Letter Cite This: Org. Lett. 2018, 20, 4848−4853
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Metal- and Oxidant-Free Modular Approach To Access N‑Alkoxy Oxindoles via Aryne Annulation Ritesh Singh,*,†,‡ Kommu Nagesh,‡,§ Doddapaneni Yugandhar,‡,§ and A. V. G. Prasanthi‡,§ †
Org. Lett. 2018.20:4848-4853. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 08/17/18. For personal use only.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli-229010, UP, India ‡ Organic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, Telangana, India S Supporting Information *
ABSTRACT: An unprecedented metal- and oxidant-free (intermolecular) approach to access N-alkoxy oxindoles via [3 + 2] cycloadition of in situ generated electrophilic species viz. aryne and (putative) aza-oxyallyl cation is reported. This approach is amenable to both C3-unsubstituted as well as C3-substituted oxindoles. A one-pot manipulation further makes this reaction highly practical. The versatility of this approach was demonstrated through valuable synthetic transformations.
O
xindoles are an important scaffold in natural products1 and pharmaceutics, which are endowed with manifold bioactivities such as anticancer,2a analgesic effects,2b calcium channel blockers,2c etc. Consequently, during past decades several elegant strategies have appeared to construct this coveted moiety with different functionalities through various pathways such as a Friedel−Craft type reaction,4 transition metal catalyzed cyclization,5 and radical cyclization,6 besides derivatization of bicyclic isatin/indole.3 Additionally, oxindoles often serve as a versatile intermediate for synthesis of various natural products7 as well as biologically active compounds (eq 3; Scheme 1).8 Owing to its profound importance, recently, there has been growing interest in the development of metal-
free reaction conditions for the construction of oxindoles. Existing methods typically are radical initiated intramolecular transformations using anilide as starting materials (which requires preassembly of desired substitutents and thus are multistep) which require harsh reaction conditions (high temperature and/or strong oxidants) and are limited to C3disubstituted oxindoles (eq 1; Scheme 1).4b,6a−c,l,9 Although Zhu4a and Zhao10 developed metal-free methods via alternate pathways, requirement of external oxidants (hypervalent iodine(III)) was necessary for efficiency. Very recently, an elegant transition-metal-free approach was reported by Liao et al. (through aza-Nazarov cyclization), but requires exotic fluorinated solvent for its success and limited to C3-substituted N-hydroxy oxindoles.11 In light of the above-mentioned limitations, development of newer and sustainable methods under benign conditions to access diversified oxindoles is highly desirable (eq 2; Scheme 1). On the other hand, cycloaddition with α-haloamides via an aza-oxyallyl cation intermediate has lately garnered significant attention.12 It participates as 3 units (2π electron) in formal [3 + 2] cycloadditions showing a reactivity profile similar to a well established electrophilic oxy-allyl cation13 and act as a LUMO partner with their counterparts which are often electron-rich and polar systems. Likewise, arynes with their highly electrophilic character and low-lying LUMO have forged their place in organic synthesis as an efficient, 2 unit participant in formal [3 + 2] cycloadditions (as 4π + 2π) with 1,3-dipoles for construction of a five-membered ring.14 Despite significant progress in the 1,3 dipolar cycloaddition reaction with arynes, [3 + 2] cycloaddition based on the 2π + 2π electron system is
Scheme 1. Previous Reports and Our Approach for Oxindole Synthesis
Received: June 26, 2018 Published: July 25, 2018 © 2018 American Chemical Society
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DOI: 10.1021/acs.orglett.8b01972 Org. Lett. 2018, 20, 4848−4853
Letter
Organic Letters unconceived. More importantly realization of α-unsubstituted haloamides as a putative aza-oxyallyl cation synthon is hitherto unknown.12c Therefore, in an attempt to provide a metal-/ oxidant-free route, herein, disclosed is our envisioned novel intermolecular disconnection approach to access both C3unsubstituted and C3-substituted N-alkoxy oxindoles under extremely mild reaction conditions where the first successful realization of conceptually novel [3 + 2] [2π + 2π] formal cycloaddition of two in situ generated electrophilic species has been achieved.24 Our work commenced with screening of various parameters in order to search for the ideal reaction conditions for an efficient and successful cycloaddition of aryne precursor, 2(trimethylsilyl) aryl triflate 1a with α-haloamide 2 (Table 1).
revealed KF/18-c in itself was sufficient to promote the reaction with equal efficiency (entry 5). No reaction without 18-c proved the necessity of F− under the phase transfer system (PTS) to act as both nucleophile and base (entry 6). An increase in aryne concentration (2 equiv) significantly improved the yield of product 3a (entry 7). Subsequent screening with different F−(PTS) sources demonstrated tetrabutyl ammonium fluoride (TBAF) as the best reagent for the dual role of base and nucleophile, perhaps due to greater basicity and solubility in THF (entries 8−10). Other solvents (diethyl ether, CF3CH2OH (TFE), (CF3)2CHOH (HFIP), and CH2Cl2) screened proved futile, and no desired product 3a was observed in any case (entries 11−13). Diluting the reaction further helped in achieving the best yield of the product 3a with a reaction time of just 30 min (entries 14− 16). No reaction was observed with N-Bn substituted substrate 2b; this indicated requirement of a N-alkoxy substituent for stabilization of a putative aza-oxyallyl cation. Reaction without addition of molecular sieves provided a lower yield of 3a, indicating the detrimental effect of adventitious moisture in the reaction medium (entry 18). With optimized reaction conditions in hand, we then studied the scope and limitation of this novel process for C3-unsubstituted oxindole synthesis. As shown in Scheme 2, C3-unsubstituted oxindoles with different N-substituents (OMe, O-Et, O-t-Butyl, OCH2C6F5,
Table 1. Optimization of [3 + 2] Cycloadditiona
entry
substrate (equiv)
F− (equiv)
1c 2c 3c 4c
1a:2a 1a:2a 1a:2a 1a:2a
5
1a:2a (1.1:1)
6
1a:2a (1.1:1)
7 8 9 10 11 12 13 14 15
1a:2a 1a:2a 1a:2a 1a:2a 1a:2a 1a:2a 1a:2a 1a:2a 1a:2a
16
1a:2a (2:1)
TBAF (6)
17
1a:2b (2:1)
TBAF (6)
18d
1a:2a (2:1)
TBAF (6)
(1.1:1) (1.1:1) (1.1:1) (1.1:1)
(2:1) (2:1) (2:1) (2:1) (2:1) (2:1) (2:1) (2:1) (2:1)
CsF (2.2) CsF (2.2) KF (2) KF/18-c (2.2) KF/18-c (4.2) KF or CsF (6) KF/18-c (6) TBAT (6) CsF/18-c (6) TBAF (6) TBAF (6) TBAF (6) TBAF (6) TBAF (6) TBAF (6)
temp (°C)
3a (%)b
THF THF THF THF
rt 0 0 0
0 20 5 30
THF
0
31
THF
0
NR
THF THF THF THF TFE/HFIP ether CH2Cl2 THF (0.05 M) THF (0.025 M) THF (0.015 M) THF (0.025 M) THF (0.025 M)
0 0 0 0 0 0 0 0 0
69 52 55 74 NR NR 0 82 85
0
84
0
NR
0
71
solvent
Scheme 2. . Reaction Scope toward C3-Unsubstituted Oxindoles
a
a
Our initial attempt with N-OBn substituted bromoacetamide derivative 2a using CsF as the F− source and K2CO3 as the base in anhydrous THF failed to give any desired product when the reaction was conducted at room temperature (messy reaction mixture, entry 1). However, conducting the reaction at 0 °C with the same reagents pleasingly gave the desired C3unsubstituted N-benzyloxy oxindole 3a, albeit in low yield (entry 2). In an attempt to increase the yield, combination of KF/K2CO3 did not show any improvement (entry 3); however, addition of 18-crown [6] (18-c) gave a better yield (entry 4). A control reaction conducted in the absence of base
and O-allyl) were readily generated using this cycloaddition strategy in high yields (entries 3b−h). Noteworthily, N-OMe substituted α-bromoamides which have previously failed to participate in the cycloaddition process with dienes12c were efficiently incorporated to achieve the desired oxindole (3b). Thereafter, to observe the steric and electronic effect on this cycloaddition process, several symmetrical/unsymmetrical aryne precursors were tested. Both electron-donating (OMe) and electron-withdrawing (F) group substituted symmetrical arynes provided excellent yields of the desired oxindoles (entries 3i and 3j). Bulky 2-naphthyl aryne also smoothly gave the desired cycloaddition product in good yield (entry 3k). Interestingly 3-OMe substituted aryne gave a single regioisomer of the oxindole product15 with nucleophilic attack (from N of aza-oxyallyl cation, 2a) on the m-position (entry
Reactions were conducted in a Schlenk tube under argon at 0 °C with 1a, 2, F− source, and 4 Å MS (200 wt %), in anhydrous THF, 30 min (see SI for details). bIsolated yields. cWith K2CO3 (2 equiv). d Without 4 Å MS. NR = No Reaction. TBAT = Tetrabutylammonium difluorotriphenylsilicate.
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Regioselectivity determined from crude 1H NMR.
DOI: 10.1021/acs.orglett.8b01972 Org. Lett. 2018, 20, 4848−4853
Letter
Organic Letters
groups) substituted N-alkoxy oxindoles were readily accessed by reacting various arynes with corresponding monoalkyl αbromoamides 4, in very good yields under standard reaction conditions (s.r.c.) (entries 5a−j). A similar regioselectivity pattern was observed as in the case for the aforementioned C3unsubstituted oxindoles (shown in Scheme 2) (entries 5k− 5o). Surprisingly, an attempt to obtain C3-aryl substituted (entry 5p) as well as C3-dimethyl substituted oxindole 7 using amide 6 via this approach failed (eq 2), perhaps due to the steric effect. Instead, uncyclized products 8 and 9 from respective N- and O-attack of the putative aza-oxyallyl cation were obtained in a 2:1 ratio. Of note, the reactivity trend of αhaloamides observed in this work is in sharp contrast to their reactivity trend observed in literature, where dialkyl substituted haloamides (6) react faster and successfully (at ambient temperature) as compared to monoalkyl (4) and unsubstituted haloamides (2), respectively.12c,d However, in our quest to utilize this strategy to access C3disubstituted N-alkoxy oxindoles, a one-pot, two-step strategy was adopted, where 1a was first reacted with bromoamide 2a. Under s.r.c., after the stipulated time, THF was removed and the crude obtained was then treated with MeI in DMSO, using potassium tert-butoxide (tBuOK) as base, which furnished C3dimethyl substituted oxindole 7 in very good yield at rt (eq 3, Scheme 5).
3l). Surprisingly, the corresponding benzyne with a small 3-Me substituent gave high selectivity for the product arising from mattack (entry 3n/3n′), perhaps due to the additive steric effect of the N-substituent on 2a. Expectedly, no steric or electronic effect on 4-Me and the modest electronic effect on 4-OMe/4-F substituted aryne was observed giving a mixture of two isomers in each case (entries 3o/3o′, 3p/3p′, and 3q/3q′, respectively). A single product was obtained from the 1naphthyl aryne owing to sterics (entry 3m). In order to make this protocol more practical, the feasibility of a one-pot process was then tested. Consequently, in a vessel containing methoxylamine hydrochloride (OMeNH2·HCl) and Et3N in anhydrous THF at 0 °C bromoacetyl bromide was added dropwise, and the reaction was allowed to stir at 0 °C. After 3 h, 4 Å MS, TBAF, and an aryne precursor, 1a, was added sequentially and the reaction was further stirred for 30 min at the same temperature, affording 3b, without significantly affecting the yield (80%). In fact, N-OMe oxindole constitutes a vital core in Gelsemium alkaloids as well as Phytoalexins, wherein compound 3b serves as a prime intermediate for total syntheses of Gelsemine,7b Gelsedilam,7a Gelsemoxonine,16 and Wasalexins1e (Scheme 3). Notably, this is the first intermolecular metal-/oxidant-free report for C3unsubstituted oxindole.17 Scheme 3. One-Pot Manipulation of 3b
Scheme 5. Application toward C3-Disubstituted Oxindoles
Next, we investigated the efficiency of this method for the synthesis of C3-substituted N-alkoxy oxindoles. As summarized in Scheme 4, C3-monoalkyl (methyl, ethyl, and n-butyl Scheme 4. Reaction Scope toward C3-Substituted Oxindoles
a
Yield in parentheses was obtained in one-pot reaction starting from 1 and corresponding α-bromoamide (see SI for details).
The synthetic utility of this cycloaddition strategy was further demonstrated by synthesizing C3-aryl substituted quaternary carbon centered N-alkoxy oxindoles. Consequently, C3-monoalkyl substituted oxindoles (5a and 5g) were treated with electrophile 1a in DMSO using tBuOK as the base and KF/18-c as the F− source, which provided C3-phenyl substituted quaternary stereocentered N-benzyloxy oxindoles (10 and 11) in excellent yields. This approach was readily extended to synthesize biologically important C3-biaryl substituted oxindole 1218 from 3a under similar reaction conditions (eq 4, Scheme 5). Importantly, a one-pot maneuvered protocol makes this process highly efficient and practical (see Supporting Information (SI) for details). In view of the observed reactivity of various bromoamides, with arynes (vide supra), plausible reaction pathways have been delineated for product formation (Scheme 6). Upon generation of aryne from 1a, it could react with either the open aza-oxyallyl cation intermediate A21a or its valence tautomer (closed intermediate), α-lactam B,20a,b generated simultaneously under s.r.c. via pathways (a) and (b), respectively, to provide the desired oxindoles.
a
Regioselectivity determined from crude 1H NMR 4850
DOI: 10.1021/acs.orglett.8b01972 Org. Lett. 2018, 20, 4848−4853
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Organic Letters Scheme 6. Putative Reaction Pathways for Oxindole Synthesis
Scheme 8. Large Scale Synthesis of 3a, Versatility of NProtecting Group, and Further Synthetic Applications
with α-haloamides. Realization of synthetically unexplored unsubstituted α-bromoamide, as a putative aza-oxyallyl cation synthon, is a notable feature in this report. Further, it is a rare system that does not require fluorinated solvents for successful cycloaddition with α-haloamides, perhaps owing to highly reactive arynes as the coupling partner. Detailed mechanistic insight along with asymmetric manipulation of this novel transformation is currently underway and will be reported in due course.
However, in view of previous reports20 where α-lactam has been proposed under a similar reaction medium (ether) and involved in a subsequent rearrangement,20c a concerted cycloaddition with transient α-lactam B generated from substrates 2a and 4 (via intermediate A) is assumed to be more favorable (pathway b), to give the desired products 3a and 5f respectively, as compared to concerted or stepwise cycloaddition with intermediate A, while α-dimethyl substituted bromo amide 6 would follow path b or c via cyclic intermediates B and C respectively, leading to unsaturated products 8 and 9. Observation of imidate 9 is consistent with involvement of aza-oxyallyl cations, as observed in the successful cycloaddition of α-dimethyl haloamide in earlier reports.12f−h,21b,c,d In order to shed some light on the possibility of the stepwise nucleophilic addition/elimination pathway in this transformation (see Scheme S1 in SI), an optically pure amide 1321e was treated with 1a under s.r.c., which furnished racemic product 5f (Scheme 7; see Figures S1−S4 in SI), clearly
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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.8b01972. Preparation and characterization information; HPLC chromatograms; 1H, 13C, and 19F NMR (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]; ritesh.cdri@gmail. com.
Scheme 7. Mechanistic Insight Using Chiral Substrate
ORCID
Ritesh Singh: 0000-0002-2000-6800 Author Contributions §
K.N., D.Y., and A.V.G.P. contributed equally.
Notes
The authors declare no competing financial interest.
indicating formation of an aza-oxyallyl cation as the intermediate in the current cycloaddition (at least in αmono-/disubstituted bromoamides).22 A gram scale synthesis of 3a (eq 5, Scheme 8), besides deprotection of the N-protecting group to access N−OH (entry 3a′, eq 6, Scheme 8) and N−H (entry 5f′, eq 7, Scheme 8) oxindoles, was also demonstrated on substrates 3a and 5f respectively. The synthetic utility of this method was further shown by efficient transformation of 3h in to N-alkoxy indole 14, a bioactive scaffold,23 via reductive dehydration and a drug analog (Semaxanib), 15, via Knoevenagel condensation (eq 8, Scheme 8). In conclusion, we have developed an elegant and novel intermolecular approach to access both C3-unsubstituted and C3-substituted oxindoles via [3 + 2] cycloaddition of arynes
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ACKNOWLEDGMENTS R.S. thanks DST (Department of Science and Technology), New Delhi for an INSPIRE Faculty (Award No. IF15-CH179) grant. Prof. Takayoshi Suzuki (KPUM, Japan) is highly acknowledged for kind support. Dr. S. J. S. Flora (Director NIPER-R) is acknowledged for support and encouragement. This is NIPER-R/Communication/043.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b01972 Org. Lett. 2018, 20, 4848−4853
Letter
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(22) An attempt to obtain a six-membered ring using β-bromo amide, a homolog of 2a, via stepwise nucleophilic addition/ elimination failed, thus favoring involvement of aza-oxyallyl cation intermediate/α-lactam in this cycloaddition (see Scheme S2 in SI). 4852
DOI: 10.1021/acs.orglett.8b01972 Org. Lett. 2018, 20, 4848−4853
Letter
Organic Letters However, no solid evidence is there at this stage to conclusively distinguish between the possible mechanisms; hence, we believe both could contribute toward the observed products 3. (23) Jump, S. M.; Kung, J.; Staub, R.; Kinseth, M. A.; Cram, E. J.; Yudina, L. N.; Preobrazhenskaya, M. N.; Bjeldanes, L. F.; Firestone, G. L. Biochem. Pharmacol. 2008, 75, 713. (24) During the course of the preparation of this manuscript, an aryne-based approach for a different class of oxindole derivatives was reported by: Pandya, V. G.; Mhaske, S. B. Org. Lett. 2018, 20, 1483.
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DOI: 10.1021/acs.orglett.8b01972 Org. Lett. 2018, 20, 4848−4853
