Regioselective zincation of indazoles using TMP₂Zn and Negishi cross-coupling with aryl and heteroaryl iodides

Abstract

The metalation of various SEM-protected functionalized indazoles with TMP₂Zn provides 3-zincated indazoles which undergo palladium-catalyzed Negishi cross-couplings in good yields.

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Indazoles are an important class of N-heterocycles which have found numerous pharmaceutical applications.¹ The direct lithiation or magnesiation of indazoles at position 3 is difficult due to a facile fragmentation of these heterocycles leading to aminonitriles (Scheme 1).²

Scheme 1

Alternatively, 3-iodoindazoles undergo a selective I/Cu-exchange with (PhMe₂CCH₂)₂CuLi³ leading to stable 3-cuprated indazoles which can be readily acylated.⁴ The lithiation,⁵ magnesiation,⁶ and zincation⁷ of isoindazoles (2H-indazoles) have been reported. Also the direct arylation⁸ of 2H-indazoles as well as the use of 3-iodoindazoles in Suzuki-⁹ or Stille¹⁰ cross-couplings is known.

However, the direct metalation and transition metal catalyzed arylation of 1H-indazoles has not been reported. This reaction is especially interesting due to the potential pharmaceutical activity of 3-arylated indazoles.^1,11 Recently, we have described the synthesis of a kinetically highly active zinc base TMP₂Zn·2MgCl₂·2LiCl (1; abbreviated TMP₂Zn; TMP = 2,2,6,6-tetramethylpiperidyl) which combines a high metalation activity with an excellent functional group tolerance.^12,13

Herein, we wish to report that TMP₂Zn (1) allows for the first time a direct metalation of a range of N-protected indazoles of type 2 under mild conditions (without concomitant ring opening) leading to bis-indazolylzincs of type 3. Their reaction with electrophiles (E) has been successfully accomplished, leading to products of type 4 (Scheme 2).

Scheme 2

Zinc reagents (3) react well with various electrophiles like allylic bromides and acid chlorides, but we have also found reaction conditions to perform direct arylationsvia Negishi cross-couplings¹⁴ with various aryl iodides.

Thus, preliminary experiments performed in order to find the optimal protecting group (PG) of indazole (2) showed that both a tert-butoxycarbonyl- (Boc; 2a) and a methoxymethyl protected indazole (MOM; 2b) readily react with TMP₂Zn (1; THF, 25 °C, 2 h) to produce the expected bis(3-indazolyl)zinc reagents (3a–b). Copper-catalyzed trapping with various electrophiles such as ethyl 2-(bromomethyl)acrylate¹⁵ or acid chlorides provides the desired 3-functionalized indazoles (4a–c) in 72–89% yield (entries 1–3 of Table 1). A 3-arylation could be realized for the first time with the MOM-protected bis-indazolylzinc reagent (3b). Its reaction with 4-iodobenzonitrile (1.2 equiv) in the presence of 2% Pd(dba)₂ (dba = dibenzylideneacetone) and 4% tfp (tfp = tri-(2-furyl)phosphine)¹⁶ at 50 °C for 8 h leads to the desired 3-arylated indazole (4d) in 76% yield. Attempts to couple bromoarenes with other catalytic systems¹⁷ were not successful. Furthermore these Negishi cross-couplings had to be performed at 50 °C. This elevated temperature proved to be a problem for the cross-coupling of further functionalized indazoles leading to partial ring opening byproducts. By switching to SEM-protected indazoles (SEM = 2-(trimethylsilyl)ethoxymethyl)¹⁸ the corresponding zinc reagents undergo Pd-catalyzed cross-couplings in high yields. Thus, the arylation of SEM-protected indazole (2c) with 4-iodobenzonitrile gives the cross-coupling product (4e) in 76% yield (entry 5). Less reactive aryl iodides, such as 4-iodoanisole (50 °C, 12 h), react now very well leading to the 3-arylated indazole (4f) in 81% yield (entry 6). A heterocyclic iodide, such as 2-iodoisoquinoline, undergoes the cross-coupling smoothly, affording the desired product (4g) in 62% yield (entry 7). This cross-coupling reaction could be extended to functionalized indazoles bearing a chlorine substituent (2d, entries 8 and 9), a bromine substituent (2e, entries 10 and 11), a methoxy group (2f, entry 12), as well as sensitive functions like a nitrile (2g, entry 13) and an ester group (2h, entry 14). The desired 3-arylated indazoles (4h–n) are produced in 45–86% yield. We verified also that these SEM-protected indazoles undergo acylation reactions. Thus, the ester substituted indazole (2h) after zincation with TMP₂Zn (1) and transmetalation with CuCN·2LiCl¹⁹ reacts with benzoyl chloride leading to the 3-benzoylated indazole (4o) in 77% yield (entry 15).

Table 1 Direct zincations of protected indazoles and subsequent reactions with various electrophiles

Entry	Indazole	Electrophile/conditions	Product/Yield^a (%)
a Yield of isolated analytically pure product. ^bA transmetalation with CuCN·2LiCl (1.1 equiv) was performed. ^cObtained by a palladium-catalyzed cross-coupling (2% Pd(dba)2; 4% tfp; 50 °C, 6–24 h).
1
2		PhCOCl
	2a	-40 to 25 °C, 2 h
3
4
	2b
5
6
	2c
7
	2c
8
9
	2d
10
11
	2e
12
13
14
15		PhCOCl
	2h	-40 to 25 °C, 2 h
16

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We have also found that the SEM protected 2H-indazole (2i) was metalated with TMP₂Zn (1) under similar conditions (25 °C, 2 h) leading after copper-catalyzed acylation with thiophene-2-carbonyl chloride to the desired ketoindazole (4p) in 81% yield (entry 16).²⁰

In summary we have reported a simple, mild and efficient method for the metalation of 1H-indazoles at position 3 with TMP₂Zn (1). The resulting indazolylzincs could be arylated via Negishi cross-couplings with various aryl iodides. Applications towards the synthesis of biologically active molecules are currently being investigated in our laboratories.

We thank the Fonds der Chemischen Industrie and the European Research Council (ERC) for financial support. We also thank BASF AG (Ludwigshafen), W. C. Heraeus GmbH (Hanau) and Chemetall GmbH (Frankfurt) for the generous gift of chemicals.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and NMR spectra of all products. See DOI: 10.1039/c2cc17804d

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