Ketal Core via

Letter pubs.acs.org/OrgLett

Construction of Nitrated Benzo[3.3.1]bicyclic Acetal/Ketal Core via Nitration of o‑Carbonyl Allylbenzenes Chieh-Kai Chan, Yu-Lin Tsai, and Meng-Yang Chang* Department of Medicinal and Applied Chemistry, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan S Supporting Information *

ABSTRACT: Intramolecular annulation of o-carbonyl allylbenzenes was achieved to construct novel nitrated [6,6,6]tricycles having an acetal or ketal motif in good yields. The expeditious one-step nitration route provides 4 or 5 new bond formations, including 2 or 3 C−N bonds and 2 C−O bonds. The structural framework of benzobicycle [3.3.1] is confirmed by X-ray crystallographic analysis. A plausible mechanism is proposed.

D

lytic homolytic cleavage of an endo-peroxide bond followed by annulation of a diradical species,5 (iv) low-valent titaniummediated pinacol-type cross-coupling of o-phthalaldehydes and o-hydroxybenzaldehydes,6a (v) oxone-promoted oxidation of the benzofuran ring leading to transient o-quinone methides and its subsequent intramolecular [4 + 2] cycloaddition,6b and (vi) Pd(II)/Cu(II)-catalyzed Wacker-type oxidative cyclization of diol.7 Although different promoters were used to form a benzo[3.3.1]bicyclic ring system (Z = C), such as metal ions or acids/Lewis acids, it remained challenging to develop a novel reaction system for constructing this core structure (Z = N). Scheme 2 shows part of our synthetic chemistry of o-carbonyl allylbenzenes (2, o-allylbenzaldehydes): a one-pot nitronium ion

omino/tandem/cascade reactions to construct complex molecules from simple building blocks have been indentified as attractive synthetic routes because they combine rapid and efficient transformations in a single reaction vessel.1 This single-step or one-pot process can reduce human effort, avoid chemical waste, involve multiple sequences of reactions, and economize cost and reaction time. In accordance with this powerful tool, much effort has been devoted to the benzofused dioxabicyclo[3.3.1]nonane core 1. Naturally occurring products having this core as the central framework include peniciketals A− C,2a integrastatins A and B,2b epicoccolide A,2c and epicoconigrone A.2d Recently, synthetic routes toward core structure 1 have been thoroughly investigated (Scheme 1).3−9 The approaches included (i) a novel cis-selective RambergBacklund reaction followed by an unusual Sn(II)-catalyzed ring closure,3 (ii) BF3·OEt2 or H2SO4-mediated intramolecular rearrangement of benzofused bicyclo[4.2.0]octane,4 (iii) photo-

Scheme 2. Our Synthetic Route to 1

Scheme 1. Routes of Benzofused Dioxabicyclo[3.3.1] Cores

(+NO2)-mediated synthetic route of core 1 with a ketal motif via intramolecular annulation of 2. The o-allyl functional group of 2 plays an important role in enabling different C−C bond formations for useful substituents during the tandem sequence. Introduction of an o-allyl substituent is expected to shorten the synthetic step of targets by utilizing a simple tandem design. The expeditious one-step transition-metal-free route sets up a novel framework having the linkage of 4 or 5 newly formed bonds, including 2 or 3 C−N bonds and 2 C−O bonds under open vessel conditions. The required starting materials for 2 were easily prepared from substituted benzaldehydes 3 in moderate overall yields according to reported procedures.10 To examine the nitration of o-carbonyl allylbenzenes, we employed 2a Received: January 23, 2017

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.7b00245 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

combination of fuming HNO3 and H2SO4 provided optimal reaction conditions (80 °C and 24 h) for one-pot cyclization. A plausible mechanism for the formation of 1a is illustrated in Scheme 3. By the initial in situ formed +NO2 (generated from the

(prepared from 3-hydroxylbenzaldehyde (3a) via a three-step protocol of O-allylation, Claisen rearrangement, O-methylation)10 as the model substrate to screen the +NO2-mediated reaction conditions. On the basis of the considered synthetic operation and use of cheaper reagent, the common combination of fuming HNO3 (97%, 0.5 mL) and H2SO4 (98%, 2 mL) was first examined under open vessel conditions (Table 1).11

Scheme 3. Plausible Mechanism

Table 1. Optimal Nitration Conditionsa

entry

reagent (mL/equiv)

solvent

temp (°C)

time (h)

1a (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14

HNO3 (0.5 mL) HNO3 (0.5 mL) HNO3 (0.5 mL) HNO3 (0.5 mL) HNO3 (0.5 mL) NaNO3 (5 equiv) NaNO3 (5 equiv) AgNO3 (5 equiv) AgNO3 (5 equiv) Cu(NO3)3 (5 equiv) Fe(NO3)3 (5 equiv) Bi(NO3)3 (5 equiv) AgNO2 (5 equiv) tBuONO (5 equiv)

H2SO4 H2SO4 H2SO4 H2SO4 H2SO4 AcOH H2SO4 AcOH H2SO4 H2SO4 H2SO4 H2SO4 H2SO4 MeNO2

25 25 80 80 150 80 80 80 80 80 80 80 80 80

12 24 12 24 12 24 24 24 24 24 24 24 24 24

13 22 80 85 51 c 35 c 18d 13d 11d 5d 26 c

mixture of fuming HNO3 and H2SO4), olefinic nitration of 2a gives I, with a secondary carbocation and one nitro substituent via the first C−N bond formation. Through subsequent carbonyl-promoted intramolecular annulation, II with an oxonium ion is formed via the first C−O bond formation. Following the involvement of the nitro group, III with a [3.3.1]bicyclic skeleton is afforded via the second C−O bond formation. Tautomerization of III leads to IV. By intermolecular α-nitration, a nitro group is installed to produce V via the second C−N bond formation. After a cascade route for tautomerization of V, VI is yielded. Finally, dehydration of VI produces 1a. With optimal conditions established (Table 1, entry 4) and a plausible mechanism proposed (Scheme 3), we examined HNO3/H2SO4-mediated nitration of 2a−e (Scheme 4). For

a

Reactions were performed at a 1.0 mmol scale with 2a, reagents (10 equiv), solvent (2 mL). bIsolated yields. cNo reaction. dComplex mixture was isolated as major products.

Scheme 4. Synthesis of 1a−e

Unfortunately, by controlling the reaction temperature and time as 25 °C and 12 h (entry 1), the yield was low (13%). Therefore, it was repeated at 24 h (entry 2), and 1a was formed in only a 22% yield. The reaction at increased temperatures (25 → 80 °C) was completed in 12 h, furnishing 1a in 80% yield (entry 3). The results prompted us to optimize the reaction to improve the yield of 1a. Furthermore, after the reaction time was increased from 12 to 24 h, a better yield (85%) of 1a was observed (entry 4) under at 80 °C. However, when the reaction temperature continued to increase to 150 °C (entry 5), the yield (51%) of 1a decreased for 12 h. With these results (80 °C, 24 h), we treated 2a with five commercially available metal nitrates (NaNO2,12 AgNO3,13 Cu(NO3)2,14 Fe(NO3)3,15 Bi(NO3)316) in AcOH or H2SO4 (2 mL) as the medium at 80 °C for 24 h. However, none of them provided higher yields of 1a than HNO3. With AcOH, no reactions were observed for NaNO3 and AgNO3 (entries 6 and 8). Changing the solvent from AcOH to H2SO4 generated only low (18, 13, 11%) or trace (5%) yields of 1a by metal-nitrate-mediated nitration of 2a (entries 7, 9−12). From the phenomenon, we understand that metal nitrates are inappropriate nitrating reagents for the formation of 1a. Furthermore, metal nitrite was also examined; however, the isolated yield of 1a only increased slightly to 26% via AgNO2mediated nitration of 2a (entry 13).17 Organic nitrite tBuONO18 was studied, but no 1a was isolated (entry 14). The structure of 1a was determined by single-crystal X-ray crystallography.19 On the basis of these observations, we concluded that the

the R group of 2a−e (R = OMe, OiPr, OnBu, OcC5H9, OBn), primary and secondary alkyl substituents provided the desired 1a−e in good yields (73−85%). No obvious yield changes were observed. This nitration was found to not be limited to a monomethoxybenzene ring as the substrate, and 2f−i (prepared from isovanillin (3b) via a three-step protocol of O-allylation, Claisen rearrangement, O-methylation)10 with a dimethoxybenzene ring also delivered 1f−i (R = OMe, OiPr, OnBu, OcC5H9) in high yields (75−86%; Scheme 5). One extra nitro group was installed at the para position of the methoxy substituent on the benzene ring to form benzo[3.3.1]bicycle. With the p-methoxy substituent, a third C−N bond formation was generated. Onestep nitration of 2f−i provides 5 new bond formations, including 3 C−N bonds and 2 C−O bonds. The structures of 1h,i were Scheme 5. Synthesis of 1f−i

B

DOI: 10.1021/acs.orglett.7b00245 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters determined by single-crystal X-ray crystallography.19 Compared to 2a−e, the additional methoxy group of 2f−i could make the electron density of the π-system more likely to participate in an additional nitration at the para position of the R group under the electrophilic substitution process. Next, nitration of biphenyls was explored. According to previous works, 2j−m were synthesized from 2-aryl-5-hydroxy-4methoxybenzaldehyde (3c, prepared from 3b by NBS-mediated bromination and Suzuki−Miyaura cross-coupling) via a threestep protocol of O-allylation, Claisen rearrangement, and Omethylation.10 Different aryl groups of 2j−m (Ar = Ph, 2MeC6H4, 2-MeOC6H4, 4-CF3C6H4) produced the desired 1j−m (Scheme 6) in moderate yields (60−72%) under the above

Scheme 9. Synthesis of 4a−e

Scheme 6. Synthesis of 1j−m

no isolation of 4e was observed. The electron-withdrawing group is inappropriate for the formation of 4. A proposed mechansim (for 2s, R = OiPr) is shown in Scheme 9. Complexation of an olefin motif having one +NO2 provided A. Subsequent carbonylpromoted intramolecular annulation afforded B. Involvement of another +NO2 caused the para-methoxy group to promote an intramolecular electrophilic cyclization of B to give C via a C−N bond formation. After the nitro-group-mediated aromatization, D was formed. Water was installed to D so that transformation from E to F was achieved via a six-membered ring opening. After a cascade route for tautomerization of F and dehydration of the resulting G occurred, H was yielded. The structure of H was determined by single-crystal X-ray crystallography.19 Although the isolated yield of H (R = OiPr) is low (8%), generation of H can explain the reaction pathway properly. With the release of formic acid and involvement of H2O, H led to I. Finally, hydrolysis of I produced 4b. From the reaction pathway, we observed that different positions of dioxygenated substituents on the benzaldehyde skeleton are a key factor affecting nitration products. Compared with the R of a 3,4-dioxygenated group (Scheme 5, near the ring junction), R on the 4,5-dioxygenated group possessed less steric hindrance such that it could trigger the ring opening of C followed by sequential aromatization. Furthermore, after the o-side chain changed from an allyl and crotyl group to a styryl group, an unexpected result was observed. Treatment of 2w with HNO3/H2SO4 provided 5a via intramolecular dehydrogenative aromatization followed by o-position nitration (Scheme 10). To explore the synthetic applications of nitrated [6,6,6]tricycles, we examined oxidation of 1o (Scheme 11). When 1o was treated with the combination of SeO2 (5 equiv)/30% H2O2 (5 mL), 6a was obtained in a 51% yield via a domino process, including allylic oxidation of 1o, ring opening of nitrated [6,6,6]tricycles, SNAr reaction of H2O and further oxidation of

conditions. For the electronic nature of aryl substituents, not only electron-neutral but also electron-withdrawing and electron-donating groups were achieved. 1n,o (Ar = 2-MeC6H4, 4-FC6H4; Scheme 7) were obtained in 79 and 84% yields, respectively, via HNO3/H2SO4-mediated Scheme 7. Synthesis of 1n,o

benzannulation of benzoketones 2n,o (prepared from a two-step route of Grignard addition of 2f and sequential PCC-mediated oxidation of the resulting secondary alcohols). The structures of 1m,o were determined by single-crystal X-ray crystallography.19 Compared to Scheme 5, no further p-nitration on the benzene ring was observed due to the steric hindrance of the aryl group. Nitration of the simplest o-allylbenzaldehyde (2p, R = H, prepared by Suzuki−Miyaura cross-coupling of o-formylphenyl boronic acid and allyl bromide) yielded 1p (82% yield; Scheme 8). When R was changed to a fluoro group (for 2q), we found Scheme 8. Synthesis of 1p,q

that a complex mixture replaced the desired 1q, showing that an electron-withdrawing group is an inappropriate substituent for HNO3/H2SO4-mediated annulation. Different results were observed when the dioxygenated group was adjusted from a 3,4- to a 4,5-position on benzaldehyde skeleton 3 (Scheme 9). Treatment of 2r−u (prepared from the three-step route of O-allylation, double Claisen rearrangement, and O-methylation)10 with HNO3/H2SO4 provided 4a−d in moderate yields (67−75%). When R was a nitro group (for 2v),

Scheme 10. Synthesis of 5a

C

DOI: 10.1021/acs.orglett.7b00245 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Tetrahedron Lett. 2002, 43, 2351. For epicoccolide A, see: (c) Talontsi, F. M.; Dittrich, B.; Schuffler, A.; Sun, H.; Laatsch, H. Eur. J. Org. Chem. 2013, 2013, 3174. For epicoconigrone A, see: (d) El Amrani, M.; Lai, D.; Debbab, A.; Aly, A. H.; Siems, K.; Seidel, C.; Schnekenburger, M.; Gaigneaux, A.; Diederich, M.; Feger, D.; Lin, W.; Proksch, P. J. Nat. Prod. 2014, 77, 49. (3) (a) Foot, J. S.; Giblin, C. M. P.; Taylor, R. J. K. Org. Lett. 2003, 5, 4441. (b) Foot, J. S.; Giblin, G. M. P.; Whitwood, A. C.; Taylor, R. J. K. Org. Biomol. Chem. 2005, 3, 756. (c) Cayley, A. N.; Gallagher, K. A.; Menard-Moyon, C.; Schmidt, J. P.; Diorazio, L. J.; Taylor, R. J. K. Synthesis 2008, 2008, 3846. (4) Mal, J.; Nath, A.; Venkateswaran, R. V. J. Org. Chem. 1996, 61, 9164. (5) Guney, M.; Coskun, A.; Topal, F.; Dastan, A.; Gulcin, I.; Supuran, C. T. Bioorg. Med. Chem. 2014, 22, 3537. (6) (a) Ramana, C. V.; Reddy, C. N.; Gonnade, R. G. Chem. Commun. 2008, 3151. (b) More, A. A.; Ramana, C. V. Org. Lett. 2016, 18, 612. (7) Tadross, P. M.; Bugga, P.; Stoltz, B. M. Org. Biomol. Chem. 2011, 9, 5354. (8) Synthesis routes of other benzofused [3.3.1]-dioxabicycles: (a) Green, J. C.; Brown, E. R.; Pettus, T. R. R. Org. Lett. 2012, 14, 2929. (b) Kim, I.; Kim, S. G.; Choi, J.; Lee, G. H. Tetrahedron 2008, 64, 664. (c) Ullah, E.; Rotzoll, S.; Schmidt, A.; Michalik, D.; Langer, P. Tetrahedron Lett. 2005, 46, 8997. (d) Srinivas, V.; Koketsu, M. J. Org. Chem. 2013, 78, 11612. (e) Yin, G.; Ren, T.; Rao, Y.; Zhou, Y.; Li, Z.; Shu, W.; Wu, A. J. Org. Chem. 2013, 78, 3132. (f) Gueney, M.; Dastan, A.; Balci, M. Helv. Chim. Acta 2005, 88, 830. (9) Synthesis routes of the central [3.3.1]-dioxabicyclic core: (a) Aiguade, J.; Hao, J.; Forsyth, C. J. Org. Lett. 2001, 3, 979. (b) Cho, Y. S.; Kim, H. Y.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Choi, J. H.; Chang, M. H. Org. Lett. 2002, 4, 2025. (c) Francisco, C. G.; Freire, R.; Herrera, A. J.; Perez-Martin, I.; Suarez, E. Org. Lett. 2002, 4, 1959. (d) Oikawa, M.; Uehara, T.; Iwayama, T.; Sasaki, M. Org. Lett. 2006, 8, 3943. (10) Synthetic applications on the o-carbonyl allylbenzenes: (a) Chang, M.-Y.; Wu, M.-H.; Chen, Y.-L. Org. Lett. 2013, 15, 2822. (b) Chan, C.-K.; Chan, Y.-L.; Chang, M.-Y. Tetrahedron 2016, 72, 547. (c) Chan, C.-K.; Tsai, Y.-L.; Chan, Y.-L.; Chang, M.-Y. J. Org. Chem. 2016, 81, 9836. (11) For HNO3: (a) Chentsova, A.; Ushakov, D. B.; Seeberger, P. H.; Gilmore, K. J. Org. Chem. 2016, 81, 9415. (b) Ogurtsov, V. A.; Shastin, A. V.; Zlotin, S. G.; Rakitin, O. A. Tetrahedron Lett. 2016, 57, 4027. (12) NaNO3: Dighe, S. U.; Mukhopadhyay, S.; Priyanka, K.; Batra, S. Org. Lett. 2016, 18, 4190. (13) AgNO3: Li, C.; Deng, H.; Li, C.; Jia, X.; Li, J. Org. Lett. 2015, 17, 5718. (14) Cu(NO3)2: Gao, M.; Xu, B. Org. Lett. 2016, 18, 4746. (15) Fe(NO3)3: Sadhu, P.; Alla, S. K.; Punniyamurthy, T. J. Org. Chem. 2015, 80, 8245. (16) Bi(NO3)3: Manna, S.; Maity, S.; Rana, S.; Agasti, S.; Maiti, D. Org. Lett. 2012, 14, 1736. (17) AgNO2: Pawar, G. G.; Brahmanandan, A.; Kapur, M. Org. Lett. 2016, 18, 448. (18) Nonmetal reagent-mediated nitration for tBuONO: (a) Lin, Y.; Kong, W.; Song, Q. Org. Lett. 2016, 18, 3702. (b) Zhang, W.; Ren, S.; Zhang, J.; Liu, Y. J. Org. Chem. 2015, 80, 5973. For NO2BF4: (c) Natarajan, P.; Chaudhary, R.; Venugopalan, P. J. Org. Chem. 2015, 80, 10498. (19) CCDC 1525439 (1a), 1525440 (1h), 1525441 (1i), 1535310 (1m), 1525442 (1o), 1525443 (4a), 1532864 (H), 1525444 (5a), and 1532720 (6a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac. uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: 44-1223-336033; e-mail: deposit@ ccdc.cam.ac.uk). (20) Selected examples on synthesis of oxygenated anthraquinones: (a) Punner, F.; Schieven, J.; Hilt, G. Org. Lett. 2013, 15, 4888. (b) Podlesny, E. E.; Kozlowski, M. C. Org. Lett. 2012, 14, 1408. (c) Xu, W.; Paira, R.; Yoshikai, N. Org. Lett. 2015, 17, 4192.

Scheme 11. Synthesis of 6a

aldehyde, and Friedel−Crafts ring closure. The intriguing conversion is novel for the formation of an oxygenated anthraquinone skeleton.20 The structure of 6a was determined by single-crystal X-ray crystallography.19 In summary, we developed HNO3/H2SO4-mediated synthesis of nitrated [6,6,6]tricycles having an acetal or ketal motif in good yields via intramolecular annulation of o-carbonyl allylbenzenes. The expeditious one-step nitration route provides 4 or 5 new bond formations, including 2 or 3 C−N bonds and 2 C−O bonds. The key products were confirmed by X-ray crystallography.

■

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00245. X-ray data of 1a (CIF), 1h (CIF), 1i (CIF), 1m (CIF), 1o (CIF), 4a (CIF), H (CIF), 5a (CIF), and 6a (CIF) Detailed experimental procedures and spectroscopic data for all new compounds (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Meng-Yang Chang: 0000-0002-1983-8570 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the Ministry of Science and Technology of the Republic of China for financial support (MOST 105-2113-M037-001).

■

REFERENCES

(1) (a) Tietze, L. F.; Gordon, B.; Kersten, G. M. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006. (b) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967. (c) Hussain, M. M.; Walsh, P. J. Acc. Chem. Res. 2008, 41, 883. (d) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (e) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167. (f) Moyano, A.; Rios, R. Chem. Rev. 2011, 111, 4703. (g) Pellissier, H. Adv. Synth. Catal. 2012, 354, 237. (h) Lu, L.-Q.; Chen, J.-R.; Xiao, W.-J. Acc. Chem. Res. 2012, 45, 1278. (2) Natural products with the benzodioxabicyclo[3.3.1]nonane core; for peniciketals A−C, see: (a) Liu, W.-Z.; Ma, L.-Y.; Liu, D.-S.; Huang, Y.-L.; Wang, C.-H.; Shi, S.-S.; Pan, X.-H.; Song, X.-D.; Zhu, R.-X. Org. Lett. 2014, 16, 90. For integrastatins A,B, see: (b) Singh, S. B.; Zink, D. L.; Quamina, D. S.; Pelaez, F.; Teran, A.; Felock, P.; Hazuda, D. J. D

DOI: 10.1021/acs.orglett.7b00245 Org. Lett. XXXX, XXX, XXX−XXX