Asymmetric nucleophilic dearomatization of diazarenes by anion-binding catalysis †

The first anion-binding organocatalyzed enantioselective Reissert-type dearomatization of diazarenes has been developed. This reaction represents a synthetic challenge since diazarenes have various reactive sites. The use of a chiral tetrakistriazole as a C–H-based hydrogen-donor catalyst allowed the straightforward highly regioand enantioselective synthesis of a variety of chiral diazaheterocycles.


Introduction
Chiral diazaheterocycles and their partial unsaturated derivatives are important naturally occurring substances and building blocks for the synthesis of bioactive compounds with a broad activity spectrum. 1A few examples of relevant natural and synthetic bioactive di-nitrogen-containing chiral heterocycles are shown in Fig. 1.
Among some interesting quinazoline derivatives, letermovir 2 is one of the top-selling antiviral drugs developed for the treatment of Cytomegalovirus infections and the alkaloid vasicine 3 is a cardiac-depressant.Moreover, based on a pyrazine moiety, matlystain B shows collagenase inhibitor properties. 4Other di-or tetrahydro-structures based on diazarenes such as quinoxaline, naphthyridine or phthalazine present relevant biological activities such as CETP inhibition against atherosclerosis, 5 anti-dyslipidemia 6 or dihydrofolate reductase inhibition towards antibiotic-resistant Gram-positive bacteria. 7espite the great diversity of applications of chiral diazaheterocycles, there is still a demand of simple, mild and direct synthesis methods.Most of the common routes to chiral diazaheterocycles require long and tedious synthesis from chiral starting materials and normally involve the generation of at least one of the N-heterocyclic rings. 1 A more appealing and straightforward approach consists of the enantioselective dearomatization of readily available diazarenes (Scheme 1). 8n this regard, the main method for inducing chirality relies on catalyzed asymmetric hydrogenation reactions of substituted azarenes (Scheme 1, (1)). 9Several methods based on enantioselective nucleophilic additions have been developed for mono N-heteroarenes. 10However, to the best of our knowledge only one example for diazarenes, the intramolecular allylic amination of pyrazines, has been described to date (Scheme 1, (2)). 11This fact could be attributed to the more challenging dearomatization of diazarenes due to the presence of a larger number of reactive sites and the possible generation of a complex mixture of products.
Recently, we have described the use of a family of triazolebased H-bond donors 12 as efficient anion-binding catalysts 13 for the asymmetric nucleophilic dearomatization of N-heteroarenes such as isoquinolines, quinolines and pyridines. 14iming at the development of a new entry for the synthesis of chiral diazaheterocycles, we decided to explore these H-donor catalysts for the related dearomatization of various types of 6-membered ring-containing diazarenes (Scheme 1, (3)).Accordingly, we anticipated successful chiral transfer from a contact ion-pair I formed between an ionic intermediate and the catalyst-counter anion complex.In this article, we present a highly enantioselective dearomatization of in situ generated N-acyldiazarene chloride salts (Reissert-type reaction) 15 with silyl ketene acetals catalyzed by a chiral tetrakistriazole.
Following previously reported procedures, 14,16 2,2,2-trichloroethyl chloroformate (TrocCl) was employed to generate in situ the required quinazolinium chloride salt in MTBE at 0 °C.Subsequent addition of the silyl ketene acetal 4 and the H-donor catalyst 1 or 2 at −78 °C (allowing the reaction mixture to warm up to room temperature overnight) delivered the dearomatized product.It is worth mentioning that there was an appreciable background reaction in the absence of a catalyst (entry 1, 56%).Fortunately the heterocycle 5a was formed regioselectively, not observing the formation of other possible isomers 6a and 7a.The catalytic reactions also showed complete regioselectivity towards 5a.From the catalysts tested in this study (entries 2-5), the triazole-based H-donor 1a proved to be the most efficient in terms of both reactivity and enantioselectivity.Thus, 5a was obtained in 65% yield and 96 : 4 er (entry 2), 19 whereas the other catalysts delivered the dearomatized product in significantly low yields (13-34%) and low to moderate enantiomeric inductions (45 : 55-61 : 39 er vs. 96 : 4 er).The change to other ethereal solvents such as Et 2 O was not beneficial, hampering the enantioselectivity (84 : 16 er, entry 6).When the reaction was carried out at a continuous temperature of −78 °C, the same enantiomeric result (96 : 4 er, entry 7) was obtained.A similar procedure at −40 °C led to 5a in a lower 86 : 14 er (entry 8).Lastly, the use of 5 mol% of catalyst 1a provided an inferior chiral induction (91 : 9 er, entry 9).Therefore, 10 mol% of catalyst loading and a slow temperature-gradient (from −78 °C to r.t.) were employed as optimal conditions for further studies.
Next, screening of the acylation reagents and silyl ketene acetals 4 was carried out (Table 2).CbzCl and methoxycarboxylic chloride could also be employed as acylating reagents (entries 2 and 3).However, a significantly lower  enantioselectivity and a deficient conversion accompanied by a poor regioselectivity were respectively observed.Silyl ketene acetals 4 derived from acetic acid presenting different substitution such as less hindered MeO (4b, entry 4) or bulkier tBuO (4c, entry 5) groups, as well as a propionic acid derivative (4d, entry 6) were then explored.Moderate to good enantioselectivities were achieved (72 : 28 to 88 : 12 er), where the initial iPrO-substituted ketene acetal 4a remained the most efficient nucleophile.
Based on these results, the screening of the substrate scope was next carried out with catalyst 1a, TrocCl, silyl ketene acetal 4a and a number of representative, readily available monoand bicyclic diazarenes in MTBE (Table 3). 19It is important to mention that the reaction could be scaled-up to approximately 40 times (0.5 g scale) without any significant detriment to the enantioselectivity of the reaction (92 : 8 er, entry 1).Moreover, the catalyst could be re-isolated in a good 74% yield and reused, delivering the same reactivity and stereochemical results.The study continued with the dearomatization of the analogous diazarene quinoxaline (3b), which also presents both nitrogen atoms in the same aromatic unit (entry 2).Although this substrate reminds of the structure of quinoline, only a complex mixture was obtained, in which the double addition of the TrocCl to both nitrogen atoms could also be observed.The dearomatization of the highly symmetric phthalazine (3c), exhibiting only one equivalent reactive α-position, yielded compound 5c in a good 93% yield and 76 : 24 enantiomeric ratio (entry 3).In the case of 1,5-naphthyridine (3d), which has one nitrogen atom in each ring, the challenge was again the control of the regioselectivity since both the C4 and  a Conditions: (i) 3a (1 equiv.)and R 1 COCl (1 equiv.)were stirred in dry MTBE at 0 °C for 30 min; then (ii) catalyst 1a (10 mol%) and 4 (2 equiv.)were added at −78 °C and stirred for 18 h while allowing to reach slowly rt.b Isolated yield.c Enantiomeric ratios determined by chiral HPLC.d Isomeric ratios 5 : 6 determined by 1 H-NMR of the crude reaction in brackets.e An inseparable mixture of 5ac, 6ac and staring material 3a.
f Reaction with a 1 : 0.8 isomeric mixture of silyl ketene acetal 4d.The diastereomeric ratio of 5af was determined by 1 H-NMR of the crude reaction.n.d.= not determined.
C2 positions of each heteroaromatic ring are prone to nucleophilic addition (entry 4).A good regioselectivity of 95 : 5 was obtained in favour of the desired C2-addition product 5d.After the separation from the minor 4-addition product 6d, compound 5d was obtained in a 86% yield and a good 83 : 17 enantiomeric ratio.Next, 1,6-naphthyridine (3e) was explored as a substrate (entry 5).Since this compound contains both the quinoline and the isoquinoline unit, it was interesting to get a deeper understanding about the reactivity, regioselectivity and enantioselectivity of this type of mixed structure.Due to the higher intrinsic reactivity of the benzylic position within the isoquinoline core, a high regioselectivity could be expected.Consequently, 5e was obtained as a single isomer and with high enantioselectivity (80 : 20 er).The  reaction with methyl-substituted 1,8-naphthyridine (3f ) proceeded smoothly, providing exclusively compound 5f in a good 74% yield and a significantly lower enantioselectivity (63 : 37 er, entry 6).This unexpected result compared to other naphthyridines cannot be easily rationalized, since in the previous work the related monoazarene quinolines provided very high enantioselectivities for this type of reaction (typically >95 : 5 er).14a As the dearomatization of the bicyclic diazarenes showed a good performance and a moderate to excellent enantioselectivity, a more challenging six-membered monocyclic was next explored.Pyridazine (3g) was again nicely enrolled in the catalytic dearomatization reaction, providing a good 93% overall yield and a 94 : 6 mixture of the 2-(5g) and 4-addition (6g) products (entry 7).Remarkably, an acceptable 73 : 27 enantiomeric ratio was obtained for the more interesting 2-addition product 5g, whereas for the minor regioisomer 6g an almost racemic compound was formed.This can be explained by the greater distance of the newly introduced stereocenter at the C4 with respect to the C2 position to the positive nitrogen present in the key ionic intermediate.Consequently, the catalyst-chloride anion complex should stay in close proximity to the nitrogen atom and therefore, the chirality transfer might be more efficient in the adjacent C2-position.Lastly, the reaction with five membered diazarenes was carried out.While N-methyl benzimidazole provided the desired dearomatized heterocycle 5h in a good yield and moderate enantioselectivity (72%, 66 : 34 er; entry 8), N-methyl pyrazole led to a complex mixture of decomposition products. 20inally, the synthetic utility of this method was demonstrated by the derivatization of 5a.Thus, the corresponding tetrahydro derivative 8 was synthesized by reduction with NaBH 4 in the presence of B(OH) 3 21,22 and the dimethyl derivative 9 by trans-esterification with in situ generated KOMe with K 2 CO 3 in MeOH (Scheme 2).Moreover, the Troc protecting group could easily be removed from 5a using Zn and NH 4 OAc at room temperature, providing the corresponding N-deprotected product 10 in 97% yield.

Conclusions
In conclusion, the first enantioselective nucleophilic dearomatization of diazarenes using an anion-binding organocatalysis approach has been developed.Tetrakistriazole-based H-bond donor catalysts were superior to other known hydrogen-bond donors, providing the corresponding products in high regioselectivities and up to 96 : 4 er.This method allows rapid access to substituted chiral di-or tetrahydro diazaheterocycles.

Experimental section
General methods MTBE and Et 2 O were distilled and dried over Na.The catalysts 1a 14 and 2a-c, [16][17][18] and the silyl ketene acetals 4, 14a,16 were prepared following the known literature procedures.The starting materials and other commercially available reagents were used without further purification.

Fig. 2 H
Fig. 2 H-donor catalysts tested in this study.
1 H-and 13 C-NMR spectra were recorded in CDCl 3 (reference signals: 1 H = 7.26 ppm, 13 C = 77.16ppm) on a Bruker ARX-300 and a Varian AV-300, 400 or 600 MHz.Chemical shifts (δ) are given in ppm and spin-spin coupling constants ( J) are given in Hz.Analytical thin layer chromatography was performed using silica gel 60 F254 and a solution of KMnO 4 served as the staining agent.Column chromatography was performed on silica gel 60 (0.040-0.063 mm).Exact masses (HRMS) were recorded on an Agilent Q-TOF 6540 UHD spectrometer using electrospray (ES) or chemical (CI) ionization techniques.Chiral High Pressure Liquid Chromatography (HPLC) analyses were performed on an Agilent 1200 series instrument.

Table 1
Optimization of the reaction with 3a a b Isolated yield.c Isomeric ratios determined by 1 H-NMR of the crude reaction.d Enantiomeric ratios determined by chiral HPLC.e Isomer 7a was not detected by NMR.f Reaction using 5 mol% of catalyst 1a.