Tandem CH-Activation-Imine-Formation Reaction: A New Route to Imidazo[2,1-a]phthalazines

Abstract

A general and efficient synthesis of imidazo[2,1-a]phthalazines by palladium- and copper-mediated coupling of N-aminoimidazoles with 2-haloaryl aldehydes with concurrent imine formation is described. This new synthesis of the imidazo[2,1-a]phthalazine ring system allows for facile introduction of different substituents around the entire core.

Imidazo[2,1-a]phthalazines have not been extensively explored as templates for drug discovery despite reported antihypertensive and anti-inflammatory activity. [¹] One explanation could be that no efficient synthesis allowing facile SAR explorations around this heterocycle has been reported. [¹] [²] Most published procedures start from or require construction of the pththalazine core and are therefore limited by the commercial availability or synthetic accessibility of suitable precursors. The most versatile synthesis, allowing for various substituents at the imidazole and pyridazine rings, involves direct cyclization of 1-aminophthalazines with α-halocarbonyl compounds. [¹c] The yields for substrates having nonaromatic substituents on the imidazole moiety similar to the ones described in this paper vary from 6-33%. No substitution around the phenyl moiety is reported.

Interested in a route that would allow facile introduction of different substitutions on the imidazo as well as the phenyl portions of the imidazo[2,1-a]phthalazine core, we investigated a reaction sequence between N-aminoimidazoles and 2-haloaryl aldehydes (Scheme  [¹] ).

Unlike substituted 1-aminophthalazines, a variety of substituted 2-haloaryl aldehydes are commercially available. N-Amination of readily available substituted imidazoles furnishes N-aminoimidazoles such as 1 [³] which contain the nitrogen of the future pyridazine ring. Palladium-catalyzed arylation of azole CH bonds with aryl halides has developed into a powerful synthetic methodology [4] and in situ benzaldehyde imine formation under cross-coupling conditions is precedented. [5] Thus, we anticipated that a mixture of N-aminoimidazole 1 and 2-bromobenzaldehyde (2) would undergo coupling and imine formation to give the desired imidazo[2,1-a]phthalazine 4.

After reviewing several published procedures, we subjected a mixture of N-aminoimidazole 1 and 1.1 equivalents of 2-bromobenzaldehyde (2) to typical conditions for direct arylations of azoles [10 mol% Pd(OAc)₂, 20 mol% PPh₃, 2 equiv CuI, 1 equiv Cs₂CO₃, DMF, 140 ˚C, 12 h] [4] and isolated 4 in around 30% yield. We increased the yield to 40-46% by shortening the reaction time to one hour. Regardless of the reaction time, we did not observe either of the two anticipated intermediates 3a or 3b by LC-MS during the course of the reaction. However, imine 3a was formed quantitatively (LC-MS) in reactions having only one of the metals present (Table  [¹] , entries 6 and 7). [6] We subjected imine 3a to the standard conditions with palladium and copper(I) iodide. We observed conversion to 4 and isolated it in the same yield as in the original reaction between 1 and 2. This demonstrated that imine 3a is a competent substrate under these arylation conditions and may be an intermediate in the reaction of 1 and 2. It can be hypothesized that once formed, 3a generates a palladacycle after oxidative insertion of the palladium into the aryl bromide bond and therefore acts as its own ligand. [7] This hypothesis is supported by the fact that reducing the phosphine ligand ratio (Table  [¹] , entry 3), changing the ligand (entry 2), [8] or removing it altogether (entry 4) [9] does not significantly influence the outcome of the reaction. However, since the yield was consistently slightly better in the presence of triphenylphosphine, it was included in the reaction conditions.

The overall yield of 46% seems modest, but one has to keep in mind that this is a two-step process without the use of any protecting groups. We already applied the optimized conditions for azole arylations published by the experts in the field. [4] Thus, we concentrated on exploring substituents around the ring after unsatisfying results from the most commonly applied changes in screening conditions such as using Pd₂(dba)₃ instead of Pd(OAc)₂, exchanging the alternative base CsF for Cs₂CO₃, increasing or decreasing the reaction temperature and lowering the amount of copper to one equivalent. Therefore, our best conditions giving consistently moderate yields between 40-46% proved to be the original conditions with a shortened reaction time of one hour.

No significant amount of isolable by-product(s) was observed. However, decomposed starting materials, possibly deaminated aminoimidazole or debrominated benzaldehyde, would be difficult to observe by LC-MS and may be lost during the workup. Minor NMR signals characteristic of aldehyde and additional ethyl ester protons were observed in the ^¹H NMR of the crude after workup.

With our optimized conditions in hand, we investigated the scope of the reaction by varying substitutions around the benzaldehyde (Table  [²] ) and the 1-aminoimidazole precursor (Table  [³] ).

Table 2 2-Bromobenzaldehyde Variations

Entry	Aldehyde	Product		Yield (%)b
1a		4		46
2		5		39
3		6		20
4		7		43
5		8		44
6		9		28
7		10		27
8		11		7
a 2-Iodobenzaldehyde did not influence the yield. b Isolated yields.

Both electron donating and electron withdrawing groups appear equally tolerated (Table  [²] , entries 1-7). We believe the aldehyde/imine functional groups dominate the electronics of the ring and that additional substituents have only minor effects on yield.

We also investigated the reaction using 2-bromoacetophenone as a model to install substituents on the pyridazine ring (Table  [²] , entry 8). The fact that ketones are in general less reactive than aldehydes in intermolecular imine formations may explain the very low yield.

Varying the 1-aminoimidazole precursor furnished the desired imidazo[2,1-a]phthalazines 12-14 (Table  [³] ) in comparable yields to the ones obtained by using different aldehydes.

Table 3 1-Aminoimidazole Variations

Entry	Imidazole	Product		Yield (%)a
1		12		25
2		13		45
3		14		31
a Isolated yields.

In summary, we have developed a general and efficient one-step synthesis for imidazo[2,1-a]phthalazines via palladium- and copper-mediated coupling of N-aminoimidazoles with 2-bromoaryl aldehydes with preceding or concurrent imine formation. This method allows the synthesis of diversely substituted derivatives on the imidazo and benzene part of the core structure. Overall, the yields are low to moderate, but acceptable taking into account the ease of this reaction and the lack of efficient alternative one-step procedures.

All chemicals used, including anhydrous solvents, were of reagent grade and used as supplied. Chromatography was carried out on silica gel, TLC on silica plates (Merck, Art. 5554). In general, the course of reactions was followed by TLC and/or LC-MS. NMR spectra were obtained on a Bruker DPX-400 spectrometer at 400 MHz. LC-MS data was recorded utilizing the electrospray (ESI) technique. HRMS data was acquired using a Thermo LTQFT Ultra Mass Spectrometer in APCI⁺ mode. This instrument achieved a mass resolution of greater than 100 000.

Imidazo[2,1- a ]phthalazines; General Procedure

In a sealed tube, 1-aminoimidazole [¹0] (0.59 mmol), bromobenzaldehyde (0.65 mmol, 1.1 equiv), PPh₃ (31 mg, 0.12 mmol, 0.2 equiv), Pd(OAc)₂ (13.3 mg, 0.06 mmol, 0.1 equiv), Cs₂CO₃ (192.2 mg, 0.59 mmol, 1.0 equiv), and CuI (224.9 mg, 1.18 mmol, 2.0 equiv) were dissolved in anhyd DMF (2 mL). The tube was evacuated and flushed with argon before it was heated at 140 ˚C for 1 h. After cooling to r.t., EtOAc (20 mL) was added and the mixture was extracted with NH₄OH (6 M, 20 mL). The aqueous layer was re-extracted with EtOAc (20 mL) and the combined organic layers were washed with brine (10 mL) and dried (MgSO₄). After removal of the solvent, the crude residue was purified on silica gel (gradients: 0-75% EtOAc in hexane).

Ethyl 2-Methylimidazo[2,1- a ]phthalazine-3-carboxylate (4)

Starting from ethyl 3-amino-5-methyl-3H-imidazole-4-carboxylate (1; 100 mg, 0.59 mmol) and 2-bromobenzaldehyde (2; 120 mg, 0.65 mmol), compound 4 was obtained as a white solid (69 mg, 46%).

^¹H NMR (400 MHz, CDCl₃): δ = 8.85 (s, 1H), 8.61 (dd, J = 8.0, 0.5 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.92 (m, 1 H), 7.78 (m, 1 H), 4.48 (q, J = 7.2 Hz, 2 H), 2.78 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 158.9 (C=O), 147.7, 144.8 (CH), 137.1, 132.3 (CH), 129.1 (CH), 126.5 (CH), 123.4, 122.1, 121.9 (CH), 116.3, 59.7 (CH₂), 15.4 (CH₃), 13.4 (CH₃).

HRMS (APCI⁺): m/z [M + H]⁺ calcd for C₁₄H₁₄N₃O₂: 256.1080; found: 256.1078.

Ethyl 8-Methoxy-2-methylimidazo[2,1- a ]phthalazine-3-carboxylate (5)

Starting from 1 (100 mg, 0.59 mmol) and 2-bromo-5-methoxy­benzaldehyde (140 mg, 0.65 mmol), compound 5 was obtained as a white solid (66 mg, 39%).

^¹H NMR (400 MHz, CDCl₃): δ = 8.75 (s, 1 H), 8.49 (d, J = 8.9 Hz, 1 H), 7.24 (d, J = 2.3 Hz, 1 H), 4.47 (q, J = 7.2 Hz, 2 H), 3.96 (s, 3 H), 2.74 (s, 3 H), 1.44 (t, J = 7.2 Hz, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 160.9, 160.2 (C=O), 149.2, 145.0 (CH), 138.7, 124.9, 124.7 (CH), 123.6 (CH), 118.8, 116.7, 107.5 (CH), 60.5 (CH₂), 55.8 (CH₃), 16.6 (CH₃), 14.5 (CH₃).

HRMS (APCI⁺): m/z [M + H]⁺ calcd for C₁₅H₁₆N₃O₃: 286.1186; found: 286.1184.

Ethyl 2-Methyl-7,9-dioxa-1,3a,4-triazadicyclopenta[ a , g ]naphthalene-3-carboxylate (6)

Starting from 1 (100 mg, 0.59 mmol) and 6-bromobenzo[1,3]di­oxole-5-carbaldehyde (149 mg, 0.65 mmol), compound 6 was obtained as a white solid (36 mg, 20%).

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.91 (s, 1 H), 7.78 (s, 1 H), 7.62 (s, 1 H), 6.31 (s, 2 H), 4.35 (q, J = 7.2 Hz, 2 H), 2.62 (s, 3 H), 1.34 (t, J = 7.2 Hz, 3 H).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.1 (C=O), 152.4, 149.9, 148.4, 144.5 (CH), 137.9, 121.1, 119.6, 115.9, 105.2 (CH), 102.9 (CH), 99.8 (CH₂), 59.9 (CH₂), 16.1 (CH₃), 14.3 (CH₃).

HRMS (APCI⁺): m/z [M + H]⁺ calcd for C₁₅H₁₄N₃O₄: 300.0978; found: 300.0977.

Ethyl 2-Methyl-8-trifluoromethylimidazo[2,1- a ]phthalazine-3-carboxylate (7)

Starting from 1 (100 mg, 0.59 mmol) and 2-bromo-5-trifluoromethylbenzaldehyde (165 mg, 0.65 mmol), compound 7 was obtained as a white solid (83 mg, 43%).

^¹H NMR (400 MHz, CDCl₃): δ = 8.92 (s, 1 H), 8.73 (d, J = 8.4 Hz, 1 H), 8.24 (s, 1 H), 8.11 (dd, J = 8.4, 1.5 Hz, 1 H), 4.50 (q, J = 7.2 Hz, 2 H), 2.79 (s, 3 H), 1.47 (t, J = 7.2 Hz, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 159.8 (C=O), 149.6, 145.1 (CH), 136.9, 131.7 (q, J = 33.3 Hz, CCF₃), 129.2 (d, J = 3.0 Hz, CH), 126.7, 124.9 (d, J = 4.0 Hz, CH), 124.1 (CH), 123.4 (d, J = 273.0 Hz, CF₃), 122.4, 118.0, 60.9 (CH₂), 16.6 (CH₃), 14.4 (CH₃).

HRMS (APCI⁺): m/z [M + H]⁺ calcd for C₁₅H₁₃F₃N₃O₂: 324.0954; found: 324.0951.

Ethyl 8-Fluoro-2-methylimidazo[2,1- a ]phthalazine-3-carboxylate (8)

Starting from 1 (100 mg, 0.59 mmol) and 2-bromo-5-fluorobenzaldehyde (132 mg, 0.65 mmol), compound 8 was obtained as a white solid (65 mg, 40%).

^¹H NMR (400 MHz, CDCl₃): δ = 8.79 (s, 1 H), 8.62 (dd, J = 9.0, 5.1 Hz, 1 H), 7.64 (m, 1 H), 7.58 (dd, J = 8.2, 2.4 Hz, 1 H), 4.48 (q, J = 7.2 Hz, 2 H), 2.76 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 162.9 (d, J = 253 Hz, CF), 159.9 (C=O), 149.3, 144.5 (d, J = 3.4 Hz, CH), 137.8, 125.9 (d, J = 8.6 Hz, CH), 124.5 (d, J = 8.6 Hz, C), 122.4 (d, J = 24 Hz, CH), 121.4, 117.3, 112.3 (d, J = 22 Hz, CH), 60.1 (CH₂), 16.5 (CH₃), 14.5 (CH₃).

HRMS (APCI⁺): m/z [M + H]⁺ calcd for C₁₄H₁₃FN₃O₂: 274.0986; found: 274.0984.

Ethyl 9-Fluoro-2-methylimidazo[2,1- a ]phthalazine-3-carboxylate (9)

Starting from 1 (100 mg, 0.59 mmol) and 2-bromo-4-fluorobenzaldehyde (132 mg, 0.65 mmol), compound 9 was obtained as a white solid (47 mg, 29%).

^¹H NMR (400 MHz, CDCl₃): δ = 8.80 (s, 1 H), 8.22 (dd, J = 8.8, 2.5 Hz, 1 H), 7.96 (dd, J = 8.8, 5.1 Hz, 1 H), 7.48 (m, 1 H), 4.48 (q, J = 7.2 Hz, 2 H), 2.76 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 165.1 (d, J = 256 Hz, CF), 159.9 (C=O), 149.2, 144.7 (CH), 137.5 (d, J = 3.9 Hz, C), 130.6 (d, J = 9.5 Hz, CH), 126.8 (d, J = 11.0 Hz, C), 119.9, 119.2 (d, J = 24.0 Hz, CH), 117.6, 108.4 (d, J = 24.0 Hz, CH), 60.8 (CH₂), 16.6 (CH₃), 14.5 (CH₃).

HRMS (APCI⁺): m/z [M + H]⁺ calcd for C₁₄H₁₃FN₃O₂: 274.0986; found: 274.0984.

Ethyl 2-Methyl-1,3a,4,9-tetraazabenz[ e ]indene-3-carboxylate (10)

Starting from 1 (100 mg, 0.59 mmol) and 2-bromopyridine-3-carbaldehyde­ (121 mg, 0.65 mmol), compound 10 was obtained as a white solid (40 mg, 26%).

^¹H NMR (400 MHz, CDCl₃): δ = 9.22 (dd, J = 4.6, 1.5 Hz, 1 H), 8.87 (s, 1 H), 8.28 (dd, J = 8.2, 1.5 Hz, 1 H), 7.72 (dd, J = 8.2, 4.6 Hz, 1 H), 4.50 (q, J = 7.2 Hz, 2 H), 2.82 (s, 3 H), 1.47 (t, J = 7.2 Hz, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 159.9 (C=O), 155.9 (CH), 150.1, 144.8 (CH), 140.9, 137.9, 135.1 (CH), 124.8 (CH), 118.8, 118.1, 60.9 (CH₂), 16.7 (CH₃), 14.4 (CH₃).

HRMS (APCI⁺): m/z [M + H]⁺ calcd for C₁₃H₁₃N₄O₂: 257.1033; found: 257.1031.

Ethyl 2,6-Dimethylimidazo[2,1- a ]phthalazine-3-carboxylate (11)

Starting from 1 (100 mg, 0.59 mmol) and 1-(2-bromophenyl)eth­anone (130 mg, 0.65 mmol), compound 11 was obtained as a white solid (11 mg, 7%).

^¹H NMR (300 MHz, CDCl₃): δ = 8.61 (d, J = 8.0 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.88-7.86 (m, 1 H), 7.78-7.74 (m, 1 H), 4.47 (q, J = 7.2 Hz, 2 H), 2.92 (s, 3 H), 2.76 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 160.2 (C=O), 152.2, 148.6, 138.4, 132.7 (CH), 129.9 (CH), 125.8 (CH), 124.5, 123.3 (CH), 117.1, 60.5 (CH₂), 20.1 (CH₃), 16.5 (CH₃), 14.4 (CH₃).

HRMS (APCI⁺): m/z [M + H]⁺ calcd for C₁₅H₁₆N₃O₂: 270.1237; found: 270.1235.

Methyl Imidazo[2,1- a ]phthalazine-3-carboxylate (12)

Starting from methyl 3-amino-3H-imidazole-4-carboxylate (100 mg, 0.71 mmol, new reference for calculation of all additional reagents) and 2-bromobenzaldehyde (2; 144 mg, 0.78 mmol), compound 12 was obtained as a white solid (40 mg, 25%).

^¹H NMR (400 MHz, CDCl₃): δ = 8.91 (s, 1 H), 8.64 (dd, J = 8.1, 0.8 Hz, 1 H), 8.29 (s, 1 H), 7.99-7.93 (m, 2 H), 7.84-7.79 (m, 1 H), 3.99 (s, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 159.5 (C=O), 146.7 (CH), 140.1, 138.6 (CH), 133.6 (CH), 130.3 (CH), 127.7 (CH), 125.3, 123.1 (CH), 120.5, 51.9 (CH₃).

HRMS (APCI⁺): m/z [M + H]⁺ calcd for C₁₂H₁₀N₃O₂: 228.0767; found: 228.0766.

Ethyl 3-Methylimidazo[2,1- a ]phthalazine-2-carboxylate (13)

Starting from ethyl 1-amino-5-methyl-1H-imidazole-4-carboxylate (100 mg, 0.59 mmol) and 2 (120 mg, 0.65 mmol), compound 13 was obtained as a white solid (67 mg, 45%).

^¹H NMR (400 MHz, CDCl₃): δ = 8.69 (d, J = 8.0 Hz, 1 H), 8.68 (s, 1 H), 7.90-7.85 (m, 2 H), 7.73-7.69 (m, 1 H), 4.50 (q, J = 7.2 Hz, 2 H), 2.89 (s, 3 H), 1.48 (t, J = 7.2 Hz, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 158.9 (C=O), 147.7, 144.8 (CH), 137.1, 132.3 (CH), 129.1 (CH), 126.5 (CH), 123.4, 122.1, 121.9 (CH), 116.3, 59.7 (CH₂), 15.4 (CH₃), 13.4 (CH₃).

HRMS (APCI⁺): m/z [M + H]⁺ calcd for C₁₄H₁₄N₃O₂: 256.1080; found: 256.1078.

Benzimidazo[2,1- a ]phthalazine (14)

Starting from benzimidazol-1-ylamine (100 mg, 0.75 mmol, new reference for calculation of all additional reagents) and 2 (153 mg, 0.83 mmol), compound 14 was obtained as a beige solid (51 mg, 31%).

^¹H NMR (400 MHz, CDCl₃): δ = 8.72 (d, J = 7.4 Hz, 1 H), 8.61 (s, 1 H), 8.08 (d, J = 7.4 Hz, 1 H), 7.99 (d, J = 8.1 Hz, 1 H), 7.91-7.87 (m, 2 H), 7.79-7.74 (m, 1 H), 7.55-7.45 (m, 2 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 143.5 (CH), 142.1, 141.4, 133.0 (CH), 131.5, 130.7 (CH), 127.8 (CH), 125.5, 125.1 (CH), 124.6, 123.9 (CH), 123.1 (CH), 120.0 (CH), 111.2 (CH).

HRMS (APCI⁺): m/z [M + H]⁺ calcd for C₁₄H₁₀N₃: 220.0869; found: 220.0867.

Acknowledgment

We thank Chris Robak for HRMS experimentation. Additional thanks go to Dr. Matthew Netherton and Dr. Neil Moss for proofreading the manuscript.

References

• 1a Hardtmann GE. inventors; US Patent 3 711  481.  Chem. Abstr. 1973, 78, 84430
• 1b Razvi M. Ramalingam T. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1992,  31:  788 
  Search in Google Scholar
• 1c Catarzi D. Cecchi L. Colotta V. Conti G. Melani F. Filacchioni G. Martini C. Giusti L. Lucacchini A. Farmaco  1993,  48:  447 
  Search in Google Scholar
• 2a Castle RN. Takano S. J. Heterocycl. Chem.  1966,  3:  381 
  Search in Google Scholar
• 2b Barlin GB. Aust. J. Chem.  1986,  39:  1803 
  Search in Google Scholar
• 2c Mavel S. Thery I. Gueiffier A. Arch. Pharm. Pharm. Med. Chem.  2002,  335:  7 
  Search in Google Scholar
• 2d Solyom S. Hamori T. Borosy AP. Tarnawa I. Berzsenyi P. Pallagi I. Med. Chem. Res.  2002,  11:  39 
  Search in Google Scholar
• 2e Shubin KM. Kuznetsov VA. Galishev VA. Tetrahedron Lett.  2004,  45:  1407 
  Search in Google Scholar
• 2f Kuznetsov VA. Shubin KM. Schipalkin AA. Petrov ML. Tetrahedron  2006,  62:  10018 
  Search in Google Scholar
• 2g Parenty ADC. Song Y.-F. Richmond CJ. Cronin L. Org. Lett.  2007,  9:  2253 
  Search in Google Scholar
• 3a Heim-Riether A. Healy J. J. Org. Chem.  2005,  70:  7331 
  Search in Google Scholar
• 3b

  N-Amination of imidazoles leads to separable regioisomers.
• 4a For a review, see: Miura M. Nomura M. Top. Curr. Chem.  2002,  219:  211 
  Search in Google Scholar
• For most recent examples of direct intermolecular Pd-catalyzed arylation of azoles, see:
• 4b Yokooji A. Okazawa T. Satoh T. Miura M. Nomura M. Tetrahedron  2003,  59:  5685 
  Search in Google Scholar
• 4c Mori A. Sekiguchi A. Masui K. Shimada T. Horie M. Osakada K. Kawamoto M. Ikeda T. J. Am. Chem. Soc.  2003,  125:  1700 
  Search in Google Scholar
• 4d Li W. Nelson DP. Jensen MS. Hoerrner RS. Javadi GJ. Cai D. Larsen RD. Org. Lett.  2003,  5:  4835 
  Search in Google Scholar
• 4e Zificsak CA. Hlasta DJ. Tetrahedron  2004,  60:  8991 
  Search in Google Scholar
• 4f Park C.-H. Ryabova V. Seregin IV. Sromek AW. Gevorgyan V. Org. Lett.  2004,  6:  1159 
  Search in Google Scholar
• 4g Alagille D. Baldwin RM. Tamagnan GD. Tetrahedron Lett.  2005,  46:  1349 
  Search in Google Scholar
• 4h Bellina F. Cauteruccio S. Mannina L. Rossi R. Veil S. J. Org. Chem.  2005,  70:  3997 
  Search in Google Scholar
• 4i Gracias V. Gasiecki AF. Pagano TG. Djuric SW. Tetrahedron Lett.  2006,  47:  8873 
  Search in Google Scholar
• 4j Bellina F. Cauteruccio S. Mannina L. Rossi R. Viel S. Eur. J. Org. Chem.  2006,  693 
• 4k Cerna I. Pohl R. Klepetarova B. Hocek M. Org. Lett.  2006,  8:  5389 
  Search in Google Scholar
• 4l Bellina F. Cauteruccio S. Rossi R. J. Org. Chem.  2007,  72:  8543 
  Search in Google Scholar
• 4m Hien-Quang D. Daugulis O. J. Am. Chem. Soc.  2007,  129:  12404 
  Search in Google Scholar
• 4n Yoshizumi T. Tsurugi H. Satoh T. Miura M. Tetrahedron Lett.  2008,  49:  1598 
  Search in Google Scholar
• 5 Caron S. Massett SS. Bogle DE. Castaldi MJ. Braish TF. Org. Process Res. Dev.  2001,  5:  254 
  CrossrefSearch in Google Scholar
• 7a Ohff M. Ohff A. Milstein D. Chem. Commun.  1999,  357 
• 7b For a review on palladacyles, see: Ghedini M. Aiello I. Crispini A. Golemme A. La Deda M. Pucci D. Coord. Chem. Rev.  2006,  250:  1373 
  Search in Google Scholar
• 8 MeP(t-Bu)₂˙HBF₄ has been reported to significantly increase yield in CH activation reaction: Wang JX. McCubbin A. Meizhong J. Laufer RS. Mao Y. Crew AP. Mulvihill MJ. Snieckus V. Org. Lett.  2008,  10:  2923 
  CrossrefSearch in Google Scholar
• 9 Direct arylations of azoles were performed under ligandless conditions; see reference 4j and: Bellina F. Cauteruccio S. Rossi R. Eur. J. Org. Chem.  2006,  1379 
  Crossref

No imine formation was observed under standard coupling conditions without one of the two metals (Pd, Cu) present.

Starting 1-aminoimidazoles, except commercially available benzimidazol-1-ylamine, were prepared according to reference 3.

References

• 1a Hardtmann GE. inventors; US Patent 3 711  481.  Chem. Abstr. 1973, 78, 84430
• 1b Razvi M. Ramalingam T. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1992,  31:  788 
  Search in Google Scholar
• 1c Catarzi D. Cecchi L. Colotta V. Conti G. Melani F. Filacchioni G. Martini C. Giusti L. Lucacchini A. Farmaco  1993,  48:  447 
  Search in Google Scholar
• 2a Castle RN. Takano S. J. Heterocycl. Chem.  1966,  3:  381 
  Search in Google Scholar
• 2b Barlin GB. Aust. J. Chem.  1986,  39:  1803 
  Search in Google Scholar
• 2c Mavel S. Thery I. Gueiffier A. Arch. Pharm. Pharm. Med. Chem.  2002,  335:  7 
  Search in Google Scholar
• 2d Solyom S. Hamori T. Borosy AP. Tarnawa I. Berzsenyi P. Pallagi I. Med. Chem. Res.  2002,  11:  39 
  Search in Google Scholar
• 2e Shubin KM. Kuznetsov VA. Galishev VA. Tetrahedron Lett.  2004,  45:  1407 
  Search in Google Scholar
• 2f Kuznetsov VA. Shubin KM. Schipalkin AA. Petrov ML. Tetrahedron  2006,  62:  10018 
  Search in Google Scholar
• 2g Parenty ADC. Song Y.-F. Richmond CJ. Cronin L. Org. Lett.  2007,  9:  2253 
  Search in Google Scholar
• 3a Heim-Riether A. Healy J. J. Org. Chem.  2005,  70:  7331 
  Search in Google Scholar
• 3b

  N-Amination of imidazoles leads to separable regioisomers.
• 4a For a review, see: Miura M. Nomura M. Top. Curr. Chem.  2002,  219:  211 
  Search in Google Scholar
• For most recent examples of direct intermolecular Pd-catalyzed arylation of azoles, see:
• 4b Yokooji A. Okazawa T. Satoh T. Miura M. Nomura M. Tetrahedron  2003,  59:  5685 
  Search in Google Scholar
• 4c Mori A. Sekiguchi A. Masui K. Shimada T. Horie M. Osakada K. Kawamoto M. Ikeda T. J. Am. Chem. Soc.  2003,  125:  1700 
  Search in Google Scholar
• 4d Li W. Nelson DP. Jensen MS. Hoerrner RS. Javadi GJ. Cai D. Larsen RD. Org. Lett.  2003,  5:  4835 
  Search in Google Scholar
• 4e Zificsak CA. Hlasta DJ. Tetrahedron  2004,  60:  8991 
  Search in Google Scholar
• 4f Park C.-H. Ryabova V. Seregin IV. Sromek AW. Gevorgyan V. Org. Lett.  2004,  6:  1159 
  Search in Google Scholar
• 4g Alagille D. Baldwin RM. Tamagnan GD. Tetrahedron Lett.  2005,  46:  1349 
  Search in Google Scholar
• 4h Bellina F. Cauteruccio S. Mannina L. Rossi R. Veil S. J. Org. Chem.  2005,  70:  3997 
  Search in Google Scholar
• 4i Gracias V. Gasiecki AF. Pagano TG. Djuric SW. Tetrahedron Lett.  2006,  47:  8873 
  Search in Google Scholar
• 4j Bellina F. Cauteruccio S. Mannina L. Rossi R. Viel S. Eur. J. Org. Chem.  2006,  693 
• 4k Cerna I. Pohl R. Klepetarova B. Hocek M. Org. Lett.  2006,  8:  5389 
  Search in Google Scholar
• 4l Bellina F. Cauteruccio S. Rossi R. J. Org. Chem.  2007,  72:  8543 
  Search in Google Scholar
• 4m Hien-Quang D. Daugulis O. J. Am. Chem. Soc.  2007,  129:  12404 
  Search in Google Scholar
• 4n Yoshizumi T. Tsurugi H. Satoh T. Miura M. Tetrahedron Lett.  2008,  49:  1598 
  Search in Google Scholar
• 5 Caron S. Massett SS. Bogle DE. Castaldi MJ. Braish TF. Org. Process Res. Dev.  2001,  5:  254 
  CrossrefSearch in Google Scholar
• 7a Ohff M. Ohff A. Milstein D. Chem. Commun.  1999,  357 
• 7b For a review on palladacyles, see: Ghedini M. Aiello I. Crispini A. Golemme A. La Deda M. Pucci D. Coord. Chem. Rev.  2006,  250:  1373 
  Search in Google Scholar
• 8 MeP(t-Bu)₂˙HBF₄ has been reported to significantly increase yield in CH activation reaction: Wang JX. McCubbin A. Meizhong J. Laufer RS. Mao Y. Crew AP. Mulvihill MJ. Snieckus V. Org. Lett.  2008,  10:  2923 
  CrossrefSearch in Google Scholar
• 9 Direct arylations of azoles were performed under ligandless conditions; see reference 4j and: Bellina F. Cauteruccio S. Rossi R. Eur. J. Org. Chem.  2006,  1379 
  Crossref

No imine formation was observed under standard coupling conditions without one of the two metals (Pd, Cu) present.

Starting 1-aminoimidazoles, except commercially available benzimidazol-1-ylamine, were prepared according to reference 3.