A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolines via intramolecular aza-Michael reaction to α,β-unsaturated esters

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97 : 3 er) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined with the activation strain model (ASM) and energy decomposition analysis (EDA).


Introduction
Heterocyclic organic compounds containing a hydroquinazoline core are commonplace amongst various natural products and potent drug substances used in the clinic. 1 These include, for instance, DPC 963, a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV treatment, 2 fungicidal 2-azolyl-3,4-dihydroquinazolines compounds 3 and the anti-human cytomegalovirus drug, letermovir (Fig. 1). 4 Although much effort has been directed towards the synthesis of hydroquinazoline compounds, 5 highly enantioselective catalytic methods are still relatively uncommon, especially for unbiased/unactivated systems (Scheme 1).In 2015, the Mashima group developed an enantioselective hydrogenation of quinazolinium salts to yield chiral tetrahydroquinazolines with excellent enantioselectivity under chiral iridium catalysis. 6 palladium-catalyzed enantioselective allylic C-H amination to generate the chiral hydroquinazoline core in good yield and high enantioselectivity was later described by Gong and coworkers. 7pecically, for dihydroquinazolines bearing a tri-uoromethyl group attached to a newly generated quaternary carbon center, an extensive range of metal and metal-free catalyzed enantioselective addition reactions to reactive cyclic ketimines using alkyne, 8 ketone, 9 nitroalkane, 10 b-keto acid, 11 nitrile, 12 alcohol 13 and isocyanoacetate 14 nucleophiles, have been developed. 15nantioselective aza-Michael reactions enabled by metal-free catalysts are other powerful and promising approaches to access such pharmaceutically relevant N-heterocycles. 16owever, in this eld, catalyst promoted addition of pronucleophilic ureas to tethered b-substituted a,b-unsaturated esters remains largely unsolved due to the high pK a of the urea and low electrophilicity of the Michael acceptor. 17,18To our knowledge only two reports describe the synthesis of the chiral hydroquinazoline core in such a way.In 2016, a single moderately enantioselective phase-transfer-catalyzed intramolecular aza-Michael reaction (IAMR) was described by Tschaen and coworkers en route to letermovir. 19In 2017, Ruck and coworkers then developed the enantioselective IAMR reaction of related guanidine containing substrates. 20However, only N-aryl nucleophiles were compatible and transformation of the guanidine IAMR product to drug molecules bearing urea motifs such as in DPC 963 (shown in Fig. 1)was not feasible.Against this backdrop, we envisaged that the enhanced Brønsted basicity and broadly tunable structure of the bifunctional iminophosphorane (BIMP) superbase catalyst system developed in our group 21 could provide the solution to the challenging pK a related reactivity and modest stereocontrol in the IAMR, and herein we wish to report our ndings.

Results and discussion
Urea 1a bearing an a,b-unsaturated tert-butyl ester was chosen as the model substrate for the IAMR reaction.An initial reactivity study of various bifunctional organocatalysts revealed that moderately Brønsted basic cinchona-derived bifunctional catalyst A failed to promote any detectable reaction in Et 2 O at room temperature aer 24 hours (Table 1, entry 1).In contrast, catalyst B bearing a superbasic iminophosphorane motif smoothly gave the desired product 2a in 96% isolated yield and 68.5 : 31.5 er under identical conditions (Table 1, entry 2).With excellent reactivity identied, a series of modications to the BIMP catalyst structure was then performed to optimise the IAMR reaction.Changing the H-bond donor from a urea to the more acidic thiourea improved the enantioselectivity to 74 : 26 er but lowered the isolated yield to 73% (Table 1, entry 3).The introduction of a second stereogenic center adjacent to the thiourea motif in the catalyst allowed for rapid library generation and solved the issue of poor reactivity (Table 1, entries 4-6).Variation of the chiral backbone and optimization of reaction conditions revealed that 10 mol% catalyst F in 0.025 M toluene Scheme 1 Previous enantioselective syntheses of hydroquinazoline.A third stereogenic center adjacent to the amide motif was then incorporated and enantioselectivity increased to 80.5 : 19.5 er with catalyst J slightly outcompeting diastereomeric catalyst I (Table 1, entries 10 & 11).Excitingly, a squaramide substitution for the thiourea (catalyst K) boosted the enantiocontrol to 94.5 : 5.5 er.
The major enhancement in selectivity likely arises from the higher acidity/H-bond donor ability of the squaramide and/or the modied 3D structure resulting from the differing bond angles at the squaramide. 22Additional catalyst structureperformance studies gave no further improvement (see ESI † for optimization details).
With the optimal conditions in hand, the scope of the enantioselective IAMR reaction was then explored (Scheme 2A).Notably, the IAMR reactions were found to typically have very clean reaction proles and no effort was made to exclude moisture or air from the scoping experiments.Varying the substituents on the quinazolinone aryl core gave rise to minimal uctuation in enantioselectivity and compatible functionalities varied from electron-donating groups to electron-withdrawing groups.Elevated temperatures of up to 80 C were required to ensure solubility of the substrates in some cases (1b and 1d).A pyridine-based substrate (1i) was also found to be well-tolerated affording the desired product in excellent yield and enantioselectivity under the standard reaction conditions.The substituent effect on the N-aryl ring was then examined.Substrates possessing single iodine, bromine and uorine atoms at various ring positions as well as a 3,5dichloro example, performed typically well providing the desired hydroquinazoline core in excellent yield and good er (1j to 1p).The rates of the cyclization reactions were found to decrease with increasing electron-richness of the N-aryl rings.For substrates 1q to 1y, extra reaction time or heating to 50 C was required to maintain the high yield without compromising enantioselectivity.However, the positional effect of the substituents on reaction enantioselectivity was negligible (1t to 1v).Interestingly, ortho substituents (such as thiomethyl, tertbutyl and ethynyl in 1w-1y) gave rise to a slight upli in enantioselectivity (96 : 4-97 : 3 er).The methodology was also applicable to less activated, higher pK a , alkyl-substituted ureas.The high Brønsted basicity of the BIMP catalyst system indeed smoothly provided N-allyl and N-benzyl substituted hydroquinazolines in almost quantitative yield and good er (85 : 15).Even less activated ureas (1ab to 1ad) demanded harsher reaction conditions to deliver the cyclized product in moderate to excellent yield and good er.Finally, the methyl ester acceptor (1ae) also proved to be a good substrate.Aer 48 hours hydroquinazoline product 2ae was obtained in almost quantitative yield in high enantioselectivity (92 : 8 er).Other conjugate acceptors including phenyl esters, enones and a,b-unsaturated amides were also examined, however satisfactory enantioselectivities were not obtained (see ESI † for details).
Increasing the reaction scale 100 fold (to 20 mmol) and decreasing the catalyst loading to 2 mol% delivered the desired product in good yield (7.9 g, 85%) without compromising enantioselectivity (92.5 : 7.5 er).Pleasingly, only a single recrystallization was required to afford essentially enantiopure 2j (Scheme 2B).Furthermore, and to demonstrate potential industrial applicability of the chemistry, various derivatizations of this product were carried out (Scheme 3).For example, removal of the tert-butyl carboxylate ester with TFA, activation as the acid chloride, and subsequent treatment with benzyl amine and methanol gave the methyl ester (3) and amide (4) in excellent to moderate yield, respectively.Suzuki coupling with an N-methyl substituted pyrazole boronic acid and Sonogashira coupling with erlotinib successfully installed various functionalities in the para-position of the N-aryl ring.
In order to paint a mechanistic picture, density functional theory calculations on the aza-Michael reaction step were performed.All calculations reported in this paper were performed using the Amsterdam Density Functional (ADF) soware. 23quilibrium structures and transition structure geometries were optimized using the BLYP functional 24,25 and the DZP basis set. 26Solvent effects of toluene were accounted for using the conductor-like screening model (COSMO) of solvation. 27Dispersion interactions were included using Grimme's DFT-D3 correction with Becke-Johnson damping. 28The zeroth-order regular approximation (ZORA) was used to account for scalar relativistic effects. 29This level is referred to as COSMO(toluene)-ZORA-BLYP-D3(BJ)/DZP.All stationary points have been veri-ed, through vibrational analysis, to be minima (zero imaginary frequencies) or transition structures (one imaginary frequency).The character of the normal mode associated with the imaginary frequency has been analyzed to ensure it resembles the reaction under consideration.Optimized structures were illustrated using CYLview20. 30Potential energies were rened by means of single point calculations using the M06-2X functional 31 and the TZ2P basis set. 26This level is denoted COSMO(toluene)-ZORA-M06-2X/TZ2P//COSMO(toluene)-ZORA BLYP-D3(BJ)/DZP.The reported Gibbs free energies in solution are calculated by adding thermal corrections computed at 298 K from vibrational frequencies obtained through numerical differentiation of the analytical gradient at COSMO(toluene)-ZORA-BLYP-D3(BJ)/DZP and a standard concentration (1 mol L À1 ) to the total electronic energy at COSMO(toluene)-ZORA-M06-2X/TZ2P//COSMO(toluene)-ZORA-BLYP-D3(BJ)/DZP.
To elucidate the origin of stereocontrol in the novel BIMP squaramide catalyzed IAMR reaction, we performed a state-ofthe-art DFT study.Due to the conformational freedom and the existence of two potential activation modes of the BIMP catalyst, we computed and compared all the possible TSs for the enantio-determining Michael reaction step involving substrate 1ae (see the ESI † for additional details). 32The most energetically preferred transition structures that lead to either (R)-or (S)product are shown in Scheme 4. The TS-ModeA-LA1-RA1-R that forms the (R)-product was found to be favoured by 1.2 kcal mol À1 , which agrees with the experimentally conrmed absolute stereochemical conguration by single crystal X-ray diffraction studies.Pleasingly, our computational approach predicted the enantioselectivity for the formation of product 2ae in 88 : 12 er, which was in excellent agreement with the experimental selectivity of 92 : 8 er.The energetically preferred TS  33 conformation in TS-ModeA-LA1-RA1-R engages in several weak stabilizing interactions.The squaramide moiety interacts with the ester carbonyl group by hydrogen bonding and with the urea carbonyl group by CO-p interaction to activate both the electrophile and the nucleophile.The "le arm" of the BIMP catalyst bearing the amide group additionally interacts with the aromatic scaffold in the substrate by both CH-p, and CO-p interactions without signicant steric repulsion.The "right arm" of the BIMP catalyst bearing the iminophosphorane moiety activates the nucleophilic urea by both hydrogen bonding and through CH-p interactions between the PPh 3 and the aromatic ring on the N atom in the case of the N-aryl substrates.In addition to these catalyst/substrate interactions, the hydrogen bonding and the CH-p interactions within the catalyst also provides the rigidity of this particular lowest energy transition structure. 34This conformation creates an ideal-t pocket within which the substrate can perfectly t that maximizes stabilizing interactions and minimizes steric repulsion during the C-N bond forming step of the Michael reaction.Analysis of non-covalent interaction (NCI) plots allows one to qualitatively visualize these weak interactions between the catalyst and the substrate (Scheme S5 and S6 †). 35Therefore, the TS that has a catalyst conformation and coordination mode of the substrate that both reduces steric repulsion and maximizes interactions is energetically preferred in this reaction.
In order to obtain deeper insight into the origin of the catalytic activity imparted by the squaramide motif of the BIMP catalyst, an activation strain analysis (ASA) and an energy decomposition analysis (EDA) were carried out on archetypal model systems.The ASM involves decomposing the electronic energy DE into the strain energy DE strain associated with the structural deformation of the hydrogen bond donor (HB) and methyl acrylate (MA) from their equilibrium geometry and the interaction energy DE int between the deformed reactants [eqn (1)]. 36The EDA separates the interaction energy (DE int ) into the following three chemically meaningful energy terms: classical electrostatic interaction (DV elstat ), Pauli repulsion (DE Pauli ) between closed-shell orbitals which is responsible for steric repulsion, and stabilizing orbital interaction (DE oi ) that (1) First, we analyzed the interaction between HB (urea, thiourea, and squaramide) and MA in the formation of complexes U-MA, TU-MA, SQ-MA (Scheme 5A).The interaction becomes more stabilizing from U-MA, TU-MA, SQ-MA (DE int ¼ À9.0 to À10.1 to À11.5 kcal mol À1 ) mainly due to the more stabilizing DV elstat term as a result of the electrostatic nature of hydrogen bonds.The DE oi term is also very important and involves signicant charge transfer from the lone pair of the oxygen atom of MA and the two s * NÀH orbitals on the HB.This ow of charge out of the substrate to the catalyst induces a polarization of the p-MO away from the C]C bond (the importance of which is explained below).The stabilizing DV elstat and DE oi interactions play a signicant role in the hydrogen bonding stabilization by the squaramide catalyst that can be seen by the decreased H/O]C bond length in SQ-MA compared to U-MA and TU-MA.
We then analyzed the transition structures and the energy barriers for the aza-Michael reaction (Scheme 5B).The uncatalyzed reaction goes with the highest reaction barrier (DG ‡ ¼ 16.3 kcal mol À1 ).The urea, thiourea, and squaramide catalyzed reactions go with barriers of 12.0, 11.2, and 8.9 kcal mol À1 , respectively.In order to elucidate the trend in the reactivity, we performed the ASA on the transition structures.The trend in Gibbs free energy activation barriers is the same as for the electronic activation energy barriers.The lower, more favourable, barrier for the squaramide catalyzed reaction compared to the uncatalyzed one (DE ‡ ¼ À8.8 vs. 2.9 kcal mol À1 ) originates from a more stabilizing interaction energy (DE ‡ int ¼ À29.2 vs. À20.0kcal mol À1 ).The differences in the DE ‡ strain also contribute to the trend but are less decisive for the overall reactivity trends (DE ‡ strain ¼ 20.4 vs. 23.0kcal mol À1 ).Next, using the EDA method, the trend in the more stabilizing DE ‡ int was analyzed.This successfully identied the role of a reduction in Pauli repulsion between the reactants being the reason for the more enhanced reactivity of the catalyzed reactions. 37 computed orbital overlap S between the p-MO HB-MA and the lone pair of the nucleophile HOMOÀ1 Nu decreases from 0.141 for TS uncatalyzed to 0.106 for TS SQ-MA , which is caused by the aforementioned polarization of the p-MO HB-MA away from the reactive carbon center of the C]C bond due to the charge transfer interaction with the hydrogen bond donor catalyst.The squaramide catalyst emerges as the best of our studied bifunctional iminophosphorane squaramide catalysts as it is able to reduce the destabilizing Pauli repulsion between the reactants and thereby impart the greatest reactivity enhancement of our intramolecular aza-Michael reaction. 38These systematic computational analyzes explain origin of reactivity and enantioselectivity in this BIMP squaramide catalyzed aza-Michael reaction.

Conclusions
In summary, an efficient and highly enantioselective BIMPcatalyzed intramolecular aza-Michael reaction affording decorated hydroquinazoline structures with excellent yields and enantiomeric ratios has been developed.A novel BIMP squaramide system was found to be effective in activating both aromatic and aliphatic ureas.DFT calculations uncovered the fact that the optimal catalyst conformation creates a pocket-like binding site for the substrate to impart enantiofacial selectivity, whilst the squaramide motif demonstrates advantages over urea and thiourea H-bond donor groups on decreasing the destabilizing Pauli repulsion between the reactants (combined ASM and EDA).The catalytic ring formation strategy demonstrated broad functional group tolerance including of esters, nitriles, heterocycles, alkenes, and alkynes, and catalyst loading can be lowered down to 2 mol% in a multi-gram scale synthesis.The hydroquinazoline aza-Michael reaction products were stable towards a series of late-stage structural derivatizations thus demonstrating relevance to pharmaceutical development.
Scheme 2 (A) Scope of the BIMP-catalyzed intramolecular aza-Michael reaction to a,b-unsaturated ester.[a] Reaction carried out at 80 C. [b] Reaction carried out at 40 C. [c] 30 hours reaction time.[d] 48 hours reaction time.[e] 72 hours reaction time.[f] 5 mol% cat.K was used.[g] Reaction carried out at 50 C. [h] Reaction carried out at 60 C. [i] 120 hours reaction time.[j] 216 hours reaction time.(B) Preparative scale synthesis of 2j.Stereochemical configuration was assigned by analogy with (R)-2j (determined by single crystal X-ray diffraction studies).33

Table 1 (
A) Optimization of reaction conditions.(B) Selected catalysts investigated Determined by HPLC analysis on chiral stationary phase.c 12 days reaction time.d 4 hours reaction time.e 10 hours reaction time.N.D. ¼ not determined.
a Yields of isolated products.b