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Synthesis 2013; 45(4): 545-555
DOI: 10.1055/s-0032-1316839
paper
© Georg Thieme Verlag Stuttgart · New York

Facile Synthesis of [1,2,3]-Triazole-Fused Isoindolines, Tetrahydroisoquino­lines, Benzoazepines and Benzoazocines by Palladium-Copper Catalysed Heterocyclisation­

Kaushik Brahma
Chemistry Division, Indian Institute of Chemical Biology (CSIR), 4, Raja S. C. Mullick Road, Kolkata 700032, India   Fax: +91(33)24735971   Email: chinmay@iicb.res.in
,
Basudeb Achari
Chemistry Division, Indian Institute of Chemical Biology (CSIR), 4, Raja S. C. Mullick Road, Kolkata 700032, India   Fax: +91(33)24735971   Email: chinmay@iicb.res.in
,
Chinmay Chowdhury*
Chemistry Division, Indian Institute of Chemical Biology (CSIR), 4, Raja S. C. Mullick Road, Kolkata 700032, India   Fax: +91(33)24735971   Email: chinmay@iicb.res.in
› Author Affiliations
Further Information

Publication History

Received: 05 November 2012

Accepted after revision: 06 December 2012

Publication Date:
04 January 2013 (online)

 
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Abstract

An elegant method for the synthesis of 1,2,3-triazoles fused with five-, six-, seven- and eight-membered benzoheterocycles, including isoindoline, tetrahydroisoquinoline, benzoazepine and benzoazocine, has been developed via palladium-copper catalysed reactions in one-pot. The broad scope of this reaction was illustrated by effecting bis-heteroannulations, synthesis of uracil derivatives of biological interest, and employment of acetylene gas as an inexpensive substrate. The reactions are experimentally simple and utilise easily accessible substrates of different types.


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Key words

1,2,3-triazoles - nitrogen heterocycles - intramolecular reactions - azide-alkyne cycloaddition - bis-heteroannulations

In recent years, novel nitrogen-containing heterocycles have found widespread applications in drug development. Notable among them are 1,2,3-triazoles, which have attracted enormous interest due to their wide range of biological activities such as antiviral,[ 1a ] antifungal,[ 1b ] anti-parasitic,[ 1c ] antimicrobial,[ 1d ] immunostimulant[ 1e ] and others.[ 1f ] Additionally, these heterocycles have remarkable metabolic stability and have proven to be important as amide surrogates in various bioactive agents.[ 2 ] Historically, the first straightforward synthesis of 1,4- and 1,5-substituted 1,2,3-triazoles as a regioisomeric mixture was achieved by Huisgen[ 3 ] during the 1960s. Later, regioselective synthesis of 1,4-substituted 1,2,3-triazoles was established[ 4 ] through copper-catalysed azide–alkyne cycloaddition (CuAAC) under mild reaction conditions. In the recent past, synthesis of 1,5-substituted 1,2,3-triazoles, the other regioisomer, was achieved by Fokin, who employed a catalytic amount of tetramethylammonium hydroxide[ 5a ] or [Cp*RuCl(PPh3)2].[5b] [c] These catalysed cycloadditions, popularly known as ‘click reactions’, have found widespread applications in areas ranging from medicinal chemistry[ 6a,b,1f ] to materials science.[ 6c–f ] Mostly terminal alkynes have been used in these reactions, resulting in 1,4- or 1,5-substituted 1,2,3-triazoles. But an elegant synthesis of fully 1,4,5-substituted 1,2,3-triazoles in one pot[ 7 ] employing azide and internal alkyne as substrates is more challenging and remains to be developed. The employment of unsymmetrical internal alkynes in these reactions often results in diminished reaction rates and poor regioselectivity. However, intramolecular azide–alkyne cycloaddition[ 8 ] (IAAC), in which regioselectivity is usually determined by the initial positions of the azide and alkyne­ groups present in the starting compounds, has emerged as a possible solution to this problem.

On the other hand, benzo-fused aza-heterocycles (e.g., isoindoline,[ 9 ] tetrahydroisoquinoline,[ 10 ] benzoazepine,[ 11 ] benzoazocine[ 12 ]) are considered as important scaffolds because of their presence as key structural units in various drugs, bioactive compounds, and natural products. Notably, benzo-heterocycles fused with 1,2,3-triazoles have been shown[ 13 ] to mimic benzolactams that are difficult to access, but which are known for effectively mimicking teleocidines.[ 14 ] Therefore, fusion of the aforesaid heterocycles with 1,2,3-triazole, resulting in the formation of compounds 1–4 (Figure [1]), could perhaps lead to potent pharmacophores and/or important building blocks in pharmaceutical research. Indeed, triazoles fused with other heterocycles have already proven to be important in drug discovery programs due to their broad spectrum of activities such as anxiolytic[ 15a ] (e.g., alprazolam and estazolam drugs), antidepressant (e.g., triazolam drug),[ 15b ] anti-allergic,[ 15c ] glycosidase inhibitor,[ 15d ] and 5-HT1A/B/D receptor antagonist.[ 15e ] In addition, compounds 5 [ 16a ] and 6 [ 16b ] are being considered as potent chemotherapeutic agents (Figure [1]). In view of the immense biological importance of this class of compounds, interest in this area has been growing in recent times.

Zoom Image
Figure 1 Important fused 1,2,3-triazoles

Literature reports indicate that fully 1,4,5-substituted 1,2,3-triazoles including fused derivatives can be synthesised primarily by two strategic approaches. One involves intermolecular regioselective dipolar cycloaddition between azide and terminal alkyne followed by metal-catalysed­ arylation of the resulting 1,2,3-triazole.[ 17 ] The alternative approach[ 18 ] involves thermal or metal-catalysed regioselective IAAC of the azido-alkyne substrates in which the acetylenic group is disubstituted. In a continuation of our work on palladium-catalysed reactions, we followed the latter approach in which substrates having azide functionality tethered to acetylene underwent metal-catalysed C-arylation at the terminal acetylene and subsequent intramolecular cycloaddition affording 1,2,3-triazoles fused with morpholine,[ 19a ] 1,4-benzoxazine,[ 19b ] 1,4-benzodiazepin-5-one,[ 19c ] 1,4-benzodiazocin-6-one,[ 19c ] and piperazine.[ 19d ] We speculated that replacement of these substrates by ortho-iodo-azides 7a–d and subsequent reaction with terminal acetylenes 8 in the presence of a palladium catalyst could allow access to 1,2,3-triazole-fused five-, six-, seven- and eight-membered benzo-heterocycles 1–4 in one pot. In this paper, we describe in detail the results achieved (Scheme [1]).[ 20 ] This straightforward synthesis of tricyclic nitrogen-containing heterocycles constitutes an important alternative strategy to the reported two-step route,[ 17d ] as shown in Scheme [1].

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Scheme 1 Synthesis of 1,2,3-triazole-fused heterocycles 1–4

The starting ortho-iodo-azides 7a–d (X = I, n = 1–4) required for this study were synthesised from their corresponding precursor alcohols 10a–d. For this, the latter, which were prepared in a few steps using reported procedures,[ 21 ] were subjected to mesylation followed by azidation as shown in Scheme [2].

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Scheme 2 Synthesis of starting substrates 7a–d. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0–5 °C, 2 h; (b) NaN3, DMF, r.t., 2 h, 94% (for 7a); (c) NaN3, DMF, 90 °C, 1 h, 90–92% (for 7b–d).

With substrates 7a–d in hand, we investigated the influence of catalyst, solvent, base and temperature on the formation of the target products. These studies revealed that bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide constitute the best catalytic system, whereas DMF and Et3N prove to be the optimal solvent and base, respectively. We also observed that carrying out the reactions by immediate heating (115 °C for 7a–c, 150 °C for 7d) instead of initial stirring at r.t. (for 12 h) followed by heating (at 115 °C for a few hours) as reported earlier[ 20 ] provided comparable yields of the products. Therefore, we modified the previous reaction conditions and elaborated the scope of this present reaction procedure by using substrates 7a–d as shown in Table [1]. For substrates 7a–b, the reactions were found to be complete within a few hours (0.5–6 h) upon heating at 115 °C, but the reactions with substrate 7c to afford the seven-membered ring-fused product 3 required 7–17 hours heating (Table [1], entries 11–15). More significantly, the reaction did not proceed at all when compound 7d was employed as a reactant. Therefore, we were forced to increase the reaction temperature to 150 °C (for 13–19 h) to achieve formation of the desired eight-membered-ring analogues 4 (Table [1], entries 16–18), albeit with moderate yields. Both aryl and alkyl acetylenes having different functional groups successfully participated in the reactions. Typically, aryl acetylenes having electron-withdrawing groups (EWGs) provided better yields than those with electron-donating groups (EDGs) as seen from Table [1] (entry 2 vs. 3, entry 7 vs. 6, entry 13 vs. 12, and entry 17 vs. 18). A sugar moiety with acetylene pendant was found to be compatible in this reaction, affording the products 2e and 3e, respectively (Table [1], entries 9 and 15). However, use of tosylated acetylene 8h led to the isolation of the unexpected product 2f (Table [1], entry 10), which is possibly formed through elimination of p-TsOH from the initially formed tosylated product under the reaction conditions.

In view of the immense importance of 5-substituted uracils,[ 22 ] and in continuation of our work on the synthesis of biologically active compounds,[ 23 ] we became interested in the demethylation of 2,4-dimethoxypyrimidine derivatives 2d and 3d (Table [1], entries 8 and 14). Accordingly, when compounds 2d and 3d were successively treated with chlorotrimethylsilane and sodium iodide in anhydrous acetonitrile at room temperature overnight, the expected uracil derivatives 11a,b [ 24 ] were produced smoothly in excellent yields (Scheme [3]).

We then studied the applicability of the regioselective IAAC reaction for bis-heteroannulations, employing 1,3-diethynyl benzene 12 as reactant (Table [2]). To our satisfaction, bis-heteroannulated products (13a–d) were formed readily when o-iodo-azides 7a–d were employed as coupling partners (Table [2], entries 1–4). Thus, this method is amenable to the synthesis of polyheteroannulated frameworks in one pot and under operationally simple palladium-catalysed reaction conditions.

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Scheme 3 Synthesis of uracil derivatives 11a and 11b

Table 1 Synthesis of Fused 1,2,3-Triazoles 1–4 a

Entry

Azide 7

n

Alkyne 8

R

Temp (°C)

Time (h)

Product

Yield (%)b

 1

7a

1

8a

115

 2.0

1a

70

 2

7a

1

8b

115

 0.5

1b

72

 3

7a

1

8c

115

 2.5

1c

65

 4

7a

1

8d

n-Bu

115

 5.5

1d

62

 5

7b

2

8a

115

 2.5

2a

76

 6

7b

2

8c

115

 2.0

2b

47

 7

7b

2

8e

115

 0.5

2c

79

 8

7b

2

8f

115

 0.75

2d

68

 9

7b

2

8g

115

 1.0

2e

54

10c

7b

2

8h

CH2CH2OTs

115

 2.5

2f

40

11d

7c

3

8a

115

12.0

3a

55

12d

7c

3

8c

115

17.0

3b

40

13

7c

3

8e

115

7.0

3c

50

14d

7c

3

8f

115

15.0

3d

32

15d

7c

3

8g

115

12.0

3e

38

16d

7d

4

8a

150

13.0

4a

40

17d

7d

4

8b

150

13.0

4b

43

18d

7d

4

8c

150

19.0

4c

38

a Reaction conditions: azide 7 (1.0 mmol), alkyne 8 (1.25 mmol), [Pd(PPh3)2Cl2] (0.035 mmol), CuI (0.07 mmol), Et3N (5.0 mmol), anhydrous DMF (5 mL), 115–150 °C, 0.5–19 h.

b Yield of chromatographically isolated pure products based on azide 7.

c Elimination of p-TsOH from the tosylated product under the reaction conditions leading to the formation of 2f.

d In addition to the expected product 3/4, the corresponding acyclic intermediate (internal alkyne), formed through coupling between terminal alkyne and o-iodo-azide 7c/7d through the Sonogashira pathway, was also isolated (12–18%).

Table 2 Synthesis of Bis-heteroannulated Products 13a–d a

Entry

Azide 7

n

Temp (°C)

Time (h)

Yield (%)b

1

7a

1

115

 2

13a (54)

2

7b

2

115

 2

13b (50)

3

7c

3

130

12

13c (47)

4

7d

4

130

15

13d (27)

a Reaction conditions: azide 7 (1.0 mmol), alkyne 12 (0.6 mmol), [Pd(PPh3)2Cl2] (0.035 mmol), CuI (0.07 mmol), Et3N (5.0 mmol), anhydrous DMF (6 mL), 115–150 °C, 2–15 h.

b Yield of chromatographically isolated pure product based on azide 7.

We also tested the feasibility of using acetylene gas as an inexpensive substrate in place of substituted acetylenes 8 to gain access to fused triazoles 1–4 (R = H, see Figure [1]) in which 1,2,3-triazoles are 1,5-disubstituted rather than fully substituted. Toward this objective, we first employed o-iodo-azide 7a as a synthon and heated the reaction at 60 °C (4 h) under balloon pressure of acetylene in the presence of [Pd(PPh3)2Cl2] (1.5 mol%), CuI (3 mol%) and K2CO3 (2 equiv) in anhydrous DMF. Pleasingly, the desired product 1a′ was formed with 60% yield along with the acyclic 1,2,3-triazole derivative 14a (where n = 1) with 24% yield (Scheme [4]). With substrate 7b, on the other hand, heating the reaction at 60 °C (4 h) under these conditions did not furnish any desired product 2a′; instead, triazole 14b (where n = 2) was isolated with 70% yield. However, carrying out this reaction at higher temperature (110 °C) succeeded in delivering the desired product 2a′, albeit in only 23% yield. We then changed this one-pot strategy and used two-step reactions as shown in Scheme [4] (results in Table [3]). Accordingly, cycloaddition of acetylene (gas) with the azido group of substrates 7b–d was first carried out at 60 °C in the presence of CuI (3 mol%) and K2CO3 (2 equiv), affording the intermediate 1,2,3-triazoles 14b–d. These crude intermediates were then directly submitted to palladium-catalysed cyclocondensation reaction, furnishing the target products 2a′–4a′ with moderate to good yields (Table [3], entries 2–4).

Zoom Image
Scheme 4 Synthesis of fused 1,2,3-triazoles 1a′, 2a′, 3a′ and 4a′ by employing acetylene (gas). Conditions A: [Pd(PPh3)2Cl2], K2CO3, TBAB, DMF, 110–130 °C; Conditions B: Pd(OAc)2, NaHCO3, TBAB, DMF, 130 °C.

Table 3 Synthesis of Fused 1,2,3-Triazoles 1a′–4a′

Entry

Substrate

Reaction temp. of the crude intermediate 14b–d (heating time)

Yield 1–4a′ (%)e

1

7a a

_

1a′ (60)

2

7b b

110 °C (4 h for 14b)c

2a′ (82)

3

7c b

130 °C (4 h for 14c)c

3a′ (52)

4

7d b

130 °C (2.5 h for 14d)d

4a′ (42)

a Azide 7a was directly converted into product 1a′ as depicted in Scheme [4].

b Reaction conditions: azide 7b–d (1.0 mmol), CuI (0.03 mmol), K2CO3 (2.0 mmol), anhydrous DMF (5 mL), 60 °C, 4 h under balloon pressure of acetylene; the resulting crude product 14b–d obtained through standard work-up was then used for next step of the reaction.

c Heating was carried out under reaction conditions A (as described in Scheme [4]).

d Heating was carried out under reaction conditions B (as described in Scheme [4]).

e Chromatographically isolated, pure product.

The structures of products 1–4 were determined on the basis of their spectral (IH and 13C NMR, IR and mass) and analytical data. In the 1H NMR spectra, signals for the N-CH2 protons appeared at δ = 5.39 ppm as a singlet for 1a. As expected, these signals shifted upfield in the products with larger rings [XX′ part of AA′XX′ and AA′BB′XX′ systems at δ = 4.61 and 4.36 ppm, respectively, for 2a and 3a, and double doublets at δ = 4.81 (J = 14.1, 6.3 Hz) and 3.61 ppm (J = 14.1, 11.7 Hz) for 4a] as the protons are no longer benzylic. The signals of the benzylic protons of 2a and 3a also appeared as components of subspectra of type AA′XX′ and AA′BB′XX′ at δ = 3.27 and 2.76 ppm, respectively, whereas in 4a, one of the signals appeared as a double doublet at δ = 2.95 ppm (dd, J = 13.8, 8.4 Hz) and the second at around δ = 2.15 ppm, overlapped by peaks for other protons. Additionally, unambiguous structural confirmation also came from X-ray diffraction analysis of the representative eight-membered-ring product 4a (Figure [2]).

Zoom Image
Figure 2 ORTEP representation of 4a

In conclusion, we have described a straightforward palladium-copper catalysed method for the synthesis of 1,2,3-triazoles fused with five-, six-, seven- and eight-membered­ benzoheterocycles, featuring isoindoline, tetrahydroisoquinoline, benzoazepine and benzo-azocine, respectively.[ 25 ] A variety of o-iodo-azides and acetylenic substrates were found to react under the reaction conditions, affording a diverse array of products with moderate to good yields. The reaction protocol was successfully utilised for the formation of one C–C and two C–N bonds in a one-pot reaction. The broad scope of this reaction was illustrated by effecting bis-heteroannulations, synthesis of uracil derivatives of biological interest, and employment of acetylene gas as an inexpensive substrate. We believe that the reaction protocol can be used in library generation based on diversity oriented synthesis for lead development and, thus, would be of interest to the practitioners of organic and medicinal chemistry.

Melting points were determined in open capillaries and are uncorrected. IR spectra were obtained with a JASCO FT/IR-4200 infrared spectrometer either neat or as KBr plates. 1H and 13C NMR spectra were recorded with Bruker-300, 500 or 600 MHz NMR spectrometers and chemical shifts are reported relative to tetramethylsilane (TMS) as internal reference. Mass spectra were recorded in ESI-TOF, EI or FAB ionization mode. HRMS were recorded with a Q-Tof Micro or JEOL JMS-700 mass spectrometer. Crystallographic data were obtained with a Bruker Kappa Apex 2 instrument. Column chromatography was performed using silica gel (60–120 or 100–200 mesh) [Merck, India]. Thin-layer chromatography (TLC) was performed on silica gel 60 F254 aluminum sheets [Merck, Germany] and visualization of the developed chromatogram was achieved by UV absorbance. Petroleum ether (PE) refers to the fraction boiling in the range 60–80 °C.

Preparations of starting materials 7a–d and their spectral data are provided in the Supporting Information.


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[1,2,3]-Triazole-Fused Products 1–4; General Procedure

The reagents [Pd(PPh3)2Cl2] (24.6 mg, 0.035 mmol), CuI (13.3 mg, 0.07 mmol) and Et3N (0.71 mL, 5.0 mmol) were sequentially added to a solution of o-iodo-azide 7a–c (1.0 mmol) in anhydrous DMF (8 mL) and the mixture was stirred at r.t. under an argon atmosphere for 20 min. Acetylenic compound 8 (1.25 mmol) dissolved in anhydrous DMF (1 mL) was added dropwise under argon. The reaction mixture was then heated at 115 °C for the requisite time (0.5–17 h, see Table [1]). After completion of the reaction (TLC), the solvent was removed in vacuo; the residue was mixed with H2O (30 mL) and extracted with EtOAc (2 × 25 mL). The combined organic extracts were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified through silica gel (100–200 mesh) column chromatography (EtOAc–PE, 15–20% v/v) to afford the corresponding product 1–3.

The same procedure was adopted for the synthesis of products 4 (employing o-iodo-azide 7d and acetylenic compound 8, see Table [1]), the only difference being that the reaction mixture was heated at 150 °C instead of 115 °C and for 13–19 h.


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3-Phenyl-8H-[1,2,3]triazolo[5,1-a]isoindole (1a)

Yield: 0.163 g (70%); light-brown solid; mp 152–154 °C (lit.[ 17d ] 153–155 °C).

IR (KBr): 3056, 2963, 1607, 1444, 1362, 1172, 982, 762, 699 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 5.39 (s, 2 H), 7.39–7.56 (m, 6 H), 7.90–7.97 (m, 3 H).

13C NMR (CDCl3, 75 MHz): δ = 50.9, 121.2, 124.1, 126.9, 128.0, 128.1, 128.3, 128.7, 128.9, 131.2, 138.9, 139.2, 141.1.

MS (ESI): m/z = 234.04 [M + H]+.

HRMS (EI, 70 eV): m/z [M]+ calcd for C15H11N3: 233.0953; found: 233.0960.


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Methyl 4-(8H-[1,2,3]Triazolo[5,1-a]isoindol-3-yl)benzoate (1b)

Yield: 0.210 g (72%); white solid; mp 196–198 °C.

IR (KBr): 2951, 1710, 1609, 1437, 1283, 1110, 766, 703 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 3.97 (s, 3 H), 5.42 (s, 2 H), 7.44–7.59 (m, 3 H), 7.93 (br d, J = 7.5 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 2 H), 8.21 (d, J = 8.4 Hz, 2 H).

13C NMR (CDCl3, 75 MHz): δ = 51.0, 52.2, 121.4, 124.3, 126.7, 127.7, 128.8, 128.9, 129.5, 130.2, 135.7, 138.3, 139.8, 141.3, 166.7.

MS (ESI): m/z = 314.14 [M + Na]+.

HRMS (EI, 70 eV): m/z [M]+ calcd for C17H13N3O2: 291.1008; found: 291.0999.


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3-(4-Methoxyphenyl)-8H-[1,2,3]triazolo[5,1-a]isoindole (1c)

Yield: 0.171 g (65%); white solid; mp 146–148 °C (lit.[ 17d ] 154–156 °C).

IR (KBr): 3069, 2838, 1614, 1576, 1507, 1451, 1419, 1358, 1301, 1250, 1174, 1029, 982, 828, 773 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 3.89 (s, 3 H), 5.38 (s, 2 H), 7.07 (d, J = 8.4 Hz, 2 H), 7.39–7.56 (m, 3 H), 7.88 (app d, J = 8.1 Hz, 3 H).

13C NMR (CDCl3, 75 MHz): δ = 50.9, 55.3, 114.3, 120.9, 123.8, 124.1, 128.1, 128.2, 128.7, 138.3, 139.1, 140.9, 159.5.

MS (ESI): m/z = 264.05 [M + H]+.

HRMS (ESI): m/z [M + Na]+ calcd for C16H13N3NaO: 286.0956; found: 286.0950.


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3-Butyl-8H-[1,2,3]triazolo[5,1-a]isoindole (1d)

Yield: 0.132 g (62%); colourless solid; mp 76–78 °C.

IR (KBr): 3067, 2926, 2860, 1448, 1302, 1163, 1006, 767, 724 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 0.97 (t, J = 7.2 Hz, 3 H), 1.38–1.51 (m, 2 H), 1.75–1.85 (m, 2 H, overlapped by H2O signal), 2.95 (t, J = 7.5 Hz, 2 H), 5.30 (s, 2 H), 7.34–7.40 (m, 1 H), 7.44–7.51 (m, 2 H), 7.61 (d, J = 7.5 Hz, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 13.7, 22.2, 25.5, 31.5, 50.8, 120.7, 124.0, 127.6, 128.4, 128.6, 139.1, 139.3, 140.5.

MS (ESI): m/z = 236.05 [M + Na]+.


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1-Phenyl-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline (2a)

Yield: 0.188 g (76%); yellow solid; mp 150–151 °C (lit.[ 17d ] 154–156 °C).

IR (KBr): 3049, 1496, 1440, 1360, 1195, 1153, 994, 759, 698 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 3.27, 4.61 (2 H each, comprising AA′XX′ system), 7.19 (td, J = 1.1, 7.4 Hz, 1 H), 7.26–7.36 (m, 2 H), 7.39–7.50 (m, 3 H), 7.60 (d, J = 7.5 Hz, 1 H), 7.71–7.75 (m, 2 H).

13C NMR (CDCl3, 150 MHz): δ = 29.3, 45.0, 124.5, 125.1, 127.5, 128.42, 128.48, 128.5, 128.7, 129.1, 129.3, 131.7, 132.8, 143.0.

MS (ESI): m/z = 248.24 [M + H]+.

HRMS (EI, 70 eV): m/z [M]+ calcd for C16H13N3: 247.1109; found: 247.1108.


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1-(4-Methoxyphenyl)-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline (2b)

Yield: 0.130 g (47%); brown gum.

IR (neat): 2934, 2839, 1614, 1513, 1465, 1364, 1297, 1250, 1180, 1031, 838 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 3.26, 4.59 (2 H each, comprising AA′XX′ system), 3.88 (s, 3 H), 7.00 (d, J = 8.7 Hz, 2 H), 7.18–7.23 (m, 1 H), 7.29–7.35 (m, 2 H), 7.59–7.66 (m, 3 H).

13C NMR (CDCl3, 75 MHz): δ = 29.1, 44.9, 55.2, 113.9, 123.9, 124.1, 125.0, 127.3, 128.3, 128.7, 128.8, 129.6, 132.6, 142.7, 159.6.

MS (ESI): m/z = 300.20 [M + Na]+.

HRMS (EI, 70 eV): m/z [M]+ calcd for C17H15N3O: 277.1215; found: 277.1212.


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1-(4-Nitrophenyl)-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline (2c)

Yield: 0.231 g (79%); yellow solid; mp 192–193 °C.

IR (KBr): 3064, 2949, 1601, 1508, 1340, 1184, 1104, 858, 768, 689 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 3.30, 4.63 (2 H each, comprising AA′XX′ system), 7.24–7.29 (m, 1 H), 7.34–7.42 (m, 2 H), 7.56 (d, J = 7.8 Hz, 1 H), 7.97 (d, J = 8.7 Hz, 2 H), 8.34 (d, J = 8.7 Hz, 2 H).

13C NMR (CDCl3, 75 MHz): δ = 29.2, 44.9, 124.0, 124.3, 124.4, 127.7, 128.8, 128.9, 129.9, 130.4, 133.2, 138.3, 140.6, 147.5.

MS (ESI): m/z = 315.02 [M + Na]+.

HRMS (EI, 70 eV): m/z [M]+ calcd for C16H12N4O2: 292.0960; found: 292.0962.


#

1-(2,4-Dimethoxypyrimidin-5-yl)-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline (2d)

Yield: 0.210 g (68%); white solid; mp 134–136 °C.

IR (KBr): 2953, 1619, 1563, 1490, 1468, 1399, 1358, 1282, 1191, 1078, 1013, 739 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 3.30, 4.65 (2 H each, comprising AA′XX′ system), 3.89 (s, 3 H), 4.09 (s, 3 H), 7.14–7.24 (m, 2 H), 7.27–7.35 (m, 2 H), 8.49 (s, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 28.9, 44.9, 53.9, 54.9, 107.1, 124.5, 124.6, 127.3, 128.2, 129.1, 131.1, 132.3, 134.8, 159.4, 165.5, 168.4.

MS (ESI): m/z = 332.06 [M + Na]+.

HRMS (EI, 70 eV): m/z [M]+ calcd for C16H15N5O2: 309.1226; found: 309.1222.


#

1-({(3aR,5R,6S,6aR)-5-[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-yloxy}methyl)-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline (2e)

Yield: 0.240 g (54%); brown gum.

IR (neat): 2986, 2935, 2099, 1639, 1377, 1215, 1162, 1074, 1022, 849, 758 cm–1.

1H NMR (CDCl3, 600 MHz): δ = 1.23 (s, 3 H), 1.32 (s, 3 H), 1.39 (s, 3 H), 1.50 (s, 3 H), 3.22–3.25 (m, 2 H), 3.97–4.03 (m, 2 H), 4.11–4.13 (m, 1 H), 4.17 (d, J = 3.0 Hz, 1 H), 4.29–4.31 (m, 1 H), 4.54–4.58 (m, 1 H), 4.61–4.66 (m, 1 H), 4.71 (d, J = 4.2 Hz, 1 H), 4.91 (d, J = 12 Hz, 1 H), 5.01 (d, J = 12 Hz, 1 H), 5.88 (d, J = 3.6 Hz, 1 H), 7.33–7.39 (m, 3 H), 7.84–7.86 (m, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 25.0, 26.0, 26.6, 26.7, 28.8, 44.6, 63.3, 67.1, 72.1, 80.9, 81.0, 82.1, 105.1, 108.8, 111.6, 124.3, 125.6, 127.7, 128.2, 129.2, 132.1, 132.3, 138.6.

MS (ESI): m/z = 465.97 [M + Na]+.

HRMS (EI, 70 eV): m/z [M]+ calcd for C23H29N3O6: 443.2056; found: 443.2049.


#

1-Vinyl-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline (2f)

Yield: 0.079 g (40%); yellow solid; mp 110–112 °C.

IR (KBr): 3062, 2930, 2836, 1450, 1300, 1158, 1002, 753 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 3.20, 4.56 (2 H each, comprising AA′XX′ system), 5.49 (dd, J = 1.5, 11.1 Hz, 1 H), 6.31 (dd, J = 1.8, 17.4 Hz, 1 H), 6.98 (dd, J = 11.1, 17.4 Hz, 1 H), 7.33–7.41 (m, 3 H), 7.71 (d, J = 6.9 Hz, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 29.2, 44.6, 117.6, 124.7, 124.8, 125.1, 127.7, 128.5, 128.9, 132.9, 140.5.

HRMS (EI, 70 eV): m/z [M]+ calcd for C12H11N3: 197.0953; found: 197.0944.


#

1-(Phenyl)-6,7-dihydro-5H-benzo[c][1,2,3]triazolo[1,5-a]azepine (3a)

Yield: 0.144 g (55%); yellow solid; mp 101–103 °C.

IR (KBr): 3059, 2926, 2856, 1605, 1448, 1361, 991, 768 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 2.44, 2.76, 4.36 (2 H each, forming AA′BB′XX′ system), 7.24–7.40 (m, 7 H), 7.71 (dd, J = 1.5, 7.8 Hz, 2 H).

13C NMR (CDCl3, 75 MHz): δ = 30.2, 30.9, 45.8, 127.1, 127.8, 127.9, 128.5, 128.9, 129.7, 129.8, 131.0, 132.9, 138.9, 143.6.

MS (ESI): m/z = 284.12 [M + Na]+.

HRMS (ESI): m/z [M + Na]+ calcd for C17H15N3Na: 284.1164; found: 284.1156.


#

1-(4-Methoxyphenyl)-6,7-dihydro-5H-benzo[c]-[1,2,3]triazolo[1,5-a]azepine (3b)

Yield: 0.117 g (40%); brown solid; mp 108–110 °C.

IR (KBr): 2935, 1610, 1512, 1465, 1359, 1296, 1248, 1180, 1025, 837, 771 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 2.42, 2.75, 4.34 (2 H each, forming AA′BB′XX′ system), 3.82 (s, 3 H), 6.89 (app d, J = 9.0 Hz, 2 H), 7.25–7.28 (m, 1 H), 7.33 (d, J = 7.2 Hz, 1 H), 7.37–7.39 (m, 2 H), 7.64 (app d, J = 9.0 Hz, 2 H).

13C NMR (CDCl3, 75 MHz): δ = 30.3, 30.9, 45.9, 55.2, 113.9, 123.6, 127.2, 128.0, 128.5, 128.9, 129.6, 129.8, 132.3, 138.9, 143.5, 159.4.

MS (ESI): m/z = 292.23 [M + H]+.

HRMS (ESI): m/z [M + Na]+ calcd for C18H17N3NaO: 314.1269; found: 314.1261.


#

1-(4-Nitrophenyl)-6,7-dihydro-5H-benzo[c][1,2,3]triazolo[1,5-a]azepine (3c)

Yield: 0.153 g (50%); yellow solid; mp 178–180 °C.

IR (KBr): 2939, 2860, 1601, 1512, 1349, 1251, 1112, 989, 858, 759 cm–1.

1H NMR (CDCl3, 600 MHz): δ = 2.47, 2.77, 4.38 (2 H each, forming AA′BB′XX′ system), 7.31–7.35 (m, 2 H), 7.44–7.47 (m, 2 H), 7.94 (d, J = 8.4 Hz, 2 H), 8.21 (d, J = 9.0 Hz, 2 H).

13C NMR (CDCl3, 150 MHz): δ = 30.1, 31.0, 46.0, 123.9, 126.9, 127.4, 127.5, 128.8, 130.2, 130.5, 134.6, 137.6, 139.1, 141.3, 147.1.

MS (ESI): m/z = 328.97 [M + Na]+.

HRMS (EI, 70 eV): m/z [M]+ calcd for C17H14N4O2: 306.1117; found: 306.1121.


#

1-(2,4-Dimethoxypyrimidin-5-yl)-6,7-dihydro-5H-benzo[c][1,2,3]triazolo[1,5-a]azepine (3d)

Yield: 0.104 g (32%); brown liquid.

IR (neat): 2949, 2867, 2097, 1693, 1616, 1559, 1484, 1393, 1354, 1281, 1196, 1075, 1020, 753 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 2.47, 2.74, 4.41 (2 H each, forming AA′BB′XX′ system), 3.61 (s, 3 H), 4.03 (s, 3 H), 7.03 (d, J = 7.5 Hz, 1 H), 7.19–7.28 (m, 1 H), 7.32–7.36 (m, 2 H), 8.53 (s, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 30.1, 31.1, 46.1, 53.6, 54.9, 106.7, 126.9, 127.9, 128.1, 129.5, 135.3, 136.8, 138.1, 158.8, 165.2, 167.9.

MS (ESI): m/z = 346.23 [M + Na]+.

Anal. Calcd for C17H17N5O2: C, 63.15; H, 5.30; N, 21.66. Found: C, 63.19; H, 5.27; N, 21.72.


#

1-({(3aR,5R,6S,6aR)-5-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-yl-oxy}methyl)-6,7-dihydro-5H-benzo[c][1,2,3]triazolo[1,5-a]azepine (3e)

Yield: 0.174 g (38%); yellow liquid.

IR (neat): 2985, 2936, 2097, 1641, 1454, 1377, 1216, 1162, 1075, 1022, 849, 756 cm–1.

1H NMR (CDCl3, 600 MHz): δ = 1.29 (s, 3 H), 1.31 (s, 3 H), 1.40 (s, 3 H), 1.50 (s, 3 H), 2.41–2.48 (m, 2 H), 2.62–2.68 (m, 2 H), 3.95–4.01 (m, 2 H), 4.12–4.15 (m, 2 H), 4.28–4.34 (m, 2 H), 4.41–4.46 (m, 1 H), 4.67 (d, J = 3.6 Hz, 1 H), 4.72 (d, J = 11.4 Hz, 1 H), 4.83 (d, J = 11.4 Hz, 1 H), 5.87 (d, J = 3.6 Hz, 1 H), 7.35–7.43 (m, 3 H), 7.62 (dd, J = 1.5, 7.5 Hz, 1 H).

13C NMR (CDCl3, 150 MHz): δ = 25.3, 26.2, 26.8, 26.81, 30.3, 31.1, 46.0, 62.9, 67.2, 72.4, 81.2, 81.5, 82.3, 105.2, 108.9, 111.8, 126.9, 127.4, 129.1, 129.9, 129.91, 136.6, 138.7, 140.6.

MS (ESI): m/z = 458.25 [M + H]+.

HRMS (EI, 70 eV): m/z [M]+ calcd for C24H31N3O6: 457.2213; found: 457.2221.


#

Phenyl-5,6,7,8-tetrahydrobenzo[c][1,2,3]triazolo[1,5-a]azocine (4a)

Yield: 0.110 g (40%); white solid; mp 154–156 °C.

IR (KBr): 3059, 2933, 2859, 1603, 1445, 1353, 1253, 1218, 982, 768, 698 cm–1.

1H NMR (CDCl3, 600 MHz): δ = 1.53–1.61 (m, 1 H), 1.81–1.92 (m, 1 H), 2.13–2.17 (m, 2 H), 2.23–2.26 (m, 1 H), 2.95 (dd, J = 8.4, 13.8 Hz, 1 H), 3.61 (dd, J = 11.7, 14.1 Hz, 1 H), 4.81 (dd, J = 6.3, 14.1 Hz, 1 H), 7.21 (dd, J = 1.2, 7.8 Hz, 1 H), 7.23–7.29 (m, 4 H), 7.43 (br d, J = 7.2 Hz, 1 H), 7.47 (td, J = 1.6, 7.4 Hz, 1 H), 7.59–7.62 (m, 2 H).

13C NMR (CDCl3, 150 MHz): δ = 29.1, 29.3, 32.6, 48.1, 126.60, 126.65, 126.7, 127.6, 128.4, 130.1, 130.4, 130.6, 131.1, 133.3, 143.6, 143.7.

MS (ESI): m/z = 298.16 [M + Na]+.

HRMS (ESI): m/z [M+ H]+ calcd for C18H18N3: 276.1501; found: 276.1504.


#

1-(4-Carbomethoxyphenyl)-5,6,7,8-tetrahydrobenzo[c][1,2,3]triazolo[1,5-a]azocine (4b)

Yield: 0.143 g (43%); white solid; mp 180–182 °C.

IR (KBr): 3061, 2944, 2858, 1717, 1609, 1437, 1278, 1109, 978, 862, 775 cm–1.

1H NMR (CDCl3, 600 MHz): δ = 1.54–1.61 (m, 1 H), 1.81–1.89 (m, 1 H), 2.12–2.19 (m, 2 H), 2.23–2.27 (m, 1 H), 2.98 (dd, J = 8.4, 13.8 Hz, 1 H), 3.62 (dd, J = 11.7, 14.1 Hz, 1 H), 3.89 (s, 3 H), 4.82 (dd, J = 6.3, 14.1 Hz, 1 H), 7.19 (dd, J = 0.6, 7.8 Hz, 1 H), 7.27 (td, J = 1.2, 8.4 Hz, 1 H, overlapped by solvent peak), 7.45 (br d, J = 7.2 Hz, 1 H), 7.50 (td, J = 1.2, 7.5 Hz, 1 H), 7.69 (app d, J = 8.4 Hz, 2 H), 7.95 (app d, J = 9.0 Hz, 2 H).

13C NMR (CDCl3, 150 MHz): δ = 29.0, 29.2, 32.7, 48.2, 52.1, 126.2, 126.4, 126.8, 129.0, 129.8, 129.9, 130.5, 130.9, 134.3, 135.6, 142.7, 143.6, 166.9.

MS (ESI): m/z = 356.23 [M + Na]+.

HRMS (ESI): m/z [M + Na]+ calcd for C20H19N3NaO2: 356.1375; found: 356.1382.


#

1-(4-Methoxyphenyl)-5,6,7,8-tetrahydrobenzo[c][1,2,3]triazolo[1,5-a]azocine (4c)

Yield: 0.116 g (38%); yellow solid; mp 158–160 °C.

IR (KBr): 2926, 2851, 1614, 1516, 1471, 1356, 1297, 1251, 1179, 1108, 1010, 835, 759 cm–1.

1H NMR (CDCl3, 600 MHz): δ = 1.52–1.59 (m, 1 H), 1.79–1.87 (m, 1 H), 2.11–2.16 (m, 2 H), 2.21–2.25 (m, 1 H), 2.94 (dd, J = 8.4, 13.8 Hz, 1 H), 3.59 (dd, J = 11.4, 14.4 Hz, 1 H), 3.78 (s, 3 H), 4.78 (dd, J = 6.0, 13.8 Hz, 1 H), 6.82 (app d, J = 9.0 Hz, 2 H), 7.19 (dd, J = 1.2, 7.8 Hz, 1 H), 7.25 (td, J = 1.2, 7.5 Hz, 1 H), 7.41 (br d, J = 7.8 Hz, 1 H), 7.46 (td, J = 1.2, 7.5 Hz, 1 H), 7.53 (app d, J = 9.0 Hz, 2 H).

13C NMR (CDCl3, 75 MHz): δ = 29.1, 29.2, 32.6, 48.1, 55.1, 113.8, 123.7, 126.6, 126.7, 127.9, 130.0, 130.3, 130.5, 132.5, 143.5, 143.6, 159.1.

MS (ESI): m/z = 306.28 [M + H]+.

HRMS (ESI): m/z [M + Na]+ calcd for C19H19N3NaO: 328.1426; found: 328.1425.


#

Synthesis of 5-(5,6-Dihydro[1,2,3]triazolo[5,1-a]isoquinolin-1-yl)pyrimidine-2,4(1H,3H)-dione (11a); Typical Procedure

To a well-stirred solution of 2d (309 mg, 1.0 mmol) in anhydrous MeCN (7.0 mL) was added anhydrous NaI (90 mg, 3.0 mmol) followed by chlorotrimethylsilane (0.4 mL, 3.0 mmol) under an argon atmosphere. The reaction mixture was then stirred at r.t. for 20 h. The solvent was evaporated under reduced pressure and the residue was triturated with aqueous sodium metabisulfite solution (3 mL) and filtered, washed with H2O (3 mL) and dried to furnish the pure product 11a.

The same procedure was adopted for the conversion of compound 3d into product 11b.

Yield: 0.239 g (85%); colourless solid; mp >300 °C.

IR (KBr): 3427, 3159, 3052, 2830, 1716, 1672, 1485, 1425, 1209, 1181, 993, 773, 637 cm–1.

1H NMR (DMSO-d 6, 500 MHz): δ = 3.21, 4.56 (2 H each, comprising AA′XX′ system), 7.26–7.34 (m, 3 H), 7.39 (br d, J = 7.5 Hz, 1 H), 7.69 (d, J = 6.0 Hz, 1 H), 11.24 (d, J = 4.5 Hz, 1 H), 11.35 (s, 1 H).

13C NMR (DMSO-d 6, 75 MHz): δ = 28.3, 44.5, 104.6, 124.5, 125.0, 127.3, 128.3, 128.9, 130.9, 132.9, 134.6, 142.6, 151.2, 162.5.

MS (ESI): m/z = 304.03 [M + Na]+.

Anal. Calcd for C14H11N5O2: C, 59.78; H, 3.94; N, 24.90. Found: C, 59.83; H, 3.91; N, 24.87.


#

5-(6,7-Dihydro-5H-benzo[c][1,2,3]triazolo[1,5-a]azepine-1-yl)pyrimidine-2,4(1H,3H)-dione (11b)

Yield: 0.242 g (82%); light-yellow solid; mp >300 °C.

IR (KBr): 3475, 3169, 3059, 2827, 1716, 1671, 1504, 1416, 1204, 1176, 990, 768, 638 cm–1.

1H NMR (DMSO-d 6, 500 MHz): δ = 2.33, 2.59, 4.26 (2 H each, forming AA′BB′XX′ system), 7.24 (d, J = 7.5 Hz, 1 H), 7.28 (t, J = 7.5 Hz, 1 H), 7.34 (t, J = 7.3 Hz, 1 H), 7.39 (d, J = 7.5 Hz, 1 H), 7.62 (d, J = 6.0 Hz, 1 H), 11.13 (d, J = 5.0 Hz, 1 H), 11.19 (s, 1 H).

13C NMR (DMSO-d 6, 75 MHz): δ = 29.6, 30.6, 45.7, 104.0, 126.9, 127.8, 129.2, 129.6, 135.3, 136.4, 138.4, 142.2, 151.1, 162.4.

MS (ESI): m/z = 318.06 [M + Na]+.

HRMS (ESI): m/z [M + Na]+ calcd for C15H13N5NaO2: 318.0967; found: 318.0963.


#

Synthesis of Bisheteroannulated Products 13a–d; General Procedure

To a well-stirred solution of o-iodo-azide 7a–d (1 mmol) in anhydrous DMF (8 mL) were added successively [Pd(PPh3)2Cl2] (24.6 mg, 0.035 mmol), CuI (13.3 mg, 0.07 mmol) and Et3N (0.71 mL, 5.0 mmol). The reaction mixture was then stirred under argon for 20 min. A solution of 1,3-diethynyl benzene 12 (0.6 mmol) dissolved in anhydrous DMF (1 mL) was then added dropwise and the reaction mixture was heated at 115 °C (except for 7d, for which heating was carried out at 150 °C) for a few hours until consumption of the starting materials was observed (TLC). Upon completion of the reaction, the solvent was removed in vacuo, the residue was mixed with H2O (30 mL) and then extracted with EtOAc (2 × 25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified through silica gel (100–200 mesh) column chromatography (EtOAc–PE, 40–50% v/v) to afford the corresponding product 13a–d.


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1,3-Bis(8H-[1,2,3]triazolo[5,1-a]isoindol-3-yl)benzene (13a)

Yield: 0.210 g (54%); greenish solid; mp 226–228 °C.

IR (KBr): 3398, 1664, 1616, 1343, 1179, 891, 767 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 5.42 (s, 4 H), 7.41–7.57 (m, 6 H), 7.69 (t, J = 7.7 Hz, 1 H), 7.99–8.05 (m, 4 H), 8.59 (s, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 50.9, 121.7, 124.1, 125.5, 126.5, 128.0, 128.5, 129.0, 129.5, 132.0, 139.0, 139.3, 141.1.

FAB-MS: m/z = 389.4 [M + H]+.

HRMS (ESI): m/z [M + Na]+ calcd for C24H16N6Na: 411.1334; found: 411.1339.


#

1,3-Bis(5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinolin-1-yl)benzene (13b)

Yield: 0.208 g (50%); yellow solid; mp 262–264 °C.

IR (KBr): 3052, 2928, 1732, 1610, 1347, 1241, 1190, 910, 770, 739 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 3.26, 4.61 (4 H each, comprising two identical AA′XX′ systems), 7.17 (t, J = 7.4 Hz, 2 H), 7.26–7.35 (m, 4 H), 7.57–7.65 (m, 3 H), 7.79 (d, J = 7.5 Hz, 2 H), 8.07 (s, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 29.3, 44.9, 124.6, 124.9, 127.7, 128.4, 128.66, 128.7, 129.18, 129.2, 129.5, 132.3, 132.7, 142.6.

FAB-MS: m/z = 417.5 [M + H]+.

HRMS (ESI): m/z [M + Na]+ calcd for C26H20N6Na: 439.1647; found: 439.1649.


#

1,3-Bis(6,7-dihydro-5H-benzo[c][1,2,3]triazolo[1,5-a]azepin-1-yl)benzene (13c)

Yield: 0.209 g (47%); yellow solid; mp 158–160 °C.

IR (KBr): 2944, 2867, 2096, 1603, 1448, 1356, 1248, 768 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 2.38, 2.61, 4.30 (4 H each, forming two identical AA′BB′XX′ systems), 7.13–7.17 (m, 2 H), 7.23–7.26 (m, 2 H), 7.29–7.30 (m, 4 H), 7.39 (t, J = 7.8 Hz, 1 H), 7.77 (dd, J = 1.0, 7.5 Hz, 2 H), 7.93 (s, 1 H).

13C NMR (CDCl3, 150 MHz): δ = 30.2, 30.9, 45.8, 125.5, 126.7, 127.0, 127.6, 128.9, 129.1, 129.5, 129.8, 131.3, 133.0, 138.6, 143.2.

FAB-MS: m/z = 445.5 [M + H]+.

HRMS (ESI): m/z [M + Na]+ calcd for C28H24N6Na: 467.1960; found: 467.1982.


#

1,3-Bis(5,6,7,8-tetrahydrobenzo[c][1,2,3]triazolo[1,5-a]azocin-1-yl)benzene (13d)

Yield: 0.128 g (27%); white solid; mp 240–242 °C.

IR (KBr): 3048, 2948, 2092, 1616, 1450, 1352, 1251, 889, 771 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 1.46–1.60 (m, 2 H), 1.73–1.83 (m, 3 H), 2.03–2.08 (m, 1 H), 2.11–2.22 (m, 4 H), 2.73 (dd, J = 8.3, 13.8 Hz, 1 H), 2.94 (dd, J = 8.5, 13.5 Hz, 1 H), 3.52–3.64 (m, 2 H), 4.72–4.82 (m, 2 H), 7.02 (d, J = 7.5 Hz, 1 H), 7.13 (t, J = 7.0 Hz, 2 H), 7.20 (br, 1 H), 7.30 (d, J = 7.5 Hz, 2 H), 7.39–7.51 (m, 4 H), 7.60 (br, 1 H), 7.87 (br, 1 H).

13C NMR (CDCl3, 150 MHz): δ = 28.9, 29.0, 29.1, 29.2, 30.9, 32.6, 48.4, 124.7, 125.9, 126.5, 126.7, 126.76, 126.82, 128.8, 129.3, 129.9, 130.1, 130.3, 130.37, 130.40, 130.6, 130.8, 143.0; additional peaks are attributed to conformational equilibrium.

MS (ESI): m/z = 495.32 [M + Na]+.

HRMS (ESI): m/z [M + Na]+ calcd for C30H28N6Na: 495.2273; found: 495.2292.


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Synthesis of 1a′

To a well-stirred solution of o-iodo-azide 7a (259 mg, 1 mmol) in anhydrous DMF (6 mL) were added successively [Pd(PPh3)2Cl2] (10.5 mg, 0.015 mmol), CuI (5.7 mg, 0.03 mmol) and K2CO3 (276 mg, 2.0 mmol), and the reaction mixture was heated at 60 °C for 4 h under balloon pressure of acetylene gas. After completion of the reaction (TLC), the solvent was removed in vacuo; the residue was mixed with H2O (50 mL) and extracted with EtOAc (2 × 25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified through silica gel (100–200 mesh) column chromatography (EtOAc–PE, 20% v/v) to afford the product 1a′ (95 mg, 60%). The acyclic product 14a (n = 1) was also isolated (69 mg, 24%) from this reaction mixture.


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8H-[1,2,3]Triazolo[5,1-a]isoindole (1a′)

Yield: 0.094 g (60%); black solid; mp 84–86 °C.

IR (KBr): 3131, 2932, 1447, 1410, 1263, 1217, 1151, 1093, 974, 850, 772 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 5.35 (s, 2 H), 7.39–7.55 (m, 3 H), 7.66 (d, J = 7.2 Hz, 1 H), 7.84 (s, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 50.9, 121.5, 124.0, 127.4, 128.3, 128.7, 140.9, 142.7.

MS (ESI): m/z = 158.14 [M + H]+.

HRMS (EI, 70 eV): m/z [M]+ calcd for C9H7N3: 157.064; found: 157.0646.


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1-(2-Iodobenzyl)-1H-1,2,3-triazole (14a)

Yield: 0.068 g (24%); white solid; mp 63–64 °C.

IR (KBr): 3078, 1469, 1435, 1209, 1114, 1084, 1010, 736 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 5.66 (s, 2 H), 7.03–7.08 (m, 2 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.60 (s, 1 H), 7.73 (s, 1 H), 7.90 (d, J = 7.8 Hz, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 58.2, 98.5, 123.7, 129.0, 129.5, 130.3, 134.1, 137.3, 139.8.

MS (ESI): m/z = 307.95 [M + Na]+.

Anal. Calcd for C9H8IN3: C, 37.92; H, 2.83; N, 14.74. Found: C, 37.88; H, 2.81; N, 14.78.


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Synthesis of products 2–4a′

To a well-stirred solution of o-iodo-azide 7b–d (0.5 mmol) in anhydrous DMF (6 mL) were added successively CuI (2.9 mg, 0.015 mmol) and K2CO3 (138 mg, 1.0 mmol), and the reaction mixture was then heated at 60 °C for 4 h under balloon pressure of acetylene gas. After completion of the reaction (TLC), the solvent was removed in vacuo; the residue was mixed with H2O (30 mL) and extracted with EtOAc (2 × 25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the corresponding crude product 14b–d, which was used directly without further chromatographic purification.

To a well-stirred solution of crude intermediate 14b/14c in anhydrous DMF (5 mL) were added successively [Pd(PPh3)2Cl2] (17.5 mg, 0.025 mmol), K2CO3 (207 mg, 1.5 mmol) and TBAB (16 mg, 0.05 mmol). The reaction mixture was then heated (110 °C for 14b, 130 °C for 14c) for 4 h under an argon atmosphere. After completion of the reaction (TLC), the solvent was removed in vacuo; the residue was mixed with H2O (30 mL) and then extracted with EtOAc­ (2 × 25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified through silica gel (100–200 mesh) column chromatography (EtOAc–PE, 10–20% v/v) to afford the corresponding product 2a′/3a′.

The same reaction procedure was adopted for the synthesis of product 4a′ using crude intermediate 14d; however, in this case, Pd(OAc)2 (11 mg, 0.05 mmol) and NaHCO3 (84 mg, 1.0 mmol) were employed in place of [Pd(PPh3)2Cl2] and K2CO3 and the reaction was heated at 130 °C for 2.5 h.


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5,6-Dihydro[1,2,3]triazolo[5,1-a]isoquinoline (2a′)

Yield: 0.070 g (82%); white solid; mp 94–96 °C.

IR (KBr): 3117, 3066, 3023, 2975, 1666, 1485, 1457, 1425, 1346, 1295, 1244, 1183, 1107, 960, 835, 773 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 3.25, 4.61 (2 H each, comprising AA′XX′ system), 7.34–7.38 (m, 3 H), 7.58–7.59 (m, 1 H), 7.95 (s, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 28.6, 44.4, 124.2, 124.5, 127.7, 128.35, 128.39, 129.2, 131.8, 133.7.

MS (ESI): m/z = 172.18 [M + H]+.

HRMS (ESI): m/z [M + Na]+ calcd for C10H9N3Na: 194.0694; found: 194.0685.


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6,7-Dihydro-5H-benzo[c][1,2,3]triazolo[1,5-a]azepine (3a′)

Yield: 0.048 g (52%); pale-yellow liquid.

IR (neat): 3129, 3065, 2942, 2862, 1451, 1359, 1246, 1200, 1108, 1022, 981, 768 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 2.45, 2.72, 4.44 (2 H each, forming AA′BB′XX′ system), 7.32–7.38 (m, 3 H), 7.39–7.47 (m, 1 H), 7.80 (s, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 30.3, 30.6, 46.3, 127.0, 127.2, 128.2, 129.6, 129.8, 131.4, 137.8, 138.3.

MS (ESI): m/z = 208.01 [M + Na]+.

HRMS (ESI): m/z [M + Na]+ calcd for C11H11N3Na: 208.0851; found: 208.0844.


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5,6,7,8-Tetrahydrobenzo[c][1,2,3]triazolo[1,5-a]azocine (4a′)

Yield: 0.042 g (42%); pale-yellow solid; mp 114–116 °C.

IR (KBr): 3132, 3012, 2939, 2854, 1440, 1354, 1237, 1202, 1104, 964, 855, 767 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 1.98 (br, 4 H), 2.45 (br, 2 H), 4.27 (br, 2 H), 7.29–7.32 (m, 2 H), 7.34 (d, J = 7.5 Hz, 1 H), 7.43–7.47 (m, 1 H), 7.68 (s, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 28.6, 28.9, 32.7, 48.4, 126.1, 126.3, 129.6, 130.2, 130.5, 132.4, 137.6, 142.8.

MS (ESI): m/z = 222.04 [M + Na]+.

HRMS (ESI): m/z [M + Na]+ calcd for C12H13N3Na: 222.1007; found: 222.1003.


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Acknowledgment

K.B. thanks CSIR, New Delhi, India for a fellowship.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis. Included are the preparation and characterization data of 7a–d, X-ray crystallographic data of 4a and copies of 1H and 13C NMR spectra of compounds 7a–d, 1–4, 11a–b, 13a–d, 1a′–4a′, 14a.
  • Supporting Information


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Figure 1 Important fused 1,2,3-triazoles
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Scheme 1 Synthesis of 1,2,3-triazole-fused heterocycles 1–4
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Scheme 2 Synthesis of starting substrates 7a–d. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0–5 °C, 2 h; (b) NaN3, DMF, r.t., 2 h, 94% (for 7a); (c) NaN3, DMF, 90 °C, 1 h, 90–92% (for 7b–d).
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Scheme 3 Synthesis of uracil derivatives 11a and 11b
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Scheme 4 Synthesis of fused 1,2,3-triazoles 1a′, 2a′, 3a′ and 4a′ by employing acetylene (gas). Conditions A: [Pd(PPh3)2Cl2], K2CO3, TBAB, DMF, 110–130 °C; Conditions B: Pd(OAc)2, NaHCO3, TBAB, DMF, 130 °C.
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Figure 2 ORTEP representation of 4a