Letter Cite This: Org. Lett. 2018, 20, 6471−6475
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Stereocontrolled Nucleophilic Fluorination at the Tertiary sp3‑Carbon Center for Enantiopure Synthesis of 3‑Fluorooxindoles Saumen Hajra,* Atanu Hazra, and Paltu Mandal Centre of Biomedical Research, Sanjay Gandhi Postgraduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow 226014, India
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S Supporting Information *
ABSTRACT: The first asymmetric nucleophilic fluorination at the sp3-tertiary carbon center has been developed using inexpensive tetrabutylammonium fluoride (TBAF) without any metal/catalyst for the synthesis of 3-fluoro-3-substituted oxindoles with excellent enantioselectivity (ee up to >99%). Regio- and stereocontrolled ring opening of spiroaziridine with retention of configuration and other experiments revealed that the fluorination proceeded through an anchimeric assistance.
ncorporation of the fluorine atom into a molecule can provide many beneficial physical and biological properties.1 This has drawn much attention in modern pharmaceutical chemistry and led to the development of a number of new drugs having the fluorine atom, in particular, at the sp3-carbon in recent times. The synthesis of chiral fluoro-organic compounds is, therefore, an active research area.2 Despite the difficulties in carbon−fluorine bond formation, chemists have made remarkable progress in the nonracemic synthesis of organo-fluoro compounds by asymmetric electrophilic fluorination by developing a number of efficient fluorinating reagents and the stereoselective C−C bond-forming reaction of preinstalled fluoro-substrates.2 Nucleophilic fluorination (NuF) reactions using fluorides are more desirable due to their low cost, especially compared to the fluorinating reagents and the fluoro-substrates. However, there are other challenges associated with the NuF chemistry derived from the high electronegativity of fluorine that lead to a high kinetic barrier, while the propensity of fluoride to form strong hydrogen bonding with water/protic solvents decreases the nucleophilicity further and difficulties in NuF at sterically hindered tertiary sp3-carbon. Asymmetric NuF at secondary sp3-carbon centers is well-studied by selection of suitable substrates, solvents, and the fluoride sources,2,3 but at the tertiary sp3-carbon centers, this is sparse in the literature.4 Its stereocontrolled reaction is still an unmet challenge. Epoxides and aziridines are the choices of suitable substrates for NuF.2 A number of successful efforts are made in asymmetric ring opening of meso-epoxides (secondary sp3 carbon center) and terminal epoxides (mostly primary sp3 carbon center) with fluoride reagents in the presence of Lewis acid catalyst, but that of aziridines is sparsely studied.2,5−7
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© 2018 American Chemical Society
Doyle and co-worker reported a very interesting asymmetric NuF of meso-aziridines (secondary sp3-carbon center) using chiral Co-salen catalyst and PhCOF as a fluoride source.6a Unlike meso-epoxides,5 it needed additional Lewis acid, Ti(NMe2)4, for better conversion and selectivity (Scheme 1, eq 1). DMPU-HF-mediated regioselective NuF of terminal aziridines was reported by Hammond and Xu et al., where nonracemic alkyl aziridines gave good enantioselectivity, but there was a complete loss of enantiopurity for phenyl aziridine and a decomposition for tertiary phenyl aziridine (Scheme 1, eq 2).6b Again, NuF without acids or Lewis acids is known to proceed through less hindered terminal attacks. 7 The nucleophilic fluorination at the tertiary sp3-carbon center of both epoxides and aziridines remains a highly challenging issue in fluorination chemistry. Recently, nonracemic synthesis of 3-fluoro-3-substituted oxindoles, which are prevalent motifs in many bioactive compounds, has attracted much attention.8,9 These chiral 3fluoro-3-substituted oxindoles are synthesized either by electrophilic fluorination of 3-substituted oxindoles or by a carbon−carbon bond-forming reaction of 3-fluorooxindoles (Scheme 1, eqs 3 and 4) and no report by NuF. In this context, we report regio- and stereospecific nucleophilic fluorination at the high sterically congested spiro-center (tertiary sp3-carbon) of nonracemic spiroaziridine oxindoles with TBAF to access 3fluoro-3-substituted oxindoles with excellent enantioselectivity (ee up to >99%; Scheme 1, eq 5). Our research experiences in the ring-opening reaction of aziridines10 and spiroaziridine oxindoles11 led us to wonder Received: August 30, 2018 Published: October 10, 2018 6471
DOI: 10.1021/acs.orglett.8b02777 Org. Lett. 2018, 20, 6471−6475
Letter
Organic Letters Scheme 1. Previous Reports and the Present Study
Scheme 2. Presumption of Stereocontrolled Nucleophilic Fluorination of Spiroaziridine
(±)-2a′ in good yield with HF-Pyridine (HF·Py) in CH2Cl2, and also with TBAF in THF (Table 1, entries 1 and 8). Among the metal fluorides, only the reaction with KF gave the desired C3-fluorinated product (±)-2a′, but with low yields (entries 3 and 4). The NuF was not successful with other alkali metal fluorides such as NaF and CsF under different conditions (for details see SI). Interestingly, no regioisomer of the fluorinated compound was detected by the 1H NMR analysis of the crude reaction mixture. After successful NuF at the tertiary sp3-carbon center of spiroaziridine (±)-1a′, the conditions were implemented to the enantiopure spiroaziridine 1a (Table 2). We were initially disheartened by the reaction of HF·Py that gave complete loss of ee (Table 2, entry 1). So the stereocontrolled NuF of 1a was further optimized with KF and TBAF under different conditions. To our delight, a reaction with KF in DMF afforded the desired 3-fluorooxindole 2a with 70% ee but in low yield (Table 2, entry 2). The same reaction in DMSO did not improve the yield. Gratifyingly, the exclusive formation of 3-fluorooxindole 2a with excellent yield (95%) and enantioselectivity (ee 98%) was achieved when the spiroaziridine 1a was treated with tetrabutylammonium fluoride (TBAF) in DMF at 0 °C within 2 h (entry 8). A TBAF-mediated reaction in DMSO also gave excellent stereocontrol (ee 98%), but with moderate yield and reactions in THF, both yield and selectivity were less than that in DMF and in DMSO. With the optimal reaction conditions in hand, the substrate generality of this NuF strategy was then explored with various spiro-aziridine oxindoles 1a−r (Figure 1). Varying the Nprotection of oxindoles N-methyl, N-benzyl, N-allyl, and NPMB gave excellent yields and enantioselectivities. Unlike earlier works on nucleophilic ring opening with neutral nucleophiles, NuF of N-unprotected spiroaziridine 1e produced a mixture of uncharacterized products, in which fluoride might act as a base, and abstraction of the proton from the N−H of oxindole led to undesired side reactions. There were no reactions for the substrates 1f and 1g with electronwithdrawing protecting groups such as N-Ts and N-Boc. The nonavailability of the electron pair on nitrogen might restrict the neighboring participation to the aziridine moiety, which supports our presumption of the anchimeric assistance of the oxindole unit. However, when spiroaziridines 1e−1g were treated with HF·Py in CH2Cl2 instead of TBAF in DMF, they gave the desired C3-fluorinated products in good yields but
whether chiral spiroaziridines 1 could undergo a stereocontrolled NuF reaction with fluoride at the spirocenter (sp3tertiary carbon). It has been previously revealed that N-sulfonyl spiroaziridines 1 are activated by the H-bonding of surface water for the stereocontrolled nucleophilic ring opening with neutral nucleophiles, and water-miscible nucleophiles undergo slow reaction with poor stereoselectivity. As fluoride has the strong affinity of H-bonding with water and in turn reduces its nucleophilicity, water and protic solvents must be avoided for the present study. On the other hand, fluoride is a better nucleophile in a polar aprotic solvent. We envisioned that the C−N bond of N-sulfonyl spiroaziridine might be polarized by a polar aprotic solvent that along with chelation of countercation would facilitate the anchimeric assistance of the oxindole unit to form intermediate A or B. This reactive intermediate could undergo NuF with fluoride to produce 3-fluorooxindoles 2 with retention of configuration via a double inversion (Scheme 2). To obtain proof-of-concept, we initiated our studies of NuF with racemic spiroaziridine (±)-1a′ and subsequently with enantiopure (S)-N-methyl spiroaziridine oxindole 1a (ee > 99%), altering solvents, temperature, and fluoride sources (Table 1 and Table 2). To our delight, the NuF of spiroaziridine (±)-1a′ gave exclusively C3-fluorinated product 6472
DOI: 10.1021/acs.orglett.8b02777 Org. Lett. 2018, 20, 6471−6475
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
entry
fluoride source
solvent
additive
temp (°C)
time (h)
yieldb (%)
1 2 3 4 5 6 7 8
HF·Py HF·Py KF KF KF TBAFc TBAFc TBAFc
CH2Cl2 DMF DMF DMSO MeOH THF THF THF
------MS 4 Å MS 4 Å
25 25 25 25 65 25 25 70
3 24 12 12 24 10 10 5
80 NR 22 18 NR 20 40 65
A solution of spiroaziridine (±)-1a′ (0.05 g, 0.16 mmol) and fluoride reagent (3 equiv) in 1 mL of solvent was stirred at specified temperature. Isolated yield. c1 M solution in THF.
a
b
Table 2. Optimization of Reaction Conditions for Stereocontrolled Nucleophilic Fluorinationa
entry
fluoride source
solvent
temp (°C)
time (h)
yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9
HF·Py KF KF TBAFd TBAFd TBAFd TBAF TBAF TBAF
CH2Cl2 DMF DMSO THF THF THF DMF DMF DMSO
25 25 25 70 25 0 25 0 25
2.5 12 12 4 8 24 1.5 2 1.5
82 25 20 60 45 32 75 95 65
0 70 ND 84 ND ND 92 98 98
a A suspended solution of spiroaziridine 1a (0.05 g, 0.17 mmol), fluoride reagent (3 equiv), and MS 4 Å in 1 mL of solvent was stirred at specified temperature. bIsolated yield. cee determined by HPLC analysis on a chiral stationary phase. d1 M solution in THF. ND = Not Determined.
with complete loss of enantioselectivity. The reaction of N-Boc substrate 1g afforded the Boc-deprotected compound 2e with HF·Py. A wide range of spiroaziridines with electronwithdrawing and electron-donating substitutions at varied positions were also tested, and all reacted smoothly to form the corresponding 3-fluorooxindoles 2a−q with excellent enantioselectivities (ee 91% to >99%) and yields. Interestingly, substrates 1h−1j with the electron-donating groups showed the higher efficiency of the reaction by taking less time than the substrates 1k−1q having the electron-withdrawing groups. Regrettably, the spiroaziridine 1r having two chloro functionalities at C4 and C7 gave enantioselectivity of only 62%. The electron-donating group in particular at the C5 position increases the electron density to the ring (without steric effect like C7) and, in turn, might enhance the donating propensity of oxindole nitrogen/oxygen toward anchimeric assistance leading to the faster reaction. In the case of 1r, both electronic and steric effects might partially have obstructed the anchimeric assistance, lowering the ee.
To confirm the structure and also to determine the absolute stereochemistry of the C3-fluoro tertiary center of 2, compound 2l was recrystallized from ethyl acetate and was subjected to X-ray crystallographic analysis. The crystal structure unambiguously confirms the stereochemistry of the C3-center of 2l as (S)-configuration derived from (S)spiroaziridine oxindole 1l (Figure 2). This confirms the retention of configuration at the C3-stereocenter and strongly establishes our presumption of anchimeric assistance. To demonstrate the general applicability and the robustness of the method, the NuF of the spiroaziridine was extended up to gram scale under the optimized conditions. The spiroaziridine 1l (1 g, 2.87 mmol) smoothly underwent a reaction with TBAF in DMF at 0 °C and produced 3fluorooxindole 2l maintaining excellent enantioselectivity (ee 99%) and yield (94%), which is a little higher than the smallscale reaction (Scheme 3). Next, deprotection of the sulfonyl group of the fluoro product was attempted. N-Sulfonyl-3fluorooxindole 2l was successful with TfOH and anisole in CH2Cl2 at 0 °C to provide the unprotected 3-(aminomethyl)6473
DOI: 10.1021/acs.orglett.8b02777 Org. Lett. 2018, 20, 6471−6475
Letter
Organic Letters
Figure 2. ORTEP diagram of compound 2l.
Scheme 3. Gram-Scale Nucleophilic Fluorination and Enantiopure Synthesis of 3-(Aminomethyl)-3fluorooxindole 3l
3-fluorooxindole 3l in good yield with high optical purity (Scheme 3). NuF reaction of nonracemic phenyl aziridine 4, which does not have a possibility of neighboring group participation, was also investigated under the optimized conditions to compare the reactivity pattern with the spiroaziridines 1. Interestingly, it gave terminal fluoro-addition (sp3 primary carbon center) product 5 as a major product, along with a minor amount of benzylic fluoro-product 6 (Scheme 4). Gratifyingly, both Scheme 4. Nucleophilic Fluorination of Phenyl Aziridine 4
fluoroamines 5 and 6 showed excellent enantiopurity, which is in contrast to the earlier report.6b This result indirectly supports the anchimeric assistance of the oxindole unit. In conclusion, we have developed the first asymmetric nucleophilic fluorination at the sp3 tertiary carbon center using inexpensive TBAF as a fluorinating agent without any metal and catalyst. This NuF of spiroaziridine oxindoles provided exclusively 3-fluoro-3-substituted oxindoles with excellent enantioselectivities (ee up to >99%) with retention of configuration, which strongly supports our presumption of anchimeric assistance of the oxindole unit. In contrary, phenyl aziridine gave the major terminal fluorination product, and interestingly, the minor benzylic fluoro product also showed
Figure 1. Enantiopure synthesis of 3-fluoro-3-substituted oxindoles 2: ent-2j and ent-2m were produced from the ring-opening reaction of (R)-spiroaziridines ent-1j and ent-1m, respectively. aReaction with HF·Py. NR = no reaction. 6474
DOI: 10.1021/acs.orglett.8b02777 Org. Lett. 2018, 20, 6471−6475
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Organic Letters
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high enantiopurity. The N-sulfonyl group of the 3-fluorooxindoles was successfully removed to synthesize enantiopure 3(aminomethyl)-3-fluorooxindoles, which can be utilized for the library synthesis and further biological evaluation. We intend to continue our research efforts toward the ring opening of spiroaziridines with other carbon-/heteronucleophiles and other allied reactions.
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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.8b02777. General information, general procedure for the synthesis of (S)-spiroaziridine oxindoles, general procedure for the synthesis of 3-fluorooxindoles and optimization of reaction conditions, characterization data for compounds, X-ray crystal structure details, references, 1H NMR, 13C NMR, and 19F NMR data of compounds, and HPLC data of compounds (PDF) Accession Codes
CCDC 1864645 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Saumen Hajra: 0000-0003-0303-4647 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank SERB, New Delhi (EMR/2016/001161), for providing financial support. A.H. and P.M. thank CSIR and UGC, New Delhi, respectively, for their fellowships. We thank the Director of CBMR for providing research facilities.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b02777 Org. Lett. 2018, 20, 6471−6475
