Amination of Phosphorodiamidate-Substituted Pyridines and Related

Letter Cite This: Org. Lett. 2018, 20, 8057−8060

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Amination of Phosphorodiamidate-Substituted Pyridines and Related N‑Heterocycles with Magnesium Amides Moritz Balkenhohl,† Benjamin Heinz,† Thomas Abegg, and Paul Knochel* Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Haus F, 81377 Munich, Germany

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S Supporting Information *

ABSTRACT: The amination of various phosphorodiamidatesubstituted pyridines, quinolines, and quinoxaline with magnesium amides R2NMgCl·LiCl proceeds at room temperature within 8 h. Several pharmaceutically active amines were suitable substrates for this amination procedure, and also the antihistaminic tripelennamine was prepared. Additionally, several heterocyclic phosphorodiamidates underwent directed ortho-metalation (DoM) using TMPMgCl·LiCl (TMP = 2,2,6,6-tetramethylpiperidyl) or TMP2Mg·2LiCl, followed by electrophilic functionalization prior to the amination step, which led to ortho-functionalized aminated N-heterocycles.

A

mercaptopyridine must be prepared from a halopyridine, making this procedure lengthy and inefficient. On another hand, hydroxypyridines (pyridones) or hydroxyquinolines (quinolones) are readily available scaffolds, which are building blocks for the synthesis of several pharmaceuticals and natural products.8 They are readily converted to the corresponding phosphorodiamidates of type 1, which are prone to undergo directed ortho-metalation (DoM), allowing the synthesis of 2,3-difunctionalized N-heterocycles.9 Herein, we report, that the treatment of such phosphorodiamidate substituted pyridines with R2NMgCl·LiCl leads to the desired aminated heterocycles in the absence of any transition-metal catalyst (Scheme 1). Thus, 2-pyridone was treated with (Me2N)2P(O)Cl (1.2 equiv) in THF to give the phosphorodiamidate 1a in 91% yield. Other N-heterocyclic phosphorodiamidates were obtained using the same or a slightly modified procedure to give the substituted Nheterocycles 1b−i in 56−94% yield.9 Next, piperidine (1.4 equiv) was dissolved in THF, cooled to 0 °C, and treated with iPrMgCl·LiCl (1.4 equiv) to give the corresponding magnesium amide R2NMgCl·LiCl within 30 min. This amide was added to a solution of 1a in THF at 0 °C and stirred at 25 °C for 8 h. After workup, the desired aminated pyridine 2a was isolated in 88% yield (Scheme 1). Other cyclic amines, such as pyrrolidine, morpholine, N-methyl piperazine, or 4-phenylpiperidine, were also converted into the corresponding amide derivatives using iPrMgCl·LiCl and employed in the amination reaction, which led to aminated pyridines 2b−e in 68−86% yield. Also, the more challenging TBDMS-protected 3hydroxypiperidine and indoline were suitable substrates for the amination protocol, which led to aminopyridines 2f−g in 52−54% yield. Acyclic amines were converted into the

minated N-heterocycles play a major role in modern pharmaceutical chemistry.1 Especially aminopyridines and -quinolines have shown to be of high importance. For example, tripelennamine and chlorothen are antihistamines, flupirtine is a nonopioid analgesic, and chloroquine is used for the treatment of malaria (Figure 1).2 A range of heteroaryl amines have been prepared via nucleophilic aminations using transition metal catalysts of Pd, Ni, Cu, Co, and Cr.3 The development of transition-metal-free amination methods is highly desirable.4 So far, 2-halo-, 2-mercapto-, and 2cyanopyridines, and 2-pyridyl trifluoromethanesulfonates or pyridine N-oxides, were employed as electrophilic substrates for transition-metal-free amination reactions.5 However, most of these methods require high temperatures or highly basic lithium amides. Recently, we have demonstrated that pyridine2-sulfonyl chloride, which was prepared from 2-mercaptopyridine, readily underwent an amination when treated with a magnesium amide of type R2NMgCl·LiCl.6 However, pyridine2-sulfonyl chloride is instable at room temperature,7 and 2-

Figure 1. Biologically active aminopyridines tripelennamine, chlorothen, flupirtine, and chloroquine. © 2018 American Chemical Society

Received: November 19, 2018 Published: December 4, 2018 8057

DOI: 10.1021/acs.orglett.8b03698 Org. Lett. 2018, 20, 8057−8060

Letter

Organic Letters Scheme 1. Synthesis of Pyridine-2-phosphorodiamidates of Type 1 Followed by Amination of 1 Using Magnesium Amides R2NMgCl·LiCl, Leading to Aminopyridines of Type 2

Scheme 3. Synthesis of 2-, 4-, and 8-Aminoquinolines 4a−l Using Magnesium Amides R2NMgCl·LiCl

Scheme 4. Synthesis of 2-Aminoquinoxalines 5a−f Using Magnesium Amides R2NMgCl·LiCl Scheme 2. Synthesis of 4-Aminopyridines 3a−g Using Magnesium Amides R2NMgCl·LiCl

leading, after amination, to pyridines 2m−p in 66−74% yield (Scheme 1). Amination at the C4-position of the pyridine ring is often difficult to achieve, mainly due to instability of the corresponding starting material. Thus, 4-bromopyridine is only stable when being stored as the corresponding HCl salt,10 and pyridine-4-sulfonyl chloride decomposes rapidly and is difficult to isolate.7 However, 4-pyridone is a commercially available solid, which can be stored at 25 °C over months. Thus, after conversion of 4-pyridone to the corresponding phosphorodiamidate (1d), several amines, including a mixed nitrogen sulfur heterocycle and azepane, were applied to the

corresponding amides, which, after amination, resulted in the formation of the pyridines 2h−k in 64−78% yield. When N′-benzyl-N,N-dimethylethylenediamine was used as substrate, the antihistaminic tripelennamine 2l was obtained in 74% yield. Additionally, prefunctionalized pyridones were transformed into the corresponding phosphorodiamidates, 8058

DOI: 10.1021/acs.orglett.8b03698 Org. Lett. 2018, 20, 8057−8060

Letter

Organic Letters Scheme 5. Directed ortho-Metalation and Functionalization of Various Phosphorodiamidates, Followed by Amination with R2NMgCl·LiCl

formed magnesium species of type 6 was then either quenched with electrophiles (E-X) such as I2 or (BrCl2C)2 or underwent Cu-catalyzed acylation reactions or Pd-catalyzed Negishi14 cross-couplings after transmetalation to Zn.15 The resulting functionalized heterocycles of type 7 were then aminated, which led to difunctionalized pyridines 8a−d, quinoline 9, and to quinoxalines 10a−c in 35−66% yield over two steps (Scheme 5). In summary, phosphorodiamidate-substituted pyridines, quinolines, and quinoxaline were readily aminated with R2NMgCl·LiCl, which led to various aminated heterocycles. Several pharmaceutically active amines were suitable for this transformation, and also the antihistaminic tripelennamine was successfully prepared. Additionally, the C4 position of both pyridine and quinoline was readily aminated. Finally, several phosphorodiamidates underwent directed ortho-metalation using TMPMgCl·LiCl or TMP 2 Mg·2LiCl followed by functionalization with various electrophiles. Subsequent amination using R2NMgCl·LiCl gave difunctionalized aminated N-heterocycles in two steps. Further extensions are currently underway in our laboratories.

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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.8b03698. Full experimental details, 1H and 13C spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

a

Yield over two steps.

ORCID

Paul Knochel: 0000-0001-7913-4332 amination protocol, yielding the 4-aminopyridines 3a−d in 69−98% yield (Scheme 2). The aminopyridines 3e−f were isolated in 43−70% yield by the reaction of the magnesium amides derived from the antidepressants nortriptyline and fluoxetine with 1d (Scheme 2). Apart from the pyridine scaffold, also hydroxyquinolines and 2-hydroxyquinoxaline were aminated. Thus, 2-, 4-, and 8hydroxyquinoline and 2-hydroxyquinoxaline were converted into the corresponding phosphorodiamidates 1e−i and submitted to the standard amination protocol. The substituted 2- and 4-hydroxyquinolines were aminated using various amines including amoxapine, which led to quinolines 4a−h in 57−90% yield (Scheme 3a). Interestingly, the phosphorodiamidate derived from 8-hydroxyquinoline or 5-chloro-8hydroxyquinoline also underwent amination, which yielded 8aminoquinolines 4i−l in 52−68% yield (Scheme 3b). Finally, the electron-rich quinoxaline derivative 1i was treated with various magnesium amides, including the amides derived from desipramine or the sterically demanding 1-methyl-3-phenylpiperazine, and the quinoxalines 5a−f were isolated in 54−89% yield (Scheme 4). Since the phosphorodiamidate functional group is a strong direct metalation group (DMG),11 it was possible to combine the amination with an ortho-functionalization. Thus, several phosphorodiamidate substituted N-heterocycles (1a,d,f,i) were treated with TMPMgCl·LiCl (TMP = 2,2,6,6-tetramethylpiperidyl)12 or TMP2Mg·2LiCl13 in THF at 0 °C for 1 h. The

Author Contributions †

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the DFG (SFB749) for financial support. We also thank Albemarle (Hoechst, Germany) for the generous gift of chemicals.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b03698 Org. Lett. 2018, 20, 8057−8060