatment with thiols or by enzymatic catalysis (Cyt-P450, GST, etc.).1 NO is a persistent radical gas molecule that has been implicated in numerous physiological processes, such as in the relaxation of vascular smooth muscle, in the inhibition of platelet aggregation, and in neurotransmission and immune regulation responses.1 As a consequence of its importance, it has been chosen as the molecule of the year in 1992,2 and the study of its function as a signaling molecule in the cardiovascular system was the theme of the Nobel Prize in Physiology or Medicine awarded to Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad in 1998.3 NO donors can react through different mechanisms, which depend on their structures. Therefore, the continuous development of new NO donors is important, in order to allow improvements in the control of their mode of action, target, and function aimed at specific applications.1 Synthetic routes toward several organic nitrates have been developed. Examples include vasodilators gliceryl trinitrate 1 (GTN) and isosorbide dinitrate 2 (ISDN),4 anti-inflammatory agent, NO-aspirin (NCX4016) 3,5 anticancer agent 4,6 anti malarial agent 5,7 postcoital antifertility agent 6,8 antineurodegenerative agent 7,9 and antidiabetes agent 8,10 among numerous others11 (Figure 1). The method most often employed for the preparation of organic nitrates is based on the nitration of alcohols using a mixture of HNO3/H2SO41,12 (Scheme 1a). Other methods that have been used to some extent include the nucleophilic displacement of alkyl (pseudo)halides (LG = OMs, OTs, Br, I)13 or the ring opening of epoxides14 by a nitrate ion, derived from different sources, such as tetrabutylammonium nitrate (TBAN),13a AgNO3,13b,c NaNO3/TBAN(cat),13d cerium am© XXXX American Chemical Society

Figure 1. Examples of organic nitrates showing activity against several diseases.

monium nitrate (CAN),14a or Bi(NO3)3.14b,c The use of combination C(NO2)4/Et3N14d or NO/O214e,f can be also employed to open epoxides (Scheme 1b). Other reported methods for the synthesis of organic nitrates include the reaction of olefins with tBuONO/O2 in the presence or absence of a reacting partner FG-X,15a,b,16 or nitrate salts, such as Hg(NO3)2, in the presence of Br2 or I2.15c Because CAN is both a strong oxidizing agent and a source for nitrate ions, it has been employed in various nitratation protocols. Indeed, it can be used to generate radicals from electron-rich nucleophilic species, followed by their addition onto olefins.15d,e Photolysis of CAN under UV-light irradiation has been used to generate nitrate radicals, which could be trapped with olefins15f and alkanes.15g CAN has been also used in the presence of a catalytic amount of N-hydroxyphthalimide Received: July 19, 2019

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DOI: 10.1021/acs.orglett.9b02522 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 1. Selection of Representative Examples for the Preparation of Organic Nitrates, Considering (a) Methods Most Often Employed; (b) Methods Used to Some Extent; (c) Relatively Unusual Methods; and (d) This Work

Table 1. Reaction Optimization

(NHPI) to oxidize benzylic positions, followed by the attack of the nitrate ion onto the resulting stabilized cation.15h In the presence of CAN, radical alkylation procedures employing olefins and ketones,15i silylenolethers,15j or catalytic generated chiral enamine intermediates15k have been also described (Scheme 1c). Due to our recent interest in the chemistry of aryldiazoacetates 1,17 we became intrigued with the possibility of trapping these donor−acceptor diazocompounds with a mild source of nitrate ions, such as M(NO3)n (Scheme 1d). Starting the screening of the desired transformation employing aryldiazoacetate 9a and several salts of type M(NO3)n, M = Ni, Co, Cu, Zn, Bi, Mn, Al, Mg, Ag, Fe, in 2 equiv (entries 1−10, Table 1), it can be observed that Cu (entry 3, Table 1), Bi (entry 5, Table 1), Al (entry 7, Table 1), and Fe (entry 10, Table 1) are the most competent metals for the production of the corresponding nitrate 10a. At this point, we questioned whether more than one nitrate ion could be donated per molecule of M(NO3)n used. When we compared a lower loading of 0.3 equiv of M(NO3)n among the most reactive salts (entries 11−13, Table 1), Fe(NO3)3 produced the highest yield, 90% (entry 13, Table 1), thus indicating that this salt is indeed capable of donating all nitrate ions. When 0.4 equiv of Fe(NO3)3 are used, a quantitative yield of 10a is obtained (entry 14, Table 1). Finally, the screening of solvents involving DCM, THF, EtOH, DMF, DMSO, toluene, MeCN, and AcOEt (entries 15−22, Table 1) showed that AcOEt also affords a quantitative yield of 10a. As a result, AcOEt has been chosen as the optimal solvent for this reaction (entry 22, Table 1), because it is a more sustainable option.18 This reaction has been also evaluated under oxygen-free conditions and produced the same result, without any change in the yield of 10a. With the optimal reaction conditions for this transformation in hand, we moved on to the evaluation of the scope of the diazocompound component (Scheme 2). The evaluation of the

a

Estimated by 1H NMR of the crude reaction mixture using 1,3,5trimethoxybenzene as internal standard. bSame yield if reaction is performed under air or in O2-free conditions.

ester moiety demonstrated that several linear, branched, cyclic, bulky, saturated and unsaturated alkoxy chains are well tolerated. Indeed, nitrates 10a−10k can be generally produced in high yields (86−99%). Of note, this reaction has been scaled up using substrate 9a, from 0.1 to 4.3 mmol, with no change in performance: in both cases, a quantitative yield for nitrate 10a is produced. Although chiral enantiopure aryldiazoacetate 9k, derived from alcohol (1R,2R,3R,5S)-(−)-Isopinocampheol, affords an excellent yield of the corresponding nitrate 10k (99%), no diastereoselectivity is observed, 1:1 dr (Scheme 2). Varying the nature of the arene moiety of 9 considering donor and acceptor substituents at ortho-, meta-, and parapositions (e.g., OMe, NHBoc, F, Cl, Br CF3, among others), while keeping the ethyl ester group unchanged, also allows the preparation of nitrates 10l−10x in a range of good to excellent yields, 75−99% (Scheme 2). Simultaneous variations of the aryl moiety and the ester group have been also investigated, as illustrated by nitrates 10y−10af. They could be also accessed in a highly efficient manner, 81−99% yield. Reaction times are B

DOI: 10.1021/acs.orglett.9b02522 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Scope of Nitrates

Figure 2. Examples of unreactive diazocompounds.

efficiently react with HNO3 (1.2 equiv) to produce the corresponding nitrates, 10a and 10u, respectively, in quantitative yield (Scheme 3a). These control experiments Scheme 3. (a) Control Experiments Using HNO3; (b) Proposed Reaction Mechanism

demonstrate the assignment of 10 as organic nitrates, rather than nitro compounds,19 and suggest that Fe(NO3)3 undergoes hydrolysis under the reaction conditions to produce HNO3, which can directly protonate aryldiazoacetates 9 to afford highly reactive intermediate 12a. Then, nucleophilic displacement promoted by the nitrate ion leads to the formation of observed organic nitrates 10. Alternatively, Fe3+ Lewis acid activated form 12b or 12c can be also involved. They can be also undergoing protonation to afford 12a20 (Scheme 3b). Although HNO3 and Fe(NO3)3 were both able to produce the corresponding nitrates 10a and 10u in similar yields (Scheme 3), Fe(NO3)3 can be considered a reagent of choice here because it is milder, less toxic, and easier to handle.21 A DSC measurement of nitrate 10a shows an exothermic event of ca. 217 J·g−1 10a, reaching maximum liberation of energy at 178 °C (see Supporting Information (SI)). The dissociation energy of the O−NO2 bond in aliphatic nitrates is estimated to be ca. 171.6 kJ mol−1.22 This weak bond can be readily cleaved to produce several other transformations. For instance, nitrate 10a can react with Et3N to afford the corresponding ketone 13a in 95% yield; it can be reduced in the presence of Zn/NH4OAc to form alcohol 13b in 55% yield; it can react with an excess of MeMgBr to produce diol 13c in 99% yield; it can react with 2-aminoethane-1-thiol to generate the corresponding N,S-ketal 13d in 42% yield; or it can react with either ethylene diamine or 1,2-diamino benzene to produce heterocycles 13e (80%) and 13f (99%), respectively (Scheme 4). Finally, the ability of nitrate 10a to produce NO was demonstrated. For this purpose, a saturated aqueous solution of 10a has been characterized by chemiluminescence under different reaction conditions. In the dark and in the absence of glutathione (GSH, a common chemical reducing agent that triggers the release of NO from common organic nitrates),1 there is no noticeable release of NO (Figure 3a, region I). When the solution of 10a is irradiated by visible light, in the absence of GSH, again there is no release of NO (Figure 3a, region II). However, when the light source is turned off and GSH is added to the reaction mixture, the release of NO becomes apparent (Figure 3a, region III). The amount of NO

generally fast, and reactions are over in less than 3 h. In some occasions, the reactions have been run overnight for convenience. In some other cases, nitrates 10 can undergo elimination reactions leading to the corresponding ketones, but this competitive pathway can be greatly minimized using shorter reaction times (Scheme 2). Among the diazocompounds tested, acceptor−acceptor diazocompounds dimethyl 2-diazomalonate 11a and ethyl 2diazo-3-oxobutanoate 11b or acceptor-only diazocompound ethyl 2-diazoacetate 11c proved to be unreactive under our optimal reaction conditions (Figure 2). Because the overall reaction leading to nitrates 10 corresponds to the formal insertion of HNO3 onto the aryldiazoacetates 9, we became interested in verifying whether HNO 3 could promote this reaction. In this regard, aryldiazoacetates 9a and 9u were evaluated, and both could C

DOI: 10.1021/acs.orglett.9b02522 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters 1

Scheme 4. Examples of Synthetic Applications Using Nitrate 10a

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H, 13C NMR spectra of all reported compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Igor D. Jurberg: 0000-0002-1133-6277 Author Contributions §

S.T. and A.A.G.F. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the Laboratory of Solid State Chemistry (Unicamp, Brazil) for the DSC measurement (see SI). The authors are grateful for a Post-Doctoral Fellowship from CAPES to S.T., a PhD Fellowship from Fapesp to A.A.G.F. (2017/22164-6), a PhD Fellowship from U. los Andes (Colombia) to Y.Q.-A., a PhD Fellowship from Fapesp to M.F.O. (2018/02520-5), and a Thematic Research Grant from Fapesp to M. G. O. (2016/02414-5). I.D.J. acknowledges a Regular Research Grant from Fapesp (2017/24017-0) and CNPq (INCT Catálise).

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Figure 3. Measurements involving the release of NO from 10a under different reaction conditions.

released increases significantly (approximately 5 times, from 78 to 402 pmol·min−1) when the visible light irradiation is operative (Figure 3a, Region IV) and decreases again to the previous level when the light source is turned off (Figure 3a, region V). This controlled change indicates the involvement of a photoactive NO-releasing intermediate, GS-NO (see SI for additional comments on the mechanism). The cumulative amount of NO released during this experiment has been also measured and correlates well with the previous observations (Figure 3b). In summary, we developed herein a straightforward, high yielding protocol for the conversion of aryldiazoacetates 9 to the corresponding organic nitrates 10. Synthetically, this unprecedented class of organic nitrates can be further transformed into a variety of structures, such as ketones, 2hydroxy-2-arylacetates, 1,2-diols, N,S-ketals, and 3-aryl-5,6dihydropyrazin-2(1H)-ones. Biologically, they carry an untapped potential that can be potentially explored in the development of new NO-releasing drugs.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02522. D

DOI: 10.1021/acs.orglett.9b02522 Org. Lett. XXXX, XXX, XXX−XXX

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