Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Catalytic Tandem Friedel−Crafts Alkylation/C4−C3 Ring-Contraction Reaction: An Efficient Route for the Synthesis of Indolyl Cyclopropanecarbaldehydes and Ketones Francesca Turnu,† Alberto Luridiana,† Andrea Cocco,† Stefania Porcu,† Angelo Frongia,† Giorgia Sarais,‡ and Francesco Secci*,†
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†
Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, S.S. 554, bivio per Sestu, 09042 Monserrato (CA), Italy ‡ Dipartimento di Scienze della Vita e dell’Ambiente, Università degli Studi di Cagliari, via Ospedale 82, 09124 Cagliari, Italy S Supporting Information *
ABSTRACT: A general strategy for the synthesis of indolyl cyclopropanecarbaldehydes and ketones via a Brønsted acidcatalyzed indole nucleophilic addition/ring-contraction reaction sequence has been exploited. The procedure leads to a wide panel of cyclopropyl carbonyl compounds in generally high yields with a broad substrate scope.
I
substrates,14 long and expensive purification steps, and high waste production (Scheme 2). In this context, a versatile one-
ndoles represent a class of privileged and powerful building blocks for organic synthesis1 and high-value pharmacophore compounds in medicinal chemistry.2 In particular, a large number of biologically active indole compounds have been identified to date.2b Of those, over 200 have also been approved as therapeutic agents for the treatment of different human diseases such as glaucoma,3 hypertension,4 depression,5 and Alzheimer’s disease6 and as anticancer,7 antiarrhythmic,8 and antiviral drugs9 or are undergoing clinical trials.2c Notably, constrained cyclopropylindoles have been investigated as lead compounds for the development of various bioactive molecules (Scheme 1), such as HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs),10 mineralocorticoid receptor antagonists (MCRAs),11 serotonin reuptake inhibitors,12 and Polo-like kinase 4 (Plk4) inhibitors.13 Despite their biological activity, direct cyclopropanation of indoles is limited to a few multistep approaches requiring the preparation of prefunctionalized
Scheme 2. Direct Indole Cyclopropanation Procedures
Scheme 1. Representative Indolylcyclopropane Bioactive Compounds
pot catalytic procedure that is able to introduce a cyclopropane moiety chemoselectively would represent a significant advance for pharmaceutical purposes. We recently initiated studies on the preparation of cyclopropylcarbaldehydes and developed a tandem acid-catalyzed thiol addition/ring-contraction reaction of 2-hydroxycyclobutanones 1.15 Continuing in this research field,16 we have successfully performed a new reaction between cyclobutanones 1 and a series of indoles 2 that furnishes Received: July 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02617 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Exploration of the Substrate Scopea,b
indolylcyclopropyl carbonyl compounds with broad scope and high chemical yields. To achieve this result, we first examined the reaction between 1a and indole 2a, conducted in neat conditions at room temperature for 24 h using 20 mol % of TsOH as the catalyst. We were delighted to find that the desired product 3a could be isolated from the reaction mixture in 29% yield, accompanied by a secondary product (10%), later identified as the indolylcyclobutanone 4a (Table 1, entry 1). Better results Table 1. Initial Screening Studiesa
entry
HA (mol %)
1 2 3 4 5 6
TsOH TsOH TsOH TsOH TsOH TsOH
7 8 9
MsOH (20) TFA (20) maleic acid (20) DPPA (20) DPPA (10) DPPA (30) DPPA (10)
10 11 12 13
(20) (20) (20) (20) (20) (20)
yield of 3a (%)b
temp.
3a:4a ratioc
− toluene toluene CH2Cl2 THF 1,4dioxane toluene toluene toluene
29 59 44 44 − −
r.t. r.t. 40 °C r.t. r.t. r.t.
3:1 6:1 1:1 4:1 − −
21 13 60
r.t. r.t. r.t.
10:1 3:1 20:1
toluene toluene toluene toluene
94 94 90 34 (48 h)
r.t. r.t. r.t. 0 °C
25:1 28:1 25:1 26:1
solvent
a Reactions were performed with 1a (50 mg, 0.58 mmol), 2a (1.1 equiv), and acid (10−30 mol %) in the solvent (1.5 mL) for 8−24 h at rt (entry 3, 40 °C, 24 h; entry 13, 0 °C, 48 h). bIsolated yields after flash chromatography. cDetermined by GC−MS analysis.
a
Reactions were performed using 1a (0.58 mmol), 2a−z (1.1 equiv), and DPPA (10 mol %) in toluene (1.5 mL) for 8−24 h at rt. bIsolated yields after flash chromatography or crystallization are given; 3:4 ratios were determined by GC−MS analysis.
were achieved when toluene was used as the solvent in reactions carried out at rt (entry 2). The use of a panel of solvents (THF and 1,4-dioxane) had a deleterious effect (entries 5 and 6). On the other hand, CH2Cl2 gave the corresponding adduct 3a in a satisfactory yield but with a poor 3a:4a ratio (entry 4). Again, a series of different Brønsted acid catalysts were evaluated in toluene. MsOH (entry 7) gave carbaldehyde 3a in 21% yield. Moreover, unsatisfactory results were achieved with TFA (entry 8), whereas maleic acid performed well (entry 9). Finally, the best result was achieved when diphenoxyphosphoric acid (DPPA) (pKa = 3.7)17 was used as the catalyst, affording the corresponding adduct 3a in 94% yield (entry 10). The catalyst loading (entries 11 and 12) and reaction temperature (entry 13) were also evaluated, and the results showed that the optimum yield of 3a was obtained using 10 mol % DPPA at room temperature in toluene. With these optimized reaction conditions in hand, we next examined the reaction scope using a series of substituted indoles (Scheme 3). A high functional group tolerance in indoles 2 emerged, allowing access to a wide variety of indolyl cyclopropanecarbaldehydes 3. The 4- or 5-substituted indoles 2b−j and benzo-fused indole 2k, independently of their substitution pattern, furnished the corresponding adducts 3b− k in uniformly good to high yields (73−96%). However, 5tosylaminoindole (2l) did not react under these conditions and was recovered unchanged after 48 h. N-Alkyl- or N-aryl-
substituted indoles 2m−t gave good conversions and yields of the corresponding compounds 3m−t. On the other hand, 2aryl-substituted indoles 2v, 2w, 2y, and 2z reacted with 1a to furnish mixtures of the corresponding cyclopropanecarbaldehydes 3 and related cyclobutanones 4, while methyl indol-1ylacetate (2u) was unreactive.18 Analogous results were obtained using N-pivaloyl- and N-Boc-substituted indoles (3u′ and 3u″). To extend this protocol to the synthesis of more complex cyclopropyl derivatives, 2-functionalized hydroxycyclobutanones 1b−e15 were reacted with a series of indoles under the above-described operational conditions (Scheme 4). Pleasingly, 1H-indolylcyclopropyl ketones 5 were isolated in good to excellent yields after 8−24 h. Indeed, N-methylindole (2m) was easily converted to the corresponding adducts 5mb and 5mc in 90% yield. Further experiments carried out with cyclobutanone 1d and indole 2a afforded p-tolylcyclopropyl ketone 5ad in good yield (80%). Moreover, reactions carried out with 3-ethyl-2-hydroxy-2-methylcyclobutanone (1e) yielded cyclopropyl derivative 5ae just in traces, accompanied by a diastereoisomeric mixture of 2,2-bis(indolyl)cyclobutanol.19 On the basis of the above-described results, a plausible mechanism for the acid-catalyzed indole cyclopropanation reaction is proposed in Scheme 5. In our hypothesis, activation B
DOI: 10.1021/acs.orglett.9b02617 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
carbocationic intermediate II.23,24 Furthermore, the direct formation of these four-membered rings from hydroxycyclobutanones 1 seems to be influenced by the stability of II and by electronic effects related to the indole substitution. Indeed, C3−C4 ring expansion of compounds 3 is fast in cyclopropylindoles bearing alkyl or aryl groups at the 2-position (e.g., 3v, 3x) and in N-alkyl-functionalized indoles (e.g., 3r). On the other hand, carbaldehydes 3 bearing electronwithdrawing groups (e.g., 3f, 3g) show a reduced tendency to undergo ring expansion and remained unchanged even after 48 h of reaction at 80 °C in the presence of 20 mol % TsOH (Scheme 6). In summary, a new tandem acid-catalyzed indole cyclopropanation reaction has been established via a metal-free cascade process under mild conditions. This method provides straightforward access to diverse indolylcyclopropyl carbonyl compounds in good to excellent yields and displays a broad substrate scope. Moreover, treatment of the carbaldehydes with catalytic amounts of Brønsted acids allows smooth access to indolylcyclobutanone derivatives in good yields. Manipulation of the carbonyl functional group of these classes of compounds and further applications of this methodology are now under investigation.
Scheme 4. Synthesis of Indolylcyclopropyl Ketones: Cyclobutanone Scopea,b,c
a
Reactions were performed using 1b−e (0.58 mmol), 2a−c,g−i,m (1.1 equiv), and DPPA (10 mol %) in toluene (1.5 mL) for 8−24 h at rt. bIsolated yields after the flash chromatography are given. cThe cis/ trans geometry and ratio were determined by NMR experiments.
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Scheme 5. Proposed Reaction Mechanism for the Synthesis of Compounds 3 and 5 and Cyclobutanones 4
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02617.
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of cyclobutanone 1a by the acid catalyst favors the nucleophilic attack of 2a, leading to the formation of cyclobutane diol adduct I.15,21 Subsequent acid-promoted C3−C4 ring contraction via carbocationic species II allows the attainment of carbaldehyde 3a.22 Finally, in order to rationalize the formation of cyclobutanone species 4, carbaldehydes 3a,f,g,r,v,x were dissolved in toluene in the presence of TsOH (10 mol %) and reacted at 40 °C (Scheme 6). Ring expansion to four-membered rings occurred in a short time (0.2−3 h) for compounds 3a,r,v,x, affording the corresponding cyclobutanones 4 in high yields (95−99%).20 This result suggests that cyclobutanones 4 are generated from carbaldehydes 3 through acid-catalyzed activation that allows the re-establishment of an equilibrium between the three-membered-ring species 3 and cyclobutane
Complete experimental section and 1H and spectra for all new compounds (PDF)
13
C NMR
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Angelo Frongia: 0000-0003-4652-9578 Francesco Secci: 0000-0003-0443-2890 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was partially supported by the Fondazione di Sardegna under the project “Innovative antioxidant molecules for the food and health industry” (CUP F71I17000180002). The authors gratefully acknowledge the Sardinia Regional Government (FIR 2018) and Consorzio Interuniversitario Nazionale di Ricerca in Metodologie e Processi Innovativi di Sintesi.
Scheme 6. Acid-Catalyzed C3−C4 Ring Expansion of Compounds 3
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REFERENCES
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(20) A series of 3/4 mixtures in variable ratio (1:1−9:1) were treated with TsOH (10 mol %) in toluene and afforded the corresponding cyclobutanones 4 in 95−99% yield (see the Supporting Information). Again, cyclopropylcarbaldehyde 3s underwent spontaneous ring expansion to 4s in CDCl3. (21) Paquette, L. A.; Hofferberth, J. E. Org. React. 2003, 62, 477. (22) This mechanism was investigated using labeled 18O-1a, which upon reaction with 2a in the presence of the acid catalyst afforded 18 O-3a in 92% yield (>75% 18O incorporation). (23) (a) Conia, J. M.; Salaun, J. Acc. Chem. Res. 1972, 5, 33. (b) Barnier, J. P.; Denis, J. M.; Salaun, J.; Conia, J. M. Tetrahedron 1974, 30, 1397. (c) Gembus, V.; Karmazin, L.; Pira, S.; Uguen, D. Bull. Chem. Soc. Jpn. 2018, 91, 319. (24) Attempts to promote a C3−C4 enantioselective ring expansion of carbaldehydes 3a and 3r using a chiral phosphoric acid such as (R)TRIP or TiPSY or a chiral sulfonic acid like CSA were unsuccessful, and cyclobutanones 4a and 4r were isolated as racemic mixtures.
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DOI: 10.1021/acs.orglett.9b02617 Org. Lett. XXXX, XXX, XXX−XXX
