Intermolecular sp 3 -C-H Amination for the Synthesis of Saturated Azacycles
The preparation of substituted azetidines and larger-ring, nitrogen-containing saturated heterocycles is enabled through efficient and selective intermolecular sp 3 -C-H amination of alkyl bromide derivatives. A range of substrates is demonstrated to undergo C-H amination and subsequent sulfamate alkylation in good to excellent yield. N-Phenoxysulfonyl-protected products can be unmasked under neutral or mild basic conditions to yield the corresponding cyclic 2° amines. The preparative convenience of this protocol is demonstrated through gram-scale and telescoped multi-step procedures. Application of this technology is highlighted in a nine step total synthesis of an unusual azetidine-containing natural product, penaresidin B.The Supporting Information is available free of charge on the ACS Publications website.Experimental details and characterization data (PDF)
<p>Saturated azacycles are ubiquitous structural elements in natural products. 1 Cyclic amines also appear in designed molecules owing to the unique and disparate physicochemical and topological properties of such heterocycles. 2,3 Pyrrolidine and piperidine derivatives can be accessed through numerous means, which rely on both conventional and modern C-N bond forming methods including C-H oxidation. [4][5][6] We have been interested in developing a general protocol for assembling substituted azacycles of differing ring size, with a specific focus on azetidine structures. The value of such amines is considerable in synthesis, pharmacology, and medicine. [7][8][9][10] Herein, we present a method for the preparation of small (n = 3-5) and medium (n = 6-8) ring-sized azacycles that capitalizes on selective, intermolecular sp 3 -C-H amination of brominated hydrocarbon substrates (Scheme 1). The efficient functionalization of substrates in which the desired site of C-H oxidation is proximal to an electron-withdrawing halogen group underscores recent advances in Rh-catalyzed amination. [11][12][13][14][15][16][17][18] Typical methods for de novo azetidine synthesis include S N 2 displacement reactions of mono-and dihalopropanes with alkyl amines, 6,7,19 aziridine ring expansion, 6,7,20,21 thermal and photochemical [2+2] cycloadditions, 6,7,22,23 and Pd-catalyzed C-N cross coupling. 6,7,24,25 Our approach for constructing azetidine derivatives involves selective, intermolecular C-H amination of bromoalkanes to introduce the requisite nitrogen center followed by ring closure. Accordingly, the scope of this method is potentially quite broad and extends beyond 4membered ring synthesis. As Rh-catalyzed C-H amination is stereospecific, access to optically active cyclic amines is also possible. Exploratory studies to develop a process for azetidine synthesis were conducted with 1-bromo-3-phenylpropane 1a (Table 1). The proximity of the electronegative Br-group in 1a to the benzylic site deactivates this position towards oxidation. Consequently, a number of reported C-H amination protocols fail to engage this substrate; others furnish small amounts of the desired product in combination with unidentifiable species (see Supporting Information Table S2 for relevant comparisons). Using a recently disclosed amination protocol developed in our lab, 27 intermolecular C-H amination of 1a with phenyl sulfamate (PhsNH 2 ) proceeds in 64% yield to furnish 2a (23% RSM). The intermediate bromoalkyl sulfamate ester efficiently cyclizes upon treatment with base to provide the corresponding azetidine 3a (see Supporting Information Table S1 for optimization). Through the application of this two-step sequence, 3a is obtained in 62% overall yield (Table 1, entry 1). The effectiveness of the amination reaction, which affords largely product and recovered starting material, allows the cyclization reaction to be telescoped in a single-flask procedure. Following this protocol, pure azetidine 3a can be isolated in 49% (Table S1; see Scheme 2 for more details).  To examine the generality of the amination method for assembling cyclic amines of varying ring size, a systematic analysis of reaction performance with phenyl-substituted bromoalkanes was conducted. Azacycles from 3-8 in size can be fashioned through our two-step sequence. For the most part, C-H amination yields improve as the distance between the Brsubstituent and the benzylic center is increased; nonetheless, even phenethylbromide 2a can be oxidized in 40% yield to generate sulfamate 2b (Table 1, entry 2). The cyclization event is consistently high yielding with the one exception involving azocane 3f (entry 6). As a final note, reactions performed with alkyl mesylate substrates show diminished product yields stemming from the inefficiency of the amination reaction (entries 1 and 5). Somewhat surprisingly, this finding holds even for 6-phenylhexyl mesylate (entry 5), thus leaving open an explanation for the suboptimal performance of the amination reaction with mesylate-derived starting materials.  b Cyclization performed with 0.1 mmol C-H aminated product in 1 mL DMF for 2 h. c Product isolated as a 1:1.8 mix of diastereomers; cyclization was conducted on pure syn-diastereomer. d Product isolated as a 1:1.1 mix of diastereomers. e Recovered starting material was not obtained due to the high volatility of this compound. f Product isolated as a 1:1 mix of diastereomers. g Product decomposition occurs on silica gel. h Amination gives a >10:1 mix of isomeric products; ring closure was conducted on a pure sample of the isomer shown.</p><p>To further explore the scope of our azacycle assembly method and to demonstrate its utility for fine chemical synthesis, substituted 1° and 2° alkyl bromide derivatives were subjected to the optimized protocol (Table 2). C-H amination generally proceeds in yields ranging from 37-71%; subsequent ring closure is efficient and affords the desired azacycle products. In several cases, Phs-protected cyclic amines are obtained in high purity following aqueous work-up without recourse to silica gel chromatography (entries 1, 4, 5).</p><p>Substrates bearing benzylic (Table 2, entries 1−4), tertiary (Table 2, entries 5−7, 11), and protected carbinol C-H bonds (Table 2, entries 8−10) are successfully converted into the corresponding azetidines. The mild conditions for cyclization are tolerant of base-sensitive functional groups including pinacolborane (entry 2), N-Boc indole (entry 3), and esters (entries 4, 7). Subjecting 1,3-dioxane and dioxolane-derived substrates (entries 8-10) to the two-step sequence affords unusual N,Oacetal azetidines, which are amenable to further modification. 28,29 As highlighted previously (see Table 1), cyclic amines of different ring size are accessible using our amination/cyclization technology. Entry 10 is notable in this regard, as the glycerol-based substrate undergoes site-selective oxidation and ring-closure with K 2 CO 3 to furnish an isolable, spirocyclic aziridine N,O-acetal.</p><p>It is possible to conduct sequential C-H amination/cyclization in a single flask with only a small diminution in overall reaction performance (Scheme 2). This modified protocol is convenient when isolation of the C-H amination product is capricious, as is sometimes the case for N,O-acetal and other derivatives.</p><p>Phenoxysulfonyl (Phs) is a convenient and chromatographically stable N-protecting group, which can be readily removed to liberate the amine product (Scheme 3). Heating a Phs-amine starting material in aqueous CH 3 CN or aqueous pyridine cleaves the Phs-group; both conditions afford the desired amine in high purity following reversed-phase chromatography (HPLC) or trituration of the oxalate salt. 30 To demonstrate the synthetic utility of our method for complex chemical synthesis, an unusual, azetidine-derived lipid penaresidin B was identified as a natural product target (Scheme 4). 31 Penaresidin B consists of a densely functionalized azetidine core with three contiguous stereocenters and a distally hydroxylated alkane side chain. Several total syntheses of penaresidin B [32][33][34] and related congeners [35][36][37][38][39][40][41] have been described, all relying on early-stage nitrogen incorporation using starting materials such as Garner's aldehyde 42 and/or multistep functional group interconversions to construct the azetidine core. The shortest of the reported syntheses of penaresidin B is 17 linear steps. 34 Accordingly, application of our C-H amination/cyclization method should streamline access to this natural product. Our route to penaresidin B capitalizes on the performance of dioxolane substrates for C-H amination. Beginning from enantiopure oxirane 5, 43 organocuprate addition to the lesshindered terminus yielded alcohol 6. Protection of the alcohol group as the p-nitrobenzoyl ester was intended to deactivate the carbinol C−H bond and the proximal 3° site towards C-H amination. Grubbs' cross-metathesis of 7 with commercially available (R)-2,2-dimethyl-4-vinyl-1,3-dioxolane afforded olefin 8, which was subsequently epoxidized to give 9 as a ~7:1 mixture of diastereomeric products.</p><p>Generation of the desired sulfamate ester 10 from 9 necessitated the development of a single-flask protocol for sequential amination/reduction owing to problems with isolation of the intermediate N,O-acetal. Subjecting 9 to standard amination conditions followed by NaBH 3 CN furnished aminoalcohol 10 as a ~5:1 mixture favoring the desired stereoisomer. This result is striking given the large number of disparate C-H bonds in 9 and the adjacent functional groups flanking the desired site of oxidation. We anticipate that this amination/reduction protocol will prove useful for the assembly of structurally related amino-polyol motifs. To complete the synthesis of penaresidin B, epoxide 10 was converted to bromohydrin 11 under the action of CeBr 3 . Bromide displacement of 10 occurred regioselectively at C4 (penaresidin B numbering) to give 11 as the only detectable prod-uct. 44,45 Finally, ring closure of the azetidine followed by sulfamate and nitrobenzoate deprotection yielded the desired target. Removal of the Phs-protecting group in 12 proved more challenging than with less functionalized azetidines (see Scheme 3). 46 Successful deprotection, however, was ultimately achieved by adapting a procedure for cross-coupling of cyclic sulfamate esters. 47 Under nickel catalysis with MeMgBr, displacement of the phenyl ring afforded the sulfated azetidine; subsequent treatment with methanolic HCl furnished the natural product. All told, the enantioselective synthesis of penaresidin B proceeds in 9 steps from commercial starting materials, a substantial decrease in the overall step count compared to previous syntheses.</p><p>We have described reaction technology for the generation of structurally diverse small and medium-sized cyclic 2° amines. This process capitalizes on site-selective, intermolecular C-H amination to first introduce the obligatory nitrogen center as a sulfamate ester. Efficient C-H oxidation is viable across a range of functionalized propyl-and longer chain alkylbromide starting materials, substrates that have not been previously documented for amination reactions. We expect this work to advance the utility of C-H amination for the preparation of complex chemicals.</p>