Received 13th January 2011, Accepted 2nd March 2011DOI: 10.1039/c1ob05069a
A variety of functionalized N-amino-3-nitrile-indole derivatives are obtained via an intramolecularhetero-cyclization of 2-aryl-3-substituted hydrazono-alkylnitriles using FeBr3 as a single electronoxidant. This approach allows the N-moiety on the side-chain to be annulated to the benzene ringduring the final synthetic step via direct oxidative aromatic C–N bond formation.
Introduction
For a class of nitrogen heterocyclic compounds with particularsubstitution patterns, N-amino substituted indole derivatives showsignificant pharmacological properties,1 which include but arenot limited to analgesic,1a anticonvulsant,1b and antioxidative1c,d
effects. In addition, some N-pyridylamino indole derivatives havefound wide applications as acetylcholinesterase inhibitors for thetreatment of Alzheimer’s disease.2
Several methods for the construction of these compounds havebeen developed (Fig. 1).3,4 A literature survey shows that thosemethods can be generalized into following categories: (1) the N-aminoindole compound was synthesized using N-functionalizedaniline (e.g. nitroso aniline, phenylhydrazine, or diphenyldiazene,etc.) as starting material (Fig. 1, Path a).3b–f (2) N-Aminationof the indole skeletons, via the hygroscopic hydroxylamine-O-sulfonic acid (HOSA) or related reagents remains overwhelminglyas the most applied method for constructing this interesting classof compounds (Fig. 1, Path b).1d,2a,3i,4 (3) The N-moiety wasannulated to the benzene ring with an indispensable ortho halogensubstituent as the last synthetic step. This approach can provideefficient syntheses of N-aminoindole derivatives via transitionmetal-catalyzed intramolecular cyclization (Fig. 1, Path c).3a,3g,h
In continuation of our work on the synthesis of indole com-pounds with different substitution patterns,5 we reported hereinthat N-amino-3-nitrile-indoles 2 can be achieved via a noveliron(III)-mediated intramolecular oxidative hetero-cyclization of2-aryl-3-substituted hydrazonoalkylnitriles 1 (Table 2), whichcontains the following features: (1) the indole ring formationallows the N-moiety to be annulated to the benzene ring duringthe last synthetic step, which enables the functionalization of thebenzenoid part with a variety of substituents at an early stage. (2)
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency,School of Pharmaceutical Science and Technology, Tianjin University, Tian-jin 300072, P. R. China. E-mail: [email protected], [email protected]; Fax: +86-22-27404031; Tel: +86-22-27404031† Electronic supplementary information (ESI) available: NMR data.CCDC reference number 772745. For ESI and crystallographic data inCIF or other electronic format see DOI: 10.1039/c1ob05069a
Fig. 1 General strategies for the syntheses of N-aminoindoles.
The annulation can be directly realized via oxidative C–N bondformation. (3) The presence of a halogen substituent at the orthoposition to the side-chain is unnecessary.
Result and discussion
We firstly subjected hydrazone substrate 1a (Table 1) to FeCl3
in CH2Cl2 to test the feasibility of the reaction. To our delight,the reaction did produce the desired N,N-dimethylaminoindole2a. However, the yields (10–20%) at complete consumption of 1awere far from satisfactory (Table 1, entries 1–4). In each case, asignificant amount of unisolated polar byproducts (baseline byTLC) were formed, which were probably derived from strongcomplexation of HCl or iron(III) salts (both are Lewis acids)with the amino moiety in the hydrazone 1a (Lewis base). Furtheroptimization study by using 1a as the substrate (Table 1) showedthat 1,2-dichloroethane (DCE) is a more desirable solvent thanCH2Cl2 since 2.5 equiv. of FeCl3 in DCE provided a better yield(36%) under the conditions (Table 1, entry 5). It was also foundthat increasing the dosage of FeCl3 to 3 equivalents led to anobvious decrease in the yield (Table 1, entries 3–6). Finally, wefound that the replacement of FeCl3 with FeBr3 provided thecyclized products in much improved yields (Table 1, entries 11–14). Attempts to counteract the complexation via the introductionof a milder Lewis base, such as acetic anhydride or propyleneoxide (PO) only resulted in lower yields (Table 1, entries 12–13).
a Reaction conditions: 1a (1 mmol) and iron(III) oxidant in 10 mL of solventat room temperature. b Yield of isolated product after chromatography.c The substrate was not totally consumed, even though the reaction mixturewas refluxed for 12 h.
Moreover, the introduction of polar nitromethane to enhance thesolubility of FeBr3 did not benefit the yield (Table 1, entry 14).6
Under the most optimal reaction conditions (Table 1, entry 11),the scope and limitations of this reaction were further explored.It is expected that each hydrazone substrate 1, prepared from a-aryl-b-ketonitrile 3 and 1,1-dimethylhydrazine via condensation,7
should possess two isomers. However, the 1H NMR spectraindicated that only hydrazones 1a–b, 1i and 1o exist as a mixture oftrans and cis isomers, with the trans isomers predominating for 1c–h, 1j–n and 1p–q.5b,8 The results listed in Table 2 demonstrate thatboth the electron-withdrawing and electron-donating aromaticsubstituents can be tolerated and all reactions proceed to afford avariety of N,N-dimethylaminoindoles in moderate yields (Table 2,entries 1–14). The reaction was also shown to be compatible withmultiple substituents on the benzene ring (Table 2, entries 3–4and 12).
Meta-substituted aromatic reactants have the possibility of pro-ducing two regioisomeric products. However, for substrates 1f–h,only 2f–h were obtained, respectively, by silica gel chromatographyas the major regioisomeric products.
An extension of the application of this heterocyclizationmethodology is to generate N-containing heterocycles containingaromatic systems other than benzene. An example of this applica-tion is the synthesis of the two unknown heterocycles 2m and 2nwith yields close to 50%.
It is worth noting that our attempt to achieve the hydrazonesubstrate with R2 being a bulkier benzyl or phenyl group, orchained alkyl group was unsuccessful, since the condensationreaction of the corresponding 1,1-dimethylhydrazine and b-ketonitrile did not occur at room temperature, while raisingthe reaction temperature only led to the formation of either aninseparable complex mixture (R2 = Bn, Ph) or an unexpected 5-aminopyrazole compound 4 (R2 = n-Pr). Although the reactionof b-ketonitrile and 1-methylhydrazine has been well known to
give the N-methylpyrazole compound,9 we did not assume thatreplacing 1-methylhydrazine with 1,1-dimethylhydrazine wouldalso afford the same pyrazole compound. However, to our surprise,the reactions gave good yields, and furthermore, both the electron-withdrawing and electron-donating aromatic substituents could betolerated (eqn (1)).
(1)
We propose the reason that condensation of b-ketonitrile 3 with1,1-dimethylhydrazine can hardly occur at room temperature isdue to the steric hindrance. Raising the reaction temperature hadprobably brought about the intramolecular cyclization followedby a tautomerization to give intermediate 5, which led to theformation of the pyrazole derivative 4 with the subsequent removalof a methyl group on the quaternary nitrogen center by anucleophile (e.g. H2NNMe2, EtOH or acetate anion) (Scheme 1).
Scheme 1 Proposed mechanism for the formation of pyrazole derivatives.
Considering that the two methyl groups on the hydrazonomoiety in the substrates are electron-donating in nature, weinitiated further studies by replacing the methyl groups with anelectron-withdrawing phthalyl group. The N,N-phthalyl hydra-zone substrates 1o–q, whether the R2 group is a chained propyl,bulkier benzyl or phenyl group, can be conveniently prepared bythe condensation of the b-ketonitriles and N-aminophthalimide.We postulated that the reaction difference of this condensationreaction from the previous case should be attributed to thedecreased nucleophilicity of the N-moiety in the N,N-phthalylhydrazone substrates, on which it was substituted by the electron-withdrawing phthalyl group, thus preventing the formation ofthe similar byproduct 5. To our delight, N,N-phthalyl hydrazonesubstrates 1o–q can also afford the desired cyclized products 2o–q in even better yields, although higher reaction temperatureand longer reaction time were required (Table 2, entries 15–17). Similarly, the results also demonstrate that both electron-withdrawing and electron-donating aromatic substituents can bewell tolerated in the process. It is worth noting that the removal of
a Reaction conditions: 1 (2 mmol) and FeBr3 (2.5 equiv.) in 20 mL of DCE at room temperature. b Major regioisomeric product was isolated bychromatography. c Yield of isolated product after chromatography.
the phthalyl group in products 2o–q may provide N-unsubstitutedaminoindole compounds, which might be used for the syntheses ofother functionalized N-substituted aminoindole derivatives. Forexample, the hydrazinolysis of 2o can afford the N-amino-3-nitrileindole 2o¢ in 88% yield (eqn (2)).10
(2)
All the structures of the N-aminoindole products are deter-mined by detailed study of their spectroscopic data and product2a is further confirmed through X-ray crystallographic analysis(Fig. 2).11
Fig. 2 X-Ray crystallography of 2a.
The mechanism of this intramolecular oxidative C–N bondformation process was postulated (Scheme 2).12 Firstly, abstractionof the benzylic hydrogen atom from 1 by a SET (single electrontransfer) process gives the carbon-based radical 6, with resonancestructure N-radical 7. Secondly, mediated by iron(III) bromide,a second SET process occurs to convert the N-radical 7 to thenitrenium ion 8. Finally, nucleophilic attack on the nitrenium ionby the benzene ring results in carbocation 9, which undergoesrearomatization via the loss of a proton, to afford title compound2.5b
Scheme 2 Proposed mechanistic pathway.
Conclusions
In summary, we have described an efficient synthesis of N-aminoindole compounds, which allows the N-moiety on theside-chain to be annulated to the substituted benzene ring viaFeBr3-mediated oxidative aromatic C–N bond formation. Via aprotection and subsequent deprotection step of the hydrazone
substrates, this method provides access to a wide range of N-aminoindoles that could only be synthesized by a limited numberof methods.3,4
Experimental1H and 13C NMR spectra were recorded on a 400 MHz BRUKERAVANCE spectrometer at 25 ◦C. Chemical shifts values are givenin ppm and referred to the internal standard TMS: 0.00 ppm.The peak patterns are indicated as follows: s, singlet; d, doublet;t, triplet; q, quartet; m, multiplet; br, broad and dd, doubletof doublets. The coupling constants J, are reported in hertz(Hz). GC-MS was performed by direct inlet on a ShimadazuGCMS-QP2010 Plus instrument. IR were recorded on a BrukerTensor 27 infrared spectrometer as KBr pellets with absorptionin cm-1. High-resolution mass spectra (HRMS) were obtainedon a Q-TOF micro (Waters) spectrometer. Melting points weredetermined with a national micromelting point apparatus withoutcorrections. TLC plates were visualized by exposure to ultravioletlight. 1,2-Dichloroethane wasdried by CaH2 before use, otherreagents and solvents were purchased as reagent grade and wereused without further purification. Flash column chromatographywas performed over silica gel 200–300 m and the eluent was amixture of EtOAc and petroleum ether, or a mixture of MeOHand CH2Cl2.
General procedure for the preparation of 17
A mixture of b-ketonitriles (10 mmol), 1,1-dimethylhydrazine orN-aminophthalimide (15 mmol), p-toluenesulfonic acid (1 mmol)with several 4 A molecular sieves in 100 mL of toluene wasstirred at room temperature (if N-amino phthalimide was used,the solution was heated to reflux) under nitrogen atmosphere, andTLC was used to monitor the reaction process. After completionof the reaction, it was filtered and the solvent was removed undervacuum. The residue was purified by column chromatographyusing a mixture of petroleum ether and EtOAc as eluent to affordthe substrate.
To a stirring solution of the 2-aryl-3-dimethylhydrazo-noalkylnitriles 1 (2.0 mmol) in DCE (20 mL) was added oneportion of the FeBr3 powder (5.0 mmol) at room temperatureunder a N2 atmosphere. TLC was used to monitor the reactionprocess until the total consumption of 1. To the solution wasthen added H2O (20 mL), and stirring was continued for anadditional 5 min. The reaction mixture was extracted with CH2Cl2
(30 mL ¥ 3) and the organic layer was dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure and thegiven residue was purified by column chromatography by using amixture of petroleum ether and EtOAc as eluent to afford the purecompounds.
A solution of phthalimidoindole compound 2o (1 mmol) in 10 mLof absolute EtOH was treated with vigorous stirring with 1.1 equiv.of hydrazine monohydrate at room temperature. After the mixturewas stirred for 2 h, the precipitate was filtered and the filtrate wasconcentrated under reduced pressure. The residue was partitionedbetween CH2Cl2 and H2O, and the aqueous phase was extractedwith 50 mL of CH2Cl2 three times. The combined organic phasewas dried over anhydrous Na2SO4, concentrated under reducedpressure, and chromatographed to afford the desired compound2o¢.
To a stirring solution of b-ketonitriles (10 mmol), 1,1-dimethylhydrazine (20 mmol) in anhydrous ethanol (50 mL) wasadded acetic acid (1 mmol). The mixture was heated to refluxwith a condenser under nitrogen atmosphere until TLC indicatedthe total consumption of the b-ketonitriles. The solvent wasremoved under vacuum and the residue was purified by columnchromatography using a mixture of CH2Cl2 and MeOH as eluentto afford the substrate.
Y.D. acknowledges the National Natural Science Foundation ofChina (#20802048) and Cultivation Foundation (B) for YoungFaculty of Tianjin University (TJU-YFF-08B68) for financialsupport. X.Q. is grateful for financial support by the ChinaPostdoctoral Science Foundation (200904507610) for this project.
Notes and references
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11 Compound 2a: Crystallized in the triclinic space group P1 with celldimensions: a = 8.8268(18) A, b = 8.9764(18) A, c = 16.501(3) A,a = 99.27(3)◦, b = 96.72(3)◦, g = 118.09(3)◦, V = 1110.1(4) A3, Dc =1.192 g cm-3, Z = 4. CCDC: 772745†.
12 One reviewer has proposed a following alternative mechanism, whichfeatures: (i) FeBr3 plays a role of Lewis acid to coordinate with the cyanogroup, which assists the tautomerization of imine 1¢ into enamine A; (ii)the formation of a N–Fe bond between A and FeBr3, with the releaseof HBr, will give imine intermediate B; (iii) the abstraction of [FeBr]from B will give ammonium intermedidate C, which will undergo thesame cyclization and aromatization process we have described; (iv) thereleased [FeBr] species will be oxidized by FeBr3 to give FeBr2.
