Double annulation of ortho - and peri -C – H bonds of fused (hetero)arenes to unusual oxepino-pyridines †

Direct difunctionalization of chemically distinct ortho - and peri -C – H bonds of fused hetero(arenes) is illustrated through an unusual one-pot domino {[4 + 2] & [5 + 2]} double annulation with alkynes for the ﬁ rst time. This process is viable under Ru( II )-catalysis using a sulfoximine directing group and builds four bonds [(C – C) – (C – N) and (C – C) – (C – O)] in a single operation. Such synthetic manifestation o ﬀ ers access to uncommon [6,7]-fused oxepino-pyridine skeletons. DFT calculations provide mechanistic insight into this double annulation of naphthoic acid derivatives with alkynes and corroborate the participation of a ruthena-oxabicyclooctene intermediate, which is responsible for the rare 7-membered ring formation.


Introduction
Diversity oriented synthesis provides efficient access to complex molecular architectures that are present in natural products, pharmaceuticals, agrochemicals, and advanced-materials. 1 This approach has sustained the development of novel therapeutic agents or probes for molecular biology, based on the resilient interaction of heterocycles with biological systems. 2,3Continuous efforts have therefore been directed towards the conception of straightforward synthetic methods for the construction of complex heteroarenes. 3In this regard, transition-metal (TM) catalyzed annulations of C-H bonds of (hetero)arenes with alkynes have proven invaluable. 4,5In particular, the TMcatalyzed direct functionalization or annulation of the ortho-C(2)-H bond of fused (hetero)arenes with alkynes are successful with acid/amide directing groups (DGs) via 5/7-membered metallacycle (Fig. 1A-I). 5With -OH, -NHR 0 , and -SR 00 DGs, the reactivity is shied towards the peri-C(8)-H bond through 5/7membered metallacycle (Fig. 1A-II). 6On the other hand, the activation of the peri-C(8)-H bond of fused (hetero)arene carboxylic acid derivatives [e.g.1-naphthoic acid] is much more challenging and underdeveloped, due probably to the involvement of a strained [6,6,6]-fused metallacycle (Fig. 2A). 7nsertion of an alkyne would not even funnel such C-H activation step, as it would lead to an even more strained [6,6,8]-fused metallacycle (Fig. 2A).Thus, the molecular rigidity and conformational strain have hampered the development of such annulations at the peri-C(8)-H bond to form 7-membered fused compounds (Fig. 2A). 8,9ecent domino one-pot double annulation of o/o 0 -C-H bonds of (hetero)arenes with alkynes have led to [6,6]-fused heteroaryls. 10,11Although important issues of regio-and chemoselectivity, cumbersome mixtures due to incomplete conversion, catalytic viability, etc., could be addressed, 12 such domino double C-H annulations were not extended to the formation of [6,7]-fused heteroarenes.To make such synthetic plan feasible, we hypothesized a Ru-catalyzed double annulation of 1-naphthoic acid derivatives with alkynes.
We believed the reaction would be initiated by N-aided C(2)-H activation and annulation with the alkyne to rst form an angularly [6,6,6]-fused benzo[h]isoquinolinol.As peri-C-H bonds of fused-arenes are susceptible to electrophilic substitution, we anticipated an O-directed ruthenation of the proximal peri-C(8)-H bond to provide Int-Z (Fig. 2B).Finally, second alkyne incorporation to Int-Z and reductive elimination would build the unusual [6,7]-fused oxepino-pyridine motif (Fig. 2B).This one-pot domino double annulation uses the methylphenyl sulfoximine (MPS)-DG.12b Thus, the sequential activation of ortho-and peri-C-H bonds and annulation results in the formation of N-and O-enabled 6-and 7-membered rings on fused (hetero)arenes by generating four bonds (C-C & C-N and C-C & C-O) in a single operation (Fig. 2B).
Importantly, benzothiophene derivative 1p smoothly reacted with 2b to afford 3pb in 82% yield.Indole-3-carboxylic acid derivatives 1q-s were used in this double annulation with 2b and 2a.The respective complex heteroarenes 3qb, 3rb, and 3sa were reliably accessed.The common N-protecting groups benzyl and MOM did not prevent the reaction.The yields are moderate in these cases, but the construction of these molecular scaffolds with three heteroatoms (i.e.S-N-O, N-N-O) in a 5,6,7-fused system is remarkable.Notably, the current synthetic plan was successful in making 8 bonds (4 C-C, 2 C-N, and 2 C-O) in a single operation; thus, an extended p-conjugated system 4a with two oxepinopyridine motifs was made.The reaction of 1a with diphenylacetylene provided polycyclic amides through linear diannulation. 11,14On the other hand, the reaction of a thioalkyne or an ynamide with 1a produced complex mixtures (Scheme 1).Lastly, the terminal alkyne phenylacetylene underwent dimerization under the optimized oxidative condition.
The site-specic introduction of a novel functionality on an unreactive site of a complex motif has tremendous signicance to the eld of complex molecule synthesis and is oen termed as late stage functionalization (LSF). 16In particular, LSF through C-H functionalization is very useful in drug discovery and draws signicant attention from the scientic community.Accordingly, a range of biologically relevant motifs moulded with MPS-bearing naphthalene-1-carboxylic acid (5a-g) were synthesized and were independently subjected to the optimized reaction conditions with 2a and 2c (Scheme 2).Thus, the desired oxepino-pyridines 6aa-b-citronellol, 6bc-camphorsultam, 6ca-(À)-boreneol, 6ec-cholesterol, 6fc-estrone, and 6gc-lithocholic acid were constructed without any structural (chemical and stereochemical) changes of the complex architecture. 14The poor-to-moderate synthetic yields are due to low conversions.Isolation of unreacted precursors justies the mass balance of the transformation.Encouraged by the broad range of oxepino-pyridines derivatives obtained (Schemes 1 and 2), the title reaction was next envisaged with two different alkynes.However, the difference in reactivity, regio-and chemoselectivity with different alkynes led to unexploitable annulation mixtures. 12To make this challenging unsymmetrical transformation viable, a two-step annulation sequence was tested.Accordingly, benzo[h]isoquinolinone 7a (0.5 mmol, 75%) was accessed from 1a and 2a when the reaction was carried out in presence of AcOH under Ru-catalysis (Scheme 3, Conditions A).Presumably the acid suppresses the second annulation through proto-demetallation. 11 Next, the annulation of 7a with 1,2-diaryl alkynes (2d-g) led to the respective [6,7]-fused oxepino-pyridines (8ad-ag) in moderate yields (Scheme 3).The structure of 8ae was unambiguously conrmed by X-ray crystallography. 14,15A deuterium scrambling study and competition experiments were then performed to gain some mechanistic insight into this annulation (Scheme 4).
In general, the p-conjugated polyfused heteroarenes show interesting photophysical properties.Thus, the absorption and emission spectra of oxepino-pyridines 3nb, 3oa, 3pb, 3qb, 3sa, 4a, and 8ae were measured in dichloromethane (1 Â 10 À5 ). 14Of note, compounds 3nb and 3ob show emission maxima at 436-512 nm with broad bandwidths and weak intensities. 14he mechanism of the title reaction has been studied computationally, employing the Gaussian 09 soware package. 17 out with the M06 functional, the 6-31G(d,p) basis set for all main group elements, and the LANL2DZ+f (ECP) 18 basis set for Ru.Single point calculations were conducted at the M06/6-311++G(d,p)-SDD+f(ECP) level of theory.Solvation energies were obtained at the single point level using SMD approach for 1,4dioxane.The discussed values are solvent-corrected Gibbs free energies at 393.15 K in kcal mol À1 (DG 393 ).The molecular system A [1a, 2-butyne (2.0 equiv.),[RuOAcL] + (L ¼ p-cymene), AcO À ] was used as a reference for the free energies (Fig. 3).Thus, A contains two acetates to ensure two deprotonation of 1a.The complexation of the putative active species [RuOAc(pcymene)] + with 1a at rst provides B with a release of 20.5 kcal mol À1 .Next, C-H metalation occurs through TS BC lying 11.9 kcal mol À1 above B to provide metallacycle C (À23.6 kcal mol À1 ).Elimination of acetic acid and insertion of 2-butyne delivers the alkyne-complex E (more stable than C by 2.6 kcal mol À1 ).Alkyne insertion does not yield the proposed metal-alkenyl complex F 0 , but rather its valence isomer F, which is a metallacyclopropene as witnessed by the distortion of the 7membered ring and by the short Ru-C distance of 1.85 Å.The formation of F is slightly endergonic by 0.3 kcal mol À1 that requires 14.9 kcal mol À1 of free energy of activation (TS EF ).Then, intramolecular nucleophilic addition to the N]S bond gives the annulation intermediate G (see arrows in F 0 ).The conversion of F to G is the rate-determining step with a barrier 25.0 kcal mol À1 (19.6 kcal mol À1 from B), which is consistent with the temperature of the reaction (120 C).Although the resulting complex G is less stable than F by 3.2 kcal mol À1 , the acetate aided dissociation of [Ru(OAc)L] + promotes spontaneous elimination of PhSOMe from the free ligand to give H, located as low as À69.0 kcal mol À1 on the energy surface.The liberation of PhSOMe, the conjugation of the anion, and the strong H-bond in H assist the loss of the sulfur moiety.
Finally, protonation of H by AcOH produces pyridine I or the pyridone species J.In line with the experimental observations, J is signicantly more stable.The mechanistic insight directed towards the second annulation for the construction of pyridinefused 7-membered oxepine ring is depicted in Fig.   the peri-H of the naphthalene moiety.The Ru-C bond is short (2.36 Å), due to the coordination of Ru to the ipso-carbon and makes the peri-H acidic.The C-H metalation of the preorganized complex K provides L (at À137.5 kcal mol À1 on the energy surface).This step requires 6.5 kcal mol À1 free energy of activation (TS KL ).Next, the substitution of acetic acid with second alkyne equivalent is endergonic by 10.9 kcal mol À1 to afford N (À126.6kcal mol À1 ).Of particular interest, the formation of 7-membered ring does not arise from the reductive elimination of a simple 8-membered metallacycle (O 00 ).Instead, at the expense of 15.9 kcal mol À1 of free energy of activation, the ruthena-oxabicyclooctene complex O, located at À132.7 kcal mol À1 , is achieved from N via TS NO .Among the Lewis depiction of O and O 0 , the structure O is supported by the Ru-C ipso distance of 2.35 Å and other geometrical parameters.Its formation can be understood as an intramolecular [2 + 2] cycloaddition between the alkyne and a Ru]C bond as shown in N 0 (a ctive valence isomer of N).This process eventually avoids the participation of a highly strained phenanthrenecontaining 8-membered ring (O 00 ).Then, the reductive elimination of O demands 25.2 kcal mol À1 free energy of activation to give P.This process is slightly endergonic and is the ratedetermining step of this second annulation process.The transfer of the RuL moiety from P to the precursor 1a produces the desired [6,7]-fused oxepino-pyridine skeleton Q and chelate R.This step is exergonic by 7.9 kcal mol À1 .Finally, as it is generally accepted, one can then propose that complex R transforms into B by Cu(OAc) 2 mediated oxidation.Based on the experimental observations and insightful computational data, the mechanism of this double annulation is sketched in Fig. 5. 4 The active Ru-catalyst {generated from [Ru(p-cymene)Cl 2 ] 2 , AgSbF 6 , and AcO À } rst coordinates to MPS and activates the C(2)-H bond of 1a to form I (D in Fig. 3).The coordination of alkyne to I and its migratory insertion leads to II (F in Fig. 3).Next, the intramolecular nucleophilic addition to the N]S bond provides III (G in Fig. 3), which is the rate-determining step of the mono-annulation.The acetate-aided expulsion of [Ru(OAc)L] + and elimination of PhSOMe leads to pyridone species IV (H in Fig. 3).Next, direct C(8)-H ruthenation of IV affords V (M in Fig. 4).Then, alkyne insertion into V generates the unusual ruthena-oxabicyclooctene complex VI (O in Fig. 4).The reductive elimination of VI gives VII (P in Fig. 4) and is the rate-determining step of the second annulation.Finally, Cu(OAc) 2 mediated transfer of RuL moiety to 1a liberates the desired [6,7]-fused oxepino-pyridine skeleton.

4
Scheme 4 Deuterium scrambling and competition studies.
In summary, we have developed an unprecedented Ru-catalyzed sulfoximine-directed one-pot domino {[4 + 2] & [5 + 2]} double annulation of 1-naphthoic acid derivatives with alkynes for the synthesis of unique [6,7]-fused oxepino-pyridine motifs.This transformation functionalizes both chemically distinct orthoand peri-C-H bonds of fused-hetero(arenes) through double annulation, making four (C-C & C-N and C-C & C-O) bonds in a single operation.In addition, two-step unsymmetrical annulations with different alkynes are also shown.The detailed DFT calculations endorse the participation of metal-cyclopropene and ruthena-oxabicyclooctene intermediates.The construction of biologically relevant drugs anchored oxepino-pyridine scaffolds, broad scope, and gram scale synthesis make the transformation synthetically viable.