Key words
benzodiazepines - N-arylation - iodonium salt - privileged scaffold - benzotriazepine
Compounds containing a 1,4-benzodiazepine scaffold are often termed as ‘privileged
structures’ and are of significant interest to organic and medicinal chemists.[1]
[2]
[3]
[4]
[5]
[6]
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[18] Many bioactive 1,4- benzodiazepines include N-arylated benzodiazepines; for example, the benzodiazepine derivative A (Figure [1]) is a bradykinin antagonist[19] and the related benzotriazepine B is an antagonist at the parathyroid hormone (PTH)-1 receptor.[20] Typically N-arylated benzodiazepines can be prepared by transition-metal- catalysed couplings,
often with copper, with various arylating agents. Generally, the reaction scope is
limited with these routes and often requires high temperatures and strong bases. [19]
,
[21]
[22]
[23]
Figure 1 Bioactive N-arylated Benzodiazepine and Benzotriazepine
Being able to generate libraries of diverse analogues, in this case by adding N-functionality to a privileged core unit, using mild and efficient methodologies,
can substantially improve SAR studies (structure–activity relationship) and optimise
the drug development process potentially repurposing privileged scaffolds for new
biological targets.[24]
[25]
We have an active interest in benzodiazepines [26]
[27] and recently reported a method to functionalise 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones via a late-stage palladacycle assisted ortho C–H activation protocol.[28]
[29] Herein we present our approach to generate a series of N1-arylated 1,4-benzodiazepines using diaryliodonium salts. The latter react with nucleophiles
in the absence of transition-metal catalysts and are commonly used in organic synthesis
as electrophilic reagents.[30]
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[32]
[33]
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Novak et al. recently reported a protocol for the N-arylation of pyrazoles.[36] A quick screen of conditions, adapting this protocol using diaryliodonium salts
with weak bases under mild conditions, showed that it was indeed possible to perform
similar arylations on the 1,4-benzodiazepine system. Upon initial screening of a number
of solvents, 1,2-dichloroethane (DCE) was found to give the best results (Table [1], entry 2). Solvents such as polypropylene glycol (PEG) and acetic acid (AcOH) gave
poor yields. Similar results were observed on pyrazoles by Novak et al. where aprotic
solvents, immiscible in water, produced the best results.
Table 1 Optimization of N-Arylation of 1,4-Benzodiazepines – Solvent Effects
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Entry
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Solvent
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Conversion (%)a
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1
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toluene
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95
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2
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DCE
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99
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3
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PEG
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–
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4
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AcOH
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–
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5
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CHCl3
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85
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a LC–MS conversion.
A number of bases were tested subsequently and both NH3 (25% w/w) and NaOH (sat. aq.) gave similar and the best results (Table [2], entries 1, 2).
Table 2 Optimization of N-Arylation of 1,4-Benzodiazepines – Base Effects
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Entry
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Base
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Conversion (%)a
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1
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NaOH (sat. aq.)
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99
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2
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NH3 (25% w/w)
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99
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3
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K2CO3
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80
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4
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NaH
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-
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a LC–MS conversion.
Scheme 1 N-Arylated 1,4-Benzodiazepines
Hence, optimal conditions appeared to use NH3 (aq.), DCE at room temperature for 30 min. Next, a series of functionalized 1,4-benzodiazepines
was N-arylated using (4-nitrophenyl)phenyliodonium triflate in good to excellent yields
(Scheme [1]). Generally, in transition-metal-free processes unsymmetrical diaryliodonium salts
give a mixture of products where both groups are transferred and the transfer of more
sterically hindered and electron-withdrawing groups is preferable.[34] However, in this case (Scheme [1]) only the nitrophenyl group was transferred. We were able to N-arylate quite sterically hindered benzodiazepines such as 3e, 3f, and 3g. Of note, 3e is a key intermediate towards A. We were also pleased to be able to conduct N-arylation on a previously ortho-arylated hindered benzodiazepine, 3h, in good yield, whose structure was also confirmed by X-ray crystallography. Such
molecules may be useful precursors to, e.g., α-helical mimetics in medicinal chemistry.[37]
[38]
The use of other unsymmetrical diaryliodonium triflates was also explored (Table [3]), which required longer reaction time and led to both aryl groups being transferred
to obtain 3i–l. As expected, the transfer of more sterically hindered or less electron-rich groups
was preferred. Further attempts to use unsymmetrical diaryliodonium salts such as
phenyl(3-methylphenyl)iodonium triflate, phenyl(4-methylphenyl)iodonium triflate,
and (2-methylphenyl)(2,4,6-trimethylphenyl)iodonium triflate gave little or no products.
Additionally, attempted N-arylation with symmetrical diaryliodonium triflates or tetrafluoroborates such as
bis(2-fluorophenyl)iodonium tetrafluoroborate and bis(4-bromophenyl)iodonium triftlate
gave, at best, traces of products.
We have briefly explored the N-arylation on a 1,3,4-benzotriazepine 6, which resulted in diarylation and yielded 7 (Scheme [2]).
Scheme 2 N-Arylation on a 1,3,4-Benzotriazepine
Interestingly, the iodonium salts were observed to undergo reaction with water present
in the reaction to give diarylether products. The ether product is only observed in
substantial amounts when the benzodiazepine substrates react poorly with the diaryliodonium
salts (Table [4]). The ether product 10 was also obtained merely by stirring the iodonium salt with water in DCE with a mild
base for 20 min at room temperature with a yield of 43%. Olofsson et al. have reported
the synthesis of related diarylethers by reacting diaryliodonium salts with phenols
in the presence of mild bases.[39]
In summary we have presented a mild metal-free route to N-arylated benzodiazepines, three of which were structurally characterized in the solid
state (3a, 3h, 3i).[40]
[41]
