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Synthesis of Cyclobutane-Fused Angular Tetracyclic Spiroindolines via Visible-Light-Promoted Intramolecular Dearomatization of Indole Derivatives Min Zhu, Chao Zheng, Xiao Zhang, and Shu-Li You J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12965 • Publication Date (Web): 17 Jan 2019 Downloaded from http://pubs.acs.org on January 17, 2019
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Journal of the American Chemical Society
Synthesis of Cyclobutane‐Fused Angular Tetracyclic Spiroindolines via Visible‐Light‐Promoted Intramolecular Dearomatization of In‐ dole Derivatives Min Zhu,†,‡ Chao Zheng,*,† Xiao Zhang,*,† and Shu-Li You*,†,‡ † State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China ‡
School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China
ABSTRACT: An intramolecular dearomatization of indole derivatives based on visible-light-promoted [2 + 2] cycloaddition was achieved via energy transfer mechanism. The highly strained cyclobutane-fused angular tetracyclic spiroindolines, which were typically unattainable under thermal conditions, could be directly accessed in high yields (up to 99%) with excellent diastereoselectivity (>20:1 dr) under mild conditions. The method was also compatible with diverse functional groups and amenable to flexible transformations. In addition, DFT calculations provided guidance on the rational design of substrates and deep understanding of the reaction pathways. This process constituted a rare example of indole functionalization by exploiting visible-light-induced reactivity at the excited states.
INTRODUCTION Polycyclic indole derivatives, which are encountered in a wide range of alkaloid natural products and biologically active molecules, have aroused broad interest in the past years.1 From the synthetic point of view, dearomatization reactions of indole derivatives are among the most straightforward avenues that rapidly access these privileged molecular scaffolds, including spiroindolenines, pyrroloindolines, and furoindolines, etc. (Scheme 1, top).2 Particularly, two general strategies that take advantage of the C3 sidechain of indoles have been established. It is well known that an ipso cyclization of a pendent electrophile at the C3 position can lead to various spiroindolenines.3 Alternatively, when an appropriate nucleophilic sidechain is available, a Friedel–Crafts alkylation at the C3 position with an external electrophile can trigger the cyclization at the C2 position, delivering fused indolines.4 Compared with these progresses, catalytic approaches towards a series of more advanced targets, namely angular tetracyclic spiroindolines, are relatively underdeveloped. Known examples are mainly restricted within intramolecular annulation in which the C2=C3 double bond of indole reacts as a dipolarophile (Scheme 1, middle).5 On the other hand, cyclobutanes are frequently found in natural products, pharmaceuticals, and agrochemicals.6 However, to assemble cyclobutanes, especially those embedded in polycyclic structures, is rather challenging due to the high strain. Notably, light-driven [2 + 2] cycloadditions have long been recognized as a straightforward method for the construction of cyclobutanes.7 Particularly, since the pioneering examples of Kutal,8a Xiao,8b Yoon8c and others, intra- or intermolecular [2 + 2] cycloaddition could be achieved under the irradiation of visible-light with the assistance of a judiciously chosen photosensitizer, which shows significant advantages in terms of convenient operation, good selectivity and functional group tolerance, and environmental friendliness.8 Mechanistically, an alkene can be excited to its first triplet state (T1) via energy transfer mechanism.9
The diradical species then undergoes [2 + 2] cycloaddition with another alkene. The groups of Meggers,10a,b Bach,10c and Feng10d independently reported that tailored catalyst coordinated substrates could be efficiently activated by visible-light, offering intriguing direct-sensitization approaches towards [2 + 2] photocycloadditions. Notably, the visible-light-promoted [2 + 2] cycloadditions were mainly restricted within functionalized alkenes including α,β-unsaturated ketones, and carboxylic acid derivatives. The corresponding reactions involving aromatic molecules were largely underdeveloped.10b,c,11 Fascinated by the distinctive reactivity of excited states, we envisioned that it might be feasible in preparing molecules that are inaccessible under thermal conditions. Here we show that visible-light-promoted intramolecular [2 + 2] cycloaddition reaction of indole derivatives provides an attractive synthesis of cyclobutanefused angular tetracyclic spiroindolines in excellent yields with extraordinary stereoselectivity (Scheme 1, bottom).12,13
REACTION DEVELOPMENT We initiated our studies by testing indole-tethered terminal olefin 1a' as the substrate (Table 1). Unfortunately, the expected [2 + 2] cycloaddition reaction did not occur with a series of common organic (I), Ru-based (II), or Ir-based (III-V) photosensitizers (Figure 1) under visible-light. Indeed, the calculated energy gap between T1 and the ground state (S0) of 1a' [ΔG(T1–S0)] is 65.0 kcal/mol, which is beyond the triplet excited state energies of I-V (40.9–60.8 kcal/mol). Notably, calculations showed that extending the conjugation of the C2=C3 double bond of the indole ring by introducing a phenyl group at the C2 position (1a) lowers the ΔG(T1–S0) value to 55.9 kcal/mol. Further incorporation of an electron-withdrawing group (EWG) on the substrate makes the corresponding ΔG(T1–S0) values even smaller. The spin density population analysis confirmed the stabilization effect to the two spin-aligned electrons in T1 state resulted from the above-mentioned substrate variation (Figure 2).
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Scheme 1. Synthesis of Angular Tetracyclic Spiroindolines via Dearomatization Reactions Privileged polycyclic indoles obtained from dearomatization X
R1
X n
Y N 2 H R
N
n
m
m
spiroindolenines pyrroloindolines (Y = NH, m =1) furoindolines (Y = O, m = 1)
Y N H R angular tetracyclic spiroindolines
Well documented
Less studied
Previous works: ground state reactions Z
Z El N H
Nu
Z El
El
cat.
Nu N H dipolarophile
Nu
N H
This work: excited state reaction Z
Z N H
R
triplet sensitizer
N H
Z
N H
R
R
diradical species mild conditions novel scaffolds
extraordinary selectivity excellent yields
Figure 1. The photosensitizers utilized in this study and their oxidation/reduction potentials (vs. SCE) and triplet-singlet energy gaps.9a
Table 1. Optimization of the Reaction Conditionsa 0.649
E E 0.295
0.373 0.432
N H
0.585
photosensitizer
solvent
yield (%)b
1
I
CH3CN
0
2
II
CH3CN
0
3
III
CH3CN
0
4
IV
CH3CN
52
5
V
CH3CN
57
c
6
V
CH3CN
75
7c
V
DCM
60
c
8
V
acetone
40
9c
V
MeOH
trace
10c
V
DMF
30
c
V
DCM/CH3CN (3:1)
85
c,d
V
DCM/CH3CN (3:1)
91
c,e
V
DCM/CH3CN (3:1)
95
c,e,f
V
DCM/CH3CN (3:1)
0
c
/
DCM/CH3CN (3:1)
0
11 12 13 14 15 a
Reaction conditions: a solution of 1a (0.1 mmol) and photosensitizer (1 mol %) in the indicated solvent (c = 0.1 M) was irradiated by 24 W blue LEDs at room temperature under argon for 48 h. b Isolated yield. c c = 0.01 M. d Photosensitizer (2 mol %). e Photosensitizer (4 mol %). f In dark.
0.307
Cl
N H
E E
N H
0.370
0.341
0.380
0.283 0.339
0.248
G(T1-S0) = 55.7 kcal/mol 98% yield
E E 0.562 0.200
0.261
N H
0.348
0.254
G(T1-S0) = 55.9 kcal/mol 95% yield
0.542 0.262 0.263
0.265 0.577 0.263
0.280
G(T1-S0) = 65.0 kcal/mol No reaction
entry
E E
0.294
CO2Me
0.167
G(T1-S0) = 48.5 kcal/mol 99% yield
E E
0.378 0.561 0.263
N 0.384 Me 0188
0.269
0.260
0.274 0.301
G(T1-S0) = 58.8 kcal/mol 29% yield
E E 0.575
N 0.343CO2Me H G(T1-S0) = 53.4 kcal/mol 97% yield
E = CO2Me
Figure 2. The calculated Mulliken spin population of selected substrates (T1) and their calculated triplet-singlet energy gaps (at (U)B3LYP/6-311+G(2d,p) level of theory). The yields of the corresponding dearomatization products are denoted (See Scheme 2).
Therefore, 1a was set as a refined model substrate. To our delight, under the irradiation of 24 W blue LEDs with photosensitizer VI or V, the expected [2 + 2] cycloaddition proceeded smoothly in CH3CN at room temperature. The desired product 2a was obtained in moderate yields (52-57%) (entries 1-5). Subsequently, evaluation of different parameters including concentrations, solvents and loadings of photosensitizer were performed (entries 6-13). In the presence of 4 mol % of V, the reaction conducted in a mixed solvent of DCM and CH3CN (3:1) with a much dilute concentration of 1a (0.01 M) led to 2a in optimal yield (95%) (entry 13). Control experiments confirmed that no reaction occurred in the absence of visible-light or photosensitizer (entries 14 and 15). Under the optimized conditions, the scope of this reaction was explored. An array of substrates with varied substitution patterns on the indole ring was tolerated (Scheme 2). It was in good agreement with the computational prediction that, in general, introducing an EWG to the substrate would be beneficial to the reaction outcomes.
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Typically, substrates bearing an EWG at the para-position of the 2Ph group underwent the desired reaction smoothly, providing angular tetracyclic spiroindolines (2d-g) in good yields (80-99%). However, the reactions of substrates with an electron-donating group (EDG) at the para position were less effective (2b, 20% yield and 2c, 75% yield). A meta-methoxy and meta-methyl substituents were also compatible with the reaction (2h, 75% yield; 2i, 93% yield). Introducing an ortho-substituent to the 2-Ph group led to diminished results, probably due to the unfavorable steric effect (2j, 27% yield and 2k, 69% yield). On the other hand, better yields of the desired products were obtained for substrates possessing an EWG at various positions of 2-Ph indoles (2p, 5-Br; 2q, 6-Cl; 2v, 6-F: 91–98% yields) than that with an EDG (2n, 5-Me; 2o, 7-Me; 2r, N-Me: 29–87% yields). Besides a dimethyl malonate, different linkages including diethyl (2s), or di-tert-butyl malonate (2t) and N-Boc (2u, 2v and 2z) were tolerated (66–98% yields). Instead of an aryl group, the reactions of substrates with a 2-ester group proceeded well (2w, 97% yield and 2x, 81% yield). Notably, the installation of an N-EWG protecting group enhanced the reactivity significantly [2m, N-Ac, 2-(oMeC6H4), 96% yield vs. 2l,
