A facile and efficient method for the synthesis of N -substituted 3-oxoisoindoline-1-carbonitrile derivatives catalyzed by sulfamic acid

A new and efficient method for the synthesis of N -substituted 3-oxoisoindoline-1-carbonitrile derivatives by a one-pot, three-component condensation reaction of 2-carboxybenzaldehyde, primary amine, and TMSCN in the presence of 10 mol % sulfamic acid (NH 2 SO 3 H) as the catalyst in EtOH under reflux temperature is described. The process is simple and environmentally benign and the catalyst is commercially available and inexpensive.


Introduction
Isoindolinone derivatives are an important class of compounds because of their therapeutic and pharmacological properties. 1 For examples, indoprofen I is shown to have anti-inflammatory activities, 2 while deoxythalidomide II is an inhibitor of tumor necrosis factor production, 3 and tricyclic -lactam III is a non-nucleosidic HIV reverse transcriptase inhibitor (Figure 1). 4 Moreover, isoindolinone compounds IV substituted at 3-position have also been shown to be potent inhibitors for DNA gyrase. 5Hence, there is a need to develop a simple and cost-effective protocol for the synthesis of isoindolinones.
The Strecker reaction between aldehyde, amine, and hydrogen cyanide is widely regarded as the first multi-component reaction (MCR). 6Its reliability, the ready availability of the starting materials, and the versatility of the resulting products make it a very important process for the diverse synthesis of -aminoacids and -aminonitriles.Recently, Strecker reactions have been reported for the multi-component synthesis of N-substituted 3-oxoisoindoline-1-carbonitrile As a part of our program aiming at developing efficient and environmentally friendly methodologies for MCRs, 8 and in continuation of our interest in the organic synthesis of heterocyclic compounds, we report herein an improved Strecker reaction for one-pot synthesis of N-substituted 3-oxoisoindoline-1-carbonitrile derivatives from 2-carboxybenzaldehyde, primary amine, and TMSCN catalyzed by sulfamic acid (Scheme 1).Scheme 1. NH2SO3H-catalyzed synthesis of N-substituted 3-oxoisoindoline-1-carbonitriles 4.

Results and Discussion
Initially, we investigated the three-component condensation reaction of 2-carboxybenzaldehyde 1, benzylamine 2a, and TMSCN 3 in different reaction conditions (Table 1).As shown in table 1, only 30% yield of the desired product 4a was obtained when the reaction was carried out under solvent-and catalyst-free conditions (Table 1, entry 1).However, the yield of product 4a could be increased to 60% in the presence of 20 mol% of NH2SO3H at 90 o C for 2 h under solvent-free (Table 1, entry 2).This result highlighted the role of NH2SO3H as a promoter for this threecomponent reaction.Further studies revealed that the reactions conducted in EtOH gave relatively higher yields than MeOH, THF, MeCN or DMF (Table1, entries 3-11).Moreover, we also found that 10 mol % of NH2SO3H was sufficient and more than this did not increase the yields (Table 1, entries 3-6).In terms of yields and reaction time, we achieved the best conditions to synthesis N-benzyl-3oxoisoindoline-1-carbonitrile 4a by using 10 mol % of NH2SO3H under refluxed temperature in EtOH (Table 1, entry 5).Having established the optimized reaction conditions, we then successfully synthesized a variety of N-substituted 3-oxoisoindoline-1-carbonitriles 4, and the results are summarized in Table 2.In all of the studied examples, the benzylamines and aryl-alkylamines could react smoothly to give the corresponding N-substituted 3-oxoisoindoline-1-carbonitrile 4 in good to excellent yields (68-90%).Benzylamines carrying either electron-donating or electro-withdrawing groups could react efficiently to give corresponding product 4 in good yields (Table 2, entries 1-5).Furthermore, phenethylamines and alkylamines were also examined for the synthesis of Nsubstituted-3-oxoisoindoline-1-carbonitrile 4. The results revealed that both phenethylamines and most of the alkylamines could work well to afford the desired products 4 in moderate yields (50-60%) under same conditions (Table 2, entries 8-13).Moreover, we also examined the condensation reaction using iso-propylamine and tert-butylamine as the starting materials in the presence of 10 mol % NH2SO3H as the catalyst in EtOH at reflux temperature for 2.5 h.
Unfortunately, in these cases, several side reactions were observed; the yields of the desired products were less than 15% as indicated by LC-MS and we failed to isolate the target products (Table 2, entries 14 and 15).
Furthermore, aromatic amines such as aniline, 4-toluidine, and 4-chloroaniline were also subjected to the conditions of this multi-component condensation (Scheme 2).Unfortunately, the products 5, shown in Scheme 2 and confirmed by LC-MS, were obtained in 85% yield, and the desired products 4 were not obtained.

Scheme 2. Reaction of 2-carboxybenzaldehyde, aniline and TMSCN in EtOH.
We propose a mechanism of the condensation as shown in Scheme 3. Initially, the condensation between 2-carboxybenzaldehyde 1 and primary amine 2 gave imine 5 in the presence of NH2SO3H.Then the Strecker reaction between TMSCN and 5 furnished 6 which dehydrated to give product 4.We have mentioned previously that the three-component condensation reaction could not proceed smoothly when using aromatic amines as the starting materials.The probable reason was that in these cases, the intermediates 5 were difficult to form the intermediate 6, which meant that the reaction could not proceed smoothly to afford the corresponding products.

Scheme 3. A possible mechanism for the formation of compound 4.
In summary, we describe a simple and efficient method for the one-pot three-component synthesis of N-substituted 3-oxoisoindoline-1-carbonitriles 4 from 2-carboxybenzaldehyde 1, primary amines 2, and TMSCN 3 in the presence of 10 mol % NH2SO3H as catalyst.This procedure not only affords the products in good yields but also avoids the problems associated with handling safety and pollution.The reactions are conducted in a green solvent (EtOH), and the toxic substrates NaCN and KCN are replaced by TMSCN which is relatively safer.Hence, it is a green and useful procedure for the synthesis of N-substituted 3-oxoisoindoline-1-carbonitriles 4.

Experimental Section
General.Melting points were measured by a WRS-1B micromelting point apparatus and are uncorrected.NMR spectra were recorded on a Bruker AMX 400 instrument using solvent peaks as DMSO-d6 solutions.HRESIMS were determined on a Micromass Q-Tof Global mass spectrometer and ESIMS were run on a Bruker Esquire 3000 Plus Spectrometer.TLC was performed on GF254 silica gel plates (Yantai Huiyou Inc., China).

Table 1 .
Optimization of the reaction conditions a bIsolated yields.