Regioselective Metalation and Functionalization of the Pyrazolo[1,5

Apr 16, 2018 - prior to the addition of the TMP-base, a switch of the metalation regioselectivity was observed. Presumably, BF3 coordinates to the nit...
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Regioselective Metalation and Functionalization of the Pyrazolo[1,5‑a]pyridine Scaffold Using Mg- and Zn-TMP Bases Moritz Balkenhohl, Bruno Salgues, Takahiro Hirai, Konstantin Karaghiosoff, and Paul Knochel* Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Haus F, 81377 Munich, Germany S Supporting Information *

ABSTRACT: A regioselective functionalization of the pyrazolo[1,5-a]pyridine scaffold using Mg- and Zn-TMP bases (TMP = 2,2,6,6-tetramethylpiperidyl) in the presence or absence of BF3·OEt2 is described. Also, various functionalized pyrazolo[1,5a]pyridines bearing an ester function (and an NHBoc or ethyl group) are magnesiated and functionalized, leading to polysubstituted heterocycles. Additionally, a sulfoxide directed ortho-metalation, followed by the transition-metal-free amination of a pyrazolo[1,5-a]pyridine sulfoxide, using a magnesium amide, is reported.

Recently, a range of TMP-Mg and TMP-Zn bases (TMP = 2,2,6,6-tetramethylpiperidyl) have been developed, which have proven to be very active metalating reagents, tolerating various functional groups, and sensitive heterocyclic structures.5,6 Furthermore, these Mg- and Zn-bases are compatible at low temperatures with strong Lewis acids, such as BF3·OEt2 or MgCl2.7 This combination (frustrated Lewis pair)7a,c,d greatly enhances the functionalization scope of such bases and allows to achieve new metalation patterns.6c,8 Herein, the straightforward functionalization of the pyrazolo[1,5-a]pyridine scaffold 1 using a combination of Mg- or ZnTMP bases and BF3·OEt2 is reported. Thus, pyrazolo[1,5a]pyridine (1) was treated with TMPMgCl·LiCl (1.2 equiv) for 15 min at −78 °C9 in THF, which results in the coordination of the TMP-base to the nitrogen atom N1, inducing a magnesiation in the C7-position. This led to the magnesium species of type 6, which, after quenching with iodine or dibromotetrachloroethane, gave the halogenated pyrazolo[1,5-a]pyridines 7a−b in 69−93% yield (Table 1, entries 1−2). Reaction of the magnesium intermediate 6 with S-methylmethanethiosulfonate gave the thiolated pyrazolo[1,5-a]pyridine 7c in 46% yield (entry 3). After transmetalation of 6 to the corresponding copper species using a CuCN·2LiCl10 solution in THF, quenching with 3-bromocyclohexene or ethyl 2-(bromomethyl)acrylate11 gave the allylated products 7d−e in 73−86% yield (entries 4−5). Such heterocyclic copper derivatives also reacted with several acid chlorides such as 2-chloro-, 2-iodo-, or 4-chlorobenzoyl chloride to give the acylated pyrazolo[1,5-a]pyridines 7f−h in 53−70% yield (entries 6−8). Reaction of 6 with DABSO (DABSO = DABCObis(sulfur dioxide)),12 followed by sulfuryl chloride and piperidine, gave the sulfonamide 7i in 55% yield (entry 9). After transmetalation of the magnesium species 6 to zinc using

N-heterocycles are important scaffolds in pharmaceutical and agrochemical research.1 Whereas common N-heterocycles, such as pyridines, quinolines, or pyrimidines, have been studied thoroughly, the functionalization of less conventional heterocycles is still in its infancy, and the metalation of such unusual scaffolds is mainly unexplored. For example, pyrazolo[1,5a]pyridines (1−5) have recently attracted much attention due to their multiple biologic activities and pharmaceutical applications.2 Pyrazolo[1,5-a]pyridine 2 is a dopamine D3 antagonist,2e 3 is a PI3 kinase inhibitor,2i and 4 and 5 act as EP1and diuretic adenosine A1 antagonists (Figure 1), making them suitable candidates for the treatment of schizophrenia, cancer, or Parkinson’s disease.2b,c,k The direct functionalization of the pyrazolo[1,5-a]pyridine scaffold is not well studied,2h,3 and especially the regioselective functionalization of the C2 position is difficult to achieve.4

Figure 1. Biologically active derivatives of the pyrazolo[1,5-a]pyridine scaffold. © XXXX American Chemical Society

Received: April 16, 2018

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DOI: 10.1021/acs.orglett.8b01204 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

magnesiation at C2 using TMPMgCl·LiCl. Thus, BF3·OEt2 was added to 1 at 0 °C for 10 min, followed by TMPMgCl·LiCl (1.2 equiv) at −78 °C, leading to the tentative magnesium species 8 after 10 min (Scheme 1). Reaction of 8 with iodine or

Table 1. Metalation and Functionalization of the Pyrazolo[1,5-a]pyridine Scaffold (1) Using TMPMgCl·LiCl and TMPZnCl·LiCl

Scheme 1. Metalation and Functionalization of Pyrazolo[1,5a]pyridine (1) in the C2 Position Using BF3·OEt2 and TMPMgCl·LiCl

dibromotetrachloroethane led to the C2 halogenated pyrazolo[1,5-a]pyridines 9a−b in 55−92% yield. Palladium-catalyzed Negishi cross-couplings of 8 after transmetalation with ZnCl2 and reaction with ethyl 4-iodobenzoate or iodobenzene gave the arylated N-heterocycles 9c−d in 67−68% yield. Coppercatalyzed acylation reactions with various acid chlorides, including 3-fluorobenzoyl chloride and 2-thiophenecarbonyl chloride, gave the acylated pyrazolo[1,5-a]pyridines 9e−h in 43−60% yield. Reaction of 8 with Tietze’s reagent15 yielded the aminomethylated N-heterocycle 9i in 51% yield (Scheme 1). Pyrazolo[1,5-a]pyridines were also functionalized in the C7 position using TMPMgCl·LiCl in the presence of a previously introduced substituent in position C2. Thus, several C2 functionalized pyrazolo[1,5-a]pyridines were treated with TMPMgCl·LiCl (1.2 equiv), leading to the magnesium species of type 10 (Scheme 2). Halogenation of 10 gave the expected products 11a−d in 49−77% yield. Interestingly, the metalation of 2-phenylpyrazolo[1,5-a]pyridine required 2.5 equiv of the TMP-base to achieve full conversion. Palladium-catalyzed Negishi cross-couplings with various aryl halides or coppermediated allylation reactions with allyl bromide or 3bromocyclohexene gave the difunctionalized N-heterocycles 11e−i in 56−99% yield. Thiolation was achieved by quenching 10 with S-methylmethanethiosulfonate or S-phenyl benzenethiosulfonate, producing the thioethers 11j−k in 52−64% yield (Scheme 2). Pyrazolo[1,5-a]pyridines bearing an ester functionality in the C3 position also underwent a metalation using TMPMgCl·LiCl, allowing facile functionalization of the C7 position. Thus, magnesiation of 12 with TMPMgCl·LiCl (1.2 equiv) led to the metalated species 13. The reaction of 13 with several electrophiles, including N-formylmorpholine and cyclopropane carbonyl chloride, gave the 3,7-bisfunctionalized pyrazolo[1,5a]pyridines 14a−i in 39−83% yield (Scheme 3).

TMPMgCl·LiCl (1.2 equiv, −78 °C, 15 min) was used. bA 1 M CuCN·2LiCl solution was used for transmetalation. c3 mol % Pd(dba)2 and 6 mol % tfp after a transmetalation with a 1 M ZnCl2 solution was used. dTMPZnCl·LiCl (1.2 equiv, 0 °C, 15 min), 3 mol % Pd(dba)2, and 6 mol % tfp were used. a

ZnCl2, a Negishi cross-coupling13 catalyzed by Pd(dba)2 (3 mol %, dba = dibenzylideneacetone) and tfp (6 mol %, tfp = tri-2furylphosphine)14 with 4-iodotoluene was performed, leading to the arylated pyrazolo[1,5-a]pyridine 7j in 69% yield (entry 10). Reaction of this zinc species with other aryl iodides such as ethyl 3- or 4-iodobenzoate gave unsatisfactory results (yields below 20%). However, when the metalation was performed with TMPZnCl·LiCl (1.2 equiv) at 0 °C for 15 min, followed by standard Negishi cross-coupling conditions, the desired crosscoupling products 7k−l were obtained in 74−97% yield (entries 11−12). Apparently, the absence of magnesium salts had a significant influence on the reaction outcome of the corresponding cross-coupling reactions. When pyrazolo[1,5-a]pyridine (1) was treated with BF3·OEt2 prior to the addition of the TMP-base, a switch of the metalation regioselectivity was observed. Presumably, BF3 coordinates to the nitrogen atom N1, which results in (i) blocking the coordination site for TMPMgCl·LiCl and (ii) an enhancement of the acidity at the C2 position. This leads to a regioselective B

DOI: 10.1021/acs.orglett.8b01204 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Metalation and Functionalization of Various Substituted Pyrazolo[1,5-a]pyridines Using TMPMgCl·LiCl

a

Scheme 4. Metalation and Functionalization of Substituted Pyrazolo[1,5-a]pyridines Bearing a Substituent in Position C3 and C5

2.5 equiv of TMPMgCl·LiCl was used.

Scheme 3. Metalation and Functionalization of Pyrazolo[1,5a]pyridine 12 Bearing an Ester Functionality in Position C3

and then quenched with S-phenyl benzenethiosulfonate. The resulting thioether was then oxidized using mCPBA (1.1 equiv) to give the sulfoxide 19 in 77% yield over two steps (Scheme 5). Scheme 5. Directed ortho-Metalation of a SulfoxideSubstituted Pyrazolo[1,5-a]pyridine Using TMPMgCl·LiCl, Followed by a Transition-Metal-Free Amination Reaction

Subsequent directed ortho-metalation17 using TMPMgCl·LiCl (1.1 equiv) at −30 °C for 15 min, followed by Negishi crosscoupling with iodobenzene gave the ortho-arylated pyrazolo[1,5a]pyridine 20 in 89% yield. Surprisingly, a sulfoxide−magnesium exchange was not possible using iPrMgCl·LiCl.18 However, a new transition-metal-free amination of a heteroaryl sulfoxide was achieved. Thus, 20 was treated with 1.2 equiv of piperidyl magnesium amide 21 at −78 °C and, after 40 min reaction time, the 6,7-difunctionalized pyrazolo[1,5-a]pyridine 22 was isolated in 55% yield (Scheme 5). In summary, the regioselective functionalization of the pyrazolo[1,5-a]pyridine scaffold in the C2 and C7 position using TMPMgCl·LiCl or TMPZnCl·LiCl in the presence or absence of the Lewis acid BF3·OEt2 is reported. A range of functionalized pyrazolo[1,5-a]pyridines were magnesiated according to the standard metalation protocol with no change in the metalation regioselectivity. Finally, the C6 position was functionalized using sulfoxide directed ortho-metalation, fol-

Additionally, ethyl or NHBoc substituted pyrazolo[1,5a]pyridines at the C5-position bearing an ester at C3 (15 and 16) did not influence the metalation selectivity, leading to 3,5,7trifunctionalized pyrazolo[1,5-a]pyridines of type 17 and 18 (Scheme 4). In the case of 16, 2.0 equiv of TMPMgCl·LiCl were required for a complete magnesiation due to a carbamate functionality deprotonation. Reaction of the corresponding magnesium species with several electrophiles, including 2bromoquinoline and 3-iodopyridine gave the trifunctionalized pyrazolo[1,5-a]pyridines 17a−d and 18a−d in 46−98% yield (Scheme 4). Sulfoxides have shown to be excellent directed metalation groups (DMGs) and are also prone to undergo sulfoxide− magnesium exchange reactions, making them versatile intermediates in heteroarene functionalization.16 Thus, pyrazolo[1,5a]pyridine (1) was magnesiated under standard conditions C

DOI: 10.1021/acs.orglett.8b01204 Org. Lett. XXXX, XXX, XXX−XXX

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lowed by a transition-metal-free amination of a heteroaryl sulfoxide using a magnesium amide. Further studies toward the amination of heteroaryl sulfoxides are currently underway in our laboratories.

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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.8b01204. Full experimental details, 1H and 13C spectra (PDF) Accession Codes

CCDC 1836475−1836479 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

Paul Knochel: 0000-0001-7913-4332 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.8b01204 Org. Lett. XXXX, XXX, XXX−XXX