Palladium-catalyzed selective C–C bond cleavage and stereoselective alkenylation between cyclopropanol and 1,3-diyne: one-step synthesis of diverse conjugated enynes

The stereoselective synthesis of 1,3-enynes from 1,3-diynes is demonstrated by palladium-catalyzed selective C–C bond cleavage of cyclopropanol. Exclusive formation of mono-alkenylated adducts was achieved by eliminating the possibility of di-functionalization with high stereoselectivity. Indeed, this protocol worked very well with electronically and sterically diverse substrates. Several studies, including deuterium labeling experiments and intermolecular competitive experiments, were carried out to understand the mechanistic details. The atomic-level mechanism followed in the catalytic process was also validated using DFT calculations, and the rate-controlling states in the catalytic cycle were identified. Furthermore, preliminary mechanistic investigations with radical scavengers revealed the non-involvement of the radical pathway in this transformation.


Introduction
Transition metal-catalysed selective cleavage of C-H and C-C bonds has gained enormous signicance in recent years owing to its potential application in chemical transformations. 1,2 Especially, the strategy involving selective cleavage of a C-H bond followed by subsequent insertion of a 2p-unsaturated unit has been recognized as one of the most attractive approaches to access diverse molecular entities from the readily available feedstock. 3 This strategy also helps in building rapid complexity following the high atom-economical process. In this context, the one-step synthesis of conjugated 1,3-enynes through this process is of great importance due to their vast abundance in various natural products and pharmaceuticals (Scheme 1). 4 Consequently, they have been well recognized as multifaceted building units in organic synthesis. 5 Moreover, these structural units also received considerable interest in materials science and medicinal chemistry. 6 Considering their profound synthetic usefulness, 1,3-diynes have been recently introduced as a coupling partner for transition-metal catalysed reactions to access conjugated 1,3enynes. 7 Nevertheless, the use of 1,3-diynes in these reactions is always associated with particular challenges. The most commonly faced challenges are: (a) difficulty in controlling stereo-and regio-selectivity and (b) difficulty in controlling mono-functionalization over di-functionalization. 3b,7 As a result, only a few protocols for the synthesis of 1,3-enynes using 1,3diynes have been described to date. 7 Ge and co-workers developed a cobalt-catalysed regiodivergent and stereoselective hydroboration of 1,3-diynes to afford boryl-functionalized enynes (Scheme 2a(i)). 7a In another report, Beller and coworkers also disclosed palladium-catalysed selective synthesis of conjugated enynes employing alkoxycarbonylation of 1,3diynes (Scheme 2a(ii)). 7b Interestingly, highly selective synthesis of 1,3-enynes was also achieved by Glorius and co-workers via Scheme 1 Representative examples of natural products and drug molecules bearing conjugated 1,3-enyne scaffolds.
manganese-catalysed C-H activation-alkenylation of arenes and heteroarenes with 1,3-diynes (Scheme 2a(iii)). 7c Because of the challenges mentioned above, reports on using 1,3-diynes to synthesize conjugated enynes are minimal. Although palladium-catalysed hydroalkylation of alkynes with cyclopropanols was developed by Yao and co-workers, 11h the possibility of selective C-C bond cleavage and alkenylation sequence for 1,3-dynes has never been attempted.
In this context, the tandem cleavage and functionalization of the C-C bond is quite challenging. It is mainly owing to the thermodynamic stability and kinetic inertness of C-C bonds. In addition, poor accessibility and poor orbital directionality of C-C bonds by the catalyst as compared to C-H bonds make them less favorable for effective interactions with transition metal complexes. Despite these difficulties, substantial efforts have been made over the last two decades to functionalize different types of C-C bonds. 2,8 Some valuable strategies employed include b-carbon elimination, 8a,c oxidative addition, 2d and aromatization driven processes. 8d In this regard, one of the recent and attractive processes includes the cleavage of the C-C bond of small rings by taking advantage of their intrinsic ring strain. 9 The thermodynamic barrier is largely offset with the aid of release of ring strain. The synthetic potential of this method was successfully demonstrated by several research groups such as the Dong, Jun, Murakami, Bower, Yu, Loh, and Marek groups to access an array of useful structural motifs. 10 Cyclopropanol obtained from Kulinkovich protocol is one of the smallest ring molecules whose ring strain has been exploited to synthesize various molecular architectures utilizing metal-homoenolates. [11][12][13] Our group has also developed the strain-driven C-C bond cleavage of cyclopropanol and cyclopropenone to furnish diverse functionalized molecular units. 14 Owing to the synthetic value of conjugated enynes and the signicance of developing new methodology using 1,3-diynes, we envisioned that the strain-driven C-C bond cleavagesubsequent alkenylation of cyclopropanol would effectively result in the formation of the desired 1,3-enynes. Herein, we report a palladium-catalysed selective C-C bond cleavage and stereo-selective mono-alkenylation of readily accessible cyclopropanol to rapidly synthesize divergent 1,3-enynes (Scheme 2b).

Results and discussion
To establish our methodology, we started by identifying the suitable reaction conditions for the palladium-catalysed C-C bond activation of cyclopropanol and the subsequent alkenylation with 1,3-diyne. Subsequently, 1-benzylcyclopropan-1-ol 1a and 1,4-diphenylbuta-1,3-diyne 2a were chosen as the model substrates in the presence of 10 mol% of a palladium catalyst. Initially, different palladium catalysts were screened in the absence of a ligand in toluene at 100 C (  [6][7][8]. Increasing or decreasing the reaction temperature (120 C and 80 C) had a deleterious effect on the reaction furnishing the desired product 3aa in 34% and 42% yields, respectively (Table 1, entries 9 and 10). Hence, we chose Pd(PPh 3 ) 4 as the catalyst in toluene at 100 C and varied the other reaction parameters. It is worth mentioning here that the reactive metal-homoenolate generated aer the b-carbon elimination from 1a may undergo protodemetalation and b-hydride elimination to give a ring-opened isomerized product and a,bunsaturated ketone respectively resulting in a signicant loss of the product yield. Therefore, we increased the equivalence of 1a. To our delight, 69% of 3aa was obtained using 2 equivalents of 1a (Table 1, entry 11). Next, we investigated the effects of different electron-rich N-heterocyclic and phosphine ligands ( Table 1, entries [12][13][14][15][16][17][18][19][20]. No improvement in the yield of 3aa was noticed using electron-rich N-heterocyclic ligands (Table 1, entries 12-15). Gratifyingly, product yield was further enhanced in the cases of P( t Bu) 3 .HBF 4 (77%) and PCy 3 (89%) (  4 and PCy 3 did not increase the product yield (Table  1, entries 23 and 24). We then performed a control experiment without the Pd(PPh 3 ) 4 catalyst. As expected, it did not produce the product, thus, conrming the key role of the catalyst in this reaction (entry 25). Hence, the use of 10 mol% of Pd(PPh 3 ) 4 , 0.2 equivalents of PCy 3 in toluene (0.25 M) at 100 C is the best optimized condition for the synthesis of 3aa (Table 1, entry 19).
Aer successfully demonstrating the scope of alkenylation with benzyl-and alkyl-substituted cyclopropanols, we focused our attention on unraveling the scope of different aryl-and heteroaryl-substituted cyclopropanols. Similar to the benzylsubstituted cyclopropanols, Me, t Bu, 2,3-di-OMe, and CF 3 substituted aryl cyclopropanols were facile, resulting in good yields of their corresponding alkenylated adducts 3oa-3ta. Pleasingly, cyclopropanols bearing furan-and thiophenesubstituents underwent the transformation efficiently, yielding 3ua and 3va in 62% and 83% yield, respectively.
Aer successfully exploring the scope of structurally and electronically distinct cyclopropanols for the developed methodology, we further investigated the scope with different 1,3-diynes (Table 3). Both electronically rich and poor 1,3-diynes furnished their corresponding alkenylated adducts 3ab-3aj in 61-94% yields. The regio-and the stereo-selectivity of the product molecule was conrmed unambiguously from the NOE experiment of 3aa. To test the synthetic practicality of the developed C-C activation protocol, we performed a 1 mmol scale reaction with 1a and 2a to produce 3aa in 78% yield.
Encouraged by the versatility of the developed transformation, we performed a series of experiments to get insight into the mechanism of the catalytic cycle. Initially, we Table 3 Scope of 1,3-diynes for the synthesis of conjugated enynes a a All reactions were carried out using Pd(PPh 3 ) 4 (10 mol%), PCy 3 (0.   3 OD as a co-solvent, 57% deuteration at the olenic proton, 75% deuteration at the benzylic proton, and 7% deuteration at the carbonyl a-position of 3aa-[d] were observed with 77% yield (Scheme 3aiii). These results reveal that not only the alcoholic protons but also the carbonyl a-protons are also the proton source for the olenic position. Furthermore, the treatment of the isolated product 3aa with CD 3 OD under the optimized conditions resulted in no deuteration at the olenic position of 3aa-[d] (Scheme 3aiv). To investigate the involvement of a radical pathway, we carried out two reactions in the presence of radical scavengers such as 2,2,6,6-tetramethylpiperidine 1oxyl (TEMPO) and 2,6-di-tert-butyl-4-methyl-phenol (BHT) (Scheme 3b). The 3aa yields of 51% and 73% in the presence of TEMPO and BHT respectively refuted the possibility of a radical pathway. Moreover, for further mechanistic insights and to understand the electronic effects, we conducted two intermolecular competitive experiments. First, a one pot competition reaction between two electronically different aryl cyclopropanols 1p and 1s was performed under the standard reaction conditions with diyne 2a, affording 3pa : 3sa in a 6.14 : 1 ratio (see ESI section 4.1.1-page S16 † for details). In a similar vein, the competition reaction between the cyclopropanols in a parallel set of reactions resulted in 3pa : 3sa in a 3.3 : 1 ratio (Scheme 4a). Similarly, another set of one pot competition reactions between two different cyclopropanols 1b and 1f (benzyl substituents) when reacted with diyne 2a, produced 3ba : 3fa in a 1 : 0.90 ratio (see ESI section 4.1.3-page S21 † for details). Clearly, these experimental observations indicate the role of direct relay of electronic effects in the aryl substrates which are absent in the benzyl substrates. Next, the one pot competitive experiment between two different diynes 2g and 2i with cyclopropanol 1a afforded 3ag : 3ai in a 1 : 1.68 ratio (see ESI section 4.2.1-page S23 † for details). Similarly, the competitive one pot reaction between diynes 2g and 2i with cyclopropanol 1o le to 3og : 3oi in a 1 : 2.16 ratio (see ESI section 4.2.2-page S25 † for details). Likewise, the competition reaction between the diynes 2g and 2i with cyclopropanol 1o in a parallel set of reactions resulted in 3og : 3oi in a 1 : 1.2 (Scheme 4a). These results reveal that alkenylation is more favourable for electronically rich cyclopropanols and electronically poor diynes.
To gain insight into the atomic-level mechanism followed in the reaction between 1a and 2a catalyzed by Pd(PPh 3 ) 4 , we performed density functional theory (DFT) calculations using the B3LYP-D3 (ref. [15][16][17] functional with 6-31G(d,p) 18 basis sets and the SDD 19 and LANL2DZ 20 pseudopotentials to represent the core electrons of Pd. The LANL2DZ and SDD pseudopotentials have successfully been used in several studies to represent the core electrons of Pd. 21,22 We performed all calculations in the presence of toluene as the solvent using the SMD 23 solvation model and mapped the (Gibbs) free energy proles along the reaction paths. The free energies were calculated by considering different pathways at the experimental temperature of 373.15 K. See the ESI † for a detailed description of the methods and the different reaction pathways considered in the DFT study. We found that the overall nature of the reaction proles for different pathways was similar when using the SDD and LANL2DZ pseudopotentials. However, the SDD gave comparatively lower barriers for the various pathways considered and hence we discuss below the mechanisms obtained using the B3LYP-D3/6-31G(d,p)/SDD level of theory.
In cross-coupling reactions involving Pd catalysts, PdL 4 dissociates to PdL 3 , which is in equilibrium with PdL 2 . 24 PdL 2 has been observed to behave as the active species and thus controls the oxidative addition step. The energy of the active species, PdL 2 was found to be 6.4 kcal mol À1 lower as compared to that of PdL 4 , where L ¼ PPh 3 . The relative energies were computed with respect to PdL 4 . Due to the complexity of the reaction, we considered different types of mechanisms for the catalytic cycle. Four different pathways were investigated: (i) Path I: oxidative addition / 1,3-diyne coordination / bcarbon elimination / syn-addition / reductive elimination ( Fig. 1 and Scheme 5), (ii) Path II: 1,3-diyne coordination / ligand exchange with cyclopropanol / syn-addition / bcarbon elimination / reductive elimination (Fig. S3 and S4 †), (iii) Path III: oxidative addition / b-carbon elimination / 1,3diyne coordination / syn-addition / reductive elimination ( Fig. S5 and S6 †), and (iv) Path IV: oxidative addition / 1,3diyne coordination / syn-addition / b-carbon elimination / reductive elimination (Fig. S7 and S8 †). The effective barriers calculated using the energy span model 25 for Paths I-IV were 39.0, 49.1, 36.1, and 43.9 kcal mol À1 respectively indicating that Path III could be the favorable mechanism with oxidative addition as the rate-determining step. However, the deuterium substituted reaction resulted in a KIE value of 1.70 (refer to the ESI † for details). This KIE value was found to be in sharp contrast to the theoretically calculated KIE (3.77, refer to the ESI † for details) computed by considering the oxidative addition barrier of 36.1 kcal mol À1 for Path III. These observations clearly revealed the non-involvement of the O-H oxidative-addition as the rate-limiting-step and hence Path III was eliminated as the possible reaction pathway. Moreover, the electronic effect seen in Scheme 4 cannot be explained if O-H activation is the ratelimiting step (Path III). Of the remaining three reaction pathways considered, Path I had the lowest effective barrier and was found to be consistent with the experimental observations as discussed below. Fig. 1 gives the complete free energy prole for the reaction path (Path I) involving various stationary points.
The molecular structures and important geometrical parameters of the stationary points are given in Fig. S1 and S9 in the ESI. † The catalytic reaction cycle begins with the approach of the active catalyst Pd(PPh 3 ) 2 and 1a towards each other to form the complex int1 having an energy of À4.7 kcal mol À1 with the H atom of the OH group of 1a pointing towards Pd (H-Pd distance ¼ 2.28Å). The next step is the oxidative addition of the alcoholic -OH group 11f,g to the Pd center to result in int2. The oxidative addition is achieved by the concerted dissociation of the O-H bond and the formation of Pd-O and Pd-H coordinate bonds via a three-membered cyclic transition state ts1 with a barrier of 36.1 kcal mol À1 with respect to int1. In int2, the Pd center is tetracoordinated with Pd-O (2.06Å) and Pd-H (1.57Å) bonds and has a square planar geometry. Then, the addition of 2a to palladium takes place to result in int3 preceded by the elimination of PPh 3 which is crucial to lower the steric hindrance and accommodate incoming 2a. It should be noted that the free rotation of the O-C bond in the intermediates (int1 and int2) leads to the formation of different conformational isomers. However, the energy differences between the conformational isomers were less than 1 kcal mol À1 . The intermediate int3 then undergoes b-carbon elimination to form int4. During this process, a PPh 3 group is rst eliminated to give int3 0 . Then, the Pd-C b bond is formed which is accompanied by the simultaneous breaking of the C a -C b and O-Pd bonds via a fourmembered cyclic transition state ts2 with a barrier of 4.5 kcal mol À1 with respect to int3 to form int3 00 . A PPh 3 group is then added to int3 00 to give int4. The intermediates int3 0 and int3 00 are not shown in Fig. 1 for clarity. What ensues is the hydrogenation of the unsaturated alkyne bond by the syn addition of Pd-H to the C^C bond to form the intermediate int5. This is a concerted step via a four-membered cyclic transition state ts3 with a barrier of 11.3 kcal mol À1 . When going from int4 to ts3, the hydrogen atom of the Pd-H bond is stretched, and the C^C bond is aligned coplanar to the square planar orientation of the Pd center to facilitate the H/C^C interaction. From ts3, the H migration results in int5 with the Pd center maintaining a planar geometry. Now, the addition of a PPh 3 group to int5 leads to the formation of the intermediate int6 with a tetra-coordinated Pd center. The nal step in the cycle is the reductive elimination process at the Pd center from int6 to the product 3aa_iso1. Here, the two Pd-C bonds in int6 are broken with the concomitant bond formation between the associated carbon atoms via a cyclic three-membered transition state ts4 with a 18.8 kcal mol À1 barrier. The product 3aa_iso1 is stabilized by À47.5 kcal mol À1 with respect to the reactants. The product 3aa_iso1 can exist in different isomeric forms (3aa_iso2, 3aa_iso3, and 3aa_iso4, Fig. S2 †) due to rotation about C-C sigma bonds that are within 4 kcal mol À1 in energies.
It is of interest to identify the rate-controlling states involved in the overall reaction. To this end, we computed the turnover frequency (TOF) for the reaction using the energetic span model. 25 From the energetics of the reaction, we can see that the TOF determining transition state (TDTS) and the TOF determining intermediate (TDI) are ts2 and int1, respectively. Hence, the effective free energy barrier (dE) for the catalytic cycle is 39.0 kcal mol À1 which is lower than that of the Paths II and IV, as noted in the energy prole (Fig. 1).
It should be noted that the competitive experiments (Scheme 4a) of the electron rich and poor cyclopropanols with diynes (2a) resulted in a ratio of 3.3 : 1 (3pa : 3sa). Moreover, reactions of the electron rich (2g) and poor (2i) diynes with cyclopropanol (1) resulted in a ratio of 1 : 1.2 (3og : 3oi). To understand this distribution in the products where electron rich cyclopropanols and electron poor diynes are favoured, we calculated the thermal rate constants using the Eyring-Polanyi equation 26,27 at 373.15 K. For the reactions involving p-Me-cyclopropanol and p-CF 3 -cyclopropanol, the k TST (3pa)/k TST (3sa) was found to be 2.3 : 1, whereas the k TST (3og)/k TST (3oi) was found to be 1 : 1.42, in close agreement with the experimentally observed product ratios. In addition, the KIE (k H /k D ) calculated from the DFT free energies of 2.56 was found to be in qualitative agreement with the experimentally determined value of 1.70, indicating the absence of any primary kinetic isotope effect in the reaction. Thus, the agreement of the calculated KIE and product ratios from the DFT energies with the experimental KIE and product ratios obtained in the electronic effect experiments, further supports Path I as the possible mechanism.
In accordance with the aforementioned mechanistic outcomes from the experiments supported by the DFT calculations at the B3LYP-D3/6-31G(d,p)/SDD level of theory and literature precedents, 11 a plausible catalytic cycle is depicted in Scheme 5. The catalytic cycle starts with the oxidative addition of cyclopropanol 11f,g 1a to the active PdL 2 (0) catalyst to form the intermediate int2.

Conclusions
In conclusion, we have developed a palladium-catalyzed novel and highly stereo-selective synthetic strategy to get an array of 1,3-enyne derivatives via selective C-C bond cleavage of cyclopropanol followed by alkenylation with 1,3-diynes. Apart from high and stereo-selectivity, excellent functional group tolerance has also been achieved with both cyclopropanol and 1,3-diynes. The protocol was found to be amenable to sterically hindered cyclopropanols such as adamantane cyclopropanol. Importantly, by eliminating the possibility of difunctionalization, exclusive mono-functionalization has also been achieved. Several mechanistic investigations including deuterium labelling experiments have been carried out. In addition, the reaction mechanism of the catalytic process was supported using DFT calculations and it was found that the step corresponding to the ring opening of cyclopropanol acted as the ratecontrolling step for the reaction. The preliminary mechanistic ndings with radical scavengers revealed non-involvement of the radical pathway in the transformation.

Data availability
We have deposited all the experimental and computational data as ESI. †

Author contributions
B. V. P. planned, conducted, and analyzed the experiments, and A. G. carried out the substrate scope and contributed in writing the rst dra of the manuscript. S. K. B. carried out the mechanistic studies. K. Y. conducted the computational studies. S. P. carried out the NOE experiments. P. C. R. supervised the overall project and U. L. supervised the computational calculations in the project. All authors contributed to discussions and commented on the manuscript.

Conflicts of interest
There are no conicts to declare.

Dedication
This work is dedicated to Prof. S. Chandrasekaran, IISc, Bangalore, on the occasion of his 75th birthday.