Letter pubs.acs.org/OrgLett
Catalyst-Free “On-Water” Regio- and Stereospecific Ring-Opening of Spiroaziridine Oxindole: Enantiopure Synthesis of Unsymmetrical 3,3′-Bisindoles Saumen Hajra,*,† Somnath Singha Roy,† Sk Mohammad Aziz,†,‡ and Dhiraj Das‡,§ †
Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow 226014, India ‡ Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India S Supporting Information *
ABSTRACT: A catalyst-free water-mediated regio- and stereospecific ring-opening reaction of nonracemic spiroaziridine oxindoles and indoles has been developed with retention of configuration. This method provides direct access to enantiopure 3,3′-mixed bisindoles with excellent yield and enantioselectivity (up to 98% ee).
W
ater has a long history as a reaction medium in carbon− carbon bond-forming reactions like Diels−Alder reaction; other reactions include aldol reaction, allylations, Claisen rearrangements, hydroformylation, cyclopropanation, metathesis reactions, Mannich reaction, Baylis−Hillman reaction, cross-coupling reactions, etc.1 Water, as a solvent, possesses a very interesting property due to its extensive H-bonding ability. In 2005, Sharpless et al. reported the feasibility of C−C bond forming reactions of hydrophobic compounds in water suspension.1f Later, the underlying molecular mechanism of these “on water” reactions was proposed by Jung and Marcus. According to them, approximately 25% of water molecules possess free OH groups at the interface and are available for potential H-bonding with the substrate.2 Such available Hbonds in water clusters can readily mimic the catalytic activity of naturally occurring enzymes like epoxide hydrolase. This enzyme helps in the hydrolysis of xenobiotic epoxides to diols by preferentially forming H-bonds with the epoxide oxygen through its tyrosine residues and facilitates the epoxide ring opening.3 More recently, development of H-bonding organocatalysts like thiourea4 also supports the notion that the enormous H-bonding capacity of water can be utilized for the effective activation of the substrate in stereocontrolled organic transformations (Figure 1). Although various on-water aziridine opening reactions have been reported, to the best of our knowledge, all these reports either include formation of the carbon−heteroatom (N/O/S) bond at less hindered sites or used Lewis acid as a catalyst for ring opening at a stereocenter.5 Surprisingly, the unique H-bonding property of water has not been utilized to date to perform any stereoselective C−C bondforming reaction without any catalyst. Hence, our approach of using water as the activator for the opening of spiroaziridine system at the more hindered chiral center is unique in this “topical area of chemistry”. Therefore, we presume that a © 2017 American Chemical Society
Figure 1. Comparison of three types of H-bonding activation of the substrates. (A) Naturally occurring enzyme epoxide hydrolase. (B) Hbonding thiourea catalyst. (C) Water cluster.
molecular scaffold with a number of hydrogen bond acceptors like spiroaziridine oxindoles6 1 might serve as a model substrate to exploit this excellent H-bond capacity of water and can itself readily undergo a stereoselective transformation. Aziridines are versatile and important synthetic equivalents in organic synthesis.7 However, the chemistry of spiroaziridine Received: June 20, 2017 Published: July 18, 2017 4082
DOI: 10.1021/acs.orglett.7b01833 Org. Lett. 2017, 19, 4082−4085
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
oxindoles has not been explored yet. Our continued interest in aziridine chemistry6,8 and recent research in oxindoles9 led us to hypothesize that chiral spiroaziridine oxindoles could be opened up stereoselectively by carbon nucleophiles like indoles to produce nonracemic 3,3′-bisindoles bearing all-carbon quaternary stereogenic centers. This remains one of the fascinating research areas in modern organic synthesis. Previously, we and other groups reported racemic C−C bond-forming reactions on water without any catalyst.1d,10 These reports and our research interest motivated us to study the catalyst-free water-mediated ring-opening reaction of chiral spiroaziridine oxindoles with indoles. A close look at the structure of N-sulfonyl spiroaziridine oxindoles 1 reveals that a substantial number of H-bond acceptors (O and N) are available in close proximity of each other. We thought that these nitrogen and oxygen atoms of the substrate should have immense capability to form H-bonds with the free −OH groups of water molecules available at the interface. Formation of Hbonds between water and spiroaziridine along with indole could definitely facilitate ring opening of the chiral spiroaziridine and produce a diverse array of 3,3′-unsymmetrical bisindoles, a core moiety of various bioactive indole alkaloids.11 To obtain the proof-of-concept, we studied the ring opening reaction of (R)-N-methylspiroaziridine oxindoles 1a with indole 2a. Compound 1a is prepared by oxidizing the sulfinyl aziridine with m-CPBA in CH2Cl2 (Scheme 1). We started with 99%
entry
solvent
temp (°C)
time (h)
yieldb (%)
ee (%)
1 2 3 4 5 6 7 8 9 10
water water water ethanol 2-propanol 2-methyl-2-propanol trifluoroethanol DCEc DCEd DCE
25 40 100 80 80 100 25 0 0 80
35 6 3.5 26 28 30 34 0.2 3.6 48
90 91 89 76 79 CM 88 88 90 83
98 95 94 93 89 97 5 0 71
a
N-Methylspiroaziridine oxindole 1a (0.34 mmol), and indole 2a (0.68 mmol), in solvent (3 mL) were stirred at the specified temperature. bIsolated yield. CM: complex mixture. 3aa: the first letter “a” originates from structure 1a, and the second letter “a” originates from structure 2a. c10 mol % of Sc(OTf)3. d10 mol % of In(OTf)3.
bonding capacity, whereas 2-methyl-2-propanol failed to produce the desired product (Table 1, entry 6). Due to the homogeneous nature of the reaction mixture, we have also detected ethanol and 2-propanol adducts (Table 1, entries 4 and 5) only by mass spectroscopy. Further, to prove the importance of H-bonding of water, we have also used CF3CH2OH as a solvent. Due to its extensive H-bonding capacity and high hydrophobicity, it was thought to mimic the H-bonding capacity of water.13 Reaction in trifluoroethanol resulted in 97% ee of the product 3aa (Table 1, entry 7), which is still lower than what was obtained with water. The importance of the H-bonding property of water to induce stereospecificity during ring opening of the spiroaziridine was further verified by carrying out this reaction in the presence (Table 1, entries 8 and 9) or absence (Table 1, entry 10) of the Lewis acids (Sc(OTf)3 and In(OTf)3) in an organic solvent like DCE. We observed racemization of the product when Lewis acid was used as a catalyst. In the absence of water, when the substrates were fully miscible in an organic solvent, the reaction rate was drastically slowed. At a higher temperature of 80 °C, the reaction took 48 h to complete. Dramatic enhancement in the reaction rate in the presence of water compared to the miscible organic solvents occurred due to the heterogenic phenomenon of the reaction mixture. This finding is in good agreement with the work of Sharpless et al.1f and Jung and Marcus.2 Next, we examined the functional group compatibility of the substrates. Various C5- and C7-substituted spiroaziridine oxindoles and substituted indoles were tested under the optimized reaction conditions (Figure 2). To check the versatility of the method, we carried out the opening reaction with both (R)- and (S)-spiroaziridine oxindoles derived from (R)- and (S)-ketemines. Substitutions at the indole ring did not have any significant effect on the reaction rate and the yield and ee of the product. N-Methylspiroaziridine oxindoles 1a with various indoles 2a−e resulted in very high ee with an excellent yield of the bisindoles (3aa−ae). It was evident that any substitution at the oxindole ring (irrespective of the electronic
Scheme 1. Synthesis of Spiroaziridine Oxindoles 1 from Sulfinyl Aziridines 4
enantiopure sulfinyl aziridine 4; however, after conversion to 1, we were unable to measure the ee due to its instability during HPLC analysis. We presumed that the ee of 1 is the same as that of the starting aziridine 4. Our initial studies revealed that water-mediated ring-opening reaction of 1a with indole readily proceeded at 25 °C and gave the C3-adduct 3aa exclusively in excellent yield (90%) and ee (98%). The rise in the reaction temperature, however, does not have much effect on the yield but proceeded faster with minute leakage of ee (entries 2 and 3). The nucleophilic character of the water molecule is well established in various substitution reactions. However, to our delight, we did not detect any water adduct product by mass spectroscopy during the course of the reaction. This also confirms the “on water” reaction mechanism. Hydrophobicity of both the substrates probably helps them to stay in close proximity and nullifies any possibility of an attack by water molecules at the spirocenter. We also studied various other H-bonding solvents to confirm the role of H-bonding of water molecules in the progression of the regio- and stereospecific ring-opening reaction. The surface structure of ethanol is known to have the CH3− groups tilting at about 45° and pointing away from the surface.12 Some free hydroxyl groups, however, may still available for H-bonding with the substrate. Thus, the reaction in ethanol and 2-propanol required heat activation of the substrate (Table 1, entries 4 and 5) due to their weak H4083
DOI: 10.1021/acs.orglett.7b01833 Org. Lett. 2017, 19, 4082−4085
Letter
Organic Letters
Scheme 2. Proposed Mechanism for Ring-Opening Reaction of Spiroaziridine Oxindole by Indole
SN2 mechanism (intermediate A), pathway B proceeds through the indolone intermediate B, and pathway C involves anchimeric assistance via the formation of a α-lactum-type aziridinone intermediate C.14 The direct SN2 pathway is expected to afford an inversion of configuration.5,8 Moreover, this pathway is unfavorable due to excess steric crowding at the stereocenter. On the other hand, if the reaction goes through the indolone intermediate, it will definitely produce racemic bisindoles. The attack of the nucleophile occurs from either side of the planar sp2-hybridized benzylic center of the intermediate B. Hence, pathway C is the possible pathway by which the spiroaziridines could open up to afford the desired products. Retention in configuration at the stereocenter of the product strongly suggests the formation of intermediate C via an SN2′-type reaction mechanism (pathway C). Furthermore, when this spiroaziridine oxindole 1a is subjected to ring opening by indole in the presence of strong Lewis acids like Sc(OTf)3 or In(OTf)3 in DCE, we exclusively obtained racemic bisindoles 3aa. Moreover, these reactions were completed within a few minutes. Additionally, unprotected spiroaziridine oxindole resulted in very poor selectivity of the product 3gb in water. Hence, a substantial amount of desired product is believed to form through the indol-2-one intermediate (pathway B), which is in line with the observations made by others.15 The indol-2-one mechanism is always a competitive pathway to the SN2′ mechanism for the opening of spiroaziridine oxindoles. Thus, the formation of the indolone intermediate during the opening of spiroaziridine oxindole rationalizes the leakage of enantioselectivity observed for both unprotected oxindoles and electron-donating oxindoles as well as during the Lewis acid promoted opening of spiroaziridine oxindole. To gain the support of our hypothesis of catalyst-free watermediated stereocontrolled C−C bond-forming reaction, we have extended the present investigation to the water-mediated opening of simple phenylaziridine 5a (90% ee) with indole 2a (Scheme 3). It is worth mentioning that 5a also possesses Hbond acceptors at close proximity and can easily be activated by H-bonding of water. We began with (R)-2-phenyl-1-tosylaziridine 5a having 90% ee and ended up with 65% ee (72% yield) of the product 6aa having the (R)-configuration, suggesting an inversion of configuration at the stereocenter. This also
Figure 2. Substrate scope. Different spiroaziridine oxindoles reacted with different indoles to give enantiopure 3,3′-mixed bisindoles. (a) Reaction was carried out at 80 °C. ORTEP diagram of the unsymmetrical 3,3′-bisindole 3aa. Hydrogens are omitted for clarification.
factor) decreased the reaction rate. Moreover, certain loss in ee of the product (3da and 3dd) was also observed when electrondonating substituents like −OMe were present in the oxindole ring of the spiroaziridine. Electron-withdrawing substituents like −Cl, −F, etc. resulted in excellent ee of the desired bisindoles. Switching of N-protection from methyl to benzyl also slowed the reaction without much reduction in ee. Unprotected spiroaziridine oxindole, however, failed to produce high enantioselectivity of the product 3gb. To determine the absolute stereochemistry of the C3quaternary center of 3aa, which may help us ascertain the mechanism of the ring-opening reaction, it was recrystallized from 2-propanol−hexane and was subjected to X-ray crystallographic analysis. The crystal structure unambiguously confirms the stereochemistry of the C3-center of 3aa as the (S)configuration derived from (R)-spiroaziridine oxindole 1a (Figure 2). This suggests the retention of configuration at the C3-stereocenter. The spiroaziridine−oxindole 1 could open up in three different mechanisms (Scheme 2). Pathway A involves a direct 4084
DOI: 10.1021/acs.orglett.7b01833 Org. Lett. 2017, 19, 4082−4085
Organic Letters
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DEDICATION This work is dedicated to Professor Amit Basak (IIT Kharagpur) on the occasion of his 65th birthday.
Scheme 3. Reaction of (R)-2-Phenyl-1-tosylaziridine (5a) and Indole 2a
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01833. Experimental details, spectroscopic and analytical data for all new compounds, and crystallographic data of compound 3aa (PDF) X-ray crystallographic data of compound 3aa (CIF)
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REFERENCES
(1) (a) Science of Synthesis: Water in Organic Synthesis; Kobayashi, S., Ed.; George Thieme Verlag KG: New York, 2012. For recent reviews, see: (b) Li, C.-J. Chem. Rev. 2005, 105, 3095. (c) Chaturvedi, D.; Barua, N. C. Curr. Org. Synth. 2012, 9, 17. (d) Lindström, U. Chem. Rev. 2002, 102, 2751. (e) Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33. (f) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275. (2) Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492. (3) Rink, R.; Kingma, J.; Spelberg, J. H. L.; Janssen, D. B. Biochemistry 2000, 39, 5600. (4) (a) Kleiner, C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315. (b) Fleming, E. M.; Quigley, C.; Rozas, I.; Connon, S. J. J. Org. Chem. 2008, 73, 948. (5) (a) Sengoden, M.; Punniyamurthy, T. Angew. Chem., Int. Ed. 2013, 52, 572. (b) Wani, I. A.; Sayyad, M.; Ghorai, M. K. Chem. Commun. 2017, 53, 4386. (c) Li, T.; Ma, X.; Qi; Sun, F.; Ma, N. Chin. J. Chem. 2014, 32, 1135. (d) Zhu, M.; Moasser, B. Tetrahedron Lett. 2012, 53, 2288. (6) Hajra, S.; Aziz, S. M.; Jana, B.; Mahish, P.; Das, D. Org. Lett. 2016, 18, 532. (7) (a) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chem. Rev. 2014, 114, 8323. (b) Luginina, J.; Turks, M. Chem. Heterocycl. Compd. 2016, 52, 773. (c) Wang, Z.; Hong, W.-X.; Sun, J. Curr. Org. Chem. 2016, 20, 1851. (d) Jarzyński, S.; Leśniak, S. Chem. Heterocycl. Compd. 2016, 52, 353. (8) (a) Hajra, S.; Maji, B.; Sinha, D.; Bar, S. Tetrahedron Lett. 2008, 49, 4057. (b) Hajra, S.; Maji, B.; Mal, D. Adv. Synth. Catal. 2009, 351, 859. (c) Hajra, S.; Bar, S. Chem. Commun. 2011, 47, 3981. (d) Hajra, S.; Sinha, D. J. Org. Chem. 2011, 76, 7334. (e) Hajra, S.; Aziz, S. M.; Akhtar, S. M. S. Chem. Commun. 2014, 50, 6913. (9) (a) Hajra, S.; Maity, S.; Maity, R. Org. Lett. 2015, 17, 3430. (b) Hajra, S.; Maity, S.; Roy, S. Adv. Synth. Catal. 2016, 358, 2300. (c) Hajra, S.; Roy, S.; Maity, S. Org. Lett. 2017, 19, 1998. (10) (a) Malhotra, R.; Ghosh, R.; Dey, T. K.; Chakrabarti, S.; Ghosh, A.; Dutta, S.; Asijaa, S.; Roy, S.; Dutta, S.; Basu, S.; Hajra, S. Eur. J. Org. Chem. 2013, 2013, 772. (b) Hirashita, T.; Kuwahara, S.; Okochi, S.; Tsuji, M.; Araki, S. Tetrahedron Lett. 2010, 51, 1847. (c) Zhang, H.-B.; Liu, L.; Chen, Y.-J.; Wang, D.; Li, C.-J. Eur. J. Org. Chem. 2006, 2006, 869. (11) (a) Arai, T.; Yamamoto, Y.; Awata, A.; Kamiya, K.; Ishibashi, M.; Arai, M. A. Angew. Chem., Int. Ed. 2013, 52, 2486. (b) Liu, R.; Zhang, J. Org. Lett. 2013, 15, 2266. (c) Trost, B. M.; Xie, J.; Sieber, J. D. J. Am. Chem. Soc. 2011, 133, 20611. (d) DeLorbe, J. E.; Jabri, S. Y.; Mennen, S. M.; Overman, L. E.; Zhang, F.-L. J. Am. Chem. Soc. 2011, 133, 6549. (e) Duffey, T. A.; Shaw, S. A.; Vedejs, E. J. Am. Chem. Soc. 2009, 131, 14. (f) Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 16162. (g) Overman, L. E.; Shin, Y. Org. Lett. 2007, 9, 339. (h) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921. (12) Gan, W.; Zhang, Z.; Feng, R. R.; Wang, H. F. J. Phys. Chem. C 2007, 111, 8726. (13) Matsugami, M.; Yamamoto, R.; Kumai, T.; Tanaka, M.; Umecky, T.; Takamuku, T. J. Mol. Liq. 2016, 217, 3. (14) (a) Angus, P. M.; Jackson, W. G. Inorg. Chim. Acta 2003, 343, 95. (b) Lengyel, I.; Sheehan, J. C. Angew. Chem., Int. Ed. Engl. 1968, 7, 25. (c) Proust, N.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 2008, 73, 6279. (15) (a) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677. (b) Zhang, H.; Hong, L.; Kang, H.; Wang, R. J. Am. Chem. Soc. 2013, 135, 14098.
supports our notion that the ring opening of simple aziridine and spiroaziridine proceeds through entirely different pathways. The loss of enantioselectivity may be attributed to the racemization of the substrate under heating conditions because the recovered 5a during the course of the reaction showed 60% ee. In summary, we have described the first catalyst/reagent-free stereocontrolled carbon−carbon bond-forming reaction simply by utilizing the H-bonding of water. The regio- and stereospecific water-mediated ring-opening reactions of chiral spiroaziridine oxindoles with indoles provide a unique and facile protocol for the direct access to enantiopure 3,3′-mixed bisindoles. In contrast to the simple aziridine, the ring-opening reaction of spiro-aziridine proceeds with retention of configuration at C3, on the basis of which a plausible mechanism is proposed. The concept of water-mediated stereocontrolled carbon−carbon bond-forming reaction is also verified with the ring-opening reaction of a less reactive phenyl aziridine. We intend to continue our research efforts toward the extension of this concept with other carbon nucleophiles and heteronucleophiles, as well as with various other substrate systems.
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Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Fax: (+91)-522-2668995. Tel: (+91)-522-2668861. ORCID
Saumen Hajra: 0000-0003-0303-4647 Author Contributions §
D.D. performed the single-crystal X-ray analysis.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank SERB, New Delhi (EMR/2016/001161), and SERB Young Scientist Award (YSS/2015/000257), for providing financial support. S.S.R. thanks SERB, New Delhi, and S.M.A. thanks CSIR, New Delhi, for their fellowships. We thank the Director of CBMR for providing research facilities. 4085
DOI: 10.1021/acs.orglett.7b01833 Org. Lett. 2017, 19, 4082−4085
