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Synlett 2013; 24(1): 49-52
DOI: 10.1055/s-0032-1317667
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© Georg Thieme Verlag Stuttgart · New York

Double Palladium-Catalyzed Synthesis of Azepines

Nina Božinović
Faculty of Chemistry, University of Belgrade, PO Box 51, Studentski trg 16, 11158 Belgrade, Serbia   Fax: +3811163298953   Email: bsolaja@chem.bg.ac.rs
,
Igor Opsenica
Faculty of Chemistry, University of Belgrade, PO Box 51, Studentski trg 16, 11158 Belgrade, Serbia   Fax: +3811163298953   Email: bsolaja@chem.bg.ac.rs
,
Bogdan A. Šolaja*
Faculty of Chemistry, University of Belgrade, PO Box 51, Studentski trg 16, 11158 Belgrade, Serbia   Fax: +3811163298953   Email: bsolaja@chem.bg.ac.rs
› Author Affiliations
Further Information

Publication History

Received: 04 October 2012

Accepted after revision: 26 October 2012

Publication Date:
27 November 2012 (online)

 
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Abstract

The synthesis of new 5H-pyridobenzazepine and 5H-dipyridoazepine compounds using as key step a palladium-catalyzed amination–cyclization reaction is reported. By choosing an appropriate combination of ligands and reactants under standardized reaction conditions, N- and S-tricyclic products can be prepared in one step from the appropriate stilbenes.


 

Key words

azepines - thiepines - palladium - double N- and S-arylation - fused heterocycles

The tricyclic 5H-dibenz[b,f]azepine (iminostilbene) core 1 is a pharmaceutically important subunit in tricyclic therapeutic agents such as carbamazepine (2) and opipramol (3, Figure [1]). Carbamazepine (2), a member of tricyclic antidepressant (TCA), was approved by the FDA in 1968 for treatment of complex partial, tonic-clonic, and mixed-type seizures.[ 1 ] Opipramol (3) is primarily used for the treatment of generalized anxiety disorders.[ 2 ] Most TCA act as reuptake inhibitors of norepinephrine, serotonin, and dopamine, but opipramol acts as a high-affinity σ-receptor agonist with modest subclass selectivity.[ 3 ]

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Figure 1 Tricyclic therapeutic agents structurally related to 5H-dibenz[b,f]azepine (1)

There are several classical efficient synthetic routes available for the synthesis of the iminostilbene moiety:[ 4 ] dehydrogenation of 10,11-dihydrodibenz[b,f]azepines,[ 5 ] dehydrobromination of 10-bromo-10,11-dihydrodi­benz[b,f]azepines,[ 4 ] Wagner–Meerwein rearrangement of 9-hydroxymethyl-9,10-dihydroacridine derivatives,[ 6 ] dehydration of 10,11-dihydro-10-hydroxydibenz[b,f]azepines,[ 4 ] and acid-catalyzed rearrangement of 1-aryl-indoles.[ 7 ] In addition, a highly efficient Pd/ligand-controlled selective synthesis of 5H-dibenz[b,f]azepines in high yield using a two-step reaction sequence has been reported.[ 8 ] Thus, using a variety of phosphines, DavePhos was established as the most effective among the ligands investigated for the synthesis of 1.

Recently, a very interesting approach to the synthesis of 5H-dibenz[b,f]azepines was developed. It comprised the reaction of three components, ortho-substituted aryl ­iodides, o-bromoanilines, and norbornadiene in a palladium-catalyzed reaction, followed by retro-Diels–Alder reaction of the norbornadiene intermediate to afford the corresponding iminostilbene products in good yields.[ 9 ]

The palladium-catalyzed double N-arylation reaction has been widely used for the construction of different heterocyclic skeletons: carbazoles,[ 10 ] thienopyrroles,[ 11 ] indoles,[ 12 ] and phenazines.[ 13 ] On the other hand, very few examples of double palladium-catalyzed amination reactions for the formation of azepine ring system are known.[14] [15] The synthesis of symmetric and unsymmetric analogues of antidepressant imipramine was investigated in the presence of Pd(OAc)2/Xphos[ 15a ] or PdII–XPhos precatalyst[ 15b ] which were recently developed by Buchwald and co-workers.[ 16 ] The yields of synthesized 3,7-disubstituted imipramines were moderate to good.

Zoom
Scheme 1 Synthesis of ethylene derivatives 8 and 9

Table 1 Palladium-Catalyzed Double Amination Reactions of 8 under Various Conditionsa,b

Entry

Pd source (mol%)

Ligand (mol%)

Yield (%)

1

Pd (OAc)2 (5)

L1 (10)

81

2

Pd (OAc)2 (10)

L1 (30)

78

3

Pd (OAc)2 (5)

L2 (10)

81

4

Pd (OAc)2 (5)

L3 (10)

19

5

Pd (OAc)2 (5)

L4 (10)

 0

a Reaction conditions: Pd(OAc)2, L, amine (3 equiv), NaOt-Bu (2.8 equiv) in toluene at 100 °C for 48 h under argon atmosphere; isolated yields.

b Reactions were monitored by TLC and GC–MS.

Herein, we report on the synthesis of new 5H-pyridobenzazepine and 5H-dipyridoazepine compounds using as the key step a palladium-catalyzed amination–cyclization reaction. We reasoned that co-operative ortho effects[ 17 ] could be exploited to obtain stilbenes (Z)-8 and (Z)-9 with good selectivity. To that end, the alcohol 4 [ 18 ] was transformed into its corresponding bromo derivative, which was used for the preparation of phosphonium salt 5. On the other hand, phosphonium salt 7 was prepared using a similar reaction sequence starting from commercially available 2-bromobenzaldehyde (Scheme [1]). The Wittig reaction of phosphonium salts with freshly prepared 4-chloropyridine-3-carbaldehyde afforded the desired expected ethylene derivatives 8 and 9. The unstable 4-chloropyridine-3-carbaldehyde was always prepared immediately before its use. After subsequent chromatographic separation Z isomer 8 was obtained in 54% yield, and corresponding E isomer in 12% yield.[ 17 ] Structural characterization of two separated isomers was achieved by 1H NMR spectroscopy (see Supporting Information). Stilbenes (Z,E)-9 were obtained in lower yields, but better stereoselectivity of two geometric isomers [(Z)-9 and (E)-9, 24:1] were observed (see Supporting Information). The geometry of compound 9 could not be established by NMR spectroscopy (C 2 symmetric), however, its Z geometry is proposed based on the high yield of the corresponding product 14 in the Pd-catalyzed double amination (87%, see Table [2]). In the next step we carried out the palladium-catalyzed double amination reaction of 8 (Table [1]).

It has been described[ 19 ] that the appropriate ligand selection is the key for successful amination, and furthermore, it was shown that dialkylbiarylphosphines provide especially active catalysts in this context. In this work, we screened the ligands using Pd(OAc)2 (5 mol% with respect to 8) as source of palladium and NaOt-Bu (2.8 equiv) as a base, in toluene at 100 °C. Using biaryl phosphane ligands, JohnPhos and SPhos (10 mol% with respect to 8), we obtained comparable yields of 10 (Table [1], entries 1 and 3), but XPhos afforded a significantly lower yield of 10 (Table [1], entry 4). Unfortunately, the reaction with dppf was inefficient (Table [1], entry 5). Higher loadings of the palladium source (10 mol% vs. 5 mol%) and ligand (30 mol% vs. 10 mol%) did not appreciably affect the yield (Table [1], entry 2 vs. entry 1).

After optimizing reaction conditions, the iminostilbene 8 and 9 were subjected to coupling reactions with various amines. The desired azepines 10–17 were obtained in fairly good yields (Table [2]).

Table 2 Palladium-Catalyzed Double Amination Reactions of 8 and 9 with Various Aminesa,b

10 c 81%

14 d 87%

11 c 61%

15 d 69%

12 c 79%

16 d 47%

13 c 61%

17 d 54%

a Reaction conditions: Pd(OAc)2 (5 mol%), JohnPhos (10 mol%), amine (3 equiv), NaOt-Bu (2.8 equiv) in toluene at 100 °C under argon atmosphere; isolated yields.

b Reactions were monitored by TLC until all of the starting material was consumed.

c Reaction time was 48 h.

d Reaction time was 24 h.

Finally, as an expansion of this study, we explored the synthesis of thiepine derivatives (Table [3]). Various methods have been reported in the literature to obtain thiepine derivatives,[ 20 ] but only one involves palladium-catalyzed reactions.[ 21 ] In our approach as a source of sulfur for C–S bond formation we used potassium thioacetate. Interestingly, no conversion was observed when 8 and 9 were subjected to the same reaction conditions as for the synthesis of the azepine analogues. However, when we replaced JohnPhos with dppf[ 22 ] (ineffective in the amination reaction above) the desired thiepines were isolated in 28% and 31% yields, respectively (Table [3]). To expand the scope of the new methodology, and to increase the yields, we explored microwave-heated double palladium-catalyzed C–S bond formation. After several different reaction parameters were explored, it was found that the reaction time could be reduced to 90 minutes at 175 °C using the same Pd/ligand loadings. Additionally, the yields of the desired compounds obtained using microwave-­accelerated protocol were higher (Table [3]).

Table 3 Synthesis of Thiepine Derivatives

18 28%a (51%)b

19 31%a (49%)b

a Reaction conditions: Pd(OAc)2 (5 mol%), dppf (10 mol%), potassium thioacetate (1 equiv), NaOt-Bu (1.2 equiv) in toluene at 70 °C for 1 h, and subsequently at 110 °C for 14 h under argon atmosphere; isolated yields.

b Reaction conditions: Pd(OAc)2 (5 mol%), dppf (10 mol%), potassium thioacetate (1.2 equiv), NaOt-Bu (1.2 equiv) in toluene at 175 °C for 90 min (microwave) under argon atmosphere; isolated yields.

To conclude, we have developed a simple and efficient palladium-catalyzed method for the synthesis of azepine derivatives.[ 23 ] In addition, to the best of our knowledge, for the first time this methodology has been applied to thiepine-core synthesis.[ 24 ] Further studies on dibenzostilbene cyclization, optimization of the reaction conditions, and evaluation of medicinal importance of these compounds are under way.


 

Acknowledgment

This research was supported by the Ministry of Education and Science of Serbia (Grant No. 172008), and NATO’s Public Diplomacy Division in the framework of Science for Peace project SfP983638.

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett. Included are detailed experimental procedures and spectra for all isolated compounds.
  • Supporting Information


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Zoom
Figure 1 Tricyclic therapeutic agents structurally related to 5H-dibenz[b,f]azepine (1)
Zoom
Scheme 1 Synthesis of ethylene derivatives 8 and 9