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The Diastereoselective Synthesis of Pyrroloindolines by Pd-Catalyzed Dearomative Cycloaddition of Vinylaziridine to 3-Nitroindoles. Daniel J Rivinoja, Yi Sing Gee, Michael G. Gardiner, John H. Ryan, and Christopher J. T. Hyland ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03248 • Publication Date (Web): 27 Dec 2016 Downloaded from http://pubs.acs.org on December 27, 2016
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The Diastereoselective Synthesis of Pyrroloindolines by PdCatalyzed Dearomative Cycloaddition of Vinylaziridine to 3Nitroindoles. Daniel J. Rivinoja†‡, Yi Sing Gee†‡, Michael G. Gardiner#, John H. Ryanˆ* and Christopher J. T. Hyland†* †School of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522, Australia. # School of Physical Sciences - Chemistry, University of Tasmania, Hobart, Tasmania 7001, Australia. ˆCSIRO Manufacturing Flagship, Ian Wark Laboratory, Bayview Avenue, Clayton, Victoria 3168, Australia. ABSTRACT:
An efficient, diastereoseletive synthesis of densely functionalized pyrroloindolines is reported. The reaction proceeds via cycloaddition of a vinylaziridine-derived Pd-stabilized 1,3-dipole to electron-deficient 3-nitroindoles. The reactions give the trans diastereoisomer with high selectivity, however, when a 4-substituent is present on the indole ring a reversal of diastereoselectivity is observed.
KEYWORDS pyrroloindolines, palladium catalysis, dearomtization, indoles, [3+2] cycloaddition, vinylaziridines.
The pyrroloindoline skeleton, is found in a large array of bioactive natural products and pharmaceutically active compounds,1 with the 3a-amino-pyrroloindolines being of particular interest due to their potent antibacterial properties,2 as well as being key intermediates for the synthesis of heterodimeric C3a-C3a' linked cyclotryptamine-based alkaloids (Figure 1).3
Figure 1. The 3a-amino-pyrroloindoline core and example of natural product psychotrimine featuring this moiety. The total synthesis of natural products containing the 3aamino-pyrroloindoline core has attracted significant attention in recent years.4 However, general synthetic methods to directly prepare skeletons with a 3a-nitrogen are only just beginning to emerge. Many current methods center on aminative cyclisation of tryptamine skeletons, however these methods do not provide easy access to systems with substitution around the pyrroloindoline ring.5 The palladium-catalyzed [3 + 2] cy-
cloaddition of zwitterionic 1,3-dipoles derived from vinylaziridines has emerged as a powerful tool for the synthesis of 5-membered nitrogen heterocycles, but dearomative processes, notably those forming pyrroloindolines are unknown.6,7,8 In contrast, Trost has developed the Pd-catalyzed trimethylenemethane [3 + 2] cycloaddition reactions to electrondeficient aromatics, including 3-nitro-1-phenylsulfonyl indoles to give C2,C3-fused cyclopentaindolines.9 Meanwhile, the azomethine ylide [3 + 2] cycloaddition with 3-nitroindoles has been reported,10 but this provides pyrrolo[3,4-b]indole derivatives, rather than the pyrrolo[2,3-b]indole skeleton, more commonly found in bioactive molecules. We speculated whether highly electron-deficient indole skeletons 2, bearing a C3 nitro group and an N-electron withdrawing group would be activated sufficiently to allow Pd-catalyzed cycloaddition with a vinylaziridine 1-derived 1,3-dipole to occur (Table 1). The product of this reaction would be a densely functionalised 3anitropyrroloindoline 3, which bears not only a nitro group capable of reduction to a C3a amine, but also a C3-vinyl group which is highly versatile in terms of subsequent manipulation. This contrasts to the previous pyrroloindoline syntheses utilizing aziridine [3+2] cycloaddition reactions with electron-rich indoles and aryl-aziridines under Lewis acid catalysis,11placing an alkyl group, rather than an N, at C3a and an aryl group at C3 – significantly decreasing the opportunity for subsequent manipulation. Herein, we report the diastereoselective synthesis of pyrroloindolines 3 by the Pd-catalyzed cycloaddition of
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vinylaziridine 1 to electron-deficient indoles 2 and observe an unusual switch in diasteroselectivity with C4-substituted indoles. Optimisation was carried out with vinylaziridine 1 and NTs-3-nitroindole 2a in the presence of catalytic Pd2(dba)3·CHCl3(Table 1). Curiously, triphenylphosphine resulted no reaction (entry 1) while the bidentate ligand dppe gave a mixture of trans and cis cycloadducts 3a/3b' in good yield, but poor dr (entry 2).12 Changing the ligand to phenanthroline, which has proved beneficial in the cycloaddition of vinylcyclopropanes to aldehydes,13 gave more encouraging results in terms of yield and dr (entry 3). Other bidentate amines were then explored (entries 4-7) with bathophenanthroline proving optimal for both yield and dr. It is interesting to note the stark contrast in dr between neocuproine and bphen (entries 4 and 6), suggesting a deleterious steric effect of the methyl substituents adjacent to the ligand N. Lowering the loading of Pd2(dba)3·CHCl3/bphen led to complete conversion and low yield (entry 7). Therefore, the substrate scope was investigated using the optimized conditions in entry 6.
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then with only 65% conversion after 24h. The N-Boc product 3e was formed with comparable dr to the parent N-Ts-3nitroindole 2a. The product resulting from this reaction is particularly interesting given versatility of having differentially protected nitrogens. Notably, while all the reactions display good to excellent selectivity for the trans diasteroisomer 3, this product could be obtained as a single diastereoisomer following column chromatography – highlighting the synthetic versatility of the process.As expected, a substrate (2f) that has an N-methyl group in place of an N-electron-withdrawing group causes the reaction to fail, most likely due a decrease in the electrophilicity of the indole skeleton.This was also the case for the N-acetylindole 2g, highlighting the limit of the electron-withdrawing group at N. Table 2. Variation of N-electron-withdrawing group and C3-electron-withdrawing group.a
Table 1. Selected optimization of yield and diastereoselectivitya
entry
ligand
solvent MeCN
% conv. nr
drc
yield (%)b
3a:3a'
-
-
1
PPh3
2
dppe
MeCN
100
82
58:42
3
phen
MeCN
100
72
91:9
e
4
neocuproine
MeCN
100
70
5
bpy
MeCN
100
72
93:7
6
bphen
MeCN
100
81
93:7
d
bphen
MeCN
40
29
89:11
7
55:45
a
Reactions carried out at 0.1 M, rt with 5 mol% Pd2(dba)3·CHCl3 and 15 mol% ligand with 1.0 eq. of 1, 1.2 eq. of 2a. 3arefers to trans diastereoisomer and 3a' to the cis. bIsolated yields. cMeasured from the 1H NMR of the crude reaction material. d2.5 mol%Pd2(dba)3·CHCl3 and 7.5 mol% bphen.eCalculated yield from 1H NMR of the reaction mixture using an internal standard.
Initially, the effect of the group at C-3 and N-1 of 2 was investigated and it was quickly found that various electronwithdrawing groups a N-1 could be accommodated by the reaction (Table 2, products 3a-e). N-Methyl and ethyl carbamates could be tolerated in the reaction, giving the trans pyrroloindolines 3b and 3c in good yield and dr. Curiously, the N-nosylated product 3d formed in lower yield than the other cycloadducts – requiring 10 mol% of the catalyst to form and
a Isolated yields. dr (trans:cis) measured from 1H NMR of the crude reaction material after work up. Isolated dr given in brackets measured from the 1H NMR of the purified material.b10 mol% Pd2(dba)3·CHCl3 and 25 mol% bphen used;65% conversion only for 3d,potentially due to the low solubility of indole 2d.
Importantly, the presence of a nitro group at C-3 of the indole was found to be critical for the reaction to proceed, with a methyl ester group (2h) and a cyano group (2i) at this position failing to produce any product, even with 10 mol% catalyst loading. These results suggest that the nature of the C-3 electron-withdrawing group is more critical than that at nitrogen.14 Attention was then turned to variation in substituents around the indole ring (Table 3). A range of indole 5- (3j-o), 6-(3q) and 7- (3r-s) substituents were tolerated, including electron withdrawing and donating groups. The high yields and drs obtained with the halogenated substrates bode well for subsequent functionalization of the products by cross-coupling reac-
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tions. A 5-methoxy substituent (2p) on the indole caused the reaction to fail, likely due to the decreased electrophilicity of this indole.15 As was the case for Table 2, the trans diastereoisomercould, in most cases, be enriched significantly following column chromatography. Table 3. Variation of substituents on the indole ringa
between the electron-rich indole skeleton and the cationic π– allyl Pd complex.18This favorable electrostatic interaction is disrupted when a substituent is present at C4 of the indole, leading to the lesshindered TS2. Support for a steric factor influencing the cis diastereoselectivity of the reaction is seen when moving from R=CH3 (dr 34:66) to R=CO2Me (dr>2:98). Alternatively, an electronic stabilization of TS2 cannot be ruled out, where the ester at C4 interacts with the terminus of the π–allyl Pd complex.As the reversible addition of 4 to the nitroindole is potentially important for determining the dr of the overall reaction, one possibility for the poor dr observed with dppe (entry 2, Table 1) may therefore be because of its reduced ability to stabilize Pd(II)-intermediate 4cf. bphen.
Scheme 1. Mechanistic proposal for diastereoselectivity.
a Isolated yields. dr (trans:cis) measured from 1H NMR of the crude reaction material after work up. Isolated dr given in brackets measured from the 1H NMR of the purified material.
Of significance is the reversal in diastereoselectivity for the reaction when a methyl group is introduced to the C-4 position, providing cis3t'as the major diastereoisomer, albeit in a relatively unselective manner. Gratifyingly, if a methyl ester group is placed at C-4 then the reaction becomes completely diastereoselective for cis3u'.16 The mechanism of the reaction likely proceeds via oxidative addition of the Pd(0)-bphen catalyst to the reactive vinylaziridine 1 (Scheme 1).8d,17The resulting 1,3-zwitterionic dipole 4 can then undergo reversible nucleophilic attack at the C2 position of the electron-deficient indole skeleton, resulting in the formation of a nitro-enolate that can undergo ring closure with theπ-allyl palladium complex. The diastereoselectivity of the reactions can be tentatively rationalized if the transition states for the final ring-closure step to the pyrroloindoline are analyzed (Scheme 1). The trans products are formed via TS1, which could potentially be stabilized by a cation-π interaction
Application of the products was investigatedand gratifyingly, the nitro group at C3a could be readily reduced with Zn/HCl to give the biologically relevant 3a-aminopyrroloindoline 5 (eq 1). The nitro group could also be completely reduced to pyrroloindoline 6 by using a radical denitration reaction (eq 2). Both of these reduction products could be obtained as single diastereoisomers, though it should be noted that the reduction of the nitro group in 3ato3a-aminopyrroloindoline5 needed to be carried out at low temperature to ensure the product was formed as a single diastereoisomer. The Boc-group of pyrroloindoline 3e could also be removed quantitatively with TMSCl/MeOH to reveal 7 (eq 3).To demonstrate the ability of the vinyl group in the pyrroloindoline products to be functionalized, a Heck reaction was carried between 3a and iodobenzene to give 8as a single regioisomer in 90% yield(eq 4). In conclusion, a new method for the synthesis of densely functionalized pyrroloindolines with a C3a nitrogen via a Pdcatalyzed dearomative cycloaddition of vinylaziridines to electron-deficient indoles has been developed. The products of these reactions are decorated with easily manipulated nitro and vinyl functionalities and can be prepared in a diastereoselective fashion. Importantly, a switch from trans to cis diastereoselectivity can be realized when a substituent is present at the C4 position of the starting indole. Work is currently underway in our laboratory develop an enantioselective variant of this reaction.
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AUTHOR INFORMATION Corresponding Authors *
[email protected]. *
[email protected] Author Contributions
‡THESE AUTHORS CONTRIBUTED EQUALLY. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures and characterization data for allnew compounds (PDF). Crystallographic data (CIF).
ACKNOWLEDGMENT CSIRO and the University of Wollongong are acknowledged for their generous funding of this project.
REFERENCES
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such as 2h and 2i,however, this aziridine proved unreactive towards our cycloaddition conditions. 15 Domingo, L. R.; Pérez, P. Org. Biomol. Chem.2011,9, 7168–7175. 16 Single crystal X-ray diffraction analysis of the major product confirmed the structure as cycloadduct 3u’ with a cis relationship between the C3-vinyl and C3a-nitro group. 17 Trost, B. M.; Morris, P. J.; Sprague, S. J. J. Am. Chem. Soc. 2012, 134, 17823–17831. 18 For evidence for the interaction of an indole ring with a quaternary trimethylammonium group via a cation-π interaction, see: Aoki, K.; Murayama, K.; Nishiyama, H. Chem. Commun. 1995, 2221–2222.
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