Conjugate Addition Routes to 2-alkyl-2,3-dihydroquinolin-4( 1H )-ones and 2-alkyl-4-hydroxy-1,2-dihydroquinoline-3-carboxylates

: Under CuBr·SMe 2 /PPh 3 catalysis (5/10 mol-%) RMgCl (R = Me, Et, n Pr, CH=CH 2 , n Bu, i Bu, n C 5 H 11 , c C 6 H 11 , Bn, CH 2 Bn, n C 11 H 23 ) readily (-78 o C) undergo 1,4-addition to Cbz or Boc protected quinolin-4( 1H )-ones to provide 2-alkyl-2,3-dihydroquinolin-4( 1H )-ones (14 examples, 54-99% yield). Asymmetric versions require AlEt 3 to Boc-protected ethyl 6-substituted 4( 1H )-quinolone-3-carboxylates (6-R group = all halogens, n / i / t -alkyls, CF 3 ) and provide 61-91% yield, 30-86% ee ; any halogen, Me, or CF 3 provide the highest stereoselectivities (76-86% ee ). Additions of AlMe 3 or Al( n C 8 H 17 ) 3 provide ~45 and ~75% ee on addition to the parent (6-R = H). Ligand ( S )-(BINOL)P-N(CHPh 2 )( c C 6 H 11 ) provides the highest ee values engendering addition to the Si face of the 4( 1H )-quinolone-3-carboxylate. Allylation and deprotection of a representative 1,4-addition product example confirm the facial selectivity (X-ray).


Introduction
Quinolone sub-structure cores 1a and their dihydro-analogues 1b (Scheme 1) constitute privileged starting materials in medicinal and natural product chemistry. The former core has been a lynchpin in antibiotic development for more than 50 years, [1] most recently in quorum sensing approaches, e.g. the moderation of bacterial activity engendered by species such as 2. [2] The latter core 1b has been deployed in the syntheses of a range of natural and biologically active molecules, for example Ma's intermediate (3) [3] , used in the synthesis of martinellic acid (a natural Bradykinin antagonist); and in the related 4; active at 7 nM towards 5-HT6 serotonin receptors. [4] Compounds 3-4 are exemplary of the recent move to explore sp 3 rich heterocycles in medicinal chemistry. [5] Such concepts are poorly explored for dihydroquinolones, with 5 being the only common 'model compound' encountered, providing significant stereoselectivities for aryl additions and being attained by either Rh- [6] or Pdcatalysed [7] ArM (M = ZnCl, BAr3), addition providing 6c (R = aryl) in 40-99+% ee, or by a variety of organocatalytic closures (0-99+% ee) leading to the same core but from different 2-aminochalcone and related intermediates. [8] As both these approaches do not presently allow access to more biologically more interesting sp 3 substituents (e.g. 3-4 etc.) we sought to study presently less explored alkyl organometallic additions to 6c. This seemed potentially profitable as catalytic enantioselective 1,4 alkyl additions to related 6a-b (Y = O, S with R = alkyl) are already known (9-96% ee). [9] Scheme 1. Quinolone and derived dihydro-analogues of relevance to this publication.

Results and Discussion
Additions to protected quinolin-4(1H)-ones (7) The protected acceptors 7a-d (within Table 1) are readily accessible from commercial quinolin-4(1H)-one, which is itself also available from 2-nitroacetophenone via standard heterocylic chemistry. [10] As stoichiometric copper reagents had already been used in copper-promoted additions to 7a (for aza analogues of the natural product Wrightiadione. [11] ), we tested this substrate under catalytic conditions, but it proved too deactivated to react. The more electron deficient 7b still performed poorly with ZnEt2 or AlEt3, under typical conjugate addition conditions. Runs 1-2 were the best outcomes we could attain from a range of conditions. As we could readily confirm that the stoichiometric cuprate MgBr[CuEt2] readily added to 7b in THF upon reaction at -78 to -20 o C affording a 65% isolated yield of 8b we trialled catalytic versions of this chemistry. In the absence of added ligands conversions were modest in THF (Run 3), and worse upon addition of Et2O (Run 4) due to the insolubility of 7b in this solvent. Remarkably, although 7b is also insoluble in 2-MeTHF at low temperature, this solvent produced a very rapid 1,4-addition (within 5 mins), which could be somewhat further promoted by simple phosphorus ligand addition (Runs 5-7). Simply increasing the overall reaction time to 1 h led to complete conversion in both the Cbz and Boc protected quinolin-4(1H)-ones (7b-c) (Runs 8-9) while the methyl carbamate (7d) was inferior (Run 10). By employing these optimal conditions of Table 1 we could show the synthetic scope of the 2-MeTHF reaction conditions (Scheme 2); which contains compounds of clear synthetic and biological utility. Species 8b-c and 9 have only been mentioned passingly in alternative methodology aimed at biologically active targets, [12] while all other isolated examples in Scheme 2 are novel. Certain limitations were noted in the chemistry of Scheme 2: (i) the lowest yields were associated with addition of MeMgX to 7b while 7c did not participate in the same reaction; (ii) the catalytic reaction is sensitive to α-branching in the Grignard (e.g. iPrMgBr and PhMgBr do not react and cC6H11MgBr give a reduced yield; (iii) Allyl Grignard did not participate in the reaction. Table 1. Optimisation of EtMgBr addition to N-protected quinolin-4(1H)-ones 7.

Run 7
MEt Having established viable catalysis we turned our attention to the potential for an asymmetric version. Using the conditions of Scheme 2 but truncating the reaction time to just 2.5 minutes for the EtMgBr 1,4-addition to 7b is instructive. In the absence of any added ligand CuBr·SMe2 (5 mol-%) a 35% conversion to 8b is already realised. In the presence the same copper loading and conditions, but with added phosphine ligands (10 mol-%) improved conversions are realised: P(OPh)3 (88%), PPh3 (73%) and P(cC6H11)3 (92%). This indicates that any ligand accelerated catalysis [13] is modest and not strongly affected by the σ/ϖ-donor characteristics of the phosphine. In line with these observations screening of a small diverse library of chiral ligands (exemplars LA-LF) [10] produced at best 1-11% ee at conversions of 21-76%. The low levels of asymmetric induction realised are likely due to diverse substrate coordination shown by Mg(II) in 2-MeTHF. [14] Additions to Boc-protected ethyl 6-substituted 4(1H)-quinolone-3-carboxylates (26) One way to overcome the issues raised by substrates 7 is to add additional coordinative groups to the acceptor to provide both greater control of the asymmetric transition state conformation and increase its reactivity allowing the use of more selective (more covalent) organometallics (ZnR2, AlR3). Substrates 23 [15] -24 [16] (Scheme 3) represent examples of such approaches. We therefore initiated study of acceptors 26 which are attractive due to their similarity to Schmalz's asymmetric synthesis of Vitamin E (94% ee for 1,4 AlMe3 addition); [17] and as Scammells has described very short preparation of the parent precursor 25a. Scheme 3. Preferred heterocyclic motifs for improved selectivity in asymmetric additions and the synthesis of preferred acceptor 26.
Synthesis of the acceptor library 26a-k proceeded as expected, [10] but two points are worth noting: (i) the use of Eaton's reagent to cyclise the 6-substituted 4-oxo-1,4-dihydroquinolines 25 is much preferred over traditional phosphoric acids or high temperature cyclisations in Ph2O and we found this can be telescoped into a one-pot procedure; (ii) in Boc protection of 25, washing with LiCl(aq) to remove DMF avoids the degradation that even mildly acidic washes would cause.
Preliminary investigations focused of asymmetric catalytic studies on 26a (Table 2). Previous studies had already revealed the ethyl ester is preferred over both smaller and larger groups (Me, CHPh2) are inferior and that phosphoramidites are the optimal ligand class. The ligand structures used in the final optimisation are shown in Scheme 4. Initial trials ( Table 2) identified Et2O as an optimal solvent (Runs 1-3) and that copper(II) triflate was the optimal pre-catalyst for asymmetric AlEt3 1,4-addition (Runs 4-6) using (S,R,R) Feringa's ligand LG as a starting phosphoramidite. Alternative additions of ZnEt2 provided poorer performance (Run 7 is representative). For AlEt3 additions cooling the reaction to -40 o C led to the highest ee value, but an increase in reaction time is required (Runs 8-9). We postulate that the success of the ether solvent is due to the relative insolubility of 26a in it at low temperature which somewhat moderates background (uncatalysed) reactions. At -40 o C in the absence of any catalyst a 74% conversion of 25a is seen at 24 h. Lower temperatures could not be used to further moderate this, as all reactions (catalysed or background) shut down at -50 o C. We have seen similar effects before. [16] Ligand modification to include addition coordination (LI, Run 11), increase in steric bulk of both the amine (LJ) or atropisomeric diol (LK) (Runs 12-13) had detrimental effects on the selectivity. The performance of the dissymmetric ligands (LL-LN) was maximised for a cyclohexyl substituent (Runs 14-16). Finally, as the reaction is close to viability at -40 o C we assured its reproducibility, performance and conversion by increasing the catalyst loadings to 4 mol-% Cu(OTf)2 and 8 mol-% LN. Using these optimised conditions we investigated the effect of the 6-substituent on the catalytic reaction performance (Scheme 5).
The behaviour of 27a-k indicate that electron withdrawing groups in the 6-position increase the stereoselectivity of AlEt3 1,4-addition. Steric demand in the 6-position has a detrimental effect on the selective transition state, but less so than electron factors. With respect to the alane, AlMe3 reversed the sense of asymmetric induction (28), but longer linear alkyl chains were tolerated and behaved similarly to AlEt3 (29). Disubstituted 30-31 are clearly not accepted by the reaction transition state, but the root cause of this issue is not apparent at present. Due to the apparent reversals of enantioselectivity (e.g. 27a vs. 28), based on sign of optical rotation and HPLC enantiomer elution order, it became important to identify the absolute sense of the asymmetric induction engendered by (S)-LN in AlEt3 addition to 26a, and by implication other combinations of acceptors and alanes. Unfortunately, all of the direct conjugate addition products 27 we encountered were oils. However, we could overcome this issue and attain a crystalline derivative by manipulation of 27a (Scheme 6). A sample of 77% ee (+)-27a was allylated under non-polar mild conditions leading to the formation of a major allyl anti diastereomer 32 with the same optical purity, within experimental error as the starting material. Deprotection of 32 with trifluoroacetic acid leads to formation of a similar mixture of stereoisomers, of which the anti-(33) species is significantly the most abundant. Fortunately, slow addition of pentane to concentrated ether solutions of the 33 mixture leads to the formation of modest crops of yellow needles of (+)-33, which by crystallography are the single isomer anti-(+)-(2S,3R)-33. [10] Thus (+)-27a also has the 2S configuration presented throughout this paper. Based on the similarity of their chiral (Chiralpak AD-H) HPLC enantiomer elution and the homology of their polarimetry results we tentatively suggest that 27a-k and 28-31 have the stereochemistry implied herein.

Experimental Section
Details of our general laboratory set-up and instrumentation have been already published. [21] Procedures and data for the processes and compounds described in this paper are within the Supporting Information.