1、 Molecules 2011, 16, 9553-9561; doi:10.3390/molecules16119553OPEN ACCESSmolecules ISSN 1420- Synthesis of Novel 2,3-Dihydro-1H-indazolesGary W. Breton * and Antonio J. LeporeDepartment of Chemistry, Berry College, PO Box 495016, Mount Berry, GA 30101, USA* Author to whom correspondence should be add
2、ressed; E-Mail: gbretonberry.edu;Tel.: +1-706-290-2661; Fax: +1-706-238-7855.Received: 8 October 2011; in revised form: 8 November 2011 / Accepted: 10 November 2011 /Published: 16 November 2011Abstract: A copper(I)-mediated one-pot synthesis of 2,3-dihydro-1H-indazole heterocycleshas been developed.
3、 This synthetic route provides the desired indazoles in moderate togood yields (55%72%) which are substantially better than those achievable with analternative two-step reaction sequence. The reaction is tolerant of functionality on thearomatic ring.Keywords: 2,3-dihydro-1H-indazole; synthesis; hete
4、rocycle; indazoles; copper coupling1. IntroductionHeterocycles are important structural units found in a wide range of biologically active compounds 1.There have been many calls for the synthesis of novel heterocyclic systems to be used as buildingblocks for the next generation of pharmaceuticals 1-
5、4. One subclass of particularly activeheterocycles are those bearing 1,2-dinitrogen substitution. For example, substituted derivatives of thepyrazole (1 in Figure 1), pyrazoline (2), and pyrazolidine (3) ring systems are of pharmaceuticalinterest for their demonstrated antibacterial, antidepressant,
6、 and/or anti-inflammatory activities(among others) 4-6. Additionally, the fused aromatic 1H-indazole (4) is well recognized for itsantihypertensive and anticancer properties 7. Surprisingly, however, the 2,3-dihydro-1H-indazolemoiety (5 in Figure 1) remains virtually unknown and untested, despite it
7、s obvious structuralsimilarities to both the pyrazolidine (3) and 1H-indazole (4) ring systems.Molecules 2011, 16 9554Figure 1. Structures of select 1,2-dinitrogen heterocycles.We are aware of only a handful of studies that have addressed the synthesis of derivatives ofindazoles 5 8-13. Zenchoff rep
8、orted on their synthesis via acid-catalyzed SN1-type ring closure ofsubstituted 2-hydroxymethyl phenylhydrazines 6 to form indazoles 7 (Scheme 1) 8. Overall yields ofapproximately 30% were reported for the combined two-step method.Scheme 1. Synthesis of substituted derivatives of 2,3-dihydro-1H-inda
9、zoles 7 viaacid-catalyzed ring-closure.Additionally, there have been a few studies in which formation of derivatives of indazole 5 havebeen observed as a result of trapping experiments on reactive intermediates 9-11. However, otherthan Zenchoffs limited work, we are unaware of the development of any
10、 general routes for thesynthesis of this class of heterocycles.In addition to being interesting compounds in their own right, 2,3-dihydro-1H-indazoles 5 have alsoserved as synthetic intermediates for their more thoroughly-studied counterparts, the 1H-indazoles 4 8.Thus, development of synthetic rout
11、es towards the synthesis of indazoles 5 similarly creates novelroutes for the synthesis of indazoles 4.The sparse number of investigations into the synthesis of this class of heterocycles is, therefore,quite surprising given that 2,3-dihydro-1H-indazoles have such strong potential for biological act
12、ivityand as convenient synthetic intermediates. Detailed investigations of their properties, however,demand robust synthetic methods for their preparation. Herein, we describe our initial investigationstowards the synthesis of this understudied class of heterocyclic compounds.Molecules 2011, 16 9555
13、2. Results and DiscussionUllman-type copper(I)-mediated coupling of bis-BOC protected hydrazine 8 to aryl and vinylhalides in DMF using CuI, 1,10-phenanthroline and Cs2CO3 is a well-established synthetic procedure(see Scheme 2) 14,15. We initially envisioned the synthesis of bis-BOC protected 2,3-di
14、hydro-1H-indazoles 10 via intramolecular coupling of the free N-H bond of hydrazines 9 at the iodo-substitutedcarbon atom to form the five-membered indazole nucleus (Scheme 3). Indeed, this proved to be anexcellent method for the synthesis of substituted indazoles, providing high yields of 10 (Schem
15、e 3).Scheme 2. Ullman-type coupling of hydrazine 8 to halogenated aromatics.Scheme 3. Intramolecular coupling of hydrazines 9 to form bis-BOC protected indazoles 10.Unfortunately, however, synthesis of the required trisubstituted hydrazine starting materials 9proved to be problematic (Scheme 4). Alt
16、hough we utilized reaction conditions optimized byRasmussen for selective monoalkylation of 8 16, only poor yields of monoalkylated productwere obtained (i.e., compounds 10ac were obtained in 25%, 27% and 16% yields, respectively).Surprisingly, bisalkylation of hydrazine 8 was the preferred reaction
17、 route. We attempted to increasethe yield of monoalkylated product by increasing the amount of starting 8 relative to starting benzylbromides 11, but this led to difficulties in separation of the product from excess 8. Additionally, otherthan 11a, which was commercially available, the required subst
18、ituted ortho-iodobenzyl bromides(compounds 11bf) needed to be synthesized from the corresponding benzylic alcohols via a two stepprocess of iodination of the aromatic ring (silver CF3CO2Ag/I2) followed by bromination at thebenzylic alcohol position (PBr3). Thus, although the intramolecular coupling
19、reactions afforded highyields (Scheme 3), the effective yields from the synthetically expensive ortho-iodobenzyl bromideswere unsatisfactorily low.Molecules 2011, 16Scheme 4. Synthesis of monoalkylated bis-BOC protected hydrazines 9.9556To bypass the problem of dialkylation, we considered the possib
20、ility of developing a one-potprocedure in which copper-mediated coupling of the initially formed monoalkylated hydrazines 9 toform indazoles 10 might be able to compete with the complicating dialkylation process. A mixture of 8and ortho-iodobenzyl bromide 11a was added slowly, via syringe pump (over
21、 a period of 7 h), to apre-heated stirring mixture of CuI, 1,10-phenanthroline and Cs2CO3. After 24 h, we were gratified tonote that the only major product detected by TLC analysis of the crude reaction mixture was thedesired indazole 10a. Reaction workup, followed by column chromatography afforded
22、10a in60% yield, a substantial increase from the effective 22% yield obtained via the two-step process(i.e., 11a9a10a) starting from the ortho-iodobenzyl bromide 11a. In addition, this procedureavoided the need for purification of the intermediate hydrazine 9a. Similarly, indazoles 9b and 9c werefor
23、med in 60% yields utilizing the one-pot procedure rather than the effective 25% and 15% yields,respectively, from the corresponding two-step procedures.Given the success of this one-pot procedure, we subjected a number of substituted ortho-iodobenzylbromides to the same reaction conditions. The yiel
24、ds were consistent at 60% (Table 1), and theproducts were obtained in pure form following column chromatography. The reaction was tolerant ofelectron-donating (i.e., OCH3) and electron-withdrawing (i.e., CO2CH3) groups.Table 1. One-pot synthesis of substituted bis-BOC protected indazoles 10 starting
25、 fromortho-iodo benzylbromides 11.Entry Substrate11a11b11c11dIndazole Product Yield (%)12345610a10b10c10d10e10f60606055726211e11fMolecules 2011, 16 95573. Experimental3.1. GeneralAll chemicals and solvents were used as received (Aldrich, St Louis, MO, USA) Anhydrous DMFwas kept under nitrogen and se
26、aled with a septum. Column chromatography was performed using230400 mesh silica gel 60. NMR spectra were recorded on a Varian 60 MHz instrument in CDCl3as solvent, unless otherwise indicated, and referenced relative to TMS (0.0 PPM). Combustionanalysis was performed by Micro Analysis Inc. (Wilmingto
27、n, DE, USA). Other than unsubstituted2-iodobenzyl bromide 11a, which was commercially available (Aldrich), benzyl bromides 11bf weresynthesized via standard aromatic iodination (I2, CF3CO2Ag) followed by bromination of the benzylicalcohol (PBr3) following procedures described in the literature 17.3.
28、2. Synthesis of Alkylated Monoalkylated Hydrazines 9acRepresentative Procedure: Preparation of 1,2-di-tert-Butyl 1-(2-iodobenzyl)-1,2-hydrazinedicarboxylate(9a) To a solution of di-tert-butyl hydrazodiformate (8, 0.71 g, 3.06 mmol) in anhydrous DMF (15 mL)was added Cs2CO3 (2 g, 2 equiv.) followed im
29、mediately by 2-iodobenzyl bromide (11a, 1 g, 3.37 mmol,1.1 equiv.). The mixture was stirred for 2 h, after which time TLC indicated consumption of thebromide. The mixture was diluted with H2O (25 mL) and washed with EtOAc (3 25 mL). Thecombined EtOAc layers were backwashed with brine (3 25 mL), drie
30、d and concentrated. Columnchromatography (SiO2, 4:1 hexanes/EtOAc as eluent) afforded 0.32 g (23% yield) of 9a as a whitesolid. 1H-NMR 7.82 (d, J = 7.4 Hz, 1H), 7.346.79 (m, 3H), 6.45 (br s, NH, 1H), 4.71 (s, 2H), 1.48(s, 9H), 1.45 (s, 9H). 13C-NMR 155.3, 155.0, 139.5, 139.3, 129.7, 129.1, 128.3, 99
31、.0, 81.5, 81.1, 58.1,28.2. Anal. Calcd. for C17H25N2O4I: C, 45.53; H, 5.62; N, 6.25; H. Found: C, 45.61; H, 5.56; N, 6.12.1,2-Di-tert-butyl 1-(2-iodo-5-methylbenzyl)-1,2-hydrazinedicarboxylate (9b). Compound 9b (0.46 g,27% yield) was isolated as a white solid following the representative procedure d
32、escribed abovestarting with 2-iodo-5-methylbenzyl bromide (11b, 1.1 g, 3.37 mmol). 1H-NMR 7.64 (d, J = 8.0 Hz,1H), 7.10 (d, J = 1.7 Hz, 1H), 6.74 (dd, J = 8.0, 1.7 Hz, 1H), 6.67 (br s, NH, 1H), 4.67 (s, 2H), 2.27 (s,3H), 1.48 (s, 9H), 1.44 (s, 9H). 13C-NMR 155.1, 154.7, 138.9, 138.6, 137.8, 130.2, 1
33、29.9, 94.7, 81.1,80.6, 57.4, 27.9, 20.7. Anal. Calcd. for C18H27N2O4I: C, 46.74; H, 5.89; N, 6.06; H. Found: C, 46.61;H, 5.84; N, 5.96.1,2-Di-tert-butyl 1-(2-iodo-5-methoxybenzyl)-1,2-hydrazinedicarboxylate (9c). Compound 9c (0.24 g,16% yield) was isolated as a thick colorless liquid following the r
34、epresentative procedure describedabove starting with 2-iodo-5-methoxybenzyl bromide (11c, 1.1 g, 3.42 mmol). 1H-NMR 7.67 (d,J = 8.7 Hz, 1H), 6.93 (d, J = 3.0 Hz, 1H), 6.55 (dd, J = 8.7, 3.0 Hz, 1H), 6.45 (br s, NH, 1H), 4.66 (s,2H), 3.76 (s, 3H), 1.48 (s, 9H), 1.45 (s, 9H). 13C-NMR 160.1, 155.3, 154
35、.9, 140.3, 140.0, 115.6,115.1, 87.1, 81.6, 81.2, 58.0, 55.3, 28.2. Anal. Calcd. for C18H27N2O5I: C, 45.18; H, 5.86; N, 5.69; H.Found: C, 43.81; H, 5.51; N, 5.55.Molecules 2011, 16 95583.3. Synthesis of 1,2-Di-tert-butyl 1H-indazole-1,2-(3H)-dicarboxylates 10ac via IntramolecularCyclizationRepresenta
36、tive Procedure: Preparation of 1,2-di-tert-Butyl 5-methyl-1H-indazole-1,2-(3H)-di-carboxylate (10b). A mixture of 9b (0.31 g, 6.7 mmol), CuI (0.13 g, 1 equiv.), 1,10-phenanthroline(0.12 g, 1 equiv.) and Cs2CO3 (0.33 g, 1.5 equiv.) in anhydrous DMF (5 mL) was stirred under anatmosphere of N2 at 80 C
37、for 24 h. The solution was cooled, and filtered through a short column ofCelite which was rinsed thoroughly with EtOAc (100 mL). The resulting mixture was filtered toremove an insoluble precipitate, concentrated to a thick brown oil, and subjected to columnchromatography (SiO2 using 4:1 hexanes/EtOA
38、c as eluent) to afford 10b (0.20 g, 91% yield) as a thickcolorless oil. 1H-NMR 7.42 (d, J = 8.8 Hz, 1H), 7.106.99 (m, 2H), 5.184.45 (m, 2H), 2.32 (s, 3H),1.56 (s, 9H), 1.50 (s, 9H). 13C-NMR 156.4, 153.0, 138.0, 134.0, 128.3, 122.6, 115.9, 82.2, 81.9, 51.5,28.2, 20.9. The glassy nature of this produc
39、t prevented us from obtaining a satisfactory C,H,N analysis.Evidence of purity is provided by the NMR spectra given in the Supplementary Material.1,2-Di-tert-butyl 1H-indazole-1,2-(3H)-dicarboxylate (10a). Compound 10a (0.21 g, 95% yield) wasisolated as a white solid following the representative pro
40、cedure starting with 9a (0.31 g, 0.68 mmol).1H-NMR 7.647.07 (m, 4H), 5.224.51 (m, 2H), 1.57 (s, 9H), 1.51 (s, 9H). 13C-NMR 156.4, 152.8,140.2, 128.2, 127.8, 124.2, 122.0, 116.1, 82.4, 82.0, 51.6, 28.2. Anal. Calcd. for C17H24N2O4: C, 63.72;H, 7.55; N, 8.75; H. Found: C, 63.81; H, 7.56; N, 8.56.1,2-D
41、i-tert-butyl 5-methoxy-1H-indazole-1,2-(3H)-dicarboxylate (10c). Compound 10c (0.11 g, 94%yield) was isolated as a white solid following the representative procedure starting with 9c (0.16 g,0.34 mmol). 1H-NMR 7.517.35 (m, 1H), 6.886.73 (m, 2H), 5.154.46 (m, 2H), 3.78 (s, 3H), 1.56(s, 9H), 1.51 (s,
42、9H). 13C-NMR 157.1, 156.3, 153.2, 133.8, 129.6, 116.9, 113.0, 108.0, 82.1, 81.8,55.6, 51.6, 28.2. Anal. Calcd. for C18H26N2O5: C, 61.68; H, 7.48; N, 8.00; H. Found: C, 61.70; H, 7.47;N, 7.87.3.4. Synthesis of 1,2-Di-tert-butyl 1H-indazole-1,2-(3H)-dicarboxylates 10af via the One-Pot ProcedureReprese
43、ntative Procedure: Preparation of 1,2-di-tert-Butyl 5-methoxy-1H-indazole-1,2-(3H)-di-carboxylate (10c). To a stirring mixture of CuI (0.58 g, 1 equiv.), 1,10-phenanthroline (0.55 g,1 equiv.) and Cs2CO3 (2 g, 2 equiv.) in anhydrous DMF (10 mL) under N2 preheated to 80 C asolution of 2-iodo-5-methoxy
44、benzyl bromide 11c (1 g, 3.06 mmol) and di-tert-butyl hydrazodiformate(8, 1.06 g, 1.5 equiv.) in anhydrous DMF (7 mL) was added via syringe pump at a rate of 1 mL/h. Theentire reaction (including injection time) was allowed to proceed for 24 h, after which time it wascooled and filtered through a sh
45、ort column of Celite which was rinsed thoroughly with EtOAc(150 mL). The resulting EtOAc mixture was filtered to remove an insoluble precipitate, concentratedto a thick brown oil, and subjected to column chromatography (SiO2 using 4:1 hexanes/EtOAc aseluent) to afford 0.64 g (60% yield) of 10c as a
46、white crystalline solid.Molecules 2011, 16 95591,2-Di-tert-butyl 1H-indazole-1,2-(3H)-dicarboxylate (10a). Compound 10a (0.97 g, 60% yield) wasisolated as a white solid following the representative procedure starting with 2-iodobenzyl bromide(11a, 1.50 g, 5.05 mmol).1,2-Di-tert-butyl 5-methyl-1H-ind
47、azole-1,2-(3H)-dicarboxylate (10b). Compound 10b (0.65 g, 60%yield) was isolated as a thick colorless liquid following the representative procedure starting with2-iodo-5-methylbenzyl bromide (11b, 1.0 g, 3.22 mmol).1,2-Di-tert-butyl 5,6-dimethyl-1H-indazole-1,2-(3H)-dicarboxylate (10d). Compound 10d
48、 (0.59 g,55% yield) was isolated as a thick colorless liquid following the representative procedure starting with2-iodo-4,5-dimethylbenzyl bromide (11d, 1.0 g, 3.10 mmol). 1H-NMR 7.36 (s, 1H), 6.96 (s, 1H),5.164.43 (m, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 1.57 (s, 9H), 1.50 (s, 9H). 13C-NMR 156.5, 153.1
49、,138.4, 136.0, 132.4, 125.6, 122.9, 117.2, 82.0, 81.7, 51.5, 28.2, 20.1, 19.4. The glassy nature of thisproduct prevented us from obtaining a satisfactory C,H,N analysis. Evidence of purity is provided bythe NMR spectra given in the Supplementary Material.1,2-Di-tert-butyl 5,6-dimethoxy-1H-indazole-1,2-(3H)-dicarboxylate (10e). Compound 10e (0.85 g,72% yield) was isolated as a thick colorless liquid fol
