Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Directing-Group-Assisted Manganese-Catalyzed Cyclopropanation of Indoles Pratip K. Dutta,† Jyoti Chauhan,† Mahesh Kumar Ravva,‡ and Subhabrata Sen*,†,‡ †
Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Budh Nagar, UP 201314, India ‡ Department of Chemistry, SRM University-AP, Amaravati, 522502, India
Org. Lett. Downloaded from pubs.acs.org by EAST CAROLINA UNIV on 03/12/19. For personal use only.
S Supporting Information *
ABSTRACT: The first manganese-catalyzed cyclopropanation of indoles is reported in moderate to excellent yield with methyl-2-diazo-2arylacetates. This new strategy involved acetyl (COCH3) as the directing group and exhibited exceptional functional group tolerance. In the absence of stereodirecting groups the desired products were obtained as a mixture of diastereomers (7:3 → 8:2). Control experiments and DFT studies elucidated the probable pathway for the formation of cyclopropane-fused indole product. Deacetylation of the final products afforded both C3-substituted NH-indoles.
B
substrate or reagent is used to demonstrate the feasibility of the protocol) and, apart from the first report, utilize a directing group that is not easy to remove. Consequently there is a window of opportunity to develop a novel methodology for the cyclopropanation of indoles with a new catalyst. Additionally we came across two reports by Wang et al. and Chang et al. involving C2 functionalization of N-pyrimidyl and NH indoles catalyzed by Mn(CO)5Br and [RuCl2(p-cymene)]2 with αketo and α-aryldiazoesters, respectively, to afford C2substituted indoles (Scheme 1a).7 Even though Mn(CO)5Brcatalyzed reaction on N-pyrimidyl indole occurred through CH activation, the Ru-catalyzed transformation of NH-indole was a carbenoid functionalization that putatively involved the cyclopropyl-fused indole as an intermediate, which the authors could not isolate.7a Accordingly, this prompted us to ponder about manganese-based catalysts with a new directing group at the indole nitrogen which could enable us to isolate the cyclopropyl-fused indole derivatives. Manganese is the third most abundant transition metal after iron and titanium. It is found in the crux of diverse enzymes required for various metabolizing reactions in the human body.8 It has been utilized in a gamut of radical-based reactions inspired from biological systems.9 In the recent years manganese catalysts have also evolved as a robust tool in organometallic C−H activation.10 In general they work through chelation and afford atomeconomical access to architecturally diverse scaffolds.11 Herein we report a bromopentacarbonylmanganese(I) [(Mn(CO)5Br]-catalyzed cyclopropanation of N-acetyl indoles with appropriate diazo reagent in good to excellent yield (Scheme 1b). Scale-up reaction demonstrated the robustness of the protocol. This is a unique example of manganese-
y virtue of their ubiquitous presence in natural products and drug intermediates, indole derivatives hold a niche position in synthetic and medicinal chemistry.1 Among various indole derivatives, cyclopropane-fused indoles are found widely among natural products and pharmaceuticals and as synthons for the synthesis of indole alkaloids. For example, Lundurine A−D isolated from Kopsia tenuis are a group of alkaloids with unique polycyclic scaffold with cyclopropane-fused indole as the central unit. Lundurine A and C ameliorate the multidrug resistance in vincristine-resistant KB cells. Lundurine B and D inhibit the proliferation of B16 melanoma cells. Additionally cyclopropane-fused indoles form key intermediates for the synthesis of indole alkaloids such as (−)-desoxyeseroline, communisin, minfiensine, and aspidofractinine.2 To date, there are four strategies used to access cyclopropane-fused indoles (Scheme 1S, SI).3−6 Three of them include diazo compounds or tosyl hydrazone-mediated, transition-metal (such as copper, iron, and cobalt) catalyzed reactions of indole derivatives.3−5 The first report about cyclopropanation of indoles was made in 2012, which involved an enantioselective strategy using copper triflate (CuOTf) and carbohydrate-based bis(oxazoline) ligands (Scheme S1).3 Interestingly only two analogues were synthesized, and one of them was extended to the synthesis of the natural product (−)-deoxyeseroline. In 2016, after about five years, Reddy and co-workers demonstrated a chemoselective protocol involving cobalt(II) porphyrin-catalyzed intramolecular cyclopropanation of N-alkyl indoles/pyrroles with alkylcarbenes.4 In another example Xu et al. reported a highly enantioselective copperand iron-catalyzed intramolecular cyclopropanation of indoles with chiral ligands.5 Very recently Chen and co-workers demonstrated a nondiazo approach involving a novel zinc carbene source to generate these compounds.6 A close scrutiny of these procedures revealed that in general they are either substrate or reagent specific (i.e., only one particular type of © XXXX American Chemical Society
Received: January 14, 2019
A
DOI: 10.1021/acs.orglett.9b00150 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. Reactions That Inspired Our Cyclopropanation of Indoles
Table 1. Optimization of the Reaction Conditions for Cyclopropanation of N-Acetyl Indoles
catalyzed, simple, efficient, and facile functionalization of indoles from readily available catalysts and reagents. In a bid to explore a suitable condition to facilitate the cyclopropanation of indoles with manganese catalyst we chose N-acetyl indole 2a and methyl 2-diazo-2-phenylacetate 3a as appropriate reaction partners. To begin, 5 mol % of a variety of manganese catalysts such as manganese acetoacetate (Mn(acac)3), manganese carbonyl (Mn(CO)10), and manganese pentacarbonyl bromide (Mn(CO)5Br) was used in the presence of 0.5 equiv of sodium acetate (NaOAc) as the base with 1,4-dioxane as the solvent at 50 °C (Table 1, entries 1−3). Among the manganese catalysts screened, Mn(CO)5Br worked the best, though with meagre yield of the desired product 4a (Table 1, entry 3). In comparison, the other two catalysts rendered no products (Table 1, entries 1 and 2). With Mn(CO)5Br as the better catalyst, we explored several reaction conditions to optimize the procedure. Consequently, screening several solvents, viz., tetrahydrofuran (THF), dichloroethane (DCE), and diethyl ether, at 50 and 80 °C (Table 1, entry 4− 7) revealed that DCE at 80 °C was by far the best protocol to generate 4a in 45% yield (Table 1, entry 7). Next, gradual increase of NaOAc from 0.5 to 2 equiv improved the yield from 45 to 70% (Table 1, entries 7−9). Screening the reaction with various bases such as potassium acetate (KOAc), diisopropylamine (DIPA), triethyl amine (TEA), potassium phosphate (K3PO4), and potassium carbonate (K2CO3) (Table 1, entries 10−14) could not improve the yield. Even increasing the catalyst content from 5 to 20% or the temperature to 100 °C could not improve the yield (Table 1, entries 15−17). Reaction in the absence of a catalyst or base afforded no products (Table 1, entries 18−19). This indicated the relevance of both of these in our reaction. Exploring few other directing groups on indole NH such as benzoyl and tertbutyloxycarbonyl (t-Boc) (Table 1, entries 20−21) proved futile. Hence the optimized procedure involved an equivalent of N-acetyl indole 2a with an equivalent of 3a in the presence of 5 mol % of Mn(CO)5Br and 2 equiv of NaOAc in dichloroethane at 80 °C, to afford the desired cyclopropanefused N-acetyl indole 4a (refer to SI).
entry
R
cat. (mol %)
base (equiv)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Me ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ t-BuO Ph
A (5) B (5) C (5) ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ C (10) C (20) ″ C (5) ″ ″
B1 ″ ″ ″ ″ ″ ″ B1 B1 B2 B3 B4 B5 B6 B1 ″ ″ ″ B1 ″
(0.5)
(1.0) (2.0) (2.0) (2.0) (2.0) (2.0) (2.0) (2.0)
(2.0)
solvent dioxane ″ ″ DCE THF Et2O DCE ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″ ″
t (°C) yield (%) 50 ″ ″ ″ ″ ″ 80 ″ ″ ″ ″ ″ ″ ″ ″ ″ 100 80 ″ ″ ″
0 16 20 25 20 15 45 60 70 65 30 0
