DOI: 10.1002/chem.201304509

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& Synthetic Methods

Gold/Acid-Co-catalyzed Direct Microwave-Assisted Synthesis of Fused Azaheterocycles from Propargylic Hydroperoxides Benito Alcaide,*[a] Pedro Almendros,*[b] and M. Teresa Quirs[a]

Abstract: The gold–acid-co-catalyzed synthesis of nine series of fused azaheterocycles with structural diversity starting from the same synthons as readily available propargylic hydroperoxides and aromatic amines has been achieved. The

Introduction Despite that a number of organic hydroperoxides are natural products of relevant biological activity,[1] this functionality attracted attention in industry,[2] and several approaches have been reported for the synthesis of the hydroperoxide moiety,[3] its synthetic utility has been somewhat limited.[4] In this context, we have recently described the preparation of stable and easily handling propargylic hydroperoxides 1 together with their gold-catalyzed rearrangements to ketones and concomitant alcoholic trapping.[5] Following our above-mentioned investigation, we became interested in the direct transformation of propargylic hydroperoxides into fused azaheterocycles[6] through a tandem sequence.[7] We recognized that the ability to employ aromatic amines in the rearrangement of propargylic hydroperoxides would provide an attractive alternative to a stepwise azaheterocycle synthesis. In addition, it would provide a platform to further expand the synthetic utility of the propargylic hydroperoxide rearrangement, since there are no examples with amine nucleophiles. The reaction between hydroperoxides and aromatic amines should afford an aminoketone intermediate, aza-Michael-type adduct, which are relevant building blocks.[8] We thought that the most convenient manner to activate the aminoketone towards an intramolecular [a] Prof. Dr. B. Alcaide, M. T. Quirs Grupo de Lactamas y Heterociclos Bioactivos Departamento de Qumica Orgnica I Unidad Asociada al CSIC, Facultad de Qumica Universidad Complutense de Madrid 28040 Madrid (Spain) Fax: (+ 34) 91-3944103 E-mail: [email protected] [b] Dr. P. Almendros Instituto de Qumica Orgnica General Consejo Superior de Investigaciones Cientficas IQOG-CSIC, Juan de la Cierva 3 28006 Madrid (Spain) Fax: (+ 34) 91-5644853 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201304509. Chem. Eur. J. 2014, 20, 3384 – 3393

overall tandem process consists in a gold-catalyzed hydroperoxide rearrangement/Michael reaction followed by a final acid-catalyzed cyclization.

condensation in situ was by using a Brønsted acid. In this article we report that the gold-catalyzed[9] reaction of propargylic hydroperoxides with a variety of aromatic amines in the presence of catalytic amounts of a protic acid results in the preparation of a small library of fused azaheterocycles.

Results and Discussion Encouraged by our previous results, we envisioned that 3,5-dimethoxyaniline would react with propargylic hydroperoxides 1 through a tandem process to furnish substituted quinolines under gold-catalyzed conditions. Quinoline derivatives are pharmacologically active compounds.[10] Initially, we chose 1-(3hydroperoxyprop-1-ynyl)-4-methoxybenzene 1 a as the starting hydroperoxide. At the outset, the use of [AuCl3] and [AuCl] were tested, but both failed to catalyze the reaction in the presence or absence of any additive. Happily, a different protocol afforded the desired quinoline 2 a in 72 % yield by exposure to the system [AuCl(PPh3)] (2.5 mol %)/[AgOTf] (2.5 mol %)/ p-toluenesulfonic acid (PTSA; 10 mol %)/H2O (200 mol %) in dichloromethane at room temperature for 42 h (Scheme 1). As such, the propargylic hydroperoxide functionality would behave as a latent carbonyl group giving a reactive a,b-unsaturated ketone, which is doubly trapped by the aromatic amine. Disappointingly, under the above conditions propargylic hydroperoxides 1 b–e gave low yields of the corresponding

Scheme 1. Controlled gold-catalyzed reaction of propargylic hydroperoxides with 3,5-dimethoxyaniline. Synthesis of 5,7-dimethoxy-2,4-disubstituted quinolines.

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Full Paper heterocyclic reaction products, because total consumption of the starting material could not be achieved after several days of reaction. Nicely, a gentle heating at 50 8C on a sealed tube both considerably decreased the reaction time and positively affected the yield. For example, the soft thermal treatment raised the yield of 2 b from 33 up to 67 % (Scheme 1). Thus, our protocol allowed the direct preparation of quinolines 2 b– e in reasonable yields (Scheme 1). The above combination of the p-acid gold catalyst with a Brønsted acid resulted in a dual activation mode of the latent alkenyl ketone. We can envision that a,b-unsaturated ketones, as intermediates, can be transferred in situ from propargylic hydroperoxides to a variety of azacycles in a one-pot procedure. Worthy of note, this is not a minor point because vinyl ketone substrates are toxic, volatile, and have a high propensity to polymerization. On the other hand, pyrazolo[1,5-a]pyrimidines play an important role in medicinal chemistry.[11] Based on our above protocol for quinoline synthesis, we optimized the tandem sequence for the reaction of hydroperoxides 1 with 3-aminopyrazole (Table 1). Nicely, from 1 a this protocol

prop-1-ynyl)-4-methoxybenzene 1 a was treated with 3-aminopyrazole under [Au(OTf)PPh3] catalysis in 1,2-dichloroethane (DCE) at 120 8C under microwave irradiation for 2.5 h, pyrazolo[1,5-a]pyrimidine 3 a was isolated in 76 % yield. A screening of solvents (toluene, tetrahydrofuran, 1,4-dioxane) revealed that the reaction is best performed in DCE. Other counterions has little effect in the reaction, because ([AgSbF6], [AgBF4], and [AgNTf2]) in combination with AuI delivered similar yields of the product. Other Au-catalysts were less effective; that is, [AuCl(IPr)] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) leads to considerable amounts of propargylic alcohol coming from decomposition of the starting hydroperoxide. Similarly, differently substituted propargylic hydroperoxides 1 b, 1 c, and 1 e also delivered the corresponding bicycles 3 in good yields (Scheme 2).

Table 1. Selective reaction between hydroperoxide 1 a and 3-aminopyrazole under modified gold-catalyzed conditions. Scheme 2. Controlled gold-catalyzed reaction of propargylic hydroperoxides with 3-aminopyrazole. Synthesis of pyrazolo[1,5-a]pyrimidines.

Entry

Catalyst

T [8 C]

t [h]

Solvent

Yield [%][a]

1

[AuCl(PPh3)]/[AgOTf]

384

CH2Cl2

72

2

[AuCl(PPh3)]/[AgOTf]

2.5

DCE

76

3

[AuCl(PPh3)]/[AgSbF6]

2.5

DCE

70

4

[AuCl(PPh3)]/[AgBF4]

3

DCE

65

5

[AuCl(PPh3)]/[AgNTf2]

2.5

DCE

68

6

[AuCl(IPr)]/[AgOTf]

4

DCE

5[b]

7

[AuCl(IPr)]/[AgSbF6]

50 sealed tube 120 microwave 120 microwave 120 microwave 120 microwave 120 microwave 120 microwave

2.5

DCE

65[b]

Scheme 3. Controlled gold-catalyzed reaction of propargylic hydroperoxides with 1H-indazol-3-amine. Synthesis of pyrimido[1,2-b]indazoles.

[a] Yield of pure, isolated product with correct analytical and spectral data. [b] Appreciable decomposition of the starting hydroperoxide 1 a was observed.

afforded the desired pyrazolo[1,5-a]pyrimidine 3 a in 72 % yield, but after prolonged exposure to the system [AuCl(PPh3)] (2.5 mol %)/[AgOTf] (2.5 mol %)/PTSA (10 mol %)/H2O (200 mol %) in dichloromethane at 50 8C on a sealed tube for 384 h. However, the conversion to the corresponding heterocycle could not be satisfied at room temperature. Considering the successful application of MW (microwave) irradiation in organic synthesis, we decided to perform this domino reaction under MW irradiation.[12] Interestingly, when 1-(3-hydroperoxyChem. Eur. J. 2014, 20, 3384 – 3393

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As depicted in Scheme 3, the pyrimido[1,2-b]indazole motif.[13] could also be obtained adapting this acid-catalyzed protocol to the use of the benzo analogue 1H-indazol-3-amine. A variety of pyrimido[1,2-b]indazole derivatives 4 were formed using our cyclative capture approach. When we performed the same tandem addition/cyclization process on propargylic hydroperoxides 1 and imidazo[1,2-a]pyridin-3-amine, the corresponding dipyrido[1,2-a:3’,2’-d]imidazoles 5 were smoothly obtained, again as the only reaction products (Scheme 4). The heterocyclic core of tricycles 5 is of potential pharmacological relevance because of its intercalation ability with DNA.[14] The indole scaffold has been recognized as the fundamental nucleus for a large number of natural and synthetic products of biological significance.[15] Therefore, methods for the synthesis of new indole derivatives are highly appreciated. We expected that the above methodology could be used for the straightforward preparation of tricyclic indole derivatives.

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Scheme 4. Controlled gold-catalyzed reaction of propargylic hydroperoxides with imidazo[1,2-a]pyridin-3-amine. Synthesis of dipyrido[1,2-a:3’,2’-d]imidazoles.

Based on this premise, we chose propargylic hydroperoxide 1 a and 1H-indol-2-amine[16] as substrates for this new type of transformation. Interestingly, under gold catalysis hydroperoxide 1 a delivered the a-carboline 6 a in addition to the nonlinear tricycle 7 a, which were easily separable by flash column Scheme 5. Controlled gold-catalyzed reaction of propargylic hydroperoxides with 1H-indol-2-amine. Synthesis of a-carbolines and benzo[cd]indol-2chromatography (Scheme 5). The present protocol was extendamines. ed to hydroperoxides 1 f–h. Similarly, their gold-catalyzed reactions with 1H-indol-2-amine furnished separable mixtures of acarbolines 6 and benzo[cd]indol2-amines 7 (Scheme 5). Despite that signals of tricycle 7 h could be detected in the 1H NMR spectrum of the crude reaction mixture, it decomposed under chromatographic separation. In the case of 1H-indol-2-amine, the nucleophilic attack of the highly reactive indole C3 position on the activated a,b-unsaturated ketone occurs, which avoids the aza-Michael event. The formation of adducts 6 and 7 can be explained invoking a Friedel– Crafts-type reaction of the indole nucleus to generate ketone 8, a common intermediate that evolves either through amino- or carbocyclization to afford tricycles 6 or 7, respectively. Although the selectivity is poor under the conditions and efforts for further improvements were in vain, it is worthy of note that Scheme 6. Controlled gold-catalyzed reaction of propargylic hydroperoxides with N-benzoyliminopyridinium fused heterocycles 6 and 7 are ylides. Synthesis of fused pyrazoles. easily separated, thus providing readily two valuable indole-type products.[17] single isomers (Scheme 6). The conversion of hydroperoxides 1 into pyrazolyl based fused heterocycles 9–11 should initially Natural products bearing an N N bond belong to a particular consist of a regioselective 1,3-dipolar capture approach in group because of its interesting structural and biological charwhich the generated a,b-unsaturated ketone serves as a dipoacteristics.[18] Besides, natural and synthetic pyrazole derivatives larophile to afford intermediates 12–14. Under the reaction are considered as drug candidates and are important synthetic conditions, tricycles 12–14 evolve to fused pyrazoles through targets.[19] Thus, the reaction of propargylic hydroperoxides debenzoylation with concomitant aromatization. with several N-benzoyliminopyridinium ylides was also exThe crucial role of the hydroperoxide functionality was explored.[20] Following the previous gold-catalyzed procedure, amined in several experiments (Scheme 7): 1) Propargylic hythe reaction of ylides with hydroperoxides 1 worked well to droperoxide 1 a was treated with 3-bromoaniline to give bprovide a series of pyrazole-embedded polycycles 9–11 as Chem. Eur. J. 2014, 20, 3384 – 3393

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Full Paper under PTSA-free reaction conditions, tricycle 4 a was obtained after slightly prolonged time (from 2.5 to 5 h). This would suggest that PTSA is not necessary for the reaction to proceed, because this process is catalyzed by gold. However, the considerable decrease of yield in the formation of tricycle 4 a (from 71 to 47 %) may point to a Brønsted acid cocatalysis. Indeed, gold salts are readily hydrolizable in presence of water and are a possible source of catalytic protons as recognized by Hashmi and others.[21] A possible pathway for the gold–acid-co-catalyzed synthesis of fused azaheterocycles from propargylic hydroperoxides and aromatic amines may or may not involve a b-aminoketone intermediate. The obtention of aza-Michael type adducts 15 a and 18O-15 b (Scheme 7) leads us to propose a mechanism, which is illustrated in Scheme 8, and occurs through b-aminoketone species. A tentative explanation for the gold–acid-cocatalyzed synthesis of fused azaheterocycles from propargylic hydroperoxides and aromatic amines is exemplified with the reaction using 3-aminopyrazole by the obtention of pyrazolo[1,5-a]pyrimidines 3 (Scheme 8). The reaction may tentatively be classified as cooperative concurrent catalysis, involving a catalytic action by the AuI salt on the alkynic site (Scheme 8, right catalytic cycle), and by the Brønsted acid on the activation of the transient aminoketonic intermediate (Scheme 8, left catalytic cycle). Scheme 7. Control experiments.

aminoketone 15 a in good yield; 2) Propargylic hydroperoxide 1 b was treated with p-anisidine in presence of H218O to give b-aminoketone 18O-15 b with 40 % 18O content; 3) Propargylic alcohol 16 a did not react neither with 3bromoaniline nor with 3,5-dimethoxyaniline, because b-hydroxyketone 17 a was formed during standard treatment but nothing else; 4) compound 18 a, the acetate of 16 a, was nearly unreactive to the exposure with 3,5-dimethoxyaniline. In short, propargylic alcohols as well as Scheme 8. Mechanistic explanation for the gold–acid-co-catalyzed reaction of propargylic hydroperoxides with 3aminopyrazole. their acetates are not suitable substrates. Under otherwise identical conditions, the particuConclusion lar characteristics of the OOH functional group allow a different mechanism to happen, which cannot apply to propargylic alWe report that hydroperoxy alkynes were directly transformed cohol derivatives. into a wide diversity of fused azaheterocycles under acidic conThe last task was to examine the effect of the Brønsted acid. ditions. This transformation involved an interesting gold-cataA control experiment that would clarify the participation of lyzed hydroperoxide rearrangement/Michael reaction followed protons as the active catalysts in the reaction was undertaken by a final acid-catalyzed cyclization. The methodology could (Scheme 7). No strong difference of reactivity using gold salts be valuable for the construction of structurally new heterocyor gold/PTSA as catalysts was observed, because when proparclic systems using propargylic hydroperoxides and aromatic gylic hydroperoxide 1 a was treated with 1H-indazol-3-amine amines as the starting materials. Chem. Eur. J. 2014, 20, 3384 – 3393

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Full Paper (Ar), 1206 (C O), 824 cm 1 (Ar); HRMS (ES): m/z calcd for C18H17NO3 : 295.1208 [M] + ; found: 295.1212.

Experimental Section General methods 1

H NMR and 13C NMR spectra were recorded on a Bruker Avance AVIII-700 with cryoprobe, Bruker Avance-300, or Varian VRX-300S. NMR spectra were recorded in CDCl3 solutions, except otherwise stated. Chemical shifts are given in ppm relative to TMS (1H, d = 0.0 ppm), or CDCl3 (13C, d = 76.9 ppm). Low- and high-resolution mass spectra were taken on an AGILENT 6520 Accurate-Mass QTOF LC/MS spectrometer using the electronic impact (EI) or electrospray modes (ES) unless otherwise stated. All commercially available compounds were used without further purification. CAUTION! Organic peroxides are potentially hazardous compounds and should be handled very carefully. If elementary precautions are taken, the work with propargylic hydroperoxides 1 is safe; we have never experienced any difficulties working with compound 1. Hydroperoxides 1 are stable compounds because: 1) 0.1 m solutions (around 50 mg) in 1,2-dichloroethane (DCE) can be safely heated at 120 8C for several hours under microwave irradiation; 2) 10 mg of hydroperoxide 1 b (neat product) can be heated at 250 8C with decomposition but not explosion; 3) They did not decompose under strong light; and 4) They are not friction/shock-sensitive because hydroperoxides 1 are not altered after gentle scratching with a spatula. Although we did not suffer any explosion, only a small amount of material should be prepared at a time, and it should be handled with great care. When handling organic peroxides, exposure to heat, light, or redox-active metal salts should be avoided. Reactions were performed on small scale and behind a safety shield.[22] Additional appropriate safety precautions such as face shields and protective clothing should be taken when dealing with large quantities

General procedure for the gold-catalyzed reaction of propargylic hydroperoxides 1 with 3,5-dimethoxyaniline: Preparation of quinolines 2 [AuCl(PPh3)] (4 mg, 0.0084 mmol), [AgOTf] (2.2 mg, 0.0084 mmol), p-toluenesulfonic acid (5.9 mg, 0.034 mmol), 3,5-dimethoxyaniline (104.2 mg, 0.68 mmol), and water (12.2 mg, 0.68 mmol) were sequentially added to a stirred solution of the corresponding propargylic hydroperoxide 1 (0.34 mmol) in dichloromethane (2.7 mL). The resulting mixture was stirred at RT or was heated in a sealed tube at 50 8C until the disappearance of the starting material (TLC). The reaction was allowed to cool to room temperature and filtered through a pack of Celite. Saturated ammonium chloride (0.7 mL) was added, before being partitioned between dichloromethane and water. The organic extract was washed with brine, dried (MgSO4), concentrated under vacuum, and purified by flash column chromatography eluting with ethyl acetate/hexanes or ethyl acetate/dichloromethane mixtures. Spectroscopic and analytical data for pure forms of compound 2 follow. Quinoline 2 a: From propargylic hydroperoxide 1 a (60 mg, 0.34 mmol), and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent gave the quinoline 2 a (72 mg, 72 %) as a pale-brown solid. M.p. 120–121 8C; 1H NMR (300 MHz, CDCl3, 25 8C): d = 3.96 (s, 3 H, OCH3), 3.97 (s, 3 H, OCH3), 3.99 (s, 3 H, OCH3), 6.50 (d, 1 H, J = 2.2 Hz, Ar), 7.04 (d, 2 H, J = 8.9 Hz, PMP), 7.09 (d, 1 H, J = 2.0 Hz, Ar), 7.66 (d, 1 H, J = 8.7 Hz, Ar), 8.12 (d, 2 H, J = 8.8 Hz, PMP), 8.45 ppm (dd, 1 H, J = 8.6, 0.6 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 161.4 (OCq), 160.7 (OCq), 157.6 (OCq), 156.0 (Cq), 150.5 (Cq), 132.5 (Cq), 131.2 (CH Ar), 128.8 (2CH PMP), 115.4 (CH Ar), 115.2 (Cq), 114.2 (2CH PMP), 100.0 (CH Ar), 97.7 (CH Ar), 55.7 (OCH3), 55.6 (OCH3), 55.4 ppm (OCH3); IR (CHCl3): n˜ = 2935 Chem. Eur. J. 2014, 20, 3384 – 3393

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Quinoline 2 b: From propargylic hydroperoxide 1 b (60 mg, 0.41 mmol), and after chromatography of the residue using ethyl acetate/dichloromethane (0.5:9.5) as eluent gave the quinoline 2 b (72 mg, 67 %) as a pale-brown oil. 1H NMR (300 MHz, CDCl3, 25 8C): d = 3.98 (s, 3 H, OCH3), 4.00 (s, 3 H, OCH3), 6.52 (d, 1 H, J = 2.2 Hz, Ar), 7.12 (d, 1 H, J = 2.1 Hz, Ar), 7.50 (m, 3 H, Ph), 7.71 (d, 1 H, J = 8.6 Hz, Ar), 8.14 (m, 2 H, Ph), 8.50 ppm (dd, 1 H, J = 8.6, 0.8 Hz, Ar); 13 C NMR (75 MHz, CDCl3, 25 8C): d = 161.5 (OCq), 158.1 (OCq), 156.0 (Cq), 150.5 (Cq), 139.9 (Cq), 131.4 (CH Ar), 129.1 (CH Ph), 128.8 (2CH Ph), 127.5 (2CH Ph), 115.9 (CH Ar), 115.6 (Cq), 100.1 (CH Ar), 98.0 (CH Ar), 55.8 (OCH3), 55.6 ppm (OCH3); IR (CHCl3): n˜ = 2929 (Ar), 1207 (C O), 831 cm 1 (Ar); HRMS (ES): m/z calcd for C17H15NO2 : 265.1103 [M] + ; found: 265.1101.

Quinoline 2 c: From propargylic hydroperoxide 1 c (60 mg, 0.26 mmol), and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent gave the quinoline 2 c (55 mg, 61 %) as a pale-brown solid. M.p. 103–104 8C; 1H NMR (300 MHz, CDCl3, 25 8C): d = 3.98 (s, 3 H, OCH3), 4.00 (s, 3 H, OCH3), 6.53 (d, 1 H, J = 2.2 Hz, Ar), 7.09 (d, 1 H, J = 2.0 Hz, Ar), 7.64 (d, 2 H, J = 8.6 Hz, Ph), 7.66 (d, 1 H, J = 8.6 Hz, Ar), 8.03 (d, 2 H, J = 8.6 Hz, Ph), 8.50 ppm (dd, 1 H, J = 8.7, 0.6 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 161.6 (OCq), 156.0 (OCq), 150.4 (Cq), 142.2 (Cq), 138.7 (Cq), 136.1 (Cq), 131.9 (2CH 4-BrPh), 131.6 (CH Ar), 129.0 (2CH 4-BrPh), 115.7 (Cq), 115.4 (CH Ar), 100.0 (CH Ar), 98.2 (CH Ar), 55.8 (OCH3), 55.7 ppm (OCH3); IR (CHCl3): n˜ = 3003 (Ar), 1206 (C O), 819 cm 1 (Ar); HRMS (ES): m/z calcd for C17H14NO2Br: 343.0208 [M] + ; found: 343.0212.

Quinoline 2 d: From propargylic hydroperoxide 1 d (60 mg, 0.39 mmol), and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent gave the quinoline 2 d (59 mg, 56 %) as a pale-brown solid. M.p. 105–106 8C; 1H NMR (300 MHz, CDCl3, 25 8C): d = 3.96 (s, 3 H, OCH3), 3.98 (s, 3 H, OCH3), 6.48 (d, 1 H, J = 2.2 Hz, Ar), 7.03 (d, 1 H, J = 2.1 Hz, Ar), 7.16 (dd, 1 H, J = 5.0, 3.7 Hz, thiophene), 7.45 (dd, 1 H, J = 5.0, 0.9 Hz, thiophene), 7.63 (d, 1 H, J = 8.7 Hz, Ar), 7.72 (dd, 1 H, J = 3.7, 1.0 Hz, thiophene), 8.42 ppm (d, 1 H, J = 8.7 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 161.6 (OCq), 156.0 (OCq), 153.0 (Cq), 150.3 (Cq), 145.6 (Cq), 131.3 (CH Ar), 128.2 (CH thiophene), 128.0 (CH thiophene), 125.6 (CH thiophene), 115.5 (Cq), 114.4 (CH Ar), 99.8 (CH Ar), 97.9 (CH Ar), 55.8 (OCH3), 55.7 ppm (OCH3); IR (CHCl3): n˜ = 1202 (C O), 820 cm 1 (Ar); HRMS (ES): m/z calcd for C15H13NO2S: 271.0667 [M] + ; found: 271.0678.

Quinoline 2 e: From propargylic hydroperoxide 1 e (60 mg, 0.37 mmol), and after chromatography of the residue using hexanes/ethyl acetate (6:1) as eluent gave the quinoline 2 e (47 mg, 45 %) as a pale-brown solid. M.p. 116–117 8C; 1H NMR (300 MHz, CDCl3, 25 8C): d = 2.90 (s, 3 H, Me), 3.94 (s, 3 H, OCH3), 3.98 (s, 3 H, OCH3), 6.50 (d, 1 H, J = 2.4 Hz, Ar), 7.14 (s, 1 H, Ar), 7.44 (s, 1 H, Ar), 7.51 (m, 3 H, Ph), 8.12 ppm (m, 2 H, Ph); 13C NMR (75 MHz, CDCl3, 25 8C): d = 161.7 (OCq), 160.5 (OCq), 158.6 (Cq), 148.1 (Cq), 140.2 (Cq), 129.1 (Cq), 129.0 (CH Ar), 128.7 (2CH Ph), 128.3 (CH Ph), 127.4 (2CH Ph), 119.1 (CH Ar), 115.6 (Cq), 98.4 (CH Ar), 55.5 (OCH3), 55.5 (OCH3), 24.5 ppm (CH3); IR (CHCl3): n˜ = 2922 (Ar), 1205 (C O), 696 cm 1 (Ar); HRMS (ES): m/z calcd for C18H17NO2 : 279.1259 [M] + ; found: 279.1261.

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Full Paper General procedure for the gold-catalyzed reaction of propargylic hydroperoxides 1 with 3-aminopyrazole: Preparation of pyrazolo[1,5-a]pyrimidines 3 [AuCl(PPh3)] (4 mg, 0.0084 mmol), [AgOTf] (2.2 mg, 0.0084 mmol), p-toluenesulfonic acid (5.9 mg, 0.034 mmol), 3-aminopyrazole (56.5 mg, 0.68 mmol), and water (12.2 mg, 0.68 mmol) were sequentially added to a stirred solution of the corresponding propargylic hydroperoxide 1 (0.34 mmol) in 1,2-dichloroethane (2.7 mL). The resulting mixture was stirred at 120 8C under microwave irradiation until disappearance of the starting material (TLC). The reaction was allowed to cool to room temperature and filtered through a pack of Celite. Saturated ammonium chloride (0.7 mL) was added, before being partitioned between dichloromethane and water. The organic extract was washed with brine, dried (MgSO4), concentrated under vacuum, and purified by flash column chromatography eluting with ethyl acetate/hexanes mixtures. Spectroscopic and analytical data for pure forms of compounds 3 follow. Pyrazolo[1,5-a]pyrimidine 3 a: From propargylic hydroperoxide 1 a (50 mg, 0.28 mmol), and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent gave the pyrazolo[1,5a]pyrimidine 3 a (48 mg, 76 %) as a yellow solid. M.p. 106–107 8C; 1 H NMR (300 MHz, CDCl3, 25 8C): d = 3.91 (s, 3 H, OCH3), 6.78 (d, 1 H, J = 2.4 Hz, Ar), 6.89 (d, 1 H, J = 4.4 Hz, Ar), 7.09 (d, 2 H, J = 9.0 Hz, PMP), 8.08 (d, 2 H, J = 9.0 Hz, PMP), 8.18 (d, 1 H, J = 2.3 Hz, Ar), 8.51 ppm (d, 1 H, J = 4.4 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 161.8 (Cq), 149.9 (Cq), 148.9 (CH Ar), 144.6 (CH Ar), 130.9 (2CH PMP), 129.0 (Cq), 123.2 (Cq), 114.1 (2CH PMP), 106.5 (CH Ar), 96.8 (CH Ar), 55.5 ppm (OCH3); IR (CHCl3): n˜ = 1255 (C O), 777 cm 1 (Ar); HRMS (ES): m/z calcd for C13H11N3O: 225.0902 [M] + ; found: 225.0909. Pyrazolo[1,5-a]pyrimidine 3 b: From propargylic hydroperoxide 1 b (50 mg, 0.34 mmol), and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent gave the pyrazolo[1,5a]pyrimidine 3 b (45 mg, 67 %) as a pale-brown oil; 1H NMR (300 MHz, CDCl3, 25 8C): d = 6.80 (d, 1 H, J = 2.4 Hz, Ar), 6.91 (d, 1 H, J = 4.3 Hz, Ar), 7.59 (m, 3 H, Ph), 8.05 (d, 2 H, Ph), 8.19 (d, 1 H, J = 2.3 Hz, Ar), 8.55 ppm (d, 1 H, J = 4.3 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 149.9 (Cq), 149.0 (CH Ar), 145.6 (Cq), 144.7 (CH Ar), 131.1 (Cq), 131.0 (CH Ph), 129.2 (2CH Ph), 128.7 (2CH Ph), 107.3 (CH Ar), 97.1 ppm (CH Ar); IR (CHCl3): n˜ = 772 cm 1 (Ar); HRMS (ES): m/z calcd for C12H9N3 : 195.0796 [M] + ; found: 195.0799. Pyrazolo[1,5-a]pyrimidine 3 c: From propargylic hydroperoxide 1 c (70 mg, 0.31 mmol), and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent gave the pyrazolo[1,5a]pyrimidine 3 c (73 mg, 86 %) as a yellow solid. M.p. 153–154 8C; 1 H NMR (300 MHz, CDCl3, 25 8C): d = 6.81 (d, 1 H, J = 2.4 Hz, Ar), 6.90 (d, 1 H, J = 4.3 Hz, Ar), 7.72 (d, 2 H, J = 8.6 Hz, 4-BrPh), 7.95 (d, 2 H, J = 8.6 Hz, 4-BrPh), 8.18 (d, 1 H, J = 2.4 Hz, Ar), 8.55 ppm (d, 1 H, J = 4.3 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 149.8 (Cq), 148.9 (CH Ar), 145.7 (Cq), 144.8 (CH Ar), 132.0 (2CH 4-BrPh), 130.7 (2CH 4BrPh), 129.9 (Cq), 125.6 (Cq), 107.1 (CH Ar), 97.3 ppm (CH Ar); IR (CHCl3): n˜ = 770 cm 1 (Ar); HRMS (ES): m/z calcd for C12H8N3Br: 272.9902 [M] + ; found: 272.9915. Pyrazolo[1,5-a]pyrimidine 3 e: From propargylic hydroperoxide 1 e (50 mg, 0.31 mmol), and after chromatography of the residue using hexanes/ethyl acetate (5:1) as eluent gave the pyrazolo[1,5a]pyrimidine 3 e (38 mg, 61 %) as a pale-brown oil. 1H NMR (300 MHz, CDCl3, 25 8C): d = 2.67 (s, 3 H, CH3), 6.66 (d, 1 H, J = 2.3 Hz, Ar), 6.78 (s, 1 H, Ar), 7.57 (m, 3 H, Ph), 8.12 (m, 2 H, Ph), 8.12 ppm (d, 1 H, J = 2.3 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 158.7 (Cq), 149.4 (Cq), 146.3 (Cq), 144.7 (CH Ar), 131.1 (Cq), 130.9 (CH Ph), 129.2 (2CH Ph), 128.7 (2CH Ph), 108.3 (CH Ar), 95.8 (CH Ar), 24.7 ppm Chem. Eur. J. 2014, 20, 3384 – 3393

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(CH3); IR (CHCl3): n˜ = 765 cm 1 (Ar); HRMS (ES): m/z calcd for C13H11N3 : 209.0953 [M] + ; found: 209.0955.

General procedure for the gold-catalyzed reaction of propargylic hydroperoxides 1 with 1H-indazol-3-amine: Preparation of pyrimido[1,2-b]indazoles 4 [AuCl(PPh3)] (4 mg, 0.0084 mmol), [AgOTf] (2.2 mg, 0.0084 mmol), p-toluenesulfonic acid (5.9 mg, 0.034 mmol), 1H-indazol-3-amine (90.5 mg, 0.68 mmol), and water (12.2 mg, 0.68 mmol) were sequentially added to a stirred solution of the corresponding propargylic hydroperoxide 1 (0.34 mmol) in 1,2-dichloroethane (2.7 mL). The resulting mixture was stirred at 120 8C under microwave irradiation until disappearance of the starting material (TLC). The reaction was allowed to cool to room temperature and filtered through a pack of Celite. Saturated ammonium chloride (0.7 mL) was added, before being partitioned between dichloromethane and water. The organic extract was washed with brine, dried (MgSO4), concentrated under vacuum, and purified by flash column chromatography eluting with ethyl acetate/hexanes mixtures. Spectroscopic and analytical data for pure forms of compounds 4 follow. Pyrimido[1,2-b]indazole 4 a: From propargylic hydroperoxide 1 a (100 mg, 0.56 mmol), and after chromatography of the residue using hexanes/ethyl acetate (3:1) as eluent gave the pyrimido[1,2b]indazole 4 a (109 mg, 71 %) as a yellow solid. M.p. 145–146 8C; 1 H NMR (300 MHz, CDCl3, 25 8C): d = 3.93 (s, 3 H, CH3), 7.13 (d, 2 H, J = 8.9 Hz, PMP), 7.28 (d, 1 H, J = 4.6 Hz, Ar), 7.32 (m, 1 H, Ar), 7.64 (ddd, 1 H, J = 8.5, 6.6, 1.0 Hz, Ar), 7.88 (d, 1H J = 8.7 Hz, Ar), 8.25 (d, 2 H, J = 8.9 Hz, PMP), 8.36 (d, 1 H, J = 8.3 Hz, Ar), 8.66 ppm (d, 1 H, J = 4.5 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 161.8 (OCq), 151.0 (Cq), 145.0 (2Cq), 145.0 (CH Ar), 131.1 (2CH PMP), 129.8 (CH Ar), 123.4 (Cq), 120.8 (CH Ar), 120.7 (CH Ar), 116.4 (CH Ar), 114.2 (2CH PMP), 113.4 (Cq), 110.4 (CH Ar), 55.5 ppm (OCH3); IR (CHCl3): n˜ = 1255 (C O), 750 cm 1 (Ar); HRMS (ES): m/z calcd for C17H13N3O: 275.1059 [M] + ; found: 275.1068. Pyrimido[1,2-b]indazole 4 b: From propargylic hydroperoxide 1 b (30 mg, 0.20 mmol), and after chromatography of the residue using hexanes/ethyl acetate (5:1) as eluent gave the pyrimido[1,2b]indazole 4 b (29 mg, 69 %) as a yellow solid. M.p. 146–147 8C; 1 H NMR (300 MHz, CDCl3, 25 8C): d = 7.33 (d, 1 H, J = 4.5 Hz, Ar), 7.36 (m, 1 H, Ar), 7.63 (m, 3 H, Ph), 7.67 (m, 1 H, Ar), 7.89 (dt, 1H J = 8.7, 0.8 Hz, Ar), 8.22 (m, 2 H, Ph), 8.38 (dt, 1 H, J = 8.3, 1.1 Hz, Ar), 8.71 ppm (d, 1 H, J = 4.5 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 151.0 (Cq), 145.3 (Cq), 145.0 (CH Ar), 134.2 (Cq), 134.0 (Cq), 131.2 (CH Ph), 129.9 (CH Ar), 129.4 (2CH Ph), 128.9 (2CH Ph), 121.0 (CH Ar), 120.8 (CH Ar), 116.5 (CH Ar), 113.4 (Cq), 111.2 ppm (CH Ar); IR (CHCl3): n˜ = 759 cm 1 (Ar); HRMS (ES): m/z calcd for C16H11N3 : 245.0953 [M] + ; found: 245.0958. Pyrimido[1,2-b]indazole 4 c: From propargylic hydroperoxide 1 c (50 mg, 0.22 mmol), and after chromatography of the residue using hexanes/ethyl acetate (5:1) as eluent gave the pyrimido[1,2b]indazole 4 c (61 mg, 85 %) as a yellow solid. M.p. 136–147 8C; 1 H NMR (300 MHz, CDCl3, 25 8C): d = 7.31 (d, 1 H, J = 4.5 Hz, Ar), 7.35 (ddd, 1 H, J = 8.2, 6.7, 0.8 Hz, Ar), 7.66 (ddd, 1 H, J = 8.8, 6.7, 1.1 Hz, Ar), 7.77 (d, 2 H, J = 8.6 Hz, 4-BrPh), 7.88 (d, 1H J = 8.7 Hz, Ar), 8.12 (d, 2 H, J = 8.6 Hz, 4-BrPh), 8.37 (dt, 1 H, J = 8.3, 1.0 Hz, Ar), 8.70 ppm (d, 1 H, J = 4.5 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 151.0 (Cq), 145.1 (Cq), 145.0 (CH Ar), 144.0 (Cq), 132.1 (2CH 4-BrPh), 130.9 (2CH 4-BrPh), 130.0 (CH Ar), 128.3 (Cq), 125.7 (Cq), 121.2 (CH Ar), 120.8 (CH Ar), 116.5 (CH Ar), 113.5 (Cq), 110.9 ppm (CH Ar); IR (CHCl3): n˜ = 750 cm 1 (Ar); HRMS (ES): m/z calcd for C16H10N3Br: 323.0058 [M] + ; found: 323.0045.

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Full Paper Pyrimido[1,2-b]indazole 4 e: From propargylic hydroperoxide 1 e (50 mg, 0.31 mmol), and after chromatography of the residue using hexanes/ethyl acetate (6:1) as eluent gave the pyrimido[1,2b]indazole 4 e (63 mg, 78 %) as a yellow solid. M.p. 157–158 8C; 1 H NMR (300 MHz, CDCl3, 25 8C): d = 2.83 (s, 3 H, CH3), 7.18 (s, 1 H, Ar), 7.27 (ddd, 1 H, J = 8.4, 6.8, 0.8 Hz, Ar), 7.61 (m, 4 H, 3H Ph + 1H Ar), 7.83 (dt, 1H J = 8.8, 0.8 Hz, Ar), 8.17 (m, 2 H, Ph), 8.34 ppm (dt, 1 H, J = 8.3, 1.0 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 155.4 (Cq), 151.2 (Cq), 144.9 (Cq), 144.6 (Cq), 131.4 (Cq), 131.0 (CH Ph), 129.6 (CH Ar), 129.4 (2CH Ph), 128.8 (2CH Ph), 120.9 (CH Ar), 120.4 (CH Ar), 116.4 (CH Ar), 112.8 (Cq), 112.1 (CH Ar), 24.5 ppm (CH3); IR (CHCl3): n˜ = 757 cm 1 (Ar); HRMS (ES): m/z calcd for C17H13N3 : 259.1109 [M] + ; found: 259.1108.

due using ethyl acetate/dichloromethane (0.5:9.5) as eluent gave the dipyrido[1,2-a:3’,2’-d]imidazole 5 e (35 mg, 43 %) as a palebrown solid. M.p. 158–159 8C; 1H NMR (700 MHz, CDCl3, 25 8C): d = 5.19 (s, 3 H, CH3), 7.42 (m, 1 H, Ph), 7.51 (t, 1 H, J = 6.9 Hz, Ar), 7.60 (t, 1 H, J = 7.5 Hz, Ph), 7.70 (t, 1 H, J = 7.7 Hz, Ph), 7.73 (s, 1 H, Ar), 7.86 (d, 1 H, J = 8.3 Hz, Ph), 8.02 (d, 1 H, J = 7.7 Hz, Ph), 8.07 (t, 1 H, J = 7.7 Hz, Ar), 8.94 (d, 1 H, J = 8.8 Hz, Ar), 9.14 ppm (d, 1 H, J = 6.6 Hz, Ar); 13C NMR (175 MHz, CDCl3, 25 8C): d = 153.9 (Cq), 146.2 (Cq), 143.6 (Cq), 138.8 (Cq), 137.4 (Cq), 131.0 (CH Ar), 130.3 (2CH Ph), 129.9 (CH Ph), 127.5 (2CH Ph), 125.1 (CH Ar), 123.7 (CH Ar), 121.4 (Cq), 116.4 (CH Ar), 115.5 (CH Ar), 24.4 ppm (CH3); IR (CHCl3): n˜ = 756 cm 1 (Ar); HRMS (ES): m/z calcd for C17H13N3 : 259.1109 [M] + ; found: 259.1115.

Pyrimido[1,2-b]indazole 4 f: From propargylic hydroperoxide 1 f (50 mg, 0.22 mmol), and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent gave the pyrimido[1,2b]indazole 4 f (50 mg, 70 %) as a yellow solid. M.p. 139–141 8C; 1 H NMR (300 MHz, CDCl3, 25 8C): d = 7.25 (d, 1 H, J = 4.3 Hz, Ar), 7.36 (ddd, 1 H, J = 8.5, 6.8, 0.9 Hz, Ar), 7.58 (m, 4 H, Ar), 7.83 (dd, 1 H, J = 7.9, 1.0 Hz, Ar), 7.88 (dt, 1 H, J = 8.8, 0.8 Hz, Ar), 8.39 ppm (dt, 1 H, J = 8.2, 1.0 Hz, Ar), 8.74 (d, 1 H, J = 4.3 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 151.1 (Cq), 144.5 (CH Ar + Cq), 144.3 (Cq), 133.6 (CH 2-BrPh), 133.0 (Cq), 131.9 (CH 2-BrPh), 131.2 (CH 2-BrPh), 129.9 (CH Ar), 127.7 (CH 2-BrPh), 123.0 (Cq), 121.2 (CH Ar), 120.8 (CH Ar), 116.8 (CH Ar), 113.6 (Cq), 112.9 ppm (CH Ar); IR (CHCl3): n˜ = 753 cm 1 (Ar); HRMS (ES): m/z calcd for C16H10N3Br: 323.0058 [M] + ; found: 323.0047.

Dipyrido[1,2-a:3’,2’-d]imidazole 5 g: From propargylic hydroperoxide 1 g (40 mg, 0.16 mmol), and after chromatography of the residue using hexanes/ethyl acetate (3:1) as eluent gave the dipyrido[1,2-a:3’,2’-d]imidazole 5 g (27 mg, 49 %) as a pale-brown solid. M.p. 162–164 8C; 1H NMR (700 MHz, CDCl3, 25 8C): d = 5.19 (s, 2 H, OCH2), 7.31 (d, 2 H, J = 7.8 Hz, PMP), 7.36 (t, 1 H, J = 7.4 Hz, Ph), 7.43 (t, 2 H, J = 7.5 Hz, Ph), 7.49 (d, 2 H, J = 7.2 Hz, Ph), 7.55 (t, 1 H, J = 6.8 Hz, Ar), 7.83 (d, 1 H, J = 4.9 Hz, Ar), 8.07 (d, 2 H, J = 8.1 Hz, PMP), 8.12 (t, 1 H, J = 7.7 Hz, Ar), 8.71 (d, 1 H, J = 4.9 Hz, Ar), 9.00 (d, 1 H, J = 7.4 Hz, Ar), 9.16 ppm (d, 1 H, J = 6.6 Hz, Ar); 13C NMR (175 MHz, CDCl3, 25 8C): d = 162.2 (OCq), 146.1 (CH Ar), 143.8 (Cq), 139.3 (Cq), 138.5 (Cq), 137.9 (Cq) 136.4 (CH Ar), 135.1 (Cq), 130.6 (2CH PMP), 128.6 (2CH Ph), 128.1 (CH Ph), 127.7 (2CH Ph), 125.2 (CH Ar), 124.7 (Cq), 122.8 (CH Ar), 116.6 (CH Ar), 116.3 (2CH PMP), 115.5 (CH Ar), 70.2 ppm (OCH2); IR (CHCl3): n˜ = 1251 (C O), 750 cm 1 (Ar); HRMS (ES): m/z calcd for C23H17N3O: 351.1372 [M] + ; found: 351.1377.

General procedure for the gold-catalyzed reaction of propargylic hydroperoxides 1 with imidazo[1,2-a]pyridin-3amine: Preparation of dipyrido[1,2-a:3’,2’-d]imidazoles 5 [AuCl(PPh3)] (4 mg, 0.0084 mmol), [AgOTf] (2.2 mg, 0.0084 mmol), p-toluenesulfonic acid (5.9 mg, 0.034 mmol), imidazo[1,2-a]pyridin3-amine (90.5 mg, 0.68 mmol), and water (12.2 mg, 0.68 mmol) were sequentially added to a stirred solution of the corresponding propargylic hydroperoxide 1 (0.34 mmol) in 1,2-dichloroethane (2.7 mL). The resulting mixture was stirred at 120 8C under microwave irradiation until disappearance of the starting material (TLC). The reaction was allowed to cool to room temperature and filtered through a pack of Celite. Saturated ammonium chloride (0.7 mL) was added, before being partitioned between dichloromethane and water. The organic extract was washed with brine, dried (MgSO4), concentrated under vacuum, and purified by flash column chromatography eluting with ethyl acetate/hexanes or ethyl acetate/dichloromethane mixtures. Spectroscopic and analytical data for pure forms of compounds 5 follow. Dipyrido[1,2-a:3’,2’-d]imidazole 5 a: From propargylic hydroperoxide 1 a (50 mg, 0.28 mmol), and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent gave the dipyrido[1,2-a:3’,2’-d]imidazole 5 a (42 mg, 55 %) as a pale-brown solid. M.p. 126–128 8C; 1H NMR (700 MHz, CDCl3, 25 8C): d = 3.93 (s, 3 H, CH3), 7.23 (d, 2 H, J = 7.2 Hz, PMP), 7.55 (t, 1 H, J = 6.6 Hz, Ar), 7.84 (d, 1 H, J = 4.5 Hz, Ar), 8.07 (d, 2 H, J = 7.0 Hz, PMP), 8.12 (m, 1 H, Ar), 8.71 (d, 1 H, J = 4.5 Hz, Ar), 9.01 (d, 1 H, J = 6.4 Hz, Ar), 9.16 ppm (d, J = 6.4 Hz, Ar); 13C NMR (175 MHz, CDCl3, 25 8C): d = 162.0 (OCq), 146.1 (CH Ar), 143.9 (Cq), 139.3 (Cq), 138.6 (Cq), 137.9 (CH Ar), 132.1 (Cq), 130.6 (2CH PMP), 125.2 (CH Ar), 124.5 (Cq), 122.7 (CH Ar), 116.6 (CH Ar), 115.5 (2CH PMP + CH Ar), 55.6 ppm (OCH3); IR (CHCl3): n˜ = 1255 (C O), 759 cm 1 (Ar); HRMS (ES): m/z calcd for C17H13N3O: 275.1059 [M] + ; found: 275.1055. Dipyrido[1,2-a:3’,2’-d]imidazole 5 e: From propargylic hydroperoxide 1 e (50 mg, 0.31 mmol), and after chromatography of the resiChem. Eur. J. 2014, 20, 3384 – 3393

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General procedure for the gold-catalyzed reaction of propargylic hydroperoxides 1 with 1H-indol-2-amine: Preparation of a-carbolines 6 and benzo[cd]indol-2-amines 7 [AuCl(PPh3)] (2.7 mg, 0.0054 mmol), [AgOTf] (1.4 mg, 0.0054 mmol), p-toluenesulfonic acid (3.8 mg, 0.022 mmol), 1H-indol-2-amine (58.2 mg, 0.44 mmol), and water (7.9 mg, 0.44 mmol) were sequentially added to a stirred solution of the corresponding propargylic hydroperoxide 1 (0.22 mmol) in 1,2-dichloroethane (1.8 mL). The resulting mixture was stirred at 120 8C under microwave irradiation until disappearance of the starting material (TLC). The reaction was allowed to cool to room temperature and filtered through a pack of Celite. Saturated ammonium chloride (0.5 mL) was added, before being partitioned between dichloromethane and water. The organic extract was washed with brine, dried (MgSO4), concentrated under vacuum, and purified by flash column chromatography eluting with ethyl acetate/hexane mixtures. Spectroscopic and analytical data for pure forms of compounds 6 and 7 follow.

Treatment of hydroperoxide 1 a with 1H-indol-2-amine From hydroperoxide 1 a (40 mg, 0.22 mmol), and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent, 18 mg (30 %) of the less polar compound 6 a and 17 mg (28 %) of the more polar compound 7 a were obtained. a-Carboline 6 a: Red solid. M.p. 143–145 8C; 1H NMR (700 MHz, CDCl3, 25 8C): d = 3.91 (s, 3 H, OCH3), 7.14 (d, 2 H, J = 8.8 Hz, PMP), 7.44 (m, 1 H, Ar), 7.63 (m, 2 H, Ar), 7.68 (d, 1 H, J = 8.1 Hz, Ar), 8.10 (d, 1 H, J = 7.8 Hz, Ar), 8.16 (d, 2 H, J = 8.8 Hz, PMP), 8.67 (d, 1 H, J = 8.1 Hz, Ar), 11.65 ppm (br s, 1 H, NH); 13C NMR (175 MHz, CDCl3, 25 8C): d = 162.7 (OCq), 145.6 (Cq), 145.1 (Cq), 138.7 (Cq), 135.0 (CH Ar), 130.2 (Cq), 129.4 (CH Ar), 129.3 (2CH PMP), 122.8 (CH Ar), 121.2 (CH Ar), 119.4 (Cq), 119.3 (Cq), 115.5 (2CH PMP), 113.1 (CH Ar), 111.7

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Full Paper (CH Ar), 55.6 ppm (OCH3); IR (CHCl3): n˜ = 3223 (NH), 1254 (C O), 748 cm 1 (Ar); HRMS (ES): m/z calcd for C18H14N2O: 274.1106 [M] + ; found: 274.1102. Benzo[cd]indol-2-amine 7 a: Red solid. M.p. 137–138 8C; 1H NMR (700 MHz, CDCl3, 25 8C): d = 3.95 (s, 3 H, OCH3), 7.13 (d, 2 H, J = 8.7 Hz, PMP), 7.16 (d, 1 H, J = 5.4 Hz, Ar), 7.48 (t, 1 H, J = 7.3 Hz, Ar), 7.56 (d, 1 H, J = 8.1 Hz, Ar), 7.66 (d, 2 H, J = 8.6 Hz, PMP), 7.79 ppm (d, 1 H, J = 8.0 Hz, Ar), 8.39 (d, 1 H, J = 5.3 Hz, Ar); 13C NMR (175 MHz, CDCl3, 25 8C): d = 161.3 (NCq), 160.6 (OCq), 149.7 (Cq), 147.8 (Cq), 140.7 (CH Ar), 138.7 (Cq), 130.0 (2CH PMP), 127.7 (CH Ar), 122.7 (CH Ar), 120.6 (CH Ar), 120.3 (Cq), 115.6 (Cq), 114.6 (Cq), 114.3 (2CH PMP), 111.7 (CH Ar), 55.4 ppm (OCH3); IR (CHCl3): n˜ = 3145 (NH2), 1252 (C O), 746 (Ar) cm 1; HRMS (ES): m/z calcd for C18H14N2O: 274.1106 [M] + ; found: 274.1094.

Treatment of hydroperoxide 1 f with 1H-indol-2-amine From hydroperoxide 1 f (50 mg, 0.22 mmol), and after chromatography of the residue using hexanes/ethyl acetate (5:1) as eluent, 18 mg (26 %) of the less polar compound 6 f and 16 mg (23 %) of the more polar compound 7 f were obtained. a-Carboline 6 f: Red solid. M.p. 97–98 8C; 1H NMR (700 MHz, CDCl3, 25 8C): d = 7.40 (m, 2 H, Ar + 2-BrPh), 7.50 (d, 1 H, J = 8.1 Hz, 2-BrPh), 7.52 (t, 1 H, J = 7.4 Hz, Ar), 7.58 (t, 1 H, J = 8.1 Hz, Ar), 7.61 (d, 1 H, J = 7.8 Hz, Ar), 7.72 (dd, 1 H, J = 6.4, 1.3 Hz, 2-BrPh), 7.78 (d, 1 H, J = 8.0 Hz, 2-BrPh), 8.13 (d, 1 H, J = 7.8 Hz, Ar), 8.61 ppm (d, 1 H, J = 7.8 Hz, Ar); 13C NMR (175 MHz, CDCl3, 25 8C): d = 144.4 (Cq), 144.2 (Cq), 139.1 (Cq), 134.0 (CH Ar), 133.5 (CH 2-BrPh), 132.4 (CH 2-BrPh), 131.8 (2-BrPh), 129.7 (CH Ar), 128.2 (Cq), 127.0 (CH 2-BrPh), 125.4 (Cq), 124.6 (Cq), 122.2 (CH Ar), 121.4 (CH Ar), 116.7 (CH Ar), 112. ppm (CH Ar); IR (CHCl3): n˜ = 3210 (NH), 751 cm 1 (Ar); HRMS (ES): m/z calcd for C17H11N2Br: 322.0106 [M] + ; found: 322.0107. Benzo[cd]indol-2-amine 7 f: Red solid. M.p. 128–129 8C; 1H NMR (700 MHz, CDCl3, 25 8C): d = 7.07 (t, 1 H, J = 7.5 Hz, 2-BrPh), 7.14 (m, 1 H, Ar), 7.44 (m, 1 H, Ar), 7.47 (m, 2 H, 2-BrPh), 7.52 (td, 1 H, J = 7.4, 0.8 Hz, 2-BrPh), 7.56 (d, 1 H, J = 8.1 Hz, Ar), 7.84 (d, 1 H, J = 7.7 Hz, Ar), 8.56 ppm (d, 1 H, J = 4.8 Hz, Ar); 13C NMR (175 MHz, CDCl3, 25 8C): d = 151.4 (NCq), 144.5 (Cq), 143.5 (CH Ar), 139.2 (Cq), 138.9 (Cq), 133.2 (CH 2-BrPh), 130.4 (CH 2-BrPh), 130.1 (CH 2-BrPh), 127.7 (CH Ar), 127.2 (CH 2-BrPh), 122.5 (CH Ar), 122.3 (Cq), 120.4 (Cq), 120.3 (CH Ar), 116.4 (Cq), 115.3 (Cq), 111.4 ppm (CH Ar); IR (CHCl3): n˜ = 3156 (NH2), 747 cm 1 (Ar); HRMS (ES): m/z calcd for C17H11N2Br: 322.0106 [M] + ; found: 322.0102.

Treatment of hydroperoxide 1 g with 1H-indol-2-amine From hydroperoxide 1 g (45 mg, 0.18 mmol), and after chromatography of the residue using hexanes/ethyl acetate (6:1) as eluent, 15 mg (24 %) of the less polar compound 6 g and 16 mg (25 %) of the more polar compound 7 g were obtained. a-Carboline 6 g: Red solid. M.p. 87–89 8C; 1H NMR (700 MHz, CDCl3, 25 8C): d = 5.18 (s, 2 H, OCH2), 7.21 (d, 2 H, J = 8.8 Hz, BnOPh), 7.43 (m, 6 H, Ph + Ar), 7.65 (m, 2 H, Ar), 7.68 (d, 1 H, J = 8.1 Hz, Ar), 8.11 (d, 1 H, J = 7.8 Hz, Ar), 8.16 (d, 2 H, J = 8.8 Hz, BnOPh), 8.69 (d, 1 H, J = 8.1 Hz, Ar), 11.83 ppm (br s, 1 H, NH); 13C NMR (175 MHz, CDCl3, 25 8C): d = 161.9 (OCq), 145.4 (Cq), 145.0 (Cq), 138.8 (Cq), 136.0 (Cq), 135.1 (CH Ar), 129.5 (CH Ar), 129.3 (2CH BnOPh), 128.8 (2CH Ph), 128.3 (CH Ph), 127.5 (2CH Ph), 127.5 (Cq), 122.9 (CH Ar), 121.2 (CH Ar), 119.6 (Cq), 119.3 (Cq), 116.3 (2CH BnOPh), 113.1 (CH Ar), 111.7 (CH Ar), 70.3 ppm (OCH2); IR (CHCl3): n˜ = 3220 (NH), 1249 (C O), 744 cm 1 (Ar); HRMS (ES): m/z calcd for C24H18N2O: 350.1419 [M] + ; found: 350.1424. Chem. Eur. J. 2014, 20, 3384 – 3393

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Benzo[cd]indol-2-amine 7 g: Red solid. M.p. 139–141 8C; 1H NMR (700 MHz, CDCl3, 25 8C): d = 5.22 (s, 2 H, OCH2), 7.18 (t, 1 H, J = 7.6 Hz, Ar), 7.21 (d, 2 H, J = 8.4 Hz, BnOPh), 7.37 (m, 1 H, Ar), 7.39 (m, 1 H, Ph), 7.45 (t, 2 H, J = 7.5 Hz, Ph), 7.52 (d, 2 H, J = 8.1 Hz, Ph), 7.53 (m, 1 H, Ar), 7.67 (d, 2 H, J = 8.3 Hz, BnOPh), 7.82 (d, 1 H, J = 8.0 Hz, Ar), 8.34 ppm (br s, 1 H, Ar); 13C NMR (175 MHz, CDCl3, 25 8C): d = 164.9 (NCq), 160.2 (OCq), 149.3 (Cq), 145.0 (Cq), 138.8 (CH Ar), 136.4 (Cq), 133.0 (Cq), 130.1 (2CH BnOPh), 128.7 (2CH Ph), 128.4 (CH Ar), 128.3 (CH Ph), 127.6 (2CH Ph), 122.7 (CH Ar), 121.3 (CH Ar), 119.9 (Cq), 116.3 (Cq), 116.2 (Cq), 115.4 (2CH BnOPh), 112.3 (CH Ar), 70.2 ppm (OCH2); IR (CHCl3): n˜ = 3210 (NH2), 1244 (C O), 745 cm 1 (Ar); HRMS (ES): m/z calcd for C24H18N2O: 350.1419 [M] + ; found: 350.1410. a-Carboline 6 h: From propargylic hydroperoxide 1 h (50 mg, 0.25 mmol), and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent gave the a-carboline 6 h (23 mg, 34 %) as a pale-brown solid. M.p. 115–152 8C; 1H NMR (700 MHz, CDCl3, 25 8C): d = 4.64 (d, 2 H, J = 5.3 Hz, OCH2), 5.35 (dd, 1 H, J = 10.5, 1.3 Hz, =CHH), 5.47 (dd, 1 H, J = 17.3, 1.4, Hz, =CHH), 6.09 (ddt, 1 H, J = 17.2, 10.6, 5.3 Hz, =CH), 7.13 (d, 2 H, J = 8.8 Hz, allylO-Ph), 7.41 (m, 1 H, Ar), 7.58 (m, 2 H, Ar), 7.66 (d, 1 H, J = 8.1 Hz, Ar), 8.09 (d, 1 H, J = 7.8 Hz, Ar), 8.13 (d, 2 H, J = 8.8 Hz, allylO-Ph), 8.60 ppm (d, 1H J = 8.1 Hz, Ar); 13C NMR (175 MHz, CDCl3, 25 8C): d = 161.1 (OCq), 147.5 (Cq), 146.7 (Cq), 138.7 (Cq), 133.5 (CH Ar), 132.5 (= CH), 132.4 (Cq), 129.0 (2CH allylO-Ph), 128.7 (CH Ar), 122.2 (CH Ar), 121.1 (CH Ar), 119.8 (Cq), 118.3 (= CH2), 118.0 (Cq), 115.9 (2CH allylO-Ph), 112.6 (CH Ar), 111.9 (CH Ar), 69.0 ppm (OCH2); IR (CHCl3): n˜ = 3207 (NH), 1247 (C O), 745 cm 1 (Ar); HRMS (ES): m/z calcd for C20H16N2O: 300.1263 [M] + ; found: 300.1257.

General procedure for the gold-catalyzed reaction of propargylic hydroperoxides 1 with N-benzoyliminopyridinium ylides: Preparation of fused pyrazoles 9–11 [AuCl(PPh3)] (4 mg, 0.0084 mmol), [AgOTf] (2.2 mg, 0.0084 mmol), p-toluenesulfonic acid (5.9 mg, 0.034 mmol), the appropriate Nbenzoyliminopyridinium ylide (0.68 mmol), and water (12.2 mg, 0.68 mmol) were sequentially added to a stirred solution of the corresponding propargylic hydroperoxide 1 (0.34 mmol) in 1,2-dichloroethane (2.7 mL). The resulting mixture was stirred at 120 8C under microwave irradiation until disappearance of the starting material (TLC). The reaction was allowed to cool to room temperature and filtered through a pack of Celite. Saturated ammonium chloride (0.7 mL) was added, before being partitioned between dichloromethane and water. The organic extract was washed with brine, dried (MgSO4), concentrated under vacuum, and purified by flash column chromatography eluting with ethyl acetate/hexanes or ethyl acetate/dichloromethane mixtures. Spectroscopic and analytical data for pure forms of compounds 9–11 follow. Pyrazolo[1,5-a]pyridine 9: From propargylic hydroperoxide 1 b (50 mg, 0.34 mmol), and after chromatography of the residue using ethyl acetate/dichloromethane (1:9) as eluent gave the fused pyrazole 9 (31 mg, 41 %) as a pale-brown solid. M.p. 98–100 8C; 1 H NMR (300 MHz, CDCl3, 25 8C): d = 7.22 (dd, 1 H, J = 7.7, 0.9 Hz, Ar), 7.62 (m, 5 H, 3H Ph + 2H Ar), 7.95 (m, 2 H, Ph), 8.40 (br s, 1 H, Ar), 8.64 ppm (d, 1 H, J = 8.4 Hz, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 190.3 (C=O), 146.9 (Cq), 140.7 (CH Ar), 134.4 (CH Ar), 133.7 (Cq), 132.7 (CH Ar), 132.2 (CH Ph), 129.1 (2CH Ph), 127.2 (2CH Ph), 124.2 (CH Ar), 122.8 (Cq), 121.0 ppm (CH Ar); IR (CHCl3): n˜ = 1661 (C=O), 709 cm 1 (Ar); HRMS (ES): m/z calcd for C14H10N2O: 222.0793 [M] + ; found: 222.0787. Pyrazolo[1,5-a]quinoline 10: From propargylic hydroperoxide 1 a (50 mg, 0.28 mmol), and after chromatography of the residue

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Full Paper using ethyl acetate/dichloromethane (0.5:9.5) as eluent gave the fused pyrazole 10 (40 mg, 48 %) as a pale-brown solid. M.p. 127– 128 8C; 1H NMR (300 MHz, CDCl3, 25 8C): d = 3.93 (s, 3 H, OCH3), 7.04 (d, 2 H, J = 8.8 Hz, PMP), 7.58 (ddd, 1 H, J = 8.0, 7.3, 1.2 Hz, Ar), 7.79 (d, 1 H, J = 9.2 Hz, Ar), 7.79 (ddd, 1 H, J = 8.5, 7.3, 1.5 Hz, Ar), 7.89 (d, 1 H, J = 7.8 Hz, Ar), 7.95 (d, 2 H, J = 8.8 Hz, PMP), 8.31 (d, 1H J = 9.3 Hz, Ar), 8.36 (s, 1 H, Ar), 8.68 ppm (d, 1 H, J = 8.5 Hz, Ar); 13 C NMR (75 MHz, CDCl3, 25 8C): d = 188.4 (C=O), 162.8 (OCq), 144.4 (CH Ar), 139.9 (Cq), 134.2 (Cq), 132.4 (Cq), 131.2 (2CH PMP), 130.3 (CH Ar), 128.9 (CH Ar), 128.5 (CH Ar), 125.8 (CH Ar), 124.1 (Cq), 117.5 (CH Ar), 116.1 (CH Ar), 114.2 (Cq), 113.8 (2CH PMP), 55.5 ppm (OCH3); IR (CHCl3): n˜ = 1604 (C=O), 1255 (C O), 686 cm 1 (Ar); HRMS (ES): m/z calcd for C19H14N2O2 : 302.1055 [M] + ; found: 302.1045.

[4]

[5]

Pyrazolo[5,1-a]isoquinoline 11 a: From propargylic hydroperoxide 1 a (50 mg, 0.28 mmol), and after chromatography of the residue using hexanes/ethyl acetate (4:1) as eluent gave the fused pyrazole 11 a (58 mg, 69 %) as a pale-brown solid. M.p. 134–135 8C; 1H NMR (300 MHz, CDCl3, 25 8C): d = 3.92 (s, 3 H, OCH3), 7.03 (d, 2 H, J = 8.9 Hz, PMP), 7.27 (d, 1 H, J = 7.3 Hz, Ar), 7.66 (m, 2 H, Ar), 7.81 (m, 1 H, Ar), 7.96 (d, 2 H, J = 8.8 Hz, PMP), 8.17 (s, 1 H, Ar), 8.36 (d, 1 H, J = 7.3 Hz, Ar), 9.21 ppm (m, 1 H, Ar); 13C NMR (75 MHz, CDCl3, 25 8C): d = 189.2 (C=O), 163.1 (OCq), 146.2 (CH Ar), 146.0 (Cq), 132.6 (Cq), 132.1 (2CH PMP), 131.0 (Cq), 130.5 (Cq), 129.6 (CH Ar), 128.0 (CH Ar), 127.1 (CH Ar), 127.0 (CH Ar), 126.1 (CH Ar), 124.5 (Cq), 115.1 (CH Ar), 113.7 (2CH PMP), 55.5 ppm (OCH3); IR (CHCl3): n˜ = 1634 (C= O),1256 (C O), 764 cm 1 (Ar); HRMS (ES): m/z calcd for C19H14N2O2 : 302.1055 [M] + ; found: 302.1047.

[6]

[7]

Pyrazolo[1,5-a]quinoline 11 b: From propargylic hydroperoxide 1 b (50 mg, 0.34 mmol), and after chromatography of the residue using hexanes/ethyl acetate (6:1) as eluent gave the fused pyrazole 11 b (49 mg, 53 %) as a pale-brown solid. M.p. 158–160 8C; 1H NMR (700 MHz, CDCl3, 25 8C): d = 7.31 (d, 1 H, J = 7.2 Hz, Ar), 7.55 (t, 2 H, J = 7.7 Hz, Ph), 7.63 (t, 1 H, J = 7.4 Hz, Ph), 7.70 (m, 2 H, Ar), 7.84 (m, 1 H, Ar), 7.94 (m, 1 H, Ph), 8.17 (s, 1 H, Ar), 8.37 (d, 1 H, J = 7.2 Hz, Ar), 9.49 ppm (d, 1 H, J = 7.9 Hz, Ar); 13C NMR (175 MHz, CDCl3, 25 8C): d = 190.3 (C=O), 147.0 (CH Ar + Cq), 140.2 (Cq), 132.2 (CH Ph), 131.7 (Cq), 130.7 (Cq), 129.8 (CH Ar), 129.7 (2CH Ph), 128.4 (2CH Ph), 128.1 (CH Ar), 127.3 (CH Ar), 127.1 (CH Ar), 126.2 (CH Ar), 124.5 (Cq), 115.4 ppm (CH Ar); IR (CHCl3): n˜ = 1641 (C=O), 697 cm 1 (Ar); HRMS (ES): m/z calcd for C18H12N2O: 272.0950 [M] + ; found: 272.0955.

[8] [9]

Acknowledgements Support for this work by MINECO (projects CTQ2012–33664C02–01 and CTQ2012–33664-C02–02) and Comunidad Autnoma de Madrid (project S2009/PPQ-1752) are gratefully acknowledged. M.T.Q. thanks the MEC for a predoctoral grant. [10]

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