Experimental and Theoretical DFT Investigations in the [2,3]-Wittig-Type Rearrangement of Propargyl/Allyl-Oxy-Pyrazolones

Here we report the synthesis of interesting 3-alkyl-4-hydroxy-1-aryl-4-(propa-1,2-dienyl)1H-pyrazol-5(4H)-ones and 9-alkyl-7-aryl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-dien-6-ones, starting from 1,2-diaza-1,3-dienes (DDs) and propargyl alcohol. The reaction proceeds through a sequence Michael-type nucleophilic attack/cyclization/[2,3]-Wittig rearrangement. In the same way, the reaction between the aforementioned DDs and allyl alcohol furnished 4-allyl-4-hydroxy-3-alkyl-1-aryl-1H-pyrazol-5(4H)-ones. A DFT study was also carried out, in order to have decisive clarifications about the mechanism.


Introduction
Heterocycles, in particular those that contain one or more nitrogen atoms, are an extremely important class of compounds widely distributed in nature, as they represent the majority of active molecules employed in biological, pharmacological, and industrial chemistry [1][2][3][4][5].
It is for this cause that organic chemists [19,20] as well as our group [21] are actively engaged in the development of new synthetic strategies for their synthesis.
On the other hand, the α-hydroxyallenes are also a valuable class of derivatives that constitute both versatile synthetic intermediates as well as the core of different compounds of synthetic or natural origin, which manifest biological activities [30][31][32][33][34][35][36].
Among the several approaches that have been employed for their synthesis [37][38][39][40][41][42][43][44][45], the [2,3]-Wittig rearrangement of propargylic ethers represents an efficient way to assemble them [46,47]. The major limitation of this versatile bond reorganization process, which has many other applications in organic synthesis, is mainly correlated to the use of strong For the formation of products 5a-c, we hypothesized a preliminary base-promoted nucleophilic attack of the hydrazonic nitrogen at the ester group of Michael adducts 3, with the loss of an alcohol molecule, to give the pyrazolone ring, followed by a further cyclization process passing through a [2,3]-Wittig-type rearrangement [59]. In order to better clarify the proposed mechanism and to have some variability on the substituents of DDs as well as to increase the scope of the reaction, we have decided to extend our studies to investigate the reactivity of differently substituted DDs such as 1-aryl-DDs 1d-g with propargyl and allyl alcohols 2a,b, respectively. The results of this study are the object of the present work.
For the formation of products 5a-c, we hypothesized a preliminary base-promoted nucleophilic attack of the hydrazonic nitrogen at the ester group of Michael adducts 3, with the loss of an alcohol molecule, to give the pyrazolone ring, followed by a further cyclization process passing through a [2,3]-Wittig-type rearrangement [59]. In order to better clarify the proposed mechanism and to have some variability on the substituents of DDs as well as to increase the scope of the reaction, we have decided to extend our studies to investigate the reactivity of differently substituted DDs such as 1-aryl-DDs 1d-g with propargyl and allyl alcohols 2a,b, respectively. The results of this study are the object of the present work.
Additionally, the attempts to carry out the reaction using strong bases at lower temperatures such as NaH at -20 • C (entry 17) or -78 • C (entry 18), as well as MeONa at -20 • C (entry 23) or t-BuONa at room temperature (entry 26) or at −20 • C (entry 27) have also failed, giving complicated reaction mixtures.
Additionally in the case of the use of 4 equiv. of K 2 CO 3 in any solvent at room temperature, only traces of 4a and 5d were obtained (entries [23][24][25][26]. The trend of the reaction improves by using four equiv. of K 2 CO 3 using 3 mL of propargy alcohol 2a as solvent/reagent at 60 • C, giving 4a and 5d in 11% and 29% yields, respectively, and these are the best conditions found in our screening ( Table 1, entry 32).
At this point, to tentatively improve the yields, we have tried some different carbonates, such as Cs 2 CO 3 (entry 33) or Na 2 CO 3 (entry 34), in the same best conditions found with K 2 CO 3 but we have obtained lower yields of 4a and 5d.
So, with these most optimal conditions possible in hand, we performed the reactions between 1-aryl-DDs 1d-g and propargyl alcohol 2a used as solvent-reagent, at 60 • C in the presence of 4 equiv. of K 2 CO 3 .
As the first step of the reaction, we hypothesized the formation of the non-isolable hydrazone intermediates 3, by means of the nucleophilic Michael-type attack of the oxygen atom of propargyl alcohol 2a to the terminal carbon atom of the azoene system of the DDs 1. The base-promoted nucleophilic attack of the hydrazonic nitrogen at the ester group of hydrazones 3, with the loss of an alcohol molecule, gives the corresponding non-isolable pyrazolone derivative I (Scheme 2).
In order to obtain decisive information to explain the subsequent Wittig rearrangement involved in the formation of the following final products 4a-d and 5d-g, a DFT study was conducted. DDs 1. The base-promoted nucleophilic attack of the hydrazonic nitrogen at the ester group of hydrazones 3, with the loss of an alcohol molecule, gives the corresponding nonisolable pyrazolone derivative I (Scheme 2).
In order to obtain decisive information to explain the subsequent Wittig rearrangement involved in the formation of the following final products 4a-d and 5d-g, a DFT study was conducted.
The base-promoted deprotonation of the intermediate I can occur at the α or α′ positions, leading to the formation of anion species II or II′, respectively (Scheme 3  It is noteworthy that the process here described is highly regioselective, since the deprotonation occurs only in the α position of the intermediate I to produce II, as this proton is more acid than the one in the α position, being activated both from an amidic carboxylic group as well as from an imino function. As a confirmation of this event, the two products of deprotonation II and II have been optimized by DFT methods. As supposed, the former II resulted in being more stable than the latter by 33.8 kcal/mol (see Supplementary Materials).
From intermediate II (Scheme 3), the two different possibilities, that is [1,2]-and [2,3]-rearrangement, have been explored. In the former, a single transition state (TS1) is necessary to obtain the final product, but the activation free energy is quite high (∆G ‡ = 49 kcal/mol) due to the strain of the incipient three-members ring in TS1 (Figure 1). On the other hand, for the [2,3]-rearrangement, two different TSs (TS2 and TS3) are necessary. In the former, the carbanion of II attacks the terminal propargylic carbon giving the conjugated base of 9-alkyl-7-aryl-1-oxa-7,8-diazaspiro [4.4]nona-3,8-dien-6-one IV. Successively, in TS3, the bond between the oxygen and the carbon 1 breaks, giving V, which after reprotonation, will lead to 4a. The free energy of TS2 and TS3 are quite similar (11.1 and 10.4 kcal/mol, respectively).
It is noteworthy that the process here described is highly regioselective, since the deprotonation occurs only in the α position of the intermediate I to produce II, as this proton is more acid than the one in the α′ position, being activated both from an amidic carboxylic group as well as from an imino function. As a confirmation of this event, the two products of deprotonation II and II′ have been optimized by DFT methods. As supposed, the former II resulted in being more stable than the latter by 33.8 kcal/mol (see Supplementary Materials).
From intermediate II (Scheme 3), the two different possibilities, that is [1,2]-and [2,3]rearrangement, have been explored. In the former, a single transition state (TS1) is necessary to obtain the final product, but the activation free energy is quite high (ΔG ǂ = 49 kcal/mol) due to the strain of the incipient three-members ring in TS1 (Figure 1). On the other hand, for the [2,3]-rearrangement, two different TSs (TS2 and TS3) are necessary. In the former, the carbanion of II attacks the terminal propargylic carbon giving the conjugated base of 9-alkyl-7-aryl-1-oxa-7,8-diazaspiro [4.4]nona-3,8-dien-6-one IV. Successively, in TS3, the bond between the oxygen and the carbon 1 breaks, giving V, which after reprotonation, will lead to 4a. The free energy of TS2 and TS3 are quite similar (11.1 and 10.4 kcal/mol, respectively).  Figure 1). However, the high activation energy determined by the DFT study for the formation of final products 4 and 5 can explain why their yields are so low. On the other hand, it is reported in the literature that the yields of Wittig rearrangement products are commonly quite low .
It is noteworthy that, commonly to trigger the Wittig rearrangements, the use of strong Brønsted bases, such as BuLi or t-BuLi , is required, and usually, the reactions happen at very low temperatures. In our system instead, much milder conditions, such as a weak base as K 2 CO 3 and a temperature of 60 • C, are able to efficiently promote the α-deprotonation and the consequent [2,3]-Wittig rearrangement. This aspect together with the possibility to conduct the synthesis under solvent-free conditions makes it eco-friendly and less harmful to the environment.
It is well known that allyl alcohol is a valuable building block in organic syntheses, due to its versatile reactivity as alkylating agent [82][83][84][85].
For this fact and also with the intent to verify if the mild conditions employed for [2,3]-Wittig rearrangement in the reaction of the DDs 1 with propargyl alcohol 2a could be extended to other substrates, we have planned to conduct the reaction between DDs 1d-h and allyl/crotyl alcohol 2b,c (Scheme 4). To our great pleasure, the reactions conducted using 2b, as solvent and reagent, at 60 • C and in the presence of 4 equiv. of K 2 CO 3 , have actually provided the corresponding 4-allyl-4-hydroxy-3-alkyl-1aryl-1H-pyrazol-5(4H)ones 6a-e (25-70%) (Scheme 4, Path A, Table 3).
However, the high activation energy determined by the DFT study for the formation of final products 4 and 5 can explain why their yields are so low. On the other hand, it is reported in the literature that the yields of Wittig rearrangement products are commonly quite low .
It is noteworthy that, commonly to trigger the Wittig rearrangements, the use of strong Brønsted bases, such as BuLi or t-BuLi , is required, and usually, the reactions happen at very low temperatures. In our system instead, much milder conditions, such as a weak base as K2CO3 and a temperature of 60 °C, are able to efficiently promote the α-deprotonation and the consequent [2,3]-Wittig rearrangement. This aspect together with the possibility to conduct the synthesis under solvent-free conditions makes it ecofriendly and less harmful to the environment.
It is well known that allyl alcohol is a valuable building block in organic syntheses, due to its versatile reactivity as alkylating agent [82][83][84][85].
For this fact and also with the intent to verify if the mild conditions employed for [2,3]-Wittig rearrangement in the reaction of the DDs 1 with propargyl alcohol 2a could be extended to other substrates, we have planned to conduct the reaction between DDs 1d-h and allyl/crotyl alcohol 2b,c (Scheme 4). To our great pleasure, the reactions conducted using 2b, as solvent and reagent, at 60 °C and in the presence of 4 equiv. of K2CO3, have actually provided the corresponding 4-allyl-4-hydroxy-3-alkyl-1aryl-1H-pyrazol-5(4H)-ones 6a-e (25-70%) (Scheme 4, Path A, Table 3).  Also in this case, the reaction proceeds through the preliminary formation of a hydrazonic adduct intermediate 3, by means of the nucleophilic attack of the oxygen of allyl alcohol 2 to the terminal carbon atom of the azoene system of the DD 1, followed by a base-promoted cyclization due to a nucleophilic attack of the hydrazonic nitrogen at the ester group of hydrazone 3, with the loss of an alcohol molecule, to give the corresponding non-isolable pyrazolone VI (Scheme 5). Now, the base-promoted loss of the hydrogen in the 4 position of the pyrazolone ring can theoretically promote both [1,2]-and [2,3]-Wittig rearrangements, however, furnishing in both cases the same final products 6a-d (Schemes 4 and 5) [17,18]. Also in this case, the reaction proceeds through the preliminary formation of a hydrazonic adduct intermediate 3, by means of the nucleophilic attack of the oxygen of allyl alcohol 2 to the terminal carbon atom of the azoene system of the DD 1, followed by a base-promoted cyclization due to a nucleophilic attack of the hydrazonic nitrogen at the ester group of hydrazone 3, with the loss of an alcohol molecule, to give the corresponding non-isolable pyrazolone VI (Scheme 5). Now, the base-promoted loss of the hydrogen in the 4 position of the pyrazolone ring can theoretically promote both [1,2]-and [2,3]-Wittig rearrangements, however, furnishing in both cases the same final products 6a-d (Schemes 4 and 5) [17,18]. So, to clarify which of the two mechanisms was involved, we tried to introduce a methyl substituent on the terminal carbon atom of the double bond of the alcohol and therefore we tested the crotyl alcohol 2c (R 4 = Me, Schemes 4 and 5) in the reaction with 1aryl-DDs 1d-g. To our large disappointment, in all cases, the reaction was unsuccessful, despite using various conditions of solvent, base, and temperature (for the conditions tested, see Table S1 in the Supplementary Materials).
We have then investigated the behavior of t-butoxycarbonyl-DD 1h, chosen as an example, by virtue of its incremented electrophilic character due to the replacement of the aryl on the N1 of the azo-ene system with the BOC moiety [62]. So, to clarify which of the two mechanisms was involved, we tried to introduce a methyl substituent on the terminal carbon atom of the double bond of the alcohol and therefore we tested the crotyl alcohol 2c (R 4 = Me, Schemes 4 and 5) in the reaction with 1-aryl-DDs 1d-g. To our large disappointment, in all cases, the reaction was unsuccessful, despite using various conditions of solvent, base, and temperature (for the conditions tested, see Table S1 in the Supplementary Materials).
We have then investigated the behavior of t-butoxycarbonyl-DD 1h, chosen as an example, by virtue of its incremented electrophilic character due to the replacement of the aryl on the N1 of the azo-ene system with the BOC moiety [62].
Then, a DFT study was carried out for the reaction between the allylic moiety and DDs, for which, given the lack of reactivity of substituted allyl alcohol, it is difficult to obtain experimental information about the mechanism. Also, in this case, the strain in the TS of the [1,2]-rearrangement (TS1A) makes this path high in energy (∆G ‡ = 57.1 kcal/mol) and not a viable option. Differently than before, the [2,3]-rearrangement is not a two-step mechanism, as the formation of the Cα-C1 bond and the O-C1 bond cleavage are concerted (TS2A). The activation barrier of the [2,3]-rearrangement is 16.2 kcal/mol, which is higher than in the case of the propargylic moiety but still viable, in principle ( Figure 2).
Then, a DFT study was carried out for the reaction between the allylic moiety and DDs, for which, given the lack of reactivity of substituted allyl alcohol, it is difficult to obtain experimental information about the mechanism.Also, in this case, the strain in the TS of the [1,2]-rearrangement (TS1A) makes this path high in energy (ΔG ǂ = 57.1 kcal/mol) and not a viable option. Differently than before, the [2,3]-rearrangement is not a two-step mechanism, as the formation of the Cα-C1 bond and the O-C1 bond cleavage are concerted (TS2A). The activation barrier of the [2,3]-rearrangement is 16.2 kcal/mol, which is higher than in the case of the propargylic moiety but still viable, in principle ( Figure 2). Both the mechanisms lead to the same product, VII, but the latter is less stable than the starting material, VI, by 1.4 kcal/mol. This difference is positive and almost constant with all the dielectric values used in the calculations, ranging from toluene to water.
Finally, if using 1-t-butoxycarbonyl-DD 1h instead of the 1-aryl-ones, the framework is slightly different. In this case, the use of allyl alcohol leads to a product that is thermodynamically favored (9, ΔG° = −1.1 kcal/mol) and it is the same with both the [1,2]-and [2,3]-rearrangements. Given the previous results (Figure 2), it is most likely that only the Both the mechanisms lead to the same product, VII, but the latter is less stable than the starting material, VI, by 1.4 kcal/mol. This difference is positive and almost constant with all the dielectric values used in the calculations, ranging from toluene to water.
Finally, if using 1-t-butoxycarbonyl-DD 1h instead of the 1-aryl-ones, the framework is slightly different. In this case, the use of allyl alcohol leads to a product that is thermodynamically favored (9, ∆G • = −1.1 kcal/mol) and it is the same with both the [1,2]and [2,3]-rearrangements. Given the previous results (Figure 2), it is most likely that only the [2,3]-rearrangement is active. The use of crotyl alcohol leads to a slightly different scenario: the [1,2]-rearrangement would lead to a substantially thermoneutral product (10, ∆G • = −0.09 kcal/mol), but, as seen before, this way is kinetically forbidden, whereas the [2,3]-rearrangement, which would be kinetically viable, leads to a product that is thermodynamically forbidden (11, ∆G • = 6.7 kcal/mol) (see Supp. Information).

General
All chemicals and solvents were purchased from commercial suppliers and used as received. 1,2-Diaza-1,3-dienes were prepared as reported [86][87][88] and used as EE/EZ isomer mixtures. Melting points were determined in open capillary tubes and are uncorrected. FTIR spectra were obtained as Nujol mulls. All 1 H NMR and 13 C NMR spectra were recorded at 400 and 100 MHz, respectively. Proton and carbon spectra were referenced internally to solvent signals, using values of δ = 7.27 ppm for proton and δ = 77.00 ppm for carbon (middle peak) in CDCl 3 . All coupling constants (J) are given in Hz. All the NH and OH exchanged with D 2 O. Precoated silica gel plates of 0.25 mm were employed for analytical thin-layer chromatography. All new compounds showed satisfactory elemental analysis. Mass spectra were recorded in the ESI-MS mode. The nomenclature was generated using ACD/IUPAC Name (version 3.50, 5 April 1998), Advanced Chemistry Development Inc., Toronto, ON, Canada.

DFT Calculations
All the geometries have been optimized with ORCA 4.1.0 [89,90], using the BP86 functional in conjunction with a def2-TZVP basis set for all the atoms. Dispersion forces were taken into account using the D3 correction with Becke−Johnson damping [91]. The effect of the solvent has been simulated through the Continuum-like Polarizable Continuum Model (C-PCM, dichloromethane if not otherwise specified). All the geometries have been confirmed to be stationary points, with zero (intermediates) or one (transition states) imaginary frequency.
The obtained products have potentially interesting properties. In fact, often, the biological activities of molecules that incorporate more scaffolds are not simply attributable to the sum of the characteristics shown by the individual functionalities, but synergistic effects can increase its effectiveness, or induce the manifestation of new characteristics.
Finally, a DFT study carried out on these reactions allowed us to obtain definitive elucidations on the mechanism which involves a [2,3]-Wittig rearrangement.
Supplementary Materials: The following are available online: experimental procedures and spectral data of all compounds, copies of 1 H-NMR and 13 C-NMR spectra of compounds 3 d,e, 4a-d, 5d-g, 6a-d, Tables S1 and S2 refer to the screening of conditions in the reaction between DDs 1d-g and crotyl alcohol 2b and to tentatively convert hydrazone 3e into the corresponding pyrazolone, respectively. DFT optimized geometries and energies.