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Synthesis of benzodiazocine-annulated heterocycles by the implementation of Pd-catalyzed intramolecular Heck reaction

Synthesis of benzodiazocine-annulated heterocycles by the implementation of Pd-catalyzed intramolecular Heck reaction

Tetrahedron Letters 51 (2010) 1736–1738 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetl...

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Tetrahedron Letters 51 (2010) 1736–1738

Contents lists available at ScienceDirect

Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Synthesis of benzodiazocine-annulated heterocycles by the implementation of Pd-catalyzed intramolecular Heck reaction K. C. Majumdar *, Krishanu Ray, Sintu Ganai Department of Chemistry, University of Kalyani, Kalyani 741 235, W.B., India

a r t i c l e

i n f o

Article history: Received 19 December 2009 Revised 21 January 2010 Accepted 25 January 2010 Available online 1 February 2010

a b s t r a c t Syntheses of hitherto unreported benzodiazocine-annulated heterocycles by the implementation of palladium-catalyzed intramolecular Heck reaction has been achieved in excellent yields. Ó 2010 Elsevier Ltd. All rights reserved.

Keywords: Benzodiazocine Heterocycles Intramolecular Heck reaction Pd(OAc)2 Pd(PPh3)4

Medium ring heterocycles are important class of synthetic targets to the organic chemists because of their presence as structural core moiety in a large number of natural products.1 In particular seven- and eight-membered heterocycles are constituents of a number of compounds with interesting pharmacological properties.2,3 However, medium-sized heterocycles particularly eightmembered or higher membered are difficult to prepare due to unfavorable entropic and enthalpic factors and transannular interactions.4 In general, the number of methods for the synthesis of medium ring heterocycles are rare in literature. Today the most powerful methodology for the construction of medium ring heterocycles is the ring closing metathesis (RCM),5,6 that some time requires high dilution conditions for successful conversion and often involves generation of byproducts such as ethylene. Currently palladium-catalyzed intramolecular Heck reaction have attracted much interest due to their excellent functional group tolerance and high selectivity. Recently we have reported the synthesis of a variety of medium-sized heterocycles by the application of this methodology.7 However, there are very few reports to the synthesis of eight-membered heterocycles containing two nitrogen or heteroatom. The addition of medium-sized rings containing two nitrogen atoms as substituents in biologically active compounds is known to increase the pharmaceutical potency of the compounds. One example is the diazocine ring. The tethering of octahydro1,4-diazocines to guanidine has produced derivatives of superior anti-hypertensive activity to that of guanidine.8 Moreover the * Corresponding author. Tel.: +91 33 2582 7521, fax: +91 33 2582 8282. E-mail address: [email protected] (K.C. Majumdar). 0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.01.088

derivatives of benzodiazocine are interesting because of their use as amoebicidal agents.9 Polycyclic benzodiazocines of natural origin are potent inhibitors of protein kinase C and cyclic nucleotidedependent protein kinases, used in experimental pharmacology10 and simple benzodiazocines have been used as homologues of benzodiazepine drugs.11 Buchwald and his co-workers have developed12 a procedure for the synthesis of benzodiazocine derivatives utilizing sequential Cu-catalyzed coupling of a b-lactam with bromo or iodo aryl amine, intramolecular attack of the amino group and ring expansion. Recently some other methodologies for the synthesis of pyrrolo benzodiazocines have been reported13–15 in good yields. However, to our knowledge there is no report on the synthesis of heterocycles-annulated diazocines except pyrrole. We therefore, became interested to undertake a study on the synthesis of bioactive diazocine-annulated quinoline, coumarin and pyrimidine derivatives by the implementation of palladium catalysts under ligand free conditions.16 Herein we report our results. The precursors (4–7) required for our present study were synthesized in 85–92% yields by refluxing the chloroacylated amides 2a–d with different tosylated bromoanilines (3a–c) in dry acetone for 4–5 h in the presence of anhydrous potassium carbonate and a small amount of sodium iodide (Finkelstein conditions17). The compounds 2a–d were in turn prepared by subsequent treatment of chloroacetyl chloride on 1a–d under phase transfer catalysis condition using TBAHS as catalyst and potassium carbonate as base (Scheme 1). We first attempted palladium-catalyzed Heck reactions with these substrates (4–7). The first set of experiment was carried

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O

X 1a, X = NEt 1b, X= O

O

O

O NHEt

N O

O

N

R1 3a R1 = H 3b R1 = Me

Br

O

O

X 4a X = NEt, R1 = H 4b X = NEt, R1 =Me 5c X = O, R1 = H 5d X = O, R1 = Me O

Br

Cl +

R1 3b R1 = Me

Et N

N

(ii) O

2c

1c

(ii)

NMe

O

N

Ts N

+

NHTs

Et N

N

(i)

Br

Cl

O

X 2a, X = NEt 2b , X= O

R1

NHTs

Me N

NHMe (i)

O

NTs

N Br

6e R1 = Me R1

NHMe (i)

Me N

NHTs

Me N

Cl

Br

+

(ii)

O 1d

O

NTs

Br

2d

R 3b R1 = Me 3c R1 = Et

7f R = Me 7g R = Et R

Scheme 1. Reagents and conditions, (i) chloroacetyl chloride, DCM–H2O, TBAHS, K2CO3, rt, 0.5 h, (ii) dry acetone, K2CO3, NaI, reflux, 4–5 h.

out with 4a18 as the model substrate. Initially the reaction was performed in dry N,N-dimethylformamide (DMF), using 10 mol % palladium acetate, potassium acetate as base in conjunction with TBAB, for 8 h under nitrogen atmosphere at 120 °C to give the cyclized product 8a19 in 65% yield. Further enhancement of the temperature of the reaction or the catalyst loading (20 mol %) did not improve the yield of the reaction. However, when the same reaction was conducted by changing the catalyst, that is, replacing Pd(OAc)2 with Pd(Ph3)4 keeping the other parameters unchanged the reaction was found to proceed at a relatively enhanced rate, that is, shorter reaction time (6 h) affording better yield of the cyclized product (90%). To optimize the reaction conditions we have conducted a series of experiments where changes were made in case of catalyst, base, and solvent. This study revealed that the catalyst, base and solvent have a pronounced effect on yield of the reaction. Among various bases used for the reaction, potassium acetate was found to provide the highest yield. The reaction was studied in different solvents like DMA, dioxane, toluene etc but

DMF was found to be the choice (Table 1). Additive TBAB plays an important role in this reaction because in the absence of TBAB the reaction does not give any cyclized product. Similar treatment of other substrates (4–7) under the above optimized condition [Pd(Ph3)4, KOAc, TBAB, DMF] gave the desired cyclized products in good to excellent yields except in the case of substrates 7f and 7g. These two substrates (7f,g) were found to give the products with Pd(OAc)2 catalysis instead of Pd(PPh3)4 in 90–92% yields within 4 h. The results are summarized in Table 2. In conclusion we have developed an important synthetic protocol for the synthesis of eight-membered benzodiazocine-annulated heterocycles by Pd-catalyzed intramolecular Heck reaction as the key step. The reaction conditions are simple, straightforward and high yielding. The reaction is highly regioselective, and affords the desired medium ring heterocycles in excellent yields. Implementation of this strategy to the synthesis of heterocyclic library is under way and will be reported later.

Table 1 Optimization of the palladium-catalyzed intramolecular Heck reactionsa

a b c d

Entry

Catalystb

Basec

Solvent

Yieldd (%)

1 2 3 4 5 6 7 8 9 10

Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(PPh3)4 Pd(PPh3)2Cl2 Pd(PPh3)4 Pd(OAc)2 Pd(PPh3)4 Pd(OAc)2 Pd(PPh3)4

KOAc K2CO3 Et3N KOAc KOAc NaOAc KOAc KOAc KOAc KOAc

DMF DMF DMF DMF DMF DMF DMA DMA Toluene Dioxane

65 <10 NR 90 75 82 48 74 NR NR

The reactions are carried out at 120 °C, TBAB was used as additive. Catalyst used 10 mol %. Base used 2.75 equiv. Yields are isolated. NR indicates no reaction.

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Table 2 Summarized results of the Heck reactiona Entry

Precursors

Time (h)

Yieldsc (%)

Products

Br

1a

O

N 4a

N

O

O N

6

O

O

N

N

6

4b

N

O

O

N 5c

O

O

N 9c

O

O

N

O

6

5d

O

N O

N NTs

N Br 6e

6

O N Br

85

7f

7b

15. 16. 90

11f O N

NTs 4

Br 7g

12. 13. 14.

NTs

N

O

c

NTs

N 10e

4

N

a

O

O NTs

6b

b

11.

N

N O

86

O

O

N 5a

8. 9. 10.

9d

O

O

O

84

Ts N O

Br

7.

O

6

Ts N 4a

88

Ts N O

Br

6.

O

8b

N

Ts N 3a

5.

Ts N O

Br

90

8a

N

Ts N 2a

4.

Ts N

Ts N

17. 18.

NTs 92

11g

Catalyst used 10 mol % Pd(PPh3)4. Catalyst used 10 mol % Pd(OAc)2. Isolated yield of products.

Acknowledgements 19.

We thank the DST (New Delhi) and CSIR (New Delhi) for financial assistance. Two of us (K.R. and S.G.) are grateful to the CSIR (New Delhi) for their research fellowships. References and notes 1. (a) Devon, T. K.; Scott, A. I.. In Handbook of Naturally Occurring Compounds; Academic Press: New York and London, 1972; Vol. 2; (b) Faulkner, D. J. Nat. Prod. Rep. 1984, 1. 251, 551; 1986, 3, 1; 1987, 4, 539; 1989, 5, 613; For a recent review, see: (c) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131. 2. For selected examples for seven-membered heterocycles, see: (a) Duong, T.; Prager, R. H.; Tippett, J. M.; Ward, A. D.; Kerr, D. I. Aust. J. Chem. 1976, 29, 2667; (b) Boros, C.; Hamilton, S. M.; Katz, B.; Kulanthaivel, P. J. Antibiot. 1994, 47, 1010; (c) Ishihara, Y.; Hirai, K.; Miyamoto, M.; Goto, G. J. Med. Chem. 1994, 37, 2292; (d) Morı´s-Varas, F.; Qian, X.-H.; Wong, C.-H. J. Am. Chem. Soc. 1996, 33, 7647. 3. For selected examples for eight-membered heterocycles, see: (a) Basil, B.; Coffee, E. C. J.; Gell, D. L.; Maxwell, D. R.; Sheffield, D. J.; Wooldridge, K. R. H. J.

Med. Chem. 1970, 13, 403; (b) Klayman, D. L.; Scovill, J. P.; Bartosevich, J. F.; Mason, C. J. J. Med. Chem. 1979, 22, 1367; (c) Vedejs, E.; Galante, R. J.; Goekjian, P. G. J. Am. Chem. Soc. 1998, 120, 3613; (d) Ma, D.; Tang, G.; Kozikowski, A. P. Org. Lett. 2002, 4, 2377; (e) Stærk, D.; Witt, M.; Oketch-Rabah, H. A.; Jaroszewski, J. W. Org. Lett. 2003, 5, 2793. (a) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95; (b) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131; (c) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757; (d) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881; (e) Yet, L. Chem. Rev. 2000, 100, 2963; (f) Ma, S.; Gu, Z. J. Am. Chem. Soc. 2006, 128, 4942. For a recent review, see: (a) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073; For selected examples, see: (b) Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron Rep. 2007, 63, 3919; (c) Paquette, L. A.; Leit, S. M. J. Am. Chem. Soc. 1999, 121, 8126; (d) Cook, G. R.; Shanker, P. S.; Peterson, S. L. Org. Lett. 1999, 1, 615; (e) Mori, M.; Kitamura, T.; Sakakibara, N.; Sato, Y. Org. Lett. 2000, 2, 543. For other recent synthesis of medium-ring heterocycles, see: (a) Majumdar, K. C.; Rahaman, H.; Muhuri, S.; Roy, B. Synlett 2006, 466; (b) Majumdar, K. C.; Islam, R.; Rahaman, H.; Roy, B. Org. Biomol. Chem. 2006, 4, 2393; (c) Majumdar, K. C.; Muhuri, S.; Rahaman, H.; Islam, R.; Roy, B. Chem. Lett. 2006, 35, 1430; (d) Majumdar, K. C.; Chattopadhyay, B.; Chakrovorty, S. Synthesis 2009, 674; (e) Monovich, L. G.; Hue´rou, Y. L.; Rönn, M.; Molander, G. A. J. Am. Chem. Soc. 2000, 122, 52. (a) Majumdar, K. C.; Cahttopadhyay, B.; Samanta, S. Tetrahedron Lett. 2009, 50, 3101; (b) Majumdar, K. C.; Samanta, S.; Chattopadhyay, B. Tetrahedron Lett. 2009, 50, 4866; (c) Majumdar, K. C.; De, R. N.; Chattopadhyay, B.; Roy, B. Synlett 2009, 2083; (d) Majumdar, K. C.; Ansary, I.; Sinha, B.; Chattopadhyay, B. Synthesis 2009, 3593; (e) Majumdar, K. C.; Mondal, S.; De, N. Synlett 2008, 2851. Mull, R. P.; Mizzoni, R. H.; Dapero, M. R.; Egbert, M. E. J. Org. Chem. 1962, 5, 944. Paudler, W. W.; Zeiler, A. G. J. Org. Chem. 1969, 34, 2138. See for example: (a) Nakayama, T.; Harada, N.; Asano, M.; Nomura, N.; Saito, T.; Mishima, A.; Okajima, K. J. Pharmacol. Exp. Ther. 2007, 322, 582; (b) Culmsee, C.; Gerling, N.; Landshamer, S.; Rickerts, B.; Duchstein, H. J.; Umezawa, K.; Klumpp, S.; Krieglstein, J. J. Mol. Pharmacol. 2005, 68, 1006; (c) MixcoatlZecuatl, T.; Flores-Murrieta, F. J.; Granados-Soto, V. Eur. J. Pharmacol. 2006, 531, 87. Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem., Int. Ed. 2002, 41, 3247. Klapars, A.; Parris, S.; Anderson, K. W.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 3529. Koriatopoulou, K.; karousis, N.; Varvounis, G. Tetrahedron 2008, 64, 10009. Potapov, V. V.; Fetisova, N. A.; Nikitin, A. V.; Ivachtchenko, A. V. Tetrahedron Lett. 2009, 50, 2790. BouzBouz, S.; Sanselme, M. Tetrahedron Lett. 2009, 50, 5884. De Vries, A. H. M.; Mulders, J. M. C. A.; Mommers, J. H. M.; Henderickx, H. J. W.; de Vries, J. G. Org. Lett. 2003, 5, 3285. (a) Gazith, M.; Noys, R. M. J. Am. Chem. Soc. 1955, 77, 6091; (b) Gardner, I. J.; Noys, R. M. J. Am. Chem. Soc. 1961, 83, 240. General procedure for the preparation of the Heck-precursor 4a: A mixture of the compound 2a (300 mg, 1.07 mmol), tosylated-2-bromoaniline 3a (421 mg, 1.29 mmol) and anhydrous K2CO3 (1.0 g) was refluxed in acetone (50 mL) for 4–6 h. in the presence of sodium iodide. The reaction mixture was cooled, filtered and the solvent was removed. The crude product was purified by column chromatography over silica gel (60–120 mesh) using petroleum ether– ethyl acetate (3:2) as eluent to give 4a in 88% yield. Compound 4a: Yield: 88%, solid; mp 190–192 °C; IR(KBr): mmax = 1648, 1676, 2925 cm 1; 1H NMR (CDCl3, 500 MHz): dH = 7.73 (d, 1H, J = 7.7 Hz), 7.61 (d, 1H, J = 9.4 Hz), 7.54 (d, 2H, J = 7.9 Hz), 7.49 (d, 1H, J = 7.7 Hz), 7.42 (d, 1H, J = 9.1 Hz), 7.28–7.33 (m, 3H), 7.17–7.20 (m, 3H), 6.77 (d, 1H, J = 9.4 Hz), 4.63 (br s, 1H), 4.36 (q, 2H, J = 7.0 Hz), 3.89 (br s, 1H), 3.24 (s, 3H), 2.39 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz) ppm. 13 C NMR (CDCl3, 100 MHz): dC = 12.7, 21.5, 37.6, 37.9, 51.7, 115.8, 121.8, 123.2, 124.4, 127.2, 127.8, 128.0, 129.2, 129.3, 130.0, 133.3, 135.0, 136.3, 137.1, 137.7, 138.1, 138.6, 143.5, 161.6, 167.8 ppm. HRMS: m/z calcd for C27H26BrN3O4S: [M++Na]: 590.0725, [M++Na+2]: 592.0708; found: 590.0725, 592.0725. General procedure for the synthesis of the compound 8a by Heck reaction: A mixture of 4a (100 mg, 0.17 mmol), tetrabutylammonium bromide (85.2 mg, 0.26 mmol) and anhydrous potassium acetate (41.6 mg, 0.42 mmol) was taken in N,N-dimethylformamide (DMF) (10 mL) under nitrogen atmosphere. Pd(PPh3)4 (10 mol %, 20.3 mg) was added and the reaction mixture was stirred at 120 °C for 6 h. The reaction mixture was cooled, water (20 mL) was added and extracted with ethyl acetate (3  30 mL). The ethyl acetate extract was washed with water (2  40 mL), followed by brine (30 mL). The organic layer was dried (Na2SO4), and the solvent was evaporated to give a crude product. This was purified by column chromatography over silica gel (230–400 mesh) using petroleum ether and ethyl acetate (3:2) as an eluent. The product 8a was isolated as a white solid in 90% yield. Similarly the other compounds 8b–11g were prepared in 84–92% yields. Compound 8a: Yield: 90%, solid; mp 216–218 °C; IR(KBr): mmax = 1656, 1680, 2925 cm 1; 1H NMR (CDCl3, 400 MHz): dH = 7.98 (d, 1H, J = 7.6 Hz), 7.65–7.70 (m, 2H), 7.54 (d, 1H, J = 9.2 Hz), 7.45 (t, 1H, J = 7.6 Hz), 7.31–7.35 (m, 3H), 7.23–7.28 (m, 3H), 6.74 (d, 1H, J = 9.2 Hz), 4.62 (s, 2H), 4.29 (q, 2H, J = 6.8 Hz), 3.23 (s, 3H), 2.51 (s, 3H), 1.37 (t, 3H, J = 6.8 Hz) ppm. 13C NMR (CDCl3, 100 MHz): dC = 12.7, 22.0, 37.5, 38.4, 49.1, 115.6, 119.7, 121.6, 123.0, 124.6, 124.8, 125.5, 125.7, 126.5, 128.7, 130.1, 132.1, 132.4, 136.1, 138.1, 138.2, 138.3, 142.7, 161.4, 166.6 ppm. HRMS: m/z calcd for C27H25N3O4S; [M++H] 488.1638; found: 488.1641.