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98 BENZOFUSED HETEROCYCLES VIA SOLID-PHASE SWAR REACTIONS
(Resin is ArgoGel/Rink)
54a (R1 = H)
54b (R1 = Me)
DIEA, DMF, 25 °Ñ
55a (R1 = H; R,R' = O) 55b (R1 = Me; R,R' = 0) 56a (R1 = H; R,R' = H) 56b (R1 = Me; R,R' = H)
SnCI2»2H20, DMF ---------------->
57a (R1 = H; R = H) 57b (R1 = Me; R = H) 58a (R1 = H; R = OH) 58b (R1 = Me; R = OH)
(i) 4-N02-benzylbromide DIEA, DMF, 25 °Ñ
(ii) TFA, CH2CI2
3.3. FORMATION OF [6,6]-FUSED SYSTEMS 99
spectively, in high purities and yields. Exposure of 55 to standard nitro-group reduction conditions (SnCl2-2H20 in DMF), however, did not furnish the expected o-alkylthio-anilines 56a and 56b or the corresponding 1,4-ben-zothiazin-3-ones 57a and 57b. Another set of products was obtained in purities exceeding 90%. These were the corresponding cyclic hydroxamic acids 58a and 58b, respectively, based on mass spectrometry (MS), nuclear magnetic resonance (NMR), and infrared (IR) data, as well as on their reactivity toward alkylating agents. Thus, treatment of 58a and 58b with p-nitrobenzyl bromide at room temperature resulted in smooth conversion to the corresponding 4-(/?-nitrobenzyloxy)-l,4-benzothiazin-3-ones 59a and 59b, respectively.
The literature contains several references to reductive cyclizations producing cyclic hydroxamic acids like those described above, though not in solid-phase chemistry.43-47 We showed that this reaction competes well with lactam formation. The relative extent of these two reaction pathways is highly dependent on the presence and the nature of other heteroatoms and substituents around the ring system as well as on the conditions used to effect the reduction.
From a pharmaceutical discovery perspective, it could be fruitful to embark on a library synthesis using cyclic hydroxamic acid templates. There are several reports describing interesting bioactivities for such compounds, particularly as inhibitors of metal-dependent enzymes 48-52 However, only three a-mercapto acid monomers are currently available from commercial sources; hence the structural diversity of products that could be easily prepared is limited. Several approaches to introducing additional points of diversity into the benzothiazinone scaffold are currently under investigation.
3.3.2. Quinoxalin-2-ones (6)
Quinoxalin-2-ones 6, the [6,6]-fused ring homologues of the 1,5-ben-zodiazepinones 4, are accessible through an analogous set of solid-phase transformations using a-amino acids in place of [5-amino acids in nucleo-philic aromatic substitution reactions of la. A solution-phase version of this reaction sequence has previously been reported by TenBrink and ñî-workers in studies of quinoxalinones as y-aminobutyric acid (GABA)/ben-zodiazepine receptor partial agonists.53,54 Although less extensively investigated than the benzodiazepinones, quinoxalinones have been applied
BENZOFUSED HETEROCYCLES VIA SOLID-PHASE S/vAR REACTIONS
as ligands for excitatory amino acid receptors,55-56 as analgesics,57 and as inhibitors of aldose reductase.58
Three groups have independently developed solid-phase synthetic approaches toward the quinoxalinones.5 8-9 In our approach, the central intermediate la was reacted with a variety of a-amino acids 60 using the aqueous solvent system [0.5 M NaHC03(aq)/acetone 1:1] described above for the synthesis of 1,5-benzodiazepinones (Scheme 9).6
(Resin is ArgoGel/Rink)
H2N COOH 60
0.5M NaHC03 (aq)/ acetone 1:1, 70 SC
2M XCH2R3 in 1M SnCI2»2H20 DMF, 45-50sC
(³) 0.25M X-CH2-R4, lithiated 4-benzyl-2-oxazolidinone THF/DMF 1:1, 25 QC (submitted twice)
(ii) TFA, CH2CI2
3.3. FORMATION OF [6,6]-FUSED SYSTEMS 101
The conditions required for complete fluorine displacement were milder for a-amino acids compared to those typically needed for (3-amino acids (60°C vs. 75°C). A wide range of a-amino acids were shown to afford the desired o-nitro-anilines 61 with purities exceeding 85%. These included all the proteinogenic amino acids, and representative Ë^-methyl amino acids, spirocyclic amino acids (e.g., 1 -amino-1 -cyclopentanecarboxylic acid), and other nonnatural amino acids. As in the benzodiazepinone case, all attempts to alkylate or acylate the secondary aniline nitrogen of 61 prior to reduction of the nitro group proved unfruitful and afforded essentially unchanged starting material. From our previous experience in the benzothiazine series (Section 3.3.1), we expected that exposure of 61 to the standard nitro-group reduction conditions (2 M SnCl2-2H20, DMF) would exclusively afford cyclic products (i.e., either lactams or hydroxamates). Indeed, the single product isolated from the reduction of 61 was identified in all cases as the corresponding lactam, with no detectable amounts of either acyclic material or cyclic hydroxamic acid being present. The driving force for spontaneous cyclization was found to be so strong that even in cases where the carboxyl function was protected in the form of a primary carboxamide or a tert-butyl ester, no traces of acyclic products could be detected. In the latter case, solid-phase, magic-angle-spinning NMR experiments demonstrated that cyclization does not occur during the TFA cleavage of the products from the resin but rather on the solid support during the reduction step. This was inferred from the solid-state NMR spectrum of the resin derived from the reduction step, which no longer showed the characteristic signal for the tert-butyl ester function, clearly evident in the starting material. In an ambitious attempt to subvert the spontaneous cyclization by capturing the intermediate primary aniline function with alkylating agents, we submitted resin 6i to a 1 M solution of SnCl2-2H20 in DMF containing, in addition, benzyl bromide at high concentration (2 M). To our surprise and delight, we were able to isolate a single product from the reaction. This was not, however, the anticipated N( 1 )-alkylated quinoxalinone, but rather the M4b alkylated compound 62, as shown by 'H NMR. Subsequently, this same product was also obtained, albeit in somewhat lower purity, by subjecting 61 to the same reagents in a stepwise manner. Rather fortuitously, we had thus discovered an expedient two-step procedure for the solid-phase synthesis of 3,4-disubstituted quinoxalin-2-ones from la. In further experiments, this protocol was shown to be of broad scope in terms of functional groups derived from both amino acids (R’/R2) and alkylating agents (R3).