Letter pubs.acs.org/OrgLett
Synthesis of Aminophenanthrenes and Benzoquinolines via Hauser− Kraus Annulation of Sulfonyl Phthalide with Rauhut−Currier Adducts of Nitroalkenes Tarun Kumar, Vaijinath Mane, and Irishi N. N. Namboothiri* Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India S Supporting Information *
ABSTRACT: The Hauser−Kraus reaction of sulfonyl phthalide with nitroalkene derivatives provides access to aminophenanthrenes, including phenanthrenesubstituted amino acids and benzoquinolines. The intermediate quinones bearing a key ketoalkyl moiety undergoes facile intramolecular enamine cyclization. Interestingly, enamines derived from primary and secondary amines undergo cyclization via C-centered nucleophilic attack to provide aminophenanthrenes, whereas those derived from ammonia undergo cyclization via N-centered nucleophilic attack leading to benzoquinolines. A one-pot protocol for the direct transformation of phthalides and nitroalkene derivatives to aminophenanthrenes and benzoquinolines has also been developed.
P
carboxylate groups.22−24 While quinones were the products in the reaction of a nitroglycal with sulfonyl phthalide22 and a nitrostyrene with cyanophthalide,23 the reaction stopped at the Michael addition stage in the case of nitroalkene with a phthalide ester.24 Our recent efforts to react sulfonyl phthalides with ohydroxynitrostyrenes led to unexpected spiro- and fused heterocycles through a cascade of elimination and rearrangements.25 In the above scenario, we envisioned that the quinones derived from reaction of sulfonyl phthalide with appropriately substituted nitroalkenes could be utilized for the synthesis of functionalized phenanthrenes and benzoquinolines. More importantly, phenathrenes and benzoquinolines, bearing multiple functional groups such as amino and/or hydroxy and aryl would be valuable compounds in bio-organic and medicinal chemistry. Amino acids bearing a phenanthrene group could also be synthesized by our approach offering convenient access to constrained amino acids and peptides with interesting and unusual properties. At the outset, the Rauhut−Currier (RC) adduct 2a of nitroalkene with MVK and sulfonyl phthalide 1 were chosen as the model HK acceptor and donor, respectively, for our reaction. These two substrates were allowed to react in the presence of bases such as Et3N, Cs2CO3, K2CO3 and t-BuOK in solvents such as THF, CH2Cl2 and benzene at room temperature. However, 1.5 equiv of Cs2CO3 in THF afforded the best results in that the annulated product 3a in good yield (65%) along with small amounts of the uncyclized Michael adduct 4a (12%) were isolated (see the Supporting Information). Various analogues of compound 2 were subsequently screened under the above optimized conditions for the preparation of naphthoquinones 3 (Table 1). In general, the yields remained
henanthrenes constitute an important class of aromatic carbocycles that widely occur in bioactive natural products and drug molecules and are isolated mainly from plants belonging to the archidaceae family.1 The wide range of biological activities exhibited by phenanthrenes include anticancer,2 antimicrobial,3 antiallergic,4 and antimalarial activities.5 The versatile biological activities of phenanthrenes and their presence in natural products motivated scientists to develop new chemical methods for their synthesis.6 The known methods include intramolecular cyclization of benzenoids, naphthalenoids, stilbenoids and biphenyloids,7 intermolecular cyclization/cycloaddition of benzenoids and naphthalenoids,8 as well as ring expansion/contraction reactions.9 Similarly, benzoquinolines10 were synthesized by inter-/intramolecular cyclization involving 1aminonaphthalene,11 dehydrogenation of N-heterocycles,12 photocyclization of 3-styrylpyridines/stilbenes,13 intramolecular cyclization of tetralone derived acylazide,14 inter-/intramolecular cyclization of biaryls,15 and rearrangements.16 The only report on the synthesis of 2-aminophenanthrenes is based on benzannulation of an alkyne without any metal catalyst.17 From another perspective, the Hauser−Kraus (HK) reaction has emerged as an eminent strategy for the synthesis of benzannulated quinones.18 Stabilized phthalides react as 1,4dipolar synthons with various Michael acceptors (1,2-dipolar synthons) such as α,β-unsaturated ketones, esters, sulfones, nitriles, and nitro compounds.19 Complex molecules, including numerous natural products, have been synthesized by this strategy which involves Michael addition, Dieckmann cyclization, and elimination.20 Various stabilizing groups such as sulfide, sulfoxide, sulfone, nitrile, halide, alkoxide, carboxylate, phosphonate, and benzotriazolyl enabled synthetic chemists to expand the scope and applications of this elegant methodology.21 Nitroalkenes have participated as 1,2-dipolar synthons in the HK reaction with various phthalides bearing sulfonyl, cyano, and © XXXX American Chemical Society
Received: June 26, 2017
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DOI: 10.1021/acs.orglett.7b01924 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
dicarbonyl functionality offered scope for further cyclization, for instance, to phenanthrene analogues under suitable reaction conditions. To this end, intramolecular cyclization of a representative naphthoquinone 3a to phenanthrene was attempted in the presence of pyrrolidine and catalytic amount of PTSA in refluxing toluene (Scheme 2). Although the expected
Table 1. Synthesis of Naphthoquinone Derivatives
entry
2, R
time (h)
3
yielda,b (%)
1 2 3 4 5 6 7 8 9 10 11 12
2a, 3-MeOC6H4 2b, 4-MeOC6H4 2c, 3,4-(MeO)2C6H3 2d, 4-MeC6H4 2e, C6H5 2f, 4-FC6H4 2g, 4-ClC6H4 2h, 4-BrC6H4 2i, 1-naphthyl 2j, 2-furyl 2k, cyclohexyl 2l, i-Pr
10 10 12 15 15 9 9 8 13 12 12 12
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l
65 64 64 57 62 70 62 66 62 75 c d
Scheme 2. Synthesis of Phenanthrene Derivatives
a
After silica gel column chromatography. bThe Michael adducts were isolated in some cases in very low (6−12%) yield. cPhthalide 1 decomposed. dRC adduct 2l decomposed.
good to high (57−75%) for this one-pot cascade reaction. Substrates bearing strongly electron-rich aryl groups 2a−c reacted in 10−12 h and delivered the annulated products 3a−c in good yields (64−65%) (Table 1, entries 1−3). Weakly activated and electroneutral aryl groups in substrates 2d, 2e, and 2i, respectively, did not have any major influence on the yield of the corresponding products 3d, 3e, and 3i (57−62%) despite the fact that the reaction times in these cases were relatively longer (13−15 h) (Table 1, entries 4, 5, and 9). A smooth and faster reaction (8−9 h) was observed in the case of weakly deactivated haloaryl compounds 2f−h to afford the corresponding quinones 3f−h in good yields (62−70%) (Table 1, entries 6−8). Formation of quinone 3 can be explained in terms of the wellestablished HK mechanism (Scheme 1). Briefly, base-mediated
phenanthrene skeleton was constructed by this method, we were pleasantly surprised to see the incorporation of pyrrolidine in the product. Interestingly, the amine base acted as a reactant and remained as an integral part of phenanthrene rather than acting as a catalyst in the cyclization. In light of this unusual result, i.e., formation of aminophenanthrenol 6a in high yield (79%), we intended to evaluate the reactivity of various amines and naphthoquinones 3 for the synthesis of substituted aminophenanthrenols 6, including amino acid derivatives. Besides 3a, quinone 3c, bearing a strongly electron-rich aryl group, also reacted well with pyrrolidine in the presence of PTSA to afford the corresponding aminophenanthrenol 6b in 78% yield (Scheme 2). Another cyclic secondary amine such as morpholine and a primary amine such as benzylamine also exhibited excellent reactivity with another quinone 3f, bearing a weakly electrondeficient aryl group, providing the corresponding phenanthrenols 6c and 6d in 84% and 82% yields, respectively. The above experiments confirmed the comparable reactivity of both secondary and primary amines with quinones 3 bearing both electron-rich and electron-deficient aryl groups. Inspired by the above results, we turned our attention to utilize proline and other selected α-amino acids as an amine source for our annulation (Scheme 2). The products, α-amino acid derivatives possessing a phenanthrenyl moiety on N, appeared to be attractive targets due to their possible applications as monomers in the synthesis of conformationally constrained and arene-rich peptides.
Scheme 1. Proposed Mechanism for the Formation of Quinones
Michael addition of sulfonyl phthalide 1 to compound 2 generates intermediate I. Intermediate I on protonation provides the Michael adduct 4, whereas intramolecular cyclization leads to intermediate II, which further rearranges to another intermediate III with the loss of sulfonyl group. Overall, this is a Dieckmann cyclization or [4 + 2]-annulation between a 1,4-dipolar synthon such as phthalide anion and a 1,2-dipolar synthon such as nitroalkene 2. Base-mediated elimination of HNO2 in intermediate III delivers the naphthoquinone 3. The above naphthoquinone derivatives 3a−j appeared to be very valuable synthetic intermediates as the presence of the 1,5B
DOI: 10.1021/acs.orglett.7b01924 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters When the ethyl ester of L-proline was treated with quinone 3f under the above conditions, the corresponding proline attached phenanthrenol 6e was isolated in 87% yield (Scheme 2). A similar reaction of valine ester with naphthoquinones 3b, 3d, and 3f, bearing a strong electron-donating group, a weak electrondonating group, and a weak electron-withdrawing group on the aromatic ring, delivered the products 6f−h in very high yields (91−92%) irrespective of the nature of substituent. Further, aromatic amino acid tryptophan also reacted smoothly with naphthoquinone 3f, and the product 6i was isolated in 90% yield. After evaluating the reactivity of secondary and primary amines for the synthesis of phenanthrenols 6, we were curious to know the reactivity of ammonia with naphthoquinones 3. Thus, a representative naphthoquinone 3b was treated with ammonium acetate in refluxing acetic acid for 2 h (Table 2, entry 1). We
Scheme 3. Mechanistic Rationale for the Formation of Aminophenanthrenes
Scheme 4. Plausible Pathway for the Formation of Quinolines
Table 2. Synthesis of Benzoquinoline Derivatives
a
entry
3, Ar
time (h)
7
yielda (%)
1 2 3 4 5 6
3b, 4-MeOC6H4 3e, C6H5 3f, 4-FC6H4 3g, 4-ClC6H4 3i, 1-naphthyl 3j, 2-furyl
2.0 1.0 1.5 2.0 2.5 1.5
7a 7b 7c 7d 7e 7f
89 85 94 91 78 70
Finally, a one-pot synthesis of phenanthrene and benzoquinoline derivatives from sulfonyl phthalide 1 and nitroalkene derivatives 2 was successfully carried out. After the formation of naphthoquinone 3 (monitored by TLC), THF was evaporated and the crude residue was subjected to the next step without further purification. To our delight, both the reactions proceeded smoothly in good overall yield (Scheme 5).
After silica gel column chromatography.
isolated benzoquinoline 7a as the sole product in 89% yield instead of the expected aminophenanthrene. This result prompted us to examine the reactivity of various other naphthoquinones 3 for the synthesis of substituted benzoquinolines 7. As in the case of 3b, quinones 3e−g reacted well with NH3 in 1−2 h to afford benzoquinolines 7b−d in excellent yields (85− 94%) (Table 2, entries 2−4). This confirmed that the electronic nature of the aryl group does not have any appreciable influence on the rate of reaction or product yield. However, benzoquinolines 7e and 7f, derived from naphthyl-substituted quinone 3i and the furyl derivative 3j, were formed in less impressive yields, 78% and 70%, respectively (Table 2, entries 5 and 6). Formation of iminium IV and its tautomeric equilibrium with enamine V/VIIIb can be visualized in the formation of both aminophenanthrene 6 and benzoquinoline 7 (Schemes 3 and 4).26 However, the subtle difference in the nucleophilicity of the enamine tautomer V, derived from primary or secondary amine, and the enamine tautomer VIIIb, derived from NH3, appears responsible for the change in product profile. While the aminophenanthrene 6 is formed via intramolecular cyclization of kinetic enamine V, derived from primary or secondary amine, through C-centered nucleophilic attack (Scheme 3), such a cyclization does not take place in the case of enamine VIIIb, derived from NH3 presumably due to its poor reactivity as a Ccentered nucleophile (Scheme 4). Instead, VIIIa, the imine tautomer of VIIIb, cyclizes through N-centered nucleophilic attack via the thermodynamic enamine (not shown) to form intermediate IX, which undergoes elimination of H2O followed by tautomerization to aromatic product aminoquinoline 7.
Scheme 5. One-Pot Synthesis of Phenanthrene and Benzoquinoline Derivatives
In summary, the Hauser−Kraus reaction of nitroalkene derived Rauhut−Currier adducts with sulfonyl phthalide provides naphthoquinones bearing an additional ketoalkyl moiety. While intramolecular cyclization of these quinones in the presence of primary and secondary amines, including amino acid derivatives, leads to aminophenanthrenes via C-centered nucleophilic attack of the in situ generated enamine, similar cyclization in the presence of ammonia delivers benzoquinolines via a N-centered nucleophilic attack. Our method provides a convenient access to N-phenanthrenyl amino acids and angularly fused benzoquinolines in a practically one-pot operation from sulfonyl phthalide and Rauhut−Currier adduct of nitroalkene with methyl vinyl ketone. C
DOI: 10.1021/acs.orglett.7b01924 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01924. X-ray data for compound 7d (CIF) X-ray data for 4-bromobenzyl ether of 6c (8) (CIF) NMR spectra for all new compounds (PDF) X-ray data for coompounds 7d and 4-bromobenzyl ether of 6c (8) and experimental procedures (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Irishi N. N. Namboothiri: 0000-0002-8945-3932 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS I.N.N.N. thanks SERB-DST India for financial assistance. T.K. and V.M. thank the CSIR India, for a senior research fellowship. We thank Mr. Saravanan Raju, Mr. Gulzar A. Bhat, Ms. Sangeeta Yadav, Ms. Deepa Nair, Ms. Pallabita Basu, and Mr. T. S. Sudheesh, Department of Chemistry, IIT Bombay, for help with X-ray data.
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DEDICATION This paper is dedicated to Prof. Anil Kumar Singh, Department of Chemistry, IIT Bombay, on the occasion of his retirement after more than 30 years of distinguished service.
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REFERENCES
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