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Original article
11 (
3
); 415-425
doi:
10.1016/j.arabjc.2016.11.001

Syntheses of non-aromatic medium and large rings synthesized via phenylnitrenium ions

, , , ,
a Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Via do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil
b Departamento de Farmácia, Faculdade de Ciências Biológicas e da Saúde, Universidade Federal dos Vales do Jequitinhonha e Mucuri, Campus JK, Rodovia MGT 367 – Km 583, Alto da Jacuba, 39.100-000 Diamantina, MG, Brazil
c Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes 3900, 14040-901 Ribeirão Preto, SP, Brazil
d Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja s/n, 18071 Granada, Spain
e Instituto Biosanitario de Granada (ibs.GRANADA), SAS-Universidad de Granada, Granada, Spain

⁎Corresponding authors at: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja s/n, 18071 Granada, Spain (J.M. Campos). ginodpnt@fcfrp.usp.br (Gino Del Ponte), jmcampos@ugr.es (Joaquín M. Campos)

Received: , Accepted: ,
© The Author(s) 2016
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Abstract

We describe the preparation of m- and p-substituted phenyl azides which, on treatment with trifluoromethanesulfonic acid in chloroform (and only in one case, after adding trifluoroacetic acid) at 0 °C, gives rise to the intermediate phenylnitrenium ions that undergo intramolecular cyclization to give six-, eight-membered carbocycles, and ten-membered heterocycles. Intramolecular cyclization of 1-(4-azidophenyl)-4-phenylbutane (3b) gives direct access to the 1,2,3,4-tetrahydronaphthalene lignan scaffold with a good yield. When the same reaction is carried out on 1-(3-azidophenyl)-4-phenylbutane (3a), the meta isomer of 3b, the 3-aminodibenzo[a,c]cyclooctadiene is obtained with a modest yield. When an ethoxycarbonyl group is introduced at position two of the butene chain [16a, as an E/Z mixture (1/4)], the ethyl 3-aminobenzo[a,c]octatriene carboxylate was the major compound, and the 10-membered heterocycle the minor one, both derived from (E)-16a. Finally, when a methyl group is located at the para position of the azido group [(E)-16b], cyclization involves the carbon atom ortho to the nitrogen atom and the ethyl 4-methyl-1-tosylaminobenzo[a,c]octatriene carboxylate is the only compound obtained, after treatment with tosyl chloride. With all these structural changes, we have switched over from the formation of mixtures of compounds to the regioselective formation of the target molecule, suggesting the corresponding mechanism of reaction and expanding the knowledge of this type of reaction.

Keywords

Anilines
Aryl azides
Cyclization
Large rings
Medium rings
Nitroarenes
Phenylnitrenium
1

1 Introduction

The chemistry of nitrenium ions has received increasing attention from theoretical, synthetic, and biological perspectives (Abramovitch and Davis, 1964; Gassman, 1970; Abramovitch, 1973; Abramovitch and Jeyaraman, 1984; Scriven and Turnbull, 1988; Simonova et al., 1992; McClelland, 1996; Novak and Lin, 1999; Falvey, 2000; Novak and Rajagopal, 2001; Srivastava et al., 2000; McIlroy and Falvey, 2001; Chiapperino et al., 2002; Kralík et al., 2015; Zhang et al., 2013). Nitrenium ions are short-lived, electrophilic reactive intermediates with the general structure RR′N+, which are isoelectronic with carbenium ions, and can exist in the singlet or the triplet state. Phenylnitrenium ions, which contain the positive charge delocalized throughout the aromatic ring, are well known but little utilized in fine chemical synthesis. Phenyl substitution of the parent nitrenium ion is stabilized, with the result that the singlet state is 87.9 kJ/mol more stable than the corresponding triplet (Ford and Herman, 1989; Falvey and Cramer, 1992; Cramer et al., 1994a). Singlet arylnitrenium ions are known to react with nucleophiles through addition mechanisms, and with aromatic systems through addition or mechanisms, while triplet nitrenium ions abstract hydrogen atoms to give amines (Cramer et al., 1994b).

We initiated our studies on acid-catalyzed intramolecular cyclizations of aryl olefins containing an azidophenyl group as an approach for the preparation of macrocyclic compounds (Abramovitch et al., 1996). Abramovitch and co-workers reported that intramolecular remote functionalization by arylnitrenium ions is a useful and versatile method for forming six- (Abramovitch et al., 1982, 1989, 2000) and seven-membered (Abramovitch et al., 1985) homo- and heterocyclic rings (Abramovitch, 1973; Abramovitch et al., 1982, 1985, 1986a, 1986b, 1989, 2000; de Souza et al., 1994; Abramovitch and Ye, 1999; Abramovitch and Shi, 1994), five- and six-membered lactones (Abramovitch et al., 1982, 1986b), dihydrophenanthridines and benzochromans (Abramovitch et al., 1986a), dehydroxepines (De Souza et al., 1994), and macrocyclic compounds (Abramovitch et al., 1989, 2000; Abramovitch and Ye, 1999; Abramovitch and Shi, 1994). The intramolecular arylations involve the trapping of aryl nitrenium ions by an internal nucleophile (Abramovitch et al., 1988). Propensity of the aryl nitrenium ion to be trapped by an internal nucleophile is explained by the delocalization of the positive change at positions ortho and para. This results in an intramolecular interaction between the charged ring and the electronic pair of the nucleophile. Typically, reactions occur at the para, ortho, or nitrogen atoms, often leading to a mixture of products (Abramovitch et al., 1989; Ohta et al., 1985; Okamoto and Shudo, 1973). Huh and Aubé have described that the N-alkyl-N-arylaminodiazonium ion loses nitrogen to generate an arylnitrenium species which then reacts with a α,α-disubstituted acetonitrile at the either para- or meta-position of the aromatic ring (Huh and Aubé, 2014). A number of ab initio calculations (Novak and Lin, 1999; Ford and Herman, 1989, 1991; Falvey and Cramer, 1992; Cramer et al., 1994a, 1994b; Anderson et al., 1993; Srivastava and Falvey, 1995; Li et al., 1989; Sullivan et al., 1998) have confirmed this. These reactions have the potential of leading to cyclic systems not easily accessed by other routes. An interesting review of the corresponding intramolecular cyclizations to give N-heterocycles via nitrene and nitrenoid intermediates has been published by Söderberg (2000).

On the other hand, from a biological point of view nitrenium ions play a major role in DNA damage caused by enzymatically activated arylamine carcinogens. Novak and Zhang state that the knowledge and expertise gained from the understanding of the biological and chemical basis for the deleterious effects of arylamine carcinogens can be put to therapeutic use to treat the same diseases, of which arylamines and heterocyclic amines have been shown to be the cause (Novak and Zhang, 2012). We report herein the formation of a number of medium-sized and large rings by the intramolecular cyclization of phenylnitrenium ions.

2

2 Results and discussion

The azido compounds 3a,b, 6a, and 16a,b were prepared by the complementary routes outlined in Schemes 1, 2 and 6. The aromatic azido group was introduced by two successive reactions: (a) reduction in the nitro group into the amine; and (b) formation of the diazonium salt and subsequent nucleophilic displacement with sodium azide (Abramovitch et al., 2003).

Syntheses of azides 3a and 3b.
Scheme 1 Syntheses of azides 3a and 3b.
Syntheses of azide (Z)-6a.
Scheme 2 Syntheses of azide (Z)-6a.

Azide 3a was synthesized according to the sequence shown in Scheme 1. The unsaturated (Z)-azide 6a (Scheme 2) was obtained in a 43% yield from the corresponding (Z)-amine 5a, which was prepared in good yield by a cross-coupling reaction between (Z)-β-bromo-3-nitrostyrene and 2-phenylethylzinc chloride, catalyzed by Pd(PPh3)4 (Del Ponte et al., 2003), followed by the chemoselective reduction of the nitro group. Compound (E)-1b was prepared according to protocols published by Saxena and Lam (2011), and after following the same reactions carried out on 1a and 2a, the azido compound 3a was obtained (Scheme 1). Moreover, compound 2a was prepared by hydrogenation of 4 (Agnihotri et al., 2015), with an excellent yield (94%).

When the 4-substituted aryl azide 3b was treated with 1 equivalent of trifluoromethanesulfonic acid (TfOH) in CHCl3 at 0 °C (molar ratio TfOH/3b = 1:1), the very stable fused six-membered ring product 7 (89%) was obtained after 2 h of reaction. When the molar ratio TfOH/3b was 2:1 the yield of 7 was the same, and the only difference was the reaction time that was reduced to several minutes. When a ratio TfOH/3b ≪ 1 (i.e., catalytic quantities of TfOH) was used, decomposition of azide was slow and gave rise to numerous products, whose separations resulted useless. The utilization of TfOH/trifluoroacetic acid (TFA) at 0 °C also produced a rapid decomposition of the azide, but instead of 7, a material of resinous appearance was observed, suggesting the predominance of competitive polymerization reactions in this reaction medium. Product 7 was assigned the 1,2,3,4-tetrahydronaphthalene structure based mainly on its spectral properties [IR 3460 and 3380 cm−1 (NH2), and its parent ion peak at m/z 223 (M+) suggested the structure of 4-(1,2,3,4-tetrahydronaphthalen-1-yl)aniline]. NMR spectroscopy further confirmed the assignments. When a catalytic quantity of TfOH was used, decomposition of 3b was slow, and favored the formation of numerous products whose purifications resulted impossibly. The cyclization probably ensues after abstraction of the benzylic proton by TfO−, leading to a delocalized 4-methylene-2,5-cyclohexadien-1-iminium ion (SN1-like mechanism), followed by the intramolecular nucleophilic Michael addition of the nearby phenyl ring located at position 4 of the aliphatic chain, as depicted in Scheme 3; nevertheless, we do not exclude the possibility that the cyclization process begins before the nitrenium ion is completely formed, which would imply an intermediate mechanism between SN1-like and SN2-like processes.

Proposed mechanism for the conversion of 3b into 7 with TfOH in CHCl3, at 0 °C.
Scheme 3 Proposed mechanism for the conversion of 3b into 7 with TfOH in CHCl3, at 0 °C.

Treatment of the meta-substituted aryl azide 3a with TfOH/TFA, at 0 °C gave 8 (Abramovitch et al., 2003) (10%, and with an extensive formation of resinous material) as shown in Scheme 4; nevertheless, 3a does not suffer any transformation when treated with TfOH in CHCl3, at 0 °C. The reaction took place slowly when the CHCl3 was substituted by TFA, giving rise to 8 (10%).

Synthesis of cyclooctadiene 8.
Scheme 4 Synthesis of cyclooctadiene 8.

Initially, decomposition of azide (Z)-6a was carried out with TfOH in CHCl3 at 0 °C (using a molar ratio TfOH/6a = 1:1), and no transformation was observed after several hours of reaction. On the contrary, the (Z)-azide 6a reacted rapidly by using 1 equivalent of TFA was added to the previous solution and the reaction was completed in only a couple of min. The same results were observed when TFA in CHCl3, in both 1:1 and 2:1 ratios in relation to the azide. In all these cases, a mixture of cyclic structures was attained with a global yield of 85%: the dibenzo[a,c]cycloctatrienes 9 (28%) and 10 (25%), as well as the ten-membered heterocycle 11 (32%), after a flash column chromatography, and treating each of the fractions with an excess of tosyl chloride. In principle, these results might be explained by the Z configuration of azide 6a, that would produce a more favorable entropic contribution to the cyclization process. Compound 9 was formed by intramolecular nucleophilic attack to the para position in relation to the nitrogen functionality, while in the formation of 10 the attack occurred at the aromatic carbon located in between the ones that are linked to the azido and alkenyl groups. Moreover, compound 11 was formed by an intramolecular nucleophilic attack to the nitrenium ion to form a C–N bond, as depicted in Scheme 5.

Reactivity of (Z)-6a.
Scheme 5 Reactivity of (Z)-6a.

Products 9, 10 and 11 were characterized by 1H and 13C NMR, MS, IR and elemental analyses.

Taking 6a as a model, we decided to study the following two structural modifications: (a) the presence of a strong electron-withdrawing group, such as the ethoxycarbonyl group, in the exocyclic double bond, having the para position in relation to the azido group free, or (b) blocked by a methyl group. The approach to the preparation of compounds 16a,b is shown in Scheme 6. The 3-azidophenyl-α,β-unsaturated ester 16a (R = H) was prepared as an E/Z mixture (1/4) according to the sequence of the classical reactions depicted in Scheme 6. All the attempts to separate (E)- and (Z)-14a-16a were unsuccessful.

Synthesis of the ten-membered dibenzo-fused heterocycle 17, the dibenzo-fused octatriene 18, and the 2H-1-benzopyran-2-one 19 (from 16a, as an E/Z: 1/4 mixture), or the dibenzo-fused octatriene 20 [from (E)-16b].
Scheme 6 Synthesis of the ten-membered dibenzo-fused heterocycle 17, the dibenzo-fused octatriene 18, and the 2H-1-benzopyran-2-one 19 (from 16a, as an E/Z: 1/4 mixture), or the dibenzo-fused octatriene 20 [from (E)-16b].

An important aspect is related to the different cyclization reaction speeds when 6a was compared to 16a. Under the same experimental conditions 16a reacted well, although more slowly than 6a, giving rise preferably to the cyclization process (18) by nucleophilic attack of a phenyl group on the para position of the azido group of 16a.

Products 17 and 18 were derived from (E)-16a, while 19 proceeded from isomer (Z)-16a. Formation of 19 is explained in Scheme 7, in which the para position of the imino group suffers a nucleophilic attack by the carbonyl group of the ethoxycarbonyl functionality to give the 6-amino-3-phenethyl-2H-1-benzopyran-2-one 19.

Proposed mechanism for the formation of 19.
Scheme 7 Proposed mechanism for the formation of 19.

The presence of a methyl group in para position in relation to the azido group makes the reaction regioselective, and the benzo-fused octatriene 20 (54%) was the only compound obtained. The presence of the ethoxycarbonyl group might trigger a different mechanism of reaction: in fact, the ethoxycarbonyl group is more basic than the azido group and a carbenium ion might be preferably produced through the conjugation of the ethoxycarbonyl moiety with the azidophenyl ring, according to Scheme 8. The reaction of (E)-16b with TfOH/CHCl3 at 0 °C (molar ratio TfOH/(E)-16b = 1.6/1) gave a residue, which was cumbersome and difficult to purify: after a flash column chromatography, recrystallization from EtOH, the ethyl 4-tosylaminodibenzo[a,c]cycloctatriene-9-carboxylate 20 was isolated. The starting azide (E)-16b was prepared as illustrated in Scheme 6.

Proposed mechanism for the formation of 20.
Scheme 8 Proposed mechanism for the formation of 20.

According to Scheme 8, the methyl group simply blocks position para in relation to the nitrenium ion, and thus favoring the nucleophilic attack of the electronic pair of the other benzene ring to the carbenium ion, located in its ortho position.

Analyzing all these data as a whole, the following can be stated from our studies via phenylnitrenium ions:

  1. Intramolecular cyclization of 1-(p-azidophenyl)-4-phenylbutane (3b) with TfOH in CHCl3 at 0 °C gave direct access to the 1-(4-aminophenyl)-1,2,3,4-tetrahydronaphthalene (7) with a good yield (89%).

  2. When the same reaction is carried out on 1-(3-azidophenyl)-4-phenylbutane (3a), the meta isomer of 3b, 3-aminodibenzo[a,c]cyclooctadiene (8) was obtained with a very modest yield (10%), by using TfOH/TFA, at 0 °C.

  3. When in the spacer of four carbon atoms of 3a, a double bond was introduced, conjugated with the phenyl-containing azido group to give 1a, and using TfOH/TFA in CHCl3 at 0 °C, the phenylnitrenium ion traps a pair of π electrons of the other phenyl ring at its para (9, 28%) and ortho (10, 25%) positions, as a consequence of delocalization of its positive charge; moreover, the direct nucleophilic attack of a pair of π electrons of the other phenyl ring to the nitrenium ion allows the formation of a C–N bond and subsequent formation of the 10-membered heterocycle 11 (32%). The better global yield (85%) in relation to the reactivity of the 1-(3-azidophenyl)-4-phenylbutane (3a, 28%) can be attributed to the configurational bias provided by the (Z)-alkene moiety.

  4. When the ethoxycarbonyl group is introduced at position two of the butene chain [16a, as an E/Z mixture (1:4)], and using TfOH in CHCl3 at 0 °C, the ethyl 3-aminobenzo[a,c]octatriene-6-carboxylate (18, 70%) was the major compound, and the 10-membered heterocycle the minor one (17, 18%), both derived from (E)-16a. If these data are compared with those accounting for the reactivity of 6a (without the ethoxycarbonyl group, Scheme 5), it can be stated that an important increment of the nucleophilic attack at the para position of the nitrenium ion [compare 9 (28%) and 18 (70%)], and at the same time, a diminution of the 10-membered heterocycle [compare 11 (32%) and 17 (18%)]. Formation of the 6-amino-3-phenethyl-2H-1-benzopyran-2-one 19 from (Z)-16a is explained in Scheme 7.

  5. Finally, when a methyl group was located at the para position (and consequently blocking this position) of the azido group of (E)-16b to give 20, cyclization involved the carbon atom ortho to the nitrogen atom, using TfOH/TFA in CHCl3 at 0 °C, and then TsCl. We consider that the ethoxycarbonyl group was more basic than the azide one, so that the carbenium ions (A and B, Scheme 8) might be formed by conjugation of the protonated ethoxycarbonyl group with the phenyl ring (SN2-like process). Taking into account the latter mechanism, we can now interpret the course of the reaction for the formation of 20: after protonation of the ethoxycarbonyl group and formation of carbenium ions, ortho and para in relation to the azido group, the free rotation through the exocyclic bond of the six-membered azido-containing carbenium ions, took place with the nucleophilic attack rapidly occurring at its ortho position, more effective than its para one.

3

3 Conclusion

Although the yields of the arylation reactions are modest, the rich chemistry of arylnitrenium ions provides a platform for additional studies in the areas of phenylnitrenium ion and heterocyclic chemistry. Further developments in this area will have a considerable interest in the fields of organic chemistry and biological activity. To complete these studies, new reactions with different acids and with various unsaturated azides, appropriately substituted with conjugated electron-withdrawing groups, and density functional theory studies are now under investigation to rationalize the cyclization outcome.

4

4 Experimental

4.1

4.1 General remarks

Melting points were taken in open capillaries on a Thermolyne melting point apparatus. Analytical thin layer chromatography (TLC) was performed using Merck Kieselgel 60 F254 aluminum sheets, the spots being developed with UV light (λ = 254 nm). For flash chromatography, Merck silica gel 60 with a particle size of 0.040–0.063 mm (230–400 mesh ASTM) was used. NMR spectra were measured using a Bruker ARX-400 (400 MHz 1H NMR and 100 MHz 13C NMR), a Bruker DPX-300 (300 MHz 1H NMR and 75 MHz 13C NMR), and a Bruker AC-200 (200 MHz 1H NMR and 50 MHz 13C NMR). Chemical shifts (δ) are quoted in parts per million (ppm) and are referenced to the residual solvent peak. Signals are designated as follows: s, singlet; bs, broad singlet; d, doublet; t, triplet; dt, double triplet; q, quartet. Infrared spectra were measured with a Perkin-Elmer 1600FT or a Nicolet model FT-IR. Electrospray mass spectra were recorded on an API III Biomolecular Mass Analyzer (PE, SCIEN) interfaced with a Macintosh II Fx data station. The mass spectrometer was operated in the positive ion mode with a spray voltage of 500 V, orifice potential 35 and 2 ms dwell time. High performance matrix assisted laser desorption time-of-flight mass spectra were recorded on a Kratos Kompact Maldi mass spectrometer with a positive ion mode. The ‘solvent’ used was dihydroxybenzoic acid. Elemental analyses were within ±0.4% of the theoretical values. Elemental analyses were performed either with a Carlo Erba instrument EA-1110, or from Atlanta Microlab.

4.2

4.2 1-(3-Aminophenyl)-4-phenylbutane 2a

A solution of (Z)-1a (0.80 g, 3.55 mmol) (Del Ponte et al., 2003) in EtOH was hydrogenated overnight under 5 atm. of pressure at rt, with a catalyst containing 5% Pd/C in a Parr apparatus. Filtration of the catalyst and evaporation of the solvent under reduced pressure gave 2a (0.75 g, 94%), as a yellowish oil. IR (NaCl/film) 3470, 3370, 1620, 1290 cm−1. 1H NMR 200 MHz, CDCl3): δ 7.15 (m, 5H), 6.85 (m, 2H), 6.51 (m, 1H), 6.35 (m, 1H), 3.4 (bs, 2H), 2.55 (m, 4H), 1.65 (m, 4H). Anal. Calcd. for C16H19N: C, 85.28; H, 8.50; N, 6.22. Found: C, 85.42; H, 8.50; N, 6.35.

4.3

4.3 1-(4-Aminophenyl)-4-phenylbutane 2b (method a)

Compound (E)-1b (Saxena and Lam, 2011) (0.80 g, 3.55 mmol) was dissolved in EtOAc (4.0 mL) and EtOH (4.0 mL). Catalytic amounts of Nickel Raney (0.002 g) were added. Hydrogenation at rt and atmospheric pressure for 8 h, followed by filtration and passing the solution through a basic alumina plug, and evaporation of the solvent gave 2b as a light yellow thick oil (0.80 g, 100%). IR (NaCl/film): 3450, 3370, 3020, 2920, 2850, 1620, 1510, 750, 700 cm−1. MS: m/z 225 (M•+), 106, 91, 77, 65. 1H NMR (CDCl3): δ 7.29–7.15 (m, 5H), 6.95 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 3.53 (bs, 2H, it exchanges with D2O, NH2), 2.60 (t, J = 7.1 Hz, 2H), 2.51(t, J = 7.2 Hz, 2H, 4H). Anal. Calcd. for C16H19N: C, 85.28; H, 8.50: N, 6.22. Found: C, 85.37; H, 8.50, N, 6.23.

4.4

4.4 1-(4-Aminophenyl)-4-phenylbutane 2b (method b)

A solution of 4 (Agnihotri et al., 2015) (4.34 g, 17.3 mmol) in EtOH (230 mL) was hydrogenated in the presence of 0.43 g of 5% Pd/C in a Parr hydrogenation apparatus at rt and atmospheric pressure until no starting material remained. The catalyst was filtered off, and after the solvent was evaporated in vacuum, 2b was obtained pure (3.66 g, 94%).

4.5

4.5 General procedure for the preparation of azido compounds 3a,b

Amines 2a and 2b (6 mmol) were diazotized with NaNO2 (6 mmol) in water (5 mL) at 0–5 °C followed by the addition of an iced 3 M H2SO4 solution (15 mL). After a few minutes, a solution of NaN3 (6 mmol) in water (5 mL) was added. The reaction mixture was stirred for 1 h and then extracted (CH2Cl2). The organic layer was washed with a 10% solution of Na2CO3, and dried (anhydrous Na2SO4). The solvent was rotaevaporated off to give the crude azides, which were purified by flash CC [CH2Cl2/acetone (95/5)].

4.5.1

4.5.1 1-(3-Azidophenyl)-4-phenylbutane 3a

Starting from 2a (1.35 g) compound 3a was obtained (0.91 g, 60%). IR (NaCl/film): 2000, 1290 cm−1. 1H NMR (200 MHz, CDCl3): δ 7.25 (m, 1H), 7.06 (m, 7H), 6.77 (m, 1H), 2.55 (m, 4H), 1.64 (m, 4H). Anal. Calcd. for C16H17N3: C, 76.46; H, 6.82; N, 16.72. Found: C, 76.76; H, 6.88; N, 16.36.

4.5.2

4.5.2 1-(4-Azidophenyl)-4-phenylbutane 3b

Starting from 2b (1.35 g) compound 3b was obtained (1.28 g, 85%). IR (NaCl/film): 2100, 1285 cm−1. MS m/z: 251 (M•+), 225. 1H NMR (200 MHz, CDCl3): δ 7.37 (dt, J = 8 and 2 Hz, 2H), 7.13 (m, 5H), 6.83 (dt, J = 8 and 2 Hz, 2H), 2.57 (m, 4H), 1.65 (m, 4H). Anal. Calc. for C16H17N3: C, 76.46; H, 6.82; N, 16.72. Found: 76.42; H, 6.97; N, 16.52.

4.6

4.6 1-Ethoxycarbonyl-1-(2-phenylethyl)triphenylphosphonium bromide 13

To a stirred solution of PPh3 (21.8 g, 83.0 mmol) in anhydrous toluene (80 mL) was added 12 (Shindo et al., 2003) (22.4 g, 83.0 mmol) dropwise at reflux under an argon atmosphere. The mixture was refluxed for 24 h and after cooling, the solvent was removed in vacuum to about one-third of the volume, a solid was formed and was collected by filtration. Recrystallization from EtOH/Et2O produced 13 as white crystals (26.6 g, 60%); mp 173–175 °C. MS: m/z 453 (M−BrH+1)+.

4.7

4.7 (E,Z)-1-(3-nitrophenyl)-2-ethoxycarbonyl-4-phenylbutene-1 14a

To 13 (8.28 g, 15.5 mmol) in dry EtOH (46 mL) under an argon atmosphere, a solution of NaOEt (0.35 g of metallic Na in 46 mL of EtOH, 15.2 mmol) was added. After stirring at rt, 3-nitrobenzaldehyde (2.35 g in 37 mL of EtOH, 23.5 mmol) was added. After 12 h (TLC monitoring) the solvent was removed in vacuum. The residue was washed (Et2O), filtered and purified by flash CC using a mixture of hexane/EtOAc/MeOH (9.0/0.5/0.5) as eluent to afford a 1/4 mixture of the (E) and (Z)-isomers of the nitro olefin 14a as a light oil (2.85 g, 57%). 1H NMR (300 MHz, CDCl3): major isomer (Z) δ 8.23 (m, 1H), 8.05 (m, 1H), 7.71 (m, 1H), 7.45 (m, 1H), 7.30 (m, 2H), 7.21 (m, 3H), 6.98 (s, 1H), 4.19 (q, J = 8 Hz, 2H), 2.62 (m, 2H), 2.31 (m, 2H), 1.30 (t, J = 8 Hz, 3H). 1H NMR (300 MHz, CDCl3): minor isomer (E) δ 8.23 (m, 1H), 8.04 (m, 1H), 7.73 (m, 1H), 7.47 (m, 2H), 7.30 (m, 2H), 7.21 (m, 3H), 4.19 (q, J = 8 Hz, 2H), 2.62 (m, 2H), 2.31 (m, 2H), 1.30 (t, J = 8 Hz, 3H). Anal. Calcd. for C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C, 69.91; H, 5.72; N, 4.25.

4.8

4.8 (E,Z)-1-(3-aminophenyl)-2-ethoxycarbonyl-4-phenylbutene-1 15a

To 14a (3.20 g, 9.85 mmol) in 78% EtOH (109 mL) was added a suspension formed by a solution of CaCl2 (1.09 g) in H2O (1.6 mL) and Zn powder (32.0 g, 0.49 mol), and the mixture was refluxed for 2 h. The suspension was filtered hot and washed (EtOH), the solvent removed in vacuum and the residue was purified by flash CC, using a mixture of hexane/EtOAc (7/3) as a eluent, and 15a was obtained (2.63 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.70 (s, 1H), 7.25 (m, 5H), 7.15 (t, J = 8.3 and 7.5 Hz, 1H), 6.70 (dd, J = 7.5 and 2.3 Hz, 1H), 6.60 (ddd, J = 8.3, 2.3 and 0.8 Hz, 1H), 6.40 (t, J = 2.3 Hz, 1H), 4.20 (q, J = 7.7 Hz, 2H), 2.80 (m, 4H), 1.30 (t, J = 7.7 Hz, 3H). Anal. Calcd. for C19H21NO2: C, 77.26; H, 7.17: N, 4.74. Found: C, 76.96; H, 7.17, N, 4.84.

4.9

4.9 (E,Z)-1-(3-azidophenyl)-2-ethoxycarbonyl-4-phenylbutene-1 16a

Compound 15a (1.63 g, 5.50 mmol) was dissolved in a solution of H2SO4 (1.93 mL of concentrated H2SO4, and 10.3 mL of H2O). The resulting solution was cooled in an ice bath and the amine 15a was diazotized with a solution of NaNO2 (0.46 g) in H2O (5.6 mL). To eliminate the excess of HNO2, a small portion of urea (0.10 g) and active carbon (0.10 g) was added, and this suspension was filtered after 1.5 h of stirring. To the filtrate in an ice bath, a solution of NaNO2 (0.60 g) in H2O (3.70 mL) was added dropwise, and the supernatant was extracted (CH2Cl2), washed (10% solution of aqueous Na2CO3), and H2O again. After separating the organic layer, drying (anhydrous Na2SO4), filtering and rotaevaporating off the CH2Cl2 solution, the residue was purified by flash CC, using CH2Cl2 as eluent to afford azide 16a as a colorless and thick oil (1.44 g, 81%). IR (NaCl/film): 2100, 1700 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.60 (s, 1H), 7.20 (m, 9H), 4.30 (q, J = 7.2 Hz, 2H), 2.80 (m, 4H), 1.30 (t, J = 7.2 Hz, 3H). Anal. Calcd. for C19H19N3O2: C, 71.01; H, 5.96: N, 13.08. Found: C, 70.80; H, 5.99, N, 12.98.

4.10

4.10 (E)-1-(3-azido-6-methylphenyl)-2-ethoxycarbonyl-4-phenylbutene-1 (E)-16b

To 14b (1.58 g, 4.85 mmol) in acetone (8 mL), a solution of 0.50 g of NH4Cl in H2O (1.9 mL) was added. The mixture was warmed with an oil bath, and after removing this bath, powder Zn (1.02 g) was added in small portions. After stabilizing the reaction, more powder Zn (0.51 g) was added and the mixture was refluxed for 1 h, filtered and evaporated. After dissolving it in H2O, extracted (CH2Cl2), dried (anhydrous Na2SO4), and filtered, the solvent was removed in vacuum. The residue was used directly for the following step. To 15b (1.3 g, 4.2 mmol) in a 3.2 M aqueous solution of H2SO4, NaNO2 (0.36 g, 5.22 mmol) dissolved in H2O (4.7 mL) was added dropwise with intense magnetic stirring. The mixture was treated with urea (0.1 g, 1.7 mmol), and stirred for 2 h. After being cooled in an iced-bath, a solution of NaN3 (0.6 g, 8.4 mmol) in water (3 mL) was added and the suspension was stirred for 2 h, then extracted (CH2Cl2), washed (10% Na2CO3), dried (Na2SO4), filtered and concentrated. The crude was purified by flash CC [hexane/EtOAc (9/1)] and (E)-16b was obtained as a white solid (1.0 g, 71%); mp: 163–165 °C. IR (NaCl/film): 2100 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.71 (s, 1H), 7.60 (s, 1H), 7.21 (m, 5H), 4.30 (q, J = 8 Hz, 2H), 4.19 (q, J = 8 Hz, 2H), 2.70 (m, 2H), 2.60 (m, 2H), 2.10 (s, 3H), 1.30 (t, J = 8 Hz, 3H). Anal. Calcd. for C20H21N3O2: C, 71.62; H, 6.31; N, 12.53. Found: C, 71.99; H, 6.46; N, 12.22.

4.11

4.11 Decomposition of azide 3b: synthesis of 1-(4-aminophenyl)-1,2,3,4-tetrahydronaphthalene 7

Compound 3b (288 mg, 1.15 mmol) was dissolved in CHCl3 (5.0 mL) and TFA (6.0 mL). A solution of TfOH (0.17 mL) in CHCl3 (5.0 mL) was added to the cold (0 °C) solution under an argon atmosphere. After 2 h the acid was neutralized with a 10% aqueous solution of Na2CO3. The organic layer was separated, washed (H2O), dried (anhydrous Na2SO4), and filtered off, and the solvent was evaporated in vacuum. The residue that was purified by flash CC, using hexane/EtOAc (7/3) as eluent, and 7 was obtained as a microcrystalline solid after recrystallization from hexane (170 mg, 66%); mp 82.5–84 °C. IR (NaCl/film): 3460, 3380, 3040, 3020, 2920, 2900, 1620, 1520, 1480, 1450, 1280, 820 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.00 (m, 4H), 6.80 (dt, J = 8.0 and 2.7 Hz, 2H), 6.60 (dt, J = 8.0 and 2.1 Hz, 2H), 4.00 (t, J = 6.0 Hz, 1H), 3.2 (bs, NH2), 2.90 (m, 2H), 2.10 (m, 1H), 1.80 (m, 3H). 13C NMR (75 MHz, CDCl3): 144.2, 139.9, 137.4, 130.0, 129.5, 128.8, 125.6, 115.0, 114.9, 44.7, 33.2, 29.7 20.9. MS m/z (relative intensity): 223 (M•+). Anal. Calcd. C16H17N: C, 86.05; H, 7.67: N, 6.27. Found: C, 86.22; H, 7.87; N, 6.41.

4.12

4.12 Decomposition of azide 3a: synthesis of 3-aminodibenzo[a,c]octadiene 8

To a solution of TFA (1.60 mL) and TfOH (0.13 mL) in a flask immersed in an iced-water bath, the azide 3a (0.35 g, 1.4 mmol) was added, under a nitrogen atmosphere and with stirring. After 8 h, TFA and TfOH were eliminated by distillation. The residue was dissolved (CH2Cl2), neutralized with a 10% solution of Na2CO3, washed (H2O), dried (anhydrous Na2SO4), filtered and rotaevaporated off, and after two flash CCs [elution with a mixture of hexane/EtOAc (9/1)], compound 8 (0.03 g, 10% yield) was obtained as a thick yellowish oil. IR (NaCl/film): 3480, 3380, 3040, 3020, 2920, 2840, 1610, 1520, 1480, 1280, 820 cm−1. 1H NMR (300 MHz): δ 7.1–7.3 (m, 4H), 7.0 (d, J = 8.5 Hz, 1H), 6.5–6.6 (m, 2H), 3.6 (bs, 2H), 2.5–2.7 (m, 2H), 2.0–2.2 (m, 2H), 1.4–1.6 (m, 4H). 13C NMR (75 MHz, CHCl3): 29.5, 29.7, 32.7, 32.8, 112.7, 115.6, 125.5, 127.2, 129.1, 129.2, 129.9, 131.4, 140.6, 142.8, 143.6, 145.9. MS m/z (relative intensity) 223 (M•+, 100). Anal. Calcd. for C16H17N: C, 86.05; H, 7.67; N, 6.27. Found: C, 85.99; H, 7.92; N, 6.09.

4.13

4.13 Decomposition of azide 6a, and subsequent tosylation: synthesis of 3-tosylaminodibenzo[a,c]octadiene 9, 1-tosylaminodibenzo[a,c]octadiene 10, and 1-tosyl-6,7-dihydrodibenzo[b,c,i]azepine 11

Azide 6a (0.249 g, 1 mmol) was dissolved in TFA (2 mL) and CHCl3 (5 mL) at 0 °C followed by dropwise addition of TfOH (1 mmol) with stirring, and under an argon atmosphere. The reaction was monitored by TLC until no azide remained. The mixture was neutralized with a 10% Na2CO3 solution, and dried (anhydrous Na2SO4) and the solvent was evaporated in vacuum. The residue was purified by a flash CC, using CH2Cl2 as eluent. The products were tosylated with TsCl (excess), and the mixture of tosylates was subjected to a second flash CC (CH2Cl2 eluent). Compound 9 (0.105 g, 28%) was obtained as a colorless oil: IR (NaCl/film): 3250, 3000, 2920, 2850–2830, 1600, 1160, and 1090 cm−1. 1H NMR (400 MHz, CDCl3) δ J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.15 (m, 2H),7.06 (d, J = 8.0 Hz, 2H), 7.02 (dd, J = 8.0 and 2.0 Hz, 2H), 6.89 (d, J = 2.0 Hz, 1H), 6.18 (d, J = 12.8 Hz, 1H), 5.60 (ddd, J = 12, 6, 2 Hz, 1H), 2.79 (dt, J = 3.7, 13.2, and 13.2 Hz, 1H), 2.66 (m, 1H), 2.53 (dt, J = 3.7, 3.7, 12.8 Hz, 1H), 2.39 (s, 3H), 2.34 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 21.5, 30.5, 33.0, 119.2, 121.7, 127.7, 127.9, 128.6, 129.4, 130.8, 131.1, 135.7, 136.2, 138.0, 140.7, 141.6, and 143.9. MS: m/z (M++1) (positive mode) 376: in the negative mode (M−1)+ 374. Calcd. for C23H21NO2S: C, 73.57; H, 5.64; N, 3.73; S, 8.54. Found: C, 73.20; H, 5.71; N, 3.78; S, 8.42.

Compound 10 (0.094 g, 25%) was obtained as a colorless oil. IR (NaCl/film): 3300, 2990, 2920, 1650, 1362, 1210, and 1180 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1 Hz), 7.34 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 8.0 Hz, 1H), 7.22 (dt, J = 7.5 and 1.3 Hz, 1H), 7.18 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.75 (dd, J = 7.5 and 1.2 Hz, 1H), 6.23 (dd, J = 12.7 and 2.6 Hz, 1H), 5.43 (ddd, J = 12.7, 5.8, and 3.0 Hz, 1H), 2.44 (s, 3H). 13C NMR (100 MHz, CDCl3): 21.5, 30.4, 32.5, 119.4, 125.3, 126.4, 127.1, 127.8, 128.1, 129.0, 129.8, 130.1, 133.9, 135.4, 136.1, 139.4, 142.1, 143.7, and 144.6. MS: m/z 375. Calcd. for C23H21NO2S: C, 73.57; H, 5.64; N, 3.73; S, 8.54. Found: C, 73.31; H, 5.50; N, 3.60; S, 8.50.

Compound 11 (0.120 g, 32%) was obtained as a colorless oil. IR (NaCl/film): 3000, 2850, 1580, 1550, 1350, 1210, 1160 and 1150 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 8.0 Hz, 2H), 7.50 (dd, J = 2.5 and 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.22 (m, 1H), 7.16 (m, 1H), 7.12 (m, 2H), 7.11 (m, 2H), 7.07 (t, J = 8.0 Hz, 1H), 6.63 (dd, J = 2.0 and 8.0 Hz,1H), 6.22 (d, J = 12.3 Hz, 1H), 5.41 (dt, J = 11.7, 7.1 Hz, 1H), 3.74 (t, J = 2.0 Hz, 1H), 3.74 (t, J = 2.0 Hz, 1H), 3.11 (dd, J = 13.1, 8.6 Hz, 1H), 2.44 (s, 3H), 2.39 (dd, J = 13.1, 10.9 Hz, 1H), 1.59 (m, 1H). 13C NMR (100 MHz, CDCl3): 21.6, 34.4, 36.9, 118.6, 123.5, 123.9, 127.5, 128.0, 129.6, 129.7, 129.8, 131.6, 134.0, 134.1, 134.5, 134.6, 137.8, 137.9, 143.9, 144.2, 147.1. Calcd. for C23H21NO2S: C, 73.57; H, 5.64; N, 3.73; S, 8.54. Found: C, 73.50; H, 5.79; N, 3.57; S, 8.80. Tosylates 9, 10 and 11 showed the same molecular mass: MS (m/z) 375.5, and also showed the fragment 221, which can be explained by the loss of tosylate, followed by protonation of the nitrogen atom.

4.14

4.14 Decomposition of azide 16a (E/Z: 1/4): synthesis of ethyl 7,8-dihydrodibenzo[b,c,i]azepine-6-carboxylate 17, ethyl 3-aminodibenzo[a,c]octadiene-6-carboxylate 18, and 6-amino-3-(2-phenylethyl)-2H-1-benzopyran-2-one 19

To a trifluoromethanesulfonic acid (TfOH, 0.39 mL, 4.36 mmol) solution in CHCl3 (15 mL), cooled in an ice bath, under an argon atmosphere and with stirring, a solution of the azide 16a (E/Z: 1/4) (0.70 g, 2.18 mmol) in CHCl3 (5 mL) was added dropwise. The reaction was monitored by TLC until no azide remained. The mixture was neutralized with a 10% Na2CO3 solution, dried (anhydrous Na2SO4), and filtered off and the solvent evaporated in vacuum. The residue was purified twice by flash CC, using a mixture of hexane/EtOAc (7/3) as eluent. Compound 17 [0.115 g, 18% (from (E)-16a)] was obtained, after a recrystallization form MeOH/hexane; mp: 78–80 °C. IR (KBr): 3180, 3060, 2980, 2950, 2920, 1700, 1260, 1240, and 1210 cm−1. MS: m/z (relative intensity) 293 (100, M+), 292 (47, M+−1), 264 (27), 220 (87), 129 (48), 115 (80). 1H NMR (300 MHz, CDCl3): δ 7.60 (s, 1H), 7.40 (m, 1H), 7.30 (m, 1 Hz), 7.20 (m, 1H), 7.15 (m, 1H), 7.00 (m, 1H), 6.75 (m, 1H), 6.60 (m, 1H), 5.30 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.40 (dd, J = 13.7 and 9.2 Hz, 1H), 3.10 (dd, J = 14.1 and 9.2 Hz, 1H), 3.00 (t, J = 2.1 Hz, 1H), 2.70 (dd, J = 13.7 and 9.4 Hz, 1H), 1.80 (dd, J = 14.1 and 9.4 Hz, 1H), 1.40 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): 168.8, 155.4, 148.6, 145.8, 141.7, 135.5, 134.4, 133.8, 132.9, 130.1, 129.1, 128.0, 121.6, 120.2, 115.9, 60.8, 36.8, 34.7, and 14.2. Calcd. for C19H19NO2: C, 77.79; H, 6.53; N, 4.77. Found: C, 77.90; H, 6.84; N, 4.91.

Compound 18 [0.045 g, 70% (from (E)-16a)] was obtained as a thick oil. 1H NMR (300 MHz, CDCl3): δ 7.60 (s, 1H), 7.20 (m, 4H), 7.00 (d, J = 8.5 Hz, 1H), 6.60 (dd, J = 8.5 and 3.0 Hz, 1H), 5.80 (d, J = 3.0 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.70 (bs, NH2), 2.80 (t, J = 10.0 Hz, 2H), 2.60 (t, J = 10.0 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): 167.1, 145.8, 141.6, 138.9, 136.3, 132.9, 130.0, 129.2, 128.9, 128.4, 126.0, 122.4, 115.4, 115.1, 61.0, 34.6, 30.2, and 14.2. Calcd. for C19H19NO2: C, 77.79; H, 6.53; N, 4.77. Found: C, 77.70; H, 6.71; N, 4.50.

Compound 29 [0.055 g, 86% (from (Z)-16a)] was obtained as a yellowish solid; mp: 173–175 °C. IR (NaCl/film): 3350, 3450, 3010, 2920, 1680, 1630, 1600, 1580, 1490, 1450, 1250, 1180, and 1090 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.25 (m, 5H), 7.20 (s, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.80 (dd, J = 8.7 and 2.7 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 3.70 (bs, NH2), 2.95 (dt, J = 8.5 Hz, 2H), 2.85 (dt, J = 8.5 Hz, 2H). 13C NMR (75 MHz, CDCl3): 162.0, 146.5, 142.8, 140.9, 138.9, 128.8, 128.5, 128.3, 126.0, 119.9, 118.5, 117.0, 111.1, 34.1, and 32.9. Calcd. for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C, 77.06; H, 5.73; N, 4.99.

4.15

4.15 Decomposition of azide (E)-16b: synthesis of ethyl 1-tosylamino-4-methyldibenzo[a,c]octadiene-6-carboxylate 26

To a TfOH (0.30 mL, 2.70 mmol) suspension in CHCl3 (5 mL), cooled to 0 °C, under an argon atmosphere and with stirring, a solution of the azide (E)-16b (0.57 g, 1.70 mmol) in CHCl3 (5 mL) was added dropwise. After some minutes the reaction was halted. The mixture was neutralized with a 10% Na2CO3 solution, extracted (CH2Cl2), dried (anhydrous Na2SO4), and filtered and the solvent evaporated in vacuum. The residue was purified twice by flash CC, using a mixture of hexane/EtOAc (7/3) as eluent. The obtained sample was treated with an excess of TsCl/pyridine (a catalytic amount) at 0 °C and under an argon atmosphere. The crude was purified by flash CC, using CH2Cl2 as eluent, and after rotaevaporating off the solvent, the sample was recrystallized (EtOH) and 20 (0.41 g, 54%) was obtained as a white microcrystalline solid; mp: 163–165 °C. IR (NaCl/film): 3380–3300, 3000–2850, 1700, 1630, 1590, 1460, 1380, 1090, and 1020 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 7.28 (dt, J = 7.5 and 1.2 Hz, 1H), 7.15 (m, 5H), 6.64 (dd, J = 7.5 and 1.2 Hz, 1H), 4.05 (m, 2H), 2.68 (ddd, J = 14.0, 11.5 and 6.9 Hz, 1H), 2.39 (s, 3H), 2.26 (ddd, J = 13.5, 6.9 and 3.7, 1H), 2.19 (s, 3H), 2.12 (ddd, J = 13.5, 11.5 and 6.4, 1H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 167.8, 143.8, 140.9, 138.3, 136.4, 136.1, 135.2, 132.7, 132.1, 131.9, 130.6, 130.0, 129.6, 129.5, 129.1, 128.2, 127.2, 126.7, 121.2, 60.9, 30.4, 29.5, 21.5, 20.0, and 14.1. Calcd. for C27H26NO4S: C, 69.62; H, 5.84; N, 3.12, S, 7.15. Found: C, 69.72; H, 5.99; N, 2.90; S, 7.35.

Acknowledgments

The Brazilian authors thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and the Coordenadoria de Aperfeiçoamento de Pessoal de Nivel Superior (CAPES) for financial support.

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