DOI: 10.1002/chem.201304270

Communication

& Tandem Catalysis

Synthesis of Oxacyclic Scaffolds via Dual Ruthenium Hydride/ Brønsted Acid-Catalyzed Isomerization/Cyclization of Allylic Ethers Erhad Ascic,[a] Ragnhild G. Ohm,[a] Rico Petersen,[a] Mette R. Hansen,[a] Casper L. Hansen,[a] Daniel Madsen,[a] David Tanner,[a] and Thomas E. Nielsen*[a, b] that undergo nucleophilic attack by the electron-rich indole moiety. We now report a purely intramolecular alternative to the traditional synthesis of THPIs starting from readily available indole-tethered allylic ethers, via tandem transition metal/ Brønsted acid-catalyzed isomerizations to form the key oxocarbenium intermediates (Scheme 1). The final step of the sequence shown in Scheme 1 is obviously related to the classical

Abstract: A ruthenium hydride/Brønsted acid-catalyzed tandem sequence is reported for the synthesis of 1,3,4,9tetrahydropyrano[3,4-b]indoles (THPIs) and related oxacyclic scaffolds. The process was designed on the premise that readily available allylic ethers would undergo sequential isomerization, first to enol ethers (Ru catalysis), then to oxocarbenium ions (Brønsted acid catalysis) amenable to endo cyclization with tethered nucleophiles. This methodology provides not only an attractive alternative to the traditional oxa-Pictet–Spengler reaction for the synthesis of THPIs, but also convenient access to THPI congeners and other important oxacycles such as acetals.

The 1,3,4,9-tetrahydropyrano[3,4-b]indole (THPI) skeleton (Figure 1) is of considerable interest in the field of medicinal chemistry, as exemplified by pharmaceuticals such as etodolac (a nonstereoidal anti-inflammatory drug),[1] pemedolac (an effective analgesic agent),[2] and HCV-371 (which displays potent antiviral activity).[3] One time-honored synthetic route to this class of heterocycles is the oxa-Pictet–Spengler reaction,[4] in which tryptophols are condensed under acidic conditions with carbonyl compounds (or masked forms thereof) to give oxocarbenium ions

Figure 1. THPI and some pharmaceutically important derivatives thereof.

[a] Dr. E. Ascic, R. G. Ohm, Dr. R. Petersen, Dr. M. R. Hansen, C. L. Hansen, D. Madsen, Prof. Dr. D. Tanner, Prof. Dr. T. E. Nielsen Department of Chemistry Technical University of Denmark 2800 Kgs. Lyngby (Denmark) Fax: (+ 45) 45-93-39-68 E-mail: [email protected] [b] Prof. Dr. T. E. Nielsen Singapore Centre on Environmental Life Sciences Engineering Nanyang Technological University Singapore 637551 (Singapore) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201304270. Chem. Eur. J. 2014, 20, 3297 – 3300

Scheme 1. Formation of oxacycles through metal-catalyzed isomerization sequences.

Pictet–Spengler cyclization of tryptamine derivatives, which normally involves acid-catalyzed intermolecular condensation with carbonyl compounds to form the corresponding iminium species. Recently, alternative methods to access such electrophiles by means of metal-catalyzed isomerization of allylic amines (via enamines) have been explored by a number of laboratories, including our own.[5] While numerous publications have dealt with the metal-catalyzed isomerization of allylic ethers to enol ethers,[6] we are unaware of “one-pot” (tandem) procedures for the sequential generation and reaction of oxocarbenium ions,[7, 8] as depicted in Scheme 1. Allylic ether 1 a was chosen as substrate for preliminary studies of the proposed tandem process (Table 1). Based on previous experience,[5] optimization was carried out using 5 mol % of Ru-, Pd- and Rh-based catalysts in refluxing toluene, and initial results indicated that RuHCl(CO)(PPh3)3 was extremely efficient for the isomerization of 1 a to 1 a’, the latter being formed as a 2:3 (E:Z) mixture of diastereomers in near-quantitative yield within 1 hour (Table 1, entry 1). Further transformation to THPI 2 a did not occur even after prolonged reaction time (22 h), indicating that the metal catalyst alone could not promote the second step of the desired tandem sequence. However, to our delight, the addition of 5 mol % of diphenyl

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Communication Table 1. Screening of catalysts for the formation of THPI 2 a.

Entry 1[b] 2[b] 3[b] 4[b] 5[d] 6[d] 7[d]

Catalyst RuHCl(CO)(PPh3)3 Pd(PPh3)4 Rh(Ph3P)3Cl Grubbs I Grubbs II Hoveyda–Grubbs I Hoveyda–Grubbs II

Table 2. Substrate scope of the tandem sequence to THBIs.

Ratio 1 a/1 a’/2 a[a] 1h

6h

22 h

Entry

Substrate

R1

R2

R3

R4

Product, yield [%][a]

0:100:0 (0:0:100)[c] 65:29:6 66:30:4 100:0:0 16:84:0 41:45:14 62:38:0

0:95:5 13:19:68 24:65:11 – – – –

0:95:5 0:0:100 0:100:00 – – – –

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

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m

H Me Et CH2OTBDPS CH2CN H H H H H H H Me

H H H H 7-Et 4-OBn 5-OMe 6-iPr 7-Et H H H 7-Et

H H H H H H H H H Me Ph H Me

H H H H H H H H H H H Me Me

2 a, 80 2 b, 83 2 c, 79 2 d, 88 2 e, 60[b] 2 f, 41 2 g, 62 2 h, 63 2 i, 70 2 j, 75 2 k, 65 2 l, 53[c] 2 m, 35[d]

[a] Determined by RP-HPLC (UV detection at 215 nm). [b] The product mixture was very clean (> 85 % of 1 a/1 a’/2 a in the reaction mixture). [c] The reaction was carried out with 5 mol % of diphenyl phosphate and 5 mol % of RuHCl(CO)(PPh3)3. [d] The purity of the product mixture was low (< 50 % of 1 a/1 a’/2 a in the reaction mixture) due to formation of the cross-metathesis dimer.

phosphate at the beginning of the reaction allowed the tandem process to proceed smoothly with a full and clean conversion of 1 a to the THPI product 2 a in 1 hour. It was noted that Pd(PPh3)4 mediated a clean conversion of 1 a to 2 a, albeit 22 h was required for full conversion (Table 1, entry 2). Wilkinson’s catalyst and Grubbs-type catalysts are known to be effective for the isomerization of allylic amines into iminium intermediates.[5] However, whereas Rh(Ph3P)3Cl led to incomplete reaction due to slow isomerization (Table 1, entry 3), the use of Ru alkylidenes led to substantial formation of the cross-metathesis dimer (Table 1, entries 4–7). With suitable reaction conditions in hand, the substrate scope was then examined. As is evident from the results presented in Table 2, a combination of 5 mol % of RuHCl(CO)(PPh3)3 and 5 mol % of diphenyl phosphate in refluxing toluene proved to be effective for a wide range of indole substrates. The variation of R1 in substrates 1 a–d was well tolerated affording THPIs 2 a–d in 79–88 % yield (Table 2, entries 1–4). Substrate 1 e was not converted to 2 e under these reaction conditions. However, a clean isomerization to the acrylonitrile intermediate was evident from UPLC- MS and 1H NMR analyses, indicating that a stronger Brønsted acid was required to bring the double bond out of conjugation towards 2 e. The problem was solved by treating 1 e with 10 mol % RuHCl(CO)(PPh3)3 at reflux for 1 hour, followed by addition of TFA (2 equiv), which afforded 2 e in 60 % yield (Table 2, entry 5). Substrates 1 f– i bearing substitution on the indole core were also suitable for the reaction, providing the corresponding products 2 f–i in slightly lower yields (41–70 %; Table 2, entries 6–9). Variation of R3 was also tolerated which led to products 2 j and 2 k in good yields (65–75 %). On the other hand, when changing the alkene substitution pattern (substrates 1 l and 1 m), approximately 15–30 mol % of catalyst was needed to obtain products 2 l and 2 m, in 53 and 35 % yield, respectively (Table 2, entries 12 and 13). The present method offers distinct advantages over the conventional oxa-Pictet–Spengler cyclization for the Chem. Eur. J. 2014, 20, 3297 – 3300

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[a] Yield of the isolated products after flash column chromatography. [b] 2 equivalent of TFA and 10 mol % of RuHCl(CO)(PPh3)3 was added. [c] 10 mol % of the catalysts were used. [d] 30 mol % of the catalyst was used in refluxing m-xylene.

synthesis of THPIs. For example, when tryptophol 3 is reacted with propanal 4 in the presence of the Lewis or Brønsted acids commonly used for this transformation, the bis(indolyl)methane byproduct 5 is invariably formed together with 2 a (Scheme 2), under standard reaction conditions. In our hands, the reaction was generally characterized by an incom-

Scheme 2. Oxa-Pictet–Spengler cyclization of tryptophol 3.

plete conversion of the starting material, accompanied by formation of numerous, unidentified byproducts, and the maximum yield of 2 a was only 35 %.[9] Formation of compounds such as 5 under classical oxa-Pictet–Spengler conditions is well documented.[10] The success of the present catalytic tandem approach to THPIs prompted the investigation of an enantioselective version. Recently, Terada and Toda demonstrated that RuHCl(CO)(PPh3)3 was compatible with chiral phosphoric acids to promote the synthesis of tetrahydroisoquinolines from allylic amines in up to 47 % ee.[5e] In addition, List and co-workers have developed a new type of chiral acid (imidodiphosphoric acid) that effectively catalyzes oxocarbenium ion cyclizations to form enantiopure acetals and spiroacetals.[11] After screening a range of acid catalysts,[12] we found that the use of 5 mol % imidodiphosphoric acid 14 together with 5 mol % of

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Communication Table 3. Substrate scope of the tandem sequence for the synthesis of acetals.

Scheme 3. Asymmetric version of the tandem sequence for the synthesis of THIP 2 b.

RuHCl(CO)(PPh3)3 in refluxing toluene provided the THPI 2 b with an ee value of 47 % and in 75 % isolated yield (Scheme 3). Current studies are being focused on improvement of the enantioselectivity. Returning to the racemic mode of catalysis, it was found that substrates that are less nucleophilic than indole could also be accommodated. Reactions with phenyl, benzothiophene, or thiophene moieties generally benefited from the addition of TsOH (5-100 mol %) together with RuHCl(CO)(PPh3)3 (5 mol %), providing a range of novel heterocycles, usually in high isolated yields (Scheme 4).

Entry Substrate

R1

R2

R3 R4 n dr

Product, yield [%][a]

1 2 3 4 5 6 7 8 9

Ph Ph Bn Me Ph H H Ph Ph

H H H Me H H H H H

H Ph H Ph H Ph H H H

7 a, 72 7 b, 95 7 c, 89 7 d, 83 7 e, 83 7 f, 68 7 g, 44 7 h, 85 7 i, 49

6a 6b 6c 6d 6e 6f 6g 6h 6i

H H H H H H Ph H H

0 2:1 0 > 20:1 0 1:1 0 > 20:1 1 8:1 1 2:1 1 – 2 6:5 3 1:1

10

11

6 j, (m = 1)

7 j, (m = 1), 13

6 k, (m = 2)

7 k, (m = 2), 29

[a] Yield of the isolated products after flash column chromatography.

oxacycles from allylic ethers.[13] The process, co-catalyzed by a ruthenium hydride species and a Brønsted acid, provides convenient access to a variety of tetrahydropyranoindoles and related heterocyclic scaffolds in good to excellent yields. This method is generally superior to the traditional oxa-Pictet– Spengler reaction, since it circumvents the formation of bis(indolyl)methane byproducts. Finally, use of a chiral imidodiphosphoric acid in tandem with the ruthenium catalyst provided up to 47 % ee in the synthesis of a THIP containing a quaternary stereogenic center. Efforts are now being made to expand the scope and improve the efficiency of the enantioselective process.

Experimental Section General procedure for the Ru hydride/Brønsted acid catalyzed tandem sequence Scheme 4. Substrate scope of the tandem sequence for the synthesis of fused oxacycles. [a] 1 equivalent of TsOH was added.

The new tandem process was also applicable to oxygenbased nucleophiles to provide an entry to acetals (Table 3). Upon exposure to 5 mol % of RuHCl(CO)(PPh3)3 and 5 mol % diphenyl phosphate in refluxing toluene, the alcohol subtrates 6 a–k underwent cyclization to form 5–8 membered acetals 7 a–k in 13–95 % yield (Table 3, entries 1–11). In general, mixtures of diastereomers were formed as expected (Table 3, entries 1, 3, 6, 8, and 9), although the cyclization of the more highly substituted substrate 6 d occurred with excellent diastereoselectivity (Table 3, entry 4). In summary, we have demonstrated an isomerization/oxocarbenium ion cyclization tandem sequence for the synthesis of Chem. Eur. J. 2014, 20, 3297 – 3300

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RuHCl(CO)(PPh3)3 (5 mol %) and diphenyl phosphate (5 mol %) were added at room temperature to a solution of allyl ether substrate in dry toluene (0.1 m) and under argon atmosphere. The reaction mixture was heated to 115 8C and was followed by TLC. Upon full consumption of the starting material, the reaction was cooled to room temperature and the contents were purified by flash column chromatography on silica gel with n-hexane/EtOAc, to obtain the desired product.

Acknowledgements The Danish Council for Independent Research (Technology and Production), the DSF Center for Antimicrobial Research, and the Lundbeck Foundation are gratefully acknowledged for financial support.

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Communication Keywords: cyclization · isomerization · oxacycles · Pictet– Spengler reaction · ruthenium [1] C. A. Demerson, N. A. Abraham, G. Schilling, R. R. Martel, C. J. Asciak, J. Med. Chem. 1983, 26, 1778. [2] A. H. Katz, C. A. Demerson, C. C. Shaw, A. A. Asselin, L. G. Humber, K. M. Conway, G. Gavin, C. Guinosso, N. P. Jensen, D. Mobilio, R. Noureldin, J. Schmid, U. Shah, D. Van Engen, T. T. Chau, B. M. Weichman, J. Med. Chem. 1988, 31, 1244. [3] A. Gopalsamy, G. Ciszeski, K. Park, J. W. Ellingboe, J. Blom, S. Insaf, J. Upeslacis, T. S. Mansour, G. Krishnamurthy, M. Damarla, Y. Pyatski, D. Ho, J. Med. Chem. 2004, 47, 6603. [4] Fore recent reviews on oxa-Pictet–Spengler cyclizations, see: a) E. L. Larghi, T. S. Kaufman, Eur. J. Org. Chem. 2011, 5195; b) E. L. Larghi, T. S. Kaufman, Synthesis 2006, 187. [5] a) K. Sorimachi, M. Terada, J. Am. Chem. Soc. 2008, 130, 14452; b) E. Ascic, C. L. Hansen, S. T. Le Quement, T. E. Nielsen, Chem. Commun. 2012, 48, 3345; c) E. Ascic, S. T. Le Quement, M. Ishoey, M. Daugaard, T. E. Nielsen, ACS Comb. Sci. 2012, 14, 253; d) E. Ascic, J. F. Jensen, T. E. Nielsen, Angew. Chem. 2011, 123, 5294; Angew. Chem. Int. Ed. 2011, 50, 5188; e) Y. Toda, M. Terada, Synlett 2013, 24, 752; f) Q. Cai, X. W. Liang, S. G. Wang, J. W. Zhang, X. Zhang, S. L. You, Org. Lett. 2012, 14, 5022; g) Q. Cai, X. W. Liang, S. G. Wang, S. L. You, Org. Biomol. Chem. 2013, 11, 1602. [6] For a review on transition metal-catalyzed isomerization of allyl ethers, see: N. Kuznik, S. Krompiec, Coord. Chem. Rev. 2007, 251, 222.

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[7] For a report on the isomerization of allylic ethers and formation of acetals catalyzed by octacarbonyldicobalt, see: B. H. J. Chang, Organomet. Chem. 1995, 492, 31. [8] For the synthesis of acetals via addition of alcohols to O-allylic compounds, see: a) S. Krompiec, M. Penkala, E. Kowalska, R. Penczek, P. Bujak, W. Danikiewicz, G. Splnik, A. Kita, I. Grudzka, Monatsh. Chem. 2011, 142, 1241; b) S. Krompiec, R. Penczek, P. Bujak, E. Kubik, J. Malarz, M. Penkala, M. Krompiec, N, Kuznik, H, Maciejewski, Tetrahedron Lett. 2009, 50, 1193; c) S. Krompiec, R. Penczek, M. Penkala, M. Krompiec, J. Rzepa, M. Matlengiewicz, J. Jaworska, S. Baj, J. Mol. Catal. A 2008, 290, 15. [9] For a full account on reaction conditions tried for this transformation see the Supporting Information. [10] a) B. Bouguerne, C. Lherbet, M. Baltas, Lett. Org. Chem. 2010, 7, 420; b) R. Ghorbani-Vaghei, H. Veisi, Mol. Diversity 2010, 14, 87; c) G. V. M. Sharma, J. J. Reddy, P. S. Lakshmi, R. P. Krishna, Tetrahedron Lett. 2004, 45, 7729. [11] a) J. H. Kim, I. Cˇoric´, S. Vellalath, B. List, Angew. Chem. Int. Ed. 2013, 52, 4474; b) I. Cˇoric´, B. List, Nature 2012, 483, 315. [12] For a full account on the reaction optimization see the Supporting Information. [13] While this manuscript was under review, a related tandem isomerization was reported in: V. M. Lombardo, C. D. Thomas, K. A. Scheidt, Angew. Chem. Int. Ed. 2013, 52, 12910. Received: October 31, 2013 Published online on February 24, 2014

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