Synthesis of Highly Substituted Adamantanones from Bicyclo[3.3.1]Nonanes Michael E

Note pubs.acs.org/joc Synthesis of Highly Substituted Adamantanones from Bicyclo[3.3.1]nonanes Michael E. Jung* and Gloria S. Lee Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States *S Supporting Information ABSTRACT: Trifluoromethanesulfonic acid and other electrophiles promote formation of the adamantanone core from the readily accessible 1,5-dimethyl-3,7-dimethylenebicyclo[3.3.1]nonan-9-one 2. Because adamantyl cation 3 can be trapped by a range of nucleophiles, including aromatic and heteroaromatic rings, alcohol, nitriles, and halides, access to a wide variety of functionality at the newly formed tertiary position is provided. he diamond-like structure of adamantane has fascinated The Friedel−Crafts alkylation of benzenoid aromatic rings T chemists since its discovery in petroleum in 1933.1 Studies with the adamantane core has been reported occasionally, but have shown that adamantane is the most stable of the C10H16 harsh conditions, including high temperature, long reaction isomers and can be easily prepared by the Lewis acid promoted times, and high pressure mercury lamps, were often employed.7 rearrangement of other C10H16 species, e.g., tetrahydrodi- In many cases, a multistep procedure is involved in which a 1- 2 fi cyclopentadiene. The rst instance of the adamantane haloadamantane is first formed and then used to generate a structure in drugs involved 1-aminoadamantane, amantadine, carbocation at the tertiary position, which is subsequently a selective antiviral agent, which was used against influenza 3 trapped by a nucleophile. Although there is one example of the upon its approval in 1966. Since then, a number of 1- cyclization of the simple unsubstituted 3,7-dimethylene- aminoadamantanes have been synthesized, and one, 3,5- bicyclo[3.3.1]nonane in anisole as solvent giving the aryl dimethyl-1-amino-adamantane, memantine, has been approved 8 ’ 4 adamantane, to our knowledge, no systematic study of the for the treatment of Alzheimer s disease. However, the − biological mechanism of action of the adamantane derivatives Friedel Crafts alkylation of adamantyl cations generated by is still unclear. this type of cyclization has been carried out. This limited For a project aimed at the total synthesis of rugulosone, 15 reaction scope therefore prompted us to investigate a more ffi (Figure 1), we prepared 1,5-dimethyl-3,7-dimethylene- e cient way of rapidly constructing substituted adamantanones. Synthesis of Adamantanones from 2. We now present a new and efficient method for the construction of adamantan-2- ones substituted at the 7-position with aryl, heteroaryl, alkoxy, amido, and alkynyl groups, starting from the 1,5-dimethyl-3,7- dimethylenebicyclo[3.3.1]nonan-9-one core 2. We envisioned forming the adamantyl cation with acid, followed by trapping with a nucleophile to obtain the tetrasubstituted adamantanone Figure 1. Rugulosone, amantadine, and memantine structures. core. Consequently, we screened various acidic conditions for the formation of the desired product, 1,3,5-trimethyl-7- phenyladamantan-2-one 4a, from 2 (Table 1). ffi Without the presence of an added nucleophile, the cation can bicyclo[3.3.1]nonan-9-one 2 by the very e cient quadruple be quenched by the benzene solvent. Thus, treatment of the alkylation of 3-pentanone with 1,1-bis(chloromethyl)ethylene, diene 2 with trimethylsilyl triflate in benzene afforded the 7- a reaction that proceeded in 90% yield.6 We were interested to phenyl-substituted adamantanone 4a in 65% yield. Other protic see if this bis(methylene) system could be used to efficiently and Lewis acids produced the same product 4a in moderate to construct various substituted adamantanones, which might fl fl serve as precursors to the corresponding adamantanes. The good yields, with tri uoromethanesulfonic acid, tri ic acid, ability to construct a large variety of substituted adamantanones being the best of those tested, giving the desired product in in a highly efficient and simple manner could allow for more rapid testing of derivatives to study both the biological activity Received: June 18, 2014 and the mechanism of action of this class of compounds. Published: October 2, 2014 © 2014 American Chemical Society 10547 dx.doi.org/10.1021/jo501368d | J. Org. Chem. 2014, 79, 10547−10552 The Journal of Organic Chemistry Note a Table 1. Conversion of Diene 2 to Table 3. Reactions of 2 with Nucleophiles To Give 4 a Trimethylphenyladamantanone 4a entry acid yield (%) 1 TMSOTf 65 · 2BF3 OEt2 78 3 AlCl3 47 4H2SO4 21 5 TFA 59 6 TfOH 90 7 Cu(OTf)2 0 8 None 0 aReaction conditions: 2 (1.05 mmol), acid (1.2 equiv), benzene (5 mL), Ar, 3 h. 90% yield. Some Lewis acid catalysts, e.g., cupric triflate, did not provide any product but only returned starting material. Substrate Scope. Next, we investigated the substrate scope of our reaction using the same mild conditions and short reaction times (Table 2). Various aromatic rings with electron- a Table 2. Reaction of 2 with Aromatic Rings 5 To Give 4 aReaction conditions: 2 (1.05 mmol), TfOH (1.2 equiv), nucleophile fi b (5.0 equiv), CH2Cl2 (5 mL), unless otherwise speci ed. Reactions c performed with nucleophile as solvent. Conc. H2SO4 as solvent. unidentified products being formed. However, the reaction of 2 in the presence of triflic acid with N-methylpyrrole 5f gave a mixture of the 2- and 3-substituted pyrrole products, 4f and 4f′, entry Nu R2 R3 R4 R5 R6 yield (%) in yields of 33 and 17%, respectively. The assignment of the 1b 5a HHHHH4a,90 structures was based on the pattern of the absorptions in the 10 2b 5b HHMeHH4b,57 proton NMR spectrum and matched literature data. In this Me H H H H 4b′,19 case, the ratio of the trapping at C2 vs C3 (1.9:1) is somewhat 3b 5c Me H H Me H 4c,47 surprising given that the reported ratio of trapping of a tert- 11 4 5d OMe H OMe H H 4d,47 butyl cation with N-methylpyrrole is 1:1.4 (C2/C3). 5 5e OMe H OMe H OMe 4e,36 Likewise, reaction of 2 with thiophene 5g in the presence of a fl ff Reaction conditions: 2 (1.05 mmol), TfOH (1.2 equiv), nucleophile tri ic acid a orded the 2- and 3-substituted products, 4g and fi ′ (5.0 equiv), CH2Cl2 (5 mL), Ar, 3 h, unless otherwise speci ed. 4g , in a 1.2:1 ratio in yields of 26 and 21%, respectively. The bReactions are performed with nucleophile as solvent. assignment was made by comparing the coupling constants for the three aromatic protons and by analogy to literature data.12 donating groups 5a−e reacted as good nucleophiles to produce In addition to trapping the adamantyl cation, generated from the substituted adamantanones 4a−e in moderate yields. Thus, 2 by protonation with triflic acid, with aromatic nucleophiles, toluene 5b gave a 76% combined yield of a 3:1 mixture of the we also investigated trapping with other simple nucleophiles. 4-methyl and 2-methyl products 4b and 4b′. p-Xylene 5c gave Again, there are reports of such nucleophilic trapping in the the expected product 4c in 47% isolated yield; similarly, m- literature,8,13 but no systematic study has been carried out. dimethoxybenzene 5d afforded the expected product 4d in 47% Thus, we treated the diene 2 with triflic acid in the presence of yield. The more hindered 1,3,5-trimethoxybenzene 5e gave the various nucleophiles, with the results shown in Table 3. expected product 4e in only 36% yield, perhaps due to the Methanol and acetic acid as nucleophilic solvents gave good steric hindrance of the only available aromatic position. Again, yields of the expected trapping of the oxygen atom to produce there have been scattered reports of the trapping of adamantyl 4h and 4i in 52 and 88% yields, respectively. The tertiary cations with benzenoid nucleophiles, but no systematic study alcohol 4j could also be prepared by treating 2 with conc. has been reported.9 As far as we can tell, no heterocycles have sulfuric acid in 74% yield. Propargyl alcohol also trapped on ever been used to trap an adamantyl cation under these oxygen to give the propargyl ether 4k in 35% yield. Somewhat conditions. Therefore, we studied the use of several five- surprisingly, phenol gave trapping only on the oxygen atom to membered heterocyclics in this regard (Table 3). Furan and N- give 4l in 36% yield, with no evidence for trapping on carbon, methylindole gave very poor results, with a multitude of either C4 or C2, being observed. In the absence of any external 10548 dx.doi.org/10.1021/jo501368d | J. Org. Chem. 2014, 79, 10547−10552 The Journal of Organic Chemistry Note trapping agent, one obtains trace amounts of the triflate 4m and Scheme 1. Cyclization of Analogues 6 To Give the symmetrical ether 4n. One can also carry out a Ritter Adamantanones 7 reaction, namely, treatment of 2 with triflic acid in acetonitrile as solvent to generate the acetamide 4o in 88% yield.14 This trapping would be useful for preparing analogues of memantine. Finally, we could also effect C−C bond formation of a nonaromatic substrate, namely, trimethylsilyl acetylene, to give the acetylene product 4p in 44% yield. We also examined the addition of electrophiles other than proton to one of the exocyclic methylenes of 2 with the idea of triggering the cyclization to produce the adamantyl cation, Scheme 2. Mechanism of 2 Forming Adamantane Core 4 which could then be trapped with simple nucleophiles (Table 4). Reports of such dual addition of electrophiles and Table 4.

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